wherein X is C=CH2 or CH2; Y is hydrogen, fluorine or hydroxy Z is hydroxy n is 1 or 2 RI is lower alkyl, R2 is a branche alkyl having 3 to 8 carbon atoms which may be substituted with halogen and/or OH, or a phenyl group which may be substituted with a branche alkyl group, optionally substituted with halogen and/or hydroxy, having 3 to 8 carbon atoms; and the dotted bond in ring D is optionally a double bond; and pharmaceutically usable salts thereof.

The present invention further relates to a process for the manufacture of compound of formula I, to pharmaceutical compositions based on compound of formula I or their salts, to the use of compound of formula I for the treatment of vitamin D dependent disorders and for the manufacture of pharmaceutical compositions for the treatment of vitamin D dependent disorders.

The term"vitamin D dependent disorders"refers to disorders which can be treated or prevented by the administration of compound having vitamin D

activity, such as vitamin D3 or derivatives, in particular hydroxylated derivatives thereof, e. g. calcitriol. Examples of such disorders are hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization and keratosis; neoplastic diseases such as leukemia; disorders of the sebaceous glands such as acne and seborrhoic dermatitis; osteoporosis; hyperparathyroidism accompanying renal failure; and diseases which require modulation of the immune system, such as transplant rejection and graft vs. host disease.

The term"lower alkyl"as used herein denotes alkyl residues containing 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, isobutyl, tert.-butyl, pentyl, amyl and 3-pentyl.

The term"branched alkyl having 3 to 8 carbon atoms which may be substituted with halogen and/or OH"as used herein denotes alkyl residues containing 3 to 8 carbon atoms as i-propyl, tert. butyl, i-butyl, these groups being optionally substituted by halogen and/or hydroxy; such groups are e. g. 2- hydroxy-2-methylpropyl, 2-hydroxy-2-trifluoromethylpropyl and, 3,3,3- trifluoro-2-hydroxy-2-trifluoromethylpropyl.

The term"halogen"as used herein denotes fluorine, chlorine, bromine or iodine, preferred halogen substituents are fluorine.

The term"phenyl group which may be substituted with an optionally substituted branche alkyl group having 3 to 8 carbon atoms"as used herein denotes for example 3- (1-hydroxy-1-methylethyl) phenyl.

In the structural formulae presented herein a broken bond (-) denotes that the substituent is below the plane of the paper and a wedged bond () denotes that the substituent is above the plane of the paper.

Compound of formula I wherein R2 is a branche alkyl having 3 to 8 carbon atoms which may be substituted with halogen and/or OH are preferred.

Especially preferred are compound of formula I wherein R2 is 2-hydroxy-2- methylpropyl, 2-hydroxy-2-trifluoromethylpropyl and 3,3,3-trifluoro-2- hydroxy-2-trifluoromethylpropyl.

A further preferred group of compound of formula I are compound wherein n is 1 and the dotted line is absent.

Especially preferred compound of formula I are:

(E)-(R)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-sec- pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-bu tyramide (E)-(S)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-seco- pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide (E)-N- [(1R, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-seco-pregna- 5, 7-dien-21-yl]-4, 4,4-trifluoro-3-trifluoromethyl-3-hydroxy-butyramide 1: 1 Mixture of (5Z, 7E)-(R)-and (S)--N-[(1S, 3R, 20S)-1,3-Dihydroxy-17a, 20a- dihomo-9,10-seco-pregna-5,7,10 (19), 17-tetraen-21-yl]-4,4,4-trifluoro-3-hydroxy- 3-methyl-butyramide 1: 1 Mixture of (E)-(R)-and (S)-N-(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo- <BR> <BR> <BR> 19-nor-9,10-seco-pregna- (5,7,17-trien-21-yl)-4,4,4-trifluoro-3-trifluoromethyl-3- hydroxy-butyramide 1: 1 Mixture of- [ (5E, 7E)- (R)- and- (S)-4,4,4-trifluoro-3-hydroxy-N- [ (lS, 3R, 20S)- 1,3-dihydroxy-20-methyl-9,10-seco-pregna-5,7,10 (19)-trien-21-yl]-3-methyl- butyramide 1: 1 Mixture of (E)-(R)- and (S)-N-[(R, 3R, 20S)-1,3-dihydroxy-20-methyl-19- nor-9, 10-seco-pregna-5,7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide E-(R)-N- [(lR,(R)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7- dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide (E)-(1R,3R,20S)-N-(1,3-Dihydroxy-20-methyl-19-nor-9,10-seco- pregna-5,7-dien- 21-yl)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyramid e (E)-(1R, 3R, 20S)-N- (1, 3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien- 21-yl)-2-hydroxy-2-methyl-propionamide 1: 1 Mixture of (5Z, 7E)- (R)- and (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N- [ (3S, 20S)-3-hydroxy-20-methyl-9,10-seco-pregna-5,7,10 (19)-trien-21-yl]- butyramide (E)-(S)-N- [(lR, 3R, 20S)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7- dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide (E)-(R)-N- [(lR, 3R, 20S)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7- dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide 1: 1 Mixture of- [ (5Z, 7E)- (R)- and (S)-N- [ (lS, 3R, 20S)-1,3-dihydroxy-20-methyl- 9,10-seco-pregna-5,7,10 (19)-trien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide

1: 1 Mixture of (E)-(R)-and (S)-N-[(lR, 3R, 20R)-1,3-dihydroxy-20-methyl-19- nor-9, 10-seco-pregna-5,7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide In accordance with the invention the novel compound of formula I wherein the dotted bond is absent can be prepared according to a process as depicted in Scheme 1 Scheme 1

wherein R1, R2, X, Y and Z have the definitions given above, R3 is a hydroxy protecting group and Y ils hydrogen, fluorine or protected hydroxy and Z'is protectedhydroxy.

According to Scheme 1 a [ (2-halo-1-alkyl-ethyl)-4a-methyl-decahydro- naphthalen-1-yloxy]-derivative (or a 4 [(2-halo-1-alkyl-ethyl)-7a-methyl- octahydro-inden-4-yloxy]-derivative, if appropriate) (2) is prepared by

halogenation of the corresponding primary alcohol (1) obtained according to the method described in EP A 0 771 789 or known from literature and is then reacted with sodium azide in a polar solvent e. g. dimethylsulfoxide or N, N- dimethylformamide to form the azide (3); subsequent reduction of the azido group and rection of the amine (4) with an acid of formula HOOCR9 yields the corresponding amides (5). The hydroxy group in the C-ring is deprotected and oxidized to yield keto intermediate (7).

The rection of a compound (7) with a compound of the formula (8) can be carried out under the conventional conditions of a Wittig rection, after optional protection of a hydroxy group present in R2, i. e. by means of a base, e. g., butyl lithium, in an inert organic solvent, such as tetrahydrofuran. The compound of formula I are obtained by cleaving the hydroxy protecting groups.

The hydroxy protecting group R3 can be any conventional hydroxy protecting group. Examples of such groups are silyl ether protecting groups such as tert.-butyl-dimethylsilanyl or tert.-butyl-diphenylsilanyl. Another example of a hydroxy protecting group is tetrahydropyranyl. The removal of the hydroxy protecting groups R3 can be effected in a manner known per se for the removal of such groups. For instance, silylether can be removed by treatment with fluoride reagents, such as hydrogen fluoride or tetrabutyl ammonium fluoride in tetrahydrofuran.

Alternatively, the novel compound of formula I wherein the dotted bond is lacking can be prepared according to a process as depicted in Scheme 2.

Scheme 2

The cyclohexylidene-ethyl-diphenyl-phosphine oxide (8) can be prepared according to the method described in EP-A 97106547.9, see Scheme 3.

Scheme 3

According to Scheme 3, the ketone (15) is converted by a Peterson rection into the ester (16) from which the alcohol (17) is obtained by reduction. Rection of (17) with N-chlorosuccinimide in the presence of dimethylsulphide gives the chloride (18). Rection of (18) with diphenyl-

phosphine-lithium and work-up with 5% H202 in ethyl acetate gives the phosphinoxide (8).

The novel compound of formula I wherein the dotted bond is a double bond can be prepared according to a process as depicted in Scheme 4 Scheme 4 The hydroxyderivative (19), prepared according to the method described in EP-A 96116735, is converted by a Mitsunobo rection using diisopropyl azodicarboxylate/triphenylphosphine to the azido derivative (20). The azido group is reduced to the corresponding amine which is then converted into the amide (21) according to the method described in Scheme 1.

The compound of formula I as described above can be administered orally or topically, preferably orally, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis, or for the treatment of neoplastic diseases such as leukemia, or for the treatment of osteoporosis and hyperparathyroidism, to warmblooded animals which need such treatment. More specifically, the compound of formula I as described above can be administered orally to an adult human in dosages that are in the range of about 0.5 to 1000 pg per day, or can be administered topically in dosages that are in the range of about 0.5 to 1000 gag per gram of topical formulation per day, for the treatment of the abovediseases.

The dosage of the compound of formula I can vary within wide limits depending on the illness to be treated, the age and the individual condition of the patient and on the mode of administration and will, of course, be fitted to the individual requirements in each particular case.

Oral dosage forms comprising compound of formula I of the invention may be incorporated in capsules, tablets and the like with pharmaceutically acceptable carrier materials. Illustrative of such carrier materials which may

be incorporated into capsules, and the like are the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, algenic acid, and the like; a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose, or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. Various other materials may be present as coating or to otherwise modify the physical form of the dosage unit.

For instance, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.

Topical dosage forms comprising compound of formula I of the invention include: ointments and creams encompassing formulations having oleaginous, absorbable, water-soluble and emulsion-type bases such as petrolatum, lanolin, polyethylene glycols and the like. Lotions are liquid preparations and vary from simple solutions to aqueous or hydroalcoholic preparations containing finely divided substances. Lotions can contain suspending or dispersing agents, for example, cellulose derivatives such as ethyl cellulose, methyl cellulose, and the like; gelatin or gums, which incorporate the active ingredient in a vehicle made up of water, alcool, glycerin and the like. Gels are semi-solid preparations made by gelling a solution or suspension of the active ingredient in a carrier vehicle. The vehicles, which can be hydrous or anhydrous, are gelled using a gelling agent, such as, carboxy polymethylene, and neutralized to a proper gel consistency with the use of alkalies, such as, sodium hydroxyde and amines, such as, polyethylenecocoamine.

As used herein, the term"topical"denotes the use of the active ingredient, incorporated in a suitable pharmaceutical carrier, and applied at the site of the disorder for the exertion of local action. Accordingly, the topical composition inclues those pharmaceutical forms in which the compound is applied externally by direct contact with the skin. The topical dosage forms comprise gels, creams, lotions, ointments, powders, aerosols and other conventional forms for applying medication to the skin obtained by admixing the compound of formula I with known pharmaceutical topical carrier materials.

The pharmacological properties of the compound of the formula I can be determined by the following test procedures:

1. Calcium liability (tolerance test in mice): This test gives a global picture of calcemic liability. Profond changes in calcium homeostasis strongly affect the weight development of the animals.

This parameter was used as a primary test for tolerance. Mice (25-30 g body weight) received daily subcutaneous administrations of the vitamin D derivative for 4 consecutive days. Body weight was registered just before and at the end of a 5 day treatment period. The"highest tolerated dose" (HTDS) in mice is the dose which results in zero weight gain during this treatment period.

For calcitriol a HTD of 0.5 pg/kg was observe. In comparison thereto, for the compound of formula I specifically named as products in the above Examples, HTD figures ranging froml to 5, ug/kg for the four less tolerated compound, up to 400 pg/kg for the four best tolerated compound were observe.

2. Vitamin D receptor activation (VDR) In order to measure the activation of the vitamin D receptor (VDR) by vitamin D analogs in cells a transcription activation assay was used. COS cells were cotransfected with the human VDR (expressed in pSG5) and a reporter gene containing three response elements (VDRE3) from the rat osteocalcine gene, the thymidine kinase basal promoter, and the luciferase reporter gene, respectively.

The following compound were tested with respect to VDR activation: A: (E)-(lR, 3R, 20S)-N- (1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7- dien-21-yl)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-buty ramide B: 1: 1 Mixture of (E)-(R)-and (S)-N-[(lR, 3R, 20S)-1,3-dihydroxy-20-methyl- 19-nor-9,10-seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-20- methyl-butyramide C: (E)-(lR, 3R, 20S)-N- (1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7- dien-21-yl)-2-hydroxy-2-methyl-propionamide D: 1: 1 Mixture of [ (5Z, 7E)- (R)- and (S)-N- [ (lS, 3R, 20S)-1,3-dihydroxy-20- methyl-9,10-seco-pregna-5,7,10 (19)-trien-21-yl]-4, 4,4-trifluoro-3-hydroxy- 3-methyl-butyramide

E: 1: 1 Mixture of (E)-(R)- and (S)-N-[(1R, 3R, 20R)-1,3-dihydroxy-20-methyl- 19-nor-9,10-seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3- methyl-butyramide F: (E)-(R)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-sec- pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide G: (E)-(S)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-sec- pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide H: (E)-N- [ (lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-sec- pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-trifluoromethyl-3-hydroxy- butyramide I: 1: 1 Mixture of- [ (5E, 7E)- (R)- and- (S)-4,4,4-trifluoro-3-hydroxy-N- [ (lS, 3R, 20S)-1,3-dihydroxy-20-methyl-9,10-seco-pregna-5,7,10 (19)-trien- 21-yl]-3-methyl-butyramide J: E- (R)-N- [ (lR, 3R, 20S)-1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna- 5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide The table shows that the tested compound are quite potent with respect to VDR activation. Moreover all of them are expected to have a greater therapeutic window than calcitriol (as indicated by the TI shift* vs calcitriol).

compound VDR act. HTD sc, HTD/VDR TI shift* (ED50, mouse, ug/kg nanomolar) Calcitriol 2.6 0.5 0.19 1 A 0.47 3 6.4 34 B 1.7 45 26.5 139 C 6.4 400 62.5 329 D 1.6 10 6.3 33 E 0.35 1 2.9 15 F 0.6 5 8.3 44 G 0.18 4.5 25 132 H 0.5 2.3 4.6 24 I 40 130 3.3 17 J 2.1 22 10.5 55 HTDsc: highest tolerated subcutaneous dose (, ug/kg) without weight loss TI shift: shift in"therapeutic index", defined as the ratio HTD/VDR of the test compound divided by the ratio HTD/VDR of calcitriol. These compound may show biological effects at tolerated doses.

3. The mouse model Orally administered vitamin D analogues can lead to epidermal thickening (acanthosis) in hairless mice. This skin effect is considered as indicative for antipsoriatic potential of vitamin D analogues. Analogues were tested for 4 days at different dosages in order to detect compound which show this epidermal effect at subtoxic and non-toxic doses (dosage leading to slight or no weight loss). At the higest tolerated dose calcitriol itself was not able to elicit skin effets. The calcitriol data were obtained from animals treated for three days.

Hairless mice (Moro hr/hr) received daily administrations of the test compound in arachis oil by gavage for 4 days, using 2-5 different dosages (3 fold increments; 2 animals per dosage group). The mice were sacrifice at day 5 and skin biopsies were taken, fixed in formalin and treated for histological evaluation. Daily measurements of body weight allowed to judge toxicity (calcemic liability) and determine the non-toxic dose level defined as the dose which is tolerated without weight loss.

The results in the table below show that compound B, is far superior to calcitriol due to a better ratio between the effective dose and the maximal <BR> <BR> tolerated dose (HTDPo). This may translate in a better separation between wanted skin effects (ED50) and toxic calcemic effets. compound ED50 HTDpo ratio (TI) TI shift HTD/ED50 calcitriol 500 1 0.002 1 compound B 80 20 0.25 125 compound J 50 8 0.16 80

ED50: dose (ug/kg) causing half-maximal epidermal thickening<BR> <BR> <BR> <BR> <BR> <BR> <BR> HTDpo: highest tolerated oral dose (llg/kg) without weight loss TI shift: shift in"therapeutic index", is defined as ratio HTD/EDDo for the test compound divided by the ratio HTD/ED50 for calcitriol 4. The pig model Orally administered vitamin D analogs can lead to epidermal proliferation in minipigs. This skin effect is considered as indicative for an antipsoriatic potential of vitamin D analogs. Compound were tested for seven days at different doses in order to detect those which showed a skin effect at non calcemic dose (no calcemic effet). The pigs were daily observe as to adverse effects such as behavior, mobility, stool. At day seven bromodeoxyuridine (4 mg/kg) was injecte intravenously into the treated pigs and 2 hours later skin biopsies (6 mm diameter) and blood were taken for analysis. The skin biopsies were fixed in formalin, and paraffin sections were prepared using standard procedures. Using standard immuno-histochemical techniques, cells in the S-phase (DNA synthesis phase) were labelle by the binding of a specific monoclonal antibody against the thymidine analogue bromodeoxyuridine. The number of labelle epidermal cells per unit of length along the surface was taken as a measure of epidermal proliferative activity (labelings index LI). Clinical chemistry was performed using Cobas Mira.

Calcitriol itself did not induce hyperproliferation even at highly toxic does (9 times the dose that induces hypercalcemia). compound Effective Calcemic TI (ratio rel. shift dose dose, Calc./Eff. *µg/kgµg/k calcitriol >22.5 3 <0.15 1 compound B 0. 5 5 10 >67 compound J I 0. 1 5 29 >196

*The effective dose is the dose that increases the normal LI at least 50% No adverse effects were noted at the effective dose. Thereforer, example 4.1 and other analogs claimed in this patent may exert beneficial effects in skindiseases.

The following pharmaceutical compositions can be prepared in a manner known per se: Example A Soft Gelatine mg/Capsule Active Ingredient 0.0001-1 Butylated Hydroxytoluene (BHT) 0.016 Butylated Hydroxyanisole (BHA) 0.016 Fractionated Coconut Oil (Neobee M-5) or Miglyol 812 q. s 160.0 ExampleB Soft Gelatine mg/Capsule Active Ingredient 0.0001-1 α-Tocopherol0.016 Miglyol 812 q. s. 160.0

Example C Tropical Cream mg/g Active Ingredient 0.005-1 Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Span 60 (Sorbitan monostearate) 2.0 Arlacel 165 (Glyceryl monostearate 4.0 and polyoxyethylene glycol stearate blend) Tween 60 (polysorbate 60) 1.0 Mineral Oil 4.0 Propylene Glycol 5.0 Propylparaben 0.05 BHA 0.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 Methylparaben 0.18 Distille Water q. s.

ExampleD Tropical ointment mg/g Active Ingredient 0.005-1 Propylenglycol exc. ad ung. pro 1 g Example 1 1.1. Preparation of (E)-(R)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19- nor-9, 10-seco-pregna-5,7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide a] (lS, 4aR, 5R, 8aR)- [5- ( (S)-2-Azido-l-methyl-ethyl)-4a-methyl-decahydro- naphthalen-1-yloxy]-tert-butyl-dimethyl-silane

wherein TBDMSi is tert.-butyldimethylsilyl 3.61 g (8.01 mmol) of (lS, 4aR, 5R, 8aR)-tert-Butyl- [5- [ (S)-2-iodo-1-methyl- ethyl]-4a-methyl-decahydro-naphthalen-1-yloxy]-dimethyl-sila ne(preparation described in EP-A 96116735) was dissolve in 16 ml of abs. N, N- dimethylformamide and treated with 1.56 g (3 eq.) of NaN3. The mixture was kept for 4.5 h at 60° and the progress of the rection monitored by thin layer chromatography. Cooling to room temperature, pouring onto crushed ice, twofold extraction with hexane, washing with NaHC03 and drying over sodium sulfate left 2.87 g of a crude product, which was pure according to 250 MHz NMR and used as such for the next step.

MS: (M) + 365, (M-t-butyl) + 308. b] (S)-2- [ (lR, 4aR, 5S, 8aR)-5- (tert-Butyl-dimethyl-silanyloxy)-8a-methyl- decahydro-naphthalen-1-yl]-propylamine 2.87 g of (lS, 4aR, 5R, 8aR [5- ( (S)-2-Azido-l-methyl-ethyl)-4a-methyl-decahydro- naphthalen-1-yloxy]-tert-butyl-dimethyl-silane was dissolve in 75 ml of AcOEt and hydrogenated over 3.6 g of 10% Pd/C, which was added in three portions, during 8h at ambient temperature and 1 atm of H2. After filtration over a pad of Celite the solvents were removed. Flash chromatography (SiO2, AcOEt/NEt3=95/5) produced 1.543 g of the title compound as slightly brown oil.

MS: (M+H) + 340, (M-t-butyl) + 282.

c] 1: 1 Mixture of (R)-and (S)-N- ( (S)-2- [ (lR, 4aR, 5S, 8aR)-5- (tert-Butyl-dimethyl-<BR> <BR> silanyloxy)-8a-methyl-decahydro-naphthalen-1-yll-propyll-4,4 ,4-trifluoro-3- hydroxy-3-methyl-butyramide 701 mg (2.06 mmol) of (S)-2- [ (lR, 4aR, 5S, 8aR)-5- (tert-Butyl-dimethyl- silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propylamine , 532 mg (1.5 eq.) of rac-3-trifluoromethyl-3-hydroxy-butyric acid, and 50 mg (0.2 eq.) of DMAP (N, N-dimethylaminopyridine) were dissolve in 20 ml of CH2Cl2. At 0° 680 mg (1.6 eq.) of DCC (dicyclohexylcarbodiimide) was added and the mixture allowed to react for 4 h at ambient temperature. The precipitated urea was filtered off and the filtrate evaporated to dryness. Flash chromatography (Si02, hexane/AcOEt=85/15) yielded in the less polar fractions 149 mg of unwanted 4,4,4-trifluoro-3-methyl-but-2-enoic acid (2- [5- (tert-butyl-dimethyl- silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propyl}-ami de and in the more polar ones 811 mg of the title compound as colorless oil. Medium pressure chromatography of the latter (Si02, hexane/AcOEt=90/10) gave in the less polar fractions 367 mg of the (R)-butyramide and in the more polar ones 314 mg of the (S)-isomer, both as white foam. For determination of abs. configuration see d] below.

MS: (M+H) + 494, (M-t-butyl) + 436. d] (R)-4,4,4-Trifluoro-3-hydroxy-N- [ (S)-2- ( (lR, 4aR, 5S, 8aR)-5-hydroxy-8a- methyl-decahydro-naphthalen-1-yl)-propyl]-3-methyl-butyramid e 1.88 g of nBu4NF#3H2O was carefully dried by stirring during 2h at room temperature over 1.8 g of 3A MS (molecular sieve). This solution was then added to 365 mg (0.739 mmol) of (R)-N-{(S)-2-[(1R, 4aR, 5S, 8aR)-5- (tert-butyl- dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-pr opyl}-4,4,4- trifluoro-3-hydroxy-3-methyl-butyramide and the mixture kept for 4 days at 50°. thin layer chromatography indicated that still some starting material was

left. Usual work-up provided a crude product which was treated once more in an analogous manner (1.88 g of dried nBu4NF 3H2O, 2 days, 50°). The rection mixture was then poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulfate, and the solvents carefully removed. Flash chromatography SiO2, hexane/AcOEt=7/3) afforded 237 mg of the title compound as white crystals. 20 mg thereof was recrystallized from hexane/trace amounts of AcOEt to give an analytically pure sample of mp.

133-134°, whose structure was secured by X-ray analysis. e] (R)-4,4,4-Trifluoro-3-hydroxy-3-methyl-N- [ (S)-2- ( (lR, 4aR, 8aR)-8a-methyl-5- oxo-decahydro-naphthalen-1-yl)-propyl]-butyramide 201 mg (0.532 mmol) of (R)-4,4,4-Trifluoro-3-hydroxy-N- [ (S)-2- ((lu, 4aR, 5S, 8aR)-5-hydroxy-8a-methyl-decahydro-naphthalen-1-yl)-propyl]- 3- methyl-butyramide was dissolve in 9 ml of abs. CH2Cl2 and reacted with 600 mg (3 eq.) of PDC (pyridinium-dichromate). After stirring for 2.5 h the mixture was filtered over a pad of Celite and the solvent removed. Flash chromatography (Si02, hexane/AcOEt=7/3) yielded 189 mg of the title compound as white foam.

MS: (M)+ 377, (M-Me) + 362, (M-Me-CF3) + 308. fl (R)-4,4,4-Trifluoro-3-hydroxy-N- [ (S)-2- ( (lR, 4aR, 8aR)-8a-methyl-5-oxo- decahydro-naphthalen-1-yl)-propyl]-3-trimethylsilanyloxy-but yramide wherein TMS signifies trimethylsilyl 188 mg (0.498 mmol) of (R)-4,4,4-Trifluoro-3-hydroxy-3-methyl-N-[(S)-2- ((1R,4aR,8aR)-8a-methyl-5-oxo-decahydro-naphthalen-1-yl)-pro pyl]- butyramide in 7 ml of abs. CH2Cl2 was treated with 0.438 ml (6 eq.) of TMS- imidazole and kept at room temperature over night. A second portion of 0.438 ml of TMS-imidazole was added and the rection allowed to proceed for two

days. Pouring onto crushed ice, extraction with ether, washing with water, and drying over sodium sulfate left a crude product, which was purifie by flash chromatography (Si02, hexane/AcOEt=8/2). Thereby, 212 mg of the title compound was obtained as white foam.

CI-MS: (M+H) + 450, (M+Na) + 472. g] (E)- (R)-N- [ (S)-2- ( (lR, 4aS, 8aR)-5- {2- [(3R, 5R)-3,5-Bis- (tert-butyl-dimethyl- silanyloxy)-cyclohexylidene]-ethylidene}-8a-methyl-decahydro -naphthalen-1-<BR> yl)-propyll-4,4,4-trifluoro-3-methyl-3-trimethylsilanyloxy-b utyramide 388 mg of carefully dried (3R, 5R)- [2- [3, 5-bis- (t-butyldimethyl-silanyloxy)- cyclohexylidenel-ethyl]-diphenyl-phosphine oxide (Tetrahedron Lett. 32,7663 (1991)) was dissolve in 6.7 ml of abs. THF (tetrahydrofurane) and treated at- 78° with 0.51 ml of nBuLi (1.5M, hexane). 15 Minutes later, 150 mg (0.334 mmol) of (R)-4,4,4-trifluoro-3-hydroxy-N- [ (S)-2- ( (lR, 4aR, 8aR)-8a-methyl-5-oxo- decahydro-naphthalen-1-yl)-propyl]-3-trimethylsilanyloxy-but yramide, dissolve in 1.5 ml of abs. THF, was added to the deep red solution. The mixture was kept for 0.25 h at -78° and for 1 h at 0° The discolored rection mixture was then poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulfate, and the solvents carefully removed.

Flash chromatography (Si02, hexane/AcOEt=9/1) afforded 39 mg of the title compound as colorless oil, besides 100 mg of recovered ketone in the more polar fractions. h] (E)-(R)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-seco- pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-bu tyramide

39 mg (0.0486 mmol) of (E)-(R)-N-([(S)-2-((1R, 4aS, 8aR)-5-{2-[(3R, 5R)-3,5-Bis- (tert-butyl-dimethyl-silanyloxy)-cyclohexylidene]-ethylidene }-8a-methyl- decahydro-naphthalen-1-yl)-propyl]-4,4,4-trifluoro-3-methyl- 3- trimethylsilanyloxy-butyramide was treated with 8 equivalents of carefully dried TBAF (tetrabutylammoniumfluoride) (0.2M inTHF) at 40° for 2 h. The rection mixture was poured onto crushed ice, extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness.

Flash chromatography (SiO2, AcOEt) yielded 38 mg of the title compound as white foam, contaminated with some TBDMS-OH.

MS: (M) +501; NMR (1H, DMSO, #, TMS): 0.74 (s, 3H), 0.83 (d, 3H), 1.33 (s, 3H), 1.0-2.7 (m, 22H), 2.77 (m, 2H), 3.20 (m, 1H), 3.79 (m, 1H), 3.87 (m, 1H), 4.37 (d, OH), 4.48 (d, OH), 5.78 (d, 1H), 6.06 (d, 1H), 6.36 (s, OH), 8.03 (br t, NH).

Example 1.2.

In analogy to example 1.1, but using in step d] the (S)-butyramide, was obtained as colorless gum (E)-(S)-N- [(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-sec- pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide MS: (M)+501 ; NMR: (1H, CDCl3, #, TMS): 0.78 (s, 3H), 0.95 (d, 3H), 1.39 (s, 3H), 1.0-2.55 (m, 23H), 2.70-2.90 (m, 3H), 3.49 (m, 1H), 4.03 (m, 1H), 4.12 (m, 1H), 5.61 (br t, NH), 5.83 (d, 1H), 6.10 (br s, OH), 6.30 (d, 1H).

Example 1.3.

In analogy to example 1. 1., but using in step cl 4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyric acid as coupling partner was obtained as colorless gum (E)-N- [ (lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo-19-nor-9,10-seco-pregna- 5,7-dien-21-yl]-4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy- butyramide MS: (M)+555, (M-H2O)+ 537. <BR> <BR> <P>NMR (1H, CDC13, O, :TMS) 0.77 (s, 3H), 0.97 (d, 3H), 1.39 (s, 3H), 1.1-2.3 (m, 20H), 2.48 (m, 1H), 2.64 (s, 2H), 2.71-2.94 (m, 3H), 3.49 (m, 1H), 4.03 (m, 1H), 4.12 (m, 1H), 5.69 (br t, NH), 5.84 (d, 1H), 6.30 (d, 1H), 7.93 (s, OH).

Example 2 2.1. Preparation of 1: 1 mixture of (5Z, 7E)- (R)-and (S)-N- [ (lS, 3R, 20S)-1,3- Dihydroxy-17a, 20a-dihomo-9,10-seco-pregna-5,7,10 (19),17-tetraen-21-yl]-4, 4,4- trifluoro-3-hydroxy-3-methyl-butyramide a] (lS, 4aS, 8aR)- [5- ( (S)-2-Azido-l-methyl-ethyl)-4a-methyl-1,2,3,4,4a, 7,8,8a- octahydro-naphthalen-1-yloxy]-tert-butyl-dimethyl-silane 3.0 g (8.85 mmol) of (S)-2- [ (4aR, 5S, 8aS)-5- (tert-Butyl-dimethyl-silanyloxy)-8a- methyl-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl]-propan-1-ol (preparation described in EP-A 96116735) was dissolve in 25 ml of abs. N, N- dimethylformamide and 15 ml of abs. toluene. 2.53 g (9.65 mmol) of Triphenylphosphine was added, followed by, at 0°, 2.01 ml (10.4 mmol) of diisopropyl azodicarboxylate and 8.85 ml of HN3 (1.17M, toluene). After 0.5 h the cooling bath was removed and the mixture kept for 18 h at ambient temperature. All solvents were removed and the residue purifie by flash chromatography (Si02, hexane, hexane/AcOEt=3/1) to yield 2.78 g of the title product as colorless oil besides 624 mg of starting alcool.

MS: (M-N2)+335 ; IR: 2095 cm~l. b] (S)-2- [ (4aR, 5S, 8aS)-5- (tert-Butyl-dimethyl-silanyloxy)-8a-methyl- 3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl]-propylamine 1.51 g (4.15 mmol) of (lS, 4aS, 8aR)-[5-((S)-2-Azido-1-methyl-ethyl)-4a-methyl- 1,2,3,4,4a,7,8,8a-octahydro-naphthalen-1-yloxy]-tert-butyl-d imethyl-silane was dissolve in 4 ml of abs. THF and treated at room temperature with a solution of 1.19 g (4.57 mmol) of triphenylphosphine in 4 ml of abs. THF. The clear solution was kept for 2.5 days at ambient temperature, before it was treated with 2.0 ml of water. After stirring for 0.75 h, the resultant mixture was distributed between water and ether, the organic layer washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash

chromatography (Si02, NEt3/AcOEt=1/9) afforded 745 mg of the title compound as colorless oil.

MS: (M) + 337. cl 1: 1 Mixture of (R)-and (S)-N-f (S)-2- [ (4aR, 5S, 8aS)-5- (tert-Butyl-dimethyl- silanyloxy)-8a-methyl-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl]-propyl}- 4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide 745 mg (2.20 mmol) of (S)-2- [ (4aR, 5S, 8aS)-5- (tert-Butyl-dimethyl-silanyloxy)- 8a-methyl-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl]-propylamine was dissolve in 22 ml of CH2Cl2.567 mg (3.28 mmol) of rac-3-Trifluoromethyl-3- hydroxy-butyric acid and 53 mg (0.2 eq.) of DMAP were added and the solution cooled down to 0°. 724 mg (3.51 mmol) of DCC was added and the cooling bath removed after 20 minutes. 35 Minutes later, starting material had disappeared according to thin layer chromatography. The precipitated urea was filtered off and the filtrate evaporated to dryness. Flash chromatography (Si02, hexane/AcOEt=85/15) yielded 1.04 g of the title compound as colorless, viscous oil.

CI-MS: (M+H)+ 492. d] 1: 1 Mixture of (R)-and (S)-4,4,4-Trifluoro-3-hydroxy-N- [ (S)-2- ( (4aR, 5S, 8aS)- 5-hydroxy-8a-methyl-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl)-propyl]-3- methyl-butyramide 1.47 g (2.98 mmol) of 1: 1 Mixture of (R)-and (S)-N-{(S)-2-[(4aR, 5S, 8aS)-5- (tert- butyl-dimethyl-silanyloxy)-8a-methyl-3,4,4a, 5,6,7,8,8a-octahydro-naphthalen- 1-yl]-propyl}-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide was treated with 20 ml of 1M nBu4NF, which had been dried by stirring over 3A MS, and kept for 2 days between 55° and 60°. The rection was quenched by pouring onto crushed ice/NH4Cl, extracted twice with ether, washed with water and brine,

dried over magnesium sulfate and evaporated to dryness. Flash chromatography (Si02, hexane/AcOEt=6/4) afforded 896 mg of the title compound as amorphous powder besides 500 mg of starting material in the less polar fractions.

MS: (M)+377, (M-CH3) + 362. e] 1: 1 Mixture of (R)-and (S)-4,4,4-Trifluoro-3-hydroxy-3-methyl-N-[(S)-2- ((4aR, 8aS)-8a-methyl-5-oxo-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl)- propyll-butyramide 276 mg (0.731 mmol) of 1: 1 mixture of (R)-and (S)-4,4,4-trifluoro-3-hydroxy-N- [ (S)-2- ( (4aR, 5S, 8aS)-5-hydroxy-8a-methyl-3,4,4a, 5,6,7,8,8a-octahydro- naphthalen-1-yl)-propyl]-3-methyl-butyramide was dissolve in 12 ml of abs.

CH2Cl2 and treated at 0° with 830 mg (3 eq.) of PDC (pyridinium-dichromate).

After stirring for 2.5 h at ambient temperature the mixture was filtered over a pad of Si02 (AcOEt) and the solvent removed. Flash chromatography (Si02, hexane/AcOEt=6/4) yielded 169 mg of the title compound as colourless oil.

MS: (M)+375, (M-CH3) + 360. fl 1: 1 Mixture of (R)-and (S)-4,4,4-Trifluoro-3-methyl-N- [ (S)-2- ( (4aR, 8aS)-8a- methyl-5-oxo-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl)-propyl]-3- trimethylsilanyloxy-butyramide 160 mg (0.426 mmol) of 1: 1 Mixture of (R)-and (S)-4,4,4-trifluoro-3-hydroxy-3- methyl-N- [ (S)-2- ( (4aR, 8aS)-8a-methyl-5-oxo-3,4,4a, 5,6,7,8,8a-octahydro- naphthalen-1-yl)-propyl]butyramide in 8 ml of abs. CH2Cl2 was treated with 0.624 ml (10 eq.) of TMS-imidazole and kept at room temperature for two days. Pouring onto crushed ice, extraction with ether, washing with water, and drying over magnesium sulfate left a crude product, which was purifie by

flash chromatography (Si02, hexane/AcOEt=7/3). Thereby, 156 mg of the title compound was obtained as colourless oil.

MS: (M) + 447, (M-CH3) + 432. g] 1: 1 Mixture of (R)-and (S)-N- [ (S)-2- ( (E)- (4aS, 8aS)-5- ( (Z)-2- [3, 5-Bis- (tert- butyl-dimethyl-silanyloxy)-2-methylene-cyclohexylidene]-ethy lidene}-8a- methyl-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl)-propyl]-4, 4,4-trifluoro-3- methyl-3-trimethylsilanyloxy-butyramide 539 mg (0.942 mmol) of carefully dried (Z)- (3S, 5R)- [2- [3, 5-bis- (t-butyldimethyl- wassilanyloxy)-2-methylene-cyclohexylidene]-ethyl]-diphenyl- phosphineoxide dissolve in 6 ml of abs. THF and treated at -78° with 1.12 ml of secBuLi (1.3M, cyclohexane). 30 Minutes later, 207 mg (0.462 mmol) of 1: 1 mixture of (R)-and (S)-4,4, 4-trifluoro-3-methyl-N-[(S)-2-((4aR, 8aS)-8a-methyl-5-oxo- 3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl)-propyl]-3-trimethylsilanyloxy- butyramide, dissolve in 4 ml of abs. THF, was added to the deep red solution.

The mixture was kept for 1 h at -78° and for 0.5 h at 0° The discolored rection mixture was then poured onto crushed ice/NH4Cl, extracted twice with ether, washed with water, dried over magnesium sulfate, and the solvents carefully removed. Flash chromatography (Si02, hexane/AcOEt=9/1 to 6/4) afforded 10 mg of the title compound as colorless oil, besides 139 mg of recòvered ketone and 379 recovered phosphine oxide in the more polare fractions. ho 1: 1 Mixture of (5Z, 7E)- (R)-and (S)-N-[(lS, 3R, 20S)-1,3-Dihydroxy-17a, 20a- dihomo-9,10-seco-pregna-5,7,10 (19),17-tetraen-21-yl]-4, 4,4-trifluoro-3-hydroxy- 3-methyl-butyramide

10 mg (0.0123 mmol) of 1: 1 mixture of (R)-and (S)-N- [ (S)-2- ( (E)- (4aS, 8aS)-5- {(Z)-2-[3,5-bis-(tert-butyl-dimethyl-silanyloxy)-2-methylene -cyclohexylidene]- ethylidenel-8a-methyl-3,4,4a, 5,6,7,8, 8a-octahydro-naphthalen-1-yl)-propyl]- 4,4,4-trifluoro-3-methyl-3-trimethylsilanyloxy-butyramide was treated with 40 equivalents of carefully dried TBAF (1M inTHF) at 60'for 2.5 h. The rection mixture was poured onto crushed ice/NH4Cl, extracted twice with AcOEt, washed with brine, dried over magnesium sulfate and evaporated to dryness.

Flash chromatography (Si02, AcOEt) yielded 5 mg of the title compound as colourless gum.

MS: (M) + 5 11, (M-H20) + 493; NMR (1H, CDC13, o, TMS): 0.78 (s, 3H), 1.03 (d, 3H), 1.38 (s, 3H), 1.1-2.2 (m, 23H), 2.25-2.4 (m, 3H), 2.47 (d, 1H), 2.60 (br dd, 1H), 2.89 (m, 1H), 3.06 (m, 1H), 3.44 (m, 1H), 4.23 (m, 1H), 4.44 (m, 1H), 5.01 (br s, 1H), 5.35 (br s, 1H), 5.42 (m, 1H), 5.62 (br m, NH), 6.05 (d, 1H), 6.17 (d, OH), 6.37 (d, 1H).

Example 2.2.

In analogy to example 2.1, but using in step g] (3R, 5R)- [2- [3, 5-bis- (t- butyldimethyl-silanyloxy)-cyclohexylidene]-ethyl]-diphenyl-p hosphineoxide (Tetrahedron Lett. 32,7663 (1991)) was obtained 1: 1 Mixture of (E)-(R)-and (S)-N-(lR, 3R, 20S)-1,3-Dihydroxy-17a, 20a-dihomo- 19-nor-9,10-seco-pregna- (5,7,17-trien-21-yl)-4,4,4-trifluoro-3-trifluoromethyl-3- hydroxy-3-methyl-butyramide as colourless gum.

CI-MS: (M+OAc) + 558, (M-H) + 498; NMR (1H, CDCl3, #, TMS): 0.77 (s, 3H), 1.03 (d, 3H), 1.37 (s, 3H), 1.2-2.55 (m, 28H), 2.7-2.9 (m, 2H), 3.06 (m, 1H), 3.48 (m, 1H), 4.10 (m, 2H), 5.44 (m, 1H), 5.62 (br m, NH), 5.88 (d, 1H), 6.16 (d, OH), 6.32 (d, 1H).

Example 3 3.1. Preparation of 1: 1 Mixture of- [ (5E, 7E)- (R)- and- (S)-4,4,4-trifluoro-3- hydroxy-N- [ (lS, 3R, 20S)-1,3-dihydroxy-20-methyl-9,10-seco-pregna-5,7,10 (19)- trien-21-yl]-3-methyl-butyramide a] [ (IR, 3aR, 4S, 7aR)-1-[(S)-2-Azido-1-methyl-ethyl]-7a-methyl-octahydro-inde n- 4-yloxy]-tert-butyl-dimethyl-silane 11 g (0. 025 mol) of tert-Butyl- [ (lR, 3aR, 4S, 7aR)-1-[(S)-2-iodo-1-methyl-ethyl]- 7a-methyl-octahydro-inden-4-yloxy]-dimethyl-silane (J. Org. Chem. 51,1269- 1272 (1986)) was dissolve in 110 ml of abs. N, N-dimethylformamide and treated with 4.91 g (3 eq.) of NaN3. The mixture was kept for 4, 5 h at 60° and the progress of the rection monitored by thin layer chromatography. Cooling to room temperature, pouring onto crushed ice, twofold extraction with hexane, washing with NaHC03 and drying over sodium sulfate left 9 g of a crude product, which was pure according to 250 MHz NMR and used as such for the next step.

MS: 323. b] (S)-2- [ (lR, 3aR, 4S, 7aR)-4- (tert-Butyl-dimethyl-silanyloxy)-7a-methyl- octahydro-inden-1-yl]-propylamine

9 g of [ (lR, 3aR, 4S, 7aR)-1-[(S)-2-Azido-1-methyl-ethyl]-7a-methyl-octahydro- inden-4-yloxy]-tert-butyl-dimethyl-silane was dissolve in 100 ml of AcOEt and hydrogenated over 0.9 g of 10% Pd/C, which was added in three portions, during 8h at ambient temperature and 1 atm of H2. After fltration over a pad of Celte the solvents were removed. Flash chromatography (Si02, AcOEt/ NEt3=95/5) produced 7.2 g of the title compound as slightly brown oil.

MS: 326. cl 1: 1 Mixture of (R)-and (S)-N- [ (S)-2- [ (lR, 3aR, 4S, 7aR)-4- (tert-butyl-dimethyl- silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propyl]-4,4,4-tr ifluoro-3-hydroxy- 3-methyl-butyramide 1 g (3 mmol) of (S)-2- [ (lR, 3aR, 4S, 7aR)-4- (tert-Butyl-dimethyl-silanyloxy)-7a- methyl-octahydro-inden-1-yl]-propylamine, 0.51 g (1 eq.) of rac-3- trifluoromethyl-3-hydroxy-butyric acid, and 0.36 g (1.1 eq.) of DMAP were dissolve in 20 ml of CH2Cl2. At 0° 0.69 g (1.1 eq.) of EDCI was added and the mixture allowed to react for 4 h at ambient temperature. The solution was washed with citric acid and evaporated to dryness. Flash chromatography (Si02, hexane/AcOEt=85/15) yielded 953 mg of the title compound as colorless oil.

MS: (M+H) + 480. d] 1: 1 Mixture of (R)-and (S)-4,4,4-trifluoro-3-hydroxy-N- [ (S)-2- [ (IR, 3aR, 4S, 7aR)-4-hydroxy-7a-methyl-cotahydro-inden-1-yl]-propyl]-3- methyl-butyramide

0.95 g of 1: 1 Mixture of (R)-and (S)-N- [ (S)-2- [ (IR, 3aR, 4S, 7aR)-4- (tert-butyl- dimethyl-silanylxoy)-7a-methyl-octahydro-inden-1-yl]-propyl] -4,4,4-trifluoro-3- hydroxy-3-methyl-butyramide was dissolve in a mixture of 1 ml THF and 4 ml of CH3CN at room temperature. 2 ml of aq. HF-solution (40%) was added and the rection monitored by thin layer chromatography. After completion of the deprotection, the rection mixture was neutralized with NaHCO3, extracted with Et20, dried over Na2SO4 and carefully evaporated. 0.37 g of the pure title compound was obtained as colourless oil.

MS: 366. e] 1: 1 Mixture of (R)-and (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-[(S)-2- [1R,3aR,7aR)-7a-methyl-4-oxo-octahydro-inden-1-yl]-propyl]-b utyramide 0.37 g (1 mmol) of 1: 1 Mixture of (R)-and (S)-4,4,4-trifluoro-3-hydroxy-N- [ (S)- 2- [ (lR, 3aR, 4S, 7aR)-4-hydroxy-7a-methyl-octahydro-inden-1-yl]-propyl]-3- methyl-butyramide was dissolve in 5 ml of abs. CH2Cl2 and ru'acte with 760 mg (2 eq.) of PDC (pyridinium-dichromate). After stirring for 2.5 h at ambient temperature the mixture was fltred over a pad of Celte and the solvent removed.. Flash chromatography (Si02, hexane/AcOEt=7/3) yielded 112 mg of the title compound as colourless oil.

MS: 364. fl 1: 1 Mixture of (R)-and (S)-4,4,4-trifluoro-3-methyl-N- [ (S)-2- [ (lR, 3aR, 7aR)- 7a-methyl-4-oxo-octahydro-inden-1-yl]-propyl]-3-trimethylsil anyloxy- butyramide

200 mg (0.55 mmol) of 1: 1 Mixture of (R)-and (S)-4,4,4-trifluoro-3-hydroxy-3- methyl-N- [ (S)-2- [ (lR, 3aR, 7aR)-7a-methyl-4-oxo-octahydro-inden-1-yl]-propyl]- butyramide in 5 ml of abs. CH2Cl2 was treated with 0.438 ml (6 eq.) of TMS- imidazole and kept at room temperature over night. A second portion of 0.438 ml of TMS-imidazole was added and the rection allowed to proceed for two days. Pouring onto crushed ice, extraction with ether, washing with water, and drying over sodium sulfate left a crude product, which was purifie by flash chromatography (Si02, hexane/AcOEt=8/2). Thereby, 160 mg of the title compound was obtained as white foam.

MS: 435. gaz 1: 1 Mixture of (5E, 7E)- (R)-and-(S)-N-[(lS, 3R, 20S)-1,3-bis- (tert-butyl- dimethyl-silanyloxy)-20-methyl-9,10-seco-pregna-5,7,10 ( 19)-trien-21-yl]-4, 4, 4- trifluoro-3-methyl-3-trimethylsilanyloxy-butyramide 580 mg of carefully dried (E)- (3S, 5R)- [2- [3, 5-bis- (tert-butyl-dimethyl- silanyloxy]-2-methylene-cyclohexylidene]-ethyl]-diphenyl-pho sphineoxide (preparation see example 7 below) was dissolve in 10 ml of abs. THF and treated at-78° with 0.62 ml of nBuLi (1.5M, hexane). 15 Minutes later, 160 mg (0.334 mmol) of 1: 1 Mixture of (R)-and (S)-4,4,4-trifluoro-3-methyl-N- [ (S)-2- [(1R,3aR,7aR)-7a-methyl-4-oxo-octahydro-inden-1-yl]-propyl]- 3- trimethylsilanyloxy-butyramide, dissolve in 1.5 ml of abs. THF, was added to the deep red solution. The mixture was kept for 0.25 h at -78° and for 1 h at 0°

The discolored rection mixture was then poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulfate, and the solvents carefully removed. Flash chromatography (Si02, hexane/AcOEt=9/1) afforded 70 mg of the title compound as colorless oil.

MS: 801. h] 1: 1 Mixture of [ (5E, 7E)- (R)- and- (S)-4,4,4-trifluoro-3-hydroxy-N- [ (lS, 3R, 20S)-1, 3-dihydroxy-20-methyl-9,10-seco-pregna-5, 7,10 ( 19)-trien-21-yl]- 3-methyl-butyramide 70 mg (0.08 mmol) of 1: 1 Mixture of (5E, 7E)- (R)-and-(S)-N-[(lS, 3R, 20S)-1,3- bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-9,10-seco-pregna- 5,7,10 (19)- trien-21-yl]-4, 4,4-trifluoro-3-methyl-3-trimethylsilanyloxy-butyramide was treated with 8 equivalents of carefully dried TBAF (0.2M in THF) at 40° for 2 h. The rection mixture was poured onto crushed ice, extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, AcOEt) yielded 61 mg of the title compound as white foam.

MS: 500.

NMR (1H, CDC13, #, TMS): 0.59 (s, 3H), 0.99 (d, 3H), 1.41 (s, 3H), 1.0-2.15 (ion, 16H), 2.29 (dt; 1H), 2.46&2.54 (d (AB); 2H), 2.86 (m, 2H), 2. 95-3.50 (m, 2H), 4.25 (ion, 1H), 4.52 (ion, 1H), 5.02 (s br; 1H), 5.15 (s br; 1H), 5.64 (br s, OH), 5.89 (d, 1H), 6.11 (br t, NH), 6.55 (d, 1H).

Example 4 4.1. Preparation of 1: 1 Mixture of (E)-(R)- and (S)-N-[(1R, 3R, 20S)-1,3- dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3- hydroxy-20-methyl-butyramide a] Methanesulfonic acid (E)-(1R, 3R, 20S)-1,3-bis- (tert-butyl-dimethyl- silanyloxy)-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl ester

wherein Mes signifies-S02CH3 2.8g (0.005 mol) of (E)-(lR, 3R, 20S)-1,3-Bis- (tert-butyl-dimethyl-silanyloxy)-20- methyl-19-nor-9,10-seco-pregna-5,7-dien-21-ol (Tetrahedron Letters 33,2937-2940 (1992)) and 0.89g of DMAP (1.5 eq) were dissolve in 50 ml of CH2Cl2 at 0° C and, under argon, 0.84 g of mesylchloride (1.5 eq) was added and the solution was stirred at room temperature over night. The rection mixture was extracted with an aqueous solution of citric acid. The organic phase was dried over sodium sulfate and evaporated to yield 3.39g of crude product which was pure according to 250 MHz NMR and used as such for the next step.

MS: 640. b] (E)-(lR, 3R, 20S)- 21-Azido- (1, 3-bis- (tert-butyl-dimethyl-silanyloxy)-20- methyl-19-nor-9,10-seco-pregna-5,7-diene 2.9 g (0.0045 mol) of Methanesulfonic acid (E)-(lR, 3R, 20S)-1,3-bis- (tert-butyl- dimethyl-silanyloxy)-20-methyl-19-nor-9,10-seco-pregna-5,7-d ien-21-yl ester was dissolve in 50 ml of DMF. 0.88 g of sodium azide (3 eq) was added and the rection mixture was heated at 60° C for two hours. The solvent was evaporated and the residue was dissolve in hexane and washed three times with water. The organic phase was dried over sodium sulfate and evaporated.

Flash chromatography (Si02, hexane/AcOEt=19.5/0.5) afforded 2.27 g of the title compound as colorless oil MS: (M) + 587. c] (E)-(lR, 3R, 20S)-[1,3-Bis-(tert-butyl-dimethyl-silanyloxy)-20-methyl-19- nor- 9,10-seco-pregna-5,7-dien-21-yl]-amine

0.588g (0.01 mol) of (E)-(lR, 3R, 20S)- 21-Azido- (1, 3-bis- (tert-butyl-dimethyl- silanyloxy)-20-methyl-19-nor-9,10-seco-pregna-5,7-diene and 0.393 g (1.5 eq) of PPh3 were dissolve in 5 ml of THF. 0.027 ml of water (1.5 eq) was slowly added under stirring. The rection mixture was heated at 60° C over night, then evaporated to dryness. The residue was dissolve in dry hexane and the insoluble PPh30 was filtered off. 0.69 g of the title compound was obtained after evaporation of the filtrate, and used as such for the next step. d] 1: 1 Mixture of (E)-(R)- and (S)-N-[(1R, 3R, 20S)-1,3-bis- (tert-butyl-dimethyl- silanyloxy)-20-methyl-19-nor-9,10-seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3- hydroxy-20-methyl-butyramide 0.152 g (0.26 mmol) of (E)-(1R, 3R, 20S)-[1,3-Bis-(tert-butyl-dimethyl- silanyloxy)-20-methyl-19-nor-9,10-seco-pregna-5, 7-dien-21-yl]-amine, 0.045 g (1 eq) of 4,4,4-trifluoro-3-hydroxy-3-methyl-butyric acid, 0.059g (1 eq) of EDCI, and 0.030 g (1.1 eq) of DMAP were dissolve in 5 ml of CH2Cl2 at 0° C. The rection mixture was stired over night at room temperature, evaporated, dissolve in AcOEt and washed with water and with an aqueous solution of citric acid. The organic phase was dried over sodium sulfate and evaporated.

Flash chromatography (Si02, hexane/AcOEt=98/2) afforded 20 mg of the title compound as colorless oil MS: (M+H) + 716. e] 1: 1 Mixture of (E)-(R)- and (S)-N-[(1R, 3R, 20S)-1,3-dihydroxy-20-methyl-19- nor-9, 10-seco-pregna-5,7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide

0.08 g (0.1 mmol) of 1: 1 Mixture of (E)-(R- and (S)-N-[(1R, 3R, 20S)-1,3-bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-19-nor-9,10-seco- pregna-5,7-dien- 21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide and 3 equivalents of TBAF were dissolve in 2 ml of dry THF. The rection mixture was stirred over night at room temperature and evaporated. Flash chromatography (Si02, iso-propanol/AcOEt=1/19) afforded 28 mg of the title compound as colorless oil MS: (M+H) + 488.

NMR (1H, CDC13, o, TMS): 0.57 (s, 3H), 1.02 (d, 3H), 1.41 (s, 3H), 1.20-2.03 (m, 16H), 2.24 (m; 2H), 2.46&2.54 (d (AB); 2H), 2.49 (m; 1H), 2.79 (m, 2H), 3.06 (m, 1H), ), 3.40 (m, 1H), 4.09 (m, 2H), 5.14 (m br; N-H), 5.88 (d, 1H), 6.09&6.12 (2s, OH), 6.32 (d, 1H).

Example 4.2.

In analogy to example 4.1., but using in step d] 4,4,4-trifluoro-3-hydroxy-3- trifluoromethyl-butyric acid as coupling partner was obtained as colorless gum (E)-(1R, 3R, 20S)-N- (1, 3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien- 21-yl)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyramid e MS: (M) + 541.

NMR (1H, CDCl3, #, TMS): 0.57 (s, 3H), 0.99 (d, 3H), 1.11-2.07 (m, 16H), 2.24 (m; 2H), 2.50 (m; 1H), 2.69 (s; 2H), 2.77 (m, 1H), 3.11 (m, 1H),), 3.41 (m, 1H), 4.09 (m, 2H), 5.78 (m br; N-H), 5.87 (d, 1H), 6.33 (d, 1H), 7.97 (s, OH).

Example 4.3.

In analogy to example 4.1., but using in step d] 3-(1-hydroxy-1-methyl-ethyl)- benzoic acid as coupling partner was obtained as colorless gum (E)-(lR, 3R, 20S)-N- (1, 3-Dihydroxy-20-methyl-19-nor-9, 10-seco-pregna-5, 7-dien- 21-yl)-3- (1-hydroxy-1-methyl-ethyl)-benzamide MS: (M) + 495.

NMR (1H, CDC13, o, TMS): 0.59 (s, 3H), 1.06 (d, 3H), 1.21-2.10 (m, 17H), 1.61 (s; 6H), 2.24 (m; 2H), 2.50 (m; 1H), 2.59 (m; 2H), 3.23 (m, 1H),), 3.57 (m, 1H), 4.09 (m, 2H), 5.88 (d, 1H), 6.14 (t br; N-H), 6.32 (d, 1H), 7.42 (t, 1H), 7.62 (dm, 2H), 7.94 (s br, 1H).

Example 4.4.

In analogy to example 4. 1., but using in step d] 2,2-dimethyl-propionic acid as coupling partner was obtained as colorless gum (E)-(lR, 3R, 20S)-N- (1, 3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien- 21-yl)-2,2-dimethyl-propionamide

MS: (M) + 417.

NMR (1H, CDCl3, #, :TMS) 0.56 (s, 3H), 0.96 (d, 3H), 1.20 (s; 9H), 1.19-2.03 (ion, 16H), 2.23 (m; 2H), 2.50 (m; 1H), 2.78 (m; 2H), 2.95 (ion, 1H),), 3.37 (ion, 1H), 4.09 (ion, 2H), 5.64 (t br; N-H), 5.89 (d, 1H), 6.32 (d, 1H).

Example 4.5.

In analogy to example 4.1., but using in step d] 2-hydroxy-2-methyl-propionic acid as coupling partner was obtained as colorless gum (E)-(lR, 3R, 20S)-N- (1, 3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien- 21-yl)-2-hydroxy-2-methyl-propionamide MS: (M) + 419.

NMR (1H, CDCl3, #, :TMS) 0.57 (s, 3H), 0.98 (d, 3H), 1.47 (s; 6H), 1.22-2.08 (m, 16H), 2.21 (m; 2H), 2.49 (m; 1H), 2.79 (m; 2H), 3.03 (m, 1H),), 3.45 (m, 2H), 4.09 (m, 2H), 5.88 (d, 1H), 6.33 (d, 1H), 6.70 (t br; N-H).

Example 4.6.

In analogy to example 4.1., but using in step a] (5Z, 7E)- (3S, 20S)-3- (tert-Butyl- dimethyl-silanyloxy)-20-methyl-9,10-seco-prepna-5,7,10 (19)-trien-21-ol (EP 78704 A1) as starting material was obtained as colorless gum 1: 1 Mixture of (5Z, 7E)- (R)- and- (S)-4,4,4-trifluoro-3-hydroxy-N- [ (3S, 20S)-3- hydroxy-20-methyl-9,10-seco-pregna-5,7,10(19)-trien-21-yl]-b utyramide MS: (M) + 483.

Example 4.7 In analogy to example 4.1 but using in step d) optically pure (R)-4,4,4- trifluoro-3-hydroxy-3-methyl-butyric acid as coupling partner was obtained as a white solid E-(R)-N- [(lR,(R)-N- [(lR, 3R, 20S)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7- dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramid.

The starting acid was prepared by preparative HPLC of the corresponding methyl ester on a chiral column followed by saponification.

MS: (M+H) + 488.

Example 5 5.1. Preparation of 1: 1 Mixture of [ (5Z, 7E)- (R)- and (S)-N- [ (IS, 3R, 20S)-1,3- dihydroxy-20-methyl-9,10-seco-pregna-5,7,10 (19)-trien-21-yl]-4, 4,4-trifluoro-3- hydroxy-3-methyl-butyramide

a] (5Z, 7E)- (lS, 3R, 20S)-21-Azido-1,3-bis- (tert-butyl-dimethyl-silanyloxy)-20- methyl-9,10-seco-pregna-5,7,10 (19)-triene

0.5 g (0.87 mmol) of (5Z, 7E)- (lS, 3R, 20S)-1,3-Bis- (tert-butyl-dimethyl- silanyloxy)-20-methyl-9,10-seco-pregna-5,7,10 (19)-trien-21-ol (J. Org. Chem. 53,3450-3457 (1988)), 0.53 g (2 eq) of Zn (N3) 2#2Py complex and 0.45 g (2 eq) of PPh3 were dissolve in 10 ml toluol. 0.26 ml (2 eq) of DEAD was slowly added and the rection mixture stirred over night at room temperature and then heated to 60° C for one additional hour. The solution was treated with a mixture of methanol/water (7/3) and extracted with hexane. The organic phase was dried over sodium sulfate and evaporated.

Flash chromatography (Si02, hexane/AcOEt=19.5/0.5) afforded 0.262 g of 1-(2- azido-1-methyl-ethyl)-4-{2-[3,5-bis-(tert-butyl-dimethyl-sil anyloxy)-2- methylene-cyclohexylidene]-ethylidene}-7a-methyl-octahydro-i ndene as a colorless oil MS: (M) + 599. b] In analogy to example 4. 1., but using in step cl (5Z, 7E)-(1S, 3R, 20S)-21- Azido-1,3-bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-9,10-seco-pregna- 5,7,10 (19)-triene as starting material was obtained as colorless gum 1: 1 Mixture of [ (5Z, 7E)- (R)- and (S)-N- [ (lS, 3R, 20S)-1,3-dihydroxy-20-methyl- 9,10-seco-pregna-5,7,10 (19)-trien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide MS: (M) + 499.

NMR (1H, CDC13, #, TMS): 0.56 (s, 3H), 0.98 (d, 3H), 1.41 (s; 3H), 1.13-2.10 (m, 15H), 2.34 (dd; 1H), 2.41&2.57 (d (AB), 2H), 2.61 (m; 1H), 2.77-3.17

(m; 2H), 3.40 (m, 1H), 4.00 (m, 1H), 4.46 (m, 1H), 5.01 (s br, 1H), 5.35 (s br, 1H), 5.63 (m; N-H), 6.03 (d, 1H), 6.09&6.14 (2s, 1H), 6.39 (d, 1H).

Example 6 6.1. Preparation of 1: 1 Mixture of (E)-(R)-and (S)-N-[(lR, 3R, 20R)-1,3- dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3- hydroxy-3-methyl-butyramide a] 2,2-Dimethyl-propionic acid (E)-(lR, 3R, 20R)-1,3-bis- (tert-butoxy-dimethyl- silanyloxy)-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl ester 2 g (3.6 mmol) of (3R, 5R)- [2- [3,5-Bis- (tert-Butyl-dimethyl-silanyloxy)- cyclohexylidene]-ethyl]-diphenyl-phosphineoxide (Tetrahedron Lett. 33,2937-40 (1992)) was dissolve in 5 ml of dry THF at- 78° C and one equivalent of BuLi in hexane was slowly added. After half an hour, 0.6 g (2 mmol) of 2,2-dimethyl-propionic acid (R)-2- [ (lR, 3aR, 7aR)-7a- methyl-4-oxo-octahydro-inden-1-yl]-propyl ester (PCT Int. Appl. WO 9622776) in 2.5 ml THF was slowly added to the deep red solution and the mixture was allowed to warm to room temperature under stirring over night. After quenching with an aqueous solution of ammonium chloride, the THF was distille of and the residue was extracted with ether, dried over sodium sulfate and the ether was removed. Flash chromatography (Si02, hexane/AcOEt=9/1) afforded 1.11g of 2,2-dimethyl-propionic acid (E)-(lR, 3R, 20R)-11,, 3-bis-(tert- butoxy-dimethyl-silanyloxy)-20-methyl-19-nor-9,10-seco-pregn a-5,7-dien-21-yl ester as colorless oil.

MS: (M) + 646. b] (E)-(lR, 3R, 20R)-1,3-Bis- (tert-butoxy-dimethyl-silanyloxy)-20-methyl-19-<BR> nor-9,10-seco-pregna-5,7-dien-21-ol

2.83 ml (2 eq) of a solution of diisobutylaluminumhydride (1.2 molar in toluene) was slowly added to a solution of 1.1 g (1.7 mmol) of 2,2-dimethyl- propionic acid (E)-(lR, 3R, 20R)-1,3-bis- (tert-butoxy-dimethyl-silanyloxy)-20- methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl ester in 2 ml of toluene at-78° C. After one hour at this temperature the rection mixture was stirred for two additional hours at room temperature before quenching with 8 ml of MeOH.

The desired alcohol was extracted with AcOEt, dried over sodium sulfate, and the organic solvent was removed. Flash chromatography (Si02, hexane/ AcOEt=8/2) afforded 0.69 g of (E)-(lR, 3R, 20R)-1,3-bis- (tert-butoxy-dimethyl- silanyloxy)-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-ol as colorless oil.

MS: (M) + 562. cl In analogy to example 4.1., but using in step a] (E)-(lR, 3R, 20R)-1,3-Bis- (tert-butoxy-dimethyl-silanyloxy)-20-methyl-19-nor-9,10-seco -pregna-5,7-dien- 21-ol was obtained as colorless foam 1: 1 Mixture of (E)-(R)-and (S)-N-[(lR, 3R, 20R)-1,3-dihydroxy-20-methyl-19- nor-9,10-seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide

NMR (1H, CDCl3, #, TMS): 0.60 (s, 3H), 0.91 (d, 3H), 1.41 (s; 3H), 1.20-2.03 (m, 15H), 2.21 (m; 2H), 2.41&2.57 (d (AB), 2H), 2.49 (m; 1H), 2.79 (m; 2H), 2.95 (m, lH), 3.64 (m, 1H+OH), 4.09 (m, 2H), 5.65 (m; N-H), 5.88 (d, 1H), 6.06&6.08 (2s, 1H: OH), 6.32 (d, 1H).

Example 6.2.

During the synthesis of example 6.1., in analogy to example 4.1., it was possible at the stage of step d] which consists of acylation of the amine with racemic 4,4,4-trifluoro-3-hydroxy-3-methyl-butyric acid to separate the two corresponding epimers, namely the 1: 1 mixture of (E)- (R)- and (S)-N- [(1R,3R, 20R)-1,3-bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-19-nor-9, 10- seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-20-methyl-butyramide using column chromatography In analogy to example 4. 1., but using in step e] the less polar epimer of (E)-(R)- or (S)-N- [(1R, 3R, 20R)-1,3-bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-19- nor-9,10-seco-pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydro xy-20-methyl- butyramide was obtained as a colorless foam (E)-(R)- or (S)-N- [ (lR, 3R, 20R)-1,3-dihydroxy-20-methyl-19-nor-9,10-sec- pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide NMR (1H, CDC13, o, TMS): 0.60 (s, 3H), 0.91 (d, 3H), 1.41 (s; 3H), 1.20-2.06 (m, 16H), 2.17 (m; 2H), 2.41&2.57 (d (AB), 2H), 2.49 (m; 1H), 2.76 (m; 2H), 2.98 (m, lH), 3.65 (m, 1H), 4.09 (m, 2H), 5.65 (m; N-H), 5.88 (d, 1H), 6.32 (m br, OH), 6.32 (d, 1H).

Example 6.3.

During the synthesis of example 6. 1., in analogy to example 4. 1., it was possible at the stage of step d] which consists of acylation of the amine with racemic 4,4,4-trifluoro-3-hydroxy-3-methyl-butyric acid to separate the two corresponding epimers"namely the 1: 1 mixture of (E)- (R)- and (S)-N-

[ (lR, 3R, 20R)-1, 3-bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-19-nor-9, 10- seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-20-methyl-butyramide using column chromatography.

In analogy to example 4. 1., but using in step e] the more polar epimer of (E)- (R)-or (S)-N-[(1R, 3R, 20R)-1,3-bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl- 19-nor-9,10-seco-pregna-5, 7-dien-21-yl]-4, 4,4-trifluoro-3-hydroxy-20-methyl- butyramide was obtained as colorless foam (R)-N-[(1R,3R,20R)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco- (E)-(S)-or pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-bu tyramide NMR (1H, CDCl3, #, TMS): 0.60 (s, 3H), 0.91 (d, 3H), 1.40 (s; 3H), 1.20-2.03 (m, 15H), 2.21 (m; 2H), 2.41&2.58 (d (AB), 2H), 2.49 (m; 1H), 2.79 (m; 2H), 2.94 (m, lH), 3.66 (m, 1H), 4.09 (m, 2H), 5.64 (m; N-H), 5.88 (d, 1H), 6.06 (s, OH), 6.31 (d, 1H).

Example 6.4. a] In analogy to example 6. 1., but using in step a] (Z)- (S)- [2- [5- (tert-Butyl- dimethyl-silanyloxy)-2-methylene-cyclohexylidene]-ethyl]-dip henyl-phosphine oxide (Perkin I, 1974,2005-2009; J. Org. Chem, 48,1414-1417 (1983)) was obtained as colorless oil (5Z,7E)- (3S, 20R)-3- (tert-Butyl-dimethyl-silanyloxy)-20-methyl-9,10-seco- pregna-5,7-dien-21-ol MS: (M) + 444. b] In analogy to example 4. 1., but using in step a] (5Z, 7E)- (3S, 20R)-3- (tert- Butyl-dimethyl-silanyloxy)-20-methyl-9,10-seco-pregna-5,7-di en-21-ol was obtained as colorless foam 1: 1 Mixture of (5Z, 7E)- (R)- and (S)-N- [ (3S, 20R)-3-hydroxy-20-methyl-9,10-sec- pregna-5,7,10 (19)-trien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl-butyramide MS: (M+H) + 484.

NMR (1H, CDC13, o, TMS): 0.60 (s, 3H), 0.90 (d, 3H), 1.40 (s; 3H), 1.20-2.38 (m, 19H), 2.40&2.58 (d (AB), 2H), 2.91 (m; 2H), 3.67 (m, 1H), 3.96 (m, 1H), 4.82 (s br, 1H), 5.06 (s br, 1H), 5.76 (m; N-H), 6.05 (d, 1H), 6.09 (s, OH), 6.23 (d, 1H).

Example 6.5. a] In analogy to example 6.1., but using in step a] (Z)- (3S, 5R)- [2- [3, 5-bis- (tert- butyl-dimethyl-silanyloxy)-2-methylene-cyclohexylidenel-ethy l]-diphenyl- phosphine oxide (J. Org. Chem. 51,3098-3108 (1997)) was obtained as colorless oil (5Z, 7E)- (1S, 3R, 20R)-1,3-bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-9,10- seco-pregna-5,7,10 (19)-trien-1-ol MS: (M) + 574. b] In analogy to example 4.1., but using in step a] (5Z, 7E)- (lS, 3R, 20R)-1,3-Bis- (tert-butyl-dimethyl-silanyloxy)-20-methyl-9,10-seco-pregna- 5,7,10 ( 19)-trien-1- ol was obtained as colorless foam 1: 1 Mixture of (5Z, 7E)- (R)-and (S)-N-[(lS, 3R, 20R)-1,3-dihydroxy-20-methyl- 9,10-seco-pregna-5,7,10 (19)-trien-21-yl]-4, 4,4-trifluoro-3-hydroxy-3-methyl- butyramide MS: (M+H) + 500.

NMR (1H, CDCl3, #, TMS): 0.60 (s, 3H), 0.90 (d, 3H), 1.40 (s; 3H), 1.20-2.07 (m, 15H), 2.31 (m; 2H), 2.41&2.56 (d (AB), 2H), 2.77-3.05 (m; 2H), 3.64 (m, 1H), 4.24 (m, 1H), 4.45 (m, 1H), 45.01 (s br, 1H), 5.34 (s br, 1H), 5.76 (m; N-H), 6.03 (d, 1H), 6.06&6.07 (2s, OH), 6.38 (d, 1H).

Example 7 Synthesis of the oxide (E)- (3S, 5R)- [2- [3, 5-bis- (tert-Butyl-dimethyl-silanyloxy]- 2-methylene-cyclohexylidene]-ethyl]-diphenyl-phosphineoxide a) (4R, 6S)-4-6-Bis- (tert-butyl-dimethylsilanyloxy)-1-acetoxymethyl- cyclohexene The allylic iodide (4R, 6S)-4, 6-bis-(tert-butyl-dimethylsilanyloxy)-1-iodomethyl- cyclohexene (J. Org. Chem. 54,3515-3517 (1989)) (10.55g; 21,86 mmol) was dissolve in dry N, N-dimethylformamide (50 ml). Cesium acetate (8.65g; 43 mmol; 2 equivalents) was crushed, azeotropically dried (with toluene) and added to the iodide. After two hours at room temperature the rection was complet. The rection mixture was poured onto an aqueous saturated sodium chloride solution and extracted twice with a AcOEt/hexane 1: 1 mixture, washed with water, dried over sodium sulfate, and the solvents were removed.

Flash chromatography (Si02, hexane/AcOEt 9/1) afforded 7.76g (85% yield) of the title compound as a colorless waxy solid.

MS: (M-H) + 413.

IR: (cm~l) 2929; 2846; 2887; 2858; 1746; 1473; 1463; 1377; 1362; 1254; 1235; 1107; 1078; 1062; 1023; 1005; 965; 876; 837; 775. b) (4R, 6S)-4-6-Bis- (tert-butyl-dimethylsilanyloxy)-1-hydroxymethyl- cyclohexene The acetate (4R, 6S)-4,6-bis- (tert-butyl-dimethylsilanyloxy)-1-acetoxymethyl- cyclohexene (7.76; 18.71mmol) was dissolve in dry methanol (60 ml).

Potassium carbonate (1. Og; 7.23 mmol; 0.39 equivalents) was added to the mixture. The rection was allowed to proceed over night at room temperature.

The rection mixture was poured onto an aqueous solution of 1N HCl and extracted twice with AcOEt, washed with water, dried over sodium sulfate and the solvent was removed. Flash chromatography (Si02, hexane/AcOEt 8/2) afforded 6.4 g (92% yield) of the title compound as colorless waxy solid.

MS: (M-CH20H) + 341; (M-tBu) + 315.

IR: (cm-1) 3280; 2953; 2928; 2857; 1472; 1461; 1445; 1384; 1360; 1254; 1104; 1080; 1060; 1018; 1002; 988; 933; 877; 838; 775. c) (4R, 6S)-4,6-Bis- (tert-butyl-dimethylsilanyloxy)-1-phenylselenyl- acetoxymethyl-cyclohexene The alcohol (4R, 6S)-4,6-bis- (tert-butyl-dimethylsilanyloxy)-1-hydroxymethyl- cyclohexene (1.00 g; 2.68 mmol) was dissolve in dry dichloromethane (15 ml).

Phenylselenyl acetic acid (850 mg; 3.49 mmol; 1.3 equivalents), DCC (1100 mg; 5.36 mmol; 2 equivalents), DMAP (165 mg; 1.34 mmol; 0.5 equivalent), were added to the mixture. The rection was allowed to proceed over night at room temperature. The rection mixture was poured onto an aqueous saturated sodium chloride solution and extracted twice with a AcOEt/hexane 1: 1 mixture, washed with water, dried over sodium sulfate, and the solvents were removed. Flash chromatography (Si02, hexane/AcOEt 9/1) afforded 1.37 g (89% yield) of the title compound as yellowish oil.

MS: (M-tBu) + 513.

IR: (cm-1) 2955; 2928; 2886; 2856; 1735; 1668; 1580; 1472; 1257; 1104; 1061; 1000; 875; 837; 775; 737; 692.

d) 2 (RS)- [(lRS, 3S, 5R)-3-5-Bis- (tert-butyl-dimethylsilanyloxy)-2-methylene- cyclohexyl)-1-yl]-2-phenylselenyl-acetic acid methyl ester Mixture of 4 stereoisomers The ester (4R, 6S)-4,6-bis- (tert-butyl-dimethylsilanyloxy)-1-phenylselenyl- acetoxymethyl-cyclohexene (610 mg; 1.02 mmol) was dissolve in dry dichloromethane (10 ml) and cooled to 0°C. Triethylamine (0.71 ml; ã. 1 mmol; 5 equivalents) was added and the mixture was stirred for 15 minutes.

Then t-butyl-dimethyl-silanyl-triflate (tBDMSOTf) (0.544 ml; 2.05 mmol; 2 equivalents) was slowly added. The mixture was allowed to reach room temperature and kept at this temperature over night.

The rection mixture was poured onto an aqueous solution of 1N HCl and extracted twice with dichloromethane, washed with water, dried over sodium sulfate and the solvent was removed.

The crude silyl-ester was dissolve in THF (20 ml); an aqueous solution of 2N NaOH (2 ml; 4 equivalents) was carefully added and allowed to react for half an hour. The rection mixture was poured onto an aqueous solution of 1N HCl and extracted twice with AcOEt, washed with water, dried over sodium sulfate and the solvents were removed.

The crude acid was dissolve in THF (10 ml) and a large excess of an ethereal solution of diazomethane was added carefully untill the rection was complete (thin layer chromatography control). Then the solvent was removed and flash chromatography (Si02, hexane/AcOEt 9/1) afforded 595 mg (95% yield) of the title compound as yellowish oil.

NMR: (1H, CDCl3, d, TMS): 7.60 (m. 2H); 7.30 (m; 3H); 5.01 and 4.90 (2s; 1H); 4.70 and 4.68 (2s; 1H); 4.40 (m; 1H); 4.21 (m; 1H); 3.98 and 3.63 (2d; 1H); 3.52 and 3.50 (2s; 3H); 2.94 (m; 1H); 2.25 (m; 1H); 2.00-1.42 (m; 3H); 0.9 (m; 18H); 0.05 (m; 12H). e) (E)- (lS, 5R)-1,5-Bis- (tert-butyl-dimethylsilanyloxy)-2-methylene-3- [ethylidene-2-carboxylic acid methyl ester]-cyclohexane The phenylselenyl-ester 2 (RS)-[(lRS, 3S, 5R)-3-5-bis- (tert-butyl-dimethyl- silanyloxy)-2-methylene-cyclohexyl)-1-yl]-2-phenylselenyl-ac etic acid methyl ester (590 mg; 1.00 mmol) was dissolve in THF (10 ml).

A solution of sodium periodate (650 mg; 3 mmol; 3 equivalents) in methanol/water 1: 1 mixture (10 ml) was added dropwise. The rection was allowed to proceed for three hours at room temperature during which time a white precipitate appeared. The rection mixture was poured onto an aqueous saturated sodium chloride solution and extracted twice with AcOEt, washed

with water, dried over sodium sulfate and the solvents were removed. Flash chromatography (Si02, hexane/AcOEt 95/5) afforded 375 mg (88% yield) of a 1: 9 mixture of the title compound and its Z-isomer as colorless waxy solid.

This mixture was then dissolve in 100 ml of hexane and irradiated in a photoreactor (Hg lamp). The E/Z isomerization rection was followed by NMR.

After 6 hours the rection was complete; the solvent was removed and the title compound was obtained in quantitative yield (isomerization step) as colorless waxy solid.

(Z)- (lS, 3R)-1,5-Bis- (tert-butyl-dimethylsilanyloxy)-2-methylene-3- [ethylidene- 2-carboxylic acid methyl ester]-cyclohexane MS: (M) 426.

NMR: (1H, CDCl3, d, TMS): 5.62 (s (br); 1H); 5.17 (t; 1H); 4.96 (t; 1H); 4.54 (dd; 1H); 3.63 (s; 3H); 2.42 (dd (AB); 1H); 2.27 (dd (AB); 1H); 1.92 (m; 1H); 1.75 (m; 1H); 0.90 (s; 9H); 0.85 (s; 9H); 0.09 (s; 6H); 0.05 (s; 6H).

(E)- (lS, 3R)-1,5-Bis- (tert-butyl-dimethylsilanyloxy)-2-methylene-3- [ethylidene- 2-carboxylic acid methyl ester]-cyclohexane MS: (M) 426.

NMR: (1H, CDC13, d, TMS): 5.91 (s (br); 1H); 5.07 (t; 2H); 4.58 (dd; 1H); 3.70 (s; 3H); 3.36 (dd (AB); 1H); 2.70 (dd (AB); 1H); 1.84 (m; 1H); 1.76 (m; 1H); 1.32 (m; 3H); 0.89 (s; 9H); 0.85 (s; 9H); 0.07 (s; 6H); 0.06 (s; 6H). f) (E)- (lS, 5R)-1,5-Bis- (tert-butyl-dimethylsilanyloxy)-2-methylene-3- [2- hydroxy-ethylidene]-cyclohexane The ester (E)-(lS, 5R)-1,5-bis- (tert-butyl-dimethylsilanyloxy)-2-methylene-3- [ethylidene-2-carboxylic acid methyl ester]-cyclohexane (4.25 g; 9.96 mmol) was dissolve in dry toluene (100 ml) and cooled to-78°C. DIBAL-H (25 ml of a 1.2M solution in toluene; 30 mmol; 3 equivalents) was added dropwise and the mixture was allowed to react for one hour. The rection was quenched with methanol (3 ml) and warmed to room temperature. Then a 1M aqueous solution of sodium potassium tartrate (30 ml) was added and vigorously stirred till two well layers separated. The organic phase was washed with water, dried over sodium sulfate and the solvent was removed. Flash chromatography (Si02, hexane/AcOEt 8/2) afforded 2.8 g (70% yield) of the title compound as colorless waxy solid.

MS: (M-OH) + 381.

IR: (cm-1) 3255; 2955; 2928; 2856; 1656; 1638; 1472; 1463; 1443; 1407; 1361; 1255; 1130; 1105; 1080; 1047; 1029; 1008; 987; 907; 897; 836; 775. g) (E)-(lS, 5R)-1,5-Bis- (tert-butyl-dimethylsilanyloxy)-2-methylene-3- [2-chloro- ethylidene]-cyclohexane N-chlorosuccinimide (NCS) (1.92 g; 14.35 mmol; 2 equivalents) was dissolve in dry dichloromethane (50 ml) and cooled to 0°C ; then dimethylsulfide (1.10 ml; 14.35 mmol; 2 equivalents) was added and the mixture was stirred for a quarter of an hour (formation of a white precipitate) and then cooled to-20°C.

The allylic alcohol (E)- (lS, 5R)-1,5-bis- (tert-butyl-dimethylsilanyloxy)-2- methylene-3-[2-hydroxy-ethylidene]-cyclohexane (2.8 g; 7.02 mmol), dissolve in dry dichloromethane (20 ml), was added dropwise. The mixture was allowed to react for half an hour at -20°C and then the temperature was allowed to reach room temperature. The rection mixture was poured onto an aqueous saturated sodium chloride solution and extracted twice with ether, washed with water, dried over sodium sulfate and the solvents were removed. Flash chromatography (Si02, hexane/AcOEt 95/5) afforded 2.82g (96% yield) of the title compound as yellowish oil.

MS: (M-Cl) + 381.

IR: (cm-1) 2955; 2928; 2886; 2858; 1652; 1472; 1463; 1256; 1124; 1104; 1080; 902; 836; 776. h) (E)- (3S, 5R]- [2- [3,5-Bis-tert-butyl-dimethyl-silanyloxy]-2-methylene- cyclohexylidene]-ethyl]diphenylphosphineoxide Diphenylphosphine (2.37 ml; 13.5 mmol; 2 equivalents) was dissolve in dry THF (40 ml) and cooled to 0°C ; then butyllithium (8.65 ml of a 1.6M sol. in hexane; 13.5 mmol; 2 equivalents) was added dropwise and the mixture was stirred for a quarter of an hour. A deep red solution was obtained.

The allylic chloride (E)-(lS, 5R)-1,5-bis- (tert-butyl-dimethylsilanyloxy)-2- methylene-3- [2-chloro-ethylidenel-cyclohexane (2.82 g; 6.76 mmol), dissolve in dry THF (20 ml), was cooled to-78°C and the above prepared lithium diphenylphosphide was added dropwise till the rection mixture took an orange color. The rection was quenched with methanol (1 ml), and then the temperature was allowed to reach room temperature.

The solvent was removed, the rection mixture was taken up in AcOEt (30 ml), cooled to 0°C, and a 10% H202 solution (30 ml) was added carefully, and the mixture was stirred for a quarter of an hour. The organic layer was washed with water, dried over sodium sulfate and the solvent was removed.

Flash chromatography (Si02, dichloromethane/AcOEt 8/2) afforded 2.86 g (72% yield) of the title compound as colorless waxy solid.

MS: (M) + 582.

IR: (cm-1) 3425; 3270; 2954; 2928; 2886; 2856; 1630; 1472; 1438; 1253; 1211; 1189; 1121; 1082; 1023; 1004; 903; 837; 776; 745; 720; 695.