Derivatives androsten(en)or its pharmaceutically acceptable mes, methods for their preparation, pharmaceutical product, the method of treatment

 

(57) Abstract:

Describes the connection of the formula I, where the values of R1- R3specified in paragraph 1 of the formula, is able to inhibit 5-reductase. Describes the method of its production, pharmaceutical preparation and method of treatment using compounds of formula I. 6 c. and 17 C.p. f-crystals, 1 PL.

This invention relates to certain substituted 17-anilide-4-Aza-5-androstane-3-Onam, in particular, as a surprisingly powerful and selective inhibitors of human 5-reductase type 1 and 2.

Androgens are responsible for many physiological functions in men and women. The action of androgens is mediated by specific intracellular hormone receptors expressed in androgenicity cells. Testosterone, the major circulating androgen secreted by the Leydig cells in the testes under the stimulating influence of pituitary luteinizing hormone (LH). However, restoring the double bond 4,5 testosterone to dihydrotestosterone (DHT) is required in some target tissues, such as prostate and skin, for the manifestation of androgen action. Steroid 5-reductase in target tissues catalyze the transition of testosterone into DHT NADP-N Itih target tissues was illuminated by studies of individuals with deficiency of steroid 5-reductase, having a rudimentary prostate and not suffering from acne or male pattern hair loss (see McGinley, J. et al., The New England J. of Medicine, 300, 1233 (1979)). Thus, it is expected that the inhibition of transfer of testosterone to DHT in these target tissues will be useful in treating a variety of androgenicity diseases, such as benign prostatic hyperplasia, prostate cancer, acne, baldness male pattern and hirsutism.

In addition, it was recently revealed that in humans there are two different isoenzymes of 5-reductase, which differ in tissue distribution, affinity for testosterone, pH profile and sensitivity to inhibitors (see Russell, D. W. et al., J. Clin. Invest., 89, 293 (1992); Russell, D. W. et al., Nature, 354, 159 (1991)). Persons with deficiency of steroid 5-reductase studied Imperato-McGinley suffer from deficiency of the enzyme 5-reductase type 2 (Russell, D. W. et al. , J. Clin.Invest., 90, 799 (1992); Russell, D. W. et al., New England J. Med. , 327, 1216 (1992)), which is the predominant enzyme in the prostate gland, while the isoenzyme type 1 predominates in the skin. The relative value sensisitivity and dual inhibitors of two isoenzymes of 5-reductase will depend on the type of curable diseases (benign prostatic hyperplasia prestatie diseases (prevention or treatment) and the expected side effects in selected patients (for example the treatment of acne in males at puberty).

Due to their considerable therapeutic potential inhibitors of testosterone 5-reductase (hereinafter referred to as "inhibitors of 5-reductase") were the subject of widespread active research, for example, see Hsia, S. and Voight, W. , J. lnvest. Derm., 62, 224 (1973); Robair, et al., J. Steroid Biochem., 8, 307 (1977); Petrow, V. et al., Steroids, 38, 121 (1981); Liang, T. et al., J. Steroid Biochem., 19, 385 (1983); Holt, D. et al., J. Med.Chem., 33, 937 (1990); US Patent N 4377584, US Patent N 4760071 and US Patent N 5017568. Two particularly promising inhibitor of 5-reductase inhibitor is MK-906 (Merck), known under the generic name of finasteride and distributed under the brand name proscar, and SKF-105657 (SmithKline Beecham), shown in scheme B.

< / BR>
Potent inhibition of isomerase (3BHSD) in cells of bovine adrenal and pork [granulosa] 4-azasteroid derivative, 4-MA, is shown in scheme C, not the drug finasteride

< / BR>
(Tan, C. H. ; Fong, C. Y.; Chan, W. K. Biochem. Biophys. Res. Comm., 144, 166 (1987) and Brandt, M.; Levy, M. A. Biochemistry, 28, 140 (1989), along with the critical role 3BHSD in the biosynthesis of steroids (Potts, G. 0. et al., Steroids, 32, 257 (1978)) suggest that the optimal inhibitor of 5-reductase type 1 and 2 must also be selective to 3BHSD adrenal man. The importance of the selectivity of an inhibitor of 5-reductase was also highlighted by reports of hepatotoxicity of some 4-azasteroid of the invention is a compound of the formula I

< / BR>
where the carbons 1 and 2 are connected by either a single or a double bond:

R1is hydrogen or methyl;

R2is hydrogen or methyl:

R3- this compound (A),

< / BR>
in which R4and R5is, independently from each other, hydrogen, lower alkyl, lower alkoxysilane, trifluoromethyl, CYANOGEN, halogen or phenyl (possibly substituted by one or more Halogens), or, when R4and R5are on adjacent carbon atoms, they form together a 5-, 6 - or 7-membered ring may contain one or more oxygen atoms or sulfur;

W and Z is methylene group, which, when taken together with the carbon atom to which they are attached, form a saturated ring system with the number of members from 3 to 12, with:

1) is independently substituted by one or more lower alkyl groups,

2) containing an oxygen atom or sulfur,

3) the above two methylene groups of the specified ring number of members from 3 to 12 is connected with a (C1-6) alkalinous group with the formation of bicycling ring system; and

X is hydrogen or halogen;

or (B)

< / BR>
in which R6is trifluoromethyl or phenyl may Zam is n (C4-7) alkyl;

or R7or R8is trifluoromethyl, halogen or phenyl, possibly substituted by one(oops) or more Halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl, and the other radical is hydrogen or halogen; and

X is hydrogen or halogen, and pharmaceutically acceptable solvate.

Other aspects of the invention are:

1. A method of inhibiting testosterone 5-reductase, which represents the contact testosterone 5-reductase with the compound of the formula I.

2. The method of treatment androgenicity or mediated by androgens diseases, which represent the impact of an effective amount of the compounds of formula I to a patient in need of such treatment.

3. Pharmaceutical preparations containing a compound of formula I as an active start.

4. The method of treatment androgenicity or mediated by androgens diseases, which represent the impact of an effective amount of the compounds of formula I to a patient in need of such treatment in combination with antiandrogens like to be.

5. A method for the treatment of benign hyperplasia of prestat is idahosa in such treatment in combination with a blocker of alpha-1-adrenergic receptors (for example, terazosina).

6. A method of treating benign prostatic hyperplasia, representing the impact of an effective amount of the compounds of formula I to a patient in need of such treatment in combination with an antiestrogen.

7. Some intermediate chemical compounds used in the preparation of compounds of formula I.

Connection.

Adept in the art of organic chemistry will recognize that many organic compounds can form complexes with solvents in which they react, or from which they are precipitated or crystallized. These complexes are known as "solvate". For example, the complex with water is called "hydrate". The solvate of the compounds of formula I are within the present invention.

Well-versed in organic chemistry also recognize that many organic compounds can exist in more than one crystalline form. For example, the crystalline form may be different in different solvate. Thus, all of the crystalline forms of the compounds of the formula I or their pharmacologically acceptable solvate are within this invention.

Applied here, the term "lower" otnositelnoy chain. Applied here, the term "branched (C4-7) alkyl" means 3-6 carbon atoms, attached through Quaternary carbon, for example t-butyl, t-amyl, etc. the Term "halogen" means fluorine, chlorine, bromine and iodine.

Examples of ring systems formed by W and Z include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl and so on, norbornyl, bicyclo[3.3.1.]nonyl, tetrahydrofuryl, tetrahydropyranyl, or tetrahydrothiopyran, but are not limited to this. Preferred ring system with the number of members from 3 to 8.

Examples of bicyclic ring systems formed when one of the methylene groups W is connected with one of the methylene groups Z with (C1-6) alkalinous group include

< / BR>
< / BR>
but is not limited to this.

Examples of 5-, 6 - or 7-membered rings formed by R4and R5include

< / BR>
< / BR>
but is not limited to this.

Sveduûŝego in the art of organic chemistry will be recognized that "the Quaternary carbon fragment (A), i.e., the carbon attached to

-NH-, phenyl group, W and Z, can be asymmetric. This asymmetry Quaternary carbon generates a couple stereausis alkyl groups or are joined with alkalinous group, you may experience other asymmetric carbon atoms, which also creates other pairs of stereoisomers. All stereoisomers of the new compounds described herein are within the scope of this invention.

Used here wavy line representing a single connection between the Quaternary carbon and W and Z, denote that these two relationships can be in the position or relative to the Quaternary carbon. The term "alpha" means that the link and the relevant portion located below the plane of the page, while the term" means that the link and the relevant portion located above the plane of the page and is depicted here in bold wedge bond. The use of these terms corresponds to the standard chemical terminology.

In a private group of compounds of formula (I) X is hydrogen. In another private group of compounds of formula (I) R2is hydrogen. In another group of compounds of formula (I) R6is trifluoromethyl or phenyl, possibly substituted by one or more Halogens or branched (C4-7) alkyl; or R7or R8is trifluoromethyl, halogen or phenyl, possibly substituted by one or more halogen or a branched the formula (I) carbon atoms 1 and 2 are connected by a double bond.

A private group of compounds of formula I are the compounds of formula IA

< / BR>
in which the carbon atoms 1 and 2 are connected by either a single or a double bond;

R1is hydrogen or methyl;

R4and R5is, independently from each other, hydrogen, lower alkyl, lower alkoxysilane, trifluoromethyl, CYANOGEN, halogen or phenyl (possibly substituted by one or more Halogens), or, when R4and R5are on adjacent carbon atoms they together form a 5, 6 or 7-membered ring may contain one or more oxygen atoms or sulfur;

W and Z is methylene group, which, when taken together with the carbon atom to which they are attached, form a saturated ring system with the number of members from 3 to 12, with:

1) is independently substituted by one or more lower alkyl groups,

2) containing an oxygen atom or sulfur,

3) the above two methylene groups of the specified ring number of members from 3 to 12 is connected with a (C1-6) alkalinous group with the formation of bicycling ring system; and

X is hydrogen or halogen.

In a private group of compounds of formula IA:

R4and R5is, independently researched the one substituted by one or more halogen), and X represents hydrogen.

Preferred compounds of formula IA, where at least one of the radicals X, R4and R5is not hydrogen. The fragments in position pair (4-) in the phenyl ring are particularly preferred.

In a private group of compounds of formula IA at least one of the radicals R4and R5is lower alkyl, lower alkoxysilane, trifluoromethyl, CYANOGEN, halogen or phenyl, in particular branched alkyl, for example t-butyl, trifluoromethyl or halogen.

In four other private groups of compounds of formula IA:

1) W and Z is methylene group, which, when taken together with the carbon atom to which they are attached, form a saturated ring system with the number of members from 3 to 12, containing only carbon atoms, and which may be independently substituted one or more lower alkyl groups; or

2) W and Z is methylene group, which, when taken together with the carbon atom to which they are attached, form a saturated ring system with the number of members from 3 to 12, containing an oxygen atom or sulfur, and which may be independently substituted one or more lower alkyl groups; or

3) W and Z is Matenrou ring system with the number of members from 3 to 12, containing only carbon atoms, and which may be independently substituted one or more lower alkyl groups, and these two methylene groups are connected (C1-6) alkalinous group with the formation of the bicyclic ring system; or

4) W and Z is methylene group, which, when taken together with the carbon atom to which they are attached, form a saturated ring system with the number of members from 3 to 12, containing an oxygen atom or sulfur, and which may be independently substituted one or more lower alkyl groups, and these two methylene groups are connected (C1-6) alkalinous group with the formation of the bicyclic ring system.

Another private group of compounds of formula I are the compounds of formula IB

< / BR>
where the carbon atoms 1 and 2 are connected by either a single or a double bond;

R1is hydrogen or methyl;

R6is trifluoromethyl, or phenyl, possibly substituted by one(oops) or more Halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl;

or R7or R8is trifluoromethyl, halogen or phenyl, possibly substituted by one(oops) or not and the other radical hydrogen or halogen; and

X is hydrogen or halogen.

In a private group of compounds of formula IB, when R7or R8is a branched (C4-7) alkyl, and X is hydrogen, R6is trifluoromethyl or phenyl, possibly substituted by one or more Halogens.

In another private group of compounds of formula IB:

R6is trifluoromethyl or branched (C4-7) alkyl; and

or R7or R8is trifluoromethyl, halogen or phenyl, substituted by one or more halogen, and the other radical is hydrogen or halogen.

In another private group of compounds of formula IB:

R6is trifluoromethyl or branched (C4-7) alkyl;

or R7or R8is trifluoromethyl and the other radical is hydrogen; and

X is hydrogen.

In another private group of compounds of formula (IB), R6and R8is independently from each other, trifluoromethyl or t-butyl, and R7and X is hydrogen.

Specific compounds of formula I are:

Link/Example

1. 17 - N-1-(4-Chlorophenyl)cyclopentanecarbonyl-4-Aza-5 - androstane-3-one

2. 17 - N-1-(4-Chlorophenyl)cyclopentanecarbonyl-4-methyl-4-Aza-5 - androstane-3-one

3. 17 - N-1-(4-Landrost-1-EN-3-one

5. 17 - N-1-(4-t-Butylphenyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one

6. 17 - N-1-(4-Chlorophenyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one

7. 17 - N-1-(4-Triptoreline)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one

8. 17 - N-1-(4-Methoxyphenyl)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one

9. 17 - N-1-(4-Forfinal)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one

10. 17 - N-1-(4-Forfinal)cyclohexylcarbonyl-4-Aza-5-androst - 1-EN-3-one

11. 17 - N-1-(4-Methoxyphenyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one

12. 17 - N-1-(3,4-Methylenedioxyphenyl) cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one

13. 17 - N-1-(4-t-Butylphenyl) cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one

14. 17 - N-1-(4-t-Butylphenyl)tetrahydropyranyloxy-4-Aza-5-androst-1-EN-3-one

15. 17 - N-1-(2,4-Dichlorophenyl)cyclopropanecarbonyl-4-Aza-5-androst-1-EN-3-one

16. 17 - N-1-(4-Triptoreline)-2,2-diethylcarbamoyl-4-Aza-5-androst-1-EN-3-one

17. 17 - N-1-(4-t-Butylphenyl)-4,4-dimethylcyclohexylamine-4 - Aza-5-androst-1-EN-3-one

18. 17 - N-1-(4-t-Butylphenyl)-4-t-butylcyclohexanol-4-Aza-androst-1-EN-3-one

19. 17 - N-1-(3-Triptoreline)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one

20. 17 - N-1-(4-t-Butylphenyl)tetrahydrothiopyrano-4-Aza-5-androst-1-EN-3-one
23. 17 - N-(2,5-Bis(Trifluoromethyl))phenylcarbamoyl-4-methyl-4-Aza-5-androstane-3-one

24. 17 - N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

25. 17 - N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androstane-3-one

26. 17 - N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-methyl-4-Aza - 5-androstane-3-one

27. 17 - N-(2,5-Di-t-butyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

28. 17 - N-(2,5-Di-t-butyl)phenylcarbamoyl-4-Aza-5-androstane-3-one

29. 17 - N-(2,5-Di-t-butyl)phenylcarbamoyl-4-methyl-4-Aza-5-androstane-3-one

30. 17 - N-(2,5-Bis(Trifluoromethyl))phenylcarbamoyl-4-Aza-7 - methyl-5-androst-1-EN-3-one

31. 17 - N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-Aza-7 - methyl-5-androst-1-EN-3-one

32. 17 - N-1-(4-Chlorophenyl)cyclopentanecarbonyl-4-Aza-7 - methyl-5-androst-1-EN-3-one

33. 17 - N-9-(4-t-Butylphenyl)bicyclo[3.3.1] nonlibrary-4-Aza-5-androst-1-EN-3-one.

In particular, a specific compound of formula I is:

17 - N-1-(4-chlorophenyl)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one.

Specific intermediate compounds of formulas III, IV and IVa are:

17 - N-1-(4-chlorophenyl)cyclopentanecarbonyl-androst-4-EN-3-one,

17 - N-1-(4-chlorophenyl)cyclopentanecarbonyl-5-oxo-A-nor-3,5 - secondrate-3-oeva acid; and

17 - N-1-(4-chlorophenyl)cyclopentanecarbonyl to be prepared by the methods described in U.S. patent 4377584 (hereinafter "584") and 4760071 (hereinafter "071"), which are given in the text only link. For example, the compounds of formula I, in which the carbon atoms 1 and 2 are connected by a single bond, can be prepared by the method shown in scheme I.

< / BR>
In scheme I, a 4-Aza-androst-5-ene-3-about the compound of the formula (IVa) into corresponding 4-Aza-5-androstane-3-one formula I through hydrogenation. For example, the hydrogenation can be carried out in acetic acid at a temperature of from 60 to 70oC and a hydrogen pressure of 40-60 psi in the presence of a catalytic oxide of platinum.

The compounds of formula IVa can be prepared by the method shown in scheme IA.

< / BR>
< / BR>
Phase I of the scheme IA, 3-oxo-4-androsten-17-carboxylic acid II is converted into the corresponding amide of formula III. This can be done by activation of the acid and reaction with the compound of the formula IIa. For example, the sequence of reactions may be represented as a transformation of the compounds of formula II in gelegenheid by exposure halogenides agent, such as oxacillin or thionyl chloride in an aprotic solvent such as toluene, methylene chloride or tetrahydrofuran at a temperature of the hydride acid, may react with an amine of the formula IIa (where the substituents correspond to the formula (I), possibly in the presence of a catalyst such as 4-N,N-dimethylaminopyridine, at a temperature of from 25 to 70oC, in an aprotic solvent such as tetrahydrofuran, with the formation of the amide of formula III.

The compounds of formula IIa, where R3is (A), i.e., cycloalkylation, prepare Kurtasovoj rearrangement of the corresponding acid, when it is available, or cannot, X. et al. J. Med. Chem., 36, 1188 (1993), i.e. by reaction of the corresponding cycloalkanones with acceptable aryl Grignard reagent with subsequent conversion of the resulting alcohol to the amine by exposure to sodium azide and triperoxonane acid with subsequent restoration azide, lithium-aluminum hydride. Substituted cyclopropylbenzene formula IIa are prepared by catalyzed radium insertion of a suitable aryl-alpha-diazepine (prepared by the method Baum, J. S. et al., Synthetic Comm., 17, 1709 (1987)) in a suitable olefin (as described Davies, H. W. et al. , Tetrahedron Lett., 30, 5057 (1989)) followed by saponification of the ester and Kurtasovoj rearrangement of the acid with the formation of the desired amine. The compounds of formula IIa, where R3is (B), i.e., substituted anilines, the.Chem. USSR (English translation) (blue et al. Organic chemistry of the USSR. (eng.translation)) 10, 512 (1974) summarized in SA 80 (25): 14623f and Reetz, M. T. et al., Angew.Chem.Int. Ed.Engl., 19, 900 and 901 (1980)).

In step 2, the compound of formula III is transformed into a derivative of 5-oxo-A-nor-3,5-secondrate-3-oewoi acid of formula IV by oxidation, for example by exposure to aqueous sodium permanganate and paradata sodium under normal conditions at reflux distilled t-butanol.

In step 3, the compound of formula IV is converted to the corresponding compound of formula IVa by exposure to a compound with the formula NH2R1such as ammonia (R1=N) or methylamine (R1=methyl), at elevated temperature in a proton or an aprotic solvent, for example at reflux distilled ethylene glycol.

The compounds of formula I can also be prepared by the mutual transformation of other compounds of formula I. for Example, the process shown in scheme IB can be used to prepare the compounds of formula I, where is a double bond between carbon atoms 1 and 2 and R1is hydrogen, i.e. the compounds of formula Ib from the corresponding compounds of formula I, i.e. compounds of formula Ia.

< / BR>
In scheme IB connection forms the I dehidrasinya system, for example 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bis(tri-methylsilyl)trifurcated in dry dioxane at room temperature for 2-5 h followed by heating at reflux distilled in 10-20 h (cm. Bhattacharya, A. et al., J. Am.Chem.Soc., 110, 3318 (1988).

< / BR>
Alternatively in scheme II, compounds of formula I, in which the carbon atoms 1 and 2 are connected by a double bond, can be prepared from 3-oxo-4-Aza-5-androst-1-ene-17 - carboxylic acids of the formula V by reaction with a compound of formula IIa as described in scheme IA, step 1. The compounds of formula V in which R2is hydrogen, can be prepared by the method Rasmusson, G. H. et al., J. Med. Chem., 29, 2298 (1986). The compounds of formula V in which R2is methyl, can be prepared in accordance with the scheme IIa.

< / BR>
< / BR>
< / BR>
< / BR>
In Step 1, the compound of formula (VI), where JO is protected by a hydroxy-group, such as triisopropylsilane, a CO2Alk is a group of ether carboxylic acids, for example methyl ester, reacts with strong oxidizing complex of heavy metal, such as chromic acid/3,5-dimethyl pyrazole in an aprotic solvent, such as dichloromethane, to form the corresponding compound of formula (VII). The compounds of formula (VI) no PCT W0 94/14833. For example, the methyl ester of 3-hydroxyethanoic acid may react with the reagent, protecting the hydroxy-group, such as triisopropylsilane, in the presence of a base such as imidazole in an aprotic solvent such as dimethyl of formamide or dichloromethane, at moderate temperatures from 25 to 55oC.

In stage 2 fragment 7-oxo compounds of formula VII is converted to the corresponding alkyl group such as methyl group, by influencing withouy reagent with subsequent catalytic hydrogenation and removal of protection with 3-hydroxy-group with formation of the corresponding compounds of formula VIII. For example, the compound of formula VII may react with methyl iodide triphenylphosphine and n-butyl lithium in an aprotic solvent such as tetrahydrofuran, in a temperature range from about -5 to 10oC, for example at 0oC, with the formation of the corresponding 7-alkylidene derived. Ekzoticheskaya double bond can then be selectively restored by exposure to chloride Tris(triphenylphosphine)rhodium in a hydrogen atmosphere with the formation of predominantly substituted 7-alkyl compounds. Protecting group at the 3-hydroxy then removed from the neck by treatment with tetrabutylammonium fluoride in tetrahydrofuran.

On stage 3 of 3-hydroxy-group of compounds of formula VIII is oxidized to form the corresponding 3-oxo-fragment with migration of the double bond with the formation of the compounds of formula IX. For example, the oxidation may be carried out by Jones reagent in alkylene, such as acetone, at a temperature approximately equal to the room.

In step 4, the compound of formula IX is oxidized by a method similar to that described in step 2 of scheme Ia with the formation of the corresponding derivative of 5-oxo-A-nor-3,5-secondrate-3-oewoi acid of formula X.

In step 5, the compound of formula X is converted to the corresponding compound of formula XI by the method similar to that described in scheme I.

In step 6, the compound of formula XI dehydrogenases manner similar to that described in scheme IB, with the formation of the corresponding 4-Aza-5-androst-1-EN-3-about the derivative. Group ether 17-carboxylic acid is then converted by saponification to the corresponding group 17-carboxylic acid with the formation of compounds of formula V. for Example, the group of ether carboxylic acids can be converted into a carboxyl group by exposure to medium to strong base in the proton or an aprotic solvent, for example an impact guy who="ptx2">

It is obvious that in the early stages of preparation of the compounds of formula I or its MES may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.

Protecting groups used in the compounds of formula I can be used in the usual way. For example, see Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie, Plenum Press, London (1973) or Protective Groups in Organic Synthesis, Theodora Green. John Wiley and Sons, New York (1981).

Delete any existing protecting groups can be performed in the usual way. Arylalkyl group, such as benzyl, can be chipped off by hydrogenolysis in the presence of a catalyst such as palladium carbon; acyl group such as N-benzyloxycarbonyl can be removed by hydrolysis, for example with hydrogen bromide in acetic acid, or by restoring, for example by catalytic hydrogenation.

Obviously, in any of the above mentioned General processes may be desirable or even necessary to protect any sensitive groups of molecules, as has just been described. Thus, the phase response, which includes deprotecting protected derivative of General formula I, or it is provided with a further aspect of the invention, these reactions may, if necessary and/or desirable to be done in any acceptable sequence followed by any of the General processes:

(i) removing any protecting groups; and

(ii) the conversion of compounds of formula I or its MES its pharmaceutically acceptable MES.

In addition to use in the last major stage of the sequence of preparation, the General methods described above for preparing compounds of this invention may also be used for introduction of the desired groups at intermediate stages of the preparation of the desired compounds. Therefore, you should note that in such multi-stage processes the sequence of reactions should be selected so that the conditions of the reactions did not affect the existing groups in the molecule, which is desired in the final product.

The compounds of formula I and intermediate II - XI indicated in schemes I and II can be cleaned by known conventional methods, for example by chromatography or crystallization.

The In vitro tests.

5-Reductase steroids.

The enzymatic activity can be determined using microsomes obtained from 1) the tissue is recombinantly baculovirus SF9 cells, which produce human 5-reductase type 1; or 3) infected with recombinant baculovirus SF9 cells that produce human 5-reductase type 2. Microsome assay were prepared by homogenization of tissue or cells with subsequent differential centrifugation of the homogenate. Extracts of microsomes were incubated with different concentrations of [1,2,6,7-3H]-testosterone, 1 mm NADP-H and varying amounts of compounds of the formula I, i.e. the test compound in buffer containing regeneration system NADP-H, capable of maintaining the concentration of NADP-N during the period from 0.5 to 240 minutes. As a control study was carried out appropriate incubation without test compounds.

For measurement IC50type 1 components of the sample, except for testosterone, preincubating for 10 minutes at pH 7.0, and after adding 100 nm testosterone samples were left to undergo reaction for 10-120 minutes For measurement IC502 type the sample components, except for testosterone, preincubating for 20 minutes at pH of 6.0, and after adding 8 nm testosterone samples were left to undergo reaction for 20-40 minutes. The percentage conversion of testosterone to DHT in the presence of testirovanie high-performance liquid chromatography (HPLC) with radiochemical detection. The results of these tests are provided as IC50listed in the table.

3-Hydroxy-5-steroid dehydrogenase/3-keto-5-steroid isomerase.

The enzymatic activity is determined using microsome assay, obtained from the tissues of the adrenal gland of man. Microsome assay were prepared by homogenization of tissue or cells with subsequent differential centrifugation of the homogenate. Extracts of microsomes were incubated with different concentrations of DHEA (dehydroepiandrosterone), 1 mm NAD+and various concentrations of compounds of formula I, i.e., test compounds, in a buffer with a pH of 7.5 during the period from 1 to 60 minutes. As a control study was carried out appropriate incubation without test compounds.

The percentage conversion of DHEA to Androstenedione in the presence of test compounds in comparison with the corresponding transformation in the control study was assessed using HPLC with radiochemical detection. The results of these analyses are given as Kilisted in the table.

In vivo evaluation of an inhibitor of 5-reductase steroids.

The activity of an inhibitor of 5-reductase steroids in vivo can be determined Sy, daily treated with testosterone at a dose of 20 μg per rat subcutaneously and test compounds (0.01 to 10 mg/kg) or oral media for 7 days. Then the animals were wordplays and their prostate glands were weighed. Reducing the weight of the prostate gland stimulated by testosterone, showed activity of the tested compounds. Simultaneously tested known inhibitors of steroid 5-reductase order to ensure consistency of research method.

Applicability.

Inhibitors of 5-reductase steroids described in this invention, useful in the treatment of androgen-reactive diseases, such as benign and malignant diseases of the prostate, particularly benign prostatic hyperplasia, in a manner similar to how apply other inhibitors of 5-reductase, such as finasteride and SKF105657. On the issue of correlation of in vitro data, in vivo in rats and clinical data in humans regarding the inhibitor of 5-reductase, see Stoner, E. et al., J. Steroid Biochem. Molec. Biol., 37, 375 (1990); Brooks, J. R. et al. , Steroids, 47, 1 (1986) and Rasmusson, G. H. et al., J. Med.Chem, 29, 2298 (1986)).

The compounds of this invention are also useful in the treatment of prostatitis, prostate cancer, TNA is these hormones diseases, for example, polycystic ovaries, can also be treated by these compounds.

The amount of the compounds of formula I required to effect the action as an inhibitor of 5-reductase, is, of course, vary in different individual animals, and shall be fully define the attending physician or veterinarian. Factors to be considered include curable disease, mode of administration, the nature of the drug, the body weight of the mammal, surface area, age and General condition, and specific applicable connection. However, an appropriate effective inhibiting 5-reductase dose is in the range from about 0.001 to about 2 mg/kg of body weight per day, preferably in the range 0.005 to about 1 mg/kg / day.

The total daily dose may be given as a single dose, multiple doses, for example from 2 to 6 times a day, or intravenous injection of specified duration. Doses in excess of the limits specified above, or not reaching them, are included in the present invention and can be used in individual patients, if this is desirable or necessary. For example, for a mammal weighing 75 kg, the dose range will be from about 0.4 mg to about 75 mg per day, and a typical dose will be pri formula I, given 4 times a day.

Drugs.

The preparations of the present invention for use in medicine are from the beginning of the current, i.e. the compounds of formula I, and its acceptable carrier and optionally other therapeutically active ingredients. The carrier must be pharmaceutically acceptable in the sense of compatibility with other ingredients of the drug and the lack of harm to the recipient.

Therefore, this invention further provides a pharmaceutical preparation consisting of the compounds of formula I and its pharmaceutically acceptable carrier.

Drugs include suitable for oral, rectal, local or parenteral (including subcutaneous, intramuscular and intravenous) administration forms. Preferred forms suitable for oral or parenteral use.

Drugs can be conveniently provided in the form of a metered filling and can be prepared by any methods well known in the art of pharmacy. All methods include the step of combining the current start with the carrier comprising one or more additional ingredients. Usually drugs prigotovlyaemym solid carrier and then, if necessary, shaping the product form desired metered filling.

The preparations of the present invention suitable for oral administration may be presented as discrete units such as capsules, tablets, lozenges, or pills, each of which contains a predetermined amount of current the beginning; as a powder or granules; or as a suspension or solution in an aqueous liquid or non-aqueous liquid such as a syrup, elixir, emulsion or hood.

A tablet may be prepared by compressing or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable device acting early in free-flowing form such as powder or granules, mixed optionally with additional ingredients, such as binders, lubricants, inert solvents, surface-active or distributing agents. Molded tablets may be prepared by forming a mixture of a powder of the current start with any suitable carrier in a suitable device.

The syrup or suspension can be prepared by adding a de is to be added any additional ingredients. Such additional ingredients may include a flavoring agent, retarding the crystallization of the sugar or an agent to increase the solubility of any other ingredient, such as polyhydric alcohol, such as glycerol or sorbitol.

Preparations for rectal application can be presented in the form of candles with conventional media, such as cocoa butter or Witepsol S55 (trademark Dynamite Nobel Chemical, Germany) as the basis of a candle.

Preparations suitable for parenteral use, traditionally consist of a sterile introductory solution acting early, preferably isotonic with the blood of the recipient. Thus, these preparations may contain distilled water, 5% dextrose in distilled water or saline solution. Used drugs also include concentrated solutions or solids containing the compound of the formula I, which upon dilution with appropriate solvent give above are suitable for parenteral use solution.

Local preparations include ointments, creams, gels and lotions, which can be prepared by conventional methods known in the pharmaceutical industry. In addition to acting on what the loud and additional pharmaceutically active agents.

In addition to the aforementioned ingredients, the preparations of this invention may also include one or more additional ingredients used in pharmaceutical preparations, such as diluents, buffers, flavoring agents, binding agents, surface-active agents, thickeners, lubricants, suspendida agents, preservatives (including antioxidants), etc.

The following examples illustrate aspects of the present invention, but should not be construed as limitations. Symbols and descriptions used in these examples, match those used in modern chemical literature, such as Journal of the American Chemical Society.

Example 1.

17 - N-1-(4-Chlorophenyl)cyclopentanecarbonyl-4-Aza-5-androstane-3-one (compound 1).

A. 17 - N-1-(4-Chlorophenyl)cyclopentanecarbonyl-androst-4-EN-3-one.

To a suspension of 3-oxo-4-androsten-17-carboxylic acid (Rasmusson, G. H. et al., J. Med.Chem., 27, 1690 (1984)) (10,44 g, from 32.9 mmol) in toluene (330 ml) and dry pyridine (3.75 ml) at 0oC is added thionyl chloride (3.6 ml, 49 mmol). The reaction mixture is stirred for 15 minutes at 0oC and then stirred at room temperature for 1 hour. Then Rea chlorophenyl)-cyclopentane (12,90 g, 65,9 mmol; prepared Kurtasovoj rearrangement of the corresponding acid), then heated to room temperature and stirred over night. Then the reaction mixture was sequentially extracted 1N HCl, 10% NaOH, water and brine, dried on sodium sulfate and filtered. The filtrate is concentrated and subjected to flash chromatography on silica gel, elwira 35-50% gradient ethyl acetate-hexane to give, after concentration, 17-N-1-(4-chlorophenyl) cyclopentanecarbonyl-androst-4-EN-3-one in the form of a white foam; yield: 8.44 grams (52%).

B. 17-N-1-(4-Chlorophenyl) cyclopentanecarbonyl-5-oxo-A-nor-3,5 - secondrate-3-oeva acid.

Located at reflux distilled solution of 17-N-1-(4-chlorophenyl) cyclopentanecarbonyl-androst-4-EN-3-one (8.44 grams of 17.1 mmol), prepared as described above at the stage A, t-butanol (130 ml), sodium carbonate (3,18 g, 25.6 mmol) and water (35 ml) for 35 minutes, add at the 75oC solution of potassium permanganate (0,67 g, 4.3 mmol), periodate sodium (25,57 g, 120 mmol) and water (190 ml). After an additional 35 minutes reflux distilled heterogeneous mixture is cooled to room temperature, filtered through a layer of brownmillerite, the hard part is rinsed out with water and the filtrate concentrated the t with CH2Cl2(Chml). Phase CH2Cl2are combined and are washed with water, dried on sodium sulfate, filtered and concentrated in vacuo to obtain 17-N-1-(4-chlorophenyl) cyclopentanecarbonyl-5-oxo-A-nor-3,5 - secondrate-3-oewoi acid in the form of a whitish solid; yield: 7.30 g (crude 83%).

This material is directly transferred to the following stage C.

C. 17-N-1-(4-Chlorophenyl) cyclopentanecarbonyl-4-Aza-androst-5-ene-3-one.

To a suspension of 17-N-1-(4-chlorophenyl) cyclopentanecarbonyl-5 - oxo-A-nor-3,5-secondrate-3-oewoi acid (4,78 g of 9.30 mmol) obtained in step B, in dry ethylene glycol (20 ml) at -5oC add ammonia (RASSC. 3.5 ml, 0.14 mol) and the mixture is stirred for 30 minutes at 0oC. the Resulting solution is heated to 170oC for 1 hour and after 1 hour at a temperature of 170oC, the reaction mixture is cooled to 30oC and add water. The resulting suspension is diluted 1N HCl, extracted with chloroform (4x100 ml), after which the extract is dried on sodium sulfate, filtered and concentrated to obtain 17-N-1-(4-chlorophenyl)cyclopentanecarbonyl-4-Aza-androst-5-ene-3-one in the form of a brown solid; yield 5,08 g (untreated 100%). This material ne-androstane-3-one.

To a solution of 17-N-1- (4-chlorophenyl)cyclopentanecarbonyl-4-Aza - androst-5-ene-3-one (see above, Rasch. of 9.30 mmol) in acetic acid (120 ml) is added platinum oxide (0.32 g). The resulting mixture nastorazivayut to 56 psi and incubated for 5 hours at 75oC, then cooled to room temperature over night. After replacing the hydrogen atmosphere of nitrogen, the reaction mixture was filtered through celite (brownmillerite) and caltowie plates are washed CH2Cl2. Add toluene and the filtrate concentrated in vacuo to an oil, purified by flowing chromatography (toluene/acetone/ethyl acetate, 6: 3: 1 to 1:3:1) to give 17 - N-1-(4 - chlorophenyl)cyclopentanecarbonyl-4-Aza-5-androstane-3-one in the form of a mixture with the corresponding 17 primary amidon; output: 0,69 g (15%). Further purification of this material by HPLC (column Hypersil BDS C8, 50% of CH3CN/water) and triturate hot ethyl acetate to give a pure sample: melting point 261-263oC, composition, Rasch. for C30H41ClN2O21/4H2O: C 71,83; H A 8.34; N 5,58. Found: C 71,85; H 8,23; N 5,59.

Example 2.

17-N-1- (4-Chlorophenyl)cyclopentanecarbonyl-4-methyl-4-Aza-5-androstane-3-one (compound 2).

Starting with 17-N-1(4-chlorophenyl)cyclopentanecarbonyl-5 - oxo-A-nor-the s C and D, with the replacement of ammonia methylamine in stage C prepare 17-N-1- (4-chlorophenyl) cyclopentanecarbonyl-4-methyl-4-Aza-5-androstane-3-one, melting point 125-130oC.

Composition, Rasch. for C31H43ClN2O21/2H2O: C 71,37; H SCORED 8.38; N 5,31.

Found: C Of 71.58; H 8,53; N 5,39.

Example 3.

17-N-1- (4-Chlorophenyl)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one (compound 3).

To a suspension of 3-oxo-4-Aza-5-androst-1-ene - 17-carboxylic acid (Rasmusson, G. H. et al., J. Med.Chem., 29, 2298 (1986)) (0,159 g, 0.50 mmol) in toluene (5 ml), dimethylformamide (0.5 ml) and pyridine (0.06 ml, 0.7 mmol) at 0oC add thionyl chloride (0.05 ml, 0.7 mmol). After 15 minutes the ice bath removed and the reaction mixture self-heated to room temperature. After 1 hour the reaction mixture was concentrated in vacuo. The residue is dissolved in dry CH2Cl2and 1-amino-1-(4-chlorophenyl)-cyclopentane (0,49 g, 2.5 mmol; prepared Kurtasovoj rearrangement of the corresponding acid) is added at room temperature followed by addition of 4-N,N-dimethylaminopyridine (0,061 g, 0.50 mmol). After 4 hours, add 1N HCl, the mixture is extracted with CHCl3(3x100 ml), then CHCl3dried on MgSO4filter and concentrate. The remainder of logo substances in concentrations. This material tracuriroot with ethyl acetate to obtain 17-N-1-(4-chlorophenyl) cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one as a white solid; yield: 129 mg (52%); melting point 307-309oC (decomposition).

Composition, Rasch. for C30H39ClN2O2: C 72,78; H 7,94; N 5,66.

Found: C 72,59; H Of 7.93; N, 5,54.

Examples 4-21.

These compounds were prepared by the method described in example 3. Amines, available on the market, were prepared by a method described in the PCT application WO 94/14833.

Example 4.

17-N-1- (4-t-Butylphenyl)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one (compound 4).

Melting point: 282-285oC.

Composition, Rasch. for C34H48N2O21/4H2O: C 78,34; H 9,38; N LOWER THAN THE 5.37.

Found: C 78,29; H 9,40; N 5,38.

Example 5.

17-N-1- (4-t-Butylphenyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one (compound 5).

Melting point: 233-236oC.

Composition, Rasch. for C35H50N2O21/2H2O: C 77,88; H 9,52; N 5,19.

Found: C 77,82; H 9,54; N To 5.21.

Example 6.

17-N-1- (4-Chlorophenyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one (compounds is B>O2: C 73,13; H 8,12; N 5,50.

Found: C 73,06; H 8,14; N 5,47.

Example 7.

17-N-1-. (4-Triptoreline)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one (compound 7).

Melting point: 294-297oC.

Composition, Rasch. for C31H39F3N2O2: C 70,43; H 7,44; N 5,30.

Found: C 70,34; H 7,46; N 5,23.

Example 8.

17-N-1- (4-Methoxyphenyl)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one (compound 8).

Melting point: 257-260oC.

Composition, Rasch. for C31H42N2O3: C 75,88; H 8,63; N 5,71.

Found: C 75,86; H To 8.57; N The Ceiling Of 5.60.

Example 9.

17-N-1- (4-Forfinal)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one (compound 9).

Melting point: 290oC.

Composition, Rasch. for C30H39FN2O2: C TO 75.28; H 8,21; N 5,85.

Found: C 75,09; H Compared To 8.26; N 5,75.

Example 10.

17-N-1- (4-Forfinal)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one (compound 10).

Melting point: 283-285oC.

Composition, Rasch. for C31H41FN2O2: C 75,58; H 8,39; N 5,69.

Found: C 75,63; H 8,45; N 5,67.

PrimeMinister melting point: 238-240oC.

Composition, Rasch. for C32H44N2O31/4H2O: C 75,48; H 8,81; N 5,50.

Found: C 75,42; H 8,78; N 5,51.

Example 12.

17-N-1- (3,4-Methylenedioxyphenyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one (compound 12).

Melting point: 255-257oC.

Composition, Rasch. for C32H42N2O4: C 74,10; H 8,16; N 5,40.

Found: C 74,07; H 8,17; N Lower Than The 5.37.

Example 13.

17-N-1- (4-t-Butylphenyl)cycloheptylmethyl-4-Aza-5-androst-1-EN-3-one (compound 13).

Melting point: 152-162oC.

Composition, Rasch. for C36H52N2O21/2 H2O: C 78,07; H 9,65; N IS 5.06.

Found: C 78,11; H For 9.64; N 5,04.

Example 14.

17-N-1- (4-t-Butylphenyl)tetrahydropyranyloxy-4-Aza-5-androst-1-EN-3-one (compound 14).

Melting point: 240-242oC.

Composition, Rasch. for C34H48N2O3: 533,375143.

Found: 533,37512 (-1,5 ppm).

Example 15.

17-N-1- (2,4-Dichlorophenyl)cyclopropanecarbonyl-4-Aza-5-androst-1-EN-3-one (compound 15).

Melting point: 297-298oC.

Composition, Rasch. for C28H34Cl

17-N-1- (4-Triptoreline)-2,2-diethylcarbamoyl - 4-Aza-5-androst-1-EN-3-one (compound 16).

Melting point: 225-228oC.

Composition, Rasch. for C33H43F3N2O2: C 71,20; H 7,79; N 5,03.

Found: C 70,92; H To 7.77; N 4,99.

Example 17.

17-N-1- (4-t-Butylphenyl)-4,4-dimethylcyclohexylamine-4-Aza-5-androst-1-EN-3-one (compound 17).

Melting point: 172-175oC.

Composition, Rasch. for C37H54N2O21/3H2O: C 78,68; H 9,76; N 4,96.

Found: C 78,58; H RS 9.69; N 4,74.

Example 18.

17-N-1- (4-t-Butylphenyl)-4-t-butylcyclohexanol-4-Aza-5-androst-1-EN-3-one (compound 18).

Melting point: 189-194oC.

Composition, Rasch. for C39H58N2O2: C 79,81; H 9,96; N 4,77.

Found: C Of 79.65; H 9,89; N 4,75.

Example 19.

17-N-1- (3-Triptoreline)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one (compound 19).

Melting point: 258-260oC.

Composition, Rasch. for C31H39F3N2O2: C 70,43; H 7,44; N 5,30.

Found: C 70,35; H 7,39; N 5,30.

Example 20.

17-N-1- (4-t-Butyltin-268oC.

Composition, Rasch. for C34H48N2O2S H2O: C 72,04; H 8,89; N 4,94.

Found: C 72,19; H 8,54; N 4,92.

Example 21.

17-N-1- (4-Biphenyl)-2,2-diethylcarbamoyl-4-Aza-5-androst-1-EN-3-one (compound 21).

Melting point: 167-174oC.

Composition, Rasch. for C38H48N2O21/2H2O: C 79,54; H 8,61; N 4,88.

Found: C 79,34; H 8,43; N 4,76.

Example 22.

17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-4-Aza-5-androstane-3-one (compound 22).

A. 17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-androst-4-EN-3-one.

To a solution of 3-oxo-4-androsten-17-carboxylic acid (Rasmusson, G. H. et al., J. Med.Chem., 27, 1690 (1984)) (17,2 g of 54.4 mmol), dry THF (180 ml) and dry pyridine (7 ml) at a temperature of 2oC add titillated (5,1 ml, and 70.8 mmol). The reaction mixture was stirred for 2oC for 20 minutes and then stirred at room temperature for 40 minutes. The reaction mixture was then filtered and the solid part was washed with toluene. The filtrate is concentrated in vacuo to an oil, which is diluted with dry THF (150 ml) and dry pyridine (7 ml). To the resulting dark solution was added 2,5-bis-(trifluoromethyl)aniline (9.4 ml, to 59.8 mmol) straitout 1N HCl and brine, dried on sodium sulfate and filtered. The filtrate is concentrated and chased through a column of 500 g of silica gel and the column with 15-30% gradient ethyl acetate/hexane to give, after concentration, 17-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-androst-4-EN-3-one in the form of a white foam; yield: 18.3 g (64%).

B. 17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-5-oxo-A-nor-3,5 - secondrate-3-oeva acid.

Located at reflux distilled solution of 17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-androst-4-EN-3-one (18.3 g, is 34.9 mmol), prepared as described above at the stage A, t-butanol (275 ml), sodium carbonate (6.3 g, 50.8 mmol) and water (36 ml) for 45 minutes add at the 75oC solution of potassium permanganate (or 0.38 g, 2.4 mmol), periodate sodium (52,2 g, 245 mmol) and water (311 ml). After an additional 15 minutes reflux distilled heterogeneous mixture is cooled to room temperature and to it was added celite (50 g). The reaction mixture was filtered through a layer of celite, the solid part was washed with water, and the filtrate concentrated in vacuo to remove t-butanol (175 ml). The resulting aqueous solution is acidified to pH 2 with 36% HCl and then extracted four times with chloroform. Layers of chloroform are combined and are washed with water, salt, RA is ethyl))phenylcarbamoyl-5-oxo-A-nor-3,5 - secondrate-3-oewoi acid in the form of a whitish solid; yield: 20.5 g (untreated 100%). This material is directly transferred to the following stage C.

C. 17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-4-Aza-androst-5-ene-3-one.

To a suspension of 17-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-5 - oxo-A-nor-3,5-secondrate-3-oewoi acid (20.5 g, 34.8 mmol) obtained in step B, in dry ethylene glycol (100 ml) at room temperature for 5 minutes, add ammonia (about 8 ml, 0.32 mol). The resulting solution is heated to 180oC for 45 minutes, incubated for 12 minutes at a temperature of 180oC, the reaction mixture is cooled to 70oC for 5 minutes add water (116 ml). The resulting suspension is cooled to 7oC, stirred for 10 minutes and filtered under vacuum. The solid part was washed with water (60 ml) and then dissolved in chloroform, washed with water and saline solution, dried on sodium sulfate, filtered and concentrated. The residue is dissolved in chloroform and expanded through a column with 110 g of silica gel and the column was washed with a gradient of isopropanol-chloroform 2-5% with obtaining 17-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-4-Aza-androst-5-ene-3-one in the form of a whitish solid; yield 16.5 g (90%).

D. 17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-4-Aza-5-Andros is kusnoy acid (120 ml) is added platinum oxide (0.9 g). The resulting mixture nastorazivayut up to 50 psi and incubated for 6 hours at 60 - 70oC. After replacing the hydrogen atmosphere of nitrogen, the reaction mixture was filtered through celite and caltowie plates are washed with acetic acid (30 ml), chloroform (60 ml) and toluene (200 ml). The filtrate is concentrated in vacuo to an oil, add toluene (200 ml) and the solution concentrated in vacuo to a foam. The foam is crystallized from ethyl acetate-heptane, and after drying in vacuo at 85oC for 1 hour, I get 17-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-4-Aza-5-androstane-3-one; yield: 4,78 g (54%); melting point 245-247oC.

The composition, about to C27H32F6N2O2: C 61,12; H BETWEEN 6.08; N 5,28.

Found: C 61,13; H 6,12; N To 5.21.

Example 23.

17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-4-methyl-4-Aza-5-androstane-3-one (compound 23).

A. 17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-4-methyl-4-Aza-androst-5-ene-3-one.

To a suspension of 17-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-5-oxo-A-nor-3,5-secondrate - 3-oewoi acid (1.7 g, 3.1 mmol) from example 1, stage B, in dry ethylene glycol (8.5 ml) at room temperature add methylamine (about 1 ml of 22.5 mmol) and the resulting solution is heated to 180oC for 1 hour. Feature and add water (10 ml). The reaction mixture was stirred at the 7oC for 10 min and filtered under vacuum. The solid part was washed with water and then dissolved in chloroform, washed with water and saline solution, dried on sodium sulfate, filtered and concentrated. Balance is maintained through the column with 110 g of silica gel and the column with a gradient of methanol-methylene chloride 2-5% with obtaining 17-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-4-methyl-4-Aza-androst-5-ene-3-one in the form of a white foam; yield: 1,11 g (66%).

B. 17-N-(2,5-bis (Trifluoromethyl))phenylcarbamoyl-4-methyl-4-Aza-5-androstane-3-one.

To a solution of 17-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-4-methyl-4-Aza-androst-5-ene-3-one (1.0 g, 1.9 mmol) in acetic acid (10 ml) is added platinum oxide (0.10 g). The resulting mixture nastorazivayut up to 50 psi and incubated for 45 min at 60-70oC. After replacing the hydrogen atmosphere of nitrogen, the reaction mixture was filtered through celite, and caltowie plates are washed with acetic acid (10 ml), chloroform (60 ml) and toluene (30 ml). The filtrate is concentrated in vacuo to an oil, add toluene (30 ml) and the solution concentrated in vacuo to a foam. Material twice subjected to chromatography on 93 g of silica gel with a gradient of methanol-methylene chloride 2-4% with the obtain, after drying in vacuo the RA melting point 103-105oC.

The composition Rasch. for C28H34F6N2O2: C 61,76; H 6,29; N 5,14.

Found: C 61,60; H 6,32; N 5,08.

Example 24.

17-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one (compound 24).

To a suspension of 3-oxo-4-Aza-5-androst-ene-17-carboxylic acid (Rasmusson, G. H. et al., J. Med.Chem., 29, 2298 (1986)) (0,021 g 0,063 mmol), dry methylene chloride (6 ml) and dry pyridine (8.1 ml, 0.1 mmol) at 0oC add thionyl chloride (6.8 ml, 0,095 mmol). The ice bath removed and the reaction mixture self-heated to room temperature. After 1 hour, add toluene (1 ml) and the reaction mixture is concentrated in vacuo. The residue is dissolved in dry methylene chloride (1.5 ml) and dry pyridine (8.5 ml, 0.11 mmol), and at room temperature, add 2-t-butyl-5-triptorelin (0,023 g, 0,126 mmol). After 13 hours add methylene chloride (20 ml) and the reaction mixture was washed with 1 M sulfuric acid, saturated sodium bicarbonate solution and saline solution, dried on sodium sulfate, filtered and concentrated in vacuo. The residue is subjected to chromatography on 7 g of silica gel with a gradient of methanol-methylene chloride 2,5-5% with obtaining 0.01 g of a white foam. This material is crystallized from ethyl acetate-hexanol is a; melting point 263-264oC.

Mass spectrometry (m/z =517 MN+.

Example 25.

17-N-(2-t - Butyl-5-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androstane-3-one (compound 25).

Compound 25 is prepared as described in example 1 using the appropriate quantity of 2-t-butyl-5 - triptorelin instead of 2,5-bis(trifluoromethyl)-aniline.

Melting point: 256-259oC.

Composition, Rasch. for C30H41F3N2O2: C 69,47; H OF 7.97; N 5,40.

Found: C 69,49; H 8,00; N 5,41.

Example 26.

17-N-(2-t - Butyl-5-trifluoromethyl)phenylcarbamoyl-4-methyl-4-Aza-5-androstane-3-one (compound 26).

Compound 26 is prepared by a method similar to that described in example 3.

Melting point: 229-232oC.

Composition, Rasch. for C31H43F3N2O2: C 69,90; H 8,14; N 5,26.

Found: C 69,79; H 8,07; N 5,19.

Example 27.

17-N-(2,5-Di-t - butyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one (compound 27).

Compound 27 is prepared by a method similar to that described in example 3.

Melting point: 165-171oC (decomposition).

9,51; N 5,43.

Example 28.

17-N-(2,5-Di-t-butyl) phenylcarbamoyl-4-Aza-5 - androstane-3-one (compound 28).

Compound 28 is prepared as described in example 1 using the appropriate amount of 2,5-di-1-butylaniline instead of 1-amino-1-(4-chlorophenyl)cyclopentene.

Melting point: 162-164oC.

Composition, Rasch. for C33H50N2O21/4H2O: C 77,52; H 9,96; N 5,48.

Found: C 77,58; H Becomes 9.97; N 5,58.

Example 29.

17-N-(2,5-Di-t-butyl) phenylcarbamoyl-4-methyl-4-Aza-5-androstane-3-one (compound 29).

Compound 29 is prepared by a method similar to that described in example 2.

Melting point: 150-152oC.

Composition, Rasch. for C43H52N2O2: C 78,41; H 10,06; N 5,38.

Found: C 78,17; H 0.01; N 5,33.

Example 30.

17-N- (2,5-bis(Trifluoromethyl)) phenylcarbamoyl-4-Aza-7-methyl-5-androst-1-EN-3-one (compound 30).

A. Methyl ether 3-triisopropylchlorosilane acid.

A suspension of methyl ester 3-hydroxyethanoic acid (J. Med.Chem. 27, 1690) (516 g, 1.55 mol) in DMF (800 ml) is heated to 55oC, with the active mechanical stirring, imidazo the Xia homogeneous after adding about half of triisopropylsilane, and the reaction temperature increased to about 70oC. the Reaction is complete TLC (35% ethyl acetate/hexane) 1.5 hours and formed a thick suspension. The reaction mixture was cooled to 0oC, with stirring, add 1 l of ice water, the solid part is collected by filtration and washed with water (500 ml) and methanol (500 ml). The resulting brown solid is suspended in methanol (1 l) and left to stir over night with obtaining after filtering methyl ester 3-triisopropylchlorosilane acid in the form of a brown solid substance purity sufficient for the subsequent stages.

B. Methyl ether 3-triisopropylsilane-7-oxo-atenolol acid.

To a suspension of ammonium sulphate (50,7 g, 507 mmol) in dichloromethane (175 ml) at 0oC add 3,5-dimethylpyrazol (48,7 g, 507 mmol) and the reaction mixture is stirred for 30 minutes. Then add methyl ester 3-triisopropylchlorosilane acid, prepared in Step A, (31 g, and 63.4 mmol) in dichloromethane (120 ml) and the reaction mixture left to stir at medium temperature for 21 hours. Then add an aqueous solution of NaOH (2N, 100 ml), followed by celite (200 CC), the reaction mixture is filtered the organic portion was washed with 2N NaOH, water and saturated aqueous NaCl and dried on MgSO4and the solvent is removed in a rotary evaporator. The residue is subjected to flash chromatography on silica gel (5-15% ethyl acetate/hexane) to give the methyl ester of 3-triisopropylsilane-7-oxo-atenolol acid as a white solid; yield: 13.8 g (43%).

Composition, Rasch. for C30H50O4Si: C 71,66; H 10,2.

Found: C 71,43; H 10,10.

C. Methyl ether 3-triisopropylsilane-7-atenolol acid.

To a suspension of potassium iodide methyltriphenylphosphonium (14 g, 34.6 mmol) in tetrahydrofuran (THF, 60 ml) at 0oC add n-utility (21,7 ml, 1.6 M in hexane, to 34.7 mmol). After stirring for 20 min, add a solution of methyl ester of 3-triisopropylsilane-7-oxo-atenolol acid (8,72 g, 17.3 mmol) in 25 ml of THF and, after 10 minutes add water (120 ml) and then saturated aqueous solution of NaHSO4(15 ml). The product is then extracted with ethyl acetate, dried on MgHSO4, concentrated to about 50 ml, is treated with chloride, Tris(triphenylphosphine)rhodium (460 mg, 0.51 mmol) and stirred overnight in a hydrogen atmosphere. The catalyst was filtered through a plug of silica gel, and then the filtrate is condensed and subjected to fluorescence - methyl-atenolol acid as a white foam; output: the 4.29 g of a mixture of 3:1 epimeres 7-7 (86%).

Composition, Rasch. for C31H54ABOUT3Si: C 74,04; H 10,82.

Found: C 74,15; H 10,88.

D. Methyl ester of 3-hydroxy-7 - methylethanol acid.

To a solution of methyl ester of 3-triisopropylsilane-7-methyl-atenolol acid (4,25 g, to 8.45 mmol) in 25 ml THF added tetrabutylammonium fluoride (17 ml, 1 M in THF, 17 mmol) followed by stirring at room temperature for 6 hours. Added water (100 ml) and ethyl acetate (150 ml), the organic portion washed with water and saturated aqueous NaCl, dried on MgSO4and concentrate. The resulting concentrate is subjected to flash chromatography on silica gel (25-40 % ethyl acetate/hexane) to give the methyl ester of 3-hydroxy-7 - methylethanol acid: yield: 2.65 g (90%).

Composition, Rasch. for C22H34ABOUT31/4H2O: C TO 75.28; H TO 9.91.

Found: C 75,67; H 9,98.

E. 17 Carbomethoxy-7-methyl-androst-4-EN-3-one.

To a solution of methyl ester of 3-hydroxy-7-methylethanol acid (6.6 g, 19 mmol) in 220 ml of acetone add 7.5 ml of Jones reagent (3.1 M, with 23.3 mmol), the reaction mixture is stirred for 1 hour and concentrated to about 40 ml of the Resulting residue was the comfort and subjected to flash chromatography on silica gel (35% ethyl acetate/gascan) to obtain 17 carbomethoxy-7-methyl - androst-4-EN-3-one as a yellow oil; output: 2,73 g (42%); mass spectrometry high resolution, Rasch. for [MN+] C22H33O3: 345,2430 found:

F. 17 Carbomethoxy-7-methyl-5-oxo-A-nor-3,5-secondrate-3 - oeva acid.

To a solution of 17-carbomethoxy-7-methyl-androst-4-EN-3-one (2.9 g, 8.4 mmol) in 60 ml of tert-butanol are added sodium carbonate (1.04 g, 8.4 mmol) in 6 ml of water, the suspension of periodate sodium (9 g, 42 mmol) and potassium permanganate (134 mg, 850 mmol) in about 35 ml of water and the reaction mixture is heated at reflux distilled within 48 hours. After cooling to room temperature the solid part is removed by filtration, washed with water and concentrated leaving an aqueous residue, which was acidified with saturated aqueous NaHSO4, extracted with ethyl acetate, washed with water and saturated aqueous NaCl, dried on MgSO4, concentrated and subjected to flash chromatography on silica gel (5-10% methanol/dichloromethane) to give 17-carbomethoxy-7 - methyl-5-oxo-A-nor-3,5-secondrate-3-oewoi acid; yield: 1.2 g, (39%); mass spectrometry high resolution, Rasch. for [MN+] C21H33O5: 365,2328 found: 365,2328.

G. 17 Carbomethoxy-7-methyl-4-Aza-androst-5-ene-3-one.

To a suspension of 17-to at -40oC add ammonia (15 ml, 4.2 mmol), the mixture is stirred for 30 min and then heated to 170oC for 45 minutes, the Reaction mixture was then cooled to room temperature and add water. The resulting suspension is extracted with ethyl acetate, the extract washed with saturated aqueous NaCl, dried on MgSO4and concentrate. The resulting concentrate is subjected to flash chromatography on silica gel (3-5% methanol/dichloromethane) to give 17-carbomethoxy-7-methyl-4-Aza-androst-5-ene-3-one; yield: 590 mg (52%); composition, Rasch. for C21H31NO3: C 73,01; H 9,04; N of 4.05; found: C 72,97; H 8,98; N of 4.04.

H. 17 Carbomethoxy-7-methyl-4-Aza-5-androstane-3-one.

To a solution of 17-carbomethoxy-7-methyl-4-Aza-androst-5-ene-3-one (590 mg, 1,71 mmol) in 20 ml acetic acid is added platinum oxide (60 mg, 0.26 mmol). The resulting mixture nastorazivayut to 40 psi, shaken for 16 hours and rinsed with nitrogen. The catalyst is filtered off and the filtrate is condensed. The resulting oil is subjected to flash chromatography on silica gel (3-5% methanol/dichloromethane) to give 17-carbomethoxy-7-methyl-4-Aza-5-androstane-3-one; yield: 465 mg (78%); mass spectrometry high resolution, Rasch. for [MN+] C21H34NO4and concentrate. The resulting concentrate is subjected to flash chromatography on silica gel (50% ethyl acetate/hexane) to give 17-carbomethoxy-7-methyl-4-Aza-5-androst-1-EN-3-one in the form of a brown foam; yield: 150 mg (83%), mass spectrometry, high-resolution, Rasch. for [MN+] C21H32NO3: 346,2382 found: 346,2382.

J. 3-Oxo-4-Aza-7-methyl-5-androst-1-ene-17-carboxylic acid.

To a suspension of 17-carbomethoxy-7-methyl-4-Aza-5-androst-1 - EN-3-one (180 mg, 0.52 mmol) in 5 ml dioxane at a temperature of 55oC add lithium hydroxide (43 mg, of 1.02 mmol) in water (2 ml) and the reaction mixture is stirred for 24 hours. Add water (25 ml), then saturated aqueous solution of NaHSO4, extracted with ethyl acetate, then washed with saturated aqueous NaCl, dried on MgSO4and concentrate to a residue, which was subjected to flash chromatogr the sodium high-resolution, Rasch. for [MN+] C20H30NO3: 332,2226 found: 332,2225.

K. 17-N-2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-Aza-7-androst-1-EN-3-one.

To a suspension of 3-oxo-4-Aza-7-methyl-5-androst-1-ene-17-carboxylic acid (50 mg, 0.15 mmol) in 1.5 ml of 0.03% DMF in toluene at 0oC added pyridine (0,030 ml of 0.37 mmol) and thionyl chloride (0,013 ml, 0.18 mmol). After 15 min the reaction mixture for 1.5 hours, warmed to room temperature, the excess reagents are removed via azeotrope and the resulting solid is suspended in 1.5 ml of toluene. The reaction mixture is treated with 4-(N, N-dimethylamino)pyridine (1 mg, catalyst), heated to 100oC and add 2,5-bis(trifluoromethyl)aniline (or 0.035 ml, 0.22 mmol). After 3.5 hours, the reaction mixture is condensed, separated ethyl acetate/saturated aqueous solution of NaHSO4and the organic phase is washed with 2N NaOH, saturated aqueous NaCl, dried on MgSO4and condense. The concentrate is purified by flash chromatography (10% ethyl acetate/dichloromethane) followed HPLS (column Hypersil BDS C8, 40-70% CY3CN/water) and lyophilizers obtaining white solid; yield: 12 mg (15%); mass spectrometry high resolution, Rasch. for [MN+] C28H33F6Nemail-4-Aza-7-methyl-5-androst-1-EN-3-one (compound 31).

To a suspension of 3-oxo-4-Aza-7-methyl-5-androst-1-ene-17-carboxylic acid, prepared as described in step J of example 31 (38 mg, 0.12 mmol), 1.5 ml of 0.03% DMF in toluene at 0oC add pyridine (0,023 ml, 0.29 mmol) and thionyl chloride (0,010 ml, 0.14 mmol). After 15 min the reaction mixture was warmed to room temperature for 1.5 hours, the excess reagents are removed via azeotrope and the resulting solid is dissolved in dichloromethane and treated with pyridine (0,025 ml, 0.30 mmol) and 2-t-butyl-5-triptoreline (50 mg, 0.23 mmol). After 24 hours the reaction mixture was diluted with dichloromethane (20 ml), washed with saturated aqueous NaHSO4, 2N NaOH and saturated aqueous NaCl, dried on MgSO4, condensed and purified by flash chromatography on silica gel (40% ethyl acetate/hexane); yield: 15 mg (25%); mass spectrometry high resolution, Rasch. for [MN+] C31H42F3N2O2: 531,3198 found: 531,3206.

Example 32.

17-N-1- (4-Chlorophenyl)cyclopentanecarbonyl-4-Aza-7-methyl-5-androst-1-EN-3-one (compound 32).

This compound is prepared by the method described in example 3, except that the appropriate amount of 3-oxo-4-Aza-7-methyl-5-androst-1-Et-1-ene-17-carboxylic acid.

Example 33.

17-N-9- (4-t-Butylphenyl)bicyclo[3.3.1] nonlibrary-4-Aza-5-androst-1-EN-3-one (compound 33).

Compound 33 is prepared by a method similar to that described in example 3, using 9-amino-bicyclo[3.3.1] nonan instead of 1-amino-1-(4-chlorophenyl)-cyclopentane.

Melting point 277-280oC.

Examples 34-57.

These compounds may be prepared by the method described in example 3. Amines, available on the market, were prepared by the method described in WO 94/14833.

34. 17-N- (5-Chloro-2-t-butyl) phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

35. 17-N- (4-Bromo-2-t-butyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

36. 17-N- (2-t-Butyl-5-phenyl)phenylcarbamoyl-4-Aza-5 - androst-1 - EN-3-one

37. 17-N- (4-t-Butyl-2-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

38. 17-N- (2-Phenyl-5-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

39. 17-N- (2-t-Butyl-5-(4-chlorophenyl) phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

40. 17-N- (2-(4-t-Butyl)phenyl-5-trifluoromethyl)phenylcarbamoyl-4 - Aza-5-androst-1-EN-3-one

41. 17-N- (2-t-Butyl-5-(4-t-butyl)phenyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

42. 17-N- (4-Chloro-2,5-bis(trifluoromethyl))phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

43. 17-N- (2-(2,4-Dichlorophenyl)-5-trifluoromethyl) is

45. 17-N-5-Bromo-2-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

46. 17-N- (4,5-Dibromo-2-trifluoromethyl) phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

47. 17-N- (5-t-Butyl-4-chloro-2-trifluoromethyl) phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

48. 17-N- (5-t-Butyl-6-chloro-2-trifluoromethyl) phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

49. 17-N- (2,4-Bis(trifluoromethyl))phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

50. 17-N- (2-t-Butyl-4-trifluoromethyl)phenylcarbamoyl-4-Aza-5-androst-1-EN-3-one

51. 17-N-1- (4-t-Butyl-2-triptoreline)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one

52. 17-N-1- (4-Cyanophenyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one

53. 17-N-1- (3-(3-Forfinal)phenyl)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one

54. 17-N-1- (5-Indanyl)cyclohexylcarbonyl-4-Aza-5-androst-1-EN-3-one

55. 17-N-1- (5-Chloro-2,4-dimetilfenil)cyclopentanecarbonyl-4-Aza-5-androst-1-EN-3-one

56. 17-N-2- (4-Triptoreline) bicyclo[3.2.1.]octadecanoyl-4-Aza-5-androst-1-EN-3-one

57. 17-N- (5-Bromo-2-t-butyl) phenylcarbamoyl-4-Aza-5 - androst-1-EN-3-one

Example 58.

Pharmaceutical drugs.

(A) Transdermal system - 1000 patch:

Ingredients - Number

Current start - 40g

Silicone fluid - 450 g

Aut colloidal silicon dioxide to increase viscosity. The resulting product is then metered in layered polymeric material, which is subsequently sealed temperature and which contains: polyester releasing layer, the adhesive for contact with the skin, composed of silicone or acrylic polymers, a control membrane, which is a polyolefin (such as polyethylene, polyvinyl acetate or polyurethane) and an impermeable outer membrane made of laminated polyester. The resulting layered cloth is then cut into patches of size 10 cm2.

(B) Tablets for oral use - per 1000 tablets:

Ingredients - Number

Active principle - a 20 g

Starch - a 20 g

Magnesium stearate 1 g

Active principle and starch granularit in water and dried. Magnesium stearate is added to the dried granules and the mixture is thoroughly stirred. The stirred mixture is pressed into tablets.

(C) Candles - 1000 spark:

Ingredients - Number

Current start - 25g

Theobromine sodium salicylate - 250 g

Witepsol S55 - 1725

Inactive ingredients are mixed and melt. Active principle then spread into the melted mixture is poured into molds and cooled.

(D) Injecting

Propylene glycol - 400 mg

Water for injection, 600 ml

Active principle and buffering agents are dissolved in the propylene glycol at a temperature of about 50oC. Then, while stirring, water for injection, and the resulting solution is filtered, poured into vials, sealed and sterilized by autoclaving.

(E) Capsules 1000 capsules:

Ingredients - Number

Active principle - a 20 g

Lactose - 450 g

Magnesium stearate 5 g

Finely ground active principle is mixed with lactose and stearate and Packed into gelatin capsules.

1. Derivatives androsten(EN)she formulas I

< / BR>
where the carbon atoms 1 and 2 are connected by either a simple or a double bond;

R1denotes hydrogen or methyl;

R2denotes hydrogen or methyl;

R3means (A)

< / BR>
where R4and R5independently of one another denote hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halogen or phenyl (possibly substituted by one or more than one halogen);

W and Z denotes a methylene group which, when taken together with the carbon atom to which they are attached, form a saturated ring system with colerado atom of oxygen or sulfur;

X denotes hydrogen;

or (B)

< / BR>
where R6denotes trifluoromethyl, phenyl, possibly substituted by one or more than one halogen or branched (C4-7)alkyl group, or a branched (C4-7)alkyl;

or R7or R8denotes trifluoromethyl, halogen or branched (C4-7)alkyl, and the other radical represents hydrogen or halogen;

X denotes hydrogen or halogen,

or its pharmaceutically acceptable MES.

2. Connection on p. 1, in which R2denotes hydrogen.

3. The compound according to any one of paragraphs.1 and 2, in which R6denotes trifluoromethyl, phenyl, possibly substituted by one or more than one halogen, or branched (C4-7)alkyl; or R7or R8represents trifluoromethyl or halogen, and the other radical represents a hydrogen or halogen.

4. The compound according to any one of paragraphs.1 to 3, in which the carbon atoms 1 and 2 are connected by a double bond.

5. The compound according to any one of paragraphs.1 - 4 of formula IA

< / BR>
in which the carbon atoms 1 and 2 are connected by either a simple or a double bond;

R1denotes hydrogen or methyl;

R4and R5independently of one another denote by Vodacom halogen);

W and Z denotes a methylene group which, when taken together with the carbon atom to which they are attached, form a saturated ring system with the number of members from 3 to 12, may 1) is substituted by one or more than one lower alkyl group, 2) containing an oxygen atom or sulfur;

X denotes hydrogen.

6. Connection on p. 5, in which R4and R5independently of one another denote hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halogen or phenyl (possibly substituted by one or more than one halogen).

7. Connection on p. 5 or 6, in which at least one of the radicals X, R4and R5is not hydrogen.

8. The compound according to any one of paragraphs.5 to 7, in which a Deputy in the para(4-)-position of the phenyl ring.

9. The compound according to any one of paragraphs.5 to 8, in which at least one of R4and R5denotes lower alkyl, lower alkoxy, trifluoromethyl, halogen or phenyl.

10. Connection on p. 9, in which at least one of R4and R5denotes branched alkyl, trifluoromethyl or halogen.

11. The compound according to any one of paragraphs.1 - 5 of formula IB

< / BR>
where the carbon atoms 1 and 2 are connected to either ethyl, phenyl, possibly substituted by one or more than one halogen, or branched (C4-7)alkyl;

or R7or R8represents trifluoromethyl or halogen, and the other radical represents hydrogen or halogen; X is hydrogen.

12. Connection on p. 11, in which, when R7or R8denotes a branched (C4-7)alkyl and X is hydrogen, R6represents trifluoromethyl or phenyl, possibly substituted by one or more than one halogen.

13. Connection on p. 11 or 12, in which R6represents trifluoromethyl or branched (C4-7)alkyl; or R7or R8represents trifluoromethyl or halogen, and the other radical represents a hydrogen or halogen.

14. Connection on p. 13, in which R6represents trifluoromethyl or branched (C4-7)alkyl; or R7or R8denotes trifluoromethyl, and the other radical represents hydrogen; X represents hydrogen.

15. The compound according to any one of paragraphs.11 to 14, in which R6and R8denote independently from each other, trifluoromethyl or tert-butyl, and R7and X denotes hydrogen.

16. Connection on p. 1, representing 17-N-1-(4-chlorophenyl)cyclopentanecarbonyl-4-am media.

18. A method of obtaining a compound according to any one of paragraphs.1 - 16, in which the carbon atoms 1 and 2 are connected by a simple relationship in which hydrogenizing compound of formula IVa

< / BR>
where R1, R2and R3such, as defined in paragraph 1, which may contain a protective group or groups, and, if necessary and/or desirable, subjecting the resulting compound to one or more further reactions, including (1) vzaimoprevrascheny into another compound of formula (I) and/or (2) removal of any protective group or groups.

19. A method of obtaining a compound according to any one of paragraphs.1 - 16, in which the carbon atoms 1 and 2 are connected by a double bond, wherein the compound of formula V

< / BR>
which may contain a protective group or groups, is subjected to the interaction with the compound of the formula IIa

H2NR3,

where R1, R2and R3such, as defined in paragraph 1, which may contain a protective group or groups, and, if necessary and/or desirable, subjecting the resulting compound to one or more further reactions, including (1) vzaimoprevrascheny into another compound of formula (I) and/or (2) removal of any protective group or groups.

tvii base prior to reaction with the compound of the formula IIa.

21. The method of obtaining the compounds of formula I, which has a double bond between carbon atoms 1 and 2 and in which R1denotes hydrogen, in which dehydrogenation compound of formula Ia

< / BR>
22. The method of treatment androgenreceptor or mediated by androgens disease in a mammal suffering from a specified disease in which the specified mammal is administered is effective against androgenreceptor or mediated by androgens disease number of compounds according to any one of paragraphs.1 - 16.

23. The method according to p. 22, where androgenization or mediated by androgens disease is a benign hyperplasia of the prostate, prostate cancer, acne, male pattern hair loss and hirsutism.

Priority points:

17.09.93 - p. 11;

12.10.93 - p. 5;

17.09.94 for the other claims.

 

Same patents:

The invention relates to new biologically active compounds, specifically to C-O-succinoyl-11-oxo-ursolic acid, its giammarino salt of the formula

< / BR>
where X = H, NH4showing immunostimulirutuyu activity

The invention relates to a plant growth regulator comprising as an active ingredient derived epoxycyclohexane represented by the General formula 1 in which R1represents a hydrogen atom, a C1-C6is an alkyl group or a C3-C6-cycloalkyl group, and R2and R3form together a C2-C3-polymethene group, as well as plant growth regulator, including derived epoxycyclohexane and brassinosteroid as active ingredients

-substituted 4-azaandrostane-3-ones and method for producing substituted 7-alkyl-androst-5-ene-3-ones" target="_blank">

The invention relates to a new method of obtaining 7-substituted 4-Aza-5-androstane-3-ones and related compounds and to the use of such compounds as inhibitors-5-reductase

- substituted 4-aseankorea" target="_blank">

The invention relates to a new method of obtaining derivatives 17- substituted 4-aseankorea General formula (I)

< / BR>
in which R is hydrogen or C1- C3alkyl; R1- carboxamidine group, mono - or disubstituted by C1- C8alkyl group(s); or a free carboxyl group, esterified C1- C5alcohol; and- single or double bond; and their salts

acyl(hydr)oxosteroid with antitumor activity" target="_blank">

The invention relates to the chemistry of steroids and related specifically to 3-OR-di-(2-chloroethyl)aminecontaining 11-acyl(HYDR)oxosteroid with antitumor activity General formula (I), where R = COCH2C6H4N(CH2CH2Cl)2; R1=-OCOCH3+-CCH;-OCOC2H5+-H; R2= H, OCOH, COCH3

The invention relates to compounds that perform new functions inhibitors of bone ratably/promoters osteogenesis

-benzaldoxime-Östra-4,9-diene, the method of production thereof, and pharmaceutical composition" target="_blank">

The invention relates to new derivatives of 11-benzaldoxime-östra 4-9-diene, the way they are received and containing these compounds medicines

benzaldoxime-Östra-4,9-diene, the method of production thereof and pharmaceutical composition" target="_blank">

The invention relates to a derivative 11-benzaldoxime-4,9-diene of the General formula I

< / BR>
where Z denotes-CO-CH3; -CO-O-C2H5; -CO-NH-phenyl; -CO-NH-C2H5; -CH3or-CO-phenyl,

and the way they are received by esterification of the corresponding 11-benzaldoxime-östra-4,9-Dien-3-one to a complex or a simple ester

The invention relates to new derivatives of 17,20-epoxides Pregnana, to a method for their production and to their use as intermediates in the synthesis of biologically active products, specifically to derived 17,20-epoxides of General formula I

< / BR>
where R-=0,-OH, and In the remains of

< / BR>
and K=O, or group

< / BR>
or

< / BR>
where n=2,3;

R1-the remainder of the ether or of ester,

wavy lines indicate the mixture of isomers
Up!