HK1018216B - New 19-nor-pregnene derivatives - Google Patents

Description

Novel 19-nor-pregnene derivatives

The present invention relates to substituted 19-nor-pregnene derivatives and to processes for preparing these compounds and to pharmaceutical compositions comprising them. The compounds of the present invention have specific and highly potent progestogenic properties and no residual androgenic activity. 19-nor-pregnene derivatives substituted in the 1, 2-position have been reported in the literature. For example, FR-A-1525916 relates to A process for the preparation of A compound represented by the formulA:

wherein R is H or an acyl group such as acetyl or hexanoyl. Furthermore, 19-nor-pregnene derivatives substituted at the 6-position have been reported in the following references:

^*relates to FR-A-1524013 of 3-enol ether pregnane derivatives prepared from 4-pregnene-3, 20-dione represented by the following formulA:

wherein 6 α -methyl-17 α -hydroxy-4-pregnene-3, 20-dione is described;

^*DE-a-2148261, which relates to a process for the preparation of 6 α -methyl-19-nor-pregnene of the formula:

wherein R is₁Is H or methyl, R₂Is (C1-C9) alkyl; or

^*Involving a composition comprising 3, 20-dioxo-6 alpha-methyl-17 alpha-acetoxy-19-des-delta⁴-pregnene drugs BE 757285. However, the 19-nor-pregnene derivatives as described above often have side effects of androgens.

On the other hand US3,891,677 reports a process for the conversion of 17, 20-isopropylidenediol-4, 5-seco-3-pregn-5-one to 6, 6-dimethyl-17 alpha-hydroxyprogesterone.

The present application now finds that 19-des-pregnene derivatives having at least two substituents in the 1-, 2-, 1, 2-and/or 6-position have a strong progestogenic activity without residual androgenic activity.

In one aspect, the invention includes compounds having the structure shown in the following general formula (I):

wherein:

R₁，R₂，R₃，R₄and R₆Each independently represents H or (C1-C6) alkyl,

R₅is H, (C1-C6) alkyl or-COR₇Wherein R is₇Is (C1-C6) alkyl,

n is 0 or 1, and

x is O or an oxime group,

provided that when n is 0, R₁，R₂，R₃And R₄At least two of which are not H and when n is 1, R₃And R₄Not both can be H.

As used herein, "alkyl" means a branched or straight chain saturated hydrocarbon group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl.

The radical-COR used here₇(wherein R is₇Is (C1-C6) alkyl) includes, for example, acetyl, propionyl, butyryl, isobutyryl, tert-butyryl, valeryl and hexanoyl, preferably acetyl.

Preferred compounds of formula (I) are those wherein R is₁，R₂And R₆Is H, R₃And R₄Is (C1-C6) alkyl, R₅is-COR₇Compounds in which n is 0 are particularly preferred, and X is O. Preferred compounds of the formula (I) are also R₁，R₂，R₄And R₆Is H, R₃Is (C1-C6) alkyl, R₅is-COR₇A compound wherein n is 1. More preferred compounds of formula (I) are R₄And R₆Is H, R₃Is (C1-C6) alkyl, R₅is-COR₇A group and n is 0. In the latter compounds, R is also preferred₁Is H and R₂Is (C1-C6) alkyl, and R₁Is (C1-C6) alkyl and R₂The compound is H, and the compound in which X is O is particularly preferable.

In another aspect, the invention relates to a process for preparing a compound of formula (I): can be prepared according to the following reaction scheme, wherein R₁，R₂，R₃，R₄，R₅，R₆N and X have the same meanings as those contained above.

Reaction scheme

R₃And R₄Compound 5, which is a (C1-C6) alkyl group, can be prepared as follows: compound 1 was prepared by a procedure similar to that described in DE-A-2148261. When R is₅＝-COR₇When desired, they were saponified with sodium hydroxide in a mixture of ethanol and tetrahydrofuran. Precipitating in water, and recrystallizing with alcohol, preferably methanol or ethanol to obtain product 1 (R)₅H). Then, they are dissolved in toluene and 1 to 10mol equivalents of ethylene glycol (preferably 5mol equivalents), triethyl orthoformate and a catalytic amount of p-toluenesulfonic acid are added. The reaction mixture is stirred at about 20 deg.C to 80 deg.C (preferably 40 deg.C) for about 2 to 8 hours. After the reaction mixture was cooled, it was poured into ice water and then extracted with a suitable organic solvent. The residue after evaporation of the solvent can be purified by crystallization or flash chromatography to give compound 2. Treatment of compound 2 with 3-chloroperoxybenzoic acid (MCPBA) in dichloromethane yielded a mixture of 5, 6-oxirane 3, which can be isolated by crystallization or flash chromatography. Adding excess R to the tetrahydrofuran solution of mixture 3 at 20 deg.C-60 deg.C over about 8 hours₄Magnesium halide, treatment of the reaction mixture with ammonium chloride solution and extraction with toluene, and evaporation of the solvent to give compound 4.

Deprotection followed by dehydration of the tertiary hydroxyl group affords compound 5, which may optionally be esterified by well known esterification methods employed in steroid chemistry or by the commonly used references: the Williamson ether Synthesis method reported in B.G.Zupancic and M.Sopcic, Synthesis (Synthesis), 1979, 123 or D.R.Benedict et al, Synthesis, 1979, 428-9, was alkylated with alkyl halides.

R₃Is (C1-C6) alkyl and R₄Compound 6 as H can be prepared as follows: hydrogenation of compound 1 or 5 with palladium or a palladium or platinum derivative in tetrahydrofuran, acetic acid or an alcohol such as methanol, ethanol or propanol gives compound 6 with the 5 β -H configuration. Chemical reduction of Compound 1 or 5 with sodium dithioniteCompound 6 having the 5 α -H configuration was originally obtained, and this method has been reported in the following documents: camps et al, tetrahedron communication (tetrahedron Lett.), 1986, 42, n.16, 4603-4609 or R.S. Dhillon et al, tetrahedron communication, 1995, 36, n.7, 1107-8.

The compounds of formula (I) can be prepared as follows: compound 7 (R. J. Abul-Hajj, J. org. chem., 1986, 51, 3059-61; C.Djerassi and C.R.Scholz, J.Am. chem. Soc., 1948, 417; R.Joly et al, bulletin of the French society of chemistry (Bull. Soc. Fr.), 1957, 366) is obtained by brominating compound 6 and then dehydrobrominating it, according to known techniques (Y.J.Abul-Hajj, J.org. chem., 1986, 51, 3059-61; C.Djerassi. and C.R.Scholz, J.Soc., 1948, 417)₁＝R₂＝H)。

Compound 5 (R)₅H) may be converted to their 20, 20-ethanedioxy derivatives and then to their 2-hydroxymethylene sodium salts and alkylated with an iodoalkane such as methyl iodide, ethyl iodide or propyl iodide to provide compound 10 (R) in accordance with the procedure described in n.w. ater et al, journal of organic chemistry, 1961, 23, 3077-83₁＝H，R₂Alkyl, n ═ 0).

Optionally, for Compound 10 (R)₁＝H，R₂Chemical reductive hydrogenation of the 4, 5-double bond in (n ═ 0) followed by bromination/dehydrobromination gives compound 7 (R)₁＝H，R₂Alkyl).

To compound 7 (R) in the presence of a copper catalyst (e.g., CuI, CuCl or CuCN)₁＝R₂H) to a lithium salt of copper (R) with lithium dialkyl (LiCu)₁)₂Or the corresponding alkylmagnesium halide to give Compound 12 (R)₁Alkyl), compound 12 may be converted to compound 10 (R) by introducing a 4, 5-double bond by techniques known in steroid chemistry₁Alkyl, R₂H, n ═ 0), or by dehydrogenation or bromination/dehydrobromination to compound 7 (R)₁Alkyl, R₂H). Compound 12 can also be obtained by analogy with Compound 10 (R)₂Alkyl, n-0) in the 2-position and then converted as described aboveConversion to Compound 7 (R)₁＝R₂Alkyl).

With compound 7 (R)₁H or alkyl, R₂H or alkyl) with dimethylene-methylenesulfoxy to give compound 9 (R)₁H or alkyl, R₂H or alkyl, n-1), dimethylmethylenesulfoxy can be obtained by reacting trimethylsulfoxonium iodide (preferably containing a base) with sodium hydride in tetrahydrofuran, dimethylformamide or dimethylsulfoxide. Compound 9 can also be obtained by reacting compound 7 with diazomethane under the catalysis of palladium or copper derivatives. In addition, Compound 7 (R)₁H or alkyl, R₂H or alkyl) can be reduced with sodium borohydride in the presence of cerium chloride to give compound 8 (R)₁H or alkyl, R₂H or alkyl), the latter by various known methods (h.e. Simmons and r.d. Smith, journal of the american society of chemistry, 1958, 80, 5323; h.e.simmons and r.d.smith, proceedings of the american society of chemists, 1959, 81, 4256; organic synthesis (org. synthesis), 1961, 41, 72; furukawa et al, tetrahedron letters 1966, 3353; furukawa et al, Tetrahedron (Tetrahedron)1968, 24, 53; denmark and Edwards, journal of organic chemistry, 1991, 56, 6974-81). The 3-hydroxy group of compound 8 can be oxidized using a number of oxidizing agents such as CrO 3/pyridine to provide compound 9.

Compound 9 (R)₁H or alkyl, R₂H or alkyl, n-0 or 1) to their silylenol ethers followed by dehydrogenation with palladium acetate in acetonitrile under reflux to give compound 10. Alternatively, a 4, 5-double bond can be introduced by dehydrobromination in a manner similar to the above-described method for obtaining compound 7. The compound 10 is condensed with hydroxylamine hydrochloride in a mixed solvent of dioxane and pyridine to obtain a compound 11.

The compounds of the invention have strong and specific progestogenic properties. They are therefore useful in the treatment of various gynaecological endocrine disorders in which estrogen/progesterone dysregulation is involved, including menstrual disorders (hypomenorrhea, secondary amenorrhea, premenstrual tension, headache, water retention, mood changes), breast disorders (periodic mastalgia, benign mastopathy, breast tumour), endometrial disorders (hyperplasia, pre-malignant variations of the tumour); or conditions requiring inhibition of gonadotropic/gonadal secretion: endometriosis in women, polycystic ovarian syndrome, prostate disease in men.

In another aspect, the compounds of the present invention are useful as contraceptives, alone or in combination with an effective amount of a sex steroid such as estradiol, alkynyl estradiol or testosterone, and alone or in combination with estrogen for post-menopausal hormone replacement therapy in women.

The progestational activity of the compounds of the present invention can be assessed by two specific experimental models: an affinity experimental model combining with a progestogen receptor (PR for short) in vitro and an in vivo experimental model of conversion of rabbit endometrium. Human PR is readily available in large quantities from cultured T47-D cell line (M.B. Mockus et al, Endocrinology, 1982, 110, 1564-1571). The relative binding affinity for PR of human T47D cells was determined as described (J. Botella et al, J. steroid biochemistry and molecular biology (J. Steroid biochem. mol. biol.), 1994, 50, 41-47, supra., by³H]ORG2058 is labeled specific ligands (g. fleischmann and m. beato, biochem. biophysics. acta.)1978, 540, 500-517) and nomegestrol acetate as nonradioactive reference progestogens. 2nM [ 2 ] for competitive incubation experiments³H]-ORG2058 Co-incubation with six different concentrations of non-labeled steroid following 1/2 for 3 hours at 4 ℃ⁿThe dilution mode of (3) is selected to be a concentration of 4-256 nM. For each experiment, competition curves were generated, and each curve calculated to inhibit 50% [3H ]]Concentration of specific binding of-ORG 2058 (IC)₅₀)。

Table 1: relative binding affinity to human T47-D cell progestagen receptor

Progestagens	IC50(a)nM	(n)	RBA
				Nomegestrol acetate	8.9±2.0	(8)	100％
Compounds of example 1	27.8±2.0	(4)	32％
				Compounds of example 4	22.8±1.7	(4)	39％
Compounds of example 5	17.7±2.4	(4)	50％

(a) Mean ± s.e.m.; (n) number of Experimental examples

Since the mid-thirty years, a specific pharmacological test has become the standard method for qualitative and quantitative analysis of pseudoprogestagen activity in vivo: it is based on the uterine properties of estrogen-exposed immature female rabbits, which, in response to small amounts of progestogen, undergo a typical endometrial conversion into a tightly packed, interlaced epithelial network called "dentelle ". The initial protocol, which included 6 days of estrogen exposure (total subcutaneous dose, 30 μ g/rabbit estradiol benzoate) followed by 5 days of progestin treatment, was first designed by C.Clauberg, Zentr.Gynakol.1930, 54, 2757-. The semi-quantitative scale used to assess microscopic intensity of dentelle was established by m.k.mcphail, journal of physiology (london), 1934, 83, 145-. This comprehensive Clauberg-McPhail method has been widely used to screen steroids for which progestogenic activity in vivo is inferred, and is still an aspect of the hormonal basic properties of any new progestogen such as norgestimate (A. Phillips et al, Contraception (Contraception), 1987, 36, 181-. The progestational potency is inversely related to the dose that elicits half the highest denselle stimulation, in other words, to reach an average McPhail class 2 level. The ED₅₀Dose-response curves were derived and expressed as total dose/rabbit/5 days. All compounds were given as a suspension of carboxymethylcellulose solution by oral gavage and then tested. The maximum oral dose is 1mg, roughly nomegestrol acetate ED₅₀5 times higher than that of a 19-degestrol-derived progestogen with strong oral activity (J.Paris et al, pharmaceutical research, 1983, 33, 710-.

Table 2: Clauberg-McPhail oral experiment (gavage)

Progestagens	ED50(a) (mu g/rabbit/5 days)	(n)	Relative activity
				Nomegestrol acetate	170±41	(5)	100％
Example 1	152±28	(3)	112％
				Example 4	66±11	(2)	258％
Example 5	＞750±6.0	(1)	＜17％

(a) Mean ± s.e.m.; (n) number of Experimental examples

For any new progestogen, residual androgen activity is an important aspect to be evaluated because androgen side effects are crucial in women. A pharmacological experimental model for screening Androgenic activity of steroids or related compounds has become standard, with castrated immature male rats, with ventral prostate and seminal vesicle hypertrophy as end point, administered orally for 10 days daily (R.I. Dorfman, Methods of Hormone Research, Vol.2, London, academic Press, (Methods in Hormone Research, volume2, London, academic Press), 1962: 275-. Medroxyprogesterone acetate is a 6 α methylpregestrene derivative known for its weak androgenic activity in addition to its main progestational activity (m.tausk and j.devisser, international encyclopedia of pharmacology and therapeutics, part 48: progesterone, progestational drugs and antiobesity drugs, volume2, oxford, Pergamon press, 1972: 35-216); therefore, it was selected as a reference for testing the residual androgen activity of the compound of the present invention.

The compounds of examples 1 and 4 were tested for residual androgen activity using the immature castrated male rat model gavage (PO) compared to medroxyprogesterone acetate and chlormadinone acetate, respectively (1, 2 α -cyclomethylenepregnene derivatives, having strong progestogenic activity); testosterone was injected subcutaneously as a standard androgen formulation.

Table 3: residual androgenic Activity of the Compounds of example 1

Steroids	Dosage (mg/animal/day)	Abdominal prostate gland (mg)	Seminal vesicle (mg)
				Castration control group	-	12.0±0.9	12.3±0.7
Testosterone, subcutaneous injection	0.05	90.4±4.4***	90.3±6.7***
				Medroxyprogesterone acetate, strong feeding method	20	29.1±1.4***	19.9±1.8**
Example 1 gavage	20	13.0±0.3ns	10.4±0.5ns

Mean ± s.e.m. of 8 animals per group;^**p is less than 0.01 and^***p is less than 0.001; ns: no statistical difference with the control group

Table 4: residual androgenic Activity of the Compound of example 4

Steroids	Dosage (mg/animal/day)	Abdominal prostate gland (mg)	Seminal vesicle (mg)
				Castration control group	-	11.8±0.6	10.4±0.6
Testosterone, subcutaneous injection	0.05	80.9±3.4***	79.0±5.3***
				Chlormadinone acetate, strong feeding method	20	15.3±1.3*	11.3±0.6ns
Example 4 gavage	20	12.1±0.4ns	11.2±0.5ns

Mean ± s.e.m. of 7 or 8 animals per group;^*p is less than 0.05 and^***p is less than 0.001; ns: there was no statistical difference from the control group.

The compounds of examples 1 and 4 were completely inactive in the growth of male accessory organs (tables 3 and 4). The stimulatory effect of chlormadinone acetate was weak, restricted to the ventral prostate, at the statistically significant border (table 4), while medroxyprogesterone acetate induced a more or less doubling of the weight of both organs (table 3). Thus, the compounds according to the invention are potent progestogens without any residual androgenic activity.

Other aspects of the invention are directed to pharmaceutical compositions comprising an effective amount of a compound of formula (I), in admixture with suitable pharmaceutically acceptable adjuvants. The composition may further comprise an effective amount of an estrogen.

Another aspect of the invention includes methods of treating and preventing endocrine-gynecological disorders, and methods of inhibiting gonadotropic/gonadal secretion. The compounds according to the invention may be administered in a therapeutically effective dose for each of the conditions described above. Administration of the active compounds described herein may be via any mode of administration permissible for use of the drug for similar indications.

The compounds to which the invention relates are generally necessary in daily dosages in the range from 0.001 to 1mg of active compound of the formula (I) per kg of body weight per day. In most cases, treatment is carried out at a dosage level of 0.002 to 0.2 mg/kg body weight per day. Thus, for administration to a human weighing 50kg, the dosage should be about 1mg per day, preferably between about 0.1-10mg per day. Depending on the clinical presentation of a particular disease, administration may be by any acceptable systemic route of administration, for example, by oral or parenteral routes such as intravenous, intramuscular, subcutaneous or transdermal routes of administration, or vaginal, ocular or nasal routes of administration, in solid, semi-solid or liquid dosage forms, for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, creams, gels, implants, patches, pessaries, aerosols, collyria, emulsions and others, preferably in unit dosage forms which facilitate fixed dose administration. The pharmaceutical compositions comprise the usual carriers or excipients and compounds of formula (I) and, in addition, may also comprise other medicaments, drugs, carriers, ingredients and the like. If desired, the pharmaceutical compositions may also contain minor amounts of non-toxic adjuvants such as wetting or emulsifying agents, pH buffering agents and others, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and the like. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising a pharmaceutical excipient and a compound of formula (I). The amount of drug in the dosage form will vary over the range employed by the practitioner, e.g., the proportion of drug in the total dosage form is from about 0.01 weight percent (wt%) to 99.99 wt%, while the excipient may also be from about 0.01 wt% to 99.99 wt%.

For the conditions mentioned above, oral administration according to a suitable daily dosage regimen is the preferred mode of administration, and this regimen may be adjusted according to the severity of the condition. For the mentioned oral administration, the selected compounds of formula (I) can be mixed with any of the usual excipients, e.g. pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate and others to make pharmaceutically acceptable non-toxic compositions. The pharmaceutical compositions can be prepared into solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and other dosage forms and can contain 0.01 to 99.99 percent by weight of the active compound of the invention. The compositions are preferably in the form of dragees or dragees and can contain diluents such as lactose, sucrose, dicalcium phosphate and the like in addition to the active ingredient; disintegrants such as starch or derivatives thereof; lubricants such as magnesium stearate and others; and binders such as starch, polyvinylpyrrolidone, gum arabic, gelatin, cellulose and their derivatives, and others.

The invention is illustrated by the following examples in which the following abbreviations are used:

s: single peak

d: double peak

t: triplet peak

q: quartet peak

m: multiple peaks

dd: two double peaks

bs: broad peak

Example 1: 17 α -Acetoxy-6, 6-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene (5) A/17 α -hydroxy-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene (1)

1N sodium hydroxide solution (300ml, 300mmol) was added to a solution of 17 α -acetoxy-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene (100g, 268mmol) in absolute ethanol and tetrahydrofuran (200ml) at room temperature over 45 min. The solution was stirred (8 hours) and poured into 4000ml of ice-water. The precipitate was filtered off and dried under vacuum at 50 ℃ (yield: 70g, 78.9%), mp: at 172 ℃.

¹H-NMR(CDCl₃，δ)：0.79(s，3H)；1.25(d，3H)；2.29(s，3H)；2.68(m，1H)；5.87(s，1H)。

B/bis- [3, 3-20, 20-ethanedioxy ] -17 alpha-hydroxy-6-methyl-19-nor-pregn-5-ene (2)

P-toluenesulfonic acid monohydrate (5.25g, 27.6mmol) was added to a suspension of compound 1(70g, 211mmol) in anhydrous ethylene glycol (1000ml), acetonitrile (700ml) and triethyl orthoformate (105ml, 633 mmol). The mixture was stirred (2 h) and neutralized with triethylamine (8ml, 57.4 mmol). The suspension was concentrated to 1000ml and poured into ice water (4000 ml). The precipitate was filtered off and dried under vacuum at 60 ℃ (yield: 81g, 92.1%), mp: 214 deg.C.

¹H-NMR(CDCl₃，δ)：0.85(s，3H)；1.40(s，3H)；1.65(s，3H)；2.80(m，1H)；4.00(m，8H)。

C/5 alpha, 6 alpha-epoxy-bis- [3, 3-20, 20-ethanedioxy ] -17 alpha-hydroxy-6 beta-methyl-19-nor-pregna (3)

A solution of MCPBA (43.29g, 200.17mmol, 80% purity) in dichloromethane (250ml) was added to a solution of Compound 2(70g, 167mmol) in dichloromethane (800 ml). The reaction mixture was stirred for 1 hour, and the organic phase was washed with sodium bisulfite and sodium bicarbonate solution after the precipitate was filtered off. The organic phase is dried over sodium sulfate and concentrated, and the residue is purified by flash chromatography on silica gel with toluene/ethyl acetate as eluent to give 20.3g of the title compound (yield: 27.63%), mp: at 220 ℃.

¹H-NMR(CDCl₃，δ)：0.80(s，3H)；1.25(s，3H)；1.35(s，3H)；4.00(m，8H)。

D/bis- [3, 3-20, 20-ethanedioxy ] -5 α, 17 α -dihydroxy-6, 6-dimethyl-19-nor-pregna (4)

A1.4M solution of methylmagnesium bromide in tetrahydrofuran/toluene (250ml, 345mmol) was added to a solution of compound 3(30g, 69mmol) in tetrahydrofuran (1200 ml). The solution was stirred at reflux overnight. The mixture was poured into a mixture of ice and saturated ammonium chloride (1000 ml). The reaction mixture was extracted with toluene, washed with water and dried (sodium sulfate). The residue after evaporation of the solvent was purified by column chromatography eluting with toluene/ethyl acetate. (yield: 15.4g, 49.55%), mp: 212 deg.C.

¹H-NMR(CDCl₃，δ)：0.85(s，3H)；0.95(s，6H)；1.35(s，3H)；4.00(m，8H)。

E/17 alpha-acetoxy-6, 6-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene

To a solution of the above compound (30.8g, 68.33mmol) in acetone (300ml) and water (30ml) was added p-toluenesulfonic acid monohydrate (1.33g, 7 mmol). The reaction mixture was stirred at room temperature for 5 hours. After neutralization with sodium bicarbonate, the mixture was poured into ice water (100ml) and extracted twice with dichloromethane. The organic layer was washed with water, dried (sodium sulfate) and concentrated to give 24.3g of 5 α, 17 α -dihydroxy-6, 6-dimethyl-3, 20-dioxo-19-nor-pregna (yield: 98.2%), mp: 224 deg.C.

¹H-NM[R(CDCl₃，δ)：0.75(s，3H)；0.91(s，3H)；1.08(s，3H)；2.29(s，3H)。

To a solution of this compound (15g, 41.20mmol) in acetic acid (120ml) was added a few drops of sulfuric acid (98%). The mixture was heated at 60 ℃ for 5 hours. Then, it was poured into a saturated solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is evaporated off to yield 12.3g of 17 α -hydroxy-6, 6-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene (yield: 96.3%), mp: at 172 ℃.

¹H-NMR(CDCl₃，δ)：0.79(s，3H)；1.15(s，6H)；2.09(s，3H)；5.97(s，1H)。

To a solution of this compound in acetic acid (120ml) and acetic anhydride (70ml) was added p-toluenesulfonic acid (2.5g, 13.2 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the excess acetic anhydride was decomposed with water. The mixture was extracted with dichloromethane and washed with 1N sodium hydroxide solution. The organic phase was dried (sodium sulfate) and concentrated. The residue was purified by flash chromatography eluting with toluene/ethyl acetate and recrystallized from diisopropyl ether (yield: 7g, 50.81%), mp: at 200 ℃.

¹H-NMR(CDCl₃，δ)：0.71(s，3H)；1.18(s，6H)；2.05(s，3H)；2.11(s，3H)；5.99(s，1H)。

Examples 2 and 3: 17 alpha-acetoxy-6 beta-ethyl-6 alpha-methyl-3, 20-dioxo-19-des-pregn-4-ene (5.a) and 17 alpha-acetoxy-6 beta-propyl-6 alpha-methyl-3, 20-dioxo-19-des-pregn-4-ene (5.b)

The following compound was obtained by the procedure described above for the preparation of compound 5 starting from compound 3, but using ethyl or propyl magnesium bromide instead of methyl magnesium bromide: 17 α -acetoxy-6 β -ethyl-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene, mp: 160 deg.C (example 2),

¹H-NMR(CDCl₃，δ)：0.7(s，3H)；0.72(t，3H)；1.08(s，3H)；2.05(s，3H)；2.11(s，3H)；5.95(s，1H)；

and 17 α -acetoxy-6 β -propyl-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene (example 3).

Example 4: 17 α -Acetoxy-1 α, 2 α -methylene-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene (10)

A1/17 alpha-acetoxy-6 alpha-methyl-3, 20-dioxo-19-nor-pregna (6)

Sodium dithionite (7.9g, 38.5mmol) was added to a solution of 17 α -acetoxy-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene (10g, 26.84mmol) in dioxane (100ml) and water (100ml) containing sodium bicarbonate (14.65g, 174.46 mmol). The reaction mixture was stirred at 50 ℃ for 1 hour, during which time the remainder of the sodium dithionite, 7.9g each, was added in three portions. The reaction mixture was cooled to room temperature and cold water was added until the solution was clear. Then, the solution was extracted with ether, dried (sodium sulfate), concentrated under reduced pressure and purified by flash chromatography (toluene/ethyl acetate) to obtain 2g of compound 6 (yield: 20%), mp: 202 ℃.

¹H-NMR(CDCl₃，δ)：0.65(s，3H)；0.86(d，3H)；2.03(s，3H)；2.09(s，3H)；2.31(m，3H)；2.62(m，1H)；2.90(m，1H)。

B1/17 alpha-acetoxy-6 alpha-methyl-3, 20-dioxo-19-nor-pregn-1-ene (7)

Compound 6(20g, 53.40mmol) and palladium acetate (14.38g, 64.05mmol) were refluxed in acetonitrile (300ml) for 8 hours. After cooling, the palladium was filtered off and the solvent was evaporated off. The residue was purified by flash chromatography on silica gel with toluene/ethyl acetate (8/2) as eluent to give 7g of compound 7 (yield: 35%), mp: 186 ℃ to 188 ℃.

¹H-NMR(CDCl₃，δ)：0.69(s，3H)；0.93(d，3H)；2.07(s，3H)；2.12(s，3H)；2.76(d，1H)；2.94(m，1H)；6.02(dd，1H)；7.11(dd，1H)。

C1/17 alpha-acetoxy-1 alpha, 2 alpha-methylene-6 alpha-methyl-3, 20-dioxo-19-nor-pregna (9)

Sodium hydride (60%) in oil (1.53g, 38.2mmol) was added to a suspension of trimethylsulfoxonium iodide (7.68g, 34.9mmol) in dimethyl sulfoxide (50ml) with stirring. The mixture was stirred at 25 ℃ for 1 h, then Compound 7(2.97g, 7.98mmol) was added. After 3 hours, the reaction mixture was poured into water. The collected solid was purified by flash chromatography on silica gel eluting with toluene/ethyl acetate to give 1g of compound 9 (yield: 33%), mp: 204 ℃.

¹H-NMR(CDCl₃，δ)：0.68(s，3H)；0.84(d，3H)；2.02(s，3H)；2.12(s，3H)；2.52(dd，1H)；2.92(m，1H)。

D1/17 alpha-acetoxy-1 alpha, 2 alpha-methylene-6 alpha-methyl-3, 20-dioxo-19-nor-pregn-4-ene

Pyridinium tribromide (3.83g, 11.38mmol) was added portionwise to a solution of compound 9(4g, 10.35mmol) in tetrahydrofuran (80 ml). After 30 minutes, the mixture is filtered, the solvent is distilled off, and the residue is extracted with dichloromethane, the extract is washed with water and dried (sodium sulfate). The solvent was distilled off to leave 5g of a brown oil, to which dimethylformamide (80ml), lithium carbonate (1.53g, 20.70mmol) and lithium bromide (0.90g, 10.35mmol) were added. The mixture was heated at 140 ℃ for 1 hour. After cooling, the salt was filtered off and the solution was concentrated under reduced pressure. The residue was extracted with dichloromethane and the extract was washed with water and dried over sodium sulfate. Purification by flash chromatography on silica gel eluting with toluene/ethyl acetate afforded 2g of the title compound (yield: 50%), mp: at 210 ℃.

¹H-NMR(CDCl₃，δ)：0.71(s，3H)；1.09(d，3H)；2.04(s，3H)；2.12(s，3H)；2.42(m，1H)；2.84(m，1H)；5.65(s，1H)。

A 2/alternatively, Compound 10 can also be prepared from 17 α -acetoxy-6 α -methyl-3, 20-dioxo-19-des-5 β -pregna, which in turn can be prepared from 17 α -acetoxy-6 α -methyl-3, 20-dioxo-19-des-5 β -pregna-4-ene by catalytic hydrogenation with palladium hydroxide in acetic acid.

B2/then, 17.1g (53mmol) of tribromopyridinium were added to a cooled solution of the resulting compound (20g, 53mmol) in tetrahydrofuran (200 ml). After two hours the mixture was filtered, poured into ice water and extracted with dichloromethane. The solvent was evaporated to give 23.8g (yield: 98.3%) of crude 17 α -acetoxy-2 α -bromo-6 α -methyl-3, 20-dioxo-19-nor-5 β -pregna, which was dehydrobrominated as described above in step D1 to give 15.9g (yield: 80%) of 17 α -acetoxy-6 α -methyl-3, 20-dioxo-19-nor-5 β -pregn-1-ene (7.a), mp: 184 ℃.

¹H-NMR(CDCl₃，δ)：0.69(s，3H)；0.9(d，3H)；2.02(s，3H)；2.1(s，3H)；2.9(m，1H)；6.02(d，1H)。

C2/17 alpha-acetoxy-3 alpha-hydroxy-6 alpha-methyl-20-oxo-19-des-5 beta-H-pregn-1-ene (8.a)

10g (27mmol) of the compound obtained in step B2 and 12g of cerium chloride heptahydrate were added to methanol (200ml) and cooled to 0 ℃ and 2.5g (54mmol) of sodium borohydride were added to the mixture in portions. Then, the mixture was stirred at room temperature for 1 hour, poured into ice water and the precipitate was collected by filtration, dried and recrystallized from diisopropyl ether to obtain 3.6g of compound 8.a (yield: 35.6%), mp: 211 ℃.

¹H-NMR(CDCl₃，δ)：0.65(s，3H)；0.92(d，3H)；2.0(s，3H)；2.1(s，3H)；2.9(m，1H)；4.32(m，1H)；5.64(d，1H)；5.96(dd，1H)。

D2/17 alpha-acetoxy-1 alpha, 2 alpha-methylene-6 alpha-methyl-3, 20-dioxo-19-des-5 beta-pregna (9.a)

To a solution of 3g (80mmol) of the compound in dichloromethane (200ml) at-25 ℃ was added dropwise 40ml of a diethyl zinc hexane solution of 1N followed by 6.45ml of diiodomethane. After standing overnight at room temperature, the white mixture was poured into ammonium chloride solution and extracted with dichloromethane. The residue after evaporation of the solvent was purified by flash chromatography on silica gel eluting with toluene/ethyl acetate to give 1.43g of 3 α -hydroxy-1 α, 2 α -methylene derivative.

¹H-NMR(CDCl₃，δ)：0.4(m，2H)；0.68(s，3H)；0.85(d，3H)；2.05(s，3H)；2.16(s，3H)；2.9(m，1H)；4.13(m，1H)。

The oxidation of the 3 α -hydroxy-1 α, 2 α -methylene derivative in acetone with Jones' reagent gave 1g of compound 9a (yield: 70%), which was converted to 10 by the same method as that described in step D1.

Example 5: 17 alpha-acetoxy-1 beta, 2 beta-methylene-6 alpha-methyl-3, 20-dioxo-19-nor-pregn-4-ene (10.a)

A/17 alpha-acetoxy-6 alpha-methyl-3, 20-dioxo-19-des-5 beta-pregna (6.a)

Compound 1(20g, 53.69mmol) was hydrogenated in methanol (200ml) containing acetic acid (5ml) and 20% palladium hydroxide on carbon (200mg) under 1 atmosphere of hydrogen. The catalyst was filtered off and the solvent was removed, followed by crystallization from ethyl acetate to yield 12.06g of compound 6.a (yield: 60%), mp: 204 ℃.

¹H-NMR(CDCl₃，δ)：0.63(s，3H)；0.80(d，3H)；2.01(s，3H)；2.10(s，3H)；2.91(m，1H)。

B/17 alpha-acetoxy-6 alpha-methyl-3, 20-dioxo-19-des-5 beta-pregn-1-ene (7.a)

Compound 7.a can be prepared as described in example 4, step B2, yield: 30%, mp: 184 ℃.

¹H-NMR(CDCl₃，δ)：0.68(s，3H)；0.92(d，3H)；2.03(s，3H)；2.09(s，3H)；2.92(m，1H)；6.03(d，1H)；7.16(dd，1H)。

C/17 alpha-acetoxy-1 beta, 2 beta-methylene-6 alpha-methyl-3, 20-dioxo-19-des-5 beta-pregna (9.b)

Compound 9.b can be prepared according to the methods described in example 4, steps C1 and D1, yield: 30%, mp: 174 ℃ and 176 ℃.

¹H-NMR(CDCl₃，δ)：0.61(s，3H)；0.79(d，3H)；2.01(s，3H)；2.11(s，3H)；2.88(m，1H)。

D/17 alpha-acetoxy-1 beta, 2 beta-methylene-6 alpha-methyl-3, 20-dioxo-19-nor-pregn-4-ene

This compound was prepared as described in example 4, step D1, yield: 19%, mp: 247 deg.C.

IR(KBr，cm^-1)：1730νC＝O；1720νC＝O；1644νC＝O；1458νC＝C。

¹H-NMR(CDCl₃，δ)：0.59(s，3H)；0.94(d，3H)；1.95(s，3H)；2.00(s，3H)；2.37(d，1H)；2.82(m，1H)；5.52(s，1H)。

Examples 6 and 7: 17 alpha-acetoxy-1 beta, 2 beta-methylene-3E-oxime-6 alpha-methyl-20-oxo-19-nor-pregn-4-ene (11) and 17 alpha-acetoxy-1 beta, 2 beta-methylene-3Z-oxime-6 alpha-methyl-20-oxo-19-nor-pregn-4-ene (11.a)

Hydroxylamine hydrochloride (0.45g, 6.46mmol) and pyridine (3.1ml) were added successively to a dioxane (50ml) solution of compound 10.a (1.24g, 3.25 mmol). The mixture was heated to reflux for 1.5 hours. Then, the reaction mixture was poured into ice water and acidified with a 1N hydrochloric acid solution. Extraction with dichloromethane and evaporation of the solvent gave 1.29g of crude product which was purified by flash chromatography using toluene/ethyl acetate as eluent. The isomer of formula E is eluted first and can be crystallized from ethanol (0.3g, yield: 28.8%), mp: 172 deg.C (example 6)

¹H-NMR(CDCl₃，δ)：0.5(q，1H)；0.65(s，3H)；1.02-1.04(d，3H)；2.05(s，3H)；2.12(s，3H)；2.95(m，2H)；5.62(s，1H)。

The second batch eluted as Z isomer, which was crystallized from a mixed solvent of absolute ethanol and diisopropyl ether (0.080g, yield: 7.7%), mp: 168 deg.C (example 7)

¹H-NMR(CDCl₃，δ)：0.681(s，3H)；1.08-1.1(d，3H)；2.05(s，3H)；2.12(s，3H)；2.95(m，1H)；6.32(s，1H)。

Example 8: 17 alpha-acetoxy-2 alpha, 6 alpha-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene (10.b)

20, 20-ethanedioxy-17 alpha-hydroxy-6 alpha-methyl-19-nor-pregn-4-ene (consisting of R₃Methyl, R₅＝H，R₆＝H，R₄Prepared as compound 5 (10g, 26.7mmol), sodium methoxide (8.25g, 152.2mmol), and ethyl formate (12.71g, 171.6mmol) were stirred at room temperature for 4 hours. The precipitate was then filtered off and washed with diethyl ether to give 11g of crude 2-hydroxymethylene sodium salt derivative which was used without further purification.

Potassium carbonate (13.5g, 98mmol) and iodomethane (46.4g, 326.8mmol) were added to a solution of this compound (11g) in acetone (180ml), and the mixture was stirred at room temperature for 12 hours. After filtration, the organic solution was poured into 1N sodium hydroxide solution, extracted with dichloromethane, dried (sodium sulphate) and concentrated in vacuo to give the crude product (12.70g), methanol (70ml) and 6.66g (166.5mmol) of sodium hydroxide in water (6.6ml) were added and the solution was refluxed for 5 hours. After cooling, the mixture was acidified with 1N hydrochloric acid to PH1 and then poured into water. The precipitate was collected by filtration, washed with water and dried. Purification by silica gel flash chromatography (toluene/ethyl acetate) gave 4.10g of the 17 α -hydroxy derivative of the objective compound (yield: 40%).

¹H-NMR(CDCl₃，δ)：0.78(s，3H)；1.10(d，6H)；2.27(s，3H)；2.68(t，1H)；2.83(s，1H)；5.87(s，1H)。

This compound was converted to the acetyl derivative according to the procedure for the preparation of compound 6.a, yield: 30%, mp: 144 deg.c.

¹H-NMR(CDCl₃，δ)：0.7(s，3H)；1.13(d，6H)；2.06(s，3H)；2.12(s，3H)；2.95(t，1H)；5.88(bs，1H)。

Example 9: 17 alpha-acetoxy-1 alpha, 6 alpha-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene (10.c)

A/17 alpha-acetoxy-1 alpha, 6 alpha-dimethyl-3, 20-dioxo-19-nor-pregnane (12)

To a suspension of copper chloride (1.59g, 16.11mmol) in tetrahydrofuran (400ml) was slowly added a solution of methyllithium (1.6N) in diethyl ether (28.76ml, 32.21mmol) under nitrogen at 0 ℃. After 1 h, a solution of compound 7(5g, 13.42mmol) in tetrahydrofuran (40ml) was added to the mixture at 0 ℃. After 6 hours, a saturated solution of ammonium chloride was carefully added dropwise over 10 minutes. The mixture was stirred for 15 minutes and then extracted with dichloromethane. The organic layer was dried (magnesium sulfate) and concentrated. The resulting crude product was purified by flash chromatography (toluene/ethyl acetate) to obtain 3g of compound 12 (yield: 57%), mp: 183 ℃ is prepared.

¹H-NMR(CDCl₃，δ)：0.66(s，3H)；0.81(d，3H)；0.86(d，3H)；2.01(s，3H)；2.10(s，3H)；2.90(t，1H)。

B/compound 10.c can be prepared in the same manner as described above for compound 10 from compound 9, yield: 35%, mp: 209 ℃.

¹H-NMR(CDCl₃，δ)：0.81(s，3H)；0.90(d，3H)；1.15(d，3H)；2.06(s，3H)；2.12(s，3H)；2.95(t，1H)；5.95(s，1H)。

Example 10: 17 alpha-acetoxy-1 beta, 6 alpha-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene (10.d)

A/17 alpha-acetoxy-1 beta, 6 alpha-dimethyl-3, 20-dioxo-19-des-5 beta-pregna (12.a)

Compound 12.a can be prepared according to the procedure for preparing compound 12, yield: 60%, mp: at a temperature of 142 ℃.

¹H-NMR(CDCl₃，δ)：0.66(s，3H)；0.83(d，3H)；0.98(d，3H)；2.06(s，3H)；2.14(s，3H)；2.92(t，1H)。

B/compound 10.d can be prepared in the same manner as described above for compound 10 from compound 9, yield: 40%, mp: 187 ℃.

¹H-NMR(CDCl₃，δ)：0.69(s，3H)；1.06(d，3H)；1.09(d，3H)；2.06(s，3H)；2.12(s，3H)；2.97(m，1H)；5.77(s，1H)。

Example 11: 17 α -Acetoxy-1, 2 α -methylene-6, 6-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene (10.e)

This compound was obtained according to the method for preparing compound 10 in example 4; mp: 215.5 ℃.

¹H-NMR(CDCl₃，δ)：0.75(s，3H)；1.12(d，6H)；2.03(s，3H)；2.11(s，3H)；2.65(m，1H)；2.95(m，1H)；5.25(s，1H)。

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

Oral administration

Example 12

Sustained release tablet

Unified formulation of different doses:

0.50 to 10.00mg of a compound represented by the formula (I)

Aerosil^*2000.37 to 0.50mg

Precirol^*ATO 51.85 to 2.25mg

Methocel^*E455.00 to 70.00mg

AvicelPH^*10110.00 to 20.00mg

Lactose is proper amount to 185.00-200.00 mg per tablet

Example 13

Quick release tablet

Unified formulation of different doses:

0.50 to 10.00mg of a compound represented by the formula (I)

AerosilR₂000.37 to 0.50mg

Precirol^*ATO 51.85 to 2.50mg

Avicel^*PH101 50.00 to 70.00mg

Explotab^*Or polyplasdone^*XL 5.00 to 25.00mg

Lactose is proper amount to 185.00-200.00 mg per tablet

Example 14

Tablet formulation

Unified formulation of different doses:

0.50 to 10.00mg of a compound represented by the formula (I)

Aerosil^*2000.30 to 0.50mg

Compritol^*1.50 to 3.00mg

Avicel^*PH 10155.00 to 70.00mg

Lactose is proper amount to 185.00-200.00 mg per tablet

Capsule

Unified formulation of different doses:

0.50 to 10.00mg of a compound represented by the formula (I)

The proper amount of oleic acid is 250.00 to 260.00mg per capsule

Coating: gelatin, antiseptic, glycerol

Vaginal administration

Example 15

Vaginal capsule for gynecology

The unified formula of the capsule comprises:

0.50 to 15.00mg of a compound represented by the formula (I)

Vaseline 150.00-200.00 mg

Sorbitol sesquioleate 150.00 to 200.00mg

The synthesized perhydrosqualene is in proper amount of 1.85g per capsule

Coating: gelatin for 2.55g soft capsule, glycerol, and antiseptic

Example 16

Vaginal suppository

The uniform formula of the suppository comprises the following components:

0.50 to 15.00mg of a compound represented by the formula (I)

Witepsol^*H35 or H37 in proper amount of 3.00g for each suppository

Example 17

Slow release pessary

A unified formula of 3.00g suppository:

0.50 to 30.00mg of a compound represented by the formula (I)

Witepsol^*H19 or H351.00 to 1.30g

Suppocire^*BM or NAI 501.00 to 1.50g

Precirol^*0.00 to 0.20g

Preparation for skin or gynecology

Example 18

Biological adhesive for skin or gynecology

Formulation of 100g of formulation:

0.10 to 1.00g of a compound represented by the formula (I)

Polyethylene glycol 0.00-6.00 g

Transcutol^*0.00 to 6.00g

Carboxypolymethylene polymers in the range of 0.50 to 1.00g

Antiseptic 0.30mg

Triethanolamine is added to pH6.5

Purified water of proper amount to 100g

Example 19

Gel for skin

Formulation of 100g of formulation:

0.10 to 2.00g of a compound represented by the formula (I)

Polyethylene glycol or Transcutol^*1.00 to 4.00g

Ethanol 20.00-40.00 g

Carboxypolymethylene polymers in the range of 0.50 to 2.00g

Triethanolamine is added to pH6.5

Purified water of proper amount to 100g

Example 20

Patch preparation

Content of the support or matrix

100g of the preparation:

0.25 to 20.00mg of a compound represented by the formula (I)

Synergist^*0.20 to 0.50g

Suspending agent (HPMC)^**Or Aerosil^*) 0.10 to 1.00g

Proper amount of ethanol or silicone oil is 100g

^*A synergist: isopropyl palmitate, propylene glycol, menthol, azone, N, N-dimethylacetamide, mono-or disubstituted pyrrolidone derivatives;^**HPMC: hydroxypropyl methylcellulose

Transdermal drug delivery

Example 21

Implant agent

Formulation of extruded 100g material:

1.00 to 5.00g of a compound of formula (I)

Polymer (EVA, poly ortho carbonate, siloxane based polymer) in a suitable amount of 100g

The temperature of the mixture should not exceed 150 deg.C to avoid destroying the active ingredients

Implants with carrier

The implant is a polysiloxane sealed tube with the length of 2.5-3.5 cm, the thickness of 0.4-0.8 mm and the diameter of 1.40-2 mm, and the preparation is prepared according to the following formulation of suspension:

100, suspension:

30.00 to 50.00g of the compound represented by the formula (I)

Proper amount of suspending agent is 100g

An implant containing 50mg of suspension

Example 22

Injection solution

5ml bottled unified formula:

10.00 to 50.000mg of a compound of formula (I)

Polyethylene glycol 4000100.00 to 200.000mg

Antiseptic 0.006mg

Sodium chloride or citric acid 0.150mg

Distilled water for injection is properly added to 5.00ml

Example 23

Injectable suspensions

Unified formulation for 2ml ampoules:

5.00 to 10.00mg of a compound represented by the formula (I)

Suspension solution:

Polysobate^*80 0.015g

sodium carboxymethylcellulose 0.010g

Sodium chloride 0.010g

Proper amount of pure water for injection to 2.00ml

Example 24

Uterus embeds ware of utensil carrier

The insert is filled with a silicone carrier having a length of 2.5 to 3.5cm and a thickness of 0.4 to 0.8 mm. The formulation was formulated as a suspension as follows:

100g of suspension:

0.60 to 1.00g of a compound represented by the formula (I)

Suspending in:

suspending agent (Aerosil)^*Or HPMC) 0.50g

Proper amount of synthesized perhydrosqualene to 100g

Example 25

Biological adhesive foaming agent for gynecology

Formulation for a 50g dispenser and 2ml aerosol valve:

0.10 to 0.25g of the compound represented by the formula (I)

Carboxypolymethylene based polymers in the range of 0.50 to 1.00g

Isobutane 5.00 to 10.00g

Excipient matrix F25/1 with proper amount to 50.00g

Suspension formulation shaken before use

The ejection dose is 2.00 to 10.00mg

Nasal administration

Example 26

Nasal suspension

Formulation of 100g suspension:

5.00 to 50.00mg of a compound of formula (I)

Aerosil^*PH10110.00 to 20.00mg

Sodium carboxymethylcellulose 5.00-50.00 mg

Phenethyl alcohol 2.00 to 10.00mg

Polysorbate^*8010.00 to 20.00mg

Purified water of proper amount to 100g

Suspension formulation shaken before use

The dispensing dose is 0.5 to 2.5mg

Ophthalmic drug delivery

Example 27

Ophthalmic solution (eye drops)

Formulation of 100g of solution. 5ml container with glass dropper:

0.50 to 1.00g of a compound represented by the formula (I)

Glycerol 5.00g

0.50 to 0.90g of povidone or sodium chloride

Sorbitol 4.00g

Preservatives (benzalkonium chloride or Cetrimide)^*) 0.01g

EDTA 0.01g

Distilled water in an amount of 100g

The solution is a sterile aqueous solution; may contain stabilizers and antibacterial agents.

The recommended dose is four times a day, one drop at a time.

Example 28

Eye ointment

100g of eye ointment. A container: flexible pipe

0.50 to 2.00g of a compound represented by the formula (I)

Cetrimide^* 0.01g

Sorbitol 4.00g

EDTA 0.01g

Hydroxypolyethylene polymers (Carbopol)^*971) 0.14 to 0.20g

A proper amount of 10% sodium hydroxide to pH6.5

Purified water of proper amount to 100g

The hose is filled with a sterile aqueous solution.

The recommended dose is one or two drops per day.

Typical examples of the compound represented by the formula (I) provided by the present invention include:

17 α -Acetoxy-6, 6-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -Acetoxy-6 β -ethyl-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -Acetoxy-6 β -propyl-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -Acetoxy-1 α, 2 α -methylene-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -Acetoxy-1 β, 2 β -methylene-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -Acetoxy-1 β, 2 β -methylene-3E-hydroxyimino-6 α -methyl-20-oxo-19-nor-pregn-4-ene

17 α -Acetoxy-1 β, 2 β -methylene-3Z-hydroxyimino-6 α -methyl-20-oxo-19-nor-pregn-4-ene

17 α -Acetoxy-2 α,6 α -dimethyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -Acetoxy-1 α,6 α -dimethyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -Acetoxy-1 β,6 α -dimethyl-3, 20-dioxo-19-nor-pregn-4-ene

17 α -acetoxy-1, 2 α -methylene-6, 6-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene.

Claims (10)

1.A compound of formula (I):

wherein:

R₁，R₂，R₃，R₄and R₆Each independently represents H or (C1-C6) alkyl,

R₅is H, (C1-C6) alkyl or-COR₇Group, wherein R₇Is (C1-C6) alkyl,

n is 1, and

x is an oxygen atom or an oximino group,

provided that R is₃And R₄Not both can be H.

2.A compound as claimed in claim 1, wherein R is₁，R₂，R₄And R₆Is H, R₃Is (C1-C6) alkyl, R₅is-COR₇Group, and R₇And X is as defined under formula (I) in claim 1.

3. The compound of claim 1 which is 17 α -acetoxy-1 α, 2 α -methylene-6 α -methyl-3, 20-dioxo-19-nor-pregn-4-ene.

4. The compound of claim 1 which is 17 α -acetoxy-1, 2 α -methylene-6, 6-dimethyl-3, 20-dioxo-19-nor-pregn-4-ene.

5.A pharmaceutical composition comprising (I) an effective dose of a compound of formula (I) as claimed in any one of claims 1 to 4 and (ii) a suitable excipient.

6. The pharmaceutical composition as claimed in claim 5, wherein the compound represented by the formula (I) is contained in an amount of 0.01 to 99.99 wt%.

7. Use of a compound of formula (I) as defined in any one of claims 1 to 4 in the manufacture of a medicament for the treatment or prevention of gynaecological disorders associated with an estrogen/progesterone imbalance.

8. Use of a compound of formula (I) as defined in any one of claims 1 to 4 in the manufacture of a medicament for inhibiting gonadotropic/gonadal secretion.

9. Use of a compound of formula (I) as defined in any one of claims 1 to 4, alone or in combination with a steroidal hormone, for the preparation of a contraceptive.

10. Use of a compound of formula (I) as defined in any one of claims 1 to 4, alone or in combination with an estrogen, in the manufacture of a medicament for hormone replacement therapy in a postmenopausal woman.