Meiosis regulating compounds

FIELD OF THIS INVENTION

[0002] The present invention relates to pharmacologically active compounds and to their use as medicaments. More particularly it has been found that the sterol derivatives described herein can be used for regulating meiosis.

BACKGROUND OF THIS INVENTION

[0003] In L. F. Fieser & M. Fieser: Steroids; Reinhold Publishing Corporation, 1967, 5α-bromocholest-ane-3β,6β-diol; 7α-bromocholestane-3β,6α-diol; 7α-bromocholestane-3β,6βdiol; 7α-bromo-cholestane-3β,5α-diol-6-one; 7pbromocholestane-3β,5α-diol-6-one; 3β-bromocholestane-2α-ol; 5α-chlorocholestane-3β,6α-diol; 5α-chlorocholestane-3β,6β-diol; 6β-chlorocholestane-3β,-5α-diol; Δ7,9(11)-cholestadiene-3β,6α-diol; Δ7,9(11)-cholestadiene-3β,6βdiol; cholestane-2α,3α-diol; cholestane-2α,3β-diol; cholestane-2β,3α-diol; cholestane-2β,3β-diol; cholestane-3α,4α-diol; cholestane-3α,4β-diol; cholestane-3β,4β-diol; cholestane-3α,5α-diol; cholestane-3β,5α-diol; cholestane-3β,6α-diol; cholestane-3β,6β-diol; cholestane-3β,22α-diol, cholestane-3β,22β-diol; cholestane-3β,7α,8α-triol; Δ5-cholestene-3β, 4α-diol; Δ5-cholestene-3β,4β-diol; Δ5-cholestene-3β,20α-diol; Δ5-cholestene-3β,22α-diol; Δ5-cholestene-3β,22β-diol; Δ5-cholestene-3β,24α-diol; Δ5-cholestene-3β,24β-diol; Δ6-cholestene-3β,5α-diol; Δ8(14)-cholestene-3β,9α-diol; Δ11-cholestene-3α,24-diol; Δ5-cholestene-3β,6-diol-7-one; Δ5-cholestene-4α-ol-3-one; Δ5-cholestene-3β,4β,7α-triol; coprostane-3α,5β-diol; coprostane-3β,5β-diol; coprostane-3β,6β-diol; coprostane-4β,5β-diol-3-one and 20β-hydroxy-20-isocholesterol are mentioned in the subject index.

[0004] In German patent application having publication no. 1,183,079, a process for preparing 4α-hydroxy-5a-cholestan-3-one is mentioned in Example 5. This compound is not stated to have any utility other than as an intermediate.

[0005] In German patent application having publication no. 1,224,738, cholestan-3β,5α,6β-triol-3β-hemisuccinate; cholestan-3β,5α,6β-triol-3β-hemisuccinate-6β-acetate; cholestan-3β,5α,6β-triol-3β-hemisuccinate-6β-formiate; cholestan-3β,5α,6β-triol-3β-sulphate and cholestan-3β,5α,6β-triol-3β-phosphate are mentioned in Examples 1-5, respectively. It is mentioned that the compounds described therein can be used for the treatment of arteriosclerosis.

[0006] In German patent application having publication no. 2,201,991 C2, a process for the preparation of insecticides such as 2β,3β,14α,22(R),25-pentahydroxycholest-7-en-6-one is described.

[0007] German patent application having publication no. 2,236,778 B2 relates to a novel insecticide, i.e., cholest-7-en-2β,3β,5β, 11α,14α,20(R)-heptahydroxy-6-one.

[0008] In German patent application having publication no. 2,409,971 B2, 5,24-cholestadien-3β-ol; 5-cholesten-3β,24,25-triol-3β-acetate; 5-cholesten-3β,24,25-triol-3β,24-diacetate; 5,25-cholestadien-3β-ol acetate; 5-cholesten-3β,25,26-triol-3β-acetate and 5-cholesten-3β,25,26-triol are mentioned in Examples 1, 1, 2, 3, 3 and 6, respectively. It is mentioned that the compounds described therein are valuable intermediates for the technical preparation of 24,25(or 25,26)-dihydroxycholecalciferol.

[0009] In German patent application having publication no. 2,453,648B2, cholest-5α-an-3β,6α-diol; cholest-5β-an-3β,6β-diol; cholest-5α-an-3,6-dione; cholest-5α-an-6β-ol-3-one and cholest-5α-an-2α-bromo-6β-ol-3-one are mentioned as intermediates in column 6.

[0010] In German patent application having publication no. 2,415,676, cholestan-3p,25-diol-3β-acetate; cholestan-3β,5α,25-triol-3β-acetate; cholestan-3β,5α,25-triol; cholestan-5α,25-diol-3-one; cholest-4-en-25-ol-3-one and cholesta-4,6-dien-25-ol-3-one are mentioned as compounds III, IV, X, Xl XII and XIII, respectively. It is suggested that the compounds described therein may be substantially stronger that vitamin D3.

[0011] In German patent application having publication no. 2,546,715 A1, a process for preparing 1α,3βdihydroxycholest-5-en and 1α,3β-dihydroxycholest-6-en is mentioned in Example 1 (compounds V and II). It is suggested that the compounds described therein are useful additives to foodstuff and can be used in vitamin compositions.

[0012] In German patent application having publication no. 2,822,486A1, 3α,6α-dihydroxy-5β-cholestan-24-one; 3α,6α,24-trihydroxy-5β-cholestan; 3-chlorocholest-5,24-dien; 3β-hydroxycholest-5-en-24-on acetate and 3-chlorocholest-5-en-24-on are mentioned in Example 3,4,5a and 6c and as formula VlI, respectively. It is mentioned that the compounds described therein can be used as intermediates for the preparation of desmosterin, derivatives thereof and other active vitamin D.

[0013] In German patent application having publication no. 3,241,172 A1, cholestan-25-fluoro-3β,22(S)-diol; cholestan-25-chloro-3β,22(S)-diol; cholestan-25-methyl-3β,22-diol; cholestan-25-methyl-3β,22-diol-3-hydrogenbutandioate and cholestan-25-methyl-3β,22-diol-bis-hydrogenbutandioate are mentioned in claims 2, 3, 5, 6 and 7, respectively. It is mentioned that the compounds described therein inhibit the activity of HMGCOA reductase and the formation of blood cholesterol.

[0014] In German patent application having publication no. 3,390,016C2, a process for preparing 1α,25-dihydroxy-26,26,26,27,27,27-hexafluorocholes-5-en is described. It is mentioned that this compound can easily be converted into a compound having vitamin D3 like activity.

[0015] In Danish patent application having publication no. 123,767, a process for preparing 2β,3β,14α,22,25-pentahydroxy-Δ7-5β-cholesten-6-one is mentioned. It is mentioned that the compounds described therein have an action on the central nervous system.

[0016] In European patent application having publication no. 15,122 B1, 25-hydroxy-3β-[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 3β[(tetrahydro-2H-pyran-2-yI)oxylcholest-5-en-24-on; 25-hydroxy-24-oxocholesterol-3β-acetate; 24-oxocholesterol-3β-acetate; 25-hydroxy-24-oxocholesterol; 24,25-dihydroxycholesterol; 3α,6α,25-trihydroxy-24-oxo-5β-cholestane; 1α,25-dihydroxy-24-oxocholesterol; 1α,24,25-trihydroxycholesterol; 3β-hydroxy-24-oxo-cholesta-5,7-dien; 3β,25-dihydroxy-24-oxocholesta-5,7-dien; 3β-hydroxy-24-oxocholesta-5,7-dien; 1α,3β-dihydroxy-24-oxocholesta-5,7-dien and 1α,3β,25-trihydroxy-24-oxocholesta-5,7-dien are mentioned in Examples 1, 1, 4, 4, 5ii, 5(1), 6i, 7, 7(2), 8iii, 8iv, 8iv, 9iii and 9iv, respectively. It is mentioned that the compounds described therein are useful intermediates convertible into active vitamin D3.

[0017] In European patent application having publication :no. 63,678B1, (24R)-3β,24,25-trihydroxycholest-5-en; (24RS)-3β,24,25-trihydroxycholest-5-en and (24R)-1β,3β,24,25-tetrahydroxycholest-5-en are mentioned in Examples 1e, 3e and 4f, respectively. It is mentioned that the compounds described therein can be used as intermediates in the preparation of vitamin D3 derivatives.

[0018] In European patent application having publication no. 322,036A1, 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholesta-8,14-dien-2α,11β-diol; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholest-8-en-2α,11β-diol; 4,4-dimethyl-24-methylene-12α-acetoxycholesta-8,14-dien-2α,3β,11β-triol; 4,4-dimethyl-24-methylene-12α-acetoxy-cholesta-8,14-dien-3β,11β-diol; 4,4-dimethyl-24-methylene-1 2c-acetoxycholest-8-en-2α,3β,11β-triol; 4,4-dimethyl-24-methylene-12α-acetoxycholest-8-en-3β,11β-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3β,11β,12α-tetraol; 4,4-d imethyl-24-methylene-3β-sulphooxycholesta-8,14-dien-2α, 11β,12α-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2α,3β,11β,12α-tetraol; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholest-8-en-2-ol-11-one and mono(4,4-dimethyl-24-methylene-12α-acetoxycholesta-8,14-dien-2α,11β-diol)-3β-succinate are described in Tables I (1+2), II (5-9) and III (11-14). It is mentioned that the compounds described therein are anti-inflammatory.

[0019] In European patent application having publication no. 349,869A2, 1α,3β-dihydroxycholest-5-ene and 1α,3β,24-trihydroxycholest-5-ene are mentioned in Examples 1 and 2, respectively. It is mentioned that the latter compound is useful for the production of 1α,24-dihydroxy-vitamin D3.

[0020] In British patent application having publication no. 2,089,810 A, cholesta-5,7-diene-3β,23(F),25-triol and cholesta-5,7-diene-3β,23(S),25-triol are mentioned in Example 1. It is mentioned that the compounds described therein should find application as a substitute for 25-hydroxy vitamin D3 in various therapeutic applications.

[0021] In Norwegian patent application having publication no. 144,264, 1α,3β-dihydroxycholest-5-en and 1α,3β,25-trihydroxycholest-5-en are mentioned in Example 1 and 3, respectively. it is mentioned that the compounds described therein can be used within the veterinary field.

[0022] In Swedish patent application having publication no. 314,978, a process wherein Δ7-cholesten-2β,3β-diol-6-one is used as starting material (for the preparation of Δ7-koprosten-2β,3β,14α-triol-6-one) is described in Example 3. The latter compound is active against insecticide metamorfose hormones.

[0023] In Swedish patent application having publication no. 330,883, 2β,3β, 14α,22(R),25-pentahydroxy-Δ7-5β-cholesten-6-one and 2β,3β,14α,22(S),25-pentahydroxy-Δ7-5β-cholesten-6-one are mentioned in Examples 4 and 5, respectively. It is mentioned that the compounds described therein have valuable pharmacological properties; however, none is specified.

[0024] In Swedish patent application having publication no. 430,508, cholest-5-en-3β,22(R,S),25-triol; cholest-5-en-25-fluoro-3β,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3β-semisuccinate; cholest-5-en-25-chloro-3β,22-diol and cholest-5-en-25-chloro-22-ol-3β-hemisuccinate are mentioned in Examples 5, 8, 9, 11 and 12, respectively. It is mentioned that the compounds described therein have pharmaceutical activities, e.g., inhibiting (HMG-CoA) reductase.

[0025] In U.S. Pat. No. 3,931,403, 3α,7α,12α,24,25-pentahydroxy coprostane; 3α,7α, 12α,25-tetrahydroxy coprostane; 3α,7α,25-trihydroxy coprostane; 3α,7α,24,25-tetrahydroxy coprostane; 5β-cholestane-3α,7α,12α,24α,25-pentol; 5β-cholestane-3α,7α,-12α,24β,25-pentol; 5β-cholestane-3α,7α,12α,25,26-pentol and 5,3cholestane-3α,7α,12α,25-tetrol are mentioned in Examples I and II. It is mentioned that the compounds described therein can be used to prepare a composition possessing antimicrobial, antibiotic and bacteriostatic properties.

[0026] In U.S. Pat. No. 4,011,250, 1α,2α,3β-trihydroxycholesta-5,7-diene and 1α,2α-dihydroxy-3β-acetoxycholesta-5-ene are described as intermediates in Example 1 and 3, respectively.

[0027] In U.S. Pat. No. 4,254,045, cholest-5-en-2,fluoro-1 a,3,diol is mentioned as compound 3. It is mentioned that the compounds described therein have vitamin D-like activity.

[0028] In U.S. Pat. No. 4,329,295, the preparation of 24-cyclopropylchol-5-ene-3β,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3β,22(S)-diol, 24-cyclopropylchol-5-ene-3β,22(S)-diol 3 hydrogen butanedioate and 24-cyclopropyl-5a-cholane-3β,22(S)-diol is described in Examples 3-6, respectively. It is mentioned that the compounds described therein inhibit the activity of HMG Co A reductase.

[0029] In U.S. Pat. No. 4,670,190, cholesta-1,4,6-trien-3-one; 1α,3β-dihydroxycholest-5-ene; 1α,3β-dihydroxy-5α-cholestane; 1α,3β-dihydroxycholesta-5,7-diene 1α,3β-25-trihydroxycholest-5-ene; 1α,25-dihydroxycholesterol; and 1α,25-dihydroxycholesterol-3-benzoate are described in Examples 1a, 1c, 2b′, 3c, 4c, 9b and 9c, respectively. It is mentioned that the compounds described therein have therapeutic applications.

[0030] Other known compounds are cholest-5-en-35,20(S)-diol (Sigma, St. Louis, Mo, USA, Cat. No. H 6378), cholest-5-en-3p,22(S)-diol, (Sigma, St. Louis, Mo, USA, Cat. No. H 5884), cholest-5-en-3β,4β-diol (Steraloid Inc., Wilton, N.H., USA, Cat. No. C 6410, Batch L 1066), cholest-5-en-3β,22(R)-diol (Sigma, St. Louis, Mo., USA, Cat. No. H 9384) and 2β,3β,14α22(R),25-pentahydroxycholest-7-en-6-one.

[0031] In none of the above publications is there any mentioning of the compounds being able to regulate meiosis. The content of the above publications is incorporated by reference.

[0032] Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1 n) of chromosomes and 2c DNA. The second rneiotic division proceeds without a DNA synthesis. This division therefore results in the formation of the haploid germ cells with only 1 c DNA.

[0033] The meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly. All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty. Thus, from early life the female has a stock of oocytes which is drawn upon until the stock is exhausted. Meiosis in females is not completed until after fertilization, and results ii, only one ovum and two abortive polar bodies per germ cell. In contrast, only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces 4 spermatozoa.

[0034] Only little is known about the mechanisms which control the initiation of meiosis in the male and in the female. In the oocyte, new studies indicate that follicular purines, hypoxanthine or adenosine, could be responsible for meiotic arrest (Downs, S. M. et al. Dev Biol 82 (1985) 454-458; Eppig, J.J. et al. Dev Biol 119 (1986) 313-321; and Downs, S. M. Mol Reprod Dev 35 (1993) 82-94). The presence of a diffusible meiosis regulating substance was first described by Byskov et aL in a culture system of fetal mouse gonads (Byskov, A. G. et al. Dev Biol 52 (1976) 193-200). A meiosis activating substance (MAS) was secreted by the fetal mouse ovary in which meiosis was ongoing, and a meiosis preventing substance (MPS) was released from the morphologically differentiated testis with resting, non-meiotic germ cells. It was suggested that the relative concentrations of MAS and MPS regulated the beginning, arrest and resumption of meiosis in the male and in the female germ cells (Byskov, A. G. et al. in The Physiology of Reproduction (eds. Knobil, E. and Neill, J. D., Raven Press, New York (1994)). Clearly, if meiosis can be regulated, reproduction can be controlled. A recent article (Byskov, A. G. et aL Nature 374 (1995), 559-562) describes the isolation from bull testes and from human follicular fluid of certain sterols that activate oocyte meiosis. Unfortunately, these sterols are rather labile and utilization of the interesting finding would thus be greatly facilitated if more stable meiosis activating compounds were available.

[0035] Compounds being known to stimulate the meiosis and being different from the compounds claimed in the present patent application are described in WO 96/27658.

[0036] The compounds described herein have advantages compared with the known compounds.

SUMMARY OF THE INVENTION

[0037] It is a purpose of the present invention to provide compounds and methods useful for relieving infertility in females and males, particularly in mammals, more particularly in humans.

[0038] It is a further purpose of the present invention to provide compounds and methods useful as contraceptives in females and males, particularly in mammals, more particularly in humans.

[0039] According to the present invention there are provided novel compounds with interesting pharmacological properties. In particular, the compounds of formula 1a, 1b and 1c are useful for regulating the meiosisin oocytes and in male germ cells.

[0040] In one aspect, the present invention relates to compounds of formula 1a:

[0041] wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected fromn the group comprising hydrogen, halogen, hydroxy and branched or unbranched C1-C6alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 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; R3 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and =NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R14, an additional bond between the carbon atoms at which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R13, an additional bond between the carbon atoms at which R4 and R3 or R6or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and =NOR23 whereir, R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and =NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R16 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R8 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl, R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8 R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl and with the further general proviso that R9, R10 and R11 are not all hydroxy and with the further general proviso that it is not 5α-bromocholestane-3β,6β-diol; 7α-bromo-cholestane-3β,6α-diol; 7α-bromocholestane-3β,6β-diol; 7α-bromocholestane-3β,5α-diol-6-one; 7β-bromocholestane-3β,5α-diol-6-one; 3β-bromocholestane-2α-ol; 5α-chlorocholestane-3β,6α-diol; 5α-chlorocholestane-3β,6β-diol; 6β-chlorocholestane-3β,5α-diol; Δ7,9(11)-cholestadiene-3β-6α-diol; Δ7,9(11)-cholestadiene-3β,6β-diol; cholestane-2α,3α-diol; cholestane-2α,3β-diol; cholestane-2β,3α-diol; cholestane-2β,3β-diol; cholestane-3α,4α-diol; cholestane-3α,4β-diol; cholestane-3β,4β-diol; cholestane-3α,5α-diol; cholestane-3β,5α-diol; cholestane-3β,6α-diol; cholestane-3β,6β-diol; cholestane-3β,22α-diol; cholestane-3β,22β-diol; cholestane-3β,7α,8α-triol; triol; Δ5-cholestene-3β,4α-diol; Δ5-cholestene-3β,4β-diol; Δ5-cholestene-3β,20α-diol; Δ5-cholestane-3β,22α-diol; Δ5-cholestene-3β,22β-diol; Δ5-cholestene-3β,24α-diol; Δ5-cholestene-3β,24β-diol; Δ6-cholestene-3β,5α-diol; Δ8(14)-cholestene-3β,9α-diol; Δ11-cholestene-3α,24-diol; Δ5-cholestene-3β,6-diol-7-one; Δ5-cholestene-4α-ol-3-one; Δ5-cholestene-3β,4β,7α-triol; coprostane-3α,5β-diol; coprostane-3β,5β-diol; coprostane-3β,6β-diol; coprostane-4β5β-diol-3-one; 20βhydroxy-20-isocholesterol; 4α-hydroxy-5α-cholestan-3-one; cholestan-3β,5α,6β-triol-3β-hemisuccinate; cholestan-3β,5α,6β-triol-3β-hemisuccinate-6pacetate; cholestan-3β,5α,6β-triol-3β-hemisuccinate-6β-formiate; cholestan-3β,5α,6β-triol-3β-sulphate; cholestan-3β,5α,6β-triol-3β-phosphate; 2β,3β,14α,22(R),25-pentahydroxycholest-7-en-6-one; cholest-7-en-2β,3β,5β,11α,14α,20(R),22(R)-heptahydroxy-6-one; 5,24-cholestadien-3β-ol; 5-cholesten-3β,24,25-triol-3β-acetate; 5-cholesten-3β,24,25-triol-3β,24-diacetate; 5,25-cholestadien-3β-ol acetate; 5-cholesten-3β,25,26-triol-3β-acetate; 5-cholesten-3β,25,26-triol; 24,25(or 25,26)-dihydroxy-cholecalciferol; cholest-5α-an-3β,6α-diol; cholest-5β-an-3β,6β-diol; cholest-5α-an-3,6-dione; cholest-5α-an-6β-ol-3-one; cholest-5α-an-2α-bromo-6β-ol-3-one; cholestan-3β,25-diol-3β-acetate; cholestan-3β,5α,25-triol-3β-acetate; cholestan-3β,5α,25-triol; cholestan-5α,25-diol-3-one; cholest4-en-25-ol-3-one; cholesta-4,6-dien-25-ol-3-one; 1α,3β-dihydroxycholest-5-en; 1α,3β-dihydroxycholest-6-en; 3α,6α-dihydroxy-5β-cholestan-24-one; 3α,6α,24-trihydroxy-5βcholestan; 3-chlorocholest-5,24-dien; 3β-hydroxycholest-5-en-24-on acetate; 3-chlorocholest-5-en-24-on; cholestan-25-fluoro-3β,22(S)-diol; cholestan-25-chloro-3β,22(S)-diol; cholestan-25-methyl-3β,22-diol; cholestan-25-methyl-3β,22-diol-3-hydrogenbutandioate; cholestan-25-methyl-3β,22-diol-bis-hydrogenbutandioate; 1α,25-dihydroxy-26,26,26,27,27,27-hexafluorocholes-5-en; 2β,3β,14α,22,25-pentahydroxy-Δ7-5β-cholesten-6-one; 25-hydroxy-3β-[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 3p-[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-en-24-on; 25-hydroxy-24-oxocholesterol-3p-acetate; 24-oxocholesterol-3β-acetate; 25-hydroxy-24-oxocholesterol; 24,25-dihydroxycholesterol; 3x,6a,25-trihydroxy-24-oxo-5β-cholestane; 1α,25-dihydroxy-24-oxocholesterol; 1α,24,25-trihydroxycholesterol; 3β-hydroxy-24-oxocholesta-5,7-dien; 3β,25-dihydroxy-24-oxocholesta-5,7-dien; 3β-hydroxy-24-oxo-cholesta-5,7-dien; 1α,3β-dihydroxy-24-oxocholesta-5,7-dien; 1α,3β,25-trihydroxy-24-oxo-cholesta-5,7-dien; (24R)-3β,24,25-trihydroxycholest-5-en; (24RS)-3β,24,25-trihydroxycholest-5-en; (24R)-1 ,3p,24,25-tetrahydroxycholest-5-en; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholesta-8,14-dien-2α,11β-diol; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholest-8-en-2α,11β-diol; 4,4-dimethyl-24-methylene-12α-acetoxycholesta-8,14-dien-2α,3β,11β-triol; 4,4-dimethyl-24-methylene-12α-acetoxycholesta-8,14-dien-3β,11β-diol; 4,4-dimethyl-24-methylene-12α-acetoxycholest-8-en-2α,3β,11β-triol; 4,4-dimethyl-24-methylene-12α-acetoxycholest-8-en-3β11β-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3β,11β,12α-tetraol; 4,4-dimethyl-24-methylene-3β-sulphooxycholesta-8,14-dien-2α,11β,12α-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2α,3β,11β,12α-tetraol; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholest-8-en-2-ol-11-one; mono(4,4-dimethyl-24-methylene-12α-acetoxycholesta-8,14-dien-2α,11β-diol)-3β-succinate; 1α,3β-dihydroxycholest-5-ene; 1α,3β,24-trihydroxycholest-5-ene; cholesta-5,7-diene-3β,23(R),25-triol; cholesta-5,7-diene-3p,23(S),25-triol; 1α,3β-dihydroxycholest-5-en; 1α,3β,25-trihydroxycholest-5-en; Δ7-cholesten-2β,3β-diol-6-one; 2β,3β,14α,22(R),25-pentahydroxy-Δ7-5β-cholesten-6-one; 2β,3β,14α,22(S),25-pentahydroxy-Δ7-5β-cholesten-6-one; cholest-5-en-3β,22(R,S),25-triol; cholest-5-en-,25-fluoro-3β,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3βsemisuccinate; cholest-5-en-25-chloro-3β,22-diol; cholest-5-en-25-chloro-22-ol-3βhemisuccinate; 3α,7α,12α,24,25-pentahydroxy coprostane; 3α,7α,12α,25-tetrahydroxy coprostane; 3α,7α,25-trihydroxy coprostane; 3α,7α,24,25-tetrahydroxy coprostane; 5β-cholestane-3α,7α,12α,24α,25-pentol; 5βcholestane-3α,7α,12α,24β,25-pentol; 5β-cholestane-3α,7α,12α,25,26-pentol; 5β-cholestane-3α,7α,12α,25-tetrol; 1α,2α,3β-trihydroxycholesta-5,7-diene; 1α,2α-dihydroxy-3β-acetoxycholesta-5-ene; cholest-5-en-2β-fluoro-1α,3βdiol; 24-cyclopropylchol-5-ene-3β,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3β,22(S)-diol, 24-cyclopropylchol-5-ene-3β,22(S)-diol 3 hydrogen butanedioate; 24-cyclopropyl-5α-cholane-3β,22(S)-diol; cholesta-1,4,6-trien-3-one; 1α,3β-dihydroxycholest-5-ene; 1α,3β-dihydroxy-5α-cholestane; 1α,3β-dihydroxycholesta-5,7-diene; 1α,3β-25-trihydroxycholest-5-ene; 1α,25-dihydroxycholesterol; 1α,25-dihydroxycholesterol-3-benzoate; cholest-5-en-3β,20(S)-diol; 2β,3β,14α,22(R),25-pentahydroxycholest-7-en-6-one and cholest-5-en-3β,22(S)-diol; cholest-5-en-3β,20(S)-diol; cholest-5-en-3β,22(S)-diol; cholest-5-en-3β,4β-diol; cholest-5-en-3β,22(R)-diol and 2β,3β,14α,22(R),25-pentahydroxy-cholest-7-en-6-one.

[0042] In another embodiment, the invention relates to esters of compound of formula Ia. Such esters are formally derived by esterification of one or more hydroxylic groups of a compound of formula Ia with an acid which, for example, can be selected from the group of acids comprising succinic acid and other aliphatic dicarboxylic acids, nicotinic acid, isonicotinic acid, ethylcarbonic acid, phosphoric acid, sulphonic acid, sulphamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids.

[0043] In still another preferred embodiment, the present invention relates to compounds of formula Ib and esters thereof as a medicament.

[0044] Compounds of formula Ib have the following structural formula:

[0045] wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected from the group comprising hydogen, halogen, hydroxy and branched or unbranched C1-C6alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 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; R3is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR7 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and =NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R4, an additional bond between the carbon atoms at which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R3, an additional bond between the carbon atoms at which R14 and R3 or R6 or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and =NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and =NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R16 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, haloger hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R3 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6 R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl, with the further general proviso that R9, R10 and R11 are not all hydroxy, and with the further general proviso that it is not cholestan-3β,5α,6β-triol-3β-hemisuccinate; cholestan-3β,5α,6β-triol-3β-hemisuccinate-6β-acetate; cholestan-3β,5α,6β-triol-3β-hemi-succinate-6β-formiate; cholestan-3β,5α,6β-triol-3β-sulphate; cholestan-3β,5α,6β-triol-3β-phosphate; cholestan-3β,25-diol-3β-acetate; cholestan-3β,5α,25-triol-3β-acetate; cholestan-3α,5α,25-triol; cholestan-5α,25-diol-3-one; cholest-4-en-25-ol-3-one; cholesta-4,6-dien-25-ol-3-one; 1α,3β-dihydroxycholest-5-en; 1α,3β-dihydroxycholest-6-en; 3α,660 -dihydroxy-5β-cholest-an-24-one; 3α,6α,24-trihydroxy-5β-cholestan; 3-chlorocholest-5,24-dien; 3β-hydroxycholest-5-en-24-on acetate; 3-chlorocholest-5-en-24-on; cholestan-25-fluoro-3β,22(S)-diol; cholestan-25-chloro-3β,22(S)-diol; cholestan-25-methyl-3β,22-diol; cholestan-25-methyl-3β,22-diol-3-hydrogenbutandioate; cholestan-25-methyl-3β,22-diol-bis-hydrogenbutandioate; 2β,3β,14α,-22,25-pentahydroxy-Δ7-5β-cholesten-6-one; (24R)-3β,24,25-trihydroxycholest-5-en; (24RS)-3β,24,25-trihydroxycholest-5-en; (24R)-1β,3β,24,25-tetrahydroxycholest-5-en; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholesta-8,14-dien-2α,11β-diol; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholest-8-en-2α,11β-diol; 4,4-dimethyl-24-methylene-12α-acetoxycholesta-8,14-dien-2α,3β,11β-triol; 4,4-dimethyl-24-methylene-12α-acetoxy-cholesta-8,14-dien-3β,11β-diol; 4,4-dimethyl-24-methylene-12α-acetoxycholest-8-en-2α,3β-11β-triol; 4,4-dimethyl-24-methylene-12α-acetoxycholest-8-en-3β,11β-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3β,11β,12α-tetraol; 4,4-dimethyl-24-methylene-3β-sulphooxy-cholesta-8,14-dien-2α,11β,12α-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2α,3β, -11β, 12α-tetraol; 4,4-dimethyl-24-methylene-3β-sulphooxy-12α-acetoxycholest-8-en-2-ol-11-one; mono(4,4-dimethyl-24-methylene-12α-acetoxycholesta-8,14-dien-2α,11β-diol)-3β-succinate; cholesta-5,7-diene-3β,23(R),25-triol; cholesta-5,7-diene-3β,23(S),25-triol; 2β,3β,-14α,22(R),25-pentahydroxy-Δ7-5β-cholesten-6-one; 2β,3β,14α,22(S),25-pentahydroxy-Δ7-5β-cholesten-6-one; cholest-5-en-3β,22(R,S),25-triol; cholest-5-en-25-fluoro-3β,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3β-semisuccinate; cholest-5-en-25-chloro-3β,22-diol; cholest-5-en-25-chloro-22-ol-3β-hemisuccinate; 3α,7α,12α,24,25-pentahydroxy coprostane; 3α,7α,-12α,25-tetrahydroxy coprostane; 3α,7α,25-trihydroxy coprostane; 3α,7α,24,25-tetrahydroxy coprostane; 5β-cholestane-3α,7α,12α,24α,25-pentol; 5β-cholestane-3α, 7α,12α,24β,25-pentol; 5pcholestane-3α,7α,12α,25,26-pentol; 5β-cholestane-3α,7α,12α,25-tetrol; cholest-5-en-2β-fluoro-1α,3β-diol; 24-cyclopropylchol-5-ene-3β,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3β,22(S)-diol, 24-cyclopropylchol-5-ene-3β,22(S)-diol 3 hydrogen butanedioate; 24-cyclo-propyl-5α-cholane-3β,22(S)-diol; cholesta-1,4,6-trien-3-one; 1α,3β-dihydroxycholest-5-ene; 1α,3β-dihydroxy-5α-cholestane; 1α,3β-dihydroxycholesta-5,7-diene; 1α,3β-25-trihydroxy-cholest-5-ene; 1α,25-dihydroxycholesteroi; and 1α,25-dihydroxycholesterol-3-benzoate, as a medicament.

[0046] In a further preferred embodiment, this invention relates to compounds of formula Ic or esters thereof in the manufacture of a medicament for use in the regulation of meiosis.

[0047] Compounds of formula Ic have the following structural formula:

[0048] wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy. are selected from the group comprising hydrogen, halogen, hydroxy and branched or unbranched C1-C6 alkyI which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 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; R3 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and =NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at whic R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R14, an additional bond between the carbon atoms at which R13 and R4 or R4 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R13, an additional bond between the carbon atoms at which R14 and R3 or R6or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and =NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and =NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R18 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R8 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl, and with the further general proviso that R9, R10 and R11 are not all hydroxy and with the further general proviso that it is not, for use in the regulation of meiosis.

[0049] In a further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof as a medicament, in particular as a medicament for use in the regulation of meiosis. The compound may be used neat or in the form of a liquid or solid composition containing auxiliary ingredients conventionally used in the art.

[0050] In the present context, the expression “regulating the meiosis” is used to indicate that certain of the compounds of the invention can be used for stimulating the meiosis in vitro, in vivo, or ex vivo. Thus, the compounds which may be agonists of a naturally occurring meiosis activating substance, can be used in the treatment of infertility which is due to insufficient stimulation of meiosis in females and in males. Other compounds of the invention, which may be antagonists of a naturally occurring meiosis activating substance, can be used for regulating the meiosis, preferably in vivo, in a way which makes them suited as contraceptives. In this case the “regulation” means partial or total inhibition.

[0051] In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the regulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.

[0052] In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the stimulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.

[0053] In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the inhibition of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.

[0054] In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the regulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.

[0055] In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the stimulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.

[0056] In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the inhibition of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.

[0057] In a yet still further preferred aspect, the present invention relates to a meth od of regulating the meiosis in a mammalian germ cell which method comprises administering an effective amount of a compound of formula Ic above or an ester thereof t o a germ cell in need of such a treatment.

[0058] In a still further aspect, the present invention relates to a me thod of regulating the meiosis in a mammalian germ cell wherein a compound of formula Ic above or an ester thereof is administered to the germ cell by administering the compound to a mammal hosting said cell.

[0059] In a still further aspect, the present invention relates to a method wherein the germ cell the meiosis of which is to be regulated by means of a compound of formula Ic above or an ester thereof is an oocyte.

[0060] In a still further aspect, the present invention relates to a method of regulating the meiosis in an oocyte wherein a compound of formula Ic above or an ester thereof is administered to the oocyte ex vivo.

[0061] In a still further aspect, the present invention relates to a method of regulating the meiosis of a male germ cell by administering a compound of formula Ic above or an ester thereof to the cell.

[0062] In a still further aspect,he present invention relates to a method whereby mature male germ cells are produced by administering in vivo or in vitro a compound of formula Ic above or an ester thereof to testicular tissue containing immature cells.

DETAILED DESCRIPTION OF THE INVENTION

[0063] Preferred compounds of formula Ia, Ib and Ic are such wherein R1 and R2 are both hydrogen.

[0064] Other preferred compounds of formula Ia, Ib and Ic are such wherein one of R1 and R2 is hydrogen while the other is methyl.

[0065] Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 and R2 are both methyl.

[0066] Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is branched or unbranched C1-C6 alkyl, optionally substituted by halogen, hydroxy or cyano.

[0067] Other preferred compounds of formula Ia, Ib and Ic are such wherein R2 is branched or unbranched C1-C6 alkyl, optionally substituted by halogen, hydroxy or cyano.

[0068] Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 is hydroxy and R2 is selected from the group comprising hydrogen and branched or unbranched C,-C6 alkyl which may be substituted by halogen, hydroxy or cyano.

[0069] Other preferred compounds of formula Ia, Ib and Ic, are such wherein R2 is hydroxy and R1 is selected from the group comprising hydrogen and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano.

[0070] Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 and R2 together designate methylene.

[0071] Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 and R2, together with the carbon atom to which they are bound, form a cyclopropane ring.

[0072] Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 and R2, together with the carbon atom to which they are bound, form a cyclopentane ring.

[0073] Other preferred compounds of formula Ia, Ib and Ic are such wherein R1 and R2, together with the carbon atom to which they are bound, form a cyclohexane ring.

[0074] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is hydrogen.

[0075] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is methylene.

[0076] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is hydroxy.

[0077] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is methoxy or acetoxy.

[0078] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is halogen.

[0079] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is oxo.

[0080] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is =NOH.

[0081] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is =NOR26, wherein R26 is C1-C3 alkyl.

[0082] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3 is hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton.

[0083] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3, together with R9, designates an additional bond between the carbon atoms at which R3 and R9 are placed.

[0084] Other preferred compounds of formula Ia, Ib and Ic are such wherein R3, together with R14, designates an additional bond between the carbon atoms at which R3 and R14 are placed.

[0085] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is hydrogen.

[0086] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is methylene.

[0087] Other preferred compounds of formula Ia, Ib and Ic are such wherein R 4is hydroxy.

[0088] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is halogen.

[0089] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is methoxy or acetoxy.

[0090] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is oxo.

[0091] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is =NOH.

[0092] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is =NOR2, wherein R27 is C1-C3 alkyl.

[0093] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4 is hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton.

[0094] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4, together with R13, designates an additional bond between the carbon atoms at which R4 and R13 are placed.

[0095] Other preferred compounds of formula Ia, Ib and Ic are such wherein R4, together with R15, designates an additional bond between the carbon atoms at which R4 and R15 are placed.

[0096] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is hydrogen.

[0097] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is halogen.

[0098] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is C1-C4 alkyl.

[0099] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is methylene.

[0100] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is hydroxy.

[0101] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is methoxy.

[0102] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is oxo.

[0103] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is =NOH.

[0104] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5 is =NOR22, wherein R22 is C1-C3 akyl.

[0105] Other preferred compounds of formula Ia, Ib and Ic are such wherein R5, together with R6, designates an additional bond between the carbon atoms at which R5 and R6 are placed.

[0106] Other preferred compounds of formula Ia, Ib and Ic are such wherein R6 is hydrogen.

[0107] Other preferred compounds of formula Ia, Ib and Ic are such wherein R6 is hydroxy.

[0108] Other preferred compounds of formula Ia, Ib and Ic are such wherein R6, together with R14, designates an additional bond between the carbon atoms at which R6 and R14 are placed.

[0109] Other preferred compounds of formula Ia, Ib and Ic are such wherein R9 is hydrogen.

[0110] Other preferred compounds of formula Ia, Ib and Ic are such wherein R9 is halogen.

[0111] Other preferred compounds of formula Ia, Ib and Ic are such wherein R9 is oxo.

[0112] Other preferred compounds of formula Ia, Ib and Ic; are such wherein R9 is hydroxy.

[0113] Other preferred compounds of formula Ia, Ib and Ic are such wherein R9, together with R10, designates an additional bond between the carbon atoms at which R9 and R10 are placed.

[0114] Other preferred compounds of formula Ia, Ib and Ic are such wherein R10 is hydrogen.

[0115] Other preferred compounds of formula Ia, Ib and Ic are such wherein R10 is halogen.

[0116] Other preferred compounds of formula Ia, Ib and Ic are such wherein R10 is hydroxy.

[0117] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is hydroxy.

[0118] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is alkoxy, aralkyloxy, alkoxyalkoxy or alkanoyloxyalkyl, each group comprising a total of up to 10 carbon atoms, preferably up to 8 carbon atoms.

[0119] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is C1-C4 alkoxy.

[0120] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is methoxy.

[0121] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is ethoxy.

[0122] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is CH3OCH2O—.

[0123] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is pivaloyloxymethoxy.

[0124] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is an acyloxy group derived from an acid having from 1 to 20 carbon atoms.

[0125] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is an acyloxy group selected from the group comprising acetoxy, benzoyloxy, pivaloyloxy, butyryloxy, nicotinoyloxy, isonicotinoyloxy, hemi succinoyloxy, hemi glutaroyloxy, butylcarbamoyloxy, phenylcarbamoyloxy, butoxycarbonyloxy, tert-butoxycarbonyloxy and ethoxycarbonyloxy.

[0126] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is sulphonyloxy.

[0127] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is phosphonyloxy.

[0128] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is oxo.

[0129] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is NOH.

[0130] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is =NOR28, wherein R28 is C1-C3 alkyl.

[0131] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is halogen.

[0132] Other preferred compounds of formula Ia, Ib and Ic are such wherein R11 is hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton.

[0133] Other preferred compounds of formula ia, Ib and Ic are such wherein R11, together with R12, designates an additional bond between the carbon atoms at which R11 and R12 are placed.

[0134] Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is hydrogen.

[0135] Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is hydroxy.

[0136] Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is C1-C3 alkyl.

[0137] Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is C1-C3 alkoxy.

[0138] Other preferred compounds of formula Ia, Ib and Ic are such wherein R12 is halogen.

[0139] Other preferred compounds of formula Ia, Ib and Ic are such wherein R13 is hydrogen.

[0140] Other preferred compounds of formula Ia, Ib and Ic are such wherein R13 is halogen.

[0141] Other preferred compounds of formula Ia, Ib and Ic are such wherein R13 is hydroxy.

[0142] Other preferred compounds of formula Ia, Ib and Ic are such wherein R13, together with R14, designates an additional bond between the carbon atoms at which R13 and R14 are placed.

[0143] Other preferred compounds of formula Ia, Ib and Ic are such wherein R14 is hydrogen.

[0144] Other preferred compoyunds of formula Ia, Ib and Ic are such wherein R14 is halogen.

[0145] Other preferred compounds of formula Ia, Ib and Ic are such wherein R14 is hydroxy.

[0146] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is hydrogen.

[0147] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is halogen.

[0148] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is methyl.

[0149] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is mthydrxyl.

[0150] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is hydroxy.

[0151] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is methoxy or acetoxy.

[0152] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is oxo.

[0153] Other preferred compounds of formula ia, Ib and Ic are such wherein R15 is =NOH.

[0154] Other preferred compounds of formula Ia, Ib and Ic are such wherein R15 is =NOR23, wherein

[0155] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is hydrogen.

[0156] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is halogen.

[0157] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is C1-C3 alkyl.

[0158] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is methylene.

[0159] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is hydroxy.

[0160] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is methoxy.

[0161] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is oxo.

[0162] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is =NOH.

[0163] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 is =NOR24, wherein R24 is C1-C3 alkyl.

[0164] Other preferred compounds of formula Ia, Ib and Ic are such wherein R16 together with R17, designates an additional bond between the carbon atoms at which R16 and R17 are placed.

[0165] Other preferred compounds of formula Ia, Ib and Ic are such wherein R17 is hydrogen.

[0166] Other preferred compounds of formula Ia, Ib and Ic are such wherein R17 is hydroxy.

[0167] Other preferred compounds of formula Ia, Ib and Ic are such wherein R18 and R19 are both hydrogen.

[0168] Other preferred compounds of formula Ia, Ib and Ic are such wherein one of R18 and R19 is hydrogen while the other is halogen.

[0169] Other preferred compounds of formula Ia, Ib and Ic are such wherein one of R18 and R19 is hydrogen while the other is hydroxy.

[0170] Other preferred compounds of formula Ia, Ib and Ic are such wherein one of R18 and R19 is hydrogen while the other is methoxy.

[0171] Other preferred compounds of formula Ia, Ib and Ic are such wherein one of R18 and R19 is fluoro and the other is hydrogen.

[0172] Other preferred compounds of formula Ia, Ib and Ic are such wherein R18 and R19 together designate oxo.

[0173] Other preferred compounds of formula Ia, Ib and Ic are such wherein R25 is hydroxymethyl.

[0174] Other preferred compounds of formula Ia, Ib and Ic are such wherein R25 is C1-C4 alkyl.

[0175] Other preferred compounds of formula Ia, Ib and Ic are such wherein R25 together with R31 designates methylene.

[0176] Other preferred compounds of formula Ia, Ib and Ic are such wherein R25 together with R31 designates oxo.

[0177] Other preferred compounds of formula Ia, Ib and Ic are such wherein R29 is hydrogen.

[0178] Other preferred compounds of formula Ia, Ib and Ic are such wherein R29 is halogen.

[0179] Other preferred compounds of formula Ia, Ib and Ic are such wherein R29 is methyl.

[0180] Other preferred compounds of formula Ia, Ib and Ic are such wherein R29 is hydroxy

[0181] Other preferred compounds of formula Ia, Ib and Ic are such wherein R29 is oxo.

[0182] Other preferred compounds of formula Ia, Ib and Ic are such wherein R30 is hydrogen.

[0183] Other preferred compounds of formula Ia, Ib and Ic are such wherein R30 is halogen.

[0184] Other preferred compounds of formula Ia, Ib and Ic are such wherein R30 is methyl.

[0185] Other preferred compounds of formula Ia, Ib and le are such wherein R30 is hydroxy.

[0186] Other preferred compounds of formula Ia, Ib and Ic are such wherein R31 is hydrogen.

[0187] Other preferred compounds of formula Ia, Ib and Ic are such wherein R31 is halogen.

[0188] Other preferred compounds of formula Ia, Ib and Ic are such wherein R31 is methyl.

[0189] Other preferred compounds of formula Ia, Ib and Ic are such wherein R31 is hydroxy

[0190] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom.

[0191] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R7 is hydrogen.

[0192] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R7 is hydroxy.

[0193] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R7 is halogen.

[0194] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R7, together with R8, designates an additional bond between the carbon atoms at which R7 and R8 are placed.

[0195] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R8 is hydrogen.

[0196] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R8 is C1-C4 alkyl.

[0197] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R8 is methylene.

[0198] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R8 is oxo.

[0199] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R8 is cyano.

[0200] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R8 is halogen.

[0201] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R8 is hydroxy.

[0202] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R20 is C1-C4 alkyl.

[0203] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R20 is trifluoromethyl.

[0204] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R2 is C3-C6 cycloalkyl.

[0205] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R21 is C1-C4 alkyl.

[0206] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R21 is C1-C4 hydroxyalkyl.

[0207] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R21 is C1-C4 haloalkyl containing up to three halogen atoms.

[0208] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R21 is methoxymethyl or acetoxymethyl.

[0209] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R21 is C3-C6 cycloalkyl.

[0210] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a carbon atom, and R20 and R21, together with the carbon atom to which they are bound, form a C3-C6 cycloalkyl ring, preferably a cyclopropyl ring, a cyclopentyl ring or a cyclohexyl ring.

[0211] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a nitrogen atom.

[0212] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a nitrogen atom, and R8 is hydrogen.

[0213] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a nitrogen atom, and R8 is hydroxy.

[0214] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a nitrogen atom, and R8 is C1-C4 alkyl.

[0215] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a nitrogen atom, and R8 is oxo.

[0216] Other preferred compounds of formula Ia, Ib and Ic are such wherein A is a nitrogen atom, and R20 and R21, independently, are selected from the group comprising C,-C4 alkyl, cyclopropyl, cyclopentyl and cyclohexyl.

[0217] Other preferred compounds of formula Ia, Ib and Ic are such wherein the long side chain in the 17 position is in the P position.

[0218] It is to be understood that the above preferred substituents can be combined in any way with each other.

[0219] Further preferred embodiments are recited in the appended claims.

[0220] As used in the present description and claims, the expression C1-C3 alkyl designates an alkyl group having from one to three carbon atoms; preferred examples are methyl, ethyl and propyl, more preferred methyl and ethyl. Similarly, the expression C1-C4 alkyl designates an alkyl group having from one to four carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl and butyl, more preferred methyl and ethyl. The expression C1-C6 alkyl designates an alkyl group having from one to six carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, more preferred methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, still more preferred methyl and ethyl.

[0221] As used in the present description and claims, the expression C1-C3 alkoxy designates an alkoxy group having from one to three carbon atoms; preferred examples are methoxy, ethoxy and propoxy, more preferred methoxy and ethoxy.

[0222] As used in the present description and claims, the expression halogen preferably designates fluoro and chloro, more preferred fluoro.

[0223] As used in the present description and claims, the expression C1-C4 alkandiyl designates branched or unbranched alkane from which two hydrogen atoms have been removed. Looking at formula I, one can see that in these alkandiyl moieties the two free bonds are bound to the same carbon atom of the sterol skeleton. General terms for alkandiyl are believed to be alkylidene and alkylene. Examples of preferred alkandiyl moities are methylene, ethene, propylene, propylidene, isopropylidene, sec.butylidene and 1,4-butylene.

[0224] As used in the present description and claims, the expression C3-C6 cycloalkyl designates a cycloalkyl group containing 3-6 carbon atoms in the ring. Preferred examples are cyclopropyl and cyclopentyl.

[0225] As used in the present description and claims, the expression acyloxy designates a monovalent substituent comprising an optionally substituted C1-6alkyl or phenyl group linked through a carbonyloxy group; such as e.g. acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy, benzoyl and the like.

[0226] The compounds of claim 1 have a number of chiral centers in the molecule and thus exist in several isomeric forms. All these isomeric forms and mixtures thereof are within the scope of the invention.

[0227] The compounds of formula I can be prepared analogously with the preparation of known compounds. Hence, synthesis of the compounds of formula I can follow the well established synthetic pathways described in the comprehensive sterol and steroid literature. The following books can be used as the key source in the synthesis: L. F. Fieser & M. Fieser: Steroids: Reinhold Publishing Corporation, N.Y. 1959; Rood's Chemistry of Carbon Compounds (editor: S. Coffrey): Elsevier Publishing Company, 1971; and especially Dictionary of Steriods (editors: R. A. Hill; D. N. Kirk; H. L. J. Makin and G. M. Murphy): Chapmann & Hall. The last one contains an extensive list of citations to the original papers covering the period up to 1990. All these books including the last mentioned citations are incorporated by reference.

[0228] The compounds of the present invention will influence the meiosis in oocytes as well as in male germ cells.

[0229] The existence of a meiosis inducing substance in nature has been known for some time. However, until recently the identity of the meiosis inducing substance or substances was unknown.

[0230] The prospects of being able to influence the meiosis are several. According to a preferred embodiment of the present invention, a compound of claim 1 or an ester thereof can be used to stimulate the meiosis. According to another preferred embodiment of the present invention, a compound of claim 1 or an ester thereof can be used to stimulate the meiosis in humans. Thus, the compounds of claim 1 and esters thereof are promising as new fertility regulating agents without the usual side effect on the somatic cells which are known from the hitherto used hormonal contraceptives which are based on estrogens and/or gestagens.

[0231] For use as a contraceptive agent in females, a meiosis inducing substance can be administered so as to prematurely induce resumption of meiosis in oocytes while they are still in the growing follicle, before the ovulatory peak of gonadotropins occurs. In women, the resumption of the meiosis can, for example, be induced a week after the preceding menstruation has ceased. When ovulated, the resulting overmature oocytes are then most likely not to be fertilized. The normal menstrual cycle is not likely to be affected. In this connection it is important to notice, that the biosynthesis of progesterone in cultured human granulosa cells (somatic cells of the follicle) is not affected by the presence of a meiosis inducing substance whereas the estrogens and gestagens used in the hitherto used hormonal contraceptives do have an adverse effect on the biosynthesis of progesterone.

[0232] According to another aspect of this invention, a meiosis inducing substance of formula 1a or an ester thereof can be used in the treatment of certain cases of infertility in females, including women, by administration thereof to females who, due to an insufficient own production of meiosis activating substance, are unable to produce mature oocytes. Also, when in vitro fertilization is performed, better results can be achieved, when a compound of formula I a or an ester thereof is added-to the medium in which the oocytes are kept.

[0233] When infertility in males, including men, is caused by an insufficient own production of the meiosis activating substance and thus a lack of mature sperm cells, administration of a compound of formula 1a or an ester thereof may relieve the problem.

[0234] As an alternative to the method described above, contraception in females can also be achieved by administration of a compound of formula 1a or an ester thereof which inhibits the meiosis, so that no mature oocytes are produced. Similarly, contraception in males can be achieved by administration of a compound of formula 1a or an ester thereof which inhibits the meiosis, so that no mature sperm cells are produced.

[0235] The route of administration of compositions containing a compound of formula 1a or an ester thereof may be any route which effectively transports the active compound to its site of action.

[0236] Thus, when the compounds of this invention are to be administered to a mammal, they are conveniently provided in the form of a pharmaceutical composition which comprises at least one compound of formula Ia or an ester thereof in connection with a pharmaceutically acceptable carrier. For oral use, such compositions are preferably in the form of capsules or tablets.

[0237] From the above it will be understood that administrative regimen called for will depend on the condition to be treated. Thus, when used in the treatment of infertility the administration may have to take place once only, or for a limited period, e.g. until pregnancy is achieved. When used as a contraceptive, the compound of formula l a or an ester thereof will either have to be administered continuously or cyclically. When used as a contraceptive by females and not taken continuously, the timing of the administration relative to the ovulation will be important.

[0238] Examples of preferred compounds according to the invention are given below:

[0239] cholesta-5-en-3α,1β-diol; cholesta-5-en-3α,1α-diol; cholesta-5-en-3α,2β-diol; cholesta-5-en-3α,2α-diol; cholesta-5-en-3α,4βdiol; cholesta-5-en-3α,4α-diol; cholesta-5-en-3α,7β-diol; cholesta-5-en-3α,7α-diol; cholesta-5-en-3α,11β-diol; cholesta-5-en-3α, 11α-diol; cholesta-5-en-3α,12β-diol; cholesta-5-en-3α,12α-diol; cholesta-5-en-3α,15β-diol; cholesta-5-en-3α,15α-diol; cholesta-5-en-3α,16β-diol; cholesta-5-en-3α,16α-diol; cholesta-5-en-3α,17β-diol; cholesta-5-en-3α,17α-diol; cholesta-5-en-3α,(20R)-diol; cholesta-5-en-3α,(20S)-diol; cholesta-5-en-3α,21-diol; cholesta-5-en-3α, (22R)-diol; cholesta-5-en-3α, (22S)-diol; cholesta-5-en-3α-,(23R)-diol; cholesta-5-en-3α,(23S)-diol; cholesta-5-en-3α,(24R)-diol; cholesta-5-en-3α,(24S)-diol; cholesta-5-en-3α,25-diol; (25R)-cholesta-5-en-3α,26-diol; (25S )-cholesta-5-en-3α,26-diol; cholesta-5-en-3β,1β-diol; cholesta-5-en-3β,1α-diol; cholesta-5-en-3β,2β-diol; cholesta-5-en-3β,2α-diol; cholesta-5-en-3β,4β-diol; cholesta-5-en-362 ,4α-diol; cholesta-5-en-3β,7β-diol; cholesta-5-en-3β,7α-diol; cholesta-5-en-3β,11β-diol; cholesta-5-en-3β,11α-diol; cholesta-5-en-3β,12β-diol; cholesta-5-en-3β,12α-diol; cholesta-5-en-3β,15β-diol; cholesta-5-en-3β,15α-diol; cholesta-5-en-3β,16β-diol; cholesta-5-en-3β,16α-diol; cholesta-5-en-3β,17β-diol; cholesta-5-en-3β,17α-diol; cholesta-5-en-3β,(20R)-diol; cholesta-5-en-3β,(20S)-diol; cholesta-5-en-3β, 21 -diol; cholesta-5-en-3β,(22S)-diol; cholesta-5-en-3β,(23R)-diol; cholesta-5-en-3β,(23S)-diol; cholesta-5-en-3β,(24R)-diol; cholesta-5-en-3β,(24S)-diol; cholesta-5-en-3β,25-diol; (25S)-cholesta-5-en-3β,26-diol; cholesta-5,24-dien-3α,1β-diol; cholesta-5,24-dien-3α,1α-diol; cholesta-5,24-dien-3α,2β-diol; cholesta-5,24-dien-3α,2α-dio; cholesta-5,24-dien-3α,4β-diol; cholesta-5,24-dien-3α,4α-diol; cholesta-5,24-dien-3α,7β-diol; cholesta-5,24-dien-3α,7α-diol; cholesta-5,24-dien-3α,11β-diol; cholesta-5,24-dien-3α,11α-diol; cholesta-5,24-dien-3α,12β-diol; cholesta-5,24-dien-3α,12α-diol; cholesta-5,24-dien-3α,15,diol; cholesta-5,24-dien-3α,15α-diol; cholesta-5,24-dien-3α,16β-diol; cholesta-5,24-dien-3α,16α-diol; cholesta-5,24-dien-3α,17β-diol; cholesta-5,24-dien-3α,17α-diol; cholesta-5,24-dien-3α,(20R)-diol; cholesta-5,24-dien-3α,(20S)-diol; cholesta-5,24-dien-3α,21-diol; cholesta-5,24-dien-3α,(22R)-diol; cholesta-5,24-dien-3α,(22S)-diol; cholesta-5,24-dien-3α,(23R)-diol; cholesta-5,24-dien-3α,(23S)-diol; cholesta-5,24-dien-3α,26-diol; cholesta-5,24-dien-3β,1β-diol; cholesta-5,24-dien-3β,1α-diol; cholesta-5,24-dien-3β,2β-diol; cholesta-5,24-dien-3β,2α-diol; cholesta-5,24-dien-3β,4β-diol; cholesta-5,24-dien-3β,4α-diol; cholesta-5,24-dien-3β,7β-diol; cholesta-5,24-dien-3β,7α-diol; cholesta-5,24-dien-3β,11β-diol; cholesta-5,24-dien-3β,11α-diol; cholesta-5,24-dien-3β,12β-diol; cholesta-5,24-dien-3β,12α-diol; cholesta-5,24-dien-3β,15β-diol; cholesta-5,24-dien-3β,15α-diol; cholesta-5,24-dien-3β,16β-diol; cholesta-5,24-dien-3β,16α-diol; cholesta-5,24-dien-3β,17β-diol; cholesta-5,24-dien-3β,17α-diol; cholesta-5,24-dien-3β,(20R)-diol; cholesta-5,24-dien-3β,(20S)-diol; cholesta-5,24-dien-3β, 21-diol; cholesta-5,24-dien-3β,(22R)-diol; cholesta-5,24-dien-3β,(22S)-diol; cholesta-5,24-dien-3β,(23R)-diol; cholesta-5,24-dien-3β,(23S)-diol; cholesta-5,24-dien-3β,26-diol; 4,4-dimethylcholesta-5-en-3α,1β-diol; 4,4-dimethylcholesta-5-en-3α,1α-diol; 4,4-dimethyl-cholesta-5-en-3α,2β-diol; 4,4-dimethylcholesta-5-en-3α,2α-diol; 4,4-dimethylcholesta-5-en-3α,7β-diol; 4,4-dimethylcholesta-5-en-3α,7α-diol; 4,4-dimethylcholesta-5-en-3α, 11β-diol; 4,4-dimethylcholesta-5-en-3α,11α-diol; 4,4-dimethytcholesta-5-en-3α12β-diol; 4,4-dimethylcholesta-5-en-3α,12α-diol; 4,4-dimethylcholesta-5-en-3α,15β-diol; 4,4-dimethyl-cholesta-5-en-3α,15α-diol; 4,4-dimethylcholesta-5-en-3α,16β-diol; 4,4-dimethylcholesta-5-en-3α,16α-diol; 4,4-dimethylcholesta-5-en-3α,17β-diol; 4,4-dimethylcholesta-5-en-3α,17α-diol; 4,4-dimethylcholesta-5-en-3α, (20R)-diol; 4,4-dimethylcholesta-5-en-3α, (20S)-diol; 4,4-dimethylcholesta-5-en-3α,21-diol; 4,4-dimethylcholesta-5-en-3α,(22R)-diol; 4,4-dimethylcholesta-5-en-3α,(22S)-diol; 4,4-dimethylcholesta-5-en-3α,(23R)-diol; 4,4-dimethyl-cholesta-5-en-3α,(23S)-diol; 4,4-dimethylcholesta-5-en-3α,(24R)-diol; 4,4-dimethylcholesta-5-en-3α,(24S)-diol; 4,4-dimethylcholesta-5-en-3α,25-diol; (25R)-4,4-dimethylcholesta-5-en-3α,26-diol; (25S)-4,4-dimethylcholesta-5-en-3α,26-diol; 4,4-dimethylcholesta-5-en-3β,1β-diol; 4,4-dimethylcholesta-5-en-3β,1α-diol; 4,4-dimethylcholesta-5-en-3β,2β-diol; 4,4-dimethylcholesta-5-en-3β,2α-diol; 4,4-dimethylcholesta-5-en-3β,7βdiol; 4,4-dimethyl-cholesta-5-en-3β,7α-diol; 4,4-dimethylcholesta-5-en-3β, 11β-diol; 4,4-dimethylcholesta-5-en-3α,11α-diol; 4,4-dimethylcholesta-5-en-3β,12β-diol; 4,4-dimethyicholesta-5-en-3β,12α-diol; 4,4-dimethylcholesta-5-en-3β,15βdiol; 4,4-dimethylcholesta-5-en-3β,15α-diol; 4,4-dimethyl-cholesta-5-en-3β,16β-diol; 4,4-dimethylcholesta-5-en-3β,16α-diol; 4,4-dimethylcholesta-5-en-3β,17β-diol; 4,4-dimethylcholesta-5-en-3β,17α-diol; 4,4-dimethylcholesta-5-en-3β,(20R)-diol; 4,4-dimethylcholesta-5-en-3β,(20S)-diol; 4,4-dimethytcholesta-5-en-3β,21-diol; 4,4-dimethylcholesta-5-en-3β,(22R)-diol; 4,4-dimethylcholesta-5-en-3β, (22S)-diol; 4,4-dimethytcholesta-5-en-3β,(23R)-diol; 4,4-dimethylcholesta-5-en-3β(23S)-diol; 4,4-dimethylcholesta-5-en-3β, (24R)-diol; 4,4-dimethylcholesta-5-en-3β,(24S)-diol; 4,4-dimethyicholesta-5-en-30,25-diol; (25R)-4,4-dimethyicholesta-5-en-3β,26-diol; (25S)-4,4-dimethylcholesta-5-en-3β,26-diol; 4,4-dimethylcholesta-5,24-dien-3α,1β-diol; 4,4-dimethylcholesta-5,24-dien-3α,1α-diol; 4,4-dimethylcholesta-5,24-dien-3α,2β-diol; 4,4-dimethylcholesta-5,24-dien-3α,2α-diol; 4,4-dimethylcholesta-5,24-dien-3α,7β-diol; 4,4-dimethylcholesta-5,24-dien-3α,7α-diol; 4,4-dimethylcholesta-5,24-dien-3α,11β-diol; 4,4-dimethylcholesta-5,24-dien-3α,11α-diol; 4,4-dimethylcholesta-5,24-dien-3α,12β-diol; 4,4-dimethylcholesta-5,24-dien-3α,12α-diol; 4,4-dimethylcholesta-5,24-dien-3α,15β-diol; 4,4-dimethylcholesta-5,24-dien-3α,15α-diol; 4,4-dimethylcholesta-5,24-dien-3α,16β-diol; 4,4-dimethylcholesta-5,24-dien-3α,16α-diol; 4,4-dimethylcholesta-5,24-dien-3α,17β-diol; 4,4-dimethyicholesta-5,24-dien-3α,17α-diol; 4,4-dimethylcholesta-5,24-dien-3α, (20R)-diol; 4,4-dimethylcholesta-5,24-dien-3α,(20S)-diol; 4,4-dimethylcholesta-5,24-dien-3α,21-diol; 4,4-dimethylcholesta-5,24-dien-3α,(22R)-diol; 4,4-dimethylcholesta-5,24-dien-3α,(22S)-diol; 4,4-dimethylcholesta-5,24-dien-3α, (23R)-diol; 4,4-dimethylcholesta-5,24-dien-3α,(23S)-diol; 4,4-dimethylcholesta-5,24-dien-3α,26-diol; 4,4-dimethylcholesta-5,24-dien-3β,1β-diol; 4,4-dimethylcholesta-5,24-dien-3β,1α-diol; 4,4-dimethylcholesta-5,24-dien-3β,2β-diol; 4,4-dimethylcholesta-5,24-dien-3β,2α-diol; 4,4-dimethylcholesta-5,24-dien-3β,7β-diol; 4,4-dimethyicholesta-5,24-dien-3α,7α-diol; 4,4-dimethylcholesta-5,24-dien-3β,11β-diol; 4,4-dimethylcholesta-5,24-dien-3β,11α-diol; 4,4-dimethylcholesta-5,24-dien-3β,12β-diol; 4,4-dimethylcholesta-5,24-dien-3β,12α-diol; 4,4-imethylcholesta-5,24-dien-3β,15β-diol; 4,4-dimethylcholesta-5,24-dien-3β,15α-diol; 4,4-dimethyicholesta-5,24-dien-3β,16-diol; 4,4-dimethylcholesta-5,24-dien-3β,16α-diol; 4,4-dimethylcholesta-5,24-dien-3β,17β-diol; 4,4-dimethylcholesta-5,24-dien-3β,17α-diol; 4,4-dimethylcholesta-5,24-dien-3β,(20R)-diol; 4,4-dimethylcholesta-5,24-dien-3β,(20S)-diol; 4,4-dimethylcholesta-5,24-dien-3β,21-diol; 4,4-dimethylcholesta-5,24-dien-3β,(22R)-diol; 4,4-dimethylcholesta-5,24-dien-3β, (22)-diol; 4,4-dimethylcholesta-5,24-dien-3β,(23R)-diol; 4,4-dimethylcholesta-5,24-dien-3β,(23S)-diol; 4,4-dimethylcholesta-5,24-dien-3β,26-diol; spiro[cholesta-5-en-3α,7β-diol-4,1′-cyclo-propane]; spiro[cholesta-5-en-3α,7α-diol;-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,11β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,11α-diolo-4,1′-cyclopropane]; spiro[cholesta-5-en-3α12β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,12α-diol-4,140 -cyclopropane]; Spiro[cholesta-5-en-3α,15β- diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,15-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,16β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,16α-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,17β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,17α-diol-4,1′-cyclopropaneJ; spiro[cholesta-5-en-3α, (20R)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,(20S)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α, 21-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,(22R)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,(22S)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,(23R)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α,(23S)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3α, (24R)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3x,(24S)-diol-4,1 ′-cyclopropane]; spiro[cholesta-5-en-3α,25-diol-4,1′-cyclopropane]; spiro[(25R)-cholesta-5-en-3α,26-diol-4,1′-cyclopropane]; spiro[(25S)-cholesta-5-en-3α,26-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,7β-diol-4,1′-cyciopropane]; spiro[cholesta-5-en-3 β,7α-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,1β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,11α-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,12β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,12α-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,15β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,15α-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,16β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,16(α-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,17β-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,17α-diol-4,1 ′-cyclopropane]; spiro[cholesta-5-en-3β(20R)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β, (20S)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,21-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,(22R)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β (22S)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,(23R)-diol-4,1′-cyclopropanel; spiro[cholesta-5-en-3β,(23S)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,(24R)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,(24S)-diol-4,1′-cyclopropane]; spiro[cholesta-5-en-3β,25-diol-4,1′-cyclopropane]; spiro[(25R)-cholesta-5-en-3β,26-diol-4,1′-cyclopropane]; spiro[(25S)-cholesta-5-en-3β,26-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,7β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,7α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,11β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,11α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,12β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,12α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,15β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,15α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,16β-diol-4,1′-cyclo-propane]; spiro[cholesta-5,24-dien-3α,16α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,17β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,17α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,(20R)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,(20S)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,21-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α, (22R)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α, (22S)-diol-4,1′-cyclopropane]; spiro[choiesta-5,24-dien-3α, (23R)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,(23S)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3α,26-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,7β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,7α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,11β-diol-4,1′-cyciopropane]; spiro[cholesta-5,24-dien-3β,11α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,12β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,12α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,15βdiol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,15α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-30,16,6diol-4,1′-cyclo-propane]; spiro[cholesta-5,24-dien-3β,16α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-30,17β-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,17α-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β, (20R)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β, (20S)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,21 -diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,(22R)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β, (22S)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3, (23R)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β, (23S)-diol-4,1′-cyclopropane]; spiro[cholesta-5,24-dien-3β,26-diol-4,1′-cyclopropane]; 3α-hydroxycholesta-5-en-1-one; 3α-hydroxycholesta-5-en-2-one; 3α-hydroxycholesta-5-en-7-one; 3α-hydroxycholesta-5-en-11 -one; 3α-hydroxycholesta-5-en-12-one; 3α-hydroxycholesta-5-en-15-one; 3α-hydroxycholesta-5-en-16-one; 3α-hydroxycholesta-5-en-22-one; 3α-hydroxycholesta-5-en-23-one; 3αt-hydroxycholesta-5-en-24-one; 3βhydroxycholesta-5-en-1-one; 3β-hydroxycholesta-5-en-2-one; 3β-hydroxy-cholesta-5-en-7-one; 3β-hydroxycholesta-5-en-11-one; 30-hydroxycholesta-5-en-12-one; 3β-hydroxycholesta-5-en-15-one; 3β-hydroxycholesta-5-en-16-one; 3β-hydroxycholesta-5-en-22-one; 3,-hydroxycholesta-5-en-23-one; 3β-hydroxycholesta-5-en-24-one; 3α-hydroxy-cholesta-5,24-dien-1-one; 3α-hydroxycholesta-5,24-dien-2-one; 3α-hydroxycholesta-5,24-dien-7-one; 3α-hydroxycholesta-5,24-dien- 11-one; 3c-hydroxycholesta-5,24-dien-12-one; 3α-hydroxycholesta-5,24-dien-15-one; 3α-hydroxycholesta-5,24-dien-16-one; 3α-hydroxycholesta-5,24-dien-22-one; 3α-hydroxycholesta-5,24-dien-23-one; 3β-hydroxy-cholesta-5,24-dien-1-one; 3β-hydroxycholesta-5,24-dien-2-one; 3,hydroxycholesta-5,24-dien-7-one; 3β-hydroxycholesta-5,24-dien-1-one; 3β-hydroxycholesta-5,24-dien-12-one; 3β-hydroxycholesta-5,24-dien-15-one; 3β-hydroxycholesta-5,24-dien-16-one; 3β-hydroxy-cholesta-5,24-dien-22-one; 3β-hydroxycholesta-5,24-dien-23-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-1-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-2-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-7-one; 4,4-dimethyl-3α-hydroxycholesta-5-en- 11-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-12-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-15-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-16-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-22-one; 4,4-dimethyl-3α-hydroxycholesta-5-en-23-one; 4,4-d imethyl-3α-hydroxycholesta-5-en-24-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-1-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-2-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-7-one; 4,4-dimethyl-3βhydroxycholesta-5-en-11-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-12-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-15-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-16-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-22-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-23-one; 4,4-dimethyl-3β-hydroxycholesta-5-en-24-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-1-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-2-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-7-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-1 1-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-12-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-15-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-16-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-22-one; 4,4-dimethyl-3α-hydroxycholesta-5,24-dien-23-one; 4,4-dimethyl-313-hydroxycholesta-5,24-dien-1-one; 4,4-dimethyl-3β-hydroxycholesta-5,24-dien-2-one; 4,4-dimethyl-3β-hydroxy-cholesta-5,24-dien-7-one; 4,4-dimethyl-3β-hydroxycholesta-5,24-dien-i 1-one; 4,4-dimethyl-3β-hydroxycholesta-5,24-dien-12-one; 4,4-dimethyl-3,-hydroxycholesta-5,24-dien-15-one; 4,4-dimethyl-3βhydroxycholesta-5,24-dien-16-one; 4,4-dimethyl-3β-hydroxycholesta-5,24-dien-22-one; 4,4-dimethyl-3 β-hydroxycholesta-5,24-dien-23-one; spiro[3α-hydroxycholesta-5-en-7-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5-en-11-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5-en-12-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5-en-15-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5-en-16-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5-en-22-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5-en-23-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5-en-24-one-4,1′-cyclopropane]; spiro[3>hydroxycholesta-5-en-7-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5-en-11-one-4,1′-cyclopropane]; spiro[3>hydroxycholesta-5-en-12-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5-en-15-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5-en-16-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5-en-22-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5-en-23-one-4,1′-cyclopropane]; spiro[3>hydroxycholesta-5-en-24-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5,24-dien-7-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5,24-dien-11-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5,24-dien-12-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5,24-dien-15-one-4,1′-cyclopropane]; Spiro[3α-hydroxycholesta-5,24-dien-16-one-4,1′-cyclopropane]; spiro[3α-hydroxycholesta-5,24-dien-22-one-4,1′-cyclopropane]; spiro[3>hydroxycholesta-5,24-dien-7-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5,24-dien-11-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5,24-dien-12-one-4,1′-cyclopropane]; spiro[3>hydroxycholesta-5,24-dien-15-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5,24-dien-1 6-one-4,1′-cyclopropane]; spiro[3β-hydroxycholesta-5,24-dien-22-one-4,1′-cyclopropane]; 4,4-dimethylcholest-5-en-1,3-dione; 4,4-dimethylcholest-5-en-3,7-dione; 4,4-dimethylcholest-5-en-3,11-dione; 4,4-dimethylcholest-5-en-3,12-dione; 4,4-dimethylcholest-5-en-3,15-dione; 4,4-dimethylcholest-5-en-3,16-dione; 4,4-dimethylcholest-5-en-3,22-dione; 4,4-dimethylcholest-5-en-3,23-dione; 4,4-dimethylcholest-5-en-3,24-dione; 4,4-dimethylcholest-5,24-dien-1,3-dione; 4,4-dimethylcholest-5,24-dien-3,7-dione; 4,4-dimethylcholest-5,24-dien-3, 11 -dione; 4,4-dimethylcholest-5,24-dien-3,12-dione; 4,4-dimethylcholest-5,24-dien-3,15-dione; 4,4-dimethylcholest-5,24-dien-3,16-dione; 4,4-dimethylcholest-5,24-dien-3,22-dione; 4,4-dimethylcholest-5,24-dien-3,23-dione; spiro[cholest-5-en-3,7-dione-4,1′-cyclopropane]; spiro[cholest-5-en-3,11 -dione-4,1′-cyclopropane]; spiro[cholest-5-en-3,12-dione-4,1′-cyclopropane]; spiro[cholest-5-en-3,15-dione4,1′-cyclopropane]; spiro[cholest-5-en-3,16-dione-4,1′-cyclopropane]; spiro[cholest-5-en-3,22-dione-4,1′-cycopropane]; spiro[cholest-5-en-3,23-dione-4,1′-cy′opropane]; spiro[cholest-5-en-3,24-dione-4,1′-cyclopropane]; spiro[cholest-5,24-dien-3,7-dione-4,1′-cyclopropane]; spiro[cholest-5,24-dien-3,11 -dione-4,1′-cyclopropane]; spiro[cholest-5,24-dien-3,2-dione-4,1′-cyclopropane]; spiro[cholest-5,24-dien-3,15-dione-4,1′-cyclopropane]; spiro[cholest-5-,24-dien-3,16-dione-4,1′-cyclopropane]; Spiro[cholest-5,24-dien-3,22-dione-4,1′-cyclopropane]; spiro[cholest-5,24-dien-3,23-dione-4,1′-cyclopropane]; 4,4-dimethyl-1β-hydroxycholesta-5-en-3-one; 4,4-dimethyl-1α-hydroxy-cholesta-5-en-3-one; 4,4-dimethyl-2β-hydroxycholesta-5-en-3-one; 4,4-dimethyl-2α-hydroxycholesta-5-en-3-one; 4,4-d imethyl-7β-hydroxycholesta-5-en-3-one; 4,4-d i methyl-7α-hydroxycholesta-5-en-3-one; 4,4-dimethyl-1 1 -hydroxycholesta-5-en-3-one; 4,4-dimethyl-11α-hydroxycholesta-5-en-3-one; 4,4-dimethyl-1 213-hydroxycholesta-5-en-3-one; 4,4-dimethyl-12α-hydroxycholesta-5-en-3-one; 4,4-dimethyl-15fl-hydroxycholesta-5-en-3-one; 4,4-dimethyl-15α-hydroxycholesta-5-en-3-one; 4,4-dimethyl-I 6R-hydroxycholesta-5-en-3-one; 4,4-dimethyl-1 6α-hydroxycholesta-5-en-3-one; 4,4-dimethyl-1 7R-hydroxycholesta-5-en-3-one; 4,4-dimethyl-1 7α-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(20R)-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(20S)-hydroxycholesta-5-en-3-one; 4,4-dimethyl-21-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(22R)-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(22S)-hydroxy-cholesta-5-en-3-one; 4,4-dimethyl-(23R)-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(23S)-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(24R)-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(24S)-hydroxycholesta-5-en-3-one; 4,4-dimethyl-25-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(25R)-26-hydroxycholesta-5-en-3-one; 4,4-dimethyl-(25S)-26-hydroxycholesta-5-en-3-one; 4,4-dimethyl-1 β-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-1α-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-2β-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-2α-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-7βhydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-7α-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-11β-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-11 cc-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-12β-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-12α-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-151-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-15α-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-1613-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-16α-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-i 71-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-17α-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-(20R)-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-(20S)-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-21hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-(22R)-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-(22S)-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-(23R)-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-(23S)-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-26-hydroxycholesta-5,24-dien-3-one; spiro[7β-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[7α-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[11β-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[11cc-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[12β-hydroxycholesta-5-en-3-one4,1′-cyclopropane]; spiro[12α-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[1513-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[15α-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[16β-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[16(α-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[17β-hydroxycholesta-5-en-3-one4,1′-cyclopropane]; spiro[17α-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(20R)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(20S)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[21-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(22R)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(22S)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(23R)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(23S)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(24R)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(24S)-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[25-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(25R)-26-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[(25S)-26-hydroxycholesta-5-en-3-one-4,1′-cyclopropane]; spiro[7βhydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[7α-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[11β-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[1 α-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[1 2R-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[12α-hydroxycholesta-5,24-dipn-3-one-4,1′-cyclopropane]; spiro[15β-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[15α-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[161-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[16α-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[17β-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[17α-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[(20R)-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[(20S)-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[21-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[(22R)-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[(22S)-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[(23R)-hydroxy-cholesta-5,24-dien-3-one-4,1′-cyclopropane]; spiro[(23S)-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane]; and spiro[26-hydroxycholesta-5,24-dien-3-one-4,1′-cyclopropane].

[0240] Pharmaceutical Compositions

[0241] Pharmaceutical compositions comprising a compound of formual IIa or an ester thereof may further comprise carriers, diluents, absorption enhancers, preservatives, buffers, agents for adjusting the osmotic pressure, tablet disintegrating agents and other ingredients which are conventionally used in the art. Examples of solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter.

[0242] Liquid compositions include sterile solutions, suspensions and emulsions. Such liquid compositions may be suitable for injection or for use in connection with ex vivo and in vitro fertilization. The liquid compositions may contain other ingredients which are conventionally used in the art, some of which are mentioned in the list above.

[0243] Further, a composition for transdermal administration of a compound of this invention may be provided in the form of a patch and a composition for nasal administration may be provided in the form of a nasal spray in liquid or powder form.

[0244] The dose of a compound of the invention to be used will be determined by a physician and will depend, inter alia, on the particular compound employed, on the route of administration and on the purpose of the use.

[0245] The compounds of formula 1a and esters thereof can be synthesized by methods known per se.

[0246] The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following exarriples may, in any combination thereof, be material for realizing the invention in diverse forms thereof.

EXAMPLES

Example 1

[0247] Testing of cholest-5-en-3β,4β-diol as meiosis activating substance in the oocyte test.

[0248] Animals

[0249] Oocytes were obtained from immature female mice (C57B1/6J×DBA/2J F1-hybrids, Bomholtgaard, Denmark) weighing 13-16 grams, that were kept under controlled lighting and temperature. The mice received an intra-peritoneal injection of 0.2 ml gonadotropins (Gonal-F, Serono, Solna, Sweden, containing 20 IU FSH, alternatively, Puregon, Organon, Swords, Ireland containing 20 IU FSH) and 48 hours later the animals were killed by cervical dislocation.

[0250] Collection and culture of oocytes

[0251] The ovaries were dissected out and the oocytes were isolated in Hx-medium (see below) under a stereo microscope by manual rupture of the follicles using a pair of 27 gauge needles. Spherical oocytes displaying an intact germinal vesicle (GV) were divided in cumulus enclosed oocytes (CEO) and naked oocytes (NO) and placed in a-minimum essential medium (α-MEM without ribonucleosides, Gibco BRL, Cat. No. 22561) supplemented with 3 mM hypoxanthine (Sigma Cat. No. H-9377), 8 mg/ml Human Serum Albumin (HSA, State Serum Institute, Denmark), 0.23mM pyruvate (Sigma, Cat. No S-8636), 2 mM glutamine (Flow Cat. No. 16-801), 100 lU/ml penicillin and 100 μg/ml streptomycin (Flow, Cat No. 16-700). This medium was designated Hx-medium.

[0252] The oocytes were rinsed three times in Hx-medium and oocytes of uniform size were divided into groups of CEO and NO. CEO and NO were cultured in 4-well multidishes (Nunclon, Denmark) in which each well contained 0.4 ml of Hx-medium and 35-45 oocytes. One control (i.e., 35-45 oocytes cultured in Hx-medium with no addition of test compound) was always run simultaneously with the test cultures, which were made with different concentrations of the compounds to be tested as indicated in the tables below.

[0253] The cultures were performed at 37° C. and 100% humidity with 5% CO2 in air. The culture time was 22-24 hours.

[0254] Examination of oocytes

[0255] By the end of the culture period, the number of oocytes with germinal vesicle (GV) or germinal vesicle breakdown (GVB) and those with polar body (PB) was counted using a stereo microscope or an inverted microscope with differential interference contrast equipment. The percentage of oocytes with GVB per total number of oocytes and the percentage of oocytes with PB per total number of oocytes was calculated in the test cultures and compared to the control culture.

[0256] Activation of meiosis in oocytes using cholest-5-en-3β,4β-diol.

[0257] Source of compound: Steraloids Inc., Wilton, NH, USA, Cat. No. C 6410, Batch No. LI 066. The results are given in the tables below:

1Testconcentration% GVB% PBμMNO:18.6 1.7control50.217.27.0CEO:27.010.8control44.425.97.0

[0258] As it appears from the tables, cholest-5-en-30,4,diol induces meiosis in both naked and cumulus enclosed oocyte when cultured in vitro.

EXAMPLE 2

[0259] Test of meiosis inhibiting substances in the oocyte test.

[0260] Germinal vesicle (GV) oocytes were obtained from immature FSH treated female mice using the same methods as described in Example 1 (see above). The oocytes were rinsed three times in Hx-medium and oocytes of uniform size were divided into groups of CEO and NO. 4,4-Dimethylcholest-8,14,24-trien-3β-ol (FF-MAS) has previously been shown to induce meiosis in CEO and NO in vitro (Byskov, A. G. et al. Nature 374 (1995) 559-562). CEO and NO were cultured in Hx-medium supplemented with 0.7-7.0 μM FF-MAS in co-culture with the test compounds in different concentrations in 4-well multidishes (Nunclon, Denmark) in which each well contained 0.4 ml of Hx-medium and 35-45 oocytes. One control (i.e., 3545 oocytes cultured in Hx-medium containing FF-MAS with no addition of test compound) was always run simultaneously with the test cultures, which were supplemented with different concentrations of the compounds to be tested.

[0261] Test results for the inhibition of meiosis in oocytes using cholest-5-en-3β,(22R)-diol (in the following designated “22R”) are given in the tables below:

2FF-MAS22RConcentrationconcentrationconcentrationratio% GVB% PBμMμMFF-MAS:22RNO:19.59.51.2—Control4.601.2251:2033.07.80.7—Control16.900.7131:192.900.7251:36CEO:21.710.80.7—Control6.93.40.7251:3639.018.97—Control213.57 12.51:2

[0262] As it appears from the tables, 22R antagonises the FF-MAS induced resumption of meiosis in a dose-related manner.

[0263] This invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof. The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and all changes which come within the meaning and range of equivalency are embraced therein.

EXAMPLE 3

[0264] 4,4-Dimethylcholesta-5,8-diene-3-one

[0265] The D-8-double bond is introduced as described in the literature [J. Lip. Res. 37, 1529, (1996)]. According to the literature procedure, cholesta-5,8-diene-3β-ol is prepared in a three step sequence. This alcohol is oxidized in a classical Oppenauer oxidation [Helv. Chim. Acta 22, 1178, (1939)] to give cholesta-4,8-diene-3-one. This ketone is used as a starting material for some of the following compounds.

[0266] Potassium tert-butylate (550 mg) is dissolved in 13 ml tert-Butanol at 45° C. A solution of cholesta-4,8-diene-3-one (470 mg) in 1.5 ml tetrahydrofuran is added dropwise. After 10 minutes, methyliodide (0,63 ml) is added. The reaction mixture is stirred for one hour. After aqueous work-up and column chromatography, 4,4- dimethyl-cholesta-5,8-diene-3-one (310 mg) is isolated.

[0267]

1
H-NMR (CDCl3): δ=0.64 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (d, J=7 Hz, 3H, H-21); 1.04 (s, 3H, H-19); 1.24 (s, 3H, 4—CH3); 1.29 (s, 3H, 4—CH3); 2.63 (m, 2H, H-7); 5.69 (t, J=3 Hz, 1H, H-6). C29H46=,MW (Molecular Weight): 410.684.

Example 4

[0268] 4,4-Dimethylcholesta-5,8-diene-3β-ol

[0269] 4,4-Dimethylcholesta-5,8-diene-3-one (100 mg) is reduced with lithiumaluminumhydride (5 mg) in 2 ml tetrahydrofuran at room temperature. The solution is stirred for one hour. After aqueous work-up and column chromatography 4,4-dimethylcholesta-5,8-diene-3β-ol (60 mg) is isolated.

[0270]

1
H-NMR (CDCl3): δ=0.63 ppm (s, 3H, H-18); 0.86 (s,x d, J=7 Hz, 6H, H-26/27); 0.94 (d, J=7 Hz, 3H, H-21); 1.12 (s, 3H, H-19); 1.15 (s, 3H, 4-CH3) 1.21 (s, 3H, 4-CH3); 2.56 (m, 2H, H-7); 3.82 (dd, J=10 Hz J=5 Hz, 1H H-3); 5.75 (t, J =3 Hz, 1H, H-6). C29H48O, MW: 412.700.

Example 5

[0271] Cholesta-5,8-diene-3βyl acetate

[0272]

1
H-NMR (CDCl3): δ=0.64 ppm (s, 3H, H-18); 0.87 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (d, J=7Hz, 3H, H-21); 1.20 (s, 3H, H-1 9); 2.03 (s, 3H, 3-OAc) 2.28 (m, 2H, H-4); 2.53 (m, 2H, H-7); 4.61 (m, 1H, H-3); 5.45 (m, 1H, H-6). C,H4602, MW: 426.683. J. Lipid Res. 37, 1529, (1996).

Example 6

[0273] 5β-Cholest-8-ene-3β,5β-diol

[0274] Cholesta-5,8-diene-3-on is epoxidized in analogy to a literature procedure [J. Med. Chem. 39, 5092, (1996)] to give 4α,5-epoxy-5α-cholest-8-en-3-on. This is reduced as described below. 4α,5-Epoxy-5α-cholest-8-en-3-on (75 mg) is dissolved in 3 ml tetrahydrofuran. Lithiumaluminumhydride (30 mg) is added at room temperature. The reaction mixture is stirred for 15 hours. After aqueous work-up and column chromatography 5βcholest-8-ene-3β,5β-diol (19 mg) and 5βcholest-8-ene-3α,5,diol (24 mg) are isolated.

[0275]

1
H-NMR (CDCl3): δ=0.63 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (d, J=7 Hz, 3H, H-21); 1.06 (s, 3H, H-19); 2.53 (broad, 1H, OH) 4.09 (m, 1H, H-3). C27H46O2, MW: 402.661.

Example 7

[0276] 5β-Cholest-8-ene-3α,5β-diol

[0277]

1
H-NMR (CDCl3): δ0.63 ppm (s, 3H, H-18); 0.87 (2×d, J=7 Hz, 6H, H-26127); 0.94 (d, J=7 Hz, 3H, H-21); 0.99 (s, 3H, H-1 9); 3.97 (m, 1H, H-3). C27H46O2, MW: 402.661.

Example 8

[0278] 4,4-Dimethylcholesta-5,7,14-triene-3-one

[0279]

1
H-NMR (CDCl3): δ=0.87 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (s, H3); 0.95 (d, J=7 Hz, 3H, H-21); 1.09 (s, 3H); 1.17 (s, 3H, 4-CH3); 1.36 (s, 3H, 4-CH3); 5.69 (s, 1H, H-14); 6.05 (d, J=10 Hz, 1H, H-7); 6.57 (d, J=10 Hz, 1H, H-6); C29H44O, MW: 408.668. J. Chem. Soc. P.T. 1, 812, (1977).

Example 9

[0280] 3β(Acetyloxy)-5α-cholest-8-ene-6α-ol

[0281] Cholesta-5,8-diene-3β-yl acetate (1.0 g) is dissolved in 250 ml diethylether. The reaction mixture is cooled to 0° C. and 2.35 ml of borane-dimethylsulphide-complex (2 M solution in tetrahydrofuran) is added. The reaction mixture is warmed to room temperature within 2 hours. Then, 26 ml water, 26 ml sodium hydroxyde solution (10 % aqueous) and 3.65 ml hydrogen-peroxyde (30%) are added at 0° C. After aqueous work-up and column chromatography 3β-(acetyloxy)-5α-cholest-8-ene-6α-ol (140 mg) is isolated.

[0282]

1
H-NMR (CDCl3): δ=0.59 ppm (s, 3H, H-18); 0.87 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (d, J =7 Hz, 3H, H-21); 0.99 (s, H3, H-19); 2.03 (s, 3H, 3-OAc); 2.26 (m, 1H); 2.48 (m, 1H); 3.72 (m, 1H, H-6); 4.69 (m, 1H, H-3); C29H48O3, MW: 444.698.

Example 10

[0283] 5α-Cholest-7-ene-3β,5α,6β-triol

[0284]

1
H-NMR (CDCl3): δ=0.59 ppm (s, 3H, H-18); 0.87 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (d, J=7 Hz, 3H, H-21); 1.08 (s, H3, H-19); 3.63 (m, IH, H-6); 4.08 (m, 1 H, H-3); 5.35 (m, 1H, H-7). C27H46O3, MW: 418.660. J. Org. Chem. 50, 1835, (1985).

Example 11

[0285] Cholesta-5,8,14-triene-3β-ol

[0286] Cholesta-5,8-diene-3β-ol (1.54 g) is dissolved in 50 ml dichloromethane. A solution of m-chloroperoxybenzoic acid (1.04 g) in 50 ml dichloromethane is added at room temperature. The reaction mixture is stirred for 5 hours.

[0287] After aqueous work-up and subsequent column chromatography 8α,9α-epoxycholest-5-en-3β-ol (740 mg) is isolated.

[0288] 8α,9α-Epoxycholest-5-en-3βol (200mg) is dissolved in dichloromethane and the solution is cooled to 0° C. 1.5 ml of a diethylaluminumcyanide-solution (1 M in toluene) is added dropwise. After addition, the reaction mixture is warmed to room temperature and stirred for additional 18 hours. After basic work-up and column chromatography, cholesta-5,8,14-triene-3βol (51 mg) is isolated.

[0289]

1
H-NMR (CDCl3): δ=0.84 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (d, J=7 Hz, 3H, H-21); 1.22 (s, H3, H-1 9); 2.59 (m, IH, H-7); 2.88 (m, 1H, H-7); 3.57 (m, 1H, H-3); 5.38 (m, 1H, H-15); 5.52 (m, 1H, H-6). C27H42O, MW: 382.630.

Example 12

[0290] 1α-Hydroxy-5β-cholestane-3-one

[0291]

1
H-NMR (CDCl3): δ=0.68 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.90 (d, J=7 Hz, 3H, H-21); 1.21 (s, H3, H-19); 3.62 (m, 1H, H-1). C27H46O2, MW: 402.661. J. Chem. Soc. P.T. 1, 2488, (1977).

Example 13

[0292] Cholest-5-ene-3β-9α-diol

[0293] 8α,9α-Epoxycholest-5-en-3β-ol(200 mg) is dissolved in 13 ml diethylamine at −20° C. Lithium (100 mg) is added in small portions. The reaction mixture is stirred for 3 hours. After aqueous work-up, a crude product (207 mg) is isolated. Crystallization from diisopropylether yields cholest-5-ene-3β,9α-diol (62 mg).

[0294]

1
H-NMR (CDCl3): δ=0.68 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.93 (d, J=7 Hz, 3H, H-21); 1.15 (s, H3, H-1 9); 2.37 (m, 1H); 3.52 (m, 1H, H-3); 5.40 (m, 1H, H-6). C27H46O2, MW: 402.661.

Example 14

[0295] 5α-Cholest-7-ene-3β-5α-diol

[0296]

1
H-NMR (CDCl3): δ=0.56 ppm (s, 3H, H-1 8); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.92 (s, 3H, H-19); 0.94 (d, J=7 Hz, 3H, H-21); 2.24 (m, IH); 4.05 (m, 1H, H-3); 5.08 (m, 1H, H-7). C27H4602, MW: 402.661. Biochem. J. 105, 1194, (1967).

Example 15

[0297] 5α-Cholestane-1α-3α-diol

[0298] 1α-Hydoxy-5βcholestane-3-one [J. Chem. Soc. Perkin. Trans. 1, 1977, 2488] (110 mg) is dissolved in 6 ml ethanol.

[0299] Sodiumborohydride (52 mg) is added at room temperature in one portion. The reaction mixture is stirred for 4 hours. After aqueous work-up and column chromatography, 5β-Cholestane-1α,3α-diol (75 mg) is isolated.

[0300]

1
H-NMR (CDCl3): δ=0.64 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.88 (d, J=7 Hz, 3H, H-21); 1.12 (s, 3H, H-1 9); 3.29 (dd, J=12 Hz, J=3 Hz, 1H, H-1); 3.77 (m, 1H, H-3). C27H48O2, MW: 404.677.

Example 16

[0301] 5α-Cholestane-3β-5β-diol

[0302]

1
H-NMR (CDCl3): δ=0.65 ppm (s, 3H, H-1 8); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.92 (d, J=7 Hz, 3H, H-21); 0.95 (s, 3H, H-19); 2.01 (m, 1H, H-4); 2.20 (dd, J=15 Hz, J=4 Hz, 1H, H-4); 3.00 (broad, 1H, OH); 4.13 (m, 1H, H-3). C27H48O2, MW: 404.677. J. Org. Chem. 27, 1433, (1962).

Example 17

[0303] 5ECholestane-3α-5β-diol

[0304]

1
H-NMR (CDCl3): δ=0.64 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.89 (s, 3H, H-19); 0.91 (d, J=7 Hz, 3H, H-21); 4.02 (m, 1 H, H-3). C27H48O2, MW: 404.677. J. Org. Chem. 27, 1433, (1962).

Example 18

[0305] 5α-Cholestane-3α-5α-diol

[0306]

1
H-NMR (CDCl3): δ=0.65 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 6H, H-26/27); 0.92 (d, J=7 Hz, 3H, H-21); 0.95 (s, 3H, H-1 9); 3.25 (broad, 1H, OH); 4.10 (m, 1H, H-3). C27H48O2, MW: 404.677. J. Chem. Soc., 4482, (1961).

Example 19

[0307] 32(Benzoyloxy)-22-hydroxy-4,4-dimethyl-5α-cholest-8(14)-ene-15,24-dione 1H-NMR (CDCl3): δ=0.85 ppm (s, 3H, H-18); 0.96-1-16 (m, 18H, H-1 9, H-21, 2x4-CH3, H-26/27); 2.6 (m, IH, H-25); 3.3 (d, J=2 Hz, 1H, 22-OH); 4.06 (m, 1H, H-22); 4.22 (m, 1H, H-7); 4.8 (dd, J=11 Hz, J=5 Hz, 1 H. H-3). C36H50O5, MW: 562.790. J. Am. Chem. Soc. 11 (1989), 278.

Example 20

[0308] 3β-(Benzoyloxy)-4,4-dimethyl-5α-cholest-8(14)-ene-15,24-dione

[0309]

1
H-NMR (CDCl3): δ=0.85 ppm (s, 3H, H-18); 0.97 -1-14 (m, 18H, 2×4—CH3, H-19, H-21, H-26/27); 2.6 (m, 1H, H-25); 4.21 (m, 1H, H-7); 4.8 (dd, J=11 Hz, J=5 Hz, 1H, H-3). C36H50O4, MW: 546.791. J. Am. Chem. Soc. 11(1989), 278.

Example 21

[0310] 3β-(Benzoyloxy)-24-hydroxy-4,4-dimethyl-5α-cholest-8(14)-ene-15-one

[0311]

1
H-NMR (CDCl3): δ=0.85 ppm (s, 3H, H-18); 0.88 - 1-04 (m, 18H, H-19, H-21, 2×4-CH3, H-26/27); 2.38 (m, 1H, H-16); 3.31 (m, 1H, H-24); 4.21 (m, 1H, H-7); 4.8 (dd, J=11 Hz, J=5 Hz, 1 H, H-3). C36H52O4, MW: 548.807. J. Am. Chem. Soc. 11(1989), 278.

Example 22

[0312] 5βCholest-7-ene-3β,5β-diol

[0313] 5,6βEpoxy-5β-cholest-7-en-3β-ol [J. Org. Chem. 50(1985), 1835] (150 mg) is dissolved in 2.5 ml of a potassium hydroxyde solution (5% in methanol). The reaction mixture is refluxed for one hour. Aqueous work-up, extraction with ethylacetate and column chromatography yields 5βcholest-7-ene-3β,5β-diol (54 mg).

[0314]

1
H-NMR (CDCl3): δ=0.55 ppm (s, 3H, H-18); 0.86 (2×d, J=7 Hz, 9H, H-26/27); 0.92 (s, 3H, H-19); 0.94 (d, J=7 Hz, 3H, H-21); 4.16 (m, 1H, H-3); 5.05 (m, 1H, H-7). C27H46O2, MW: 402.661.

Example 23

[0315] 5β-Cholest-6-ene-3β,5β,8β-triol 1H-NMR (CDCl3): 5=0.66 ppm (s, 3H, H-18); 0.87 (3 x d, J=7 Hz, 9H, H-21/26J27); 1.28 (s, 3H, H-1 9); 2.24 (m, I H); 2.77 (m, 1 H); 3..48 (m, 1 H, H-3); 5.64 (d, J=11 Hz, I H); 5.88 (d, J=11 Hz, 1H). C27H4603, MW: 418.660. J. Org. Chem. 50 (1961), 1835.

Example 24

[0316] 5α-Cholest-8-ene-3β,6α-diol

[0317]

1
H-NMR (CDCl3): δ=0.60 ppm (s, 3H, H-18); 0.87 (2×d, J=7 Hz, 6H, H-26/27); 0.94 (d, J=7 Hz, 3H, H-21); 0.98 (s, 3H, H-1 9); 2.48 (m, 1H); 3.62 (m, 1H, H-3); 3.75 (m, 1H, H-6). C27H46O2, MW: 402.661. Proc. Chem. Soc. London, 450, (1961).

Example 25

[0318] 5β-Cholest-8-ene-3β,6β-diol

[0319] 3β-(Acetyloxy)-5α-cholest-8-ene-6α-ol (124 mg) is dissolved in 20 ml ethanol. Solid potassium hydroxyde (710 mg) is added and the reaction mixture is stirred for 2 hours. After aqueous work-up, 5β-cholest-8-ene-3β,6β-diol (96 mg) is isolated.

[0320]

1
H-NMR (CDCl3): δ=0.65 ppm (s, 3H, H-18); 0.87 (2×d, J=7 Hz, 6H, H-26/27); 0.93 (d, J=7 Hz, 3H, H-21); 1.14 (s, 3H, H-1 9); 2.33 (m, 2H); 3.83 (m, 2H, H-3/6). C27H46O2, MW: 402.661.

Example 26

[0321] (24R,S)-4,4-Dimethyl-5α-cholesta-8,14-dien-3β,24-diol

[0322]

1
H-NMR (CDCl3): 5.36 ppm (s, 1H); 3.33 (m, 1 H); 3.23 (dd, I H); 1.05 (s, 3H); 1.02 (s, 3H); 0.92 (m, 9H); 0.84 (s, 3H); 0.81 (s, 3H).

[0323] This compound was separated into the (24R) and the (24S) isomers.

	Number	Date	Country
Parent	09333391	Jun 1999	US
Child	09764203	Jan 2001	US
Parent	PCT/DK97/00584	Dec 1997	US
Child	09333391	Jun 1999	US

Meiosis regulating compounds

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