Meiosis regulating compounds

Abstract

Certain novel sterol derivatives can be used for regulating the meiosis in oocytes and in male germ cells.

1 . Novel compounds of the general formula I:  
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen, halogen, methyl, hydroxy or oxo;  
         R 2  is selected from the group comprising hydrogen, hydroxy, C 1 -C 3  alkyl, vinyl, C 1 -C 3  alkoxy and halogen, or R 2  designates, together with R 3 , an additional bond between the carbon atoms at which R 2  and R 3  are placed;  
         R 3  is selected from the group comprising hydrogen, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, halogen, lower alkyl or a perfluoro(lower alkyl) group; or R 3  designates, together with R 2  an additional bond between the two carbon atoms at which R 2  and R 3  are placed; or R 3  designates, together with R′ 3 , oxo or a group of the general formula ═NOR 38  wherein R 38  is hydrogen or lower alkyl;  
         R′ 3  designates hydrogen or hydroxy; with the proviso that R 3  and R′ 3  are not, simultaneously, hydrogen;  
         R 4  and R′ 4 , which are different or identical with the proviso that they are not both hydroxy, are selected from the group comprising hydrogen, halogen, hydroxy and C 1 -C 6  alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R 4  and R′ 4  together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; or R 4  designates, together with R ′4  and R 5 , a methano bridge between the carbon atoms in 4 and 5 position or an additional bond between the carbon atoms in 4 and 5 position;  
         R 5  is hydrogen, halogen, hydroxy, lower alkyl, cyano, hydroxymethyl, a carbaldehyde, an oxime derived from a carbaldehyde, a carboxylic acid, a primary or secondary amide derived from a carboxylic acid, an ester with a C 1 -C 6 -alcohol group; or R 5  designates, together with R 6 , an additional bond between the carbon atoms at which R 5  and R 6  are placed;  
         R 6  is hydrogen, hydroxy, halogen or oxo, or R 6  designates, together with R 5  or R 7 , an additional bond between the carbon atoms at which R 6  and R 5  or R 7  are placed;  
         R 7  is selected from the group comprising hydrogen, hydroxy, lower alkoxy, acyloxy, halogen and lower alkyl; or R 7  designates, together with R 6  or R 8 , an additional bond between the carbon atoms at which R 7  and R 6  or R 8  are placed;  
         R′ 7  is hydrogen, or, if R 7  is lower alkyl, R′ 7  is hydrogen or hydroxy; or R 7  designates, together with R′ 7 , methylene, oxo or a group of the general formula ═NOR 36 , wherein R 36  is hydrogen or lower alkyl;  
         R 8  is hydrogen, hydroxy or halogen, or R 8  designates, together with R 7 , R 9  or R 14 , an additional bond between the carbon atoms at which R 8  and R 7 , R 9  or R 14  are placed;  
         R 9  is hydrogen, hydroxy or halogen, or R 9  designates, together with R 8  or R 11 , an additional bond between the carbon atoms at which R 9  and R 8  or R 11  are placed;  
         R 11  is selected from the group comprising hydrogen, hydroxy, lower alkoxy, acyloxy, halogen and lower alkyl, or R 11  designates, together with R 9  or R 12 , an additional bond between the carbon atoms at which R 11  and R 9  or R 12  are placed;  
         R′ 11  is hydrogen or, if R 11  is lower alkyl, R′ 11  is hydrogen or hydroxy, or R 11  designates, together with R′ 11 , methylene, oxo or a group of the general formula ═NOR 37 , wherein R 37  is hydrogen or lower alkyl;  
         R 12  is selected from the group comprising hydrogen, halogen, C 1 -C 4  alkyl, methylene, hydroxy, lower alkoxy, acyloxy, oxo and a group of the general formula ═NOR 33  wherein R 33  is hydrogen or C 1 -C 3  alkyl, or R 12  designates, together with R 11 , an additional bond between the carbon atoms at which R 11  and R 12  are placed;  
         R 14  is hydrogen or hydroxy, or R 14  designates, together with R 15 , an additional bond between the carbon atoms at which R 14  and R 15  are placed;  
         R 15  is selected from the group comprising hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula ═NOR 32  wherein R 32  is hydrogen or C 1 -C 3  alkyl, or R 15  designates, together with R 14  an additional bond between the carbon atoms at which R 15  and R 14  are placed;  
         R 16  is selected from the group comprising hydrogen, halogen, C 1 -C 3  alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula ═NOR 34  wherein R 34  is hydrogen or lower alkyl, or R 16  designates, together with R 17 , an additional bond between the carbon atoms at which R 16  and R 17  are placed;  
         R 17  is hydrogen or hydroxy, or R 17  designates, together with R 16 , an additional bond between the carbon atoms at which R 17  and R 16  are placed;  
         R 20  is selected from the group comprising hydrogen, lower alkyl and hydroxymethyl, or R 20  and R′ 20  together designate methylene or oxo;  
         R′ 20  is hydrogen, halogen, lower alkyl or hydroxy;  
         R′ 22  is hydrogen, hydroxy or oxo;  
         R 22  represents phenyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, lower alkoxy, halogen, amino, cyano, carboxy, a group of the general formula —COOR 39 , N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio;  
         benzyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, lower alkoxy, halogen, amino, cyano, carboxy, a group of the general formula —COOR 39 , oxo, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio;  
         cyclohexyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen, amino, cyano, carboxy, a group of the general formula —COOR 39 , oxo, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio;  
         cyclohexylalkyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, lower alkoxy, halogen, amino, cyano, carboxy, a group of the general formula —COOR 39 , oxo, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio;  
         alkyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, alkoxy, halogen, amino, cyano, carboxy, a group of the general formula —COOR 39 , oxo, N-acylamino, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio; or  
         alkenyl optionally substituted by one or more of the following groups which substituents may be different or identical: hydroxy, lower alkoxy, halogen, amino, cyano, carboxy, a group of the general formula —COOR 39 , oxo, N-alkylamino or N,N-dialkylamino wherein the N-alkylamino or N,N-dialkylamino substituent optionally is substituted by carboxy, lower alkoxy or lower alkylthio;  
         and R 39  represents lower alkyl or aralkyl,  
         and additionally, when R 1 , R 2 , R′ 4 , R 5 , R 11 , R 12 , R 15 , R 16 , R′ 20  and R′ 22  are each hydrogen, R 3  is hydrogen, lower alkyl or perfluoro(lower alkyl), R′ 3  is hydroxy, or R 3  designates, together with R′ 3 , oxo, R 4  is hydrogen or together with R 5  a methano bridge or together with R 5  an additional bond, R 5  is lower alkyl, cyano, hydroxymethyl, a carbaldehyde, an oxime derived from a carbaldehyde, a carboxylic acid, a primary or secondary amide derived from a carboxylic acid, an ester with a C 1 -C 6 -alcohol group or together with R 4  a methano bridge or together with R 4  an additional bond, R 7  is together with R 8  an additional bond or hydrogen, if R 8  and R 9  or R 8  and R 14  stand together for an additional bond, R 8  is together with R 7  or with R 9  or with R 14  an additional bond, R 9  is together with R 8  an additional bond or a hydrogen atom, if R 7  and R 8  or R 9  and R 14  stand together for an additional bond, R 14  is together with R 8  an additional bond or a hydrogen atom, if R 7  and R 8  or R 8  and R 9  stand together for an additional bond, R 17  is hydrogen in the alpha position, R 19  is methyl in the beta position, and R 20  is methyl in the alpha position, then R 22  is 3-methylbutyl;  
         with the proviso that the following compounds are disclaimed: cholesta-4,7-dien-3-one;  
         cholesta-4,8-dien-3-one; cholesta-4,8(14)-dien-3-one; cholesta-4,7-dien-3α-ol; cholesta-4,7-dien-3β-ol; 5-cyano-5,-cholest-7-en-3-one; 5-cyano-5β-cholest-7-en-3β-ol; 5-methyl-5,-cholest-7-en-3-one; 5-methyl-50-cholest-7-en-3β-ol; 5-methyl-50-cholest-7-en-3β-ol; 3β,7α-dihydroxycholest-5-ene; 3β,7β-dihydroxycholest-5-ene; 3β-hydroxycholest-5-en-7-one; 3β-hydroxycholest-7-one; 7α-hydroxycholest-4-en-3-one; cholest-3,6-dione; 3β-hydroxycholest-6-one; 3β,6β-dihydroxycholestane; cholest-4-en-3,6-dione; 3β,5α,6β-trihydroxycholestane; 3β,5α-dihydroxycholestane-; 3β,4β-dihydroxycholest-5-ene; cholest-2-en-6one; cholest-4,6-dien-3-one; cholest-4,7-dien-3-one; cholest-3,5-dien-7-one; 19-nor-21-methylpregna-4,9-dien-17α-hydroxy-3,20-dione; 19-nor-21-methylpregna-4,9-dien-17α-acetoxy-3,20-dione; 19-nor-21,21-dimethylpregna-4,9-diene-17α-hydroxy-3,20-dione; 177α-21,21-dimethyl-19-nor-pregna-4,9-dien-3,20-dione; 3α-acetoxy-24-nor-cholan-23-one; 3α-hydroxy-26,27-di-nor-23-trans-5β-cholest-23-en-25-carboxylic acid methyl ester; 3α-hydroxy-26,27-di-nor-5β-cholesta-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-5β-cholesta-25-carboxylic acid methyl ester; 3-keto-4-bromo-26,27-di-nor-5β-cholesta-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-cholest-4-en-25-carboxylic acid methyl ester; 3β-acetoxy-26,27-di-nor-cholesta-3,5-dien-25-carboxylic acid methyl ester; 3β-hydroxy-26,27-di-nor-cholest-5-en-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-cholest-4,6-dien-25-carboxylic acid methyl ester; 3β-hydroxy-26,27-di-nor-cholesta-3,5,7-trien-25-carboxylic acid methyl ester; and 3β-hydroxy-26,27-di-nor-cholesta-5,7-dien-25-carboxylic acid methyl ester; 3β,22-diacetoxy-cholesta-5-en-25-ol; 3β,22-diacetoxy-25-fluorocholesta-5-ene; 22-hydroxycholesta-5-en-25-fluoro-3β-hemisuccinate; 3β,22-diacetoxy-25-dichlorocholesta-5-ene; 3β,22-dihydroxy-25-chlorocholesta-5-ene; 22-hydroxy-25-chlorocholesta-5-en-3β-hemisuccinate; 3β,22-di-hydroxy-25-bromocholesta-5-ene; 3β,22-dihydroxy-25-fluorocholesta-5-ene; cholenic acid; 3β-acetoxycholesta-5-en-25-des-dimethyl-24-one; 3,24-diacetoxycholesta-25-des-dimethyl-5,23-diene; 3β-acetoxycholesta-25-des-methyl-5-en-24-difluoro-25-one; 3β-acetoxy-24-di-fluorocholesta-5,7-dien-25-ol; 3β-hydroxycholest-5-en-24-one; 3β-acetoxycholest-5-en-24-one; 5β-cholest-24-one; 5β-cholestan-24α-homo-24-one; 3α,6α-dihydroxy-5β-cholest-24-one; 3α,6α-diacetoxy-5,-cholest-24-one; 3α,6α-diacetoxy-5β-cholest-24α-homo-24-one; 3α,6α-dihydroxy-5β-cholest-24α,2413-bis-homo-24-one; 3α-hydroxy-53-cholest-24-one; 3α-acetoxy 5β-cholesta-24-one; 3α-benzoyloxy-5β-cholesta-24-one; 3α-ethyloxycarbonyloxy-5β-cholesta-24-one; 3α-hydroxy-5β-cholestan-24α-homo-24-one; 3α-hydroxy-24α,24β-bis-homo-5β-cholestane; 3β-hydroxycholesta-5,7-dien-24-one; 3β-acetoxycholesta-5,7-dien-24-one; 1α,3β-dihydroxycholesta-5,7-diene-24-one; 1α,3β-diacetoxycholesta-5,7-diene-24-one; chenodeoxycholic acid; ursodeoxycholic acid; trimebutyn salt of chenodeoxycholic acid; trimebutyn salt of ursodeoxycholic acid; 3β,25-dihydroxycholest-5-en-24-one; 3β-acetoxy-cholest-5-en-24-one; 3β-acetoxy-25-hydroxycholest-5-en-24-one; 3β,25-dihydroxycholest-5-en-24-one; 3β-hydroxycholest-5-en-24-one; 3β-hydroxy-25-hydroperoxycholest-5-en-24-one; 3β,24,25-trihydroxycholest-5-ene; 1α,3β-dihydroxycholest-5-en-24-one; 1α,3β,25-trihydroxy-cholest-5-en-24-one; 1α,3β,24,25-tetrahydroxycholest-5-en-24-one; 3α-acetoxy-7α-bromo-cholest-5-ene; 3α-acetoxycholesta-5,7-diene; 3α-acetoxy-25-hydroxycholesta-5,7-diene; 313,25-dihydroxy-26,27-hexafluorocholest-5-ene; 1α,3β,25-trihydroxy-26,27-hexafluoro-cholest-5-ene; 3α,7α,12α,24R,26,27-hexahydroxycholestane; 3α-hydroxy-7-cholanic acid; 3α,7α-dihydroxycholanic acid; 3α,7β-dihydroxycholanic acid; and lithium 3α,7β-dihydroxycholanate; cholesta-1,4,6-trien-3-one; cholest-5-en-1α,3β-diol; 1α-hydroxycholesta-4,6-diene-3-one; 1α,3β-dihydroxycholest-5-ene; 25-hydroxycholesta-1,4,6-triene-3-one; 1α,3β-25-trihydroxycholest-5-ene; 3α,71-dihydroxydeoxycholic acid; 3α,7α-dihydroxydeoxycholic acid; 7-ketodeoxycholic acid; 3α,7β-dihydroxydeoxycholic acid; cholic acid; 7-ketocholic acid; 3α,7β,12α-cholic acid; 12-ketocholic acid; cholic acid; 3α-hydroxy-7-ketocholic acid; 3α,7α-diacetoxycholic acid; 3α,7α-diacetoxy-12-ketocholic acid; 3α,7α-dihydroxydeoxycholic acid; 7-ketodeoxycholic acid; 3α,7β-dihydroxydeoxycholic acid; 3α,7β-dihydroxy-12-ketocholic acid; cholic acid; cholic acid methyl ester; 3-acetylcholic acid methyl ester; 3-(2-propenyl)-cholic acid methyl ester; 3-(3-hydroxypropyl)cholic acid-3-methyl ester; desoxycholic acid; 12-ketodesoxycholic acid; 3β-acetyloxy-12-keto-desoxycholic acid; 3β-(hydroxyethyloxy)-cholic acid methyl ester; 3β-(hydroxypropyloxy)cholic acid methyl ester; 3β-(hydroxybutyl-oxy)cholic acid methyl ester; 3β-(hydroxypentyloxy)cholic acid methyl ester; 3β-(hydroxy-hexyloxy)cholic acid methyl ester; 3β-(hydroxydecanoyloxy)cholic acid methyl ester; 3β-(2-hydroxyethyloxyethyloxy)cholic acid methyl ester; 3β-(2-hydroxypropyloxy)cholic acid methyl ester; 3β-(hydroxyethyloxy)desoxycholic acid methyl ester; 3β-(hydroxypropyloxy)desoxycholic acid methyl ester; 3β-(hydroxypentyloxy)desoxycholic acid methyl ester; 30-(hydroxy-decyloxy)desoxycholic acid methyl ester; 3β-(2-hydroxyethyloxy)chenodesoxycholic acid methyl ester; 3β-(3-hydroxypropyloxy)chenodesoxycholic acid methyl ester; 3β-(5-hydroxy-pentyloxy)chenodesoxycholic acid methyl ester; 30-(10-hydroxydecyloxy)chenodesoxycholic acid methyl ester; 3β-(2-hydroxyethyloxy)litocholic acid methyl ester; 3β-(3-hydroxypropyl-oxy)litocholic acid methyl ester; 3β-(5-hydroxypenthyloxy)lithocholic acid methyl ester; 3β-(10-hydroxydecayloxy)lithocholic acid methyl ester; 3β-(benzyloxyethyloxy)cholic acid methyl ester; 3β-(benzyloxyethyloxy)cholic acid tert.butyl ester; 3β-(2-hydroxyethyloxy)cholic acid tert.butyl ester; 3β-(2-hydroxyethyloxy)-7α,12α-diacetyloxycholic acid methyl ester; 3β-(propionyloxy)-7α,12α-diacetyloxy-24-carboxylic acid methyl ester; chenodeoxycholic acid; sitosterol; 3α-hydroxycholestane; 3β-hydroxycholestane; 25-fluorocholest-5-en-3β,22-diol; 25-chlorocholest-5-en-3β,22-diol; 22-hydroxy-25-fluorocholest-5-en-3β-hemisuccinate; 22-hydroxy-25-chlorocholest-5-en-3β-hemisuccinate; cholesta-5-en-3β,22,25-triol; (3β,5α,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol; (3β,5α,20R)-4,4,20-trimethyl-21-(3-methyl-phenyl)pregna-8,14-dien-3-ol; and (3β,5α,20R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-3-ol; and esters, salts, active metabolites and prodrugs thereof.