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Title:
NEW SUBSTITUTED 19-NOR-PREGNANE DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/1997/027209
Kind Code:
A1
Abstract:
The invention relates to compounds of formula (I) in which R1, R2, R3, R4, R5, R6, X and n are as defined in the specification, and to pharmaceutical compositions containing them. These compounds are potent progestogens which are devoid of residual androgenic activity.

Inventors:
MAILLOS PHILIPPE (FR)
VERDAN CHRISTINA (FR)
DELANSORNE REMI (FR)
PARIS JACQUES (FR)
PASCAL JEAN-CLAUDE (FR)
Application Number:
PCT/EP1997/000312
Publication Date:
July 31, 1997
Filing Date:
January 16, 1997
Export Citation:
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Assignee:
THERAMEX (MC)
MAILLOS PHILIPPE (FR)
VERDAN CHRISTINA (FR)
DELANSORNE REMI (FR)
PARIS JACQUES (FR)
PASCAL JEAN CLAUDE (FR)
International Classes:
C07J7/00; C07J13/00; C07J17/00; C07J41/00; C07J53/00; (IPC1-7): C07J7/00; A61K31/57; C07J41/00; C07J53/00
Foreign References:
FR2111097A51972-06-02
DE2048231A11971-04-29
US3759962A1973-09-18
FR2271833A11975-12-19
FR2199993A11974-04-19
DE2014834A11970-11-05
CH509997A1971-07-15
Other References:
J. PARIS ET AL: "The Pharmacological Profile of TX 066 (17.alpha.-Acetoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione)", ARZNEIMITTEL FORSCHUNG DRUG RESEARCH., vol. 33, no. 5, 1983, AULENDORF DE, pages 710 - 715, XP002005431
I. DUC ET AL: "Antiandrogenic Properties of Nomegestrol Acetate", ARZNEIMITTEL FORSCHUNG DRUG RESEARCH., vol. 45, no. 1, 1995, AULENDORF DE, pages 70 - 74, XP002005432
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Claims:
CLAIMS
1. A compound having the following general formula (I): wherein : each of Rj and R.
2. is hydrogen or a (CχCg)alkyl, Ri and R.
3. being not simultaneously hydrogen ; R.
4. is hydrogen, a (CχC6)alkyl or a (CχC6)alkoxy ; R.
5. is hydrogen, a (CιCg)alkyl or a group CORg where R6 is a (CιCg)alkyl ; R.
6. is hydrogen or a (CχC6)alkyl ; n is zero or one ; X is oxygen or a hydroxyimino group ; and the dotted line may represent a double bond ; provided that when n = 0, R3 is hydrogen only if both R^ and R2 arc a (CχC6)alkyl.
7. 2 A compound according to claim 1, wherein R^ and R3 are a (CχCg)alkyl, R2 and R5 are hydrogen, R4 is a group COR5, n is zero and R and X arc as defined for (I) in claim 1.
8. 3 A compound according to claim 1, wherein R is a (CiQ alkyl, R3 and R5 are hydrogen, R4 is a group COR6, n is one, and X, RT and Rβ are as defined for (I) in claim 1; 4 A compound according to claim 1, wherein R^ and R4 are a (CχCή)alkyl, R2, R3 and R5 are hydrogen, n is one and X is as defined for (I) in claim 1.
9. 5 A compound according to claim 1, wherein R^ and R2 are a (C Cg)alkyl, R3 and R5 are hydrogen, R4 is a group CORg, n is zero and R and X are as defined for (I) in claim 1.
10. 6 A compound according to claim 3 or 4, wherein X is oxygen.
11. A pharmaceutical composition containing (i) an effective amount of a compound of formula (I) according to any one of claims 16 and (ii) suitable excipients.
12. A pharmaceutical composition according to claim 7, which contains from 0.01 wt% to 99.99 wt% of the compound of formula (I).
13. A pharmaceutical composition according to claim 7 or 8, which is a contraceptive composition.
14. A contraceptive composition according to claim 9, which further contains an effective amount of an oestrogen.
15. Use of a compound of formula (I) according to any one of claims 16 for the preparation of a medicament intended for treating or preventing gynaecological disorders associated to an oestrogen progesterone imbalance.
16. Use of a compound of formula (I) according to any one of claims 16 for the preparation of a medicament intended for inhibiting oestrogen transformation of endometrium .
17. Use of a compound of formula (I) according to any one of claims 16 for the preparation of a medicament intended for inhibiting gonadotropic/gonadal secretions.
18. Use of a compound of formula (I) according to any one of claims 16, alone or in combination with an oestrogen, for the preparation of a contraceptive agent.
19. Use of a compound of formula (I) according to any one of claims 16, alone or in combination with an oestrogen for the preparation of a medicament intended for postmenopausal hormone replacement therapy.
Description:
New substituted 19-nor-pregnane derivatives

The invention relates to substituted 19-nor-prcgnane derivatives, methods of making these compounds and pharmaceutical compositions containing them. The compounds of this invention have excellent progestational properties while being devoid of residual androgenic activity.

Various substituted 19-nor pregnane derivatives having progestational properties have been described in the literature. For example, GB-A-1 104 968 describes 3- oximino steroi

in which R is hydrogen, methyl, ethyl, chlorine, bromine or fluorine ; R' is hydrogen or a (C2-Ci2)alkanoyl and R" is hydrogen or methyl ; said compounds being prepared from the 3-oxo derivatives.

DE-A-2 148 261 describes a method of preparing 6α-methyl-19-nor-pregnenes of the formula :

CH, in which Rj is hydrogen or methyl and R2 is a (Cj -Cojaiky 1. BE 757 285 relates to pharmaceuticals containing 3,20-dioxo-6α-methyl-17α- acetoxy- 19-nor-Δ^-pregnene. In addition, 15,16-methyicnesteroids, among which 3-O-Δ4-19-nor-17β-Ac-

17α-OH-15α,16α-mcthyleneandrostane and 3-O-Δ 4 -19-nor-17β-Ac-17α-

OAc-15α,16α-mcthylcncandrostane, are described in Chem. Ber. 107, 128-134

(1974).

19-nor progesterone derivatives such as those described above usually exhibit however androgenic side effects.

The Applicant has now found that 19-nor pregnane derivatives which possess at least two substituents in position 6-, 7-, 15- and/or 15,16- display excellent progestational activity and are devoid of residual androgenic activity. A first aspect of this invention thus encompasses compounds having the structure represented by the following general formula (I):

wherein : each of R j and R2 is hydrogen or a (Cι-Cg)alkyl, Rj and R2 being not simultaneously hydrogen ;

R3 is hydrogen, a (Cι-Cg)alkyl or a (Cι-C6)alkoxy ;

R4 is hydrogen, a (Cι-C6)alkyl or a group -CORg where Rβ is a (Cι-C6)alkyl ;

R5 is hydrogen or a (C^-Cgjalkyl ; n is zero or one ; X is oxygen or a hydroxyimino group ; and the dotted line may represent a double bond ; provided that when n = 0, R3 is hydrogen only if both R and R2 are a (Cι-C6)alkyl.

As used herein, the term "alkyl" means a linear or branched saturated hydrocarbon radical, such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

As used herein the term "alkoxy" means the group -OR wherein R is alkyl as defined above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy and hexyloxy.

As used herein the group -CORfi wherein R6 is alkyl as defined above includes,

for example, acetyl, propionyl, butyryl, isobutyryl, t-butyryl, valeryl and hexanoyl.

Among the compounds of formula (I), those wherein R and R3 are a (C x - Cg)alkyl, R2 and R5 arc hydrogen, R4 is a group -COR5, particularly an acetyl group, and n is zero are preferred. Also preferred are the compounds of formula (I) wherein R j is a (Cι-Cg)alkyl, R3 and R5 are hydrogen, R4 is a group -CORg, particularly an acetyl group, and n is one, those where X is oxygen being especially preferred. Further preferred are the compounds of formula (I) wherein Rj and R4 are a (C -C )aϊkyl, R2, R3 and R5 arc hydrogen and n is one, those where X is oxygen being especially preferred. Other preferred compounds of formula (I) include those wherein R and R2 are a (Cι~C )alkyl, R3 and R5 are hydrogen, R4 is a group -CORg, particularly an acetyl group, and n is zero. Another aspect of this invention relates to a method of preparing the compounds of formula (I) : these compounds can be made following the Reaction Scheme below wherein Rj, R2, R3, R4, R5, R , n and X have the same meaning as set forth above.

REACTION SCHEME

REACTION SCHEME

Compounds of formula 1.1 arc prepared according to procedures described by B.M. Trost et al., J. Am. Chem. Soc. 1976, 98(16), 4887-902, or by J.R. Bull et al., J. Chem. Res. Synop. 1979, (7), 224-5. Referring to reaction scheme in step 1, compounds of formula 2.1 (n = 0, R3 = alkyl) are prepared using the procedures of M.B. Grocn et al., Rec. Trav. Chim. Pays-Bas 1979, 98 (4), 239-49, or R.V. Coombs (US patent 3,766,224). Compounds of formula 2.1 (n = 1, R3 = H) are prepared by a Corey reaction of a compound of formula 1.1 with a dimethylsulfoxonium methylide produced by the reaction of trimethylsulfoxonium iodide with sodium hydride in tetrahydrofurane or dimethylsulfoxide. They can also be prepared by the reaction of diazomethane catalyzed by palladium or copper derivatives.

Compounds of formula 2.1 (n = 0, R3 = alkoxy) can be prepared using the procedure described by E.N. Cantrall et al., J. Org. Chem. (1964), 29, 64. Compounds of formula 2.1 are condensed with an alkyl-triphenylphosphonium bromide in a dimethylsulfoxide/sodium hydride mixture at a temperature from about 10'C to 40*C, preferably at 20'C.

After about 1 to 24 hours, preferably 8 to 12 hours, products of formula 3.1 are separated from the reaction mixture by precipitation in water followed by crystallization from an alcohol, preferably methanol or ethanol.

Compounds of formula 3.1 are oxidized by a complex of N-methylmorpholine oxide-hydrogen peroxide catalysed by osmium tetraoxide, or N-triethylamine oxide-hydrogen peroxide catalysed by osmium tetraoxide in tert-butanol at a temperature from about 0*C to 40*C, preferably at 20*C for about 2 to 12 hours, preferably 6 hours. The reaction mixture is treated with a solution of sodium sulfite (Na2≤θ3) and compounds of formula 4.1 are obtained by precipitation in water or flash -chromatography. Other oxidizing agents such as KMNO4 in an acetone water mixture can be used in this step following a process described by AJ. Fatiadi (Synthesis 1987, 85). Compounds of formula 5.1 are then dissolved in toluene to which is added 1 to 10 molar equivalents, preferably 5 molar equivalents of ethylene glycol, tricthylorthoformate and a catalytic amount of p-toluenesulfonic acid. The reaction mixture is stirred at a temperature of about 20*C to 80 * C, preferably 40*C, for about 2 to 8 hours, preferably 6 hours. Then, the reaction mixture is cooled and poured into iced water and extracted with a suitable organic solvent, such as

toluene, diethyl ether and the like. When the solvent is removed under reduced pressure, a residue is formed which can be purified by crystallization from an alcohol or by flash-chromatography to yield compounds of formula 5.1. Compounds of formula 5.1 are submitted to Birch reduction following the procedure of A . Birch et al., J. Chem. Soc. (1949), 2531, yielding compounds of formula 6.1.

The tertiary hydroxy group can be optionally esterified by known processes used for esterification in steroid chemistry or alkylated by an alkyl halide according to the conventional methods of Williamson ether synthesis such as described by B. G. Zupancic et al., Synthesis (1979), 123 or by D.R. Benedict et al., Synthesis (1979), 428-9 to give compounds of formula 7.1 (R4 = H, -CORg or alkyl). The corresponding alkyl enol ethers of formula 8.1 are obtained by reaction with a trialkylortho formate, preferably triethylorthoformate in an alcohol such as methanol, ethanol, propanol or n-butanol, preferably ethanol, with a catalytic amount of toluene sulfonic acid. The reaction temperature can be, for example, between room temperature and the boiling temperature of the reaction mixture. The alkyl enol ethers arc reacted with a Vilsmeier-Hack formylating agent in DMF at a temperature below 0*C, preferably -10 * C, giving compounds of general formula 9.1. Sodium borohydride reduction of compounds 9.1 in a mixture of DMF and CH3OH followed by dehydration with a strong mineral acid such as H2SO4, HCl or HBr, preferably sulfuric acid, yield compounds of formula 10.1. Alternatively, compounds of formula 9.1 can be directly converted to 12.1 by a process similar to that described by D. Burn et al., Tetrahedron (1965), 21, 1619-24. Treatment of compounds 10.1 with palladium-on-charcoal in refluxing alcohol such as methanol, ethanol or isopropanol gives, after filtration of the catalyst and crystallization from an appropriate solvent, compounds of formula 11.1. Alternatively, compounds of formula 10.1 can be directly converted to compounds of formula 12.1 by hydrogenation. The pure isomers are obtained by crystallization or by preparative HPLC.

Reaction of compounds of formula 12.1 with aπ excess of hydroxylamine hydrochloride in a mixture of an alcohol, preferably ethyl alcohol, or dioxane, and pyridine at a temperature between 20*C and the reflux temperature of the solvent, preferably 60*C, leads to compounds of formula 13.1. The E and Z hydroxyimino derivatives are obtained by crystallization from a suitable solvent or by flash-

chromatography.

Addition of a lithium dialkylcuprate LiCu(R2)2. or of the corresponding alkylmagnesium halide under copper catalysis (for example Cul or CuCN) to compounds of formula 11.1 followed by isomerisation of the double bond in acidic condition yield compounds of formula 14.1 . These can be converted to 13.1 by addition of hydroxylamine.

The compounds of this invention are potent progestogens which are devoid of androgenic side effects ; they are therefore useful for treating a variety of gynaecological disorders related to an oestrogen progesterone imbalance in premenopausai women, for example : abnormal uterine bleeding (oligomenorrhea, amenorrhea, functionnal uterine hemorrhage...), premenstrual tension, dysmenoπhea, benign breast disease, breast tumors, premenstrual complaints such as headache, depression, water retention, mastodynia or mood alteration. Due to their pharmacological properties, in particular their potent antigonadotropic activity, they can also be used in several other indications, such as for example the inhibition of oestrogen transformation of normal endometrium to hyperplasic or malignant states, or for the inhibition of gonadotropic/gonadal secretions (for example in the treatment of endometriosis and polycystic ovary syndrome in women and of prostate diseases in men). The invention compounds can also be used alone as contraceptive agents in both sexes, or in combination with an oestrogen, such as for example oestradiol or ethynyl oestradiol, in contraceptive formulations for premenopausai women ; they can also be used alone or in combination with an oestrogen in hormonal replacement therapy for postmenopausal women. The progestational activity of the compounds of formula (I) can be evaluated in two specific experimental models : the affinity for the progesterone receptor (PR) in vitro, and the cndometrial tranformation of the rabbit uterus in vivo. Human PRs are readily available in high amounts from the T47-D cell line in culture (M.B. Mockus et al., Endocrinology, 1982, 110 : 1564-1571). Relative binding affinities (RBA) for the human T47-D cell PR are determined as previously described (J. Botella et al., J. Steroid Biochem. Molec. Biol., 1994, 50 : 41-47) using [ 3 H]-ORG 2058 as the labelled specific ligand (G. Fleischmann et al., Biochim. Biophys. Acta, 1978, 540 : 500-517) and nomcgestrol acetate as the non-radioactive reference progestin. Competitive incubations were performed against 2 nM of [ 3 H]-ORG 2058 for 3 hours at 4 * C with six different

concentrations of non-labelled steroid, chosen between 4 and 256 nM following a l 2 n dilution scheme. Displacement curves were fitted for each experiment, and the concentration inhibiting 50% of the specific binding of [ 3 H]-ORG 2058 was calculated for each curve (IC50).

The affinity of test compounds of the invention for human PR is given in Table 1 below :

Table 1 : Relative binding affinity to human T47-D cell progesterone receptor

Progestin ICsn in nM (n) RBA

Nomegestrol acetate 16.4 ± 1.3 (13) 100%

Example 1 38.0 ± 10.3 (4) 43%

Example 2 28.8 ± 5.6 (3) 57%

Example 6 21.1 ± 6.0 (4) 78%

Example 7 19.7 ± 3.0 (4) 83%

Example 8 21.1 ± 6.0 (4) 78%

Example 9 32.3 ± 5.3 (4) 51%

Example 11 25.5 ± 5.3 (3) 64%

(a) mean ± s.e.m. ; (n) number of experiments

One specific pharmacological test has been standardized in vivo for the detection and quantitation of pseudogestagenic activity since the mid-30's : it is based on the property of the uterus of estrogen-primed immature female rabbits to respond to very slight amounts of progestin by a typical endometrial transformation into a densely packed and interlaced epithelial network called "dentelle". The original test schedule, which includes 6 days of estrogen priming (total subcutaneous dose of 30 μg/rabbit of estradiol benzoate) followed by 5 days of progestational treatment, was designed as early as 1930 by C. Clauberg, Zentr. Gyndkol. 1930, 54 : 2757-2770. The semi-quantitative scale used to grade the intensity of the microscopical appearance ofthe "dentelle" was set up by M.K. McPhail, /. Physiol (London), 1934, 83, 145-156. This overall Clauberg-McPhail procedure has been extensively used to screen steroids for putative progestational activity in vivo and is still part of the basic hormonal profile of any new progestin such as norgestimate (A. Phillips et al., Contraception, 1987, 36, 181-192) or desogestrel (J. Van der Vies et al., Arzneim. ForschJDrug Res. 1983, 33, 231-236).

The progestational potency is inversely related to the dose needed to induce a half- maximal stimulation of the "dentelle", i.e. to record a mean McPhail grade equal to 2. This ED50 is deduced for the dose-response curve and expressed in total dose/rabbit/5 days. All compounds were tested for activity only following oral administration. The maximal administred dose was 0.75 mg, roughly coπesponding to 5 times the ED50 of nomegestrol acetate, a potent orally active 19-norprogesterone-dcrived progestin (J. Paris et al., Arzneim. ForschJDrug Res., 1983, 33, 710-715).

The oral activity of test compounds of the invention is given in Table 2 below :

Table 2 : Claubcrg-McPhail test by oral administration

Progestin ED50 Relative

(mg/rabbit/5 days) activity

Example 1 > 0.750 < 18%

Example 2 0.080 165%

Example 6 > 0.750 < 18%

Example 7 0.245 54%

Example 8 0.133 99%

Example 10 0.600 22%

Example 11 0.100 132%

Nomegestrol acetate 0.132 ± 0.013( a ) 100% (0.108/0.150/0.138)

(a) mean ± s.e.m. of 3 different experiments in which the cited examples were tested in parallel

The residual androgenic potential is an important feature to evaluate for any new progestin, because it is highly predictive of androgenic side-effects in women. One pharmacological model of androgenic activity has been standardized to screen steroids or related compounds in immature castrated male rats, using the hypertrophy of the ventral prostate and seminal vesicles as the endpoint, following 10 daily administrations (R.I. Dorfman, in Methods in Hormone Research, volume 2, LONDON, Academic Press, 1962 : 275-313 ; A.G. Hilgar et D.J. Hummel, Androgenic and Myogenic Endocrine Bioassay Data, edited by the U.S.

Department of Health, Education and Welfare, WASHINGTON D.C, 1964). Medroxyprogestcrone acetate is a 6α-methylpregnenc derivative which, besides its main progestational activity, is well-known for its weak androgenic properties (M. Tausk et J. de Visser, In International Encyclopedia of Pharmacology and Therapeutics, Section 48 : Progesterone, Progestational Drugs and Antifertility Agents, volume II, OXFORD, Pcrgamon Press, 1972 : 35-216) ; it was therefore chosen as a reference compound in the testing for residual androgenic activity of test examples according to the invention.

The compounds of examples 2 and 7 were tested for residual androgenic properties in the immature castrated male rat model by oral administration (PO), in comparison with medroxyprogesteroπe acetate, in two different experiments (ventral prostate and seminal vesical hypertrophy), as described above ; testosterone was used as a standard androgenic agent by subcutaneous injection (SQ.

Table 3 : Residual androgenic activity of the compound of example 2

Steroid Dose Ventral Prostate (mg) Seminal Vesicle (mg)

(mg animal/day)

Castrated controls - 14.6 ± 1.4 10.4 ± 0.4

Testosterone, SC 0,05 85.1 ± 5.9** 85.9 ± 6.8**

Medroxyproges- 20 23.1 ± 1.1* 22.1 ± 1.1** teronc acetate, PO

Example 2, PO 20 13.0 ± 1.1 ns 12.1 ± 0.7 ns mean ± s.e. . of 8 animals per group ; * p < 0.05 and ** p < 0.01 ns : not statistically different from controls.

Table 4 : Residual androgenic activity of the compound of example 7

Steroid Dose Ventral Prostate (mg) Seminal Vesicle (mg) (mg/animal/day)

Castrated controls 12.0 ± 0.9 12.3 ± 0.7 Testosterone, SC 0,05 90.4 ± 4.4* ** 90.3 ± 6.3**

Medroxyproges- 20 29.1 ± 1.4"** 19.9 ± 1.8** terone acetate, PO

Example 7, PO 20 16.5 ± 0.9 ** 13.9 ± 0.8 ns mean ± s.e.m. of 8 animals per group ; * p < 0.05 and ** p < 0.01 ns : not statistically different from controls .

The compound of example 7 exhibits a very limited androgenic potential, which reaches statistical significance on ventral prostate weights but not on seminal vesicle weights (Table 3), and the compound of example 2 is totally devoid of any activity on the growth of male accessory sex organs, up to at least 20 mg/animal/day (Table 4). By comparison, medroxyprogesterone acetate reproducibly induces approximately twice the values obtained for the above compounds at the same dose (Tables 3 and 4).

Thus, the compounds of the present invention are excellent progestogens with no residual androgenic activity.

According to another aspect, the invention further relates to pharmaceutical compositions containing an effective amount of a compound of formula (I), mixed with suitable pharmaceutical excipients. Said compositions may further comprise an effective amount of an oestrogen.

Another aspect of the invention comprises a method of treating or preventing gynaecological disorders ; a method of inhibiting oestrogen transformation of endomctrium ; and a method of inhibiting gonadotropic gonadal secretions. The compounds of this invention are administered at a therapeutically effective dosage, i.e., a dosage sufficient to provide treatment for the disease states previously described. Administration of the active compounds described herein can be via any of the accepted modes of administration for agents used in similar indications. Generally, a daily dose is from 0.001 to 1 mg kg of body weight per day of the compound of formula (I). Most conditions respond to a treatment comprising a dosage level in the order of 0.002 to 0.2 mg/kg of body weight per day. Thus, for administration to a 50 kg person, the dosage would be about 2 mg per day, preferably between about 0.5 to 5 mg per day. Depending on the specific disease state, administration can be via any accepted systemic route, for example, via oral route, parenteral route such as intravenous, intramuscular, subcutaneous or percutaneous route, or vaginal, ocular or nasal

route, in solid, semi-solid or liquid dosage forms, such as for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, cream, gel, implant, patch, pessary, aerosols, emulsions or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or vehicle and an active compound of formula (I) and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

The compounds of this invention are generally administered as a pharmaceutical composition which comprises a pharmaceutical vehicle in combination with a compound of formula (I). The level of the drug in a formulation can vary within the full range employed by those skilled in the art, e.g., from about 0.01 weight percent (wt%) to about 99.99 wt% of the drug based on the total formulation and about 0.01 wt% to 99.99 wt% excipient.

The preferred manner of administration, for the conditions detailed above, is oral administration using a convenient daily dosage regimen which can be adjusted according to the severity of said conditions. For such oral administration, a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of the compound of formula (I) in any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccarine, talcum, cellulose, glucose, gelatine, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain between 0.01 wt% and 99.99 wt% of the compound of formula (I). Preferably the compositions will take the form of a sugar coated pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, and the like ; a disintegrant such as starch or derivatives thereof ; a lubricant such as magnesium stearate and the like ; and a binder such as starch, polyvinylpyrrolidone, gum acacia, gelatine, cellulose and derivatives thereof, and the like.

97/27209 PCΪYEP97/00312

14

EXAMPLES

The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as a limitation of the scope of the invention but merely as being illustrative and representative thereof. In these examples, the following abbreviations are used :

MeOH : methanol

EtOH : ethanol

Ac : acetyl OAc : acetoxy

AeOEt : ethyl acetate

DMF : dimethylformamide

THF : tetrahydrofuran

Pd/C : palladium-on-charcoal P07AI2O3 : palladium-oπ-alumina

DMSO : dimethylsulfoxide

DDQ : 2,3-dichloro-5,6-dicyanobeπzoquinone s : singlet d : doublet t : triplet q : quadruplet bs : broad singlet dd : doubled doublet m : multipiet

EXAMPUE 1

17α-acetoxy-6,15β-dimethyl-3,20-dioxo-19-nor-pregna-4,6 -diene

(11. LA : Ri = CH3, R 3 = CH3, R 4 = Ac, R 5 = H, n = 0)

A/ 3-methoxy-15β-methyl-19-nor-pregna-l,3,5(10)-17(20)-tetraen e (Z or E) (3.1.a : R3 = CH3, R5 =H, n = 0)

Sodium hydride (60 % dispersion in oil, 4.88 g, 122 mmol) was added to a round- bottomed flask fitted with a magnetic stirrer bar. The sodium hydride dispersion was washed with dry hexane to remove the oil and 200 ml of dry dimethylsulfoxide were added to the flask. Ethyl-triphenylphosphonium bromide (37.77 g, 101 mmol) was added to the dispersion and the solution was stirred at

20*C under nitrogen for 2 hours. Then 3-methoxy-15β-methyl-estra-l,3 5(10)- triene-17-one (2.1.a) obtained as described in "Rccueil des travaux chimiques des Pays Bas" (vol 98, n*4, 1979) was added to the solution and the mixture was stirred for 22 hours at room temperature. The mixture was poured into 2 L of iced water and stirred for 1 hour, then filtered and recrystallized from ethanol to give 3. I.a (9.17 g, yield : 73 %), mp : 97*C.

*H-NMR (CDCl3,δ) : 0.99 (d, 3H) ; 1.02 (s, 3H) ; 1.69 (d, 3H) ; 3.70 (s, 3H) ; 6.65 (d, IH) ; 6.75 (dd, IH) ; 7.21 (d, IH).

B/ 17α-hydroxy-3-methoxy- 15β-methyl-20-oxo- 19-nor-prcgna- 1 ,3,5(10)- triene (4.1.a : R3 = CH3, R5 = H, n = 0)

A solution of osmium tetraoxide in pyridine (20 g/L ; 11 ml) was added to a suspension of compound 3.1.a (9.17 g ; 29.5 mmol) in 200 ml of 2-hydroxy-2- methylpropane. Then, a complex of N-methylmorpholine oxide-hydrogen peroxide prepared as described in Reagents for Organic Synthesis, Fieser and Fieser vol. 1, p. 690 (4.9 g, 29 mmol) was added. The solution was stirred for 6 hours. The reaction mixture was treated with 150 ml of 0.5 % sodium sulfite solution, stirred for 1 hour and filtered. The filtrate was evaporated to dryness and the crude product was flash-chromatrographed using toluene/ethyl acetate (95/5) as eluting solvent to give 5.7 g of 4.1.a (yield : 56 %), mp : 61 # C. IR (KBr, cm" 1 ) : 3335 vOH ; 1687 vC = O H-NMR (CDC13,δ) : 0.91 (s, 3H) ; 1.08 (d, 3H) ; 2.31 (s, 3H) ; 2.94 (s, IH) ; 3.48 (d, 2H) ; 3.78 (s, 3H) ; 6.63 (d, IH) ; 6.71 (dd, IH) ; 7.20 (d, IH). C/ 20-(ethylencdioxy)-17α-hydroxy-3-methoxy-15β-methyl-19-nor - pregna-1,3,5 (10) triene (5.1.a : R3 = CH3, R5 = H, n = 0) p-toluencsulfonic acid (600 mg, 3.12 mmol), compound 4.1.a (12.06 g, 35.2 mmol), ethylene glycol (250 ml, 6.98 mol) and triethylorthoformate (50 ml, 297 mmol) in toluene (120 ml) were stirred together for 5 hours. Precipitation in water and extraction with toluene gave, after evaporation, a crude product which was ehromatographed using a toluene/ethyl acetate mixture (95/5) as eluting solvent to give 12 g of 5.1.a (yield : 88 %), mp : 113*C. IR (KBr, cm -1 ) : 3574 vOH iH-NMR (CDCl 3 ,δ) : 0.99 (s, 3H) ; 0.99 (d, 3H) ; 1.40 (s, 3H) ; 3.73 (s, 3H) ; 6.19 (dd, IH) ; 6.51 (d, IH) ; 7.19 (d, IH). D/ 17α-hydroxy-15β-methyl-3,20-dioxo-19-nor-prcgna-4-ene (6.1.a : R3 = CH3, R 5 = H, n = 0)

Compound 5.1.a (12.36 g, 32 mmol) was dissolved in 160 ml of dry THF and 12 ml of ethanol were added. The solution was then poured into ammoniac (250 ml) at -30*C. Lithium (2.4 g, 345 mmol) was added portionwise at -30*C, and the dark solution was stirred at -30*C for 1 hour. Ethanol (12 ml) was added and the solution was stirred for 15 hours at room temperature. Then ammoniac was removed, methanol (250 ml) and 50 % HCl solution (100 ml) were added, followed by an extraction with dichloromethane. The organic layer was dried (Na2SO4) and evaporated under reduced pressure giving 10.17 g of crude 6.1.a (yield : 96 %), mp : 218*C. UV ma - 239 1

IR (KBr, cm" 1 ) : 3439 vOH ; 1701 vC = O ; 1651 vC = O conjugated -NMR (CDCl 3 ,δ) : 1.88 (s, 3H) ; 2.01 (d, 3H) ; 3.21 (s, 3H) ; 4.00 (s, IH) ; 6.76

(s, IH).

E/ 17α-acetoxy-15β-methyl-3,20-dioxo-19-nor-pregna-4-ene (7.1.a : R3 = CH3, R4 = Ac, R5 = H, n = 0) p-toluenesulfonic acid (1.2 g, 6.24 mmol) was added to a suspension of 6.1.a (10.7 g, 30 mmol) in a mixture of acetic acid (80 ml, 1.38 mmol) and acetic anhydride (40 ml, 42 mmol). The solution was stirred for 18 hours. The solution was poured into water. Extraction with OfoCb 8 avc an °i' v product which was treated in a mixture of CH2CI2 (100 ml) and methanol (100 ml) with concentrated HCl (8 ml), and stirred for 18 hours. Water was added to the mixture and the product was extracted with CHoCh and ehromatographed using toluene/ethyl acetate (6/4) as eluting solvent to give 7.4 g of 7. I.a (yield : 67 %), mp : 243 * C. UVλmax : 238 nm IR (KBr, cm "1 ) : 1733 vC = O ; 1713 vC = O ; 1656 vC = O conjugated

!H-NMR (CDCl 3 ,δ) : 0.84 (s, 3H) ; 1.03 (d, 3H) ; 2.06 (s, 3H) ; 2.12 (s, 3H) ; 5.86 (s, IH).

F/ 17α-acetoxy-3-ethoxy-15β-methyl-20-oxo-19-nor-pregna-3,5(6 )- diene (8.1.a : R3 = CH3, R4 = Ac, R5 = H, n = 0, alkyl = ethyl) p-toluenesulfonic acid (40 mg, 0.21 mmol), 7.1.a (7.34 g, 19.7 mmol), triethyl orthoformate (7 ml, 42 mmol) and ethanol (60 ml) were stirred together for 4 hours. Then triethylamine (TEA) (4 ml) was added and the entire solution was poured into 500 ml of aπ ice/water mixture, stirred for 1 hour, filtered and recrystallized from ethanol containing a small amount of TEA to give 1.87 g of 8.1.a (yield : 23 %), mp : 232'C.

IR (KBr, cm" 1 ) : 1732 vC = O ; 1708 vC = O ;

UVλma : 241 nm

G/ 17α-acetoxy-3-ethoxy-6-formyl-15β-methyl-20-oxo-19-nor- pregna-3,5 (6)-diene (9.1.a : R3 = CH3, R4 = Ac, R5 = H, n = 0, alkyl = ethyl) In a round-bottomed flask POCI3 (0.6 ml, 6.3 mmol) was added to DMF (2.88 ml,

37 mmol) at -lO'C. This solution was added to a suspension of compound 8.1.a

(1.8 g, 4.4 mmol) in DMF (10 ml) at -12'C. The red mixture was stirred for 2 hours at -12'C, and treated with 175 mg of NaHCO3 followed by a solution of

CH3COOK (12 ml) and water (30 ml). The product was extracted with CH2CI2' evaporated in vacuo to give 1.82 g of 9.1.a (yield : 94 %), mp : 171 * C. UV jj -ax : 324 and 221 nm

IR (KBr, cm" 1 ) : 1734 vC = O ; 1652 vC = O ; 1608 vC = O iH-NMR (CDCl 3 ,δ) : 0.81 (s, 3H) ; 1.01 (d, 3H) ; 1.48 (t, 3H) ; 2.08 (s, 3H) ; 2.11

(s, 3H) ; 6.37 (s, IH) ; 10.23 (s, IH). H/ 17α-acetoxy-15β-methyl-6-methyliden-3,20-dioxo-19-nor-preg na-

4-cne (10.1.a : R 3 = CH3, R4 = Ac, R5 = H, n = 0)

A round-bottomed flask was fitted with a magnetic stirred bar, then compound

9.1-a (1.82 g, 4.2 mmol), DMF (6 ml) and EtOH (6 ml) were added. NaBH 4 (170 mg, 4.5 mmol) was added portionwise. Then, 50 % sulfuric acid solution (0.8 ml) was added to the mixture. The solution was poured into iced water (200 mi) and the precipitate was filtered off to give 1.52 g of crude lO.La (yield : 93 %), mp :

200*C. uv λmax : 263 nm

IR (KBr, cm "1 ) : 1732 vC = O , 1714 vC = O ; 1659 vC = O iH-NMR (CDCl 3 ,δ) : 0.83 (s, 3H) ; 1.05 (d, 3H) ; 2.04 (s, 3H) ; 2.10 (s, 3H) ; 4.97

(s, IH); 5.19 (s, IH) ; 6.10 (s, IH).

I/ 17α-acetoxy-6,15β-dimethyl-3,20-dioxo-19-nor-pregπa-4,6-d iene

(ll.La : R = CH3, R 3 = CH3, R 4 = Ac, R5 = H, n = 0)

A mixture of lO.I.a (980 mg, 2.54 mmol), Pd/C (5 % with 50 % H 2 O) (1.6 g) and MeOH (180 ml) was refluxed during 30 min. The solution was filtered off to remove the catalyst. Then, the crude product obtained by evaporating the solvent was flash-chromatographed using toluene/ethyl acetate as eluting solvent (7/3) to give 480 mg of 11. I.a (yield : 49 %), mp : 244 # C. UV λrnax : 292 nm IR (KBr. cm" 1 ) : 1736 vC = O ; 1710 vC = O ; 1654 vC = O

iH-NMR (CDCl 3 ,δ) : 0.88 (s, 3H) ; 1.08 (d, 3H) ; 1.88 (s, 3H) ; 2.08 (s, 3H) ; 2.1 (s, 3H) ; 5.95 (s. IH) ; 6.15 (s, IH).

EXAMPLE 2

17α-acetoxy-6α,15β-dimethyl-3,20-dioxo-19-nor-prcgna-4 -eπe (12.1.a : R3 = CH3, R4 = Ac, R5 = H, n = 0)

Compound 11. La (360 mg, 0.93 mmol) was hydrogenated over 100 mg of P07AI2O3 in 20 ml of EtOH with 0.3 ml of cyclohexene under stirring. The reaction was complete after 1 hour at the reflux temperature. The palladium catalyst was filtered off. The crude product was obtained by removing the solvent. Crystallization of the crude product from isopropyl ether gave 100 mg of the title compound (yield : 28 %), mp : 203*C. IR (KBr, cm" 1 ) : 1734 vC = O ; 1714 vC = O ; 1661 vC = O δH (CDCI3) : 0.85 (s, 3H) ; 1.08 (d, 3H) ; 1.15 (d, 3H) ; 2.05 (s, 3H) ; 2.1 (s, 3H) ; 5.9 (s, IH) EXAMPLE ?

17α-acetoxy-6β,15β-dimcthyl-3,20-dioxo-19-nor-prcgna-4 -eπe (12.1.b : R3

= CH3, R4 = Ac, R5 = H, n = 0)

Preparative HPLC of the mother liquid of 12.1.a yielded the 6β-methyl isomer.

EXAMPLES 4-5 17α-acetoxy-6α,15β-dimethyl-3-(E and Z)-hydroxyimiπo-20-oxo-pregna-4- ene (13.1.a : R 2 = H, R3 = CH3, R 4 = Ac, R 5 = H, n = 0)

A mixture of 12.1.a (1 g, 2.58 mmol), hydroxylamine hydrochloride (250 mg, 3.1 mmol), pyridine (0.4 ml, 4.9 mmol) and methanol (10 ml) was refluxed for 2 hours. Evaporation of the solvent gave a crude product which was ehromatographed using a toluene/ethyl acetate mixture (9/1) as eluting solvent to give 560 mg of 17α-acetoxy-6α,15β-dimethyl-3-E-hydroxyimino-20-oxo- pregna-÷4-enc (yield : 54 %), mp : 235'C (example 4),

IR (KBr, cm" 1 ) : 3331 vOH ; 1741 and 1702 vC = O iH-NMR (CDCI3, δ) : 0.83 (s, 3H) ; 1.04 (d, 3H) ; 1.13 (d, 3H) ; 2.04 (s, 3H) ; 2.09 (s, 3H) ; 5.92 (s. lH) ; and 80 mg of 17α-acetoxy-6α,15β-dimethyi-3-Z-hydroxyimino-20-oxo- pregna-4-ene (yield : 8 %), mp : 122 * C (example 5),

IR (KBr, cm" 1 ) : 2923 vOH ; 1736 and 1706 vC = O iH-NMR (CDCI3, δ) : 0.82 (s, 3H) ; 1.03 (d, 3H) ; 1.10 (d, 3H) ; 2.06 (s, 3H) ; 2.11 (s, 3H) ; 6.60 (s, lH).

EXAMPLE S

17α-acetoxy-6-methyl-15β,16β-methylene-3,20-dioxo-19-n or-prcgna-4,6- dieπe (ll.I.b : R 3 = H, R4 = Ac, R5 = H, n = 1)

A/ 3-methoxy-15β,16β-mcthylenc-19-nor-pregna-l,3,5(10),17(20) -tetraene (3.1.b : R 3 = H, R5 = H, n = 1)

3.1.b was prepared from 3-methoxy-15β,16β-methylene-19-nor-17-oxo- pregna-l,3,5(10)-triene obtained as described by O. Schmidt et al., Chem. Ber.

101, 939 (1968) following the process described for 3.1.a (yield : 96 %), mp : 76*C.

IR (KBr, cm" 1 ) : 1605 vC = C iH-NMR (CDσ 3 ,δ) : 0.5 (m, IH) ; 1 (s, 3H) ; 1.7 (d, 3H) ; 3.75 (s, 3H) ; 5.38 (q,

IH) ; 6.75 (m, 2H) ; 7.1 (d, lH).

B/ 17α-hydroxy-3-methoxy-15β,16β-methyleπe-20-oxo-19-nor-pr egna- l,3,5(10)-tricne (4.1.b : R3 = H, R5 = H, n = 1)

4.1.b was prepared from 3.1.b as described for 4.1.a (yield : 47 %), mp : 134*C. IR (KBr, cm" 1 ) : 3508 vO-H ; 1693 vC = O iH-NMR (CDCl3,6) : 0.7 (m, IH) ; 0.8 (s, 3H) ; 2.4 (s, 3H) ; 3.1 (s, IH) ; 6.7 (m,

2H) ; 7.1 (d, IH).

Cl 20-(ethyleπcdioxy)- 17α-hydroxy-3-methoxy- 15β, 16β-methy lene- 19-nor- pregna-1,3,5 (lθ)-trienc (5.1.b : R3 = H, R5 = H, n = 1) 5.1.b was obtained from compound 4.1.b as described for 5.1.a (yield : 95 %), mp :

166*C.

IR (KBr, cm" 1 ) : 3507 vOH ; 1280 vC-0 iH-NMR (CDCI 3 ,δ) : 0.45 (m, IH) ; 1.05 (s, 3H) ; 1.5 (s, 3H) ; 3.75 (s, 3H) ; 5 ( ,

4H) ; 6.67 (m, 2H) ; 7.1 (d. lH). D/ 17α-hydroxy-15β,16β-methylene-19-nor-3,20-dioxo-pregna-4- ene

(ό.I.b : R 3 = H, R 5 = H, n = 1) ό.I.b was prepared from 5. Lb using the same process than for ό.I.a (yield : 63 %), mp : 175'C.

IR (KBr, cm" 1 ) : 3461 vOH ; 1706 vC = O (20) ; 1661 vC = O (3) ; 1609 vC =C iH-NMR (CDCl 3 ,δ) : 0.65 (m, IH) ; 0.85 (s, 3H) ; 2.4 (s, 3H) ; 3.05 (s, IH) ; 5.85

(s, IH).

E 17α-acetoxy-15β,16β-methylene-3,20-dioxo-19-nor-pregna-4- ene (7.1.b :

R3 = H, R = Ac, R5 = H, n = l)

7.1.b was obtained from ό.I.b as described for compound 7. I.a (yield : 79 %), mp : 207*C.

IR (KBr, cm "1 ) : 1732 vC = O ; 1715 vC = O ; 1659 vC = O ; 1615 vC = C iH-NMR (CDCl 3 ,δ) : 0.65 (m, IH) ; 0.8 (s, 3H) ; 2.05 (s, 3H) ; 2.3 (s, 3H) ; 5.89

(s, lH)

F/ 17α-acetoxy-3-ethoxy- 15β,16β-methylene-20-oxo- 19-nor-ρregna- 3,5(6)-diene (δ.I.b : R3 = H, R4 = Ac, R5 = H, alkyl = ethyl, n = 1) δ.I.b was prepared from 7. b using the same process than for 8.1. a (yield : 69 %), mp : 164'C.

IR (KBr, cm "1 ) : 1735 vC = O ; 1707 vC = O ; 1646-1619 vC iH-NMR (CDCl 3 ,δ) : 0.65 (m, IH) ; 0.8 (s, 3H) ; 1.25 (t, 3H) ; 2.1 (s, 3H) ; 2.3 (s, 3H) ; 3.7 (q, 2H) ; 5.85 (s, IH) ; 5.9 (s, IH)

G/ 17α-acctoxy-3-ethoxy-6-formyl-15β,16β-methylene-20-oxo-19 -nor- prcgna-3,5-dicnc (9.1.b : R3 = H, R4 = Ac, R5 = H, alkyl = ethyl, n = 1)

9.1.b was obtained from 8.1.b by following the same process than for 9.1.a (yield :

93 %), mp : 199*C. IR (KBr, cm "1 ) : 1721 vC = O ; 1645-1607 vC = C iH-NMR (CDCl 3 ,δ) : 0.65 (m, IH) ; 0.75 (s, 3H) ; 1.35 (t, 3H) ; 2.1 (s, 3H) ; 2.3

(s, 3H) ; 3.9 (m, 2H) ; 6.35 (s, IH) ; 10.25 (s, IH)

H/ 17α-acetoxy-15β,16β-methylene-6-methylidenc-3,20-dioxo-19 -nor- prcgna-4-cne (lO.I.b : R3 = H, R4 = Ac, R5 = H, n = 1) lO.I.b was obtained from 9.1.b by the same process than for lO.I.a (yield : 93 %), mp : 212'C.

IR (KBr, cm "1 ) : 1732 vC = O ; 1717 vC = O ; 1659 vC = O : 1625-1585 vC = C iH-NMR (CDC-3,6) : 0.75 (m, IH) ; 0.8 (s, 3H) ; 2.1 (s, 3H) ; 2.4 (s, 3H) ; 5-5.2

(2s, 2H) ; 6.15 (s, IH) I/ 17α-acctoxy-6-mcthyl-15β,16β-methylene-3,20-dioxo-19-nor- pregna-

4,6-diene (11. b : R 3 = H, R = Ac, R 5 = H, n = 1)

11. Lb as obtained from lO.I.b as described for compound 11. I.a (yield : 75 %), mp : 205*C.

IR (KBr, cm "1 ) : 1724 vC = O ; 1720 vC = O ; 1662 vC = O ; 1624-1576 vC = C iH-NMR (CDCl 3 ,δ) : 0.75 (m, IH) ; 0.85 (s, 3H) ; 1.9 (s, 3H) ; 2.1 (s, 3H) ; 2.35

(s, 3H) ; 6 (s, lH) ; 6.3 (s, IH).

EXAMPLE 7 17α-acctoxy-6α-methyl-15β,16β-methylene-3,20-dioxo-19-no r-pregna-4- enc (12.1.b : R t = CH3, R 3 = H, R 4 = Ac, R 5 = H, n = 1) 12.1.b was prepared from 11. Lb following the same process than for 12.1.a (yield :

20 %), mp : 159*C.

IR (KBr, cm" 1 ) : 1724 vC = O ; 1722 vC = O ; 1674 vC = O ; 1604 vC = C iH-NMR (CDCl 3 ,δ) : 0.7 ( , IH) ; 1.18 (d, 3H) ; 2.1 (s, 3H) ; 2.35 (s, 3H) ; 5.9 (s,

IH) EXAMPLE S

17α-ethoxy-15β,16β-methylene-6α-methyl-3,20-dioxo-19- nor-prcgna-4- ene (12.I.C : R = CH 3 , R3 = H, R4 = C 2 H 5 , R 5 = H, n = 1) To a stirred suspension of 12.1.b (1.2 g, 3.1 mmol) in ethanol was added dropwise a solution of NaOH in water (10 %) until the pH was greater than 10 and the mixture was refluxed for 4 hours. Then, the mixture was extracted with CH2CI2 and washed with water. The solvent was removed under vacuum and the crude product was purified by column chromatography on silica gel (toluene/AcOEt 6.5/3.5) to give 0.62 g of 17α-hydroxy-15β,16β-methylene-6α-methyl-19-nor-3,20- dionc-prcgπa-4-ene (yield : 70 %). IR (KBr, cm" 1 ) : 1706 vC = O ; 1668 vC = O ; 1610 vC = C ; 3446 vO-H

To a stirred mixture of 17α-hydroxy-15β,16β-methylenc-6α-methyl-19-nor- 3,20-dione- pregna-4-enc (6.2 g, 18 mmol) and KOH (37 mmol) in DMSO (60 ml) at 23 * C was added dimethylsulfate (5 ml, 36 mmol). After 2 hours, the solution was poured into cold water (500 ml). The crude product was filtered off, dissolved in acetone (100 ml) and HCl (20 %) was added to the solution until the pH was 1. After 2 hours, the reaction mixture was concentrated under vacuum, extracted with CH2CH, washed with water and concentrated to give a residue which was flash-chromatographed on silica gel (toluene/AcOEt 9/1) to give 2 g of a crude product which was crystallized from isopropyl ether (yield : 10 %), mp : 147*C. iH-NMR (CDCl 3 ,δ) : 0.55 ( , IH) ; 0.75 (s, 3H) ; 1.15 (d, 3H) ; 1.25 (t, 3H) ; 2.2

(s, 3H) ; 3.15 (m, IH) ; 3.65 (m, IH) ; 5.9 (s, IH).

EXAMPLE 9

17α-ethoxy- 15β, 16β-methylene-6-methyl-20-oxo- 19-nor-pregna-4,6-diene (ll.I.c : R3 = H, R4 = C 2 H 5 , R 5 = H, n = 1)

3,17α-diethoxy- 15β, 16β-methy lene-6-methyl- 19-nor-20-one-pregna-3- 5(6)-diene was obtained from 12.I.C following the same process than for 8.1.a (yield : 88 %). iH-NMR (CDCI 3 ,δ) : 0.5 (m, IH) ; 0.7 (s, 3H) ; 1.2 (t, 3H) ; 1.7 (s, 3H) ; 2.15 (s, 3H) ; 3.15 (m. IH) ; 3.6 (q, 2H) ; 3.8 (m, IH) ; 5.45 (s, IH).

To a stirred solution of the above compound (2.6 g, 6.5 mmol) in a mixture of acetone (60 ml) and water (1.6 ml) was added DDQ (1.7 g, 7.7 mmol). After 20 min., the reaction mixture was concentrated under vacuum. The residu was flash- chromatographed twice (toluene/AcOEt : 8/2). Recrystallization from isopropyl ether gave 175 mg of ll.I.c (yield : 7 %), mp : 185*C.

X H-NMR (CDC1 3 ,6) : 0.6 (m, IH) ; 0.8 (s, 3H) ; 1.2 (t, 3H) ; 1.9 (s, 3H) ; 2.2 (s, 3H) ; 3.2 (m, IH) ; 3.7 (m, IH) ; 5.9 (s, IH) ; 6.3 (s, IH). EXAMPLE 10 17α-acetoxy-6α,7α-dimcthyl-15β,16β-methylene-3,20-dioxo -19-nor- prcgna-4-ene (14.1.a : R2 = CH3, R3 = H, R4 = Ac, R5 = H, n = 1)

To a stirred suspension of Cul (13.3 g, 70 mmol) in Et2θ (135 ml) at 0*C was added a solution of MeLi (1.6 M) in Et2θ (88 ml, 140 mmol). After 0.5 hour, a solution of 11. b (5.4 g, 14 mmol) in THF (70 ml) was added dropwise to the mixture at -5'C over 0.5 hour. The reaction was quenched by addition of NH4CI solution (1000 ml). The cuprous salts were filtered off on Celite® and the filtrate was extracted by toluene, washed with water and concentrated under vacuum. The residue was flash-chromatographcd (toluene/AcOEt : 9/1) and the crude product was recrystallized from Et2θ to give pure 17α-acetoxy-6,7α-dimethyl-15β,16β -methylene- 19-nor-3,20-dioxo-pregna-5(6)-ene (yield : 7 %). iH-NMR (CDCl 3 ,δ) : 0.55 (m, IH) ; 0.7 (s, 3H) ; 0.9 (d, 3H) ; 1.6 (s, 3H) ; 2.05 (s, 3H) ; 2.1 (s, 3H)

A solution of the above compound (0.4 g, 1 mmol) in a mixture of acetone (10 ml) and water (5 ml) was acidified with concentrated HCl until the pH was 1. After 6 hours, the reaction mixture was concentrated, extracted with CH2CI2, washed with water and the solvent was removed. The crude product was ehromatographed on silica gel (toluene/AcOEt : 7/3 v/v) to give 0.2 g of the title compound (yield : 50 %), mp : 170*C. iH-NMR (CDCl 3 ,δ) : 0.7 (m, IH) ; 0.75 (d, 3H) ; 0.85 (s, 3H) ; 1.1 (d, 3H) ; 2.1 (s, 3H) ; 2.3 (s, 3H) ; 5.85 (s, IH). EXAMPLE 11

17α-acetoxy-6α,7α-dimethyl-3,20-dioxo-19-πor-pregna-4 -eπe

(14.1.b : R 2 = CH3, R3 = H, R = Ac, R5 = H, n = 0)

17α-acetoxy-3-ethoxy-6-methyl-19-nor-20-one-prcgna-3-5(6 )-diene was obtained from 17α-acetoxy-6α-methyl-3,20-dioxo-19-nor-prcgna-4-cne prepared using the procedures described in DE-A-2 148 261 following the same

process than for 8.1.a (yield : 90 %).

IR (KBr, cm" 1 ) : 1730 vC = O ; 1652-1621 vC = C iH-NMR (CDCl 3 ,δ) : 0.6 (s, 3H) ; 1.3 (t, 3H) ; 2.0 (s, 3H) ; 2.1 (s, 3H) ; 3.75 (m,

2H) ; 5.4 (s, IH). This compound (15 g, 3.75 mmol) was dissolved in acetone/water and treated with

DDQ as described before for 11. Lc After a flash-chromatography (toluene/AcOEt

73) to remove the hydroquinone, the crude product (3.7 g) was used without other purification and following the process described for 14.1.a,

0.6 g of pure 17α-acetoxy-6,7α-dimcthyl-19-nor-3,20-dioxo-prcgna-5(6)-en e was obtained (yield : 4 %). iH-NMR (CDCl 3 ,δ) : 0.7 (s, 3H) ; 0.9 (d, 3H) ; 1.6 (s, 3H) ; 2.05 (s, 3H) ; 2.1 (s,

3H)

Compound 14.1.b was obtained from the previous compound following the same process than for 14.1.a (yield : 30 %), p : 222*C. iH-NMR (CDCl 3 ,δ) : 0.65 (d, 3H) ; 0.7 (s, 3H) ; 1.2 (d, 3H) ; 2.0 (s, 3H) ; 2.1 (s,

3H) ; 5.8 (s, IH).

EXAMPLE 12

17α-acetoxy-7α-ethyl-6α-methyl-3,20-dioxo-19-nor-pregn a-4-ene (14.I.C : R 2 = C2H5, R3 = H, R4 = Ac, R5 = H, n = 0) Using the procedure described for 14. Lb but replacing methyllithium by ethyl- magnesium chloride in the alkylation step, compound 14. Lc was obtained in 17 % yield, mp : 200* C. iH-NMR (CDCI3, δ) : 0.70 (s, 3H) ; 0.98 (m, 3H) ; 1.12 (d, 3H) ; 2.05 (s, 3H) ; 2.15 (s, 3H) ; 2.60 (m, IH) ; 5.89 (s, IH). EXAMPLES 13-14

17α-acctoxy-3-(Z and E)-hydroxyimino-6α,7α-dimethyl-20-oxo-19-nor- prcgna-4-enc (13.1.b : R2 = CH3, R3 = H, R4 = Ac, R5 = H, n = 0) To a solution of 17α-acetoxy-6α,7α-dimethyl-3,20-dioxo-19-nor- pregna-4- ene (2 g, 5.18 mmol) in dioxane (100 ml) was added successively hydroxylamine hydrochloride (0.755 g, 10.36 mmol) and pyridine (5 ml). The mixture was heated to reflux for 1 hour. Then, the reaction mixture was poured into iced water and acidified with a IN HCl solution. Extraction with methylene chloride and evaporation of the solvent gave 1.92 g of a crude product which was flash- chromatographed using toluene/AcOEt as eluting solvent. The first product eluted was the E isomer and was crystallized from ethanol (0.650

g, yield : 31.3 %), mp > 250*C (example 13). iH-NMR (CDC1 3 , δ) : 0.647-0.652 (d, 3H) ; 0.69 (s, 3H) ; 1.071-1.10 (d, 3H) ; 2.05 (s, 3H) ; 2.12 (s, 3H) ; 2.95 (m, 2H) ; 5.88 (s, IH) ; 8.25 (bs, IH). It was followed by the Z isomer which was crystallised from a mixture of absolute ethanol and diisopropyl ether (0.170 g, yield : 16.4 %), mp : 208*C (example 14). iH-NMR (CDCI3, δ) : 0.635-0.671 (d, 3H) ; 0.688 (s, 3H) ; 1.11-1.15 (d, 3H) ; 2.05 (s, 3H) ; 2.123 (s, 3H) ; 2.95 (m, IH) ; 6.548 (s, IH). EXAMPLES 15-31

The following examples illustrate the preparation of representative pharmaceutical formulations containing a compound of formula (I) :

Pharmaceutical formulations for oral administration

EXAMPLE 15 Tablets with delayed release. Unit formulation for various dosages :

Compound of formula (I) 0.50 to 10.00 mg

Aerosil® 200 0.37 to 0.50 mg

Precirol® ATO 5 1.85 to 2.25 mg

Methocel® E4 55.00 to 70.00 mg

Avicel® PH 101 10.00 to 20.00 mg

Lactose qs for 1 tablet of 185.00 to 200.00 mg

EXAMPLE 16

Tablets with fast release.

Unit formulation for various dosages :

Compound of formula (I) 0.50 to 10.00 mg

Aerosil® 200 0.37 to 0.50 mg

Precirol® ATO 5 1.85 to 2.50 mg

Avicel® PH 102 50.00 to 70.00 mg

Explotab® or polyplasdone® XL 5.00 to 25.00 mg

Lactose qs for 1 tablet of 185.00 to 200.00 mg

EXAMPLE 17

Tablets.

Unit formulation for various dosages :

Compound of formula (I) 0.50 to 10.00 mg

Aerosil® 200 0.30 to 0.50 mg

Compritol® 1.50 to 3.00 mg

Avicel® PH 101 55.00 to 70.00 mg

Lactose qs for 1 tablet of 185.00 to 200.00 mg

Capsules.

Unit formulation for various dosages

Compound of formula (I) 0.50 to 10.00 mg

Oleic acid qs for 1 capsule of 250.00 to 260.00 mg

Coating : gelatine, preservatives, glycerol

Pharmaceutical formulations for vaginal administration

EXAMPLE 18

Vaginal gynaecologic capsule.

Unit formulation for a capsule :

Compound of formula (I) 0.50 to 15.00 mg

Vaseline 150.00 to 200.00 mg

Sorbitol sesquioleate 150.00 to 200.00 mg

Synthetic perhydrosqualene qs for 1 capsule of 1.85 g

Coating : gelatine, glycerol, preservatives for a soft capsule weighing 2.55 g

EXAMPLE 19 Vaginal suppository. Unit formulation for a suppository :

Compound of formula (I) 0.50 to 15.00 mg

Witepsol® H35 or H37 qs for a suppository of 3.00 g

EXAMPLE 20

Vaginal suppository with slow release.

Unit formulation for a suppository of 3.00 g :

Compound of formula (I) 0.50 to 30.00 mg

Witepsol® H19 or H35 1.00 to 1.30 g

Suppocire® BM or NAI50 1.00 to 1.50 g

Precirol® 0.00 to 0.20 g

Pharmaceutical formulations for cutaneous or gynaecologic use

EXAMPLE 21

Bioadhesive gel for cutaneous or gynaecologic use.

Formula for 100 g :

Compound of formula (I) 0.10 to 1.00 g Polyethylene glycol 0.00 to 6.00 g Transcutol® 0.00 to 6.00 g

Carboxypolyvinyl polymer 0.50 to LOO g Preservatives 0.30 mg

Triethanolamine qs pH 6.5 Purified water qs for 100 g

EXAMPLE 22

Gel for cutaneous use. Formula for 100 g :

Compound of formula (I) 0.10 to 2.00 g Polyethylene glycol or Transcutol® 1.00 to 4.00 g

Ethyl alcohol 20.00 to 40.00 g

Carboxypolyvinyl polymer 0.50 to 2.00 g

Triethanolamine qs pH 6.5 Purified water qs for 100 g

EXAMPLE 23 Patches.

Content of the reservoir or matrix. Preparation for 100 g :

Compound of formula (I) 0.25 to 20.00 mg Enhancer* 0.20 to 0.50 g

Suspending agent (HPMC** or Aerosil®) 0.10 to LOO g Ethyl alcohol or silicone oil qs for 100 g

enhancer = isopropyl palmitate, propyleneglycol, menthol, azone, N,N- dimethylacctamide, mono- or disubstituted pyrrolidone derivatives ; •HPMC = hydroxypropylmethyl cellulose

Pharmaceutical formulations for percutaneous administration

EXAMPLE 24

Implants.

Formulation for 100 g of material to be extruded :

Compound of formula (I) 1.00 to 5.00 g

Polymers (EVA, Polyorthocarbonates) qs for 100 g

The temperature of the mixture shall not exceed 150 * C in order not to impair the active ingredient.

Implants with reservoir.

The implant is a sealed silastic tubing having a length of 2.5 to 3.5 cm, a thickness of 0.4 to 0.8 mm and a diameter of 1.40 to 2mm. The preparation is formulated as a suspension as follows :

For 100 g of suspension

Compound of formula (I) 30.00 to 50.00 g

Suspending agent qs for 100 g

50 mg of the suspension for one implant.

EXAMPLE 25 Injectible depot. Unit formulation for a flask of 5 ml :

Compound of formula (I) 10.00 to 50.000 mg

Polyethylene glycol 4000 100.00 to 200.000 mg

Preservatives 0.006 mg

Sodium chloride and citrate 0.150 mg

Distilled water for injection qs for 5.00 ml

EXAMPLE 26 Injectible suspension.

Unit formulation for a 2 ml ampoule :

Compound of formula (I) 5.00 to 10.00 mg

Suspension solution

Polysorbate® 80 0.015 g

Sodium carboxymethylcellulose 0.010 g Sodium chloride 0.010 g Purified water for injection qs for 2.00 ml

EXAMPLE 27

Intra -uterine device with reservoir.

Device with a silastic reservoir having a length of 2.5 to 3.5 cm and a thickness of 0.4 to 0.8 mm. The preparation is formulated as a suspension as follows : For 100 g of suspension :

Compound of formula (I) 0.60 to OO g suspended to :

Suspending agent (Aerosil® or HPMC) 0.50 g Synthetic perhydrogenalene qs for 100 g

EXAMPLE 28

Bioadhesive gynaecological foam. Formula for a dispenser of 50 g and a spray valve (2 ml) :

Compound of formula (I) 0.10 to 0.25 g

Carboxypolyvinyl polymer 0.50 to LOO g

Isobutane 5.00 to 10.00 g

Excipient base F25/1 qs for 50.00 g

Shake the suspension before use. Dispensed dosage from 2.00 to 10.00 mg.

Pharmaceutical formulation for nasal administration

EXAMPLE 29

Nasal suspension.

Formulation for 100 g of suspension :

Compound of formula (I) 5.00 to 50.00 mg

Aerosil® PH 101 10.00 to 20.00 mg

Sodium carboxymethylcellulose 5.00 to 50.00 mg

Phenylethyl alcohol 2.00 to 10.00 mg

Polysorbate® 80 10.00 to 20.00 mg Purified water qs for 100 g

Shake the suspension before use. Dispensed dosage from 0.5 to 2.5 mg.

Pharmaceutical formulations for ophthalmic administration EXAMPLE 30

Ophthalmic solution (collyrium). Formulation for 100 g of solution. Container of 5 ml with glass droppers :

Compound of formula (I) 0 JO to LOO g

Glycerol 5.00 g

Polyvidone or sodium chloride 0.50 to 0.90 g

Sorbitol 4.00 g

Preservatives (benzalkonium chloride or Cetrimide®) 0.01 g

EDTA 0.01 g

Distilled water qs for 100 g

The solution is a sterile aqueous solution ; it may contain stabilisers and antimicrobial agents. The recommended dose is one drops four times daily.

EXAMPLE 31

Ophthalmic gel.

Formulation for 100 g of gel. Container : collapsible tube :

Compound of formula (I) 0.50 to 2.00 g

Cetrimide® 0.01 g

Sorbitol 4.00 g

EDTA 0.01 g Carboxypolyvinyl polymers (Carbopol® 971) 0.14 to 0.20 g Sodium hydroxydc 10 % qs pH 6.5 Purified water qs for 100 g

The sterile aqueous gel is packed in a collapsible tube. The recommended dose is one drop one or two times daily.

Typical examples of the compounds of formula (I) provided by this invention include :

. 17α-acetoxy-6, 15 β-dimet hy I -3 ,20-dioxo- 19-nor-pregna-4,6-diene . 17α-acetoxy-6c-,15β-dimethyl-3,20-dioxo-19-nor-pregna-4-en e . 17α-acctoxy-6β,15β-dimethyl-3,20-dioxo-19-nor-prcgna-4-en e . 17α-acetoxy-6α,15β-dimethyl-3-E-hydroxyimino-20-oxo-19-no r-prcgna- 4-ene

. 17α-acetoxy-6α,15β-dimethyl-3-Z-hydroxyimino-20-oxo-19-no r-pregna- 4-ene

. 17α-acetoxy-6-methyl-15β,16β-methylene-3,20-dioxo-19-nor- prcgna-4,6- diene

. 17α-acetoxy-6α-methyl-15β,16β-methylene-3,20-dioxo-19-no r-pregna-4- ene . 17α-ethoxy-15β,16β-methylene-6α-methyl-3,20-dioxo-19-nor -pregna-4- ene

. 17α-ethoxy-15β,16β-methylene-6-methyl-20-oxo-19-nor-pregn a-4,6- diene . 17α-acetoxy-6α,7α-dimethyl-15β,16β-methylene-3,20-dioxo -19-nor- prcgna-4-ene

. 17α-acetoxy-7α-ethyl-6α-methyl-3,20-dioxo-19-nor-pregna-4 -ene

. 17α-acetoxy-6α,7α-dimethyl-3,20-dioxo-19-πor-pregna-4-en e

. 17α-acetoxy-6α-methyl-7α-ethyl-3,20-dioxo-19-nor-pregna-4 -eπe

. 17α-acetoxy-3-Z-hydroxyimino-6α,7α-dimethyl-20-oxo-19-nor -pregna- 4-ene

. 17α-acetoxy-3-E-hydroxyimino-6α,7α-dimethyl-20-oxo-19-nor -pregna- 4-ene