MXPA01009970A - 14&bgr;-H-STEROLS, PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AND USE OF THESE DERIVATIVES FOR THE PREPARATION OF MEIOSIS REGULATING MEDICAMENTS - Google Patents

Abstract

The present invention relates to pharmaceutically active 14&bgr;-H-sterols, to pharmaceutical compositions comprising them and to the use of these novel compounds for the preparation of medicaments. More particularly it has been found that the 14&bgr;-H-sterols of the invention can be used for regulating meiosis.

Description

14ß-H-ESTER0LES, PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND AND USE OF THEIR DERIVATIVES FOR THE PREPARATION OF MEDICINES THAT REGULATE THE MEIOSIS The present invention relates to pharmaceutically active sterols, to pharmaceutical compositions comprising them as active substances and to the use of these new compounds for the preparation of medicaments. More particularly, it has been found that the sterols of the invention can be used to regulate meiosis. Meiosis is the unique and final event of the germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, the exchange between maternal and paternal genes takes place before the pairs of chromosomes in the two daughter cells are separated. These contain only half the number (ln) of chromosomes and 2c DNA. The second meiotic division proceeds without a DNA synthesis. Therefore, this division results in the formation of haploid germ cells with only DNA le. The meiotic events are similar in the germ cells of the male and the female, but the programming in time and the processes of differentiation which lead to the ovules and sperm differ profoundly. All germ cells of females enter the prophase of the first meiotic division early in life, often before birth, but all stop as oocytes later in the prophase (dictiato state) until ovulation after puberty. In this way, from early life, the female has a reserve of oocytes that are extracted until the reserve is exhausted. Meiosis in females does not end until after fertilization, and results in only one egg and two polar abortive corpuscles per germ cell. In contrast, only some of the germ cells of the male enter meiosis from puberty and lead to a germ cell root population throughout life. Once initiated, meiosis in the male cell continues without significant delay and produces 4 sperm cells. Little is known about the mechanism that controls the onset of meiosis in the male and female. In the oocyte, new studies indicate that follicular purines, hypoxanthine or adenosine, may be responsible for meiotic arrest [Downs, S.M. et al., Dev. Biol 82 (1985) 454-458; Epplg. J. J. et al., Dev. Biol. 119 (1986) 313-321; and Downs, S.M. Mol.

Reprod. Dev 35 (1993) 82-94]. The presence of a disseminating meiosis regulating substance was first described by Bys ov et al. in a fetal mouse gonad culture system [Byskov, AG Et al., Dev. Biol. 52 (1976 (193-200).) A substance of meiosis activation (MÁS) was secreted by the ovary of the fetal mouse in at which meiosis was initiated, and a meiosis prevention substance (MPS) was released from the morphologically differentiated testes with non-meiotic germ cells at rest.It was suggested that the relative concentrations of MÁS and MPS regulated the start, stop and Resumption of meiosis in the germ cells of the male and female (Byskov, A. G. et al., In The Physiology of Reproduction in [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., Na ture 374 (1995), 559-562] describes the isolation of bull testes and human follicular fluid from certain sterols (T-MAS and FF-MAS) that activate meiosis of oocytes. The compounds known to regulate meiosis are described in W096 / 27658, O97 / 00884, 098/28323 and W098 / 52965.

It is a purpose of the present invention to provide the compounds useful as contraceptives in females and males, particularly in humans via the inhibition of meiosis. The present invention relates to 14β-H-sterols of the General Formula I: wherein R3 designates a hydrogen atom or together with R3 'an additional bond, R3' designates a hydrogen atom or together with R3 an additional bond, R4 designates a hydrogen atom or a methyl group, R4 'designates a hydrogen atom or a methyl group, R7 designates a hydrogen atom or together with R an additional bond, R8 designates a hydrogen atom or together with R7 or together with R9 an additional bond, R denotes a hydrogen atom or together with R8 or together with R11 an additional bond, R15 denotes a hydrogen atom, a hydroxy group, a halogen atom or together with R15 'an oxo group or together with R15 an additional bond or together with R22' an oxygen bridge, R15 'designates a hydrogen atom, a linear or branched alkyl group of 1 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms or together with R15 an oxo group, R16 designates a hydrogen atom, a hydroxy group , a halogen atom or together with R15 an additional bond or together with R22 an additional bond, R22 designates a hydrogen atom, an optionally substituted, linear or branched alkyl or alkenyl group of 1 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms optionally substituted or together with Rld an additional bond or together with R22 'a linear or branched alkylidene group of 1 to 8 atoms carbon R22 'designates a hydrogen atom, a hydroxy group or together with R15 an oxygen bridge or together with R22 a linear or branched alkylidene group of 1 to 8 carbon atoms or esters thereof. As used in the present description and the claims, an alkyl group, when used alone or in combination, can be a straight or branched alkyl group. The term "alkyl of 1 to 8 carbon atoms" denotes a alkyl group having from 1 to 8 carbon atoms: preferred examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ter- butyl, pentyl, iso-pentyl, hexyl and cyclohexyl. The term "alkenyl" refers to an unsaturated alkyl group. Preferred examples are vinyl, allyl, isopropenyl and phenyl. The term halogen means fluorine, chlorine, bromine or iodine as used in the present description and the claims, a statement that for example R 15 together with R 15 'is an oxo group means that oxo (= 0) is present at position 15 and, consequently, there is no hydrogen atom in the 15-position. The term "aryl group" of 6 to 10 carbon atoms (Cß-Cio) designates a phenyl group, which is optionally substituted by halogen, alkoxy of 1 to 4. carbon atoms, hydroxy or alkyl groups of 1 to 4 carbon atoms. The term linear or branched alkylidene group of 1 to 8 carbon atoms (C? -8) means an alkylidene group having from 1 to 8 carbon atoms. This group is connected via a double bond to the carbon 22 of the steroid. Preferred examples are methylene, ethylidene, propylidene, isopropylidene, butylidene, iso-butylidene, pentylidene, iso-pentylidene, neo-pentylidene and cyclohexylidene. Surprisingly, it was found that the β configuration of the hydrogen at position 14 (numbering of the carbon atoms according to the IUPAC nomenclature is important for the inhibition activity of meiosis.) In the presence of the 14β- H-sterols, the effect of meiosis activation of FF-MAS is diminished or completely extinguished The regulatory substances of meiosis described so far are either derived from 14-aH and 14-cholestane [Byskov, AG Et al. , Na ture 374 (1995), 559-562] and show either a meiosis activation activity or a low inhibitory activity In contrast, the 14β-H-sterols of this invention strongly antagonize the effect of FF-MAS that it occurs naturally and in this way they are inhibitors of meiosis. These findings make the compounds described have a special interest for contraception. Preferred compounds of Formula I are those that inhibit the collapse of the germinal vesicle by at least 20%, preferably at least 40%, especially preferred by at least 60%, when tested in an oocyte test as described in Example 13 and which does not activate meiosis in an oocyte test as described in Example 12. The compounds of General Formula I have a number of chiral centers in the molecule and thus exist in various isomeric forms. All of these isomeric forms and mixtures thereof are within the scope of the invention (unless otherwise indicated). Preferred compounds of Formula I are such with a 3ß-0H group and a? 8 double bond. In addition, compounds of Formula I are preferred, wherein R 15 designates a hydrogen atom to a hydroxy group. Other preferred compounds of Formula I are such, wherein R22 designates an optionally substituted, linear or branched alkyl group of 1 to 8 carbon atoms or together with R22 'a linear or branched alkylidene group of 1 to 8 carbon atoms.

In another embodiment, the present invention relates to esters of compounds of the General Formula I. These esters are derived formally by esterification of one or more hydroxyl groups of a compound of the Formula I with an acid which can be selected, example, of the group of acids comprising succinic acid, glutaric 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 monocarboxylic acids lieos, aliphatics. Especially preferred compounds of the formula I of the present invention are the following: 4,4-dimethyl-5a, 14β-cholesta-8-en-3β-ol 4,4-dimethyl-5a, 14β-cholesta-8-en -3β, 15β-diol 4, 4-dimethyl-5a, 14β-cholesta-8-en-3β, 15a-diol 4, 4-dimethyl-5a, 14β-cholesta-8,15-diene-3β-ol 4, 4-dimethyl-5a, 14β-cholesta-7,9 (11), 15-trien-3β-ol 4,4-dimethyl-5a, 14β-cholesta-8, 15, 23 (E) -trien-3ß-ol 4, 4-dimethyl-5a, 14β-cholesta-8, 15, 24-trien-3β-ol 4, 4-dimethyl-5a, 14β-cholesta-8, 24-diene-3β, 15β-diol 4, 4- dimethyl-5a, 14β-ergosta-8, 22-diene-3β-ol 4,4-dimethyl-5a, 14β-ergosta-8, 22-diene-3β, 15β-diol 4, 4-dimethyl-5a, 14β- ergosta-8, 22 -diene-3β, 15a-diol 4, 4-dimethyl-5a, 14ß-ergosta-8, 15, 22-trien-3ß-ol 4, 4-dimethyl-24-nor-5a, 14β-cholesta-8-en-3ß-ol 4, 4- dimethyl-24-nor-5a, 14β-cholesta-8-ene-3β, 15β-diol 4, 4-dimethyl-24-nor-5a, 14β-cholesta-8-ene-3β-, 15a-diol 4, 4 -dimethyl-24-nor-5, 14β-cholesta-8, 15-dien-3β-ol butanediamine, 4,4-dimethyl-5a, 14β-cholesta-8, 15-dien-3β-ol butanediazole acid; , 4-dimethyl-5a, 14ß-ergosta- 8, 15, 22-trien-3ß-ol (20R) -4, 4, 20-trimethyl-16β, 21-cyclo-5a, 14β-pregn-8-ene- 3ß, 15a-diol (20R) -4, 4, 20-trimethyl-16β, 21-cyclo-5a, 14β-pregn-8-ene-3β, 15β-diol (20S) -20-hydroxymethyl-4, 4- dimethyl-5a, 14β-pregn-8-ene-3β, 15β-diol The compounds of the general formula I according to the invention can be synthesized analogously with the preparation of known compounds. Therefore, the synthesis of the compounds of Formula I can follow well established synthesis routes described in the comprehensive literature of sterols and steroids. The following books can be used as a key source in the synthesis: L. F. Fieser & M. Fieser: Steroids: Reinhold Publishing Corporation, NY 1959; Rood 's Chemistry of Carbon Compounds (editor: S. Cof Frey): Elsevier Publishing Company, 1971; and especially 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 articles covering the period up to 1990. In particular, the compounds of the present invention are synthesized according to the following general procedures: The sterols that are used as starting materials can be synthesize according to the literature procedures: 4, 4-dimethyl-5a-cholesta-8, 14-dien-3ß-ol [Biochem. J. 132 (1973), 439], 4, 4-dimethyl-5a-ergosta-8, 14, 22-tren-3β-ol [as benzoate: J. Org chem. 51 (1986), 4047], 5a-cholesta-8, 14-dien-3ß-ol [J. Am. Chem. Soc. 75 (1953), 4404], 5a-ergosta-8, 14, 22-trien-3ß-ol [J. Org.

Chem. 53 (1988), 1563]. In the following, only compounds with the 4,4-dimethyl group are described in detail. Compounds that are unsubstituted at position 4 are obtained by analogous routes. The 14β-H-derivatives can be synthesized from δ 8,14-diene 1 systems via alcohol protection, epoxidation and subsequent epoxide opening (scheme 1). The 3-alcohol is You can protect with a benzoate. Epoxidation can be achieved with reagents such as dimethyldioxirane, hydrogen peroxide in the presence of different catalysts, m-CPBA and other percents. The rearrangement to deconjugated ketone 4 can be achieved by treatment with different lewis acids or acids such as boron trifluoride [see. Chem. Pharm. Bul l. 38 (1990), 1796]. Scheme 1: The reactions can be carried out in the presence of different steroidal side chains (Rs) such as cholesterol side chain, ergosterol, sitosterol or stigmasterol. If the 15-ketones of General Formula 4 are reduced with lithium aluminum hydride, they are obtained the 3β, 15β-diols of the General Formula 5. The corresponding 15α-alcohols can be obtained as minor diastereomers of the General Formula 6 of the reduction with sodium borohydride. Subsequent deprotection of the 3-OH-group gives the 3β, 15a-diols of the General Formula 7 (Scheme 2).

Scheme 2: The 8,15-diene of the General Formula 10 can be obtained by the following sequence. The reduction with sodium borohydride of the ketone 4 gives 15β-alcohol 8 as the main diastereomer. Removal to the 8,15-diene of the General Formula 9 can be carried out with Martin's sulfur. The deprotection gives the desired alcohols of General Formula 10 (Scheme 3).

Scheme 3 The derivatives that saturate at position 15 can be obtained by the following route. The 15β-alcohols of the General Formula 8 can be reacted with methanesulfonic acid chloride. Then, mesylate 11 can be reduced with lithium aluminum hydride. Compounds of General Formula 12 are obtained (Scheme 4).

Scheme 4 Side chain modifications can be made via the ozonolysis of the ergosterol side chain in the compound of Formula 4 (with Resteroi = ergosterol side chain). After the reducing treatment with sodium borohydride, the 22-alcohol 13 can be transformed to a leaving group such as a tosylate (Scheme 5). This tosylate 14 can be coupled with different branched or linear, alkyl, alkenyl or aryl grignard reagents under copper catalysis to give the compounds of the General Formula 15.

Scheme 5: is eroi = ergosterol side chain These compounds can be transformed into the corresponding 3,15-diols (see Scheme 2),? 8,15-dienes (Scheme 3) or the 15-saturated compounds (Scheme 4) as described above. Another modification of side chain type compounds 24-keto, 24-hydroxy- or? 24 can be obtained by the following route. Ozonolysis of compound 4 and subsequent treatment with triphenylphosphine gives aldehyde 16. This can be coupled in an aldol reaction with isopropyl methyl ketone to give compound 17 as a mixture of diastereomers. The removal with Martin's sulfur, the hydrogenation and the subsequent reduction gives the diol 20 as a mixture of diastereomers (Scheme 6).

Scheme 6 Resteroi = side chain of ergos terol The diols 20 can be removed to the following sterols. The treatment with Martin's sulfur gives a mono- and bis-eliminated product. Subsequent cleavage of the benzoate can be easily achieved by reduction to give diol 23 and triene 24, respectively (Scheme 7).

Scheme 7 Compounds with an additional bond between C16 and C22 can be maintained by the following route. Tosylate 14 can be treated with a lithium diisopropylamide-type base or different grignard compounds to deprotonate the ketone in the 16-position. The enolate alkylates the 22-tosylate intramolecularly to give the pentacycle 25. This can be treated with hydride. aluminum and lithium to give the diols 26 and 27 (Scheme 8).

Scheme 8: A further object of the present invention are pharmaceutical compositions comprising one or more compounds of the General Formula I as active substances. The compositions may further comprise pharmaceutically acceptable excipients well known in the art such as carriers, diluents, absorption enhancers, preservatives, buffers, osmotic pressure adjusting agents, tablet disintegrating agents and other ingredients that are conventionally used in the art. 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. These liquid compositions may be suitable for injection or for use in conjunction with ex-vem and in-vvv fertilization. The liquid compositions may contain other ingredients that are conventionally used in the art, some of which are mentioned in the above list. Additionally, a composition for transdermal administration of a compound of this 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 sprinkler in liquid or powder form. The dose of a compound of the invention to be used will be determined by a physician and will depend among other factors on the particular compound employed, the route of administration and the purpose of use. In general, the compositions of the invention are prepared by intimately binding the active compound to the liquid or solid auxiliary ingredients and then, if necessary, forming the product in the desired formulation.

Usually, not more than 1000 mg, preferably not more than 100 mg, and in some preferred cases, not more than 10 mg of a compound of the Formula I will be administered to mammals, for example, to humans, per day. The present invention relates to the use of the compounds of the General Formula I for the preparation of a medicament for the regulation of meiosis. The compounds of the present invention include meiosis in the oocytes as well as in the germ cells of males. The compounds of the General Formula I are promising as new fertility regulating agents without the usual side effects on somatic cells that are known from the hormonal contraceptives used to date that are based on estrogen and / or progestin. In this regard, 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 regulatory substance of meiosis, while the estrogens and progestins used in contraceptives Hormones used to date have an adverse effect on the biosynthesis of progesterone. Contraception can be achieved in females by administering a compound of the invention that inhibits meiosis, so that mature oocytes are not produced. Similarly, male contraception can be achieved by administering a compound of the invention that inhibits meiosis, so that mature sperm cells are not produced. In a further aspect, the present invention relates to a method for regulating meiosis, which comprises administering to a subject in need of this regulation, an effective amount of one or more compounds of the General Formula I. The route of administration of the compositions containing a compound of the invention can be any route that effectively transports the active compound to its site of action. Thus, when the compounds of this invention are to be administered to a mammal, they are conveniently provided in the form of a pharmaceutical composition comprising at least one compound of the invention, in conjunction with a pharmaceutically acceptable carrier. For oral use, these compositions are preferably in the form of capsules and tablets. When used as a contraceptive, the The compounds of the invention will have either to be administered continuously or cyclically. In a further aspect, the present invention relates to the use of a group of 14β-hydrogen in a sterol compound to increase the inhibitory activity of a substance inhibiting meiosis. The present invention is further illustrated by the following examples: Ex emp1o 1_ \ 4, 4-dimethyl-5, 14β-ergosta-8, 22-diene-3β, 15β-diol a) 4, 4-dimethyl-5a, ergosta-8, 14, 22-trien-3β-yl-benzoate. ml of benzoyl chloride in two portions to a solution of 30.9 g of 4,4-dimethyl-5a-ergosta-8, 22-diene-3ß-ol in 154 ml of pyridine at 60 ° C. The reaction was stirred for 1 hour at the same temperature and then poured into ice water. The precipitate was collected, washed with ice-cooled ethanol, recrystallized from dichloromethane / methanol and dried for 12 hours to give 32g of 4,4-dimethyl-5a-ergosta-8, 14, 22-trien-3ß-il. -benzoate (mp 146 ° C). 1H-NMR (CDC13): d = 0.80-1.12 (8x CH3); 4.75 (dd, J = 16 Hz, 4 Hz, 1H, H-3a); 5.22 (m, 2H, H-22/23); 5.38 (s, broad, 1H, H-15); 7.46 (t, 2H); 7.57 (t, 1H); 8.07 (d, 2H). b) 4, 4-dimethyl-14, 15a-epoxy-5a-ergosta-8, 22-dien-3-yl-benzoate A solution of 18 g of 4,4-dimethyl-5a-ergosta-8, 14, 22 -trien-3-yl-benzoate in 60 ml of dichloromethane was cooled to 10 ° C. After the addition of 3 g of m-nitro-fluoroacetophenone and 10 ml of saturated NaHCO 3 solution, the reaction was stirred for 15 minutes. Then, 12 ml of hydrogen peroxide (aqueous, 30%) were added and the solution was stirred at 10 ° C for 20 hours. 20 mL of saturated sodium thiosulfate solution was added and the mixture was stirred for 20 minutes, diluted with dichloromethane, washed with sodium hydroxide solution (aqueous, 5%), water and brine. Drying (MgSO) and removal of the solvents in vacuo gave the crude epoxide (20 g), which was further reacted without purification. c) 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-ergosta-8, 22-di-15-one 20 g of the crude epoxide were dissolved in 300 ml of dioxane. The mechanically stirred yellow solution was treated with 2.5 ml of trifluor boron lutein. etterate for 30 minutes and then poured into ice water. The precipitate was collected, washed with ice-cold water and dried. The crude material was purified by chromatography to give 11.55 g of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-ergosta-8, 22-di-15-one (p.f. 176 ° C). X H NMR (d5-pyridine): d = 0.85 (2x d, J = 7 Hz, 6H, H-27/26); 0.91 (s, 3H, 4-β-CH 3); 0.93 (d, J = 7 Hz, 3H, H-28); 1.05 (s, 3H, H-18); 1.06 (s, 3H, 4-a-CH3); 1.07 (s, 3H, H-19); 1.13 (d, J = 7 Hz, 3H, H-21); 4.89 (dd, J = 12 Hz, 4 Hz, 1H, H-3a); 5.37 (m, 2H, H-22/23); 7.49 (t, 2H); 7.57 (t, 1H); 8.27 (d, 2H). d) 4, 4-dimethyl-5, 14β-ergosta-8, 22-diene-3β, 15β-diol 50 ml of LiAlH was added to a stirred solution of 300 mg of 3β-benzoyloxy-4,4-dimethyl-5a , 14β-ergosta-8, 22-dien-15-one in 30 ml of diethyl ether and the mixture was stirred for 30 minutes at room temperature. Then, 1 ml of saturated ammonium chloride solution was added. After 10 minutes, the solution was filtered and the solvent was removed in vacuo. The residue was separated by chromatography to give 100 mg of 4,4-dimethyl-5a, 14β-ergosta-8, 22-diene-3β, 15β-diol XH NMR (CDC13): d = 0.78-1.2 (8 x CH3); 3.24 (dd, J = 12 Hz, 4 Hz, 1H, H-3a); 3.7 (dd, broad, J = 4 Hz, 4 Hz, 1H, H-15a); 5.24 (m, 2H, H-22/23).

Example 2 4, 4-dimethyl-5a, 14β-ergosta-8, 22 -diene-3β, 15a-diol a) 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-ergosta-8, 22-dien-15a -diol A solution of 1 g of 3β-benzoyloxy-4,4-dimethyl-5-a, 14β-ergosta-8, 22-di-15-one in 75 ml of tetrahydrofuran and 25 ml of methanol was treated with 750 mg of sodium borohydride. After stirring at room temperature for 30 minutes, 1 ml of saturated aqueous solution of ammonium chloride was added and the mixture was stirred for 15 minutes at room temperature. Filtration, removal of the solvent in vacuo and purification by chromatography gave 60 mg of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-ergosta-8, 22-di-15a-ol in addition to 770 mg of the corresponding 15β- alcohol . XH NMR (CDC13): d = 0.8-1.12 (8 x CH3); 4.07 (t, broad, J = 4 Hz, 1H, H-15β); 4.76 (dd, J = 12 Hz, 4 Hz, H, H-3a); 5.23 (m, 2H, H-22/23); 7.44 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). b) 4, 4-dimethyl-5a, 14ß-ergosta-8, 22-diene-3β-15a-diol A solution of 40 mg of 3β-benzoyloxy-4, 4- dimethyl-5a, 14β-ergosta-8, 22-dien-15a-ol in 10 ml of diethyl ether was treated with 10 mg of lithium aluminum hydride for 30 minutes at room temperature as described in Example Id. column chromatography, 25 mg of 4,4-dimethyl-5a, 14β-ergosta-8,22-diene-3β, 15a-diol was isolated as a white solid (mp 148 ° C). 2 H NMR (CDC13): d = 0.78-1.7 (8 x CH3); 3.25 (dd, J = 11 Hz, 5 Hz, 1H, H-3); 4.04 (t, J = 4 Hz, 1H, H-15CC); 5.22 (m, 2H, H-22/23); Example 3: 4, 4-dimethyl-5a, 14β-cholesta-8, 15-dien-3β-ol a) 4, 4-dimethyl-5 -colesta-8, 14-dien-3-yl-benzoate A solution of 1.0 g of 4,4-dimethyl-5a-cholesta-8,14-dien-3ß-ol in 5 ml of pyridine was treated with 1.5 ml of benzoyl chloride. After stirring for 3 hours at room temperature, the solution was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with aqueous HCl at 0.1 N, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oil which was purified by column chromatography to give 900 mg of 4,4-dimethyl-5a-cholesta-8, 14-diene. 3-yl-benzoate as a white solid (mp 158 ° C). 1 H NMR (CDCl 3): d = 0.83 (s, 3 H, H-18); 0.87 + 0.88 (2x s, 3H, H-26/27); 0.95 (d, J = 6 Hz, 3H, H-21); 4.76 (dd, J = 11 Hz, 5 Hz, 1H, H-3a); 5.38 (s, broad, 21, H-15); 7.45 (t 2H); 7.57 (t, 1H); 8.06 (d, 2H). b) 4, 4-dimethyl-14, 15a-epoxy-5a-cholesta-8-en-3-yl-benzoate To a well-stirred suspension of 4,4-dimethyl-5a-cholesta-8, 14-dien-3β -l-benzoate in 120 ml of dichloromethane was added a solution of dimethyldioxirane (130 ml, 0.09-0.11 M in acetone) at 0 ° C. After stirring for 30 minutes at 0 ° C, the reaction mixture was concentrated in vacuo to dryness. The resulting crude epoxide was used without purification. c) 3β-benzoyloxy-4,4-dimethyl-5, 14β-cholesta-8-en-15-one A solution of 1,4-dimethyl-14,15a-epoxy-5a-cholesta-8-en-3-yl-benzoate in 15 ml of dioxane was treated with 0.1 ml of boron trifluoride-ethyl ether complex . The solution was stirred for 20 minutes at room temperature and then poured into saturated, aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography gave 440 mg of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8-en-15-one as a white solid (p.f.153 ° C). XH NMR (CDC13): d = 0.83-1.1 (7x CH3); 2.31 (s, broad, 1H, H-14β); 4.76 (dd, J = 11 Hz, 5 Hz, 1H, H-30C); 7.44 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). d) 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-cholesta-8-en-15β-ol A solution of 3β-benzoyloxy-4,4-dimethyl-5α, 14β-cholesta-8-en- 15-one (440 mg, 0.83 mmol) in dry tetrahydrofuran (15 mL) and methanol (1 mL) was treated at room temperature with sodium borohydride (125 mg). After 2 hours, the solution was poured into 0.1N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white foam, which was used without further purification. e) 4, 4-dimethyl-5a, 14β-cholesta-8, 15-dien-3β-yl-benzoate A solution of 500 mg of 3β-benzoyloxy-4, 4- dimethyl-5, 14β-cholesta-8-en-15β-ol in 10 ml of dichloromethane was cooled to 0 ° C and 1.1 g of Martin's sulfur were added in one portion. The reaction was stirred for 1 hour at room temperature. The solvents were removed in vacuo. Purification of the residue by chromatography gave 315 mg of 4,4-dimethyl-5a, 14β-cholesta-8,15-dien-3-yl-benzoate as a silky solid, which was used directly. f) 4, 4-dimethyl-5, 14β-cholesta-8, 15-dien-3ß-ol A solution of 315 mg of 4,4-dimethyl-5a, 14β-cholesta-8,15-diene-3ß-il -benzoate in dry diethyl ether was treated with 35 mg of lithium aluminum hydride as described in Example Id. Column chromatography of the crude product and subsequent recrystallization gave 135 mg of 4,4-dimethyl-5a, 14β- cholesta-8, 15-dien-3ß-ol as white needles (mp 138 ° C). NMR? H (CDC13): d = 0.81 (s, 3H, H-18); 0.83 - 1.02 (6 x CH); 2.49 (s, broad, 1H, H-14β); 3.24 (m, 1H, H-3); 5.64 + 5.79 (2x m, 1H, H-15/16) Example 4: 4, 4-dimethyl-24-nor-5, 14β-cholesta-8, 15-diene-3β-ol a) (20S) -3β-benzoyloxy-20-hydroxymethyl-4, 4-dimethyl-5a, 14ß-pregn-8-en-15-one and (2 OS) -3β-benzoyloxy-20- hydroxymethyl-4,4-dimethyl-5a, 14β-pregn-8-en-15β-ol A solution of 2.18 g of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-ergosta-8, 22-diene-15 -one (Example le) in 88 ml of dichloromethane, 30 ml of methanol and 1 ml of pyridine was cooled to -70 ° C. An oxane / oxygen mixture (1: 4) was passed through the solution for 12 minutes (controlled by TLC chromatography). Then, 130 mg of sodium borohydride was added and the stirred reaction mixture was allowed to warm to 0 ° C over a period of 2 hours and poured into saturated aqueous solution of ammonium chloride. The solution was extracted with ethyl acetate and the combined extracts were further washed with water and brine and then dried over sodium sulfate. The solution was filtered and evaporated in vacuo. The crude product was purified by chromatography to yield 1.28 g (2 OS) -3β-benzoyloxy-20-hydroxymethyl-4, 4-dimethyl-5a, 14β-pregn-8-en-15-one (mp 238.8 ° C) and 330 mg of the corresponding 15β-hydroxy compound. XH NMR (CDC13): d = 0.9-1.1 (4x CH; 1.16 (d, J = 6 Hz, 3H, H-21); 2.33 (s, broad, 1H, H-14β); 3.42 (m, 1H, H-22a); 3.63 (m, 1H, H-22b); 4.75 (dd, J = 11 Hz, 4 Hz, 1H, H-3CC); 7.45 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). b) (2 OS) -3β-benzoyloxy-4, 4, 2 O-trimethyl-21-toluol sulfo-nyloxy-5a, 14β-pregn-8-en-15-one A solution of 385 mg of (20S) - 3β-benzoyloxy-20-hydroxymethyl-4,4-dimethyl-5a, 14β-pregn-8-en-15-one in 5 ml of pyridine was cooled to 0 ° C. After the addition of 190 mg of p-toluenesulfonic chloride, the reaction mixture was stirred for a period of 20 hours at 6 ° C and then poured into brine and stirred for 20 minutes. The precipitate was collected, washed with ice-cold water and dried at 50 ° C in vacuo. The crude product (500 mg) was used without further purification. c) 3β-benzoyloxy-4, 4-dimethyl-24-nor-5a, 14β-cholesta-8-en-15-one 3.42 g of 2-methylpropyl bromide were slowly added to the stirred suspension of magnesium (powder , 1.6 g) in 25 ml of anhydrous tetrahydrofuran for a period of 30 minutes at 50 ° C to give a clear solution of Grignard reagent. The mixture was then cooled to -10 ° C and 3.32 ml of a Li2CuCl4 solution (prepared by mixing 99 mg of cupric chloride, 86 mg of lithium chloride and 10 ml of tetrahydrofuran) was added dropwise. The reaction mixture was stirred for 1 hour -30 ° C, after which a solution of 0.5 g of (2 OS) -3β-benzoyloxy-4, 4, 20-trimethyl-21-toluolsulfonyloxy-5a, 14β-pregn-8- was added at 0 ° C. en-15-one in 10 ml of tetrahydrofuran. After 2 hours at 0 ° C, the mixture was stirred at room temperature overnight. Ethyl acetate and saturated ammonium chloride solution were added and the solution was stirred for 15 minutes. The organic extracts were washed with 1N HCl, water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography to give 250 mg of 3β-benzoyloxy-4,4-dimethyl-24-nor-5a, 14β-cholesta-8-en-15-one as a white foam. 1 H NMR (CDC13): d = 0.82-1.09 (7x CH3); 2.31 (s, broad, 1H, H-14β); 4.75 (dd, J = 11 Hz, 4 Hz, 1H, H-3a); 7.44 (t, 2H),; 7.57 (t, 1H); 8.05 (d, 2H). d) 3β-benzoyloxy-4,4-dimethyl-24-nor-5a, 14β-cholesta-8-en-15β-ol 130 mg of 3β-benzoyloxy-4,4-dimethyl-24-nor-5a was treated, 14β-cholesta-8-en-3-one with 100 mg of sodium borohydride as described in Example 2a. The aqueous treatment produced 130 mg of 3β-benzoyloxy-4,4-dimethyl-24-nor-5a, 14β-cholesta-8-en-15β-ol as a white foam, which was used directly. e) 4,4-dimethyl-24-nor-5a, 14ß-cholesta-8,15-dien-3-yl-benzoate 400 mg of Martin's sulfur in one portion was added to a solution of 100 mg of 3-benzoyloxy -4,4-dimethyl-24-nor-5a, 14β-cholesta-8-en-15β-ol in 10 ml of dichloromethane. The mixture was stirred at room temperature for 18 hours. Evaporation under reduced pressure and chromatography gave 100 mg of 4,4-dimethyl-24-nor-5a-14β-cholesta-8,15-dien-3-yl-benzoate as an oil which was used without further purification. f) 4,4-dimethyl-24-nor-5a, 14β-cholesta-8,15-diene-3ß-ol 100 mg of 4,4-dimethyl-24-nor-5a, 14β-cholestazole benzoate was treated. 8,15-dien-3β-yl with 20 mg of lithium aluminum hydride as described in Example Id. Column chromatography of the crude product and recrystallization (hexane / ethyl acetate) gave 36 mg of 4.4. -dimethyl-24-nor-5a,, 14β-cholesta-8, 15-dien-3β-ol (mp 104.3 ° C). NMR? H (CDC13): d = 0.82 (s, 3H, H-18); 0.83-1.03 (6x CH3); 2.49 (s, broad, 1H, H-14β); 3.24 (m, 1H, H-30C, 5.65 + 5.8 (m, 1 H, H-15/16).

Example 5: 4, 4-dimethyl-24-nor-5, 14β-cholesta-8-en-3β-ol a) 15β-methanesulfonyloxy-4,4-dimethyl-24-nor-5a, 14β-8- benzoate eno-3ß-yl. 40 mg of 3β-benzoyloxy-4,4-dimethyl-24-nor-5a, 14β-cholesta-8-en-15β-ol in 3 ml of pyridine were treated with 0.2 ml of methanesulfonic chloride at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were combined and washed with 1N HCl, water and brine, dried over sodium sulfate and filtered. Removal of the solvents gave 40 mg of 15β-methanesulfonyloxy-4,4-dimethyl-24-nor-5a, 14β-cholesta-8-ene-3β-yl benzoate which was used directly. b) 4, 4-dimethyl-24-nor-5a, 14β-cholesta-8-en-3β-ol 44 mg of 15β-methanesulfonyloxy-4,4-dimethyl-24-nor-5, 14ß-benzoate were treated cholesta-8-ene-3β-yl with 10 mg of lithium aluminum hydride as described in Example Id. The crude product was purified by chromatography to provide 32 mg of 4,4-dimethyl-24-nor-5a, 14β -cholesterol-8-en-3ß-ol. XH NMR (CDC13): d = 0.81 (s, 3H, H-18); 0.82-1.03 (6x CH3; 3.25 (dd, J = 11 Hz, 4 Hz, 1H, H-3a).

Example 6: 4, 4-dimethyl-24-nor-5a, 14β-cholesta-8-ene-3β, 15β-diol 30 mg of 3β-benzoyloxy-4,4-dimethyl-24-nor-5a, 14β was treated -cholesterol-8-en-15β-ol with 10 mg of lithium aluminum hydride as described in Example Id. The crude product was purified by column chromatography to give 23 mg of 4,4-dimethyl-24-nor- 5a, 14β-cholesta-8-ene-3β, 15β-diol as a white foam. XH NMR (CDC13): d = 0.82 (s, 3H, H-18); 0.84-1.04 (6x CH3); 3.25 (d, broad, J = 12 Hz, 1H, H-3a); 3.7 (q, broad, J = 7 Hz, 1H, H-15a).

Examples 7 and 8: (20R) -4, 4, 20-trimethyl-16β, 2 l-cyclo-5a, 14β-pregn-8-ene-3β, 15β-diol and (20R) -4, 4, 20- trimethyl-16β, 21-cyclo-5, 14β-pregn-8-ene-3β, 15a-diol a) (20R) -3β-benzoyloxy-4, 4, 20-trimethyl-16β, 21-cyclo-5a, 14β -pregn-8-en-15-one 1.10 g of (2 OS) -3β-benzoyloxy-4,4, 20-trimethyl-21-toluolsulfonyloxy-5a, 14β-pregn-8-en-15-one were treated with 52 mmol of phenylmagnesium bromide analogously to Example 4c. After chromatography, 560 mg of (20R) -3β-benzoyloxy-4, 4, 20-trimethyl-16β, 21-cyclo-5a, 14β-pregn-8- were isolated en-15-one, in addition to other products, which result from the substitution of tosylate by the phenyl grignard reagent. b) (20R) -4, 4, 20-trimethyl-16β-21, cyclo-5a, 14β-pregn-8-ene-3β, 15β-diol and (20R) -4, 4, 20-trimethyl-16β- 21, cyclo-5a, 14β-pregn-8-ene-3β, 15a-diol 460 mg of (20R) -3β-benzoyloxy-4,4, 20-trimethyl-16β-21, cyclo-5a, 14β- were treated pregn-8-en-15-one with 50 mg of lithium aluminum hydride as described in Example Id. The crude product was purified by column chromatography to give 40 mg of (20R) -4.4, 20- trimethyl-16β, 21, cyclo-5a, 14β-pregn-8-ene-3β, 15β-diol and 30 mg of (20R) -4, 4, 20-trimethyl-16β, 21, cyclo-5a, 14β-pregn -8-ene-3β, 15a-diol as white solids. (20R) -4, 4, 20-trimethyl-16β, 21, cyclo-5a, 14β-pregn-8-ene-3β, 15β-diol: XH NMR (CDC13): d = 0.73 (s, 3H, H- 18); 0.82 (s, 3H, H-19); 1.02 (s, 6H, 4-CH3); 1.09 (d, J = 8 Hz, 3H, H- 21); 2.72 (m, 1H, H-160C); 3.25 (m, 1H, H-3); 4.07 (q, J = 8 Hz, 1H, H-150C) (20R) -4,4, 20-dimethyl-16β, 21-cyclo-5a, 14β-pregn-8-ene-3β, 15a-diol X H NMR (CDCl 3) d = 0.79 (s, 3 H, H-18); 0.85 (s, 3H, H- 19); 1.0-1.08 (3 * CH3); 2.34 (d, J-6 Hz, 1H, H-14β); 2.68 (m, 1H, H-16a); 3.25 (m, 1H, H-3a); 4.07 (d, J = 6Hz, 1H, H-15ß) Example 9: 4, 4-dimethyl-5a, 14β-cholesta-8, 24-diene-3β, 15β-diol a) (2 OS) -3β-benzoyloxy-4, 4-dimethyl-15-oxo-5a, 15β-pregn-8-ene-20-carbaldehyde A solution of 2.2 g of 3β-benzoyloxy, 4-4 dimethyl-5a, 14ß-ergosta-8, 22-dien-15-one in 87 ml of dicloromethane and 53 ml of methanol was cooled to -78 ° C. A mixture of ozone / oxygen (1: 4) was passed into the solution for 16 minutes. 2.62 g of triphenylphosphine were added and the solution was brought to room temperature. The solvents were removed in vacuo and the residue was purified by chromatography to give 1.26 g of (2 OS) -3β-benzoyloxy-4, 4-dimethyl-15-oxo-5a, 15β-pregn-8-ene-20-carbaldehyde (mp 205 ° C). 1 H NMR (d5-pyridine): d = 0.90 (s, 3H, H-19); 0.98 (s, 3H, H-18); 1.04 (s, 6H, 4-CH3); 1.2 (d, J = 6 Hz, 3H, H-21); 2.41 (s, broad, 1H, H-14β); 4.83 (dd, J = 11 Hz, 4H, 1H, H-3a); 7.5 (t, 2H); 7.58) (t, 1H); 8.27 (d, 2H); 9.82 (d, J = 2 Hz, lH, H-22) b) 3β-benzoyloxy-22-hydroxy-4,4-dimethyl-5, 14β-cholesta-8-ene-15, 24 -dione 25.8 ml of a solution of n-butyllithium (1.6 M, hexane) at 6 were added. ml of diisopropylamine in 48 ml of tetrahydrofuran at -78 ° C. The mixture is stirred for 20 minutes. A solution of 4.5 ml of 3-methyl-2-butanone in 10 ml of tetrahydrofuran was added and the mixture was stirred at -78 ° C for 15 minutes. The resulting kinetic enolate was transferred via a cannula under nitrogen in a cooled (-78 ° C) solution of 6.0 g of (20S) -3β-benzoyloxy-4, 4-dimethyl-15 -oxo-5a, 14β-pregn-8-en-20-carbaldehyde in 40 ml of tetrahydrofuran. The mixture was brought to 0 ° C for a period of one hour and then poured into saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, and the combined organic extracts were further washed with water and brine and then dried over sodium sulfate. Removal of the solvents in vacuo gave a residue which was separated by column chromatography to give 6.26 g of 3β-benzoyloxy-22-hydroxy-4,4-dimethyl-5a, 14β-cholesta-8-ene-15, 24- Diona as an oil. NMR 1 (CDC13): d = 0.92-1.2 (7 x CH3); 2.33 (s, broad, H, H-14β); 4.1 (m, H, H-22); 4.74 (dd, J = 11 Hz, 4 Hz, 1H, H-3a); 7.45 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H) c) 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-cholesta-8, 22-diene-15.24 -dione A solution of 4.78 g of 3β-benzoyloxy-22-hydroxy-4, 4-dimethyl-5a, 14β -cholesterol-8-ene-15, 24-dione in 60 ml of dichloromethane was cooled to 0 ° C and 9.31 g of Martin's sulfur in one portion were added. The reaction mixture was stirred for 30 minutes at 0 ° C. The solvents were removed in vacuo. Purification of the residue by column chromatography gave 4.18 g of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8,22-diene-15,24-dione (mp 163 ° C). 1 H NMR (CDC13): d = 0.9-1.2 (7 x CH 3); 2.31 (s, broad, 1H, H-14β); 4.75 (dd, J = 11Hz, 4 Hz, 1H, H-3CC); 6.14 (d, J = 16 Hz, 1H, H-23); 6.71 (m, 1H, H-22); 7.45 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). d) 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8-ene-15,24-dione 500 mg of palladium in carbon were added (10%) to a solution of 4.2 g of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8,22-diene-15,24-dione in 60 ml of ethyl acetate. The mixture was stirred under a hydrogen atmosphere for 3 hours. The mixture filter. Removal of the solvent in vacuo gave 4.22 g of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8-ene-15, 24-dione as a white crystalline acid (mp 129 ° C). XH NMR (CDC13): d = 0.92-1.16 (7 x CH3); 2.33 (s, broad, H, H-14β); 4.74 (dd, J = 11 Hz, 4 Hz, 1H, H-3a), 7.45 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). e) 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-cholesta-8-ene-15,24-diol and 3β-benzoyloxy-24-hydroxy-4, 4-dimethyl-5α, 14β-cholesta- 8-en-15-one A solution of 4.2 g of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8-ene-15, 24-dione in 45 ml of CH 2 C 12 was treated with 1.8 g of complex of tert-butylamine-borane. The solution was refluxed for one hour. After cooling to 0 ° C, 30 ml of HCl (1N, aqueous) was added. The mixture was stirred for one hour at 0 ° C. It was washed with HCl (1N, aqueous), water, saturated, aqueous NaHCO3 solution and brine. After drying over sodium sulfate, the solvents were removed in vacuo. Column chromatography gave 1.71 g of 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-cholesta-8-ene-15, 24-diol and 1.82 g of 3β-benzoyloxy-24-hydroxy-4, 4-dimethyl. -5a, 14ß-cholesta-8-en-15-one as white foams. 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-cholesta-8-ene-15, 24-diol: XH NMR (CDC13): d = 0.88-1.1 (7 x CH3); 3.33 (m, 1H, H-24); 3.74 (m, 1H, H-15); 4.75 (dd, J = 11 Hz, 4 Hz, 1H, H-3CC); 7.45 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). 3β-benzoyloxy-24-hydroxy-4,4-dimethyl-5a, 14β-cholesta-8-en-15-one; 1 H NMR (CDC13): d = 0.88-1.1 (7 x CH3); 2.32 (s, broad, 1H, H-14β); 3.33 (m, 1H, H-24); 4.74 (dd, J = 11 Hz, 4 Hz, 1H, H-3CC); 7.45 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). f) 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-cholesta-8, 24-dien-15β-ol and 4, 4-dimethyl-5a, 14β-cholesta-8-, 15, 24-trien-3β -yl-benzoate 1.0 g of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8-en-15,24-diol was treated with 3.88 g of Martin's sulfuran as described in Example 3e. Purification by column chromatography gave 305 mg of 3β-benzoyloxy-4, 4-dimethyl-5a, 14β-cholesta-8, 24-diene-15β-ol as a white foam and 870 mg of 4,4-dimethyl-5 , 14β-cholesta-8, 15, 24-trien-3β-yl-benzoate as a white foam. 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8,24-diene-15β-ol: XH d 5 -pyridine NMR): d = 1.15 (s, 1H, H-18); 2.84 (m, 1H, H-7a); 4.1 (, 1H, H-15); 4.93 (dd, J = 11 Hz, 4 Hz, 1H, H-3a); 5.24 (t, J = 8 Hz, 1H, H-24); 7.45 (t, 2H); 7.57 (t, 1H); 8.25 (d 2H). 4, 4-dimethyl-5a, 14β-cholesta-8,15, 24-trien-3-yl-benzoate 1 H-NMR (CDC13): d = 1.4 (s, 3H, H-19); 2.19 (m, 1H, H-17a); 2.51 (s, broad, 1H, H-14β); 4.75 (dd, J = 11 Hz, 4 Hz, 1H, H-3a); 5.1 (t, J = 8 Hz, 1H, H-24); 5.65 (m, 1H, H-16); 5.79 (m, 1H, H-15); 7.45 (t, 2H); 7.57 (t, 1H); 8.05 (d, 2H). g) 4, 4-dimethyl-5a, 14β-cholesta-8, 24-diene-3β, 15β-diol 120 mg of 3β-benzoyloxy-4,4-dimethyl-5a, 14β-cholesta-8, 24- were treated diene-15β-ol with 30 mg of lithium aluminum hydride as described in Example Id. The crude product was purified by flash column chromatography to give 80 mg of 4,4-dimethyl-5a, 14β-cholesta-8 , 24-diene-3β, 15β-diol as a white foam. NMR? H (CDCl 3): d = 0.8-1.03 (5x CH 3); 1.6 + 1.68 (2x s, 3H, H-24/27); 3.24 (m, 1H, H-3a); 3.70 (m, 1H, H-15a); 5.10 (t, J = 7 Hz, 1H, H-24) Example 10: 4, 4-dimethyl-5a, 14β-cholesta-8, 15, 24-trien-3ß-ol 30 mg of 4,4-dimethyl-5a, 14β-cholestase-8, 15, 24-three were treated -3β-yl-benzoate (Example 9f) with 20 mg of lithium aluminum hydride as described in Example Id. The crude product was purified by column chromatography to give 20 mg of 4,4-dimethyl-5a, 14β -cholesterol-8, 15, 24-trien-3ß-ol as a white solid (p.f.105 ° C). XH NMR (CDC13): d = 0.81 (s, 3H, H-18); 0.94-1.02 (4x CH3); 2.5 (s, broad, 1H, H-14β); 3.23 (m, 1H, H-3a); 5.11 (t, J = 9 Hz, 1H, H-24); 5.64 (m, 1H, H-15 / 16a); 5.79 (m, 1H, H-15 / 16b).

Example 11: (2 OS) -20-hydroxymethyl-4,4-dimethyl-5a, 14β-pregn-8-ene-3β, 15β-diol 60 mg of (20S) -20-hydroxymethyl-4, 4- were treated dimethyl-5, 14β-pregn-8-ene-3β, 15β-diol with 20 mg of lithium aluminum hydride as described in Example Id. The crude product was purified by column chromatography to give 42 mg of (20S ) -20-hydroxymethyl-4,4-dimethyl-5a, 14β-pregn-8-ene-3β, 15β-diol (p.p.214 ° C).

X H NMR (CDCl 3): d = 0.82 (s, 3 H, H-18); 0.93-1.04 (3x CH3); 1.07 (d, J = 6 Hz, 3H, H-21); 3.23 (m, 1H, H-3a); 3. 49 (m, 1H, H-22a), 3.68 (m, 1H, H-22b); 3.72 (m, 1H, H-15a).

Example 12: Test of substances of activation of meiosis in the oocyte test. Animals Oocytes were obtained from immature female mice (C57BI / 6J X DBA / 2J Fl-hybrids, Bo holtgaard, Denmark) weighing 13-16 grams, which were kept under controlled lighting and controlled temperature.

The mice received an intraperitoneal injection of 0. 2 ml of gonadotropins (Gonal, F. Serono, Solna, Switzerland, 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.

Oocyte collection and culture The ovaries were dissected and the oocytes were isolated in Hx medium (see below) under a stereoscopic microscope by manual breakage of the follicles using a pair of 27 gauge needles. The bare, spherical oocytes (NO) exhibit a vesicle intact germ (GV) were placed in a minimal essential medium (α-MEM without ribonucleosides, Gibco BRL, Cat. No. 22561) supplemented with 3 mM hypoxanthine (Sigma Cat. No. H-9377), 8 mg / ml of Human Serum Albumin (HSA, State Serum Institute, Denmark), 0.23 mM pyrubate (Sigma, Cat. No. S-8636), 2 mM glutamine (Flow Cat No. 16-801), 100 IU / ml of penicillin and 100 μg / ml streptomycin (Flow, Cart No. 16-700). This medium was designated H medium. The oocytes were rinsed three times in Hx medium and cultured in 4-cavity multilayers (Nuncion, Denmark) in which each tablet contained 0.4 ml of Hx medium and 35-45 oocytes. A control (ie, 35-45 oocytes cultured in Hx medium without addition of the test compound) was always run simultaneously with the test cultures, which were made with different concentrations of the compounds to be tested. The cultures were carried out at 37 ° C and 100% humidity with 5% C0 in air. The culture time was 22-24 hours.

Examination of oocytes At the end of the culture period, the number of oocytes with germinal vesicle (GV) or germinal vesicle rupture (GVB) and those with polar corpuscle (PB) were counted using a stereoscopic microscope or an inverted microscope with a differential interference contrast equipment. The percentage of oocytes with GVB by total number of oocytes and percentage of oocytes with PB by the total number of oocytes was calculated in the test cultures and compared to the control culture.

Example 13: Test of substances that inhibit meiosis in the oocyte test. Germ cell vesicle oocytes were obtained (GV) of female mice treated with FSH, immature using the same methods as described in Example 1 (see above). The naked oocytes (NO) were rinsed three times with Hx medium. It has previously been shown that 4,4-dimethylchocolate-B, 14, 24-trien-3ß-ol (FF-MAS) induces meiosis in NO in vi tro (Byskov, AG et al., Nature 374 (1995) 559 -562). NO were cultured in Hx medium supplemented with 5 μM FF-MAS in co-culture with the test compounds in different concentrations in multipacks of 4 cavities (Nuncion, Denmark) in which each cavity contained 0. 4 ml of medium Hx and 35-45 oocytes. A positive control (ie, 35-45 oocytes cultured in Hx medium containing FF-MAS without addition of compound from test) was always run simultaneously with the test cultures, which were supplemented with different concentrations of the compounds to be tested. In addition, a negative control (35-45 oocytes cultured in Hx medium alone) was run simultaneously with the positive control.

Examination of oocytes At the end of the culture period, the number of oocytes with germinal vesicle (GV) or germinal vesicle rupture (GVB) and those with polar corpuscle (PB) were counted using a stereoscopic microscope or an inverted microscope with a differential interference contrast equipment. The percentage of oocytes with GVB plus PB by the total number of oocytes was calculated in the test cultures and in the culture groups of positive and negative controls). The relative inhibition of the test compound was calculated by the following formula: Inhibition of test compound (%) = 100% - [(GVB + PB (test compound) -GVB + PB (negative control)) x 100 / GVB + PB (positive control) - GVB + PB (negative control)] % Oocytes with stopped meiosis are characterized by intact nuclei with a prominent nucleolus, known as germinal vesicle (GV). Upon re-initiation of meiosis, the nucleolus and the nuclear envelope disappeared and this is characterized by a rupture of the GV, which is then called germinal vesicle rupture (GVB). A few hours later, the oocyte completed a reductional division and produced the so-called first polar corpuscle (PB).

Results: TABLE 1: Relative Inhibition [%] of meiosis in nude mouse oocytes Hx = Hypoxanthine GV = germinal vesicle GVB = germinal vesicle break PB = polar corpuscles n = number of

Claims (10)

1. CLAIMS 1. Compounds of the General Formula I wherein R designates a hydrogen atom or together with R3 'an additional bond, R3' designates a hydrogen atom or together with R3 an additional bond, R4 designates a hydrogen atom or a methyl group, R4 'denotes a hydrogen atom or a methyl group, R7 designates a hydrogen atom or together with R8 an additional bond, R8 designates a hydrogen atom or together with R7 or together with R9 an additional bond, R9 designates a hydrogen atom or together with R8 or together with R11 an additional bond, R15 designates a hydrogen atom, a hydroxy group, a halogen atom or together with R15 'an oxo group or together with R15 an additional bond or jointly with R22 'an oxygen bridge, R15 'designates a hydrogen atom, a linear or branched alkyl group of 1 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms or together with R15 an oxo group, R16 designates a hydrogen atom, a hydroxy group , a halogen atom or together with R15 an additional bond or together with R22 an additional bond, R22 designates a hydrogen atom, an optionally substituted, linear or branched alkyl or alkenyl group of 1 to 8 carbon atoms, an aryl group of 6 to 10 carbon atoms optionally substituted or together with R16 an additional bond or together with R22 'a linear or branched alkylidene group of 1 to 8 carbon atoms R22' designates a hydrogen atom, a hydroxy group or together with R15 a bridge of oxygen or together with R22 a linear or branched alkylidene group of 1 to 8 carbon atoms or esters thereof.
2. 2. The compounds according to claim 1, wherein R3 and R3 'denote hydrogen atoms.
3. 3. The compounds according to claim 1 or 2, wherein R8 and R9 together designate an additional bond.
4. 4. The compounds according to any of claims 1 to 3, wherein R15 designates a hydrogen atom to a hydroxy group.
5. 5. The compounds according to any of claims 1 to 4, wherein R22 designates a linear or branched alkyl group, optionally substituted, of 1 to 8 carbon atoms or together with R22 'a linear or branched alkylidene group of 1 to 8. carbon atoms.
6. 6. The compounds according to any of claims 1 to 5, because it comprises: 4, 4-dimethyl-5a, 14β-cholesta-8-en-3β-ol 4,4-dimethyl-5a, 14β-cholesta-8 -neo-3β, 15β-diol 4, 4-dimethyl-5a, 14β-cholesta-8-en-3β, 15a-diol 4, 4-dimethyl-5a, 14β-cholesta-8, 15-dien-3β-ol 4, 4-dimethyl-5a, 14ß-cholesta-7, 9 (11), 15 -trien-3ß-ol 4, 4-dimethyl-5a, 14ß-cholesta-l 15, 23 (E) -trien-3ß-ol 4, 4-dimethyl-5a, 14β-cholesta-15, 24-trien-3β-ol 4,4-dimethyl-5a, 14β-cholesta-24-diene-3β, 15β-diol 4, 4-dimethyl-5a, 14β-ergosta-1 22-dien-3β-ol 4,4-dimethyl-5a, 14ß-ergosta-S 22-diene-3β, 15β-diol 4, 4-dimethyl-5a, 14ß-ergosta-S 22-diene-3β, 15a-diol 4, 4-dimethyl-5a, 14β-ergosta-γ 15, 22-trien-3β-ol 4,4-dimethyl-24-ñor-5oc, 14β-cholesta-8-en-3β-ol 4, 4-dimethyl -24-nor-5a, 14β-cholesta-8-ene-3β, 15β-diol 4, 4-dimethyl-24-nor-5a, 14β-cholesta-8-ene-3β-, 15 -diol 4, 4-dimethyl-24-nor-5a, 14β-cholesta-8, 15-dien-3β-ol butandanate, 4,4-dimethyl-5a, 14β-cholesta-8, 15-dien-3ß-ol butanediazole acid 4,4-dimethyl-5a, 14ß-ergosta-8, 15, 22-trien-3ß-ol (20R) -4, 4, 20-trimethyl-16β, 21-cyclo-5, 14β-pregn-8 acid -neo-3β, 15a-diol (20R) -4, 4, 20-trimethyl-16β, 21-cyclo-5a, 14β-pregn-8-ene-3β, 15β-diol (20S) -20-hydroxymethyl-4 , 4-dimethyl-5a, 14β-pregn-8-ene-3β, 15β-diol
7. 7. Pharmaceutical compositions because they comprise one or more of the compounds of the Formula General I according to any one of claims 1 to 6 together with an excipient pharmaceutically acceptable.
8. 8. The use of the compounds of the General Formula I according to any of claims 1 to 6 for the preparation of a meiosis regulating drug.
9. 9. The use according to claim 8, for the preparation of a contraceptive medicament for the treatment of females or males, preferably humans.
10. 10. The use of a 14β-hydrogen group in a sterol to increase the inhibitory activity of a substance that inhibits meiosis.