##STR1## The invention relates to 20-aralkyl-5.alpha.-pregnane derivative having general formula (I), or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is (H,OR), (H,OSO.sub.3 H) or NOR; R is H, (C.sub.1-6)alkyl or (C.sub.1-6)acyl; each of R.sub.2 and R.sub.3 is independently hydrogen or (C.sub.1-6)alkyl; X is a straight chain divalent C.sub.1-8 hydrocarbon radical, optionally comprising a double or a triple bond; or X is --(CH.sub.2).sub.m --CR.sub.7 R.sub.8 --; m=0-4; at least one of R.sub.7 and R.sub.8 is (C.sub.1-4)alkyl, hydroxy, (C.sub.1-4)alkoxy or halogen; the other, if present, being hydrogen; or R.sub.7 and R.sub.8 together represent O or NOR'; R' is H, (C.sub.1-6)alkyl or (C.sub.1-6)acyl; each of R.sub.4, R.sub.5 and R.sub.6 is independently hydrogen, hydroxy, (C.sub.1-4)alkoxy, halogen, NR.sub.9, R.sub.10 or (C.sub.1-4)alkyl, optionally substituted by hydroxy, alkoxy, halogen or oxo; each of R.sub.9 and R.sub.10 is independently hydrogen or (C.sub.1-4)alkyl; and the dotted lines indicate a .DELTA..sup.7 or a .DELTA..sup.8 double bond, or a pair of conjugated double bonds selected from .DELTA..sup.7,14, .DELTA..sup.8,14 and .DELTA..sup.6,8(14). The compounds of the invention have meiosis activating activity and can be used for the control of fertility.

This application is a 371 of PCT/EP98/02989 filed on May 11, 1998.
 FIELD OF THE INVENTION
 The invention relates to 20-aralkyl-5.alpha.-pregnane derivatives, to
 pharmaceutical compositions containing the same, as well as to the use of
 these 20-aralkyl-5.alpha.-pregnane derivatives for the preparation of a
 medicament for the control of fertility.
 BACKGROUND OF THE INVENTION
 Sexual reproduction involves a cyclic alternation of diploid and haploid
 states: diploid cells divide by the process of meiosis to form haploid
 cells, and the haploid cells fuse in pairs at fertilization to form new
 diploid cells. The process of meiosis is characterized by two meiotic
 divisions (I and II), unique to both male and female germ cells. During
 the process two cell divisions, following one round of DNA replication,
 give rise to four haploid cells from one single diploid cell. Chromosomal
 crossover events, during which paternal and maternal genetic material is
 exchanged, occur during the prophase of the first meiotic division. At the
 end of the first meiotic division one member of each chromosome pair,
 composed of two sister chromatids is distributed to each daughter cell.
 The second meiotic division segregates each sister chromatide into a
 separate haploid cell. Male and female germ cells are subject to similar
 meiotic divisions but differ in the regulation of these processes.
 In the male meiosis is a continuous process in germ cells derived from a
 population of immature germ cells, the stem cell spermatogonia. After
 sexual maturation of the male, spermatogonia from this stem cell
 population embark on meiosis. The first and second meiotic division
 proceed without interruption and eventually give rise to four mature
 spermatozoa.
 In the female, primary oocytes start the first meiotic division already
 during the embryonic stage but they remain arrested in the prophase
 (dictyate stage) until the female becomes sexually mature. Meiosis resumes
 at the time of ovulation (egg maturation) after which the first meiotic
 division is completed and the second meiotic division is initiated. In
 most vertebrates the second meiotic division is arrested at the metaphase
 and only completed after fertilization. At the end of the first and of the
 second meiotic division the cytoplasm divides asymmetrically to produce
 two secondary oocytes, each with a haploid number of single chromosomes,
 but greatly differing in size: one is a small polar body, which eventually
 degenerates, and the other is a large cell containing all the
 developmental potential. Finally one mature ovum is produced.
 The stage at which the developing oocyte is released from the ovary and is
 ready for fertilization differs in different species. In both
 invertebrates and vertebrates ovarian accessory cells respond to
 polypeptides (gonadotropins) produced elsewhere in the body so as to
 control the maturation of the oocyte and eventually (in most species)
 ovulation.
 In humans the primary oocytes of the newborn female are arrested in
 prophase of meiotic division I and most are surrounded by a single layer
 of follicle cells; such an oocyte with its surrounding cells constitute
 the primordial follicle. A small portion of primordial follicles
 sequentially begin to grow to become developing follicles: the follicle
 cells enlarge and proliferate to form a multilayered envelope around the
 primary oocyte; the oocyte itself enlarges and develops the zona
 pellucida, an extracellular matrix consisting largely of glycoproteins,
 and cortical granules, specialized secretory vesicles just under the
 plasma membrane in the outer region, the cortex of the egg cytoplasm [when
 the egg is activated by a sperm, these cortical granules release their
 contents by exocytosis; the contents of the granules act to alter the egg
 coat so as to prevent other sperms from fusing with the egg].
 The developing follicles grow continuously and some of them develop a
 fluid-filled cavity, or antrum, to become antral follicles. Development of
 such follicles is dependent on gonadotropins (mainly follicle stimulating
 hormone-FSH) secreted by the pituitary gland and on estrogens secreted by
 the follicle cells themselves. Starting at puberty, a surge of secretion
 by the pituitary of another gonadotropin, luteinizing hormone (LH),
 activates a single antral follicle to complete its development: the
 enclosed primary oocyte matures to complete the meiotic division I as the
 stimulated follicle rapidly enlarges and ruptures at the surface of the
 ovary, releasing the secondary oocyte within. As is the case with most
 mammals, the secondary oocyte is triggered to undergo division II of
 meiosis only if it is fertilized by a sperm.
 Studies on the mechanisms controlling initiation and regulation of the
 meiotic process in male and female germ cells suggest a role for cyclic
 nucleotides in mediating meiotic arrest. Spontaneous maturation of oocytes
 can be prevented by compounds that maintain elevated cAMP levels [Eppig,
 J. and Downs, S. (1984) Biol. Reprod. 30: 1-11]. Purines, like adenosine
 or hypoxanthine, are thought to be involved in the cAMP mediated
 maintenance of meiotic arrest [Eppig, J., Ward-Bailey, P. and Coleman, D.
 (1985) Biol. Reprod. 33: 1041-1049].
 The presence of a meiosis regulating substance in a culture system of fetal
 mouse gonads was first described by Byskov, A. et al. [(1976) Dev. Biol.
 52: 193-200]. It was suggested that the concentrations of a meiosis
 activating substance (MAS) and a meiosis preventing substance (MPS)
 regulate the meiotic process in concert [Byskov, A. et al. (1994). In "The
 physiology of reproduction", Eds. Knobil, E. and Neill, J., Raven Press,
 New York].
 More recently
 (3.beta.,5.alpha.,20R)-4,4-dimethylcholesta-8,14,24-trien-3-ol (FF-MAS),
 isolated from human follicular fluid, and
 (3.beta.,5.alpha.,20R)-4,4-dimethylcholesta-8,24-dien-3-ol, isolated from
 bull testes, were identified by Byskov, A. et al. [(1995) Nature 374:
 559-562] as endogenous meiosis activating substances in human and bovine,
 respectively. These sterols proved to be able to activate the resumption
 of meiosis in cultured cumulus enclosed and naked mouse oocytes.
 Derivatives of the endogenous sterols, having either a saturated or an
 unsaturated cholestane side chain, have been disclosed in the
 international patent applications WO 96/00235, WO97/00883 and WO97/00884
 (NOVO NORDISK A/S) as meiosis regulating substances.
 A drawback of these cholestanes is that they are prone to rapid
 deactivation in the body [Hall, P. F. (1985) Vitamins and Hormones 42:
 315], thereby restricting their therapeutic potential as fertility control
 agents.
 A need therefore exists for regulators of the meiotic process having
 improved in vivo activity.
 SUMMARY OF THE INVENTION
 To this end the invention resides in 20-aralkyl-5.alpha.-pregnane
 derivatives having the general formula I, or pharmaceutically acceptable
 salts thereof,
 ##STR2##
 wherein
 R.sub.1 is (H,OR), (H,OSO.sub.3 H) or NOR;
 R is H, (C.sub.1-6)alkyl or (C.sub.1-6)acyl;
 each of R.sub.2 and R.sub.3 is independently hydrogen or (C.sub.1-6)alkyl;
 X is a straight chain divalent C.sub.1-8 hydrocarbon radical, optionally
 comprising a double or a triple bond; or X is --(CH.sub.2).sub.m
 --CR.sub.7 R.sub.8 --;
 m=0-4;
 at least one of R.sub.7 and R.sub.8 is (C.sub.1-4)alkyl, hydroxy,
 (C.sub.1-4)alkoxy or halogen; the other,
 if present, is hydrogen; or
 R.sub.7 and R.sub.8 together represent O or NOR';
 R' is H, (C.sub.1-6)alkyl or (C.sub.1-6)acyl;
 each of R.sub.4, R.sub.5 and R.sub.6 is independently hydrogen, hydroxy,
 (C.sub.1-4)alkoxy, halogen,
 NR.sub.9,R.sub.10 or (C.sub.1-4)alkyl, optionally substituted by hydroxy,
 alkoxy, halogen or oxo;
 each of R.sub.9 and R.sub.10 is independently hydrogen or (C.sub.1-4)alkyl;
 and
 the dotted lines indicate a .DELTA..sup.7 or a .DELTA..sup.8 double bond,
 or a pair of conjugated double bonds selected from .DELTA..sup.7,14,
 .DELTA..sup.8,14 and .DELTA..sup.6,8(14) ;
 provided that
 (3.beta.,4.alpha.,24E)-25-(4-hydroxyphenyl)-4-methyl-26,27-dinorcholesta-7
 ,24-dien-3-ol (gramisterol) is excluded.
 The disclaimer relates to the disclosure by Hiroitho et al [J. Am. Oil.
 Chem. Soc. 50, 300-302 (1973)] of the 20-aralkyl-5.alpha.-pregnane
 derivative having formula I wherein R.sub.1 is (H,OH); R.sub.2 is H and
 R.sub.3 is CH.sub.3, or R.sub.2 is CH.sub.3 and R.sub.3 is H; X is
 --(CH.sub.2).sub.2 --CH.dbd.CH--; R.sub.4 and R.sub.5 are H; R.sub.6 is
 OH, and wherein the doffed line represents a .DELTA..sup.7 double bond,
 i.e.
 (3.beta.,4.alpha.,24E)-25-(4-hydroxyphenyl)-4-methyl-26,27-dinorcholesta-7
 ,24-dien-3-ol (gramisterol), as a 4-methylsterol component of vegetable
 oils of wheat germ and other plant tissues.
 It has been found that the 20-aralkyl-5.alpha.-pregnane derivatives having
 the general formula I show improved meiosis activating activity.
 The invention further resides in a pharmaceutical composition comprising a
 20-aralkyl-5.alpha.-pregnane derivatives having the general formula I.
 Pharmaceutical compositions which comprise
 (3.beta.,4.alpha.,24E)-25-(4-hydroxyphenyl)-4-methyl-26,27-dinorcholesta-7
 ,24-dien-3-ol (gramisterol) are within the ambit of the present invention.
 A further aspect of the invention resides in the use of a
 20-aralkyl-5.alpha.-pregnane derivative having the general formula I for
 the manufacture of a medicament for the control of fertility.
 DETAILED DESCRIPTION OF THE INVENTION
 The term (C.sub.1-6)alkyl as used in the definition of formula I means a
 branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl,
 pentyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and
 methyl. Likewise, the term (C.sub.1-4)alkyl means an alkyl group having
 1-4 carbon atoms.
 The term (C.sub.1-6)acyl means an acyl group derived from a carboxylic acid
 having from 1-6 carbon atoms, like hexanoyl, pentanoyl, pivaloyl, butyryl,
 propanoyl, acetyl and formyl. Also included within the definition of
 (C.sub.1-6)acyl are acyl groups derived from dicarboxylic acids, like
 hemi-glutaroyl, hemi-succinoyl, and hemi-maloyl. A preferred
 (C.sub.1-6)acyl group is hemi-succinoyl.
 The term (C.sub.1-4)alkoxy means an alkyloxy having 1-4 carbon atoms, like
 butyloxy, propyloxy, isopropyloxy, ethyloxy, and, preferably, methyloxy.
 The term halogen means F, Cl, Br or I. When halogen is a substituent at an
 alkyl group, like in the definition of R.sub.7 and R.sub.8, Cl and F are
 preferred, F being most preferred.
 It is understood that the 20-aralkyl-5.alpha.-pregnane derivatives of the
 invention have the natural configurations 9.alpha., 10.beta., 13.beta.,
 14.alpha., 17.beta.. Preferred compounds according to the invention are
 the 20-aralkyl-5.alpha.-pregnane derivatives of formula I wherein R.sub.1
 is (H,OR) and the dotted lines indicate the pair of conjugated double
 bonds selected from .DELTA..sup.7,14, .DELTA..sup.8,14 and
 .DELTA..sup.6,8(14). Among these preferred compounds those with the
 .DELTA..sup.8,14 double bonds are especially preferred. Most preferred are
 the compounds of the invention wherein the configuration of the 3-OR
 substituent is the .beta.-configuration.
 Highly preferred compounds of the invention are the
 20-aralkyl-5.alpha.-pregnane derivatives having the general formula I
 wherein R.sub.1 is (H,OR), R is H or (C.sub.1-6)acyl; each of R.sub.2 and
 R.sub.3 is independently hydrogen or (C.sub.1-6)alkyl; X is --CH.sub.2 --;
 R.sub.4, R.sub.5 and R.sub.6 have the previously given meaning; the dotted
 lines indicate a pair of conjugated .DELTA..sup.8,14 double bonds; and
 wherein the configuration of the 3-OR substituent is the
 .beta.-configuration.
 The configuration at position 20 of the 20-aralkyl-5.alpha.-pregnane
 derivatives can be either R or S, preferably R. The compounds of the
 invention wherein X is a divalent hydrocarbon radical comprising a double
 bond may have either the E or the Z configuration around the double bond.
 Both isomers are within the ambit of the present invention.
 Particularly preferred compounds according to the invention are:
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol,
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-[4-(trifluoromethyl)phenyl]pregn
 a-8,14-dien-3-ol,
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-6,8(14)-dien-3-ol,
 (3.beta.,5.alpha.,20S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-22-yn-3
 -ol,
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-24-(4-methylphenyl)chola-8,14-dien-23-y
 n-3-ol,
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-[4-(trifluoromethyl)phenyl]pregn
 a-8,14-dien-3-ol hydrogen butanedioate.
 The meiosis activating activity of the 20-aralkyl-5.alpha.-pregnane
 derivatives of the invention is measured in an in vitro oocyte assay as
 the ability to overcome the hypoxanthine maintained meiotic arrest in
 denuded oocytes (DO).
 The compounds can be used to stimulate meiosis in both male and female and
 thus can be used as fertility regulating agents. Fertility regulation, or
 fertility control, comprises contraception and infertility treatment.
 For female contraception a 20-aralkyl-5.alpha.-pregnane derivative
 according to formula I can be used for induction of premature maturation
 of oocytes which are still inside the ovary, before the naturally
 occurring gonadotropin surge [reduced fertility by inducing premature
 maturation of oocytes has been demonstrated in rats by Mattheij, J. et al
 (1993), Gynecol. Obstet. Invest. 36: 129-135]. On in vivo administration
 the compounds of the invention specifically affects germ cells and
 therefore have the advantage of maintenance of endogenous hormonal levels
 and subsequently maintenance of normal cycle length. Such a contraceptive
 method will not cause unwanted side-effects sometimes associated with
 steroidal contraception (e.g. thrombosis, mood, unscheduled bleeding,
 malignant breast disease). In this connection it is important to note that
 the compounds of the invention do no bind to steroid receptors since no
 binding was found for progesterone receptor, androgen receptor, estrogen
 receptor and glucocorticoid receptor. Furthermore, it was found that
 compounds did not have an effect on steroid synthesis or metabolism in
 human adrenal cells at a dose level which induces oocyte maturation in
 vitro.
 A further advantage of the 20-aralkyl-5.alpha.-pregnane derivatives of the
 invention is their inability to induce maturation in incompetent oocytes
 (isolated from pre-antral follicles), which indicates that the compounds
 will not affect the entire oocyte reserve in the ovaries. Only oocytes
 from antral follicles (competent oocytes) can be induced to mature by the
 compounds of the invention.
 For treatment of female infertility caused by the absence of mature oocytes
 the compounds of the invention can be administered in vivo to timely
 stimulate the maturation of competent oocytes.
 For treatment of male infertility caused by a shortage of the number of
 mature spermatozoa the compounds of the invention can be administered in
 vivo to stimulate the maturation of spermatogonia.
 The compounds of the invention can also be used for suppletion of culture
 media for in vitro fertilization procedures in order to improve oocyte
 quality.
 The 20-aralkyl-5.alpha.-pregnane derivative of this invention have the
 natural configurations 9.alpha., 10.beta., 13.beta., 14.alpha., 17.beta.,
 and possess also one or more additional chiral carbon atoms. The compounds
 may therefore be obtained as a pure diastereomer, or as a mixture of
 diastereomers. Methods for obtaining the pure diastereomers are well known
 in the art, e.g. crystallization or chromatography.
 For therapeutic use, salts of the compounds of formula I are those wherein
 the counterion is pharmaceutically acceptable. However, salts of acids
 according to formula I [i.e. compounds wherein R.sub.1 is (H,OSO.sub.3 H)]
 and acid addition salts of bases according to formula I [i.e. compounds
 wherein R.sub.4, R.sub.5 and/or R.sub.6 are NR.sub.9 R.sub.10 ], may also
 find use, for example, in the preparation or purification of a
 pharmaceutically acceptable compound. All salts, whether pharmaceutically
 acceptable or not, are included within the ambit of the present invention.
 Examples of salts of acids according to the invention are mineral salts
 such as sodium salt, potassium salt, and salts derived from organic bases
 like ammonia, imidazole, ethylenediamine, triethylamine and the like.
 Examples of acid addition salts include those derived from mineral acids
 such as hydrochloric acid, phosphoric acid, sulphuric acid, preferably
 hydrochloric acid, and organic acids like citric acid, tartaric acid,
 acetic acid, lactic acid, maleic acid, malonic acid, fumaric acid,
 glycolic acid, succinic acid, and the like.
 The compounds of formula I or a pharmaceutically acceptable salt thereof,
 also referred to herein as the active ingredient, may be administered
 enterally or parenterally. The exact dose and regimen of administration of
 the active ingredient, or a pharmaceutical composition thereof, will
 necessarily be dependent upon the therapeutic effect to be achieved
 (treatment of infertility; contraception), and will vary with the
 particular compound, the route of administration, and the age and
 condition of the individual subject to whom the medicament is to be
 administered.
 In general parenteral administration requires lower dosages than other
 methods of administration which are more dependent upon adsorption.
 However, a dosage for humans preferably contains 0.0001-25 mg per kg body
 weight. The desired dose may be presented as one dose or as multiple
 subdoses administered at appropriate intervals throughout the day, or, in
 case of female recipients, as doses to be administered at appropriate
 daily intervals throughout the menstrual cycle. The dosage as well as the
 regimen of administration may differ between a female and a male
 recipient.
 In case of in vitro or ex vivo applications, like in IVF applications, the
 compounds of the inventions are to be used in the incubation media in a
 concentration of approximately 0.01-5 .mu.g/ml.
 The present invention thus also relates to pharmaceutical compositions
 comprising a 20-aralkyl-5.alpha.-pregnane derivative according to formula
 I, i.e. including pharmaceutical compositions comprising
 (3.beta.,4.alpha.,24E)-25-(4-hydroxyphenyl)-4-methyl-26,27-dinorcholesta-7
 ,24-dien-3-ol (gramisterol), in admixture with pharmaceutically acceptable
 auxiliaries, and optionally other therapeutic agents. The auxilliaries
 must be "acceptable" in the sense of being compatible with the other
 ingredients of the composition and not deleterious to the recipients
 thereof.
 Pharmaceutical compositions include those suitable for oral, rectal, nasal,
 topical (including transdermal, buccal and sublingual), vaginal or
 parenteral (including subcutaneous, intramuscular, intravenous and
 intradermal) administration. The compositions may be prepared by any
 method well known in the art of pharmacy, for example, using methods such
 as those described in Gennaro et al., Remington's Pharmaceutical Sciences
 (18th ed., Mack Publishing company, 1990, see especially Part 8:
 Pharmaceutical Preparations and Their Manufacture).
 Such methods include the step of bringing in association the active
 ingredient with any auxilliary agent. The auxilliary agent(s), also named
 accessory ingredients, include those conventional in the art (Gennaro,
 supra), such as, fillers, binders, diluents, disintegrants, lubricants,
 colorants, flavoring agents and wetting agents.
 Pharmaceutical compositions suitable for oral administration may be
 presented as discrete dosage units such as pills, tablets or capsules, or
 as a powder or granules, or as a solution or suspension. The active
 ingredient may also be presented as a bolus or paste. The compositions can
 further be processed into a suppository or enema for rectal
 administration.
 For parenteral administration, suitable compositions include aqueous and
 non-aqueous sterile injection. The compositions may be presented in
 unit-dose or multi-dose containers, for example sealed vials and ampoules,
 and may be stored in a freeze-dried (lyophilised) condition requiring only
 the addition of sterile liquid carrier, for example, water prior to use.
 Compositions, or formulations, suitable for administration by nasal
 inhalation include fine dusts or mists which may be generated by means of
 metered dose pressurised aerosols, nebulisers or insufflators.
 The 20-aralkyl-5.alpha.-pregnane derivatives of the invention can also be
 administered in the form of implantable pharmaceutical devices, consisting
 of a core of active material, encased by a release rate-regulating
 membrane. Such implants are to be applied subcutaneously or locally, and
 will release the active ingredient at an approximately constant rate over
 relatively large periods of time, for instance from weeks to years.
 Methods for the preparation of implantable pharmaceutical devices as such
 are known in the art, for example as described in European Patent
 0,303,306 (AKZO N.V.).
 The compounds of the invention may be produced by various methods known in
 the art of organic chemistry in general, and especially in the art of the
 chemistry of steroids [see for example: Fried, J. and Edwards, J. A.,
 "Organic Reactions in Steroid Chemistry", Volumes I and II, Van Nostrand
 Reinhold Company, New York, 1972].
 The 20-aralkyl-5.alpha.-pregnane derivatives of formula I can generally be
 prepared from unsaturated 20-methylpregna-3,21-diol derivatives of formula
 II,
 ##STR3##
 in which R.sub.2 and R.sub.3 are independently hydrogen or
 (C.sub.1-6)alkyl; R.sub.11 is an acyl protecting group, such as benzoyl,
 acetyl, pivaloyl and the like; and wherein the dotted lines represent a
 .DELTA..sup.7 or a .DELTA..sup.8 double bond, or a pair of conjugated
 double bonds selected from .DELTA..sup.6,8(14), .DELTA..sup.7,14 and
 .DELTA..sup.8,14.
 Starting material for the preparation of the intermediates of formula II is
 for example (20S)-3-oxopregn-4-en-20-carboxaldehyde, which aldehyde can be
 obtained by ozonolysis from stigmasta-4,22-dien-3-one as described by T.
 Veysoglu et al [Synthesis 807 (1980)] and which is also commercially
 available (Sigma, USA). The aldehyde is selectively reduced to
 (20S)-21-hydroxy-20-methylpregn-4-en-3-one [B. M. Trost et al, J. Amer.
 Chem. Soc. 105, 5075 (1983)], whereupon the resulting hydroxy function is
 protected as an ether, e.g. the ethoxyethyl ether, the tetrahydropyranyl
 (THP) ether, or a silylether, such as the triisopropylsilyl ether, the
 t-butyldimethylsilyl ether, or the t-butyldiphenylsilyl ether, and the
 like.
 Suitable protective groups are known in the art, for example from Greene,
 T. W. and Wuts, P. G. M.: Protective Groups in Organic Synthesis, Second
 Edition, Wiley, N.Y., 1991.
 Optionally, the resulting hydroxy protected
 (20S)-21-hydroxy-20-methylpregn-4-en-3-one can be mono- or dialkylated at
 C-4, for instance, it can be dimethylated. Alkylation can be performed
 using standard procedures, such as the potassium
 tert-butoxide-methyliodide method [R. E. Dolle et al, J. Org. Chem. 51,
 4047 (1986)], the use of lithium diisopropylamide (LDA)-methyliodide
 (MeI), and similar methods known in the art.
 Optionally, the .DELTA..sup.4 compound can be converted to a .DELTA..sup.5
 derivative by reaction with a base followed by quenching with water [J. B.
 Jones et al, Can. J. Chem. 46, 1459 (1968)].
 The carbonyl group at C-3 can subsequently be reduced to hydroxy with the
 use of reducing agents like for example lithium aluminium hydride, sodium
 borohydride, or other hydride reducing agents known in the art. The
 resulting 3-hydroxy compounds can be protected as an ester, e.g. an
 acetate ester, a benzoate ester, or a pivalate ester, and the like. A
 .DELTA..sup.5 system can be converted to a .DELTA..sup.5,7 -diene system
 by the sequence: bromination at C-7 followed by dehydrobromination. The
 bromination reaction can be carried out thermally [Schroepfer, G. J. Jr.,
 et al, Chem. Phys. Lipids 47, 187 (1988)] or photochemically [Prelle, A.
 et al, Heterocycles 28, 333 (1989)]. In either case, brominating agents
 which can be used are N-bromosuccinimide,
 1,3-dibromo-5,5-dimethylhydantoin and the like. Dehydrobrominating agents
 include N,N-diisopropylethylamine, 2,4,6-trimethylpyridine,
 trimethylphosphite, tetrabutylammonium fluoride, and others.
 A .DELTA..sup.5,7 diene system can now be converted to a
 .DELTA..sup.6,8(14) diene system, a .DELTA..sup.7,14 diene system, or a
 .DELTA..sup.8,14 diene system. Methods used are known in the art. For
 conversion to the .DELTA..sup.6,8(14) derivative, see e.g. Kaneko, C. et
 al, Chem. Pharm. Bull. 26, 3582 (1978). For conversion to the
 .DELTA..sup.7,14 derivative, see e.g. Wilson, W. K. et al, J. Org. Chem.
 53, 1713 (1988). For conversion to the .DELTA..sup.8,14 derivative, see
 e.g. Schroepfer, G. J. Jr., et al, Chem. Phys. Lipids 47, 187 (1988) or
 Dolle, R. E. et al, J. Org. Chem. 53, 1563 (1988). Conversion of a
 .DELTA..sup.5,7 diene system to a .DELTA..sup.6,8(14) diene system, a
 .DELTA..sup.7,14 diene system, or a .DELTA..sup.8,14 diene system may
 result in mixtures of these isomers. Methods for obtaining the pure
 compounds are well known in the art e.g. crystallization or chromatography
 using a silica column loaded with a silver salt. .DELTA..sup.7 Compounds
 are obtained from the .DELTA..sup.5,7 diene system by reduction with
 lithium in liquid ammonia [Lederer, F. et al, Bull. Soc. Chim. Fr. 1295
 (1965)] or by hydrogenation. Hydrogenation catalysts which can be used
 include Raney nickel [Gautschi, F. et al, J. Biol. Chem. 233, 1343
 (1958)], Wilkinson's catalyst [Canonica, L. et al, Steroids 11, 287
 (1968)] and others. .DELTA..sup.8 Derivatives are prepared from
 .DELTA..sup.8,14 dienes by the sequence: selective hydroboration of the
 .DELTA..sup.14 double bond followed by deoxygenation of the 15-hydroxy
 compound produced [Dolle, R. E. et al, J. Amer. Chem. Soc. 111, 278
 (1989)]. The preparation of the unsaturated 3-protected
 20-methylpregna-3,21-diol derivatives of formula II is completed by
 deprotection of the 21-hydroxy function.
 Manipulation of the .DELTA..sup.5,7 diene system can be accompanied by
 deprotection of the hydroxy group at C-21. If not, the hydroxy group has
 yet to be deprotected.
 The 21-aryl-20-methylpregn-3-ol derivatives (X=--CH.sub.2 --) of the
 invention are obtained by oxidation of the compounds of formula II to the
 corresponding pregna-20-carboxaldehydes, followed by a condensation
 reaction of these aldehydes with an unsubstituted or suitably substituted
 phenylmetal compound, deoxygenation at C-21 of the 3-protected
 21-aryl-20-methylpregna-3,21-diol derivatives produced and, finally,
 deprotection of the hydroxy group at C-3.
 The oxidation of the 21-hydroxy group can be carried out by using an
 Oppenauer oxidation, a Swern oxidation, a Moffatt oxidation, a Dess-Martin
 oxidation, or by the use of chromium(VI) reagents like Jones reagent,
 pyridinium dichromate, pyridinium chlorochromate and similar reagents
 known in the art.
 Unsubstituted or substituted phenylmetal compounds which can be used in the
 condensation reaction with the pregna-20-carboxaldehydes include
 aryllithium-, arylmagnesium-, arylzinc- or arylcerium compounds.
 Replacement of the ensuing 21-hydroxy group by hydrogen (deoxygenation) in
 the 3-protected 21-aryl-20-methylpregna-3,21-diol derivatives can be
 carried out by esterification with methyl oxalyl chloride followed by
 reaction with tributyltin hydride/2,2'-azabis(isobutyronitrile). The
 deoxygenation might also be accomplished by a Barton deoxygenation
 reaction or similar techniques known in the art [M. Ramaiah, Tetrahedron
 43, 3541 (1987)], or by conversion of the 21-hydroxy group to a leaving
 group such as a halogen like chlorine, bromine, or iodine, or in
 particular the tosyloxy group or the mesyloxy group, followed by reduction
 with a hydride reducing agent, or by the use of Raney nickel, or with e.g
 triethylsilane in combination with a Lewis acid. Finally, deprotection of
 the 3-hydroxy function is accomplished using standard methods.
 The unsaturated 23-aryl-24-norcholan-3-ol compounds (X=--CH.sub.2
 --CH.sub.2 --) of the invention can be prepared from the unsaturated
 3-protected 20-methylpregna-3,21-diol derivatives of formula II as
 follows. The hydroxy function at C-21 can be converted to a leaving group,
 such as a halogen like chlorine, bromine, or iodine, or in particular the
 tosyloxy group or mesyloxy group, whereupon the products thus obtained can
 be converted by reaction with potassium cyanide or sodium cyanide to
 20-methylpregna-21-carbonitrile derivatives. The latter can be converted
 to the corresponding 21-carboxaldehydes by treatment with a reducing agent
 such as diisobutylaluminium hydride or other reducing agents capable of
 converting a carbonitrile group into a carboxaldehyde group. Since the
 reduction also leads to deprotection of the hydroxy function at C-3, the
 3-hydroxy group is to be reprotected as an ether, e.g. a ethoxyethyl ether
 or a THP ether, a silylether, e.g. a trimethylsilyl ether, or an acyl
 protecting group as described above. The final conversion to the
 23-aryl-24-norcholan-3-ol compounds of the invention can be carried out by
 the sequence (vide supra): reaction with an unsubstituted or suitably
 substituted phenylmetal compound, replacement of the 23-hydroxy group by
 hydrogen by deoxygenation and, finally, deprotection of the 3-hydroxy
 group.
 The compounds of the invention in which X is a straight chain divalent
 C.sub.3 -hydrocarbon radical can be prepared using procedures similar to
 those described for 23-aryl-24-norcholan-3-ol derivatives described above.
 First, the compounds of formula II are converted to an aldehyde having the
 required number of methylene groups in the side chain. Then, addition of
 an unsubstituted or suitably substituted phenylmetal compound,
 deoxygenation of the hydroxy compound formed and, finally, deprotection of
 the 3-hydroxy group is carried out as described above. Techniques for
 homologation are known in the art, see for example Mathieu, J. et al:
 Formation of C--C Bonds, Vol. I-III, Georg Thieme Publishers, Stuttgart,
 1973.
 The compounds of the invention in which X represents --(CH.sub.2).sub.m
 --CR.sub.7 R.sub.8 -- wherein m=0-4 and wherein R.sub.7 is hydroxy and
 R.sub.8 is hydrogen can be prepared in a similar way as described above.
 In this case, the hydroxy group which is formed by reaction with the
 arylmetal compound is maintained, i.e. the deoxygenation is left out. The
 arylcarbinols produced can optionally be converted, using methods well
 known in the art of general chemistry, to other compounds of formula I,
 namely the compounds of the invention in which X represents
 --(CH.sub.2).sub.m --CR.sub.7 R.sub.8 -- wherein m=0-4 and wherein R.sub.7
 and R.sub.8 are independently (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, or
 halogen, or wherein R.sub.7 and R.sub.8 together represent O, or NOR',
 wherein R' is H, (C.sub.1-6)alkyl, or (C.sub.1-6)acyl.
 The compounds of the invention in which X is a straight chain divalent
 C.sub.1-8 hydrocarbon radical can also be prepared from intermediates of
 formula II by converting the 21-hydroxy group to a leaving group, as
 already described, followed by a transition metal mediated, e.g.
 copper(I)-catalyzed, reaction with a suitably substituted phenylmetal
 compound or suitably substituted .omega.-phenylalkylmetal compound [Li,
 Mg, Zn; see Morisaki. M. et al, Chem. Pharm. Bull. 28, 606 (1980); and
 Lipshutz, B. H. et al in Org. Reactions 41, p. 135, Wiley, N.Y., 1992].
 The compounds of the invention in which X is a straight chain divalent
 C.sub.1 -hydrocarbon radical containing a double bond can be prepared by
 Wittig reaction of pregna-20-carboxaldehydes or
 20-methylpregna-21-carboxaldehydes, whose synthesis is described above, or
 of cholan-24-al derivatives, and so on, with unsubstituted or suitably
 substituted benzyltriphenylphosphonium halides, or unsubstituted or
 suitably substituted .omega.-phenylalkyltriphenylphosphonium halides. For
 methods used for the Wittig olefination reaction, see Maercker, A. in Org.
 Reactions 14, p. 270, Wiley, N.Y., 1965. Alternatively, Peterson reactions
 can be used, see Ager, D. J. in Org. Reactions, 38, p. 1, Wiley, N.Y.,
 1990.
 The compounds of the invention in which X is a straight chain divalent
 C.sub.1-8 hydrocarbon radical containing a double bond can also be
 prepared by a metal mediated coupling of 24-norchol-22-enes, chol-23-enes,
 or 26,27-dinorcholest-24-enes, and so on, substituted at C-23, C-24, C-25,
 respectively, with halogen (Cl, Br, I) or a triflate group, with an
 unsubstituted or suitably substituted phenylmetal compound or
 .omega.-phenylalkylmetal compound (e.g. Al, Li, Mg, Zn, B, Sn, Cu, Zr).
 They can also be prepared by a similar reaction of 24-norchol-22-enes,
 chol-23-enes, or 26,27-dinorcholest-24-enes, and so on, substituted at
 C-23, C-24, C-25, respectively, with a metal (Al, Li, Mg, Zn, B, Sn, Cu,
 Zr), with a suitably substituted phenylhalide or .omega.-phenylalkylhalide
 (Cl, Br, I), or sulfonate. Methods used are known in the art, see Knight,
 D. W. in Comprehensive Organic Synthesis 3, p. 241 and 481, Pergamon
 Press, Oxford, 1991; or K. Tamao, ibid. 3, p. 435.
 The compounds of the invention in which X is a straight chain divalent
 C.sub.1-8 hydrocarbon radical containing a triple bond can be prepared by
 a transition metal mediated coupling of 24-norchol-22-ynes, chol-23-ynes,
 or 26,27-dinorcholest-24-ynes with a suitably substituted phenyl halide
 [Cl, Br, I; see Takahashi, S. et al, Synthesis 627 (1980)]. Other
 compounds in this class can be prepared by metallation (e.g. Li, Mg, Na,
 K, Al) of said acetylene derivatives followed by reaction with suitably
 substituted .omega.-phenylalkyl halides or sulfonate esters [Garratt, P.
 J. in Comprehensive Organic Synthesis, 3, p. 271, Pergamon Press, Oxford,
 1991]. Alternatively, they can be prepared by reaction of
 20-methylpregn-21-ol derivatives, 24-norcholan-23-ol derivatives, or
 cholan-24-ol derivatives, and so on, in which the hydroxy group is
 converted to a leaving group (vide supra), with an unsubstituted or
 suitably substituted .omega.-phenylalk-1-ynylmetal compound.
 Compounds of formula I in which R.sub.1 is (H,OH) may serve as starting
 material for the synthesis, using methods known in the art, of compounds
 of formula I in which R.sub.1 is (H,OR), (H,OSO.sub.3 H) or NOR, and R is
 H, (C.sub.1-6)alkyl, or (C.sub.1-6)acyl.

The invention is further illustrated by the following examples.
 ##STR4##
 ##STR5##
 EXAMPLE 1
 (3.beta.,5.alpha.,20R)-4,4,20-Trimethyl-21-phenylpregna-8,14-dien-3-ol. (1)
 (Scheme I)
 i)--A solution of (20S)-3-oxopregn-4-ene-20-carboxaldehyde (2) (125 g) in
 dry ethanol (1250 ml) was cooled to -10.degree. C., whereupon a solution
 of sodium borohydride (4.4 g) in dry ethanol (80 ml) was added in 30 min.
 After stirring the mixture for 2 h at -10.degree. C., the reaction was
 quenched by adding a 50% aqueous solution of acetic acid. The reaction
 mixture was concentrated under reduced pressure to 25% of its original
 volume and then poured into ice-water (5 l). The resulting suspension was
 stirred overnight and filtered. The residue was washed with water and
 dried to give (20S)-21-hydroxy-20-methylpregn-4-en-3-one (3) (124 g) which
 was used in the following step without further purification.
 ii)--A solution of the alcohol 3 (124 g) obtained in the previous step and
 of imidazole (176 g) in dry N,N-dimethylformamide (1730 ml) was cooled to
 10.degree. C. t-Butyldimethylsilyl chloride (112 g) was added in one
 portion and the mixture was stirred at room temperature for 2 h. Then it
 was poured into a mixture of ice-water (10 l) and of a saturated aqueous
 solution of sodium hydrogen carbonate (750 ml). The resulting suspension
 was filtered and the residue was washed with water. Drying of the residue
 afforded
 (20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-20-methylpregn-4-en-3-one
 (4) (169.3 g), which was used in the following step without further
 purification.
 iii)--A mixture of potassium t-butoxide (169.5 g) and dry t-butanol (3750
 ml) was warmed to 45.degree. C. A solution of the ketone 4 (169.3 g) in
 dry tetrahydrofuran (375 ml) was added and the mixture was stirred for 10
 min. lodomethane (187.5 ml) was added in 10 min. and stirrring was
 continued for 3 h. The reaction mixture was concentrated under reduced
 pressure to a volume of 1.5 l and then poured into ice-water (10 l). After
 stirring of the mixture for 2 h the suspension was filtered. The residue
 was washed with water, dried and purified by crystallization from acetone
 to give
 (20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylpregn-5-e
 n-3-one (5) (136.9 g).
 iv)--A solution of the ketone 5 (140 g) obtained in the previous step in
 dry tetra-hydrofuran (1400 ml) was added in 30 min. to an ice-cooled
 suspension of lithium aluminium hydride (35 g) in tetrahydrofuran (1750
 ml). After stirring of the mixture for 1 h at room temperature, the
 reaction was quenched by addition of a saturated aqueous solution of
 sodium sulfate (152 ml), followed by water (39 ml). Ethyl acetate (1750
 ml) was added, and the mixture was filtered over celite. The filtrate was
 concentrated under reduced pressure to give
 (3.beta.,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylp
 regn-5-en-3-ol (6) (136.3 g), which was used in the following step without
 further purification.
 v)--A solution of the alcohol 6 (132.5 g) obtained in the previous step in
 dry pyridine (1310 ml) was cooled to 0.degree. C. Benzoyl chloride (65.7
 ml) was added in 5 min. and the reaction mixture was stirred for 1 h at
 room temperature. Then it was poured into ice-water (6650 ml) and the
 resulting suspension was stirred over-night. The precipitate was collected
 by filtration and washed with water (40-50.degree. C.). The residue was
 dried and purified by crystallization from acetone to give
 (3.beta.,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylp
 regn-5-en-3-ol benzoate (7) (113.6 g).
 vi)--A mixture of the benzoate 7 (94.0 g) obtained in the previous step,
 dry toluene (810 ml), dry cyclohexane (810 ml) and N-bromosuccinimide
 (36.1 g) was heated under reflux for 10 min. The reaction mixture was
 cooled, another portion of N-bromosuccinimide (36.1 g) was added, and
 reflux was continued for another 10 min. The reaction mixture was cooled,
 a saturated aqueous solution of sodium thiosulfate (1620 ml) was added and
 the resulting mixture was stirred for 30 min. The organic phase and the
 aqueous phase were separated and the latter extracted two times with
 toluene. The combined organic phases were dried over sodium sulfate and
 concentrated under reduced pressure. A solution of the crude product thus
 obtained in dry toluene (2835 ml) and N,N-diisopropylethylamine (284 ml)
 was heated under reflux for 1 h. Then it was cooled and washed with a
 saturated aqueous solution of sodium hydrogen carbonate, a saturated
 aqueous solution of ammonium chloride and with brine, the aqueous phase
 each time being extracted with ethyl acetate. The combined toluene and
 ethyl acetate solutions were dried over sodium sulfate and concentrated
 under reduced pressure to give
 (3.beta.,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylp
 regna-5,7-dien-3-ol benzoate (8) (134 g) which was used in the following
 step without further purification.
 vii)--A mixture of compound 8 (32.3 g), toluene (84 ml), ethanol (96%; 588
 ml) and concentrated hydrochloric acid (84 ml) was heated under reflux for
 3 h. The mixture was cooled and poured into a saturated aqueous solution
 of sodium hydrogen carbonate (1 l). The product was extracted into ethyl
 acetate; the combined organic phases were washed with brine, dried over
 sodium sulfate, and concentrated under reduced pressure. Column
 chromatography afforded a 3:1 mixture (17.4 g) of
 (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol
 3-benzoate (9) and
 (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-6,8(14)-diene-3,21-diol
 3-benzoate. The mixture was used as such in the next step.
 viii)--A solution of dry dimethyl sulfoxide (1.97 ml) in dry
 dichloromethane (76 ml) was cooled to -78.degree. C., and a solution of
 oxalyl chloride (1.53 ml) in dry dichloromethane (38 ml) was added in 30
 min. Stirring was continued for another 5 min. and a solution of the
 mixture (5.0 g) obtained under vii in dry tetrahydrofuran (36 ml) was
 added in 20 min. Stirring at -78.degree. C. was continued for 5 h, after
 which triethylamine (7.3 ml) was added and the mixture was allowed to rise
 to room temperature. Water was added and the product was extracted into
 dichloromethane. The combined organic phases were washed with water, dried
 over sodium sulfate, and concentrated under reduced pressure to afford
 (3.beta.,5.alpha.,20S)-3-(benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-car
 boxaldehyde (10) (6.14 g), which was used in the following step without
 further purification.
 ix)--A solution of the aldehyde 10 (2.0 g), obtained in the previous step,
 in dry tetrahydrofuran (17 ml) was added dropwise to a 1 M solution of
 phenylmagnesium bromide (13 ml) in tetrahydrofuran. The reaction mixture
 was stirred at room temperature for 3 h. A saturated aqueous solution of
 ammonium chloride was added and the product was extracted into ethyl
 acetate. The combined organic phases were washed with water, dried over
 sodium sulfate, and concentrated under reduced pressure to give
 (3.beta.,5.alpha.,20S)-4,4,20-trimethyl-21-phenylpregna-8,14-diene-3,21-di
 ol 3-benzoate (11) (3.0 g) which was used in the following step without
 further purification.
 x)--A solution of the alcohol 11 (3.0 g) in dry dichloromethane (26.7 ml)
 and dry pyridine (5.2 ml) was added dropwise to an ice-cooled solution of
 methyl oxalyl chloride (1.95 ml) in dry dichloromethane (9.7 ml). The
 mixture was stirred at room temperature for 1 h. Water was added and the
 product was extracted into ethyl acetate. The combined organic phases were
 washed with a 4 M aqueous solution of hydrochloric acid and with water,
 dried over sodium sulfate, and concentrated under reduced pressure to give
 (3.beta.,5.alpha.,20S)-4,4,20-trimethyl-21-phenylpregna-8,14-diene-3,21-di
 ol 3-benzoate 21-(methyl ethanedioate) (12) (3.58 g), which was used in the
 following step without further purification.
 xi)--A solution of methyl ethanedioate 12, the product obtained in the
 previous step, in dry toluene (150 ml) was heated at reflux temperature.
 Tributyltin hydride (2.5 ml) was added followed by
 2,2'-azabis(isobutyronitrile) (35 mg). Addition of portions (35 mg) of the
 latter compound was repeated every 15 min. until the reaction was complete
 (5 h). The reaction mixture was cooled, water was added, and the product
 was extracted into dichloromethane. The combined organic phases were
 washed with water, dried over sodium sulfate, and concentrated under
 reduced pressure. Column chromatography afforded
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol
 benzoate (13) (0.84 g).
 xii)--Potassium hydroxide (0.45 g) was added to a solution of compound 13
 (0.84 g) in a mixture of tetrahydrofuran (8.4 ml), methanol (8.4 ml) and
 water (0.45 ml). The mixture was heated under reflux overnight. After
 cooling, water was added and the resulting precipitate collected by
 filtration. The residue was washed with water and dried. Column
 chromatography and crystallization from dichloromethane/acetone afforded
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol (1)
 (0.29 g). M.p. 179-186.degree. C. The product contained 30% (w/w) of
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-6,8(14)-dien-3-ol.
 EXAMPLE 2
 Starting from
 (3.beta.,5.alpha.,20S)-3-(benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-car
 boxaldehyde 10, described under viii of Example 1, and using reaction steps
 analogous to those described under ix-xii of Example 1, the following
 compounds were prepared:
 A)--(3.beta.,5.alpha.,20R)-4,4,20-Trimethyl-21-(3-methylphenyl)pregna-8,14-
 dien-3-ol. M.p. 140.5-143.5.degree. C.
 B)--(3.beta.,5.alpha.,20R)-4,4,20-Trimethyl-21-[4-(trifluoromethyl)phenyl]p
 regna-8,14-dien-3-ol. M.p. 169-171.degree. C.
 EXAMPLE 3
 (3.beta.,5.alpha.,20R)-4,4,20-Trimethyl-21-phenylpregna-6,8(14)-dien-3-ol
 i)--Hydrogen chloride gas was passed into a solution of
 (3.beta.,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylp
 regna-5,7-dien-3-ol benzoate (compound 8; Example 1, step vi; 25.0 g) and
 acetic anhydride (40 ml) in chloroform (250 ml) for 30 min. The mixture
 was heated at reflux temperature for 50 min.; addition of hydrogen
 chloride gas was continued for the first 20 min. After cooling to
 0.degree. C., an aqueous solution of ammonium hydroxide (5%) was added,
 and the mixture was stirred for 1.5 h. The product was extracted into
 dichloromethane; the combined organic phases were washed with a saturated
 aqueous solution of sodium hydrogencarbonate and brine, dried over sodium
 sulfate and concentrated under reduced pressure to give
 (3.beta.,5.alpha.,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-t
 rimethylpregna-6,8(14)-dien-3-ol benzoate (24.6 g). The product was used as
 such in the next step.
 ii)--A solution of the compound (17.6 g) described under i in acetone (352
 ml) was treated with a 6 M aqueous solution of hydrochloric acid (3.52
 ml). After stirring of the reaction mixture for 3 h at 50.degree. C., the
 mixture was concentrated under reduced pressure. The residue was poured
 into water and the product extracted into ethyl acetate. The combined
 organic phases were washed with water, dried over sodium sulfate, and
 concentrated under reduced pressure. Column chromatography afforded
 (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-6,8(14)-diene-3,21-diol
 3-benzoate (7.69 g).
 iii)--Following procedures analogous to those described under viii-xii of
 Example 1, the product of the previous step was converted to
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-6,8(14)-dien-3-ol.
 M.p. 218-220.degree. C.
 EXAMPLE 4
 (3.beta.,5.alpha.,20S)-4,4,20-Trimethyl-21-(3-methylphenyl)pregna-8,14-dien
 e-3,21-diol
 i)--Following a procedure analogous to that described under ix of Example
 1,
 (3.beta.,5.alpha.,20S)-3-(benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-car
 boxaldehyde (compound 10; described in Example 1 under viii; 0.5 g) was
 converted to
 (3.beta.,5.alpha.,20S)-4,4,20-trimethyl-21-(3-methylphenyl)pregna-8,14-die
 ne-3,21-diol 3-benzoate (0.31 g).
 ii)--Following a procedure analogous to that of step xii of Example 1, the
 product obtained in the previous step (0.31 g) was converted to
 (3.beta.,5.alpha.,20S)-4,4,20-trimethyl-21-(3-methylphenyl)pregna-8,14-die
 ne-3,21-diol (53 mg). M.p. 169-173.degree. C.
 EXAMPLE 5
 (3.beta.,5.alpha.,20R)-4,4-Dimethyl-23-(2-methylphenyl)-24-norchola-8,14-di
 en-3-ol
 i)--p-Toluenesulfonic anhydride (20 g) was added to an ice-cooled solution
 of (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol
 3-benzoate (compound 9; prepared as described under vii of Example 1; 10
 g) in dry pyridine (40 ml). The reaction mixture was stirred overnight at
 room temperature and then poured into water (400 ml). After stirring of
 the mixture for 1 h, the resulting precipitate was collected by filtration
 and washed with water. Drying at 50.degree. C. under reduced pressure gave
 (3.beta.,5.alpha.,20S)-4,4,20-trimethyl-21-[[(4-methylphenyl)sulfonyl]oxy]
 -pregna-8,14-dien-3-ol benzoate (14.1 g), which was used in the following
 step without further purification.
 ii)--A suspension of the tosylate (9.12 g) described under i in dry
 dimethyl sulfoxide (31 ml) was heated at 50.degree. C. Potassium cyanide
 (3.86 g) was added and the mixture was stirred for 6 h. Dry dimethyl
 sulfoxide (31 ml) was added and stirring was continued for another 10 h.
 After cooling, the mixture was poured into ice-water (600 ml). The
 precipitate was collected by filtration and washed with water. Drying at
 50.degree. C. under reduced pressure gave
 (3.beta.,5.alpha.,20R)-3-(benzoyloxy)-4,4,20-trimethylpregna-8,14-diene-21
 -carbonitrile (6.45 g), which was used in the following step without
 further purification.
 iii)--Diisobutylaluminium hydride (64 ml of a 20% solution in toluene) was
 added to a solution of the nitrile (6.40 g) described under ii in dry
 toluene (64 ml). The mixture was stirred overnight at room temperature
 whereafter the reaction was quenched with a 4 M aqueous solution of
 hydrochloric acid (71 ml). After filtration, the product was extracted
 into ethyl acetate. The combined organic phases were washed with water,
 dried over sodium sulfate, and concentrated under reduced pressure to give
 (3.beta.,5.alpha.,20R)-3-hydroxy-4,4,20-trimethylpregna-8,14-diene-21-carb
 oxaldehyde (4.59 g), which was used in the following step without further
 purification.
 iv)--Pyridinium p-toluenesulfonate (0.29 g) was added to a solution of the
 aldehyde (4.59 g) described under iii in dry dichloromethane (28 ml) and
 ethyl vinyl ether (9.1 ml). After stirring of the mixture for 1 h pyridine
 (1 ml) was added. The mixture was washed with water, dried over sodium
 sulfate, and concentrated under reduced pressure to give
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-
 diene-21-carboxaldehyde (5.64 g), which was used in the following step
 without further purification.
 v)--Following a procedure analogous to that described under ix of Example
 1, the carboxaldehyde obtained in the previous step (1.0 g) was converted
 to
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-23-(2-methylphe
 nyl)-24-norchola-8,14-dien-23-ol (1.63 g).
 vi)--Following a procedure analogous to that described under x of Example
 1, the alcohol (1.60 g) obtained in the previous step was converted to
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-23-(2-methylphe
 nyl)-24-norchola-8,14-dien-23-ol methyl ethanedioate (2.11 g).
 vii)--Following a procedure analogous to that described under xi of Example
 1, the methyl ethanedioate (2.11 g) obtained in the previous step was
 converted to
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-23-(2-methylphe
 nyl)-24-norchola-8,14-diene (3.64 g).
 viii)--A solution of the compound (3.64 g) described under vii in acetone
 (20 ml) was treated with a 4 M aqueous solution of hydrochloric acid (2
 ml). After stirring of the reaction mixture for 1 h, the mixture was
 poured into water and the product extracted into ethyl acetate. The
 combined organic phases were washed with water, dried over sodium sulfate,
 and concentrated under reduced pressure. Crystallization from
 dichloromethane/acetone afforded
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-(2-methylphenyl)-24-norchola-8,14-d
 ien-3-ol (0.40 g). M.p. 184-186.degree. C.
 EXAMPLE 6
 Starting from
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-
 diene-21-carboxaldehyde, described under iv of Example 5, and using
 reaction steps analogous to those described under v-viii of Example 5, the
 following compounds were prepared:
 A)--(3.beta.,5.alpha.,20R)-4,4-Dimethyl-23-(3-methylphenyl)-24-norchola-8,1
 4-dien-3-ol. M.p. 159-161.degree. C.
 B)--(3.beta.,5.alpha.,20R)-4,4-Dimethyl-23-[2-(trifluoromethyl)phenyl]-24-n
 orchola-8,14-dien-3-ol. M.p. 130-147.degree. C. The product contained 45%
 of
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-[2-(trifluoromethyl)phenyl]-24-norc
 hola-6,8(14)-dien-3-ol.
 EXAMPLE 7
 (3.beta.,5.alpha.,20R)-4,4-Dimethyl-23-phenyl-24-norchola-8,14-dien-3-ol
 and
 (3.beta.,5.alpha.,20R)-3-hydroxy-4,4-dimethyl-23-phenyl-24-norchola-8,14-d
 ien-23-one
 i)--A mixture of
 (3.beta.,20S)-21-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,20-trimethylp
 regna-5,7-dien-3-ol benzoate (compound 8; Example 1, step vi; 46.5 g),
 chloroform (400 ml), and a solution of HCl in acetic acid (1 M, 400 ml)
 was stirred for 45 min. at room temperature and then heated under reflux
 for another 45 min. Another portion of the diene mentioned above (46.5 g)
 was treated in the same way. The reaction mixtures of both experiments
 were cooled, put together and concentrated under reduced pressure to
 remove the chloroform. The residue was poured into a solution of sodium
 hydroxide (150 g) in water (2.5 l). The resulting precipitate was
 collected by filtration, washed with water and dried. The crude product
 was crystallized from acetone to afford a 6:1 mixture (51.4 g) of
 (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol
 21-acetate 3-benzoate and
 (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-6,8(14)-diene-3,21-diol
 21-acetate 3-benzoate. The mixture was used as such in the next step.
 ii)--Potassium hydroxide (13.5 g) was added to a solution of the product
 obtained in the previous step (62 g) in tetrahydrofuran (400 ml), methanol
 (250 ml) and water (100 ml). The mixture was stirred for 1 h at room
 temperature and then poured into water (10 l). The resulting precipitate
 was collected by filtration, washed with water and dried to give
 (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol
 3-benzoate (58 g). The product was used in the following step without
 further purification.
 iii)--Following procedures analogous to those described under i-iii of
 Example 5 the alcohol obtained in the previous step was converted to give
 (3.beta.,5.alpha.,20R)-3-hydroxy-4,4,20-trimethylpregna-8,14-diene-21-carb
 oxaldehyde.
 iv)--A solution of the aldehyde (12.3 g) mentioned above in dry pyridine
 (150 ml) was cooled to 4.degree. C. Benzoyl chloride (8 ml) was added in 5
 min. and the reaction mixture was stirred for 1.5 h at room temperature.
 Then it was poured into water (2 l) and the resulting mixture was stirred
 overnight. The product was extracted into dichloromethane and the combined
 organic phases were concentrated under reduced pressure to give
 (3.beta.,5.alpha.,20R)-3-(benzoyloxy)-4,4,20-trimethylpregna-8,14-diene-21
 -carboxaldehyde (16.1 g). The product was used in the following step
 without further purification.
 v)--Following a procedure analogous to that described under ix of Example
 1, the aldehyde obtained in the previous step (15.0 g) was converted to a
 mixture of 23R and 23S phenylcarbinols which could be separated by column
 chromatography to afford
 (3.beta.,5.alpha.,20R,23R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol 3-benzoate (2.15 g) and
 (3.beta.,5.alpha.,20R,23S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol 3-benzoate (2.95 g).
 vi)--A suspension of Raney nickel in water (100 g) was added to a solution
 of
 (3.beta.,5.alpha.,20R,23R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol 3-benzoate (1.95 g) in ethanol (150 ml) and the mixture was
 stirred at room temperature for 96 h. The Raney nickel was removed by
 filtration. In another experiment
 (3.beta.,5.alpha.,20R,23S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol 3-benzoate (1.30 g) was treated in the same way. The filtrates of
 both experiments were put together and concentrated under reduced
 pressure. The crude product was purified by chromatography to afford
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-3-ol
 benzoate (1.00 g) and
 (3.beta.,5.alpha.,20R)-3-(benzoyloxy)-4,4-dimethyl-23-phenyl-24-norchola-8
 ,14-dien-23-one (0.40 g).
 viiA)--Following a procedure analogous to that described under iv of
 Example 1
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-3-ol
 benzoate (1.20 g) was converted to the 3-hydroxy compound to give, after
 crystallization from ethanol,
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-3-ol
 (0.65 g). M.p. 164.3-165.7.degree. C.
 viiB)--Sodium hydroxide (0.40 g) was added to a solution of
 (3.beta.,5.alpha.,20R)-3-(benzoyloxy)-4,4-dimethyl-23-phenyl-24-norchola-8
 ,14-dien-23-one (0.70 g) in tetrahydrofuran (10 ml), methanol (10 ml),
 dichloromethane (1 ml) and water (1 ml). The reaction mixture was heated
 at reflux temperature for 6 h, cooled, and neutralized with acetic acid (1
 ml). The product was extracted into dichloromethane and the combined
 organic phases were concentrated under reduced pressure. Crystallization
 of the crude product from ethanol gave
 (3.beta.,5.alpha.,20R)-3-hydroxy-4,4-dimethyl-23-phenyl-24-norchola-8,14-d
 ien-23-one (0.30 g). M.p. 196.4-197.2.degree. C.
 EXAMPLE 8
 (3.beta.,5.alpha.,20R,23R)-4,4-Dimethyl-23-phenyl-24-norchola-8,14-diene-3,
 23-diol
 Following a procedure analogous to that described under iv of Example 1
 (3.beta.,5.alpha.,20R,23R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol 3-benzoate (Example 7, step v; 0.75 g) was converted to the
 3-hydroxy compound to give, after crystallization from ethanol,
 (3.beta.,5.alpha.,20R,23R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol (0.28 g). M.p. 199.2-200.7.degree. C.
 EXAMPLE 9
 (3.beta.,5.alpha.,20R,23S)-4,4-Dimethyl-23-phenyl-24-norchola-8,14-diene-3,
 23-diol
 Following a procedure analogous to that described under iv of Example 1
 (3.beta.,5.alpha.,20R,23S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol 3-benzoate (Example 7, step v; 0.75 g) was converted to the
 3-hydroxy compound to give, after crystallization from ethanol,
 (3.beta.,5.alpha.,20R,23S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-diene-3
 ,23-diol (0.13 g). M.p. 208.0-209.3.degree. C.
 EXAMPLE 10
 (3.beta.,5.alpha.,20R,22E)-4,4-Dimethyl-23-phenyl-24-norchola-8,14,22-trien
 -3-ol
 i)--Potassium t-butoxide (1.12 g) was added to a suspension of
 benzyltriphenylphosphonium chloride (4.22 g) in dry toluene (30 ml). The
 mixture was heated at 70.degree. C. for 45 min.
 (3.beta.,5.alpha.,20S)-3-(Benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-car
 boxaldehyde (compound 10; Example 1, step viii; 1.0 g) was added and
 heating was continued for 1 h. After cooling, the mixture was poured into
 water and the product extracted into ethyl acetate. The combined organic
 phases were washed with water, dried over sodium sulfate, and concentrated
 under reduced pressure. Column chromatography afforded
 (3.beta.,5.alpha.,20R,22E)-4,4-dimethyl-23-phenyl-24-norchola-8,14,22-trie
 n-3-ol benzoate (0.70 g).
 ii)--Following a procedure analogous to that of step xii of Example 1, the
 product obtained in the previous step (0.70 g) was converted to
 (3.beta.,5.alpha.,20R,22E)-4,4-dimethyl-23-phenyl-24-norchola-8,14,22-trie
 n-3-ol (0.23 g). M.p. 131-144.degree. C. The product contained 30% of
 (3.beta.,5.alpha.,20R,22E)-4,4-dimethyl-23-phenyl-24-norchola-6,8(14),22-t
 rien-3-ol.
 EXAMPLE 11
 (3.beta.,5.alpha.,20R,23E)-4,4-Dimethyl-24-phenylchola-8,14,23-trien-3-ol
 i)--Following a procedure analogous to that described under i of Example
 10,
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-
 diene-21-carboxaldehyde (Example 5, step iv; 0.500 g) was converted to
 (3.beta.,5.alpha.,20R,23E)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-24-phenylch
 ola-8,14,23-triene (0.86 g).
 ii)--Following a procedure analogous to that described under viii of
 Example 5, the product obtained in the previous step (0.24 g) was
 converted to the 3-hydroxy compound. Column chromatography afforded
 (3.beta.,5.alpha.,20R,23E)-4,4-dimethyl-24-phenylchola-8,14,23-trien-3-ol
 (0.139 g). M.p. 126.8-127.4.degree. C. The compound contained 30% of
 (3.beta.,5.alpha.,20R,23Z)-4,4-dimethyl-24-phenylchola-8,14,23-trien-3-ol.
 EXAMPLE 12
 (3.beta.,5.alpha.,20S)-4,4-Dimethyl-23-phenyl-24-norchola-8,14-dien-22-yn-3
 -ol
 i)--Pyridinium chlorochromate (8.79 g) was added to a solution of
 (3.beta.,5.alpha.,20S)-4,4,20-trimethylpregna-8,14-diene-3,21-diol
 3-benzoate (Example 7, step ii; 12.6 g) in dry dichloromethane (130 ml).
 The reaction mixture was stirred at room temperature for 1.5 h. Another
 portion of pyridinium chlorochromate (1.50 g) was added and stirring was
 continued for another 1.5 h. The reaction mixture was filtered and the
 filtrate was poured into a saturated aqueous solution of sodium
 hydrogencarbonate. The product was extracted into dichloromethane and the
 combined organic phases were washed with water, dried over magnesium
 sulfate and concentrated under reduced pressure, to afford
 (3.beta.,5.alpha.,20S)-3-(benzoyloxy)-4,4-dimethylpregna-8,14-diene-20-car
 boxaldehyde (10.3 g). The product was used in the following step without
 further purification.
 ii)--A suspension of (chloromethyl)triphenylphosphonium chloride (17.5 g)
 in dry tetrahydrofuran (140 ml) was cooled to 0.degree. C. Sodium
 t-butoxide (4.64 g) was added and the mixture was stirred for 20 min. A
 solution of the aldehyde obtained in the previous step (10.3 g) in dry
 tetrahydrofuran (80 ml) was added and the reaction mixture was stirred at
 0.degree. C. for 30 min. and at room temperature for another 2 h. Ethyl
 acetate was added and the mixture was concentrated to remove the
 tetrahydrofuran. Then it was washed with water and a mixture of a
 saturated aqueous solution of sodium hydrogencarbonate and brine. The
 organic phase was dried over magnesium sulfate and concentrated under
 reduced pressure. Column chromatography afforded
 (3.beta.,5.alpha.,20S)-23-chloro-4,4-dimethyl-24-norchola-8,14,22-trien-3-
 ol benzoate (7.01 g).
 iii)--Following a procedure analogous to that described under iv of Example
 1, the product obtained in the previous step (7.01 g) was converted to
 (3.beta.,5.alpha.,20S)-23-chloro-4,4-dimethyl-24-norchola-8,14,22-trien-3-
 ol (6.28 g).
 iv)--Following a procedure analogous to that described under iv of Example
 5, the product obtained in the previous step (6.28 g) was converted to
 (3.beta.,5.alpha.,20S)-23-chloro-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-24-no
 rchola-8,14,22-triene (6.98 g).
 v)--A solution of the product of the previous step (6.98 g) in dry
 tetrahydrofuran (75 ml) was cooled to -20.degree. C. n-Butyllithium in
 hexanes (1.6 M, 28.5 ml) was added in 20 min. and the reaction mixture was
 stirred at -20.degree. C. for 15 min. and then at 0.degree. C. for 3.5 h.
 Water was added and the product was extracted into ethyl acetate. The
 combined organic phases were washed with brine, dried over magnesium
 sulfate and concentrated under reduced pressure. Column chromatography
 afforded
 (3.beta.,5.alpha.,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-24-norchola-8,1
 4-dien-22-yne (4.34 g).
 vi)--A mixture of the product of the previous step (0.50 g), iodobenzene
 (0.16 ml), palladium(II) acetate (16 mg), triphenylphosphine (62 mg) and
 copper(I) iodide (18 mg) in pyrrolidine (7 ml) was degassed and then
 heated at reflux temperature for 3 h. The reaction mixture was poured into
 a saturated aqueous solution of ammonium chloride and the product was
 extracted into ethyl acetate. The combined organic phases were washed with
 a saturated aqueous solution of ammonium chloride and brine and dried over
 magnesium sulfate. Column chromatography afforded
 (3.beta.,5.alpha.,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-23-phenyl-24-no
 rchola-8,14-dien-22-yne (0.62 g).
 vii)--Following a procedure analogous to that described under viii of
 Example 5, the product obtained in the previous step (0.61 g) was
 converted to the 3-hydroxy compound. Column chromatography afforded
 (3.beta.,5.alpha.,20S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-22-yn-
 3-ol (0.25 g). M.p. 136.degree. C. The compound contained 20% of
 (3.beta.,5.alpha.,20S)-4,4-dimethyl-23-phenyl-24-norchola-6,8(14)-dien-22-
 yn-3-ol.
 EXAMPLE 13
 Starting from
 (3.beta.,5.alpha.,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-24-norchola-8,1
 4-dien-22-yne, described under v of Example 12, and using reaction steps
 analogous to those described under vi and vii of that Example, the
 following compounds were prepared:
 A)--(3.beta.,5.alpha.,20S)-23-(4-Methoxyphenyl)-4,4-dimethyl-24-norchola-8,
 14-dien-22-yn-3-ol. M.p. 165.5.degree. C. The product contained 30% of
 (3.beta.,5.alpha.,20S)-23-(4-methoxyphenyl)-4,4-dimethyl-24-norchola-6,8(1
 4)-dien-22-yn-3-ol.
 B)--(3.beta.,5.alpha.,20S)-23-(4-Chlorophenyl)-4,4-dimethyl-24-norchola-8,1
 4-dien-22-yn-3-ol. The product contained 25% of
 (3.beta.,5.alpha.,20S)-23-(4-chlorophenyl)-4,4-dimethyl-24-norchola-6,8(14
 )-dien-22-yn-3-ol.
 EXAMPLE 14
 (3.beta.,5.alpha.,20R)-4,4-Dimethyl-24-phenylchola-8,14-dien-23-yn-3-ol
 i)--Following procedures analogous to those described under ii and v of
 Example 12,
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-
 diene-21-carboxaldehyde (Example 5, step iv) was converted to
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylchola-8,14-dien-
 23-yne.
 ii)--Following procedures analogous to those described under vi and vii of
 Example 12, the alkyne described above was converted to
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-24-phenylchola-8,14-dien-23-yn-3-ol.
 M.p. 84.8-85.7.degree. C. The product contained 15% of
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-24-phenylchola-6,8(14)-dien-23-yn-3-ol
 .
 EXAMPLE 15
 Starting from
 (3.beta.,5.alpha.,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylchola-8,14-dien-
 23-yne, described under i of Example 14, and using reaction steps analogous
 to those described under vi and vii of Example 12, the following compounds
 were prepared:
 A)--(3.beta.,5.alpha.,20R)-24-(4-Methoxyphenyl)-4,4-dimethylchola-8,14-dien
 -23-yn-3-ol. M.p. 91.3-92.6.degree. C. The product contained 15% of
 (3.beta.,5.alpha.,20R)-24-(4-methoxyphenyl)-4,4-dimethylchola-6,8(14)-dien
 -23-yn-3-ol.
 B)--(3.beta.,5.alpha.,20R)-24-(4-Chlorophenyl-4,4-dimethylchola-8,14-dien-2
 3-yn-3-ol. M.p. 128.2-129.4.degree. C. The product contained 15% of
 (3.beta.,5.alpha.,20R)-24-(4-chlorophenyl)-4,4-dimethylchola-6,8(14)-dien-
 23-yn-3-ol.
 C)--(3.beta.,5.alpha.,20R)-4,4-Dimethyl-24-(2-methylphenyl)chola-8,14-dien-
 23-yn-3-ol. M.p. 136.5-137.8.degree. C.
 D)--(3.beta.,5.alpha.,20R)-4,4-Dimethyl-24-(4-methylphenyl)chola-8,14-dien-
 23-yn-3-ol. M.p. 111.2-112.1.degree. C.
 EXAMPLE 16
 (3.beta.,5.alpha.,20R)-20-Methyl-21-phenylpregna-8,14-dien-3-ol and
 (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-6,8(14)-dien-3-ol
 i)--Following a procedure analogous to that described under v of Example 1,
 (3.beta.,17Z)-pregna-5,17-dien-3-ol [82.7 g; see Drefahl, G. et al, Chem.
 Ber. 604 (1965)] was converted to (3.beta.,17Z)-pregna-5,17-dien-3-ol
 benzoate (104.7 g).
 ii)--A solution of the product (25.3 g) obtained in the previous step in
 dry dichloromethane (500 ml) was cooled to 15.degree. C. Paraformaldehyde
 (11.3 g) was added, followed by boron trifluoride diethyl etherate (0.78
 ml). The mixture was stirred for 45 min. and then filtered to remove the
 excess paraformaldehyde. Sulfuric acid (6 M, 31.3 ml) and methanol (250
 ml) were added and the mixture was stirred at room temperature for 5 h. It
 was neutralized with an aqueous solution of sodium hydroxide (2 M) and
 then poured into water. The product was extracted into dichloromethane;
 the combined organic phases were dried over of sodium sulfate and
 concentrated under reduced pressure to give
 (3.beta.,20S)-20-methylpregna-5,16-diene-3,21-diol 3-benzoate (26.5 g).
 The product was used in the following step without further purification.
 iii)--A solution of the alcohol obtained in the previous step (13.3 g) in
 dichloromethane (135 ml) and ethanol (135 ml), containing platinum on
 activated carbon (10%, 4.18 g), was hydrogenated at room temperature and
 atmospheric pressure. The solution was filtered and concentrated under
 reduced pressure. Crystallization from dichloromethane/acetone afforded
 (3.beta.,20S)-20-methylpregn-5-ene-3,21-diol 3-benzoate (10.6 g).
 iv)--A solution of the alcohol obtained in the previous step (22.2 g) in
 dry dichloromethane (444 ml) was added to a suspension of pyridinium
 chlorochromate (44.3 g) in the same solvent (443 ml). After 2.5 h stirring
 at room temperature the reaction mixture was cooled to 5.degree. C. An
 aqueous solution of sodium bisulfite (90 g) in water (511 ml) was added
 and stirring was continued for 1 h. The mixture was poured into water (3
 l) and filtered over a mixture of silica and celite. The product was
 extracted into dichloromethane and the combined organic phases were
 concentrated under reduced pressure. The residu was dissolved in a mixture
 of ethyl acetate and tetrahydrofuran and washed with water. The organic
 phase was dried over sodium sulfate and treated with activated carbon,
 filtered, and concentrated to give
 (3.beta.,20S)-3-(benzoyloxy)pregn-5-ene-20-carboxaldehyde (19.0 g). The
 product was used in the following step without further purification.
 v)--Following a procedure analogous to that described under ix of Example
 1, the aldehyde obtained in the previous step (19.0 g) was converted to a
 mixture of (3.beta.,20S,21R)-20-methyl-21-phenylpregn-5-ene-3,21-diol
 3-benzoate and (3.beta.,20S,21S)-20-methyl-21-phenylpregn-5-ene-3,21-diol
 3-benzoate (together 17.7 g).
 vi)--A solution of the mixture of alcohols obtained in the previous step
 (15.3 g) and triethylsilane (5.26 ml) in dry dichloromethane (306 ml) was
 cooled to 0.degree. C. Boron trifluoride diethyl etherate (4.2 ml) was
 added and the mixture was stirred for 1.5 h. The mixture was poured into a
 saturated aqueous solution of sodium hydrogencarbonate and the product was
 extracted into dichloromethane. The combined organic phases were washed
 with brine, dried over sodium sulfate and concentrated under reduced
 pressure. Crystallization of the crude product from diethyl ether afforded
 (3.beta.,20R)-20-methyl-21-phenylpregn-5-en-3-ol benzoate (10.7 g).
 vii)--A solution of the benzoate obtained in the previous step (8.88 g) in
 dry cyclohexane (450 ml) containing 1,3-dibromo-5,5-dimethylhydantoin
 (3.78 g) was heated under reflux for 1 h. The reaction mixture was cooled
 and poured into water. The product was extracted into ethyl acetate and
 the combined organic phases were washed with brine, dried over sodium
 sulfate and concentrated under reduced pressure. The residu (11.3 g) was
 dissolved in dry tetrahydrofuran (180 ml) and treated with a solution of
 tetrabutylammonium fluoride in tetrahydrofuran (1 M, 52.8 ml). The mixture
 was stirred overnight at room temperature. Then it was poured into water
 and the product was extracted into ethyl acetate. The combined organic
 phases were washed with brine, dried over sodium sulfate and concentrated
 under reduced pressure. Crystallization and column chromatography of the
 crude product afforded
 (3.beta.,20R)-20-methyl-21-phenylpregna-5,7-dien-3-ol benzoate (4.48 g).
 viii)--Following a procedure analogous to that described under vii of
 Example 1, the diene obtained in the previous step (3.2 g) was isomerized.
 Repeated crystallization of the crude product (3.3 g) from acetoneldiethyl
 ether and chromatography afforded
 (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-8,14-dien-3-ol benzoate
 (1.51 g) and
 (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-6,8(14)-dien-3-ol
 benzoate (0.75 g).
 ixA)--Following a procedure analogous to that described under iv of Example
 1, (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-8,14-dien-3-ol
 benzoate (0.90 g) was converted to the 3-hydroxy compound. Repeated
 crystallization from diethyl ether/heptane gave
 (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-8,14-dien-3-ol (0.39 g).
 M.p. 156-157.degree. C.
 ixB)--Following a procedure analogous to that described under iv of Example
 1, (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-6,8(14)-dien-3-ol
 benzoate (0.75 g) was converted to the 3-hydroxy compound. Chromatography
 and freeze-drying from dioxane/t-butanol gave
 (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-6,8(14)-dien-3-ol (0.21
 g).
 EXAMPLE 17
 (3.beta.,5.alpha.,20R)-4,4-Dimethyl-23-(2-methylphenyl)-24-norchola-8,14-di
 en-3-ol hydrogen butanedioate
 A mixture of
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-(2-methylphenyl)-24-norchola-8,14-d
 ien-3-ol (0.15 g), described under Example 5, dry pyridine (2.2 ml),
 succinic anhydride (0.82 g), and 4-dimethylaminopyridine (5 mg) was heated
 overnight at 60.degree. C. The reaction mixture was cooled and
 subsequently poured into water and the product extracted into ethyl
 acetate. The combined organic phases were washed with a 2 M aqueous
 solution of hydrochloric acid and with water, dried over sodium sulfate,
 and concentrated under reduced pressure. Crystallization of the crude
 material from acetone afforded
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-(2-methylphenyl)-24-norchola-8,14-d
 ien-3-ol hydrogen butanedioate (0.106 g). M.p. 144-147.degree. C.
 EXAMPLE 18
 In a manner analogous to that described in Example 17, the following
 compounds were prepared:
 A)--(3.beta.,5.alpha.,20R)-4,4,20-Trimethyl-21-phenylpregna-8,14-dien-3-ol
 hydrogen butanedioate from
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien-3-ol
 (compound 1, described in Example 1). The product contained 30% of
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-6,8(14)-dien-3-ol
 hydrogen butanedioate.
 B)--(3.beta.,5.alpha.,20R)-4,4,20-Trimethyl-21-[4-(trifluoromethyl)phenyl]p
 regna-8,14-dien-3-ol hydrogen butanedioate from
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-[4-(trifluoromethyl)phenyl]preg
 na-8,14-dien-3-ol (described in Example 2B). M.p. 147-151.degree. C.
 C)--(3.beta.,5.alpha.,20R)-4,4-Dimethyl-23-[2-(trifluoromethyl)phenyl]-24-n
 orchola-8,14-dien-3-ol hydrogen butanedioate from
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-[2-(trifluoromethyl)phenyl]-24-norc
 hola-8,14-dien-3-ol (described in Example 6B). The product contained 30% of
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-[2-(trifluoromethyl)phenyl]-24-norc
 hola-6,8(14)-dien-3-ol hydrogen butanedioate.
 D)--(3.beta.,5.alpha.,20R,22E)-4,4-Dimethyl-23-phenyl-24-norchola-8,14,22-t
 rien-3-ol hydrogen butanedioate from
 (3.beta.,5.alpha.,20R,22E)-4,4-dimethyl-23-phenyl-24-norchola-8,14,22-trie
 n-3-ol (described in Example 10). The compound contained 40% of
 (3.beta.,5.alpha.,20R,22E)-4,4-dimethyl-23-phenyl-24-norchola-6,8(14),22-t
 rien-3-ol hydrogen butanedioate.
 EXAMPLE 19
 The Oocyte Assay
 General:
 Oocytes arrested in meiose contain diffused chromosomes which are
 surrounded by an intact nuclear envelope known as the germinal vesicle
 (GV). Upon reinitiation of meiosis by the midcycle gonadotropin surge, the
 chromosomes recondense and the GV breaks down (GVBD). In vivo, the oocyte
 is exposed to hypoxanthin (HX), which maintains the oocyte arrested in the
 meiotic prophase. This meiotic arrest can be mimicked in vitro by addition
 of hypoxanthin to the culture medium. The activity of the compounds of the
 invention is measured as the ability to overcome the hypoxanthin
 maintained meiotic arrest in denuded oocytes (DO), i.e. the induction of
 meiotic resumption in vitro.
 Isolation of Cumulus Enclosed Oocytes:
 Ovaries are obtained from immature female mice (B6D2-F1, strain
 C57BL.times.DBA). At the age of 19, 20 or 21 days the mice are injected
 subcutaneously with a single dose of 20 IU Humegon (Organon, The
 Netherlands) in saline.
 Forty-eight hours after Humegon injection mice are killed by cervical
 dislocation. The ovaries are removed, freed of extraneous tissue and
 placed in a multidish containing 1 ml preparation medium at 37.degree. C.
 L-15 Leibovitz medium (Gibco, pH 7.3.+-.0.1) supplemented with bovine
 serum albumin (3 mg.ml.sup.-1), L-glutamine (0.23 mM), sodium pyruvate (2
 mM) and hypoxanthin (4 mM) is used as preparation medium. The antral
 follicles of the ovaries are punctured under a dissecting microscope using
 two 27-gauge needles attached to two 1 ml syringes. Cumulus enclosed
 oocytes (CEO) of uniform size are selected with a mouth-controlled pipette
 and rinsed in 0,5 ml fresh preparation medium. About 20 CEO are obtained
 from one ovary.
 Isolation of Denuded Oocytes:
 Oocytes freed from cumulus cells, i.e. denuded oocytes (DO) are obtained by
 gently flushing CEO through a fine-bore mouth-controlled pipette. DO are
 rinsed twice in fresh culture medium and stored in culture medium at
 37.degree. C. in 100% humidified atmosphere with 5% CO.sub.2 in air.
 Experimental Design:
 The oocyte assay is performed in 3 blocks, each block represents the
 ovaries of one mouse (randomized block design). At t=0 DO of the first
 ovary of the first mouse, are spread over well 1 and 3 and oocytes of the
 second ovary over well 2 and 4 of a 4-well multidish containing 0.5 ml of
 culture medium to which a 20-aralkyl-5a-pregnane derivative of the
 invention is added (first block). Culture medium was used as control. The
 same procedure is performed for the second and third mouse (block 2 and
 3). The culture medium used is MEM alpha medium (Gibco, pH 7.3.+-.0.1)
 saturated with CO.sub.2 and supplemented with bovine serum albumin (3
 mg.ml.sup.-1), L-glutamine (0.23 mM), sodium pyruvate (2 mM) and
 hypoxanthin (4 mM). In total, each control or test compound is tested on
 30 oocytes (10 oocytes per block). At t=0 the number of DO with intact
 germinal vesicles (GV) or germinal vesicle break-down (GVBD) is counted
 under an inverted microscope with differential interference contrast
 equipment. Only oocytes with an intact GV are used in the experiment.
 Oocytes are cultured 22 hours at 37.degree. C. in 100% humidified
 atmosphere with 5% CO.sub.2 in air. At the end of the culture period the
 number of oocytes with GV or GVBD per group is counted. For statistical
 analysis the percentage germinal vesicle breakdown is calculated for each
 group in one block. These percentages are subjected to arcsin
 transformation, and differences between control and test compounds are
 analyzed by an ANOVA test for a randomized block design. Results are
 presented in Table I.
 TABLE I
 Percentage germinal vesicle breakdown (GVBD) in oocytes
 following culturing in the presence of test compounds (DO assay).*
 GVBD
 (%) Ex-
 periment
 Compound (Example) (control)
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien- 100(0)
 3-ol (1)
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-(3-methylphenyl)pregna- 97(8)
 8,14-dien-3-ol (2A)
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-[4-(trifluoro- 98(0)
 methyl)phenyl]pregna-8,14-dien-3-ol (2B)
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-6,8(14)- 100(0)
 dien-3-ol (3)
 (3.beta.,5.alpha.,20S)-4,4,20-trimethyl-21-(3-methylphenyl)pregna- 19(4)
 8,14-diene,3,21-diol (4)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-(2-methylphenyl)-24-norchola- 28(0)
 8,14-dien-3-ol (5)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-(3-methylphenyl)-24-norchola- 60(8)
 8,14-dien-3-ol (6A)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-[2-(trifluoro- 0(0)
 methyl)phenyl]-24-norchola-8,14-dien-3-ol (6B)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien-
 3-ol (7A)
 (3.beta.,5.alpha.,20R)-3-hydroxy-4,4-dimethyl-23-phenyl-24-
 norchola-8,14-dien-23-one (7B)
 (3.beta.,5.alpha.,20R,23R)-4,4-dimethyl-23-phenyl-24-norchola-8,14-
 diene-3,23-diol (8)
 (3.beta.,5.alpha.,20R,23S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-
 diene-3,23-diol (9)
 (3.beta.,5.alpha.,20R,22E)-4,4-dimethyl-23-phenyl-24-norchola- 0(0)
 8,14,22-trien-3-ol (10)
 (3.beta.,5.alpha.,20R,23E)-4,4-dimethyl-24-phenylchola-8,14,23-trien-
 67(0)
 3-ol (11)
 (3.beta.,5.alpha.,20S)-4,4-dimethyl-23-phenyl-24-norchola-8,14-dien- 100(3)
 22-yn-3-ol (12)
 (3.beta.,5.alpha.,20S)-23-(4-methoxyphenyl)-4,4-dimethyl-24-norchola- 5(0)
 8,14-dien-22-yn-3-ol (13A)
 (3.beta.,5.alpha.,20S)-23-(4-chlorophenyl)-4,4-dimethyl-24-norchola- 60(0)
 8,14-dien-22-yn-3-ol (13B)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-24-phenylchola-8,14-dien-23-yn-3-
 28(3)
 ol (14)
 (3.beta.,5.alpha.,20R)-24-(4-methoxyphenyl)-4,4-dimethylchola-8,14- 51(6)
 dien-23-yn-3-ol (15A)
 (3.beta.,5.alpha.,20R)-24-(4-chlorophenyl-)4,4-dimethylchola-8,14- 39(6)
 dien-23-yn-3-ol (15B)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-24-(2-methylphenyl)chola-8,14- 4(0)
 dien-23-yn-3-ol (15C)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-24-(4-methylphenyl)chola-8,14- 100(0)
 dien-23-yn-3-ol (15D)
 (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-8,14-dien-3-
 ol (16A)
 (3.beta.,5.alpha.,20R)-20-methyl-21-phenylpregna-6,8(14)-dien-3-
 ol (16B)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-(2-methylphenyl)-24-norchola- 81(0)
 8,14-dien-3-ol hydrogen butanedioate (17)
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-phenylpregna-8,14-dien- 38(6)
 3-ol hydrogen butanedioate (18A)
 (3.beta.,5.alpha.,20R)-4,4,20-trimethyl-21-[4-(trifluoro- 100(0)
 methyl)phenyl]pregna-8,14-dien-3-ol hydrogen
 butanedioate (18B)
 (3.beta.,5.alpha.,20R)-4,4-dimethyl-23-[2-(trifluoromethyl)phenyl]- 98(6)
 24-norchola-8,14-dien-3-ol hydrogen butanedioate (18C)
 (3.beta.,5.alpha.,20R,22E)-4,4-dimethyl-23-phenyl-24-norchola- 100(6)
 8,14,22-trien-3-ol hydrogen butanedioate (18D)
 (3.beta.,5.alpha.,20R)-4,4-dimethylcholesta-8,14,24-trien- 84(4)
 3-ol (FF-Mas)
 *Each compound was tested at a concentration of 10 .mu.M.