Derivatives of 19-norpregnane, the pharmaceutical composition, the compounds

 

(57) Abstract:

Describes new derivatives of 19-norpregnane General formula I, in which R1, R2, R3and R4each independently represents hydrogen or (C1-C6)alkyl, R5-COR7the group, in which R7is (C1-C6)alkyl, R6is hydrogen, n = 0 or 1 and X is oxygen or hydroxyisopropyl, provided that when n = 0, at least two of R1, R2, R3and R4different from hydrogen, and that when n = 1, R1and R4are not both hydrogen. These compounds are excellent POCs that did not possess residual androgenic activity. Also described pharmaceutical composition, containing the compounds of formula I. 4 C. and 14 C.p. f-crystals, 4 PL.

(I)

The invention relates to substituted derivatives of 19-norpregnane, methods of producing these compounds and pharmaceutical compositions containing them.

Compounds according to this invention have a specific and strong progestational (contributing to the onset or continuation of the pregnancy) properties and have no residual androgenic activestates to a method for producing compounds of the formula:

< / BR>
in which R is hydrogen or acyl residue, such as acetyl or hexanoyl.

In addition, derivatives of 19-norpregnane, substituted in position 6 is described in the following documents:

FR-A-1 524 013, which refers to a derivative of 3-enol ether Pregnana obtained from 4-pregnen-3,20-diones of the formula:

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creditorinitiated-methyl-17-hydroxy-4-pregnen-3,20-dione;

DE-A-2148261,kotoryjraspolagaet-methyl-19-norpregnane formula:

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in which R1is hydrogen or methyl group and

R2is (C1-C9) alkyl group; or

BE 757 285, which relates to pharmaceutical remedies containing 3,20-dioxo-6-methyl-17-acetoxy-19-nor-4-pregnen.

Derivatives of 19-norpregnane, such as derivatives described above, however, usually have androgenic side effects.

On the other hand, the transformation 17-20,isopropylidenedioxy-4,5-SECO-3-pregnin-5-she 6,6-dimethyl-17-hydroxyprogesterone described in U.S. patent 3 891 677.

The applicant has found that derivatives of 19-norpregnane, which have at least two substituents in position 1-, 2-, 1,2 - and/or 6, show a strong pravastatinonline, therefore encompasses compounds having the structure represented by the following General formula (I);

< / BR>
in which R1, R2, R3, R4and R6each independently represent hydrogen or (C1-C6)alkyl group,

R5is hydrogen, (C1-C6)alkyl or-COR7the group, in which R7is (C1-C6)alkyl group,

n represents zero or one, and

x is oxygen or hydroxyimino group, provided that when n= 0, at least two of R1, R2, R3and R4different from hydrogen, and when n=1, R3and R4are not both hydrogen.

Used herein, the term "alkyl" means a branched or linear, saturated hydrocarbon radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, ISO-butyl, tert-butyl, pentyl and hexyl.

Used here, the group-COR7in which R7is (C1-C6)alkyl includes, for example, acetyl, propionyl, butyryl, isobutyryl, tert-butyryl, valeryl and hexanol, and acetyl is preferred.

Preferred compounds of formula (I) are compounds in Kotor>is a group-COR7and n represents zero, and those compounds in which X is oxygen, are particularly preferred. Also preferred are the compounds of formula (I) in which R1, R2, R4and R6are hydrogen, R3is (C1-C6)alkyl, R5is a group-COR7and n equals one. Also preferred are the compounds of formula (I) in which R4and R6are hydrogen, R3is (C1-C6)alkyl, R5is a group-COR7and n is equal to zero. Among the latter is also preferred are compounds in which R1is hydrogen and R2- (C1-C6)alkyl, and compounds in which R1is (C1-C6)alkyl and R2is hydrogen, and especially preferred compounds in which X is oxygen.

According to another aspect of the invention relates to a method for producing compounds of formula (I): they can be obtained by following the reaction scheme (see end of description): in which R1, R2, R3, R4, R5, R6, n and X have the same meanings as above.

Connections ASS="ptx2">

Connection 1 receive, using a process similar to the process described in DE-A-2 148 261. In the case when R5=COR7they Malaysia sodium hydroxide in a mixture of ethanol and tetrahydrofuran. Products 1 (R5=H) was isolated by precipitation in water, followed by crystallization in alcohol, preferably in methanol or ethanol. They are then dissolved in toluene, to which is added from 1 to 10 molar equivalents of ethylene glycol, preferably 5 molar equivalents, three-utilitiarian and a catalytic amount of para-toluensulfonate acid. The reaction mixture is stirred at a temperature of from about 20oC to 80oC, preferably at 40oC, for about 2 to 8 hours. The reaction mixture is cooled and poured into ice water and extracted with a suitable organic solvent. The residue obtained after evaporation of the solvent can be purified by crystallization or flash chromatography to obtain compound 2.

Treatment of compounds 2 3-chloroperoxybenzoic acid (MCPBA) in methylene chloride gives a mixture of 5,6-oxirane 3, which emit by crystallization or by flash chromatography. Adding an excess of R4-manipulowania to connect 8 hours, and treating the reaction mixture with a solution of ammonium chloride, extraction with toluene and evaporation of the solvent result in connections 4.

Removing protection from a subsequent dehydration of the tertiary hydroxy-group network connection 5, which may be optional tarifitsirovana known methods used in the chemistry of steroids, or alkylated with alkylhalogenide in accordance with the traditional methods of synthesis of ethers by the Williamson, such as the methods described B. G. Zupan-cic and M. Sopcic, Synthesis, 1979, 123, and D. R. Benedict et al. Synthesis, 1979, 428-429.

Compounds 6, where R3is (C1-C6)alkyl and R4is hydrogen, can be obtained as follows.

Connection 6 with 5-H configuration is obtained by hydrogenation of compounds 1 or 5 in tetrahydrofuran, acetic acid or alcohol, such as methanol, ethanol or propanol, palladium or a derivative of palladium or platinum.

Connection 6 with 5-H configuration can be obtained by chemical recovery of compounds 1 or 5 dithionite sodium, using the method described by F. Camps et al. Tetrahedron Lett., 1986, 42, No. 16, 4603-4609 or R. S. Dhilion et al., Tetrahedron Lett., 1995, 36, N 7, 1107-1108.

The compounds of formula (I) can be obtained as follows.

Bromuro the deposits (Y. J. Abul-Hajj, J. Org.Chem., 1986, 51, 3059-3061; C. Djerassi and C. R. Scholz, J. Am. Chem. Soc., 1948, 417; R. Joly et al., Bull. Soc. Chim. Fr., 1957, 366) gives compound 7 (R1= R2= H).

Compound 5 (R5=H) can be converted into their 20,20-ethyoxy derivatives, then transformed into a 2-hydroxymethylene sodium salt and alkylated using alkylated, such as methyliodide, ethyliodide or propyliodide, following the method described by N. W. Atwater et al., in J. Org. Chem., 1961, 23, 3077-3083, in order to obtain compound 10 (R1=H, R2=alkyl, n=0).

Optional chemical reduction by hydrogenation of 4,5-double bond of compounds 10 (R1= H, R2= alkyl, n= 0) with subsequent bromirovanii/dehydrobrominated gives compound 7 (R1=H, R2=alkyl).

Adding dialkylamino lithium LiCu(R1)2or the corresponding halide alkaline in terms of copper catalysis (e.g., CuI, CuCl or CuCN) to compounds 7 (R1= R2=H) gives compound 12 (R1=alkyl), which can be converted into compound 10 (R1=alkyl, R2=H, n=0), using the well-known in the chemistry of steroids methodology for conducting reactions for the introduction of a 4,5-double bond, or converted into compound 7 (R1=alkyl, R2=H) by dehydrogenation or by brovedani such a process to obtain compound 10 (R2=alkyl, n= 0), which are then converted into compound 7 (R1=R2=alkyl) as described above.

Compound 9 (R1=H or alkyl, R2=H or alkyl, n=1) obtained by the reaction between the compounds 7 (R1=H or alkyl, R2=H or alkyl) and matilida dimethylsulfoxide obtained by the reaction of iodide trimethylsulfoxonium (preferably with base) with gigaram sodium in tetrahydrofuran, dimethylformamide or dimethyl sulfoxide. They can also be obtained by the reaction of compounds 7 with diazomethane, catalyzed palladievye or copper derivatives. Alternatively, compound 7 (R1=H or alkyl, R2=H or alkyl) can be recovered by sodium borohydride in the presence of cerium chloride in compound 8 (R1=H or alkyl, R2=H or alkyl), which is subjected to the reaction of the Simmons-Smith accordance with various described known methods of carrying out the reaction (H. E. Simmons and R. D. Smith, J. Am.Chem.Soc., 1958, 80, 5323; H. E. Sim-mons and R. D. Smith, J. Am.Chem.Soc., 1959, 81, 4256; Org.Synthesis, 1961, 41, 72; J. Furukawa et al. Tetrahedron Lett., 1966, 3353; J. Furukawa et ai. Tetrahedron, 1968, 24, 53; S. E. Denmark and Edwards, J. Org.Chem., 1991, 56, 6974-6981).

Oxidation of 3-hydroxy-group of compounds 8 different oxidants, such as CrO3/perid silyl-simple enol ether and digitalout palladium acetate in boiling (under reflux) acetonitrile with the to obtain compound 10. Alternatively, a 4,5-double bond can be introduced by bromirovanii with subsequent dehydrobrominated, using a process similar to the process described above for compounds 7. The condensation of compounds 10 hydroxylamine hydrochloride in a mixture of dioxane and pyridine gives the compound (11).

Compounds according to this invention have a specific and strong progestational properties. Therefore, they are suitable for the treatment of a number of endocrine-gynecological disorders associated either with the imbalance of estrogen/progesterone, including menstrual disorders (panamania, oligomenorrhea, secondary amenorrhea, premenstrual tension, headache, water retention, modification (change) of mood), diseases of the breast (cyclic mastalgia, benign disease of the breast, breast tumor); or with conditions requiring inhibition of gonadotropic/gonadal secretions: endometriosis, polycystic ovarian syndrome in women, diseases of the prostate gland in men.

On the other hand, the compounds according to this invention can be used as contraceptive agents, alone or in the n, and, in addition, either alone or in combination with estrogen for the conduct of hormone-replacement therapy in the postmenopausal period in women.

Progestational activity of the compounds according to the present invention mainly can be estimated in two specific experimental models: affinity with progesterone receptor (PR) in vitro and in endometrial changes in the uterus of the rabbit in vivo. The human progesterone receptor are readily available in large quantities from T47-D grown cells (M. B. Mockus et al. Endocrinology, 1982, 110, 1564-1571). The relative binding properties (affinity) (RBA) for human T47-D cell receptor progesterone define, as before described (J. Botella et al., J. Steroid Biochem. Molec. Biol. , 1994, 50, 41-47), using 3[H]-ORG 2058 as a labeled specific ligand (G. Fieischmann and M. Beato, Biochim.Biophys. Acta, 1978, 540, 500-517) and acetate nomegestrol as non-radioactive standard progestin. Comparative incubation (cultivation) were performed about 2 nm3[H]-ORG 2058 for 3 hours at 4oC with six different concentrations of unlabeled steroid selected between 4 and 256 nm, following the scheme of dilution 1/2n. Offset curves closely match each experiment, and for the 2058 (IC50)(Table 1).

One specific pharmacological test was standardized in vivo for the detection and quantitative determination pseudohalogens activity since the mid 30-ies: it is based on the property of the uterus estrogen-introduced young female rabbits react to very small amounts of progestin by typical endometrial transformation in compacted and woven epithelial network, called "dental" (dentelle). Initial test mode, which includes 6 days of administration of estrogen (total subcutaneous dose of estradiol benzoate - 30 micrograms/rabbit) followed progestational treatment for 5 days, was developed in 1930 C. Clauberg, Zentr. Gynakol. , 1930, 54, 2757-2770. Semiquantitative analysis used for selection (evaluation) of the intensity of the microscopic appearance of dentalia was set M. K. McPhail, J. Physiol. (London), 1934, 83, 145-156. This General method of research on Clauberg-McPhail was widely used for making selection steroids with suspected progestational activity in vivo and is still part of the research for the main hormonal profile of a new progestin, such as norgestimate (A. Phillips et al., Cotraception, 1987, 36, 181-192), and razionale associated with dose necessary in order to induce premaxillae excitation of dentalia, i.e., recording medium scale McPhail equal to 2. This is the ED50get out of the curve, dose-dependent, and is expressed as total dose/rabbit/ 5 days. All compounds were tested, only following oral introduction by forced feeding, in suspension in karboksimetilcelljuloza solution. Maximum input dose was 1 mg roughly equivalent to 5 times the value of the ED50acetate nomegestrol, a potent orally active progestogen derived from 19-norprogesterone (J. Paris et al., Arzneim. Forsch./Drug Res., 1983, 33, 710-715)(table).

Residual androgenic potential is an important characteristic that should be evaluated for any new progestin due to the high predictability of occurrence of androgenic side effects in women. One pharmacological model of androgenic activity in young castrated male animals rats has been standardized for picking steroids or related compounds using the abdominal hypertrophy of the prostate gland and the seminal vesicle as an end point (stage), following a 10-day techniques (R. I. Dorfman, Research Methods the Gorm, apartment U.S. Health, Education and Welfare, Washington D. C. , 1964). Acetate medroxyprogesterone is 6-methyl-pregnan-derived, which, in addition to its main progestational activity, is well known for its mild androgenic properties (M. Tausk and J. de Visser, in International Encyclopedia of Pharmacology and Therapeutics, Section 48: Progesterone, Progestational Drugs and Contraceptives, volume II, Oxford, Pergamon Press, 1972, 35-216); it, therefore, was chosen as a reference compound for testing some compounds on the residual androgenic activity according to this invention.

The compounds of examples 1 and 4 were tested for residual androgenic activity in the model of a young castrated male rats by forced feeding (PO) compared respectively with acetate medroxyprogesterone and acetate ciproteron (1,2-cyclometer-pregnen derived from strong progestational activity); testosterone was used as a standard androgenic agent by subcutaneous injection (SC).

The compounds of examples 1 and 4 were completely inactive in relation to growth of male secondary sexual organs (table 3 and 4). In the Noah gland, on the border of statistical errors (table 4), while acetate medroxyprogesterone caused more or less double the increase in weight of both bodies (table 3).

Thus, the compounds according to the present invention are potent POCs, lacking any residual androgenic activity.

Thus, according to another aspect of the invention relates to pharmaceutical compositions containing an effective amount of the compounds of formula (I), mixed with suitable pharmaceutically acceptable excipients (environment for drugs). These compositions can also include an effective amount of estrogen.

Another aspect of this invention includes a method of treating or preventing endocrine-gynecological disorders (diseases) and a method of inhibiting gonadotropic/gonadal secretions. Compounds according to the present invention may be appointed at a therapeutically effective dosage for each condition specified above. The reception of the active compounds described herein may be implemented in any of the acceptable forms of administration of agents used for the same indications.

Normal sa body per day of the active compounds of formula (I). Most conditions respond to treatment, including dose level of the order of from 0.002 to 0.2 mg/kg of body weight per day. Thus, when assigning treatment to a person weighing 50 kg, the dosage range would be about 1 mg per day, preferably between about 0.1 and 10 mg per day.

Depending on the specific clinical status of the disease can be accomplished by any acceptable systematic system of administration, such as orally or parenterally, as by intravenous, intramuscular, subcutaneous, or introduction by injection or through vaginal, ocular or nasal path, in solid, semisolid, or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions, creams, gel, capillary tube, patch, pessaries, sprays, candle, emulsions or the like, preferably in integer units of dosage forms, suitable for light reception set (assigned) dosages. The pharmaceutical compositions will include a conventional carrier or binder and a compound of formula (I) and in addition, may include other medicinal agents, pharmaceutical agents, carriers, useful additives the treatment, may also contain smaller amounts of additional non-toxic substances, such as wetting (wetting agents or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, monolaurate sorbitan, triethanolamine oleate, etc.

The compounds of this invention are usually administered in the form of a pharmaceutical composition which comprises a pharmaceutical binder in combination with the compound of the formula (I). The amount of medication in the finished shape can vary within the full range employed by specialists in this field, for example from about 0.01 weight percent (wt.%) to about 99,99 weight. % drugs, based on the total composition, and from about 0.01 wt.% to 99.99 wt.% environment for medicines.

The preferred method of taking medication for conditions listed above, is oral using traditional daily dosing regime, which can be adjusted in accordance with the stage (extent) of the disease. For such oral administration of pharmaceutically acceptable non-toxic composition is prepared by introduction of selected compounds of formula (I) in any one used in the current m is, akharin sodium, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. Such mixtures are in the form of solutions, suspensions, tablets, pills, capsules, powders, ready-made forms with prolonged release of the active substance, and the like. Such mixtures may contain from 0.01 wt.% to 99.99 wt.% the active compounds according to this invention. Preferably, the mixture was in the form (represented) sugar coated pills or tablets and, therefore, to contain together with the active ingredient in a diluent, such as lactose, sucrose, dicalcium phosphate and the like; a leavening agent, such as starch or its derivatives; a lubricating substance, such as magnesium stearate and the like; and a binder, such as starch, polyvinylpyrrolidone, gum allocation of acacia, gelatin, cellulose and its derivatives, and the like. The invention is illustrated by the examples presented below. In these examples, use the following abbreviation:

s: singlet

d: doublet

t: triplet

q: quadruplet

m: multiplet

dd: double doublet

bs: broad singlet

EXAMPLE 1: a 17-Acetoxy-6,6-dimethyl-3,20-deoxy-19 - norpregna-4-ene (5)

A) 17-Hydroxy-6-in absolute ethanol and tetrahydrofuran (200 ml) was added for 45 min at normal temperature 1N solution of sodium hydroxide (300 ml, 300 mmol). The solution was stirred (8 hours) and was poured into ice water (4000 ml). The precipitate was filtered and dried at 50oC under vacuum (yield: 70 g, 78.9 per cent), mp (melting point): 172oC.

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

C) Bis-[3,3-20, 20-ethyoxy] -1-hydroxy-6-methyl - 19-norpregna-5-ene (2)

To a suspension of compound 1 (70 g, 211 mmol) in anhydrous ethylene glycol (1000 ml), acetonitrile (700 ml) and triethylorthoformate (105 ml, 633 mmol) was added monohydrate paratoluenesulfonyl acid (5,25 g, 27.6 mmol). The mixture was stirred for 2 hours and then neutralized with triethylamine (8 ml, 57,4 mmol). After concentration to 1000 ml of the suspension was poured into water (4000 ml). The precipitate was filtered and dried at 60oC under vacuum (yield: 81 g, 92.1 per cent), melting point: 214oC.

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

C) 5, 6-Epoxy-bis[3,3-20,20-ethyoxy] -17-hydroxy-6-methyl-19-norpregna (3)

To a solution of compound 2 (70 g, 167 mmol) in methylene chloride (800 ml) was added a solution of MCPBA (43,29 g, 200,17 mmol, 80% purity) in methylene chloride (250 ml). The reaction mixture was stirred for 1 hour. The precipitate was filtered and the organic phase was washed with NaHSO3and with a solution of bicarbonate soda is as silica gel using toluene/ethyl acetate as eluent to obtain a 20.3 g of target compound (yield: 27,63%), melting point: 220oC.

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

D) Bis-[3,3-20,20-ethyoxy] -5, 17-dihydroxy-6,6 - dimethyl-19-norpregna (4)

To a solution of compound 3 (30 g, 69 mmol) in tetrahydrofuran (1200 ml) was added 1.4 M methylmagnesium in a mixture of tetrahydrofuran and toluene (250 ml, 345 mmol). The solution was stirred while boiling under 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 (Na2SO4). Evaporation of the solvent gave a residue, which was subjected to chromatography using toluene/ethyl acetate as eluent (yield: 15,4 g, 49,55%), melting point: 212oC.

1H-NMR (CDCl3, ): 0.85 (s, 3H), 0.95 (s, 6H), 1.35 (s, 3H), 4.00 points (m, 8H).

E) 17-Acetoxy-6,6-dimethyl-3,20-dioxo-19-norpregna-4-EN

To the above compound (30,8 g, 68,33 mmol) in acetone (300 ml) and water (30 ml) was added monohydrate para-toluensulfonate acid (1,33 g, 7 mmol). The reaction mixture was stirred at room temperature for 5 hours. After neutralization with NaHCO3the mixture was poured into ice water (100 ml) and was extracted twice with methylene chloride. Oldrati-6,6-dimethyl-3,20-dioxo-19-norpregnane (yield: 98.2 per cent), melting point: 224oC.

1H-NMR (CDCl3, ): 0.75 (s, 3H), 0.91 (s, 3H), 1.08 (s, 3H), 2.29 (s, 3H).

To a solution of this compound (15 g, 41,20 mmol) in acetic acid (120 ml) was added a few drops of H2SO4(98%). The mixture was heated at 60oC for 5 hours. Then it was poured into the solution, saturated NaHCO3, and was extracted with methylene chloride. The organic phase asusual (Na2SO4) and evaporated in order to obtain 12.3 g of 17-hydroxy-6,6-dimethyl-3,20-dioxo-19-norpregna-4-ene (yield: 96,3%), melting point: 172oC.

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

To a solution of this compound (12.3 g, 35,7 mmol) in acetic acid (120 ml) and acetic anhydride (70 ml) was added para-toluensulfonate acid (2.5 g, 13,2 mmol). The mixture was stirred for 12 hours at room temperature. After completion of the reaction the excess of anhydride was decomposed with water. The mixture was extracted with methylene chloride and washed with 1N aqueous solution of sodium hydroxide. The organic phase was dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography using toluene/ethyl acetate as eluent and recrystallized in isopropyl ether (yield: 7 g, 50,81%), is 2">

EXAMPLES 2 and 3: 17-Acetoxy-6-ethyl-6-methyl-3,20-dioxo-19-norpregna-4-ene (5a) and 17-acetoxy-6-propyl-6-methyl-3,20-dioxo-19-norpregna-4-ene (5b)

Starting from compound 3 (choosing connection 3 as the source) using the process described for compounds 5, but replacing methylacrylamide ethyl - or PROPYLENEIMINE obtained the following compounds:

17-Acetoxy-6-ethyl-6-methyl-3,20-dioxo-19-norpregna-4-ene, melting point: 160oC (example 2),

1H-NMR (CDCl3, ): 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-acetoxy-6-propyl-6-methyl-3,20-dioxo-19-norpregna-4-ene (example 3).

EXAMPLE 4: 17-Acetoxy-1, 2-methylene-6-methyl-3,20-di - oxo-19-norpregna-4-ene (10)

A1) 17-Acetoxy-6-methyl-3,20-dioxo-19-norpregna (6)

To a solution of 17-acetoxy-6-methyl-3,20-dioxo-19-norpregna-4-ene (10 g, 26,84 mmol) in dioxane (100 ml) and water (100 ml) containing NaHCO3(14,65 g, 174,46 mmol), was added dithionite sodium (7.9 g, a 38.5 mmol) and the reaction mixture was stirred at 50oC for 1 hour, during which adds additional dithionite sodium three portions of 7.9 g each. The reaction mixture was cooled to room temperature and added cold water until until the solution became transparent. After this, the solution was EXT is ecografia (toluene/ethyl acetate) to obtain 2 g of compound 6 (yield: 20%), melting point: 202oC.

1H-NMR (CDCl3, ): 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-Acetoxy-6-methyl-3,20-dioxo-19-norpregna-1-ene (7)

A mixture of compound 6 (20 g, 53,40 mmol) and Pd(OAc)2(14,38 g, 64,05 mmol) in acetonitrile (300 ml) was boiled under reflux for 8 hours. After cooling, the palladium was filtered, and the solvent was evaporated. The residue was subjected to flash chromatography on silica gel, using toluene/ethyl acetate (8/2) as eluent to obtain 7 g of compound 7 (yield: 35%), melting point: 186-188oC.

1H-NMR (CDCl3, ): 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-Acetoxy-1,2-methylene-6-methyl-3,20-dioxo-19-norpregna (9)

To a stirred suspension of iodide trimethylsulfoxonium (of 7.68 g, 34,91 mmol) in dimethyl sulfoxide (50 ml) was added sodium hydride in oil (60%) (1,53 g of 38.2 mmol). The mixture was stirred at 25oC for 1 hour and then added compound 7 (2,97 g 7,98 mmol). After 3 hours the reaction mixture is poured into water. Collect the resulting solid

substances by filtration and flash chromatography on silica gel, using 1H-NMR (CDCl3, ): 0.68(s, 3H), 0.84(d, 3H), 2.02 (s, 3H), 2.12 (s, 3H), 2.52 (dd, 1H), 2.92 (m, 1h).

Di) 17-Acetoxy-1,2-methylene-6-methyl-3,20-dioxo-19-norpregna-4-EN

To a solution of compound (9) (4 g, 10,35 mmol) in tetrahydrofuran (80 ml) was added portion pyridineboronic (3,83 g, 11,38 mmol). After 30 minutes, the mixture was filtered, evaporated and the residue extracted with methylene chloride, washed with water and dried (Na2SO4). Evaporation of the solvent gave 5 g of brown oil to which was added dimethylformamide (80 ml), Li2CO3(1,53 g, 20,70 mmol) and LiBr (0,90 g, 10,35 mmol). The mixture was heated at 140oC for 1 hour. After cooling, the salts were removed by filtration, and the solvent was concentrated under reduced pressure. The precipitate was extracted with methylene chloride, washed with water and dried over Na2SO4. Flash chromatography on silica gel using toluene/ethyl acetate as eluent gave 2 g of the compound (yield: 50%), melting point: 210oC.

1H-NMR (CDCl3, ): 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).

A2) Alternatively, compound 10 can also be obtained from the 17-acetoxy-6-methyl-3,20-dioxo-19-nor-5-pregnane obtained by hydrogenation of 17-acetoxy-6-m is="ptx2">

B2Then to the cooled solution of final compound (20 g, 53 mmol) in THF (200 ml) was added 17.1 g (53 mmol) of pyridineboronic. After 2 hours the mixture was filtered, poured into ice water and was extracted with methylene chloride. Evaporation of the solvent gave a 23.8 g (yield: 93.8% of) raw (untreated) 17-acetoxy-2-bromo-6-methyl-3,20-dioxo-19-nor-5-pregnane, which was dehydrobrominated, following the conditions described above for stage D1to poluchit,9 g(yield:80%)on 17-acetoxy-6-methyl-3,20-dioxo-19-nor-5-pregn-1-ene (7a), melting point: 184oC.

1H-NMR (CDCl3, ): 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-Acetoxy-3-hydroxy-6-methyl-20-oxo-19-nor-5-H-pregna-1-ene (8a)

To 10 g (27 mmol) of the compound obtained in stage B2and 12 g of the heptahydrate of cerium chloride in methanol (200 ml), cooled to 0oC, was added in portions 2.5 g (54 mmol) of sodium borohydride. Then the mixture was stirred for 1 hour at room temperature, poured into ice water and the precipitate collected by filtration, abusively and recrystallized from diisopropyl ether to obtain 3.6 g of compound 8a (output: 35,6%), melting point: 211oC.

1H-NMR (CDCl3, ): 0.65 (s, 3H), 0.92 (d, 3H), 2.0 (s, 3H), 2.1 (s, 3H),
To 3 g (80 mmol) of compound 8A in dichloroethane (200 ml) at -25oC was added dropwise 40 ml of a 1N solution of diethylzinc in hexane followed by the addition of 6.45 ml diiodomethane. After keeping for 1 night at room temperature a mixture of white poured into a solution of ammonium chloride and was extracted with methylene chloride. Evaporation of the solvent gave a residue, which was subjected to flash chromatography on silica gel using toluene/ethyl acetate as eluent to obtain 1,43 g of 3-hydroxy-1, 2-methylene-derived.

1H-NMR (CDCl3, ): 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).

Oxidation of 3-hydroxy-1, 2-methylene-derivative in acetone with Jones reagent gave 1 g of compound 9a (70% yield), which was converted into compound 10 in the same manner as described for stage D1.

EXAMPLE 5: 17-Acetoxy-1, 2-methylene-6-methyl-3,20-dioxo-19-norpregna-4-ene (10a)

A) 17-Acetoxy-6-methyl-3,20-dioxo-19-nor-5-pregnan (6a)

Compound 1 (20 g, 53,69 mmol) in methanol (200 ml) containing acetic acid (5 ml) and 20% Pd(OH)2(200 mg) on charcoal, hydronaut under the pressure of 1 ATM of hydrogen. Filtration of the catalyst and removal of solvent followed crystallizer is 3, ): 0.63 (s, 3H), 0.80 (d, 3H), 2.01 (s, 3H), 2.10 (s, 3H), 2.91 (m, 1H).

B) 17-Acetoxy-6-methyl-3,20-dioxo-19-nor-5-pregn-1-EN

Compound 7a was obtained in 30% yield, following the methodology described in example 4 for the stage IN2, melting point: 184oC.

1H-NMR (CDCl3, ): 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-Acetoxy-1, 2-methylene-6-methyl-3,20-dioxo-19-nor-5-pregnan (9b)

Compound 9b was obtained with 30% yield, following the methodology described in example 4 for stages C1and D1, melting point: 174-176oC.

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

(D) 17-Acetoxy-1,2-methylene-6-methyl-3,20-dioxo-19-norpregna-4-EN

This connection receive from 19% yield, following the methodology described in example 4 for stage D1, melting point: 247oC.

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

1H-NMR (CDCl3, ): 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-Acetoxy-1, 2-methylene-3E-hydroxy-imino-6-methyl-20-oxo-19-norpregna-4-ene (11) and 17-acetoxy-1,2-methylene-3Z-hydroxyimino-6-methyl-20-oxo-19-norpregna-4-ene (11a)

To a solution of compound 10a (1.24 g, 3.2 ml). The mixture was heated for 1.5 hours under reflux. Then the reaction mixture was poured into ice water and acidified using 1N hydrochloric acid. Extraction with methylene chloride and evaporation of the solvent gave 1.29 g of the crude product, which was subjected to flash chromatography using toluene/ethyl acetate as eluent.

First suirvey product was E isomer and crystallized from ethanol (0.3 g, yield: 28,8%), melting point: 172oC (example 6).

1H-NMR (CDCl3, ): 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).

Second suirvey the product was represented by Z isomer and he was crystallized from a mixture of pure ethanol and diisopropyl ether (0.080 g, output: 7,7%), melting point: 168oC (example 7).

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

EXAMPLE 8: 17-Acetoxy-2,6-methyl-3,20-dioxo-19-norpregna-4-ene (10b)

A solution of 20,20-ethyoxy-17-hydroxy-6-methyl-19-norpregna-4-ene (obtained from compound 5, R3=CH3, R5=H, R6=H, R4=H) (10 g, to 26.7 mmol), sodium methoxide (8,25 g, 152,2 mmol) and ethyl formate (12,71 g, 171,6 mmol) was stirred at room temperature for 4 hours. Then saggitarian (sodium salt of 2-hydroxymethylene), which was used without further purification.

To this compound (11 g) in acetone (180 ml) was added potassium carbonate (13.5 g, 98 mmol) and methyliodide (46.4 g, 326,8 mmol) and the mixture was stirred at room temperature for 12 hours. After filtration, the organic solution was poured into a 1N solution of sodium hydroxide, extracted with methylene chloride, dried (Na2SO4) and concentrated under vacuum to obtain the crude product (12,70 g), to which was added methanol (70 ml) and a solution of 6.66 g (KZT 166.5 mmol) of sodium hydroxide in water (6.6 ml) and the solution boiled under reflux for 5 hours. After cooling, the mixture was acidified to pH 1 1N hydrochloric acid and then poured into water. The precipitate was collected, washed with water and dried. Flash chromatography on silica gel (toluene/ethyl acetate) gave 4,10 g of 17-hydroxy-derivative named (given the title) of the compound (yield: 40%).

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

It was converted into its acetyl derivative, following the methodology described for compound 6a, with 30% yield, melting point: 144oC.

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


To a suspension of copper chloride (1,59 g, 16,11 mmol) in tetrahydrofuran (400 ml) at 0oC under nitrogen was slowly added motility (1,6 N) diethylamide (28,76 ml, 32,21 mmol). After 1 hour to the mixture at 0oC was added a solution of compound 7 (5 g, 13,42 mmol) in tetrahydrofuran (40 ml). After 6 hours, a saturated solution of ammonium chloride was added cautiously dropwise within 10 minutes. This mixture was stirred for 15 minutes, then was extracted with dichloromethane. The organic layer was dried (MqSO4) and concentrated. The resulting crude product was subjected to flash chromatography (toluene/ethyl acetate), and then received 3 g of compound 12 (yield: 57%), melting point: 183oC.

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

C) Using the same methodology described for connection 10 from compound 9 got connection 10c with the release of 35%, melting point: 209oC.

1H-NMR (CDCl3, ): 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-Acetoxy-1, 6-dimethyl-3,20-dioxo-19-norpregna-4-ene (10d)

A) 17-Acetoxy-1,6-dimethyl-3,20-dioxo-19-nor-5-pregnan (12a)

Compound 12a was obtained with 60% yield by following method PREV (d, 3H), 0.98 (d, 3H), 2.06 (s, 3H), 2.14 (s, 3H), 2.92 (t, 1H).

C) Using the same method as the method described to obtain compound 10 from compound 9 got connection 10d with a 40% yield, melting point: 187oC.

1H-NMR (CDCl3, ): 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-Acetoxy-1,2-methylene-6,6-dimethyl-3,20 - dioxo-19-norpregna-4-ene (10e)

This compound was obtained following the methodology of the synthesis described in example 4 for the connection 10; melting point: 251,5oC.

1H-NMR (CDCl3, ): 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 typical finished pharmaceutical forms containing the compound of formula (I):

For oral conciliation

EXAMPLE 12: Tablets with delayed action.

A single composition for various dosages:

The compound of formula (I) - 0,50-10,00 mg

Aerosil200 - 0.37 to 0.50 mg

PrecirolATO 5 - 1.85 to 2.25 mg

MethocelE4 - 55,00-70,00 mg

Avicel PH101 - 10,00-20,00 mg

Lactose: the number 1 tablet - 185,00-200,00 mg

EXAMPLE 13: Tablets fast action.

Ed 0.37-0.50 mg

PrecirolATO 5 - 1,85-2,50 mg

Avicel PH102 - 50,00-70,00 mg

Expotabor polyplasdoneXL - 5,00-25,00 mg

Lactose: the number 1 tablet - 185,00-200,00 mg

EXAMPLE 14:

Tablets

A single composition for various dosages:

The compound of formula (I) - 0,50-10,00 mg

Aerosil200 - 30-0,50 mg

Compritol- 1,50-3,00 mg

Avicel PH101 - 55,00-70,00 mg

Lactose: the number 1 tablet - 185,00-200,00 mg

Capsules

A single composition for various dosages:

The compound of formula (I) - 0,50-10,00 mg

Oleic acid: number 1 capsule - 250,00-260,00 mg

Coating (shell): gelatin, preservatives, glycerin.

For vaginal use

EXAMPLE 15: Vaginal gynecological capsule,

A single composition for capsules:

The compound of formula (I) - 0,50-15,00 mg

Vaseline - 150,00-200,00 mg

Sesquioleate of sorbitol - 150,00-200,00 mg

Synthetic perhydrosqualene number for capsules weight 1.85 g

Shell: gelatin, glycerin, protective shell liquid (soft) capsules with the weight of 2.55 g

EXAMPLE 16: Vaginal suppository (candle)

A single composition for suppositories:

Soy is EMER 17: Vaginal suppository slow action

A single composition for suppositories weighing 3.00 g:

The compound of formula (I) - 0,50-30,00 mg

WitepsolH19 or H35 - 1,00-1,30 g

SuppocireBM or NA150 - 1,00-1,50 g

Precirol- 0,00-0,20 g

For skin or gynecological applications

EXAMPLE 18: Biogateway gel for skin or gynecological applications

Recipe for 100 g:

The compound of formula (I) - 0,10-1,00 g

The glycol - 0,00-6,00 g

Transcutol- 0,00-6,00 g

Carboxypolymethylene polymer - 0,50-1,00 g

Protective equipment - 0,30 g

Triethanolamine: count to a pH of 6.5

Purified water: count to 100 g

EXAMPLE 19: Gel for dermal applications

Recipe for 100 g:

The compound of formula (I) - 0,10-2,00 g

The glycol or Transcutol- 1,00-4,00 g

Ethyl alcohol - 20,00-40,00 g

Carboxypolymethylene polymer - 0,50-2,00 g

Triethanolamine: number pH 6.5

Purified water: count to 100 g

EXAMPLE 20: Plaster (bandage)

The content in the "reservoir" or the matrix.

Getting 100 g:

The compound of formula (I) - 0,25-20,00 mg

Substance*a synergistic effect of the compounds of formula (I) of 0.20-0.50 g

Suspendisse agent (HPMC**or Aerosil the action of the formula (I): isopropyl, propylene glycol, menthol, azone, N, N - dimethylacetamide, mono - or disubstituted derivatives of pyrrolidone;

**HPMC: hypromellose

To apply through the skin

EXAMPLE 21:

Implants (capillary tubes introduced into living tissue)

The composition for 100 g of the material that you want to push (squeeze):

The compound of formula (I) - 1,00 - 5,00 g

Polymers (EVA, polycholorinated, polymers, silicon-based): the amount for 100 g

The temperature of the mixture should not exceed 150oC in order not to degrade the quality of the active component.

Implants with a reservoir

The implant is a silicone sealed tube length from 2.5 to 3.5 cm, thickness from 0.4 to 0.8 mm and a diameter of from 1.40 to 2.00 mm Recipe made for the suspension as follows:

For 100 g:

The compound of formula (I) - 30,00-50,00 g

Suspendisse agent: amount for 100 g quantity

50 mg suspension for a single implant.

EXAMPLE 22: the Deposited composition for injection

A single composition to a flask with a volume of 5 ml:

The compound of formula (I) - 10,00-50,000 mg

Polyethylene glycol 4000 - 100,00-200,000 mg

Preservatives - 0.006 mg

Sodium chloride or salt lemon rd

A single composition for ampoules of 2 ml

The compound of formula (I) - 5,00-10,00 mg

The suspension solution:

Polysorbate80 - 0,015 grams

Carboxymethylcellulose sodium - 0,010 g

Sodium chloride - 0,010 g

Purified water for injection: Qty for 2,00 ml

EXAMPLE 24: the Intrauterine device (means) with a reservoir

The device with a silicone reservoir in length from 2.5 to 3.5 cm and a thickness of 0.4 to 0.8 mm Prescription composed for the preparation of suspensions as follows:

To 100 g of suspension:

The compound of formula (I), suspendiruemye in: - 0,60-1,00 g

Suspendisse agent (Aerosilor HPMC) - 0.50 g

Synthetic perhydrosqualene: the amount for 100 g

EXAMPLE 25: Biogateway gynecological foam

The recipe for the distributor 50 g and sprinklers (2 ml:

The compound of formula (I) - 0,10-0,25 g

Carboxypolymethylene polymer - 0,50-1,00 g

Isobutane - 5,00-10,00 g

Filler F25/1: the number for 50,00 g

Before use, the suspension is shaken.

Distributable dosage from 2.00 to 10.00 mg

For nasal application

EXAMPLE 26: Suspension for nose

The composition for 100 g of suspension:

The compound of formula (I) - 5,00-50,00 mg

Polysorbate80 - 10,00-20,00 mg

Purified water: quantity of 100 g

Before use, the suspension is shaken.

Dividing the dose from 0.5 to 2.5 mg.

For ophthalmic applications

EXAMPLE 27: Ophthalmic solution (suppository, candle)

The composition for 100 g of solution. The container 5 ml glass dispensers to receive drops:

The compound of formula (I) - 0,50-1,00 g

Glycerol - 5,00 g

Polyvidone or sodium chloride - 0,50-0,90 g

Sorbitol - 4,00 g

Preservatives (benzalkonium chloride or Cetrimide) - 0.01 g

EDTA, 0.01 grams

Distilled water: the amount for 100 g

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

Recommended dose is one drop four times a day.

EXAMPLE 28: Eye gel

The composition for 100 g of gel. Container: collapsible tube.

The compound of formula (I) - 0,50-2,00 g

Cetrimide0.01 g

Sorbitol - 4,00 g

EDTA, 0.01 grams

Carboxypolymethylene polymer: (Carbopol971) - 0.14 to 0.20 g

Sodium hydroxide 10%: number pH 6.5

Distilled water: the amount for 100 g

Sterile water-based gel fill in skini formula (I), provided by this invention include:

17-acetoxy-6,6-dimethyl-3,20-dioxo-19-norpregna-4-EN

17-acetoxy-6-ethyl-6-methyl-3,20-dioxo-19-norpregna-4-EN

17-acetoxy-6-propyl-6-methyl-3,20-dioxo-19 - norpregna-4-EN

17-acetoxy-1,2-methylene-6-methyl-3,20-dioxo-19-norpregna-4-EN

17-acetoxy-1,2-methylene-6-methyl-3,20-dioxo-19-norpregna-4-EN

17-acetoxy-1,2-methylene-3E-hydroxyimino-6-methyl-20-oxo-19-norpregna-4-EN

17-acetoxy-1,2-methylene-3Z-hydroxyimino-6-methyl-20-oxo-19-norpregna-4-EN

17-acetoxy-2,6-dimethyl-3,20-dioxo-19-norpregna-4-EN

17-acetoxy-1,6-dimethyl-3,20-dioxo-19-norpregna-4-EN

17-acetoxy-1,6-dimethyl-3,20-dioxo-19-norpregna-4-EN

17-acetoxy-1,2-methylene-6,6-dimethyl-3,20-dioxo-19-norpregna-4-ENM

1. Derivatives of 19-norpregnane General formula I

< / BR>
where R1, R2, R3, R4and R6each independently represent hydrogen or (C1- C6)alkyl;

R5is-COR7the group, in which R7is (C1- C6)alkyl, R6is hydrogen;

n = 0 or 1;

X is oxygen or hydroxyimino group

provided that, when n = 0, at least two of R1, R2, R3and R4different from the water in which R1, R2are hydrogen, R3and R4are (C1- C6)alkyl, n = 0.

3. Derived under item 1, in which R1, R2, R4are hydrogens, R3is (C1- C6)alkyl and n = 1.

4. Derived under item 1, in which R4is hydrogen, R3is (C1- C6)alkyl, n = 0.

5. Derived under item 4, in which R1is hydrogen and R2is (C1- C6)alkyl.

6. Derived under item 4, in which R1is (C1- C6)alkyl and R2is hydrogen.

7. Derived under item 5 or 6, in which X is oxygen.

8. Derived under item 1, which is 17-acetoxy-6,6-dimethyl-3,20-dioxo-19-nor-pregna-4-Yong.

9.Proizvodnja.1,koterayama-acetoxy-1,2-methylene-6-methyl-3,20-dioxo-19-nor-pregna-4-Yong.

10. Derived under item 1, which is 17-acetoxy-1,2-methylene-6,6-dimethyl-3,20-dioxo-19-nor-pregna-4-Yong.

11. Pharmaceutical composition having progestogenic activity and containing (i) an effective amount of the compounds of formula I according to any one of paragraphs.1 - 10 and (ii) suitable fillers.

12. The pharmaceutical is required under item 11 or 12, which is a contraceptive composition.

14. Contraceptive composition according to p. 13, which additionally contains an effective amount of sex steroid.

15. The compound of formula I according to any one of paragraphs.1 - 10 used as an active ingredient of a medicinal product for the treatment or prevention of gynecological disorders related to an imbalance between estrogen and progesterone.

16. The compound of formula I according to any one of paragraphs.1 - 10 used as an active ingredient of a medicine for inhibiting gonadotropic/gonadal secretions.

17. The compound of formula I according to any one of paragraphs.1 - 10, one or in combination with sex steroid used as an active ingredient of the contraceptive agent.

18. The compound of formula I according to any one of paragraphs.1 - 10, one or in combination with estrogen used as the active ingredient of a medicine for hormone-replacement therapy in the postmenopausal period.

 

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< / BR>
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