Specification
FIELD OF THIS INVENTION
The present invention relates to certain pharmacologically active compounds, to pharmaceutical compositions containing certain compounds as active substance and to their use as medicaments. More particularly, it has been found that the derivatives described herein can be used for regulating the meiosis.
BACKGROUND OF THIS INVENTION
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 (1n) of chromosomes and 2c DNA. The second meiotic division proceeds without a DNA synthesis. This division, therefore, results in the formation of the haploid germ cells with only 1c DNA.
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 fertilisation, and results in 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 ceil proceeds without significant delay and produces 4 spermatozoa.
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 a/. Dev.BioL 82 (1985) 454-458; Eppig, J.J. et at. Dev. Biol. 119 (1986) 313-321; and Downs, S.M. Mol.Reprvd.Dev.
35 (1993), 82-94). The presence of a diffusible meiosis regulating substance was first described by Byskov et a/, in a culture system of fetal mouse gonads (Byskov, A.G. et al. in 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. in 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 utilisation of the interesting finding would thus be greatly facilitated if more stable rpeiosis activating compounds were available.
In AustJ.Chem. 35 (1982), 629-640, Horn et al. deals with compounds possibly having biological activity (insect moulting hormones). Examples of compounds specifically mentioned therein are 5-cyano-5(3-cholest-7-en-3-one; 5-cyano-5(3-cholest-7-en-3|3-ol; 5-methyl-5{3-cholest-7-en-3-one; 5-methyl-5p-choIest-7-en-3β-ol; and 5-methyl-5p-cholest-7-en-3p-ol.
In Bull.Soc.Chim.Fr. (1971), 2037-2047, Levisalles et al., cholesta-4,8(14)-dien-3-one is described as an intermediate.
In Just.Lieb.Ann.Chem. 542 (1939), 218-224, Windaus et al. mentions cholesta-4,7-dien-3-one; cholesta-4,7-dien-3a-ol; and cholesta-4,7-dien-3p-ol as intermediates.
In Pharm.Bull. 1 (1953), 224-227, Arima mentions cholesta-4,8-dien-3-one as intermediate.
In Lipids 13 (1978), 704 et seq., Kandutsch et al. describes some cholestane derivatives which may be potent inhibitors of sterol synthesis. Compounds specifically mentioned therein are, in Fig. 1, 3p,7a-dihydroxycholest-5-ene; 3p,7J3-dihydroxycholest-5-ene; 3(3-hydroxycholest-5-en-7-one; 3p-hydroxycholest-7-one; 7a-hydroxycholest-4-en-3-one; in Fig. 2 (compounds 1-5), cholest-3,6-dione; 3(3-hydroxycholest-6-one; 3p,6p-dihydroxycholestane; cholest-4-en-3,6-dione; 3p,5ct,6p-trihydroxycholestane; in Fig. 3, 3p,5a-dihydroxycholestane; 3p,4p-dihydroxycholest-5-ene; and, in Fig. 4 (compounds 1, 3, 4 and 5), cholest-2-en-6-one; cholest-4,6-dien-3-one; cholest-4,7-dien-3-one; cholest-3,5-dien-7-one.
Danish patent application with publication number 130,992, deals with compounds possibly having progestomimetic properties. Examples of compounds specifically mentioned
therein are 19-nor-21-methylpregna-4,9-dien-17a-hydroxy-3,20-dione; 19-nor-21-methyl-pregna-4,9-dien-17a-acetoxy-3,20-dione; 19-nor-21,21-dimethylpregna-4,9-diene-17a-hydroxy-3,20-dione; and 17a-21,21-dimethyl-19-nor-pregna-4,9-dien-3,20-dione.
In the Danish patent application with publication number 136,909, 3ct-acetoxy-24-nor-cholan-23-one; 3a-hydroxy-26,27-di-nor-23-trans-5|3-cholest-23-en-25-carboxylicacid methyl ester; 3a-hydroxy-26,27-di-nor-5p-choiesta-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-5p-cholesta-25-carboxylic acid methyl ester; 3-keto-4-bromo-26,27-di-nor-5p-cholesta-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-cholest-4-en-25-carboxylic acid methyl ester; 3p-acetoxy-26,27-di-nor-cholesta-3,5-dien-25-carboxylic acid methyl ester; 3(3-hydroxy-26,27-di-nor-cholest-5-en-25-carboxylic acid methyl ester; 3-keto-26,27-di-nor-cholest-4, 6-dien-25-carboxylic acid methyl ester; 3p-hydroxy-26,27-di-nor-cholesta-3,5,7-trien-25-carboxylic acid methyl ester; and 3p-hydroxy-26,27-di-nor-cholesta-5,7-dien-25-carboxylic acid methyl ester are mentioned as intermediates.
Danish patent application with publication number 146,390, deals with compounds possibly having pharmacological properties, e.g. an inhibiting action on the production of serum cholesterol. Examples of compounds specifically mentioned therein are 3(3,22-di-acetoxycholesta-5-en-25-ol; 3p,22-diacetoxy-25-fluorocholesta-5-ene; 22-hydroxycholesta-5-en-25-fluoro-3p-hemisuccinate; 3p,22-diacetoxy-25-dichlorocholesta-5-ene; 3p,22-dihydroxy-25-chlorocholesta-5-ene; 22-hydroxy-25-chlorocholesta-5-en-3p-hemisuccinate; 3p,22-dihydroxy-25-bromocholesta-5-ene; and 3p,22-dihydroxy-25-fluorocholesta-5-ene.
In the Danish patent applications with publication numbers 156,726 and 156,644, cholenic acid; 3p-acetoxycholesta-5-en-25-des-dimethyl-24-one; 3,24-diacetoxycholesta-25-des-dimethyl-5, 23-diene; 3p-acetoxycholesta-25-des-methyl-5-en-24-difluoro-25-one; and 3p-acetoxy-24-difluorocholesta-5,7-dien-25-ol are mentioned as intermediates.
In the Danish patent application with publication number 158,790, 3p-hydroxy-cholest-5-en-24-one; 3p-acetoxycholest-5-en-24-one; 5p-cholest-24-one; 5P-cholestan-24a-homo-24-one; 3a,6a-dihydroxy-5p-cholest-24-one; 3a,6a-diacetoxy-5p-cholest-24-one; 3a,6a-diacetoxy-5p-cholest-24a-homo-24-one; 3a,6a-dihydroxy-5p-cholest-24a,24p-bis-homo-24-one; 3a-hydroxy-5p-cholest-24-one; 3a-acetoxy 5p-cholesta-24-one; 3a-benzoyl-oxy-5p-cholesta -24-one; 3a-ethyloxycarbonyloxy-5p-cholesta- 24-one; 3a-hydroxy-5p-cholestan-24a-homo-24-one;3a-hydroxy-24a,24p-bis-homo-5p-cholestane;3p-hydroxy-cholesta-5,7-dien-24-one; 3p-acetoxycholesta-5,7-dien-24-one; 1 cc,3p-dihydroxycholesta-5,7-diene-24-one; and 1a,3p-diacetoxycholesta-5,7-diene-24-one are mentioned as intermediates.
Danish patent application with publication number 159,456, deals with compounds possibly having utility in the treatment of gall diskinese. Examples of compounds specifically mentioned therein are chenodeoxycholic acid; ursodeoxycholic acid; trimebutyn salt of che-nodeoxycholic acid; and trimebutyn salt of ursodeoxycholic acid.
In the Danish patent application with publication number 162,648, 3p,25-dihydroxy-cholest-5-en-24-one; 3β-acetoxycholest-5-en-24-one; 3(3-acetoxy-25-hydroxychoiest-5-en-24-one; 3p,25-dihydroxycholest-5-en-24-one; 3p-hydroxycholest-5-en-24-one; 3(3-hydroxy-25-hydroperoxycholest-5-en-24-one; 3p,24,25-trihydroxycholest-5-ene; 1a,3(3-dihydroxy-cholest-5-en-24-one; 1 a,3p,25-trihydroxycholest-5-en-24-one; 1 a,3p,24,25-tetrahydroxy-cholest-5-en-24-one are mentioned as intermediates.
In the Danish patent application with publication number 165,410, 3
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