MXPA00012686A - Meiosis regulating compounds - Google Patents

Abstract

Certain novel sterol derivatives having no hydroxy group in the 3 position can be used to regulate the meiosis in oocytes and in male germ cells.

Description

COMPOUNDS TO REGULATE THE MEIOSIS FIELD OF THE INVENTION The present invention relates to certain pharmacologically active compounds, to new pharmaceutical compositions containing certain compounds as an active substance and to the new use of certain compounds as medicaments. More particularly, it has been found that the compounds described herein can be used to regulate eosis. BACKGROUND OF THE INVENTION Meiosis is the only and final event of the germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, an exchange is made between the maternal and paternal genes before the pairs of chromosomes separate into the two daughter cells. These contain only half the number (ln) of chromosomes and DNA 2 C. The second meiotic division proceeds without DNA synthesis. Therefore, this division results in the formation of aploid germ cells with only DNA le. The meiotic events are similar in male and female germ cells, but the period of time and differentiation processes that produce the ovule and the Ref: 125870 sperm differ profoundly. All female germ cells enter the prophase of the first meiotic division in an early stage of life, often before birth, but all remain as oocysts in a later stage of the prophase (dictiato state) until ovulation after the birth. puberty. Thus, from an early stage of life, the woman has a number of oocysts that are removed until that amount is finished. Meiosis in women is not complete until after fertilization and results in only one egg and two abortive polar bodies per germ cell. In contrast, only some of the male germ cells enter oseosis from puberty and leave a population of germ cells during life. Once initiated, meiosis in the male cell proceeds without significant delays and produces four sperm cells. Little is known about the mechanisms that control the onset of iosis in male and female cells. In the oocysts, new studies indicate that follicular purines, hypoxanthine and adenosine, could be responsible for meiotic arrest (Downs, SM, et al., In Dev. Bio, 82 (1985), 454-458; Eppig, JJ, et al., in Dev. Biol. 119 (1986), 313-321; and Downs, SM, in Mol. Reprod Dev. 35 (1993), 82-94). The presence of a substance regulating diffusible meiosis was first described by Byskov et al. in a fetal mouse gonad culture system (Byskov, a.G. et al., in Dev. Biol. 52 (1976), 193-200). A miosis activating substance (MAS) was secreted by the murine fetal ovary, where miosis continued and a meiosis preventive substance (MPS) was released from the morphologically differentiated testes, with resting non-meiotic germ cells. It was suggested that the relative concentrations of MAS and MPS regulated the initiation, arrest and resumption of miosis in male and female germ cells (Byskov, AG et al., In The Physiology of Reproduction (editors: Knobil, E., and Neill, JD, Raven Press, New York (1994).) Clearly, if meiosis can be regulated, reproduction can be controlled.In the journal Nature 374 (1995), 559-562, Byskov et al., Describe the isolation of testicles. of bull and human follicular fluid, of certain sterols that activate the meiosis of oocysts Unfortunately, these sterols are very weak and the use of this interesting finding, therefore, could be greatly facilitated if activating compounds were available. The most stable meiosis, Biochim Biophys, Acta 1299 (1996), 313, describes the mechanism and structural requirements for the transformation of substrates by a specific transferase and mentions, eg, coloest-4, 8, 24-triene and the 25-azaco lest-5-ene (compounds 21 and 42 of Fig. 2). Bull newsletter. Chem. Soc. Belg. 92 (1983), 731, describes magnetic resonance spectra of some steroids, e.g. of cholestane (compound g of Table V). The magazine Collect. Czech Chem. Comm. 63 (1998), 549, discusses the preparation of some steroids, e.g. of cholesta-3, 5-diene; cholest-2-ene; and cholest-5-ene (compounds 2, 5 and 7). Environ. Sci. Tech. 23 (1989), 688, discusses the chemical composition of environmental tobacco smoke and mentions, e.g., cholesta-3, 5-diene; 24-methylchocolate-3, 5-diene; 24-ethylcholesterol-3, 5, 22-diene; and 24-ethylcholesterol-3, 5-diene (compounds e, f, g and h in Figure 6). Geochim Cosmochim 51 (1987), 3051, deals with steroid geochemistry in the minimum oxygen zone of the North Pacific Ocean in the eastern tropical area and mentions, for example, colest-2-ene and colest-3, 5-diene (compounds 5 and 8 of Table 6). Geochim Cosmochim 55 (1991), 1065, discusses the analysis and presence of 26 carbon atoms in petroleum and parent rocks and mentions, eg, 24-nor-5a-cholestane and 24-nor-5β-cholestane (lBb and IBa compounds). of Figure 3).

Geochim Cosmochim Acta 57 (1993), 4539, describes the norcolestano in siliceous sediments of Miocene Onnagawa in Japan and mentions, e.g., (20R) -5β, 14a, 17a (H) -cholesterol; (20R) -5a, 14β, 17β, (H) -cholesterol; (20R) -5a, 14a, 17a (H) -cholesterol; (20R) -5β, 14a, 17a (H) -24-methylcholesterol; (20R) -5a, 14a, 17a (H) -24-methylcholestane; (20R) -5β, 14a, 17a (H) -24-ethylcholesterol and (20R) -5a, 14a, 17a (H) -24-ethylcholesterol (peaks 3a, 3b, 6, 8, 10, 12 and 13). The Initial eports of the Deep Sea Drilling Project 62, 923, is about lipids of the alubial limestone and mentions, e.g., 4-methyl-5 a-24-norcoleestane; 5a-cholestane; 5ß-cholestane; cholest-4-ene; cholest-5-ene and 4-methylcholesterol (compounds L, O and N of Table 1, compounds XlVa and XVa of Table 3 and compound 9 of Table 14). Initial Reports of the Deep Sea Drilling Project 63, 763, deals with the preliminary lipid analysis of sediments from the North Pacific Ocean in its East region and mentions, e.g., (20S) -5a, 14a, 17a-cholestane; (20R) -5a, 14a, 17a-cholestane; 19-nor-5a-cholestane; 5ß-cholestane; 5a-cholestane; cholest-2-ene; cholesta-3, 5-diene; cholest-4-ene; and cholest-5-ene (compounds Vlli and VIIj of Table 1, compounds XVj, VIIj and VIIj of Table 2, compounds XIj and XIVj of Table 3 and compounds XIIj and XIIIj of Table 5). Initial Reports of the Deep Sea Drilling Project 63, 837, describes the organic geochemistry of sediments from the southern California coastline and mentions, e.g., nor-cholestane; 5a-8β, 14β-cholestane and 5β, 8β, 14β-cholestane (compounds IX and X). Initial Reports of the Deep Sea Drilling Project 64, 837, describes the organic petrography and extractable hydrocarbons from the Gulf of California sediment and mentions, e.g., 5a-norcolestane, 5β-cholestane; cholest-4-ene; colet-5-ene and 5a-cholestane (peaks e, f, h, i and j of Table 2). The J. Chromatog magazine. 116 (1976), 207, deals with the chromatography of saturated steroid hydrocarbons in alumina and mentions, e.g., 5β-cholestane; 5a, 14β-cholestane; 5a, 17β (H) -cholesterol; (20S) -5a, 17β (H) -cholesterol; (24R) -24-methyl-5β-cholestane; (24S) -24-methyl-5β-cholestane; 5a, 8a, 14β-cholestane; (20S) -5a-cholestane; (24R) -24-methyl-5a-cholestane; (24S) -24-ethyl-5a-cholestane; (24S) -24-ethyl-5a-cholestane; 5a-cholestane; 4a-methyl-5a-cholestane; 4β-methyl-5a-cholestane and (24S) -24-methyl-5a-cholestane (Table I).

J. Org. chem. 37 (1972), 2108, describes the chemistry of a diazoketone and its derivatives obtained from colanic acid and mentions, eg, 24-hydroxymethylcolan-24-one and 24-hydroxymethylcolan-24-ol (compounds 6 and 12) . The magazine Marine and Petroleum Geology 5 (1988), 205, deals with the evaluation of geochemical and biological markers of depositional environments using oils from the Brazilian sea and mentions, eg, al (20S) -5a, 14a, 17a-cholestane and al (20R) -5a, 14a, 17a- cholestane (compounds 8 and 10). OPPI Briefs, 16, deals with the synthesis of modified side chain steroids by means of a Wittig reaction and mentions, e.g., colest-24-ene and 24-cyclohexylcolan-24-ene (compounds V and VI). Org. Geochem. 9 (1986), 331, deals with the lipid composition of a crab, its feces and particulate organic matter in the Equatorial North Pacific Ocean and mentions, e.g., cholest-2-ene; cholesta-3, 5-diene; 24-methylcholest-2-ene; and 24-ethylcholest-2-ene (compounds 2, 5, 9 and 15 of Table 1). Org. chem. 19 (1991), 351, deals with structural investigations of macromolecular oil fractions rich in sulfur and a kerogen by sequential chemical degradation and mentions, e.g., 24-propylcolestane (Fig. 15).

In a publication by C. Djerassi in Rearrangement Reactions in Organic Mass Spectroscopy, 199, he mentions for example 5a-cholestane (Fig. 1). In the journal Steroids 18 (1971), 649, steroidal triphenyl salts are described as versatile intermediates for side chain modifications and mentions, eg, colest-24-ene and 24-cyclohexylcolan-24-ene (compounds 4 and 5) . Tetrahedron Letters 22 (1981), 2583, deals with the reduction of dissolved metals by terminal or crown ether and mentions, e.g., 5 a-cholestane and cholest-5-ene (compounds 3 and 6). Tetrahedron Letters 34 (1973), 3175, deals with the identification of alkylated stearanes of 24 carbon atoms by P.M.R spectroscopy. and mentions, e.g., 5a-cholestane and 24-dimethyl-5a-colane (compounds 1 and 2). In the last 21 publications mentioned, no description was found about the pharmacological properties of the specific compounds cited in said publications. Compounds known to stimulate meiosis and are different from the compounds claimed in the present Patent Application are described in International Patent Applications Nos. WO 96/00235, 96/27658, 97/00884, 98/52965 and 98/55498. The compounds described herein have advantages compared to the known compounds. BRIEF DESCRIPTION OF THE INVENTION A main purpose of the present invention is to provide compounds that can be used to regulate meiosis. One purpose of the present invention is to provide compounds and methods useful for alleviating infertility in women and men, particularly mammals, more particularly in humans. In a further objective, the present invention relates to the use of the compounds of the general formula Ib (set forth in the claims, below) and esters, salts, active metabolites and prodrugs thereof, for alleviating infertility in women and men , particularly in mammals, more particularly in humans. In still another preferred embodiment, the present invention relates to compounds of the general formula Ib and esters, salts, active metabolites and prodrugs thereof, as a medicament. In another preferred embodiment, the present invention relates to compounds of the general formula Ib or esters, salts, active metabolites and prodrugs thereof, in the manufacture of a medicament for use in the regulation of meiosis. In another preferred aspect, the present invention relates to the use of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, as a medicament, in particular as a medicament for use in the regulation of meiosis. The compound can be used as such or in the form of a liquid or solid composition containing the auxiliary ingredients conventionally used in the art. In the present context, the expression "regulate meiosis" is used to indicate that certain compounds of the formulas la and Ib can be used to stimulate meiosis in vitro, in vivo or ex vivo. Thus, compounds that can be agonists of a meiosis-activating substance of natural origin, can be used in the treatment of infertility due to sufficient stimulation of meiosis in women and men. Other compounds of the formulas la and Ib, which can be antagonists of a meiosis-activating substance of natural origin, can be used to regulate meiosis, preferably in vivo, so as to make them suitable as contraceptives. In this case, the term "regulation" means partial or total inhibition.

In still another preferred aspect, the present invention relates to the use of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, in the regulation of the meiosis of an oocyst, in particular a mammalian ossice. , more particularly a human oocyst. In yet another preferred aspect, the present invention relates to the use of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, in the stimulation of the meiosis of an oocyst, in particular a mammalian oocyst, more particularly an oocyst human. In yet another preferred aspect, the present invention relates to the use of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, in the inhibition of the meiosis of an oocyst, in particular a mammalian oocyst. , more particularly a human oocyst. In still another preferred aspect, the present invention relates to the use of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, in the regulation of the meiosis of a male germ cell, in particular a cell male mammalian germinal, more particularly a human male germ cell.

In still another preferred aspect, the present invention relates to the use of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, in the stimulation of the meiosis of a male germ cell, in particular a cell male mammalian germinal, more particularly a human male germ cell. In yet another preferred aspect, the present invention relates to the use of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, in the inhibition of the meiosis of a male germ cell, in particular a cell male mammalian germinal, more particularly a human male germ cell. In yet a more preferred aspect, the present invention relates to a method for regulating meiosis in a mammalian germ cell, wherein the method comprises administering an effective amount of a compound of the above formula Ib or an ester, salt, metabolite active and prodrug thereof, to a germ cell that needs such treatment. In still another aspect, the present invention relates to a method for regulating meiosis in a mammalian germ cell, wherein a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, is administered to the Germinal cell administering the compound to a mammal that hosts said cell. In still another aspect, the present invention relates to a method wherein the germ cell whose meiosis is to be regulated by means of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, is an oocyst . In a further aspect, the present invention relates to a method for regulating meiosis in an oocyst, wherein a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, is administered to the oocyst ex vivo. In yet another aspect, the present invention relates to a method for regulating meiosis of a male germ cell by administering a compound of the above formula Ib or an ester, salt, active metabolite and prodrug thereof, to the cell. In yet another additional aspect, the present invention relates to a method by which mature male germ cells are produced by in vivo or in vi tro administration of a compound of the above formula Ib or an ester, salt, active metabolite and prodrug of it, to the testicular tissue that contains immature cells.

In still another additional aspect, the present invention relates to compounds having superior in vitro properties. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, compounds with interesting pharmacological properties are provided. The compounds described herein are useful for regulating meiosis in oocysts and in male germ cells. Surprisingly, it has been found that compounds of the formula Ib that do not have a hydroxy group in the 3-position have a favorable action in the regulation of meiosis. One reason for this surprising action is that a 3-hydroxy group is present in the natural coleterol and in the compounds involved in the biosynthesis thereof, including 4,4-dimethyl-5a-cholesta-8, 14, 24-trien- 3ß-ol (hereinafter referred to as FF-MAS) and 4,4-dimethyl-5a-cholesta-8, 24-dien-3ß-ol. The preferred compounds of the formulas la and Ib are those that have at least one double bond. Other preferred compounds of the formulas la and Ib are those wherein R 1 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R 1 is a halogen.

Other preferred compounds of the formulas la and Ib are those wherein R 1 is methyl. Other preferred compounds of the formulas la and Ib are those wherein R 1 is hydroxy. Other preferred compounds of the formulas Ib are those in which R1 is oxo. Other preferred compounds of the formulas la and Ib are those wherein R2, together with R3, designate an additional bond between the carbon atoms in which R2n and R3 are placed. Other preferred compounds of the formulas la and Ib are those wherein R2 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R2 is hiroxy. Other preferred compounds of the formulas Ib are those in which R2 is alkyl of 1 to 3 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R 2 is alkoxy of 1 to 3 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R2 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R3 is hydrogen.

Other preferred compounds of the formulas la and Ib are those wherein R3 is alkyl of 1 to 4 carbon atoms. The preferred compounds of the formulas la and Ib are those wherein R4 and R'4 are both hydrogen. Other preferred compounds of the formulas la and Ib are those wherein one of R4 and R'4 is hydrogen, while the other is methyl. Other preferred compounds of the formulas la and Ib are those wherein R4 and R'4 are both methyl. Other preferred compounds of the formulas la and Ib are those in which R 4 is a branched or unbranched alkyl of 1 to 6 carbon atoms, optionally substituted with a halogen, hydroxy or cyano group. Other preferred compounds of the formulas la and Ib are those wherein R'4 is a branched or unbranched alkyl of 1 to 6 carbon atoms, optionally substituted with halogen, hydroxy or cyano. Other preferred compounds of the formulas la and Ib are those wherein R 4 is hydroxy and R 4 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms branched or unbranched, which may be substituted by halogen, hydroxy or cyano.

Other preferred compounds of the formulas la and Ib are those wherein R4 and R'4 together denote a methylene radical. Other preferred compounds of the formulas la and Ib are those wherein R4 and R * 4, together with the carbon atom to which they are linked, form a cyclopropane ring. Other preferred compounds of the formulas la and Ib are those in which R4 and R * 4 together with the carbon atom to which they are linked, form a cyclopentane ring. Other preferred compounds of the formulas la and Ib are those wherein R4 and R, together with the carbon atom to which they are linked, form a cyclohexane ring. Other preferred compounds of the formulas la and Ib are those wherein R5 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R5 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R5 is hydroxy. Other preferred compounds of the formulas la and Ib are those wherein R6 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R6 is halogen.

Other preferred compounds of the formulas la and Ib are those wherein R6 is oxo. Other preferred compounds of the formulas la and Ib are those wherein R6 is hydroxy. Other preferred compounds of the formulas Ib are those in which R6, together with R5, designate an additional bond between the carbon atoms in which R5 and R6 are placed. Other preferred compounds of the formulas la and Ib are those wherein R7 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R7 and R'7 together are methylene. Other preferred compounds of the formulas la and Ib are those wherein R7 is hydroxy. Other preferred compounds of the formulas Ib are those in which R7 is methoxy or acetoxy. Other preferred compounds of the formulas la and Ib are those wherein R7 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R7 and R'7 together are oxo. Other preferred compounds of the formulas la and Ib are those wherein R7 and R * 7 together are the group = N0H. Other preferred compounds of the formulas la and Ib are those wherein R7 and R * 7 together are a group of the general formula = NOR36, wherein R36 is alkyl of 1 to 3 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R7 is hydroxy and R'7 is alkyl of 1 to 4 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R7, together with R6 designate an additional bond between the carbon atoms in which R7 and R6 are placed. Other preferred compounds of the formulas la and Ib are those wherein R7, together with R8, designate an additional bond between the carbon atoms in which R7 and R8 are placed. Other preferred compounds of the formulas la and Ib are those wherein R8, together with R9, designate an additional bond between the carbon atoms in which R8 and R9 are placed. Other preferred compounds of the formulas la and Ib are those wherein R8 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R8 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R8 is hydroxy. Other preferred compounds of the formulas la and Ib are those wherein R9 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R9 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R9 is hydroxy. Other preferred compounds of the formulas Ib are those in which R11 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R11 and R'11 together are methylene. Other preferred compounds of the formulas la and Ib are those wherein R 11 is hydroxy. Other preferred compounds of the formulas la and Ib are those wherein R 11 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R 11 is methoxy or acetoxy. Other preferred compounds of the formulas Ib are those where R11 and R'11 together are oxo. Other preferred compounds of the formulas la and Ib are those wherein R1 and R * 11 together are the group = NOH. Other preferred compounds of the formulas la and Ib are those in which R11 and R'11 together form the group of the general formula = NOR37, wherein R37 is alkyl of 1 to 3 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R11 is hydroxy and R'11 is alkyl of 1 to 4 carbon atoms.

Other preferred compounds of the formulas la and Ib are those wherein R 11, together with R 9, designate an additional bond between the carbon atoms in which R 11 and R 9 are placed. Other preferred compounds of the formulas la and Ib are those wherein R 11, together with R 12, designate an additional bond between the carbon atoms in which R 11 and R 12 are placed. Other preferred compounds of the formulas la and Ib are those wherein R 12 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R 12 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R 12 is alkyl of 1 to 4 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R12 is methylene. Other preferred compounds of the formulas la and Ib are those wherein R12 is hydroxy. Other preferred compounds of the formulas la and Ib are those wherein R 12 is methoxy or acetoxy. Other preferred compounds of the formulas la and Ib are those wherein R12 is oxo. Other preferred compounds of the formulas la and Ib are those wherein R12 is the group = N0H.

Other preferred compounds of the formulas la and Ib are those wherein R12 is a group of the general formula = NOR33, wherein R33 is an alkyl of 1 to 3 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R 14 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R 14 is hiroxy. Other preferred compounds of the formulas la and Ib are those wherein R 14, together with R 8, designate an additional bond between the carbon atoms in which R 14 and R 8 are placed. Other preferred compounds of the formulas la and Ib are those wherein R15 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R15 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R15 is alkyl of 1 to 4 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R15 is methylene. Other preferred compounds of the formulas la and Ib are those wherein R15 is hydroxy. Other preferred compounds of the formulas la and Ib are those wherein R15 is methoxy.

Other preferred compounds of the formulas la and Ib are those wherein R15 is oxo. Other preferred compounds of the formulas la and Ib are those wherein R15 is the group = NOH. Other preferred compounds of the formulas la and Ib are those in which R15 is a group of the general formula = NOR32, wherein R32 is alkyl of 1 to 3 carbon atoms. Other preferred compounds of the formulas Ib are those in which R15, together with R14, designate an additional bond between the carbon atoms in which R15 and R14 are placed. Other preferred compounds of the formulas la and Ib are those wherein R16 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R16 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R16 is alkyl of 1 to 3 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R16 is methylene. Other preferred compounds of the formulas la and Ib are those wherein R16 is hydroxy. Other preferred compounds of the formulas la and Ib are those wherein R16 is methoxy.

Other preferred compounds of the formulas la and Ib are those wherein R16 is oxo. Other preferred compounds of the formulas la and Ib are those wherein R16 is the group = NOH. Other preferred compounds of the formulas la and Ib are those wherein R16 is the group of the general formula = N0R34, wherein R34 is alkyl of 1 to 3 carbon atoms. Other preferred compounds of the formulas la and Ib are those wherein R16 together with R17 designate an additional bond between the carbon atoms in which R16 and R17 are placed. Other preferred compounds of the formulas la and Ib are those wherein R17 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R17 is hydroxy. Other preferred compounds of the formulas la and Ib are those wherein R17 is in the a position. Other preferred compounds of the formulas la and Ib are those wherein R 20 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R 20 is hydroxymethyl. Other preferred compounds of the formulas la and Ib are those wherein R 20 is alkyl of 1 to 4 carbon atoms.

Other preferred compounds of the formulas la and Ib are those wherein R20 together with R * 20 designate a methylene group. Other preferred compounds of the formulas la and Ib are those wherein R20 together with R * 20 designate an oxo group. Other preferred compounds of the formulas la and Ib are those wherein R'20 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R'20 is halogen. Other preferred compounds of the formulas la and Ib are those wherein R'20 is methyl. Other preferred compounds of the formulas la and Ib are those wherein R'20 is hiroxy. Other preferred compounds of the formulas la and Ib are those wherein R'22 is hydrogen. Other preferred compounds of the formulas la and Ib are those wherein R22 is 3-methylbutyl. Other preferred compounds of the formulas la and Ib are those wherein R22 is isobutyl. Other preferred compounds of the formulas la and Ib are those wherein R22 is phenyl. Other preferred compounds of the formulas la and Ib are those wherein the long side chain at position 17, i.e. -C (R u) (R -?) -CH (R '2 ¿2¿) s -C (R ^ J) (R ~ J) -C (R24) (R'24) -A (R25) ( R'25) (R "25), is in position B. It should be understood that the above preferred substituents can be combined in any way with each other Examples of preferred and interesting compounds of the general formulas la and Ib are as follows: -5-en-16β-ol; cholest-5-en-16-one; 4, 4-dimethylcholesterol-2,5-dien-16β-ol; cholestan-16β-ol; cholesta-3, 5-diene-16β -ol; cholest-5-en-15ß-ol; cholest-5-en-17a-ol; cholest-5-en-15a-ol; cholest-5-en-16a-ol; 4, 4-dimethylcolest-5 -in-16ß-ol; cholest-3-in-16ß-ol; cholest-4-in-16ß-ol; cholest-2-in-16ß-ol; cholesta-2, 4-dien-16ß-ol; cholesta -2, 5-dien-16β-ol, cholesta-5, 24-dien-16β-ol, cholesta-5, 8-dien-16β-ol, cholesta-5, 7-dien-16β-ol; 4, 4 -dimethylcholesterol-5, 7-diene-16β-ol; 3-methylcholesterol-2, 5-diene-16β-ol; 3ß-methylcolest-5-en-16β-ol; 3a-methylcolest-5-en-16β-ol 3, 4, 4-trimethylchocolate-2, 5-dien-16β-ol; 4, 4-dimethylchocolate-5, 8-diene-16β-ol cholesta-5,8-dien-15β-ol; cholesta-5, 7-dien-15β-ol; 4, 4-dimethylcholest-5-en-15β-ol; 4, 4-dimethylcholest-5-en-15a-ol; 20-methyl-21-phenylpregna-5-en-16β-ol; 20-methyl-21-cyclopentylpregna-5-en-16β-ol; 24-norcolest-5-en-16β-ol; 24-norcolest-16ß-ol; 24-norcolest-5-en-15β-ol; 20-methyl-21- (3-methylphenyl) pregna-5-en-16β-ol; 20-methyl-21- (3-hydroxyphenyl) -pregna-5-en-16β-ol; 20-methyl-21- (3-hydroxyphenyl) -pregna-16β-ol; 20-methyl-21- (3-methylphenyl) -pregna-15β-ol; 4, 4, 20-trimethyl- (4-methylphenyl) -pregna-5-en-16β-ol; cyclohexyl ester of 16β-hydroxy-5-en-24-oic acid; cholesta-5-en-16β, 25-diol; 24-nor-cholestan-15ß-ol; 20-methyl-21-benzylpregna-3, 5-diene-16β-ol; 24-nor-4, 4-dimethylcholest-5-en-16β-ol; 4,4,20-trimethyl-21- (cyclopentyl) -pregna-5-en-16β-ol; 16β-hydroxycholest-5-en-24-one; (20S) -colest-5-en-16β, 20-diol; (20R) -colest-5-en-16β, 20-diol; (20S) -24-norcolest-5-en-16β, 20-diol; (20R) -24-norcolest-5-en-16β, 20-diol; (20S) -colest-5,24-diene-16β, 20-diol; (20R) -colest-5, 24-diene-16β, 20-diol; (20S) -24-norcolest-5, 23-diene-16β, 20-diol; (20R) -24-norcolest-5, 23-diene-16β, 20-diol; (20S) -23, 24-dinorcolest-5-en-16β, 20-diol; (20R) -23, 24-dinorcolest-5-en-16β, 20-diol; (20S) -20-methyl-21-phenylpregna-5-en-16β, 20-diol; (20R) -20-methyl-21-phenylpregna-5-en-16β, 20-diol; N-dimethylamide of (20S) -16β, 20-dihydroxy-5-en-24-oic acid; N-dimethylamide of (20R) -16β-20-dihydroxy-5-en-24-oic acid; N-dimethylamide of (20S) -20-hydroxy-5-en-24-oic acid; N-dimethylamide of (20R) -20-hydroxy-5-en-24-oic acid; 16β-hydroxycholest-5-ene; cholest-5-in-16-one; 16β-hydroxycolestan; and (25R) -16β, 26-dihydroxycholest-5-ene. The preferred compounds of the formulas la and Ib are those which when tested by the method to be described below with respect to their agonist properties (penultimate example, see below), show a relative activity of at least 50, preferably when minus 80 or, when tested by the method to be described below with respect to their antagonist properties (last example, see below), show an IC50 value of less than 10 μM, preferably less than 2 μM. Examples of other preferred compounds are those that are not active in the estrogen receptor and preferably compounds that are not active in other hormone receptors currently known. Examples of such other hormone receptors are the progesterone receptor, the androgen receptor and the glucocorticoid receptor. Likewise, the compounds should not affect the entire ovarian reserve of the ovaries. In addition, preferred embodiments are mentioned in the appended claims. As used in the present description and claims, the term "lower alkyl group" when used alone or in combinations, may be a straight or branched chain alkyl group. Preferably, the alkyl group contains no more than 6 carbon atoms. Preferred examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, preferably methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, still more preferably methyl and ethyl. In a preferred embodiment of the present invention, the lower alkyl group contains no more than 4 carbon atoms, preferably no more than 3 carbon atoms. As used in the present description and claims, the term "lower alkoxy" refers to a straight or branched chain alkoxy group that preferably contains no more than 6 carbon atoms, preferably no more than 4, more preferably no more than 3. carbon atoms. Preferred examples are methoxy, ethoxy and propoxy, with methoxy and ethoxy being more preferred. As used in the present description and claims, the term "halogen" preferably designates fluoro and chloro radicals, preferably fluoro. As used in the present description and claims, the term "cycloalkyl of 3 to 6 carbon atoms" designates a cycloalkyl group containing from 3 to 6 carbon atoms in the ring. Preferred examples are cyclopropyl and cyclopentyl.

As used in the present description and claims, the term "acyloxy" designates a monovalent substituent comprising an optionally substituted alkyl group of 1 to 6 carbon atoms or phenyl group linked through a carbonyloxy group; such as for example acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy, benzoyl and the like. As used in the present description and claims, the expression, eg, "R1 is oxo", means that an oxo group (= 0) is present at position 1 (consequently, there is no hydrogen atom at position 1). ). Analogous considerations apply to analogous situations. In other cases, two symbols together may represent an oxo group, e.g., R4 and R'4. As used in the present description and claims, the expression, eg, "R12 is methylene", means that a methylene group (= CH2) is present at position 12 and, consequently, there is no hydrogen atom in this position. Analogous considerations apply for analogous situations. In other cases, two symbols together may represent a methylene group, e.g., R4 and R'4. The salts of the compounds of the formulas la and Ib are preferably pharmaceutically acceptable salts, especially acid addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, puruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid addition salts include salts of hydrochloric, hydrobromic, sulfuric and phosphoric acids, and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Science, 66 (1977), 2 et seq. The esters of the compound of the general formula Ia or Ib are formally derived by the esterification of one or more hydroxyl groups of a compound of the formula la or Ib, 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, sulfonic acid, sulfamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids.

A metabolite of a compound of the formulas Ia or Ib is an active derivative of a compound of the formula Ia or Ib which is produced when the compound of the formula Ia or Ib is metabolized. The metabolites of the compounds of the formulas Ia or Ib can be identified either by administration of a compound of the formula Ia or Ib to a host and an analysis of blood samples from the host, or by incubation of a compound of formula la or Ib with liver cells in vitro and an incubation analysis. A prodrug of a compound of the formula Ia or Ib is a compound that is transformed into a compound of the formula Ia or Ib in vivo, or having the same active metabolites as a compound of the formula Ia or Ib. The compounds of the formulas la and Ib have a number of chiral centers in the molecule and, therefore, there are several isomeric forms. All of these isomeric forms and mixtures thereof are within the scope of the present invention. The compounds of the general formulas la and Ib can be prepared analogously to the preparation of known compounds. Thus, the synthesis of the compounds of the formulas la and Ib can follow the established synthetic routes described in the extensive scientific literature on sterols and steroids. The following books can be used as references in the synthesis: L.F. Fieser & M. Fieser: Steroids: Reinhold Publishing Corporation, NY 1959; Rood's Chemistry of Carbon Compounds (ed.: S. Coffrey): Elsevier Públishing Company, 1971; J. Fried h J.A. Edwards: Organic Reactions in Steroid Chemistry, Vol. I and II, Van Nostrand Reinhold Company, New York, 1972; and especially the Dictionary of Steroids (editors: R.A. Hill; D.N. Kirk; H.L.J. Makin and G.M. Murphy): Chapman & Hall. The latter contains an extensive list of citations to the original documents covering a period up to 1990. All these books, including these last mentioned citations, are incorporated herein by reference. In addition, information from all previous publications (including patent descriptions) dealing with the preparation of compounds similar to the compounds of the formulas la and Ib is incorporated by reference. The compounds according to the present invention will have an influence on the meiosis of the oocysts, as well as on male germ cells. The existence of a meiosis-inducing substance in nature has been known for some time. However, until recently the identity of the substance or substances inducing meiosis was unknown.

The prospects with the ability to influence meiosis are several. In accordance with a preferred embodiment of the present invention, a compound of the formula Ia or Ib or an ester, salt, active metabolite and prodrug thereof, can be used to stimulate meiosis. In accordance with another preferred embodiment of the present invention, a compound of the formula Ia or Ib or an ester, salt, active metabolite and prodrug thereof, can be used to stimulate meiosis in humans. Thus, the compounds of the formulas or Ib and esters, salts, active metabolites and prodrugs thereof, are promising as new agents for regulating fertility, without the usual side effects on somatic cells that are known to cause contraceptives. Hormones that are used, which are based on estrogen and / or gestagens. To be used as a contraceptive agent in women, a meiosis-inducing substance can be administered in such a way that prematurely induces the resumption of meiosis in oocysts, while these are still in the growing follicle, before the ovulatory peak of the oocysts occurs. the gonadotropins. In women, the resumption of meiosis, for example, can be induced a week after the previous menstruation has ceased. When ovulated, oocysts overmature results are more likely not to be fertilized. The normal menstrual cycle is not likely to be affected. In this context, it is important to note 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, while the estrogens and progestins used as hormonal contraceptives do have a adverse affect on the biosynthesis of progesterone. According to another aspect of the present invention, a meiosis-inducing substance of the formulas Ia or Ib, or an ester, salt, active metabolite and prodrug thereof, can be used in the treatment of certain cases of infertility in females , including women, by administering the substance to those who, due to insufficient own production of some meiosis-activating substance, are unable to produce mature oocysts. Likewise, when in vit.ro fertilization is carried out, better results can be achieved when a compound of the formula or Ib or an ester, salt, active metabolite and prodrug thereof, is added to the medium in which they are grown. oocysts When infertility in males, including males, is caused by insufficient self-production of some meiosis-activating substance and, therefore, there is a lack of mature sperm cells, the administration of a compound of the formula I or Ib or an ester , salt, active metabolite and prodrug thereof, can alleviate the problem. As an alternative to the method described above, the contraceptive effect in women can also be achieved by administering a compound of the formula Ia or Ib or an ester, salt, active metabolite and prodrug thereof, which inhibits meiosis in such a way no mature oocysts are produced- Similarly, the contraceptive effect in men can be achieved by administration of a compound of the formula la or Ib or an ester, salt, active metabolite and prodrug thereof which inhibits meiosis in such a way that do not produce mature sperm. The route of administration of the compositions eme contain a compound of the formula Ia or Ib or an ester, salt, active metabolite and prodrug thereof, can be eliminated via effectively transporting the active compound to its site of action. Thus, when the compounds of the formula Ia or Ib are to be administered to a mammal, these, conveniently, are provided in the form of a pharmaceutical composition which comprises at least one compound of the formula Ia or Ib or an ester, salt, active metabolite and prodrug thereof, in relation to a pharmaceutically acceptable carrier. For oral administration, such compositions are preferably in the form of capsules or tablets. From the above, it will be understood that the administration regime used will depend on the disorder being treated. Thus, when used in the treatment of infertility, administration could be performed only once, or for a limited period, e.g. until pregnancy is achieved. When used as contraceptives, the compounds of the formulas or Ib or esters, salts, active metabolites and prodrugs thereof, will have to be administered continuously or cyclically. When used as contraceptives for women and not taken continuously, an administration with a calendar related to ovulation will be important. Pharmaceutical Compositions Pharmaceutical compositions comprising a compound of the formula Ia or Ib or an ester, salt, active metabolite and prodrug thereof, may further comprise carriers, diluents, absorption improvers, preservatives, pH regulators, agents for adjusting the osmotic pressure, tablet disintegrating agents and other ingredients that are conventionally used in the art. Some examples of solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin., tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point waxes and cocoa butter. 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 that are conventionally employed in the art, some of which were mentioned in the above list. In addition, a composition for transdermal administration of a compound of the present invention can be provided in the form of a patch and a composition for nasal administration can be provided in the form of a nasal spray, in liquid or powder. The dose of a compound of the formula I or Ib to be used will be determined by the physician and will depend, inter alia, on the particular compound employed, the route of administration and the purpose of use. In general, the compositions according to the present invention are prepared by an intimate association of the active component with the liquid or solid auxiliary ingredients and then, if necessary, the product is shaped to obtain the desired formulation. Normally no more than 1000 mg, preferably no more than 100 mg and in some preferred cases no more than 10 mg, of a compound of the formula Ia or Ib to mammals, e.g., to humans, per day will be administered. None of the compounds of the formulas la and Ib have been shown to be toxic when administered to humans in an amount of 1000 mg per day. The present invention will be further illustrated with the following examples, which, however, should not be considered as limiting the scope of the protection. The features described in the foregoing description and in the following examples may, in combination, be material for devising various forms of the invention. EXAMPLE 1 16β-hydroxisolext-5-ene To a mixture of (25R) -colest-5-en-3β, 16β, 26-triol (10 g, 24 mmol, prepared according to the procedure described by Arunachalam et al. J. Org. Chem. 46 (1981), 2966-2968), pyridine (150 ml) and dichloromethane (150 ml) was added toluene sulfonylchloride (5.7 g, 30 mmol) and the mixture was stirred overnight. Ice water was added and the aqueous phase was extracted with dichloromethane. The organic phase was washed with 4N HCl, concentrated under reduced pressure and the residue was purified by flash chromatography, to obtain (25R) -3,26-ditosilcolest-5-en-16β-ol (4.2 g) and (25R) -26-tosyloxicolest-3-en-3, 16-diol (6.3 g). The 1H-NMR spectrum (CDCI3, d) showed characteristic signals in: 2.43 (s, 6H), 3.45 (q, ÍH), 3.72-3.92 (m, 2H), 4.25-4.40 (m, ÍH), 5.23 ( , ÍH), 7.32 (m, 4H), 7.78 (m, 4H). To a solution of (25R) -3,26-ditosylcolest-5-en-16β-ol (360 mg, 0.5 mmol) in tetrahydrofuran (hereinafter referred to as THF); 5 ml) was added 1M lithium tetraborohydride (16 ml). Water was added and the aqueous phase was extracted with dichloromethane and washed with dilute HCl, with an aqueous solution of sodium bicarbonate and with brine. Concentration under reduced pressure and purification by flash chromatography yielded the title compound (60 mg), melting point 107-108 ° C. The spectrum of ^? - NMR (CDC13, d) showed characteristic signals at: 0.83 (s, 3H), 0.90 (s, 3H), 1.00 (s, 3H), 2.15-2.3 (m, 2H), 4.30-4.41 (m, ÍH, H-16), 5.25 (d, ÍH, H-6). The 13 C-NMR spectrum (CDC13, d) showed characteristic signals in: 72.9 (C-16), 119.1 (C-6), 144.2 (C-5).

The mass spectrum showed characteristic peaks in: 386.4 (M +). EXAMPLE 2 Coles -5-en-16-one 16β-Hydrocolest-5-ene (Example 1.80 mg, 0.2 mmol) was dissolved in glacial acetic acid (4 ml) and sodium acetate trihydrate (680 mg, 5 mg) was added. mmol) followed by a dropwise addition of chromium trioxide (20 mg, 0.2 mmol) in glacial acetic acid and water (0.3 ml of a 2: 1 mixture). After 2 hours, methanol (2 ml) was added and the mixture was concentrated. Water was added and the aqueous phase was extracted with dichloromethane. The organic phases were combined and the combined was washed with sodium bicarbonate, with water and with brine. Removal of the solvent and recrystallization from methanol afforded the title compound (18 mg). The 1H-NMR spectrum (CDCI3, d) showed characteristic signals in: 5.25 (d, ÍH, H-6). The 13 C-NMR spectrum (CDC13, d) showed characteristic signals at: 118.6 (C-6) 144.2 (C-5 (, 219.3 (C-16).) The mass spectrum showed characteristic peaks in: 384. 2 (M +).

EXAMPLE 3 16β-hydroxycoles year 16β-Hydroxycholest-ene (Example 1, 20 mg) was hydrogenated at atmospheric pressure over platinum on carbon. Filtration and chromatography afforded the title compound (17 mg). The XH-NMR spectrum (CDC13, d) showed characteristic signals at 4.30-4.40 (m, ÍH.H-16). The mass spectrum showed characteristic peaks in: 388.3 (M +). EXAMPLE 4 (25R) -16β, 26-dihydroxycholest-5-ene A solution of tetrahydrodiosgenin (2.5 g, 5.9 mmol), tert-butyldimethylsilyl chloride (1.1 g, 7.1 mmol) and imidazole (1.6 g, 24 mmol) in dimethylformamide , stirred for 48 hours at 40 ° C, emptied in water (200 ml) and extracted with ethyl acetate. Purification by flash chromatography afforded (25R) -3,16-dihydroxy-26-tert-butyldimethylsilyloxylest-5-ene (1.3 g). The spectrum of ""? -RMN (CDCI3, d) showed characteristic signals at: -0.05-0.003 (d, 6H), 0.88 (s, 9H), 3.30-3.60 (3H, m, H-3 and 2H-26 ), 4.30-4.40 (m, ÍH, H-16), 5.35 (m, ÍH.H-6). (25R) -3-, 16β-Dihydroxy-26-tert-butyldimethylsilyloxyleslest-5-ene (0.76 g, 1.4 mmol) and toluene sulfonylchloride (0.54 g, 2. 8 mmol) in pyridine (20 ml) were stirred for 48 hours. hours at room temperature. Concentration under reduced pressure and flash chromatography yielded (25R) -3-tosyloxy-16β-hydroxy-26-tert-butyldimethylsilyloxylest-5-ene (0.855 g). The 1H-NMR spectrum (CDC1, d) showed characteristic signals at: 0.05-0.03 (d, 6H), 0.88 (s, 9H), 2.45 (s, 3H), 3.30-3.49 (2H, m, 2H-26 ), 4.30-4.40 (m, 2H, H-3 and H-16), 5.30 (m, HH, 6), 7.30 (d, 2H), 7.73 (d, 2H). To an amount of (25R) -3-toxyloxy-16β-hydroxy-26-tert-butyldimethylsilyloxylest-5-ene (0.85 g, 1.2 mmol) was added Superhydride (30 mL 1M in THF) and the reaction mixture was stirred for 72 hours at room temperature, it was poured into ice water and extracted with ethyl acetate. Removal of the solvent under reduced pressure and flash chromatography yielded 16β-hydroxy-26-tert-butyldimethylsilyloxylest-5-ene (0.53 g). The 1H-NMR spectrum (CDCI3, d) showed characteristic signals in: -0.05-0.03 (d, 6H), 0.88 (2.9H), 3.30-3.49 (2H, m, 2H-26), 4.30-4.40 ( m, ÍH, H-16), 5.30 (m, ÍH.H-6). To an amount of 16β-hydroxy-26-tert-butyldimethylsilyloxylester-5-ene in THF, ammonium tetrabutylfluoride (0.6 g) was added and the reaction mixture was stirred overnight at room temperature.

Removal of the solvent under reduced pressure and flash chromatography afforded the title compound.

The spectrum of ^ -RN (CDCI3, d) showed characteristic signals in: 3.40-3.52 (2H, m, 2H-26), 4.30-4.40 (m, ÍH, H-16), 5.30 (d, ÍH. 6). EXAMPLE 5 An agonist effect assay can be performed in oocysts, as follows: Oocytes were obtained from immature female mice (C57BL76J x DBA / 2J Fl, Bomholtgaard, Denmark) from 13 to 16 grams of body weight, which were kept at controlled temperature (20-22 ° C), controlled light (lights on from 06:00 to 18:00) and relative humidity (50-70%). The mice received an intraperitoneal injection of 0.2 ml of gonadotropin (Gonal-F, Serono) containing 20 IU of FSH and 48 hours later the animals were sacrificed by cervical dislocation. The ovaries were dissected and the oocysts were isolated in Hx medium (see below) under a stereoscopic microscope by manual rupture of the follicles using a pair of 27-gauge needles. The spherical oocysts showed an intact germ-cell vesicle (hereinafter referred to as VG) and were divided into enclosed oocyst clusters (hereinafter referred to as COE) and bare oocysts (from now on designated as OD) and placed in minimal essential medium (a-MEM) without ribonucleosides, Gibco BRL, Catalog No. 22561) supplemented with 3 mg / ml bovine serum albumin (BSA, Sigma Catalog No. A-7030), 5 mg / ml human serum albumin (HSA, Statens Seruminstitute, Denmark ), 0.23 mM of purivate (Sigma, Catalog No. S-8636), 2 mM glutamine (Flow No. of Cat. 16-801), 100 IU / L of penicillin and 100 μg / ml of streptomycin (Flow, No of Cat. 16-700). This medium was supplemented with 3 mM hypoxanthine (Sigma, Cat. No. H-9377) and was designated as Hx medium. The oocysts were rinsed three times in Hx medium and the oocysts of uniform size were divided into groups of COE and OD. The COE and OD were grown in 4-well plates (Nuncion, Denmark) where each well contained 0.4 ml of Hx medium. A control well was always cultivated (i.e., 35-45 oocysts cultured in an identical medium without the addition of the test compound), simultaneously with the 3 test wells (35-45 oocysts per well supplemented with the test compound). The oocysts were cultured in a humidified atmosphere of 5% C02 in air for 24 hours at 37 ° C. For the end of the culture period, the number of oocysts with germinal vesicle (from now on referred to as VG), with rupture of germinal vesicle (from now on referred to as RVG) and with polar body (from here onwards) was counted. designated as CP), respectively, using a stereomicroscope (Wildt, Leica MZ 12). The percentage of RVG, defined as the percentage of oocysts that suffered RVG among the total number of oocysts in that well, was calculated as follows:% RVG = (number of RVG + number of CP / total number of oocysts X 100. CP% was defined as the percentage of socistos that showed an extruded polar body among the total number of oocysts in that well The effect of the tested compounds was indexed against the control level and 4,4-dimethyl-5a-cholesta-8 , 14, 24-trien-3ß-ol (hereinafter referred to as FF-MAS), where the controls and the FF-MAS were indexed to an effect between 0 and 100, respectively.The relative effect of the compound tested was calculated as follows: Relative effect = ((% RVG test -% RVG control) / (% RVG FF-MAS -% RVG control)) x 100. Using this test on the compounds prepared in Examples 1 and 4 , an RVG of 72 and 63% was found, respectively, and the relative RVG was 88 and 73%, respectively.

EXAMPLE 6 An oocyst antagonist effect assay can be performed as follows: Animals Oocytes were obtained from immature female mice (C57BI / 6J) x DBA / 2J hybrids Fl, Bomholtgaard, Denmark) from I3 to 16 grams of body weight, which were kept under controlled light and temperature. Mice received an intraperitoneal injection of 0.2 ml of gonadotropins (Gonal F, Serono, Solna, Sweden, containing 20 IU of FSH, alternatively, Puregon, Organon, Swords, Ireland, containing 20 IU of FSH) and 48 hours later the animals were sacrificed by cervical dislocation. Test of meiosis inhibiting substances in the oostosis test The ovaries were dissected and the oocysts were isolated in Hx medium (see below) under a stereoscopic microscope by manually breaking the follicles using a pair of 27 gauge needles. Naked spherical oocysts (OD) showing an intact terminal vesicle (VG) were placed in minimal essential medium (MEM-a) without ribonucleosides, Gibco BRL, Cat. No. 22561) supplemented with 3 mM hypoxanthine (Sigma, No. from Cat. H-9377), 8 mg / ml human serum albumin (HSA, Statens Seruminstitut, Denmark), 0.23 mM pyruvate (Sigma, Cat. No. S-8636), 2 mM glutamine (Cat Flow No. 16-801), 100 IU / ml penicillin and 100 μg / ml streptomycin (Flow, Cat. No. 16-700). This medium was designated as Hx medium. The naked oocysts (OD) were rinsed three times with Hx medium. It has previously been shown that 4,4-dimethyl-5a-cholesta-8, 14, 24-trien-3ß-ol (FF-MAS) induces meiosis in OD in vitro (Byskov, AG et al., Nature 374 (1995) , 559-562). OD were grown in Hx medium supplemented with 5 μM FF-MAS in co-culture with the test compounds, at different concentrations, in 4-well plates (Nuncion, Denmark) where each well contained 0.4 ml of the medium and 35-45 oocysts. A positive control was always simultaneously tested (i.e., 35-45 oocysts cultured in Hx medium containing FF-MAS without adding the test compound) with the test cultures, which was supplemented with different concentrations of the compounds to be tested. In addition, a negative control (35-45 oocysts cultured in Hx medium alone) was also tested simultaneously with the positive control. Oocysts examination At the end of the culture period, the number of oocysts with germinal vesicle (VG) or rupture of the germinal vesicle (RVG) and those with polar body (CP) using a stereoscopic microscope or an inverted microscope with equipment was counted. of differential interference contrast. The percentage of oocysts with RVG + CP between the total number of oocysts in the test cultures and in the control culture groups (positive and negative) was calculated. The relative inhibition of the test compound was calculated by the following test: Inhibition of the test compound (in percent) = 1UU - (GVB test compound - VB negative control) X 1 UU / (RVG) positive control ~ trV negative control / J * En In the case of a dose-response curve, the IC50 (dose causing 50% inhibition) was calculated. Using this assay in the compound prepared in Example 4, a CP of 5% was found. EXAMPLE 7 An in vitro fertilization (IVF) assay can be performed as follows: Naked oocysts (OD) enclosed oocysts (COE) clusters from immature mice were isolated and cultured (C57B116J x DBAJ / 2) F? under the same conditions as those described in the oocyst agonist effect assay (Example 5). After 18 hours, the oocysts that exhibited germinal vesicle rupture (RVG) were washed with hypoxanthine-free culture medium and transferred to pre-prepared insemination plates, which consisted of a mobile sperm preparation with the caudal epididymis the male mouse. The plates were subsequently incubated under the defined gas conditions (5% CO 2) at 37 ° C in a modified α-MEM medium for IVF. Neither the insemination medium nor the IVF medium contained hypoxanthine. The examination of the oocysts was carried out 20 to 22 hours after insemination, in order to verify the fertilization and to record the number of embryos of two cells. The percentage of fertilization (= fertilization index) was determined from the count of the oocysts that had been divided into two-cell embryos. Using this assay in the compound prepared in Example 1, a fertilization rate of 62% was found (the rate of fertilization in the control animals was 22%). It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (22)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. New compounds of the general formula la: characterized in that R1 is a hydrogen atom, a halogen, methyl, hydroxy or oxo radical; R 2 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, vinyl, lower alkoxy and halogen, or R 2 designates, together with R 3, an additional bond between the carbon atoms in which R 2 and R 3 are placed; R3 is hydrogen or lower alkyl; or R3 designates, together with R4, an additional bond between the carbon atoms in which R3 and R4 are placed; or R3 designates, together with R2, an additional bond between the carbon atoms in which R2 and R3 are placed; R4 and R'4, which are identical or different provided both are not hydroxy, are selected from the group consisting of hydrogen, halogen, hydroxy and lower alkyl which may be substituted by halogen, hydroxy or cyano, or where R4 and R'4 together designate a methylene or oxo group, or together with the carbon atom to which they are linked, form a cyclopropane ring, a cyclopentane ring or a cyclohexane ring; or R4, R'4 and R5 together designate an additional bond between the carbon atoms at positions 4 and 5, R5 is hydrogen, halogen or hydroxy, or R5 together with R6 designates an additional bond between the carbon atoms in which R5 and R6 are placed; R6 is hydrogen, hydroxy, halogen or oxo, or Rd designates, together with R5 or R7, an additional bond between the carbon atoms in which R6 and R5 or R7 are placed; R7 is selected from the group consisting of hydrogen, hydroxy, methoxy, acyloxy, halogen and lower alkyl, or R7 designates, together with R6 or R8, an additional bond between the carbon atoms in which R7 and R6 or R8 are placed; and R'7 is hydrogen or, if R7 is lower alkyl, R * 7 is hydrogen or hydroxy; or R7 and R * 7 together denote an oxo, methylene group or a group of the general formula -ÑOR36, wherein R36 is hydrogen or lower alkyl; R8 is hydrogen, hydroxy or halogen, or R8 designates, together with R, Ry or R, an additional bond between the carbon atoms in which R and R7, R9 or R14 are placed; R9 is hydrogen, hydroxy or halogen, or R9 designates, together with R8 or R11, an additional bond between the carbon atoms in which R9 and R8 or R11 are placed; R11 is selected from the group consisting of hydrogen, hydroxy, methoxy, acyloxy, halogen and lower alkenyl, or R designates, together with R or R 12, an additional bond between the carbon atoms in which R11 and R9 or R12 are placed; and R'11 is hydrogen or, if R11 is lower alkynyl, R * 11 is hydrogen or hydroxy; or R11 together with R'11 form an oxo, methylene or a group of the general formula = NOR37, wherein R37 is hydrogen or lower alcruyl; R12 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, acyloxy, oxo and a group of the general formula = NOR33, wherein R33 is hydrogen or lower alkyl, or R12 designates together with R11 an additional bond between the carbon atoms in which R > n and R, R is hydrogen or hydroxy, or R 1 designates together with R15 an additional bond between the carbon atoms in which R14 and R15 are placed R15 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula = NOR32, wherein R32 is hydrogen or lower alkyl, or R15 designates together with R14 an additional bond between the carbon atoms in which R14 and R15 are placed; R16 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula = NOR34, wherein R34 is hydrogen or lower alkyl, or Rld designates together with R17 a bond additional between the carbon atoms in which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates together with -R16 an additional bond between the carbon atoms in which R17 and R16 are placed; R 20 is selected from the group consisting of hydrogen, lower alkyl and hydroxymethyl, or R 20 R together denote a methylene or oxo group; R '20 is hydrogen, halogen, lower alkyl or hydroxy, R'22 is hydrogen, hydroxy or oxo; R22 represents a group of the general formula: -C (R> 2"3) v (R • '2" 3), - C (R> 24). (R "2z5o) (R" 25), wherein R23 and R'23 both are hydrogen, or one of R23 and R'23 is hydrogen, while the other is halogen, hydroxy or methoxy, or R23 and R '23 together they designate an oxo group, R'24 is hydrogen when R24 is different from oxo, and R'24 is absent when R24 is oxo, and A is a carbon atom or a nitrogen atom, and when A is an atom of carbon, R25 is selected from the group consisting of hydrogen, hydroxy, and halogen, and R24 is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, methylene, and oxo, or R > 25 designates together with R a bond additional between the carbon atoms in which R24 are placed R; R is selected from the group consisting of lower alkyl, trifluoromethyl and cycloalkyl of 3 to 6 carbon atoms; R "25 is selected from the group consisting of lower alkyl, hydroxy (lower alkyl), halogen (lower alkyl) containing up to 3 halogen atoms, methoxymethyl, acetoxymethyl and cycloalkyl of 3 to 6 carbon atoms, or R * 25 and R "25, together with the carbon atom in which they are placed, form a cycloalkyl ring of 3 to 6 carbon atoms; and wherein A is a nitrogen atom, R25 designates a lone pair of electrons; and R24 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, cyano, and oxo; and R'25 and R "25 are independently lower alkyl or cycloalkyl of 3 to 6 carbon atoms, or R22 is phenyl, toluyl, hydroxyphenyl, cyclopentyl, cyclohexyl, isobutyl or cyclohexyloxycarbonylmethyl, and esters, salts, active metabolites and prodrugs of these, on the condition that the following compounds are rejected: cholest-4, 8, 24-triene, 25-aza-cholest-5-ene, cholesta-3,5-diene, cholest-2-ene, choles- 5-ene, 24-methylcholesterol-3, 5-diene, 24-ethyl-2-ethacrylate, 3, 5, 22-diene, 24-ethylhexethate-3, 5-diene, 24-nor-5a-cholestane, 24-nor-5ß- cholestane; (20R) -5β, 14, 17a (H) -cholesterol; (20R) -5a, 14β, 17β (H) -cholesterol; (20R) -5a, -14a, 17a (H) -cholesterol; (20R) -5β, 14a, 17a (H) -24-methylcholesterol; (20R) -5a, 14a, 17a (H) -24-methylcholestane; (20R) -5β, 14a, 17a (H) -24-ethylcholesterol; (20R) -5a, 14a, 17a (H) -24-ethylcholesterol; 4-methyl-5a-24-norcolestane; 5a-cholestane; 5ß-cholestane; cholest-4-ene; 4-methylcholestane; (20S) -5a, 14a, 17a-cholestane; 19-nor-5a-cholestane; cholest-4-ene; norcolestane; 5a, 8β, 14β-cholestane; 5β, 8β, 14β-cholestane; 5a-norcolestane; 5a, 17β (H) -cholesterol; (20S) -5a, 17β (H) -cholesterol; (24R) -24-methyl-5β-cholestane; (24S) -24-methyl-5β-cholestane; 5a, 8a, 14β-cholestane; (20S) -5a-cholestane; (24R) -24-methyl-5a-cholestane; (24S) -24-ethyl-5a-cholestane; (24S) -24-ethyl-5a-cholestane; 4a-methyl-5a-cholestane; 4β-methyl-5a-cholestane; (24S) -24-methyl-5a-cholestane; 24-hydroxymethylcolan-24-one; 24-hydroxymethylcolan-24-ol; cholest-24-ene; 24-cyclohexylcolan-24-ene; 24-methylcholest-2-ene; 24-ethylcholest-2-ene; 24-propylcholetane; cholest-25-ene; 24-cyclohexylcolan-24-ene; and 24-dimethyl-5a-colane.
2. 2. The compounds according to claim 1, characterized in that R1 is a hydrogen atom; R2 is selected from the group consisting of hydrogen or R2 designates, together with R3, an additional bond between the carbon atoms in which R2 and R3 are placed; R3 is hydrogen or lower alkyl; or R designates, together with R4, an additional bond between the carbon atoms in which R3 and R4 are placed; R4 and R * 4, which are identical or different provided both are not hydroxy, are selected from the group consisting of hydrogen, hydroxy and lower alkyl, or where R4, R * 4 and R5 together designate an additional bond; R5 is hydrogen, or R5 together with R6 designates an additional bond between the carbon atoms in which R5 and R6 are placed; R6 is hydrogen, or R6 designates, together with R5 or R7, an additional bond between the carbon atoms in which Rd and R5 or R7 are placed; R7 is hydrogen or hydroxy, or R7 designates, together with R6 or R8, an additional bond between the carbon atoms in which R7 and R6 or R8 are placed; and R'7 is hydrogen or, R7 and R * 7 designate together an oxo or methylene group; R8 is hydrogen, or R8 designates, together with R7, R9 or R14, an additional bond between the carbon atoms in which R8 and R7, R9 or R14 are placed; R9 is hydrogen, or R9 designates, together with R8 or R11, an additional bond between the carbon atoms in which R9 and R8 or R11 are placed; R11 is hydrogen or hydroxy, or R11 designates, together with R9, an additional bond between the carbon atoms in which R9 and R11 are placed; and R'11 is hydrogen; R12 is hydrogen; R14 is hydrogen; or R14 designates together with R15 an additional bond between the carbon atoms in which R14 and R15 are placed; R15 is hydrogen, hydroxy or oxo; R16 is hydrogen, hydroxy or oxo; or R16 designates together with R17 an additional bond between the carbon atoms in which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates together with R16 an additional bond between the carbon atoms in which R17 and R16 are placed; R 20 is hydrogen or lower alkyl, or R 20 and R 20 together denote a methylene or oxo group; R * 20 is hydrogen, halogen, lower alkyl or hydroxy, R'22 is hydrogen, hydroxy or oxo; and R22 is phenyl, toluyl, hydroxyphenyl, cyclopentyl, cyclohexyl, isobutyl, 3-methylbutyl or cyclohexyloxycarbonylmethyl; and esters, salts, active metabolites and prodrugs thereof.
3. 3. The compounds according to any of claims 1 or 2, characterized in that the substituents are any of the preferred substituents specifically mentioned in the above description.
4. 4. The compounds according to any of the preceding claims, characterized in that they are cholest-5-en-16β-ol; cholest-5-in-16-one; 4,4-dimethylchocolate-2, 5-diene-16β-ol; cholestan-16ß-ol; cholesta- 3, 5-dien-16β-ol; cholest-5-en-15ß-ol; cholest-5-en-17a-ol; cholest-5-en-15a-ol; cholest-5-in-16a-ol; 4, 4-dimethylcholest-5-en-16β-ol; cholest-3-in-16ß-ol; cholest-4-en-16ß-ol; cholest-2-en-16ß-ol; cholesta-2, 4-dien-16β-ol; cholesta-2,5-dien-16ß-ol; cholesta-5, 24-dien-16ß-ol; cholesta-5, 8-dien-16ß-ol; cholesta-5, 7-dien-16β-ol; 4, 4-dimethylchocolate-5, 7-diene-16β-ol; 3-methylchocolate-2, 5-diene-16β-ol; 3β-methylcolest-5-en-16β-ol; 3a-methylcolest-5-en-16β-ol; 3,4,4-trimethylchocolate-2, 5-diene-16β-ol; 4, 4-dimethylchocolate-5, 8-diene-16β-ol; cholesta-5, 8-dien-15ß-ol; cholesta-5, 7-dien-15ß-ol; 4, 4-dimethylcholest-5-en-15β-ol; 4, 4-dimethylcholest-5-en-15a-ol; 20-methyl-21-phenylpregna-5-en-16β-ol; 20-methyl-21-cyclopentylpregna-5-en-16β-ol; 24-norcolest-5-en-16β-ol; 24-norcolest-16ß-ol; 24-norcolest-5-en-15β-ol; 20-methyl-21- (3-methylphenyl) -pregna-5-en-16β-ol; 20-methyl-21- (3-hydroxyphenyl) -pregna-5-en-16β-ol; 20-methyl-21- (3-hydroxyphenyl) -pregna-16β-ol; 20-methyl-21- (3-methylphenyl) -pregna-15β-ol; 4, 4, 20-trimethyl- (4-methylphenyl) -pregna-5-en-16β-ol; cyclohexyl ester of 16β-hydroxy-5-en-24-oic acid; cholesta-5-en-16β, 25-diol; 24-norcolestan-15ß-ol; 20-methyl-21-benzylpregna-3, 5-diene-16β-ol; 24-nor-4, 4-dimethylcholest-5-en-16β-ol; 4, 4, 20-trimethyl-21- (cyclopentyl) -pregna-5-en-16β-ol; 16β-hydroxycholest-5-en-24-one; (20S) -colest-5-en-16β, 20-diol; (20R) -colest-5-en-16β, 20-diol; (20S) -24-norcolest-5-en-16β, 20-diol; (20R) -24-norcolest-5-en-16β, 20-diol; (20S) -colest-5, 24-diene-16β, 20-diol; (20R) -colest-5,24-diene-16β, 20-diol; (20S) -24-norcolest-5, 23-diene-16β, 20-diol; (20R) -24-norcolest-5, 23-diene-16β, 20-diol; (20S) -23, 24-dinorcolest-5-en-16β, 20-diol; (20R) -23,24-dinorcolest-5-en-16β, 20-diol; (20S) -20-methyl-21-phenylpregna-5-en-16β, 20-diol; (20R) -20-methyl-21-phenylpregna-5-en-16β, 20-diol; N-dimethylamide of (20S) -16β, 20-dihydroxy-5-en-24-oic acid; N-dimethylamide of (20R) -16β-20-dihydroxy-5-en-24-oic acid; N-dimethylamide of (20S) -20-hydroxy-5-en-24-oic acid; N-dimethylamide of (20R) -20-hydroxy-5-en-24-oic acid; 16β-hydroxycholest-5-ene; cholest-5-in-16-one; 16β-hydroxycholestane; and (25R) -16β, 26-dihydroxycholest-5-ene.
5. 5. The use of the compounds of the general formula Ib: characterized in that R1 is a hydrogen atom, a halogen, methyl, hydroxy or oxo radical; R 2 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, vinyl, lower alkoxy and halogen, or R 2 designates, together with R 3, an additional bond between the carbon atoms in which R 2 and R 3 are placed; R3 is hydrogen or lower alkyl; or R3 designates, together with R4, an additional bond between the carbon atoms in which R3 and R4 are placed; or R3 designates, together with R2, an additional bond between the carbon atoms in which R2 and R3 are placed; R4 and R'4, which are identical or different provided that both are not hydroxy, are selected from the group consisting of hydrogen, halogen, hydroxy and lower alkyl, which may be substituted by halogen, hydroxy or cyano, or wherein R 4 and R 4 together denote a methylene or oxo group or, together with the carbon atom to which they are attached, form a cyclopropane ring, a cyclopentane ring or a cyclohexane ring; or R4, R and R5 together designate an additional bond between the carbon atoms at positions 4 and 5, R5 is hydrogen, halogen or hydroxy, or R5 together with R6 designates an additional bond between the carbon atoms in which they are placed R5 and R6; R6 is hydrogen, hydroxy, halogen or oxo, or Rd designates, together with R5 or R7, an additional bond between the carbon atoms in which Rd and R5 or R7 are located; R7 is selected from the group consisting of hydrogen, hydroxy, methoxy, acyloxy, halogen and lower alkyl, or R7 designates, together with R6 or R8, an additional bond between the carbon atoms in which R7 and R6 or R8 are placed; and R'7 is hydrogen or, if R7 is lower alkyl, R'7 is hydrogen or hydroxy; or R7 and R'7 designate together an oxo, methylene group or a group of the general formula = N0R3d, wherein R3d is hydrogen or lower alkyl; R8 is hydrogen, hydroxy or halogen, or R8 designates, together with R7, R9 or R14, an additional bond between the carbon atoms in which R8 and R7, R9 or R14 are placed; R9 is hydrogen, hydroxy or halogen, or R9 designates, together with R8 or R11, an additional bond between the carbon atoms in which R9 and R8 or R11 are placed; R11 is selected from the group consisting of hydrogen, hydroxy, methoxy, acyloxy, halogen and lower alkyl, or R11 designates, together with R9 or R12, an additional bond between the carbon atoms in which R11 and Rq or R12 are placed; and R'11 is hydrogen or, if R11 is lower alkyl, R'11 is hydrogen or hydroxy; or R11 together with R'11 form an oxo, methylene or a group of the general formula = NOR37, wherein R37 is hydrogen or lower alkyl; R12 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, acyloxy, oxo and a group of the general formula = NOR33, wherein R33 is hydrogen or lower alkyl, or R12 designates together with R11 an additional bond between the carbon atoms in which R11 and R12 are placed, R14 is hydrogen or hydroxy, or R14 together with R15 designates an additional bond between the carbon atoms in which R14 and R15 are placed; R15 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula = NOR32, wherein R32 is hydrogen or lower alkyl, or R15 designates together with R14 a bond additional between the carbon atoms in which R15 and R14 are placed; R16 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula = N? R34, wherein R34 is hydrogen or lower alkyl, or Rld designates together with R17 an additional bond between the carbon atoms in which Rld and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates together with R16 an additional bond between the carbon atoms in which R17 and Rld are placed; R20 is selected from the group consisting of hydrogen, lower alkyl and hydroxymethyl, or R20 and R'20 together denote a methylene or oxo group; R * 20 is hydrogen, halogen, lower alkyl or hydroxy, R * 22 is hydrogen, hydroxy or oxo; R22 represents a group of the general formula: -C (R23) (R'23) -C (R24) (R, 2) -A (R25) (R'25) (R "25), wherein R23 and R '23 both are hydrogen, or one of between R23 and R * 23 is hydrogen, while the other is halogen, hydroxy or methoxy, or R23 and R'23 together designate an oxo group, R'24 is hydrogen when R24 is different of oxo, and R'24 is absent when R24 is oxo, and A is a carbon atom or a nitrogen atom, and when A is a carbon atom, R25 is selected from the group consisting of hydrogen, hydroxy and halogen; and R24 is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, methylene and oxo, or R25 designates together with R24 an additional bond between the carbon atoms in which R24 and R25 are placed; R * 25 is selected of the group consisting of lower alkyl, trifluoromethyl and cycloalkyl of 3 to 6 carbon atoms: R "25 is selected from the group consisting of lower alkyl, hydroxy (lower alkyl), halogen (alkyl), lower) containing up to 3 atoms of halogen, methoxymethyl, acetoxymethyl and cycloalkyl of 3 to 6 carbon atoms, or R * 25 and R "25, together with the carbon atom in which they are placed, form a cycloalkyl ring of 3 to 6 carbon atoms; and when A is a nitrogen atom, R25 designates a lone pair of electrons; and R24 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, cyano, and oxo; and R'25 and R '25 are, independently, lower alkyl or cycloalkyl of 3 to 6 carbon atoms; or R22 is phenyl, toluyl, hydroxyphenyl, cyclopentyl, cyclohexyl isobutyl or cyclohexyloxycarbonylmethyl; and esters, salts, active metabolites and prodrugs thereof, as medicaments.
6. 6. The use according to the preceding claim, characterized in that the compound is any of the compounds mentioned in any of claims 2 to 4.
7. 7. The compounds of the general formula Ib: wherein R1 is a hydrogen atom, a halogen, methyl, hydroxy or oxo radical; R 2 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, vinyl, lower alkoxy and halogen, or R 2 designates, together with R 3, an additional bond between the carbon atoms in which R 2 and R 3 are placed; R3 is hydrogen or lower alkyl; or R3 designates, together with R4, an additional bond between the carbon atoms in which R3 and R4 are placed; or R3 designates, together with R2, an additional bond between the carbon atoms in which R2 and R3 are placed; R4 and R, which are identical or different provided both are not hydroxy, are selected from the group consisting of hydrogen, halogen, hydroxy and lower alkyl, which may be substituted by halogen, hydroxy or cyano, or where R 4 and R 4 together denote a methyl or oxo group or, together with the carbon atom to which they are attached, form a cyclopropane ring, a cyclopentane ring or a cyclohexane ring; or R4, R'4 and R5 together designate an additional bond between the carbon atoms at positions 4 and 5, R5 is hydrogen, halogen or hydroxy, or R5 together with R6 designates an additional bond between the carbon atoms in which R5 and R6 are placed; Rd is hydrogen, hydroxy, halogen or oxo, or R6 designates, together with R5 or R7, an additional bond between the carbon atoms in which R6 and R5 or R7 are placed; R7 is selected from the group consisting of hydrogen, hydroxy, methoxy, acyloxy, halogen and lower alkyl, or R7 designates, together with R6 or R8, an additional bond between the carbon atoms in which R7 and Rd or R8 are placed; and R * 7 is hydrogen or, if R7 is lower alkyl, R * 7 is hydrogen or hydroxy; or R7 and R * 7 together denote an oxo, methylene or a group of the general formula = NOR36, wherein R3d is hydrogen or lower alkyl; R8 is hydrogen, hydroxy or halogen, or R8 designates, together with R7, R9 or R14, an additional bond between the carbon atoms in which R8 and R7, R9 or R14 are placed; R9 is hydrogen, hydroxy or halogen, or R9 designates, together with R8 or R11, an additional bond between the carbon atoms in which R9 and R8 or R11 are placed; R11 is selected from the group consisting of hydrogen, hydroxy, methoxy, acyloxy, halogen and lower alkyl, or R11 designates, together with R or R ", an additional bond between the carbon atoms in which R11 and R9 or R12 are placed. and R'11 is hydrogen or, if R11 is lower alkyl, R'11 is hydrogen or hydroxy, or R11 together with R'11 form an oxo, methylene or a group of the general formula = NOR37, wherein R37 is hydrogen or lower alkyl; R12 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, acyloxy, oxo and a group of the general formula = NOR33, wherein R33 is hydrogen or lower alkyl, or R12 designates together with R11 an additional bond between the carbon atoms in which R11 and R12 are placed, R14 is hydrogen or hydroxy, or R14 designates together with R15 an additional bond between the carbon atoms in which R14 and R15 are placed.; R15 is selected from the group consisting of hydrogen or, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula = NOR32, wherein R32 is hydrogen or lower alkyl, or R15 designates together with R14 an additional bond between the carbon atoms in the which are placed R15 and R14; R16 is selected from the group consisting of hydrogen, halogen, lower alkyl, methylene, hydroxy, lower alkoxy, oxo and a group of the general formula = N0R34, wherein R34 is hydrogen or lower alkyl, or Rld designates together with R17 a bond additional between the carbon atoms in which Rld and R1 are placed "7; R17 is hydrogen or hydroxy, or R17 designates together with R16 an additional bond between the carbon atoms in which R17 and R16 are placed; R 20 is selected from the group consisting of hydrogen, lower alkyl and hydroxymethyl, or R 20 and R 20 together denote a methylene or oxo group; R'20 is hydrogen, halogen, lower alkyl or hydroxy, R * 22 is hydrogen, hydroxy or oxo; R22 represents a group of the general formula: -C (R23) (R'23) -C (R24) (R, 24) -A (R25) (R'25) (R "25), wherein R23 R both are hydrogen, or one of R 23 and R '23 is hydrogen, while the other is halogen, hydroxy or methoxy, or R23 and R'23 together designate an oxo group, R * 24 is hydrogen when R24 is different of oxo, and R * 24 is absent when R24 is oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R 25 is selected from the group consisting of hydrogen, hydroxy and halogen; and R24 is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, methylene and oxo, or R25 together with R24 designates an additional bond between the carbon atoms in which R24 and R25 are placed; R'25 is selected from the group consisting of lower alkyl, trifluoromethyl and cycloalkyl of 3 to 6 carbon atoms; R "25 is selected from the group consisting of lower alkyl, hydroxy (lower alkyl), halogen (lower alkyl) containing up to 3 halogen atoms, methoxymethyl, acetoxymethyl and cycloalkyl of 3 to 6 carbon atoms, or R * 25 and R "25, together with the carbon atom in which they are placed, form a cycloalkyl ring of 3 to 6 carbon atoms; and when A is a nitrogen atom, R25 designates a lone pair of electrons; and R24 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, cyano, and oxo; and R'25 and R "25 are, independently, lower alkyl or cycloalkyl of 3 to 6 carbon atoms, or R, 22 is phenyl, toluyl, hydroxyphenyl, cyclopentyl, cyclohexyl, isobutyl or cyclohexyloxycarbonylmethyl, and esters, salts, active metabolites and prodrugs thereof , for use in the regulation of meiosis
8. 8. The compounds according to the preceding claim, characterized in that the compound is any of the compounds mentioned in any of claims 2 to 4.
9. 9. The use of a compound of the formula General Ib described above, for the preparation of a medicament for regulating meiosis
10. 10. The use of a compound of the general formula Ib described above, for the preparation of a medicament for the treatment of infertility in mammals, preferably in humans humans (men and women)
11. 11. The use of a compound of the general formula Ib described above, for the preparation of an anti-cancer agent. ptivo, preferably for human beings (men and women).
12. 12. The use of a compound of the general formula Ib described above, in a fertilization culture medium that also contains a mammalian germ cell, preferably a human cell.
13. The use according to any of the preceding claims, characterized in that the compound is any of the compounds set forth in any of claims 2 to 4.
14. 14. A method for regulating meiosis, characterized in that it comprises administering to a subject that needs of such regulation, an effective amount of a compound of formula Ib described above.
15. 15. A method for regulating meiosis in a mammalian germ cell, characterized in that it comprises administering an effective amount of a compound of the general formula Ib described above to a germ cell in need of such treatment.
16. 16. A method characterized in that a compound of the general formula Ib described above is administered to a germ cell by administration of the compound to a mammal that hosts said cell.
17. 17. A method according to any of the preceding claims, characterized in that the germ cell whose meiosis is to be regulated is an oocyst.
18. 18. A method according to any of the preceding claims, characterized in that a compound of the general formula Ib described above is administered to an oocyst ex vivo or in vitro.
19. 19. A method according to any of the preceding claims, characterized in that the germ cell whose meiosis is to be regulated, is a male germ cell.
20. 20. A method according to any of the preceding claims, characterized in that mature male germ cells are produced by the administration of a compound of the general formula Ib described above to testicular tissue in vivo, ex vivo or in vitro.
21. 21. A method according to any of the preceding claims, characterized in that the compound is any of the compounds set forth in any of claims 2 to.
22. 22. Any novel feature or combination of the features described herein.