FIELD OF THE INVENTION The present invention relates generally to the field of steroids and, in particular, to novel 17-a-substituted, 11-ß-substituted-4-aryl and 21-substituted 19- norpregnadienedione analogs which possess potent antiprogestational activity with minimal antiglucocorticoid activity.

BACKGROUND OF THE INVENTION There have been numerous attempts over the past few decades to prepare steroids with antihormonal activity. These have been reasonably successful where antiestrogens and antiandrogens are concerned. However, the discovery of effective antiprogestational and antiglucocorticoid steroids has proved to be a formidable task for the steroid chemist. It has been generally recognized for some years, however, that antiprogestational steroids would find wide applicability in population control, while antiglucocorticoids would be extremely valuable in the treatment of, for example, Cushing's syndrome and other conditions characterized by excessive endogenous production of cortisone. In the last decade, largely through the efforts of Teutsch, et al. of the Roussel- Uclaf group in France, a new series of 19-nortestosterone derivatives has been synthesized with strong affinity for the progesterone and glucocorticoid receptors and with marked antiprogestational and antiglucocorticoid activity in vivo. This important discovery revealed the existence of a pocket in the progesterone/glucocorticoid receptors that is able

to accommodate a large I 1 (3-substituent on selected 19-nortestosterone derivatives. By suitable selection of such a substituent, steroids with antihormonal properties were obtained.

The pioneering studies of Teutsch, et al. on the synthesis of antiprogestational and antiglucocorticoid steroids is summarized in a recent review article (G. Teutsch in Adrenal Steroid Antagonism. Ed. M. IL. Agarwal, Walter de Gruyter and Co., Berlin, 1984. pp. 43-75) describing the work leading to the discovery of RU-38, 486, the first steroid of this type selected for clinical development. RU-38, 486 or mifepristone was found to be an effective antiprogestational/contragestative agent when administered during the early stages of pregnancy (IPPF Medical Bulletin 20 ; No. 5, 1986). In addition to these antiprogestational properties, mifepristone has very significant antiglucocorticoid activity and was successfully used by Nieman, et al., J. Clin. Endocf°inology Metab., 61 : 536, (1985)) in the treatment of Cushing's syndrome. In common with the vast majority of steroidal hormone analogs, mifepristone additionally exhibits a range of biological properties. Thus, for example, it exhibits growth-inhibitory properties towards estrogen- insensitive T47Dco human breast cancer cells (Horwitz, Endocrinology, 116 : 2236, 1985).

Experimental evidence suggests that the metabolic products derived from mifepristone contribute to its antiprogestational and antiglucocorticoid properties (Heikinheimo, et al., J.

Steroid 26 : 279 (1987)).

Ideally, for purposes of contraception, it would be advantageous to have compounds which possess antiprogestational activity without (or with minimal) antiglucocorticoid activity. Although there have been a number of attempts to modify the mifepristone structure in order to obtain separation of the antiprogestational activity from the antiglucocorticoid activity, this goal has not yet been fully achieved. As such, there remains a need in the art for the development of new steroids which possess antiprogestational activity with minimal antiglucocorticoid activity.

SUMMARY OF THE INVENTION The present invention provides new steroids which possess potent antiprogestational activity with minimal antiglucocorticoid activity. More particularly, the present invention provides compounds having the general formula :

wherein : Rl is a functional group including, but not limited to,-OCH3,-SCH3,-N (CH3) 2, -NHCH3,-NC4Hg,-NCsHloS-NC4HgO,-CHO,-CH (OH) CH3,-C (O) CH3,-O (CH2) 2N (CH3) 2, -O (CH2) 2NC4Hg and-O (CH2) 2NC5HIO ; R2 is a functional group including, but not limited to, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e. g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy, etc.), acyloxy (e. g., formyloxy, acetoxy, priopionyloxy, heptanoyloxy, glycinate, etc.), allcylcarbonate, cypionyloxy, S-allcyl,-SCN, S-acyl and -OC (O) R6, wherein R6 is a functional group including, but not limited to, alkyl (e. g., methyl, ethyl, etc.), alkoxyalkyl (e. g.,-CH20CH3) and alkoxy (-OCH3) ; R3 is a functional group including, but not limited to, alkyl (e. g., methyl, methoxymethyl, etc.), hydroxy, alkoxy (e. g., methoxy, ethoxy, methoxyethoxy, vinyloxy, etc.), and acyloxy ; R4 is a functional group including, but not limited to, hydrogen and alkyl ; and X is a functional group including, but not limited to, =O and =N-OR, wherein Rs is a member selected from the group consisting of hydrogen and alkyl.

As explained above, the compounds of the present invention possess potent antiprogestational activity with minimal antiglucocorticoid activity and, thus, they are suitable for long term use in the treatment of human endocrinologies or other conditions in steroid-sensitive tissues. Specific conditions for treatment include, but are not limited to, endometriosis (Kettel, L. M., et al., Fertil Steril, 56 : 402-407 ; Murphy, A. A., et al., Fertil Steil, 6 : 3761-766 ; Grow, D. R., et al., J : Clin. Endocrinol. Metab., 81 : 1933-1939.) uterine leiomyoma (Murphy, A. A., et al., Ibid, ; Murphy, A. A., et al., J Cliya. Eradocrinol. Metab., 76 : 513-517), uterine fibroid (Brogden, R. N., et al., Drugs, 45 : 384 : 409), meningioma (Brogden, R. N., et al., Ibis. ; Poisson, M., et al., J. Neurooncol., 1 : 179-189 ; Carroll, R. S., et al., Cancer Res., 53 : 1312-1316 ; Mahajan, D. K., and London, S. N., Fertil Steril, 68 : 967-976 (1997)), and metastatic breast cancer (Brogden, R. N., et al., Id. ; Rochefort, H., Trends in Pharmacol. Sci., 8 : 126-128 ; Horwitz, K. B., Endocr. Rev., 13 : 146-163 (1992) Mahajan,

D. K. and London. S. N., Id.). Other uses include, but are not limited to, contraception (Wood, A. J. J., N. engl. J. Med., 329 : 404-412 (1993) ; Ulmann, A., et al., Sci. Amer., 262 : 42-48 (1990)), emergency postcoital contraceptive (Reel, J. R., et al., Contraception, 58 : 129-136 (1998)) and inducement of cervical ripening.

As such, in addition to providing compounds of Formula I, the present invention provides methods wherein the compounds of Formula I are advantageously used, inter alia, to antagonize endogenous progesterone ; to induce menses ; to treat endometriosis ; to treat dysmenorrhea ; to treat endocrine hormone-dependent tumors (e. g., breast cancer, uterine leiomyomas, etc.) ; to treat meningiomas ; to treat uterine fibroids ; to inhibit uterine endometrial proliferation ; to induce cervical ripening ; to induce labor ; and for contraception.

Other features, objects and advantages of the invention and its preferred embodiments will become apparent from the detailed description which follows.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 through 11 illustrate the synthetic schemes used to prepare the compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS In one aspect, the present invention provides compounds having the following general formula : In Formula I, Rl is a functional group including, but not limited to,-OCH3,-SCH3, -N (CH3) 2,-NHCH3,-NC4H8,-NCsHIo,-NC4H80,-CHO,-CH (OH) CH3,-C (O) CH3, -O (CH2) 2N (CH3) 2,-O (CH2) 2NC4H8, and-O (CH2) 2NC5Hlo. R2 is a functional group

including, but not limited to, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e. g, methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy, etc.), acyloxy (e. g., formyloxy, acetoxy, priopionyloxy, heptanoyloxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl,-SCN, S-acyl and-OC (O) R6, wherein R6 is a functional group including, but not limited to, alkyl (e. g., methyl, ethyl, etc.), alkoxyalkyl (e. g.,-CH20CH3) and alkoxy (-OCH3). R3 is a functional group including, but not limited to, alkyl, hydroxy, alkoxy and acyloxy. R4 is a functional group including, but not limited to, hydrogen and alkyl.

Finally, X is a functional group including, but not limited to, =O and =N-OR5, wherein R5 is a member selected from the group consisting of hydrogen and alkyl. In a preferred embodiment, Rl, R2, R3, R4 and X are selected with the proviso that if Rl is-N (CH3) 2, R3 is acetoxy ; R4 is methyl and X is =O, then R2 is not hydrogen.

The tenn"alkyl"is used herein to refer to a branched or unbranched, saturated or unsaturated, monovalent hydrocarbon radical having from 1-12 carbons and, preferably, from 1-6 carbons. When the alkyl group has from 1-6 carbon atoms, it is referred to as a"lower alkyl."Suitable alkyl radicals include, for example, methyl, ethyl, n- propyl, i-propyl, 2-propenyl (or allyl), n-butyl, t-butyl, i-butyl (or 2-methylpropyl), etc. As used herein, the term alkyl encompasses"substituted alkyls."Substituted alkyl refers to alkyl as just described including one or more functional groups such as lower alkyl, aryl, aralkyl, acyl, halogen (i. e., alkylhalos, e. g., CF3), hydroxy (e. g., hydroxymethyl), amino, alkylamino, acylamino, acyloxy, alkoxy (e. g., methoxymethyl), mercapto and the like.

These groups may be attached to any carbon atom of the lower alkyl moiety.

The term"alkoxy"is used herein to refer to the-OR group, where R is a lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl.

Suitable alkoxy radicals include, for example, methoxy, ethoxy, phenoxy, t-butoxy (e. g., methoxyethoxy, methoxymethoxy, etc.), etc.

The term"acyloxy"is used herein to refer to an organic radical derived from an organic acid by the removal of a hydrogen. The organic radical can be further substituted with one or more functional groups such as alkyl, aryl, aralkyl, acyl, halogen, amino, thiol, hydroxy, alkoxy, etc. An example of such a substituted organic radical is glycinate (e. g.,-OC (O) CH2NH2). Suitable acyloxy groups include, for example, acetoxy, i. e., CH3COO-, which is derived from acetic acid, formyloxy, i. e., H. CO. O-, which is

derived from formic acid and cypionyloxy, which is derived from 3-cyclopentylpropionic acid.

The term"halogen"is used herein to refer to fluorine, bromine, chlorine and iodine atoms.

The term"hydroxy"is used herein to refer to the group-OH.

The term"acyl"denotes groups-C (O) R, where R is alkyl or substituted alkyl, aryl or substituted aryl as defined herein.

The term"aryl"is used herein to refer to an aromatic substituent which may be a single ring or multiple rings which are fused together, linked covalently, or linked to a common group such as an ethylene or methylene moiety. The aromatic ring (s) may include phenyl, naphthyl, biphenyl, diphenylmethyl, 2, 2-diphenyl-1-ethyl, and may contain a heteroatom, such as thienyl, pyridyl and quinoxalyl. The aryl group may also be substituted with halogen atoms, or other groups such as nitro, carboxyl, alkoxy, phenoxy, and the like.

Additionally, the aryl group may be attached to other moieties at any position on the aryl radical which would otherwise be occupied by a hydrogen atom (such as 2-pyridyl, 3- pyridyl and 4-pyridyl).

The term"alkyl carbonate"is used herein to refer to the group-OC (O) OR, where R is allcyl, substituted alkyl, aryl, or substituted aryl as defined herein.

The term"S-alkyl"is used herein to refer to the group-SR, where R is lower alkyl or substituted lower alkyl.

The term"S-acyl"is used herein to refer to a thioester derived from the reaction of a thiol group with an acylating agent. Suitable S-acyls include, for example, S- acetyl, S-propionyl and S-pivaloyl. Those of skill in the art will know that S-acyl refers to such thioester regardless of their method of preparation.

The terms"N-oxime"and"N-alkyloxime"are used herein to refer to the group =N-OR5, wherein R5 is, for example, hydrogen (N-oxime) or alkyl (N-alkyloxime).

Those of skill in the art will know that the oximes can consist of the syn-isomer, the anti- isomer or a mixture of both the syn-and anti-isomers.

Within Formula I, certain embodiments are preferred, namely those in which Rl is-N (CH3) 2 ; those in which R2 is halogen or alkoxy ; those in which R3 is acyloxy ; those in which R4 is alkyl (e. g., methyl and ethyl) ; and those is which X is =O and =N-oR5, wherein R5 is hydrogen or alkyl. More particularly, compounds which are preferred are

those in which Rl is-N (CH3) 2 ; R2 is halogen ; R3 is acyloxy ; and R4is allçyl. Within this embodiment, compounds which are particularly preferred are those in which R2 is F, Br or Cl ; and R4 is methyl. Also preferred are compounds in which Rl is-N (CH3) 2 ; R2 is alkyl ; R3 is acyloxy ; R4 is alkykl ; and X is =O. Also preferred are compounds in which Rl is- N (CH3) 2 ; R2is alkoxy ; R3 is acyloxy ; R4 is allcyl ; and X is=O. Within this embodiment, compounds which are particularly preferred are those in which R2 is methoxy or ethoxy ; and R3 is acetoxy or methoxy. Also preferred are compounds in which Rl is-N (CH3) 2 ; R2 is hydroxy ; R3 is acyloxy ; R4 is alkyl ; and X is =O. Also preferred are compounds in which R1 is -N(CH3)2; R2 and R3 are both acyloxy, R4 is alkyl; and X is=O. Within this embodiment, compounds which are particularly preferred are those in which W and R3 are both acetoxy. Also preferred are compounds in which Rl is-N (CH3) 2 ; R2 is S-acyl ; R3 is hydroxy or acyloxy ; R4 is alkyl ; and X is =O. Also preferred are compounds in which Rl is -N (CH3) 2 ; R2 is cypionyloxy ; R3 is acetoxy ; R4 is alkyl ; and X is =O. Also preferred are compounds in which Rl is-N (CH3) 2 ; R2 is methoxy ; R3 is acetoxy ; R4 is allcyl ; and X is =0 and =N-OR5, wherein R5is, for example, hydrogen or alkyl (e. g., methyl, ethyl, etc.). Also preferred are compounds in which Rl is-N (CH3) 2 ; W and R3 are both acetoxy ; R4 is alkyl ; and X is =O and =N-OR wherein R is, for example, hydrogen or alkyl (e. g., methyl, ethyl, etc.).

Exemplar compounds falling within the above preferred embodiments include, but are not limited to, 17α-acetoxy-21-fluoro-11ß-(4-N,N-dimethylaminiophenyl)- 19-norpregna-4, 9-diene-3, 20-dione, 17a-acetoxy-21-chloro-11 ß-(4-N,N- dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione, 17α-acetoxy-21-bromoro-11ß- (4-N, N-dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione, 17-, 21-diacetoxy-1 (3- (4-N, N-dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione, 17a-hydroxy-21- acetylthio-11ß-(4-N,N-dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione, 17a- acetoxy-21-acetylthio-11ß-(4-N,N-dimethylaminophenyl)-19-no rpregna-4, 9-diene-3, 20- dione, 17ß-acetoxy-21-ethoxy-11ß- (4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene- 3, 20-dione, 17α-acetoxy-21-methyl-11ß-(4-N,N-dimethylamino-phenyl)-19- norpregna-4, 9- diene-3, 20-dione, 17α-acetoxy-21-methoxy-11ß-(4-N,N-dimethylaminophenyl)-19- norpregna-4, 9-diene-3, 20-dione, 17α-acetoxy-21-ethoxy-11ß-(4-N,N- dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione, 17a-acetoxy-21- (3'- cyclopentylpropionyloxy)-11 (4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-

3, 20-dione, 17a-acetoxy-21-hydroxy-11 ß-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9- diene-3, 20-dione, 17 a, 21-diacetoxy-1 1ß-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9- diene-3, 20-dione 3-oxime, 17a-acetoxy-21-methoxy-11 3- (4-N, N-dimethylaminophenyl)- 19-norpregna-4, 9-diene-3, 20-dione 3-oxime, 17 α-acetoxy-11ß-[4-(N- methylamino) phenyl]-19-norpregna-4, 9diene-3, 20-dione, and 17a, 21-diacetoxy-11ß-[4-(N- methylamino) phenyl]-19-norpregna-4,9-diene-3, 20-dione.

In addition to the foregoing, certain other embodiments are preferred, namely those in which R1 is -N(CH3)2,-NC4H8,-NC5H10,-NC4H8O,-(O) CH3, -O (CH2) 2N (CH3) 2,-O (CH2) 2NC4H8,-O (CH2) 2NC5Hlo, and-O (CH2) 2NC5H10 ; those in which R2 is hydrogen, alcyloxy, alkoxy,-SAc,-SCN,-OC (O) CH2N (CH3) 2, and-OC (O) R6, wherein R6 is a functional group including, but not limited to, alkyls (e. g.,-CH2CH3), alkoxy esters (e. g.,-CH20Me) and alkoxys (e. g.,-OCH3.) ; those in which R3 is allcyl, alkoxy, acyloxy and hydroxy ; those in which R4 is alkyl (e. g., methyl and ethyl) ; and those is which X is =O or =N-oR5, wherein R5 is hydrogen or alkyl. Also preferred are compounds in which Rl is-N (CH3) 2 ; R2 is hydrogen ; R3 is methoxymethyl ; R4 is methyl ; and X is =O. Also preferred are compounds in which Rl is-N (CH3) 2 ; R2 is hydrogen ; R3 is -OC (O) H,-OC (O) CH2CH3 or-OC (O) C6Hl3 ; R4 is methyl ; and X is =O. Also preferred are compounds in which R1 is -NC4H8,-NC5HU10,-NC4H8O,-C(O)CH3 or-SCH3 ; R2 is hydrogen ; R3 is acetoxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which R1 is -N(CH3)2 or -NC5H10 ; R2 is hydrogen ; R3 is methoxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which R1 is -NC5H10 or-C (O) CH3 ; R2 and R3 are both acetoxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which Rl is -C (O) CH3 ; W is-SAc ; R3 is acetoxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which Rl is-C (O) CH3,-N (CH3) 2,-NC4H8 or-NC5HIo ; R2 and R3 are both methoxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which R1 is -NCsHIo,-C (O) CH3 or-O (CH2) 2N (CH3) 2 ; R2 is methoxy ; R3 is acetoxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which Rl is-N (CH3) 2 ; R2 is-OC (O) CH2CH3, -OC (O) OCH3,-OC (O) OCH20CH3,-OCH=CH2,-OC (O) CH2N (CH3) 2 or-SCN ; R3 is acetoxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which Rl is -N (CH3) 2 ; R2 is-OC (O) H ; R3 is-OC (O) H ; R4 is methyl ; and X is =O. Also preferred are compounds in which Rl is-N (CH3) 2 ; W is-OC (O) H ; R3 is hydroxy ; R4 is methyl ; and X is =O. Also preferred are compounds in which R1 is -NC5HU10 ; R2 is hydrogen ; R3 is acetoxy ;

R4 is methyl ; and X is =N-ORS, wherein R5 is hydrogen. Also preferred are compounds in which Rl is-N (CH3) 2 or-NC5HIo ; R2 is hydrogen or methoxy ; R3 is methoxy or ethoxy ; R4 is methyl ; and X is =N-OR, wherein R is hydrogen.

Exemplar compounds falling within the above preferred embodiments include, but are not limited to, 17α-formyloxy-11ß-[4-(N,N-dimethylamino)phenyl]-19- norpregna-4, 9-diene-3, 20-dione ; 17α-propionoxy-11ß-[4-(N,N-dimethylamino)phenyl]-19- norpregna-4, 9-diene-3, 20-dione ; 17α-heptanoyloxy-11ß-[4-(N,N-dimethylamino)phenyl]- 19-norpregna-4, 9-diene-3, 20-dione ; 17a-methoxymethyl-llp- [4- (N, N dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione ; 17α-acetoxy-11ß-(4-N- pyrrolidinophenyl)-19-norpregna-4, 9-diene-3, 20-dione ; 17a-acetoxy-11 (3- (4-N piperidinophenyl)-19-norpregna-4, 9-diene-3, 20-dione ; 17a-acetoxy-11 (3- (4-N morpholinophenyl)-19-norpregna-4, 9-diene-3, 20-dione ; 17α-acetoxy-11ß-(4-acetylphenyl)- 19-norpregna-4, 9-diene-3, 20-dione ; 17a-acetoxy-11 P- (4-methylthiophenyl)-19-norpregna- 4, 9-diene-3, 20-dione ; 17α-methoxy-11ß-[4-(N,N-dimethylamino)phenyl]-19-norpregna - 4, 9-diene-3, 20-dione ; 17a-methoxy-ll (3- (4-N-piperidinophenyl)-19-norpregna-4, 9-diene- 3, 20-dione ; 17α,21-diacetoxy-11ß-(4-NJ-iperidinophenyl)-19-norpregna-4 ,9-diene-3,20- dione ; 17a, 21-diacetoxy-1 (3- (4-acetylphenyl) 19-norpregna-4, 9-diene-3, 20-dione ; 17a- acetoxy-11 (3- (4-acetylphenyl)-21-thioacetoxy-19-norpregna-4, 9-diene-3, 20-dione ; 17a, 21- dimethoxy-11 (3- [4- (A/,//-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione ; 17a, 21-dimethoxy-11 3- (4-N-pyrrolidinophenyl)-19-norpregna-4, 9-diene-3, 20-dione ; 17α,231-dimethoxy-11ß-(4-N-piperidinophenyl)-19-norpregnja -4, 9-diene-3, 20-dione ; 17a, 21-dimethoxy-11 (3- (4-acetylphenyl)-19-norpregna-4, 9-diene-3, 20-dione ; 17a-acetoxy- 11ß-(4-acetylphenyl)-21-methoxy-19-norpregna-4, 9-diene-3, 20-dione ; 17a-acetoxy-1 J3- {4- [2'- (N, N-dimethylamino) ethoxy] phenyl}-21-methoxy-19-norpregna-4, 9-diene-3, 20- dione ; 17a, 21-diformyloxy-llp- [4- (NN-dimethylamino) phenyl]-19-norpregna-4, 9-diene- 3, 20-dione ; 17α-acetoxy-11ß-[4-(N,N-dimethylamino)phenyl]-21-propionyl oxy-19- norpregna-4, 9-diene-3, 20-dione ; 17α-acetoxy-11ß-[4-(N,N-dimethylamino)phenyl]21-(2'- methoxyacetyl) oxy-19-noipregna-4, 9-diene-3, 20-dione ; 17a-acetoxy-21-hydroxy-l lp- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione-21-methyl carbonate ; <BR> <BR> <BR> <BR> 17α-11ß-[4-(N,N-dimethylamino)phenyl]-21-(1'-ethenyloxy)-1 9-norpregna-4,9- diene-3, 20-dione ; 17α-acetoxy-11ß-[4-(N,N-dimethylamino)phenyl]-21-(2'-N,N- dimethylamino) acetoxy-19-norpregna-4, 9-diene-3, 20-dione ; 17α-acetoxy-11ß-[4-(N,N-

dimethylamino) phenyl]-21-thiocyanato-19-norpregna-4, 9-diene-3, 20-dione ; 17a-acetoxy- 11 ß-(4-N-piperidinophenyl)-l 9-norpregna-4, 9-diene-3, 20-dione 3-oxime ; 17a-methoxy- 11 (3- [4- (N, N-dimethylamino) phenyl]-l9-norpregna-4, 9-diene-3, 20-dione 3-oxime ; 17a- methoxy-1 (3- (4-N-piperidinophenyl)-19-norpregna-4, 9-diene-3, 20-dione 3-oxime ; and 17a, 21-dimetnoxy-11 j3- [4- (N, N dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione 3-oxime.

The compounds of the present invention can readily be synthesized in a variety of ways using modern synthetic organic chemistry techniques. Typically, the compounds of the present invention are prepared using the synthetic schemes set forth in Figures 1-11. In general, there are five strategic steps that are useful in the synthesis of the antiprogestational agents of the present invention. They are : (1) C21-substitution ; (2) construction of the 17a-hydroxy-20-ketone pregnane side chain with the natural configuration via the SNAP reaction ; (3) modification of the 17a-hydroxy moiety ; (4) regiospecific synthesis of the epoxide and 1, 4-conjugate grignard addition of a variety of 4- substituted aryl compounds ; and (5) deketalization at C3 and 20 and concomitant dehydratration at C5. Each of these five strategic steps is described in greater detail hereinbelow. Moreover, a more detailed description of the synthetic protocols used to prepare the compounds of the present invention is set forth in the Example Section. It will be readily apparent to those of skill in the art that the particular steps, or combination of steps, used will vary depending on the compound being synthesized.

1. 21-Substitution In particular embodiments of the present invention, a number of different functional groups, such as F, Cl, Br, Me, hydroxy, alkoxy (e. g., methoxy, ethoxy, etc.), acyloxy (i. e., formyloxy, acetoxy, propionyloxy, etc.), cypionyloxy, methoxyacetoxy, and acylthio, have been introduced at C-21 of lead compound 17a-acetoxy-11 (3- (4-N, N dimethylaminophenyl)-19-norpregna-4, 9-diene-3, 20-dione (CDB-2914 or C-21H or 69B) using the synthetic schemes set forth in Figures 1, 2 and 3. For instance, a Silicon Nucleophilic Annulation Process (SNAP) on 17p-cyanohydrin (5) was used to prepare all of the 21-halogenated compounds with the exception of the 21-fluoro compound. This compound, however, was readily obtained by reacting the 21-mesylate with KF in acetonitrile in the presence of a crown ether. In addition, the 17a-acetoxy-21-ol compound

(41) was obtained selectively from the ethoxyethylidenedioxy derivative (18) by means of buffered hydrolysis, whereas the 17a-ol-21-acetate derivative (8) was prepared from reacting the 21-halo compound with KOAc. It is interesting to note that both the 21-acetate and the 17a-acetate produced the 17a, 21-diol (9) by a base catalyzed methanolosis.

Thereafter, this 17a, 21-diol was readily converted to the 17a, 21-diacetate (15) by a mixed anhydride procedure. With regard to the synthesis of 17cc-acetoxy-21-cypionate (40), the hydroxyl group at C-21 of the 17a, 21-diol (9) was first converted to the corresponding cypionate (39) and then the 17a-OH group was acetylated. The 17a-acetoxy-21- thioacetate (17) was obtained by reaction of the 21-iodo compound generated in situ from the corresponding bromo compound (7B), with potassium thioacetate followed by acetylation of the 17a-alcohol as shown in the synthetic scheme set forth in Figure 1.

Moreover, the 21-methyl analog (28) was prepared following the synthetic route set forth in Figure 2. The key reactions in this scheme are (1) the conversion of the 17a-cyanohydrin to the 17a-trimethylsilyloxy, 17a-aldehyde, and (2) the creation of the 21- methylprogesterone skeleton (21- 22).

In addition, the 21-methoxy analog (38) was obtained following the synthetic scheme set forth in Figure 3. The key step in this scheme is the reaction of the 17a, 21-diol protected at C-3 and C-20 with Meerwein's trimethyloxonium tetrafluoroborate salt in the presence of the sterically more hindered, less nucleophilic base, 1, 8- bis (dimethylamino) naphthalene, as the proton sponge to selectively methylate the less- hindered 21-hydroxyl group. The subsequent epoxidation of the crude 21-methoxy compound (34) produced a 2 : 1 mixture of a and P epoxides as evidenced by IH NMR. The crude epoxide (35) was subjected directly to the copper (I) catalyzed conjugate Grignard addition, assuming 66% of the crude epoxide was the desired-epoxide, hydrolysis and acetylation gave the 21-methoxy compound (38) with a purity of 98%. Following similar procedures, the 21-ethoxy compound (46) was obtained using triethyloxonium tetrafluoroborate salt. Treatment of the 21-acetete (15) and 21-methoxy compound (38) with hydroxylamine HC1 followed by adjustment of the pH to pH 7 provided the desired 3- oximes, 47 and 48, respectively, as a mixture of syn-and anti-isomers. Under these conditions, the sterically hindered C-20 ketone was intact as evidenced by IR spectroscopy.

In addition, using methods similar to those described above, additional functional groups, such as propionyloxy- (126a), 2-methoxyacetoxy- (126b),

methylcarbonate (126c), 2-(N,Ndimethylamino) acetoxy- (133), and thiocyanato- (138) were readily synthesized (see, e. g., Figure 10 and 11). Their synthetic methodology is straightforward. All of these compounds were derived from the previously prepared I 7a, 21-dihydroxy-11 (3- [4- (N, N dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (9 in Figure 1 or 124 in Figure 11). The C21- (1-ethenyl) oxy analog (129) was obtained from the C17a-acetoxy-21-ol (128) by reaction with ethyl vinyl ether in the presence of mercury (II) trifluoroacetate. Compound 128 was, in turn, obtained from hydrolysis of the 17a, 21-cyclic ortho ester (18 in Figure 1 or 127 in Figure 11). Reaction of the C17a, 21- diol (9 in Figure 1 or 124 in Figure 11) with methyl chlorofonnate in pyridine gave the methyl carbonate at C21 (125c). Subsequent acetylation at C17 led to the target compound 126c (see, Figure 11). Treatment of the C17a, 21-diol (9 or 124) with methoxyacetyl chloride, followed by acetylation, provided 126b (see, Figure 11). The synthesis of the 21- thiocyanato analog (138), which is illustrated in Figure 11, involved the preparation of the 21-mesylate (136), followed by thiocyanation at C21 (137) using the modified procedure of Abramson, H. N., et al. (I. Phara. Sci. 65 : 765-768 (1976)). Subsequent acetylation at C17 led to the target compound (138). The 21-(N, N-dimethylamino) acetoxy (133) analog was obtained by preparing the 21-chloroacetate (130), acetylation of the 17a-OH (131) and converting the latter to the 21-iodoacetate (132) followed by the reaction of 132 with dimethylamine (see, Figure 10). This order of sequence did not result in hydrolysis of the 21-ester group. It is pointed out that an attempt to prepare the 21-iodoacetate (132) directly from the diol (124) was not as successful.

The 17a, 21-diformate (139), which is illustrated in Figure 10, was synthesized by perchloric acid catalyzed formylation of the 17a, 21-diol (124) following the procedure of Oliveto, E. P., et al. (J Anz. Chem. Soc., 77 : 3564-3567 (1955)). NMR analysis of this material indicated a 55 : 45 mixture of the 17a, 21-diformate (139) resonating at 8. 029 (s, C17-OCHO) and 8. 165 ppm (s, C21-OCHO), respectively, and the 21-monoformate (140) at 8. 172 ppm (s, C21-OCHO). Therefore, chromatographic separation was essential to obtain the pure 17a, 21-diformate (139).

Syntheses of the 17a, 21-dimethoxy derivatives (113a, 113b, 133c and 133d) were achieved via oxidation at C-21 to afford the 21-hydroxy derivative (107) of the 17a- methoxy compound (94) following a modification of the procedure reported by Moriarty, R. M. et al., J. Cizem. Noc. Chem. Commu71s) 641-642 (1981), and Velerio, et al., Steroids,

60 : 268-271 (1995). Subsequent 0-methylation provided the key 17a, 21-dimethoxy intermediate (108) (see, Figure 8). Reduction of the 20-ketone (108) to the 204-ol (109) followed by epoxidation at C5 and C10, copper (I) catalyzed conjugate Grignard addition to the 5a, 10a-epoxide (110), selective oxidation of the secondary alcohol, 20-ol (111) using IBX to the 20-ketone (112), hydrolysis and acetylation, led to the target 17a, 21-dimethoxy derivatives (113).

2. Silicon Nucleophilic Annelation Process (SNAP) As described herein silylation of p-cyanohydrin ketal with halomethyldimethylsilyl chloride afforded the chloro-or bromomethyldimethylsilyl ether.

The reductive SNAP reaction provided the 17a-hydroxy-20-ketopregnane side chain with the natural configuration at C17 (Livingston, D. A., et al., J. Am. Chem. Soc., 112 : 6449- 6450 (1990) ; Livingston, D. A., Adv. Med. Chez., 1 : 137-174 (1992) ; U. S. Patent No.

4, 092, 693, which issued to Livingston, D. A., et al. (May 1, 1990) ; U. S. Patent No.

4, 977, 255, which issued to Livingston, D. A., et al. (December 11, 1990). Alternatively, the formation of the halomethyldimethylsilyl ether, followed by treatment with lithium diisopropyl amide, provided the 21-substituted-17a-hydroxy-20-ketopregnanes.

3. 17a-Substitution All 17a-esters illustrated in Figures 4-11 were prepared from their 17a- hydroxy precursors. With the exception of the 17a-formate (69A) and the 17a, 21- difonnate (139), all 17a-esters were also obtained via a mixed anhydride procedure (Carruthers, N. I. e1t al., J. Org Chem., 57 : 961-965 (1992)).

17a-methoxy steroid (93) became available in large quantities from the 17a- hydroxydienedione (92) leading to a new series of antiprogestational agents, such as compounds 97 and 113. Methylation of 17a-hydroxy group was most efficiently carried out using methyl iodide and silver oxide with acetonitrile as a cosolvent as described in the general procedure of Finch, et al. (J. Org. Chemin., 40 : 206-215 (1975)). Other syntheses of 17a-methoxy steroids have been reported in the literature (see, e. g., Numazawa, M. and Nagaoka, M., J. Cliein. Soc. Cominun., 127-128 (1983) ; Numazawa, M. andNagaoka, M., J Org. Cheyn., 50 : 81-84 (1985) ; Glazier, E. R., J : Org Chem., 27 : 4397-4393 (1962).

The 17a-methoxymethyl compound (91) was obtained in 0. 7% overall yield via the 14-step sequence illustrated in Figure 5 starting from estrone methyl ether (77). No

attempts were made to optimize the yield. The general strategy involved : (1) Construction of the 20-ketopregnane side chain ; (2) Formation of the 17, 20-enol acetate and subsequent alkylation with bromomethyl methyl ether ; (3) Elaboration of the 3-ketal-5 (10), 9 (11)- diene ; (4) Epoxidation ; (5) Conjugate Grignard addition ; and (6) Hydrolysis.

4. llp-Aryl-4-Substitution The introduction of a variety of 4-substituted phenyl group at C11ß into 19- norprogesterone requires the 5a, 10a-epoxide. Epoxidation of 2, 23, 34, 42, 50, 88, 94, 99, 109 and 119 has been known to be problematic (see, Wiechert, R. and Neef, G., J. Steroid Biochem., 27 : 851-858 (1987)). The procedure developed by Teutsch, G., et al. (Adrenal Steroid Antagonism (Agarwal, M. K., ed.), 43-75, Walter de Gruyter & Co., Berlin, N. Y.

(1984)), i. e., H2O2 and hexachlor or fluoroacetone, proved to be regioselective, but not highly stereoselective. A mixture of 5a, 10a-epoxide and the corresponding 50, 10 (3-isomer was formed in approximately a 3 : 1 ratio. However, reduction of the C20-ketone (108) to the C20-ol (109) prior to epoxidation, resulted in a 9 : 1 ratio of the desired 5a, 10a-epoxide.

Treatment of the 5a, 10a-epoxides with 3-5 equivalents of Grignard reagents prepared from various 4-substituted aryl bromides (see, Yur'ev, Y. K., et al., Izvest. Akad.

Nauk. 5. S. S. R., Otdel Khim NauAc, 166-171 (CA 45 : 10236f, (1951)) ; Wolfe, J. P. and Buchwald, S. L., J. Org. Chem., 62 : 6066-6068 (1997) ; Veradro, G., et al., Synthesis, 447- 450 (1991) ; Jones, D. H., J. Chem. Soc. (C), 132-137 (1971) ; Detty et al., J :Am. Claem.

Soc., 105 : 875-882 (1983), and Rao, P. N. et al., Steroids, 63 : 523-550 (1998)) in the presence of copper (I) chloride as a catalyst provided the desired 11 (3-4-substituted phenyl steroids. It is noted that 4-bromothioanisole was purchased from the Aldrich Chemical Co.

(Milwaukee, Wisconsin). Evidence of the I 1 (3-orientation of the 4-substituted phenyl substituent was shown by the upfiled shift of the C 18 methyl group (6 = 0. 273-0. 484 ppm in CDC13), which is in agreement with Teutsch's observations (see, Teutsch, G. and Belanger, A., Tetrahedron Lett., 2051-2054 (1979)).

The presence of an unprotected 20-ketone resulted in low yields or in undesirable Grignard product mixtures. This was circumvented by reduction of the 20- ketone (analysis of this material by NMR indicated a single isomer ; no further work was done for identification of this single isomer) prior to epoxidation and subsequent oxidation of the 20-alcohol by use of iodoxybenzoic acid (IBX) (Dess, D. B. and Martin, J. C., J Org.

Chem., 48 : 4155-4156 (1983) ; Frigerio, M. and Santagostino, M., Tetrahedron Letters,

35 : 8019-8022 (1994) ; and Frigerio, M. et al., J. Org. Chem., 60 : 7272-7276) after Grignard addition (see, Figure 8).

In case of Figures 5 and 6, the C3-ketone group was protected as a monoethyleneketal, and the C20-ketone was found to be intact when the Grignard reaction was followed during the multi-step procedures. For the syntheses of the 17a, 21-diacetoxy derivatives (Figure 7), the strategy was to accomplish the conjugate addition prior to the SNAP reaction using the multi-step process described herein.

5. Deketalization Deketalization with concomitant dehydration at C-5 in acidic media proceeded smoothly to provide the 4, 9-diene-3, 20-dione.

Quite surprisingly, the compounds of Formula I possess potent antiprogestational activity with minimal antiglucocorticoid activity. As a result of their antiprogestational activity, the compounds of Formula I can advantageously be used, inter alia, to antagonize endogenous progesterone ; to induce menses ; to treat endometriosis ; to treat dysmenorrhea ; to treat endocrine hormone-dependent tumors ; to treat meningioma ; to treat uterine leiomyonas, to treat uterine fibroids ; to inhibit uterine endometrial proliferation ; to induce labor ; to induce cervical ripening, for hormone therapy ; and for contraception.

More particularly, compounds having antiprogestational activity are characterized by antagonizing the effects of progesterone. As such, the compounds of the present invention are of particular value in the control of hormonal irregularities in the menstrual cycle, for controlling endometriosis and dysmenorrhea, and for inducing menses.

In addition, the compounds of the present invention can be used as a method of providing hormone therapy either alone or in combination with estrogenic substances in postmenopausal women, or in women whose ovarian hormone production is otherwise compromised.

Moreover, the compounds of the present invention can be used for control of fertility during the whole of the reproductive cycle. For long-term contraception, the compounds of the present invention can be administered either continuously or periodically depending on the dose. In addition, the compounds of the present invention are of particular value as postcoital contraceptives, for rendering the uterus inimical to implantation, and as"once a month"contraceptive agents.

A further important utility for the compounds of the present invention lies in their ability to slow down growth of hormone-dependent tumors and/or tumors present in hormone-responsive tissues. Such tumors include, but are not limited to, kidney, breast, endometrial, ovarian, and prostate tumors, e. g., cancers, which are characterized by possessing progesterone receptors and can be expected to respond to the compounds of this invention. In addition, such tumors include meningiomas. Other utilities of the compounds of the present invention include the treatment of fibrocystic disease of the breast and uterine.

Compounds suitable for use in the above method of the present invention can readily be identified using in vitro and in vivo screening assays known to and used by those of skill in the art. For instance, a given compound can readily be screened for its antiprogestational properties using, for example, the anti-McGinty test and/or the anti- Clauberg test described in the examples. In addition, a given compound can readily be screened for its ability to bind to the progesterone and/or glucocorticoid receptors or to inhibit ovulation using the assays described in the examples. Moreover, a given compound can readily be screened for its ability to inhibit tumor cell growth (e. g., malignant tumor growth, i. e., cancer) or to abolish tumorigenicity of malignant cells in vitro or in vivo. For instance, tumor cell lines can be exposed to varying concentrations of a compound of interest, and the viability of the cells can be measured at set time points using, for example, the alamar Blue assay (commercially available from BioSource, International of Camarillo, California). Other assays known to and used by those of skill in the art can be employed to identify compounds useful in the methods of the present invention.

The compounds according to the present invention can be administered to any warm-blooded mammal such as humans, domestic pets, and farm animals. Domestic pets include dogs, cats, etc. Farm animals include cows, horses, pigs, sheep goats, etc.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the disease treated, the mammalian species, and the particular mode of administration. For example, a unit dose of the steroid can preferably contain between 0. 1 milligram and 1 gram of the active ingredient. A more preferred unit dose is between 0. 001 and 0. 5 grams. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed ; the age, body

weight, general health, sex and diet of the individual being treated ; the time and route of administration ; the rate of excretion ; other drugs which have previously been administered ; and the severity of the particular disease undergoing therapy, as is well understood by those of slcill in the area.

The compounds of the present invention can be administered by a variety of methods. Thus, those products of the invention that are active by the oral route can be administered in solutions, suspensions, emulsions, tablets, including sublingual and intrabuccal tablets, soft gelatin capsules, including solutions used in soft gelatin capsules, aqueous or oil suspensions, emulsions, pills, lozenges, troches, tablets, syrups or elixirs and the like. Products of the invention active on parenteral administration can be administered by depot injection, implants including Silastic TM and biodegradable implants, intramuscular and intravenous injections.

Compositions can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents. Tablets containing the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, such as maize starch, or alginic acid ; binding agents, such as starch, gelatin or acacia ; and lubricating agents, such as magnesium stearate, stearic acid and talc. Tablets can be uncoated or, alternatively, they can be coated by known methods to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay such as glyceryl monostearate or glyceryl stearate alone or with a wax can be employed.

Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such

excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e. g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e. g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e. g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e. g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e. g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.

Ophthalmic formulations, as is lalown in the art, will be adjusted for osmolarity.

Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water can be formulated from the active ingredients in admixture with a dispersing, suspending and/or wetting agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

The pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of

these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.

This suspension can be formulated according to the knows art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1, 3-butanediol.

Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables.

The compounds of this invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

They can also be administered by in intranasal, intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations.

Products of the invention which are preferably administered by the topical route can be administered as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are intended neither to limit or define the invention in any manner.

EXAMPLES Preparation of the Compounds of Formula I EXAMPLE 1 This example illustrates the preparation and properties of 17a-acetoxy-21- fluoro-11ß-[4-(N,N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (13) via the Silicon Nucleophilic Annulation Process (SNAP) of 5.

Step 1. 3, 3-Ethylenedioxy-17ß-cyanio-17α-trimethylsilyloxyestra-5(10 ),9(11)- diene (2) : Under nitrogen, a solution of the cyanohydrin ketal (1, 15 g, 43. 9 mmol) in pyridine (85 mL) was treated with chlorotrimethylsilane (28 mL = 27. 11 g, 221 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction was monitored by Thin Layer Chromatography (TLC) in 2% acetone in CH2C12. The reaction mixture was poured into a 50 : 50 mixture of ice/saturated sodium bicarbonate solution (1L), stirred until the ice was melted, and extracted with hexanes (3x). The organic extracts were washed with water (2x), brine (lx), combined, dried over Na2S04, and concentrated in vacuo. The remaining pyridine was azeotropically removed in vacuo with heptane to give 18 g of the crude product as a foam. Crystallization from ether/hexanes gave 16. 35 g of the pure silyl ether (2) as a white solid in 90% yield ; m. p. = 100-102°C. FTIR (KBr, diffuse reflectance) Viiiax 2880, 2232 and 1254 cm-1.

NMR (CDC13) 8 0. 11 (s, 9 H, OSiMe3), 0. 73 (s, 3 H, C18-CH3), 3. 83 (s, 4 H,- OCH2CH20-) and 5. 49 (br s, 1 H, 11 ß-H).

Step 2. 3, 3-Ethylenedioxy-5α,10α-epoxy-17ß-cyano-17α-trimjethylsil yloxyestra- 9(11)-ene (3): Hydrogen peroxide (30%, 6 mL, 58. 6 mmol) was added to a vigorously stirred mixture of hexafluoroacetone trihydrate (11. 8 g, 53. 6 mmol) and Na2HP04 (6. 8 g, 47. 9 mmol) in CH2Cl2 (150 mL) cooled to 0°C in an ice bath. After stirring at 0°C for 30 minutes, a solution of the silyl ether (2, 16 g, 38. 7 mmol) in CH2Clz (10 mL), pre-cooled to 0°C was added. The mixture was then stirred at 0°C for 8 hr. At that time TLC in 5% acetone/CH2Cl2 indicated incomplete reaction and the mixture was then stirred overnight at 4°C. The reaction mixture was diluted with CH2C12 (200 mL) and washed with 10% sodium sulfite solution (2x), saturated sodium bicarbonate solution (lx) and brine (lx).

The organic layers were combined, dried over Na2S04, filtered and concentrated in vacuo to give 16. 8 g of the crude epoxide mixture which consists of a 70 : 30 mixture of the 5α,10α-epoxide and 5, 10p-epoxide. Crystallization of the crude mixture from ether/hexanes afforded 8. 5 g of the pure 5a, 10a-epoxide (3) as a white solid in 51 % yield ; m. p. =164-165°C. FTIR (KBr, diffuse reflectance) v,,,,,, 2940, 2872, 2228 and 1252 crn 1.

NMR (CDCl3) 8 0. 23 (s, 9 H, OSiMe3), 0. 91 (s, 3 H, C18-CH3), 3. 91 (s, 4 H, OCH2CH20) and 6. 12 (br s, 1 H, Cll-CH=).

Step 3. 3, 3-Ethylenedioxy-5 a--ltydroxy-11ß [4-(N,N-dimethylamino)phenyl]- 17, ß-cyano-17α-trimethylsilyloxyestr-9(10)-ene (4): Magnesium (2. 6 g, 107 mmol) was added to a 1. 0 L, 3-neck flask equipped with a magnetic stir bar, addition funnel and a condenser. A crystal of iodine was added followed by dry THF (100 mL) and a few drops of 1, 2-dibromoethane. The mixture was stirred under nitrogen and heated in a warm water bath until evidence of reaction was observed. A solution of 4-bromo-N, N-dimethylaniline (19. 6 g, 98 mmol) in dry THF (100 mL) was then added dropwise over a period of 20 min. and the mixture stirred for an additional 1. 5 hours. Solid copper (I) chloride (1 g, 10. 1 mmol) was added followed 30 minutes later by a solution of the 5a-, 10a-epoxide (3, 8. 4 g, 19. 55 mmol) in dry THF (10 mL). The mixture was stirred at room temperature for 1 hr., then quenched by the addition of saturated NH4C1 solution (100 mL). With vigorous stirring, air was drawn through the reaction mixture for 30 minutes. The mixture was diluted with ether (250 mL) and the layers allowed to separate. The THF/ether solution was washed with 10% NH4C1 solution (3x), 2 N NH40H solution (3x) and brine (lx). The organic layers were combined, dried over Na2S04, filtered and concentrated in. vacuo to give the crude product.

Crystallization of the crude product from ether gave 8. 6 g of the pure product 4 as a white solid in 80% yield ; m. p. = 222-224°C dec. FTIR (KBr, diffuse reflectance) v,,, 3221, 2951, 2232, 1613, 1517 and 1253 cm~l. NMR (CDC13) 8 0. 20 (s, 9 H, OSiMe3), 0. 5 (s, 3 H, C18-CH3), 2. 83 (s, 6 H, NMe2), 3. 9 (m, 4 H, OCH2CH20), 4. 3 (m, 1 H, C11α-CH), 6. 63 (d, J=9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 03 (d, J=9Hz, 2', 6'aromatic-CH's).

Step 4, 11ß[4-(N,N-Dimethylamino)phenyl]-17ß-cyanoi-17α-hydroxyes tra-4,9- dien-3-one (5) : A solution of the Grignard adduct (4, 8. 5 g, 15. 4 mmol) was dissolved in THF (50 mL) and the system was flushed with nitrogen. Glacial acetic acid (150 mL) and

water (50 mL) were added and the mixture was heated at 50°C for 4 hrs. The volatile substances were removed i7i vacuo under a stream of nitrogen and the residual acid neutralized with NH40H. The mixture was extracted with CH2C12 (3x). The organic fractions were washed with water (2x), brine (lx), combined, dried over Na2S04, filtered and concentrated i7i vacuo. Crystallization of the residue from ether gave 3. 1 g of cyanohydrin (5) as a pale yellow solid. Chromatography of the mother liquors eluting with 50% EtOAc in hexanes followed by crystallization gave 1. 8 g of an additional product.

Total yield of the cyanohydrin 5, was 4. 9 g in 76. 2% yield ; m. p. = 152-154°C. FTIR (KBr, diffuse reflectance) via-3384, 2950, 2231, 1646, 1606 and 1520 em-1. NMR (CDCl3) 6 0. 67 (s, 3 H, C18-CH3), 2. 97 (s, 6 H, NMe2), 4. 38 (br s, 1 H, Clla-CH), 5. 83 (s, 1 H, C4-CH=), 6. 7 (d, J=9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 1 (d, J= 9 Hz, 2H, 2', 6' aromatic-CH's).

Step 5. 11ß-[4-(N,N-Dimethylamino)phenyl]-17ß-cyano-17α- bromotzetlzyldimetlzylsilyloxyestra-4, 9-dien-3-osze (6) : Under nitrogen, a solution of cyanohydrin (5) (4. 8 g, 11. 52 mmol), triethylamine (2. 5 mL, 17. 8 mmol) and dimethylaminopyridine (DMAP) (0. 4 g, 3. 3 mmol) in dry THF (50 mL) was treated with bromomethyldimethylsilyl chloride (2 mL, 14. 66 mmol). The mixture was stirred overnight at room temperature, diluted with hexanes, filtered through Celite and concentrated in vncuo. Flash chromatography of the residue using 40% EtOAc in hexanes gave 4. 8 g of the pure silyl ether (6) as a white solid in 73. 4% yield ; m. p. = 176-177°C. FTIR (KBr, diffuse reflectance) #m 2950, 2882, 2229, 1660, 1613 and 1519 cm- R (CDC13) 8 0. 41 (s, 6 H, OSi (CH3) 2), 0. 6 (s, 3 H, C18-CH3), 2. 61 (s, 2 H,-SiCHzBr), 2. 91 (s, 6 H, NMe2), 4. 4 (br m, 1 H, Cl la-CH), 5. 77 (s, 1 H, C4-CH=), 6. 66 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 05 (d, J = 9 Hz, 2', 6'aromatic-CH's).

Step 6A. 17α-Hydroxy-21-chloro-11ß-[4-(N,N-dimethylamino)phenyl]-19 norpregna-4, 9-diene-3, 20-dione (7A) : Under anhydrous conditions and using a mechanical stirrer, a solution of the silyl ether (6) (370 mg, 0. 71 mmol) in dry THF (7. 0 mL) was cooled to-78°C and treated dropwise with a 1. 5 M solution of lithium diisopropylamide in cyclohexane (1. 2 mL, 1. 77 mmol). The reaction mixture was stirred at-78°C for 45 min. and then warmed to-40°C.

The reaction was quenched by addition of 4 N HC1 (10 mL) and allowed to warm to room temperature. The excess acid was neutralized with the cautious addition of saturated

NaHC03 solution. The mixture was extracted with EtOAc. The organic extracts were washed with H20, and brine, combined, and dried over Na2S04. Evaporation of the solvent gave 378 mg of the crude product. The material was chromatographed eluting with 7. 5% acetone/CH2Cl2 to afford 179 mg of the 21-chloro ketone (7A) as a stable foam in 54% yield. MS (EI) m/z (relative intensity) 467 (M+, 70), 431 (M+-36, 8), 134 (18) and 121 (100) FTIR (KBr, diffuse reflectance) v,,,,, 3363, 2940, 1727, 1641 and 1517 ciri 1. NMR (CDC13) 8 0. 37 (s, 3 H, C18-CH3), 2. 90 (s, 6 H, NMe2), 4. 40 (br. d, 1 H, Clla-CH), 4. 5 (dd., 2 H, J = 15 Hz, J'= 12 Hz, C21-CH2C1), 5. 77 (s, 1 H, C4-CH=), 6. 67 and 7. 0 (d, 4 H, aromatic- CH's).

Generation of (7A) from (5) :"One Pot" (Step 5 and 6) Chloromethyldimethyl- silylation/LDA Reaction : A solution of cyanohydrin (5) (2. 25 g, 5. 4 mmol), TEA (1. 02 mL, 7. 29 mmol) and DMAP (165 mg, 1. 35 mmol) in THF (20 mL) was treated with chloromethyl dimethylsilylchloride (0. 82 mL, 6. 21 mmol). The reaction was stirred overnight and diluted with THF (30 mL). The mixture was chilled to-78°C and treated dropwise with LDA (1. 5 M/CHI2, 14. 4 mL). The mixture was stirred at-78°C for 45 min. and then warmed to-40°C. The reaction was quenched by addition of 4N HCI and allowed to warm to room temperature. The excess acid was neutralized with saturated NaHC03 solution and diluted with water. The aqueous mixture was extracted with methylene chloride. The organic extracts were washed with H2O, brine, combined and dried over Na2S04. Evaporation of the solvent gave 3. 24 g of the residue. The material was chromatographed eluting with 7. 5% acetone/CH2Cl2) to afford 1. 13 g of 7A in 45% yield, which was identical in all respects to the 21-chloroketone (7A) obtained from the previously described two step procedure.

Step 6B. 17α-Hydroxy-21-bromo-11ß-[[4-(N,N-dimethylamino)phenyl]-19 - norpregna-4,89-diene-3,20-dione (7B): Under anhydrous conditions and using a mechanical stirrer, a solution of the silyl ether 6 (2. 9 g, 5. 11 mmol) in dry THF (80 mL) was cooled to-78°C and treated dropwise with a 1. 5 M solution of lithium diisopropylamide (LDA) in cyclohexane (10. 2 mL, 15. 3 mmol). After 1 hr., the reaction mixture became very viscous, i. e., almost a gel.

The reaction was quenched at-78°C by addition of 4 N HBr (50 mL, 200 mmol) and the mixture allowed to warm to room temperature. The excess acid was neutralized by slow

addition of concentrated NH40H solution (15 mL) and the mixture was poured into water (100 mL) and extracted with CH2Cl2 (3x). The organic extracts were washed with water (3x), combined, filtered through Na2S04 and concentrated in vacuo to give 3. 1 g of the crude product as a foam. Purification via Flash chromatography gave a 94 : 6 mixture of the 21-bromo- (7B) and 21-chloro- (7A) derivative evidenced by a reverse phase HPLC on a NovaPak column eluting with MeOH/H2O/Et3N (70 : 30 : 0. 033) at a flow rate of 1. 0 mL/min at X = 302 nm. MS (EI) m/z (relative intensity) : 513 (M++2, 10), 512 (M+, 20), 431 (18) and 121 (100). FTIR (KBr, diffuse reflectance) v,,,,,, 3327, 2948, 1723, 1660, 1611 and 1518 cm~l. NMR (CDC13) 8 0. 3 (s, 3 H, C18-CH3), 2. 80 (s, 6 H, NMe2), 4. 3 (br m, 3 H, Cl la-CH and C21-CH2Br), 5. 65 (s, 1 H, C4-CH=), 6. 55 (d, J = 9 Hz, 2 H, 3', 5'aromatic- CH's) and 6. 9 (d, J = 9 Hz, 2', 6'aromatic-CH's). This mixture was used for the subsequent reaction without further purification.

Step 7. 17α-Hydroxy-21-acetoxy-11ß-[4-(N,N-dimethylamino)phenyl]-1 9- norpregna-4, 9-diene-3, 20-diosze (8) : Under nitrogen, a solution of a 94 : 6 mixture of the 21-halogenated steroid (7A and 7B) (1. 8 g, 3. 5 mmol) and potassium acetate (10 g, 102 mmol) in acetone was refluxed for 2 hrs. At the end of that time, TLC (10% acetone/CH2Cl2) indicated no presence of starting material. The reaction mixture was cooled to room temperature, filtered, concentrated in vacuo, diluted with water (200 mL) and extracted with CH2Cl2 (3x). The organic extracts were washed with water (2x), combined, filtered through Na2S04 and concentrated in vacuo to give 1. 6 g of the crude acetate (8) as a foam in 93% yield. A small portion of the pure acetate (8) was solidified by trituration with ether for characterization. This solid did not have a proper melting point and remained a solid when heated to 300°C. MS (EI) m/z (relative intensity) : 491 (M+, 72), 431 (6), 314 (17) and 121 (100). FTIR (KBr, diffuse reflectance) v,, a,, 3326, 2949, 1752, 1733, 1639, 1613, 1588 and 1519 cm I. NMR (CDC13) 8 0. 43 (s, 3 H, C18-CH3), 2. 27 (s, 3 H, OAc), 3. 0 (s, 6 H, NMe2), 4. 5 (br. d, 1 H, Cl la-CH), 5. 25 (dd, J1 = 29. 7 Hz, J2 = 24 Hz, 2 H, CH20Ac), 5. 87 (s, 1 H, C4-CH=), 6. 77 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 17 (d, J = 8. 7 Hz, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C30H37NO5 J/2H2O : C, 71. 97 ; H, 7. 65 ; N, 2. 80.

Found : C, 72. 16 ; H, 7. 48 ; N, 2. 90.

Step 8. 17α, 21-Dihydroxy-11ß-[4-(N,N-dimethylamino)phenyl]-19-norpregnj a- 4, 9-diene-3, 20-dio71e (9) : A solution of the 21-acetate (8) (1. 6 g, 3. 25 mmol) in MeOH (100 mL) was deoxygenated by bubbling through it a slow stream of nitrogen for 30 minutes. A similarly deoxygenated 0. 5 M solution of I (HCO3 in deionized water (10 mL, 5 mmol) was added and the mixture heated to reflux under nitrogen and monitored by TLC (5% i-PrOH/CH2Cl2) which indicated a complete reaction after 2 hr. The mixture was neutralized with 1M AcOH solution and the methanol removed in vacuo under a stream of nitrogen. The residue was taken up in CH2Cl2 and washed with water (3x). The organic layers were combined, dried over Na2S04, filtered and concentrated in vacuo to give 1. 6 g of the residue. This material was purified by Flash chromatography using 3% i- PrOH/CH2Cl2) followed by precipitation from methanol with water to give 1. 1 g of the diol (9) as a yellow amorphous solid in 75% yield ; m. p. = softens at 130°C. FTIR (KBr, diffuse reflectance) v"3391, 2946, 1712, 1654, 1612 and 1518 cm'\ NMR (CDC13) 5 0. 35 (s, 3 H, C18-CH3), 2. 91 (s, 6 H, NMe2), 4. 5 (m, 3 H, C11α-CH and CH2-OH), 5. 77 (s, 1 H, C4- CH=), 6. 67 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 0 (d, J = 8. 7 Hz, 2 H, 2', 6' aromatic-CH's). MS (EI) m/z (relative intensity) : 449 (M+, 51), 431 (14), 419 (9), 389 (27), 3432 (9) and 121 (100). Anal. Calcd. for C28H35NO4##H2O: C, 73. 33 ; H, 7. 91 ; N, 3. 05.

Found : C, 73. 52 ; H, 7. 70 ; N, 3. 06.

Step 9. 17α-Hydroxy-21-mesyloxy-11ß-[4-(N,N-dimethylamino)phenyl]- 19- norpregna-4,9-diene-3,20-dione (10): Under nitrogen, a solution of the diol (9) (0. 5 g, 1. 11 mmol) and triethylamine (0. 25 mL, 1. 8 mmol) in dry pyridine (10 mL) was cooled to 0°C in an ice bath and treated with methanesulfonyl chloride (0. 125 mL, 1. 615 mmol). After stirring at 0°C for 1 hr., TLC (10% acetone/CH2C12) of a quenched (EtOAc/H20) aliquot indicated complete reaction. Cold water (50 mL) was added and the mixture extracted with CH2C12 (3x). The organic layers were washed with water (3x), combined, dried over Na2S04, filtered and concentrated in vacuo. Azeotropic in vacuo removal of trace pyridine using heptane gave 0. 62 g of the residue. Purification via Flash chromatography using 10% acetone/CH2Cl2 followed by trituration with Et20 gave 0. 46 g of the pure 21-mesylate (10) as a yellow solid in 78. 4% yield ; m. p. = 146-149°C. FTIR (KBr, diffuse reflectance) v,,,,, 3298, 2947, 2738, 1630, 1614, 1518 and 1174 cm~l. NMR (CDCl3) 6 0. 39 (s, 3 H, C18- CH3), 2. 91 (s, 6 H, NMe2), 3. 2 (s, 3 H, OS02CH3), 4. 4 (br d, 1 H, Cl la-CH), 5. 27 (dd,

Jl = 27 Hz, J2 = 18Hz, 2 H, C21-CH20Ms), 5. 79 (s, 1 H, C4-CH=), 6. 69 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 07 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's).

Step 10. 17α-Hydroxy-21-fluoro-11ß-[4-(N,N-dimethylamino)phenyl]-19 - norpregna-4,9-diene-3,20-dione (11) and 17-Spirooxetano-3'-oxo-11ß- [4- (N, N-dimetltylamino) plzezylJ-19-norpregna-4, 9-dien-3-one (12) : Under nitrogen, a mixture of the 21-mesylate (10) (0. 4 g, 0. 758 mmol), potassium fluoride (0. 5 g, 8. 6 mmol) and 18-Crown-6 (0. 5 g, 1. 9 mmol) in anhydrous CH3CN (15 mL) was heated to reflux and monitored by TLC (6% acetone/CH2Cl2) which indicated consumption of starting material and formation of two major products after 1 hr.

The reaction mixture was cooled to room temperature, diluted with water (150 mL) and extracted with CH2C12 (3x). The organic extracts were washed with water (3x), combined, dried over Na2S04, filtered and concentrated if2 vacuo. The mixture was separated via flash chromatography using 6% acetone/CH2Cl2 to give 0. 158 g of the 21-fluoro compound (11) as a pale yellow solid in 46% yield ; m. p. 132-135°C.

FTIR (KBr, diffuse reflectance) 3492-3303, 2948, 1733, 1652, 1610 and 1519 cm-1. NMR(DCCL3)# 0. 40 (s, 3 H, C18-CH 3), 2. 90 (s, 6 H, NMe2), 4. 4 (br d, 1 H, C 11 a-CH), 5. 26 (dd, JHF=48. 6 Hz, Jl = 16. 2 Hz, J2 =22 Hz, 2 H, CH2F), 5. 77 (s, 1 H, C4-CH=), 6. 67 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 01 (d, J = 9 Hz, 2 H, 2', 6' aromatic-CH's). MS (EI) m/z (relative intensity) : 451 (M+, 33) and 121 (100). In addition to the aforementioned compound 11, 0. 177 g of the oxetan-3'-one (12) was obtained as an off- white amorphous powder in 54. 1% yield ; m. p. = softens at 95°C. MS (EI) : m/z (relative intensity) 431 (M+, 38), 134 (14) and 121 (100) FTIR (KBr, diffuse reflectance) v, nax 2941, 1809, 1663, 1613 and 1519 cm-1. Analysis by a reverse phase HPLC on a NovaP'alc Cl8 column eluted with CH3CN/H20/Et3N (50 : 50 : 0. 033) at a flow rate of 1 mL/min and at X = 302 nm indicated this material to be of 97% purity whose retention time (tR) is 13. 39 min.

NMR (CDCl3) 8 0. 55 (s, 3 H, C18-CH3), 2. 91 (s, 6 H, NMe2), 4. 45 (br d, J = 6. 7 Hz, 1 H, Clla-CH), 5. 03 (dd, Jl = 17. 1 Hz, J2 = 15. 3 Hz, 2 H, C21-CH2), 5. 79 (s, 1 H, C4-CH=), 6. 69 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's), 7. 03 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's).

Anal. Calcd. for C2gH33NO3 : C, 77. 93 ; H, 7. 71 ; N, 3. 25. Found : C, 77. 80 ; H, 7. 62 ; N, 3. 11.

Step 11. 17a-Acetoxy-21-fluoro-IIA [4- (NN-dimethylamino) phellyll-19- nosp-egna-4, 9-diene-3, 20-dio7ze (13) : Under nitrogen, trifluoroacetic anhydride (1. 75 mL, 12. 39 mmol), glacial acetic acid (0. 7 mL, 12. 14 mmol) and dry CH2C12 (10 mL) were combined and stirred at room temperature for #hr. The mixture was cooled to 0°C in an ice bath and toluenesulfonic acid monohydrate (0. 1 g, 0. 53 mmol) was added. A solution of the 21- fluoro-17a-alcohol (11) (0. 28 g, 0. 62 mmol) in dry CH2C12 was then introduced via syringe and the mixture stirred at 0°C for 6. 5 hrs. After that time, TLC (10% acetone/CH2Cl2) indicated a complete reaction. The mixture was diluted with water (3x), neutralized with concentrated NH40H solution and extracted with CH2Cl2 (3x). The organic extracts were washed with water (3x), combined, filtered through Na2S04 and concentrated in vacuo to give 0. 32 g of the crude product as a foam. Purification via flash chromatography (5% acetone/CH2Cl2) followed by trituration with heptane and pentane gave 0. 18 g of the pure 21-fluoro-17a-acetate (13) as a white amorphous solid in 58. 8% yield ; m. p. 169-173°.

Analysis by a reverse phase HPLC on a NovaPak C18 column eluted with MeOH/H20/Et3N (70 : 30 : 0. 033) at a flow rate of 1 mL/min and at , = 302 nm indicated this material to be of 98. 9% purity which has a retention time of tR = 5. 97 min. MS (EI), m/z (relative intensity) : 493 (M+, 32), 134 (14), 122 (13) and 121 (100). FTIR (KBr, diffuse reflectance) v,,,, 2946, 1739, 1662, 1612 and 1510 cm-1,.

NMR (CDC13) 8 0. 40 (s, 3 H, C18-CH3), 2. 10 (s, 3 H, OAc), 2. 90 (s, 6 H, NMe2), 4. 4 (br d, 1 H, C11α-CH), 4. 95 (dq, JHF = 48 Hz, Jl = 16 Hz, J2 =22Hz, 2 H, CH2F), 5. 80 (s, 1 H, C4-CH=), 6. 67 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 03 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C3oH36FN04 : C, 73. 00 ; H, 7. 35 ; N, 2. 84.

Found : C, 72. 96 ; H, 7. 47 ; N, 2. 84.

EXAMPLE 2 This example illustrates the preparation and properties of 17a-acetoxy-21- chloro-11 I P- [4- (NN-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (14A).

A solution of trifluoroacetic anhydride (2. 2 mL, 15. 56 mmol) in CH2C12 (25 mL) was treated with acetic acid (0. 89 mL, 15. 56 mmol). The mixture was stirred at room temperature for 30 min. and p-toluenesulfonic acid (137 mg, 0. 72 mmol) was added.

The mixture was chilled to 0°C and a solution of 7A (364 mg, 0. 78 mmol) in CH2C12 (2. 0 mL) was added. The mixture was stirred for 2 hrs. and quenched with cautious addition of

saturated NaHC03 solution. The mixture was extracted with CH2C12. The organic extracts were washed with H20 and brine, combined and dried over Na2S04. Evaporation of the solvent gave 412 mg of a stable foam. The material was chromatographed eluting with 5% acetone in CH2C12 to afford 210 mg of 14A in 53% yield as an amorphous foam which persisted recrystallization from a variety of solvents. Analysis by a reverse phase HPLC on a NovaPak Cis column, eluted with 30% aq. MeOH with 0. 033% TEA at a flow rate of 1. 0 mL/min at X = 260 nm showed the material to be approximately 95% pure. Therefore, the material was purified by preparative HPLC on a Whatman Magnum Partisil 10-ODS-3 column eluted with aqueous MeOH with 0. 033% TEA at a flow rate of 10 mL per minute at X = 325 nm to afford 158 mg of 14A as an amorphous yellow foam in 48% yield. FTIR (KBr, diffuse reflectance) v,,, 2947, 1731, 1660, 1610 and 1518 cm~l. NMR (CDC13) 6 0. 40 (s, 3 H, C18-CH3), 2. 13 (s, 3 H, C17a-OAc), 2. 90 (s, 6H, N (CH3) 2), 4. 23 (dd, J = 15 Hz, J'= 9 Hz, 2 H, C21-CH2C1), 4. 4 (br d, 1 H, Cl la-CH), 5. 72 (s, 1 H, C4-CH=), 6. 67 and 7. 0 (d, 4 H, aromatic-CH). MS (EI) m/z (relative intensity) : 510 (M+, 6), 509 (M+-1, 16), 134 and 121 (100). Anal. Calcd. for C3oH36NO4Cl : C, 70. 64 ; H, 7. 11 ; N, 2. 75. Found : C, 70. 46 ; H, 7. 10 ; N, 2. 76.

EXAMPLE 3 This example illustrates the preparation and properties of 17a-acetoxy-21- bromo-11ß-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4, 9-diene-3, 20-dione (14B).

Step 1. Purificatiost of 7B The pure 21-bromo compound (7B) was isolated from a 90 : 10 mixture of the 21-halo product (7B : 7A) by means of Waters Prep LC system on a NovaPak Cl8 column (40 x 100 mm) eluted with 30% aq. MeOH and 0. 03% Et3N at a flow rate of 35 mL/min and at X = 334 nm. A total amount of 0. 75 g of a 90 : 10 mixture (7B : 7A) was chromatographed in 10 runs of 75 mg each to give of 0. 5 g of the pure 21-bromo compound (7B) as a pale yellow solid in 67% yield. This material was >99% pure by analytical HPLC. FTIR (KBr, diffuse reflectance) v7 3327, 2948, 1723, 1660, 1611 and 1518 cm~l.

NMR CDCl3) 6 0. 3 (s, 3 H, C18-CH3), 2. 80 (s, 6 H, NMe2), 4. 33 (dd, Jl = 12 Hz, J2 = 9 Hz, 2 H, C21-CH2Br), 4. 40 (br d, 1 H, Clla-CH), 5. 65 (s, 1 H, C4-CH=), 6. 55 (d, J= 9 Hz, 2 H, 3', 5'aromatic-CH's), 6. 9 (d, J = 9 Hz, 2', 6'aromatic-CH's).

Step 2. Preparation of the Target Compound (14B) Under nitrogen, a mixture of trifluoroacetic anhydride (1. 64 mL, 11. 68 mmol), glacial acetic acid (0. 67 mL, 11. 62 mmol) and dry CH2C12 (10 mL) was stirred at room temperature for 30 min and then cooled to 0°C in an ice bath. p-Toluenesulfonic acid monohydrate (0. 1 g, 0. 52 mmol) was added followed by a solution of the 21-bromo alcohol (7B) (0. 3 g, 0. 59 mmol) in dry CH2C12 (2 mL). The reaction mixture was stirred at 0°C and monitored by TLC (10% acetone/CH2Cl2) which indicated a complete reaction in 2 hrs. The mixture was diluted with water (10 mL), neutralized with concentrated NH4OH solution and extracted with CH2C12 (3x). The organic extracts were washed with H20 (3x), combined, filtered through Na2S04 and concentrated in vacuo to give 0. 35 g of the residue as a foam. This material was purified by flash chromatography using 5% acetone/CH2Cl2 followed by crystallization from Et2O/hexanes to give 0. 24 g of the 21-bromo acetate (14B). Analysis by NMR indicated a significant amount of ether as solvent of crystallization. This material was then dissolved in CH2Cl2 (3 mL) and the solvent blown down to give an oil. Trituration with heptane followed by washing with pentane and drying in vacuo gave 0. 16 g of the pure 21-bromo compound (14B) as a white crystalline solid in 49% yield : m. p. = 141-145°C. MS (EI) m/z (relative intensity) : 555 (M+ + 2, 82), 553 (M+, 76), 475 (13), 414 (8), 372 (13), 134 (15) and 121 (100). FTIR (KBr, diffuse reflectance) v"2ax 2933, 1730, 1664, 1613, 1596 and 1519 cm-'. NMR (CDC13) 8 0. 40 (s, 3 H, C18-CH3), 2. 13 (s, 3 H, OAc), 2. 80 (s, 6 H, NMe2), 4. 07 (dd, Ji = 14 Hz, J2 = 7 Hz, 2 H, C21-CH2Br), 4. 40 (br d, 1 H, Cl la-CH), 5. 83 (s, 1 H, C4-CH=), 6. 67 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's), 7. 07 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C3oH36BrNO4'1/5H20 : C, 64. 98 ; H, 6. 54 ; Br, 14. 41 ; N, 2. 53. Found : C, 64. 82 ; H, 6. 62 ; N, 2. 27.

EXAMPLE 4 This example illustrates the preparation and properties of 17a, 21-diacetoxy- 11ß-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4, 9-diene-3, 20-dione (15).

Under nitrogen, a mixture of trifluoroacetic anhydride (4. 0 mL, 28. 3 mmol), glacial acetic acid (1. 6 mL, 27. 7 mmol) and dry CH2C12 (10 mL) was stirred at room temperature for 30 min. and then cooled to 0°C in an ice bath. p-Toluenesulfonic acid monohydrate (0. 1 g, 0. 53 mmol) was added followed by a solution of the 17a, 21-diol (9, 0. 345 g, 0. 77 mmol) in dry CH2Cl2 (2 mL). The reaction mixture was stirred at 0°C and

monitored by TLC (10% acetone/CH2Cl2) which indicated a complete reaction in two hrs.

The mixture was diluted with H20 (10 mL), neutralized with concentrated NH40H solution and extracted with CH2CI2 (3x). The organic layers were washed with H20 (3x), combined, filtered through Na2S04 and concentrated in vacuo to give 0. 4 g of the residue as a foam.

This material was purified by flash chromatography using 5% acetone/CH2Cl2 followed by trituration with heptane and pentane to give 0. 24 g of the 17a, 21-diacetate (15) as a yellow amorphous solid in 58. 4% yield : m. p. = 128-134°C. Analysis by a reverse phase HPLC on a NovaPak Cl8 column eluted with CH3CN : H2O : Et3N (1 : 1 : 0. 033) at a flow rate of 1 mL/min and at X = 302 nm indicated 15 to be of >98% purity which has a retention time of 12 min. MS (EI) m/z (relative intensity) : 533 (M+, 24), 134 (14), 122 (11) and 121 (100).

FTIR (KBr, diffuse reflectance) v,,, 2942, 1738. 1663, 1611, 1518 and 1233 cm~l. NMR (CDC13) 6 0. 33 (s, 3 H, C18-CH3), 2. 10 (s, 3 H, C17a-OAc), 2. 13 (s, 3 H, C21-OAc), 2. 90 (s, 6 H, NMe2), 4. 43 (br d, 1 H, Cl la-CH), 4. 84 (dd, Jl = 29. 7 Hz, J2 = 18 Hz, 2 H C21- CH2Br), 5. 80 (s, 1 H, C4-CH=), 6. 67 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's), 7. 05 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C32H39NO61/3H20 : C, 71. 22 ; H, 7. 41 ; N, 2. 60. Found : C, 71. 27 ; H, 7. 35 ; N, 2. 61.

EXAMPLE 5 This example illustrates the preparation and properties of 17a-acetoxy-21- acetylthio-11 (3- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (17).

Step 1. 17α-Hydroxy-21-acetylthio-11ß-[4-(N,N-dimethylamino)phenyl ]-19- norpregna-4, 9-diene-3, 20-dione (1 6) : The 17a-Hydroxy-21-bromo compound (7B) (2. 79 g, 5. 44 mmol) dissolved in acetone (150 mL) was refluxed with sodium iodide (8. 16 g, 54. 4 mmol) for 1 hr in an atmosphere of nitrogen and then filtered directly into a suspension of potassium thioacetate (6. 2 g, 54. 4 mmol) in acetone (150 mL). After refluxing for an additional 2. 5 hrs, the reaction mixture was cooled to room temperature, filtered, concentrated in vacuo, diluted with H20 and extracted with CH2C12. The organic fractions were washed with H20 and brine, combined and dried over sodium sulfate. The filtrate was evaporated and the residue was purified via flash silica gel column (6% acetone/CH2Cl2) to afford 1. 99 g of 16 as a yellow foam in 72. 1 % yield. Crystallization of the foam from EtOAc/hexanes gave yellow crystals with m. p. 197-198°C. FTIR (KBr, diffuse reflectance) V7Xz 3483, 2943, 1722,

1696, 1642, 1615, 1585 and 1520 cm-1, NMR (CDCl3) # 0. 40 (s, 3 H, C18-CH3), 2. 41 (s, 3 H, Ac), 2. 93 (s, 6 H, NMe2), 3. 32 (s, 1 H, C17α-OH), 3. 65 and 4. 31 (AB-System, J = 16. 5 Hz, 2 H, C21-CH2), 4. 36 (br d, 1 H, C11α-CH), 5. 73 (s, 1 H, C4-CH=), 6. 66 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 07 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 507 (M+). Anal. Calcd. for C3oH3704NS : C, 70. 79 ; H, 7. 35 ; N, 2. 76 ; S, 6. 31. Found : C, 70. 97 ; H, 2. 75 ; N, 2. 76 ; S, 6. 29.

Step 2. Preparatiost of the target eoinpouiid (17) : Under nitrogen, trifluoroacetic anhydride (8. 5 mL, 61. 95 mmol), glacial acetic acid (3. 5 mL, 60. 7 mmol) and dry CH2C12 (100 mL) were combined and stirred at room temperature for 20 min. The mixture was cooled to 0°C in an ice bath and p- toluenesulfonic acid monohydrate (0. 5 g, 2. 65 mmol) was added. A solution of the 17a- alcohol (16) (1. 99 g, 3. 99 mmol) in dry CH2C12 was added and the mixture stirred at 0-5°C for 10 hr. The mixture was neutralized with saturated NaHC03 solution and extracted with CH2C12 (3x). The organic fractions were washed with H20 (3x), combined and dried over Na2S04. The filtrate was evaporated and the residue was purified via flash silica gel column (4. 6% acetone/CH2Cl2) to afford 1. 73 g of 17 as a yellow foam in 80. 4% yield : m. p.

= 123-124°C. MS (EI) m/z (relative intensity) : 549 (M+). FTIR (KBr, diffuse reflectance) #M ax 2946, 1736, 1692, 1663, 1611 and 1518 cm~i (CDCl3) 6 0. 39 (s, 3 H, C18-CH3), 2. 18 (s, 3 H, OAc), 2. 38 (s, 3 H, SAc), 2. 92 (s, 6 H, NMe2), 3. 91 (s, 2 H, 21-CH2), 4. 44 (br d, 1 H, C11α-CH), 5. 78 (s, 1 H, C4-CH=), 6. 67 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 08 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C32H39NO5S : C, 69. 92 ; H, 7. 15 ; N, 2. 55 ; S, 5. 83. Found : C, 69. 66 ; H, 7. 12 ; N, 2. 58 ; S, 5. 59.

EXAMPLE 6 This example illustrates the preparation and properties of 17a-acetoxy-21- # methyl-11 ß-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4, 9-diene-3, 20-dione (28) : Step 1. 3, 3-Ethylenedioxy-17α-trimethylsilyloxyestra-5(10),9(11)-dien j-17α- aldehyde (21).

The cyano trimethylsilyl ether (2) (16 g, 38. 7 mmol) was dissolved in THF (30 mL, distilled from lithium aluminum hydride (LAH)) in oven-dried glassware, and t- butyl methyl ether (300 mL) was added. The mixture was cooled to 0°C in an ice bath. diisobutylaluminum hydride (DIBAL-H) (75 mL, 1 M in toluene) was added to the mixture

over 30 min. using an addition funnel. The reaction mixture was stirred under nitrogen at room temperature and monitored by HPLC (on a NovaPak Cis column eluted with CH3CN/H20/75 : 25). The reaction was complete after 4 hr. It was cooled to 0°C in an ice bath and aq. acetic acid (40 mL, 50%) was added. The mixture was diluted with H20 and extracted with ether (3x). The ether extracts were washed with 10% acetic acid, H20, saturated NaHCO3 solution, H20 and brine. The combined organic layers were dried over Na2S04 and concentrated in vacuo to yield 15. 11 g of the crude aldehyde (21). Flash chromatography using 1% THF/CH2C12 gave 10. 6 g of the pure product as a white solid in 65% yield ; m. p. = 105-109°C. MS (EI) m/z (relative intensity) : 416 (M+, 30), 270 (47), 169 (44), 129 (47), 99 (73), 86 (31) and 73 (100). FTIR (KBr, diffuse reflectance) v7ntlx 2910 and 1731 cm\ NMR (CDC13) 6 0. 11 (s, 9 H, Si (CH3) 3), 0. 67 (s, 3 H, C18-CH3), 3. 98 (s, 4 H, OCH2CH20), 5. 60 (br s, 1 H, Cl1-CH=) and 9. 67 (s, 1 H, C17P-CHO). Anal. Calcd. for C24H3604Si-l/6hexane (C6Hi4) : C, 69. 67 ; H, 8. 60. Found : C, 69. 07 ; H, 8. 79.

Step 2. 3, 3-Ethylenedioxy-17α-trimethylsilyloxy-20#-hydroxy-21-methyu l-19- nhorpregna-5(10),9(11)-diene(22).

In oven-dried glassware, the crude aldehyde (21) (30. 35 g, 72. 8 mmol) was dissolved in THF (432 mL, distilled from LAH) and cooled to 0°C under nitrogen. Ethyl magnesium bromide (37 mL, 3 M in ether) was transferred via double-tipped needles to an additional funnel and then slowly added to the reaction mixture. The mixture was stirred at room temperature and monitored by TLC (2% acetone/CH2C12). Reaction was complete in 3 hr, so mixture was cooled to 0°C and saturated NH4Cl solution (310 mL) was added slowly. THF was evaporated in vacuo. The mixture was extracted with ether (3x) and brine, and dried over Na2S04. The solvent was evaporated, yielding 31. 03 g of the crude 20-hydroxy product (22) as a foam in 95% yield. This material was directly used without further purification in the subsequent reaction. FTIR (KBr, diffuse reflectance) vmtlx 3503 and 2951 cm-1. NMR (CDCl3) 8 0. 16 (s, 9 H, Si (CH3) 3), 0. 75, 0. 78 (2s, C18-CH3 for 20a- and 20p-isomers), 1. 01 (t, J = 6 Hz, 3 H, C21-CH3), 3. 98 (s, 4 H, 3-OCH2CH20-) and 5. 60 (br s, 1 H, C11-CH=). MS (EI) m/z (relative intensity) : 447 (M+, 4. 2), 418 (17), 387 (32), 356 (70) and 297 (100).

Step 3. 3, 3-Etlaylenedioxy-17a-trimetlaylsilyloxy-21-nietlayl-19-zoypr egna-5 (10), 9 (11)-dien-20-one (23) : The C-20 alcohol (22) (25. 34 g, 56. 7 mmol) was dissolved in acetone and stirred at 0°C in an ice bath. Jones'reagent (42 mL) was added slowly to the above solution until the reaction mixture remained an orange color. Then isopropanol was added until the green color persisted. Ice H20 (2 L) was added and stirred well. The mixture was extracted with EtOAc (3x), washed with H20 (2x), saturated NaHCO3, H20 and brine. The combined organic layers were dried over Na2S04 and concentrated in vacuo to give 18. 83 g of the crude ketone (23). Flash chromatography using 1 % ether/CHZC12 gave 7. 3 g of the purified product as a foam in 29% yield. NMR (CDC13) 6 0. 10 (s, 9 H, Si (CH3) 3), 0. 51 (s, 3 H, C18-CH3), 1. 04 (t, J = 7 Hz, 3 H, C21-CH3), 3. 99 (s, 4 H, C3-ketal) and 5. 61 (br s, 1 H, C11-CH=).

Step 4. 3, 3-Ethylenedioxy-5α,10α-epoxy-17α-trimethylsilyloxy-21-met hyl-19- norpregna-9(11)-en-20-one(24): Hexafluoroacetone trihydrate (2. 20 g, 10 mmol) and CH2Cl2 (23 mL) were stirred vigorously under nitrogen in an ice bath. Solid Na2HP04 (0. 78 g, 6 : 5 mmol) was added. 30% Hydrogen peroxide (1. 50 mL) was poured into the mixture. It was stirred 30 min. A chilled solution of the C-20 ketone (23) (3. 00 g, 6. 75 mmol) in CH2C12 (23 mL) was added slowly with a pipette. The reaction mixture was stirred overnight in the cold room at 4°C. TLC (2% acetone/CH2Cl2) showed reaction complete in the morning.

CHUCK was added to the reaction mixture and it was washed with Na2S03 (2x), saturated NaHC03, and brine. Organic extracts were dried over Na2S04 and concentrated to give 2. 98 g of a 77 : 25 mixture of the crude oc :-epoxide (24) according to NMR in 95% yield.

This mixture was directly used in the subsequent reaction without further purification.

NMR (CDC13) 6 0. 10 (s, 9 H, Si (CH3) 3), 0. 51 (s, 3 H, C18-CH3), 1. 05 (t, J= 6 Hz, 3 H, C21-CH3), 3. 94 (s, 4 H, 3-OCH2CH20-), 5. 90 (br s, 1 H, C1 1-CH= for-epoxide) and 6. 09 (br s, 1 H, C11-CH= for a-epoxide).

Step 5. 3,3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N,N-dimethylamino)phe nyl]-17α- trimethylsilyloxy-21-methyl-19-norpregn-9(10)-en-20-one (25) : Mg (2. 80 g, 116. 2 mmol), which was washed with 0. 1 N HCl, then H20 and acetone and dried m vacuo, was weighed into dry round-bottomed flask equipped with a reflux condenser. A small crystal of iodine was added and the system was flushed with

nitrogen and flame-dried. The flask was cooled to room temperature and 68. 5 mL of THF distilled from LAH was added via syringe. 1, 2-Dibromoethane (approx. 0. 5 mL) was added and the mixture was stirred at room temperature. After bubbling began and the color of 12 disappeared, a solution of 4-bromo-N, N dimethylaniline (20. 43 g, 102. 1 mmol) in THF (34 mL) was added via syringe. The mixture was stirred until most the Mg had reacted. Copper (I) chloride (1. 13 g, 114. 2 mmol) was added as a solid and stirred for 20 min. The crude epoxide (24) (7. 33 g, 15. 91 mmol) in THF (49 mL) was then added using a syringe. The reaction mixture was stirred at room temperature for 30 min, at which time the reaction was complete by TLC (2% acetone/CH2Cl2). Saturated NH4C1 solution (25 mL) was added and stirred for 30 min while air was pulled through by slight vacuum.

The mixture was diluted with H20, extracted with CH2C12 (3x), washed with H20 (2x) and brine, dried over Na2S04, and evaporated under reduced pressure. The residue was purified by flash chromatography using 3% acetone/CH2Cl2) to afford 4. 27 g of the pure product (25) in 46. 1% yield. IR (KBr, diffuse reflectance) , 3531, 2940, 1708, 1614, and 1518 cm~l. NMR (CDC13) 8 0. 09 (s, 9 H, Si (CH3) 3), 0. 19 (s, 3 H, C18-CH3), 1. 02 (t, J = 7 Hz, 3 H, C21-CH3), 2. 88 (s, 6 H, N (CH3) 2), 3. 99 (m, 4 H, C3-OCH2CH20-), 4. 26 (br d, 1 H, C1 l-c-CH), 6. 85 (dd, J = 41 Hz, J'= 10 Hz, 4 H, aromatic-CH). MS (EI) m/z (relative intensity) : 581 (M+, 46), 563 (34), 391 (37), 134 (65) and 121 (100).

Step 6. 3, 3-Ethylenedioxy-5α,17α-dihydroxy-11ß-(4-N,N-dimethylamino phenyl)- 21-metllyl-19-norpregsz-9 (10)-en-20-one (26) : Tetrabutylammonium fluoride (18. 1 mL, 1 M in THF) was stirred with molecular sieves under nitrogen for approx. 1 hr. The 17a-trimethylsilyloxy compound (25) (3. 50 g, 6. 0 mmol) in THF (21 mL) which was distilled from LAH, was added to the mixture and stirred at room temperature for 1 hr. H20 was added and the THF was removed in vacuo. EtOAc was added to the mixture and was filtered through Celite. The product was extracted with EtOAc, washed with H20 and brine, and dried over Na2S04.

Evaporation of the solvent gave 3. 19 g of the crude 5a, 17a-dihydloxy compound (26) in quantitative yield. This material was directly used without further purification in the subsequent reaction. IR (I<Br, diffuse reflectance) v,,, 3506, 2934, 1704, 1613 and 1518 cm~l. NMR (CDC13) 6 0. 36 (s, 3 H, C18-CH3), 1. 03 (t, J = 7 Hz, 3 H, C21-CH3), 2. 84 (s, 6 H, N (CH3) 2), 4. 00 (s, 4 H, C3-OCH2CH20-), 4. 16 (d, 1 H, Cl la-CH) and 6. 85 (dd, J =

29 Hz, J'= 10 Hz 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 509 (M+, 20), 491 (11), 134 (27) and 121 (100) Step 7. 17α-Hydroxy-21-methyl-11ß-[4-(N,N-dimethylamino)phenyl]-19 - norpregiia-4, 9-dieiie-3, 20-dione (27) : The 5a, 17α-dihydroxy compound (26) (3. 19 g, 6. 26 mmol) was dissolved in THF (25 mL). Glacial acetic acid (75 mL) was added, followed by H20 (25 mL). The mixture was stirred overnight at room temperature at which time TLC (10% acetone/CH2Cl2) showed reaction complete in the morning. The THF and acetic acid were removed under high vacuum and the residue was extracted with EtOAc (3x) and washed with saturated NaHCO3 solution, Hz0 and brine. The combined organic extracts were dried over Na2S04 and concentrated in vacuo to afford 2. 81 g of the crude diene dione 17-alcohol (27) as a foam in 100% yield. IR (I (Br, difffise reflectance) #max 3419, 2942, 1705, 1655, 1612 and 1581 cm~l. NMR (CDC13) 8 0. 40 (s, 3 H, C18-CH3), 1. 02 (t, J = 7 Hz, 3 H, C21-CH3), 2. 88 (s, 6 H, N (CH3) 3), 4. 37 (br d, 1 H, C1 lc-CH), 5. 76 (s, 1 H, C4-CH=) and 6. 85 (dd, J = 24 Hz, J'= 9 Hz, 4 H, aromatic-CH's), MS (EI) m/z (relative intensity) : 447 (M+, 25), 211 (4), 134 (23) and 121 (100).

Step 8. Preparation of the target compound (28): In oven-dried glassware, trifluoroacetic anhydride (18. 75 mL) and glacial acetic acid (7. 2 mL) were added to CH2Cl2 (50 mL) and stirred for 30 min. under nitrogen at room temperature. Solid p-toluenesulfonic acid monohydrate (1. 19 g) was added and the mixture was cooled to 0°C in an ice bath. The 17-alcohol (27) (2. 77 g, 6. 17 mmol) in CH2C12 (22 mL) was added and the reaction mixture was stirred at 0°C for 1. 5 hr.

Saturated IL2CO3 was carefully added dropwise until the bubbling of C02 ceased. The mixture was diluted with H20, extracted with CH2Cl2 (3x), and washed with H20 (2x) and brine. The organic layers were filtered through Na2S04 and concentrated under reduced pressure to yield 3. 12 g of the crude product (28). The crude acetate was purified by flash chromatography using 3. 5% acetone/CH2Cl2 and fractions >98% pure by HPLC (70% MeOH/30% H20/0. 03% TEA) were triturated in heptane to form 600 mg of a pale yellow amorphous solid in 20% yield. Analysis of the solid by HPLC using the same eluent at #=- 260 nm indicated it to be 100% purity : m. p. = 125-133°C ; [a] 27D = + 163. 16° (c = 1. 0, CHC13). FTIR (KBr, diffuse reflectance) v 1732, 1713 and 1662 cm~l. MS (EI) rn/z (relative intensity) : 489 (M+, 27), 372 (4), 251 (4), 134 (14) and 121 (100). NMR (CDC13), 8

0. 330 (s, 3 H, C18-CH3), 1. 039 (t, J = 7. 2 Hz, 3 H, C21-CH3), 2. 112 (s, 3 H, C17a-OAc), 2. 904 (s, 6 H, N (CH3) 2), 4. 380 (d, J = 6. 6 Hz, 1 H, C11α-CH), 5. 773 (s, 1 H, C4-CH=), 6. 635 (d, J = 8. 4 Hz, 2 H, 3', 5'aromatic-CH's) and 6. 978 (d, J = 8. 7 Hz, 2 H, 2', 6' aromatic-CH's). Anal. Calcd. forC3lH3uO4N : C, 76. 04 ; H, 8. 03 ; N, 2. 86. Found : C, 76. 03 ; H, 8. 05 ; N, 2. 91.

EXAMPLE 7 This example illustrates the preparation and properties of 17a-acetoxy-21- hydroxy-11(3- [4- (N, N-dimethylarnino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (41).

Step 1. Synthesis of 17cK, 21-(1-Ethoxyethylidenedioxy)-114Ç4 (N, N- dimethylamino)phenyl]-19-norpregna-4,89-diene-d3,20-dione (18): A solution of the 17a, 21-diol (9) (1. 0 g, 1. 11 mmol), triethyl orthoacetate (2 mL, 10. 9 mmol) and pyridinium p-toluenesulfonate (0. 1 g, 0. 4 mmol) in benzene (50 mL) was heated to reflux under nitrogen in a system equipped with a Dean-Stark trap for removal of water. After 1 hr of reflux, monitoring by TLC (5% acetone/CH2Cl2) indicated a complete reaction. Pyridine (1 mL, 12. 4 mmol) was added and the reaction mixture concentrated in vacuo under a stream of nitrogen at 40-50 °C. The residue was diluted with water (approx. 100 mL) and extracted with CH2C12 (3x). The combined organic extracts were washed with H20 (2x) and brine (lx), filtered through Na2S04 and concentrated in vacuo. Purification of the residue via Flash chromatography (3% acetone/CH2C12) followed by crystallization from ether/pentane gave 0. 81 g of the intermediate ethoxyethylidenedioxy compound (18) as a white amorphous solid in 70% yield. FTIR (KBr, diffuse reflectance) v,, a, 2947, 1716, 1660, 1614, 1599 and 1518 cm-1. MS (EI) m/z (relative intensity) : 519 (M+, 65), 308 (23), 134 (31) and 121 (100).

NMR (CDC13) 8 0. 33 (s, 3 H, C18-CH3), 1. 13 (t, J = 7. 5 Hz, 3 H, OCH2CH3), 1. 60 (s, 3 H, ethylidenedioxy CH3), 2. 90 (s, 6 H, NMe2), 3. 59 (q, J = 7. 5 Hz, 2 H, OCH2CH3), 4. 13 (dd, J1 = 25. 8, J2 = 17. 4 Hz, 2 H, C21-CH2), 4. 43 (br. d, J = 8. 4 Hz, 1 H, Cl la-CH), 5. 80 (s, 1 H, C4-CH=), 6. 67 (d, J = 9 Hz, 2 H, 3'. 5'aromatic-CH's) and 7. 07 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C32H41NO5 : C, 73. 96 : H, 7. 95 ; N, 2. 70. Found : C, 73. 70 ; H, 7. 89 ; N, 2. 73.

Step 2. Preparatiot of tlze target compomzd (41) : Under nitrogen, a mixture of the crude ethoxyethylidenedioxy compound (18, 0. 56 g., 1. 11 mmol), 0. 2 M NaOAc (3 mL, 0. 3 mmol) in methanol (30 mL) was heated to reflux. Monitoring by TLC (5% acetone/CH2Cl2) indicated a complete reaction in 3. 5 hours. The methanol was removed in vacuo under a stream of nitrogen, the residue diluted with water (-50 mL) and extracted with CH2C12 (3x). The organic fractions were combined, washed with H2O (2x) and brine (lx), dried over Na2S04, filtered and concentrated in vacuo to give 0. 56 g of the crude 21-ol, 17a-acetate (41) as a foam.

Purification of this material via flash chromatography (7. 5% acetone/CH2Cl2) followed by trituration with ether/pentane gave 0. 32 g of the target compound, 21-OH, 17a-acetate as an off-white solid in 84% yield ; m. p. = 205-210°C. The NMR indicated this product contains 5. 3% of the 17a-OH, 21-OAc (8) isomer as a contaminant. Compound 41 is extremely labile to base, rapidly converting to compound 8 under the reverse-phase conditions (MeOH/H2O/Et3NJ) normally employed for HPLC analysis of related compounds. This transesterification occurs at an appreciate rate even when the solvent system is buffered at pH 7. 0 with phosphoric acid. The purity of the acetate mixture (8 and 41) was ascertained at >99% by normal phase HPLC analysis (Waters Associates . Porasil Silica using CH3CN/CH2C12 (40 : 60) with a flow rate of 2 mL/min at X = 302 nm). Under these conditions, the two acetates have an identical retention time of 4. 69 min. MS (EI) m/z (relative intensity) : 491 (M+, 45), 431 (32), 134 (7) and 121 (100). FTIR (KBr, diffuse reflectance) y,,, 3362, 2949, 2886, 1730, 1656, 1611, 1597 and 1518 cm-'. NMR (300 MHz, CDC13) 8 0. 37 (s, 3 H, C18-CH3), 2. 11 (s, 3 H, C17α-OAc), 2. 90 (s, 6 H, NMe2), 4. 23 (d, J = 17. 4, 1 H, C21-CH2), 4. 36 (d, J = 17. 4 Hz, 1 H, C21-CH2), 4. 39 (d, J = 6 Hz, 1 H, C11α-CH), 5. 78 (s, 1 H, C4-CH=), 6. 63 (d, J = 8. 7 Hz, 2 H, 3', 5'aromatic-CH's), 6. 97 (d, J = 8. 7 Hz, 2', 6'aromatic-CH's). The presence of the 17a-OH, 21-OAc isomer (8) to the extent of 5. 3% could be detected by the appearance of two doublets, one at 4. 88 and the other at 5. 11, both with J = 18. 3 Hz.

EXAMPLE 8 This example illustrates the preparation and properties of 17a-acetoxy-21- (3'-cyclopentylpropionyloxy)-113- [4- (N, N-dimethylamino) phenyl]-19-norpregnadiene- 3, 20-dione (40).

Step 1. 17α-Hydroxy-21-*(3-cycliopentylpropionyloxy)-11ß-[4-(N,N- dimethylaminohenyl]-19-norpregna-4,9-diene-3,20-dione (39): Under nitrogen, a solution of the diol (9, 0. 5 g, 1. 11 mmol) in dry benzene (20 mL) and pyridine (1 mL, 12. 4 mmol) was treated with 3-cyclopentylpropionyl chloride (0. 2 mL, 1. 31 mmol). The reaction mixture was stirred at room temperature and monitored by TLC (10% acetone/CH2Cl2) which indicated about a 50% reaction after 1 hr. Additional cypionyl chloride (0. 2 mL, 1. 31 mmol) was introduced and the reaction was stirred a further 1 hr. at room temperature. Analysis by TLC at that time indicated a complete reaction. The reaction mixture was concentrated in vacuo under a stream of nitrogen and the residue was diluted with water. The mixture was extracted with CH2C12 (3x). The organic fractions were combined, and washed with H20 (2x), brine (lx), dried (Na2SO4), filtered and concentrated in vacuo to give 0. 63 g of the residue as an oil. Purification of this material by flash chromatography using 7% acetone/CH2Cl2 gave 0. 51 g of the 17a- hydroxy 21-cypionate (39) as an oil. Trituration of this material with ether afforded 0. 43 g of a pure solid (39) in 67% yield ; m. p. = 137-140°C. MS (EI) m/z relative intensity : 573 (M+, 46), 431 (11), 134 (15) and 121 (100). FTIR (KBr, diffuse reflectance) v"t 3509, 2944, 1726, 1643, 1613 and 1520 cm~i (CDC13) 6 0. 38 (s, 3 H, C18-CH3), 2. 90 (s, 6 H, NMe2), 4. 4 (br d, J = 6 Hz, C 11 a-CH), 5. 03 (dd, Ji=31. 5Hz, J2=18Hz, 2H, C21-CH2-), 5. 76 (s, 1 H, C4-CH=), 6. 67 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 07 (d, J = 9 Hz, 2 H, 2', 6'aromatic-CH's).

Step 2. Preparation of the target compomzd (40) : Under nitrogen, trifluoroacetic anhydride (2. 0 mL, 14. 2 mmol), glacial acetic acid (0. 8 mL, 13. 99 mmol) and dry CHsClz (10 mL) were combined and stirred at room temperature for % z hr. The mixture was cooled to 0°C in an ice bath and p-toluenesulfonic acid monohydrate (1 g, 0. 53 mmol) was added to it. A solution of the 17a-hydroxy-21- cypionate (39, 0. 4 g, 0. 7 mmol) in dry CH2C12 was then introduced and the reaction mixture stirred at 0°C and monitored by TLC (5% acetone/CH2Cl2). After 2 hr. at 0°C it became apparent that this particular reaction was proceeding at a much slower rate than observed for other 17a-acetylations. The ice-bath was removed and the reaction was then stirred and monitored by TLC at room temperature. After 6 hr. at room temperature, TLC indicated -75% conversion. The reaction mixture was then diluted with H20 (10 mL), neutralized with concentrated NH40H solution and extracted with CH2Cl2 (3x). The organic fractions

were combined, washed with H2O (2x), brine (lx), filtered through Na2S04 and concentrated in vacuo to give 0. 53 g of the residue as an oil. Purification via flash chromatography (5% acetone/CH2Cl2) gave 0. 21 g of the pure 17-acetate (40) as a foam.

This material was dissolved in EtOH (-2 mL) and precipitated as a yellow amorphous solid upon dilution with H20, sonication and cooling to give 0. 21 g of the pure solid (40) in 28% yield : mp. softens at 96°C. MS (EI) mlz (relative intensity) : 615 (M+, 80), 555 (10), 372 (18), 134 (14) and 120 (100) FTIR (KBr, diffuse reflectance) vmh 2950, 2868, 1737, 1664, 1612 and 1519 crri 1. NMR (CDC13) 8 0. 43 (s, 3 H, C18-CH3), 2. 11 (s, 3 H, OAc), 2. 91 (s, 6 H, NMe2), 4. 42 (br d, J = 6 Hz, C1 lcc-CH), 4. 84 (dd, J = 29 Hz, J2 = 17 Hz, 2 H, 21-CH2- OCyp), 5. 80 (s, 1 H, C4-CH=), 6. 70 (d, J = 9 Hz, 2 H, 3', 5'aromatic-CH's) and 7. 07 (d, 9 Hz, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C3sH49NO6"/4C5HI2 : C, 74. 38 ; H, 8. 27 ; N, 2. 21. Found : C, 74. 39 ; H, 8. 28 ; N, 2. 20.

EXAMPLE 9 This example illustrates the preparation and properties of 27a-acetoxy-21- methoxy-11 ß-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-d ione (38).

Step 1. 17α-Bromomethyldimethylsilyloxy-17ß-cyano-3,3-ethylenediox yestra- 5 (10), 9 (11)-diene (29) : Under nitrogen and anhydrous conditions, a solution of the cyanohydrin ketal (1, 35. 45 g (104 mmol)), dimethylaminopyridine (6. 33 g, 52 mmol) and dry Et3N (21. 7 mL, 155 mmol) in dry THF (300 mL) was stirred at room temperature overnight.

After that time, TLC using 2% acetone/CH2C12 indicated approximately 95% completion of reaction. The mixture was diluted with hexanes (-250 mL), stirred at-10 minutes, filtered through Celite and concentrated in vacuo to give the residue (46. 38 g) evidenced by TLC to consist of a mixture of the expected product (29) plus DMAP hydrochloride salt. This material was purified via silica flash chromatography using ether as eluent to give the silyl ether (29, 35. 53 g, 69. 5%). This material was used directly in the subsequent reaction without further purification or characterization.

Step 2. 17α-Hydroxy-21-bromo-19-nhorpregna-4,89-diene-3,20-dione (30) : Under nitrogen, a solution of the crude 17a-bromo compound (29, 35. 53 g, 72 mmol) in dry THF (1200 mL) was cooled to-78°C in a dry ice/isopropanol bath and treated dropwise with a 1. 5 M solution of lithium diisopropylamide in cyclohexane

(105 mL, 157. 5 mmol) over a period of-15 minutes. This mixture was stirred at-78°C for 1 hr. Aqueous HBr (4. 45 M, 350 mL, 1. 56 mol) was added slowly and the mixture allowed to warm to room temperature, and stirred for 30 min. A TLC using 5% acetone/CH2Cl2 taken at that time indicated an incomplete reaction (3 products). The mixture was then stirred again at room temperature overnight. Analysis by TLC at that time indicated formation of 1 major product. The reaction mixture was then cooled in an ice bath, carefully neutralized with concentrated NH40H solution (105 mL) and extracted with EtOAc (3x). The organic fractions were washed with H20 (2x), combined, dried over Na2S04 and concentrated in vacuo. Trituration of the solid residue with ether gave the 17a- hydroxy-21-bromo compound (30, 17. 14 g) in 60. 4% yield as an off-white powder. FTIR (KBr, diffuse reflectance) v 3476, 2948, 1726, 1644, 1598 and 1572 em-'. NMR (DMSO-d6 + CDC13) 6 0. 70 (s, 3 H, C18-CH3), 4. 43 (dd Jl = 27 Hz, J2 = 15 Hz, 2 H, C21- CHzBr) and 5. 60 (s, 1 H, C4-CH=). MS (EI) m/z (relative intensity) : 392 (M+, 11), 313 (100), 159 (77) and 91 (71).

Step 3. 1 7a-lzydroxy-21-acetoxy-19-norpregiia-4, 9-dieiie-3, 20-dione (31) : The 21-bromo-17a-hydroxy compound (30, 6. 57 g, 16. 7 mmol) was added to a 3-neck 1L flask which had been purged with nitrogen, equipped with a condenser and a magnetic stir bar. Acetone (500 mL) was added, followed by potassium acetate (17. 3 g, 176. 2 mmol). The suspension was stirred magnetically and brought to reflux under nitrogen. Several minutes after reaching reflux, a solution formed. After 1/2hr, the reaction was examined by TLC (silica : 5% acetone in CH2C12). All starting material had been converted to the product. The reaction was allowed to cool to room temperature, precipitated KBr was removed by filtration, and the solution evaporated in vacuo. The crude product (6. 63 g) was obtained, taken up in CH2C12 and washed with H20 (2x), followed by brine (lx). The combined organic extracts were filtered through Na2SO4 and evaporated in vacuo to obtain 6. 41 g of the 21-acetoxy-17a-hydroxy compound (31) in 99% yield. FTIR (KBr, diffuse reflectance) vntt 3474, 2946, 1744, 1720, 1645 and 1607 cm'\ NMR (CDC13) 6 0. 80 (s, 3 H, C18-CH3), 2. 13 (s, 3 H, C21-OAc), 5. 0 (dd, 2 H, C21-CH2, Jl = 24 Hz, J2 = 9Hz) and 5. 68 (s, 1 H, C4-CH=). MS (EI) m/z (relative intensity) : 372 (M+, 55), 312 (68), 271 (69), 253 (97) and 213 (100).

Step 4. 17α,21-Dihydroxy-19-norpregna-4,9-diene-3,20-dione (32): A suspension of the 21-acetoxy-17a-hydroxy compound (31, 9. 43 g, 25. 32 mmol) in MeOH (800 mL) was deoxygenated by purging with nitrogen for 1/2 hr. A similarly deoxygenated 0. 5 M solution of I (HCO3 (78 mL, 39 mmol) was added to the suspension and the mixture brought to reflux under nitrogen. Almost immediately after addition ofKHCOs, a solution formed. After l/2 hr at reflux, the reaction mixture was examined by TLC (silica ; 5% isopropanol in CH2CI2). The reaction was >95% complete.

The reaction was allowed to cool to room temperature, then neutralized by addition of 2. 24 mL (39 mmol) of glacial acetic acid. CH30H was evaporated i7z vacuo. The residue was taken up in 500 mL of CH2Cl2 and washed with H20 (3x). Combined organic extracts were dried by filtration through Na2S04, and evaporated in vacuo to recover an amorphous yellow material (32, 8. 50 g) in 100% yield. This material was readily crystallized from hot acetone (100 mL). The crystals were collected on a Buchner funnel, triturated well with ether, and air dried. It gave 4. 82 g of 32 in 57. 6% yield. Additional material was obtained by chromatography of the mother liquors. FTIR (KBr, diffuse reflectance) v..... 3517, 2944, 1714, 1657, 1598 and 1578 cm-1. NMR (CDCl3) # 0. 82 (s, 3 H, C18-CH3), 4. 53 (dd, 2 H, C21-CH2-, J1 = 42 Hz, J2 = 21 Hz), 5. 72 (s, 1 H, C4-CH=). MS (EI) m/z (relative intensity) : 330 (M+, 100), 253 (83), 228 (98), 213 (95) and 91 (91).

Step 5. 3, 20-bis-Etliylenedioxy-17c21-dilzydroxy-19-norpregna-5 (10), 9 (11)-dielle (33) : A quantity of 3. 8 g (11. 5 mmol) of the 17a, 21-dihydroxy compound (32, 200 mg, 1. 05 mmol) ofp-toluenesulfonic acid, and 300 mL of ethylene glycol were placed in a 500 mL of round bottom flask equipped with a vacuum distillation head. The mixture was heated in an oil bath and the temperature was maintained at 100-105°C,. Ethylene glycol was distilled iii vacuo (5 mm Hg), at a temperature of 75°C. The reaction continued for 3 hr. and was allowed to cool to room temperature. Saturated NaHCO3 solution was added and the mixture extracted with CH2C12. The organic extract was washed with H20 (lx) and brine (lx). The organic extracts were dried by filtration through Na2SO4 and evaporated iii vacuo. Crude diketal (6. 2 g) was obtained. Examination of this material by TLC (silica, 5% isopropanol in CHzCL) indicated almost all starting material had been converted to the diketal as a major product with Rf = 0. 38, an intermediate product as a minor product with Rf = 0. 63, or a third material with Rf = 0. 63 which increases if the

reaction is allowed to go too long. The crude material was crystallized from 30 mL of hot CH2C12. The crystals were collected on a Buchner runnel, triturated well with ether and air dried to give 3. 01 g of 33 in 62. 5% yield. This product was considered sufficiently pure to be carried out on the next reaction. Highly pure material was obtained by flash column chromatography using 5% isopropanol in CH2Cl2. FTIR (KBr, diffuse reflectance) v,,, 3418 and 2896 cm' ; no evidence of any absorptions in the CO region. NMR (CDC13) 5 0. 8 (s, 3 H, C18-CH3), 3. 88 (m, 10 H, C3-and C20-OCH2CHzO-, C21-CH2), 4. 0 (s, 4 H, C3- OCH2CH20-), 5. 58 (br s, 1 H, C11-CH=). MS (EI) m/z (relative intensity) : 418 (M+, 2), 387 (1. 4), 297 (3) and 103 (100).

Step 6. 3, 20-bis-(Etllylezzedioxy)-17z ydroxy-21-methoxy-19-norpregna- 5 (10),9(11)-diene (34): To a solution of the 17a, 21-dihydroxy diketal (33, 2, 0 g, 4. 78 mmol) in CH2C12 (250 mL) was added 7. 20 g (33. 6 mmol) of solid 1, 8-bis (dimethylamino)- naphthalene ("proton sponge") followed by 4. 97 g (33. 6 mmol) of trimethyloxonium tetrafluoroborate. The heterogeneous mixture was stirred in an ice bath under nitrogen, and allowed to come to room temperature as the bath melted. After 2. 5 hr., TLC (silica ; 5% isopropanol in CH2C12) indicated the reaction was complete. The mixture was transferred to a separatory funnel and washed with ice cold 1N HC1 (250 mL), saturated NaHCO3 solution and H20. The combined organic extracts (3x) were dried by filtration through solid Na2S04 and evaporated in vacuo. Examination by TLC indicated the resulting yellow oil was heavily contaminated with a base. The oil was taken up in CH2C12 (75 mL) and stirred vigorously with Dowex 50 x 8-200 (80 mL, dry volume) for 15 minutes. This effectively removed all the remaining proton sponge. The mixture was filtered and the Dowex washed well with CH2C12. Methylene chloride was evaporated in vacuo and the residue dried overnight under high vacuum to give a pale foam, 1. 63 g in 79% yield. This material was sufficiently pure to carry on to the next reaction. Highly pure material was obtained by flash column chromatography eluting with 20% EtOAc in CH2C12, followed by crystallization from a small amount of methanol with water. FTIR (KBr, diffuse reflectance) #max 3510, 2898, 1720, 1450 and 1370 cm~1. NMR (CDC13) 8 0. 8 (s, 3 H, C18- CH3), 3. 43 (s, 3 H, C21-OCH3), 3. 67 (dd, 2 H, C21-CH2, Jl = 18 Hz, J2 = 10. 5 Hz), 4. 0 (s, 4 H, C3-OCH2CH20), 4. 09 (m, 8 H, C3= and C20-OCH2CH20) and 5. 58 (br s, 1 H,

C11-CH=). MS (EI) m/z (relative intensity) : 432 (M+, 1. 4), 387 (3), 297 (2. 6) and 117 (100).

Step 7. 3, 20-bis- (Ethylenedioxy)-5α,10α-epoxy-17α-hydroxy-21-methoxy-19- norpreg-9 (11)-ezte () : Solid Na2HP04 (0. 45 g, 3. 14 mmol) and 30% H202 (0. 84 mL) were added to a vigorously stirred solution of hexafluoroacetone trihydrate (1. 24 g, 0. 79 mL, 5. 7 mmol) in CH2C12 (13 mL). The mixture was stirred under nitrogen in an ice bath for % 2 her. A chilled solution of the 21-methoxy-17a-hydroxy compound (34, 1. 63 g, 3. 77 mmol) in CH2C12 (13 mL) was added slowly via pipette. The reaction was transferred to the cold room and allowed to stir overnight at 4°C. The next morning, examination by TLC (silica ; 25% EtOAc in CH2C12) indicated all starting material had been converted to a mixture of two more polar components. Methylene chloride (25 mL) was added and the mixture washed with 10% Na2S03 (2x), saturated NaHCO3 solution and H20. The combined organic extracts (3x) were dried by filtration through Na2S04, evaporated in vacuo and dried several hours under high vacuum to give 1. 86 g of an amorphous solid in quantitative yield, which consists of at least, 4 epoxides evidenced by'H NMR.

NMR (CDCl3) 8 0. 77 (s, 3 H, CIS-CHs), 3. 40 (s, 3 H, C21-OCH3), 3. 60 (dd, C21-CH2, Jl = 15 Hz, J2 = 9 Hz), 3. 9 (s, C3-OCH2CH20), 4. 0 (m, C3-and C20- OCH2CH20), 5, 83 (br s, Cl 1-CH= of (3-epoxide) and 6. 03 (br s, Cl 1-CH= of a-epoxide).

Step 8. 3, 20-bis-(Ethylenediox)-5α,17α-dihydroxy-11ß-[4-(N,N- dimetlzylarrzisao) phenyl]-21-methoxy-19-norpregn-9(10)-ene(36): A 100 mL round bottom flask was equipped with a magnetic stirrer, a reflux condenser and a rubber septum and flame dried under a stream of N2. Magnesium (0. 50 g, 20. 7 mmol) was added, followed by a crystal of iodine, dry THF (20 mL) and 1-2 drops of dibromoethane. The mixture was heated in a warm H20 bath under N2 for approximately l/2 hr, but there were no observable change. A solution of 4-bromo-N, N-dimethylaniline (3. 77 g, 18. 85 mmol) in THF (10 mL) was added via syringe over a period of several minutes and rinsed with an additional THF (10 mL). There was evidence of reaction immediately as the magnesium turned dark. After stirring for 1. 5 hr., solid copper (I) chloride (0. 21 g, 2. 07 mmol), was added and the reaction mixture stirred another l/2 hr.

Crude epoxide (assumed 3. 77 mmol from the previous reaction) was added as a solution in THF (5 mL) and rinsed in with an additional THF (5 mL). The reaction was allowed to stir

1 hr at room temperature and then quenched by the addition of saturated ammonium chloride (50 mL). Air was drawn through the mixture with vigorous stirring for 1/2 hr.

Ether was added and the layers allowed to separate. The organic solution was washed with 10% NH4Cl (2x), 2 N NH40H (3x) and brine (Ix). Organic fractions were combined, dried over Na2S04, filtered and evaporated in vacuo to obtain 3. 37 g of crude material. Analysis by TLC (silica ; 20% acetone in CH2C12) indicated formation of a new more polar compound. Flash column chromatography (silica ; 20% acetone in CH2C12), yielded 0. 890 g of the pure product in 63% yield, assuming 66% of the starting material was the desired Sa, l0a-epoxide). FTIR (KBr, diffuse reflectance) v.... 3494, 2936, 1612 and 1518 cvn~l.

NMR (CDC13) 8 0. 47 (s, 3 H, C18-CH3), 2. 90 (s, 6 H,-N (CH3) 2), 3. 43 (s, 3 H, C21-OCH3), 4. 03 (m, 10 H, C3-and C20-OCH2CH20-and C21-CH2), 6. 67 (d, 2 H, aromatic-CH's, J = 9 Hz), and 7. 10 (d, 2 H, aromatic-CH's, J = 9 Hz). MS (EI) m/z (relative intensity) : 569 (M+, 4), 551 (11), 506 (4), 134 (27), 121 (49) and 117 (100). Anal. Calcd. for C33H4707N : C, 69. 57 ; H, 8. 31 ; N, 2. 46. Found : C, 69. 40 ; H, 8. 19 ; N, 2. 53.

Step 9. 17α-Hydroxy-21-methoxy-11~-[4-(N,N-dimethylamino)phenyl]-19 - notpregsia-4, 9-diehe-3, 20-dione (37) : The diketal (36, 1. 81 g, 3. 18 mmol) was dissolved in THF (20 mL) and the solution stirred magnetically at room temperature under nitrogen. Trifluoroacetic acid (60 mL) was added followed by H20 (20 mL). After 1 hr., the reaction was examined by TLC (silica ; 20% acetone in CH2C12 ; neutralized with cone. NH40H before developing).

All starting material had been converted to the product. The reaction was neutralized by the careful addition of cone. NH40H (55 mL). Enough additional NH40H was added to bring the pH between 6 and 7. The product was extracted by CH2C12 (3x). The organic extracts were combined, washed with H20 (lx) and dried by filtration through Na2S04.

Evaporation in vacuo followed by drying overnight under high vacuum gave 37 as an amber glass (1. 42 g, 96. 3%). The resulting oil was crystallized by trituration with H20 and scratching and sonicating to produce a fine bright yellow powder. FTIR (KBr, diffuse reflectance) v,,,,, 3408, 2943, 1722, 1663, 1612 and 1518 cm-1. NMR (CDC13) # 0. 37 (s, 3 H, C18-CH3), 2. 90 (s, 6 H,-N (CH3) 2), 3. 43 (s, 3 H, C21-OCH3), 4. 43 (dd, 2 H, C21-CH2, Jl = 27 Hz, J2 = 18 Hz), 5. 77 (s, 1H, C4-CH=), 6, 65 (d, 2 H, aromatic-CH's, J = 9 Hz) and 7. 03 (d, 2 H, aromatic-CH's, J = 9 Hz). MS (EI) m/z (relative intensity) : 463 (M, 20), 134

(21) and 121 (100). Anal. Calcd. for C29H3704N-2/3H20 : C, 73. 23 ; H, 8. 12 ; N, 2. 94.

Found : C, 73. 09 ; H, 7. 88 ; N, 2. 97.

Step 10. Preparatioiz of the target cosnpound (38) : A mixture of CH2Ck (35 mL), trifluoroacetic anhydride (6. 0 mL) and glacial acetic acid (2. 43 mL) was allowed to stir at room temperature under nitrogen. After Yz hr, the mixture was cooled to 0°C in an ice water bath and p-toluenesulfonic acid (350 mg) was added. A solution of the 17C-hydroxy-2 1-methoxy compound (37, 730 mg, 1. 57 mmol) was added in CH2C12 (4 mL) and rinsed in with CH2C12 (2 x 4 mL). After stirring 1. 5 hr at 0°C, examination by TLC (silica ; 10% acetone in CH2C12, after neutralization by NH40H) indicated the reaction was > 95% complete. The reaction mixture was diluted with H20 (35 mL) and neutralized with concentrated NH40H. The product was extracted by CH2Cl2 (3x) and brine (lx). The combined organic extracts were dried by filtration through Na2S04 and evaporated in vacuo to give 0. 91 g of the crude product. Flash column chromatography on silica using 10% acetone in CH2C12 followed by evaporation in vacuo and drying under high vacuum produced 38 as a pure pale yellow foam (0. 6 g, 75. 8%).

Treatment with pentane followed by sonicating produced a fine powder : m. p. softens at 116°C. HPLC analysis on a NovaPak Cis column eluted with 70% CH30H in H20 with 0. 03% Et3N at a flow rate of 1 mL per min at X = 302 indicated the product 38 to be 98. 06% pure with a retention time of tR = 5. 08 min. FTIR (diffuse reflectance, KBr) v", ax 2940, 1734, 1663, 1612, 1518, 1446, 1370, 1235, and 1124 cm~l. NMR (CDC13) 8 0. 38 (s, 3 H, C18-CH3), 2. 08 (s, 3 H, OAc), 2. 90 (s, 6 H, NMe2), 3. 42 (s, 3 H, C21-OCH3), 4. 20 (dd, 2 H, C21-CH2, Jl = 24 Hz, J2 = 15 Hz), 5. 80 (s, 1 H, C4-CH=), 6. 67 (d, 2 H, aromatic- CH's, J = 9 Hz) and 7. 0 (d, 2 H, aromatic-CH's, J = 9 Hz). MS (EI) m/z (relative intensity) : 505 (M+, 75), 445 (1. 1), 430 (8%), 372 (2. 7), 134 (16) and 121 (100). Anal. Calcd. for C3lH390sN : C, 73. 64 ; H, 7. 77 ; N, 2. 77. Found : C, 73. 34 ; H, 7. 74 ; N, 2. 70.

EXAMPLE 10 This example illustrates the preparation and properties of 17a-acetoxy-21- ethoxy-1 I (3- [4- (N, N dimethylamino) phenyl]-19-noipregna-4, 9-diene-3, 20-dione (46).

Step 1, 3,20-bis-(Ethylenedioxy)-17α-hydroxy-21-ethoxy-19-norpregna - 5(10),9(11)-diene(42): To a cold solution of the 17a, 21-dihydroxy diketal (33, 5. 66 g, 13. 53 mmol) in CH2C12 (700 mL) in an ice bath under nitrogen was added 20. 3 g (94. 7 mmol) of solid 1, 8-bis(dimethylamino) naphthalene ("proton sponge"), followed by triethyloxonium tetrafluoroborate (18. 0 g, 94. 7 mmol). The reaction mixture was allowed to gradually warm to room temperature as the ice bath melted. After 1 hr, TLC (silica ; 5% isopropanol in CH2Cl2) indicated the reaction was >95% complete. The reaction was quenched after a total time of 2 hr by the addition of H20. The mixture was transferred to a separatory funnel and washed with H2O (2x). The combined organic fractions were dried by filtration through Na2S04 and evaporated in vacuo. The resulting residue was taken up in EtOAc and washed with ice cold 1 N HC1 (2x), saturated NaHC03 and H2O. Combined organic fractions were filtered through Na2S04 and evaporated in vacuo to recover 6. 86 g of an oil.

Purification of this oil by flash column chromatography on silica using 5% acetone in CH2C12 gave 4. 37 g of a colorless foam in 72. 4% yield : m. p. = softens at 62°C. FTIR (KBr, diffuse reflectance) , 3485, 2889, 2738, 1440, 1371, 1216, 1120 and 1058 cm1.

NMR (300 MHz, CDC13) 5 0. 8 (s, 3 H, C18-CH3), 1. 22 (t, 3 H, C21-OCH2CH3, J= 6. 9 Hz), 3. 0 (s, 1 H, C17a-OH), 3. 46-3. 82 (m, 4 H, C21-CH2 and C21-OCH2CH3), 3. 98 (s, 4 H, C3-OCH2CH20-), 3. 84-4. 28 (m, 8 H, C3-and C20-OCH2CH20), and 5. 55 (br s, 1 H, Cll- CH=). MS (EI) m/z (relative intensity) : 446 (MF, 2), 400 (0. 9), 387 (6. 6), 369 (2. 8), 297 (5. 5) and 131 (100).

Step 2. 3, 20-bis-(Ethylenedioxy)-5α,10α-epoxy-17α-hydroxy-21-ethoxy -19- zioipregn-9 (11)-eize (43) : To a solution of hexafluoroacetone trihydrate (2. 05 mL, 14. 7 mmol) in CH2C12 (35 mL), was added solid Na2HP04 (1. 17 g, 8. 24 mmol) followed by 30% H2O2 (2. 2 mL). The mixture was stirred vigorously in an ice bath under nitrogen for #hr. A chilled solution of the 21-ethoxy-17a-hydroxy compound (42, 4. 37 g, 9. 79 mmol) in CH2C12 (35 mL) was added slowly via pipette. The reaction was transferred to the cold room and allowed to stir overnight at 4°C. The next morning, examination of the reaction mixture by TLC (silica ; 5% acetone in CH2C12) indicated all of the starting material had been converted to two more polar components in approximately a 2 : 1 ratio. The reaction mixture was transferred to a separatory funnel and washed with 10% Na2S03 (2x), saturated NaHCO3, H20 and brine. The combined organic fractions were filtered through Na2S04

and evaporated in vacuo to recover 4. 84 g of a colorless foam. Trituration of this crude product with Et2O produced a white solid. The solid was collected on a Buchner funnel and dried overnight in vacuo to give 1. 73 g of white crystals in 38. 1% yield. Examination of this material by TLC and NMR indicated it was pure 5a, 10a-epoxide (43). Purification of the mother liquors by flash column chromatography on silica eluting with 7% acetone in CH2C12 gave an additional 0. 6 g of 5a, 10a-epoxide (43). Total yield of purified Sa, 10a- epoxide (43) was 2. 33 g (51. 3%) : m. p. = 154-166° (dec). FTIR (KBr, diffuse reflectance) v,,,,, 3566, 2934, 2890, 2441, 1375, 1212, 1118, 1064 and 1044 cni-1. TQMR (CDCl3) 8 0. 78 (s, 3 H, C18-CH3), 1. 2 (t, 3 H, C21-OCH2CH3, J= 6 Hz), 2. 88 (s, 1 H, C17α-OH), 3. 33-3. 73 (m, 4 H, C21-CH2 and C21-OCH2CH3), 3. 93 (s, 4 H, C3- OCH2CH20-), 3. 73-4. 27 (m, 8 H, C3-and C20-OCH2CH20), 6. 03 (br, s, 1 H, C1I-CH=).

MS (EI) m/z (relative intensity) : 462 (M+, 1. 1), 403 (8. 9), 385 (5. 9), 131 (100) and 87 (32).

Step 3. 3,20-bis-(Ethylenedioxy)-5α,17α-dihydroxy-11ß-[4-(N,N- dimethylamino) ?phenyl]-21-ethoxy-19-norpregn-9(10)-ene(44): A three-neck round bottom flask (250 mL) was equipped with a magnetic stirrer, a condenser, a glass stopper and a rubber septum and flame dried under a stream of nitrogen. Magnesium was added (655 mg, 24. 5 mmol), followed by a crystal of iodine, 25 mL of dry THF, and 1-2 drops of dibromoethane. After heating in a warm water bath for approximately 1/2 hr under nitrogen, no observable change occurred. A solution of 4- bromo-N, N-dimethylanilille (4. 9 g, 24. 5 mmol) in 13 mL of dry THF was added via syringe over a period of several minutes and rinsed in with an additional 13 mL of THF. A reaction occurred almost immediately as the THF began to reflux and the surface of the magnesium turned dark. Approximately 10 min. after the addition of the 4-bromo-N, N-dimethylaniline, heating was discontinued, but the reaction was allowed to remain in the bath. After stirring for 1. 5 hr, copper (I) chloride (267 mg, 2. 7 mmol) was added as a solid and stirring continued for another 1/2 hr. The Sa, 10a-epoxide (43, 2. 27 g, 4. 9 mmol) was added via syringe as a solution in 6. 5 mL of dry THF and rinsed in with 6. 5 mL of THF. After 2 hr, examination of the reaction mixture by TLC on silica (20% acetone in CH2Cl2 ; quenched with saturated M-LCl before developing) indicated all epoxide had been converted to a new more polar material. The reaction was quenched by the addition of saturated NH4C1 (65 mL) and air was drawn through the mixture for 1/2 hr with vigorous stirring. The reaction mixture was transferred to a separatory funnel, ether added, and the layers allowed

to separate. The organic fraction was washed with 10% NH4CI (lx), 2 N NH40H (lx) and brine (lx). The combined organic fractions (3x) were filtered through Na2S04 and evaporated in vacuo to obtain 5. 62 g of crude material. This crude product was purified by flash column chromatography on silica. The column was first washed with CH2Cl2 to remove impurities with high Rf before eluting the product with 20% acetone in CH2C12.

Appropriate fractions were combined and evaporated in vacuo to give a crystallizing oil.

Crystallization of this material from a minimum amount of hot ether afforded 2. 09 g of a pale blue powder (44) in 73% yield ; m. p. = 199-201°C (dec). FTIR (KBr, diffuse reflectance) #max 3591, 3529, 3421, 2971, 2882, 1615, 1562, 1519, 1443, 1354, 1190, 1122 and 1053 cm~l. NMR (CDC13) 6 0. 47 (s, 3 H, C18-CH3), 1. 23 (t, 3 H, C21-OCH2CH3, J = 6 Hz), 2. 90 (s, 6 H,-N (CH3) 2), 3. 43-3. 80 (m, 4 H, C21-CH2 and C21-OCH2CH3), 3. 80- 4. 33 (m, 9 H, C3-and C20-OCH2CH20-, and Clla-CH), 6. 67 (d, 2 H, aromatic-CH's, J = 9 Hz), 7. 10 (d, 2 H, aromatic-CH's, J = 9 Hz). MS (EI) m/z (relative intensity) : 538 (M+, 14), 565 (19), 506 (13) and 131 (100). Anal. Calcd. for C34H4907N : C, 69. 96 ; H, 8. 46 ; N, 2. 40. Found : C, 69. 78 ; H, 8. 37 ; N, 2. 35. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 4. 17α-Hydroxy-21-ethoxy-11ß-[4-(N,N-dimethylamino)phenyl]-19 -<BR> <BR> <BR> <BR> 7lorpregna-4, 9-diene-3, 20-a'ione (45) : The hydroxy diketal (44, 2. 0 g, 3. 43 mmol) was dissolved in THF (20 mL) and stirred magnetically at room temperature under nitrogen. Trifluoroacetic acid (60 mL) was added followed by H20 (20 mL). After 40 min, TLC (20% acetone in CH2C12, neutralized with conc. NH40H before developing) indicated the reaction had gone to completion. The reaction was allowed to continue another hour before neutralizing by the careful addition of conc. NH40H (55 mL). Additional NH40H was added to bring the pH to 6-7, CH2Cl2 was added, the mixture transferred to a separatory funnel, and the layers allowed to separate. The organic phase was washed again with H20 (lx), and brine (1x).

Combined CH2C12 extracts (3x) were filtered through Na2S04 and evaporated in vacuo to give 1. 73 g of an amber foam. Purification by flash column chromatography on silica eluting with 20% acetone in CH2C12 afforded 1. 28 g of pure 45 as a bright yellow foam in 78% yield : m. p. = softens at 96°C. FTIR (KBr, diffuse reflectance)- 3440, 2944, 2880, 1721, 1658, 1612, 1518, 1443, 1347, 1211 and 1136 cml. NMR (CDC13) 6 0. 40 (s, 3 H, C18-CH3), 1. 3 (t, 3 H, C21-OCH2CH3, J = 6 Hz), 2. 93 (s, 6 H,-N (CH3) 2), 3. 4-3. 8 (m, 3 H, C21-OCH2CH3 and C17a-OH), 4. 13-4. 63 (m, 3 H, C21-CH2 and Clla-CH), 5. 80 (s, 1 H,

C4-CH=), 6. 68 (d, 2 H, aromatic-CH's, J = 9 Hz), 7. 05 (d, 2 H, aromatic-CH's, J = 9 Hz).

MS (EI) m/z (relative intensity) : 477 (M+, 42), 280 (14), 134 (26) and 121 (100). Anal.

Calcd. for C3oH3g04N-H2O : C, 74. 50 ; H, 8. 21 ; N, 2. 90. Found : C, 74. 46 ; H, 8. 21 ; N, 2. 93.

Step 5. Preparatiout of the target compound (46) : A mixture of trifluoroacetic anhydride (9. 77 mL), and glacial acetic acid (3. 9 mL) in CH2C12 (50 mL) was allowed to stir H hr under nitrogen at room temperature.

The mixture was cooled to 0°C in an ice bath and toluenesulfonic acid monohydrate (0. 57 g, 3 mmol) was added. A solution of the 17a-hydroxy-21-ethoxy compound (45, 1. 22 g, 2. 55 mmol) in CHxClz (10 mL) was added to the above mixture, and then rinsed in with 10 mL of CH2C12. After stirring 2 hr at 0°C, the reaction was examined by TLC (silica ; 10% acetone in CH2C12, neutralized with cone. NH40H before developing) and was found to be >95% complete. The reaction mixture was diluted with H20 (50 mL) and neutralized by the careful addition of conc. NH40H. More CH2Cl2 and H20 were added, the mixture was transferred to a separatory funnel, and the layers allowed to separate. The organic fraction was washed again with H20 and brine. Combined CH2C12 extracts (3x) were filtered through Na2S04 and evaporated in vacuo to give 1. 35 g of an amber foam.

This crude product was purified twice by flash column chromatography on silica eluting with 8% acetone in CH2C12. Appropriate fractions were combined, evaporated in vacuo, chased with ether to obtain 0. 81 g of a foam. Treatment with pentane produced a pale yellow powder. The powder was dried overnight in vacuo at 58°C to remove all traces of solvent. Total yield of pure 46 was 491 mg in 37% ; m. p. = softens at 104°C. HPLC analysis on Phenomenex Prodigy 5 ODS-2 column (150 x 4. 6 mm) eluted with 30% H20 with 0. 03% triethylammonium phosphate (pH 7. 0) in CH30H at a flow rate of 1 mL per min at X = 302 indicated the product 46 to be 98. 76% pure with a retention time (tR) of 16. 64 min. FTIR (KBR, diffuse reflectance) v,,, 2945, 2890, 1734, 1663, 1612, 1562, 1518, 1446, 1368 and 1235 cm~l. NMR (CDC13) 6 0. 43 (s, 3 H, C18-CH3), 1. 28 (t, 3 H, C21-OCH2CH3, J= 6 Hz), 2. 15 (s, 3 H, C17a-OAc), 2. 95 (s, 6 H,-N (CH3) 2), 3. 63 (q, 2 H, C21-OCH2CH3, J = 6 Hz), 4. 03-4. 60 (m, 3 H, C21-CH2 and Clla-CH), 5. 87 (s, 1 H, C4-CH=), 6. 72 (d, 2 H, aromatic-CH's, J = 9 Hz) and 7. 08 (d, 2 H, aromatic-CH's, J = 9 Hz). MS (EI) m/z (relative intensity) : 519 (M+, 34), 459 (4. 5), 372 (7. 4), 134 (18) and 121 (100). Anal. Calcd. for C32H4, 05N : C, 73. 95 ; H, 7. 96 ; N, 2. 70. Found : C, 73. 84 ; H, 8. 20 ; N, 2. 65.

EXAMPLE 11 This example illustrates the preparation and properties of 17a, 21-diacetoxy- 11 (3- [4- (N, N dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione 3-oxime as a mixture of syn and anti-isomers (47) : A solution of the diacetate (15, 0. 5 g, 0. 937 mmol) and hydroxylamine hydrochloride (0. 651 g, 937 mmol) in absolute ethanol (25 mL) was stirred at room temperature under nitrogen. After 2. 5 hr, TLC (10% acetone in CH2C12) indicated a complete reaction. The reaction mixture was diluted with H20 (200 mL), adjusted to a pH 7 with saturated NaHCO3 solution, and extracted with CH2C12 (3x). The organic fractions were washed with H20 (2 x) and brine (1 x), combined, dried (Na2S04), filtered and concentrated in vacuo to give 0. 56 g of residue as a foam. Purification by flash chromatography (5% acetone/CH2Cl2) followed by precipitation from ether solution with pentane gave 0. 3 g of the oxime (47) in 58% as an off-white amorphous powder. Analysis by HPLC on a NovaPak Cis column eluted with CH3CN : H2O : Et3N 45 : 55 : 0. 033 at a flow rate of 2 mL per min at X = 274 nm indicated approximately 98% purity consisting of a 32 : 68 mixture of the syn-and anti-isomers. Analysis by NMR indicated a syn : anti ratio of 43 : 57 : m. p. = sinters at 151 °C, and then decomposes. FTIR (KBr, diffuse reflectance) vu 2946, 1737, 1612 and 1518 cm-1. NMR (CDCl3) 8 0. 40 (s, 3 H, C18-CH3), 3. 93 (s, 6 H, NMe2), 4. 40 (br. s, 1 H, C I I a-CH), 4. 87 (dd, Jl = 29. 7 Hz, J2 = 18 Hz, 2 H, C21-CH20Ac), 5. 97 (s, 0. 57 H, C4-CH= for anti-isomer), 6. 63 (s, 0. 43 H, C4-CH= for syn-isomer), 6. 70 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's) and 7. 10 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 549 ((M+H) +, 63) and 275 (100).

EXAMPLE 12 This example illustrates the preparation and properties of 17a-acetoxy-21- methoxy-111 3- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione 3-oxime as a mixture of syn and anti-isomers (_) : A solution of the 21-methoxy compound (38, 0. 1 g, 0. 2 mmol) and hydroxylamine hydrochloride (0. 139 g, 2 mmol) in absolute ethanol (5 mL) was stirred at room temperature under nitrogen. After 1 hr, TLC (10% acetone in CH2Cl2) indicated a complete reaction. The reaction mixture was diluted with H2O, adjusted to a pH of 7 with saturated NaHCO3 solution, and extracted with CH2C12 (3 x). The organic fractions were washed with H20 (2 x) and brine (1 x), combined, dried over Na2S04 filtered and

concentrated in vacuo to give the crude product as a foam. This material was combined with 0. 12 g additional crude product in a previous batch and the total amount (0. 21 g) was purified by flash chromatography (15% acetone/CH2Cl2) followed by trituration with pentane to give 0. 12 g of the oxime (48) in 58% yield as a white amorphous powder.

Analysis by HPLC on a NovaPal C18 column eluted with MeOH : H20 : Et3N 65 : 35 : 0. 0033 at a flow rate of 1 mL/min at X = 276 nm indicated approximately 97% purity of a mixture of the syn-and anti-isomers. The retention times of the two isomers were too close together (tR = 8. 8 and 9. 2 min) to give an accurate integration ratio. Analysis by NMR indicated a syn : anti ratio of 26 : 74 ; m. p. = sinters at 142°C and melts at 146-162°C. FTIR (KBr, diffuse reflectance) v,,,, 2938, 1733, 1613 and 1517 cm-1. NMR (300 MHZ, CDC13) 6 0. 36 (s, 3 H, C18-CH3), 2. 10 (s, 3 H, 17a-OAc), 2. 89 (s, 6 H, NMe2), 3. 41 (s, 3 H, OCH3), 4. 10 (d, 1 H, C21-CH2, J = 16. 8 Hz), 4. 30 (m, 2 H, 1 la-H plus 21-CH2), 5. 88 (s, 0. 74 H, C4-CH= for anti-isomer), 6. 53 (s, 0. 26 H, C4-CH= for syn-isomer), 6. 62 (d, 2H, 3', 5' aromatic-CH's), J = 8. 7 (Hz) and 6. 99 (d, 2 H, 2', 6'aromatic-CH's, J = 8. 7 Hz). MS (EI) m/z (relative intensity) : 521 (M, 100) and 261 (67).

EXAMPLE 13 This example illustrates the preparation and properties of 17a-formyloxy- llp- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (69A) (Figure 4).

17a-Hydroxy-llp- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (61, 140 mg, 0. 323 mmol) was dissolved in 96% formic acid (2. 44 g, 50. 9 mmol) in an argon atmosphere and cooled to 0°C in an ice bath (Oliveto, E. P., et al., J. Am. Chem. Soc., 77 : 3564-3567 (1955)). P205 (500 mg, 1. 76 mmol) was added as a solid and after stirring five minutes, the reaction mixture was allowed to wann to room temperature. After 1. 5 hr, saturated NaHCO3 was added, carefully to neutralize the mixture. The mixture was extracted with EtOAc (3x) and washed with H20 and brine and dried over Na2S04.

Another similar reaction was run starting with 500 mg (1. 15 mmol) of the 17a-hydroxy compound (61). Two products from the above two reactions were combined and chromatographed on dry column silica gel using CH2Cl2 : CH3C (O) CH3 (9 : 1) to afford the crude product as a yellow foam (69A), which was indicated by HPLC to be 97% pure. This material was rechromatographed using the same solvent system to give 185 mg of the good product (69A) as an amorphous off-white solid. Analysis by HPLC indicated 98. 8% purity.

The yield was 28% ; and m. p. = softens at 115°C. FTIR (KBr, diffuse reflectance) v,,,,,,

2941, 1722, 1664, 1611 and 1518 cm~t (CDC13) : 5 0. 38 (s, 3 H, C18-Me), 2. 13 (s, 3 H, C21-Me), 2. 91 (s, 6 H, N (CH3) 2), 4. 44 (d, 1 H, Clla-CH), 5. 8 (br s, 1 H, C4-CH=), 6. 68 and 7. 06 (dd, 4 H, aromatic-CH's) and 8. 11 (br s, 1 H, Cl 7a-HC=O). MS (EI) m/z (relative intensity) : 461 (M+, 36. 2), 400 (2. 1), 134 (15. 4), 121 (100), and 91 (3. 0). Anal.

Calcd. for C29H3sNO4 1/4H20 : C, 74. 73 ; H, 7. 68 ; N, 3. 01. Found : C, 74. 64 ; H, 7. 65 ; N, 3. 05.

EXAMPLE 14 This example illustrates the preparation and properties of 17a-Propionoxy- 4-(N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (69C) (Figure 4).

Trifluoroacetic anhydride (0. 48 g, 4. 29 mmol) and propionic acid (0. 61 g, 4. 29 mmol) were added to benzene, andp-toluenesulfonic acid monohydrate (0. 186 g, 1. 31 mmol) as a solid was added to the mixture. The mixture was stirred at room temperature for 1/2 hr. The 17a- hydroxy steroid (61, 581 mg, 1. 34 mmol) was dissolved in benzene and added to the above mixture. The mixture was stirred at room temperature for 6 hr. The mixture was poured into ice cold sodium NaHC03 solution and extracted with EtOAc. The EtOAc extracts were washed with H20, brine and dried over Na2S04, and evaporated in vacuo. The product obtained was purified by flash column chromatography using EtOAc : hexane (4 : 6) as solvent. The product was crystallized from isopropanol to give 145 mg of crude 69C as white crystals. In checking this material by reverse phase HPLC, it was found that an impurity was present which could not be separated from the desired product by chromatography on silica gel. The mother liquor was concentrated in vacuo, and the ester was purified by chromatography on an ODS-3 10/50 Whatman column using MeOH : H20 (9 : 1) as a solvent and monitoring the separation using a Waters Model 481 variable wavelength detector at 365 nm and at a flow rate of 9 mL/min. Fractions were collected and similar fractions were combined. Good material from the above two was combined and recrystallized from isopropanol to give 299 mg of 69C as white crystals in 80% yield ; m. p. = 125-126°C. FTIR (KBr, diffuse reflectance) : Via,, 2946, 2882, 1730, 1662, 1610, 1596 and 1516 cm-1. NMR(CDCl3) : 8 0. 363 (s, 3 H, C18-Me), 2. 086 (s, 3 H, C21-Me), 2. 905 (s, 6 H,-NMe2), 4. 386 (d, 1 H, Clla-CH), 5. 775 (s, 1 H, C4-CH=), 6. 634 and 6. 979 (d, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 489 (M+, 42. 2), 400 (6. 5), 372 (6. 7), 134 (20. 2), 121 (100), and 57 (11. 7). Anal. Caled. for C3lH3gNO4 1/2 C3HgO : C, 75. 14 ; H, 8. 29 ; N, 2. 70. Found : C, 75. 03 ; H, 8. 43 ; N, 2. 83.

EXAMPLE 15 This example illustrates the preparation and properties of 17a- Heptanoyloxy-11 p- [4- (N, N-dimethylamino) phenyl]-19-noipregna-4, 9-diene-3, 20-dione (69D) (Figure 4). The above procedure was followed using heptanoic acid- (0. 56 g, 4. 29 mmol) instead of propionic acid on the 17a-hydroxy compound (61, 581 mg, 1. 34 mol). The reaction was run at room temperature for 17 hr. After work, the crude product was purified by flash chromatography using EtOAc : hexane (4 : 6). The slightly impure product was chromatographed on an ODS-3 10/50 column using CH30H at a flow rate of 9 mL per min, monitored at 365 nm. T his afforded 335 mg of an oil (69D) in 48. 5% yield. This oil was solidified on standing at room temperature as an off-white solid ; m. p. = softens at 68°C. FTIR (KBr, difuse reflectance) : Vmax 2943, 1731, 1664, 1612 and 1518 crri 1. NMR (CDCl3) : 5 0. 36 (s, 3 H, CIS-CI43), 2. 1 (s, 3 H, C21-CH3), 2. 93 (s, 6 H, N (CH3) 2), 4. 44 (br d, 1 H, Cl la-CH), 5. 82 (br s, 1 H, C4-CH=), 6. 68 and 7. 04 (d, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 545 (M+, 37. 4), 400 (7. 7), 372 (7. 4), 134 (18. 6) and 121 (100). Anal. Calcd. for C35H47NO4 1/2 H2O : C, 75. 81 ; H, 8. 66 ; N, 2. 53.

Found : C, 75. 89 ; H, 8. 55 ; N, 2, 71.

EXAMPLE 16 This example illustrates the preparation and properties of 17a- Methoxymethyl-llp- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (91) (Figure 5).

Step 1. 3-Methoxy-19-norpregna-1,3,5(10),17(20)-tetraene (78): Sodium hydride (50% in mineral oil, 14. 72 g, 306. 6 mmol) was weighed into a dry 3-neck flask and the oil was removed by washing with dry pentane (3x). The residual pentane was removed under a stream of nitrogen. DMSO (255 mL) freshly distilled from CaH2 was added. The mixture was stirred and heated at 60-65°C until gas evolution had ceased and the mixture was homogeneous. The dimsyl anion solution was cooled to room temperature and a solution of ethyl triphenylphosphonium iodide (135. 0 g, 306. 6 mmol) in DMSO (510 mL) was added to give a brick-red solution of the ylide. A solution oestrone methyl ether (77, 19. 5 g, 68. 6 mmol) in benzene (freshly distilled from sodium, 390 mL) was added to the DMSO solution and the mixture was stirred at 60°C for 18 hr. The

solution was cooled to room temperature and poured into ice/water (1000 mL). The aqueous mixture was extracted with hexanes (3x). The hexane extracts were washed with H20 (3x) and brine (lx). The combined hexane extracts were dried over Na2S04 and evaporation of the solvent gave 19. 17 g of an oily material. This material was dissolved in petroleum ether and percolated through a column of neutral alumina. Evaporation of the solvent gave a solid (78). The material was crystallized from methanol/ether to afford 10. 95 g of 78 in 54% yield as a white crystalline solid ; m. p. = 70-75°C (Lit m. p. = 76. 5- 77. 5°C : Kribner, et al., J. Org. Chenu., 31 : 24-26 (1966)). Elution of the alumina column with EtOAc allowed for the recovery of 8. 0 g of 77. NMR (CDCl3) : 6 0. 9 (s, 3 H, C18- CH3), 1. 70 (d, J = 6 Hz, C21-CH3), 3. 80 (s, 3 H, C3-OCH3), 5. 2 (m, 1 H, C20-CH=), 6. 8 (m, 2 H, 2', 4'-aromatic-CH's), and 7. 27 (d, 1 H, J = 8 Hz, l'-aromatic-CH).

Step 2. 3-Methoxy-19-norplwegna-1, 3, 5 (10), 16-tetraene-20-one (79).

A fine stream of oxygen was bubbled through a solution of the 17-ethylidene compound (78, 4. 0 g, 13. 5 mmol) in pyridine (100 mL) containing hematoporphyrine (80 mg, 1 mol%) for 16 hr while being illuminated with six 15 watt fluorescent lights.

Acetic anhydride (20 mL) was added to the pyridine solution and the mixture was stirred for 2. 5 hr. The mixture was poured into cold H20 and extracted with CH2C12 (3x). The metylene chloride extracts were sequentially washed with 5. 0 N HC1 (3x), H20 (lx), saturated NaHCO3 (lx) and brine (lx). The combined methylene chloride extracts were dried over Na2S04 and evaporation of the solvent gave a black solid. The material was dissolved in hot EtOAc, treated with charcoal, and filtered through Celite. Evaporation of the solvent gave 4. 15 g of a yellow solid. Crystallization of this yellow solid from EtOAc afforded 2. 45 g of 79 in 58. 5% yield ; m. p. = 182-185°C (Lit m. p. = 186-188°C : Kribner, et al., J. Org Chem., 34 : 3502-3505 (1969)).

Step 3. 3-Methoxy-19-norpregna-1,3,5(10)-trien-20-one (8)): A solution of the enone (79, 4. 0 g, 12. 89 mmol) in benzene (160 mL) containing 10% Pd/C (400 mg, 3 mol%) was hydrogenated at atmospheric pressure. The reaction was allowed to stir for 16 hr. The mixture was filtered through Celite under nitrogen. Evaporation of the solvent gave 3. 96 g of the 20-ketone (80) (Kribner, et al., J, Org, Chem., 34 : 3502-3505 (1969)) as a light yellow solid in 98% yield. NMR (CDC13) :

6 0. 63 (s, 3 H, C18-CH3), 2. 15 (s, 3 H, C21-CH3), 3. 80 (s, 3 H, C3-OCH3), 6. 70 (m, 2 H, 2', 4'aromatic-CH's) and 7. 2 (d, 2 H, J = 8 Hz, 1'aromatic-CH).

Step 4. 3-Methoxy-20-acetoxy-19-norpregna-1,3,5(10),17(20)-tetraene (81): A mixture of the 20-ketone (80, 3. 0 g, 9. 60 mmol) and p-toluenesulfonic acid (1. 13 g, 5. 94 mmol) in acetic anhydride (200 mL) was heated at 150°C in an oil bath while the solvent was slowly distilled through a short path column (Temp. Head = 130- 134°C) over 5 hr. The remaining solvent was removed at reduced pressure. The residue was partitioned between cold ether and cold saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with Et2O (2x). The EtzO layers were washed with H2O, brine, combined and dried over sodium sulfate. Evaporation of the solvent gave 3. 67 g of the enol acetate (81) (Krubiner, A. M. et al., R Org. Chem., 34 : 3502- 3505 (1969)), a stable yellow foam. This product was purified via flash chromatography eluting with 20% EtOAc/hexane to afford 1. 78 g of 81 in 52% yield as a mixture of E and Z isomers. NMR (CDC13) : 6 0. 87 and 0. 92 (s, C18-CH3), 1. 80 (br s, 3 H, C21-CH3), 2. 13 (s, 3 H, C21-OCOCH3), 6. 80 (m, 2 H, 2', 4'aromatic-CH's) and 7. 20 (d, J = 8 Hz, 1 H, 1' aromatic-CH). MS (EI) m/z (relative intensity) : 354 (M+), 312, 297 (100), 173, 147 and 123.

Step 5. 3-Methoxy-17α-methoxymethyl-19-norpregna-1,3,5(1))-triene-2 0-one (82) : A solution of the enol-acetate (81, 1. 7 g, 4. 8 mmol) in ether (70 mL) was added dropwise over'4 hr to a cold (0°C) ether solution of methyl lithium (8. 3 mL of a 1. 3 M solution, 10. 8 mmol). After 1/2 hr, a sodium bicarbonate-quenched aliquot showed very little enol-acetate remaining. Bromomethyl methyl ether (7. 2 mL of a 2. 0 M/ether solution, 14. 4 mmol) was added to the above lithium enolate solution. The mixture was stirred at 0°C for l/2 hr, then allowed to warm to room temperature over 1 hr. The mixture was poured into ice/water and extracted with Et2O. The ether layers were washed with H20 and brine, combined and dried over anhydrous Na2S04. Evaporation of the solvent gave 1. 78 g of 82. The product was isolated by flash chromatography eluted with 17. 5% EtOAc/hexane to afford 600 mg of 82 as a yellow foam in 35% yield. NMR (300 MHz, CDC13) : 6 0. 672 (s, 3 H, C18-CH3), 2. 171 (s, 3 H, C21-CH3), 3. 310 (s, 3 H, 17a- CH20CH3), 3. 40 and 3. 90 (d, 2 H, J = 8. 4 Hz, 17a-CH20CH3), 3. 761 (s, 3 H, C3-OCH3),

6. 82 (m, 2 H, 2', 4'aromatic-CH's), and 7. 20 (d, 1 H, J = 8 Hz, 1'aromatic-CH). MS (EI) m/z (relative intensity) : 356 (M+), 227 (100), 173, 147 and 115.

Step 6. 3-Methoxy-17α-methoxymethyl-19-norpregna-1,3,5(10)-trien-20 -ol (83): A solution of the 20 ketone (82, 600 mg, 1. 68 mmol) in THF/EtOH was treated with NaBH4 (135 mg, 3. 5 mmol) dissolved in cold H20 (3 mL). The mixture was stirred at 50°C for 5 hr. The mixture was chilled in an ice bath and excess NaBH4 was destroyed with the cautious addition of acetic acid. The mixture was diluted with H20 and extracted with CH2C12. The CH2C12 extracts were washed with H20 and brine, combined and dried over Na2SO4. Evaporation of the solvent gave 580 mg of 83 as a mixture of 20a- (minor) and 20p- (major) epimers as a light yellow oil. Flash chromatography eluting with 2% acetone/CH2Cl2 of a small sample allowed for the isolation of the 20a-epimer with Rf = 0. 35 and the 20) 3-epimer with Rf = 0. 50. Their assignments were based on 300 MHz NMR analysis. NMR (CDCl3) for 20a-OH : 8 0. 797 (s, 3 H, C18-CH3), 1. 254 (d, 3 H, J = 6. 3 Hz, C21-CH3), 3. 376 (s, 3 H, C17a-CH20CH3), 3. 435 and 3. 875 (d, 2 H, J = 8. 7 Hz, C17a- CH20CH3), 3. 769 (s, 3 H, C3-OCH3), 6. 85 (m, 2 H, 2', 4'aromatic-CH's), and 7. 165 (d, 1 H, J = 8. 4 Hz, 1'aromatic-CH). NMR (CDC13) for 20 (3-OH : 8 0. 998 (s, 3 H, C18-CH3), 1. 218 (d, 3 H, J = 6. 3 Hz, C21-CH3), 3. 311 (s, 3 H, Cl7a-CH20CH3), 3. 371 and 3. 612 (d, 2 H, J = 8. 7 Hz, Cl7a-CH2 OCH3), 3. 755 (s, 3 H, C3-OCH3), 6. 85 (m, 2 H, 2', 4'aromatic- CH's) 7. 165 (d, 1 H, J =8. 4 Hz, 1'aromatic-CH). MS (EI) m/z (relative intensity) : 358 (M+), 282, 227, 174 (100) and 147.

Step 7. 3-Methoxy-17α-methoxymethyl-19-norpregna-2,5(10)-dien-20-ol (84): A solution of the 20-alcohol (83, 760 mg, 2. 12 mmol) in THF/t-BuOH (1 : 1, 50 mL) was added to redistilled ammonia (50 mL). While stirring vigorously, lithium metal (294 mg, 42. 2 mmol), cut into small pieces, was added. Within 2 min, the mixture turned blue and was stirred at ammonia reflux (-35°C) for 5 hr. The reaction was quenched through the addition of methanol (15 mL). The ammonia was evaporated under a stream of nitrogen. The residue was diluted with H20 and extracted with CH2C12. The CH2Cl2 extracts were washed with H20 and brine, combined and dried over Na2S04. Evaporation of the solvent gave 874 mg of 84 (14. 4% over theoretical yield) as a stable yellow foam.

This 1, 4-dihydro derivative (84) was used without further purification in the next reaction.

NMR (CDC13) : 8 1. 0 (s, 3 H, C18-CH3), 1. 20 (d, 3 H, J = 6. 3 Hz, C21-CH3), 3. 3 (s, 3 H,

Cl7a-CH2OCH3), 3. 56 (s, 3 H, C3-OCH3) and 4. 67 (br, m, 1 H, C2-CH=). FTIR (KBr, duffuse reflectance) vm= 1666 and 1694 ciri 1.

Step 8. 17a-Metlioxyniethyl-19-norpregna-5 (10)-en-3-oiz-20-ol (85) : A solution of the 1, 4-dihydro derivative (84, 710 mg, 1. 97 mmol) in acetic acid, THF, H2O (3 : 1 : 1, SO mL) was stirred at 40-45°C. Within 45 minutes, TLC analysis indicated complete consumption of the starting material. The solvent was removed in vacuo and the residue was taken up in H20 and the aqueous mixture was extracted with CH2C12. The CH2C12 extracts were washed with H20 and brine, combined and dried over Na2S04. Evaporation of the solvent afforded 684 mg of 85 in 96% yield as a stable light yellow foam. NMR (CDCl3) : 5 1. 0 (s, 3 H, CIS-CHs), 1. 21 (d, 3 H, J = 6. 3 Hz, C21-CH3), 3. 31 (s, 3 H, C17a-CH20CH3), 3. 35 and 3. 72 (d, 2 H, J = 8. 4 Hz, Cl7a-CH20CH3).

Step 9. 17α-Methoxymethyl-19-norpregna-4,9-dien-3-on-20-ol(86): A solution of 85 (584 mg, 1. 69 mmol) in pyridine (2. 5 mL) was added to a pyridine (5. 2 mL) solution of pyridinium bromide perbromide (594 mg, 1. 86 mmol) pre- heated to 80°C. The mixture was heated at 80-90°C for 1 hr. The mixture was poured into cold 2. 5 N HC1 (50 mL). The aqueous mixture was extracted with EtOAc.

The EtOAc extracts were washed with 2. 5 N HC1 (50 mL), saturated NaHCO3 solution and brine. The combined EtOAc extracts were dried over Na2S04.

Evaporation of the solvent gave 540 mg of 86 as a yellow foam in 92. 2% yield. The material was used without further purification in the following reaction. NMR (CDC13) : 8 3. 33 (s, 3 H, Cl7a-CH2OCH3), 5. 67 (br s, 1 H, C4-CH=).

Step 10. 17α-Methoxymethyl-19-norpregna-4,9-dien-3,20-dione (87): A solution of the mixture of 20a and 20p-ol (86, 540 mg, 1. 57 mmol) in acetone (15 mL) was chilled in an ice bath and treated dropwise with Jones reagent until the orange color ou Crop persisted. The mixture was stirred at 0°C for 10 min, then the excess CrVI was destroyed with the addition of 2-propanol until the green color ouf Crop persisted.

The mixture was diluted with H20 and the aqueous mixture was extracted with EtOAc.

The EtOAc extracts were washed with H20 and brine, combined and dried over Na2S04.

Evaporation of the solvent gave 540 mg of a stable foam. Flash chromatography, eluting with 5% acetone/CH2Cl2, gave 202 mg of the 3, 20-diketone (87) in 37. 6% yield as a stable

yellow foam. NMR (CDCl3) : 6 0. 83 (s, 3 H, C18-CH3), 2. 19 (s, 3 H, C21-CH3), 3. 30 (s, 3 H, C17α-CH2OCH3), 3. 36 and 3. 85 (d, 2 H, J = 8. 7 Hz, Cl7a-CH20CH3), and 5. 72 (br s, 1 H, C4-CH=). FTIR (KBr, diffuse reflectance) v 1703, 1662 and 1605 crri 1. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 11. 3,3-Ethylenedioxy-17α-methoxymethyl-19-norpregna-5(10),9(11 )-dien-<BR> <BR> <BR> <BR> <BR> <BR> 20-one (88) : A solution of the 3, 20-diketone (87, 202 mg, 0. 59 mmol) in CH2C12 (16 mL) was treated with triethyl-orthoformate (123 u. L, 0. 74 mmol), ethylene glycol (81. 4 pL, 1. 46 mmol) and p-toluenesulfonic acid (ca. 1. 0 mg). The mixture was stirred for 1 l/z hr, chilled in an ice bath, and diluted with saturated NaHCO3,. The aqueous mixture was extracted with CH2Cl2. The CH2Cl2 extracts were washed with H2O and brine, combined, and dried over Na2S04. Evaporation of the solvent gave 219 mg of the ketal (88) as a yellow foam in 96% yield. NMR (CDCl3) : 6 0. 63 (s, 3 H, C18-CH3), 2. 17 (s, 3 H, C21- CH3), 3. 30 (s, 3 H, Cl7a-CH20CH3), 3. 37 and 3. 82 (d, 2 H, J= 8. 7 Hz, Cl7a-CH2OCH3), 4. 0 (s, 4 H, C3-OCH2CH20-), and 5. 57 (br m, 1 H, Cl 1-CH=).

Step 12. 3,3-Ethylenedioxy-5α,10α-epoxy-17α-methoxymethyl-19-norpr egna- 9(11)-en-20-one (89): A mixture of hexafluoroacetone trihydrate (148. 44 mg, 0. 67 mmol), 30% hydrogen peroxide (76 suL, 0. 67 mmol) and disodium hydrogen phosphate (52. 5 mg, 0. 37 mmol) in CH2Cl2 (2. 0 mL) was stirred at 0°C for #hr,. A solution of the ketal (88, 200 mg, 0. 52 mmol) in CH2Cl2 was added to the above mixture and the mixture was stirred at 4°C for 18 hr. The mixture was diluted with a 10% sodium sulfite solution and was extracted with CH2Cl2. The CH2C12 extracts were washed with H20 and brine, combined and dried over Na2S04. Evaporation of the solvent gave 200 mg of the epoxide (89) as a mixture of 5a, 1 Oa-and 5S, 1 Oß-epoxides as a yellow foam in 95. 5% yield. NMR (CDC13) : 5 0. 67 (s, 3 H, C18-CH3), 2. 17 (s, 3 H, C21-CH3), 3. 33 (s, 3 H, C17α-CH2OCH3), 3. 94 (br s, 4 H, C3-OCH2-CH20-), 5. 85 (br m, C11-CH= of 5ß,10ß-epoxide), and 6. 05 (br m, C11 CH= of 5a, 10a-epoxide).

Step 13. 3-Ethylenedioxy-5a-hydroxy-11ß-[4-(N,N-dimethylamino)phenyl ]-17a- methoxymethyl-19-norpregnj-9-en-20-one (90): Magnesium (604. 6 mg, 24. 88 mmol) was added to an oven-dried flask while hot. Under an atmosphere of nitrogen, a single crystal of iodine was added and the magnesium was agitated to evenly coat the magnesium. After cooling to room temperature,

one drop of dibromoethane was added, followed by the addition of THF (10 mL). While the mixture was rapidly stirred, a solution of 4-bromo-N, N-dimethylaniline (2. 1 g, 10. 5 mmol) in THF (10 mL) was added slowly. During the addition, the mixture was warmed to 50-60°C. Within 15 min, the iodine color quenched and the mixture maintained reflux without external heating. The reaction mixture was stirred for 1 l/2 hr and allowed to cool to room temperature. Copper (1) chloride (249. 5 mg, 2. 52 mmol) was added and the mixture was stirred for % 2 her. From the above mixture, 2. 0 mL (1. 0 mmol, 2 eq.) was removed via syringe and placed into a dry flask. A solution of the epoxide (89, 200 mg, 0. 5 mmol) was added to the Grignard reagent prepared above. After l/2 hr stirring, TLC analysis using a solvent system of 5% acetone/CH2Cl2 indicated the reaction was incomplete. Therefore, 2. 0 mL additional Grignard reagent was added. Within #hr, TLC indicated complete consumption of the starting material. The reaction mixture was diluted with saturated NIT-CL solution and the mixture was stirred for 1/2 hr while air was bubbled through the mixture. The aqueous mixture was extracted with CH2Ck. The CH2Cl2 extracts were washed with saturated NH4C1 solution, H20 and brine. The combined CH2C12 extracts were dried over Na2SO4. Evaporation of the solvent gave 350 mg of the crude product. Following chromatography, 126 mg of 90 was obtained as a stable yellow foam in 48% yield NMR (CDCl3) : 50. 28 (s, 3 H, C18-CH3), 2. 10 (s, 3 H, C21-CH3), 2. 87 (s, 6 H,-N (CH3) 2), 3. 27 (s, 3 H, C17α-CH2OCH3), 3. 90 (br m, 4H, C3-OCH2-CH2O-), 4. 25 (br m, 1 H, Cl la-CH), 6. 61 and 7. 05 (d, 4 H, J = 9 Hz, aromatic-CH's).

Step 14. Preparation of the target compound 91 : A solution of 90 (126 mg, 0. 24 mmol) in acetic acid/THF/H2O (3 : 1 : 1, 5. 0 mL) was heated at reflux for 11/2 or. The solvent was removed ira vacuo and the residue was diluted with saturated NaHC03 solution. The aqueous mixture was extracted with CH2C12.

The CH2C12 extracts were washed with H20 and brine, combined, and dried over Na2S04.

Evaporation of the solvent gave 111 mg of a stable foam. Flash chromatography eluted with 7% acetone/CH2Cl2 gave 75 mg of 91 in 68% yield as a stable foam. The material resisted crystallization from a variety of solvents and HPLC analysis on NovaPak Cig column, eluted with 30% aq. MeOH with 0. 033% TEA at a flow rate of 1. 0 ml per min at X = 302 nm showed this material to be only 95% pure. Therefore, this material was purified via preparative HPLC on Nova Pak Cl8 column (40 x 100 mm RCM) eluted with 30% aq.

MeOH with 0. 033% TEA at a flow rate of 1. 0 mL per min and at X = 330 nm to afford 47

mg of 91 as a stable off-white foam with a purity of 98. 8% ; m. p. = softens at 110°C and melts at 115-117°C. FTIR (KBr, diffuse reflectance) v,,/lx 2940, 2074, 1868, 1704, 1663, 1612, 1560 and 1518 cm~l. NMR (300 MHz, CDC13) : b 0. 356 (s, 3 H, C18-CH3), 2. 148 (s, 3 H, C21-CH3), 2. 905 (s, 6 H,-N (CH3) 2)., 3. 300 (s, 3 H, C17a-CH20CH3), 3. 339 and 3. 858 (d, 2 H, J= 8. 1 Hz, C17a-CH20CH3), 4. 335 (d, 1 H, J= 6. 3 Hz, Clla-CH), 5. 758 (s, 1 H, C4-CH=) and 6. 638 & 6. 992 (d, 4 H, J = 8. 4 Hz, aromatic-CH's). MS (EI) m/z (relative intensity) : 461 (M+, 36. 6), 134 (25. 4) and 121 (100). Anal. Calcd. for C3oH39NO3 : C, 78. 05 ; H, 8. 52 ; N, 3. 03. Found : C, 77. 29 ; H, 8. 40 ; N, 2. 97.

EXAMPLE 17 This example illustrates the preparation and properties of 17a-Acetoxy-11 [4- (N-pyrrolidino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (70) (Figure 4).

Step 1. 3, 2-bis-Ethylenedioxy-17α-hydroxy-19-norpregna-5(10),9(11)-di ene (50) : A mixture of 17a-hydroxy-19-norpregna-4, 9-diene-3, 20-dione (92, 10 g, 31. 8 mmol), ethylene glycol (11. 10 g, 178. 7 mmol), freshly distilled triethyl orthoformate (14g, 94. 1 mmol) and toluenesulfonic acid monohydrate (0. 3 g, 1. 58 mmol) in CH2C12 (150 mL) was stirred at room temperature under nitrogen overnight. Analysis by TLC (5% acetone in CH2C12) at that time indicated a complete reaction. Solid NaHC03 (-1 g) was added and the mixture was diluted with CH2C12 (-100 mL) and poured into H20. The mixture was extracted with CH2C12 (3x). The organic fractions were washed with H20 (3x), filtered through sodium sulfate, combined and concentrated i72 vacuo to give 12 g of the crude product 50 as a yellow foam. Crystallization of this crude material from CH2Cl2/MeOH containing a trace of pyridine gave 9. 8 g of the pure diketal 50 as a light yellow solid in 77% yield ; m. p. 169-171°C. FTIR (KBr, diffuse reflectance) #max 3484 and 2912 cm-1. NMR (300 MHz, CDC13) : 8 0. 792 (s, 3 H, C18-CH3), 1. 378 (s, 3 H, C21-CH3), 3. 816 and 4. 047 (m, 4 H, C20-ketal), 3. 983 (s, 4 H, C3-ketal) and 5. 555 (m, 1 H, C11- CH=). MS (EI) m/z (relative intensity) : 402 (M+, 100. 0), 366 (2. 5), 340 (20. 8) 270 (59. 9) and 99 (50. 1).

Step 2. 3, 20-bis-Ethylenedioxy-17α-hydroxy-5α,10α-epoxy-19-norpregn a-9(11)- este (51) : Hydrogen peroxide (30%, 3. 3 mL, 32. 31 mmol) was added to a solution of hexafluoroacetone trihydrate (3. 34 g, 16. 17 mmol) in CH2C12 (53 mL) cooled to 0°C. Solid Na2HP04 (1. 48 g, 10. 43 mmol) was added and the mixture stirred at 0°C for 1/2 or. A solution of the 3, 20-ketal (50, 6. 0 g, 14. 9 mmol) in CH2C12 (45 mL), precooled to 0°C, was added over a period of 10 min and the reaction mixture was stirred overnight at 5°C.

Analysis by TLC (5% acetone in CH2Clz) at that point indicated absence of the starting material. The reaction mixture was diluted with CH2C12 (-100 mL) and washed with 10% Na2SO3 solution (2x) and saturated NaHCO3 solution (2x). The organic fractions were filtered through Na2S04, combined and concentrated in vacuo to give 7 g of 51 of a white foam. Trituration of the epoxide mixture (a and p) with ether afforded 3. 05 g of the pure 5a, 10a-epoxide 51 as a white solid in 48. 9% yield ; m. p. = 172-173°C. FTIR (KBr, diffuse reflectance) v, 3439, 2950, 1705, 1642 and 1593 cm-'. NMR (300 MHz, CDC13) 8 0. 789 (s, 3 H, C18-CH3), 1. 365 (s, 3 H, C21-CH3), 3. 810-4. 094 (m, 8 H, C3-and C20-ketals) and 6. 013 (m, 1 H, C11-CH=). MS (EI) m/z (relative intensity) : 418 (M+, 0. 5), 400 (1. 4), 293 (0. 9), 131 (2. 5), 99 (4. 3) and 87 (100. 00).

Step 3, 3,20-bis- Ethylenedioxy-5α,17α-dihydroxy-11~-[4-(N-pyrrolinino)pheny l]- 19-norpregn-9-ene (53) : Magnesium (0. 98 g, 40. 31 mmol) was added to a 250 mL, 3-neck flask with a magnetic stirrer and a reflux condenser. A crystal of iodine was added, followed by dry THF (20 mL) and a few drops of 1, 2-dibromoethane. A solution of N- (4- bromophenyl) pyrrolidine (Yur'e v YK et al., Izvest Akad Nauk SS. S. R., Otdel Klzini Nauk, 166-171 (1951) : CA, 45 : 10236f (1951)) (8. 3 g., 36. 71 mmol) in dry THF was then added and the mixture was stirred under nitrogen and heated to reflux. After heating for 45 min, most of the magnesium had reacted. The reaction was cooled to room temperature and solid copper (I) chloride (0. 36 g, 3. 62 mmol) was added followed l/2 hr later by a solution of the 5a, 10a-epoxide (51, 3. 05 g, 7. 29 mmol) in dry THF (20 mL). The reaction mixture was stirred at room temperature for 1 hr, then cooled to 0°C in an ice bath and quenched by the addition of saturated NH4C1 (~15 mL). With vigorous stirring, air was drawn through the reaction mixture for 1/2 hr to oxidize Cu (I) to Cu (II). The mixture was diluted with H20 (-100 mL) and extracted with CH2C12 (3x). The organic fractions were washed with H20 (3x), combined, dried over Na2S04, filtered and concentrated in vacuo to give 8. 36 g of

residue. Trituration of this material with pentane followed by decanting the mother liquors removed the phenylpyrrolidine by-product. Trituration of 4 g of the residue with ether gave the Grignard adduct (53, 3. 66 g) as blue-grey solid in 88. 8% yield. A small amount of this material was purified by flash chromatography using 10% acetone in CH2C12 followed by crystallization from CH2Cl2/ether for purposes of characterization : m. p. = 251-254°C (dec.). FTIR (KBr, diffuse reflectance) v", 3580, 3537, 2948, 2871, 2822, 1614 and 1517 cm-l. NMR (CDC13) 5 0. 484 (s, 3 H, CI8-CH3), 1. 383 (s, 3 H, C21-CH3), 1. 977 (m, 4 H, pynolidine p-CH2), 3. 245 (m, 4 H, pyrrolidine a-CH2), 3. 765-4. 038 (m, 8 H, C3-ketal and C20-ketal), 4. 186 (d, 1 H, J = 6. 3 Hz, Clla-CH), 6. 461 (d, 2 H, J = 8. 4 Hz, 3', 5' aromatic-CH's) and 7. 047 (d, 2 H, J = 8. 7 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 565 (M+, 23. 2), 547 (20. 5), 160 (14. 2), 147 (61. 5) and 87 (100. 00). Anal. Calcd. for C34H47NO6 1/lOH20 : C, 71. 75 ; H, 8. 38 ; N, 2. 47. Found : C, 71. 98 ; H, 8. 47 ; N, 2. 52.

Step 4. 17α-Hydroxy-11ß-[4-(N-pyrrolidino)phenyl]-19-norpregna-4,9 -diene- 3, 20-dione (62) : A suspension of the Grignard adduct (53, 3. 45g, 6. 1 mmol) in EtOH (110 mL) was deoxygenated by bubbling nitrogen through it for ~i/2 hr. A similarly deoxygenated 8. 5% H2S04 solution (11 mL, 17. 53 mmol) was added and the resulting clear solution was heated to reflux under nitrogen. After 25 min., TLC (20% acetone/CH2Cl2 ; overspotted with concentrated NH40H) indicated a complete reaction. The reaction mixture was cooled to 0°C in an ice bath, diluted with H20 (-100 mL) and adjusted to a pH of-8. 0 using concentrated NH40H solution.

The resulting suspension was extracted with CH2C12 (3x). The organic fractions were washed with H20 (2x), filtered through Na2S04, combined and concentrated in vacuo to give 2. 53 g of crude product which was purified by flash chromatography (10% acetone/CH2Ck) followed by trituration with ether to give 2. 24 g of the pure 17a-hydroxy derivative (62) as an off-white solid in 80% yield ; m. p. = softens at 130°C. FTIR (KBr, diffuse reflectance) vmax 3457, 2946, 2892, 2834, 1706, 1662, 1616 and 1518 cm~l. NMR (CDC13) 8 0. 490 (s, 3H, C18-CH3), 1. 978 (m, 4 H, pyrrolidine (3-CH2's), 2. 254 (s, 3 H, C21- CH3), 3. 243 (m, 4H, pyrrolidine a-CH2's), 4. 361 (d, 1 H, J = 6. 9 Hz, Clla-CH), 5. 752 (s, 1 H, C4-CH=), 6. 465 (d, 2 H, J = 8. 4 Hz, 3', 5'aromatic-CH's), and 6. 93 (d, 2 H, J = 8. 4 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 459 (M+, 45. 5), 160 (10. 8), 147

(100. 0) and 91 (3. 5). Anal. Calcd. for C30H37NO3 2/5H20 : C, 77. 19 ; H, 8. 16 ; N, 3. 00.

Found : C, 77. 27 ; H, 8. 15 ; N, 3. 12.

Step 5 Preparation of tlze target coynpouszd 70 : Under nitrogen, trifluoroacetic anhydride (19. 37 g, 92. 22 mmol), glacial acetic acid (5. 67 g, 94. 42 mmol) and dry CH2C12 (10 mL) were combined and stirred at room temperature for 1 hr. Toluenesulfonic acid monohydrate (0. 9 g, 4. 73 mmol) in CH2Cl2 (30 mL) was added and the mixture cooled to 0°C in an ice bath. A solution of the 17a-hydroxy compound (62, 2. 12 g, 4. 61 mmol) in dry CHzClx (5 mL) was added and the reaction mixture was stirred at 0°C and monitored by TLC (20% acetone/CH2CI2, overspotted with concentrated NH40H) which indicated a complete reaction after 1 hr. The mixture was diluted with H2O (~10 mL), stirred at 0°C for another 15 min, then carefully adjusted to a pH of-8 using pH paper with dropwise addition of concentrated NH40H solution (-16 mL). The mixture was diluted with H20 (-200 mL) and extracted with CH2Cl2 (3x). The organic fractions were washed with H20 (3x), filtered through sodium sulfate, combined and concentrated ira vacuo to give 2. 3 g of crude product as a yellow foam. This material was purified by flash chromatography (5% acetone/CH2Cl2) followed by crystallization from 90% EtOH to give 1. 87 g of the pure 17a-acetate as a light yellow solid in 80. 7% yield ; m. p. = 149-154°C. Reverse phase HPLC on Waters NovaPak Cl8 column eluted with 0. 05 M ILH2PO4 buffer [pH = 3. 0]/CH3CN, (40 : 60) at a flow rate of 1 mL/min and at X = 302 nm indicated this material to be > 99% pure with a retention time (tR) of 8. 98 min. FTIR (KBr, diffuse reflectance) v,,,, 2946, 2880, 1734, 1715, 1665, 1614 and 1518 cm~l. NMR (CDC13) 6 0. 376 (s, 3 H, C18-CH 3), 1. 978 (m, 4H, pyrrolidine p- CHH2's), 2. 091 (s, 3 H, C17α-OAc), 2. 132 (s, 3 H, C21-CH3), 3. 241 (m, 4 H, pyrrolidine a- CH2's), 4. 386 (d, 1 H, J = 7. 2 Hz, Cl la-CH), 5. 771 (s, 1 H, C4-CH=), 6. 465 (d, 2 H, J = 8. 4 Hz, 3', 5'aromatic-CH's) and 7. 030 (d, 2 H, J = 8. 4 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 501 (1@, 33. 80), 426 (2. 3), 160 (10. 7) and 147 (100. 0). Anal.

Calcd. for C32H39NO4-3/4H20 : C, 74. 61 ; H, 7. 92 ; N, 2. 72. Found : C, 74. 58 ; H, 7. 69 ; N, 2. 87.

EXAMPLE 18 This example illustrates the preparation and properties of 17a-Acetoxy-11 (3- [4- (N-Piperidino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (71) (Figure 4).

Step 1. 3, 20-bis-Ethylenedioxy-5α,17α-dihydroxy-11ß-[4-(N-piperidin jo)_phenyl]- 19-norpregn-9-ene (54): Magnesium (1. 74 g, 71. 7 mmoll) was weighed into a 250 mL round bottom two-neck flask equipped with a reflux condenser, a magnetic stirring bar and a rubber septum. A small crystal of iodine was added and the system was flushed with dry nitrogen.

The system plus contents were flame dried under nitrogen. The system was cooled to room temperature and freshly distilled THF (60 mL) was added via syringe. A small amount (-0. 1 mL) of dry dibromoethane was added and the mixture stirred at room temperature. After evidence of reaction was observed (disappearnance of 12, color, bubble formation on the surface of magnesium), a solution of N- (4-bromophenyl) piperidine (Wolfe, J. P. and Buchwald, S. L., J ; Org. Chem., 62 : 6066-6068 (1997) ; and Veradro, G. et al., Synthesis, 447-450 (1991)) (17. 21 g, 71. 7 mmol) in dry THF (40 mL) was added via syringe. The mixture was then stirred in a hot water bath for 3. 5 hr, after which time the majority of the magnesium metal had reacted. The mixture was cooled to room temperature and copper (I) chloride (710 mg, 7. 17 mmol) was added as a solid, and the mixture was then stirred in a hot water bath for 3. 5 hr, after which time the majority of the magnesium metal had reacted. The mixture was cooled to room temperature and copper (I) chloride (710 mg, 7. 17 mmol) was added as a solid and the mixture stirred at room temperature for 1/2 hr. The 5a, 10a-epoxide (51, 6. 0 g, 14. 3 mmol) in dry THF (40 mL) was added via syringe and the mixture stirred at room temperature for 1/2 hr. At this time, a small aliquot of the reaction mixture was withdrawn, quenched with saturated NH4C1 solution, and extracted with a small amount of EtOAc. A TLC (10% acetone in CHzClz) of the organic layer indicated the absence of the starting material. Saturated NH4C1 solution (-100 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for l/2 hr while air was drawn through the reaction mixture (to oxidize copper) via a 6 inch needle inserted through the rubber septum by applying a partial vacuum to the top of the condenser. The contents of the flask was diluted with H20 (-250 mL) and extracted with CH2C12 (3x). The organic fractions were washed with saturated NH4Cl solution (lx), H20 (lx), brine (lx) and then dried over anhydrous Na2S04. The organic fraction was filtered and concentrated in vacuo to yield 26. 8 g of an oil. The material was placed on a flash column and eluted and using 10% acetone in CH2C12 yielding 5. 25 g of 54 as an off-white solid in 63. 87% yield ; m. p. = 211-214°C (sealed tube). FTIR (KBr, diffuse reflectance) v,, ndD 3508, 2933, 2790, 1609 1511, 1441, 1365 and 1234 cm~l. NMR (CDC13) 6

0. 45 (s, 3 H, C18-CH3), 1. 38 (s, 3 H, C21-CH3), 3. 05-3. 2 (m, 4 H,-N- (CH2) 2-), 3. 8-4. 05 (m, 8 H, 3-and 20-ketals), 4. 1 (d, 1 H, C11α-CH) and 6. 8-7. 1 (dd, 4 H, aromatic-CH's).

Anal. Calcd. for C35H4506N : C, 72. 51 ; H, 8. 52 ; N, 2. 41. Found : C, 71. 84 ; H, 8. 60 ; N, 2. 46. MS (EI) m/z (relative intensity) : 579 (M+).

Step 2. 17α-Hydroxy-11ß-[4-(N-Piperidino)phenyl]-19-nhorpregna-4,9 -diene-3,20- dione (63) : Nitrogen was bubbled through a mixture of EtOH (120 mL) and H2SO4 (8. 5%, 15 mL) for l/2 hr to remove oxygen. The Grignard adduct (54, 4. 0 g, 6. 89 mmol) was added as a solid with stirring. The mixture was put into an oil bath preheated to 95°C for % 2 her. The mixture was cooled in an ice bath and quenched with saturated K2C03 (pH = -10). The reaction mixture was diluted with H2O (250mL) and extracted with CH2C12 (3x).

The organic fractions were washed with saturated NaHCO3 (lx), H2O (1x), brine (1x), combined, dried over anhydrous Na2S04 and concentrated in vacuo to give 3. 35 g of a foam. This material was purified by flash column chromatography using 10% acetone in CH2C12 to yield 2. 95 g of a crude product (63) which was crystallized from CH2C12 and ether to yield 2. 45 g of an off-white crystalline product (63) in two crops in 61. 4% yield ; m. p. = 219-221°C. FTIR (KBr, diffuse reflectance) #max 3433, 2942, 1708, 1654, 1605, 1512 and 1234 crri 1. NMR (CDC13) 6 0. 45 (s, 3 H, C18-Me), 2. 25 (s, 3 H, C21-Me), 3. 05- 3. 2 (m, 4 H,-N- (CH2) 2-), 4. 35 (d, 1 H, C11α-CH), 5. 75 (s, 1 H, C4-CH=), 6. 8-7. 0 (dd, 4 H, aromatic-CH). MS (EI) m/z (relative intensity) : 161 (100), 174 (11. 43) and 473 (75. 71, M+). Anal. Calcd. for C3lH3903N : C, 78. 61 ; H, 8. 30 ; N, 2. 96. Found : C, 77. 59 ; H, 8. 29 ; N, 3. 03.

Step 3. Preparation of the target compound 71: The diketon (63, 1. 7 g, 3. 59 mmol) was dissolved in CH2CI2 (50 mL) and cooled to 0°C in an ice bath. In a separate round bottom flask, trifluoroacetic anhydride (15. 11g, 71. 78 mmol) and acetic acid (4. 75 g, 71. 78 mmol) were added to CH2C12 (100 mL), flushed with dry nitrogen and stirred at room temperature for l/2 hr. This mixed anhydride was then placed in an ice bath and cooled to 0°C. The cold mixed anhydride solution was then added to the steroid solution and treated withp-toluenesulfonic acid (628 mg, 3. 3 mmol). The reaction mixture was stirred for 2 hr at 0°C. The reaction was quenched with saturated K2C03 (pH =-10), diluted with H20 and extracted with CH2C12 (3x). The organic layers were washed with H20 (2x) and brine (lx), dried over Na2sSO4,

filtered and concentrated to yield 3. 38 g of crude material. A flash column using 10% acetone in CHzClz yielded 1. 66 g of 71 as an off-white solid in 54. 1% yield. The crude product 71 was recrystallized from CHUCK and Et20. The material retained CH2C12 and was dried in a heating pistol in vacuo over refluxing benzene for 5 days to afford 895 mg of 71 as an off-white solid in 48. 4% yield ; m. p. =175-183°C (sealed tube). FTIR (KBr, diffuse reflectance) vmblx 2936, 1733, 1717, 1654, 1609, 1512, 1450, 1372, 1259 and 1235 cm~i (300 MHz, CDCl3) 8 0. 340 (s, 3 H, C18-Me), 2. 091 (s, 3 H, C17-OAc), 2. 131 (s, 3 H, C21-CH3), 3. 120 (m, 4H,-N- (CH2) 2-), 4. 370 (m, 1 H, Clla-CH), 5. 778 (s, 1H, C4- CH=) and 6. 810-7. 000 (m, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 161 (100), 174 (11. 11) and 515 (M+, 59. 72).

Reverse-phase HPLC analysis on Waters NovaPak Cl8 column eluted with MeOH : H20 in the ratio of 70 : 30 with 0. 05% TEA at a flow rate of 1 mL/min and at 260 nm indicated it to be 99. 5% pure. Anal. Calcd. for C3lH4lO4N l/2EtOE : C, 76. 86 ; H, 8. 01 ; N, 2. 72. Found : C, 76. 64 ; H, 8. 06 ; N, 2. 69.

EXAMPLE 19 This example illustrates the preparation and properties of 17α-Acetoxy-11ß- [4- (N-Morpholino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (72) (Figure 4) : Step 1. 3,20-bis-Ethylenedioxy-5α,17α-dihydroxy-11ß-[4-(N-morphol ino)phenyl]- 19-norpregn-9-ene (55) : Magnesium (0. 90 g, 37. 02 mmol) was added to a 250 mL 3-neck flask equipped with a magnetic stirrer and a reflux condenser. A crystal of iodine was added followed by dry THF (20 mL) and a few drops of 1, 2-dibromoethatne. A solution of N- (4- bromophenyl) morpholine (Jones, D. H., J Chem. Soc. (C), 132-137 (1971)) (7. 8 g, 32. 21 mmol) in dry THF (30 mL) was then added and the mixture was stirred under nitrogen and heated to reflux. After 45 min of stirring, most of the magensium had reacted.

The reaction was cooled to room temperature, and solid copper (I) chloride (0. 32 g, 32. 3 mmol) was added followed 1/2 hr later by a solution of the 5a, 1 Oa-epoxide (51, 2. 7 g, 6. 45 mmol) in dry THF (20 mL). The reaction mixture was stirred at room temperature for 1 hr, then cooled to 0°C in an ice bath and quenched by the addition of saturated NH4Cl solution (~10 mL). With vigorous stirring, air was drawn through the reaction mixture for 112, hr to oxidize Cu (I) to Cu (II). The mixture was extracted with CH2C12 (3x) and the

organic fractions washed with H20 (3x). The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give 8 g of residue. Trituration of this material with ether gave the pure adduct (55, 2. 1 g) as an off-white solid. The mother liquors were concentrated in vacuo and the residue purified by flash chromatography (20% acetone/CH2Cl2) to give an additional 0. 6 g of the product (55). Total yield of 55 was 2. 7 g in 72% yield ; m. p. = 243-245°C. FTIR (KBr, diffuse reflectance) V7CC 3578, 3539, 2978, 2949, 2887, 2868, 2821, 1610 and 1511 cm~l. NMR (CDC13) 8 0. 450 (s, 3 H, C18-CH3), 1. 377 (s, 3 H, C21-CH3), 3. 110 (m, 4 H, morpholine-O-CH2CH2N)-), 3. 789-4. 039 (m, 10 H, C3-ketal, C20-ketal and morpholine-O-CH2CH2N), 4. 202 (d, 1 H, J = 6. 9 Hz, C11α- CH), 6. 791 (d, 2 H, J = 8. 7, 3', 5'aromatic-CH's) and 7. 107 (d, 2 H, J = 2', 6'aromatic- CH's). MS (EI) m/z (relative intensity) : 581 (M+, 11. 0), 563 (8. 6), 366 (2. 5), 163 (18. 5) and 87 (100. 0). Anal. Calcd. for C34H47NO7# 2/3H2O : C, 68. 79 ; H, 8. 20 ; N, 2. 36. Found : C, 68. 84 ; H, 8. 01 ; N, 2. 36.

Step 2. 17α-Hydroxy-11ß-[4-(N-morpholinophenyl]-19-norprena-4,9-di ene-3,20- dione (64) : A suspension of the Grignard adduct (55, 2. 56 g, 4. 4 mmol) in EtOH (80 mL) was deoxygenated by bubbling nitrogen through it for-V2hr. A similarly deoxygenated 8. 5% H2SO4 solution (8 mL, 12. 75 mmol) was added, and the resulting clear solution was heated to reflux under nitrogen. After 25 min, TLC (20% acetone/CH2C12, overspotted with concentrated NH40H) indicated a complete reaction. The reaction mixture was cooled to 0°C in an ice bath, diluted with H20 (-100 mL) and adjusted to a pH of-8. 0 using concentrated NH40H solution. The resulting suspension was extracted with CH2Cl2 (3x). The organic fractions were washed with H2O (2x), filtered through Na2SO4, combined and concentrated in vacuo to give 2. 2 g of a yellow foam. Trituration of this material with ether gave the pure 17a-hydroxy compound (64, 1. 8 g) as a white solid in 86% yield ; m. p. = 218-220°C. FTIR (KBr, diffuse reflectance) #m 3426, 2950, 2852, 1710, 1652, 1580 and 1511 NMR (CDC13) 8 0. 450 (s, 3 H, C18-CH3), 2. 255 (s, 3 H, C21- CH3), 3. 115 (m, 4 H, morpholine-OCH2CH2N-), 3. 843 (m, 4 H, morpholine-OCH2CH2N), 4. 373 (d, 1 H, J = 7. 2 Hz, C 11 a-GH), 5. 763 (s, 3 H, C4-CH=), 6. 804 (d, 2 H, J = 8. 7 Hz, 3', 5'aromatic-CH's) and 7. 028 (d, 2 H, J = 8. 7 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 475 (M+, 58. 5), 374 (4. 9), 322 (5. 4), 176 (14. 2) and 163 (100. 0). Anal.

Calcd. for C30H37NO4 1/lOH20 : C, 75. 47 ; H, 7. 85 ; N, 2. 93. Found : C, 75. 46 ; H, 7. 90 ; N, 3. 04.

Step 3. Preparation of tlae target cotsMpouid 72 : Under nitrogen, trifluoroacetic anhydride (14. 9 g, 70. 94 mmol), glacial acetic acid (4. 31 g, 71. 7 mmol) and dry CH2C12 (25 mL) were combined and stirred at room temperature for 1 hr. Toluenesulfonic acid monohydrate (0. 7 g, 3. 68 mmol) was added and the mixture cooled to 0°C in an ice bath. A solution of the 17a-hydroxy compound (64, 1. 66 g, 3. 49 mmol) in dry CH2C12 (5 mL) was added and the reaction mixture was stirred at 0°C and monitored by TLC (20% acetone/CH2C12, overspotted with NH40H) which indicated a complete reaction after 1 hr. The mixture wad diluted with H20 (-10 mL), stirred at 0°C for another 15 min, then carefully adjusted to a pH of #8 (with pH paper) with dropwise addition of concentrated NH40H solution (-16 mL). The mixture was diluted with H20 (-200 mL) and extracted with CH2C12 (3x). The organic fractions were washed with water (3x), filtered through Na2S04, combined and concentrated in vacuo to give 1. 8 g of the residue as a yellow foam. This material was purified via flash chromatography (10% acetone/CH2Cl2), followed by trituration with ether to afford 1. 2 g of the pure 17a-acetate (72) as an off-white solid in 67. 5% yield. Analysis by NMR indicated this material retained a large amount of ether which could be removed by drying in vacuo at 153°C ; m. p. = 194-196°C. FTIR (KBr, diffuse reflectance) v 2950, 2885, 1738, 1710, 1663, 1608 and 1513 ami 1. NMR (CDC13) 6 0. 342 (s, 3 H, C18-CH 3), 2. 096 (s, 3 H, C21- CH3), 2. 132 (s, 3 H, C17α-OAc), 3. 116 (m, 4 H, morpholine-OCH2CH2N), 3. 847 (m, 4 H, morpholine-OCH2CH 2N), 4. 398 (d, 1 H, J = 6. 9 Hz, C11α-CH), 5. 785 (s, 1 H, C4-CH=), 6. 810 (d, 2 H, J = 8. 7 Hz, 3', 5'aromatic-CH's) and 7. 030 (d, 2 H, J = 8. 7 Hz, 2', 6' aromatic-CH's). MS (EI) m/z (relative intensity) : 517 (M+, 51. 2), 442 (5. 1), 414 (6. 6), 176 (16. 0) and 163 (100. 0). Anal. Calcd. for C32H39NOs l/2H2O : C, 74. 04 ; H, 7. 60 ; N, 2. 70.

Found : C, 74. 04 ; H, 7. 60 ; N, 2. 84.

Analysis by HPLC on a Waters NovaPak, Cis eluted with 0. 05 M KH2PO4 buffer, pH = 3. 0/CH3CN (55 : 45) at a flow rate of 1 mL/min and and at X = 302 nm indicated this material to be >99% pure with a retention time (tR) of 8. 7 min.

EXAMPLE 20 This example illustrates the preparation and properties of 17a-Acetoxy-11 (3- (4-acetylphenyl)-19-norpregna-4, 9-diene-3, 20-dione (73) (Figure 4).

Step 1 3, 20-bis-Etlaylenedioxy-Sa, l7a-dihydroxy-llf-4- (2-metlzyl-1, 3-dioxolan- 2-yl)phenyl]-19-morpregn-9-ene (56) : Magnesium turnings (435 mg, 17. 9 mmol) were weighed into a 100 mL round bottom two-neck flask equipped with a reflux condenser, a magnetic stirrer and a rubber septum. A small crystal of iodine was added and the system was flushed with dry nitrogen and flame dried. After the system had cooled to room temperature, freshly distilled THF (20 mL) was introduced via syringe followed by a small amount of dry dibromoethane (-0. 1 mL). After evidence of reaction was observed (disappearance of I2 color, bubble formation on metal), a solution of the ketal of 4-bromoacetophenone (see, Detty, M. R., et al., J Am. Chen-a. Soc., 105 : 875-882 (1983) ; and Rao, P. N., et al,, Steroids, 63 : 523-530 (1998)) (4. 35 g, 17. 9 mmol) in dry THF (10 mL) was added via syringe. The mixture was then stirred in a hot water bath for 2 hr. (After 35 min, an additional 10 mL of THF was added as a white precipitate formed and the reaction mixture thickened). The reaction was cooled to room temperature and copper (I) chloride (177 mg, 1. 79 mmol) was added and the mixutre stirred at room temperature for #hr (the precipitate went back into solution with the addition of the copper chloride). The 5α, 10a-epoxide (51, 1. 5 g, 3. 58 mmol) in dry THF (10 mL) was added via syringe and the reaction mixture stirred at room temperature for 45 min. At this time, TLC (10% acetone in CH2C12) showed no starting material. Saturated NH4C1 solution (-20 mL) was added and the mixture stirred at room temperature for 1/2 hr while air was drawn through the reaction mixture to oxidize the copper. The contents of the flask were diluted with H20 (-100 mL) and extracted with CH2C12 (3x). The organic fractions were washed with saturated NH4C1 solution (1x), H20 (lx), and brine (lx), and then dried over anhydrous Na2S04, filtered and concentrated in vacuo to yield an oil. The oil was purified on a flash column (10% acetone in CH2C12) yielding 1. 3 g of a stable white foam. The material was crystallized from ether to yield 880 mg of 56 as a white crystalline solid in 42. 3% yield ; m. p. = 185-188°C. FTIR (KBr, diffuse reflectance) vax 3501, 2940, 1609, 1443, 1371, 1181 and 1042 cm~l. NMR (CDC13) 6 0. 45 (s, 3 H, C18-CH3)m, 1. 4 (s, 3 H, CH3 from ethylene ketal of acetophenone at C11ß-), 1. 6 (s, 3 H, C21-CH3), 3. 6-4. 2 (br m, 12 H, C3-and C20-ketals and ketal of acetophenone

at Clip-), 4. 3 (br d, 1 H, C11α-CH), and 7. 05-7. 47 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 582 (M+). Anal. Calcd. for C34H460g : C, 70. 08 ; H, 7. 96. Found : C, 70. 00 ; H, 8. 05.

Step 2. 1 7a-Hydroxy-llß-(4-Acetylphenyl)-l 9-szorpregna-4, 9-diesle-3, 20-dione (65) : Nitrogen was bubbled through a mixture ofEtOH (25 mL) and 8. 5% H2S04 (2 : 5 mL) for l/2 hr to remove oxygen. The Grignard adduct (57, 750 mg, 1. 28 mmol) was added as a solid with stirring. The mixture was put into an oil bath preheated to 95°C for 1 hr. The mixture was cooled in an ice bath and quenched with saturated K2CO3 to bring the pH to #10, The mixture was diluted with H20 (125 mL) and extracted with CH2Cl2 (3x). The organic fractions were washed with saturated NaHCO3 (lx), H20 (lx), brine (lx), combined and dried over anhydrous Na2SO4. This material was concentrated in vacuo to give 600 mg of 65 as an oil. The material was purified on a flash column (10% acetone in CH2C12) to yield 560 mg of 65. This material was crystallized from CH2C12 and ether to give 475 mg of 65 as a white solid in 85. 9% yield ; m. p. = foams/honeycombs at 112- 115°C. FTIR (KBr, diffuse reflectance) #max 3390, 2976, 1709, 1679, 1655, 1601, 1360 and 1275 cm''. NMR (CDCl3) 8 0. 4 (s, 3 H, C18-CH3), 2. 25 (s, 3 H, C21-CH3), 2. 6 (s, 3 H, I ß- 4-phenylacetyl CH3), 3. 25 (s, 1H, C17α-OH), 4. 5 (br d, 1 H, Clla-CH), 5. 8 (s, 1 H, C4- CH=) and 7. 2-8. 0 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 432 (M+, 88. 7), 414 (11, 3), 389 (25. 4), 371 (21. 1), 346 (100. 0), 331 (46. 5), 319 (22. 5), 280 (15. 5), 235 (16. 9), 200 (14. 1), 147 (18. 3), 133 (18. 3), 115 (12. 7), 105 (15. 5) and 91 (21. 1) Step 3. Preparatiofa of the target cofapound 73 : The triketone (65, 375 mg, 0. 87 mmol) was dissolved in CH2C12 (10 mL) and cooled to 0°C in an ice bath. In a separate round bottom flask, trifluoroacetic anhydride (3. 65 g, 17. 3 mmol) and acetic acid (1. 14 g, 17. 3 mmol) were added to CH2C12 (10 mL), flushed with dry nitrogen and stirred at room temperature for #hr. The mixed anhydride was then placed in an ice bath and cooled to 0°C. The cold mixed anhydride solution was then added to the triketone (65) solution and treated withp-toluenesulfonic acid (152 mg, 0. 79 mmol). The reaction mixture was stirred for 45 min at 0°C. The reaction was quenched with saturated K2CO3 (pH = 10), diluted with H20 and extracted with CH2Cl2 (3x). The organic layers were combined, washed with H20 (2x), brine (lx), dried over sodium sulfate, filtered and concentrated to yield 425 mg of crude 73. The crude product

73 was purified on a flash column (10% acetone in CH2C12) to yield 340 mg of compound 73. Crystallization from CH2C12 and ether afforded 305 mg of 73 as a white solid in 73. 96% yield ; m. p. = 243-246°C.

Analysis by reverse phase HPLC on a Waters Nova Pak Cls column eluted with MeOH : H20 in the ratio of 70 : 30 at a flow rate of 1 mL/min and at X = 260 nm indicated it to be 99. 6% pure. FTIR (KBr, diffuse reflectance) vnz 2791, 1729, 1712, 1681, 1595, 1362, and 1257 cm-1, NMR (CDC13) 6 0. 3 (s, 3 H, CIS-Me), 2. 10 (s, 3 H, C17α- OAc), 2. 15 (s, 3 H, C21-CH3), 2. 55 (s, 3 H, 11ß-4-phenylacetyl CH3), 4. 5 (br d, 1 H, Clla- CH), 5. 8 (s, 1 H, C4-CH=) and 7. 2-8. 0 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 474 (M+, 2. 8), 414 (36. 6), 399 (14. 0), 389 (8. 5) and 371 (100). Anal. Calcd. for C3oH3405Et20 : C, 74. 85 ; H, 7. 44. Found : C, 74. 94 ; H, 7. 19.

EXAMPLE 21 This example illustrates the preparation and properties of 17a-Acetoxy-l ß- (4-methylthiophenyl)-19-norpregna-4, 9-diene-3, 20-dione (74) (Figure 4).

Step 1. 3, 20-bis-(Etltylenedioxy)-5a, 1 7a-diAtydroxy-11ß-(4-methylthiopAI enyl)-19- norpregii-9-ene (57) : Magnesium (290 mg, 11. 9 mmol) was weighed into a 100 mL round bottom two-necked flask equipped with a reflux condenser, a magnetic stirrer and a rubber septum A small crystal of iodine was added and the system was flushed with dry nitrogen. The system plus contents were flame dried under nitrogen. The system was cooled to room temperature and freshly distilled THF (20 mL) was added via syringe. A small amount (-0. 1 mL) of dry dibromoethane was added and the mixture stirred at room temperature.

After evidence of reaction was observed (disappearance of I2 color, bubble formation on the surface of magnesium), a solution of 4-bromothioanisole (available from Aldrich Chemical Co. (Milwaukee, Wisconsin)) (2. 43 g, 11. 9 mmol) in dry THF (10 mL) was added via syringe. The mixture was then stirred in a hot water bath for 1. 5 hr, after which time the majority of the magnesium metal had reacted. The mixture was cooled to room temperature and copper (I) chloride (118 mg, 1. 19 mmol) was added as a solid and the mixture stirred at room temperature for #hr. The 5α. 10a-epoxide (51, 1. 0 g, 2. 38 mmol) in dry THF (10 mL) was added via syringe and the mixture stirred at room temperature for 1 hr. At this time, a small aliquot of the reaction mixture was withdrawn, quenched with

saturated NH4C1 solution, and extracted with a small amount of EtOAc. A TLC (10% acetone in CH2Cl2) of the organic layer indicated absence of starting material. Saturated NHLtCl solution (20 mL) was added to the reaction mixture and the mixture was stirred at room temperature for l/2 hr while air was drawn through the reaction mixture (to oxidize copper) via a 6-inch needle inserted through the rubber septum by applying a partial vacuum to the top of the condenser. The contents of the flask were diluted with H2O (-100 mL) and extracted with CH2C12 (3x). The organic fractions were washed with saturated NH4Cl solution (lx), H20 (lx), brine (lx), then dried over anhydrous sodium sulfate. The organic fractions was filtered and concentrated in vacuo to yield 5. 75 g of 57 as an oil. This oil was placed on a flash column and eluted with 10% acetone in CH2C12 yielding 850 mg of 57 as a white stable foam. The foam was crystallized from ether to yield 675 mg of 57 as a white solid ; m. p. = 158-159°C. FTIR (KBr, diffuse reflectance) vmbD-3571, 3539, 2944, 1490, 1447, 1190 and 1076 cm~l. NMR (CDC13) # 0. 45 (s, 3 H, C18-CH3), 1. 36 (s, 3 H, C21-CH3), 2. 45 (s, 3 H, C1 10-4-CH3S-phenyl), 3. 8-4. 1 (br m, 8 H, C3-and C20-ketals), 4. 25 (br d, I H, Cl la-CH) and 7. 17 (s, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 542 (M+). Anal. Calcd. for C31H42O6S : C, 68. 60 ; H, 7. 80 ; S, 5. 91. Found : C, 68. 52 ; H, 7. 76 ; S, 5. 84.

Step 2. 17α-Hydroxy-11ß-(4-methylthiophenyl)-19-norpregna-4,9-dien e-3,20- diozle (66) : Nitrogen was bubbled through a mixture of EtOH (20 mL) and 8. 5% H2S04 (2. 0 mL) for # hr to remove oxygen. The Grignard adduct (57, 500 mg, 0. 92 mmol) was added as a solid with stirring. The mixture was put into an oil bath preheated to 95°C for /2 hr. The mixture was cooled in an ice bath and quenched with saturated K2CO3 (pH = 10). The reaction mixture was diluted with H2O (125 mL) and extracted with CH2C12 (3x).

The organic fractions were washed with saturated NaHCO3 (lx), H20 (lx), brine (lx), combined and then dried over anhydrous Na2SO4. It was concentrated in vacuo to give 500 mg of 66 as an oil. This oil was purified by flash chromatography (10% acetone in CH2C12) to yield 350 mg of the crude 66. Crystallized from CH2C12 and ether gave 330 mg of 66 as a white crystalline product ; m. p. = foams/honeycombs at 102-106°C. FTIR (KBr, diffuse reflectance) #m 3409, 2975, 2887, 1707, 1650, 1608, 1493 and 1207 cm-1. NMR (CDCl3) 6 0. 45 (s, 3 H, C18-CH3), 2. 25 (s, 3 H, C21-CH3), 2. 5 (s, 3 H, llp-4-CH3S-phenyl), 3. 1 (s, 1 H, C 7a-OH), 4. 4 (br d, 1 H, C11α-CH), 5. 8 (s, 1 H, C4-CH=) and 6. 95-7. 3 (dd, 4 H,

aromatic-CH's). MS (EI) m/z (relative intensity) : 436 (M+, 100), 418 (14. 1), 350 (76. 1), 335 (35. 2), 323 (16. 9), 296 (14. 1), 281 (16. 9), 249 (16. 9), 235 (39. 4), 211 (18. 3), 137 (87. 3) and 91 (19. 7). Anal. Calcd for C27H3203S : C, 74. 28 ; H, 7. 39. Found : C, 73. 01 ; H, 8. 27.

Step 3. Preparation of tite target compound 74 : The 17a-hydroxy compound (66, 275 mg, 0. 63 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0°C in an ice bath. In a separate round flask, trifluoroacetic anhydride (2. 65 g, 12. 6 mmol) and acetic acid (0. 83 g, 12. 6 mmol) were added to CH2Cl2 (10 mL), and the mixture was flushed with nitrogen and stirred at room temperature for % 2 her. The mixed anhydride was then placed in an ice bath and cooled to 0°C. The cold mixed anhydride solution was then added to the 17a-hydroxy compound (66) and treated withp-toluenesulfonic acid (110 mg, 0. 58 mmol). The reaction mixture was stirred for 1 hr at 0°C. The reaction was quenched with saturated Ik2CO3 (pH = 10), diluted with H20 and extracted with CH2 Cl2 (3x). The organic layers were washed with water (2x), brine (lx), dried over anhydrous Na2S04. filtered and concentrated to yield 320 mg of 74 as a crude product. The 17a-acetate (74) was purified on a flash column (10% acetone in CH2C12) to yield 250 mg of 74. Crystallization from CH2C12 and ether gave 210 mg of the pure 74 as a white solid in 70. 5% yield ; m. p. = 234-236°C. HPLC analysis on a Waters Nova Pak a Cis column eluted with MeOH : H20 in the ratio of 70 : 30 at a flow rate of 1 mL/min and at X = 260 nm indicated it to be 99. 7% pure. FTIR (KBr, diffuse reflectance) v7n »-943, 1729, 1713, 1660, 1594, 1491, 1438, 1363 and 1258 cm-1. NMR (CDCl3)# 0. 38 (s, 3 H, C18- CH3), 2. 10 (s, 3 H, C17α-OAc), 2. 15 (s, 3 H, C21-CH3), 2. 45 (s, 3 H, llp-4-CH3S-phenyl), 4. 45 (d, 1 H, C11α-CH), 5. 8 (s, 1 H, C4-CH=) and 7. 0-7. 35 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 478 (M+. 28. 2), 418 (28. 2), 403 (28. 2), 375 (100), 347 (11. 3), 294 (15. 5), 281 (8. 5), 265 (18. 3), 251 (42. 3), 236 (15. 5), 151 (18. 3), 137 (60. 6) and 91 (9. 9).

Anal. Calcd. for C29H3404S : C, 72. 77 ; H, 7. 16 ; S, 6. 70. Found : C, 72. 07 ; H, 7. 07 ; S, 6. 81.

EXAMPLE 22 This example illustrates the preparation and properties of 17a-Methoxy-11 (3- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (97a) (Figure 6) :

Step 1. 17a-Hydroxy-l9-no1preg7la-4, 9-diene-3, 20-dione (92) : Under nitrogen, the diketal (50, 20. 0 g, 49. 7 mmol) was dissolved in a mixture of THF (333 mL) and Hz0 (333 mL) followed by trifluoroacetic acid (1 L, 13. 46 mmol). The reaction mixture was then stirred at room temperature for 2 hr, after which time, TLC (10% acetone in CH2C12, overspotted with concentrated NH4OH indicated a complete reaction. The reaction mixture was cooled in an ice bath and neutralized by the dropwise addition of concentrated (29. 5%) NH40H (862 mL,-13. 46 mol) over a period of about an hour. The reaction mixture was diluted with H20 (-500 m L) and extracted with methylene chloride (3x). The organic fractions were washed with saturated NaHCO3 (lx) and H20 (lx), brine (lx), then filtered through anhydrous sodium sulfate, combined and concentrated in vacuo. Crystallization of the residue from acetone/hexanes gave 12 g of the pure product 92 as a white crystalline solid in 76. 8% yield ; m. p. = 203-205°C. FTIR (KBr, diffusion reflectance) Vynax 3438, 2950, 1702, 1642 and 1593 cm~l. 1H NMR (300 MHz, CDC13) 8 0. 857 (s, 3 H, C18-CH3), 2. 289 (s, 3 H, C21-CH3) and 5. 669 (s, 1 H, C4-CH=).

13C NMR (CDC13) : 8 14. 703, 23. 901, 25. 341, 25. 714, 27. 515, 27. 615, 30. 260, 30. 765, 33. 470, 36. 971, 39. 086, 47. 846, 50. 696. 89. 565 (C17), 122. 015 (C4), 125. 440 (C10).

145. 632 (C9). 157. 339 (C5), 199. 824 (C3) and 211. 201 (C20). MS (EI) m/z (relative intensity) : 314 (M+, 100), 296 (13. 6), 271 (58. 0), 213 (67. 0) and 91 (35. 9). Anal. Calcd. for C20H2603 : C, 76. 40 ; H, 8. 34. Found : C, 76. 23 ; H, 8. 29.

Step 2. 7a-Methoxy-19-iioipregiia-4, 9-dieiie-3, 20-dione (93) : A suspension of the 17a-hydroxy dienedione (92, 19 g, 31. 80 mmol) in CH3CN (167 mL) was stirred magnetically under nitrogen. Methyl iodide (134 mL ; freshly opened) was added and a solution formed immediately. Silver oxide (8. 1 g, 35. 0 mmol) was added, the joints were well-greased to prevent evaporation of methyl iodide, and the flask was wrapped in foil to protect the contents from light. The mixture was brought to a gentle reflux and the reaction allowed to proceed overnight. The next morning, analysis by TLC (5% acetone in CH2C12) indicated virtually all the starting material had been converted to a single, less polar component. The reaction was allowed to cool to room temperature and filtered through a Celite filter cake on a sintered glass funnel. The filtrate was evaporated iN vacuo to recover a thick syrup. Crystallization from boiling CH30H afforded small white crystals. The crystals were collected on a Buchner funnel, triturated with cold CH30H, and dried under vacuum to recover 5. 74 g. Flash chromatography of the mother

liquors (5% acetone in CH2Clz) afforded 1. 69 g of additional material. The total purified product recovered was 7. 43 g of 93 as white crystals in 71. 1% yield ; m. p. =154-155°C.

FTIR (KBr, diffuse reflectance) #max 2952, 1704, 1660, 1614 and 1583 cxri 1. 1H NMR (300 MHz, CDC13) 8 0. 739 (s, 3 H, C18-CH3), 2. 164 (s, 3 H, C21-CH3), 3. 141 (s, 3 H, C17a-OCH3) and 5. 672 (s, 1 H, C4-CH=). 13C NMR (CDC13) : 8 14. 264, 23. 156, 23. 431.

23. 775. 25. 547. 25. 753. 26. 431. 27. 445. 30. 755, 30. 793. 37. 054, 39. 220, 47. 243, 51. 348.

52. 258. 96. 714 (C17), 122. 057 (C4), 125. 228 (C10), 145. 588 (C9), 157. 192 (C5), 199. 637 (C3) and 210. 479 (C20). MS (EI) m/z (relative intensity) : 328 (M+, 5. 8), 285 (66), 253 (64) and 213 (100). Anal. Calcd. for C2IH2803 : C, 76. 79 ; H, 8. 59. Found : C, 76. 64 ; H, 8. 59.

Step 3. 3, 3-Ethylenedioxy-17α-methoxy-19-norpregna-5(10),9(11)-dien-2 0-one (94) : Under nitrogen, a mixture of the 17a-methoxydione (93, 17. 0 g, 51. 76 mmol), triethylorthoformate (42. 5 mL, 250 mmol), ethylene glycol (14 mL, 250 mmol) andp-toluenesulfonic acid monohydrate (0. 5 g, 2. 6 mmol) in dry CH2C12 (500 mL) was stirred at room temperature for 2 hr. After that time, TLC (2% acetone in CH2Cl2) indicated absence of starting material with formation of one major product. The reaction mixture was diluted with CH2C12 (-200 mL) and washed with saturated NaHCIO3 solution (1x). H20 (lx) and brine. The organic fractions were filtered through anhydrous sodium sulfate, combined and concentrated in. vacuo. Recrystallization of the residue from hot methanol containing a trace of pyridine gave 16. 2 g of the pure 3-ketal 94 as a white solid in 84. 1% yield ; m. p. = 123-125°C. FTIR (KBr, diffuse reflectance) v, n, x 2927 and 1705 cm~l. lH NMR (300 MHz, CDC13) 8 0. 553 (s, 3 H, C18-CH3), 2. 147 (s, 3 H, C21- CH3), 3. 147 (s, 3 H, C17α-OCH3)m, 3. 983 (s, 4 H, C3-ketal) and 5. 568 (br s, 1 H, Cll-CHs 13C NMR (CDC13) : # 15. 746, 23. 123, 24. 026, 24. 570. 26. 422. 27. 972, 31. 150, 31. 298, 31. 839, 38. 233, 41. 238, 46. 079, 47. 391, 52. 318, 64. 325, 64. 448, 96. 792, 108. 131, 117. 907, 126. 081, 129. 914 and 135. 998 (signal/noise ratio obscured C20 at-210 ppm). Anal. Calcd. for C23H3204 : C, 74. 16 ; H, 8. 66. Found : C, 74. 16 ; H, 8. 68.

Step4. 3,3-Ethylenedioxy-5α,10α-epoxy-17α-methoxy-19-norpregn-9( 11)-en-20- one(95): Hydrogen peroxide (30% 3. 0 mL, 29. 3 mmol) was added to a vigorously stirred mixture of hexafluoroacetone trihydrate (4. 0 mL, 28. 7 mmol) in CH2C12 (70 mL)

cooled to 0°C in an ice bath. After stirring at 0°C for l/2 hr, solid Na2HPO4 (2. 1 g, 14. 8 mmol) was added followed by a solution of the 3-ketal (94, 7. 0 g, 18. 8 mmol) in CH2C12 (70 mL), precooled to 0°C. The mixture was then stirred at 5°C overnight. The reaction mixture was diluted with CH2C12 (-200 mL) and washed with 10% Na2S03 solution (lx) and H20 (2x). The organic fractions were filtered through anhydrous Na2S04, combined and concentrated in vacuo to give 7. 29 g of 95 as a white foam in quantitative yield. Attempts to crystallize out the 5a, 10a-epoxide by trituration with ether/pentane or mixtures of CH2C12 and pentane were unsuccessful. Analysis by NMR indicated a 4 : 1 mixture of the 5a, 10a- and the 5ß, 10 (3-epoxides. NMR (300 MHz, CDC13) : 8 0. 554 (s, 3 H, C18-CH3), 2. 139 (s, 3 H, C21-CH3), 3. 8-4. 0 (m, 4 H, C3-ketal CH2's), 5. 845 (m, 0. 2 H, Cl I-CH= of P-epoxide) and 6. 034 (m, 0. 8H, C11-CH= of a-epoxide).

Step 5. 3, 3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N,N-dimethylamino)pheny l]-17α- methoxy-189-norpregnj-9(10)-en-20-one (96a) : Magnesium (2. 49 g, 102. 45 mmol) was added to a 2. 0 L, 3-neck flask with a mechanical stirrer, addition funnel and a condenser. The system was flushed with nitrogen and flame dried. After cooling, dry THF (100 mL) and 1, 2-dibromoethane (0. 2 mL) were added. The mixture was stirred under nitrogen and heated in a warm water bath until evidence of the reaction was observed. A solution of 4-bromo-N, N-dimethylaniline (18. 81 g, 94 mmol) in dry THF (100 mL) was then added via the addition funnel and the mixture stirred and heated in a warm water bath until reaction initiated. Solid copper (I) chloride (1. 86 g, 18. 8 mmol) was added followed l/2 hr later by a solution of the 4 : 1 epoxide mixture (95, 7. 29 g, 18. 8 mmol = assumed 5. 47 g of the 5a, 10a-epoxide (14. 10 mmol)) in dry THF (125 rnL). The reaction mixture was stirred at room temperature for 1. 5 hr, then quenched by the addition of saturated NH4C1 solution (250 mL). In order to oxidize Cu (I) to Cu (II), air was drawn through the reaction mixture for l/2 hr with vigorous stirring. The mixture was then extracted with ether (3x). The organic fractions were washed with H20 (3x), combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give 14. 5 g of residue as a green-blue oil. This material was purified via Flash chromatography using CH2C12 followed by 4% acetone in CH2C12 to give 4. 4 g of the pure compound 96a as a grey foam in 62. 7% yield based on the 4 : 1 a : 0 ratio. FTIR (KBr, diffuse reflectance) v.....

3526, 2944, 1707, 1613, and 1518 cm~l. NMR (300 MHz, CDC13) 8 0. 223 (s, 3 H, C18- CH3), 2. 155 (s, 3 H, C21-CH3), 2. 894 (s, 6 H, N (CH3) 2), 3. 105 (s, 3 H, C17α-OCH3), 3. 896

-3. 995 (m, 4 H, C3-ketal CH2's), 4. 255 (m, 1 H, Cl la-CH), 6. 624 (d, 2 H, J = 9. 0 Hz, 3', 5' aromatic-CH's), and 7. 03 (d, 2 H, J = 9. 0 Hz, 2', 6'aromatic-CH's). Anal. Calcd. for C3iH43N05-l/5H20 : C, 72. 54 ; H, 8. 52 ; N, 2. 73. Found : C, 72. 36 ; H, 8. 52 ; N, 2. 52.

Step 6 Preparation of tlle target co7npou71d 97a : Under nitrogen, a solution of the Grignard adduct (96a, 3. 73 g, 7. 32 mmol) in THF (40 mL) was treated with H20 (40 mL) and glacial AcOH (120 mL). After stirring overnight at room temperature, TLC (5% acetone in CH2C12) indicated incomplete hydrolysis. The mixture was heated to-50°C in a warm water bath for 1 hr, after which time TLC indicated a complete reaction. The mixture was cooled in an ice bath and neutralized with the addition of concentrated NH40H (141 mL). The mixture was then further diluted with H20 (-200 mL) and extracted with CH2C12 (3x). The organic fractions were washed with H20 (2x), filtered through anhydrous Na2S04, combined and concentrated in vacuo to give 4. 0 g of residue as a yellow foam. This material was purified by flash chromatography (3% acetone in CH2C12) to give 1. 6 g of the pure title compound (97a) as a foam along with 1. 2 g of additional material contaminated with a by-product having a slightly higher Rf. Crystallization of the first fraction from boiling heptane afforded the pure title compound (97a, 1. 2 g) as an off-white solid in 36. 6% yield ; m. p. = 164-166°C. FTIR (KBr, diffuse reflectance) v 2953, 1707, 1666, 1614, 1601 and 1520 crri 1. NMR (300 MHz, CDC13) 8 0. 297 (s, 3 H, C18-CH3), 2. 18 (s, 3 H, C21-CH3), 2. 903 (s, 6 H, N (CH3) 2), 3. 141 (s, 3 H, Cl7a-OCH3), 4. 355 (d, l H, J = 7. 2 Hz, Cl la-CH), 5. 745 (s, 1 H, C4-CH=), 6. 638 (d, 2 H, J = 9. 0 Hz, 3', 5'aromatic-CH's) and 6. 994 (d, 2 H, J = 9. 0 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 447 (M+, 72. 8), 372 (6. 5), 251 (15. 1), 134 (30. 2) and 121 (100).

Analysis by HPLC on a Waters Assoc. NovaPak C1s column eluted with MeOH/H20/Et3 N, 75 : 25 : 0. 05 at a flow rate of 1 mL per min and X = 302 nm indicated compound 97a to be 98. 33% pure with tR of 9. 00 min. Anal. Calcd. for C29H37NO3 1/12H2O : C, 77. 56 ; H, 8. 34 ; N, 3. 12. Found : C, 77. 59 ; H, 8. 34 ; N, 3. 10.

EXAMPLE 23 This example illustrates the preparation and properties of 17a-Methoxy-l lés- [4- (N-piperidino) pllenyl]-19-norpregna-4, 9-diene-3, 20-dione (97b) (Figure 6) :

Step 1 3, 3-Ethylenedioxy-5α-hydroxy-17α-methoxy-11ß-[4-(N- piperidino)phenyl]-19-norpregna-5(10,9(11)-dien-20-one (96b): Magnesium (845 mg, 34. 7 mmol) was added to a 500 mL, 3-neck flask equipped with a reflux condenser, a magnetic stiner and a rubber septum.. A small crystal of iodine was added and the system flushed with nitrogen and flame dried. After cooling, dry THF (20 mL) and 1, 2-dibromoethane (0. 2 mL) were added. The mixture was stirred under nitrogen and heated in a warm water bath until evidence of the reaction was observed. A solution of N- (4-bromophenyl) piperidine (Veradro, et al., Synthesis, 447-450 (1991)) (8. 35 g, 34. 7 mmol) in dry THF (30 mL) was then added via syringe and the mixture stirred and heated in a warm water bath for 3 1/2 hr. Solid copper (I) chloride (688 mg, 6. 95 mmol) was added followed 1/2 ho later by a solution of the epoxide mixture (95, 2. 7 g, assumed 6. 95 mmol) in dry THF (30 mL). The reaction mixture was stirred at room temperature for 45 min, then quenched by the addition of saturated NH4C1 solution. In order to oxidize Cu (I) to Cu (II), air was drawn through the reaction mixture for % 2 her with vigorous stirring. The mixture was then extracted with CH2C12 (3x). The organic fractions were washed with saturated NH4C1 solution, H20 and brine, combined, dried over Na2S04, filtered and concentrated iii vacuo to give 11. 3 g of the residue as a dark oil. The material was purified via flash chromatography (5% acetone in CH2C12) twice to give 1. 22 g of the Grignard adduct 96b as a white foam in 32% yield ; m. p. =126 -131°C (dec). FTIR (KBr, diffuse reflectance) v,, 3523, 2938, 1707, 1610, 1511 and 1447 cm-1. NMR (300 MHz, CDC13) 8 0. 207 (s, 3H, C18-Me), 1. 682 (m, 6 H,- (CH2) 3- of piperidine), 2. 147 (s, 3H, C21- CH3), 3. 103 (s, 3 H, C17a-OCH3), 3. 05-3. 2 (m, 4 H, -N(CH2)2-, 3. 8-4. 05 (m, 4 H, C3- ketal), 4. 23 (m, 1 H, C11α-CH) and 6. 78-7. 05 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 549 (M+, 59. 7), 531 (18. 1), 174 (20. 8), 161 (100) and 99 (11. 1). Anal.

Calcd. for C34H4705N : C, 74. 28 ; H, 8. 62 ; N, 2. 55. Found : C, 73. 45 ; H, 8. 51 ; N, 2. 53.

Step 4. Preparation of tlte target compouztd 97b : Under nitrogen, a solution of the Grignard adduct (96b, 1. 0 g, 1. 81 mmol) in THF (10 mL) was treated with H20 (10 mL) and glacial HOAc (30 mL). After stirring overnight at room temperature, TLC (5% acetone in CH2Cl2) indicated incomplete deketalzation and dehydration. The reaction mixture was heated to-50°C in a warm water bath for 2 hr, after which time TLC indicated a complete reaction. The mixture reaction was cooled in an ice bath and neutralized with the addition of concentrated NH40H

(#35 mL). The mixture was then further diluted with H20 (-100 mL) and extracted with CH2Cl2 (3x). The organic fractions were washed with H20, brine, combined, dried over Na2S04, and concentrated in vacuo to give 900 mg of foam. The crude material was purified by flash chromatography (5% acetone in CH2C12) to give 630 mg of the target compound 97b as a foam. Recrystallization of the compound 97b from EtOH afforded 325 mg of the target compound 97b as an off-white solid in 35. 7% yield. HPLC analysis of 97b on a Waters NovaPak Cis column eluted with MeOH/H2O (80 : 20) with 0. 05% Et3N at a flow rate of 1 mL/min and k = 260 nm indicated this compound to be 97. 7% pure. FTIR (KBr, diffuse reflectance) v, n= 2934, 1708, 1665, 1610 and 1512 cm\ NMR (300 MHz, CDC13) 8 0. 273 (s, 3 H, C18-CH 3), 2. 174 (s, 3 H, C21-CH 3), 3. 139 (s, 3 H, Cl7a-OCH3), 4. 35 (d, 1 H, Cl la-CH), 5. 746 (s, 1 H, C4-CH=) and 6. 8-7. 0 (dd, 4 H, aromatic-CH's).

MS (EI) m/z (relative intensity) : 487 (84. 3), 412 (4. 3), 318 (8. 6), 251 (7. 14), 206 (11. 4), 174 (15. 7) and 161 (100). Anal. Calcd. for C32H4103N : C, 78. 85 ; H, 8. 42 ; N, 2. 87. Found : C, 78. 00 ; H, 8. 37 ; N, 3. 00.

EXAMPLE 24 This example illustrates the preparation and properties of 17a, 21-Diacetoxy- 11 ß- [4-(N-piperidino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (106a) (Figure 7) : Step 1. 3, 3-EtAlylenedioxy-1 7ß-cyano-1 7a-trimethylsilyloxyesttra-5 (10), 9 (11)- diene (99): Under nitrogen, pyridine (136. 9 g, 1740 mmol) solution of the cyanohydrin ketal (98, 25 g, 73. 22 mmol) was treated with chlorotrimethylsilane (44g, 394 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into a 50 : 50 mixture of ice/saturated NaHCO3 solution (-1. 2 L), stirred until the ice had melted, and extracted with hexane (3x). The organic extracts were washed with H20 (3x), brine (lx), combined, dried over anhydrous Na2S04, and concentrated in vacuo. The remaining pyridine was azeotropically removed in vacuo with heptane. Crystallization of the residue from pentane gave 26. 1 g of the pure silyl ether (99) as a white solid in 86. 2% yield ; m. p. = 99-101°C. FTIR (KBr, diffuse reflectance) v"/,-2944, 2908, 2231 and 1253 cm~l. NMR (300 MHz, CDC13) 8 0. 229 (s, 9 H, C17α-OSi (CH3) 3), 0. 894 (s, 3 H, C18-CH3), 3. 987 (s, 4 H, 3-OCH2CH20) and 5. 615 (t, 1 H, J = 2. 55 Hz, C11-CH=). MS (EI) m/z (relative intensity) : 413 (M+, 100. 0), 398 (5. 5), 385 (24. 0), 371 (6. 4), 237 (33. 9) and 69. 3 (86. 0).

Step 2. 3, 3-EtAtylenedioxy-5a, 10a-epaxy-173-cyano-17a-trimetsylsilylaxyestr- 9 (11)-ene (100) : Hydrogen peroxide (30%, 12 mL, 117. 12 mmol) was added to a vigorously stirred mixture of hexafluoroacetone trihydrate (20. 20 g, 112. 5 mmol) in CH2C12 (185 mL) cooled to 0°C in an ice bath. The reaction mixture was stirred at 0°C for #hr, and solid Na2HP04 (1 lg, 77. 5 mmol) was added followed by an ice-cold solution of the silyl ether (99, 25 g, 60. 44 mmol) in CH2C12 (185 mL). The mixture was then stirred at 0°C for 5 hr, then at 5°C overnight. Analysis by TLC (5% acetone in CHsClz) at that time indicated a complete reaction. The reaction mixture was diluted with CH2C12 (-200 mL) and washed with 10% Na2SO3 solution (lx), H20 (lx) and brine (lx). The organic fractions were filtered through anhydrous sodium sulfate, combined and concentrated i7i vacuo.

Trituration of the residue with ether afforded 16. 66 g of the pure 5a, 10a-epoxide (100) as a white solid in 64. 16% yield ; m. p. 156-160°C. FTIR (KBr, diffuse reflectance) vmtZx 2955, and 2228 cm~l. NMR (300 MHz, CDC13) 8 0. 219 (s, 9 H, OSi (CH3) 3), 0. 894 (s, 3 H, C18- CH3), 3. 85-3. 97 (s, 4 H, C3-OCH2CH20) and 6. 082 (t, 1 H, J = 2. 6 Hz, C11-CH=).

MS (EI) m/z (relative intensity) : 429 (M+, 18. 5), 401 (2. 8), 343 (11. 1), 238 (9. 5), 99 (100. 0) and 86 (36. 2).

Step 3. 3,3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N-piperidino)phenyl]- 17ß-cyano- 17α-trimethyl- silyloxyestr-9-ene (101a): Magnesium (0. 95 g, 39. 1 mmol) was added to a 500 mL, 3-neck flask equipped with a magnetic stirrer, rubber septum and a condenser. A crystal of iodine was added followed by dry THF (50 mL) and two drops of 1, 2-dibromoethane. A solution of N- (4-bromophenyl) piperidine (see, EXAMPLE 23, Step 1) (10. 24 g, 42. 64 mmol) in dry THF (50 mL) was then added, and the mixture was stirred under nitrogen and heated to reflux for 1 hr. At the end of that time, all of the magnesium metal had reacted. The reaction was allowed to cool to room temperature, and solid copper (I) chloride (0. 7 g, 7. 07 mmol) was added followed #hr later by a solution of the 5a, 10a-epoxide (100, 5. 55 g, 12. 92 mmol) in dry THF (50 mL). The mixture was stirred at room temperature for 1. 5 hr. Analysis by TLC (5% acetone in CH2Cl2) of a small aliquot quenched with NH4C1 solution and extracted with EtOAc indicated a complete reaction. The reaction mixture was cooled in an ice bath and quenched by the addition of saturated NH4C1 solution (15 mL). The reaction mixture was allowed to warm to room temperature, and air was drawn through the reaction mixture for #hr to oxidize Cu (I) to Cu (II). The mixture was extracted wtih CH2C12 (3x)

and the organic fractions washed with H2O (3x). The organic fractions were combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo. Trituration of the residue with pentane gave 7. 37 g of 101 a as an off-white solid in 97% yield. ; m. p. = 127-130°C.

FTIR (KBr, diffuse reflectance) v", ax 3510, 2945, 2228, 1611 and 1510 cni 1. NMR (300 MHz, CDC13) 8 0. 241 (s, 9 H, 17a-OSi (CH3) 3, 0. 533 (s, 3 H, C18-CH3), 3. 107 (t, 4 H, J = 5. 6 Hz, piperidine α-CH2's), 3. 884-4. 043 (s, 4 H, C3-OCH2CH20) 4. 284 (d, 1H, J = 6. 9 Hz, Cl la-CH), 6. 831 (d, 2H, J = 8. 7 Hz, 3', 5'aromatic-CH's) and 7. 060 (d, 2H, J = 8. 7 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 590 (M+, 38. 1), 572 (10. 3), 320 (4. 0), 174 (12. 1), 161 (100. 0), 100 (1. 7), 99 (7. 8) and 71 (7. 0) Anal. Calcd. for C3sHsoN204si-1/3C5H11 : C, 71. 61 ; H, 8. 85 ; N, 4. 56. Found : C, 71. 79 ; H, 8. 89 ; N, 4. 49. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 4. 17ß-cyano-11ß-[4-(N-piperidino)phenylk]-17α-hydroxyestra- 4,9-dien-3-one<BR> <BR> <BR> <BR> <BR> (102a) : A solution of the Grignard adduct (101a, 7. 27 g, 12. 3 mmol) was dissolved in THF (25 mL) and the system was flushed with nitrogen. Glacial acetic acid (75 mL) and H20 (25 mL) were added and the mixture was heated to 65°C for 3 hr. Analysis by TLC (5% acetone in CHzClz) at that time indicated a complete reaction. The mixture was cooled to 0°C in an ice bath and the acetic acid was neutralized by slow addition of concentrated NH40H solution (28%, #90 mL) to a final pH of-8 by pH paper. The mixture was diluted with HU2O and extracted with CH2C12 (3x). The organic fractions were washed with H20 (3x), filtered through anhydrous Na2S04, combined and concentrated 7 ? vacuo. Trituration of the residue with ether gave 3. 8 g of the cyanohydrin (102a) as a white crystalline solid.

The mother liquors were concentrated and purified by flash column chromatography (5% acetone in CH2C12) to afford an additional 0. 65 g of 102a after trituration with pentane.

Total yield of the cyanohydrin (102a) was 4. 45 g in 79. 2% yield ; m. p. = 205-208°C.

FTIR (KBr, diffuse reflectance) : #max 3436, 3211, 2939, 2855, 2234, 1658, 1634, 1609 and 1512 cm-1. NMR (300 MHz, CDC13) : 8 0. 641 (s, 3 H, C18-CH3), 3. 125 (t, 4 H, J = 5. 7 Hz, piperidine a-CH2's), 4. 427 (d, 1 H, J = 5. 1 Hz, Cl la-CH), 5. 782 (s, 1 H, C4-CH=), 6. 862 (d, 2 H, J = 9 Hz, 3', 5' aromatic-CH's) and 7. 031 (d, 2H, J = 9 Hz, 2', 6'aromatic-CH's).

MS (EI) m/z (relative intensity) : 456 (M+, 0. 3), 429 (61. 1), 401 (1. 5), 174 (6. 9), and 161 (100. 0). Anal. Calcd. forC30H36N2021/l0H2O : C, 78. 60 ; H, 7. 96 ; N, 6. 11. Found : C, 78. 64 ; H, 7. 94 ; N, 6. 11.

Step 5. 17ß-cyano-11ß-[4-(N-piperidino)phenyl]-17α- cstloroanethyldietltylsilyloxyestra-4, 9-dien-3-one (103a) : Under nitrogen, a solution of the cyanohydrin (102a, 4. 39 g, 9. 61 mmol) and dimethylaminopyridine (0. 4 g, 3. 27 mmol) in dry THF (50 mL) and triethylamine (1. 8 g, 17. 79 mmol) was treated with chloromethyldimethylsilyl chloride (2. 0 mL = 2. 17 g, 15. 18 mmol). After stirring overnight at room temperature, TLC (2% acetone in CH2CI2) indicated a complete reaction. The reaction was diluted with ether (50 mL) and stirred for an additional l/2 hr. The resulting suspension was filtered through Celite and the filtrate concentrated in vacuo. The residue was taken up in ether/CH2CI2 (9 : 1) and the solution/suspension was passed through a silica gel flash chromatography column using ether as eluent. Fractions containing the product were combined and concentrated in vacuo to give 5. 4 g of the chloromethyl silyl ether (103a) as a white foam in quantitative yield.

Attempts to crystallize or soldify the crude product using a variety of solvents were unsuccessful. This material was used in the subsequent reaction without further purification. NMR (300 MHz, CDC13) : 8 0. 403 and 0. 410 (both s, 6 H, OSi (CH3) 2), 0. 607 (s, 3 H, C18-CH3), 2. 904 (s, 2 H, (CH3) 2SiCH2Cl), 3. 123 (t, 4 H, J = 5. 6 Hz, piperidine a- CH2's), 4. 399 (d, 1 H, J = 6 Hz, C 11 a-CH), 5. 775 (s, 1 H, C4-CH=), 6. 863 (d, 2 H, J = 8. 6 Hz, 3', 5'aromatic-CH's) and 7. 027 (d, 2 H, J = 8. 6 Hz, 2', 6'aromatic-CH's).

Step 6. 17α-Hydroxy-11ß-[4-(N-piperidino)phenyl]-21-chlooro-19-nor pregna-4,9- diene-3, 20-dione (104a) : Under nitrogen and anhydrous conditions, a solution of the chloromethyl silyl ether (103a, 5. 1 g, 9. 05 mmol) in dry THF (150 mL) was cooled to-78°C, and treated dropwise with a 2. 0 M solution of lithium diisopropylamide (LDA) in THF/heptane (19 mL, 38 mmol). The reaction was stirred at-78°C for 2 hr and then quenched at-78°C by the slow addition of 4 N HCl (100 mL, 400 mmol). The mixture was allowed to warm and stirred at room temperature for 1 hr. The reaction was cooled to 0°C and the excess acid was neutralized by slow addition of concentrated NH40H solution (-25 mL). The reaction mixture was diluted with H20 (-100 mL) and extracted with CH2Cl2 (3x). The organic fractions were washed with H20 (2x), filtered through anhydrous Na2SO4, combined and concentrated in vacuo to give 5. 6 g of a residue as a yellow foam.

This material was triturated with EtOAc to give 2. 64 g of the pure 21-chloro product (104a) as a yellow solid. Concentration of the mother liquors followed by flash column chromatography (7. 5% acetone in CH2C12) and trituration with EtOAc gave an

additional 0. 54 g of the product. Total yield of the 21-chloro intermediate (104a) was 3. 18 g in 69. 17% yield ; m. p. = 231-234°C. FTIR (KBr, diffuse reflectance) : #max 3395, 2939, 1730, 1649, 1602 and 1512 cm~l. NMR (300 MHz, CDC13) : # 0.382 (s, 3 H, C18- CH3), 3. 104 (t, 4 H, J = 5. 4 Hz, piperidine a-CH2's), 4. 343 and 4. 614 (dd, 25 H, J = 16. 5 Hz, C21-CH2), 4. 380 (d, 1 H, J = 6. 0 Hz, C11α-CH), 5. 762 (s, 1 H, C4-CH=), 6. 826 (d, 2 H, J = 8. 9 Hz, 3', 5'aromatic-CH's) and 6. 981 (d, 2 H, J = 8. 9 Hz, 2', 6'aromatic- CH's). MS (EI) m/z (relative intensity) : 507 (M+, 23. 7), 471 (18. 0), 318 (6. 5), and 161 (100. 0). Anal. Calcd. for C31H38ClNO3 1/6CH2Cl2 : C, 71. 06 ; H, 743 ; N, 2. 66 ; Cl, 8. 98.

Found : C, 71. 06 ; H, 7. 55 ; N, 2. 73 ; Cl, 8. 78.

Step 7. 17a-Hydroxy-llfl- [4- (N-piperidino) pheizylj-21-acetoxy-19-norpregiza-4, 9- diene-3, 20-dioz1e (105a) : The 21-chloro intermediate (104a, 3. 0 g, 5. 9 mmol) and anhydrous potassium acetate (6. 0 g, 61. 14 mmol) in dry CH3CN (75 ml) was heated to reflux under nitrogen and monitored by TLC (10% acetone in CH2Cl2) which indicated a complete reaction after 3 hr. The reaction mixture was cooled to room temperature, diluted with CH2C12 (-50 mL), filtered and concentrated in vacuo to give 4. 1 g of the residue as a yellow solid. This material was crystallized from CH2C12/acetone to give 2. 63 g of the pure 17a- ol-21-acetate (105a) as an off-white solid in 83. 8% yield ; m. p. = 277-281°C. FTIR (KBr, diffuse reflectance) : vmaX 3440, 2937, 1742, 1727, 1648, 1601 and 1513 cm-1. NMR (300 MHz, CDC13) : # 0. 379 (s, 3 H, C18-CH3), 2. 174 (s, 3 H, C21-OAc), 3. 101 (t, 4 H, J = 5. 4 Hz, piperidine a-CH2's), 4. 376 (d, 1 H, J = 6. 6 Hz, C11α-CH), 4. 864 and 5. 106 (dd, 2 H, J = 17. 3 Hz, C21-CH2), 5. 762 (s, 1 H, C4-CH=), 6. 836 (d, 2 H, J = 9 Hz, 3', 5'aromatic- CH's) and 7. 016 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 531 (M+, 28. 3), 513 (2. 9), 501 (3. 2), 471 (7. 4), 174 (11. 6) and 161 (100. 0). Anal. Calcd. forC33H4iNOs-l/5CH2Cl2 : C, 72. 68 ; H, 7. 61 ; N, 2. 55. Found : C, 72. 73 ; H, 7. 53 ; N, 2. 70.

Step 8. Preparation of the target compound 106a: A mixture of trifluoroacetic anhydride (7. 9 g, 37. 6 mmol) and glacial acetic acid (2. 21 g, 36. 7 mmol) in dry CH2Cl2 (25 mL) was stirred at room temperature under nitrogen for 1 hr. p-Toluenesulfonic acid monohydrate (0. 79 g, 4. 15 mmol) was added, and the mixture was cooled to 0°C in an ice bath. A solution of the 17a-ol-21-acetate (105a, 2. 0 g, 3. 76 mmol) in dry CH2C12 (35 mL) was added and the reaction mixture stirred at 0°C for 2. 5 hr. Assays by TLC (5% acetone in CH2C12) at that time indicated >90% of the

starting material had been consumed. H20 (-10 mL) was added and the reaction stirred at 0°C for 10 min. Additional H2O (-50 mL) was added and the reaction allowed to warm to room temperature. The pH of the reaction mixture was carefully adjusted to 9. 0 with concentrated NH40H and the mixture was extracted with CH2C12 (3x). The organic fractions were washed with H2O (2x), brine (1x), filtered through anhydrous Na2SO4, combined and concentrated ill vacuo to give 2. 3 g of a yellow foam. Purification of this crude 106a by flash chromatographies (7. 5% acetone in CH2Clz) followed by crystallization from ether gave the 17a, 21-diacetate 106a in two crops, both as white crystalline solids.

Crop 1 (0. 68 g), m. p. = 188 - 189°C, Crop 2 (0. 672 g), m. p. = 186-188°C. Total was 1. 352 g in 62. 6% yield. Analysis of 106a by HPLC on a Water Associates NovaPak Cis eluted with CH 3CN/0. 05 M I (H2PO4 [pH = 3. 0] at a flow rate of 1 mL per minute and X- 302 nm) indicated the first crop to be 99. 1% pure and the second crop to be 98. 1% pure.

FTIR (KBr, diffuse reflectance) : may 2939, 2858, 2793, 1748, 1729, 1669, 1600 and 1509 cm~l. NMR (300 MHz, CDCl3) : 8 0. 417 (s, 3 H, C18-CH 3), 2. 125 (s, 3 H, C17α-OAc), 2. 168 (s, 3H, C21-OAc), 3. 104 (t, 4 H, J = 5. 35 Hz, piperidine a-CH2's), 4. 386 (d, 1 H, J = 6. 6 Hz, C11α-CH), 4. 403 and 4. 946 (dd, 2H, J = 16. 8 Hz, C21-CH20Ac), 5. 781 (s, 1 H, C4-CH=), 6. 832 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's) and 7. 011 (d, 2 H, J = 9 Hz, 2', 6' aromatic-CH's). MS (EI) m/z (relative intensity) : 573 (M, 46. 3), 513 (11. 5), 174 (10. 4) and 161 (100. 0). Anal. Calcd. for C35H43NO6 : C, 73. 27 ; H, 7. 55 ; N, 2. 44. Found : C, 73. 18 ; H, 7. 60 ; N, 2. 50.

EXAMPLE 25 This example illustrates the preparation and properties of 17α,21-Diacetoxy- llß-(4-acetylphenyl) l9-norpregna-4, 9-diene-3, 20-dione (106b) (Figure 7) : Step 1. 3,3-Ethylenedioxy-5α-hydroxy-11ß-[4-(2-methyl-1,3-dioxolan -2- yl) phenyl]-17ß-cyano-17α-trimethylsilyloxyestr-9-ene (101b) : Under nitrogen and in flame-dried glassware, dry THF (240 mL) was added to magnesium turnings (2. 3 g, 94. 6 mmol). Solid bromoacetophenone ketal (see, EXAMPLE 20, Step 1) (20. 79 g, 85. 5 mmol) was added and the mixture heated to refux.

After l/2 hr of reflux, evidence of Grignard fonnation such as cloudiness and color change was observed. Heating was discontinued and the mixture stirred for 1 hr, after which time most of the magnesium had reacted and a substantial amount of the precipitated Grignard

ragent was observed. Solid CuCl (4 g, 40. 4 mmol) was added and the mixture was stirred at room temperature for 15 min, after which time the solid reagent went back into solution. A solution of the 5a, 10a-epoxide (100, 17. 5 g, 40. 73 mmol) in THF (150 mL) was added and the reaction mixture was stirred at room temperature for 1 hr. After that time, TLC (5% acetone in CH2Cl2) of a small aliqout quenched with saturated NH4Cl solution indicated a complete reaction. The reaction was quenched by the addition of saturated NH4C1 solution (-50 mL). In order to oxidize Cu (I) to Cu (II), air was drawn through the reaction mixture for % 2 her. The resulting blue mixture was diluted with ether (500 mL) and washed with Hz4 (2x), brine (lx), dried over anhydrous Na2S04, filtered and concentrated in vacuo to give 41 g of the residue as an oil. Crystallization of this crude material from ether gave the pure 101b (23. 0 g) as a white solid in 95% yield ; m. p. = 192-193°C. FTIR (KBr, diffuse reflectance) : V.. a, 3515, 2951, 2884, 2230, 1619, 1505 and 1102 cm'\ NMR (CDCl3) : 8 0. 25 (s, 9 H, Si (CH3) 3), 0. 5 (s, 3 H, C 8-CH3), 1. 67 (s, 3 H, Cll) 3- (acetophenone ketal CH3), 3. 67-4. 17 (m, 8 H, C3-OCH2CH20-), 4. 37 (m, 2 H, Cl la-CH plus OH), 7. 17 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's) and 7. 37 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's). MS (EI) m/z (relative intensity) : 593 (M+, 3. 6), 578 (6. 0), 575 (9. 1), 560 (2. 5), 366 (5. 2), 99 (27. 3) and 87 (100. 0). Anal. Calcd. for C34H47NO6Si : C, 68. 77 ; H, 7. 98 ; N, 2. 36. Found : C, 68. 69 ; H, 7. 87 ; N, 2. 43. <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 2. 1 7, l-cyano-1 7a-AIydroxy-11ß-(4-cetlphelzyl)-estra-4, 9-dien-3-one<BR> <BR> <BR> <BR> (102b) : A solution of the Grignard adduct (101b, 23 g, 38. 7 mmol) was dissolved in THF (100 mL) and the system was flushed with nitrogen. Glacial acetic acid (314. 7 g, 524 mmol) and H20 (100 mL) were added and the mixture was stirred overnight at room temperature. At that time, TLC (10% acetone/CH2Cl2) indicated an incomplete reaction.

The reaction mixture was then heated to reflux for 1 hr, after which time TLC indicated a complete reaction.

The volatiles were removed in vacuum at 50°C and the residue diluted with H20 (-250 mL) and saturated NaHCO3 solution (-125 mL). The subsequent precipitate was extracted with EtOAc (5x) with some difficulty in that the crude product was relatively insoluble in most solvents used. The organic fractions were washed with H20 (2x), brine (lx), combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.

Trituration of the residue with ether gave the cyanohydrin (102b, 16. 3 g) as a light yellow

solid in 100% yield ; m. p. = 141-143°C (dec). FTIR (KBr, diffuse reflectance) : vmaX 3362, 2966, 2946, 2232, 1619, 1730, 1658 and 1600 cm~l. NMR (CDC13+ d6DMSO) : 6 0. 57 (s, 3 H, C18-CH3), 2. 60 (s, 3 H, Cllß-(4-phenyl-C (O) CH3), 4. 57 (br s, 1 H, Clla-CH), 5. 80 (s, 1 H, C4-CH=), 7. 40 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's) and 7. 97 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's). MS (EI) m/z (relative intensity) : 415 (M+, 0. 5), 404 (0. 4), 388 (100. 0), 292 (65) and 97 (51. 0). Anal. Calcd. for C27H29N03-1/3H20 : C, 76. 93 ; H, 7. 09 ; N, 3. 32.

Found : C, 77. 04 ; H, 6. 99 ; N, 3. 45. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 3. 11ß-(4-acetylphenyl)-17ß-cyano-17α-bromethyldimethylsilyl oxyestra-4,9-<BR> <BR> <BR> <BR> <BR> diesl-3-o) le (103b) : Under nitrogen, a solution of the cyanohydrin (102b, 15 g, 36. 12 mmol), Et3N (6. 53 g, 64 mmol) and DMAP (2. 6 g, 21. 3 mmol) in dry THF (180 mL) was treated with bromomethyldimethylsilyl chloride (9. 70 g, 54 mmol). The mixture was stirred overnight at room temperature, diluted with ether (500 mL), filtered through Celite and concentrated in vacuo. The relative insolubility of this material (103b) precludes chromatographic purification useing ether as eluent. The crude material (103b) was used directly in the subsequent reaction without further purification or characterization.

Step 4. 17α-Hydroxy-11ß-(4-acetylphenyl)-21-bromo-19-norpregna-4,9 -dienj-3- one (104b) : Under anhydrous conditions and using a mechanical stirrer, a solution of the silyl ether (103b) (assumed 20. 34 g, 36. 12 mmol) in dry THF (500 mL) was cooled to- 78°C and treated dropwise with a 1. 5 M solution of lithium diisopropylamide (LDA) in cyclohexane (100 mL, 150 mmol). After 1 hr, the reaction mixture became very viscous, almost a gel. The reaction was quenched at-78°C by addition of 4. 45 M HBr (500 mL, 890 mmol) and the mixture allowed to warm to room temperature. After stirring at room temperature for 1 hr, the excess acid was neutralized by slow addition of concentrated NH40H solution (-60 mL). The mixture was further diluted with H20 (-200 mL) and extracted with CH2Cl2 (3x). The organic fractions were washed with H20 (3x), combined, filtered through Na2S04 and concentrated in vacuo to give 20 g of the residue as a foam.

This material was purified via flash chromatography eluted with (10% acetone in CH2C12) to give 2. 6 g of the 21-bromo product (104b) as a white solid in 14. 1% yield. FTIR (KBr, diffuse reflectance) : vmax 3340, 2946, 1723, 1693, 1679, 1645 and 1601 cm'\ NMR (CDC13) : 8 0. 33 (s, 3 H, C18-CH3), 2. 19 (s, 3 H, llp- (4-phenyl-C (O) CH3), 4. 30-4. 70 (m,

3 H, Cl la-CH and C21-CH2Br), 5. 83 (s, 1 H, C4-CH=), 7. 33 (d, 2 H, J = 9 Hz, 2', 6' aromatic-CH's) and 7. 93 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's). MS (EI) m/z (relative intensity) : 512 (M+, 24. 1), 466 (100), 432 (48. 5), 431 (48. 5), 430 (86, 4), 371 (71. 9) and 91 (76. 0).

Step S. 1 7a-Hydroxy-11ß-(4-cetylphenyl9-21-acetoxy-19-norpregna-4, 9-diene- 3,20-dione (105b): A mixture of the 21-bromo drivative (104b, 2. 5 g, 4. 89 mmol), anhydrous KOAc (20 g, 203. 8 mmol) in dry CH3CN (100 mL) was heated to reflux under nitrogen.

After 2 hr, TLC (10% acetone in CH2C12) indicated a complete reaction. The reaction mixture was cooled to room temperature, filtered and concentrated ira vacuo to give 2. 6 g as a foam. This material was purified via flash chromatography (12% acetone in CH2C12) followed by cyrstallization from EtOAc to give 1. 5 g of the pure 17a-ol-21-acetate (105b) as a light yellow solid in 62. 6% yield ; m. p. = softens at 110°C. FTIR (KBr, diffuse reflectance) : Vmax 3467, 2948, 1749, 1727, 1727, 1681, 1380, 1664 and 1603 cm~l. NMR (CDC13) : 8 0. 31 (s, 3 H, C18-CH3), 2. 15 (s, 3 H, Cl7a-OC (O) CH3), 2. 57 (s, 3 H, llp-4- phenyl-C (O) CH3), 4. 5 (br d, 1 H, Cl la-CH), 5. 01 (dd, 2 H, Jl= 18. 7 Hz, J2 = 18 Hz, C21- CH20Ac), 5. 81 (s, 1 H, C4-CH=), 7. 34 (d, 1 H, J = 8. 2 Hz, 2', 6'aromatic-CH's), 7. 35 (d, 1 H, J = 6. 8 Hz, 2', 6'aromatic-CH's) and 7. 93 (d, 2 H, J = 8. 2 Hz, 3', 5'aromatic-CH's).

MS (EI) m/z (relative intensity) : 490 (M+, 88. 0), 430 (100. 0), 344 (80. 0), 236 (44. 0), and 91 (55. 0). Anal. Calcd. for C3oH3406-1/5CH2Cl2 : C, 70. 99 ; H, 6. 79. Found : C, 70. 83 ; H, 6. 65.

Step 6. Preparatioh of the target compound 106b : Under nitrogen trifluoroacetic anhydride (11. 15 g, 53. 2 mmol), glacial acetic acid (3. 25 g, 54. 2 mmol) in dry CH2C12 (35 mL) were combined and stirred at room temperature for 1/2 hr. p-Toluenesulfonic acid monohydrate (0. 5 g, 2. 63 mmol) was added and the reaction mixture was cooled to 0°C in an ice bath. A solution of the 17a-ol-21- acetate (105b, 1. 28 g, 2. 61 mmol) in dry CH2C12 (10 mL) was precooled to 0°C and then added. The reaction mixture was stirred at 0°C. After 45 min, TLC (10% acetone in CH2C12) indicated a complete reaction. The mixture was quenched at 0°C with concentrated NH40H solution (-10 mL,-148 mmol), allowed to warm to room temperature, and diluted with H20 (-50 mL). The pH of the aqueous fraction was adjusted to 5 with concentrated NH40H solution and the mixture extracted with CH2C12 (3x). The

organic fractions were washed with H2O (3x), combined, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give 1. 8 g of the crude product as a foam. The crude material was purified via flash chromatography (5% acetone in CH2Cl2) to give 1. 1 g of the purified diacetate (106b) as a foam. Crystallization of this foam from EtOAc/heptane afforded 0. 78 g of the pure solid (106b) as a white crystalline solid in 56. 1% yield. ; m. p. = 197-199°C. Reverse phase HPLC analysis on Phenomenex Prodigy 5 ODS-2 column eluted with H2O/CH3CN, 1 : 1 at a flow rate of 1 mL/min and at X = 302 mn indicated this material to be >99% pure with a retention time (tR) of 5. 6 min. FTIR (KBr, diffuse reflectance) : vmaX 2951, 1757, 1678, 1664 and 1604 cm~ 1, NMR (CDCl3) : 8 0. 33 (s, 3 H, C18-CH3), 2. 07 (s, 3 H, C17a-OC (O) CH3), 2. 10 (s, 3 H, C21-OAc), 2. 50 (s, 3 H, Clip-4- phenyl-C (O) CH3), 4. 43 (m, 1 H, Cl la-CH), 4. 77 (dd, 2 H, Jl= 32. 9 Hz, J2 = 14. 9 Hz, C21- CH2OAc), 5. 77 (s, 1 H, C4-CH=), 7. 23 (d, 2 H, J = 8 Hz, 2', 6'aromatic-CH's), and 7. 83 (d, 2H, J = 8 Hz, 3', 5'aromatic-CH's). MS (EI) m/z (relative intensity) : 532 (M+, 6. 2), 472 (17. 3), 412 (11.. 3), 371 (100. 0) and 91 (14. 3). Anal. Calcd. for C32H3607'1/7H20 : C, 71. 81 ; H, 6. 83. Found : C, 71. 89 ; H, 6. 87.

EXAMPLE 26 This example illustrates the preparation and properties of 17a-Acetoxy-11 (4-acetylphenyl)-21-thioacetoxy-19-norpregna-4, 9-diene-3, 20-dione (106c) (Figure 7) : Step 1. 1 7a-Hydroxy-llß-(4acetylphenyl)-21-thioacetoty-19-l orpregBZa-4, 9- diene-3, 20-dione (105c): A mixture of the 21-bromo derivative (104b, 5. 746 g, 11. 23 mmol), sodium iodide (16. 84 g, 112. 3 mmol), potassium thioacetate (12. 83 g, 112. 3 mmol) in dry acetone (600 mL) was heated to reflux under nitrogen. After 4 hr, TLC (50% EtOAc in hexanes) indicated a complete reaction. The reaction was cooled to room temperature, filtered, concentrated in vacuo, diluted with H20 (-200 mL) and extracted with CH2C12 (3x). The organic fractions were washed with H20 (1x) and brine (lx), combined, dried over anhydrous sodium sulfate, concentrated in vacuo to give the crude product as a yellow foam. This material was purified by flash chromatography (50% EtOAc in hexanes) followed by crystallization from EtOAc/hexanes to afford the pure 17a-ol-21-thioacetate (105c, 3. 25 g, 57. 1%) as a white crystalline solid ; m. p. = 159-160°C. FTIR (KBr, diffuse reflectance) : #max 3325, 2950, 1723, 1688, 1637 and 1590 cm~l. NMR (CDC13) : 8 0. 33 (s,

3 H, C18-CH3), 2. 4 (s, 3 H, C21-SC (O) CH3), 2. 57 (s, 3 H, Cllß-4-phenyl-C (O) CH3), 4. 0 (dd, 2 H, Jl = 48. 6 Hz, J2 = 18 Hz, C21-CH2SAc), 4. 57 (br d, 1 H, Cl la-CH), 5. 8 (s, 1 H, C4-CH=), 7. 37 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's), and 7. 93 (d, 2 H, J = 9 Hz, 3', 5' aromatic-CH's). MS (EI) m/z (relative intensity) : 506 (@, 29. 1), 488 (14. 4), 474 (16. 6), 431 (100. 0) and 346 (78. 1). Anal. Calcd. for COsS-HsO : C, 68. 68 ; H, 6. 92 ; S, 6. 11.

Found : C, 68. 99 ; H, 6. 73 ; S, 6. 06.

Step 2. Preparation of the target compound 106c: Under nitrogen, trifluoroacetic anhydride (17. 43 g, 82. 89 mmol), glacial acetic acid (7. 17 g, 118. 45 mmol), p-toluenesulfonic acid monohydrate (1. 0 g, 5. 3 mmol) and dry CH2C12 (100 mL) were combined and stirred at room temperature for l/2 h. The mixture was cooled to 0°C in an ice bath and a solution of the 17a-ol-21-thioacetate (105c, 3. 0 g, 5. 92 mmol) in dry CH2C12 (50 mL) was added. The mixture was stirred at 0°C for 6 hr after which time TLC (4% acetone/CH2Cl2) indicated a complete reaction. The mixture was neutralized with cold saturated NaHC03 and extracted with CH2C12 (3x). The organic fractions were washed with brine (2x), combined, dried over sodium sulfate and concentrated in vacuo to give the crude product as a foam. Purification of this material by Flash chromatography eluting 4% acetone/CH2C12 followed by crystallization from EtOAc/hexanes gave 2. 34 g of the pure compound 106c as a yellow crystalline solid ; m. p. = 204-205°C. FTIR (KBr, diffuse reflectance) : Vmax 2948, 1734, 1702, 1676, 1663 and 1602 cm-'. NMR (CDC13) : 8 0. 30 (s, 3 H, C18-CH3), 2. 15 (s, 3 H, Cl7a-OC (O) CH3), 2. 33 (s, 3 H, C21-SC (O) CH3), 2. 57 (s, 3 H, Cl (3-4-phenyl-C (O) CH3), 3. 94 (dd, 2 H, Jl = 20. 7 Hz, J2 = 14. 4 Hz, C21-CH2SAc), 4. 53 (br d, 1 H, Cl la-CH), 5. 83 (s, 1 H, C4-CH=), 7. 37 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's), and 7. 93 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's). MS (EI) m/z (relative intensity) : 548 (M+, 6. 3), 488 (18. 4), 413 (27. 4), 371 (100. 0) and 280 (24. 0). Anal. Calcd. for C32H3606S 1/10H2O : C, 69. 82 ; H, 6. 63 ; S, 5. 82. Found : C, 68. 83 ; H, 6. 67 ; S, 5. 59.

EXAMPLE 27 This example illustrates the preparation and properties of 17a, 21- Dimethoxy-11 lp- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (113a) (Figure 8) :

Step 1. 3, 3-Ethylenedioxy-17α-methoxy-21-hydroxy-19-norpregna-5(10), 9 (11)- dien-20-one (107) : To a solution of the 17a-methoxy-3-ketal (94, 10. 0 g, 27. 1 mmol) in dry THF (150 mL) was added iodobenzene diacetate (Moriarty, et al., J. Chem. Soc., Claem.

Comme., 641-642 (1981) ; Velerio, et al., Steroids, 60 : 268-271 (1995)) (34. 59 g, 4x) as a solid. The suspension was stirred under nitrogen and cooled to 0°C. H20 (7. 73 mL, 429. 6 mmol, 16x) was added, followed by 0. 5 M KO-tBu solution (1400 mL, 700 mmol, 26x) via transfer needle. (A 50 : 50 (v/v) mixture of freshly opened methanol (700 mL) and 1. 0 M potassium t-butoxid in THF (700 mL ; Aldrich) was prepared and cooled to 0°C to give a 0. 5 M base solution). Upon completion of addition the reaction mixture was removed from the ice bath and the solution alowed to warm to room temperature. The reaction was monitored every hour by TLC (5% acetone in CH2C12) and after 4 hr, virtually all of the starting material had been converted to approximately a 80 : 20 mixture of two more polar components. The reaction mixture was diluted with H20 (500 mL) and brine (500 mL) and extracted into ether (3x). Organic fractions were washed again with H20 and brine. Combined organic extracts were dried by filtration through Na2SO4, evaporated in vacuo, and further dried under high vacuum to recover 13. 84 g of an orange oil.

Purification by flash chromatography (5% acetone in CH2C12) gave 6. 0 g of a pale yellow- white foam (107) in 57. 5% yield. Trituration with pentane produced 107 which was dried under vacuum to recover 5. 36 g of a white powder in 51. 0% yield ; m. p. = 147-152°C.

FTIR (KBr, diffuse reflectance) : may 3478, 2900, 2825, 1712, 1437, 1384 and 1372 cm~l.

NMR (300 MHz, CDC13) : 8 0. 550 (s, 3 H, C18-CH3), 3. 159 (s, 3 H, Cl7a-OCH3), 3. 981 (s, 4 H, C3-OCH2CH2O), 4. 251 and 4. 471 (AB, 2 H, JAB = 19. 81 Hz, C21-CH2) and 5. 544 (br s, 1 H, C11-CH=). MS (EI) m/z (relative intensity) : 388 (M+, 54. 8), 356 (13. 8), 297 (100. 0), 211 (65. 0), 169 (51. 1) and 99 (56. 3). Anal. Calcd. for C23H320s-l/4H20 : C, 70. 29 ; H, 8. 34. Found : C, 70. 21 ; H, 8. 12.

Step 2. 3, 3-Ethylenedioxy-17α,21-dimethoxy-189-norpregna-5(10),9(11)- dien-20- one (108) : To a solution of the 3-ketal-21-hydroxy compound (107, 5. 0 g, 12. 87 mmol) in 500 mL of 1, 2-dimethoxyethane (DME) was added Proton-Sponge [1, 8- bis (dimethylamino) naphthalene] (13. 79 g, 64. 35 mmol, 5x) as a solid. The solution was cooled to 0°C in an ice water bath and trimethyloxonium tetrafluoroborate (9. 52 g, 64. 35 mmol, 5x) was added as a solid. The suspension was kept at 0°C under nitrogen, for

3 hr. At that time, TLC (5% acetone in CH2C12) indicated all of the starting material had been cleanly converted to the slightly less polar 3-ketal-17a, 21-dimethoxy compound (108). H20 and EtOAc were added, the mixture was transferred to a separatory funnel, and the layers allowed to separate. The organic fraction was washed with ice-cold 1 N HCI (2x), H20 (lx), saturated NaHCO3 (lx), H20 (lx), and brine (lx). Combind EtOAc extracts (3x) were dried by filtration through Na2S04 and evaporated in vacuo. The resulting colorless oil was dried overnight under high vacuum to recover a white foam (108, 5. 28 g) in quantitative yield. Analysis by TLC and NMR indicated the crude material was sufficiently pure to carry directly on to the next reaction. A small amount was triturated with pentane and dried overnight under high vacuum to give 120 mg of 108 as a white solid ; m. p = 104-110°C. FTIR (KBr, diffuse reflectance) : Vmax 2926, 2884, 2828, 1722, 1447, 1380, 1322 and 1252 cm~l. NMR (300 MHz, CDC13) : 6 0. 585 (s, 3 H, C18-CH3), 3. 175 (s, 3 H, C17a-OCH3), 3. 442 (s, 3 H, C21-OCH3), 3. 983 (s, 4 H, C3-OCH2CH20), 4. 182 and 4. 367 (AB, 2 H, JAB = 18. 01 Hz, C21-CH2) and 5. 555 (br s, 1 H, Cl l-CH=). MS (EI) m/z (relative intensity) : 402 (M+, 27. 7), 370 (7. 2), 297 (100. 0), 211 (62. 1), 169 (41. 6) and 99 (62. 7). Anal. Calcd. for C24H3405-3/5H20 : C, 69. 74 ; H, 8. 58. Found : C, 69. 82 ; H, 8. 43.

Step 3. 3, 3-Etliylenedioxy-17a, 21-dimetlioxy-19-norpregna-5 (10), 9 (11)-dien-20- ol (109) : The 3-ketal 17a, 21-dimethoxy-20-one (108, 5. 0 g, 12. 42 mmol) was dissolved in dry THF (100 mL) and 2 equivalents of LiAlH4 (25 mL, 25 mmol, 1. 0 M in ether) were added via syringe. The solution was stirred magnetically at room temperature under nitrogen. After 15 minutes, examination by TLC (5% acetone in CH2C12) indicated the starting material had been cleanly converted to a single, more polar product (109). The reaction mixture was cooled in an ice bath, and saturated Na2S04 (-2-3 mL) was added dropwise via pipette. When the reaction was quenched, several scoops of Na2S04 were added and the mixture allowed to stir 1 hr. Filtration through a sintered glass funnel, followed by evaporation in vacuo produced a concentrated syrup. The syrup was taken up in H20 and CH2C12, transferred to a separatory funnel, and the layers allowed to separate.

The organic fraction was washed again with brine. Combined CH2C12 extracts (3x) were dried by filtration through Na2S04 and evaporated in vacuo. The resulting white foam was dried further under high vacuum to recover 4. 69 g of the crude 109. Purification of this

crude product by flash chromatography (5% isopropanol in CH2C12) gave 4. 24 g of 109 as a white foam in 84. 4% yield.

The two purest fractions were combined and taken up in a minimum amount of acetone/hexane. After standing six days at room temperature, large, colorless crystals had formed. The crystals were collected by centrifugation, washed with several portions of hexane, and dried under high vacuum to recover 177 mg. Analysis by TLC (10% acetone in CH2C12) indicated the crystals were of the highest purity. Analysis of this material by NMR indicated a single isomer. No further work was done for identification of this single isomer. A second crop of 78 mg with only a trace of impurity was obtained from the mother liquors ; m. p. =111-115°C. FTIR (KBr, diffuse reflectance) : via"3576, 3456, 2930, 2891, 2827, 1460 and 1372 cm 1. NMR (300 MHz, CDC13) : 8 0. 824 (s, 3 H, C18- CH3), 3. 298 (s, 3 H, Cl7a-OCH3), 3. 392 (s, 3 H, C21-OCH3), 3. 416 (dd, 1 H, Jl = 9. 30 Hz, J2 = 8. 10 Hz, C21-CH2), 3, 490 (dd, 1 H, J l = 9. 30 Hz, J 2 = 3. 30 Hz, C21-CH2), 3. 923 (dd, 1 H, =J1 = 8. 10 Hz, J2 = 3. 30 Hz, C20-CH), 3. 980 (s, 4 H, C3-OCH2CH20) and 5. 595 (br s, 1 H, C11-CH=). MS (EI) m/z (relative intensity) : 404 (MF, 2. 1), 372 (5. 7), 329 (1. 7), 297 (100. 0) and 211 (35. 7). Anal. Calcd. for C24H3605 1/5C6H14 : C, 71. 76 ; H, 9. 27. Found : C, 71. 83 ; H, 9. 04.

Step 4. 3,3-Ethylenedioxy-5α,10α-epoxy-17α,21-dimethoxy-19-norpre gn-9(11)- e7l-20-ol (110) : To a solution of hexafluoroacetone (2. 01 mL, 14. 39 mmol) in CH2C12 (50 mL), was added solid Na2HP04 (1. 36 g, 9. 59 mmol) and 30% H202 (2. 16 mL, 21. 1 mmol). The mixture was transferred to the cold room and stirred vigorously for l/2 hr at 4°C. A chilled solution of the 20-alcohol (109, 3. 88 g. 9. 59 mmol) in CH2C12 (25 mL) was added via pipette and rinsed in with additional CH 2C12 (25 mL). After stirring overnight at 4°C, TLC (7. 5% acetone in CH2C12) indicated virtually all of the starting material had been converted to one major, more polar product with only a trace of by- products. The reaction mixture was transferred to a separatory funnel and washed with 10% Na2S03 (lx), H20 (lx), and brine (lx). Combined CH 2C12 extracts (3x) were dried by filtration through Na2SO4 and evaporated i7t vacuo to recover a foam. NMR analysis of the crude material indicated the a and ß epoxides were present in approximately a 9 : 1 ratio.

Trituration with ether produced 2. 27 g of the pure 5a, 10 a epoxide (110) as a white powder in 56. 3% yield ; m. p. = 146-153°C. FTIR (KBr, diffuse reflectance) : via 3558, 2939,

1638, 1446, 1373 and 1247 cm-1. NMR (300 MHz, CDC13) : 8 0. 824 (s, 3 H, C18-CH3), 3. 273 (s, 3 H, C17α-OCH3), 3. 389 (s, 3 H, C21-OCH3), 3. 402 (dd, 1 H, Jl = 9. 61 Hz, J2 = 8. 10 Hz, C21-CH2), 3, 476 (dd, 1 H, Jl = 9. 1 Hz, J2 = 3. 30 Hz, C21-CH2), 3. 908 (m, 5 H, C3-OCH2CH20 and C20-CH) and 6. 053 (br s, 1 H, Cl 1-CH=). MS (EI) m/z (relative intensity) : 420 (M+, 1. 7), 402 (6. 0), 370 (6. 2), 345 (20. 0), 313 (77. 8), 295 (100. 0) and 99 (95. 4). Anal. Calcd. for C24H3605'1/OH20 : C, 68. 25 ; H, 8. 64. Found : C, 68. 31 ; H, 8. 71.

Step 5. 3,3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N,N-dimethylamino)phe nyl]- 17a, 21-dimetlioxy-19-norpregn-9-en-20-ol (Illa) : A dry 50 mL 2-neck flask was equipped with a stirrer, a reflux condenser, and a rubber septum. Magnesium (191 mg, 7. 85 mmol) was added and the entire apparatus was dried fruther, under a stream of nitrogen, with a heat gun. After cooling slightly, one crystal of iodine was added. The apparatus was allowed to cool completely and dry THF (4 mL) was added followed by one drop of 1, 2-dibromoethane. A solution of 4-bromo- N, N-dimethylaniline (1. 43 g, 7. 14 mmol) in THF (2 mL) was added via transfer needle and rinsed in with additional THF (2. 0 mL). The mixture was warmed gently with a heat gun to initiate reaction (as evidenced by bleaching of color) and then allowed to stir 1 hr at ambient temperature. Copper (I) chloride (78. 2 mg, 0. 79 mmol) was added as a solid and stirring continued for 20 min. A solution of the 5a, 1 Oa-epoxide (110, 1. 0 g, 2. 38 mmol) in THF (4. 0 mL, heated gently to achieve a solution) was added via transfer needle and rinsed in with additional THF (2 x 2. 0 mL). After stirring 2 hr at room temperature, the reaction was quenched by the addition of saturated NH4Cl (16 mL). Air was drawn through the mixture for l/2 hr with vigorous stirring. The mixture was transferred to a separatory funnel, ether was added, and the layers allowed to separate. The organic fraction was washed again with H20 (lx), and brine (lx). Combined ether extracts (3x) were dried by filtration through Na2S04 and evaporated in vacuo to recover an oily residue. Trituration with ether produced a solid 111 a. The crystals were collected on a Buchner funnel, triturated with additional ether, and dried under high vacuum to recover 1. 02 g of a beige solid (111a) in 79% yield ; m. p. = 195-199°C. FTIR (KBr, diffuse reflectance) : via,, 3534, 3418, 2938, 2875, 2820, 1868, 1614, 1560, 1519, 1443, 1353 and 1328 cm'\ NMR (300 MHz, CDCl3) : 50. 493 (s, 3 H, C18-CH3), 2. 896 (s, 6 H,-N (CH3) 2), 3. 289 (s, 3 H, C17a-OCH3), 3. 362 (s, 3 H, C21-OCH3), 3. 340-3. 448 (m, 2 H, C21-CH2), 3. 747-4. 075 (m, 5 H, C3-OCH2CH20 and C20-CH), 4. 171 (br s, 1 H, C 11 a-CH), 6. 635 (d, 2 H, J = 8. 70 Hz, 3', 5'aromatic-CH's)

and 7. 070 (d, 2 H, J = 8. 70 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 541 (M+, 61. 0), 523 (19. 7), 416 (7. 6), 134 (37. 4), 121 (100. 0) and 99 (20. 2). Anal. Calcd. for C32H47NO6 : C, 70. 95 ; H, 8. 74 ; N, 2. 59. Found : C, 70. 92 ; H, 8. 77 ; N, 2. 65.

Step 6. 3, 3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N,N-dimethylamino)pheny l]- 17a, 21-dimetAtoxy-19-norpregn-9 (10)-en-20-one (112aJ : (a) Preparation of o-iodoxybenzoic acid (Dess, etal., J : Org Chem., 48 : 4155-4156 (1983)) : The initial preparation of IBX gave a material which appeared to be a mixture as evidenced by 13C NMR. Although the oxidant was not homogenous, 3 equivalents of this material (assuming 100% IBX) cleanly converted the 20-OH (alla) to the 20-ketone (112a). The preparation of IBX has been since modified to obtain a homogeneous material with'H NMR and 13C NMR identical to the reported spectra (Frigerio, et al., Tet. Letters, 35 : 8019-8022 (1994)). Only 1. 5 equivalents are necessary for oxidation (Frigerio, et al., Tet. Letters, 35 : 8019-8022 (1994) ; Frigerio, et al., J Org. Chem., 60 : 7272-7276 (1995)). This new material was used for the preparation of 112b and 112c.

Potassium bromate (7. 6 g, 45. 5 mmol) was added over a 10 minute period to a vigorously stirred suspension of 2-iodobenzoic acid (8. 52 g, 34. 4 mmol) in 0. 73 M H2S04 (150 mL). Upon completion of addition, the mixture was warmed to 65°C in a water bath.

Over the next hour, bromine was evolved as was evidenced by a change in color from orange to white. At that time, a second aliquot of potassium bromate (7. 6 g, 45. 5 mmol) was added and stirring continued at 65°C for an additional 2 hr. The mixture was cooled to room temperature, filtered on a Buchner funnel, and washed with H20, followed by acetone. The resulting white solid was dried in vacuo to recover 7. 74 g in 80. 2% yield.

'H NMR (300 MHz, DMSO) : 8 7. 845 (t, 1 H, J = 7. 20 Hz), 7. 96-8. 06 (m, 2 H) and 8. 148 (d, 1 H, J = 7. 80 Hz). 13C NMR (300 MHz, DMSO) : 8 125. 011, 130. 093, 131. 398, 132. 963, 133. 406, 146. 525 and 167. 499.

(b) Oxidation of the 20-ol (llla) to the 20-one (112a) : To a solution of IBX (2. 42 g, 8. 64 mmol) in DMSO (16. 0 mL) at ambient temperature, under nitrogen, a solution of the Grignard product (llla, 1. 56 g, 2. 88 mmol) in DMSO (16. 0 mL) was added via transfer needle. Additional DMSO (2 x 4. 0 mL) was used to rinse in residual steroid.

The resulting purple solution was stirred l/2 hr. At that time, examination by TLC (10% acetone in CHzClz ; aliquot was diluted in H20 and extracted into EtOAc) revealed all of the starting material had been cleanly converted to a single, less polar product. The reaction

was transferred to a separatory funnel, H20 and CH2C12 were added, and the layers allowed to separate. The organic fractions were washed again with H20 (lx) and then brine (lx).

Combined CH2C12 exracts (3x) were dried by filtration through Na 2SO 4 and evaporated in vacuo. The resulting residue was dried overnight under high vacuum to recover a brownish-purple gum (1. 79 g). The gum was taken up in CH2C12 and filtered through silica (-250 mL) on a sintered glass funnel. After eluting with CH2C12 to remove DMSO (2 x 250 mL), the pure product was eluted with 10% acetone in CH2C12 (2 x 250 mL). Fractions containing the product were combined, evaporated in vacuo and dried briefly under high vacuum to afford 1. 29 g of 112a as a colorless foam in 83% yield. A small sample (-100 mg) was reserved, triturated with pentane, and dried to give a white crystalline solid ; m. p. = 160-165°C. FTIR (KBr, diffuse reflectance) : vmax 3514, 2938, 2824, 1724, 1616, 1521, 1520, 1447 and 1354 cm\ NMR (300 MHz, CDC13) : 6 0. 250 (s, 3 H, C18-CH3), 2. 894 (s, 6 H,-N (CH3) 2), 3. 137 (s, 3 H, Cl7a-OCH3), 3. 435 (s, 3 H, C21-OCH3), 3. 998 (m, 4 H, C3-OCH2CH 2O), 4. 231 and 4. 363 (AB, 2 H, JAB = 18. 01 Hz, C21-CH2), 4. 250 (br d, 1 H, Clla-CH), 4. 288 (br s, I H, C5a-OH), 6. 619 (d, 2 H, J = 8. 85 Hz, 3', 5'aromatic- CH's) and 7. 016 (d, 2 H, J = 8. 85 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 539 (M+, 71. 4), 521 (34. 8), 134 (52. 9), 121 (100. 0) and 99 (23. 5). Anal. Calcd. for C32H4sNO6 : C, 71. 21 ; H, 840 ; N, 2. 60. Found : C, 71. 41 ; H, 8. 60 ; N, 2. 63.

Step 7. Preparation of the target compound 113a : To a solution of the 3-ketal-Sa-hydroxy-20-one (112a, 1. 20 gm 2. 22 mmol) in THF (15. 0 mL), was added glacial acetic acid (45. 0 mL, 783 mmol), followed by H20 (15. 0 mL). The mixture was brought to reflux under nitrogen. After 1 hr., TLC (25% EtOAc in CH2C12) indicated the 3-ketal had been hydrolyzed to give the slightly less polar ketone. The reaction was allowed to cool to room temperature and left overnight under nitrogen. Concentrated NH40H (53. 0 mL, 783 mmol) was added to neutralize the reaction and additional NH40H was added to bring the mixture to pH 7. 0 (paper). The mixture was transferred to a separatory funnel and extracted into CH2C12 (3x). The organic fractions were washed again with H2O (lx) and brine (lx). Combined CH2C12 extracts were dried by filtration through Na2S04 and evaporated in vacuo to give 1. 21 g of a yellow oil. The crude product was purified twice by flash chromatography (7. 5% acetone in CH2C12). Fractions containing the pure product were combined and evaporated to give a yellow gum.

Trituration with heptane produced 350 mg of a pale yellow powder. All remaining material

(impure fractions plus mother liquors) was combined and rechromatographed to give an additional 305 mg : Total yield was 655 mg of 113a in 61. 7% yield ; m. p. = 132-136°C.

HPLC analysis of 113a on a Waters Assoc. NovaPak Cig column eluted with 30% 50 mM I<H2PO4 (pH = 3. 0) in MeOH at a flow rate of 1 mL per min and at k = 302 nm indicated a purity of 97. 9% with a retention time (tR) of 7. 87 min. FTIR (KBr, diffuse reflectance) : Vmax 2946, 1724, 1665, 1599, 1518, 1445 and 1348 cm~l. NMR (300 MHz, CDC13) : 8 0. 322 (s, 3 H, C18-CH3), 2. 904 (s, 6 H,-N (CH3) 2), 3. 173 (s, 3 H, Cl7a-OCH3), 3. 453 (s, 3 H, C21-OCH3), 4. 234 and 4. 375 (AB, 2 H, JAB = 17. 86 Hz, C21-CH2), 4. 367 (s, 1 H, Cl la-CH), 5. 750 (s, 1 H, C4-CH=), 6. 634 (d, 2H, J = 8. 55 Hz, 3', 5'aromatic-CH's) and 6. 979 (d, 2 H, J = 8. 55 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 477 (M+, 83. 2), 372 (10. 3), 251 (17. 1), 209 (20. 4), 134 (35. 3) and 121 (100. 0). Anal. Calcd. for C30H39NO4 : C, 75. 44 ; H, 8. 23 ; N, 2. 93. Found : C, 75. 54 ; H, 8. 14 ; N, 2. 94.

EXAMPLE 28 This example illustrates the preparation and properties of 17a, 21- Dimethoxy-llp- [4- (N-pyrrolidino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (113b) (Figure 8) : Step 1. 3, 3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N-pyrrolidino)phenyl]-1 7α,21- dimethoxy-19-norpregn-9-en-20-ol (111b) : A dry 100 mL 2-neck flask was equipped with a stirring bar, a reflux condenser, and rubber septum. Magnesium (248 mg, 10. 2 mmol) was added, and the entire apparatus was dried further under a stream of nitrogen with a heat gun. After cooling slightly, one crystal of iodine was added.

The apparatus was allowed to cool completely and dry THF (5. 0 mL) was added followed by one drop of 1, 2-dibromoethane. A solution of N- (4-bromophenyl) pyrrolidine (see, EXAMPLE 17, Step 3) (2. 1 g, 9. 27 mmol) in THF (2. 5 mL) which was warmed gently to achieve solution, was added via transfer needle and rinsed in with additional THF (2. 5 mL). The mixture was brought to reflux and after 2 hr, almost all of the magnesium had been consumed. The cloudy, dark gray mixture was allowed to cool to room temperature and copper (I) chloride (101 mg, 1. 02 mmol) was added as a solid. After stirring 1. 5 hr at room temperature, a solution of the 5a, 10a-epoxide (110, 1. 3 g, 3. 09 mmol) in THF (5. 0 mL) which was heated gently to achieve a solution,

was added via a transfer needle and rinsed in with additional THF (5. 0 mL). After stirring 1 hr at room temperature, the reaction was quenched by the addition of saturated NH4C1 (20 mL). Air was drawn through the mixture for l/2 hr with vigorous stirring. The mixture was transferred to a separatory funnel, H20 and ether were added, and the layers allowed to separate. The organic fraction was washed again with H20 (lx), and brine (lx). Combined ether extracts (3x) were dried by filtration through Na2S04, evaporated in vacuo, and dried further under high vacuum to recover a greenish-brown oil (2. 47 g). Examination by TLC (15% acetone in CH2C12) revealed one major, slightly less polar product and a trace of impurities. Trituration with pentane or pentane/ether failed to produce a solid. Purification by flash chromatography (15% acetone in CH2Cl2) gave 978 mg of pure lllb as a white foam. Fractions containing 410 mg of the impure product were rechromatographed to recover 152 mg of an additional pure material lllb. The total yield of the purified product 111b was 1. 13 gas a white foam in 64. 4% yield. Trituration of this foam with pentane, followed by washing with heptane produced a white powder. The white powder was dried overnight in a drying pistol with benzene to give 727. 1 mg of lllb in 41. 5% yield. ; m. p. = 135-143°C. FTIR (KBr, diffuse reflectance) may 3469, 2945, 2820, 1614, 1517, 1487, 1462, 1442, 1371, 1239, 1192, 1122 and 1076 cm~ R (300 MHz, CDC13) : 6 0. 505 (s, 3 H, C18-CH3), 3. 247 (m, 4 H, pyrrolidyl a-CH2), 3. 288 (s, 3 H, Cl7a-OCH3), 3. 364 (s, 3 H, C21-OCH3), 3. 339-3. 448 (m, 2 H, C21-CH2), 3. 808 (m, 1 H, C20-CH), 4. 000 (m, 4 H, C3-OCH2CH20), 4. 12-4. 21 (m, 1 H, C11α-CH), 4. 392 (s, 1 H, C5a-OH), 6. 460 (d, 2 H, J = 8. 70 Hz, 3', 5'aromatic-CH's) and 7. 056 (d, 2 H, J = 8. 70 Hz, 2', 6'aromatic- CH's). MS (EI) m/z (relative intensity) : 567 (M+, 34. 0), 549 (33. 1), 442 (12. 9), 160 (30. 3), 147 (100. 0) and 99 (14. 9). Anal. Calcd. for C34H49NO6 : C, 71. 93 ; H, 8. 70 ; N, 2. 47.

Found : C, 72. 03 ; H, 8. 71 ; N, 2. 46.

Step 2. 3, 3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N-pyrrolidinio)phenyl]1 7α,21- dimethoxy-19-norpregn-9-en-20-o7te (112b) : To a suspension of IBX (EXAMPLE 27, Step 6 (a)) (501 mg, 1. 79 mmol) in dimethylsulfoxide (DMSO) was added a solution of the Grignard adduct (lllb, 677 mg, 1. 19 mmol) in DMSO (6. 0 mL). Additional DMSO (2 x 2. 0 mL) was used to rinse in residual lllb. Almost inunediately upon addition of lllb, a green solution formed which rapidly changed to purple. After 1 hr, examination by TLC (15% acetone in CH2C12) ; aliquot was diluted with H20 and extracted into EtOAc) revealed all of the starting material

had been cleanly converted to a single, less polar product. The reaction mixture was transferred to a 500 mL separatory funnel and diluted with H20 and brine. The product was extracted into EtOAc (3x). The organic fractions were washed again with H20 (lx), then brine (lx). Combined EtOAc extracts (3x) were dried by filtration through anhydrous Na2S04 and evaporated in vacuo. The resulting residue was dried overnight under high vacuum to recover 0. 85 g of a purple foam. Purification by flash chromatography (15% acetone in CH2C12) gave 494 mg of 112b as a pale yellow foam in 73. 1 % yield. A small amount was triturated with heptane and dried in a drying pistol with benzene to give 51 mg of a pale yellow solid for analysis ; m. p. = 120-125°C. FTIR (KBr, diffuse reflectance) : vmax 3540, 2946, 2830, 1722, 1666, 1613, 1517, 1488, 1462, 1445, 1372, and 1188 cm~l.

NMR (300 MHz, CDC13) : 8 0. 264 (s, 3 H, C18-CH3), 3. 135 (s, 3 H, Cl7a-OCH3), 3. 242 (m, 4 H, pyrrolidyl a-CH2), 3. 433 (s, 3 H, C21-OCH3), 3. 997 (m, 4 H, C3-OCH2CH20), 4. 232 and 4. 381 (AB, 2 H, JAB = 17. 86 Hz, C21-CH2), 4. 366 (br s, 1 H, Cl la-CH), 5. 747 (s, 1 H, C4-CH=), 6. 463 (d, 2 H, J = 8. 40 Hz, 3', 5'aromatic-CH's) and 7. 002 (d, 2 H, J = 8. 40 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 565 (M+, 14. 9), 547 (72. 7), 503 (7. 7), and 147 (100. 0). Anal. Calcd. for C34H47N06-1/3C3H60-1/20 C7Hi6 : C, 72. 51 ; H, 8. 34 ; N, 2. 33. Found : C, 72. 67 ; H, 8. 13 ; N, 2*31.

Step 3. Preparatio71 of tlte target compouiid 113b : To a solution of the 3-ketal-20-ketone (112b, 443 mg, 0. 78 mmol) in THF (5. 0 mL), was added glacial acetic acid (15 mL, 261 mmol), followed by water (5. 0 mL).

After 5 hr, TLC (10% acetone in CH2C12 ; neutralized with concentrated NH40H before developing) indicated that most of the 3-ketal had been hydrolysed to give the slighly less polar ketone. The reaction was allowed to continue overnight. The next morning, all of the starting material had been converted to the product with only a trace of impurities. The reaction mixture was neutralized by the addition of concentrated NH40H (17. 6 mL, 261 mmol, pH 7 by pH paper). The mixture was transferred to a separatory funnel and extracted with CHUCK (3x). The organic fractions were washed again with H20 (lx), and brine (lx), Combined CHzClz extracts were dried by filtration through anhydrous Na2S04 and evaporated in vacuo to give 450 mg of a yellow film. The crude product was purified twice by flash chromatography (10% acetone in CH2C12). Fractions containing highly pure product were combined and evaporated to give 311 mg of a pale yellow glass.

Trituration with heptane produced 264 mg of a pale yellow solid. At this point, inspection of this material by HPLC indicated a purity of 95. 7%. The product was rechromatographed (7. 5% acetone in CH2Ck) and again triturated with heptane to produce 190 mg of a pale yellow powder. No additional purification was achieved.

Attempts to further purify the sample by normal phase HPLC were also unsuccessful. Finally, the sample was recrystallized from hot heptane and dried overnight in a drying pistol with heptane to give 97. 1 mg of a beige powder in 24. 4% yield ; m. p.

122. 5-126°C. Analysis by HPLC on a Waters Assoc. NovaPak Cl8 column eluted with 30% 50 mM KH2P04 [pH = 3. 0] in MeOH at a flow rate of 1 mL per min and at X = 302 nm, indicated a purity of 94. 97% with a retention time (tR) of 21. 475 min. FTIR (KBr, diffuse reflectance) : vn 2944, 2826, 1726, 1667, 1614, 1518, 1488, 1465, and 1379 cry.

NMR (300MHz, CDCl3) : 8 0. 339 (s, 3 H, C18-CH3), 3. 172 (s, 3 H, C17a-OCH3), 3. 242 (m, 4 H, pyrrolidyl a-CH2), 3. 450 (s, 3 H, C21-OCH3), 4. 232 and 4. 381 (AB, 2 H, JAB = 18. 01 Hz, C21-CH2), 4. 366 (br s, 1 H, C1 la-CH), 5. 747 (s, 1 H, C4-CH=), 6. 463 (d, 2 H, J = 8. 55 Hz, 3', 5'aromatic-CH's) and 6. 962 (d, 2 H, J = 8. 55 Hz, 2', 6'aromatic-CH's).

MS (EI) m/z (relative intensity) : 503 (M+, 59. 3), 398 (4. 9), 251 (8. 6), 160 (17. 6) and 147 (100. 0). Anal. Calcd. for C32H4iN04-l/6C7Hi6-l/6H20 : C, 76. 11 ; H, 8. 47 ; N, 2. 68 Found : C, 76. 04 ; H, 8. 40 ; N, 2. 69.

EXAMPLE 29 This example illustrates the preparation and properties of 17a, 21- Dimethoxy-1 1 ß- [4-(N-piperidino) phenyl]-1 9-norpregna-4, 9-diene-3, 20-dione (113c) (Figure 8) : Step 1. 3, 3-Ethylenedioxy-5α-hydroxy-11ß-[4-(N-piperidino)phenyl]-17 α,21- dimethoxy-19-nor pregn-9-enj-20-ol (111c): A dry 50 mL 2-neck flask was equipped with a stirring bar, a reflux condenser and a rubber septum. Magnesium (137 mg, 5. 64 mmol) was added and the entire apparatus was dried father under a stream of nitrogen with a heat gun. After cooling slightly, one crystal of iodine was added. The apparatus was allowed to cool completely and dry THF (4 mL) was added followed by 1 drop of 1, 2-dibromoethane. A solution of N- (4-bromophenyl) piperidine (see, EXAMPLE 23, Step 1) (1. 23 g, 5. 13 mmol) in THF (2. 0 mL) was added via a transfer needle and rinsed in with additional THF (2. 0 mL). The

reaction mixture was brought to reflux for 1 hr. At that time, the Grignard reagent had formed as evidenced by consumption of almost all of the magnesium and bleaching of the iodine color. The cloudy, dark gray mixture was allowed to cool to room temperature and copper (I) chloride (55. 4 mg, 0. 56 mmol) was added as a solid. After stirring l/2 hr, a solution of the 5a, 10a-epoxide (110, 1. 0 g, 2. 38 mmol) in THF (4. 0 mL ; heated gently to achieve a solution) was added via transfer needle and rinsed in with additional THF (4. 0 mL). After stirring 2 hr at room temperature, the reaction was quenched by the addition of saturated NH4Cl (16 mL). Air was drawn through the mixture for 1/2 hr with vigorous stirring. The mixture was transferred to a separatory funnel, H2IO and ether were added, and the layers allowed to separate. The organic fraction was washed with H2O (1x)j, and brine (lx). Combined ether extracts (3x) were dried by filtration through anhydrous Na2S04, evaporated itz vacuo, and dried further under high vacuum to recover 1. 73 g of an amber gum. Examination of the gum by TLC (15% acetone in CH2C12) revealed a single, slightly more polar product and trace of the epoxide. Trituration with ether failed to produce a solid. The crude product was purified by flash chromatography (15% acetone in CH2C12). Fractions containing the pure product 111 c were combined and evaporated to give 0. 36 g of a white foam. Fractions containing the product plus the epoxide were rechromatographed to give 0. 43 g of additional pure product 111c. The total yield of the purified product obtained was 0. 79 g of lllc as a white foam in 56. 7% yield. A small amount was triturated with heptane and dried overnight in a drying pistol with acetone to give 73. 8 mg of a white powder (111c) which was reserved for analysis ; m. p. = 162- 171°C. FTIR (KBr, diffuse reflectance) : May 3470, 2934, 2868, 2816, 1610, 1511, 1440 and 1380 crri l. NMR (300 MHz, CDC13) : 8 0. 475 (s, 3 H, C18-CH 3), 3. 091 (m, 4 H, piperidyl a-CH2), 3. 285 (s, 3 H, C17α-OCH3), 3. 361 (s, 3 H, C21-OCH3), 3. 34- 3. 45 (m, 2 H, C21-CH2), 3. 794 (m, 1 H, C20-CH), 3. 998 (m, 5 H, C3-OCH2CH20 and C20-OH), 4. 178 (brs, IH, Clla-CH), 4. 389 (s, IH, C5a-OH), 6. 810 (d, 2H, J = 8.85 Hz, 3', 5' aromatic-CH's) and 7. 073 (d, 2 H, J = 8. 85 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 581 (M+, 39. 0), 563 (24. 4), 456 (5. 9), 174 (24. 9), 161 (100. 0) and 99 (12. 1).

Anal. Calcd. for C35H51NO6 : C, 72. 26 ; H, 8. 84 ; N, 2. 41. Found : C, 72. 31 ; H, 8. 78 ; N, 2. 36.

Step 2. 3,3-Ethylenedioxy-5α-hydroxy-11ß-]4-N-piperidino)phenyl]-1 7α,21- dimethoxy-19-norpregn-9-enj-20-one (112c) To a suspension of IBX (0. 49 g, 1. 76 mmol) in DMSO (7. 0 mL) was added a solution of the Grignard adduct (lllc, 0. 68 g, 1. 17 mmol) in DMSO (6. 0 mL). Additional DMSO (2 x 2. 0 mL) was used to rinse in residual lllc. Almost immediately upon addition of 111 c, a purple solution formed. The reaction was allowed to stir 2 hr at ambient temperature without any precautions against oxygen or moisture. At that time, the color had turned from purple to deep red. Examination of this solution by TLC (15% acetone in CH2C12 ; aliquot was diluted with H20 and extracted into EtOAc) revealed all of the starting material had been cleanly converted to a single, less polar product. The reaction mixture was transferred to a separatory funnel, H20 and CH2C12 were added, and the layers allowed to separate. The organic fraction was washed again with H20 (lx) and brine (lx).

Combined CH2C12 extracts (3x) were dried by filtration through anhydrous sodium sulfate and evaporated iyi. vacuo. The resulting residue was dried overnight under high vacuum to recover 0. 72 g of a purple gum. Purification by flash chromatography (15% acetone in CH2C12) gave 572 mg of a colorless gum. Trituration with heptane afforde 529 mg of 112c as a white solid in 77. 8% yield. A small amount was reserved and dried further in a drying pistol with acetone for analysis ; m. p. = 107-111°C. FTIR (KBr, diffuse reflectance) : Vmax 3534, 2931, 2823, 1721, 1609, 1511 and 1450 cm-1. NMR (300 MHz, CDC13) : 8 0. 234 (s, 3 H, C18-CH3), 3. 089 (m, 4 H, piperidyl a-CH 2), 3. 134 (s, 3 H, C17a-OCH3), 3. 429 (s, 3 H, C21-OCH3), 3. 995 (m, 4 H, C3-OCH2CH20), 4. 213 and 4. 355 (AB, 2 H, J AB = 18. 01 Hz, C21-CH2), 4. 212-4. 306 (m, 2 H, Cl la-CH and C5a-OH), 6. 803 (d, 2 H, J = 8. 70 Hz, 3', 5'aromatic-CH's) and 7. 021 (d, 2 H, J = 8. 70 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 579 (MF, 38. 7), 561 (16. 1), 174 (23. 7), 161 (100. 0) and 99 (12. 1) Anal. Calcd. for C35H49NO6 : C, 72. 51 ; H, 8. 52 ; N, 2. 42. Found : C, 72. 47 ; H, 8. 58 ; N, 2. 35.

Step 3. Preparatioii of the target compouizd 113c.- To a solution ofthe 3-ketal-20-ketone (112c, 471 mg, 0. 81 mmol) in THF (5. 0 mL) was added glacial acetic acid (15 mL, 261 mmol) followed by H20 (5. 0 mL). The mixture was brought to reflux under nitrogen. After 3 hr, TLC (10% acetone in CH2C12 ; neutralized with NH40H before developing) indicated the 3-ketal had been hydrolyzed to give the slightly less polar ketone. The reaction mixture was allowed to cool to room

temperature and neutralized by the addition of concentrated NH40H (17. 6 mL, 261 mmol, pH 7 by a pH paper). The mixture was transferred to a separatory funnel and extracted into CHzClx (3x). The organic fractions were washed again with H2O (lx), and brine (lx).

Combined CH2C12 extracts were dried by filtration through anhydrous Na2S04 and evaporated in vacuo to recover 426 mg of a yellow glass. This crude product was purified by flash chromatography (5% acetone in CH2C12). Fractions containing highly pure product were combined and evaporated to give a pale yellow glass 113c. Trituration of 113c with heptane produced a pale yellow solid. The product was dried overnight in a drying pistol with benzene to give 189. 6 mg of 113c as a pale yellow solid in 45. 7% yield ; m. p. = 108-112°C. Analysis by HPLC on a Waters Assoc. NovaPak Cl8 column eluted with 30% 50 mM KH 2PO 4, pH 3. 0 in MeOH at a flow rate of 1 mL per min and at k = 302 nm, indicated a purity of 97. 22% with a retention time (tR) of 3. 73 min. FTIR (KBr, diffuse reflectance) : vmaX 2935, 2822, 1723, 1664, 1609, 1511, 1488, 1451 and 1386 cm\ NMR (300 MHz, CDC13) : 8 0. 304 (s, 3 H, C18-CH3), 3. 100 (m, 4 H, piperidyl a-CH2), 3. 172 (s, 3 H, Cl7a-OCH3), 3. 450 (s, 3 H, C21-OCH3), 4. 227 and 4. 370 (AB, 2 H, JAB = 18. 01 Hz, C21-CH2), 4. 366 (br s, I H, Clla-CH), 5. 753 (s, 1 H, C4-CH=), 6. 821 (d, 2 H, J = 8. 70 Hz, 3', 5'aromatic-CH's) and 6. 985 (d, 2 H, J = 8. 70 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 517 (M+, 57. 8), 412 (4. 6), 318 (6. 6), 174 (15. 8), and 161 (100. 0). Anal. Calcd. for C33H43NO4 : C, 76. 56 ; H, 8. 37 ; N, 2. 71. Found : C, 76. 45 ; H, 8. 37 ; N, 2. 70.

EXAMPLE 30 This example illustrates the preparation and properties of 17a, 21- Dimethoxy-llß-(4-acetylphenyl)-19-norpregna-4, 9-diene-3, 20-dione (113d) (Figure 8) : Step 1. 3,3-Ethylenedioxy-5α-hydroxy-11ß-[4-(2-methyl-1,3-dioxolan -2- yl) phenyl 7a, 21-dimethoxy-19-norpregfa-9-en-20-ol (llld) : Magnesium turnings (289 mg, 11. 89 mmol) were weighed into a 100 mL round bottom two-neck flask equipped with a reflux condenser, a magnetic stirrer, and a rubber septum. A small crystall of iodine was added and the system was flushed with nitrogen and flame dried. After cooling to room temperature, freshly distilled THF (10 mL) was introduced via syringe followed by a small amount of dry dibromoethane (-0. 1 mL).

After evidence of reaction was observed (disappearance of I2 color, and bubble formation

on metal), a solution of the ketal of 4-bromoacetophenone (see, Example 20, Step 1) (2. 89 g, 11. 89 mmol) in dry THF (10 mL) was added via syringe. The mixture was then stirred in a hot water bath for 2 hr until the majority of the magnesium was consumed. After the reaction mixture was cooled to room temperature, solid copper (I) chloride (11. 8 mg, 1. 19 mmol) was added and the mixture was stirred at room temperature for 1/2 or. The epoxide (110, 1. 0 g, 2. 38 mmol) in dry THF (10 mL) was added via syringe. The reaction mixture was stirred at room temperature for 1 hr then quenched with the addition of saturated NH4C1 solution (-20 mL), and the mixture was stirred at room temperature for 1/2 hr while air was drawn through the reaction mixture to oxidize Cu (I) to Cu (II). The contents of the flask were diluted with water (-100 mL) and extracted with CH2CI2 (3x). The organic extracts were washed with saturated NH4C1 solution (lx), water (lx) and brine (lx), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 4. 3 g of oil.

This was purified on a flash column (10% acetone in CH2Cl2) to yield 850 mg of 111d as a white foam which was triturated with ether to produce a white crystalline solid in 61. 2% yield ; m. p. = 145-150°C (Material changed to amber gel) and gel melts at 173-177°C.

FTIR (KBr, diffuse reflectance) : Vmax 3461, 2946, 2877, 2812, 1663, 1602, 1540, 1505, 1457 and 1372 cni 1. NMR (300 MHz, CDCl3) : 8 0. 443 (s, 3H, C18-CH3) 1. 636 (s, 3 H, CH3 of acetophenone ketal), 3. 289 (s, 3 H, C17a-OCH3), 3. 358 (s, 3 H, C21-OCH3), 3. 741- 4. 015 (m, 8 H, C3-and C11ß-4- acetyl ketals), 4. 244 (br s, 1 H, C11α-CH), 7. 165-7. 327 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 584 (M+). Anal. Calcd. for C34H48Og : C, 69. 86 ; H, 8. 22. Found : C, 69. 63 ; H, 8. 28.

Step 2. 3, 3-Ethylenedioxy-5α-hydroxy-11ß-[4-(2-methyl-1,3-dioxolan-2 - yl) phenylJ-17a, 21-dinzetlaoxy-19-faopregsa-9-en-20-one (112d) : Under nitrogen, IBX (1. 149 g, 4. 104 mmol) was dissolved in DMSO (8 mL) over a period of 10 min. A solution of the Grignard product (111d, 800 mg, 1. 368 mmol) in DMSO (8 mL) was added via pipette to the above solution and the reaction mixture stirred at room temperature for #hr. At that time, TLC (10% acetone in CH2C12 ; aliquot was diluted in water and extracted into EtOAc) showed the starting material had been converted to a single less polar product. The reaction was diluted with H20 (-150 mL) and extracted with CHzClz (3x). The organic layers were washed with H20 (lx) and brine (lx), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 820 mg of 112d as an off-white foam. This was purified on a flash column (10% acetone in CH2C12). The

product was originally obtained as a foam and was triturated with pentane and dried in vacuo to yiled 540 mg of 112d as a white solid in 73% yield ; m. p. = 102-106°C (shrinkage to an amber gel) ; 111-113°C (gel bubbles) ; 123-133°C (gel melts). FTIR (KBr, diffuse reflectance) : Vmax 3526, 2939, 2884, 2825, 1722, 1665 and 1604 crn 1. NMR (300 MHz, CDCIs) : # 0. 190 (s, 3 H, C1 8-CH 3), 1. 625 (s, 3 H, CH3 of acetophenone ketal), 3. 146 (s, 3 H, Cl7a-OCH3), 3. 445 (s, 3 H, C21-OCH3), 3. 742 and 4. 015 (m, C3 and Clip-4- acetylphenyl ketal), 4. 310 (d, 1 H, Cl la-CH), 7. 119-7. 332 (dd, 4 H, aromatic-CH's) MS (EI) m/z (relative intensity) : 582 (M+). Anal. Calcd. for C34H4608 : C, 70. 08 ; H, 7. 96 Found : C, 70. 11 ; H, 8. 01. FTIR (KBr. diffuse reflectance) : May 3526, 2939, 2884, 2825, 1722, 1665 and 1604 cm~l. NMR (300 MHz, CDC13) : 6 0. 190 (s, 3H, C18-CH3), 1. 625 (s, 3 H, CH3 of acetophenone ketal), 3. 416 (s, 3 H, C17a-OCH3), 3. 445 (s, 3 H, C21-OCH3), 3. 742 and 4. 015 (m, C3 and C11, B-4-acetylphenyl ketals), 4. 310 (d, 1 H, Clla-CH), 7. 119- 7. 332 (dd, 4 H, aromatic-CH). MS (EI) m/z (relative intensity) : 582 (M+). Anal. Calcd. for C34H460S : C, 70. 08 ; H, 7. 96 Found : C, 70. 11 ; H, 8. 01.

Step 3. preparation of the target compound 113d; Nitrogen was bubbled through a mixture of EtOH (925 mL) and 8. 5% sulfuric acid for l/2 hr to remove oxygen. The 20-ketone (112d, 520 mg, 0. 892 mmol) was added as a solid with stirring to the above solution. The mixture was put into an oil bath preheated to 95°C and was refluxed under nitrogen for 1 hr. The reaction mixture was cooled in an ice bath and quenched with saturated K2CO3 solution (pH _ 10), diluted with water (-125 mL) and extracted with CH2C12 (3x). The organic fractions were washed with water and brine, dried over anhydrous Na 2SO4, filtered and concentrated ilz vacuo to give 460 mg of the crude product. Flash chromatography (10% acetone in CH2C12) gave 377 mg of an off-white pale yellow solid. This was crystallized from a mixture of distilled ether and CH2C12 to yield 360 mg of 113d in 81% yield as a white crystalline solid in two batches. The product 113d retained CH2C12 and required extreme drying : m. p. = 133-136°C (foams) and 172-178°C (foam melts). FTIR (KBr, diffuse reflectance) : vmax 2942, 1719, 1681, 1665, 1600, 1409, 1359 and 1272 cm~l. NMR (300 MHz, CDC13) : # 0. 264 (s, 3 H, C18-CH3), 2. 571 (s, 3 H, CH3 of acetophenone ketal), 3. 185 (s, 3 H, C17a-OCH3), 3. 449 (s, 3 H, C21-OCH3), 4. 183 and 4. 385 (dd, 2 H, C21-CH2-), 4. 456 and

4. 481 (d, 1 H, Clla-CH), 5. 90 (s, 1 H, C4-CH=), 7. 247-7. 7883 (dd, 4 H, aromatic-CH's).

MS (EI) m/z (relative intensity) : 476 (M+, 35), 403 (93), 371 (100), 331 (67) and 91 (26).

Anal. Calcd. for C30H36Os : C, 75. 63 ; H, 7. 56. Found : C, 74. 78 ; H, 7. 58.

EXAMPLE 31 This example illustrates the preparation and properties of 17a-Acetoxy-11 I [4- (N-piperidino) phenyl]-21-methoxy-19-norpregna-4, 9-diene-3, 20-dione (123a) : Step 1. 17α-Hydroxy-21-chloro-19-norpregna-4,9-diene-3,20-dione (115): The 3-ketal cyanohydrin (98, 50g, 73. 22 mmol) was magnetically stirred with freshly distilled THF (550 mL) under nitrogen at room temperature. 4- Dimethylaminopyridine (DMAP) (4. 47 g, 36. 59 mmol) was added as a solid. Freshly distilled Et3N (27. 60 mL, 197. 68 mmol) followed by freshly distilled chloro- (chloromethyl) dimethylsilane (25. 1 mL, 190. 36 mmol) was added via syringe. The reaction was allowed to stir overnight at room temperature. The next day TLC on silica (2% acetone in CH2CI2) showed all starting material had been converted to the silyl ether.

The reaction mixture was cooled to-78°C in a dry ice bath with isopropanol, and then diluted with THF (800 mL). Lithium diisopropylamide (LDA) (2. 0 M, 300 mL, 600 mmol) was added dropwise to the reaction via an additional funnel over a period of 45 min. Once addition was complete, the reaction was stirred for 1. 5 hr at-78°C. HC1 (4 N, 1250 mL, 5 mol) was added via the addition funnel. The dry ice bath was removed, and the reaction was allowed to stir overnight at room temperature. The reaction mixture was then cooled to 0°C and neutralized by the addition of concentrated NH40H (305 mL). The mixture was transferred to a separatory funnel and extracted with EtOAc (3x), washed with H20 (2x) and brine (lx). The organic fractions were combined, filtered through Na2S04 and evaporated in vacuo. The resulting solid was triturated with ether (1000 mL), collected on a Buchner funnel, and washed with additional ether. After drying overnight in vacuo, 38. 90 g of 115 as a dark yellow solid was recovered in 76. 61% yield. Analysis by TLC on silica (5% acetone in CH2Cl2) showed the material was suitable to carry directly on to the next reaction ; m. p. = 204-207°C. FTIR (KBr, diffuse reflectance) : Vmax 3465, 2946, 1729, 1664, 1599 and 1573 cm'\ NMR (300 MHz, CDC13) : 8 0. 833 (s, 3 H, C18-CH3), 4. 352 and 4. 655 (AB, 2 H, JAB = 16. 8 Hz, C21-CH2) and 5. 687 (s, 1 H, C4-CH=) MS (EI) m/z (relative intensity) : 350 (M+, 33. 1), 348 (100. 0), 253 (63. 7), 213 (71. 5) and 91 (62. 6).

Step 2. 17a-&num ydroxy-21-acetoxy-19-norpregna-4, 9-diene-3, 20-dione (116) : The 21-chloro compound (115, 37. 90 g, 108. 64 mmol), KOAc (111. 83 g, 1139. 63 mmol) and acetonitrile (927 mL) were mechanically stirred. The suspension was brought to reflux under nitrogen. After 2. 5 hr, TLC on silica (5% acetone in methylene chloride) indicated the reaction had gone to completion. The reaction mixture was allowed to cool to room temperature, and precipitated KC1 was removed by filtration through a sintered glass funnel. Acetonitrile was evaporated in vacuo, and the resulting residue was taken up in CH2C12 and H20. The mixture was transferred to a separatory funnel, extracted with CH2Cl2 (3x), and washed with H2O (2x) and brine (lx). The organic fractions were combined, filtered through Na2S04 and evaporated in vacuo to give 36. 26 g of 116 in 89. 61% crude yield. The solid material was taken up in hot acetone (150 mL) and CH2Cl2 (150 mL). The solution was scratched, seeded and stored in the freezer for 4 hr. The crystals were then filtered through a Buchner funnel and dried in vacuo to recover 10. 71 g of the 17a-ol-21-acetate (116) in 52. 14% yield. The mother liquor was evaporated in vacuo and purified by flash column chromatography eluted with 10% acetone in CH2C12.

Fractions containing the 17a-ol-21-acetate (116) were combined and evaporated in vacuo to recover 2. 58 g of a golden yellow solid in 12. 61%. The total yield of the purified 17a-ol- 21-acetate (116) was 13. 29 g of a golden yellow solid in 64. 7% yield ; m. p. = 213-218°C.

FTIR (KBr, diffuse reflectance) : may 3475, 2947, 2951, 1744, 1720, 1646, 1606, 1578, 1367 and 1235 cni 1. NMR (300 MHz, CDC13) : 8 0. 841 (s, 3 H, C18-CH3), 2. 182 (s, 3 H, C21-OAc), 4. 868 and 5. 081 (AB, 2 H, JAB = 17. 4 Hz, C21-CH2) and 5. 683 (s, 1 H, C4-CH=) MS (EI) m/z (relative intensity) : 372 (M+, 78. 3), 354 (9. 7), 312 (75. 6), 253 (100. 0) and 91 (69. 3).

Step 3. 17α,21-Dihydroxy-19-norpregna-4,9-diene-3,20-dione (117): The 17a-ol-21-acetate (116) (35. 15 g, 94. 37 mmol) was suspended in freshly opened MeOH (2870 mL) and deoxygenated by bubbling nitrogen through the mixture for 45 min. I (HCO3 (deoxygenated, 0. 5 M, 283 mL, 141. 74 mmol) was added, and the suspension was mechanically stirred and brought to reflux under nitrogen. After 10 minutes at reflux, TLC on silica (5% isopropanol in CH2C12) showed the reaction to be complete. The reaction mixture was cooled to room temperature, neutralized by the addition of HOAc (8. 15 mL), and MeOH was evaporated in vacuo. The reaction mixture was extracted with CH2C12 (3x), and washed with H20 (2x) and brine (lx). The combined

organic fractions were filtered through Na2S04 and evaporated in vacuo to recover 29. 83 g of the solid in 95. 7% yield. The solid was taken up in acetone with a small amount of CH2C12. The solution was scratched, seeded and stored in the freezer for 1 hr. The resulting crystals were collected on a Buchner funnel, rinsed with acetone and dried in vacuo to recover the first crop. The mother liquor was concentrated and stored in the freezer overnight to afford a second crop of crystals. The combined solid recovered was 16. 15 g in 51. 8% crude yield. The mother liquors were evaporated in vacuo and purified by flash column chromatography eluted with 5% isopropanol in CH2Cl2. Fractions containing the diol (117) were combined and evaporated in vacuo to recover 4. 86 g. The total yield of 117 was 19. 75 g of a light yellow solid in 76. 7% ; m. p. = 197-204°C. FTIR (KBr, diffuse reflectance) : vax 3917, 2954, 2869, 1715, 1635, and 1590 em-1. NMR (300 MHZ, CDC13) : 8 0. 827 (s, 3 H, C18-CH3), 4. 323 and 4. 690 (AB, 2 H, JAB = 19. 81 Hz, C21-CH2) and 5. 686 (s, 1 H, C4-CH=). MS (EI) m/z (relative intensity) : 330 (M+, 100. 0), 312 (10. 1), 253 (61. 7), 213 (64. 5), 174 (26. 1) and 91. (38. 5).

Step 4. 3, 20-bis-Etl1lylenedioxy-17a, 21-Dihydroxy-19-norpregna-5 (10), 9 (11)- diene (118) : The diol (117, 9. 88 g, 29. 89 mmol) and freshly opened ethylene glycol (750 mL) were magnetically stirred. p-Toluenesulfonic acid monohydrate (0. 49 g, 2. 60 mmol) was added to the suspension as a solid. The ethylene glycol was distilled in vacuo at 81°C under 2 mm Hg. After distilling for 3 hr, the mixture was cooled to room temperature and poured into saturated NaHCO3 (250 mL) and H20 (250 mL). The mixture was extracted with CH 2Cl2 (3x), washed with H20 (2x) and brine (lx). The organic fractions were combined, filtered through sodium sulfate and evaporated in vacuo to recover a solid.

Analysis by TLC on silica (5% isopropanol in CH2C12) showed all of the starting material to be converted to an 85 : 15 mixture of 3, 20-diketal to 3-ketal with a small amount of by- product. The resulting solid was triturated with ether, collected on a Buchner funnel, washed with additional ether and dried in vacuo to recover 6. 46 g of 118 in 51. 64% yield.

The mother liquor was evaporated in vacuo and purified through flash chromatography eluting with 4% isopropanol in CH2C12. This recovered 0. 6 g of the light beige, solid diketal in 4. 8% yield. The total yield of the solid diketal (118) was 7. 06 g of a light beige solid in 56. 44% yield ; m. p. = 173-176°C. FTIR (KBr, diffuse reflectance) : via 3452, 2892, 1652, 1436, 1370, 1223 and 1055 cm-l. NMR (300 MHz, CDC13) : 8 0. 795 (s, 3 H,

C18-CH3), 3. 686 and 3. 894 (AB, 2 H, JAB = 12. 61 Hz, C21-CH2), 3. 987 (s, 4 H, C3- OCH2CH2O-), 4. 130 (m, 4 H, C20-OCH2CH20-) and 5. 555 (br s, 1 H, C11-CH=). MS (EI) m/z (relative intensity) : 418 (M+, 5. 6), 400 (0. 7), 387 (3. 9), 314 (3. 5), 211 (4. 6) and 103 (100. 0).

Step 5. 3, 20-bis-Ethylenedioxy-17a-liydroxy-21-methoxy-19-norpregiza- 5 (10), 9(11)-diene (119): To a solution ofthe diketal (118, 0. 5 g, 1. 19 mmol) in CH2C12 (50mL) was added 1, 8-bis- (dimethylamino) naphthalene ("Proton Sponge", 1. 28 g, 5. 97 mmol) followed by trimethyloxonium tetrafluoroborate (0. 88 g, 5. 97 nunol). The mixture was mechanically stirred in an ice bath under nitrogen. The ice bath was allowed to melt to bring the reaction to room temperature. The reaction mixture was stirred for 3 hr, at which time TLC (5% isopropanol in CH2Cl2) indicated the reaction had gone to completion. The mixture was poured into a separatory funnel and washed with H2O (2x). The CH 2C12 extracts (3x) were combined, filtered through Na2S04 and evaporated in vacuo. The resulting residue was taken up in EtOAc, washed with ice-cold 1 N HC1 (2x), H20 (lx), saturated NaHC03 (lx), H2 O (1x), and brine (lx). Combined EtOAc fractions (3x) were filtered through Na2SO4 and evaporated in vacuo to give 0. 5 g of 119 as a yellow foam in 97. 14% yield.

The material was of adequate purity to carry onto the subsequent epoxidation. The reaction was repeated to produce a total of 13. 57 g of the 21-methoxy compound (119). NMR (300 MHz, CDC13) : 6 0. 798 (s, 3 H, C18-CH3), 3. 415 (s, 3 H, C21-OCH3), 3. 546 and 3. 715 (AB, 2 H, JAB = 10. 51 Hz, C21-CH2), 3. 985 (s, 4 H, C3-OCH 2CH 20-), 4. 05 (m, 4 H, C20- OCH2CH20-) and 5. 54 (br s, 1 H, C11-CH=). Decomposition of analytical sample precluded further analysis.

Step 6. 3, 20-bis-Ethylenedioxy-Sa, 10a-epoxy-17a-laydroxy-21-aetlaoxy-19- norpregn-9 (11)-ene (120) : Hexafluoroacetone trihydrate (6. 49 mL, 46. 64 mmol) and CH2Cl2 (100 mL) were mechanically stirred vigorously at 4°C. Solid Na2HP04 (3. 67 g, 25. 91 mmol) and 30% H202 (7. 01 mL, 68. 39 mmol) were added and stirred for 15 minutes at 4°C. A cold solution of the 21-methoxy compound (119, 13. 45 g, 31. 09 mmol) in CH2C12 (100 mL) was added to the mixture via an additional funnel over a period of 1 hr. The reaction mixture was allowed to stir overnight at 4°C. Examination by TLC (25% EtOAc in CH2C12) showed all of the starting material had been converted to a mixture of the a and ß epoxides in about a

2 : 1 ratio. The mixture was transferred to a separatory funnel and washed with 10% Na2S03 (lx), saturated NaHCO3 (lx) and H20 (lx). Combined CH2C12 extracts (3x) were filtered through Na2S04 and evaporated in vacuo to recover 14. 06 g of the epoxide (120) as a white foam in quantitative yield. The 2 : 1 mixture of a-and (3-epoxides was used directly for the subsequent Grignard reaction. NMR (300 MHz, CDC13) : 8 0. 700 (s, 3 H, C18-CH3), 3. 407 (s, 3 H, C21-OCH3), 3. 539 and 3. 692 (AB, 2 H, JAB = 10. 51 Hz, C21-CH2), 4. 051 (m, 8 H, C3-and C20-OCH 2CH 2O-), 5. 819 (br s, 0. 3 H, Cl 1-CH= of (3-epoxide), and 5. 997 (br s, 0. 6 H, C11-CH= of a-epoxide). Decomposition of analytical sample precluded further analysis.

Step 7. 3,20-bis-Ethylenedioxy-5α,17α-dihydroxy-11ß-[4-(N-piperid ihno)phenyl]- 21-nethoxy-19-szorpreg12-9-ene (121a) : Magnesium (1. 27 g, 52. 25 mmol), a crystal of iodine, dry THF (55 mL), and one drop of 1, 2-dibromoethane were stirred together in dry glassware over nitrogen. A solution of N- (4-bromophenyl) piperidine (see, EXAMPLE 23, Step 1) (13. 80 g, 57. 48 mmol) in dry THF (45 mL) was added to the reaction flask, then rinsed in with an additional 10 mL of THF. The mixture was heated until all of the magnesium metal was gone. The reaction was allowed to reflux for 1. 5 hr, and then cooled to room temperature.

Copper (I) chloride (0. 57 g, 5. 75 mmol) was added and stirring continued for 1 hr. A solution of the epoxide (120, 4. 69 g, 10. 45 mmol) in dry THF was added to the reaction and rinsed in with an additional 10 mL of THF. The reaction was stirred under nitrogen, at room temperature, for 1 hr. The reaction was quenched with saturated NH4C1 (138 mL).

Air was drawn through the mixture with vigorous stirring for 20 min. The mixture was transferred to a separatory funnel, extracted with ether (3x), washed with H20 (2x) and brine (lx). The combined organic fractions were dried with Na2S04 for l/2 hr, and evaporated in vacuo to recover 12. 97 g of the crude product. Analysis by TLC (20% acetone in CH2C12) showed many impurities. The crude material was triturated with pentane to recover 4. 45 g of a pale green solid. Analysis by TLC (20% acetone in CH2Ck) showed a small amount of by-product still present. The precipitate was further purified by flash column chromatography (10% acetone in CH2Cl2). Fractions containing the pure Grignard adduct (121a) were combined and evaporated in vacuo to recover 2. 56 g of an aqua-green solid in 40. 17% yield. The mother liquors from the trituration were combined and evaporated in vacuo to recover 8. 15 g of material. Purification of this material by flash

column chromatography (20% acetone in CH2Cl2)& afforded 0. 29 g of a green gum. All recovered products were combined and triturated with ether to recover a total of 2. 16 g of Grignard adduct (121a) in 33. 9% yield ; m. p. = 218-220°C. FTIR (KBr, diffuse reflectance) : Via., 3508, 2940, 1609 and 1509 cm~l. NMR (CDC13) : 8 0. 449 (s, 3 H, C18- CH3), 3. 094 (t, 10 H,-NCsHio), 3. 437 (s, 3 H, C21-OCH3), 3. 989 (m, 10 H, C3 and C20- OCH2CH20-and C21-CH2-), 6. 822 (d, 2 H, J = 8. 85, 3', 5'aromatic-CH's) and 7. 067 (d, 2 H, J = 8. 85 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 609 (M+, 29. 1), 591 (46. 6), 364 (8. 6), 174 (29. 2), 161 (100. 0) and 117 (96. 4). Anal. Calcd. for C36HsiN7-1/3H20 : C, 70. 22 ; H, 8. 46 ; N, 2. 27. Found : C, 70. 10 ; H, 8. 33 ; N, 2. 40.

Step 8. 17α-Hydroxy-11~-[4-(N-piperidin)phenyl]-21-methoxy-19norpre gna- 4, 9-diene-3, 20-dione (122a) : A solution of the Grignard adduct (121 a, 2. 10 g, 3. 44 mmol) in THF (20 mL) was mechanically stirred under nitrogen at room temperature. Trifluoroacetic acid (60 mL, 764. 26 mmol) and H2O (20 mL) were added, and the mixture was stirred under nitrogen for 3 hr. Examination by TLC (20% acetone in CH2C12) showed the reaction had gone to completion. The reaction mixture was cooled in an ice bath, and NH40H (51. 46 mL) was slowly added to neutralize the reaction to a pH of 7 by pH paper. The mixture was transferred to a separatory funnel, extracted with EtOAc (3x). The organic fractions were washed with H20 (2x) and brine (lx). The combined EtOAc fractions were dried with Na2S04 and evaporated in vacuo to give 1. 70 g of an amber foam. The crude product was purified by flash column chromatography (20% acetone in CH2C12) to recover 1. 16 g of 122a as a bright yellow foam in 66. 95% yield ; m. p. = 211 - 216°C. FTIR (KBr, diffuse reflectance) : vmax 3429, 2941, 1721, 1648, 1601 and 1511 crri 1. NMR (CDCl3) : # 0. 391 (s, 3 H, C18-CH3), 2. 979 (t, 10 H,-NC5 Hio), 3. 454 (s, 3 H, C21-OCH3), 4. 243 and 4. 383 (AB, 2H, JAB = 17. 71 Hz, C21-CH2-), 5. 762 (s, 1 H, C4-CH=), 6. 820 (d, 2 H, J = 8. 55 Hz, 3', 5'aromatic-CH's) and 6. 980 (d, 2 H, J = 8. 55 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 503 (M+, 57. 9), 318 (5. 8), 174 (12. 3) and 161 (100. 0). Anal.

Calcd. for C32H4lNO4 1/3H20 : C, 75. 42 ; H, 8. 24 ; N, 2. 75. Found : C, 75. 23 ; H, 8. 04 ; N, 2. 94.

Step 9 Preparation of the target compound 123a: A mixture of CH2C12 (50 mL), trifluoroacetic anhydride (11. 70 g, 55. 65 mmol) and glacial acetic acid (3. 35 g, 55. 59 mmol) was stirred under nitrogen at

room temperature for J/2 hr. The mixture was cooled in an ice bath, andp-toluenesulfonic acid monohydrate (0. 47 g, 2. 45 mmol) was added. The 17a-OH (122a, 1. 12 g, 2. 22 mmol) dissolved in CH2Cl2 (7. 5 mL) was transferred to the reaction flask and then rinsed in with an additional 8 mL of CH2Cl2. The reaction mixture was stirred at 0°C for 2 hr.

Examination by TLC (10% acetone in CH2C12) showed the reaction had gone to completion. The reaction was kept at 0°C and diluted with H2O (30 mL), then neutralized by the addition of NH40H (11. 45 mL). Additional NH40H was added until the pH of 6-7 by pH paper was reached. The mixture was transferred to a separatory funnel, the layers allowed to separate and CH2C12 fractions then washed with H20 (lx) and brine (lx). The organic fractions were filtered through Na2S04 and evaporated in vacu to give 1. 21 g of a dark yellow foam. The crude product was purified by flash column chromatography (10% acetone in CH2C12) to give 1. 08 g of 123a as a bright yellow foam. The purified product was then triutrated with pentane to give 0. 92 g of 123a as a pale yellow powder in 76% yield ; m. p. = 142-144°C. FTIR (KBr, diffuse reflectance) : via,, 2941, 2360, 2338, 1737, 1664, 1608 and 1512 cm~l. NMR (CDCl3) : 8 0. 378 (s, 3 H, C18-CH3), 2. 105 (s, 3 H, C17a-OAc), 3. 095 (t, 10 H,-NC5Ho), 3. 413 (s, 3 H, C21-OCH3), 4. 099 and 4. 307 (AB, 2 H, J AB = 17. 11 Hz, C21-CH 2-), 4. 377 (d, 1 H, J = 6. 60 Hz, Clla-CH), 5. 779 (s, 1 H, C4- CH=), 6. 810 (d, 2 H, J = 8. 70 Hz, 3', 5'aromatic-CH's) and 6. 973 (d, 2 H, J = 8. 70 Hz, 2', 6' aromatic-CH's). MS (EI) m/z (relative intensity) : 545 (M+, 34. 5), 485 (8. 6), 412 (2. 2), 174 (10. 1), 161 (100. 0) and 105 (2. 5). Anal. Calcd. for C34H43NO5'1/1OH20 : C, 74. 59 ; H, 7. 95 ; N, 2. 56. Found : C, 74. 58 ; H, 7. 89 ; N, 2. 65.

EXAMPLE 32 This example illustrates the preparation and properties of 17a-Acetoxy-11 (4-acetylphenyl)-21-methoxy-19-norpregna-4, 9-diene-3, 20-dione (123b) (Figure 9) : Step 1. 3,20-bis-Ethylenedioxy-5α,17α-dihydroxy-11ß-4-(2-methyl-1 ,3-dioxolan- 2-yl) pA1eny&num -21-netSzoxy-19-norpregn-9-ene (121b) : A 3-neck 1 L flask was euipped with a mechanical stirrer, an addition funnel, and a reflux condenser and flame-dried under a stream of nitrogen. Magnesium (3. 90 g, 146 mmol) was added, followed by one iodine crystal, 150 mL of dry THF, and 1-2 drops of 1, 2-dibromoethane. The mixture was stirred under nitrogen and heated in a warm water bath, but no reaction occurred. 4-Bromoacetophenone ethylene ketal (see,

EXAMPLE 20, Step 1) (35. 5 g, 146 mmol) was added as a solution in THF (100 mL) via the addition funnel and then rinsed in with additional THF (40 mL). Upon completion of addition, the mixture was heated to reflux to initiate formation of the Grignard reagent.

Heating was discontinued and the mixture allowed to stir 1. 5 hr as the water bath gradually cooled to room temperature. Copper (I) chloride (1. 59 g, 16. 06 mmol) was added as a solid and stirring continued for another l/2 hr. The mixture of epoxides (120, 13. 11 g, 29. 2 mmol, -66% a-epoxide) was added as a solution in THF (50 mL) via the addition funnel and rinsed in with additional THF (20 mL). After stirring 1. 5 hr at room temperature, TLC (20% acetone in CH2C12 ; quenched with saturated NH4C1 and extracted into EtOAc) indicated the reaction was >95% complete. The reaction was quenched by the addition of 200 mL of saturated NH4C1 and air was drawn through the mixture for 1/2 hr with vigorous stirring. Ether was added, the mixture was transferred to a separatory funnel, and the layers allowed to separate. The organic layer was washed with 10% NH4C1, H20 and brine.

Combined ether extracts (3x) were filtered through Na2SO4 and evaporated ii7 vacuo to give 35. 23 g of the crude product (121b). Purification by flash column chromatography (20% acetone in CH2C12) afforded 7. 24 g of a pale foam. Trituration of this foam with ether and pentane produced 5. 93 g of the product (121b) as a beige powder in 50. 2% yield (based on 66% of the mixture as a-epoxide). NMR (CDC13) : 8 0. 4 (s, 3 H, C18-CH3), 1. 63 (s, 3 H, CH3 of C1 lß-4-C6H4C (O) (CH3), 3. 45 (s, 3 H, C21-OCH3), 3. 57-4. 40 (m, 15 H, C3- OCH2CH2O-, Cl (3-OCHZCHZO- and C20-OCHZCH20-, Cl la-CH and C21-CH2-), 7. 2 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's) and 7. 83 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's). MS (EI) rn/z (relative intensity) : 612 (M+, 0. 1), 594 (3. 3), 549 (15. 0), 459 (2. 7), 117 (100. 0) and 87 (74. 7). Decomposition of the analytical sample precluded further analysis.

Step 2. 17α-Hydroxy-11ß-(4-acetylphenyl)-21-methoxy-19-norpregna-4 ,9-diene- 3, 20-diole (122b) : The Grignard adduct (121b, 5. 81 g, 9. 48 mmol) was dissolved in THE (60 mL) and stirred magnetically, under nitrogen, at room temperature. Trifluoroacetic acid (180 mL) was added followed by H20 (60 mL). After 1. 5 hr, examination by TLC (20% acetone in CH2C12 ; neutralized with NH40H before developing) indicated all of the starting material had been converted to a slightly less polar product. The reaction mixture was neutralized by the careful addition of N-H40H (165 mL) via an addition funnel. Enough additional NH40H was added to bring the pH to 7. 0 by pH paper. H20 was added, the

mixture was transferred to a separatory funnel, and extracted with EtOAc. The organic fraction was washed again with H20 and brine. Combined EtOAc fractions (3x) were filtered through Na2S04 and evaporated in vacuo to give 6. 60 g of a foam. Purification of the crude product by flash column chromatography (20% acetone in CH2C12) afforded a yellow solid (122b). Crystallization from a minimum amount of hot EtOAc gave large, bright yellow crystals. The crystals were collected on a Buchner funnel and dried overnight under high vacuum at 70°C to recover 2. 84 g of 122b. A TLC of the mother liquors indicated they were pure enough to carry on to the subsequent reaction. The mother liquors were evaporated in vacuo and dried under high vacuum over the weekend to recover 0. 46 g.

The total yield of the 17a-OH (122b) was 3. 3 g as bright yellow crystals in 75. 25% yield.

A small amount of the crystalline product was dried in vacuo at 110°C over the weekend for purposes of characterization. The crystals were fused and pulverized with a spatula ; m. p. = 105-109°C (softens). Analysis by HPLC on a Phenomenex Prodigy 5 ODS-2 column (150 x 4. 6 mm) eluted with 50% CH3CN in H20 at a flow rate of 1 mL per min and X = 302 nm indicated a purity of >99% with a retention time (tR) of 5. 02 min. FTIR (KBr, diffuse reflectance) : vm,, x 3444, 2944, 1722, 1662, 1602, 1407 1359 and 1271 cm\ NMR (CDC13) : 6 0. 33 (s, 3 H, C18-CH3), 2. 57 (s, 3 H, C11p-4-C6H4-C (O) CH3), 3. 47 (s, 3 H, C21-OCH3), 4. 23-4. 47 (AB, 2 H, JAB = 18 Hz, C21-CH2-), 4. 52 (br d, 1 H, Clla-CH), 5. 48 (s, I H, C4-CH=), 7. 3 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's) and 7. 92 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's). MS (EI) m/z (relative intensity) : 462 (M+, 100. 0), 430 (11. 2), 389 (27. 0), 346 (97. 9) and 91 (22. 3). Anal. Calcd. for C29H3405-9/20C4Hg02 : C, 73. 66 ; H, 7. 55. Found : C, 73. 66 ; H, 7. 29.

Step 3. Preparation of tAle target compolnd 123b : A mixture of trifluoroacetic anhydride (32. 78 g, 156 mmol) and acetic acid (9. 38 g, 156 mmol) in CH2C12 (100 mL) was allowed to stir 1/2 hr at room temperature under nitrogen. The mixture was cooled to 0°C in an ice H20 bath andp-toluenesulfonic acid monohydrate (1. 30 g, 6. 86 mmol) was added as a solid. The 17a-OH (122b, 2. 89 g, 6. 24 mmol) was added as a solution in 25 mL of CH2C12 and rinsed in with additional CH2C12 (25 mL). After 45 min, TLC (10% acetone in CH2C12) indicated the reaction had gone to completion. The reaction was neutralized by the careful addition of NH40H (31. 6 mL, 416 mmol). Additional NH40H was added to bring the pH to 7 by pH papaer. Water was added and the mixture transferred to a separatory funnel. The organic fractions were

washed with H20 and brine. Combined CH2C12 extracts (3x) were filtered through Na2S04 and evaporated in vacuo to recover 3. 13 g of crude material. Purification by flash chromatography (10% acetone in CH2C12) provided 1. 56 g of a crystallizing oil. Additional fractions containing a small amount of a less polar impurity were also combined and evaporated to give 1. 04 g of an oil. Pure fractions were crystallized from a minimum amount of boiling EtOAc, triturated with pentane and dried 3 nights in a drying pistol at 110°C to give 0. 99 g of 123b as pale yellow crystals. The crystals fused at this temperature, but were readily pulverized for analysis. Mother liquors were combined with the impure fractions and crystallized from EtOAc to give an additional 0. 9 g. Total yield of 123b was 1. 89 g as a pale yellow solid in 60. 1% yield ; m. p. = 113°C (softens).

Analysis by HPLC on a Phenomenex Prodigy 5 ODS-2 column (150 x 4. 6 mm) eluted with 50% CH3CN in Hz0 at a flow rate of 1 mL per min and X = 302 nm indicated a purity of 99. 7% with a retention time (tR) of 7. 69 min. FTIR (KBr, diffuse reflectance) : via 2942, 1730, 1680, 1602, 1432, 1408, 1368 and 1266 cm-1. NMR (CDCl3) : 6 0. 33 (s, 3 H, C18-CH3), 2. 10 (s, 3 H, C17α-OAc), 2. 57 (s, 3 H, Cllp- C (O) CH3), 3. 42 (s, 3 H, C21-OCH3), 4. 07 & 437 (AB, 2 H, JAB = 18 Hz, C21-CH2-), 4. 50 (br d, 1 H, C11α-CH), 5. 83 (s, 1 H, C4-CH=), 7. 28 (d, 2 H, J = 9 Hz, 2', 6'aromatic-CH's) and 7. 92 (d, 2 H, J =9 Hz, 3', 5' aromatic-CH's). MS (EI) m/z (relative intensity) : 504 (M+, 3. 3), 447 (17. 9), 389 (28. 4), 371 (100. 0) and 91 (13. 8). Anal. Calcd. for C31H36O6#1/6CH2Cl2#1/2H2O : C, 70. 92 ; H, 7. 13. Found : C, 71. 06 ; H, 6. 91.

EXAMPLE 33 This example illustrates the preparation and properties of 17a-Acetoxy-11 {4- [2'- (N, N-dimethylamino) ethoxy] phenyl}-21-methoxy-19-norpregna-4, 9-diene-3, 20- dione (123c) : Step 1. 3, 20-bis(Ethylenedioxy)-5α,17α-dihydroxy-11ß-{4-[2'-(N,NM dinzetlzylaraizo) ethoxy]phenyl}-21-methoxy-19-norpregna-4,9-diene-3,20- dione (121c) Magnesium (0. 58 g, 23. 85 nunol), a crystal of iodine, distilled THF (27 mL) and one drop of 1, 2-dibromoethane were stirred together in dry glassware over nitrogen. A solution of 4- [2- (dimethylamino) ethoxy] phenyl bromide (Robertson, et al., J Org. Chem., 47 : 2387-2393 (1982)) (6. 41 g, 26. 24 mmol) in distilled THF was added to the reaction flask, then rinsed with an additional 5 mL of THF. The mixture was heated until all the

magnesium was gone. The reaction was allowed to reflux for 2 hr., and then cooled to room temperature. Copper (I) chloride (0. 26 g, 2. 63 mmol) was added and stirring continued for 1 hr. A solution of the 5a, 10a-epoxide (120, 14 g, 2. 63 mmol) in distilled THF and rinsed with an additional 5 mL of THF. The reaction was stirred over nitrogen at room temperature for 1 hr. After cooling the reaction flask in an ice water bath, the reaction was quenched with water (79 mL). Air was drawn through the mixture with vigorous stirring for 20 min. The mixture was transferred to a separatory funnel, extracted with ether (3x), washed with water (2x) and brine (lx). The combined organic fractions were dried over sodium sulfate for % 2 hr. and evaporated in vacuo to recover 3. 21 g of a thick amber oil. Ether (50 mL) was added to this material, and a small precipitate was visible. The organic product was found to remain in the mother liquor. After removing the ether, the crude material was triturated with hexanes and a small amount of ether. A small precipitate formed, but once again the product was found in the filtrate by TLC (10% isopropanol in CEI2C12). The crude material of 1. 27 g recovered was a dark, amber oil. The material was further purified by flash column chromatography (10% isopropanol in CH2C12 with 0. 1% Et3N). All by-products were removed, and the product was flushed off the column with 10% isopropanol in CH2C12 with 1% Et3N to recover 0. 76 g of a yellow gum.

The material was triturated with ether and a small amount of CH2C12. After storing in the freezer overnight, a small precipitate formed, and the ether (containing the product) was decanted off to obtain 0. 56 g of material. The crude product was further purified by another flash column (10% isopropanol in CH2C12 with 1% Et3N) to recover 0. 50 g of a yellow oil.

This material was analyzed by HPLC on a NovaPak Cis column eluted with 55% CH3CN in H20 with 0. 05% Et3N at a flow rate of 0. 5 mL/min and at X = 280 nm and indicated a purity of 17. 83%. The material was then purified by prep HPLC on a Waters Assoc. Prep Nova- Pak HR Cis (6p) column (40 x 10 mm) eluted with 55% CH3CN in H20 with 0. 05% Et3N at a flow rate of 25 mL per min and at k = 280 nm. Further analysis by HPLC on a Waters Assoc. NovaPak Cl8 column eluted with 55% CH3CN in H20 with 0. 05% Et3N at a flow rate of 0. 4 mL per min and at X = 280 nm indicated a purity greater than 99. 99% with tR of 10. 21 min. CH3CN was removed from the fraction containing the product, and the aqueous layer with product material was extracted with EtOAc (3x). The organic fractions were then washed with H20 (x) and brine (x), dried over Na2SO4 and evaporated in vacuo to recover 0. 35 g of white foam (121c) in 11. 95% yield. A small amount of the material was

triturated with pentane to use as the analytical sample, and the remainder of it was carried onto the hydrolysis ; m. p. = 179-183°C. FTIR (KBr, diffuse reflectance) : Vmax 3508, 2942, 2894, 2818, 2772, 1610, 1580 and 1509 cm~l. NMR (300 MHZ, CDC13) : 6 0. 443 (s, 3 H, C18-Me), 3. 435 (s, 3 H, C21-OMe), 4. 048 (m, 10 H, C3-and C20-OCH2CH20-and C21- CH2), 6. 803 (d, 2 H, J = 8. 70 Hz, aromatic-CH's) and 7. 099 (d, 2 H, J = 8. 70 Hz, aromatic- CH's). MS (EI) m/z (relative intensity) : 614 (M+, 0. 3), 595 (1. 3), 568 (4. 3), 550 (5. 5), 117 (20. 1), 71 (3. 6) and 58 (100. 0).

Step 2. 17α-Hydroxy-11ß-{4-[2'-(N,N-dimethylaminoi)ethoxy]phenyl}- 21- methoxy-19-7torpregna-4, 9-diezle-3, 20-dione (122c) : The Grignard product (121c, 0. 30 g, 0. 49 mmol) in THF (3 mL) was mechanically stirred under nitrogen at room temperature. Trifluoroacetic acid (9 mL, 121. 14 mmol) and water (3 mL) were added, and the mixture was stirred for 2. 5 hr under nitrogen. Examination by TLC (silica, 10% isopropanol in CH2C12 with 0. 1% Et3N) was difficult to analyze ; therefore, the reaction was allowed to stir overnight at room temperature under nitrogen. Another TLC (silica, 10% isopropanol in CH2C12 with 0. 1% Et3N)& was done, but the results were difficult to read due to the fact that the product was still very polar. The reaction was assumed to be complete and diluted with water (35 mL).

The flask was then cooled in an ice bath, and a cold solution of 2M NaOH (61 mL) was slowly added to neutralize the reaction to a pH of 7 (by pH paper), although the mixture quickly went to a pH of 12. The reaction mixture was extracted with CH2C12 (3x) and washed with water (2x) and brine (lx). The combined organic fractions were filtered through sodium sulfate and evaporated iii vacuo to recover 0. 19 g (0. 38 mmol) of a yellow oil (122c). The crude product was purified by flash column chromatography (20% isopropanol in CH2C12 with 0. 2% Et3N) to recover 0. 15 g of a yellow foam (122c). A small amount of the material was triturated with pentane to use as the analytical sample, and the remainder of it was carried onto the acetylation ; m. p. = 78-82°C. FTIR (KBr, diffuse reflectance) : via 2944, 1722, 1665, 1607, 1509, 1461 and 1237 cm'. NMR (300MHZ, CDC13) : 8 0. 376 (s, 3 H, C18-Me), 3. 454 (s, 3 H, C21-OMe), 5. 770 (s, 1 H, C4-CH=), 6. 821 (d, 2 H, aromatic-CH's) and 7. 099 (d, 2 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 505 (M+, 1. 5), 473 (0. 5), 436 (3. 8), 72 (13. 8) and 58 (100. 0).

Step 3. Preparation of tAle target compound 123c : A mixture of CH2C12 (6 mL), trifluoroacetic anhydride (0. 90 mL, 6. 44 mmol), and glacial acetic acid (0. 37 mL, 6. 44 mmol) were stirred at room temperature under nitrogen for % 2 her. The mixture was cooled in an ice bath, andp-toluenesulfonic acid monohydrate (0. 05 g, 0. 28 mmol) was added. The 17-OH (122c, 0. 13 g, 0. 26 mmol) dissolved in CH2C12 (2 mL) was transferred to the reaction flask and then rinsed with an additional 0. 5 mL of CH2C12. The reaction was stirred at 0°C for 5 hr. Examination by TLC (20% isopropanol in CH2C12 with 0. 2% Et3N) showed the reaction had gone to completion. The ice bath was maintained and water (20 mL) was added. The reaction was neutralized by the addition of cold 2 M NaOH (14 mL) until the pH of 7-8 (by pH paper) was reached. The mixture was transferred to a separatory funnel, the layers allowed to separate, and CH2C12 fractions then washed with water (2x) and brine (lx). The organic fractions were filtered through sodium sulfate and evaporated in vacuo to recover 0. 15 g of a dark, yellow foam. The crude product was purified by flash column chromatography (20% 20% isopropanol in CH2C12 with 0. 2% Et3N) to give 0. 08 g of a bright yellow foam.

These purified fractions were then triturated with ether to recover 0. 02 g of a pale yellow powder (123c). The mother liquor was further triturated with pentane to give an additional 0. 04 g of 123c. Analysis by NMR showed the material was contaminated with stop cock grease ; therefore all collected material was combined and further purified by flash column chromatography (20% isopropanol in CH2C12 with 0. 2% EtsN) to give 0. 05 g of a yellow powdery foam in 33. 78% yield. This material was then triturated with pentane to yield 0. 03 g of a pale yellow powder (123c) in 19. 10% yield ; m. p. = 115-127°C (sintered at 73- 78°C). FTIR (KBr, diffuse reflectance) : Vmax 2947, 1728, 1665, 1607 and 1509 crri 1.

NMR (300 MHZ, CDC13) : 8 0. 365 (s, 3 H, C18-Me), 2. 105 (s, 3 H, C17-OAc), 2. 332 (s, 6 H,-N (CH3) 2), 3. 414 (s, 3 H, C21-OME), 5. 793 (s, 1 H, C4-CH=), 6. 808 (d, 2 H, aromatic-CH's) and 7. 030 (d, 2 H, aromatic-CH's). Anal. Calcd. for C33H43NO6 1/5H20 : C, 72. 10 ; H, 7. 88 ; N, 2. 55. Found : C, 71. 63 ; H, 7. 91 ; N, 2. 53.

EXAMPLE 34 17a-Acetoxy-11ß-{4- [2'-(N-piperidino) ethoxy] phenyl}-21- methoxy-19-norpregna-4, 9-diene-3, 20-dione (123d) : This procedure was similar to that employed for the production of 123c.

Step 1. 3,20-bis-(Ethylenediioxy)-5α,17α-dihydroxy-11ß-{4-[2'-(N- pineridino) ethoxy]phenyl}-21-methoxy-19-norpregna-4,9-diene-3,20- dione (121d) : Magnesium (1. 11 g, 45. 59 mmol), a crystal of iodine, distilled THF (52 mL, distilled over Na and benzophenone), and one drop of 1, 2-dibromoethane were stirred together in dry glassware over nitrogen. A solution of 4- [2- (N- piperidinophenyl) ethoxy] phenyl bromide (Lednicer, et al., S : Med. Chem., 8, 52-57 (1965) (14. 26 g, 50. 16 mmol) in distilled THF (50 mL) was added to the reaction flask, then rinsed with an additional 10 mL of THF. The mixture was heated until all of the magnesium was gone. The reaction was allowed to reflux for 2 hr., and then cooled to room temperature.

Copper (I) chloride (0. 50 g, 5. 03 mmol) was added and stirring continued for 1 hr. A solution of the epoxide (120, 7. 50 g, 16. 72 mmol) in distilled THF (74 ml) was transferred to the reaction vessel. The reaction was stirred over nitrogen, at room temperature, for one hour. The reaction was cooled in an ice water bath and quenched with water (186 mL). Air was drawn through the mixture with vigorous stirring for 20 minutes. The mixture was transferred to a separatory funnel, extracted with ether (3x), and washed with water (2x) and brine (lx). The combined, organic fractions were dried with sodium sulfate for 1/2 hr, and evaporated in vacuo to recover 17. 32 g (26. 49 mmol) of a thick amber oil. Analysis by TLC (silica, 10% isopropanol in methylene chloride with a few drops of Et3N) showed a very polar, streaking product. The entire crude material was carried directly on to the hydrolysis. Due to the extreme polarity of the crude Grignard product, analytical work was not performed.

Step 2. 17α-Hydroxy-11ß-{4-[2'-(N-piperidino)ethoxy]phenyl}-21-met hoxy-19-<BR> <BR> <BR> <BR> norpregna-4, 9-dieBte-3, 20-dione (122d) : The Grignard product (121d, 10. 93 g, 16. 72 mmol) dissolved in THF (103 mL) was mechanically stirred over nitrogen at room temperature. Trifluoroacetic acid (307. 10 mL, 4133. 60 mmol, 13. 46 M) and water (103 mL) were added, and the mixture was stirred over nitrogen, at room temperature, overnight. The reaction was diluted with water (750 mL) and cooled in an ice water bath. Ice cold 4 M NaOH (1030 mL) was slowly added to neutralize the reaction to a pH of 7-8 (by pH paper). The mixture was transferred to a separatory funnel, extracted with methylene chloride (3x), and washed with water (2x) and brine (lx). The combined methylene chloride fractions were dried with sodium sulfate and evaporated in vacuo to recover 15. 33 g of the crude 122d as a gold foam in 16. 8% yield.

Step 3 Preparatioyz of the target compoufzd 123d : Treatment of the 17a-hydroxy compound (122d, 0. 25 g, 0. 46 mmol) in CH2C12 with a mixed anhydride (11. 28 mmol) prepared from trifluoroacetic anhydride, acetic acid andp-toluenesulfonic acid monohydrate in CH2C12 at 0°C for 4. 5 hr and work up in the usual way followed by purification of the crude product (123d) by Preparative HPLC on a Waters Assoc. Prep NovaPal HR C18, 6 urn, 4 x 100 mm) eluted with 50% CH3CN in H20 with 0. 05% Et3N at a flow rate of 25 mL per min and at , = 302 run, provided 0. 10 g of 123d as a light yellow powder in 9. 4 % yield ; m. p. = 85-89°C (sintered at 74-78°C). FTIR (KBr, diffuse reflectance) : V,,, a, 2938, 1730, 1662, 1608 and 1509 cm~ 1. NMR (300 MHZ, CDC13) : 8 0. 369 (s, 3 H, C18-CH3), 2. 106 (s, 3 H, C17a-OAc), 2. 501 (m, 4 H, piperidino a-CH2), 2. 748 (t, 2 H, OCH2CH2N), 3. 413 (s, 3 H, 21-OCH3), 4. 055 (t, 2 H, OCH2CH2N), 5. 787 (s, 1 H, C4-CH=), 6. 783 (d, 2 H, J = 9. 00 Hz, aromatic-CH's), and 7. 010 (d, 2 H, J = 9. 00 Hz, aromatic-CH's). MS (EI) m/z (relative intensity) : 590 (M+, 87), 445 (41), 371 (100), 355 (71), 299 (39) and 269 (26). Anal. Calcd. for C36H47NO6 75/100 H20 : C, 73. 15 ; H, 8. 04 ; N, 2. 37. Found : C, 72. 96 ; H, 8. 11 ; N, 2. 27. Analysis by HPLC on a Waters Assoc. NovaPak Cl$ column eluted with 50% CH3CN in H20 with 0. 05% Et3N at a flow rate of 1 mL per min and at X = 302 nm indicated a purity of 99. 16% of 123d with tR of 9. 95 min.

EXAMPLE 35 This example illustrates the preparation and properties of 17a, 21- Diformyloxy-11 ß- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione (139) : Under nitrogen, a solution of the diol (124, 1. 0 g, 2. 22 mmol) in formic acid (96%, 50 mL) was treated with perchloric acid (Oliveto, et al., J. Am. Chefn. Soc., 77 : 3564- 3567 (1955)) (70%, 0. 5 mL, 5. 816 mmol) and the reaction mixture was stirred at room temperature overnight. Analysis by TLC (10% acetone/CH2Cl2) of a small aliquot neutralized with cold NH40H and extracted with EtOAc indicated absence of the starting material and formation of two less polar products in roughly equal proportions. The reaction was diluted with H20 (-200 mL), cooled in an ice bath, and carefully adjusted to a pH of 7. 5 with concentrated NH40H. The resulting suspension was extracted with CH2C12 (3x). The organic fractions were washed with H2O (2x), filtered through anhydrous sodium sulfate, combined and concentrated in vacuo to give 1. 3 g of the residue as a yellow foam.

Analysis by NMR indicated the crude mixture to consist mainly of the 17a-hydroxy-21- formate (140) and the desired 17a, 21-diformate (139) in approximately a 45 : 55 ratio.

Separation of the two products was accomplished by flash chromatography (8% acetone/CH2CIz) to afford 0. 62 g of the diformate (139) and 0. 49 g of the monoformate (140). The diformate (139) was taken up in ether, blown down and triturated with pentane to give 0. 53 g of a yellow solid inidcated by HPLC on a Waters NovaPak C18 column elued with CH3CN/0. 05 M KH2PO4 (45 : 55) (pH = 3. 0) at a flow rate of 1 mL per min and X = 302 mn) to be only 97% pure. This material was rechromatographed using 7% acetone/CH2Cl2 and reprecipitated from EtzO/pentane to give 0. 235 g of the pure diformate (139) as a yellow amorphous solid in 20. 9% yield ; m. p. = softens at 110-112°C. Analysis by HPLC on a Waters NovaPak Cis column eluted with CH3CN/0. 05 M KH2P04 (45 : 55) [pH = 3. 0] at a flow rate of 1 mL per min and X = 302 nm) to be 98. 6% pure with a retention time (tR) of 6. 56 min. FTIR (KBr, diffuse reflectance) : Vmax 2948, 1726, 1662, 1612, 1518, and 1169 cm~l. NMR (CDC13) : 6 0. 460 (s, 3 H, C18-CH3), 2. 908 (s, 6 H,- N (CH3) 2), 4. 407 (d, 1 H, J = 7. 2 Hz, Clla-CH), 4. 816 and 5. 070 (dd, 2 H, C21-CH2-), 5. 781 (s, 1 H, C4-CH=), 6. 651 (d, 2 H, 3', 5'aromatic-CH's), 7. 006 (d, 2 H, 2', 6'aromatic-CH's), 8. 029 (s, 1 H, C17a-OC (O) H) and 8. 165 (s, 1 H, C21-OC (O) H). MS (EI) m/z (relative intensity) : 505 (M+, 21. 0), 459 (8. 6), 431 (7. 6) 134 (13. 1) and 121 (100). Anal. Calcd. for

C34H44N206'1/5H2O : C, 70. 76 ; H, 701 ; N, 2. 75. Found : C, 70. 76 ; H, 7. 01 ; N, 2. 85.

Trituration of the monoformate fraction from the chromatography afforded 0. 265 g of compound 140 as a light yellow solid. NMR indicates the presence of 20-formate (140) at 8. 172 ppm. NMR (CDC13) : 8 0. 39 (s, 3 H, C18-CH3), 2. 902 (s, 6 H,-N (CH3) 2), 4. 384 (d, l H, J= 6. 9 Hz, Clla-CH), 5. 031 and 5. 193 (dd, 2 H, J= 17. 71 Hz, C21-CH2-), 5. 759 (s, 1 H, C4-CH=), 6. 656 (d, 2 H, 3', 5'aromatic-CH's), 7. 015 (d, 2 H, 2', 6'aromatic-CH's), and 8. 172 (s, 1 H, C21-OC (O) H).

EXAMPLE 36 This example illustrates the preparation and properties of 17a-Acetoxy-11 [4- (N, N-dimethylamino) phenyl]-21-propionyloxy-19-norpregna-4, 9-diene-3, 20-dione (126a) (Figure 11) : Step 1. 17α-Hydroxy-11ß-[4-(N,N-dimethylamino)phenyl]-21-propionyl oxy-19- nofpregna-4, 9-diene-3, 20-diofze (125a) : Under nitrogen, a solution of the diol (124, 1. 0 g, 2. 22 mmol) in dry benzene (20 mL) and pyridine (1 mL, 12. 4 mmol) was treated with propionyl chloride (0. 22 mL, 2. 53 mmol). This addition caused an immediate precipitation of a large gummy mass, probably due to formation of a mixture of the hydrochloride salts of starting material and product. Since the dimethylaminophenyl moiety is probably more basic than pyridine, any HC1 formed during the reaction would protonate the 11 l (4-N, N-dimethylaminophenyl) group rather than pyridine. Addition of triethylamine (1 mL, 7. 11 mmol) resulted in dissolution of the precipitated mass with formation of a small amount of solid precipitate.

The reaction mixture was then stirred at room temperature and monitored by TLC (10% acetone in CHzClz) which indicated about a 60% reaction after 1 hr. Additional propionyl chloride (0. 22 mL, 2. 53 mmol) was introduced and the reaction was stirred a father 1 hr at room temperature. Analysis by TLC at that time indicated a complete reaction. The reaction mixture was concentrated in vacuo under a current of nitrogen and the residue was diluted with H20. The mixture was extracted with CH2C12 (3x). The organic fractions were washed with H20 (2x), brine (lx), then concentrated, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give 1. 2 g of the residue as a yellow foam. This material was purified by flash chromatography (10% acetone in CH2Cl2) to give 1. 1 g of the 21-propionyloxy-17a-ol (125a). Crystallization of this material from EtOAc/heptane

afforded 0. 43 g of the pure 125a in 67% yield. FTIR (KBr, diffuse reflectance) : Vmax 3331, 2940, 1749, 1734, 1640, 1612 and 1518 cm~l. NMR (300 MHz, CDC13) : 6 0. 37 (s, 3 H, C18-CH3), 1. 17 (t, 3 H, J = 7. 5 Hz, propionyl CH3), 2. 90 (s, 6 H,-N (CH3) 2), 4. 40 (br d, J = 6 Hz, Cl la-CH), 5. 03 (dd, 2 H, Jl = 30, J2 = 18 Hz, C21-CH2-O), 5. 77 (br s, 1 H, C4-CH=), 6. 67 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's) and 7. 07 (d, 2 H, J = 9 Hz, 2', 6'aromatic- CH's).

Step 2. PrepasXatiost of the tasget compoulld 126a : Under nitrogen, trifluoroacetic anhydride (11. 18 g, 53. 2 mmol), glacial acetic acid (3. 26 g, 54. 2 mmol) and dry CH2Cl2 (35 mL) were combined and stirred at room temperature for #hr. The mixture was cooled to 0°C in an ice bath and toluenesulfonic aicd monohydrate (0. 5 g, 2. 63 mmol) was added. A solution of the 21-propionyloxy-17a-ol (125a, 1. 28 g, 2. 61 mmol) in dry CH2Cl2 was then introduced and the mixture stirred at 0°C and monitored by TLC (10% acetone in CHzCl2) which indicated a complete reaction after 2 hr. The ice-bath was removed and the reaction was allowed to warm to room temperature. The mixture was then diluted with H20 (100 mL), adjusted to a pH of 6. 5 with concentrated NH 40H solution and extracted with CHxClz (3x). The organic fractions were washed with H20 (2x), brine (lx), combined, filtered through sodium sulfate and concentrated in vaczio to give 1. 1. g of the residue. Purification via flash chromatography (5% acetone in CH2C12) followed by trituration with heptane gave 0. 49 g of the pure 21- propionyloxy-17a-acetate (126a) as a light yellow amorphous solid in 55% yield ; m. p. = softens at 86°C. NMR (CDC13) : # 0. 43 (s, 3 H, C18-CH3), 1. 11 (t, 3 H, J = 8 Hz, propionyl CH3), 2. 07 (s, 3 H, OAc), 2. 89 (s, 6 H,-N (CH3) 2), 4. 43 (br d, Cl la-CH, J = 6 Hz), 4. 85 (dd, 2 H, Jl = 28 Hz, J2 = 17 Hz, C21-CH2-O-), 5. 77 (s, 1 H, C4-CH=), 6. 63 (d, 2 H, J = 7. 8 Hz, 3', 5'aromatic-CH's) and 7. 0 (d, 2 H, J = 7. 8 Hz, 2', 6'aromatic-CH's). Anal. Calcd. for C33H41NO6 : C, 72. 37 ; H, 7. 55 ; N, 2. 56. Found : C, 72. 23 ; H, 7. 71 ; N, 2. 50.

EXAMPLE 37 This example illustrates the preparation and properties of 17a-Acetoxy-11 [4- (N, N-dimethylamino) phenyl]-21- (2'-methoxyacetyl) oxy-19-norpregna-4, 9-diene-3, 20- dione (126b) (Figure 11) :

Step 1. 17α-Hydroxy-11ß-[4-(N,N-dimethylamino)phenyl]-21-(2'- metlaoxyacetyl) oxy-19-norpregna-4, 9-diene-3,20-dione (125b) : Under nitrogen, a solution of the 17a, 21-diol (124, 1. 0 g, 2. 22 mmol), pyridine (1 mL, 12. 41 mmol) and triethylamine (1 mL, 7. 11 mmol) in dry benzene (40 mL) was treated with methoxyacetyl chloride (0. 5 mL, 5. 47 mmol). The reaction mixture was stirred at room temperature for 4 hr, after which time TLC (5% isopropanol in CH2C12) indicated a complete reaction. Solvents were removed in vacuo under a current of nitrogen and the residue was diluted with H20 (-50 mL) and extracted with CH2C12 (3x). The organic fractions were washed with H2O (3x), filtered through anhydrous Na2S04, combined and concentrated in vacuo to give 1. 4 g of the residue as a yellow solid. This material was purified by flash chromatography (3% isopropanol in CH2CI2) to give 1. 05 g of the product as a yellow foam. Crystallization from ether containing a small amount of CH2C12 gave 0. 73 g of the pure 21- (2'-methoxy)-acetyloxy-derivative 125b as an off-white solid in 62. 9% yield ; m. p. = 197 - 199°c. FTIR (KBr, diffuse reflectance) : Vmax 3329, 2948, 2888, 1754, 1729, 1637, 1602 and 1518 cm~l. NMR (300 MHz, CDC13) : 8 0. 399 (s, 3 H, C18-CH3), 2. 906 (s, 6 H,-N (CH3) 2), 3. 488 (s, 3 H, C21-OCH3), 4. 181 (s, 2 H, C21- OC (O) CH2-), 4. 384 (d, 1 H, J = 4. 384, C11A-CH), 4. 975 and 5. 234 (both d, 2 H, J = 17. 4 Hz, C21-CH2), 5. 760 (s, 1 H, C4-CH=), 6. 654 (d, 2 H, J = 8. 7 Hz, 3', 5'aromatic- CH's) and 7. 012 (d, 2 H, J = 8. 7 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 521 (M+, 26. 4), 431 (7. 1), 134 (17. 3) and 121 (100. 0). Anal. Calcd. for C31H39NO3 : C, 71. 38 ; H, 7. 54 ; N, 2. 69. Found : C, 71. 48 ; H, 7. 59 ; N, 2. 64.

Step 2. Preparation of t) ze target costipound 126b : Under nitrogen, trifluoroacetic anhydride (2. 98 g, 14. 16 mmol), glacial acetic acid (0. 84 g, 13. 98 mmol) and dry CH2C12 (5 mL) were combined and stirred at room temperature for 1/2 hr. Toluenesulfonic aeid monohydrate (0. 15 g, 0. 79 mmol) was added and the mixture cooled to 0°C in an ice bath. A solution of the 21- (2'-methoxy) acetyloxy- 17a-ol (125b, 0. 612 g, 1. 173 mmol) in dry CH2C12 (2 mL) was added and the reaction was stirred at 0°C and monitored by TLC (3% isopropanol in CH2C12) which indicated a complete reaction after 4 hr. The mixture was diluted with H20 (~10 mL), stirred at 0°C for another 15 minutes, then carefully neutralized with dropwise addition of concentrated NH40H solution (-3 mL). The mixture was extracted with CH2CI2 (3x). The organic fractions were washed with H20 (2x) and brine (1x). filtered through anhydrous Na2S04,

combined and concentrated in vacuo to give 0. 72 g of the residue as an oil. This material was purified via flash chromatography (20% EtOAc in CH2C12) to give 0. 34 g of 126b as a yellow foam. Trituration of this material with pentane gave 0. 26 g of the pure title compound (126b) as a light yellow amorphous solid in 39. 3% yield ; m. p. =110-113°C.

Analysis of 126b by HPLC on a Waters NovaPak, Cl8 column, eluted with 0. 05 M KH 2PO 4 buffer [pH = 3. 0]/MeOH, 35 : 65 at a flow rate of 1 mL per min and at X = 302 nm indicated this material to be >99% pure with a retention time (tR = 6. 04 min). FTIR (KBr, diffuse reflectance) : vmaX 2947, 1766, 1737, 1663, 1612 and 1518 crri 1. NMR (300 MHz, CDC13) : 80. 447 (s, 3 H, C18-CH3), 2. 129, (s, 3 H, C17α-OAc), 2. 907 (s, 6 H,- N (CH3) 2), 3. 473 (s, 3 H, C21-OC (O) CH20CH 3), 4. 176 (s, 2 H, C21-OC (O) CH2-), 4. 392 (d, 1 H, J = 6 Hz, Cl la-CH), 4. 792 and 5. 029 (both d, 2 H, J = 17. 4 Hz, C21-CH2), 5. 777 (s, 1 H, C4-CH=), 6. 644 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's) and 7. 002 (d, 2 H, J = 9 Hz, 2', 6'-aromatic-CH's). MS (EI) m/z (relative intensity) : 563 (M+, 42. 8), 503 (12. 6), 134 (17. 2) and 121 (100. 0). Anal. Calcd. for C33H41NO7, C, 70. 32 ; H, 7. 33 ; N, 2. 48. Found : C, 70. 14 ; H, 7. 59 ; N, 2. 41.

EXAMPLE 38 This example illustrates the preparation and properties of 17a-Acetoxy-21- hydroxy-1 1 ß- [4-(N, N-dimethylamino) phenyl]-19-norpregna-4,9-diene-3,20-dione-21- methyl carbonate (126c) (Figure 11) : <BR> <BR> <BR> <BR> Step 1. 17α, 21-Dihydroxy-11ß-[4-(N,Ndimethylaminio)phenyl]-190-norpregn ja-<BR> <BR> <BR> 4, 9-diene-3, 20-dione-21-metllyl carbonate (125c) : The 17a, 21-diol (10) (124, 250 mg, 1. 80 mmol) was dissolved in CH2C12 (10 mL) and pyridine (0. 2 mL) was added followed by methyl chloro formate (0. 245 g, 2. 59 mmol). The mixture was stirred at room temperature for 20 min. TLC after 5 min showed the reaction complete. The mixture was evaporated ill vacuo and dissolved in CH2CIz. The dichloromethane was washed with H20 (2x), brine and dried over anhydrous Na2S04. The solvent was evaporated in vacuo. Benzene was added and evaporated to remove traces of pyridine. CH2C12 was added and evaporated to give 273 mg of the 17a- hydroxy-21-methyl carbonate (125c) in 29. 9% yield.

NMR (CDC13) : # 0. 381 (s, 3 H, C18-CH3), 2. 899 (s, 6 H,-N (CH3) 2), 3. 820 (s, 3 H, C21-OC (O) OCH3), 4. 369 (m, 1 H, C11α-CH), 4. 914 and 5. 178 (dd, 2 H, C21-

CH2-), 5. 747 (br s, 1 H, C4-CH=), 6. 644 (d, 2 H, 3', 5'aromatic-CH's) and 7. 002 (d, 2 H, 2', 6'aromatic-CH's).

Step 2. Preparation of the target compomzd 126c : CH2C12 (15 mL) was stirred at room temperature and trifluoroacetic acid anhydride (2. 29 g, 10. 9 mmol) and acetic acid (0. 714 g, 11. 8 mmol) were added. The mixture was stirred at room temperature in a nitrogen atmosphere for 1/2 hT. p- Toluenesulfonic acid monohydrate (1. 90 g, 1. 1 mmol) was added and the mixture cooled to 0°C in an ice bath. The 17a-hydroxy-21-methyl carbonate (125c, 273 mg, 0. 54 mmol) was dissolved in CH2 C12 and cooled to 0°C and then added to the stirred mixed anhydride. The reaction was complete in 6 hr. Saturated NaHCO3 was added to neutralize the reaction and the mixture was extracted with CH2C12 (3x). The CH2C12 extracts were washed with H20, brine and dried over anhydrous Na2S04. The solvent was evaporated, benzene was added and evaporated again. CH2C12 was added and evaporated again. Chromatography on flash colomn silica gel using CH2Cl2 : acetone, 95 : 5 gave a product that was only 95% pure.

Chromatography was run again using the same system followed by checking each fraction by HPLC on a NovaPak Cis column eluting with MeOH : H20 : Et3N (70 : 30 : 0. 05) at a flow rate of 1 mL per min and at = 260 nm. Good fractions were collected and combined to give 116. 1 mg of the good product. The remainder of the product was rechromatographed using CH2Cl2 : EtOAc (90 : 10) and checking fractions by HPLC as above gave an additional 38. 1 mg of the good product. The good product was combined and dried in vacuo to a foam and dried at 45°C. A small amount of ether in the product was present. The foam was dried in a vacuum at 80°C to give 131. 6 mg of 126c as a yellow foam in 44. 3% yield ; m. p. = 130-160°C. FTIR (KBr, diffuse reflectance) : via 2961, 1759, 1731, 1663, 1612, 1518 and 1278 cm~l. NMR (CDC13) : 6 0. 436 (s, 3 H, C18-CH3), 2. 125 (s, 3 H, C17a- OAc), 2. 907 (s, 6 H,-N (CH3) 2), 3. 828 (s, 3 H, C21-OC (O) OCH3), 4. 391 (d, 1 H, Cl la- CH), 4. 735 and 4. 961 (dd, 2 H, C21-CH2-), 5. 778 (s, 1 H, C4-CH=), 6. 638 (d, 2 H, 3', 5' aromatic-CH's) and 6. 995 (d, 2 H, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 549 (M+, 32), 489 (7. 0), 134 (16. 0) and 121 (100. 0). Anal. Calcd. for C32H39NO7 : C, 69. 92 ; H, 7. 15 ; N, 2. 55. Found : C, 69. 62 ; H, 7. 25 ; N, 2. 61.

EXAMPLE 39 This example illustrates the preparation and properties of 17α-Acetoxy-11ß- [4- (N, N-dimethylamino) phenyl]-21-(1'-ethenyloxy)-19-norpregna-4,9-diene-3,20-dione (129) (Figure 11) : Step 1. 17α,21-(1'-Ethoxyethylidenedioxy)-11ß-[4-(N,lN-dimethylami no)phenyl]- 19-l orpregna-4, 9-die7l e-3, 20-dio7l e (127) : The 17a, 21-diol (10) (124, 1. 6 g, 3. 56 mmol), triethyl orthoacetate (5. 59 g, 3. 45 mmol), and pyridinium tosylate (200 mg, 0. 93 mmol) were dissolved in dry benzene in a nitrogen atmosphere and heated at reflux for 75 min using a Dean Stark trap to remove water. The reaction was complete at this time. Pyridine (1 mL) was added and the solvent was evaporated using nitrogen and vacuum. Water was added and the mixture was extracted with CH2Cl2 (3x). The CH2Cl2 extracts were washed with H20, brine and dried over anhydrous Na2S04. The solvent was evaporated i7 vacuo. Purification by dry column chromatography, recrystallization and finally flash column chromatography using CH2Cl2 : acetone (97 : 3) gave 1. 028 g of the ortho ester (127) in 55. 8% yield. NMR (CDC13) : 6 0. 334 (s, 3 H, C18-CH3), 1. 620 (s, 3 H, C17a, 21-ethylidenedioxy-CH3), 2. 909 (s, 6 H, N (CH3) 2), 3. 55 (q, 2 H, C21-ethylidendioxy-OCH2CH3), 4. 404 (br d, 1 H, Clla-CH), 5. 769 (s, 1 H, C4-CH=), 6. 641 (d, 2 H, 3', 5'aromatic-CH's) and 7. 003 (d, 2 H, 2', 6' <BR> <BR> <BR> <BR> aromatic-CH's).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 2. 17α-Acetoxy-11ß-[4-(N,N-dimethylamino)phenyl]-21-hydroxy-1 9- norpregna-4, 89-diene-3,20-dione (128) : The cyclic ortho ester (127, 1. 028 g, 1. 99 mmol) was suspended in methanol (60 mL) in a nitrogen atmosphere and NaOAc solution (8. 2 mL, 0. 1 M) and HOAc solution (16. 4 mL, 0. 2 M) were added. The mixture was heated at reflux for 3 hr. The solvent was evaporated using nitrogen and vacuum. H20 (-50 mL) was added and the mixture was extracted wtih CH2CI2 (3x). The organic fractions were washed with H 20, brine and dried over anhydrous Na2S04 to give 1. 0112 g of the 17 a-acetoxy-21-hydroxy compound (128) as an off-white powder containing a trace amount of the 17a-hydroxy-l lp- [4- (N, N- dimethylamino) phenyl]-21-acetoxy-19-norpregna-4, 9-diene-3, 20-dione compound (8). The crude product was chromatographed on flash column silica gel using CH2Cl2 : acetone (8 : 2) as the solvent. Fractions were collected and each fraction was checked by TLC. Fractions

&num 5-7 were essentially pure 128 and were combined to give 108. 5 mg of good product. The residue was crystallized from ether to give 75 mg of an additional pure 128. The total amount of the product 128 was 183. 5 mg as an off-white powder in 18. 8% yield ; m. p. = 205-210°C. NMR (CDC13) : 6 0. 364 (s, 3 H, C18-CH3), 2. 112 (s, 3 H, C17a-OAc), 2. 902 (s, 6 H,-N (CH3) 2), 4. 190-4. 405 (br d and m, 3 H, Cl la-CH and C21-CH2-), 5. 779 (br s, 1 H, C4-CH=), 6. 629 (d, 2 H, 3', 5'aromatic-CH's) and 6. 967 (d, 2 H, 2', 6'aromatic-CH's).

Step 3. Preparation of t he target compound 129 : The 21-hydroxy compound (128, 682 mg, 1. 39 mmol) was dissolved in CH2C12 (14 mL) in a nitrogen atmosphere and ethyl vinyl ether (5. 27 g, 7. 32 mmol) was added. Mercury (II) trifluoroacetate (25 mg, 0. 059 mmol) was added and the mixture was stirred in a nitrogen atmosphere at room temperature for 22 hr. The mixture was poured onto dry column silica gel which had been washed with CH2C12 in a sintered glass funnel.

The compound was eluted with EtOAc and the solvent was evaporated in vacuo. The residue (744 mg) was chromatographed on Flash column silica gel using CH2C12 : acetone (95 : 5) as the solvent. A total of 141 mg of good product 129 was obtained as a yellow foam in 19. 6% yield. The compound 129 was dried to remove ether ; m. p. = 114-116°C.

Analysis of 129 by HPLC on a NovaPak C18 column eluted with MeOH : H20 : Et3N (70 : 30 : 0. 05) at a flow rate of 1 mL per min and at k = 260 nm indicated it to be better than 99% pure. FTIR (KBr, diffuse reflectance) : may 2948, 1733, 1662, 1613, 1560, 1518, 1446, 1369, 1278 and 1235 crri 1. NMR (CDC13) : 8 0. 408 (s, 3 H, C18-CH3), 2. 118 (s, 3 H, C17a-OAc), 2. 901 (s, 6 H,-N (CH3) 2), 4. 096-4. 662 (m, 6 H, C21-Ovinyl H, Cl la-CH and C21-CH2-), 5. 779 (br s, 1 H, C4-CH=), 6. 625 (d, 2 H, 3', 5'aromatic-CH's), and 6. 967 (d, 2 H, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 517 (M+, 73), 134 (18. 0) and 121 (100. 0). Anal. Calcd. for C32H39N06-1/3H20 : C, 73. 40 ; H, 7. 64 ; N, 2. 67. Found : C, 73. 49 ; H, 7. 62 ; N, 2. 84.

EXAMPLE 40 This example illustrates the preparation and properties of 17a-Acetoxy-11 (3- [4- (N, N-dimethylamino) phenyl]-21- (2'-N, N-dimethylamino) acetoxy-19-norpregna-4, 9- diene-3, 20-dione (133) (Figure 10) :

Step 1. 17α-Hydroxy-21-(2'-chloroacetoxy)-11ß-[4-(N,N-dimethylamin o)phenyl]- 19-norpregna-4,9-diene-3,20-dione (130) : The 17a, 21-diol (124, 500 mg, 1. 15 mmol) was dissolved in pyridine (7 mL) and cooled to 0°C in an argon atmosphere. Chloroacetic anhydride (705 mg, 4. 12 mmol) was dissolved in pyridine and added dropwise to the stirred diol (124) solution.

The mixture was stirred at 0°C for 2 hr. TLC showed very little reaction. The reaction was allowed to warm to room temperature. Additional chloroacetic anhydride (200 mg, 1. 17 mmol) was added and the reaction was continued. When the reaction was complete, H20 (2 mL) was added followed by additional water (70 mL). The mixture was extracted with EtOAc (3x). The EtOAc extracts were washed with H20, brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo. The mixture was azeotropically evaporated with benzene (2x), dissolved in EtOAc, filtered through Celite and evaporated in vacuo to give 475 mg of the 21-chloroacetate (130) in 78. 3% yield. It was used for the next reaction without purification. NMR (DC13) : 8 0. 381 (s, 3 H, C18- CH3), 2. 908 (s, 6 H,-N (CH3) 2), 4. 201 (s, 2 H, CH2C1), 4. 999 and 5. 271 (d, 2 H, C21-CH2-), 5. 754 (s, 1 H, C4-CH=), 6. 669 (d, 2 H, 3', 5'aromatic-CH's), and 7. 016 (d, 2 H, 2', 6' <BR> <BR> <BR> <BR> aromatic-CH's).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 2. 17a-Acetoxy-11/3-4- (N, N-dimethylamino) plzenyll-21- (2 ! clzloroacetoxy)-<BR> <BR> <BR> <BR> 19-norpregna-4, 9-diene-3, 20-dione (131) : Trifluoroacetic anhydride (4. 12 g, 19. 62 mmol), and acetic acid (1. 21 g, 20. 15 mmol) were added to CH2Cl2 (35 mL) in an argon atmosphere and stirred at room temperature for/2 hr. p-Toluenesulfonic acid monohydrate (155 mg, 5. 26 mmol) was added and the mixture was cooled to 0°C. The 17a-hydroxy-21-chloroacetate (130, 475 mg, 0. 97 mmol) was dissolved in CH2C12 (10 mL), cooled to 0°C, and added to the mixed anhydride solution. The mixture was stirred at 0°C overnight. The reaction was complete.

Saturated NaHCO3 solution was added to neutralize the mixture and the mixture was extracted with CH2C12 (3x). The CH2C12 extract was washed with H20, brine and dried over anhydrous Na 2SO 4. The solvent was evaporated in vacuo. Chromatography on dry column silica gel using CH2Cl2 : acetone (9 : 1) as solvent gave 286. 2 mg of the 17a-acetoxy- compound 131 in 56% yield. NMR (CDC13) : 8 0. 437 (s, 3 H, C18-CH3), 2. 130 (s, 3 H, 17a-OAc), 2. 923 (s, 6 H,-N (CH3) 2), 4. 201 (s, 2 H, C21-OC (O) CH2C1), 4. 395 (d, 1 H,

Clla-CH), 4. 804 and 5. 041 (d, 2 H, C21-CH20-), 5. 779 (s, 1 H, C4-CH=), 6. 697 (d, 2 H, 3', 5'aromatic-CH's) and 7. 017 (d, 2 H, 2', 6'aromatic-CH's).

Step 3. 17α-Acetoxy-11ß-[4-(N,N-dimethylamino)phenyl]-21-(2'-iodoa cetoxy)- 19-norpregna-4,89-diene-3,20-dione (132): The 17a-acetoxy-21- (2'-chloroacetoxy) compound (131, 286 mg, 0. 47 mmol) was dissolved in CH3CN (50 mL) in an argon atmosphere. Nal (650 mg, 4. 34 mmol) was added and the mixture was heated at reflux in an argon atmosphere for 45 min. After l/2 hr, an aliquot was removed and checked by NMR. The reaction was complete after 1/2 hr. The mixture was cooled to room temperature and filtered. The solvent was evaporated in vacuo. The residue was dissolved in CH2C12 and filtered to remove solid salts. The solid was washed well with CH2C12 and the solvent was evaporated in vacuo to give 328. 5 mg of the iodoacetoxy compound 132 in 73% yield. NMR (CDC13) : 8 0. 431 (s, 3 H, C18-CH3), 2. 133 (s, 3 H, C17a-OAc), 2. 911 (s, 6 H,-N (CH3) 2), 3. 812 (d, 2 H, C21-CH20), 4. 394 (d, 1 H, C1 la-CH), 4. 741 and 4. 996 (d, 2 H, C21-CH2O-), 5. 777 (s, 1 H, C4-CH=), 6. 677 (d, 2 H, 3', 5'aromatic-CH's), and 7. 008 (d, 2 H, 2', 6'aromatic- CH's).

Step 4. Preparatiooz of tlie target cosnpouzd 133 : The 21-iodoacetate (132, 328 mg, 0. 52 mmol) was dissolved in THF (25 mL) and cooled to 0°C in an argon atmosphere. Dimethylamine (2. 5 mL, 2 M in THF) was added and the mixture was stirred at 0°C in an argon atmosphere. TLC after 10 min showed the reaction complete. The solvent was evaporated in vacuo on the rotary evaporator at room temperature. H20 was added and the mixture was extracted wtih EtOAc (3x). The EtOAc extracts were washed with H20, brine and dried over anhydrous Na2S04. The solvent was evaporated in vacuo to give 276. 8 mg of the crude compound 133. The crude product was chromatographed on a flash column using EtOAc : CH3CN (70 : 30). Two fractions were obtained. The first fraction gave 84. 5 mg which was 95% pure by HPLC analysis and the other gave 66. 8 mg which was 90% pure by HPLC analysis.

Total yield of 133 was 151. 3 mg as a yellow foam in 58% yield. FTIR (KBr, diffuse reflectance) : Vmax 2947, 1737, 1663, 1612, and 1518 crn~l. NMR (CDC13) : 50. 440 (s, 3 H, C18-CH3), 2. 126 (s, 3 H, 17a-OAc), 2. 386 (s, 6 H,-C (O) CH2N (CH3)2), 2. 906 (s, 6 H, -N (CH3) 2), 3. 308 (t, 2 H, C21-OC (O) CH2NMe2), 4. 393 (d, 1 H, C11α-CH), 4. 754 and 5. 004 (dd, 2 H, 21-CH2-), 5. 773 (s, 1 H, C4-CH=), 6. 643 (d, 2 H, 3', 5'aromatic-CH's), and

7. 006 (d, 2 H, 2', 6'aromatic-CH's). Anal. Calcd. for C34H44N206'1 H2O : C, 68. 69 ; H, 7. 74 ; N, 4. 71. Found : C, 68. 66 ; H, 7. 80 ; N, 4. 70.

EXAMPLE 41 This example illustrates the preparation and properties of 17a-Acetoxy-l l- [4- (N, N-dimethylamino) phenyl]-21-thiocyanato-19-norpregna-4, 9-diene-3, 20-dione (138) (Figure 11) : Step 1. 17α-Hydroxy-11ß-[4-(N,N-dimethylaminio)phenyl]-21- methanesulfonyloxy-19-norpregna-4,9-diened-3,20-dione (136) : Under nitrogen, a solution of the diol (124, 1. 0 g, 2. 22 mmol) and triehtylamine (0. 72 g, 7. 11 mmol) in dry pyridine (20 mL) was cooled to 0°C in an ice bath treated with methanesulfonyl chloride (0. 74 g, 6. 46 mmol). The reaction mixture was stirred at 0°C and monitored by TLC (10% acetone/CH2C12) which indicated a complete reaction after two hours. The reaction mixture was diluted with H20 (-100 mL) and extracted with CH2C12 (3x). The organic fractions were washed with H20 (2x), filtered through Na2S04, combined and concentrated ira vacuo to give 1. 3 g of the residue as a yellow oil. This material was purified by flash chromatography using 10% acetone/CH2Cl2 followed by trituration with ether to give 0. 83 g ofthe 21-mesylate-17a-ol (136) as a yellow solid in 63. 6% yield ; m. p. = 143-146°C. FTIR (KBr, diffuse reflectance) : Vmax 3298, 2947, 1738, 1630, 1614, 1518 and 1174 cm-l. NMR (300 MHz, CDC13) : 5 0. 375 (s, 3 H, C18-CH3), 2. 899 (s, 6 H,-N (CH3) 2), 3. 190 (s, 3 H, C21-OS02CH3) 4. 371 (br d, 1 H, J = 6. 6 Hz, Clla-CH), 5. 128 and 5. 353 (dd, 2 H, J = 18 Hz, C21-CH2-), 5. 746 (s, 1 H, C4- CH=), 6. 645 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's), and 6. 994 (d, 2 H, J = 9 Hz, 2', 6' aromatic-CH's).

Step 2. 17α-Hydroxy-11ß-[4-(N,N-dimethylamino)phenyl]-21-thiocyana to-19- iiorpregiia-4, 9-diene-3, 20-dioize (137) : Under nitrogen, a solution of the 21-mesylate-17a-ol (136, 0. 65 g, 1. 23 mmol) and dry potassium thiocyanate (0. 3 g, 3. 09 mmol) in dry dimethylformamide (DMF) (15 mL) was heated to 95-105°C. After about 15 min of heating, a very fine precipitate was observed. The reaction mixture was cooled to room temperature, diluted with H2O (-100 mL) and extracted first with CH2C12 (3x) and then with EtOAc (3x) when it became apparent that the product was not very soluble in CH2C12. The organic fractions

were washed with H ? O (2x), filtered through anhydrous Na2S04, combined and concentrated in vacuo to give a yellow solid residue. Trituration of this material with ether gave 0. 598 g of the pure 17a-ol-21-thiocyanate (137) as a light yellow solid in 99% yield ; m. p. = 226°C (dec). FTIR (KBr, diffuse reflectance) : vmaX 3360, 2940, 2145, 1728, 1640, 1597 and 1518 cni-1. NNM (300 MHz, CDC13) : 6 0. 356 (s, 3 H, C18-CH3), 2. 907 (s, 6 H, -N (CH3) 2), 4. 188 and 4. 629 (dd, 2 H, J = 17. 1 Hz, C21-CH2) 4. 403 (br d, 1 H, J = 6. 0 Hz, C 11 a-CH), 5. 762 (s, 1 H, C4-CH=), 6. 696 (d, 2 H, J = 8. 4 Hz, 3', 5'aromatic-CH's), and 7. 023 (d, 2 H, J = 8. 4 Hz, 2', 6'aromatic-CH's). MS (EI) m/z (realtive intensity) : 490 (M+, 25. 90), 465 (3. 8), 414 (7. 8), 389 (6. 5), 134 (15. 6) and 121 (100. 0). Anal. Calcd. for C29H34N203S-4/5 H20 : C : 68. 96 ; H, 7. 10 ; N, 5. 55 ; S, 6. 35. Found : C, 68. 90 ; H, 6. 92 ; N, 5. 58 ; S, 5. 96.

Step 3. Preparation the target compound 138 : Under nitrogen, trifluoroacetic anhydride (5. 20 g, 24. 79 mmol), glacial acetic acid (1. 57 g, 26. 23 mmol) and dry CH2C12 (5 mL) were combined and and stirred at room temperature for 1 hr. p-Toluenesulfonic acid monohydrate (0. 05 g, 0. 26 mmol) was added, and the reaction mixture was cooled to 0°C in an ice bath. A solution of the 17a-ol- 21-thiocyanate (137, 0. 4 g, 0. 815 mmol) in dry CH2C12 (2 mL) was added and the reaction mixture was stirred at 0°C and monitored by TLC (10% acetone in CH2C12) which indicated a complete reaction after 2 hr. The mixture was diluted with H20 (~10 mL), stirred at 0°C for about Y2 hr, then carefully neutralized with dropwise addition of concentrated NH40H solution (-5 mL). The mixture was extracted with CH2C12 (3x). The organic fractions were washed with H20 (2x), filtered through anhydrous Na2S04, combined and concentrated in vacuo to give 0. 43 g of the residue as a yellow oil. This material was combined with product obtained from two previous batches (total amount of crude product = 0. 675 g from a total of 0. 6 g of 137). This material was purified via flash chromatography (7. 5% acetone in CH2C12) to give 0. 3 g of 138 as a light yellow foam. This material was taken up in a minimum amount of CH2C12, blown down, and the residue triturated with ether to give 0. 256 g of the pure title compound 138 as an off-white solid in 39. 3% yield ; m. p. = 181°C (dec).

Analysis by HPLC on a Waters NovaPak, Cis column eluted with 0. 05 M KH2PO4 buffer [pH = 3. 0]/MeOH, (35 : 65) at a flow rate of 1 mL per minute and at X = 302 nm indicated this material to be >99% pure. FTIR (KBr, diffuse reflectance) : Vmax

2935, 2158, 1736, 1658, 1611 and 1518 cm 1. NMR (300 MHz, CDCl3) : 6 0. 401 (s, 3 H, C18-CH3), 2. 153 (s, 3 H, C17a-OAc), 2. 914 (s, 6 H,-N (CH3) 2), 4. 060 and 4. 236 (dd, 2 H, J = 16. 2 Hz, C21-CH2) 4. 407 (br d, 1 H, J = 6. 9 Hz, Cl la-CH), 5. 783 (s, 1 H, C4-CH=), 6. 649 (d, 2 H, J = 9 Hz, 3', 5'aromatic-CH's), and 6. 985 (d, 2 H, J = 9 Hz, 2', 6'aromatic- CH's). MS (EI) m/z (realtive intensity) : 532 (M+, 29. 9), 134 (13. 5) and 121 (100. 0). Anal.

Calcd. for C3lH36N204S1/9H20 : C, 69. 64 ; H,, 6. 83 ; N, 5. 24 ; S, 6. 00. Found : C, 69. 63 ; H, 6. 95 ; N, 5. 12 ; S, 5. 84.

EXAMPLE 42 This example illustrates the preparation and properties of 17a-Acetoxy-11 (3- [ (4- (N-piperidino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione 3-oxime (141) (Figure 4) : Under nitrogen, a solution of the dienedione (71, 200 mg, 0. 38 mmol) in absolute EtOH (25 mL) was treated with a 1 0-fold excess of solid hydroxylamine hydrochloride (269 mg, 3. 87 mmol). The reaction mixture was stirred at room temperature for 1 1/4 hr. At that time, TLC (10% acetone in CH2C12) showed no starting material and two major more polar spots. The reaction was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with methylene chloride (3x). The orange fractions were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 290 mg of off-white powder. Flash chromatography (10% acetone in methylene chloride) gave 177 mg of the material. Trituration with pentane with sonication gave 163 mg of 141 as an off-white solid in 80. 8% yield after drying. HPLC analysis indicated a syn : anti ratio of 1 : 3. 2 ; m. p. = 167-172°C. FTIR (KBr, diffuse reflectance) : Vmax 3237, 2932, 2855, 1735, 1714, 1610, 1512, 1452, 1369 and 1236 cm-l.

NMR (300 MHZ, CDC13) : 8 0306 (s, 3 H, C18-CH3), 2. 086 (s, 3 H, C17a-OAc), 2. 125 (s, 3 H, C21-CH3), 3. 10 (m, 4 H,-CH2CH2-N-of piperidine ring) 4. 33 (m, 1 H, Clla-CH), 5. 869 (s, 1 H, C4-CH= of anti-oxime), 6. 525 (s, 1 H, C4-CH= of syn-oxime) and 6. 805- 6. 975 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 530 (M+). Anal. Calcd. for C33H4204N2 : C, 74. 72 ; H, 7. 92 ; N, 5. 28. Found : C, 73. 73 ; H, 8. 16 ; N, 5. 16.

EXAMPLE 43 This example illustrates the preparation and properties of 17a-Methoxy-110- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione 3-oxime (142a) (Figure 6) :

Under nitrogen, a solution of the dienedione (97a, 0. 4 g, 0. 89 mmol) in absolute EtOH (25 mL) was treated with a 10-fold excess of solid hydroxylamine hydrochloride (0. 62 g, 8. 92 mmol). The reaction mixture was stirred at room temperature for 1 hr, after which time TLC (10% acetone/methylene chloride, overspotted with con.

NH40H) indicated a complete reaction. The reaction mixture was diluted with water (-100 mL), adjusted to a pH of-8. 0 with concentrated NH40H solution, and extracted with methylene chloride (3x). The organic fractions were purified via flash chromatography (10% acetone/methylene chloride) followed by trituration with pentane to give the purified oxime (142a, 0. 22g) as an off-white amorphous solid in 53% yield ; m. p. = 148-162°C.

Analysis by NMR indicated this material to consist of a mixture of 39 : 61 ratio of the syn and anti-isomers. HPLC analysis on a Waters NovaPak Cl8 ODS column eluted with acetonitrile/0. 05 M KH2PO4 [pH=3. 0] 1 : 1 at a flow rate of 1 mL per min and at , = 276 nm indicated a purity of 96. 5%. FTIR (KBr, diffuse reflectance) : Vmax 3270, 2942, 1708, 1613 and 1517 cm-1. NMR (300 MHZ, CDC13) : 6 0. 259 (s, 3 H, C18-CH3 of anti- isomer), 0. 269 (s, 3 H, C18-CH3 of syn-isomer), 2. 176 (s, 3 H, C21-CH3 of syn-isomer), 2. 182 (s, 3 H, C21-CH3 of anti-isomer), 2. 898 (s, 6 H,-NMe2), 3. 150 (s, 3 H, C17a-OCH3), 4. 298 (br d., 1 H, J = 7. 2 Hz, Cl 1 a-CH), 5. 840 (s, 0. 64 H, C4-CH= of azlti-oxime), 6. 490 (s, 0. 37 H, C4-CH= of syn-oxime), 6. 638 (m, 2 H, 3', 5'aromatic-CH's) and 7. 012 (m, 2 H, 2', 6'aromatic-CH's). MS (EI) m/z (relative intensity) : 462 (100, M+), 446 (43. 4), 431 (15. 9), 134 (38. 5) and 121 (48. 3). Anal. Calcd. for C29H3gN203-l/5H20 : C, 74. 71 ; H, 8. 30 ; N, 6. 01. Found : C, 74. 65 ; H, 8. 31 ; N, 6. 03.

EXAMPLE 44 This example illustrates the preparation and properties of 17a-Methoxy-1 I [4- (N-piperidino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione 3-oxime (142b) (Figure 6) : Under nitrogen, a solution of the dienedione (97b, 250 mg, 0. 513 mmol) in absolute EtOH (25 mL) was treated with a 10-fold excess of solid hydroxylamine hydrochloride (38 mg, 5. 13 mmol). The reaction mixture was stirred at room temperature for 1 1/4 hr. At that time, TLC (10% acetone in methylene chloride) showed no starting material and two major more polar products. The reaction was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with methylene chloride (3x). The organic fractions were washed with water and brine, dried over anhydrous sodium sulfate,

filtered and concentrated ifz vacuo to yield 260 mg of yellow foam.. Flash chromatography (10% acetone in methylene chloride) gave 186 mg of the material. Trituration with pentane with scratching and sonication gave 172 mg of the product 142b after drying. HPLC analysis indicated this material to be 94% pure. Two additional flash column chromatography, trituration with pentane and drying again in vacuo yielded 143 g of 142b as an off-white solid in 55. 5% yield ; m. p. = 157-162°C (amber gel) and 195-200°C (gel melts). HPLC analysis on a Waters NovaPak CIS ODS column eluted with MeOH : water (80 : 20) with 0. 05% Et3N at a flow rate of 1 mL per min and at X = 260 nm indicated a purity of 97. 9%. FTIR (KBr, diffuse reflectance) : may 3183, 2934, 1707, 1610, 1511, 1450, 1385, 1349 and 1234 cn : i 1. NMR (300 MHZ, CDC13) : 8 0. 239 (s, 3 H, C18-CH3), 2. 175 (s, 3 H, C21-CH3), 3. 07-3. 150 (m, 4 H,-N-CH2CH2-of piperidine ring), 3. 13 (s, 3 H, C17a-OCH3), 4. 28-4. 30 (d., 1 H, Cl la-CH), 5. 840 (s, 0. 69 H, C4-CH= of anti-oxime), 6. 493 (s, 0. 31 H, C4-CH= of syn-oxime), 6. 8-7. 0 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 502 (M+). Anal. Calcd. for C32H4203N2 : 76. 46 ; H, 8. 42 ; N, 5. 57.

Found : C, 75. 38 ; H, 8. 60 ; N, 5. 39 EXAMPLE 45 This example illustrates the preparation and properties of 17a, 21-dimethoxy- 11 (3- [4- (N, N-dimethylamino) phenyl]-19-norpregna-4, 9-diene-3, 20-dione 3-oxime (143) (Figure 8) : A solution of the 17a, 21-dimethoxydienedione (113a, 0. 3 g, 0. 63 mmol) in absolute EtOH (20 mL) was treated with a 10-fold excess of solid hydroxylamine hydrochloride (0. 44 g, 6. 3 mmol). The reaction mixture was stirred at room temperature for 2. 5 h, after which time, TLC (10% acetone in methylene chloride, overspotted with con.

NH40H) indicated a complete reaction. The reaction mixture was diluted with water (-100 mL), adjusted to pH of-8. 0 with concentrated NH40H solution, and extracted with methylene chloride (3x). The organic fractions were washed with water (3x) then filtered through anhydrous sodium sulfate, combined and concentrated in vacuo to give 0. 37 g of the crude product (143) as a yellow foam. This material was purified via flash chromatography (10% acetone in methylene chloride) followed by trituration with pentane to give 0. 17 g of the purified oxime (143). Analysis by HPLC on a Waters NovaPak Cl8 ODS column eluted with acetonitrile : 0. 05 M KH2P04 buffer [pH 3. 0] ; 1 : 1 at a flow rate of

1 mL per min and at X = 276 nm indicated a purity of only 92%. This material was purified via flash chromatography (10% acetone/methylene chloride) followed by precipitation from acetonitrile with water to give 0. 11 g of 143 as a white powder in 35. 5% yield for which HPLC analysis indicated it to be 96. 2% pure ; m. p. 129-135°C. FTIR (KBr, diffuse refelectance) : vmax 3290, 2938, 1722, 1613 and 1518 cm'. NMR (300 MHZ, CDC13) : 80. 288 (s, 3 H, C18-CH3), 2. 898 (s, 6 H, NMe2), 3. 165 (s, 3 H, Cl7a-OCH3), 3. 454 (s, 3 H, C21-OCH3), 4. 245 and 4. 380 (dd, 2 H, J = 17. 9 Hz, C21-CH 2) 4. 301 (d., 1 H, J = 6. 9 Hz, Cl la-CH), 5. 842 (s, 0. 82 H, C4-CH= of anti-oxime), 6. 496 (s, 0. 18 H, C4- CH= of syn-oxime), 6. 633 (m, 2 H, 3', 5'aromatic-CH's) and 6. 997 (m, 2 H, 2', 6' aromatic-CH's). MS (EI) m/z (relative intensity) : 492 (M+, 100), 476 (12. 9), 134 (59. 8) and 121 (65. 0). Anal. Calcd. for C3oH40N204-l/lOH20 : C, 72. 87 ; H, 8. 19 ; N, 5. 67. Found : C, 72. 97 ; H, 8. 18 ; N, 5. 44.

EXAMPLE 46 This example illustrates an unusual and novel oxidative N-demethylation method and properties of 17a-acetoxy-11 (3- [4- (N-methylamino) phenyl-21-methoxy-19- norpregna-4, 9-diene-3, 20-dione (145) (Figure 3) : A mixture of the dimethylaminophenyl compound (38, 500 mg, 0. 98 mmol) and calcium oxide (471 mg, 8. 40 mmol) in THF (4 mL) and methanol (3 mL) was chilled in an ice bath. Iodine (1. 255 g, 4. 94 mmol) in THF (2 mL) was added. The reaction was stirred at 0°C for 1. 5 hr and diluted with CH2C12. The mixture was filtered and the filtrate sequentially yielded 591 mg of crude material. Flash chromatography using 10% acetone in CH2C12 gave 204 mg of 145 as an off-white solid in 49 % yield. This was combined with material from other reactions (170 mg total) and purified as one batch. Two flash column chromatographies yielded 296 mg of material which was triturated with pentane accompanied with scratching and sonication. After drying in vacuo, 280 mg of 145 were obtained ; m. p. = 177-182°C. FTIR (KBr, diffuse reflectance) : may 3407, 2949, 1733, 1662, 1615, 1519, 1448, 1370 and 1236 cm-1. NMR (300 MHZ, CDC13) : 8 0. 403 (s, 3 H, C18-CH3), 2. 105 (s, 3 H, C17a-OAc), 2. 796 (s, 3 H,-NCH3), 3. 412 (s, 3 H, 21-OCH3), 4. 073-4. 333 (dd, 2 H, 21-CH2OMe), 4. 352-4. 376 (d, 1 H, Cl la-CH), 5. 775 (s, 1 H, C4- CH=), and 6. 489-6. 933 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 491 (M+). Anal. Calcd. for C30H37NO5 : C, 73. 29 ; H, 7. 59 ; N, 2. 85. Found : C, 73. 22 ; H, 7. 84 ;

N, 2. 87. Analysis by HPLC on a Waters Assoc. NovaPak Cl8 column eluted with MeOH/H20 (65 : 35) with 0. 05% Et3N at a flow rate of 1 mL per min and at X = 260 mu indicated a purity of 98. 1% of 145.

EXAMPLE 47 This example illustrates an unusual and novel oxidative N-demethylation method and properties of 17a, 21-diacetoxy-I1 (3- [4- (N-methylamino) phenyl-I9-norpregna- 4, 9-diene-3, 20-dione (144) : This compound was prepared in a manner similar to that of the above Example 46. Our initial concern was whether the 21-acetate would undergo hydrolysis when exposed to the demethylation reaction conditions. Treatment of the dimethylaminophenyl compound (15) with iodine-calcium oxide in THF/MeOH proceeded similarly and smoothly to that of Example 46 without hydrolysis of the 21-acetate.

A mixture of the dimethylaminophenyl compound (15, 775 mg, 1. 45 mmol) and calcium oxide (692 mg, 12. 34 mmol) in THF (6. 4 mL) and MeOH (4. 8 mL) was chilled in an ice bath. Iodine (1. 84 g, 7. 25 mmol) was added as a solid and the mixture stirred under nitrogen in the ice bath for 2 hr. At that time the reaction was diluted with CH2C12 and filtered. The filtrate was washed with 15% sodium thiosulfate solution, H20, brine, and then dried over Na2S04. Evaporation of the solvent yielded 1. 38 g of the crude product (144). Flash column chromatography using 10% acetone in CH2C12 gave 490 mg of the product (144) as an off-white solid in 65% yield which was 90% pure by HPLC. This was combined with material from other batches (135 mg) and after two additional flash column chromatographies yielded 482 g which was 92% pure. An additional flash column chromatography was performed followed by trituration of the material with pentane, sonication and scratching. 330 mg of the demethylated product (144) were obtained ; m. p. = 135-142°C. FTIR (KBr, diffuse reflectance) : may 3394, 2942, 2883, 1737, 1662, 1613, 1519, 1370 and 1234 cm\ NMR (300 MHz, CDC13) : 6 0. 448 (s, 3 H, C18-CH3), 1. 266 (s, 1 H,-NH), 2. 134-2. 176 (s, 6 H, C17a-OAc and C21-OAc), 2. 810 (s, 3 H,-NCH3), 4. 375- 4. 399 (d, 1 H, CI la-CH), 4. 670-4. 981 (dd, 2 H, 21-CH2OAc), 5. 787 (s, 1 H, C4-CH=), and 6. 523-6. 980 (dd, 4 H, aromatic-CH's). MS (EI) m/z (relative intensity) : 519 (M+). Anal.

Calcd. for C31H37NO6 : C, 71. 65 ; H, 7. 18 ; N, 2. 70. Found : C, 71. 59 ; H, 7. 31 ; N, 2. 59.

Analysis by HPLC on a Waters Assoc. NovaPak Cl8 column eluted with CH3CN/H20

(50 : 50) with 0. 05% Et3N at a flow rate of 1 mL per min and at X = 260 nm indicated a purity of 98. 8 % of 144.

Biological Properties of the Compounds of Formula I MATERIALS AND METHODS Statistical Analysis Statistical analysis was performed using standard methods and a PROPHET data management system operating on SUN Microsystems OS 4. 4. 1 (Bliss, Cl., The Nfatistics of Bioassay, New York, Academic Press (1952) ; Hollister, C., Nucleic Acids Research, 16 : 1873-1875 (1988)). Raw data, statistical and regression analysis are available.

AntiMcGinty Test (McGinty, et al., Endocrix2010gy, 24 : 829-832 (1939)) Immature female rabbits of the New Zealand White breed (approx. 1 kg body weight) were maintained under standard laboratory conditions and received a subcutaneous injection of 5 llg estradiol in 10% ethanol/sesame oil daily for 6 consecutive days. Twenty-four hours after the last injection of estradiol (day 7) animals underwent sterile abdominal surgery to ligate a 3-4 cm segment of both uterine horns. The experimental compound in appropriate solvent (usually 10% ethanol/sesame oil) was injected intraluminally into the ligated segment of one uterine horn and the vehicle alone into the ligated segment of the contralateral horn. Injection volume was limited to 0. 1 ml, and care was taken to prevent leakage. A stimulating dose of progesterone (0. 8 mg/day) was administered subcutaneously to each rabbit daily for the next three days (days 7, 8 and 9) for the purpose of inducing endometrial proliferation. All animals were sacrificed on day 10 when a segment central to the ligatures was removed and fixed in 10% neutral buffered formalin and submitted for histological processing. Five micron sections stained with hematoxylin and eosin (H&E) were evaluated microscopically for the degree of endometrial glandular proliferation according to the method of McPhail (McPhail, J.

Physio, 83 : 145 (1934). The percent inhibition of endometrial proliferation for each rabbit was calculated and the mean of the group of five animals recorded.

AiitiClauberg Test (Clauberg, C., Zeiitr. GynakoL, 54 : 2757-2770 (1930)) Immature female rabbits of the New Zealand White breed (approx. 1 kg body weight) were maintained under standard laboratory conditions and received a subcutaneous injection of 5 llg estradiol in 10% ethanol/sesame oil daily for 6 consecutive days. Twenty-four hours after the last dose of estradiol (day 7) animals received progesterone by subcutaneous injection (0. 8 mg/day) and the experimental compound in appropriate vehicle (usually 10% ethanol/sesame oil) orally or subcutaneously for five consecutive days. One group of rabbits received progesterone only. Twenty-four hours after the last dose all animals were sacrificed for removal of the uterus which was cleaned of all fat and connective tissue, weighed to the nearest 0. 2 mg and placed in 10% neutral buffered formalin for subsequent histological processing. Five micron sections stained with hematoxylin and eosin (H&E) were evaluated microscopically for the degree of endometrial glandular proliferation according to the method of McPhail (McPhail, supra).

The percent inhibition of endometrial proliferation at each dose level of the experimental compound was derived by comparison with the progesterone-stimulated animals alone.

Postcoital Test Adult female rats of the Sprague-Dawley strain were maintained under standard laboratory conditions, 14 hours of light and 10 hours of darkness each day and cohabited with proven fertile males when in proestrus. Spenn-positive animals were randomly assigned to control and experimental groups. The day vaginal sperm were found in vaginal washings constituted day 0 of gestation. Rats received experimental compounds or vehicle (control) daily by the oral route on days 0-3 or 4-6 and were sacrificed between days 10 and 17 to record the number and condition of conceptuses.

Antiovulatory Test Immature female rats of the Sprague-Dawley strain weighing 200 to 250 g were maintained under standard laboratory conditions, 14 hours of light and 10 hours of darkness each day. Vaginal washings were obtained daily and evaluated microscopically to establish the estrous cycle of each animal. Animals exhibiting two consecutive four-day cycles were used in the test. Each dose group consisted of eight rats and one group served as the vehicle control. Animals were dosed at noon on the day of proestrus and sacrificed 24 hours later when ova can usually be visualized in the distended ampulla of the oviduct

using a dissecting microscope. The oviducts were excised, an incision made in the distended ampulla and the ova teased out in a drop of water on a microscope slide so that the number shed could be counted. Historically, control animals shed between 12 and 14 ova during each estrous cycle. Agents which inhibit ovulation usually exhibit an"all or none"effect ; it is rare that ovulation is"partially"inhibited. Treatment groups were compared with the control group using a 95% contingency table or the EDloo was established with additional dose levels.

Relative Binding Affiiiities for the Progesterone and Glucocorticoid Receptors Uteri and thymus glands were obtained from estradiol-primed immature female rabbits of the New Zealand White strain for preparation of cytosols for the progesterone and glucocorticoid receptor assays, respectively. Tissues were excised and immediately placed in ice cold TEGDM buffer (10 mM Tris, pH 7. 4 ; 1. 5 mM EDTA ; 10% glycerol vol/vol/ ; 1 mM dithiothreitol [DTT] ; and 20 mM sodium molybdate). The tissues were dissected free of connective tissue and fat, weighed and minced finely. Minced tissues were homogenized in 3 volumes TEGDM/gm with four 10 second bursts of a VirTis Cyclone set at half maximum speed with a 30 second cooling period (in ice) between bursts. Homogenates were centrifuged at 109, 663 g at 4°C for 1 hour to yield the soluble cytosol fraction. Aliquots of cytosol were snap frozen and stored at-75°C.

All binding assays were carried out at 2-6°C for 16-18 hours. The following radioactive ligands were used : [1, 2-3H (N)]-progesterone (50. 0 Ci/mmole) for the progesterone receptor (PR). [6, 7-3H (N)-dexamethasone (39. 2 Ci/mmole) for the glucocorticoid receptor (GR) and [2, 4, 6, 7-3H (N)]-estradiol for the estrogen receptor. For the progesterone receptor RBA assays 0. 02 ml uterine cytosol or TEDGM buffer, 0. 05 ml of various concentrations of test compounds or progesterone, 0. 13 ml TEGDM buffer and 0. 05 ml [3H]-progesterone were added to duplicate tubes. For the glucocorticoid receptor RBA assays 0. 1 ml thymus cytosol or TEDGM buffer, 0. 05 ml of various concentrations of test compounds or dexamethasone, 0. 05 ml TEGDM buffer and 0. 05 ml [3H]- dexamethasone were added to duplicate tubes. For the estrogen receptor RBA assays 0. 05 ml uterine cytosol, 0. 1 ml TEGDM buffer, 0. 05 ml of various concentrations of test compounds or estradiol and 0. 05 ml [3H]-estradiol were added to duplicate tubes. The concentrations of the test compounds, progesterone, dexamethasone and estradiol ranged from 0. 05 to 100 nM and the concentrations of the competitors ranged from 0. 5 to 500 nM.

Total binding was measured at radioligand concentrations of 3. 5 nM and nonspecific binding was measured in the presence of a 200-fold excess of unlabeled progesterone (PR), dexamethasone (GR) or diethylstilbestrol (ER), respectively.

In all incubations bound and free ligand were separated using dextra-coated charcoal (DCC). A 0. 1 ml aliquot of DCC (0. 5% charcoal/0. 05% Dextran T-70) was added to each tube. The tubes were vortexed and incubated on ice for 10 minutes. Five-tenths ml TEG buffer (without DTT or molybdate) was then added to all tubes to improve supernatant recovery following centrifugation. The charcoal was pelleted by centrifugation at 2, 100 g for 15 minutes at 4°C. The supernatants containing the [3H]-steroid receptor complexes were decanted into vials containing 4 ml Optifluor (Packard Instrument Co.), vortexed, equilibrated in a liquid scintillation counter for 30 minutes and then counted for 2 minutes.

This provided the quantity of receptor bound [3H]-steroid at each competitor concentration.

The standard curves and the ECso (Effective Concentration) for each standard curve and curve for each test compound was determined by entering the counting data (receptor bound [3H]-progesterone, [3H]-dexamethasone or [3H]-estradiol) into a four parameter sigmoidal computer program (RiaSmartt) Immunoassay Data Reduction Program, Packard Instrument Co., Meriden, Connecticut. The RBA for each test compound was calculated using the following equation : <BR> <BR> <BR> <BR> <BR> EC50 Standard<BR> <BR> RBA = X 100<BR> <BR> EC50 Test Compound where ECso Standard = molar concentration of unlabeled progesterone, dexamethasone or estradiol required to decrease bound [3H]-progesterone (PR), [3H]-dexamethasone (GR) or [3H]-estradiol to 50% of the respective buffer control (100% bound radioligand) and EC50 Test Compound = molar concentration of test compound required to decrease bound [3H]- progesterone (PR), [3H]-dexamethasone (GR) or [3H]-estradiol to 50% of the respective buffer control (100% bound radioligand).

RESULTS EXAMPLE 1 Results of the antiMcGinty and oral antiClauberg tests as well as the relative binding affinities of these compounds are shown in Table 1, infra. Compared to the lead compound (CDB-2914, 21-H), the 21-acetoxy (15) and the 21-methoxy (38) analogs

exhibited 2. 79 and 3. 61 times, respectively, the antiprogestational potency as assessed by the oral antiClauberg test with a substantial reduction in glucocorticoid binding affinity.

Further, the results of the antiMcGinty test of the 21-acetoxy analog (15) following intraluminal administration closely paralleled those observed in the antiClauberg test following oral dosing. Since mifepristone (CDB-2477) is frequently used as a reference standard, Table 2, 7lfra, contains data comparing the antiprogestational activity and relative binding affinity for the progesterone and glucocorticoid receptors of CDB-2914 with this standard. Recent studies have shown a good correlation between relative binding affinity for the glucocorticoid receptor and a biological test based upon the antagonism of dexamethasone-induced thymus involution in adrenalectomized male rats.

The halogenated analogs (13, 14A, 14B) did not show significant differences in antiprogestational activity nor relative binding affinity to the progesterone receptor from the lead compound, CDB-2914. Other 21-substituted analogs generally exhibited reduced antiprogestational activity with the exception of the cypionate (40) which was about 50% more potent in the antiClauberg test. This may be due to hydrolysis to the corresponding 21-hydroxy compound. However, the presence of additional bulkiness at position 21 does not always favor an increase in biological activity (see 14B) and enhanced relative binding affinity for the progesterone receptor was not necessarily indicative of greater antiprogestational activity (see 12). Thus the window of opportunity for enhanced antiprogestational activity with a reduction in relative binding affinity for the glucocorticoid receptor for 21-substituted analogs of the lead compound (CDB-2914) is highly restricted and was identified only after numerous analogs had been synthesized and tested.

Table 1 ANTIPROGESTATIONAL ACTIVITY AND RELATIVE BINDING AFFINITY FOR THE PROGESTERONE AND GLUCOCORTICOID RECEPTORS COMPOUND ANTIPROGESTATIONAL'RELATIVE BINDING AFFINITY2 Appln. CDB AntiMcGinty AntiClauberg Progesterone Glucocorticoid No. No. 69B 2914 100 100 122 12 4062 26 29 261 32 13 4058 103 80 125 109 14A 3876 75 68 127 90 14B 4031 71 130 175 15 4059 300 279 103 51 16 4102 >2 6 77 17 4101 65 37 54 28 4030 32 129 126 38 4124 361 103 52 40 4125 155 74 37 41 4152 140 62 71 46 4167 130-210 83 46

Antiprogestational Activity AntiMcGinty : see text ; CDB-2914 = 100 (assigned) AntiClauberg, oral : see text ; CDB-2914 = 100 (assigned) 2Relative Binding Affinity Progesterone receptor (estrogen-primed rabbit uterus) progesterone = 100% Glucocorticoid receptor (estrogen-primed rabbit thymus) dexamethasone = 100% Table 2 CDB NO. No. Progester Glucocortic antiClauberg2 Postcoital3 Antiovulator4 2914 69B 122 (234) 114 100 2 1 3875 69A 164 30 97 3247 69C 91 49 10 2* 3248 69D 40 89 weak (subcu) inactive (ã) 2* 4243 91 171 59 inactive 4418 70 79 /2 #25 4363 71 123 (203) 20 253 0. 5 >16 4399 72 109 110 35 4176 74 131 32 <10 4324 97a 120 52 110 4398 97b 47 38 99 4455 106A 4241 106b 136(172) 14 34 4400 113A 117 (237) 62 229 4454 113B 59 34 4417 113c 63 45 70 4239 123A 174 (140) 11 45-83 4416 123b 64 45 77 4393 139 30 79 inactive 4247 126a 95 43 170 4362 126b 76 15 125 4374 126c 68 67 224 4361 129 155 20 303 4306 133 82 13 95 4352 138 63 14 57

'Progesterone receptor (estrogen-primed rabbit uterus) ; progesterone = 100% Figure in () is relative binding affinity of the human isoform A progesterone receptor Glucocorticoid receptor (estrogen-primed rabbit thymus) dexamethasone = 100%.

2antiClauberg-oral except where indicated ; CDB-2914 = 100 (assigned).

3Postcoital - oral, rat MED100 (mg/day) days 0-3 or *days 4-6 subcu ; day sperm in vaginal washings = day 0.

4Antiovulatory-oral, rat MEDloo (mg) single dose at noon on day of proestrus.

Table 3 RELATIVE BINDING AFFINITIES AND ANTIPROGESTATION ACTIVITY OF CDB-2914 AND MIFEPRISTONE (CDB-2477) RELATIVE BINDING AFFINITY ANTIPROGESTATIONAL ACTIVITY DRUG PROGESTERONE GLUCOCORTICOID ANTIMCGINITY ANTICLAUBERG CDB-2914 114- (n=18) 127-24 (n=12) 0. 56 3. 27 CDB-2477 150-17 (n=l 1) 221-35 (n=6) 1. 0 (assigned) 1. 0 (assigned)

Progesterone = 100% ; immature estrogen-primed rabbit uterus 2Dexamethasone = 100% ; immature estrogen-primed rabbit thymus Intraluminal administration to estrogen-primed immature rabbits ; CDB-2477 = 1. 0 (assigned) Oral administration to estrogen-primed immature rabbits ; CDB-2477 = 1. 0 (assigned) EXAMPLE2 A7ltiClauberg Data from antiClauberg tests following oral administration are shown in Tables 1 and 2. Compounds 15, 38, 40, 41, 46, 71, 97a, 113a, 126a, 126b, 126c and 129 exhibited greater activity than the standard, 69B. Previous studies have shown that 69B is significantly more potent than mifepristone (3. 27 X ; 95% C. I. = 1. 41-7. 58) in this test.

Compounds 15, 38, 71 and 129 represent four of the most potent antiprogestational compounds known, and their low binding affinity for the glucocorticoid receptor would predict minimal antiglucocorticoid activity.

Postcoital Compound 71 exhibited about four times the postcoital contraceptive activity of the standard, compound 69B, following oral administration on days 0-3 of gestation.

Antiovulatory Compound 71 was not fully active at a dose level 16 times the MEDico for the standard, compound 69B, and compound 113a exhibited only about 6% of the antiovulatory activity of the standard.

-Relative Binding Afftiiityfor tlte Progesterone and Glucocorticoid Receptors Relative binding affinities for the progesterone receptor (estrogen-primed rabbit uterine cytosol) and glucocorticoid receptor (estrogen-primed rabbit thymic cytosol)

are shown in Table 1. Several compounds were also tested for binding affinity for the human isoform A progesterone receptor. Compounds 12, 13, 14A, 14B, 15, 28, 38, 69A, 91, 71, 72, 73, 97a, 106b, 113a, 113d, 122b and 129 showed binding affinities greater than that observed for the standard, compound 69B. On the other hand, most of the compounds tested exhibited reduced binding affinity for both the progesterone and the glucocorticoid receptor.

DISCUSSION Many members of a series of derivatives of 19-norprogesterone possess potent antiprogestational activity following oral administration in experimental animals.

They exhibit high binding affinity for the progesterone receptor (rabbit uterine) and only modest relative binding affinity for the glucocorticoid receptor (rabbit thymus). This is reflected in standard antiprogestational assays showing strong inhibition of progesterone- induced alterations of rabbit uterine endometrium. It is anticipated that the reduced binding affinity for the glucocorticoid receptor will reflect diminished biological antiglucocorticoid activity.

Table 3 compares the relative binding affinity for the progesterone and glucocorticoid receptors as well as the antiprogestational activity as measured by antiClauberg and antiMcGinty tests for the standard, compound 69B, and mifepristone (CDB-2477). Mifepristone exhibited greater binding affinity for both receptor proteins and was more potent than the standard, compound 69B, in the antiMcGinty test. However, the standard was 3 times as potent as mifepristone in the antiClauberg test following oral administration. This finding has not been satisfactorily explained, but may be due to the differential pharmacokinetics of these two steroids following oral administration. Higher blood levels of 69B have been observed following oral administration to several species, thus indicating a greater oral bioavailable for the standard.

Antiprogestational agents including mifepristone are known to prevent implantation in the rat (Dao, B., et al., Contraception, 54 : 243-258 (1996) ; Reel, J., et al., Contraception, 58 : 129-136 (1998)), guinea pig (Batista, M., et al., Am. J. Obstet. Gynecol., 165 : 82-86 (1991), and man (Baulieu, E., Clinical Applications ofMifepristoyae (RU486) and Other (Donaldson, M., Dorflinger, L., Brown, S. and Benet, L. (eds.), National Academy Press, pp. 72-119 (1993)). Compound 71 was four times as potent as the standard, compound 69B, in preventing pregnancy when orally administered on days 0-

3 of presumptive gestation. Curiously, compound 71 was only about 5% as potent as the standard in inhibiting ovulation. Both compound 69B and mifepristone have been shown to inhibit ovulation in the rat (Dao, et al., supra), and mifepristone has been shown to affect ovulation in human subjects (Baulieu, et al., supra). Compound 69B has been shown to affect both follicular development and ovulation as well as endometrial maturation in human subjects following a single oral dose (unpublished data).

Compound 113a exhibited high binding affinity for both the rabbit progesterone receptor (isoform B) and the human progesterone receptor (isofonn A). This was reflected in potent antiprogestational activity in vivo where it was more than twice as active at the standard, compound 69B. It also showed reduced binding affinity for the glucocorticoid receptor and was about half as effective as compound 69B in preventing pregnancy in the postcoital test. Strangly, this compound was only 6% as active as the standard in inhibiting ovulation. Thus, compound 113a may represent an antiprogestational steroid with high tissue specificity.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.