16-substituted 4-aza-androstane, compounds, methods of inhibiting pharmaceutical composition

 

(57) Abstract:

Describes the new 16-substituted 4-Aza-androstane General formula I

< / BR>
where the values of R1- R4specified in paragraph (1 formulas, which are selective inhibitors of the isoenzyme of 5-reductase. Describes how to inhibition of 5-reductase or its isoenzyme, methods of treatment of acne vulgaris, androgenous alopecia, excessive body hair growth in women, benign prostatic hyperplasia, prostatitis and/or prevent prostate cancer, the method stops and treatment Antonovo alopecia and promoting hair growth, the method of inhibiting the conversion of testosterone to dihydrotestosterone in mammals. The invention relates also to pharmaceutical compositions containing a therapeutically effective amount of the compounds of General formula I. 6 C. and 17 C.p. f-crystals, 2 tab.

The present invention relates to new compounds, new compositions, and methods of their use and methods of preparation, and data connections in General pharmacologically useful as therapeutic agents, the mechanism of action is based on selective inhibition of the isoenzyme of 5-reductase 1.

The main mediator activity of androgens in some azueta in the affected body under the action of testosterone-5-reductase (or just 5-reductase). Inhibitors of 5-reductase inhibitors are used to prevent or mitigate symptoms hyperandrogenemia stimulation in these bodies (see, in particular, U.S. Patent 4377584 (published 22 March 1983) and 4760071 (published July 26, 1988), received by the company Merck & Co., Inc. "). It is known that there is a second isoenzyme of 5-reductase, which interacts with the tissues of the skin, in particular, the hairy part of the scalp (see , in particular, G. Harris et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (Nov. 1992)). Isoenzyme, which interacts with the tissues of the skin, for convenience, designated as 5-reductase 1 (or 5-reductase type 1) and isoenzyme, which interacts mainly with the tissues of the prostate gland, known as 5-reductase 2 (or 5-reductase type 2).

When treating sensitive to androgens painful conditions, particularly benign prostatic hyperplasia and/or prevention and treatment of prostate cancer, it is desirable to use a single dosage unit, which is active against both isozymes in the prostate gland, so as to substantially inhibit the production of dihydrotestosterone. It is also desirable to have a single medicinal unit, which has a high select the smash her in the treatment of diseases of the skin and scalp scalp, in particular, acne vulgaris, islet of baldness in men and excessive body hair growth in women, in addition, a selective inhibitor of 5-reductase 1 could be used in combination with an inhibitor of 5-reductase 2, for example, finasteride (trade name PROCAR) for therapeutic treatment hyperandrogenic conditions such as benign prostatic hyperplasia, and/or prevent or treat prostate cancer and in the treatment of diseases of the skin and scalp scalp, such as acne vulgaris, seborrhea, excessive hair growth in women and androgenica alopecia. Next, an inhibitor of 5-reductase 1 of the present invention could be used in combination with means for causing the disclosure of membrane potassium channels, such as Minoxidil in the treatment of these skin conditions and hairy part of the scalp. Thus, the subject invention are compounds that have sufficient activity in the inhibition of the isoenzyme of 5-reductase 1.

The new compounds of the present invention have the formula

< / BR>
and are selective inhibitors of 5-reductase 1. The aim of the present invention are compounds that are inde is positive cancer, prostatitis and/or for preventing or treating prostate cancer. Another objective of the present invention are compounds which alone or in combination with inhibitors of 5-reductase 2 are useful for the treatment of acne vulgaris, excessive hair growth in women, androgenous alopecia (also known as androgenetic alopecia or islet male pattern baldness) and lack of content in plasma high-density lipoprotein, the compounds of the present invention are used to achieve one or more of these goals.

The new compounds of the present invention have the structural formula 1

< / BR>
or are a pharmaceutically acceptable salt or ester, where

C1-C2carbon-carbon bond may be a simple bond or a double bond, the dotted line;

R1selected from the group comprising a hydrogen atom and (C1-C10) alkyl;

R2selected from the group comprising a hydrogen atom and (C1-C10) alkyl;

one of R3and R4selected from the group including a hydrogen atom or methyl and the other is chosen from the group including:

(a) G-C(O)NRbRcwhere Rband Rcindependently represent a hydrogen atom, (C1-C6)alkyl, aryl or aryl(C1-C6)alkyl; alkyl part may have from 1 to 3 of the following substituents: halogen; (C1-C4)alkoxy group; or a trifluoromethyl; and the aryl part may have from 1 to 3 of the following substituents: halogen; (C1-C4)alkyl, (C1-C4)alkoxy group; or a trifluoromethyl;

(g) (C1-C10)alkyl-S-;

(h) (C2-C10)alkenyl-X;

where (C1-C10)alkyl in (g) and (C2-C10)alkenyl in (h) can be substituted or not substituted from 1 to 3 of the following substituents:

i) halogen; hydroxyl group; cyano group; nitro group; mono-, di - or trihalomethyl; oxo group; hydroxy - sulfonylurea group; carboxyl group;

ii) hydroxy, (C1-C6)alkyl, (C1-C6)alkylalkoxy group; (C1-C6)alkylthio group; (C1-C6)alkylsulfonyl group; and (C1- C6)alkoxycarbonyl group; where (C1-C6)alkyl fragment may be optionally substituted from 1 to 3 of the following substituents: halogen; (C1-C4)alkoxygroup; or trifluoromethyl;

iii) aaltio-group may be optionally substituted from 1 to 3 of the following substituents: halogen; (C1-C4)alkyl, (C1-C4)alkoxy group; or a trifluoromethyl;

iv) group-C(O)NRbRc; -N(Rb)-C(O)-Rc; -NRbRc; where the values of Rband Rcstated previously;

(i) aryl-S-;

(j) heteroaryl-X-, where heteroaryl is a 5-, 6 - or 7 - membered heteroaromatic ring containing at least one member selected from the group comprising: a single oxygen atom in the ring; one sulfur atom in the ring; 1-4 nitrogen atom in the ring or a combination thereof; heteroaromatic ring may be condensed with one benzene ring, or heteroaromatic ring; where the aryl in (i) and heteroaryl in (j) may not be replaced or substituted from 1 to 3 of the following substituents:< / BR>
v) halogen; hydroxyl group, cyano group; a nitro group; a mono-, di - or trihalomethyl; mono-, di - or trihalomethane group; (C2-C6)alkenyl; (C3-C6)cycloalkyl; formyl group; hydrochlorine group; carboxyl group; ureido-group;

vi) (C1-C6)alkyl; hydroxy(C1-C6)alkyl, (C1-C6)alkyloxy group; (C1-C6)alkyloxy(C1-C6)alkyl, (C1-C6)alkylcarboxylic group; (C1-C61-C6)alkylsulfonamides group; (C1-C6)alkylarylsulfonate group; (C1-C6)allyloxycarbonyl group; (C1-c6)allyloxycarbonyl(C11-C6)alkyl; RbRcN-C(O)(C1-C6)alkyl, (C1-C6)alkanolamine(C1-C6)alkyl; aroylamino(C1-C6)alkyl; while (C1-C6)the alkyl part may be substituted by from 1 to 3 of the following substituents: halogen; (C1-C4)alkoxy group; or a trifluoromethyl;

vii) aryl; aryloxy group; arylcarbamoyl group; aaltio group; arylsulfonyl group; arylsulfonyl group; arylsulfonate group; aryloxyalkyl group; aryl part can be substituted by from 1 to 3 of the following substituents: halogen; (C1-C4)alkyl, (C1-C4)alkoxy group; or a trifluoromethyl;

viii) group-C(O)NRbRc; -O-C(O)-NRbRc; -N(Rb)-C(O)-Rc; -N(RbRc; where the values of Rband Rcmentioned previously in (f); and the group - N(Rb)-C(O)-ORgwhere Rgmeans (C1-C6)alkyl or aryl, with the alkyl part may be substituted by from 1 to 3 of the following substituents: halogen atom; (C1-C4 halogen; (C1-C4)alkyl, (C1-C4)alkoxy group; or a trifluoromethyl; a group-N(Rb)-C(O)NRcRd; where Rddenotes a hydrogen atom; (C1-C6)alkyl and aryl; wherein said (C1-C6)alkyl and aryl can be substituted, as mentioned above in (f) for Rband Rc;

(ix) a heterocycle, a 5-, 6 - or 7-membered ring containing at least one member selected from the group comprising: a single oxygen atom in the ring; one sulfur atom in the ring; 1-4 nitrogen atom in the ring or a combination thereof; the heterocycle may be aromatic, unsaturated or saturated, and the heterocycle may be condensed with a benzene ring, and the heterocycle may be substituted by 1 to 3 substituents as specified above in paragraphs. v), (vi), (vii), (viii), except when ix) denotes a heterocycle; and

(k) R3and R4together may denote a carbonyl oxygen atom;

(I) R3and R4together can denote the group =CH-Rgwhere the value of Rgspecified in viii), where:

X is chosen from the group including:

-O-; -S(O)n-; -C(O)-; -CH(Re)-; -C(O)-O-*-C(O)-N(Re)-*; - N(Re-C(O)-O-*; -O-C(O)-N(Re)-*; -N(Re)C(O)-N(Re)-: -O-CH(Realkyl or unsubstituted or substituted heteroaryl, as indicated in (j); the asterisk (*) indicates a relationship in position 16 patterns 1 and n is 0, 1 or 2.

Valid only such combinations of substituents and/or options that result in stable compounds.

One of the embodiments of the present invention are the compounds of formula 1 in which R1denotes hydrogen or methyl, and R2denotes hydrogen or methyl.

The following embodiment of the present invention are the compounds of formula 1 in which one of the substituents R3and R4selected from the group comprising hydrogen or methyl and the other is chosen from the group including:

(b) cyano group;

(C) a fluorine atom;

(e) a hydroxyl group;

(g) (C11-C10)alkyl-S-; or (C1-C10)alkyl-X-, in which alkyl may be substituted by aryl, and aryl, in turn, can be substituted by 1-2 halogen atoms, or (C1-C6)alkyl;

(h) (C2-C10)alkenyl - X;

(i) aryl-S-;

(j) heteroaryl-X-, where heteroaryl is a 5-, 6 - or 7 - membered heteroaromatic ring containing 1-2 nitrogen atoms in the ring; where the aryl in (i) and heteroaryl in the group; trihalomethyl; trihalomethane group; or trihalomethane group; (C1- C6)alkyl; aryl; (C1-C6)alkylsulfonyl, (C1-C6)alkylaryl - sulphonamido-group;

xi) the group-NRbIc; Rb-C(O)-N(Rc)-; where Rband Rwithindependently represent a hydrogen atom, (C1-C6)alkyl, aryl or aryl(C1-C6)alkyl, this alkyl group may be substituted by from 1 to 3 of the following substituents: halogen; (C1-C4)alkoxy group; or a trifluoromethyl and aryl group may be substituted by from 1 to 3 of the following substituents: halogen; (C1-C4)alkyl, (C1-C4)alkoxy group; or a trifluoromethyl;

(xii) a heterocycle, a 5-membered aromatic ring containing one nitrogen atom in the ring; and (k) R3and R4together may denote a carbonyl oxygen atom; and where:

X is chosen from the group including:

-O-; -S(O)n-; -CH(Re)-; -C(O)-N(Re)-*-O-C(O)-N(Re)-*; where Redenotes a hydrogen atom, (C1-C3)alkyl, aryl, aryl (C1-C3)alkyl; an asterisk (*) indicates a relationship in position 16 patterns 1 and n is 0 or 2.

Examples of new compounds in this androstan-3,16-dione;

4-Aza-4-methyl-5-androstane-3,16-dione

3-oxo-4-Aza-4-methyl-16-hydroxy-5-androstane;

3-oxo-4-Aza-4-methyl-16 -(benzylaminocarbonyl)-5 - androstane;

3-oxo-4-Aza-4-methyl-16-benzoylamine-5-androstane;

3-oxo-4-Aza-4-methyl-16-methoxy-5-androstane;

3-oxo-4-Aza-4-methyl-16-allyloxy-5-androstane;

3-oxo-4-Aza-4-methyl-16 -(n-propyloxy)-5-androstane;

3-oxo-4-Aza-4-methyl-16-hydroxy-5-androstane;

3-oxo-4-Aza-4-methyl-16 -(phenoxy)-5-androstane;

3-oxo-4-Aza-7-methyl-16 -(phenoxy)-5-androst-1-ene;

3-oxo-4-Aza-4-methyl-16-methoxy-5-androstane;

3-oxo-4-Aza-4-methyl-16 -(4-chlorphenoxy)-5-androstane;

3-oxo-4-Aza-7-methyl-16 -(4-chlorphenoxy)-5-androst-1-ene;

3-oxo-4-Aza-7-methyl-16 -(4-chlorphenoxy)-5-androstane;

3-oxo-4-Aza-7-methyl-16 -(3-chloro-4-methylphenoxy)-5-androstane;

3-oxo-4-Aza-7-methyl-16 -(4-methylphenoxy)-5-androstane;

3-oxo-4-Aza-7-methyl-16 -(4-methylphenoxy)-5-androstane-1-ene;

3-oxo-4-Aza-7-methyl-16 -[4-(1-pyrrolyl)phenoxy]-5-androstane-1-ene;

3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-methoxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl 16 allyloxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3,3-dimethylallyl)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(n-PR-hydroxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-ethoxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-benzyloxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-methylthio-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(n-propylthio)-5 - androstane;

3-oxo-4-Aza-4,7-dimethyl-16-fluoro-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-cyano-5-androstane;

3-oxo-4-Aza-4-methyl-16 -(1-hexyl)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(n-propyl)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-benzyl-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 (4-Chlorobenzyl)-5-androstane;

3-oxo-4-Aza-4,16-dimethyl-16-methoxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-cianfrocca)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3-cianfrocca)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-nitrophenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(1-naphthyloxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3-chloro-4-methylphenoxy)-5-androstane;

3 oxo-4-Aza-4,7-dimethyl-16 -(4-methylphenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(tert-butoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3-methyl-1-Butylochka)-5 - androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(n-propyloxy)-5 - androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-triptoreline) -5 - androstane;

3-oxo-4-Aza-4,7-dimethy the -4,7-dimethyl-16-ethylsulfonyl-5-androstane;

3-oxo-4-Aza-4 7-dimethyl-16 -(4-methylsulfinylphenyl)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -[4-(4-tolilsulfonil) phenoxy]-5-androstane

3-oxo-4-Aza-4,7-dimethyl-16 -(3-pyridyloxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -[(4-phenyl)phenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-pertenece)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(2-pyrazinone)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -[4-(5-oxazolyl)phenoxy]-5-androstane;

3-oxo-4-Aza-4,7-dimethyl - 16 -(2-pyrimidinone)-5-androstane;

3-oxo-4-AAA-4,7-dimethyl-16 -[4-(1-peril)phenoxy]-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-aminophenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-acetylaminophenol)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-benzylaminopurine)-5-androstane:

3-oxo-4-Aza-4,7-dimethyl-16 -(4-chlorphenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-phenoxy-5 - a-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(2-chlorophenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3-chlorophenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-chlorphenoxy)-5 androst-1-ene;

3-oxo-4-Aza-4,7-dimethyl-16-(4-chlorobenzylidene)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-benzylidene-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-(4-methylbenzylidene)-5-and the 5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-(3-pyridylmethyl)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 methanesulfonyl-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-thiophenoxy-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 (4 chlorothiophene)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-fortifies)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-methylthiophene)- 5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-methoxythiophene)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-phenylsulfonyl-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16-phenylsulfonyl-5-androstane:

3-oxo-4-Aza-4,7 , 16-trimethyl-16 -(4 - triptoreline)-5-androstane;

3-oxo-4-Aza-4,7 ,16-trimethyl-16-hydroxy-5-androstane;

3-oxo-4-Aza-4,7 ,16-trimethyl-16-methoxy-5-androstane;

their pharmaceutically acceptable salts and analogues of the above compounds in which the C1-C2carbon-carbon bond is a double bond and/or R1denotes a hydrogen atom and/or R2means in appropriate cases, a hydrogen atom or methyl.

In another embodiment, the present invention of formula 1 are further constrained by the compounds in which C1-C2carbon - carbon bond is a simple bond, R1denotes methyl, R2abonnerede.

Some examples of compounds in this implementation method of the present invention include, but are not limited to:

3-oxo-4-Aza-4,7-dimethyl-16 -(4-cianfrocca)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3-cianfrocca)- 5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-nitrophenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(1-naphthyloxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3-chloro-4 - methylphenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-methylphenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-triptoreline)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-triftormetilfosfinov)- 5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-methylsulfinylphenyl)- 5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 - [4-(4 - tolilsulfonil)phenoxy]-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -[(4-phenyl)phenoxy]- 5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 (4 fervency)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 [(4-(5-oxazolyl)phenoxy]-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -[4-(1-peril)phenoxy]-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-aminophenoxy)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-acetylaminophenol)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(4-benzylaminopurine)-5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(2-chlorophenoxy)- 5-androstane;

3-oxo-4-Aza-4,7-dimethyl-16 -(3-chlorophenoxy)-5-androstane;

and their pharmaceutically acceptable salts.

A useful compound according to the present invention is 3 - oxo-4-Aza-4,7-dimethyl-16 -(4-chlorphenoxy)-5-androstane; or its pharmaceutically acceptable salt.

In the context of the present invention "alkyl" represents an aliphatic hydrocarbon group with both branched and straight chain containing a certain number of carbon atoms, in particular methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, ISO-propyl (i-WG), ISO-butyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), out-of pencil etc. "Alkyloxy - group" (or "alkoxy group") refers to an alkyl group that contains the specified

the number of carbon atoms attached through an oxygen bridge, in particular, methoxy group, ethoxy group, propyloxy group, etc. "Alkenyl" includes hydrocarbon group with a straight or branched chain, containing one or more carbon-carbon double bonds that may be located in any stable position in the carbon chain, such as ethynyl, propenyl or allyl, butenyl, pentenyl, etc., the Present invention covers all E, Z Dias number of deputies, preferably from 1 to 3 of the following substituents:

i) halogen; hydroxyl group; cyano group; nitro group; mono-, di - or trihalomethyl; oxo group; hydroxysultaine group; carboxyl group;

ii) hydroxy, (C1-C6)alkyl, (C1-C6)alkylalkoxy group; (C1-C6)alkylthio group; (C1-C6)alkylsulfonyl group; (C1-C6)alkoxycarbonyl group; where (C1-C6)alkyl portion may be optionally substituted from 1 to 3 of the following substituents: halogen; (C1-C4)alkoxy group; or a trifluoromethyl;

iii) aristeo group; aryl; aryloxy group; arylsulfonyl group; aryloxyalkyl group; in which the aryl part may be optionally substituted from 1 to 3 of the following substituents: halogen; (C1-C4)alkyl, (C1-C4)alkoxygroup; or trifluoromethyl;

iv) group-C(O)NRbRc; -N(Rb)-C(O)-Rc; -NRbRc; where the values of Rband Rcstated previously; and halogen refers to fluorine, chlorine, bromine or iodine.

The term "oxo group" in the context of the present invention denotes an oxo radical, which may be located in any stable position the digital acyl or arolina groups in other positions in the carbon chain.

In the context of the present invention, the term "aryl", i.e., (C6- C10)aryl means phenyl or naphthyl including 1-naphthyl or 2-naphthyl, as substituted, or not substituted, as indicated below.

In the context of the present invention "heteroaryl" includes 5-, 6-or 7-membered heteroaromatic radical containing at least one member selected from the group comprising: a single oxygen atom in the ring; a sulfur atom in the ring; 1-4 nitrogen atoms in the ring or a combination thereof; heteroaryl ring may be condensed with benzene ring, or heteroaromatic ring. This class includes both unsubstituted and substituted the following heteroaromatic rings include pyridyl, furyl, peril, thienyl, isothiazolin, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, hinely, hintline, ethenolysis, benzofuran, isobenzofuran, benzothiazyl, pyrazolyl, indolyl, isoindolyl, purinol, carbazolyl, isoxazolyl, thiazolyl, isothiazolin, oxazolyl, benzothiazolyl and benzoxazolyl. Heteroaryl ring may be attached in the structural formula 1 via a heteroatom, in particular, a nitrogen atom, or carbon atom in the ring, resulting in a stable structure. Heteroaryl Kohl and heteroaryl groups, can be substituted by from one to three, preferably one or two substituents that are independently chosen from:

v) a halogen atom; hydroxyl group; cyano group; nitro group; mono-, di - or trihalomethyl; mono-, di - or trihalomethyl; mono-, di - or trihalomethane group; (C2-C6)alkenyl; (C3-C6)cycloalkyl, formyl group; Hydrosulphite group; carboxyl group; ureido - group;

vi) (C1-C6)alkyl; hydroxy(C1-C6)alkyl, (C1-C6)alkyloxy group; (C1-C6)alkyloxy(C1-C)6of alkyl (C1- -C6)alkylcarboxylic group; (C1-C6)alkylsulfonyl group; (C1-C6)alkylthio group; (C1-C6)alkylsulfonyl group; (C1-C6)alkylsulfonamides group; (C1-C6)allyloxycarbonyl group, (C1- C6)allyloxycarbonyl(C1-C6)alkyl;

RbRcN-C(O)(C1-C6)alkyl, (C1-C6)alkanolamine(C1-C6)alkyl; aroylamino(C1-C6)alkyl; while (C1-C6)alkyl part may be substituted by from 1 to 3 of the following substituents: halogen; (C1-C4)ALCO is lonley group; arylsulfonyl group; arylsulfonate group; aryloxyalkyl group; the aryl part may be substituted by from 1 to 3 of the following substituents: halogen; (C1-C4)alkyl, (C1-C4)alkoxy group; or a trifluoromethyl;

viii) group-C(O)NRbRc; -O-C(O)-NRbRc; -N(Rb)-C(O)-Rc; -NRbRc; Rb-C(O)-N(Rc)-; where Rband Rcmentioned previously in (e), and group-N(R)-C(O)-OR, where in this case Rcmeans (C1-C6)alkyl or aryl; -N(Rb)-C(O)-ORcRdwhere in this case Rddenotes a hydrogen atom, (C1-C6)alkyl and aryl; where the (C1-C6)alkyl and aryl can be substituted by the substituents mentioned above in (e) for Rband Rc;

(ix) a heterocycle, a 5-, 6 - or 7-membered ring containing at least one member selected from the group comprising: a single oxygen atom in the ring; one sulfur atom in the ring; 1-4 nitrogen atom in the ring or a combination thereof; the heterocycle may be aromatic, unsaturated or saturated, and the heterocycle may be condensed with a benzene ring, and the heterocycle may be substituted by one to three substituents="ptx2">

Condensed heterocyclic systems include: purine, imidazolides, imidazothiazole, pyridopyrimidines, pyridopyrimidines, pyrimidopyrimidine, imidazopyridine, pyrrolopyridine, imidazopyridine etc.

"Heterocyclic" groups include fully unsaturated aforementioned heteroaryl ring, as well as their corresponding dihydro-, tetrahydro - and hexahydrotriazine derived from partially unsaturated and fully saturated variants of cyclic systems. Examples include: dihydroimidazole, dihydrooxazolo, dihydropyridin, tetrahydrofuryl, dihydropyrrol, tetrahydrothieno, dihydroisoxazole, 1,2-dehydrobenzperidol, 1,2 - dihydrotetrazolo, 1,2-dihydropyrazine, 1,2-dihydropyrimidin, 1,2-dihydrohelenalin, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4 - tetrahydrobenzene, 1,2,3,4-tetrahydrobenzene, 1,2,3,4 - tetrahydrobenzene, 1,2,3,4-tetrahydropyrazolo, 1,2,3,4 - tetrahydroindole, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4 - tetrahydropyranyl, 1,2,3,4-tetrahydrocarbazole, 1,2,3,4 - tetrahydroisoquinoline, 1,2,3,4-tetrahydrofuryl, 1,2,3,4 - tetrahydrooxazolo, 1,2,3,4-tetrahydrobenzene and 1,2,3,4 - tetrahydroisoquinoline etc.

The heterocyclic group may contain the same batch" (or "alkoxy"), "aryl" or "heteroaryl" appear in the title of the substituent in the formula I (in particular, alcoxyacylates), they have the same values as above for "alkyl", "alkenyl", "alkyloxy" (or "alkoxy", "aryl" or "heteroaryl", respectively. The indicated number of carbon atoms (in particular, C1-C10) refer independently to the number of carbon atoms in the alkyl or alkenylphenol fragment or alkyl or alkenylphenol part of a larger substituent in which alkyl or alkenyl included as an integral part.

In the scope of claims of the present invention also includes pharmaceutically acceptable salts of the compounds of formula 1, in the structure which are basic or acidic groups. If you have acidic Deputy, in particular-COOH, for use in the dosage forms may be obtained from ammonium, sodium, potassium, calcium salt, etc., If there is a core group, i.e., amino group or having the properties of the Foundation of the heteroaryl radical, such as, in particular, 4-pyridyl, for use in the dosage forms may be obtained acidic salt, such as hydrochloride, hydrobromide, acetate, almoat etc.

In addition, if the5)alkilany, pivaloyloxymethyl, etc. and esters known from the field of technology for modifying solubility or change the settings during the hydrolysis, for use in formulation, slowly emit drug or formulation containing precursors of drugs.

The above salts include the following: acetate, lactobionate, bansilalpet, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, salt almond acid, bitartrate, mesilate, borate, bromide, chloride, methylnitrate, calcium salt of ethylenediaminetetraacetic acid, methyl sulfate, camsylate, salt mucus acid, carbonate, napsylat, chloride, nitrate, clavulanate, salt, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, salt ethylenediaminetetraacetic acid, oxalate, Etisalat, pamoate (embonate), astolat, palmitate, Eilat, Pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, picolylamine, sulfate, hexylresorcinol, subacetate, salt geranamine, succinate, hydrobromide, salt tannin, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate is ATA with water or common organic solvents. This solvate included in the scope of claims of the present invention.

The term "therapeutically effective amount" means the amount of drug or pharmaceutical agent that causes a biological or medical response of a tissue, system, animal or human, which examines the researcher, veterinarian, medical doctor or other specialist in the field of medicine.

Compounds of the present invention contain chiral centers and can exist as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all of these isomeric forms and their mixtures are included in the scope of claims of the present invention. Moreover, some of the crystalline forms of the compounds of the present invention may exist in polymorphic forms and all of them are included in the scope of claims of the present invention.

In addition the aim of the present invention are methods of treatment hyperandrogenemia States androgenous alopecia, including islet baldness in men, acne vulgaris, seborrhea, excessive body hair growth in women, by oral, systemic, parenteral or local introduction of etani with the tools, able to open the membrane potassium channels, in particular, Minoxidil; antiandrogen, in particular, flutamide; retinoids, in particular, tretinoin or isotretinoin; antagonists-1-receptor, in particular, terazosina.

The term "treatment androgenous alopecia" means stopping and turning androgenous alopecia and promote hair growth. The next objective of the present invention are methods of treatment of benign prostatic hyperplasia, prostatitis and treatment and/or prevention of prostate cancer by oral, systemic, or parenteral appointment of the new compounds of the formula I, both independently and in combination with inhibitors of 5-reductase 2.

The aim of the present invention are also pharmaceutical compositions, suitable for local, oral, systemic and parenteral administration for use in the new methods of treatment proposed in the present invention. Compositions containing compounds of the present invention as active ingredients for use in the treatment of the above hyperandrogenemia States can be entered in the form of a variety of therapeutic desirablity in such oral dosage forms, as tablets, capsules (each of which includes compositions with delayed time of allocation of the drugs or compounds for prolonged excretion of the drug), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or be administered by injection. In addition, they can be administered as an intravenous (both bolus, and infusion), intraperitoneal, subcutaneous, local, without occlusion and occlusion, or intramuscular form; the use of all these forms is well known to experts in the field of pharmacy.

Proposed in the present invention the pharmaceutical compositions include pharmaceutical compositions containing a pharmaceutically acceptable carrier and a therapeutically affective amount of the compounds of formula I of this invention, these pharmaceutical compositions optionally contain:

(1) a therapeutically effective amount of an inhibitor of 5-reductase 2 or its pharmaceutically acceptable salt, in particular, finasteride, epristeride or turosteride;

(2) a substance that stimulates the disclosure of membrane potassium channel, or its pharmaceutically acceptable salt, in particular, Minoxidil;

(3) therapeu sotretinoin;

(4) a therapeutically effective amount of antiandrogen or its pharmaceutically acceptable salt, in particular, flutamide, spironolactone or casodex.

Daily dose of the compounds for adults can vary in the range from 0.1 to 1000 mg per day. For oral administration the compositions are preferably prepared in the form of having or not having a notch tablets containing 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0 and 55.0 mg of active ingredient, for the purpose of recruiting for the patient corresponding to the symptoms dosage. The effective amount of the drug usually comes at a dosage of from about 0.002 mg per kg of body weight to about 50 mg per kg of body weight per day. A more preferred range is from 0.01 mg/kg to 7 mg/kg / day.

Compounds of the present invention mainly administered in single daily dose or the total daily dose may be injected into doses of two, three or four times a day. Moreover, the compounds of the present invention can be through the nose by means of local application suitable for insertion through the nose of the media or through the skin by means of dosing forms or patches, are well known in the art. For an introduction to the form, th is Ali the selection of medicines for a long time, and not as individual servings.

In the treatment of androgenic alopecia, including islet male pattern baldness, acne vulgaris, seborrhea, and excessive body hair growth in women, the compounds of the present invention can be administered as pharmaceutical compositions containing the active compound in combination with a pharmaceutically acceptable carrier suitable for local use. Pharmaceutical compositions for local injection can be prepared in the form of a solution, cream, ointment, gel, lotion, shampoo or spray, suitable for application to the skin. These pharmaceutical compositions for local administration, containing compounds of the present invention typically contain approximately from 0.001% to 15% weight. active compounds in a mixture with a pharmaceutically acceptable carrier.

When treating acne vulgaris, androgenous alopecia, including islet male pattern baldness, seborrhea, excessive hair growth in women, benign prostatic hyperplasia, prostatitis and the prevention and/or treatment of prostate cancer compounds of the present invention can be used by themselves or in combination with a therapeutically effective amount of inhumanities dosage forms. Additionally, in the treatment of diseases of the skin and scalp scalp associated with acne vulgaris, androgenous alopecia, including islet male pattern baldness, seborrhea, excessive hair growth in women, the compounds of the present invention and an inhibitor of 5-reductase 2 can be prepared in the form of a composition suitable for topical administration. Also can be used combined therapy, in which the compounds of formula I and an inhibitor of 5-reductase 2 are assigned separately in the form of oral, systemic, parenteral or local dosage forms. For example, the compound of the formula I and, in particular, finasteride can be entered in the form of single oral or local dosage forms or each agent may be administered in separate dosage forms, in particular, separate oral dosage forms, or finasteride may be in the form of oral composition in combination with a dosage form of compound 1, suitable for local purposes (see. U.S. patents 4377584 and 4760071, which describes the dosages and formulations for inhibitors of 5-reductase. In that case, if the active substances are applied as separate dosage forms, they can be administered simultaneously or each is uchitsya and other inhibitors of 5-reductase type 2, useful in the above methods. Not limiting the present invention examples include: 17 -(N-tert-butylcarbamoyl)androsta-3,5-diene-3 - carboxylic acid (epistemic, Smith & Beecham, SKF 105657), described in WO 91/13550 and WO 93/19758; and a 17 - [N-ISO-propyl-N- (isopropylcarbamate)carbarnoyl]-4-methyl-4-Aza-5-androstane-3-one (turosteride, Farmitalia, FCE 26073), which is described in U.S. Patent 5155107, and their derivatives.

Further, the introduction of the compounds of the present invention in combination with a therapeutically effective amount of a substance that stimulates the disclosure of membrane potassium channels, such as Minoxidil, cromakalim, pinacidil, compounds selected from the class S-triazine, Thian-1-oxide derivatives benzopyran and pyridinoline or their pharmaceutically acceptable salts, can be used in the treatment of androgenous alopecia, including islet male pattern baldness. The active ingredients can be administered in a single dose for local use, with each active substance may be administered in separate dosage forms, in particular, in separate formulations for local purposes, or in the form of oral dosage forms containing the compound of the formula I, in combination with a dosage forms, soderjasimi, published February 20, 1992, which are the dosages and formulations containing stimulants disclosure membrane calcium channels. In that case, if the active substances are applied as separate dosage forms, they can be administered simultaneously or each of them may be in different time periods.

Moreover, the treatment of acne ordinary and/or androgenous alopecia can be used combined therapy involving the introduction of a therapeutically effective amount of the compounds of formula I, both independently and in combination with an inhibitor of 5-reductase 2, or alternatively in combination with a therapeutically effective amount of a retinoid, in particular, retinova acid or its complex ester or amide, such as tretinoin (RETIN A) or isotretinoin (ACCUTANE, Roche, see U.S. Patent 3006939, 3746730 and 4556518).

In addition the treatment of acne vulgaris, androgenous alopecia, seborrhea, excessive body hair growth in women, benign prostatic hyperplasia, prostatitis and the prevention and/or treatment of prostate cancer can be used combined therapy comprising introducing an effective amount of the compounds of formula I together with terapeutiche claims of the present invention also includes a method of treating benign prostatic hyperplasia, which includes a step of introducing to a mammal in need of such treatment, a therapeutically effective amount of the compounds of formula I in combination with an inhibitor of 5-reductase 2. This method includes the use of antagonist-1-receptor, in particular, terazosin (Abbott, see U.S. Patent 4026894, 4251532).

In the scope of claims of the present invention also includes a method of inhibiting the biosynthetic conversion of testosterone to dihydrotestosterone in need of treatment of mammals, including the stage of introduction of a given mammal a therapeutically effective amount of the compounds of formula I or a therapeutically effective amount of the compounds of formula I in combination with an inhibitor of 5-reductase 2.

In the scope of claims of the present invention also includes a method of inhibiting 5-reductase or its isoenzyme in a mammal in need of such treatment, comprising the stage of introduction of a given mammal a therapeutically effective amount of the compounds of formula I or a therapeutically effective amount of the compounds of formula I in combination with an inhibitor of 5-reductase 2.

Dosage regimes when using connections nastojascee the condition of the patient; the severity of the disease, the treatment is carried out; the route of administration of drugs; the condition of the kidneys and liver of the patient; the specific connection. The ordinary skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or stop disease progression. Optimal assessment of the achievement of the concentrations of the drugs for an interval of values that lead to the achievement of result, without causing toxic effects, requires the use of dosage regimes, based on the kinetics of drug delivery to the desired organs. This requires consideration of the distribution, equilibrium, and elimination of drugs.

In the methods of the present invention described in the present description, the compounds are active ingredients and are typically administered in a mixture with pharmaceutically suitable diluents, fillers and carriers (denoted by the General term "holders") who are mostly selected in accordance with desired form of administration, i.e. tablets for oral administration, capsules, elixirs, syrups, etc., as it is usually practiced in pharmacy.

So, for peroral is a relatively inert carrier, suitable for oral purposes, such as ethanol, glycerol, water, etc. in Addition, if necessary, the mixture may include suitable binders, lubricants, loosening tools and dyes. Suitable binders are, but not limited to, starch, gelatin, natural sugars such as glucose or lactose, allocated from corn sweeteners, natural or synthetic resins, such as gum, tragakant or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc., lubricating substances, which are used in these dosage forms include, but not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc., Loosening tools include, but not limited to, starch, methylcellulose, agar, bentonite, xanthan gum resin, etc.

Liquid forms contain odorant and suspendresume or dispersing means, such as synthetic or natural resins, for example, tragakant, gum, methylcellulose, etc.

Other used dispersing agents are glycerol, etc. For parenteral administration, the required sterile suspensions and solutions. Isotone introduction.

Agents for local injection that contains the active components of the drug can be mixed with a variety of media, well known from the technical field, such as, for example, alcohols, aloe Vera gel, allantoin, glycerine, oil with vitamins a and E, mineral oil, ministerpresident of polypropylenglycol, etc. education, in particular, alcohol solutions, cleaning compounds, cleansing creams, gels, skin, skin lotions, and shampoos in the form of creams or gels. Cm. in particular, European patent application 0285382.

Compounds of the present invention can be administered in the form of a liposomal delivery system, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Compounds of the present invention can also be delivered using as individual carriers monoclonal antibodies, attached to the molecule compounds, the compounds of the present invention can also join soluble polymers that can be used as carriers. Ukna, polyhydroxyethylmethacrylate or polyethyleneoxide-polylysine, substituted palmitoleate remains. In addition, the compounds of the present invention can join biodegradable polymers used for the implementation of controlled selection of medicines, for example, polylactic acid, poly - Epsilon-caprolactone, polyhydroxyalkanoic acid, polyarteritis, polyacetale, policyidreference, polycyanoacrylates and cross stitched or amputations block copolymers of hydrogels.

Compounds of the present invention can easily be obtained in accordance with the following schemes reactions and Examples or in accordance with their modifications when using readily available starting compounds, reagents and conventional methods of synthesis. You can also use a modification of the above reactions, which are well known to experts in the art and not considered in detail here. Specific definitions for the variables shown in the diagrams (in particular) R = CH3), are given only for illustration and do not limit the present invention. The following abbreviations are used: Ph denotes phenyl; AC denotes anal group; t-Bu represents tert-butyl; Et oogum to be obtained in the following ways. First turn 4-Aza-4-methyl-5-androstane-3,17-dione (a) isomeric 3,16-dione 1, using the following sequence of reactions: (1) the process of joining And solidities in tert-butanol in the presence of tert-butoxide potassium with the formation of intermediate 16-oximo-17-ketone; (2) the restoration of the 17-keto group, hydrazine hydrate and potassium hydroxide in ethylene glycol at elevated temperatures with the formation of the 16-oxime; and (3) splitting 16-oxime group in connection with either the hydrolysis of an aqueous solution of acetic acid when heated or sodium bisulfite followed by treatment with an aqueous solution of hydrochloric acid with the formation of compound 1. The restoration of the 16-ketone 1 in 16-alcohol 2 conduct an appropriate hydride reducing agent such as sodium borohydride in methanol or three-fluoro-butylbromide lithium in tetrahydrofuran (THF). Alcohol 2 turn in its alkyl derivatives of 3 or 4, generating a first alkoxide anion with potassium hydride in N,N-dimethylformamide (DMF) or with potassium hydroxide in dimethyl sulfoxide (DMSO) followed by the addition of suitable allylbromide or alkylated. 16 - (n-propyloxy)derivative 5 is obtained from the previous 16 -(allyloxy)derived 4 catalytic who m turn in 1-amine With a catalytic hydrogenation in the presence of a heterogeneous catalyst, such as platinum oxide, in an aqueous solution of acetic acid. The acylation of the connection is performed using the appropriate acid anhydride or carboxylic acid in the presence of an acid acceptor, such as pyridine, triethylamine and 4-dimethylaminopyridine. In this way receive connections 6 and 7. Carbamates, such as compound 8 is shown in Scheme 3, get, treating alcohol 2 appropriate isocyanate in the presence of organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine.

Presented in figure 4 inhibitors can be obtained in the following way. 16-Alcohol transform 16-alcohol 9 step 4-nitrobenzoic acid in the presence of diethyl ether diazodicarbonyl acid and triphenylphosphine with the formation of an intermediate compound 16 -(p-nitrobenzoate) D followed by hydrolysis in an aqueous solution of a base in a suitable alcohol. Alkylation of compound (9) is conducted similarly to that described for alcohol 2, with the formation of the target 16-alkyl ether, such as 16-methoxypropane (example 10), shown in Scheme 4. "

Presented in scheme 5 7-methyl inhibitors receive the same as described previously for the EN-3,17-dione (E).

Presented in Scheme 6 7-methyl inhibitors obtained as follows. The connection 20 receive, acting on alcohol 12 tert-butyltrichlorosilane in the presence of organic sulfonic acids, such as triftoratsetata. 16 aryloxy derivatives, such as 21-24, get, producing alkoxide anion of the alcohol 12 with potassium hydride or sodium in tetrahydrofuran or N,N-dimethylformamide, or by using potassium hydroxide in dimethyl sulfoxide, followed by adding the appropriate fervently.

Presented in figure 7 7-methyl inhibitors receive the same as described previously for the compounds are given in figure 4, however, as starting compounds are used, the intermediate product 7-methyl-16-ol 12. The inversion of configuration at position 16 with the formation of compound F is carried out in accordance with the transformation of Mitsunobu, as shown in Scheme 7. O-Alkylation with the formation of 15-ethers, such as 26, is carried out, as already described earlier.

Presented in figure 8 inhibitors obtained as follows. Add methylacrylamide in tetrahydrofuran or ketone 1 or 11 leads to the corresponding 16-methyl-16-alcohol 27 or 28. On-Alkidnyh derivatives, such as in examples 29 and 30.

Presented in figure 9 inhibitors receive the following ways. Turn 7-methyl-16- -alcohol 25 in 16-thiol N processing teoksessa acid in the presence of di-ISO-propyl ester of azodicarboxylic acid and triphenylphosphine with the formation of an intermediate compound 16-thioacetate G, which is then hydrolized in the presence of a base and get thiol N. The alkylation is carried out, receiving mercaptide anion with sodium hydride or sodium hydride in tetrahydrofuran or N,N - dimethylformamide, followed by addition of an appropriate alkylhalogenide. This method is used in examples 31-33. The corresponding sulfones, such as 34, are acting on the intermediate thioethers 31-33 oxidant, such as organic nagkalat or peroxymonosulfate sodium (OXONE) in methanol.

Presented in figure 10 inhibitors receive the following synthetic methods. p-Nitrophenoxy derived 50 restore palladium on coal at room temperature in an atmosphere of hydrogen with the formation of p-aminophenoxy derivative 51. Amin further acelerou using acetyl chloride in methylene chloride in the presence of pyridine with the formation of p-AC is stuudy p-benzoylamine similar 53. Otherwise, amino 51 handle chloride Totila and get p-tosylamide similar 54.

In figure 11 the inhibitors obtained as follows. Protected with N-2,4-dimethoxybenzyl group 16 - alcohol 55 treated with p-perchlorobenzene and potassium hydride in dimethylformamide with the formation of p-chlorophenoxy derived 56, which is then treated triperoxonane acid in methylene chloride, to remove the protective N-2,4-dimethoxybenzyl group, and receive the connection 57. It is treated with gaseous hydrogen and palladium on coal in methanol, to remove the chlorine atom of the phenyl ring, and get phenoxypropane 58. In this connection act iodide stands and sodium hydride in dimethylformamide to methylation of the nitrogen atom in the ring and get the connection 61. Otherwise, the connection 58 is treated with DDQ and BSTFA in toluene, forming a double bond in position 1, and get a connection 59. On a similar recovery scheme of 1,2-dihydroanthracene 57 get p-chlorodrol-1-ene 60. His next position was identified in 1, processing iodide stands and sodium hydride in dimethylformamide, and get a connection 62.

Presented in figure 12 inhibi is 4-methyl-3-chloroperbenzoic and potassium hydride in dimethylformamide with the formation of 4-methyl-3 - chlorophenoxy derived 63, which is then treated triperoxonane acid in methylene chloride, to remove the protective N-2,4-dimethoxybenzyl group, and get a connection 64. It is treated with gaseous hydrogen and palladium on coal in methanol, to remove the chlorine atom of the phenyl ring, and get p-methylenediphosphonate 65. In this connection act iodide stands and sodium hydride in dimethylformamide, with the aim of methylation of the nitrogen atom in the ring and get the connection 67. Otherwise, the connection 65 is treated with a solution of DDQ and BSTFA in toluene, forming a double bond in position 1, and get a connection 66.

Presented in figure 13 inhibitors obtained as follows. The original 16-alcohol treated with 25 methansulfonate in pyridine containing 4-dimethylaminopyridine, and get mesilate 77. It, in turn, are processed with the proper thiophenols in anhydrous THF containing sodium hydride, and get thiophenoxy derived 78, 4 Hortefeux derived 79, 4 fortifies derived 80, 4 methylthiophene derived 81 and 4 methoxythiophene derived 82. Processing thiophenoxy derived 78 m-chlormadinone acid in methylene chloride for 1 hour at a temperature of 0oC, is, however, for three hours, get phenylsulfonyl derived 84.

Presented in figure 14 inhibitors obtained as follows. 16-Ketone (II) is treated with a suitable arylmethylidene in the conditions of the Wittig reaction, using sodium hydride in DMF, at a temperature of 80-100oC, and obtain the corresponding 4 - chlorobenzylidene 71, benzylidene 72 and 4-methylbenzylidene 73 counterparts. Their restore in ethanol in an atmosphere of hydrogen, using as catalyst 5% radium in coal and receive the corresponding 4-chlorobenzophenone derived 74 and 4 - methylbenzophenone derived 75. Also in two stages, a 3 - pyridylmethylene similar 76.

The following examples are given in order to explain the methods of obtaining the compounds of the present invention. It should be understood that the examples in no way limit the present invention. Further, it is not necessary to consider the following examples as the only examples that make up the essence of the present invention, so that the combination of compounds or their fragments may be the object of the present invention. For professionals it should be clear that known variations of the conditions and ways of implementation of the constraints is not specified, given in degrees Celsius.

The original 4-Aza-4-methyl-5-androstane-3,17-dione (compound a in the above Scheme 1) can be obtained in accordance with the methods described in the publication Rasmussop et al., J. Med. Chem., Vol. 27, p. 1690-1701 (1984). The original 4-Aza-4,7 - dimethyl-5-androstane-3,17-dione can be obtained by the method described in Example 36.

Example 1

4-Aza-4-methyl-5-androstane-3,16-dione

Stage 1: 4-Aza-4-methyl-5-androstane-3,17-dione-16-oxime

To 2-methyl-2-propanol (14 ml) in a round bottom flask nitrogen purging add tert-piperonyl potassium (740 mg, 6,59 mmol). After formed a clear solution, with stirring, add 4-Aza-4-methyl-5-androstane-3,17-dione (1.0 g, 3,30 mmol) and stirring is continued for one hour, thereby forming a solution of a Golden color. To the reaction mixture dropwise add soliditet (0,884 ml, to 6.58 mmol) and leave overnight to mix at room temperature, thereby forming a solution of a dark orange color. The mixture is diluted with an equal volume of water and acidified to approximately pH 2 with 2N hydrochloric acid. Add diethyl ether and the resulting solid is filtered off, washed with ether, dried in vacuum and get the target connection the 6-oxime (596 mg, to 1.79 mmol) in ethylene glycol (5 ml) was added 98% hydrazine (57 μl, of 1.74 mmol) and powdered potassium hydroxide (568 mg, 10,12 mmol). The mixture is heated for 16 hours to a temperature of 140oC, cooled and neutralized with 2 N hydrochloric acid. The obtained solid is filtered off, washed with water, dried in vacuum and get the target compound mass spectrum: m/z 318 (M).

Stage 3: 4-Aza-4-methyl-5-androstane-3,16-dione

A mixture of 4-Aza-4-methyl-5 androstane-3-one-16-oxime (218 mg, 0,684 mmol) and sodium bisulfite (249 mg, of 23.9 mmol) in 50% aqueous ethanol (10 ml) is refluxed for 3 hours. Add diluted hydrochloric acid (0.5 N, 33 ml) and methylene chloride (50 ml) and vigorously stirred mixture for several minutes. The organic layer is separated and washed with sodium bicarbonate solution, saturated salt solution, dried (over sodium sulfate) and evaporated. The target product was then purified by the method of flash chromatography on silica gel, using as eluent 15% solution of acetone in methylene chloride, and get the target connection. FAB mass spectrum: m/z 304 (M+1). 400 MHz PMR (chloroform-d): 0,89 (singlet, 3H), 0,91 (singlet, 3H), 2,90 (singlet, 3H), 3,05 (doublet of doublets, 1H).

Example 2.

3-Oxo-4-Aza-4-methyl-16-g bath with ice and for 1 hour add sodium borohydride (38 mg, 0,989 mmol). Dilute the reaction mixture with water and extracted with methylene chloride (2 x 20 ml). The organic extracts are combined, washed with saturated salt solution, dried (over sodium sulfate) and evaporated. The target product was then purified using the evaporative chromatography on silica gel, using as eluent a 10% solution of acetone in methylene chloride, and get the target connection. Mass spectrum: m/z 391 (M). 400 MHz PMR (chloroform-d): 0,88 (singlet, 6H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,21 (singlet, 3H), 3,83 (multiplet, 1H).

Example 3.

3-oxo-4-Aza-4-methyl-16-methoxy-5-androstane.

To a solution of 3-oxo-4-Aza-4-methyl-16-hydroxy-5 - androstane (35 mg, 0,115 mmol) in dimethyl sulfoxide (1.0 ml) is added powdered potassium hydroxide (32 mg, 0,575 mmol). After stirring for 15 minutes at room temperature in a nitrogen atmosphere add itmean (36 μl, 0,575 mmol) and stirring is continued for another 4 hours.

The mixture is diluted with diethyl ether (30 ml), washed with water, saturated salt solution, dried (Na2S04) and evaporated. The target product was then purified flash chromatography on silica gel with application of a mixture of 10% acetone/methylene chloride as eluent with Polus.88 (s, 6N); 2.90 (s, 3H); 3.00 (DD, 1H); 3.21 (s, 3H); 3.83 (m, 1H).

Example 4

3-Oxo-4-Aza-4-methyl-16-allyloxy-5-androstane

The specified connection receive according to the method similar to that shown in Example 3, instead of taking iodine bromide allyl bromide. Mass spectrum: m/z 345 (M). 400 MHz PMR (chloroform-d): 0,88 (singlet, 3H), 0,90 (singlet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets 1H), 3,90 (multiplet, 2H), 3,99 (multiplet, 1H), 5,11-5,27 (multiplet, 2H), of 5.83-5,93 (multiplet, 1H).

Example 5

3-Oxo-4-Aza-4-methyl-16 -(n-propyloxy)-5-androstane

A solution of 3-oxo-4-Aza-4-methyl-16 allyloxy - 5-androstane in ethyl acetate (0,85 ml) hydronaut in hydrogen atmosphere in the presence of platinum oxide (4 mg) for 30 minutes at room temperature. The catalyst is removed by filtration through filter element Millex-HV with a pore size of 0.45 μm. Cleanse method flash chromatography on silica gel, using as eluent a 10% solution of acetone in methylene chloride, and get the target connection. Mass spectrum: m/z 348 (M+1). 400 MHz PMR (chloroform-d): 0,88 (singlet, 3H), 0,89 (singlet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,28 (triplet, 2H), 3,92 (multiplet, 1H).

Example 6

3-Oxo-4-Aza-4-methyl - 16 - (acetamido)-5-androstane

Stage 1: 3-oxo-4-Aza-4-methyl-16-amino-5-EN is left overnight to gidrirovaniya at room temperature and at atmospheric pressure in the presence of platinum oxide (50 mg). The catalyst was removed by filtration through filter element Millex-HV with a pore size of 0.45 μm. The residue is dissolved in methylene chloride (50 ml) and the solution washed with saturated sodium bicarbonate solution, saturated salt solution, dried (over sodium sulfate) and evaporated, receiving targeted Amin.

Stage 2 :3-oxo-4-Aza-4-methyl-16 -(acetamido)- 5-androstane

Amine, obtained in stage 1 (56 mg, 0,184 mmol), dissolved in methylene chloride (1.0 ml), added pyridine (0.6 ml), 4 - dimethylaminopyridine (5 mg) and acetic anhydride (0.3 ml) and stirred at room temperature for 2 hours. Dilute the reaction mixture methylene chloride, the organic layer separated, washed with water, 1N hydrochloric acid, saturated sodium bicarbonate solution, saturated salt solution, dried (over sodium sulfate) and evaporated. The target product was then purified using the evaporative chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride, and get the target connection. Mass spectrum: m/z 346 (M).

400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,87 (singlet, 3H), 1.93 and (singlet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 4,28 (multiplet, 1H), 5,54 (doublet, 1H)

Example 7

3-Oxo-4-Aza-4-methyl who e 6, taking instead of acetic anhydride and benzoyl chloride. Mass spectrum: m/z 408 (M).

400 MHz PMR (chloroform-d): 0,89 (singlet, 3H), 0,90 (singlet, 3H), 2,90 (singlet, 3H), 3,01 (doublet of doublets, 1H), 4,48 (multiplet, 1H), 6,12 (doublet, 1H).

Example 8

3-Oxo-4-Aza-4-methyl-16-benzylaminocarbonyl - 5-androstane

To a solution of 3-oxo-4-Aza-4-methyl-16-hydroxy - 5-androstane (40 mg, 0,131 mmol) in methylene chloride (2 ml) was added triethylamine (67 μl, 0,481 mmol), 4-dimethylaminopyridine (2 mg) and basilidians (50 μl, 0,405 mmol). The reaction mixture is stirred for 48 hours at room temperature, evaporated and purified by the method of flash chromatography on silica gel, using as eluent 15% solution of acetone in methylene chloride, and get the target connection. FAB mass spectrum: m/z 439 (M-H).

400 MHz PMR (chloroform-d): 0,87 (singlet, 6N), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 4,33 (multiplet, 2H), 4,90 (multiplet, 1H), 5,11 (multiplet, 1H).

Example 9

3-Oxo-4-Aza-4-methyl-16-hydroxy-5-androstane

Stage 1: 3-oxo-4-Aza-4-methyl-16 (4 nitrobenzyloxy)-5-androstane

To a solution of 3-oxo-4-Aza-4-methyl-16-hydroxy-5-androstane (34 mg, 0,0111 mmol) in dry benzene (1.5 ml) is added triphenylphosphine (35 mg, 0,134 mmol), 4-nitrobenzoic) acid (22 EE nitrogen for 1 hour to a temperature of 80oC (oil bath temperature). The benzene evaporated under reduced pressure and the crude product is purified by chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride, and get the target product containing a small amount of triphenylphosphine (97 mg), which amyraut as described in Stage 2.

Stage 2: 3-oxo-4-Aza-4-methyl-16-hydroxy-5-androstane

The crude product from step 1 (97 mg) is suspended in ethanol (0.5 ml) and treated with 0.4 N sodium hydroxide solution (0,36 ml, 0.144 mmol). After stirring for 90 minutes at room temperature, the reaction mixture is neutralized by adding a few drops of glacial acetic acid, extracted with ethyl acetate (2 x 20 ml), washed with water (20 ml), saturated salt solution, dried (over sodium sulfate) and evaporated. The product is purified by chromatography on silica gel, using as eluent 20% solution of methanol in methylene chloride. Mass spectrum: m/z 305 (M).

400 MHz PMR (chloroform-d): 0,70 (singlet, 3H), 0,85 (singlet, 3H), 2,90 (singlet, 3H), 3,02 (doublet of doublets, 1H), 4,47 (multiplet, 1H).

Example 10

C-Oxo-4-Aza-4-methyl-16-methoxy-5-androstane

To a solution of 3-oxo-4-Aza-4-methyl-16 - hydroxy-5-and is. the donkey stirring at room temperature under nitrogen atmosphere for 15 minutes, add methyl iodide (20 μl, 0,325 mmol) and allowed to mix overnight. Dilute the reaction mixture with ether (25 ml), the organic layer separated, washed with water (2 x 10 ml), saturated salt solution, dried (over sodium sulfate) and evaporated. The target product was then purified by the method of flash chromatography on silica gel, using as eluent a 10% solution of acetone in methylene chloride, and get the target connection. Mass spectrum: m/z 319 (M).

400 MHz PMR (chloroform-d): 0,70 (singlet, 3H), 0,87 (singlet, 3H), 2,90 (singlet, 3H), 3,01 (doublet of doublets, 1H), 3, 22 (singlet, 3H), 3,92 (multiplet, 1H).

Example 11

4-Aza-4,7-dimethyl-5-androstane - 3,16-dione

Stage 1:4-Aza-4,7 dimethyl-5 androstane-3,17-dione-16-oxime

To 2-methyl-2-propanol (28 ml) in a round bottom flask nitrogen purging add tert-piperonyl potassium (1.35 g, 12.1 mmol). After formed a clear solution, with stirring, add 4-Aza-4,7-dimethyl-5-androstane-3,17-dione (1.92 g, 6.0 mmol) and stirring is continued for one hour, thereby forming a solution of a Golden color. To the reaction mixture is added dropwise isoamyl-nitrite (1,63 ml, 12.1 mmol) and leave overnight displaced the major volume of water, acidified to approximately pH 2 with 2N hydrochloric acid and extracted with diethyl ether (3 x 50 ml). Combine the ether extracts, washed with saturated salt solution, dried (over sodium sulfate) and evaporated. The obtained solid product was subjected to purification by chromatography on silica gel, using as eluent 5% solution of methanol in methylene chloride, and get the target connection.

Stage 2: 4-Aza-4,7-dimethyl-5-androstane-3-one-16-oxime

To a mixture of 4-Aza-4,7-dimethyl-5-androstane-3,17-dione-16 - oxime (2.7 g, 7,79 mmol) in ethylene glycol (30 ml) was added 98% hydrazine (0,27 ml, to 8.57 mmol) and powdered potassium hydroxide (2,62 g, 46.8 mmol). The mixture is heated for 3 hours to a temperature of 140oC, cooled, diluted with water (100 ml), neutralized with concentrated hydrochloric acid, the precipitate brown is filtered off and dried (1.7 g). The obtained solid product was subjected to purification by chromatography on silica gel, using as eluent initially 2% solution of methanol in methylene chloride, then 5% solution of methanol in methylene chloride, and get the target connection.

Stage 3: 4-Aza-4,17-dimethyl-5-androstane-3,16-dione

A mixture of 4-Aza-4,7-dimethyl-5-androstan refrigerator for 48 hours. The cooled mixture is diluted with water (25 ml) and extracted with methylene chloride (CH ml), the organic extracts are combined and washed with sodium bicarbonate solution, dried (over sodium sulfate) and evaporated. The target product was then purified using the evaporative chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride, and get the target connection. Mass spectrum: m/z 317 (M).

400 MHz PMR (chloroform-d): 0,88 (singlet, 3H), 0,89 (singlet, 3H), 1.00 m (doublet, 3H), 2,90 (singlet, 3H), 3,07 (doublet of doublets, 1H).

Example 12

3-Oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane

A solution of 4-Aza-4,7 - dimethyl-5-androstane-3,16-dione (390 mg, of 1.23 mmol) in methanol (8 ml) is cooled in a bath of ice and within 30 minutes, add sodium borohydride (140 mg, 3,68 mmol). Dilute the reaction mixture with water and extracted with methylene chloride (3 x 50 ml). The organic extracts are combined, washed with saturated salt solution, dried (over sodium sulfate) and evaporated. The target product was then purified by the method of flash chromatography on silica gel, using as eluent first 10% solution of acetone in methylene chloride, then 10% solution of acetone in methylene chloride, and get the target connection. Mass spectrum: m/z, 1H), 4,36 (multiplet, 1H).

Example 13

3-Oxo-4-Aza-4,7-dimethyl-16 methoxy-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane (20 mg, 0,063 mmol) in dimethylsulfoxide (0.5 ml) is added powdered potassium hydroxide (18 mg, 0,313 mmol). After stirring at room temperature under nitrogen atmosphere for 15 minutes, add methyl iodide (20 μl, 0,313 mmol) and allowed to mix overnight. Dilute the reaction mixture with diethyl ether (25 ml), the organic layer separated, washed with water, saturated salt solution, dried (over sodium sulfate) and evaporated. The target product was then purified by the method of flash chromatography on silica gel, using as eluent a 1.5% solution of methanol in methylene chloride, and get the target connection. Mass spectrum: m/z 334 (M+1).

400 MHz PMR (chloroform-d): 0.83 (singlet, 3H), 0,89 (singlet, 3H), of 1.03 (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,34 (singlet, 3H), 3,80 (multiplet, 1H).

Example 14

3-Oxo-4-Aza-4,7-dimethyl-16-acyloxy-5-androstane

The specified connection receive according to the method similar to that shown in Example 13 choose ethyl iodide instead of methyl iodide and potassium hydride in N, N-dimethylformamide instead of potassium hydroxide. Mass speigle, 3H), 3.00 and (doublet of doublets, 1H), 3,39 (multiplet, 2H), 4,40 (multiplet, 1H).

Example 15

3-Oxo-4-Aza-4,7-dimethyl-16-allyloxy-5-androstane

The specified connection receive according to the method similar to that shown in Example 13, instead of taking iodine bromide allyl bromide. Mass spectrum: m/z 359 (M).

400 MHz PMR (chloroform-d): 0.83 (singlet, 3H), 0,91 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,90 (multiplet, 2H), 3.96 points (multiplet, 1H), 5,11 - of 5.29 (multiplet, 1H), 5,85-5,93 (multiplet, 1H).

Example 16

3-Oxo-4-Aza-4,7-dimethyl-16 - benzyloxy - 5-androstane

The specified connection receive according to the method similar to that shown in Example 14, instead of taking iodide, methyl bromide, benzyl. Mass spectrum: m/z 409 (M).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0.95 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 4,01 (multiplet, 1H), 4,43 (Quartet, 2H), 7,31 (multiplet, 5H).

Example 17

3-Oxo-4-Aza-4,7-dimethyl-16 - (3,3-dimethylallyl)-5-androstane

The specified connection receive according to the method similar to that shown in Example 13, taking instead of methyl iodide methyl 3,3-dimethylallyl.

400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,90 (singlet, 3H), 1,02 (doublet, 3H), 1,67 (singleton 18

3-Oxo-4-Aza-4,7-dimethyl-16 -(n-propyloxy)-5-androstane

A solution of 3-oxo-4-Aza-4,7-dimethyl-16-allyloxy - 5-androstane (13,0 mg, being 0.036 mmol) in ethyl acetate (0.5 ml) hydronaut at atmospheric pressure in the presence of platinum oxide (4 mg) for 30 minutes at room temperature, the catalyst was removed by filtration through filter element Millex-HV with a pore size of 0.45 μm. Cleanse method flash chromatography on silica gel, using as eluent a 1% solution of methanol in methylene chloride, and get the target connection. Mass spectrum: m/z 361 (M).

400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,89 (singlet, 3H), of 0.89 (triplet, 3H), 1,05 (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,29 (triplet, 2H), 3,89 (multiplet, 1H).

Example 19

3-Oxo-4-Aza-4,7-dimethyl-16 -(3-methyl-1-butyl-oxy)-5-androstane

A solution of 3-oxo-4-Aza-4,7-dimethyl-16 -(3,3 - dimethylallyl)-5-androstane (12.0 mg) in ethyl acetate (0.5 ml) hydronaut at atmospheric pressure in the presence of oxide of 10% palladium on coal (3 mg) for 30 minutes at room temperature. The catalyst was removed by filtration through filter element Millex-HV with a pore size of 0.45 μm. Cleanse method flash chromatography on silica gel, using as eluent 2% solution of methanol (singlet, 3H), 0.88 to (singlet, 3H), of 1.03 (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3.33 and (multiplet, 2H), 3,88 (multiplet, 1H).

Example 20

3-Oxo-4-Aza-4,7 - dimethyl-16 - (tert-butoxy)-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy - 5-androstane (20 mg, 0,063 mmol) in methylene chloride (0.5 ml), cooled in a bath with ice, add tert-butyltrichlorosilane (23 μl, 0,126 mmol) and triftormetilfullerenov (0,56 μl, 0,0063 mmol), allow the reaction mixture to warm to room temperature and after one hour pay an additional amount of tert-butyltrichlorosilane (23 μl) and triftoratsetata high (0.56 ml). After one hour add the third portion of each reagent and the reaction mixture was stirred at room temperature for 5 hours. Dilute the reaction mixture with diethyl ether (50 ml), the organic layer is separated, washed with 1N aqueous sodium hydroxide solution (10 ml), 1N hydrochloric acid (10 ml), saturated sodium bicarbonate solution, dried (over sodium sulfate) and evaporated. The target product was then purified by the method of flash chromatography on silica gel, using as eluent a 10% solution of acetone in methylene chloride, and get the target connection. Mass spectrum: m/z 375 (M).

Example 21

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-cianfrocca)-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane (20 mg, 0,063 mmol) in N,N-dimethylformamide (0.5 ml) is added powdered potassium hydride (35% weight. ) (15 mg, 0,126 mmol). Stirred at room temperature under nitrogen atmosphere for 15 minutes, add 4-perbenzoate (38 mg, 0,315 mmol) and stirred at room temperature for 2 hours. Diluted with a mixture of methylene chloride (25 ml) and poured into ice water. The aqueous layer was extracted with methylene chloride (3 x 25 ml), the organic extracts are combined, washed with saturated salt solution, dried (over sodium sulfate) and evaporated. The target product is cleaned by the method of flash chromatography on silica gel, using as eluent initially a 1.5% solution of methanol in methylene chloride, and then 2% solution of methanol in methylene chloride, and get the target connection. Mass spectrum: m/z 420 (M).

400 MHz PMR (chloroform-d): 86 (singlet, 3H), 0,92 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 3,02 (doublet of doublets, 1H), 4,76 (multiplet, 1H), 6.87 in (multiplet, 2H), 7,53 (multiplet, 2H).

Example 22

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-trifluoromethyl - phenoxy)-5 - androsta arid instead of 4 - perbenzoate. Mass spectrum: m/z 463 (M).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,93 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 3,02 (doublet of doublets, 1H), 4,76 (multiplet, 1H), 6,88 (multiplet, 2H), 7,50 (doublet, 2H).

Example 23

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-chlorphenoxy)-5 androstane

The specified connection receive according to the method similar to that shown in Example 21, choose 1-chloro-4-torbenson instead of 4 - perbenzoate. Mass spectrum: m/z 430 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,93 (singlet, 3H), of 1.03 (doublet, 3H), 2,90 (singlet, 3H), 3,02 (doublet of doublets, 1H), 5,28 (multiplet, 1H), 6,74 (doublet, 2H), 7,19 (doublet, 2H).

Example 24

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-pertenece)-5 - androstane

The specified connection receive according to the method similar to that shown in Example 21 choose 1,4-differenza instead of 4 - perbenzoate. Mass spectrum: m/z 414 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,94 (singlet, 3H), 1.04 million (doublet, 3H), 2.91 in (singlet, 3H), 3,02 (doublet of doublets, 1H) and 4.65 (multiplet, 1H), 6.75 in (multiplet, 2H), 6,92 (multiplet, 2H).

Example 25

3-Oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane

Stage 1: 3-oxo-4-Aza-4,7-dimethyl-16 - (4-nitrobenzyloxy)-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane (178 mg, 0.5 is) and diethyl ester of azodicarboxylic acid (176 μl, 1.12 mmol). The reaction mixture is heated in a nitrogen atmosphere for 1 hour to a temperature of 80oC (oil bath temperature). The benzene evaporated under reduced pressure and the crude product is purified by chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride, and get the target product containing a small amount of triphenylphosphine (404 mg), which amyraut as described in Stage 2.

400 MHz PMR (chloroform-d); 0,80 (singlet, 3H), 0.88 to (singlet, 3H), of 1.03 (doublet, 3H), 2,90 (singlet, 3H), 3,05 (doublet of doublets, 1H), 5,48 (multiplet, 1H).

Stage 2: 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane

The crude product from step 1 (404 mg) is suspended in ethanol (5 ml) and treated with 0.4 N sodium hydroxide solution (1,82 ml, 0,728 mmol). After stirring for 90 minutes at room temperature, the reaction mixture is neutralized by adding a few drops of glacial acetic acid, extracted with ethyl acetate (100 ml), washed with water (2 x 25 ml), saturated salt solution, dried (over sodium sulfate) and evaporated. The product is purified by chromatography on silica gel, using as eluent 20% solution of acetone in methylene chloride. The mass spectrum; m/z 319 (M).

multiplet, 1H).

Example 26

3-Oxo-4-Aza-4,7-dimethyl-16 -(n-propyloxy)- 5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane (20 mg, 0,063 mmol) in N,N-dimethylformamide (0.5 mg) is added potassium hydride (35% weight. ) (15 mg, 0,126 mmol). Stirred in nitrogen atmosphere at room temperature for 15 minutes, add allyl bromide (27 μl, 0,315 mmol) and stirred for 2 hours. Add a further quantity of potassium hydride (15 mg) and allyl bromide (27 μl) and allowed to mix overnight. Dilute the reaction mixture with diethyl ether (50 ml) and water (10 ml). The organic layer is separated, washed with 1N hydrochloric acid (10 ml), water (1.0 ml), saturated sodium bicarbonate solution, dried (over sodium sulfate) and evaporated. The target product was then purified using the evaporative chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride. The resulting product hydronaut in ethyl acetate (0.5 ml) in the presence of 10% palladium on coal for 2 hours. The catalyst is removed by filtration through filter element Millex-HV with a pore size of 0.45 μm. Purify using the evaporative chromatography on silica gel, using as eluent a 10% solution of isopropy, 3H), 0,52 (singlet, 3H), of 0.90 (triplet, 3H), 1,02 (doublet, 3H), 2,90 (singlet, 3H), 3,02 (doublet of doublets, 1H), 3,29 (triplet, 2H), 3,98 (multiplet, 1H).

Example 27

3-Oxo-4-Aza-4,16-dimethyl-16-hydroxy-5-androstane

To a solution of 4-Aza-4-methyl-5-androstane-3,16-dione (50 mg, 0,165 mmol), cooled to minus 40oC dropwise with stirring, add methylanisole (3.0 M solution in diethyl ether) (275 μl, 0,825 mmol). Allow the reaction mixture to warm to room temperature and stirred for 2 hours in nitrogen atmosphere. Terminate the reaction by adding a saturated solution of ammonium chloride (25 ml) and extracted with methylene chloride (2 x 50 ml). The organic extracts are combined, washed with saturated salt solution, dried (over sodium sulfate) and evaporated, the target product was then purified by the method of flash chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride, and get the target connection. Mass spectrum: m/z 319 (M).

400 MHz PMR (chloroform-d): 0,88 (singlet, 3H), and 0.98 (singlet, 3H), 1,31 (singlet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H).

Example 28

3-Oxo-4-Aza-4,7 -16-trimethyl-16-hydroxy-5-androstane

The specified connection receive according to the method similar to that shown in Example 27, BP> 400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), and 0.98 (singlet, 3H), 1,01 (doublet, 3H), 1,30 (singlet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H).

Example 29

3-Oxo-4-Aza-4,16-dimethyl-16-methoxy-5-androstane

To a solution of 3-oxo-4-Aza-4,16-dimethyl-16-hydroxy-5-androstane (31 mg, 0,097 mmol) in N,N-dimethylformamide (0.5 ml) is added potassium hydride (35% weight) (23 mg, 0,194 mmol). Stirred in nitrogen atmosphere at room temperature for 15 minutes, add methyl iodide (32 μl, 0,485 mmol) and allowed to mix overnight at room temperature. Dilute the reaction mixture with diethyl ether, the organic layer is separated, washed with 2N hydrochloric acid (10 ml), water (10 ml), saturated sodium bicarbonate solution, dried (over sodium sulfate) and evaporated, the target product was then purified using the evaporative chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride. Mass spectrum: m/z 333 (M).

400 MHz PMR (chloroform-d): 0,88 (singlet, 3H), 0,90 (singlet, 3H), 1,22 (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,17 (singlet, 3H).

Example 30

3-Oxo-4-Aza-4,7 -16-trimethyl-16-methoxy - 5-androstane

The specified connection receive according to the method similar to that shown in Example 29, the ACC-spectrum: m/z 347 (M).

400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,90 (singlet,

3H), 1,02 (doublet, 3H), 1,22 (singlet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,18 (singlet, 3H).

Example 31

3-Oxo-4-Aza-4,7-dimethyl-16-mutanty-5-androstane

Stage 1: 3-oxo-4-Aza-4,7-dimethyl-16-acetylthio-5-androstane

B round bottom flask with a capacity of 25 ml nitrogen atmosphere place dry tetrahydrofuran (4 ml) and triphenylphosphine (177 mg, 0,676 mmol). The flask was cooled in a bath with ice, add di-ISO-propyl ester of azodicarboxylic acid (133 μl, 0,676 mmol) and the mixture was stirred at 0oC for 30 minutes. The reaction mixture was added a solution of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy - 5-androstane (108 mg, 0,338 mmol) and teoksessa acid (49 μl, 0,676 mmol) in tetrahydrofuran (2.0 ml). The reaction mixture is stirred for 1 hour at a temperature of 0oC, and then 1 hour at room temperature. The mixture is evaporated and purified by the method of flash chromatography on silica gel, using as eluent a 1.0% solution of acetone in methylene chloride and obtain the target product (containing a small amount of triphenylphosphine).

400 MHz PMR (chloroform-d): 0,80 (singlet, 3H), 0,82 (singlet, 3H), 1.00 m (doublet, 3H), 2,28 (singlet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,80 (mult is tion in Stage 1 (208 mg), in ethanol (4.0 ml) under nitrogen atmosphere add to 0.4 N sodium hydroxide solution (1.8 ml, 0,716 mmol). After stirring for 1 hour at room temperature, the reaction mixture is neutralized by adding a few drops of glacial acetic acid, extracted with ethyl acetate (100 ml), washing the extract with water (2 x 10 ml), saturated salt solution, dried (over sodium sulfate) and evaporated. Pure 16 - mercaptan is obtained after purification by chromatography on silica gel, using as eluent 20% solution of acetone in methylene chloride.

400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,93 (singlet, 3H), 1,02 (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,28 (multiplet, 1H).

Stage 3: 3-oxo-4-Aza-4,7-dimethyl-mutanty-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-mercapto - 5-androstane (18 mg, 0,054 mmol) in dry tetrahydrofuran (0.5 ml) is added sodium hydride (80% dispersion in mineral oil) (3.2 mg, to 0.108 mmol) under nitrogen atmosphere. After stirring at room temperature under nitrogen atmosphere for 15 minutes, add methyl iodide (17 μl, 0,270 mmol) and stirred at room temperature for 3 hours. Dilute the reaction mixture methylene chloride (50 ml), the organic layer was separated, washed kiteley chromatography on silica gel, using as eluent 10% solution of ISO-propyl alcohol in hexane, and get the target connection. Mass spectrum: m/z 349 (M).

400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,91 (singlet, 3H), 1.04 million (doublet, 3H), 2,10 (singlet, 3H), 2,90 (singlet, 3H), 3,01 (doublet of doublets, 1H), is 3.08 (multiplet, 1H).

Example 32

3-Oxo-4-Aza-4,7-dimethyl-16-atencio-5-androstane

The specified connection receive according to the method similar to that shown in Example 31 choose ethyl iodide in Stage 3 instead of iodotope bromide. Mass spectrum: m/z 363 (M). 400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,91 (singlet, 3H), of 1.03 (doublet, 3H), 1.24 (the triplet, 3H), 2.57 m (Quartet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 3,18 (multiplet, 1H).

Example 33

3-Oxo-4-Aza-4,7-dimethyl-16 -(1-property)-5-androstane

The specified connection receive according to the method similar to that shown in Example 31, by taking 1-iodopropane in Stage 3 instead of methyl iodide. Mass spectrum: m/z 377 (M).

400 MHz PMR (chloroform-d): 0,82 (singlet, 3H), 0,90 (singlet, 3H), and 0.98 (triplet, 3H), of 1.03 (doublet, 3H), of 2.51 (triplet, 2H), 2,90 (singlet, 3H), 3,01 (doublet of doublets, 1H), 3,13 (multiplet, 1H).

Example 34

3-Oxo-4-Aza-4,7-dimethyl-16-econsultancy-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-atencio-5-androstenediol at room temperature for 2 hours, add an additional amount of OXONE (19 mg) in water (0.5 ml) and stirred for 10 minutes. The reaction mixture was diluted with water (25 ml) and extracted with methylene chloride (3 x 50 ml). The organic extracts are combined, washed with saturated salt solution, dried (over sodium sulfate) and evaporated. The product was then purified using the evaporative chromatography on silica gel, using as eluent 2% solution of methanol in methylene chloride, and get the target connection. Mass spectrum: m/z 395 (M). 400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,92 (singlet, 3H), of 1.03 (doublet, 3H), 1.39 in (triplet, 3H), 2.91 in (singlet, 3H), 2,99 (Quartet, 2H), 3.00 and (doublet of doublets, 1H), 3,41 (multiplet, 1H).

Example 35

3-Oxo-4-Aza-4,7-dimethyl-16-fluoro-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane (18 mg, 0,056 mmol) in methylene chloride (0.5 ml) at room temperature add diethylaminoacetate (19 μl, 0.144 mmol). Stirred for 1 hour at room temperature, the reaction mixture is diluted with methylene chloride (25 ml). The organic layer was separated, washed with water (25 ml), saturated sodium bicarbonate solution (10 ml), saturated salt solution (10 ml), dried (over sodium sulfate) and evaporated. The product was then purified by the method will evaporate, the get the target connection. Mass spectrum m/z 321 (M).

400 MHz PMR (chloroform-d): 0,87 (singlet, 3H), 0,92 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 3,01 (doublet of doublets, 1H), 5,12 (multiplet, 1H).

Example 36

Getting 4-Aza-4,7-dimethyl-5-androstane-3,17-dione (Compound E in Scheme 5)

Stage 1: Synthesis of 3-acetoxy-androst-5-ene-17-ol

To a solution of 100 mg (0,303 mmol) 3-acetoxy-androst-5-ene-17-she's in 3 ml of ethanol at a temperature of minus 10oC added under stirring to 22.9 mg (0,606 mmol) sodium borohydride. Stir the mixture for 1.3 hours, add 10 ml of water, the ethanol evaporated in vacuo, and the residue is extracted with ethyl acetate. The organic layer was washed with aqueous potassium carbonate solution, saturated salt solution, dried over sodium sulfate and evaporated, receiving the remainder of the crude product. The structure confirms the range of PMR.

Stage 2: Synthesis of 17-tert-butyldimethylsilyl ester 3 - acetoxy-androst-5-ene-17-ol

To a solution of 4.5 g (13,55 mmol) androstane-17-ol from the previous step in 50 ml of dimethylformamide at a temperature of 23oC added 2.76 g (40-65 mmol) of imidazole, and then 3,063 g (20,32 mmol) tert-butyldimethylsilyloxy. The reaction mixture is stirred until the early formation of solids. EXT is estvo filtered and washed with water. The solid is dissolved in ethyl acetate, the organic layer was washed with saturated salt solution, dried over sodium sulfate and evaporated, receiving targeted 17-ol, having a silyl protection. The structure confirms the spectrum of Poland.

Stage 3: 17-tert-butyldimethylsilyl ether 7-one-17-ol

To a solution of 5.6 g (12,55 mmol) 17-ol containing tert - butyldimethylsilyloxy protection, obtained at the previous step, in 100 ml of acetonitrile at a temperature of 23oC add 3,958 g (43,92 mmol) of 90% gidroperekisi tert-butyl and 138 mg of hexacarbonyl chromium. Boil the mixture in a nitrogen atmosphere under reflux for 24 hours, poured into 1 l of water, the solid is filtered off, the residue was washed with 500 ml of water and dissolved in 350 ml of methylene chloride. The organic layer was washed with saturated salt solution, dried over sodium sulfate and evaporated, to give crude product. Its clear column chromatography on silica gel, elwira 7% solution of ethyl acetate in hexane, and get the target connection. The structure confirms the range of PMR.

Stage 4: Synthesis of 17-tert-butyldimethylsilyl ester of 3,7 - dihydroxy-7-methylandrosta-5-ene-17-ol

To a solution of 440 mg (0,956 mmol) of the product obtained at predidushije. Then the reaction mixture was stirred at room temperature for 24 hours and poured into saturated aqueous solution of ammonium chloride. THF evaporated in vacuo, the aqueous phase is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and evaporated, receiving the remainder of the crude product. Its structure is confirmed using PMR spectrum and used in the next stage without further purification.

Stage 5: Synthesis of 17-tert-butyldimethylsilyl ether 7 - methylandrosta-4,6-Dien-3-one-17-ol

The above reaction product of a Grignard reagent (3.5 g, 7,142 mmol) dissolved in a mixture of 50 ml toluene and 50 ml of cyclohexanone, and then 20 ml of the solvents evaporated in vacuo. To the residue add 4,54 g ISO-propoxide aluminum and boil the reaction mixture under reflux for 15 hours. The mixture is cooled, diluted with ethyl acetate, washed with a solution of sodium tartrate, potassium, saturated salt solution, the organic layer is evaporated in vacuo and distilled water vapor. The residue is extracted with ethyl acetate, washed with saturated salt solution, dried, purified column chromatography on silica gel, elwira 5% solution of ethyl acetate in hexane, and get the target compounds is oru 370 mg of product, obtained in the previous phase, 5.5 ml of liquid ammonia, 1 ml THF, 1 ml of toluene small portions add 50 mg of metallic lithium. The resulting blue solution is stirred for 2 hours and add a solution of 1,2-dibromethane in 2 ml of THF. The solution is stirred at minus 78oC for 10 minutes, add 250 mg of ammonium chloride and stirred for 10 minutes. The excess ammonia is removed by evaporation in a stream of nitrogen, dilute the reaction mixture with saturated salt solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried and evaporated, to give crude product, which is used in the next stage without further purification.

Step 7: Synthesis of tert-butyldimethylsilyl ether 7 - methylandrosta-4-EN-3-one-17-ol

To a solution of 432 mg of the product obtained in the previous phase, in 4 ml of THF is added in nitrogen atmosphere with stirring, 150 μl of 1,8-diazabicyclo[5,4,0)undec-7-ene. The resulting mixture is refluxed for 1.5 hour, cooled, diluted with a solution of ammonium chloride. THF evaporated in vacuo and the residue extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over sodium sulfate and / ethyl acetate in hexane.

Step 8: synthesis of 17 -(tert-butyldimethylsilyloxy)-7-methyl-5 - oxo-A-nor-3,5-secondrate-3-new acid

To a solution of 884 mg of the product obtained in the previous phase, in 15 ml of tert-butyl alcohol at 80oC add 248 mg of sodium carbonate in 1.5 ml of water and then added dropwise over 15-20 minutes add the mixture 2,273 g periodate sodium and 16.8 mg of potassium permanganate in 8 ml of water. The reaction mixture is heated to a temperature of 80oC for 2 h, cooled, filtered, the residue washed with water and evaporated in vacuo, the residue acidified with aqueous hydrochloric acid, extracted with ethyl acetate and the organic layer was washed with aqueous solution of sodium bisulfite, saturated salt solution, dried and evaporated, receiving the connection 9. The structure confirms the range of PMR.

Step 9: Synthesis of tert-butyldimethylsilyl ether, 4,7-dimethyl-4-Aza-androst-5-ene-3-one-17-ol

To a solution of 840 mg of the product obtained in the previous phase in 5 ml of ethylene glycol added 1.5 g of sodium acetate and 737 mg of methylamine hydrochloride. Stirred the reaction mixture for 4 hours at a temperature of 180oC, cooled, diluted with water, extracted with ethyl acetate, the extract is dried and evaporated, to give crude product. Eg To a solution of 700 mg of the product, obtained at the preceding stage in 20 ml of acetonitrile at 0oC add 500 ál of hydrofluoric acid. Stirred the reaction mixture for 1 hour, neutralize hydrofluoric acid aqueous solution of sodium carbonate, diluted with water, acetonitrile evaporated in vacuum and the residue extracted with ethyl acetate. The organic layer is dried and evaporated, to give crude product which is then purified by preparative chromatography on silica gel, elwira a mixture of chloroform/acetone (3:1).

Stage 11: synthesis of 4,7-dimethyl-4-Aza-androstane-3-one-17-ol

To a solution of 350 mg of the product obtained in the previous phase, 10 ml of acetic acid was added 100 mg of platinum dioxide and serves hydrogen. The reaction mixture was shaken overnight at room temperature under hydrogen pressure of 275 kPa. The solution is filtered and evaporated. The residue is extracted with ethyl acetate, the organic layer is evaporated in vacuo, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution, saturated salt solution, dried, evaporated and get the target connection. Mass spectrum: m/z 320 (M+1).

Step 12: synthesis of 4-Aza-4,7-dimethyl-5-androstane-3,17 - dione

To a solution of 1,013 g (3,176 mmol) of the product obtained in the previous stud g (4.76 mmol) of N-methylmorpholin-N-oxide, and then perruthenate of tetrapropylammonium, 55 mg (strength of 0.159 mmol). The reaction mixture is stirred for 2 hours, diluted with 150 ml ethyl acetate and filtered. The filtrate is evaporated to dryness and get the crude product which is recrystallized from ethyl acetate and get pure product with so pl. 135-136oC.

Elemental analysis: mol. weight = 317,48

calculated for C20H31NO2: C 75,67; H, 9,84, N, TO 4.41;

(found: C, 75,16; H, 10,22; N, 4,13.

Mass spectrum: m/z 318 (M+1).

Methodology the following examples (37-49) is similar to the method of Example 21, with the replacement of 4-perbenzoate corresponding 4 - ftoroproizvodnykh.

Example 37

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-methylsulfinylphenyl) -5-androstane

Mass spectrum: m/z 474 (M+1).

400 MHz PMR (chloroform-d): 085 (singlet, 3H), 0,93 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H), 4,80 (multiplet, 1H), 6,92 (doublet, 2H), 7,81 (doublet, 2H).

Example 38

3-Oxo-4-Aza-4,7-dimethyl-16 -(3-pyridyloxy)-5-androstane

Mass spectrum: m/z 397 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,94 (singlet, 3H), 1.04 million (doublet, 3H), 2.91 in (singlet, 3H), 3,02 (doublet of doublets, 1H), 4.75 in (multiplet, 1H), 7,21 (multiplet, 2H), by 8.22 (multiplet, 2H).

Example 39

3-Oxo-4-Aza-glet, 3H), 0,96 (singlet, 3H), 1,05 (doublet, 3H), 2.91 in (singlet, 3H), 3,02 (doublet of doublets, 1H), 4,76 (multiplet, 1H), 6,9 (doublet,2H), 7,26 (doublet, 2H), 7,43 (multiplet, 2H), 7,52 (multiplet, 4H).

Example 40

3-Oxo-4-Aza-4,7-dimethyl-16 -(3-chlorophenoxy)-5-androstane

Mass spectrum: m/z 431 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,93 (singlet, 3H), 1,05 (doublet, 3H), 2,90 (singlet, 3H), 4,68 (multiplet, 1H), of 6.71 (multiplet, 1H), 6,80 (multiplet, 1H), 6,88 (multiplet, 1H), 7,13 (multiplet, 1H).

Example 41

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-triftormetilfosfinov)-5-androstane

Mass spectrum: m/z 480 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,94 (singlet,

3H) 1,04 (doublet, 3H), 2.91 in (singlet, 3H), 3,02 (doublet of doublets, 1H). 4,69 (multiplet, 1H), 6,78 (multiplet, 1H), 7,09 (multiplet, 2H).

Example 42

3-Oxo-4-Aza-4,7-dimethyl-16 - (2-chlorophenoxy)-5-androstane

Mass spectrum: m/z 431 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,99 (singlet, 3H), 1.04 million (doublet, 3H), 2.91 in (singlet, 3H), 3,03 (doublet of doublets, 1H), 4,80 (multiplet, 1H), for 6.81 (multiplet, 2H), 7,24 (multiplet, 2H), 7,32 (multiplet, 2H).

Example 43

3-Oxo-4-Aza-4,7-dimethyl-16 -(2-pyrazinone)-5-androstane

Mass spectrum: m/z 398 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0.95 (singlet, 3H), 1.04 million

Example 44

3-Oxo-4-Aza-4,7-dimethyl-16 -(2-pyrimidinone)-5-androstane

Mass spectrum: m/z 398 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0.95 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 3,02 (doublet of doublets, 1H), to 5.35 (multiplet, 1H), 6.89 in (multiplet, 1H), 8,15 (doublet, 2H).

Example 45

3-Oxo-4-Aza-4,7-dimethyl-16 -[4-(1-peril)phenoxy]-5-androstane

Mass spectrum: m/z 461 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0.95 (singlet, 3H), 1,05 (doublet, 3H), 2.91 in (singlet, 3H), 4,73 (multiplet, 1H), 6.30-in (multiplet, 2H), of 6.96 (multiplet, 2H), 7,25 (multiplet, 2H).

Example 46

3-Oxo-4-Aza-4,7-dimethyl-16 -(3-cianfrocca)-5-androstane

Mass spectrum: m/z 420 (M).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,93 (singlet, 3H), 1.04 million (doublet, 3H), 2.91 in (singlet, 3H), 3,02 (doublet of doublets, 1H), 4,71 (multiplet, 1H), 7,05 (multiplet, 1H), 7,32 (multiplet, 1H).

Example 47

3-Oxo-4-Aza-4,7-dimethyl-16 -(1-naphthyloxy)-5-androstane

Mass spectrum: m/z 445 (M).

400 MHz PMR (chloroform-d): 0,86 (singlet, 3H), of 1.03 (singlet, 3H), 1,07 (doublet, 3H), 2,92 (singlet, 3H), 3,02 (doublet of doublets, 1H), 6,70 (doublet, 1H), 7,32 (multiplet, 2H), 7,78 (multiplet, 1H), 8,24 (1H).

Example 48

3-Oxo-4-Aza-4,7-dimethyl-16 -(3-chloro-4-methylphenoxy)-5-androstane

Mass spectrum: m/z 44, H) 4,76 (multiplet, 1H), 6,62 (multiplet, 1H), for 6.81 (multiplet, 1H), 7,12 (doublet, 1H).

Example 49

3-oxo-4-Aza-4,7-dimethyl-16 - [4-(5-oxazolyl)phenoxy]- 5-androstane

Mass spectrum: m/z 463 (M+1).

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0.95 (singlet, 3H), 1,05 (doublet, 3H), 2.91 in (singlet, 3H), 4,76 (multiplet, 1H), 6,86 (doublet, 2H), 7,21 (singlet, 1H), 7,53 (doublet, 2H), 7,84 (singlet, 1H).

Example 50

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-nitrophenoxy)-5-androstane

The specified connection receive according to the method similar to that shown in Example 21, choose 1-fluoro-4-nitrobenzene instead of 4 - perbenzoate.

400 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,94 (singlet, 3H), 1,05 (doublet, 3H), 2,92 (singlet, 3H), 3,03 (doublet of doublets, 1H), 1,81 (Quartet, 1H), 6.87 in (doublet, 2H), 8,17 (doublet, 2H).

Example 51

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-aminophenoxy)-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16 -(4 - nitrophenoxy)-5-androstane (163 mg, 0.36 mmol) in ethyl acetate (8 ml) and methanol (8 ml) is added 10% palladium on coal (25 mg,0,23 mmol). Stirred for 4 hours in hydrogen atmosphere at room temperature. Filtered through celite and evaporated, getting 148 mg of the target compound. Cleaning is not required. Mass spectrum m/z: 411 (M+1).

400 MHz PMR (halblech, 2H), 6,78 (doublet, 2H).

Example 52

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-acetylaminophenol)-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16 (4 - aminophenoxy)-5-androstane (48 mg, 0,116 mmol) in methylene chloride (1 ml) and pyridine (0.037 ml, 0.46 mmol) is added acetic anhydride (0,22 ml, 0.23 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol). The reaction mixture was stirred in nitrogen atmosphere overnight at room temperature, diluted with methylene chloride (50 ml), the organic layer separated, washed with water (50 ml) and saturated salt solution (50 ml). Dried the organic layer over sodium sulfate and evaporated. The crude product is purified preparative thin-layer chromatography (silica gel, 1000 microns), elwira 5% solution of methanol in methylene chloride, and obtain 51 mg of the target compound. Mass spectrum: m/z 453 (M+1).

400 MHz PMR (chloroform-d): 0.84 (singlet, 3H), 0,93 (singlet, 3H), 1.04 million (doublet, 3H), 2.13 and (singlet, 3H), 2,92 (singlet, 3H), 3,03 (doublet of doublets, 1H), 4,68 (Quartet, 1H), 6,76 (doublet, 2H), 7,11 (doublet, 2H), 7,33 (doublet, 2H).

Example 53

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-benzylaminopurine)-5-androstane

The specified connection receive according to the method similar to that shown in Example 52, taking benzoyl chloride instead of acetic acid is P> 400 MHz PMR (chloroform-d): 0.84 (singlet, 3H), 0,94 (singlet, 3H), 1,05 (doublet, 3H), 2,92 (singlet, 3H), 3.04 from (doublet of doublets, 1H), 4,73 (Quartet, 1H), 6,82 (doublet, 2H), 7,94 (multiplet, 5H), 7,72 (singlet, 1H), 7,84 (doublet, 2H).

Example 54

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-methylsulfonymethane)-5-androstane

The specified connection receive according to the method similar to that shown in Example 52 choose chloride tosyl instead of acetic anhydride and triethylamine instead of pyridine and not using 4 - dimethylaminopyridine. Mass spectrum: m/z 565 (M+1).

400 MHz PMR (chloroform-d): 0.84 (singlet, 3H), 0,93 (singlet, 3H), of 1.03 (doublet, 3H), 2.37 (singlet, 3H), 2,92 (singlet, 3H), 3,02 (doublet of doublets, 1H), 4,63 (Quartet, 1H), 6,34 (singlet, 2H), 6,67 (doublet, 2H), 6,91 (doublet, 2H), 7,19 (doublet, 2H), 7,56 (doublet, 2H).

Example 55

3-Oxo-4-Aza-4-(2,4-dimethoxybenzyl)-7-methyl - 16-hydroxy-5-androstane

The connection 55 get similar method of synthesis of compounds 12, shown in figure 5, except that the corresponding benally analogue (Compound E in figure 5) are obtained by the method described in Example 36, in which instead of methylamine using 2,4-dimethoxybenzene.

Example 56

3-Oxo-4-Aza-4-(2,4-dimethoxybenzyl)-7-methyl-16 -(4 - chlorphenoxy)-5-androstane

The criminal code is ensil)-7-methyl-16-hydroxy-5-androstane instead of 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane. No cleaning before carrying out the following reaction is not carried out.

Example 57

3-Oxo-4-Aza-7-methyl-16 -(4-chlorphenoxy)-5-androstane

To a solution of 3-oxo-4-Aza-4-(2,4-dimethoxybenzyl)- 7-methyl-16 -(4-chlorphenoxy)-5-androstane (130 mg, 0.23 mmol) in methylene chloride (1 ml) add triperoxonane acid (1 ml). The reaction mixture was allowed to mix overnight at room temperature. The solvent is evaporated and the residue is dissolved in methylene chloride. The organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution. Dried the organic layer over sodium sulfate and evaporated. The crude product is purified preparative thin-layer chromatography (silica gel, 1000 microns), elwira 20% solution of acetone in methylene chloride, and get the target connection.

400 MHz PMR (chloroform-d) 0,86 (singlet, 3H), 0,93 (singlet, 3H), 1,01 (doublet, 3H), 3,07 (doublet of doublets, 1H), 4,67 (Quartet, 1H), 5,49 (singlet, 1H), 6.73 x (doublet, 2H), 7,18 (doublet, 2H).

Example 58

3-Oxo-4-Aza-7-methyl-16-phenoxy-5-androstane

To a solution of 3-oxo-4-Aza-7-methyl-16 -(4-chlorphenoxy)-5-androstane in methanol are added 20% palladium on coal. The resulting solution was shaken in a hydrogen atmosphere under pressure 331

imagele, elwira 20% solution of acetone in methylene chloride, and get the target connection.

400 MHz PMR (chloroform-d): 0,86 (singlet, 3H), 0.95 (singlet, 3H), 1,01 (doublet, 3H), is 3.08 (doublet of doublets, 1H), 4,71 (Quartet, 1H), 5,48 (singlet, 1H), for 6.81 (doublet, 2H), 6,88 (triplet, 1H), 7,24 (triplet, 2H).

Example 59

3-Oxo-4-Aza-7-methyl-16-phenoxy-5-androstane-1-EN

To a solution of 3-oxo-4-Aza-7-methyl-16-phenoxy-5-androstane (145 mg, 0.35 mmol) in toluene (3 ml) was added DDQ (95 mg, 0.42 mmol), BSTFA (360 mg, 1.4 mmol) and triftormetilfullerenov acid (Android 4.04 mg, or 0.027 mmol). Leave the resulting solution was mixed overnight in a nitrogen atmosphere, then add methylacetoacetate (4,06 mg, 0.035 mmol), the solution is stirred for one hour and left to simmer over night under reflux. Poured into water (75 ml) containing sodium carbonate (160 mg) and sodium bisulfite (120 mg). The aqueous phase is extracted with methylene chloride (3 x 40 ml), the organic extracts are combined, washed with water (50 ml) and saturated salt solution (50 ml). Dried over sodium sulfate and evaporated, the crude product was purified flash chromatography on silica gel, elwira 15% solution of acetone in methylene chloride, and get the target connection.

400 MHz PMR (chloroform-d): 0,92 (singlet, 3H), 0,96 (si is oblet, 2H), 6.89 in (triplet, 1H), 7,24 (triplet, 2H).

Example 60

3-Oxo-4-Aza-7-methyl-16 -(4-chlorphenoxy) 5-androstane-1-EN

The specified connection receive according to the method similar to that shown in Example 55, taking 3-oxo-4-Aza-7-methyl-16 -(4-chlorphenoxy)- 5-androstane instead of C-oxo-4-Aza-7-methyl-16-phenoxy - 5-androstane.

400 MHz PMR (chloroform-d): 0,92 (singlet, 3H), 0.95 (singlet, 3H), 1,02 (doublet, 3H), 3,34 (doublet of doublets, 1H), 4,67 (Quartet, 1H), 5,27 (singlet, 1H), 5,80 (doublet, 1H), 6.73 x (doublet, 2H), 6,78 (doublet, 1H), 7,18 (doublet, 1H).

Example 61

3-Oxo-4-Aza-4,7-dimethyl-16-phenoxy-5-androstane

To a solution of 3-oxo-4-Aza-4,7-dimethyl-16-phenoxy-5-androstane (60 mg, 0.16 mmol) in N,N-dimethylformamide (1 ml) is added sodium hydride (8 mg, 0.21 mmol) as a 60% dispersion in mineral oil. Stirred for 30 minutes at room temperature in a nitrogen atmosphere and add methyl iodide (40 mg, 0.28 mmol). Left to mix overnight. The reaction mixture was diluted with ethyl acetate (50 ml), the organic layer is separated, washed with 1N hydrochloric acid (50 ml), water (50 ml) and saturated salt solution (10 ml), dried over sodium sulfate and evaporated. The crude product is purified by the method of flash chromatography on silica gel, using as eluent a 10% dissolve 3H), 0.95 (singlet, 3H), 1,05 (doublet, 3H), 2.91 in (singlet, 3H), 3,02 (doublet of doublets, 1H), 4.72 in (Quartet, 1H), for 6.81 (doublet, 2H), 6.89 in (triplet, 1H), 7,24 (triplet, 1H).

Example 62

3-Oxo-4-Aza-4,7-dimethyl-16 -(4-chlorphenoxy)-5-androstane

The specified connection receive according to the method similar to that shown in Example 61, choose 3-oxo-4-Aza-7-methyl-16 -(4 - chlorphenoxy)-5-androst-1-ene instead of 3-oxo-4-Aza - 7-methyl-16-phenoxy-5-androstane.

400 MHz PMR (chloroform-d): 0,87 (singlet, 3H), 0.95 (singlet, 3H), 1,07 (doublet, 3H), 2,93 (singlet, 3H), 3,34 (doublet of doublets, 1H), 4,68 (Quartet, 1H), of 5.84 (doublet, 2H), 6,69 (doublet, 1H), 6.73 x (doublet, 2H), 7,18 (doublet, 1H).

Example 63

3-Oxo-4-Aza-4-(2,4-dimethoxybenzyl)-7-methyl-16 -(3-chloro - 4 methylphenoxy)-5-androstane

The specified connection receive according to the method similar to that shown in Example 56, taking a 2-chloro-4-vtortola instead of 1-chloro - 4-fervently. Product cleaning before carrying out the following reaction is not carried out.

Example 64

3-Oxo-4-Aza-7 - methyl-16 -(3-chloro-4-methylphenoxy)- 5-androstane

The specified connection receive according to the method similar to that shown in Example 56, choose 3-oxo-4-Aza-4-(2,4 - dimethoxybenzyl)-7-methyl-16 -(3-chloro-4-methylphenoxy)-5-androstane instead of 3-oxo-4-Aza-4-(2,4-dimethoxybenzyl)-7-methyl-16 -(4 - chlorite, 3H), is 3.08 (doublet of doublets, 1H), 4,66 (Quartet, 1H), 5,59 (singlet, 1H), 6,62 (multiplet, 1H), for 6.81 (doublet, 1H), 7,06 (doublet, 1H).

Example 65

3-Oxo-4-Aza-7-methyl-16 -(3-chloro-4-methylphenoxy)- 5-androstane

The specified connection receive according to the method similar to Example 58, choose 3-oxo-4-Aza-7-methyl-16-chloro - 4-methylphenoxy)-5 - androstane instead of 3-oxo-4-Aza - 7-methyl-16 - (4-chlorphenoxy)-5-androstane

400 MHz PMR (chloroform-d): 0,86 (singlet, 3H), 0,94 (singlet, 3H), of 1.03 (doublet, 3H), 2,25 (singlet, 3H), 4,69 (Quartet, 1H), of 6.71 (doublet, 2H), 7,03 (doublet, 2H).

Example 66

3-Oxo-4-Aza-7-methyl-16 -(4-methylphenoxy)-5-androstane-1-EN

The specified connection receive according to the method similar to that shown in Example 59, taking 3-oxo-4-Aza-7-methyl-16 -(4-methylphenoxy)- 5-androstane instead of 3-oxo-4-Aza-7-methyl-16-phenoxy-5-androstane.

400 MHz PMR (chloroform-d): 0,92 (singlet, 3H), 0,96 (singlet, 3H), of 1.03 (doublet, 3H), 2,25 (singlet, 3H), 3,34 (doublet of doublets, 1H), 4,68 (Quartet, 1H), 5,35 (singlet, 1H), 5,81 (doublet, 1H), of 6.71 (doublet, 2H), 6,79 (doublet, 1H), 7,03 (doublet, 2H).

Example 67

3-Oxo-4-Aza-7-methyl-16 -(4-methylphenoxy)-5-androstane

The specified connection receive according to the method similar to that shown in Example 61, choose 3-oxo-4-Aza-7-methyl-16 -(4 - methylphenoxy)-5-PRA is inglet, 3H), 1.04 million (doublet, 3H), 2,25 (singlet, 3H), 2.91 in (singlet, 3H), 3,05 (doublet of doublets, 1H), 4,69 (Quartet, 1H), of 6.71 (doublet, 2H), 7,54 (doublet, 1H).

Example 68

3-Oxo-4-Aza-4,7-dimethyl-16-fluoro-5-androstane

This compound is obtained by treatment of the intermediate (12) (Scheme 5) dimethylaminoacetonitrile in methylene chloride at room temperature followed by chromatography on silica gel; yield 64%. Mass spectrum: m/z 321 (M).

400 MHz PMR (chloroform-d): 0,87 (singlet, 3H), 0,92 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (singlet, 3H), 5,12 (multiplet, H).

Example 69

3-Oxo-4-Aza-4,7-dimethyl-16-cyano-5-androstane

The specified connection receive, converting the intermediate compound (25) (Scheme 7) in his methansulfonate derived by processing methanesulfonamido or methanesulfonyl anhydride in methylene chloride in the presence of organic bases such as pyridine and triethylamine, and 4-dimethylaminopyridine. Substitution methanesulfonate group exercise, warming the specified compound in a suitable solvent such as N,N-dimethylformamide or dimethylsulfoxide,

in the presence of sodium cyanide or potassium.

Example 70

3-Oxo-4-Aza-4-methyl-16 -(1-hexyl)-5-androstane

Stage 1: 3-oxo-what KSIL-triphenylphosphorane (141 mg, 0.33 mmol) and freshly tetrahydrofuran (1 ml). The mixture is cooled to 0oC and add utility (2.5 M solution in hexane, 132 ml, 0.33 mmol), the mixture acquires a bright orange color. Stirred at 0oC for 10 minutes and add a solution of 4-Aza-4-methyl-5-androstane-3,16-dione (50 mg, 0,165 mmol) in tetrahydrofuran (0.5 ml). Allow the mixture to warm to room temperature and left to mix overnight. Poured into a mixture of water (10 ml) and ethyl acetate (20 ml), the organic layer is separated, washed with 0.5 N hydrochloric acid (2 x 10 ml), saturated salt solution, dried (over sodium sulfate) and evaporated. The target connection purified flash chromatography on silica gel, elwira 1% solution of methanol in methylene chloride. The compound obtained (up 29.6 mg) is used without further purification.

Stage 2: 3-oxo-4-Aza-4-methyl-16 -(1-hexyl)-5-androstane

A solution of the product obtained in stage 1 (22 mg) in ethyl acetate (0.5 ml) hydronaut in the presence of platinum oxide (5 mg) under hydrogen pressure supplied from a cylinder for 1 hour at room temperature. The catalyst is filtered off through a replaceable filter Millex-HV and the filtrate evaporated. The target product was then purified chromatography evaporative R.: m/z 374 (M+1). 400 MHz PMR (chloroform-d): 2,42 (doublet of doublets, 2H), 2,90 (singlet, 3H), 3.00 and (doublet of doublets, 1H).

Example 71

4-Aza-4,7-dimethyl-16 (4-chlorobenzylidene)-5-androstane-3-one

In accordance with reaction Scheme 14, a solution of 4-Aza-4,7-dimethyl-5-androstane-3,17-dione (11) (32 mg, 0.1 mmol), sodium hydride (5 mg, of 1.02 equiv. ), diethyl ether 4-chlorobenzylthio acid (27 mg, of 1.02 EQ.) DMF (0.5 m) is heated within 1 hour to a temperature of 80oC. the Reaction mixture is cooled, diluted with dichloromethane and washed with water (x2), saturated salt solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The target product was then purified by chromatography on silica gel, using as eluent a mixture of hexane/ISO-propanol (4:1) to give a mixture of E/Z isomers of 5:1. Mass spectrum: m/z 389.

500 MHz PMR (chloroform-d): 0.75 in (singlet, 3H), 0,82 (singlet, 3H), 0,90 (singlet, 3H), 2,96 (singlet, 3H), is 3.08 (doublet of doublets, 1H), 6,34 (singlet, 0,4 N) 6,41 (singlet, 0.6 N), 7,18 - 7,38 (multiplet, 5H).

Example 72

4-Aza-4,7-dimethyl-16-benzylidene-5-androstane-3-one

The specified connection receive similar 4-Aza-4,7-dimethyl - 16 -(4-chlorobenzylidene)-5-androstane-3-ONU (71), taking diethyl ether benzylphosphonic acid instead of diethyl ether 4 - chlorobenzylthio Ki the years, 3H), is 3.08 (doublet of doublets, 1H), 6,28 (singlet, 0.4 H), 6.35mm (singlet, 0.6 N), 7,15 - 7,35 (multiplet, 5H).

Example 73

4-Aza-4,7-dimethyl-16-(4-methylbenzylidene)-5-androstane-3-one

The specified connection receive similar 4-Aza-4,7-dimethyl - 16 -(4-chlorobenzylidene)-5-androstane-3-ONU (71), taking diethyl ether 4-methylbenzylphosphonate acid instead of diethyl ether chlorobenzylthio acid. Mass spectrum: m/z 404.

500 MHz PMR (chloroform-d): 0,78 (singlet, 3H), 0,85 (singlet, 3H), 1,1 (doublet, 3H), 2,32 (singlet, 3H), 2,94 (singlet, 3H), is 3.08 (doublet of doublets, 1H), 6.30-in (singlet, 0,4 N) 6,38 (singlet, 0.6 N), 7,10-7,24 (multiplet, 5H).

Example 74

4-Aza-4,7-dimethyl-16-(4-Chlorobenzyl)-5-androstane-3-one

To a solution of 4-Aza-4,7-dimethyl-16 -(4-chlorobenzylidene)-5-androstane-3-one (71) (33 mg) in ethanol (4 mg) is added 5% ruthenium on coal, and the resulting suspension black is stirred in an atmosphere of nitrogen supplied from a cylinder. After 2 hours the mixture is filtered, removing the catalyst, evaporated and purified on silica gel (hexane:acetone, 3:1) and receive the mixture of isomers in a ratio of 3:1. Mass spectrum: m/z 427.

500 MHz PMR (chloroform-d): 0.84 (singlet, 3H), 0,36 (singlet, 3H), 1,02 (doublet, 3H), 2,92 (broadened singlet, 2.7 km N), 2,93 (broadened singlet, 1,3 H), 2,98 (singlet, 3H), 3,02 (doublet of doublets, 1BR> The specified connection receive according to the method similar to the method for producing 4-Aza-4,7-dimethyl-16 -(4-Chlorobenzyl)-5-androstane-3 - one (74). Mass spectrum: m/z 408.

500 MHz PMR (chloroform-d): 0,86 (singlet, 6N), 2,33 (singlet, 3H), 2.95 and (singlet, 2H), 2,96 (singlet, 1H), 3,05 (doublet of doublets, 1H), 7,06-7,11 (multiplet, 4H).

Example 76

4-Aza-4,7-dimethyl-16-(3-pyridylmethyl)-5-androstane-3-one

The specified connection receive according to the method similar to the method for producing 4-Aza-4,7-dimethyl-16 -(4-Chlorobenzyl)-5-androstane-3 - one (74), taking as starting compound 3-pyridylmethylamine. Mass spectrum: m/z 395.

500 MHz PMR (chloroform-d) 0,89 (singlet, 3H), 0.88 to (singlet, 3H), of 1.03 (doublet, 3H), 2,93 (broadened singlet, 3H), 2.95 and (broadened singlet, 2H), 2,94 (broadened singlet, 1H), 3.04 from (doublet of doublets, 1H), 7,10 (doublet, 2H), 7,25 (doublet, 2H), 7,58 (singlet, 1H), 8,55 (singlet, 2H).

Example 77

4-Aza-4,7-dimethyl-16-methanesulfonyl-5-androstane-3-one

In accordance with reaction Scheme 13, to a solution of 4-Aza - 4,7-dimethyl-16-hydroxy-5-androstane-3-one (2) (65 mg, 0.2 mmol) in anhydrous dichloromethane added a catalytic amount of 4-dimethylaminopyridine, and then methanesulfonyl anhydride (455 mg, 1.1 equiv.). After 15 minutes the reaction mixture is diluted with dihormati the m salt, dried over anhydrous magnesium sulfate, filtered and evaporated, obtaining the target compound with the desired degree of purity. Mass spectrum: m/z 398.

500 MHz PMR (chloroform-d): 0,78 (singlet, 3H), 0,85 (singlet, 3H), 1,02 (doublet, 3H), 2.95 and (singlet, 3H), 2.95 and (broadened singlet, 2H), 3,1 (doublet of doublets, 1H), 5,18 (multiplet, 1H).

Example 78

4-Aza-4,7-dimethyl-16-thiophenoxy-5-1-androstane-3-one

To a solution of thiophenol (50 μl, 2.5 equiv.) in anhydrous THF added sodium hydride (20 mg, 2.6 equiv.). Stirred for 20 minutes and add a solution of 4-Aza-4,7-dimethyl - 16-methanesulfonyl-5-androstane-3-one (77) (65 mg, 0.2 mmol) in tetrahydrofuran and stirred the mixture for 20 h at room temperature. Terminate the reaction by adding a 1M solution of ammonium chloride and diluted with ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The target connection purify by chromatography on silica gel (hexane ISO-propanol, 9:1). Mass spectrum: m/z 412.

500 MHz PMR (chloroform-d): 0,86 (singlet, 3H), 0.95 (singlet, 3H), 1.06 (the doublet, 3H), 2,54 (singlet, 3H), 3,06 (doublet of doublets, 1H), 3,65 (multiplet, 1H), 7,26-7,70 (multiplet, 1H).

Example 79

4-Aza-4,7-dimethyl-16 -(4-chlorphenoxy-16-thiophenoxy-5-androstane-3-one (78), choose 4-chlorothiophenol instead of thiophenol. Mass spectrum: m/z 446.

500 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,96 (singlet, 3H), 1.04 million (doublet, 3H), 2,94 (singlet, 3H), 3,02 (doublet of doublets, 1H), 3,61 (multiplet, 1H), 7,22 (doublet, 2H), 7,32 (doublet, 2H).

Example 80

4-Aza-4,7-dimethyl-16 -(4-fortifies)-5-androstane - 3-one

The specified connection receive according to the method similar to the method for producing 4-Aza-4,7-dimethyl-16-thiophenoxy-5-androstane-3-one (78) choose 4-portifino instead of thiophenol. Mass spectrum: m/z 431.

500 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,96 (singlet, 3H), 1,05 (doublet, 3H), 2,92 (singlet, 3H), 3,03 (doublet of doublets, 1H), 3,51 (multiplet, 1H), 6,99 (doublet, 2H), 7,35 (doublet, 2H).

Example 81

4-Aza-4,7-dimethyl-16 (4 methylthiophene)-5-androstane-3-one

The specified connection receive according to the method similar to the method for producing 4-Aza-4,7-dimethyl-16-thiophenoxy-5-androstane-3-one (78) choose 4-methylthiophenol instead of thiophenol. Mass spectrum: m/z 426.

500 MHz PMR (chloroform-d): 0.75 in (singlet, 3H), 0.95 (singlet, 3H), 1,1 (doublet, 3H), 2,31 (singlet, 3H), 2,94 (singlet, 3H), 3,02 (doublet of doublets, 1H), 3,59 (multiplet, 1H), 7,09 (doublet, 2H), 7,22 (doublet, 2H).

Example 82

4-Aza-4,7-dimethyl-16 -(4-methylthiophene)- 5-androstane-3-one

The specified connection p is ethoxythiophene instead of thiophenol. Mass spectrum: m/z 443.

500 MHz PMR (chloroform-d): 0,81 (singlet, 3H), 0,93 (singlet, 3H), 1,18 (doublet, 3H), 2,93 (singlet, 3H), 3,02 (doublet of doublets, 1H), 3,50 (multiplet, 1H), 2,81 (singlet, 3H), 7,45 (doublet, 2H), 7,22 (doublet, 2H).

Example 83

4-Aza-4,7-dimethyl-16-phenylsulfonyl-5-androstane-3-one

To a solution of 4-Aza-4,7-dimethyl-16-thiophenoxy-5-androstane-3-one (78) (20 mg, 0.05 mmol) in dichloromethane at a temperature of 0oC add m-chlormadinone acid (11 mg, 1 equiv.) and stir the solution for 1 hour. Dilute the reaction mixture with dichloromethane and washed with 1 M sodium bicarbonate solution, water, saturated salt solution and dried over anhydrous sodium sulfate. The target connection purify by chromatography on silica gel and receive a mixture of diastereomers of 4.6:1. Mass spectrum: m/z 428.

500 MHz PMR (chloroform-d): 0.83 (singlet, 3H), 0,92 (singlet, 3H), 1,01 (doublet, 3H), 2,92 (singlet, 3H), 3,01 (doublet of doublets, 1H), 3,19 (multiplet, 0,85 N), 3,55 (multiplet, 0,15 N), 7,5-7,70 (multiplet, 5H).

Example 84

4-Aza-4,7-dimethyl-16-phenylsulfonyl-5-androstane-3-one

A solution of 4-Aza-4,7-dimethyl-16-phenylsulfonyl-5-androstane-3-one (83) (12 mg, 0.03 mmol) in dichloromethane is treated within 3 hours m-chlormadinone acid (9 mg, 1.5 equiv.). Diluted regset over anhydrous sodium sulfate. The target connection purify by chromatography on silica gel (hexane:ISO - propanol, 7:3). Mass spectrum: m/z 444.

500 MHz PMR (chloroform-d): 0,85 (singlet, 3H), 0,91 (singlet, 3H), 2.95 and (singlet, 3H), 3,05 (doublet of doublets, 1H), 3,55 (multiplet, 0,15 N), 7,41 (triplet, 1H), 7,55 (triplet, 2H), of 7.90 (doublet, 1H).

Example 85

3-Oxo-4-Aza-4,16-dimethyl-5-androstane

The specified connection receive, turning easily accessible 4 - Aza-4,16-dimethyl-5-androstane-3,17-dione 17-triplet. The restoration of the triflate using normal methods get the target 16-methyl derivative. Mass spectrum: m/z 304 (M+1).

400 MHz PMR (chloroform-d): 0,76 (singlet, 3H), 0,85 (singlet, 3H), 1.04 million (doublet, 3H), 2,90 (3H doublet), 3,01 (doublet of doublets, 1H).

Biological assays

Getting 5-reductase inhibitor prostate and scalp scalp

Samples of human tissues pulverized in the low-temperature mill and homogenized a 40 mm solution of potassium phosphate, pH 6.5, 5 mm magnesium sulfate, 25 mm potassium chloride, 1 mm phenylmethylsulfonyl, 1 mm dithiothreitol containing 0.25 M sucrose using a homogenizer (Potter-Elvehjem. The crude containing cores the sediment obtained by centrifugation of the homogenate with an acceleration of 1500 x g for 15 minutes. Neoc is up to a final concentration of 20%. Suspension enzymes frozen at minus 80oC. When stored under these conditions, the inhibitors of the prostate and scalp the scalp is stable for at least 4 months.

Methods cloning of enzymes

To determine the values IC50the tested inhibitor of 5-reductase 1 and 2 dissolved in ethanol and serially diluted to the desired concentration. Downregulation of baculoviruses recombinant 5-reductase type 1 pre-incubated with inhibitor (0.1 to 1000 nm) in 40 mm sodium phosphate, pH 7.0, 500 μm NADPH, 1 mm dithiothreitol and 1 mg/ml bovine serum albumin for 4oC at a temperature of 18oC. Initiate the reaction by adding [7-3H] -testosterone (NEN, 20 CI/mmol) and NADPH to a final concentration of 0.3 μm and incubated in an incubator at a temperature of 37oC for 90 minutes. Similarly, downregulation of baculoviruses recombinant 5-reductase type 2 pre-incubated with inhibitor (0.1 to 10000 nm) in 40 mm sodium citrate, pH 5.5, 500 μm NADPH, 1 mm dithiothreitol and 1 mg/ml bovine serum albumin for 4oC at a temperature of 18oC. Initiate the reaction by adding [7-3H-testosterone (NEN, 20 CI/mmol) and NADPH is monitored using a detector with subsequent separation by liquid chromatography high-resolution reversed-phase column, Wahtman RACII C18, 1 ml/min of 0.1% triperoxonane acid in a mixture of water:methanol (42:58), retention time: testosterone and 6.3 min, 5-dihydrotestosterone and 9.7 min).

Analysis of 5-reductase

The reaction mixture for analysis with 5-reductase type 1 contains 40 mm sodium phosphate, pH 6.5, 5 mm [7-3H]- testosterone, 1 mm dithiothreitol and 500 μm NADPH in a final volume of 100 μl. The reaction mixture for analysis with 5-reductase type 2 contains 40 mm sodium nitrate, pH 5.5, 0.3 ám [7-3H]-testosterone, 1 mm dithiothreitol and 500 μm NADPH in a final volume of 100 μl. Usually the analysis is initiated by adding 50 - 100 µg of homogenate of the prostate or 75-200 μl of homogenate hairy part of the scalp and maintained at a temperature of 37oC. After 10 to 50 minutes, the reaction is interrupted, extragere with 250 μl of a mixture containing 70% cyclohexane and 30% of ethyl acetate and 10 mcg of dihydrotestosterone and testosterone. The aqueous and organic phases are separated by centrifugation speed 14000 rpm in a centrifuge Eppen-Dorf. The organic phase is subjected to liquid chromatography high resolution (column with silica gel Whatman partisil 5 length 10 cm; balance a mixture of 70% cyclohexane and 30% of ethyl acetate at 1 ml/min, time odergivaniya high resolution includes a gradient system. Model 680 firms Waters, provided with a device for automatic change of the samples. Model A Hitachi, tunable UV detector. Model 757 firm Applied Biosystems, and the radioactivity analyzer, model A120 company Radiomatic. For the conversion of testosterone into 5 dihydrotestosterone watch by means of a radioactivity detector, mixing the resulting stream with one volume Flo Scint I (Radiomatic). B these conditions, the formation of dihydrotestosterone has a linear dependence on at least 25 minutes. The only steroids that detect for preparations of the prostate and scalp scalp are testosterone, 5-dihydrotestosterone and androstandiol.

The study of inhibition

Compounds dissolved in 100% ethanol. The value of the IC50denote the concentration of inhibitor required to reduce the activity of the enzyme by 50% relative to control samples. The value of the IC50determine, using sestietaznyj titration method, the concentration of the inhibitor range from 0.1 to 1000 nm.

Individual compounds of the present invention have, using the previously described assay for inhibition of 5-reductase type 1 and type 2. When the inhibition of 5-the ia IC50in the range from about 0.3 nm to about 200 nm. When the inhibition of 5-reductase type 2 the same compounds have values IC50more than 155 nm, with the majority of connections matter IC50more than 1000 nm, each connection has at least two fold greater selectivity for inhibition of 5-reductase type 1 than 5-reductase type 2, with most of the compounds have at least ten-fold greater selectivity for inhibition of 5-reductase type 1 than 5-reductase type 2. These results Prove the usefulness of the compounds of the present invention in the treatment of androgenetic States.

The connection, which in the context of the present invention referred to as inhibitor of 5-reductase type 2, is a compound that inhibits isoenzyme of 5-reductase type 2 in the above analysis is analogous to the connection, which in the context of the present invention referred to as inhibitor of 5-reductase type 1, is a compound that inhibits isoenzyme of 5-reductase type 1 in the above analysis.

Analysis of the cells of the dermal papilla man

Dermal papillae are a small group of the mi and form the basis for hair growth. It was shown that these cells have the activity of 5-reductase, and therefore it is possible to test inhibitors of 5-reductase in the cultures of these cells.

Isolation and cultivation of cells of the dermal papilla is carried out in accordance with the methodology described in A. G. Messenger, "The Culture of Dermal Papilla Cells from Human Hair Follicles", Br. J. Dermatol. 110: 385-689 (1984) and S. Itami et al., "5-Reductase Activity in Cultured Dermal Papilla Cells from Beard Compared with Reticular Dermal Fibroblasts", J. Invest Dermatol. 94: 150-152 (1990). When conducting research using cells dermal papilla beard and hair top of the head are two different individuals. All experiments carried out after the merge on the fifth or sixth subcultures. Merged monolayers twice washed with phosphate buffered physiological saline solution, soskrebajut from the bottom of the Cup with rubber sticks and collected in a glass centrifuge. The cell suspension centrifuged for 10 minutes at a temperature of 4oC with a speed of 1500 Rev/min the precipitate is again suspended at a temperature of 4oC in 20 mm buffer solution Tris - HCI, pH 7.5, containing 250 mm sucrose, 1 mm magnesium chloride and 2 mm calcium chloride, pumping 10 times with a needle number 25. The crude product homogenized in made of glass and Teflon homogenizer is etoc centrifuged with an acceleration of 800 x g for 10 minutes and get wet sediment cores. The liquid above the precipitate centrifuged with an acceleration of 10000 x g for 15 minutes and get wet sediment the mitochondria. The liquid above the sediment then centrifuged with acceleration 100000 x g for 60 minutes and receive sediment micromodem and the cytosol. Each fraction is washed twice and re-suspended in buffer solution.

The standard for incubation mixture contains 40 nm [3H]- testosterone, 1 mm NADPH, 100 mm sodium nitrate, pH 5.5, 100 mm Tris-HCI, pH 7.5, and 50 μl of homogenizate cells to a final volume of 100 μl. Each vial contains 50 to 100 µg of cell protein. The incubation is conducted for 30 minutes at a temperature of 37oC. during incubation the completeness of the reaction is proportional to the time. The optimum pH value for the citrate buffer is pH 4.5 to 6.5 and to buffer Tris-HCI optimum pH value is 7.0, and 9.0. The protein content determined by the method of Lowry et al., "Protein Measurement with the Folin Phenol Reagent", J. Biol. Chem. 193: 265-275 (1951).

After incubation, the reaction is interrupted, diluted 4 - fold volume of a mixture of chloroform-methanol (21: 1, V/V) containing 110 mg of each of steroid-carriers. Extracted steroids were analyzed by thin-layer chromatography, as described in the publication Gjmez et al., "In Vitro Meta recrystallization. The activity of 5-reductase is expressed by the sum of the resulting dihydrotestosterone, androstanediol and androstendione. [1,2-3H]- Testosterone (55,2 CI/mmol) obtained from New England Nulear Corporation (Boston, Massachusetts), and not containing the label steroids are derived from the Sigma Chemical Company (St. Louis, Missouri). Serum fetal cows receive from the company Hazleotn (Lenexa, Kansas). All other links have a purity of reagents.

Model eels fluffy rats

Adult furry rats represent a variety of rats, which slowed down the growth of wool, and the oily brown covers all of their skin on the back, and which, as shown, an abnormally high secretion of sebaceous glands after puberty is caused by circulating androgens. Get the 0.1, 0.05 and 0.025% solutions private interest of an inhibitor of 5-reductase in media containing propylene glycol, ISO-propanol, ISO-propyl ester of myristic acid and water (50/30/2/18%) and usually put them on the back adult males fluffy rats, 0.2 ml of each animal per day for 4 weeks. The control animals given only the media, but five of them castrated. Two weeks seborrhea decreases depending on dozzy tissues incubated in ethylenediaminetetraacetic acid (20 mm) in phosphate buffer at a temperature of 37oC for 1.5 hour. Hair fat units attached to the epidermis, separated and fixed with formalin for immune staining bromodeoxyuridine. Synthesizing DNA cells expressing bromodeoxyuridine-positive nuclei, located on the external border of the glands. The number of S-phase cells per share is determined using the device for microalloy. Using formalin fixed skin, frozen sections stained 1% osmium and measure the size of the share. Positive inhibitor of 5-reductase suppresses allocation of secretion of sebaceous glands by inhibiting the rate of turnover of cancer cells and show a reduced interest rate.

Below is the description of example methods that can be used to determine the growth of hair.

Methods of obtaining macro photography and General photography to determine hair growth

A. methods of obtaining a macro photos

Accommodation: ID

Area determine the amount of hair.

Equipment: Film Kodak T-max with 24 frames from the same batch of emulsion

Camera: Nikon N-6000

Lens: Nikkor 60mm f2.8

Flash: Nikon SB-21B Macroflash

Device: Registering surf permitted variable is defined amount of hair. The film emulsion, lighting, aperture, exposure and reproduction remain constant.

1. The surface on the head of the patient to count the hair is prepared as follows. A small spot (about 1 mm) is applied before conducting research on the very edge of the bald area in the upper Central part thereof using a tattoo machine or manually with a needle and ink). The area is approximately 6-15 mm square, on the edge of the bald area short clip out (approximately 2 mm). Cut the hair removed from the place, which will be photographed, with the help of a tampon. In order to facilitate the removal of hair, you can apply the blowing with compressed air and/or rubbing alcohol.

2. The increase in the magnitude of the reproduction of each lens is fixed and is 1:1,2.

Aperture: Each photo will receive when set to f/22.

Film: Use T-Max 100 (24 frames).

3. Surface to count the hair of the patient. Three exposures (- 2/3,0, and + 2/3).

Experienced specialist imposes a transparent film on the photo and using the marker causes a black dot over every visible hair. Map compiled by points on a transparent film, process the th, corresponding to the place of testing, the number of visit and number of accommodation of the patient in order to depersonalize the data. After 6 months compared to baseline photograph and a photograph taken after 6 months, and analyze data for a specified period of time. After 12 months compared basic photography and pictures taken after 6 months and 12 months, and analyze preliminary results

The method of determining hair growth set out in the publication of E. A. Olsen and E. Delong, J. American Academy of Dermatology, vol. 23, p. 470 (1990).

B. Methods of obtaining total pictures

Accommodation: color photograph/identity of the patient

The General picture

Equipment: Tape: Kodachrom KR-64 with 24 frames from the same batch of emulsion

Camera: Nikon N-6000

Lens: Nikkor 60mm f2.8

Flash: Nikon SB-23

Colour photograph/identity of the patient

Technique photography

Photographs taken in the clinic, the only valid variable is the overall look. All extraneous items (clothes, furniture, walls, etc.,) are removed from the photographed field.

1. Before cutting hair make the overall picture of the patient's head is fixed in the floor which should close the bald area.

2. The increase in the magnitude of the reproduction of each lens is fixed and is 1:6.

Aperture: Each photo will receive when set to f/11.

Film: Use Kodachrome (24 frames).

3. Pictures of the patient. Take three pictures with zero compensation.

Although the invention is described and illustrated with reference to certain variations in its implementation, for professionals is obvious that can be conducted by various changes, modifications and substitutions that do not contradict the essence and scope of the claims of the present invention. For example, can be used effective dose different from those provided in the present description, depending on the sensitivity of a mammal, the treatment of which is carried out with regard to the above compounds of the present invention. Similarly, the observed specific pharmacological response may vary according to and depending on the particular active compounds, and in those cases, when you use drugs, the media, and the type of composition and how it is administered, and it is assumed that such variations or differences correspond to the essence and practice nastojashego of the invention, which should be interpreted as widely as possible within reasonable limits.

Example 86

Obtain 7-methyl-16 -[2-(5-phenyl)pyrazinone)]-4 - Aza-5-androst-1-EN-3-one (1)

To a solution of 7-methyl-16 -(4-methansulfonate)-4-Aza -5-androst-1-EN-3-one (30 mg, 0.079 in mmol) in dimethylsulfoxide (150 ml) in an atmosphere of N2was added 2-hydroxy-5-phenylpyridine (19.2 mg, 0,095 mmol) [S. Sugiura et a I., Yakugaku Zasshi 1969, 89, 1646-1651] and cesium carbonate (41 mg, 0,126 mmol) and the mixture was stirred at 60oC for 18 hours. The cooled reaction mixture was diluted with water and the resulting precipitate was filtered, washed with water and dried. Preparative thin layer chromatography on plates of silica gel with elution with a mixture of dichloromethane: acetone 4:1 gave specified in the title compound as white solid.

NMR (CDCl3): 0,97 (s, 3H); 1.04 million (s, 3H); of 1.07 (d, 3H); 3,39 (DD, 1H); from 5.29 (s, 1H); of 5.40 (m, 1H); of 5.84 (DD, 1H); 6,83 (d, 1H); 7,39-to 7.50 (m, 3H); a 7.92 (d, 2H); of 8.25 (s, 1H); 8,51 (s, 1H); m/e (E1)-457.

The following compounds were obtained in the same way.

Example 87

7-methyl-16 -[2-(5-(4-tolyl)pyrazinone)] -4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=472.

Example 88

7-methyl-16 -[2-(5-(4-methoxyphenyl)pyrazinone)]-4 - Aza-5-andil)phenyl) pyrazolone)]-4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=536.

Example 90

7-methyl-16 -[2-(5-(3,4-acid), pyrazolone)] -4-Aza-5 androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=518.

Example 100

7-methyl-16 -[2-(6-methyl)pyridyloxy)]-4-Aza-5 - androst-1-EN-3-one.

NMR (CDCl3): of 0.95 (s, 3H); 1,00 (s, 3H); of 1.05 (d, 3H); 2,47 (s, 3H); to 3.38 (DD, 1H); from 5.29 (m, 1H); 5,52 (SHS, 1H); of 5.81 (DD, 1H); 6,47 (d, 1H); of 6.68 (d, 1H); is 6.78 (d, 1H); 7,45 (m, 1H).

Example 101

7-methyl-16 -[2-(4-methyl)pyridyloxy)]-4-Aza-5 - androst-1-EN-3-one.

NMR (CDCl3): 0,94 (s, 3H); and 0.98 (s, 3H); of 1.03 (d, 3H);

2,31 (s, 3H); to 3.36 (DD, IH); are 5.36 (m, 1H); 5,54 (SHS, 1H); of 5.81 (DD, 1H); of 6.52 (d, IH); 6,69 (d, 1H); is 6.78 (d, 1H); 8,00 (d, 1H).

Example 102

7-methyl-16 - [3-(6-methyl)pyridyloxy)] 4-Aza - 5-androst-1-EN-3-one. M/e, (E1) (e-ei)=394.

Example 103.

7-methyl-16 -[3-(5-chloro)pyridyloxy) 3-4-Aza-5-androst-1-EN-3-one. M/e (E1)=414.

Example 104

7-methyl-16 -[3-(5-methyl)pyridyloxy)]-4-Aza-5 - androst-1-EN-3-one.

NMR (CDCl3): 0,94 (s, 3H); and 0.98 (s, 3H); of 1.05 (d, 3H); 2,39 (s, 3H); to 3.38 (DD, 1H); was 4.76 (m, 1H); 5,41 (SHS, 1H); of 5.81 (DD, 1H); 6,79 (d, 1H); 7,16 (s, 1H); 8,04 (s, 2H).

Example 105

7-methyl-16 -[3-(6-acetylamino)pyridyloxy]-4-Aza-5-androst - 1-EN-3-one. M/e, the ionization electrostrictive, m+1=438.

Example 106

7-met is,37 (DD, 1H); a 4.83 (m, 1H); 5,39 (SHS, 1H); 5,80 (DD, 1H); 6,79 (d, 1H); 7,14 (t, 2H); 7,30 (m, 1H); a 7.62 (d, 1H); to $ 7.91 (DD, 2H); 8,30 (d, 1H).

Example 107

7-methyl-16 -[4-(2,6-dimethyl)pyridyloxy]-4-Aza-5 - androst-1-EN-3-one.

NMR (CDCl3): of 0.95 (s, 3H); 0,97 (s, 3H); of 1.06 (d, 3H); 2,54 (C, 6N); to 3.38 (DD, 1H); 4,78 (m, 1H); 5,59 (SHS, 1H); of 5.81 (DD, 1H); 6,45 (s, 2H); 6,77 (d, 1H).

Example 108

7-methyl-16 -[4-(6-phenyl)pyrimidinone]-4-Aza-5 - androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=458.

Example 109

7-methyl-16 -[2-(6-phenyl]pyrimidinone]- 4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=458.

Example 110

7-methyl-16 -[2-(5,6-diphenyl)-1,3,4 - triazinone]-4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=535.

Example 111

7-methyl-[16 -(2-hinomisaki)]-4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=431.

Example 112

7-methyl-[16 -(3-athinaiki)]-4-Aza - 5 androst-1-EN-3-one M/e, the ionization electrostrictive, m+1=431.

Example 113

7-methyl-[16 -(1-athinaiki)]-4-Aza-5-androst-1-EN-3-one M/e, the ionization electrostrictive, m+1=431.

Example 114

7-methyl-16 -[2-(4-methylsulphonyl)pyrimidinone] - 4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=460.

Example 115

7-methyl-164 (CL, 1H); of 5.82 (DD, 1H); 5,90 (d, 1H); to 6.80 (d, 1H); of 8.09 (d, 1H).

Example 116

7-methyl-16 -[5-(1-methyl-3-trifluoromethyl]-1H - pyrazolidone]-4-Aza-5-androst-1-EN-3-one.

NMR (CDCl3): to 0.92 (s, 3H); to 0.96 (s, 3H); was 1.04 (d, 3H); to 3.34 (DD, 1H); the 3.65 (s, 3H); 4,69 (kV, 1H); 5,58 (SHS, 1H); 5,67 (s, 1H); of 5.81 (d, 1H); 6,79 (d, 1H).

Example 117

7-methyl-16 -[3-(1-methyl-5-trifluoromethyl]-1H-pyrazolidone] -4-Aza-5-androst-1-EN-3-one.

NMR (CDCl3): 92 (s, 3H); to 0.96 (s, 3H); 1.04 million (1, 3H); to 3.34 (DD, 1H); to 4.73 (q, 1H); by 5.87 (SHS, 1H); 5,79 (d, 1H); 6,79 (d, 1H); to 7.09 (m, 1H); 7.18 in (t, 1H); is 8.16 (d, 1H); 8,21 (s, 1H).

Example 118

Obtain 7-methyl-16 -(2-pyrimidinone)-4-Aza - 5-androst-1-EN-3-one (28)

To a suspension KN (35% dispersion in oil, 95 mg, 0,825 mmol) in DMF (2 ml) was added 7-methyl-16-hydroxy-4 - Aza-5-androst-1-EN-3-one (30 mg, 0.079 in mmol). The mixture was stirred at room temperature for 30 minutes in an atmosphere of N2added 2-chloropyrimidine (200 mg, of 1.65 mmol) and continued stirring for 3 days. The reaction mixture was carefully diluted with water and the resulting precipitate was filtered, washed with water and dried. Column chromatography on silica gel with elution with a mixture of 15% acetone: dichloromethane gave specified in the title compound as white solid.

NMR (CDCl3): 0,93 (s, 3H); 1,03 (CSS="ptx2">

The following compounds were obtained in a similar way

Example 119

7 methyl-16 -(2-pyridyloxy)-4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=381.

Example 120

7-methyl-16 -[2-(5-carbylamine)pyridyloxy)] -4-Aza-5 - androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=424.

Example 121

7-methyl-16 -(3-pyridyloxy) -4-Aza-5-androst-1-EN-3-one.

NMR (CDCl3): to 0.92 (s, 3H); to 0.96 (s, 3H); was 1.04 (d, 3H); to 3.34 (DD, 1H); to 4.73 (q, 1H); by 5.87 (CL, IH), 5,79 (d, 1H); 6,79 (d, 1H); to 7.09 (m, 1H); 7.18 in (t, 1H); is 8.16 (d, 1H); 8,21 (s, 1H).

Example 122

7-methyl-16 -(4-pyridyloxy)-4-Aza-5-androst-1-EN-3 - one. M/e, the ionization electrostrictive, m+1=381.

Example 123

7-methyl-16 -[2-(4-phenyl)pyrimidinone]-4-Aza - 5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=458.

Example 124

7-methyl-16 -[2-(6-chloro)pyrazinone]-4-Aza - 5-androst-1-EN-3-one.

NMR (CDCl3): to 0.92 (s, 3H); to 0.96 (s, 3H); of 1.02 (d, 3H); to 3.34 (DD, 1H); 5,27 (SHS, 1H); of 5.34 (q, 1H); 5,80 (d, 1H); is 6.78 (d, 1H); with 8.05 (s, 1H); 8,08 (s, 1H).

Example 125

7-methyl-16 -[2-(3,6-dimethylpyrazine)]-4-Aza-5 - androst-1-EN-3-one.

NMR (CDCl3): to 0.92 (s, 3H); and 0.98 (s, 3H); of 1.02 (d, 3H); to 2.35 (s, 3H); is 2.37 (s, 3H); at 3.35 (DD, 1H); 5,27 (SHS, 1H); of 5.39 (q, 1H); 5,80 (d, 1H); 6,79 (d, 1H); for 7.78 (s, 2H).

Example 126

7-methyl-, H); 5.25-inch (SHS, 1H); 5,52 (kV, 1H); 5,79 (d, 1H); 6,79 (d, 1H); to 6.88 (d, 1H); to 7.32 (d, 1H). Mass spectrum: M/e 416 (M+1).

Example 127

7-methyl-16 -[3-(6-phenyl)pyridazinone]-4-Aza - 5-androst-1-EN-3-one.

NMR (CDCI3): to 0.92 (s, 3H); 0,99 (s, 3H); was 1.04 (d, 3H); to 3.34 (DD, 1H); 5,27 (SHS, 1H); 5,64 (kV, 1H); 6,79 (d, 1H); 6,98 (d, 1H); was 7.45 (m, 3H); of 7.75 (d, 1H); 7,98 (d, 2H). Mass spectrum: m/e 458 (m+1).

Example 128

7-methyl-16 -(2-benzoxazolinone) -4-Aza-5-androst-1 - EN-3-one. M/e, the ionization electrostrictive, m+1=381.

Example 129

7-methyl-16 -(2-benzothiazolylazo)-4-Aza-5-androst-1-EN-3-one. M/e, the ionization electrostrictive, m+1=437.

Examples preparative forms of pharmaceutical compositions

Tablet:

Ingredients Quantity (mg

Connection Example 3 - 25

Starch - 35

Microcrystalline cellulose - 30

Polyvinylpyrrolidone (10% solution in water) - 4

Natrocarbonatite - 4,5

Magnesium stearate and 0.5

Talc - 1

100

Suspension

Ingredients - Number

The compound of example 66 25 mg

The sodium carboxymethyl cellulose 25 mg

The syrup 1.25 ml

A solution of benzoic acid 0.10 ml

The corrigentov - on-demand

Dyes - on-demand

Purified water To 5 ml

Aerosol n is tanol - 29,5

The propellant 22 (Chlorodifluoromethane) - 70

Tablets

Ingredients Quantity (mg

The compound of Example 3

Flutamide (antiandrogen) - 25

Cellulose, microcrystalline - 70

Silicon dioxide, fine - 20

Stearic acid - 10

Just - 150N

1. 16-substituted 4-Aza-androstane General formula I

< / BR>
or their pharmaceutically acceptable salt or ester,

where C1C2carbon - carbon bond may be a simple bond or a double bond, the dotted line, R1selected from the group comprising hydrogen and (C1-C10)alkyl, R2selected from the group comprising hydrogen and (C1-C10)alkyl; one of R3and R4selected from the group comprising hydrogen and methyl, and the other is chosen from the group consisting of amino group, cyano group, fluorine, methyl, hydroxyl group, group-C(O)NRbRcwhere Rband Rcindependently denote hydrogen, phenyl or phenyl (C1-C6)alkyl, while the alkyl part may be substituted by from 1 to 3 of the following substituents: halogen, (C1-C4)alkoxy group, or trifluoromethyl, (C1-C10)alkyl-X-, where X represents-O-, -S(O)nwhere n, the de n is 0, 1, 2, aryl-X-, where aryl represents phenyl, benzyl, X is-O-, -S(O)nwhere n is 0, 1, 2-C(O)NRe, - N(Re) C(O)-O-CH(Re), where Re is hydrogen, heteroaryl-X-, where X represents-O-, -CH(Re), where Re is hydrogen, heteroaryl is triazinyl, hinely, ethanolic, isoxazolyl, pyrazolyl, pyridazinyl, benzoxazolyl, benzothiazolyl, pyridyl, peril, thienyl, pyrazinyl, pyrimidinyl, oxazolyl, Persil, naphthyl, where aryl and heteroaryl may be not substituted or is substituted by from 1 to 3 of the following substituents: halogen, amino group, cyano group, nitro group, a mono, di - or trihalomethyl, mono-, di - or trihalomethane group, (C1-C6)alkyl, tigraphy, fordigraph, (C1-C6)alkyl-tigraphy, (C2-C6)alkenyl, (C1-C6)alkylsulfonyl, phenyl, (C1-C6)alkoxyphenyl, (C1-C6)alkylsulfonyl, di(C1-C6)alkoxyphenyl, halogenfree, phenylthiourea, phenylsulfonyl, phenylsulfinyl, acetylamino, benzoylamino, methylsulfinylpropyl, carbylamines, perriam, talila, and C1-C6the alkyl part may be substituted by from 1 to 3 of the following substituents: galaroza or a group-CH-Rgwhere Rgrepresents phenyl or phenyl substituted by halogen or (C1-C6)alkyl.

2. Connection on p. 1, where R1denotes hydrogen or methyl and R2denotes hydrogen or methyl.

3. Connection on p. 1, where heteroaryl selected from unsubstituted and substituted pyridyl, parrila, teinila, pyrazinyl, pyrimidinyl: chinoline, izochinolina, isoxazolyl, oxazolyl, benzothiazolyl and benzoxazolyl.

4. Connection on p. 3, where the specified heteroaryl may be substituted by one or two substituents.

5. Connection on p. 2, where one of the substituents R3and R4selected from the group comprising hydrogen or methyl and the other is chosen from the group consisting of cyano group, a fluorine atom, a hydroxyl group, (C1-C10)alkyl-X-, where X represents-O-, -S(O)nwhere n is 0, 1, 2, -C(O)NRe, -CHRe, where Re is hydrogen, (C2-C10)alkenyl-X-, where X represents-O-, -S(O)nwhere n is 0, 1, 2; aryl-X-, where aryl represents phenyl, benzyl; X represents-O-, -S(O)nwhere n equals 0, 1, 2, -C(O)NRe, - N(Re) C(O)-O-, -CHRe, where Re represents hydrogen, heteroaryl-X-, where X represents-O-, -CH(Re), where Re is hydrogen; heteroaryl is triazinyl, chinoline, pyrimidinyl, oxazolyl, Persil, naphthyl, where the aryl and heteroaryl can be unsubstituted or substituted from 1 to 2 the following substituents: halogen, cyano group, nitro group, trihalomethyl, trihalomethane group, a C1-C6-alkyl, tigraphy, fordigraph, C1-C6alkylthiol, C2-C6alkenyl, C1-C6alkylsulfonyl, phenyl, (C1-C6)alkoxyphenyl, (C1-C6)alkylsulfonyl, di(C1-C6)alkoxyphenyl, halogenfree, phenylthiourea, phenylsulfonyl, phenylsulfinyl, acetylamino, benzoylamino, methylsulfinylpropyl, carbylamines, perriam, talila, and C1-C6the alkyl part may be substituted by from 1 to 3 of the following substituents: halogen, C1-C4alkoxy group, trifluoromethyl, R3and R4together may denote a carbonyl oxygen atom.

6. Connection on p. 1, selected from the group comprising 4-Aza-4,7-dimethyl-5-androstane-3,16-dione, 4-Aza-4-methyl-5-androstane-3,16-dione, 3-oxo-4-Aza-4-methyl-16-hydroxy-5-androstane, 3-oxo-4-Aza-4-methyl-16--(benzylaminocarbonyl)-5--androstane, 3-oxo-4-Aza-4-methyl-16-benzoylamino-5-androstane, 3-oxo-4-Aza-4-mestan, 3-oxo-4-Aza-4-methyl-16-hydroxy-5-androstane, 3-oxo-4-Aza-4-methyl-16-(phenoxy)-5-androstane, 3-oxo-4-Aza-7-methyl-16-(phenoxy)-5-androst-1-ene, 3-oxo-4-Aza-4-methyl-16-methoxy-5-androstane, 3-oxo-4-Aza-4-methyl-16-(4-chlorphenoxy)-5-androstane, 3-oxo-4-Aza-7-methyl-16-(4-chlorphenoxy)-5-androst-1-ene, 3-oxo-4-Aza-7-methyl-16-(4-chlorphenoxy)-5-androstane, 3-oxo-4-Aza-7-methyl-16-(3-chloro-4-methylphenoxy)-5-androstane, 3-oxo-4-Aza-7-methyl-16-(4-methylphenoxy)-5-androstane, 3-oxo-4-Aza-7-methyl-16-(4-methylphenoxy)-5-androst-1-ene, 3-oxo-4-Aza-7-methyl-16-[4-(1-pyrrolyl)phenoxy] -5-androst-1-ene, 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-androstane, 3-oxo-4-Aza-4, 7-dimethyl-16-methoxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16-allyloxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16-(3,3-dimethylallyl)-5-androstane, 3-oxo-4-Aza-4, 7-dimethyl-16-(n-propyloxy)-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16-(isobutoxy)-5-androstane, 3-oxo-4-Aza-4,16-dimethyl-16-hydroxy-5-androstane,

3-oxo-4-Aza-4,7-dimethyl-16-acyloxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--benzyloxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16-hydroxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--methylthio-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(n-propylthio)-5--androstane,

3-oxo-4-Aza-4,7-dimethyl-16-fluoro-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16-cyano-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(1-g is-oxo-4-Aza-4,7-dimethyl-16--(4-Chlorobenzyl)-5--androstane, 3-oxo-4-Aza-4,16-dimethyl-16--methoxy-5-alpha-androstane,3-oxo-4-Aza-4,7--(4-cianfrocca)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(3-cianfrocca)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-nitrophenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(1 naphthyloxy)-5--androstane,

3-oxo-4-Aza-4,7-dimethyl-16--(3-chloro-4-methylphenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-methylphenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(tert-butoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(3-methyl-1-Butylochka)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(n-propyloxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-triptoreline)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-triftormetilfosfinov)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-ethylthio-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--ethylsulfonyl-5-androstane,

3-oxo-4-Aza-4,7-dimethyl-16--(4-methylsulfinylphenyl)-5--androstane,

3-oxo-4-Aza-4,7-dimethyl-16--[4-(4-tolilsulfonil)phenoxy] -5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(3-pyridyloxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--[(4-phenyl)phenoxy] -5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-pertenece)-5--androstane,< / BR>
3-oxo-4-Aza-4,7-dimethyl-16--(2-pyrazinone)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--[4-(5-oxazolyl)phenoxy] -5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(2-pyrimidinyl and)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-acetylaminophenol)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-benzylaminopurine)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-chlorphenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-phenoxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(2-chlorophenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(3-chlorophenoxy)-5--androstane,

3-oxo-4-Aza-4,7-dimethyl-16--(4-chlorphenoxy)-5--androst-1-ene, 3-oxo-4-Aza-4,7-dimethyl-16-(4-chlorobenzylidene)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-benzylidene-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16-(4-methylbenzylidene)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-(4-Chlorobenzyl)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-(4-methylbenzyl)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-(3-pyridylmethyl)-5--androstane,

3-oxo-4-Aza-4,7-dimethyl-16--methanesulfonyl-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16-thiophenoxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-chlorothiophenol)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-fortifies)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-methylthiophene)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-methoxythiophene)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-phenylsulfonyl-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--phenylsulfonyl-5-androstane, 3-oxo-4-Aza-4,7--16--trimethyl-16--(4-triptoreline)-5--androstane,

3-oxo-4-Aza-4,Oli.

7. Connection on p. 5, where C1-C2carbon - carbon bond is a simple bond, R1denotes methyl, R2denotes methyl, R3selected from unsubstituted or substituted alloctype, and R4denotes hydrogen.

8. Connection on p. 1, selected from the group comprising 3-oxo-4-Aza-4,7-dimethyl-16--(4-cianfrocca)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(3-cianfrocca)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-nitrophenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(1 naphthyloxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(3-chloro-4-methylphenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-methylphenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-triptoreline)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-triftormetilfosfinov)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-methylsulfinylphenyl)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--[4-(4-tolilsulfonil]phenoxy-5-androstane, 3-oxo-4-Aza-4,7-dimethyl-16--[(4-phenyl)phenoxy] -5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-pertenece)-5--androstane,< / BR>
3-oxo-4-Aza-4,7-dimethyl-16--[4-(5-oxazolyl)phenoxy] -5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--[4-(1-peril)phenoxy] -5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-aminophenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(4-acetylaminophenol)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16-phenoxy-5-androstane,3-oxo-4-Aza-4,7-dimethyl-16--(2-chlorophenoxy)-5--androstane, 3-oxo-4-Aza-4,7-dimethyl-16--(3-chlorophenoxy)-5--androstane, and their pharmaceutically acceptable salts.

9. Connection 3-oxo-4-Aza-4,7-dimethyl-16--(4-chlorphenoxy)-5--androstane or its pharmaceutically acceptable salt.

10. 3-oxo-4-Aza-7--methyl-16--(4-methylphenoxy)-5--androst-1-ene.

11. The method of inhibition of 5-reductase or its isoenzyme comprising introducing to a mammal in need of such inhibition, an active agent, characterized in that the method comprises the introduction of a therapeutically effective amount of the compounds under item 1 or therapeutically effective amount of the compounds under item 1 in combination with an inhibitor of 5-reductase 2.

12. A method of inhibiting the biosynthetic conversion of testosterone to dihydrotestosterone in a mammal in need of such treatment, including the introduction of a given mammal active agent, wherein the administered active agent is a therapeutically effective amount of the compounds under item 1 or therapeutically effective amount of the compounds under item 1 in combination with an inhibitor of 5-reductase 2.

13. Pharmaceutical is asepticheski acceptable carrier and a therapeutically effective amount of the compounds on p. 1.

14. The pharmaceutical composition according to p. 13, characterized in that it further includes a therapeutically effective amount of an inhibitor of 5-reductase 2 or its pharmaceutically acceptable salt.

15. The pharmaceutical composition according to p. 14, wherein the inhibitor of 5-reductase 2 is finasteride, epristeride, turosteride.

16. The pharmaceutical composition according to p. 13, characterized in that said connection under item 1 is 3-oxo-4-Aza-4,7-dimethyl-16--(4-chlorphenoxy)-5--androstane or its pharmaceutically acceptable salt.

17. The pharmaceutical composition according to p. 13, characterized in that it further includes a therapeutically effective amount of a compound stimulating the disclosure of membrane potassium channel, or its pharmaceutically acceptable salt.

18. The pharmaceutical composition under item 17, characterized in that said connection, stimulating disclosure membrane potassium channel, is Minoxidil or its pharmaceutically acceptable salt.

19. The pharmaceutical composition under item 17, characterized in that it further includes a pharmaceutically acceptable carrier suitable for local purposes.

20. Pharmacopoeial salt.

21. The pharmaceutical composition according to p. 20, characterized in that said retinoid is tretinoin, isotretinoin or its pharmaceutically acceptable salt.

22. The pharmaceutical composition according to p. 13, characterized in that it further includes antiandrogen or its pharmaceutically acceptable salt.

23. The pharmaceutical composition according to p. 22, characterized in that the specified antiandrogens is flutamide, spironolactone, casodex or their pharmaceutically acceptable salt.

 

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

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 compounds that perform new functions inhibitors of bone ratably/promoters osteogenesis

The invention relates to a new method of treatment of patients, such as people with benign prostatic hyperplasia (BPH), which includes treatment by assigning a therapeutically effective amount of an inhibitor 5- reductase in combination with blocker1- adrenergic receptor

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

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