Fluorinated derivatives 17-substituted-4-aza-5- androstane-3-one, a pharmaceutical composition

 

(57) Abstract:

Mutirovannye derivatives of 17-substituted-4-Aza-5-androstane-3-one of General formula I, where In-bond; R is H, alkyl; R1-H alkyl, optionally substituted by one or more fluorine atoms or benzyl group; R2is hydrogen, fluorine, alkyl, possibly substituted by fluorine, phenyl or benzyl; R3Is H, F, alkyl, possibly substituted by F, or phenyl; R4Is H, F, Y double bond, A is H, F, alkyl, possibly substituted by one or more fluorine atoms, and wherein Y is a single bond, hydrogen, or the group

< / BR>
where R6, R7and R8independently is hydrogen or alkyl, possibly substituted by one or more fluorine atoms, A-C(R6R7. Pharmaceutical composition containing as active ingredient the compound I, has inhibitory testosterone -5 reductase activity. 2 S. and 4 C.p. f-crystals, 1 PL.

The present invention relates to fluorinated derivatives of 17-substituted 4-Aza-5-androstane-3-one, method of production thereof and to pharmaceutical compositions containing them. These compounds act as inhibitors of androgen action by suppressing testosterone-5-reductase.

In some tissues, reacting to anteroom (DHT) (Bruchowsry N., Wilson J. D.; J. Biol. Chem. 24, 5953, 1968). The conversion of testosterone into DHT is catalyzed by the enzyme 5-reductase, and if the 5-reductase is inhibited, reduced the formation of dihydrotesterone, and its specific androgenic effect is attenuated or prevented.

Inhibitors of 5-reductase can find a medical use for the treatment of hyperandrogenic conditions, for example, some diseases of the prostate, such as benign prostatic hyperplasia or prostate cancer, and some conditions hair and skin, such as acne, seborrhea, hirsutism in women and characterized by male pattern baldness (Siiteri, P. K., Wilson J. D.; J. Clin.Invest., 49, 1737, 1970; Price V. H., Arch.Dermatol., 111, 1496, 1975; Sandberg, A. A., Urology, 17, 34, 1981). In the treatment of breast cancer can also benefit from the use of an inhibitor of 5-reductase, as it is known that the tumor is exacerbated by the presence of androgens. Androst-4-EN-3-one-17 carboxylic acid and its methyl ester (Voigt and Hsia, Endocrinology 92, 1216 (1973); Canadian Patent N 970692) are among the first steroid compounds that are described as inhibitors of 5 reductase.

Two 5,10-secosteroids with a 3-keto-4,5-diene system in a larger ring, as found, are selective inhibitors epidemically 5 R the logs as reported, are enzyme-activated inhibitors of testosterone-5 reductase (Blohm et al., Biochem. Biophys. Res. Comm., 95, 273-280 (1980); U.S. patent 4317817).

Other series of enzyme-directed irreversible inhibitors of 5 reductase obtained by introducing a 6-methylene component in the basics of 3-keto-4progestins and androgens (Petrow et al., Steroids, 38, 352-353 (1981); U.S. patent 4396615).

It was later reported unsaturated derivatives of 3-carboxyterminal as noncompetitive inhibitor of 5-reductase in relation to testosterone (Biorg. Chem., 17, 372-376 (1989); European patent application N 0289327).

4-azasteroid are undoubtedly the most studied steroid inhibitors 5 reductase. Of the compounds known in this area, reported in a very large number of publications and patents. In particular, 17 acylamide and their metabolites are described in: J. Med. Chem., 27, 1690-1701 (1984), J. Med. Chem. , 29, 2298-2315 (1986); European patent application N 0004949; U.S. patent 4377584; European patent application N 0155096; patent 4845104; European patent application N 0462662; European patent application N 0484094 A2; U.S. patent 4859681; WO 91/12261.

The invention provides compounds of the following formula (I)

< / BR>
where the symbols independently represent kalenovoj chain;

R is a hydrogen atom or a C1-C4alkyl group, unsubstituted or substituted by one or more fluorine atoms;

R1is a hydrogen atom, a C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, or benzyl group;

R2is: a) a hydrogen atom, a fluorine atom, a C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, C5-C7cycloalkyl group or a C6-C9cycloalkylation group; or

b) aryl, or C7-C10arylalkyl group, or unsubstituted or substituted in the end one or more substituents selected from halogen, C1-C4of alkyl, C1-C4alkoxy-, hydroxy - and trifloromethyl;

R3is: a) hydrogen atom, a fluorine atom or a C1-C4alkyl group, unsubstituted or substituted by one or more fluorine atoms; or

b) aryl, or C7-C10arylalkyl group, or unsubstituted or substituted in the ring by one or more substituents selected from halogen, C1-C4of alkyl, C1-C4alkoxy, hydroxy and trifloromethyl;

R4is a hydrogen atom, fluorine atom or a C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms; and

when Y is a single bond, a is a hydrogen, fluorine or the group

,

in which R6, R7and R8independently are hydrogen, fluorine or C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms; or when Y is a double bond, a is a group,

,

in which each of R6and R7is independently hydrogen, fluorine or C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms; with the proviso that at Ceret one of the groups R, R1, R2, R3, R4, R5and A contains at least one fluorine atom.

In the formulas that describe the dashed line (.....) shows Deputy configuration, i.e. below the plane of the ring, and wedge-shaped line indicates a substituent in the configuration, i.e. above the plane of the ring. The configuration of the chiral centers in the side chain is not marked; the invention includes as the only "R" or "S" epimere, and a mixture of "RS".

The metabolites and the metabolic precursors of the compounds of formula (I) are the alkyl groups can be straight or branched chain.

C1-C4the alkyl group can be, for example, stands, ethyl, isopropyl, n-bootrom or tert-bootrom. C1-C4the alkyl group can be unsubstituted or substituted by one or more, preferably one, two or three fluorine atoms, and may be, for example, trifluoromethyl, 2,2,2-triptorelin, formation or deformation.

C1-C6the alkyl group can be, for example, stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl, second-bootrom, tert-bootrom, n-Pentium, isopentyl, neopentyl, n-hexyl or isohexyl. C1-C6the alkyl group can be unsubstituted or substituted by one or more, preferably from one to six or one, two or three fluorine atoms, and may be, for example, formation, deformation, trifluoromethyl, 2,2,2-triptorelin, 3,3,3-Cryptocom-1-yl or 4,4,4-triflorum-1-yl, 1-cryptomelane-1-scrap, 2-trifloromethyl-1-yl, 1,1,1,3,3,3-geksaftorpropena-2-yl, 4,4,5,5,5-pentafluorophenyl or 3,3,3,2,2-pentafluoropropane-1-yl.

C5-C7cycloalkyl group can be, for example, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclohexyl.

C6-C9cyclo is>cycloalkyl)stands or (C5-C7cycloalkyl) - ethyl, in particular, cyclohexylmethyl, cyclohexylethyl or cycloheptylmethyl, preferably by cyclohexylmethyl.

The aryl group may be, for example, phenyl, unsubstituted or substituted by one or more substituents, preferably one Deputy, such as chloro-, bromo-, fluoro-, C1-C4by alkyl, preferably by stands, C1-C4alkoxy, preferably methoxy, hydroxy or triptoreline groups, in particular, 4-were, 4-hydroxyphenyl, 4-methoxyphenyl, 4-cryptomaterial or 4-florfenicol.

C7-C10arylalkyl group may be, for example, phenyl (C1-C4alkyl), preferably benzyl, unsubstituted or substituted in the ring by one or more, preferably one or two substituents, such as chloro-, bromo-, fluoro-, C1-C4alkoxy, preferably methoxy, hydroxy or triptoreline groups, in particular, 4-hydroxybenzyl, 4-methoxybenzyl, 4-hydroxy-3-methoxybenzyl, 3,4-dimethoxybenzyl, 3-Formentera, 4-Formentera or 3-fluoro-4-hydroxybenzyl.

C1-C6straight or branched Allenova circuit is R>< / BR>
When R is C1-C4alkyl group, unsubstituted or substituted by one or more fluorine atoms, it is preferably methyl or 2,2,2-triptorelin;

when R1is C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, it is preferably methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 2,2,2-cryptonet-1-yl, 1-trifloromethyl-1-yl, 1,1,1,3,3,3-geksaftorpropena-2-yl, 2-trifloromethyl-1-yl or 2,2,3,3,3-pentaphobe-1-yl;

when R2is C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, it is preferably methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, vermeil, trifluoromethyl, 2,2,2-cryptonet-1-yl, 1-trifloromethyl-1-yl, 3,3,3-cryptochromes, 1,1,1,3,3,3-geksaftorpropena-2-yl, 2-trifloromethyl-1-yl or 4,4,4-triptorelin;

when R2is C5-C7cycloalkyl group, it is preferably cyclohexyl;

when R2is C6-C9cycloalkyl group, this is preferably cyclohexylmethyl;

when R2is the aryl group is preferably phenyl; when R2is unsubstituted C7-C10arylalkyl g the th group, this, preferably, p-cryptomelane;

when R3is C1-C4alkyl group, unsubstituted or substituted by one or more fluorine atoms, it is preferably methyl, vermeil or trifluoromethyl;

when R3is the aryl group is preferably phenyl;

when R3is unsubstituted C7-C10arylalkyl group, it is preferably benzyl;

when R3is substituted C7-C10arylalkyl group, this is preferably p-cryptomelane;

when R5is C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, it is preferably methyl, n-butyl, trifluoromethyl or pentafluoroethyl;

when a is a group

< / BR>
it is, preferably, methyl, vermeil, deformity, trifluoromethyl, ethyl or n-propyl;

when a is a group

,

this, preferably,

Preferred compounds of formula (I) are those in which:

1) the symbol represents a single or double bond;

B is a bond;

R is hydrogen, stands or 2,2,2-trifluoromethyl;

R1is hydrogen;

R2is the 4,4-tricornutum, 2-trifloromethyl-1-yl, 1-trifloromethyl-1-yl, formation, benzyl or phenyl;

R3is hydrogen or stands;

R4is hydrogen;

R5is stands, trifluoromethyl or n-bootrom;

Y is a single bond; and

A is a group

,

in which

R6is hydrogen or fluorine and R7and R8are both hydrogen atoms or fluorine;

provided that at least one of the groups R, R2, R5or A contains at least one fluorine atom;

2) the symbol represents a single or double bond;

B is a bond;

R is hydrogen, stands or 2,2,2-triptorelin;

R1is hydrogen;

R2is hydrogen, stands, isopropyl, isobutyl, second-bootrom, tert-bootrom, trifluoromethyl, 3,3,3-cryptocaryon, 4,4,4-tricornutum, 2-trifloromethyl-1-yl, 1-trifloromethyl-1-yl, formation, benzyl or phenyl;

R3is hydrogen;

R4no;

R5is stands, trifluoromethyl or n-bootrom;

Y is a double bond; and

A is a group

< / BR>
in which

R7and R8are both atoms is separated by at least one fluorine atom.

3) the symbol represents a single or double bond;

R is hydrogen, stands or 2,2,2-triptorelin;

R1is hydrogen, 2,2,2-triptorelin, 2,2,3,3,3 - pentaphobe-1-yl, stands, ethyl, isopropyl, isobutyl or tert-bootrom;

R2is hydrogen, stands, isopropyl, formation, trifluoromethyl, benzyl or phenyl;

R3is hydrogen, stands, formation, trifluoromethyl, benzyl or phenyl;

R4is hydrogen or fluorine;

R5is hydrogen, fluorine or trifluoromethyl;

B is a bond;

Y is a single bond; and

A is hydrogen or fluorine;

provided that at least one of the groups R, R1, R2, R3, R4, R5or A contains at least one fluorine atom.

Examples of preferred compounds of the invention are:

1) N-(4,4,4-Cryptor-3-methyl-but-2-yl)-4-methyl-3-oxo-4-Aza - 5 androstane-17 carboxamide;

2) N-(1,1,1-Cryptor-3-methyl-but-2-yl)-4-methyl-3-oxo-4-Aza - 5 androstane-17 carboxamide;

3) N-(4,4,4-Cryptor-3-methyl-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

4) N-(1,1,1-Cryptor-3-methyl-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

5) N-(5-m is-3-oxo-4-Aza-5 androstane-17 carboxamide;

7) N-(5-methyl-2-deformities-3-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

8) N-(3-deformities-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

9) N-(4,4,4-Cryptor-3-metrobot-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

10) N-(1,1,1-Cryptor-3-metrobot-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

11) N-(4,4,4-Cryptor-3-metrobot-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

12) N-(1,1,1-Cryptor-3-metrobot-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

13) N-(5-methyl-2-deformations-3-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

14) N-(3-deformational-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

15) N-(5-methyl-2-deformations-3-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

16) N-(3-deformational-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

17) N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

18) N,N-di-(2,2,2-triptorelin)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide;

19) N-(1,1,1,3,3,3-geksaftorpropena-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 / carboxamid;

20) N, N-di-(1,1,1,3,3,3-geksaftorpropena-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

21) N-methyl-N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

22) N-isobutyl-N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1-ene-17 Carbo who yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

25) N-(1,3-debtor-2-formerprof-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

26) N-(5,5,5-Cryptor-2,4-dimethylpent-3-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

27) N-(4,4,4-Cryptor-2,3-dimethylbutan-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

28) N-(4,4,4-Cryptor-3-methylbut-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

29) N-(5,5,5-Cryptor-2,4-dimethylpent-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

30) N-(4,4,4-Cryptor-2,3-dimethylbutan-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

31) N-(4,4,4-triflorum-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

32) N-(5,5,5-Cryptor-2-methylpent-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

33) N-(4,4,4-Cryptor-2-methylbut-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

34) N-(4,4,4-Cryptor-3-methylene-but-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

35) N-(5,5,5-Cryptor-4-methylene-2-methylpent-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

36) N-(4,4,4-Cryptor-3-methylene-2-methylbut-2-yl)3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

37) N-(2,2,2-triptorelin)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

38) N-(isopropyl-N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

39) N-isopropyl-N-(2,2,3,3,3-pentafluoropropyl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

40) N-(2,2,2-tryptophanate)-3-oxo-4-Aza-5 is N-(2,2,2-Cryptor-1,1-diphenylether)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

43) N-(1,1,1-Cryptor-2-methylprop-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide; and

44) N-(1,1,1,3,3,3-hexamer-2-methylpropyl)-3-oxo-4-Aza-5 androst-1-ene-17 / carboxamid.

Structural formulae of the above-mentioned compounds in accordance with their numbers placed at the end of the descriptive text indicating the substituents defined in formula (I):

The compounds of formula (I) can be obtained by a process including:

A) reaction of compounds of formula (II)

< / BR>
where the symbol

, R and B mean that defined above and a is an activating group with the function of carboxyl, with the compound of formula (III) or its salt

< / BR>
where the symbol

, R1, R2, R3, R4, R5and A denote that defined above, obtaining thus the compounds of formula (I), in which the symbol R, R1, R2, R3, R4, R5, B and A denote what is defined above; or

B) reaction of compounds of formula (IV)

< / BR>
where the symbol

R, R1, R2, R3and B denote that defined above and R5is C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, with a compound of formula (V)

< / BR>
or (VI)

< / BR>
where

obtaining thus the compounds of formula (I), where the symbol R, R1, R2, R3and B denote that defined above, R5is C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, Y is a double bond, R4absent and a is a group

,

where

R6and R7indicates that defined above; or

C) recovering the compound of formula (VII)

,

where

the symbol R, R1, R2, R3R5and B are those defined above, and R4is hydrogen, obtaining thus the compounds with formula (I), where R, R1, R2, R3, R5and B denote that defined above, R4and A are both hydrogens, and Y is a single bond; and, if desirable,

D) hydrogenation of the compounds of formula (I), where R, R1, R2, R3and B denote that defined above, R4no, R5is hydrogen or C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, Y is a double bond and a is a group

,

where

R6and R7indicate that defined above, to obtain the connection is defined above, R4is hydrogen, R5is hydrogen or C1-C6alkyl group, unsubstituted or substituted by one or more fluorine atoms, and a is a group

,

where

R8is a hydrogen atom and R6and R7indicate what is defined above; and/or

E) dehydrogenating the compounds of formula (I), where R, R1, R2, R3, R4, R5, B and A denote that defined above and X is a single bond,

obtaining thus compounds with formula (I), where Y, R1, R2, R3, R4, R5, B and A denote that defined above, and X is a double bond; and, if desired, separate the mixture of isomers of formula I into individual isomers.

In the compound of formula (II), the group Z is an activating group with the function of carboxyl, useful for the formation of amide and peptide bonds; it may be, for example, one of the following groups:

< / BR>
< / BR>
The reaction of the compound of formula (II) with the compound of the formula (III), in accordance with process variant A) can be carried out, for example, in a solvent such as, for example, methylene chloride, ethyl acetate, tetrahydrofuran, dimethylformamide, benzene or toluene, at a temperature in p is Erno 48 hours.

If the compound of formula (III) is in the form of salt must be added the stoichiometric amount of organic base, such as pyridine or three-C1-C6-alkylamine, preferably triethylamine, to the reaction mixture.

The reaction of the compound of formula (IV) with the compound of the formula (V) according to process variant (B) can be carried out under conventional reaction conditions Horner-Wordsworth-Emmons (Horner-Wadsworth-Emmons).

For example, the reaction can be carried out by reaction of the substances of the formula (V), dissolved in anhydrous solvent such as, for example, ethyl ether or tetrahydrofuran, with alkylamides lithium, such as, for example, diisopropylamide lithium alkyl or lithium derivative, such as butyl lithium or sodium hydride, at a temperature from about -78oC to about 0oC in an inert atmosphere of nitrogen or argon in a period of time ranging from an hour to 3 hours, then the compound of formula (IV), dissolved in tetrahydrofuran, is added to the reaction mixture, and the reaction proceeds at temperatures varying in the range from room temperature to the temperature of the distillation of the reaction mixture in a period of time ranging from several who eacce the compounds of formula (IV) with the compound of the formula (VI) according to variant B) of the process can be carried out in a conventional reaction conditions of the Wittig.

For example, the reaction can be carried out by reacting the compounds of formula (VI) with a strong base, such as, for example, lithium-alkylamide (for example, lithium diisopropylamide), or alkyl-lithium (e.g., butyl lithium) or an alkali metal hydride (e.g. sodium hydride) or an alkali metal alkoxide (e.g. potassium tert-piperonyl), in a solvent such as, for example, diglyme (diglyme), dimethylsulfoxide (DMCO), tetrahydrofuran, diethyl ether, benzene, toluene or a mixture thereof, at a temperature ranging from about -78oC to room temperature, preferably in an inert atmosphere of nitrogen or argon.

Thus obtained ylides is then processed by the compound of formula (IV) and the reaction proceeds at a temperature varying from room temperature to the temperature of reflux distilled mixture in a period of time ranging from several hours to several days.

The recovery of the substance with the formula (VII), in accordance with process variant C) can for example be carried out by treating the compounds of formula (VII) tri-n-butyl tin hydride, sometimes in the presence of azobis(isobutyronitrile) (AIBN) as an initiator radical, in a solvent such as, for example, toluene at a temperature that is from about 1 hour to 4 hours.

Hydrogenation of compounds of formula (I) in accordance with process variant (D) may, for example, be carried out in a solvent such as, for example, methanol, ethanol, ethyl acetate, in the presence of from about 10% to 30% of a hydrogenation catalyst, such as, for example, 5% Pd/C or 10% Pd/C, Ni-Raney, when the hydrogen pressure of 1 atmosphere at room temperature for a time ranging from an hour to 3 hours.

Dehydrogenase substance with the formula (I) in accordance with process variant E), which preferably is performed for compounds with formula (I) in which R is hydrogen, can be carried out by treating the appropriate dehydrogenation means, such as, for example, chloranil, benzylamino anhydride or dichlorodicyanoquinone (DDQ) in an anhydrous solvent such as, for example, chlorobenzene, dioxane, xylene, toluene or benzene, optionally in the presence of BSTFA [bis(trimethylsilyl)triptorelin]. The reaction temperature may range from room temperature to the temperature of reflux distilled solvent, and the reaction time may vary from about 2 hours to about 24 hours.

Preferably the reaction is carried out in an inert atmosphere, for example, the local atmosphere substances by known methods.

The compounds of formula (III) are commercially available or they can be synthesized by known methods. For example, by restoring the appropriate tripteroides (see JOC 24, 1256-1259 (1959)) or from the corresponding ketones (Tetr, Lett., 31 (39), 5547-5550 (1990)), or by restoring the corresponding N-hydroxylamino (JOC 32, 3197 (1967)) or isocyanates (DE-A-3326875 and DE-A-3611195).

The compounds of formula (III), where R2, R3and R5have all the values defined above, except hydrogen, and R1is hydrogen, Y is a single bond, and A and R4are fluorine atoms, can be obtained by hydrolysis of the carbamate of formula (VIII)

< / BR>
where

R2, R3and R5have all the values defined above, except hydrogen:

R10is C1-C4alkyl group, preferably ethyl group or a benzyl group.

Hydrolysis, for example, is carried out by treating the carbamate in a solvent such as, for example, dioxane, tetrahydrofuran or ethanol with 48% Hydrobromic acid at a temperature of distillation of the reaction mixture in a period of time varying from 5 hours to 24 hours. Carbamate with formula (VIII) is obtained by reaction organicheskim substance, including magnesium, with the formula (X)

R3- MgX,

where

R3indicates that defined above, Mg is an atom of magnesium and X is a halogen, preferably chlorine, bromine or iodine.

The reaction is carried out in a nonaqueous solvent such as, for example, diethylether or tetrahydrofuran, at temperatures varying from -10oC to the temperature of reflux distilled reaction mixture, for a time varying from 30 minutes to 4 hours.

The compound of formula (IX) can be obtained by reaction of compounds of formula (XI)

R10OOC - N = PPh3,

where

R10indicates that defined above,

with the compound of the formula (XII)

< / BR>
where

R2and R5indicates that defined above. The reaction between azaphospholones (XI) and fluorinated ketone (XII) is carried out under normal conditions, described in the literature for the reaction of Wittig for uzasadnienie.

Compounds of formula (X), (XI) and (XII) are known compounds or they can be synthesized by known methods.

Compounds with formula (IV) can be obtained, for example, by reaction of the compounds with formula (II) with -/ aminoketones formula (XIII)

< / BR>
where

R1, RoC to about 100oC, optionally in the presence of organic bases, such as, for example, pyridine, p-dimethylaminopyridine or triethylamine, in a period of time ranging from an hour to five days. The compounds of formula (XIII) are often used as derivatives of N-salts (for example, in the form of hydrochloride or trifurcation). In this case, the reaction mixture must be added the stoichiometric amount of organic base, such as pyridine or three-C1-C6-alkylamine, preferably triethylamine.

The compound of formula (VII) can be obtained by reaction of compounds of formula (XIV)

< / BR>
where

the symbol B, R, R1, R2, R3, R5indicate that defined above:

R4is hydrogen,

with the compound of the formula (XV)

< / BR>
The reaction, for example, is performed by heating in a flask with reflux condenser a mixture of the alcohol of formula (XIV) and an excess of 1,1-thiocarbonyldiimidazole formula (XV) in anhydrous solvent such as, for example, 1,2-dichloroethane, methylenchlorid atmosphere, for example, nitrogen.

The compounds of formula (XIV) can be obtained, for example, by reaction of compounds of formula (II) where the symbol R and B denote that defined above, with a compound of formula (XVI)

< / BR>
where

R1, R2, R3and R5indicate that defined above:

R4is hydrogen.

The reaction can be carried out, for example, in a solvent such as, for example, methylene chloride or ethyl acetate, at a temperature varying from 0oC to 70oC, optionally in the presence of organic bases, such as, for example, C1-C6trialkylamine, preferably triethylamine, in a period of time ranging from 2 hours to 24 hours.

The compounds of formula (XVI) are often used in the form of salts derived, preferably, hydrochloride, and the amino group is formed "in situ" in the presence of organic bases, such as, for example, C1-C6-trialkylamine, preferably triethylamine.

The compounds of formula (XV) and (XVI) are commercially available substances, or they can be obtained by known methods.

The compounds of formula (V), (VI) and (XIII) are known compounds or they can be Sint the testosterone-5 reductase, and so are strong antiandrogen. For example, the inhibitory effect of the compounds of this invention on 5 reductase was determined in vitro and in vivo according to the method reported below.

Definition suppression 5 reductase in vitro.

Suppression of 5 reductase was estimated using the fraction of particles homogenates hyperplastic human prostate as the source of enzyme. The fraction of particles was obtained by centrifugation of the homogenate prostate when 140000g. The resulting precipitate was filtered several times, resuspendable buffer and stored at -80oC in samples containing 10 mg protein/ml

Study 5 reductase was performed in a final volume of 0.5 ml in 40 mm Tris-HCl buffer pH 5.5, containing 1 mm dithiothreitol, 5 mm NADP, 1 μm [14C]-testosterone, aliquot the sample enzyme preparation and various inhibitors. After 30 min incubation at 37oC the reaction was stopped by adding 2 ml of cold diethyl ether, and the organic phase was separated, evaporated under nitrogen atmosphere and resuspendable in ethyl acetate. Metabolites of testosterone in this extract was shared by TLC (thin layer chromatography) on silica gel F 254 boards (Merck) using chloroform, acetone stayed and were analyzed by quantitative graphs, printable TLC analyzer (Berthold). Fractional 5 recovery of testosterone was calculated as the ratio14C-radioactivity in the regions 5 of the recovered metabolites (5 dihydrotestosterone, 3 - and 3 androstendiol) to total radioactivity in the fields of testosterone and 5 recovered metabolites. The concentration of each compound required to reduce the activity of the control 5 reductase by 50% (IC50was determined according to a schedule based % suppression versus log concentration of inhibitor.

Inhibition of 5-reductase in vivo.

Used standard test androgenic effect in rats. Rats-males 22 days of age that has not reached sexual maturity, castrated by cutting the scrotum under light ether anesthesia. On the seventh day after blindness was performed reimbursement of androgens by subcutaneous implantation elastically tubes (Dow-Corning, Model N 602-265) 1 cm long, filled with a mixture of 25% of testosterone and 75% of cholesterol. Then rats orally injected compound (7 animals/group) once daily for 7 consecutive days. 24 hours after the last dose, rats were killed and ventral prostate were removed and weighed. Control animals (testoster not implanted testosterone capsules (castrated control).

The average percentage suppression of T-induced reactions hypertrophy was calculated by the following formula:

% suppression = 100 (BTC- B1)/(BTC- BQC)

where BTCBQCand B1are average weight of prostate from testosterone control, castrated control and treated with the inhibitor group, respectively.

As an example the results obtained by some representatives of the compounds of this invention, shown in the table.

From the results shown in the table , shows that the new compounds are very active inhibitor of 5-reductase, both in vitro and in vivo. In view of the above activity, the compounds of this invention, therapeutically applicable in situations where it is desirable reduction in androgenic effect by suppressing 5 inhibitors, such as, for example, benign prostatic hyperplasia, prostate cancer or breast and some skin conditions and hair, such as, for example, acne, seborrhea, hirsutism in women and characterized by male pattern baldness. Mammal, e.g. a human or an animal can thus be treated in a way that includes the use for this purpose farmacevticheskaya completely insignificant, so that they can be safely used in therapy. The compounds of this invention can be used in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, pills, coated with sugar or film of liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion; or topically, for example in the form of creams.

The dosage depends on age, weight, condition of the patient and the method of administration; for example, the dosage, acceptable for oral administration in adults can vary from about 1 to 200 mg per dose, from 1 to 3 times a day.

As already mentioned, the invention includes pharmaceutical compositions comprising substances of the invention in a mixture with pharmaceutically acceptable excipient (which can be a carrier or a diluent).

Pharmaceutical compositions containing substances of the invention are usually obtained by conventional methods and used in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the active component of the diluents, for example lactose, dextrose, saccharose, cellulose, corn starch or to the calcium and/or polyethylene glycols; connecting means, e.g. starches, Arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregated means, for example, starch, alginic acid, alginates or starch glycolate, sodium; effervescent mixtures; dyestuffs; sweeteners; humectants; such as lecithin, Polysorbate, laurylsulfate; and mostly non-toxic and pharmaceutically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be produced in a known manner, for example, by a process of mixing granulating, tabletting, sugar coating or coating film. Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular, the syrup, which should be used by patients with diabetes, may contain as carriers only products nametablesize to glucose, or metabolisable in a very small amount to glucose, for example, sorbitol.

Suspensions and emulsions can contain, in cacalote or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain, together with the active substance pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycol, e.g. propylene glycol, and, if desirable, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of a sterile aqueous isotonic saline solution.

Candles may contain together with the active substance is a pharmaceutically acceptable base, such as cocoa butter, polyethylene glycol, surfactant - ether of polyoxyethylenesorbitan and fatty acids or lecithin.

Dosage forms for topical use can be used generally accepted basis.

The present invention, furthermore, is a compound of formula (I) for use in the method of treatment of the human or animal body by therapy, in particular for use as an inhibitor of testosterone-5 - reductase.

The present invention, furthermore, is the use of compounds the reductase.

The following examples further illustrate the invention.

Reported NMR data determined in deuterium chloroform (CDCl3), unless otherwise noted, and reported as parts per million ()/ towards the bottom fields from tetramethylsilane.

The nomenclature used in the examples, the numbering of the compounds is shown here below:

< / BR>
Example 1.

N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid ((1): X = double bond; Y = single bond; B = connection; R = H; R1= H; R2= H; R3= H; R4= F; R5= F; A = F).

A mixture of 2-pyridyl-3-oxo-4-Aza-5 androst-1-ene-17 carbothioate (102,5 mg) and 2,2,2-triptorelin (0,55 ml) in anhydrous tetrahydrofuran (2.5 ml) was heated in a flask under reflux for 4 hours.

The solvent was removed under vacuum and the yellow solid residue was purified by thin layer chromatography (eluent: ethyl acetate/methylene chloride to 20:1), thus receiving 110 mg of the compound indicated in the title in the form of a white crystalline solid (so pl. 220-221oC, methylene chloride).

NMR (CDCl3, ): 6,77 (d, 1H, H(1)), and 5.8 (DD, 1H, H(2)), to 5.56 (t, 1H, CONHCH2CF3), 5,52 (sh. s, 1H, NH), 4,18 and 3.70 (2 m, 2H, CONHCH2CF3), and 3.31 (DD, < / BR>
By using the appropriate starting material and following the same procedure was also derived compounds listed below.

N-(4,4,4-Cryptor-3-methyl-but-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(1,1,1-Cryptor-3-methyl-but-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(4,4,4-Cryptor-3-methyl-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(1,1,1-Cryptor-3-methyl-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(5-methyl-2-deformity-Gex-3-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(3-deformity-hept-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(5-methyl-2-deformity-Gex-3-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(3-deformity-hept-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(4,4,4-Cryptor-3-methylene-but-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(1,1,1-Cryptor-3-methylene-but-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(4,4,4-Cryptor-3-methylene-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(1,1,1-Cryptor-3-methylene-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(5-methyl-2-deformation-Gex-3-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(3-deformation-hept-2-yl)-4-methyl-3-oxo-4-Aza-5 on tormation-hept-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N,N-di-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(1,1,1,3,3,3-geksaftorpropena-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 / carboxamid;

N,N-di-(1,1,1,3,3,3-geksaftorpropena-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

N-methyl-N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1 - ene-17 carboxamide;

N-isobutyl-N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1 - ene-17 carboxamide;

N-(1-fluoro-2-methylprop-2-yl)-3-oxo-4-Aza-5 androst-1 - ene-17 carboxamide;

N-(1,3-debtor-2-methylprop-2-yl)-3-oxo-4-Aza-5 androst-1 - ene-17 carboxamide;

N-(1,3-debtor-2-formerprof-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

Example 2.

N-(2,2,2-triptorelin)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamid ((I) : X = single bond, Y = single bond; B = connection; R = CH3: R1= H; R2= H; R3= H; R4= F; R5= F; A = F).

To a suspension of 2,2,2-triptorelin hydrochloride (948,5 mg) in anhydrous tetrahydrofuran (10 ml) was added triethylamine (0,973 ml). After stirring for 15 min at room temperature was added solid 2-pyridyl-4-methyl-3-oxo-4-Aza-5 androstane-17 carbothioate (426 mg) and the mixture was heated in a flask under reflux for 4 hours.

Volatiles were removed under vacuum and the crude product ocialist, specified in the title (so pl. 242-244oC).

NMR (CDCl3): the 5.65 (m, 1H, NH), 4,5-3,5 (m, 2H, CH2CF3), and 3.1 (DD, 1H, H(5 )), to 2.9 (s, 3H, N-CH3), of 0.87 (s, 3H, CH3(19)), to 0.67 (s, 3H, CH3(18)).

Elemental analysis

For C22H33F3N2O2< / BR>
Calculated,%: C 63,75; H 8,0; N 6,76

Found,%: C 63,44; H 7,78; N 6,67

Following the same procedure and using the appropriate starting materials, there were obtained the following substances:

N-isopropyl-N-(2,2,2-triptorelin)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

N-isopropyl-N-(2,2,3,3,3-pentafluoropropyl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

Example 3.

(22RS)-N-(2,2,2-tryptophanate)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid ((I) : X =double bond; Y = single bond; B = connection; R = H; R1= H; R2= Ph; R3= H; R4= F; R5= F; A = F).

To a solution of (RS)-2,2,2-Cryptosporidium hydrochloride (205 mg) in anhydrous dimethylformamide (4 ml) was added triethylamine (0,270 ml). After stirring at room temperature for 30 minutes was added solid 2-pyridyl-3-oxo-4-Aza-5 androst-1-ene-17 carbothioate (200 mg) and the mixture was heated to 100oC for 8 hours.

The reaction mixture was diluted with water and extragere the functions, dried over sodium sulfate and the solvent evaporated under reduced pressure.

The residue was purified by thin-layer chromatography on silica gel (eluent: ethyl acetate/methylene chloride to 20:1) to give 125 mg of the substance specified in the header (so pl. 260-265oC).

NMR (CDCl3) 7,38 (s, 5H, Ph), 6,77 (d, 1H, H(1)), 5,95-5,70 (m, 3H, H(2) + NH(21) + CH(CF3)Ph), to 5.21 (s, 1H, NH(4)), to 3.33 (DD, 1H, H(5 )), of 0.99 and 0.94 (2s, 3H, CH3(19)), to 0.72 and 0.56 (2s, 3H, CH3(18)).

MC (m/z): 474 M+., 459 M-.CH3+, 454 M-HF+..

Following a similar procedure, there was obtained N-(1,3-debtor-2 - formerprof-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid.

Example 4.

(RS)-1-trifluoromethyl-1-femilet-1-ylamine hydrochloride [(III) : Y = single bond; R1= H; R2= Ph; R3= CH3; R4= F; R5= F; A = F]

A mixture of trifurcation [(XII): R2= Ph, R5= F] (1,536 ml), N-carbatetraphenylporphin ((XI): R10= Et) (3,494 g) in anhydrous toluene (25 ml) was heated in a flask under reflux for 24 hours.

Volatile components were removed under vacuum and the solid residue suspended in diethyl ether/petroleum ether (50:50) and filtered; the filtrate is evaporated under vacuum obtaining oil ( thus 1.40 g of N-carbethoxy-2,2,2-Cryptor-1-phenyl-ethanamine ((IX): R10= Et; R2= Ph; R5= F) as a colourless oil.

NMR (CDCl3) : of 7.3 to 7.7 (m, 5H, Ph), 4,25 (q, 2H, COOCH2) 1,2 (t, 3H )

IR (pure): 1725, 1680 cm-1< / BR>
A solution of N-carbethoxy-2,2,2-Cryptor-1-fenilatilamin (210 mg) in anhydrous diethyl ether (5.0 ml) was added dropwise at room temperature to freshly IM solution Metalmania-iodide in diethyl ether (8.0 ml); then the reaction mixture was heated in a flask under reflux for 0.5 hours and which at room temperature for 1 hour.

After cooling to 0oC in an ice bath, the reaction was suppressed IN hydrochloric acid (10 ml) and the mixture was extracted with diethyl ether. The organic extracts were washed with water, IN sodium thiosulfate, brine solution and dried over sodium sulfate. After removal of the solvent under vacuum the crude product was purified by thin layer chromatography on silica gel (eluent: petroleum ether 4: 1) to give 730 mg (RS)-ethyl-N-(1-trifluoromethyl-1-phenylethyl) carbamate (VIII): R10= Et, R2= Ph; R3= CH3; R5= F) in the form of a white solid.

NMR (CDCl3) : of 7.3 and 7.6 (m, 5H, Ph), 5,55 (sh.S., 1H, NH), of 4.05 (2H square, COOCH2CH3), was 2.05 (m, 3H, PhCCH3(CF3)), 1,20 is voennyi in dioxane (6.0 ml), was treated with 48% Hydrobromic acid (2 ml), and the mixture was heated in a flask under reflux for 16 hours.

After cooling and dilution with water, the solution washed with diethyl ether, podslushivaet to pH 12-13 IN sodium hydroxide and was extracted with diethyl ether; the organic extracts were washed with saline and dried over sodium sulfate. The drying agent was filtered and added to 2.2 N hydrochloric acid (1 ml) and the solvent was removed under reduced pressure; the crude oily product thus obtained, was led from acetonitrile, getting 435 mg of the substance specified in the header.

MC (m/z): 189 M+.; 174 M-.CH3+; 120 M-.CF3+< / BR>
Example 5.

(22RS)-N-(1,1,1-Cryptor-2-phenylprop-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid ((I): X = double bond; Y = single bond; B = connection; R = H; R1= H; R2= Ph; R3= CH3; R4= F; R5= F; A = F).

2-pyridyl-3-oxo-4-Aza-5 androst-1-ene-17 carbothioate (205 mg) was dissolved in methylene chloride (2.5 ml) containing methyliodide (63 μl). After shaking for 15 minutes at room temperature (RS)-1-trifluoromethyl-1-femilet-1-ylamine (160 mg) dissolved in 3 ml Dima is 5 ml) and was extracted with methylene chloride.

The organic extracts washed with 1 N hydrochloric acid, water, and obezvozhivani sodium sulfate, and the solvent evaporated under reduced pressure.

The solid residue was collected with ethyl acetate: insoluble solid residue was filtered and the filtrate was subjected to chromatography on silica gel (eluent: ethyl acetate/methylene chloride to 20:1) to yield 47 mg of the substance specified in the header, which was aterials by treatment with n-pentane (so pl. 151-155oC).

NMR (CDCl3) of 7.48-to 7.35 (m, 5H, Ph), 6,79 (DD, 1H, H(1)), 5,88 (d, 1H, NH (21)), of 5.81 (DD, 1H, H(2)), 5,48 (c, 1H, NH(4)), and 3.3 (DD, 1H, H(5 )), is 2.05 and 2.07 (2s, 3H, NHCH3(CF3)Ph), and 0.98 and 0.97 (2s, 3H, CH3(19)), to 0.72 and 0.68 (2s, 3H, CH3(18)), MC (m/z): 488 M+; 473 M-.CH3+; 173.C(CF3)(CH3)pH-+< / BR>
Following the same procedure and using the appropriate starting materials, there were obtained the following substances:

N-(2,2,2-Cryptor-1,1-diphenylether)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

N-(1,1,1-Cryptor-2-methylprop-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

N-(1,1,1,3,3,3-hexamer-2-methylpropyl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid

Example 6.

(22RS)-N-(4,4,4-Cryptor-3-methylene-but-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 / carboxamid ((I) : X = double bond; Y = CF3).

Methyltriphenylphosphonium iodide (44 mg) was added in portions to a stirred solution of tert. of potassium butyl (9 mg) in dimethylsulfoxide (0.5 ml) under nitrogen atmosphere at room temperature.

After ten minutes, the yellow solution thus obtained ylides were processed by adding dropwise, a solution of (22RS)- N-(1,1,1-Cryptor-2-exabot-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide (30 mg) in 1.5 ml of dimethylsulfoxide. The solution became bright in a few minutes.

After dilution with ethyl acetate, the reaction mixture was washed with water, dried over sodium sulfate, and the solvent evaporated under reduced pressure. The crude oily substance was purified by thin-layer chromatography (eluent: methylene chloride/acetone 50:50) to obtain 21 mg of the title.

NMR (CDCl3) : is 6.78 (d, 1H, H(1)), and 5.8 (DD, 1H, H(2)), of 5.75 (d, 1H, NH (21)), 5,55 (sh. S. 1H, NH(4)), the ceiling of 5.60 and 5.35 (2 m, 2H, C=CH2), 4,70 (m, 1H, NHCH(CH3)), to 3.33 (DD, 1H, H(5 )), to 1.35 (d, 3H, NHCH(CH3)), 0,97 (c, 3H, CH3(19)), 0,70 (c, 3H, CH3(18)).

Following a similar procedure, we obtained the substances listed below:

N-(5,5,5-Cryptor-4-methylene-2-methylpent-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

N-(4,4,4-Cryptor-3-methylene-2 is negrocan-17 carboxamide;

N-(1,1,1-Cryptor-3-methylene-but-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(4,4,4-Cryptor-3-methylene-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(1,1,1-Cryptor-3-methylene-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamid.

Example 7.

(22RS-23RS)-N-(4,4,4-Cryptor-3-methylbut-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamid ((I) : X = single bond; Y = single bond; B = connection; R = H; R1= H; R2= CH3; R3= H; R4= H; A = CH3; R5= CF3).

A solution of (22R, S)-N-(2-trifloromethyl-1-EN-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide (21 mg) in ethyl acetate was hydrogenosomal under pressure (30 lb/in2) at room temperature for 3 hours in the presence of 10% Pd/C (4 mg).

The catalyst was filtered and the solvent evaporated under vacuum.

The residue was chromatographically on silica gel (eluent: methylene chloride/acetone 50:50) to obtain 16 mg of the substance specified in the header.

NMR (CDCl3) : 5,67 (c, 1H, NH(4)), and 5.30 (d, 1H, NH(21)), 4,35 (m, 1H, NHCH(CH3)); 3,03 (DD, 1H, H(5) to 2.35 (m, 1H, -CH(CH3CF3), of 1.23 (2D, 6H, NHCH(CH3)CH(CH3CF3), 0,87 (c, 3H, CH3(19)), 0,70 (c, 3H, CH3(18)).

Following a similar procedure, there were obtained the following substances:
l)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(4,4,4-Cryptor-3-methyl-but-2-yl)-4-methyl-3-oxo-4-Aza-5 - androstane-17 carboxamide;

N-(1,1,1-Cryptor-3-methyl-but-2-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(1,1,1-Cryptor-3-methyl-but-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(5-methyl-2-deformity-Gex-3-yl)-4-methyl-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(3-deformity-hept-2-yl)-4-methyl-3-oxo-4-Aza-5 - androstane-17 carboxamide;

N-(5-methyl-2-deformity-Gex-3-yl)-3-oxo-4-Aza-5 androstane-17 carboxamide;

N-(3-deformity-hept-2-yl)-3-oxo-4-Aza-5 androstane-17 carboxamid.

Example 8.

N-(4,4,4-Cryptor-4-methylbut-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid ((I) : X = double bond; Y = single bond; B = connection; R = H; R1= H; R2= CH3; R3= H; R4= H; A=CH3; R5=CF3).

To N-(4,4,4-Cryptor-3-methylbut-2-yl)-3-oxo-4-Aza-5 androsten-17 carboxamido ((I) : X = single bond; B = single bond; Y = single bond; R = H; R1= H; R2= CH3; R3= H; R4= H; A = CH3; R5= CF3) (55 mg), suspended in chlorobenzene (5.0 ml), was added to the anhydride benzylamino acid (64 mg) and the mixture was heated in a flask under reflux for 4 hours.

The solvent was removed under vacm solution of sodium chloride, was obezvozhivani sodium sulfate, and the solvent evaporated under reduced pressure.

Cleaning the brown crude product through chromatography on silica gel (eluent:methylene chloride/ethyl acetate/methanol 50:45:5) gave 28 mg of the substance specified in the header.

NMR (CDCl3) : is 6.78 (d, 1H, H(1)), 5,80 (DD, 1H, H(2)), 5,67 (c, 1H, NH(21)), and 5.30 (d, 1H, NH(21)), 4,35 (m, 1H, NHCH(CH3)-), to 3.33 (DD, 1H, H(5 )), to 2.35 (m, 1H, CH(CH3CF3), of 1.23 (2D, 6H, NHCH(CH3)CH(CH3CF3), 0,97 (c, 3H, CH3(19)), 0,68 (c, 3H, CH3(18)).

Following a similar procedure, we obtained the substances listed below:

N-(5,5,5-Cryptor-2,4-dimethylpent-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

N-(4,4,4-Cryptor-2,3-dimethylbutan-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid.

Example 9.

(22RS)-N-(4,4,4-triflorum-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid ((I): X = double bond; Y = single bond; B = connection; R = H; R1= H, R2= CH3; R3= H, R4= H; A = H; R5= CF3).

(22RS-23RS)-N-(4,4,4-Cryptor-3-hydroxymet-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide [(XIV): X = double bond; B = single bond; R = H; R1= H; R2= CH3; R3= H; R4= H; R5= CF3] (50 mg) was dissolved in 1,2-dichloromethane (1.3 ml) price was heated at 75oC (oil bath temperature) for 3 hours.

Purification of the reaction mixture by thin layer chromatography on silica gel (eluent: methylene chloride/ethyl acetate/methanol 50:45:5) gave yield 61 mg (22RS-23RS)-N-(4,4,4-Cryptor-3-(((imidazol-1-yl)thiocarbonyl)oxy) but-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid ((VII): X = double bond; B = connection; R = H; R1= H; R2= CH3; R3= H, R4= H; R5= CF3).

The anti-hydride (0,049 ml) in toluene (2.5 ml) was heated in a flask with reflux, and a solution of N-(4,4,4-Cryptor-3-(((imidazol-1-yl)-thiocarbonyl)oxy)but-2-yl)-3 - oxo-4-Aza-5 / androst-1-ene-17 carboxamide (51 mg) in toluene (1.3 ml) was added dropwise over 15 minutes, and the mixture was heated in a flask under reflux for 85 minutes.

The solvent was removed under reduced pressure, and the residue was purified by thin layer chromatography on silica gel (eluent: methylene chloride/ethyl acetate/methanol 50:45:5) with the release of the product from the header (27 mg).

MS (m/z): 426 M+.; 411 M-.< / BR>
NMR (CDCl3) : is 6.78 (d, 1H, H(1)), 5,80 (DD, 1H, H(2)), 5,67 (s, 1H, NH(4)), and 5.30 (d, 1H, NH(21)), 4,35 (m, 1H, NCHCH(CH3)-), to 3.33 (DD, 1H, H(5 )), 2,42 and 2,28 (2m, 2H, -CH2CF3), a 1.25 (d, 3H, -NHCH(CH3)-), of 0.97 (s, 3H, Me(19)), to 0.68 (s, 3H, Me (the substances, listed below

N-(5,5,5-Cryptor-2-methylpent-3-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamide;

N-(4,4,4-Cryptor-2-methylbut-2-yl)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid.

Example 10.

Tablets with risk for oral administration containing each 250 mg of active substance was produced in the following way:

Ingredients (for 10,000 tablets), g

N-(2,2,2-Tryptophanate)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid - 2500

Corn starch - 275

Powder talc - 187

Calcium stearate - 38

The active substance was granulated with a 4% weight/volume aqueous solution of methylcellulose. To the dried granules are added to the mixture of other ingredients, and the final mixture is compressed into tablets of appropriate weight.

Example 11.

Dogcatemy hard gelatin capsules for oral use, containing in each capsule 250 mg of active substance was produced as follows.

The composition of 10,000 capsules, g:

N-(2,2,2-Tryptophanate)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid - 2500

Lactose - 1000

Corn starch - 300

Powder talc - 65

Calcium stearate - 35

The active substance is mixed with a mixture of starch-lactose, for which the applications with the content in each 250 mg of active substance was produced as follows.

Ingredients (for 10,000 tablets), g:

N-(2,2,2-Tryptophanate)-3-oxo-4-Aza-5 androst-1-ene-17 carboxamid - 2500

Corn starch - 280

The talcum powder - 180

Calcium stearate - 40

The active ingredient is granulated with a 4% weight/volume aqueous solution of methylcellulose. To the dried granules are added to the mixture of other ingredients, and the final mixture is compressed into tablets of appropriate weight.

1. Fluorinated derivatives of 17-substituted-4-Aza-5-androstane-3-one of General formula I

< / BR>
where the symbol independently represents a single or double bond;

In - connection;

R is hydrogen, C1-C4is an alkyl group;

R1is hydrogen, C1-C6is an alkyl group, unsubstituted or substituted by one or more fluorine atoms or benzyl group;

R2is hydrogen, a fluorine atom, a C1-C6is an alkyl group, unsubstituted or substituted by one or more fluorine atoms, or R2is phenyl, benzyl;

R3is hydrogen, a fluorine atom, a C1-C4-alkyl, unsubstituted or substituted by one or more fluorine atoms, phenyl;

R4is hydrogen, fluorine atom or is absent, when Y is a double bond;

R5is hydrogen, a fluorine atom, a C1-C6-as the Torah or the group,

< / BR>
where R6, R7, R8independently is hydrogen or C1-C6is an alkyl group, unsubstituted or substituted by one or more fluorine atoms, And group

< / BR>
where each of R6and R7has the specified values.

2. The compound of formula I under item 1, characterized in that it is single bond or double bond, is a bond, R is hydrogen or methyl, R1is hydrogen, R2is hydrogen, methyl, phenyl, R3is hydrogen, methyl, R4is hydrogen, R5is methyl, trifluoromethyl, Y is a single bond, And group

< / BR>
where R6is hydrogen or fluorine, and R7and R8are both hydrogen atoms or fluorine.

3. The compound of formula I on p. 1, wherein is a single or double bond, is a bond, R is hydrogen, methyl or 2,2,2-trifluoromethyl, R1is methyl, phenyl, R3is hydrogen, R4no, R5is methyl, trifluoromethyl, Y is a double bond, A - team,

< / BR>
where both hydrogen, provided that at least one of the groups R2, R5contains at least one fluorine atom.

4. The compound of formula I on p. 1, wherein is a single or double bond, R is hydrogen, methyl or 2,2,2-triptorelin, R1is hydrogen, 2,2,2-triptorelin, R2is hydrogen, maticora, trifluoromethyl, In - bond, Y is a single bond, a hydrogen, a fluorine atom, provided that one of the groups R2, R5contains a fluorine atom.

5. The compound of formula I on p. 1, wherein a represents N-(2,2-debtor-2-trifluoromethyl-1-methyl-1 - phenylethyl)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, N-(2,2,2-Cryptor-1-benzyl-1-phenylethyl)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, N-(2,2,2-Cryptor-1-ethyl-1-phenylethyl)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, N-(2,2,2-Cryptor-1-methyl-1-phenylethyl)-3-oxo-4-Aza-4-methyl-5-carboxamide, N-(2,2,2-Cryptor-1-methyl-1-phenylethyl)-3-oxo-4-Aza-4-methyl-5-carboxamid, N-(2,2,2-Cryptor-1-methyl-1 - phenylethyl)-3-oxo-4-Aza-5-androstane-17-carboxamide, N-(2,2,2-triptorelin)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, N-(2,2,2-triptorelin)-4-methyl-3-oxo-4-Aza-5-androstane-17-carboxamide, N-(4,4,4-Cryptor-3-methylbut-2-yl)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, N-(4,4,4-Cryptor-3-methylene-but-2-yl)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, N-(1,1,1-Cryptor-2-phenylprop-2-yl)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide, N-(4,4,4-Cryptor-3-methylbut-2-yl)-3-oxo-4-Aza-5-androstane-17-carboxamide, N-(2,2,2-Cryptor-1,1-diphenylether)-3-oxo-4-Aza-5-androst-1-ene-17-carboxamide.

6. Pharmaceutical composition having inhibitory testosterone-5-reductase activity, as the active ingredient it contains an effective amount of the compounds of formula I on p. 1.

 

Same patents:

-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

The invention relates to new derivatives of 4-aseankorea General formula (1),

< / BR>
in which R is hydrogen or C1-3alkyl group; X is chlorine, bromine or iodine and- single or double bond

The invention relates to the field of veterinary medicine and can be used for contraception animals

The invention relates to the synthesis of biologically active analogues of steroid hormones, specifically to obtain 6-oxa-8-isanalogous steroid estrogens, having hypolipidemic activity and which intermediate compounds for the synthesis of other classes of substances

The invention relates to compounds of General formula I in the form 22R and 22S-ephemerol, where X1and X2are the same or different and each represents a hydrogen atom or a fluorine atom, provided that X1and X2at the same time are not hydrogen atoms; methods for their preparation; pharmaceutical preparations containing them; and the use of these compounds in the treatment of inflammatory and allergic diseases

The invention relates to inhibitors of steroid alpha-reductase have the following formula:

< / BR>
where Y is oxygen or sulfur; R is the group: (a) OR4where R4is hydrogen or C1-C6alkyl group; b)where each of R5and R6independently hydrogen or C1-C6alkyl group;)where R7is hydrogen or C1-C6alkyl group, W is a group; (I)where R8- C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group, phenyl group or benzilla group; or (II)where R9- C1-C6alkyl group or a C5-C6cycloalkyl group, or (III)where R5and R6defined above; g)where each of R10and R11- independently hydrogen or C1-C6an alkyl group or both in the static ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; n is an integer from 2 to 4; R1is hydrogen, C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group or aryl group; each of R2and R6independently selected from the group consisting of hydrogen, C1-C6of alkyl, C5-C6cycloalkyl, C6-C9cycloalkenyl and aryl, or R2and R3together with the nitrogen atom to which they are bound, form pentatominae or hexatone rich heterophilically ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; the symboldenotes a single or double bond, provided that when is a double bond, the hydrogen in the 5-position is absent, and its pharmaceutically acceptable salts

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to the substituted 4-benzylaminoquinolines and their heteroanalogs of the general formula (I): P-L-G (I) wherein G means compound of the formula: G(I) wherein K means -OR(7), -NH-CH2-CH2-SO3H, -NH-CH2-CO2H wherein R(7) means hydrogen atom, CH3; R1-R6 mean independently of one another hydrogen atom, -OR(10), -R(10) being one of residues R1-R6 means a bond with L always; R(10) means hydrogen atom, (C1-C4)-alkyl; L means (C1-C15)-alkyl being one or some structural CH2-fragments can be replaced for -C≡C-, -NR(11)-, -CO-, -O- wherein R(11) means hydrogen atom; P means: or wherein A means nitrogen atom (N); B means CH; D means CH; E means CH; R16-R24 mean independently of one another hydrogen atom, F, Cl atoms, (C1-C4)-alkyl being alkyl residues can be mono- or multiple-substituted with fluorine atom, NR(25)R(26), OR(25), COR(25), COOR(25), CONR(25)R(26) being one of residues R16-R(24) means a bond with L always; R25 and R26 mean independently of one another hydrogen atom, (C1-C4)-alkyl or benzyl. Also, invention relates to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and to a drug based on thereof for prophylaxis of supersaturation of bile with cholesterol. Invention provides preparing new compounds and a drug based on thereof that can be used for prophylaxis and treatment of patients suffering with gallstones.

EFFECT: improved preparing method, valuable medicinal properties of compounds and drugs.

10 cl, 32 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising drospirenone as the first active agent in the amount corresponding to daily dose from 2 to 4 mg in administration of the composition, and ethynylestradiol as the second active agent in the amount corresponding to daily dose from 0.01 to 0.05 mg in combination with one or some pharmaceutically acceptable vehicles or additives. Drospirenone as a component of the pharmaceutical composition is in the finely divided form. The preparation comprises some separately packages and individually taken medicinal units placed in the unit package and designated for oral administration for at least 21 days at a time and indicated daily medicinal units comprise the combination of drospirenone and ethynylestradiol. The preparation can comprise 7 and less daily doses no containing any active agent or containing ethynylestradiol only. The combination of ethynylestradiol and drospirenone provides the safety contraceptive activity due to using the maximal dose of drospirenone being without adverse effects, in particular, excessive diuresis.

EFFECT: improved and valuable properties of combination.

34 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out laparoscopy and administering Danazol at a dose of 400 mg twice a day for 6 months. Danazol treatment being over and normal prolactinemia being observed in biphasic menstrual cycle, Parlodel is administered at a dose of 2.5 mg twice a day for three menstrual cycles long period.

EFFECT: enhanced effectiveness in normalizing hormone background and pregnancy taking place.

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: method relates to composition containing estrogen as the first active ingredient in amount sufficient to treatment of diseases, disorders, and symptoms associated with deficit of endogen estrogen levels in women; and drospyrenon as the second ingredient in amount sufficient to endometrium protection from unfavorable estrogen effects. Methods for treatment also are disclosed. Preparations of present invention are useful in combination therapy for continuous, subsequent or intermittent administration.

EFFECT: method for replacement hormonotherapy in women of improved efficiency.

46 cl, 7 ex

FIELD: organic chemistry, steroids, biology.

SUBSTANCE: invention relates to steroid compounds of the general formula (X):

wherein in fragment of the formula XA:

each bond between C6 and C7, between C7 and C8, between C8 and C9, between C8 and C14 and between C14 and C15 is a single or double bond under condition that each atom C6, C7, C8, C9, C14 and C15 is bound with adjacent C-atom by a single bond or one double bond; CR3 means -CHOH; A means methylene or ethylene group; R4 and R4' mean (C1-C4)-alkyl, hydrogen atom (H); R20 means (C1-C4)-alkyl; R23 and R23' mean in common piperidine-1-yl, morpholine-4-yl, pyrrolidine-1-yl, piperazinyl possibly substituted with -OH, benzene, pyridine, pyrimidine, phenyl, alkoxycarbonyl group, or R23 means H and R23' means substituted alkyl. These compounds can be used for stimulation of meiosis in human oocytes. In proposed compounds steroid differs specifically as nitrogen atom of amino-group is bound with C17-atom of steroid skeleton by spacer A.

EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) , their pharmaceutically acceptable salts, solvates, stereoisomers wherein in each case R1 and R2 mean independently hydrogen atom, possibly substituted alkyl, aryl, heteroalkyl wherein heteroatom means nitrogen atom, heteroaryl wherein a heteroatom means nitrogen, oxygen or sulfur atom; or R1 and R2 in common with N-atom to which they are bound can form a heterocyclic structure as a moiety of organic group comprising 6-12 carbon atoms and comprising optionally 1-6 heteroatoms chosen from nitrogen and oxygen atoms; R3 and R4 mean hydrogen atom or a protective group under condition that R and/or R4 represents part of the hydroxyl protective group; № from 1 to 17 mean carbon atoms wherein C-atoms at № 1, 2, 4, 11, 12, 15 and 16 can be substituted with two from R5 groups; C17-atom can be substituted with one of the following groups: =C(R5)(R5), =C=C(R5)(R5) or two from groups - R5 and -OR6; C-atoms at № 5, 8, 9, 10, 13 and 14 can be substituted with group R5 wherein R means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-halogenalkyl; R6 means H, protective group, such as -OR6-protected OH-group wherein the group -OR6 can form cyclic protective structure for vicinal -OH groups. Proposed compounds can be components of pharmaceutical composition and useful in treatment and/or prophylaxis of different states including inflammation, asthma, allergic disease, chronic obstructive pulmonary disease, allergic dermatitis, solid neoplasms, ischemia and cardiac arrhythmia.

EFFECT: improved treatment method, valuable medicinal properties of substances and pharmaceutical composition.

53 cl, 10 tbl, 24 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes novel halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids of the general formula (I) wherein each R20 and R20a means independently fluorine, chlorine, bromine atom, (C1-C4)-alkyl, hydrogen atom (H), cyano-group; R4 and R10 mean hydrogen atom or methyl group; both R1 and R2 represent hydrogen atom and form an additional bond. Compounds are inhibitors of 5α-reductase and can be used in treatment of diseases caused by the enhanced blood and tissue testosterone and dihydrotestosterone level.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 5 dwg, 1 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: method involves applying Sarsasapogenin in combination with one or several compounds taken from group consisting of Smilagen and Anzurogenin-D, for preparing composition for treating Parkinson disease or for treating postural hypotension, autism, chronic fatigue syndrome, heavy myasthenia gravis, Lambert-Eaton disease, Gulf War Syndrome and syndrome caused by professional contact with organophosphorous compounds. Sarsasapogenin selectively increases muscarinic receptors M1 activity, contributing to stimulating synaptic transmission, without М2 receptors activity being influenced (which evoke negative feedback and muscarinic transmission interruption).

EFFECT: enhanced effectiveness of treatment.

3 cl, 8 tbl

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