US2004048838A1PendingUtilityA1
Meiosis regulating compounds
Priority: Jun 23, 1995Filed: Sep 9, 2003Published: Mar 11, 2004
Est. expiryJun 23, 2015(expired)· nominal 20-yr term from priority
C07J 41/0016C07J 9/00
49
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Claims
Abstract
Sterol derivative compounds, structurally related to natural compounds which can be extracted from bull testes and from human follicular fluid, useful for regulating meiosis in oocytes and in male germ cells. Some of these compounds are useful in the treatment of infertility, whereas other compounds are useful as contraceptives.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of regulating meiosis in a mammalian germ cell comprising administering to a germ cell in need of such regulation, an effective amount of a compound of formula (I)
wherein R 1 and R 2 , independently, are selected from the group consisting of hydrogen and branched or unbranched C 1 -C 6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R 1 and R 2 together designate methylene or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R 3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR 26 wherein R 26 is hydrogen or C 1 -C 3 alkyl, halogen, and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 3 designates, together with R 9 or R 14 , an additional bond between the carbon atoms to which R 3 and R 9 or R 14 are bound; R 4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR 27 wherein R 27 is hydrogen or C 1 -C 3 alkyl, halogen, and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 4 designates, together with R 13 or R 15 , an additional bond between the carbon atoms to which R 4 and R 13 or R 15 are bound; R 5 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, oxo, and ═NOR 22 wherein R 22 is hydrogen or C 1 -C 3 alkyl, or R 5 designates, together with R 6 , an additional bond between the carbon atoms to which R 5 and R 6 are bound; R 6 is hydrogen or R 6 designates, together with R 5 , an additional bond between the carbon atoms to which R 5 and R 6 are bound; R 9 is hydrogen or R 9 designates, together with R 3 or R 10 , an additional bond between the carbon atoms to which R 9 and R 3 or R 10 are bound; R 10 is hydrogen or R 10 designates, together with R 9 , an additional bond between the carbon atoms to which R 10 and R 9 are bound; R 1 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, ═NOR 28 wherein R 28 is hydrogen or C 1 -C 3 alkyl, halogen and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 11 designates, together with R 12 , an additional bond between the carbon atoms to which R 11 and R 12 are bound; R 12 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, vinyl, C 1 -C 3 alkoxy and halogen, or R 12 designates, together with R 11 , an additional bond between the carbon atoms to which R 12 and R 11 are bound; R 13 is hydrogen or R 13 designates, together with R 4 or R 14 , an additional bond between the carbon atoms to which R 13 and R 4 or R 14 are bound; R 4 is hydrogeno R 14 designates together with R 3 , R 6 or R 13 , an additional bond between the carbon atoms to which R 14 and R 3 or R 6 or R 13 are bound; R 15 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and ═NOR 23 wherein R 23 is hydrogen or C 1 -C 3 alkyl, or R 15 designates, together with R 4 , an additional bond between the carbon atoms to which R 15 and R 4 are bound; R 16 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, methylene, hydroxy, methoxy, oxo and ═NOR 24 wherein R 24 is hydrogen or C 1 -C 3 alkyl, or R 16 designates, together with R 17 , an additional bond between the carbon atoms to which R 16 and R 17 are bound; R 17 is hydrogen or hydroxy or R 17 designates, together with R 16 , an additional bond between the carbon atoms to which R 17 and R 16 are bound; R 18 and R 19 are, independently, hydrogen or fluoro; R 25 is selected from the group consisting of hydrogen, C 1-4 alkyl, methylene, hydroxy and oxo; A is a carbon atom or a nitrogen atom; when A is a carbon atom, R 7 is selected from the group consisting of hydrogen, hydroxy and fluoro, and R 8 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene and halogen, or R 7 designates, together with R 8 , an additional bond between the carbon atoms to which R 7 and R 8 are bound; R 20 is selected from the group consisting of C 1 -C 4 alkyl, trifluoromethyl and C 3 -C 6 cycloalkyl and R 21 is selected from the group consisitning of C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C 3 -C 6 cycloalkyl, or R 20 and R 21 , together with the carbon atom to which they are bound, form a C 3 -C 6 cycloalkyl ring; and when A is a nitrogen atom, R 7 designates a lone pair of electrons and R 8 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and oxo; R 20 and R 21 are, independently, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; provided that the compound of formula (I) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
Cholest-7-ene-3β-ol;
4-Methylcholest-7-ene-3β-ol;
4-Ethylcholest-7-ene-3β-ol;
4,4-Dimethylcholest-7-ene-3β-ol;
4α-Methyl-40-ethylcholest-7-ene-3β-ol;
4α-Ethyl-40-methylcholest-7-ene-3β-ol;
4,4-Diethylcholest-7-ene-3β-ol;
4-Propylcholest-7-ene-3β-ol;
4-Butylcholest-7-ene-3β-ol;
4-Isobutylcholest-7-ene-3β-ol;
4,4-Tetramethylenecholest-7-ene-3β-ol;
4,4-Pentamethylenecholest-7-ene-3β-ol; Cholest-8-ene-3β-ol;
4-Methylcholest-8-ene-3β-ol;
4-Ethylcholest-8-ene-3β-ol;
4,4-Dimethylcholest-8-ene-3β-ol;
4α-Methyl-4β-ethylcholest-8-ene-3β-ol;
4α-Ethyl-40-methylcholest-8-ene-3β-ol;
4,4-Diethylcholest-8-ene-3β-ol;
4-Propylcholest-8-ene-3β-ol;
4-Butylcholest-8-ene-3β-ol;
4-Isobutylcholest-8-ene-3β-ol;
4,4-Tetramethylenecholest-8-ene-3β-ol;
4,4-Pentamethylenecholest-8-ene-3β-ol;
Cholest-8(14)-ene-3β-ol;
4-Methylcholest-8(14)-ene-3β-ol;
4-Ethylcholest-8(14)-ene-3β-ol;
4,4-Dimethylcholest-8(14)-ene-3β-ol;
4α-Methyl-4β-ethylcholest-8(14)-ene-3β-ol;
4α-Ethyl-4β-methylcholest-8(14)-ene-3β-ol;
4,4-Diethylcholest-8(14)-ene-3β-ol;
4-Propylcholest-8(14)-ene-3β-ol;
4-Butylcholest-8(14)-ene-3β-ol;
4-Isobutylcholest-8(14)-ene-3β-ol;
4,4-Tetramethylenecholest-8(14)-ene-3β-ol;
4,4-Pentamethylenecholest-8(14)-ene-3β-ol;
Cholesta-8,14-diene-3β-ol;
4-Methylcholesta-8,14-diene-3β-ol;
4-Ethylcholesta-8,14-diene-3β-ol;
4,4-Dimethylcholesta-8,14-diene-3β-ol;
4α-Methyl-4β-ethylcholesta-8,14-diene-3β-ol;
4α-Ethyl-40-methylcholesta-8,14-diene-3β-ol;
4,4-Diethylcholesta-8,14-diene-3β-ol;
4-Propylcholesta-8,14-diene-3β-ol;
4-Butylcholesta-8,14-diene-3β-ol;
4-lsobutylcholesta-8,14-diene-3β-ol;
4,4-Tetramethylenecholesta-8,14-diene-3β-ol;
4,4-Pentamethylenecholesta-8,14-diene-3β-ol;
Cholesta-8,24-diene-3β-ol;
4-Methylcholesta-8,24-diene-3β-ol;
4-Ethylcholesta-8,24-diene-3β-ol;
4,4-Dimethylcholesta-8,24-diene-3β-ol;
4α-Methyl-4β-ethylcholesta-8,24-diene-3β-ol;
4α-Ethyl-4β-methylcholesta-8,24-diene-3β-ol;
4,4-Diethylcholesta-8,24-diene-3β-ol;
4-Propylcholesta-8,24-diene-3β-ol;
4-Butylcholesta-8,24-diene-3β-ol;
4-Isobutylcholesta-8,24-diene-3β-ol;
4,4-Tetramethylenecholesta-8,24-diene-3β-ol;
4,4-Pentamethylenecholesta-8,24-diene-3β-ol;
Cholesta-8,14,24-triene-3β-ol;
4-Methylcholesta-8,14,24-triene-3β-ol;
4-Ethylcholesta-8,14,24-triene-3β-ol;
4,4-Dimethylcholesta-8,14,24-triene-3β-ol;
4α-Methyl-4β-ethylcholesta-8,14,24-triene-3β-ol;
4α-Ethyl-4β-methylcholesta-8,14,24-triene-3β-ol;
4,4-Diethylcholesta-8,14,24-triene-3β-ol;
4-Propylcholesta-8,14,24-triene-3β-ol;
4-Butylcholesta-8,14,24-triene-3β-ol;
4-Isobutylcholesta-8,14,24-triene-3β-ol;
4,4-Tetramethylenecholesta-8,14,24-triene-3β-ol; and
4,4-Pentamethylenecholesta-8,14,24-triene-3β-ol; and esters and ethers thereof.
2 . The method of claim 1 , provided that it is not a compound of formula (II)
wherein R 1 * and R 2 *, independently, are selected from the group consisting of hydrogen, branched or unbranched C 1 -C 6 alkyl which may be substituted by halogen or hydroxy or wherein R 1 * and R 2 *, together with the carbon atom to which they are bound, form a cyclopentane ring or a cyclohexane ring; R 13 * and R 14 * together designate an additional bond between the carbon atoms to which they are bound in which case R 3 * is hydrogen and R 6 * and R 5 * are either hydrogen or together they designate an additional bond between the carbon atoms to which they are bound; or R 3 * and R 14 * together designate an additional bond between the carbon atoms to which they are bound in which case R 13 * is hydrogen and R 6 * and R 5 * are either hydrogen or together they designate an additional bond between the carbon atoms to which they are bound; or R 6 * and R 14 * together designate an additional bond between the carbon atoms to which they are bound in which case R 13 *, R 3 * and R 5 * are all hydrogen; R 8 * and R 7 * are hydrogen or together they designate an additional bond between the carbon atoms to which they are bound; and B* is either hydrogen or an acyl group, or a group which together with the remaining part of the molecule forms an ether.
3 . The method of claim 1 , wherein R 1 and R 2 are both hydrogen; both methyl; one is hydrogen and the other is methyl; or together designate methylene, or wherein R 1 and R 2 , together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring.
4 . The method of claim 1 , wherein R 1 is branched or unbranched C 1 -C 6 alkyl, optionally substituted by halogen, hydroxy or cyano, and wherein R 2 is branched or unbranched C 1 -C 6 alkyl, optionally substituted by halogen, hydroxy or cyano.
5 . The method of claim 1 , wherein R 3 is hydrogen, methylene, hydroxy, methoxy, acetoxy, halogen, oxo, ═NOH, or wherein R 3 is ═NOR 26 and R 26 is C 1 -C 3 alkyl, or wherein R 3 is hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton.
6 . The method of claim 1 , wherein R 3 , together with R 9 , designates an additional bond between the carbon atoms to which R 3 and R 9 are bound, or wherein R 3 , together with R 14 , designates an additional bond between the carbon atoms to which R 3 and R 14 are bound.
7 . The method of claim 1 , wherein R 4 is hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOH, ═NOR 27 , wherein R 27 is C 1 -C 3 alkyl, or wherein R 4 is hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or wherein R 4 , together with R 13 , designates an additional bond between the carbon atoms to which R 4 and R 13 are bound, or wherein R 4 , together with R 15 , designates an additional bond between the carbon atoms to which R 4 and R 15 are bound.
8 . The method of claim 1 , wherein R 5 is hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, oxo, ═NOH, ═NOR 22 , wherein R 22 is C—C 3 alkyl, wherein R 5 , together with R 6 , designates an additional bond between the carbon atoms to which R 5 and R 6 are bound.
9 . The method of claim 1 , wherein R 6 is hydrogen, or wherein R 6 , together with R 14 , designates an additional bond between the carbon atoms to which R 6 and R 14 are bound.
10 . The method of claim 1 , wherein R 9 is hydrogen, or wherein R 9 , together with R 10 , designates an additional bond between the carbon atoms to which R 9 and R 10 are bound.
11 . The method of claim 1 , wherein R 10 is hydrogen.
12 . The method of claim 1 , wherein R 1 is hydroxy, alkoxy, aralkyloxy, alkoxyalkoxy or alkanoyloxyalkyl, each group comprising a total of up to 10 carbon atoms, C 1 -C 4 alkoxy, methoxy, ethoxy, CH 3 OCH 2 O—, pivaloyloxymethoxy, an acyloxy group derived from an acid having from 1 to 20 carbon atoms, an acyloxy group selected from the group consisting of acetoxy, benzoyloxy, pivaloyloxy, butyryloxy, nicotinoyloxy, isonicotinoyloxy, hemi succinoyloxy, hemi glutaroyloxy, butylcarbamoyloxy, phenylcarbamoyloxy, butoxycarbonyloxy, tert-butoxycarbonyloxy and ethoxycarbonyloxy,
13 . The method of claim 1 , wherein R 11 is sulphonyloxy, phosphonyloxy, oxo, ═NOH, ═NOR 28 , wherein R 28 is C 1 -C 3 alkyl, or wherein R 11 is halogen, hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or wherein R 11 , together with R 12 , designates an additional bond between the carbon atoms to which R 11 and R 12 are bound.
14 . The method of claim 1 , wherein R 12 is hydrogen., C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or halogen.
15 . The method of claim 1 , wherein R 13 is hydrogen, or R 13 , together with R 14 , designates an additional bond between the carbon atoms to which R 13 and R 14 are bound.
16 . The method of claim 1 , wherein R 14 is hydrogen.
17 . The method of claim 1 , wherein R 15 is hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOH, or wherein R 15 is ═NOR 23 , and R 23 is C 1 -C 3 alkyl.
18 . The method of claim 1 , wherein R 16 is hydrogen, C 1 -C 3 alkyl, methylene, hydroxy, methoxy, oxo, ═NOH, or R 16 is ═NOR 24 , wherein R 24 is C 1 -C 3 alkyl, or R 16 , together with R 17 , designates an additional bond between the carbon atoms to which R 16 and R 17 are bound.
19 . The method of claim 1 , wherein R 17 is hydrogen or hydroxy.
20 . The method of claim 1 , wherein R 18 and R 19 are both hydrogen both fluoro, or one is fluoro and the other is hydrogen.
21 . The method of claim 1 , wherein R 25 is hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, or oxo.
22 . The method of claim 1 , wherein A is a carbon atom.
23 . The method of claim 1 , wherein R 7 is hydrogen, hydroxy, fluoro, or R 7 , together with R 8 , designates an additional bond between the carbon atoms to which R 7 and R 8 are bound.
24 . The method of claim 1 , wherein R 8 is hydrogen, C 1 -C 4 alkyl, methylene, or halogen
25 . The method of claim 1 , wherein R 20 is C 1 -C 4 alkyl, trifluoromethyl, or C 3 -C 6 cycloalkyl.
26 . The method of claim 1 , wherein R 21 is C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, or C 3 -C 6 cycloalkyl.
27 . The method of claim 1 , wherein R 20 and R 21 , together with the carbon atom to which they are bound, form a C 3 -C 6 cycloalkyl ring.
28 . The method of claim 1 , wherein A is a nitrogen atom.
29 . The method of claim 28 , wherein R 8 is hydrogen. C 1 -C 4 alkyl, or oxo.
30 . The method of claim 28 , wherein R 20 and R 21 independently, are selected from the group consisting of C 1 -C 4 alkyl, cyclopropyl, cyclopentyl and cyclohexyl.
31 . The method of claim 1 , wherein the germ cell is an oocyte.
32 . The method of claim 31 , wherein the compound is administered to an oocyte ex vivo.
33 . The method of claim 31 , wherein the germ cell is a male germ cell.
34 . A method of producing mature male germ cells by administration of a compound to testicular tissue, wherein the compound is a compound of formula (I)
wherein R 1 and R 2 , independently, are selected from the group consisting of hydrogen and branched or unbranched C 1 -C 6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R 1 and R 2 together designate methylene or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R 3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR 26 wherein R 26 is hydrogen or C 1 -C 3 alkyl, halogen, and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 3 designates, together with R 9 or R 14 , an additional bond between the carbon atoms to which R 3 and R 9 or R 14 are bound; R 4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR 27 wherein R 27 is hydrogen or C 1 -C 3 alkyl, halogen, and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 4 designates, together with R 13 or R 15 , an additional bond between the carbon atoms to which R 4 and R 13 or R 15 are bound; R 5 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, oxo, and ═NOR 22 wherein R 22 is hydrogen or C 1 -C 3 alkyl, or R 5 designates, together with R 6 , an additional bond between the carbon atoms to which R 5 and R 6 are bound; R 6 is hydrogen or R 6 designates, together with R 5 , an additional bond between the carbon atoms to which R 5 and R 6 are bound; R 9 is hydrogen or R 9 designates, together with R 3 or R 10 , an additional bond between the carbon atoms to which R 9 and R 3 or R 10 are bound; R 10 is hydrogen or R 10 designates, together with R 9 , an additional bond between the carbon atoms to which R 10 and R 9 are bound; R 11 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, ═NOR 28 wherein R 28 is hydrogen or C 1 -C 3 alkyl, halogen and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 11 designates, together with R 12 , an additional bond between the carbon atoms to which R 11 and R 12 are bound; R 12 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, vinyl, C 1 -C 3 alkoxy and halogen, or R 12 designates, together with R 11 , an additional bond between the carbon atoms to which R 12 and R 11 are bound; R 13 is hydrogen or R designates, together with R 4 or R 14 , an additional bond between the carbon atoms to which R 13 and R 4 or R 14 are bound; R 14 is hydrogen or R designates, together with R 3 , R 6 or R 13 , an additional bond between the carbon atoms to which R 14 and R 3 or R 6 or R 13 are bound; R 13 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and ═NOR 23 wherein R 23 is hydrogen or C 1 -C 3 alkyl, or R 13 designates, together with R 4 , an additional bond between the carbon atoms to which R 15 and R 4 are bound; R 16 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, methylene, hydroxy, methoxy, oxo and ═NOR 24 wherein R 24 ishydrogenor C 1 -C 3 alkyl, or R 6 designates, together with R 7 , an additional bond between the carbon atoms to which R 16 and R 17 are bound; R 17 is hydrogen or hydroxy or R 17 designates, together with R 16 , an additional bond between the carbon atoms to which R 17 and R 16 are bound; R 18 and R 19 are, independently, hydrogen or fluoro; R 25 is selected from the group consisting of hydrogen, C 1-4 alkyl, methylene, hydroxy and oxo; A is a carbon atom or a nitrogen atom; when A is a carbon atom, R 7 is selected from the group consisting of hydrogen, hydroxy and fluoro, and R 8 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene and halogen, or R 7 designates, together with R 8 , an additional bond between the carbon atoms to which R 7 and R 8 are bound; R 20 is selected from the group consisting of C 1 -C 4 alkyl, trifluoromethyl and C 3 -C 6 cycloalkyl and R 21 is selected from the group consisitning of C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C 3 -C 6 cycloalkyl, or R 20 and R 21 , together with the carbon atom to which they are bound, form a C 3 -C 6 cycloalkyl ring; and when A is a nitrogen atom, R 7 designates a lone pair of electrons and R 8 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and oxo; R 20 and R 21 are, independently, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; provided that the compound of formula (1) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
Cholest-7-ene-3β-ol; 4-Methylcholest-7-ene-3β-ol; 4-Ethylcholest-7-ene-3β-ol; 4,4-Dimethylcholest-7-ene-3β-ol; 4α-Methyl-4β-ethylcholest-7-ene-3β-ol; 4α-Ethyl-4β-methylcholest-7-ene-3β-ol; 4,4-Diethylcholest-7-ene-3β-ol; 4-Propylcholest-7-ene-3β-ol; 4-Butylcholest-7-ene-3β-ol; 4-Isobutylcholest-7-ene-3β-ol; 4,4-Tetramethylenecholest-7-ene-3β-ol; 4,4-Pentamethylenecholest-7-ene-3β-ol; Cholest-8-ene-3β-ol;
4-Methylcholest-8-ene-3β-ol; 4-Ethylcholest-8-ene-3β-ol; 4,4-Dimethylcholest-8-ene-3β-ol; 4α-Methyl-4β-ethylcholest-8-ene-3β-ol; 4β-Ethyl-4β-methylcholest-8-ene-3β-ol; 4,4-Diethylcholest-8-ene-3β-ol;
4-Propylcholest-8-ene-3β-ol; 4-Butylcholest-8-ene-3β-ol; 4-Isobutylcholest-8-ene-3β-ol; 4,4-Tetramethylenecholest-8-ene-3β-ol; 4,4-Pentamethylenecholest-8-ene-3β-ol; Cholest-8(14)-ene-3β-ol;
4-Methylcholest-8(14)-ene-3β-ol; 4-Ethylcholest-8(14)-ene-3β-ol; 4,4-Dimethylcholest-8(14)-ene-3β-ol;
4-Methyl-4β-ethylcholest-8(14)-ene-3β-ol; 4α-Ethyl-4β-methylcholest-8(14)-ene-3β-ol;
4,4-Diethylcholest-8(14)-ene-3β-ol; 4-Propylcholest-8(14)-ene-3β-ol; 4-Butylcholest-8(14)-ene-3β-ol;
4-Isobutylcholest-8(14)-ene-3β-ol; 4,4-Tetramethylenecholest-8(14)-ene-3β-ol; 4,4-Pentamethylenecholest-8(14)-ene-3β-ol; Cholesta-8,14-diene-3β-ol; 4-Methylcholesta-8,14-diene-3β-ol; 4-Ethylcholesta-8,14-diene-3β-ol; 4,4-Dimethylcholesta-8,14-diene-3β-ol; 4α-Methyl-40-ethylcholesta-8,14-diene-3β-ol; 4α-Ethyl-40-methylcholesta-8,14-diene-3β-ol; 4,4-Diethylcholesta-8,14-diene-3β-ol; 4-Propylcholesta-8,14-diene-3β-ol;
4-Butylcholesta-8,14-diene-3β-ol; 4-Isobutylcholesta-8,14-diene-3β-ol; 4,4-Tetramethylenecholesta-8,14-diene-3β-ol; 4,4-Pentamethylenecholesta-8,14-diene-3β-ol; Cholesta-8,24-diene-3β-ol; 4-Methylcholesta-8,24-diene-3β-ol; 4-Ethylcholesta-8,24-diene-3β-ol; 4,4-Dimethylcholesta-8,24-diene-3β-ol; 4α-Methyl-4β-ethylcholesta-8,24-diene-3β-ol; 4α-Ethyl-4β-methylcholesta-8,24-diene-3β-ol; 4,4-Diethylcholesta-8,24-diene-3β-ol; 4-Propylcholesta-8,24-diene-3β-ol; 4-Butylcholesta-8,24-diene-3β-ol; 4-Isobutylcholesta-8,24-diene-3β-ol;
4,4-Tetramethylenecholesta-8,24-diene-3β-ol; 4,4-Pentamethylenecholesta-8,24-diene-3β-ol; Cholesta-8,14,24-triene-3β-ol; 4-Methylcholesta-8,14,24-triene-3β-ol; 4-Ethylcholesta-8,14,24-triene-3β-ol; 4,4-Dimethylcholesta-8,14,24-triene-3β-ol; 4α-Methyl-4β-ethylcholesta-8,14,24-triene-3β-ol; 4α-Ethyl-4β-methylcholesta-8,14,24-triene-3β-ol; 4,4-Diethylcholesta-8,14,24-triene-3β-ol; 4-Propylcholesta-8,14,24-triene-3β-ol; 4-Butylcholesta-8,14,24-triene-3β-ol; 4-Isobutylcholesta-8,14,24-triene-3β-ol; 4,4-Tetramethylenecholesta-8,14,24-triene-3β-ol; and 4,4-Pentamethylenecholesta-8,14,24-triene-3β-ol; and esters and ethers thereof.
36 . A method of promoting meiotic maturation in an oocyte, comprising culturing the oocyte in the presence of a compound of formula (I)
wherein R 1 and R 2 , independently, are selected from the group consisting of hydrogen and branched or unbranched C 1 -C 6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R 1 and R 2 together designate methylene or, together with the carbon atom to which they are bound, formula cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R 3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR 26 wherein R 26 is hydrogen or C 1 -C 3 alkyl, halogen, and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 3 designates, together with R 9 or R 14 , an additional bond between the carbon atoms to which R 3 and R 9 of R 14 are bound; R 4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, ═NOR 27 wherein R 27 is hydrogen or C 1 -C 3 alkyl, halogen, and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 4 designates, together with R 13 or R 15 , a additional bond between the carbon atoms to which R 4 and R 13 or R 15 are bound; R 5 is selected from the group consisting, of hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, oxo, and ═NOR 22 wherein R 22 is hydrogen or C 1 -C 3 alkyl, or R 5 designated, together with R 6 , an additional bond between the carbon atoms to which R 5 and R 6 are bound; R 6 is hydrogen or R 6 designates, together with R 5 , an additional bond between the carbon atoms to which R 5 and R 6 are bound; R 9 is hydrogen or R 9 designates, together with R 3 or R 10 , an additional bond between the carbon atoms to which R 9 and R 3 or R 10 are bound; R 10 is hydrogen or R 10 designates, together with R 9 , an additional bond between the carbon atoms to which R 10 and R 9 are bound; R 11 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, ═NOR 28 wherein R 28 is hydrogen or C 1 -C 3 alkyl, halogen and hydroxy and C 1 -C 4 alkyl bound to the same carbon atom of the sterol skeleton, or R 11 designates, together with R 12 , an additional bond between the carbon atoms to which R 11 and R 12 are bound; R 12 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, vinyl, C 1 -C 3 alkoxy and halogen, or R 12 designates, together with R 1 , an additional bond between the carbon atoms to which R 12 and R 11 are bound; R 13 is hydrogen or R 13 designates, together with R 4 or R 14 , an additional bond between the carbon atoms to which R 13 and R 4 or R 14 are bound; R 14 is hydrogen or R 1 designates, together with R 3 , R 6 or R 13 , an additional bond between the carbon atoms to which R 14 and R 3 or R 6 or R 13 are bound; R 15 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and ═NOR 23 wherein R 23 is hydrogen or C 1 -C 3 alkyl, or R designates, together with R 4 , an additional bond between the carbon atoms to which R 15 and R 4 are bound; R 16 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, methylene, hydroxy, methoxy, oxo and ═NOR 24 wherein R 24 is hydrogen or C 1 -C 3 alkyl, or R 16 designates, together with R 17 , an additional bond between the carbon atoms to which R 16 and R 17 are bound; R 17 is hydrogen or hydroxy or R 17 designates, together with R 16 , an additional bond between the carbon atoms to which R 17 and R 16 are bound; R 18 and R 19 are, independently, hydrogen or fluoro; R 25 is selected from the group consisting of hydrogen, C 1-4 alkyl, methylene, hydroxy and oxo; A is a carbon atom or a nitrogen atom; when A is a carbon atom, R 7 is selected from the group consisting of hydrogen, hydroxy and fluoro, and R 8 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, methylene and halogen, or R 7 designates, together with R 8 , an additional bond between the carbon atoms to which R 7 and R 8 are bound; R 20 is selected from the group consisting of C 1 -C 4 alkyl, trifluoromethyl and C 3 -C 6 cycloalkyl and R 21 is selected from the group consisitning of C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C 3 -C 6 cycloalkyl, or R 20 and R 21 , together with the carbon atom to which they are bound, form a C 3 -C 6 cycloalkyl ring; and when A is a nitrogen atom, R 7 designates a lone pair of electrons and R 8 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and oxo; R 20 and R 21 are, independently, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; provided that the compound of formula (1) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
Cholest-7-ene-3β-ol; 4-Methylcholest-7-ene-3β-ol; 4-Ethylcholest-7-ene-3β-ol; 4,4-Dimethylcholest-7-ene-3β-ol; 4α-Methyl-4β-ethylcholest-7-ene-3β-ol; 4α-Ethyl-4β-methylcholest-7-ene-3β-ol; 4,4-Diethylcholest-7-ene-3β-ol; 4-Propylcholest-7-ene-3β-ol; 4-Butylcholest-7-ene-3β-ol; 4-Isobutylcholest-7-ene-3β-ol; 4,4-Tetramethylenecholest-7-ene-3β-ol; 4,4-Pentamethylenecholest-7-ene-3β-ol; Cholest-8-ene-3β-ol;
4-Methylcholest-8-ene-3β-ol; 4-Ethylcholest-8-ene-3β-ol; 4,4-Di methylcholest-8-ene-3β-ol; 4α-Methyl-4β-ethylcholest-8-ene-3β-ol; 4α-Ethyl-4β-methylcholest-8-ene-3β-ol; 4,4-Diethylcholest-8-ene-3β-ol;
4-Propylcholest-8-ene-3β-ol; 4-Butylcholest-8-ene-3β-ol; 4-lsobutylcholest-8-ene-3β-ol; 4,4-Tetramethylenecholest-8-ene-3β-ol; 4,4-Pentamethylenecholest-8-ene-3β-ol; Cholest-8(14)-ene-3β-ol;
4-Methylcholest-8(14)-ene-3β-ol; 4-Ethylcholest-8(14)-ene-3β-ol; 4,4-Dimethylcholest-8(14)-ene-3β-ol;
4α-Methyl-4′-ethylcholest-8(14)-ene-3β-ol; 4α-Ethyl-4β-methylcholest-8(14)-ene-3β-ol;
4,4-Diethylcholest-8(14)-ene-3β-ol; 4-Propylcholest-8(14)-ene-3β-ol; 4-Butylcholest-8(14)-ene-3β-ol;
4-Isobutylcholest-8(14)-ene-3β-ol; 4,4-Tetramethylenecholest-8(14)-ene-3β-ol; 4,4-Pentamethylenecholest-8(14)-ene-3β-ol; Cholesta-8,14-diene-3β-ol; 4-Methylcholesta-8,14-diene-3β-ol; 4-Ethylcholesta-8,14-diene-3β-ol; 4,4-Dimethylcholesta-8,14-diene-3β-ol; 4α-Methyl-4′-ethylcholesta-8,14-diene-3β-ol; 4αEthyl-4′-methylcholesta-8,14-diene-3β-ol; 4,4-Diethylcholesta-8,14-diene-3β-ol; 4-Propylcholesta-8,14-diene-3β-ol;
4-Butylcholesta-8,14-diene-3β-ol; 4-Isobutylcholesta-8,14-diene-3β-ol; 4,4-Tetramethylenecholesta-8,14-diene-3β-ol; 4,4-Pentamethylenecholesta-8,14-diene-3β-ol; Cholesta-8,24-diene-3β-ol; 4-Methylcholesta-8,24-diene-3β-ol; 4-Ethylcholesta-8,24-diene-3β-ol; 4,4-Dimethylcholesta-8,24-diene-3β-ol; 4α-Methyl-4′-ethylcholesta-8,24-diene-3β-ol; 4α-Ethyl-4β-methylcholesta-8,24-diene-3β-ol; 4,4-Diethylcholesta-8,24-diene-3β-ol; 4-Propylcholesta-8,24-diene-3β-ol; 4-Butylcholesta-8,24-diene-3β-ol; 4-Isobutylcholesta-8,24-diene-3β-ol;
4,4-Tetramethylenecholesta-8,24-diene-3β-ol; 4,4-Pentamethylenecholesta-8,24-diene-3β-ol; Cholesta-8,14,24-triene-3β-ol; 4-Methylcholesta-8,14,24-triene-3β-ol; 4-Ethylcholesta-8,14,24-triene-3β-ol; 4,4-Dimethylcholesta-8,14,24-triene-3β-ol; 4α-Methyl-4β-ethylcholesta-8,14,24-triene-3β-ol; 4α-Ethyl-4β-methylcholesta-8,14,24-triene-3β-ol; 4,4-Diethylcholesta-8,14,24-triene-3β-ol; 4-Propylcholesta-8,14,24-triene-3β-ol; 4-Butylcholesta-8,14,24-triene-3β-ol; 4-Isobutylcholesta-8,14,24-triene-3β-ol; 4,4-Tetramethylenecholesta-8,14,24-triene-3β-ol; and 4,4-Pentamethylenecholesta-8,14,24-triene-3β-ol;
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