EP1658306A1

EP1658306A1 - Delta 15 -d-homosteroids having an androgenic effect

Info

Publication number: EP1658306A1
Application number: EP04764445A
Authority: EP
Inventors: Ralf Wyrwa; Sven Ring; Günter Kaufmann; Walter Elger; Birgitt Schneider
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 2003-08-21
Filing date: 2004-08-19
Publication date: 2006-05-24
Also published as: AU2004268040A1; US7388003B2; CA2534831A1; ECSP066441A; MXPA06002034A; WO2005021573A1; JP2007502801A; KR20060091295A; IL173608A0; BRPI0413787A; US20050131076A1

Abstract

The invention relates to Delta<15>-D-homosteroids of general formula (I), methods for the production thereof, and pharmaceutical compositions containing said compounds. The inventive compounds of general formula (I) are provided with androgenic activity.

Description

Δ ¹⁵ -D homosteroids with androgenic effects

The invention relates to Δ ¹⁵ -D homosteroids of the general

formula

a process for their preparation, pharmaceutical compositions containing these compounds and their use for the preparation of medicaments with androgenic action.

Δ ¹⁵ -D homosteroids of the estran and androstane series are not yet known. However, are known from US Pat. No. 4,155,918 and Avery et al., Steroids, 1990, vol. 55, pp. 59-64) Δ ¹⁶ -D-homosteroids which have androgenic and antigonadotropic activity.

The object of the present invention is to provide further androgenically active compounds and to provide a technically simple and effective process for their preparation.

This object is achieved by Δ ¹⁵ -D homosteroids of the general formula

wherein R ¹ for a C ^ alkyl group and R ² for a hydroxy group, a group OC (O) -R ²⁰ , OC (O) NH-R ²⁰ or OR ²⁰ , wherein R ^{20 is} a Cι-ι ₂ alkyl group, a C _3-8 cycloalkyl group, an aryl group or an aryl-C- _M alkyl group which is optionally substituted,

R ^ά for a hydrogen atom or ad- ₆ -alkyl, vinyl, ethynyl or C _n F _2n + r group, with n = 1, 2, 3 and

R ^{4 represents} a hydrogen atom or

R represents a hydrogen atom or a de-alkyl, vinyl, ethynyl or C _n F _2n + ι group, with n = 1, 2, 3,

R ^ά for a hydroxyl group, a group OC (O) -R ²⁰ , OC (O) NH-R ²⁰ or OR ²⁰ , where R ^{20 is} a Cι_ι ₂ alkyl group, a C _3-8 cycloalkyl group, an aryl group or an aryl -C-ι- alkyl group, which is optionally substituted, means, and

R ⁴ for a hydrogen atom or R ² and R ³ together for an oxygen atom and

R ⁴ for a hydrogen atom or ² for a hydroxy group, a group OC (O) -R ²⁰ , OC (O) NH-R _Ü 20 ^u or OR ²⁰ , where R ^{20 is} a Cι_ι ₂ alkyl group, a C _3-8 - Cycloalkyl group, an aryl group or an arylC _1-4 alkyl group, which is optionally substituted, means, and

R ³ and R ⁴ together form a double bond and

STEROID stand for a steroidal partial ring system of the formulas A, B, C, D, E and F:

B

where in A and C in the 1,2 position there can be one additional double bond and in B in the 9,10 position and 11,12 position there can be one or two additional double bonds,

R ^{7 is} a hydrogen atom, a halogen atom, a hydroxyl group or a C _n F _{2n +} ι-

Group with n = 1, 2, 3 means

X represents an oxygen atom, two hydrogen atoms or a hydroxyimino group, R ^{8 represents} a hydrogen atom, a methyl or ethyl group,

R ^{9 represents} a hydrogen atom or a halogen atom or together with R ^{10 represents} a double bond,

R ^{10 represents} a hydrogen atom, a hydroxy group, a methyl or ethyl group or together with R ^{9 stands} for a double bond, R ^{11 represents} a hydrogen atom, a C _-4 alkyl group, a nitrile group, a

Hydroxymethylene or formyl group means

R ^{12 is} a hydrogen atom, a or means a nitrile group,

R ¹¹ and R ^{12 together} with the meanings mentioned above together

Are methylene bridge, R ^{13 is} a hydrogen atom or together with R ^{7 is} a double bond, R ^{16 represents} a hydrogen atom or together with R ³ a double bond,

R ^{15 represents} a hydroxyl group, R ¹⁴ and R ^{15 represent} a hydrogen atom or together for a double bond, a [2,3c] oxadiazole ring, a [3,2c] isoxazole ring or one

[3,2c] pyrazole ring,

R ^{17 represents} a hydrogen atom or a methyl group,

Y stands for an oxygen or nitrogen atom, the meandering lines on R ⁴ , R ⁷ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ mean that these substituents can be in the α or β position , and their pharmaceutically acceptable salts.

The compounds according to the invention have androgenic activity.

The Cι _-4 alkyl group is a branched or unbranched alkyl radical, which is preferably formed by a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or tert-butyl group.

The C ₆ alkyl group is a branched or unbranched alkyl radical, which is preferably by a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or tert-butyl group, n- Pentyl, i-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl group is formed.

The -CC ₂ alkyl group is a branched or unbranched alkyl radical, which is preferably replaced by a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, i-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl group, an octyl, nonyl, decyl or Undecyl group is formed.

The C ₃ -s-cycloalkyl group is preferably a mono- or bicyclic group, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term aryl group stands for a substituted or unsubstituted aryl radical having preferably 6 to 15 carbon atoms, such as a phenyl group, a substituted phenyl group, such as a halophenyl group or a nitrophenyl group, or a naphthyl group. The term aryl-C - -alkyl group should preferably be an alkyl radical substituted with an aryl radical, which together preferably have 7 to 15 carbon atoms, the aryl radical and / or alkyl radical being further substituents, such as preferably a halogen atom, a hydroxyl or a methoxy - or can carry nitrile group. Particularly preferred aryl radicals are a free or aromatically substituted benzyl group, such as a benzyl group or a halogenobenzyl group.

The term halogen atom stands for a fluorine, chlorine, bromine or iodine atom.

If STEROID stands for a steroidal ring system of partial formula A, R ⁷ preferably denotes a hydrogen atom, a chlorine atom denotes a bromine atom, a hydroxyl group or a trifluoromethyl group, R ¹⁰ preferably denotes a hydrogen atom, a hydroxyl or a methyl group, R ⁹ preferably denotes a hydrogen atom or a fluorine atom , R ^{8 is} preferably a hydrogen atom or a methyl group, the methyl group being particularly preferred.

If STEROID stands for a steroidal ring system of partial formula B, R ⁷ preferably denotes a hydrogen atom, a chlorine atom, a bromine atom or a hydroxyl group or a trifluoromethyl group and R ⁸ preferably denotes a hydrogen atom or a methyl group, the methyl group being particularly preferred.

If STEROID stands for a steroidal ring system of partial formula C, R ⁷ preferably denotes a hydrogen atom, a chlorine atom, a bromine atom or a hydroxyl group or a trifluoromethyl group and R ¹¹ , R ¹² preferably denotes a hydrogen atom. In addition, a double bond in the 1,2 position is preferred. For R ¹⁷ , H or CH _{3 is} equally preferred.

If STEROID stands for a steroidal ring system of the partial formula D, R ⁷ preferably denotes a hydrogen atom, a chlorine atom, a bromine atom or a hydroxy group or a trifluoromethyl group, R ⁸ preferably denotes a hydrogen atom or a methyl group, with a methyl group being particularly preferred, and R ¹³ and R preferably together represent a double bond and Y preferably represents an oxygen atom.

If STEROID stands for a steroidal ring system of partial formula E, R ⁸ preferably denotes a hydrogen atom or a methyl group, with a methyl group being particularly preferred, R ¹² preferably stands for a hydrogen atom, R ¹³ and R ¹⁶ preferably stand for a hydrogen atom or together for one Double bond, R ¹⁵ preferably each represents a hydroxyl group or R ¹⁴ and R ¹⁵ preferably together represent a [3,2c] pyrazole ring,

If STEROID stands for a steroidal ring system of sub-formula F, R ¹¹ preferably denotes a C ₄ alkyl group or nitrile group.

R ¹ preferably denotes a methyl group or an ethyl group, the methyl group being particularly preferred.

R ² preferably denotes a hydroxyl group, a formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, [(trans-4-butylcyclohexyl) carbonyl] ~ oxy group, phenylpropionyloxy group, iso-butyryloxy group, heptanyloxy group, undecanyloxy group or phenylaminocarbonyloxy group, particularly preferably being the hydroxyloxy group,

R ³ preferably denotes a methyl, a trifluoromethyl, an ethyl, a pentafluoromethyl or an ethynyl group, the methyl, ethyl, trifluoromethyl and pentafluoromethyl group being particularly preferred.

R ⁴ preferably represents a hydrogen atom.

Particularly preferred Δ ¹⁵ -D-homosteroids are listed below: 1) 17ass-hydroxy-D-homo-androstane-4,15-dien-3-one, 2) 17ass, 4-dihydroxy-D-homo-androstane-4, 15-dien-3-one, 3) 17ass-hydroxy-4-chloro-D-homo-androstane-4,15-dien-3-one, 4) 17ass-hydroxy-4-bromo-D-homo-androstane 4,15-dien-3-one, 5) 17ass-hydroxy-4-trifluoromethyl-D-homo-androstane-4,15-dien-3-one, 6) 17ass, 11β-dihydroxy-D-homo-androstane-4,15-dien-3-one,

7) 17ass, 1β-dihydroxy-D-homo-9α-fluoro-androstane-4,15-dien-3-one,

8) 17ass-hydroxy-D-homo-androstan-1, 4, 15-trien-3-one,

9) 17ass-hydroxy-D-homo-4-chloro-androstan-1, 4.15-triene-3-one, 10) 17ass, 4-dihydroxy-D-homo-androstane-1, 4.15-triene- 3-one,

11) 17ass-hydroxy-7α-methyl-D-homo-androstan-1, 4, 15-trien-3-one,

12) 17ass-hydroxy-7α-methyl-4-chloro-D-homo-androstan-1, 4,15-trien-3-one,

13) 17ass-hydroxy-17α-methyl-androstan-4, 15-dien-3-one,

14) 17ass-hydroxy-17aα-trifluoromethyl-7α-methyl-androstan-4,15-dien-3-one, 15) 17ass, 4-dihydroxy-17aα-trifluoromethyl-androstan-4, 15-dien-3-one,

16) 17ass-hydroxy-17a-trifluoromethyl-4-chloro-androstane-4, 15-dien-3-one,

17) 17ass-hydroxy-7α-methyl-D-homo-androstan-4, 15-dien-3-one,

18) 17ass-hydroxy-17α-pentafluoroethyl-androstan-4, 15-dien-3-one,

19) 17ass, hydroxy-D-homo-estra-4,15-dien-3-one, 20) 17ass, 4-dihydroxy-D-homo-estra-4,15-dien-3-one,

21) 17ass-hydroxy-4-chloro-D-homo-estra-4,15-dien-3-one,

22) 17ass-hydroxy-4-bromo-D-homo-estra-4,15-dien-3-one,

23) 17ass-hydroxy-4-trifluoromethyl-D-homo-estra-4,15-dien-3-one,

24) 17ass-hydroxy-17aα-methyl-D-homo-estra-4,15-dien-3-one, 25) 17ass-hydroxy-17aα-methyl-4-chloro-D-homo-estra-4, 15- dien-3-one,

26) 17ass-hydroxy-17aα-trifluoromethyl-D-homo-estra-4, 15-dien-3-one,

27) 17ass-hydroxy-17aα-pentafluoroethyl-D-homo-estra-4,15-dien-3-one,

28) 17ass-hydroxy-7α-methyl-D-homo-estra-4,15-dien-3-one,

29) 17ass-hydroxy-7α-methyl-4-chloro-D-homo-estra-4,15-dien-3-one, 30) 17ass-hydroxy-D-homo-estra-1, 4, 5-triene 3-one,

31) 17ass-hydroxy-D-homo-4-chloro-estra-1, 4,15-trien-3-one,

32) 17ass, 4-dihydroxy-D-homo-estra-1, 4,15-trien-3-one,

33) 17ass-hydroxy-7α-methyl-D-homo-estra-1, 4,15-trien-3-one,

34) 17ass-hydroxy-7α-methyl-4-chloro-D-homo-estra-1, 4,15-trien-3-one, 35) 13-ethyl-17ass-hydroxy-D-homo-gona-4, 15-dien-3-one,

36) 13-ethyl-17ass-hydroxy-4-chloro-D-homo-gona-4,15-dien-3-one,

37) 13-ethyl-17ass-hydroxy-7α-methyl-D-homo-gona-4,15-dien-3-one,

38) 13-ethyl-17ass-hydroxy-17aα-methyl-D-homo-gona-4,15-dien-3-one, 39) 13-ethyl-17ass-hydroxy-17aα-methyl-4-chloro-D-homo-gona-4, 15-dien-3-one, 40) 13-ethyl-17ass-hydroxy-D-homo-gona- 1, 4,15-trien-3-one, 41) 13-ethyl-17ass-hydroxy-4-chloro-D-homo-gona-1, 4,15-trien-3-one, 42) 13-ethyl- 17ass-hydroxy-7α-methyl-D-homo-gona-1,4,15-trien-3-one, 43) 13-ethyl-17ass-hydroxy-7α-methyl-4-chloro-D-homo-gona- 1, 4,15-trien-3-one, 44) 17ass-hydroxy-D-homo-5α-androst-15-en-3-one, 45) 2-oxa-17ass-hydroxy-D-homo-5α- androst-15-en-3-one 46) 17ass-hydroxy-D-homo-5α-androstan-1, 15-dien-3-one, 47) 2-hydroxymethylene-17ass-hydroxy-D-homo-5α-androst -15-en-3-one,

Another object of the invention is a technically simple and effective process for the preparation of Δ ¹⁵ -D-homosteroids of the general formula (I).

Known compounds of the general formula (II) (M.A. Avery et al., Steroids, 1990, 55, 59-64; A. Fürst et al., 1976, US 3,984,476.)

in R ¹ and STEROID, which have the meaning given above, in the presence of acids, such as, for example, p-toluenesulfonic acid, with acylating agents, such as, for example, isopropenyl acetate (Hosoda, H. et al., Chem. Phar. Bull., 23, 1975, 3141-3145), acetic anhydride (Rasmusson, GH, Arth, GE, Steroids, 22, 1973, 107-111) or the like to the dienole acetates in a known manner and then using reducing agents, such as NaBH, to give the corresponding 17ass hydroxy-D -homo-Δ ¹ asteroids reduced.

Known steroid base bodies can be used to prepare the compounds of general formula II with substructures A to F. The following steroid base bodies can be used, for example: For the steroid base body A: androst-4-en-3,17-dione and dehydroepiandrosterone. For the steroid body B: estrone, 7-methyltrone. For the steroid base bodies C, D and E: epiandrosterone. For the steroid base F: 5 -Androst-2-en- 17-one made of epiandrosterone (US-A-

3,098,851). The functional groups contained in the partial structures of the starting materials for the steroid base bodies A to F can optionally be protected by methods known to the person skilled in the art.

Thus, keto groups in the starting materials of substructures A to F can be protected as ketals or thioacetals by methods known to the person skilled in the art. The substituents R ⁷ to R ^{15 can be introduced} into the partial structures A to F either before or after the incorporation of the D-homo-Δ ¹⁵ cycle by methods known to the person skilled in the art. For the formation of pharmaceutically acceptable salts of the compounds of the general formula I according to the invention, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids include acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, oxalic acid, Salicylic acid, tartaric acid, citric acid, lactic acid, malic acid, mandelic acid, cinnamic acid and methanesulfonic acid.

The compounds of the invention have androgenic activity, as shown in Table 1 below.

Table 1: Relative binding affinities / RBA on the androgen receptor compared to testosterone and methyltrienolone

17ass-hydroxy-7α-methyl-D-homoestra-4,16-dien-3-one is described as an androgen with antigonadotropic properties in Steroids, 1990, 55, 59-64. However, 17ass-hydroxy-7α-methyl-D-homoestra-4,16-dien-3-one shows only a small amount

Receptor binding affinity for the androgen receptor of 2% (reference DHT = 100%).

Completely unexpectedly and surprisingly, the Δ ¹⁵ -D homo-

Steroids have a much higher binding affinity to the androgen receptor. They bind Δ ¹⁵ -D-homo compounds in comparison with 17ass-hydroxy-7α-methyl-D-homoestra-4,16-dien-3-one (Steroids 1990, 55, 59-64) with> 12% (reference DHT = 100%) to the androgen receptor. The androgenic activity of the Δ ¹⁵ -D-homo-steroids according to the invention is therefore different from that of the 17ass-hydroxy-7-methyl-D-homoestra-4,16-dien-3-one known from the literature (steroids, 1990, 55, 59-64).

These test results open up a variety of compounds for the invention

Possibilities for fertility control in men and women, hormone replacement therapy (HRT) in men and women or the treatment of hormone-related diseases in men and women, such as endometriosis, breast cancer or hypogonadism.

The present invention therefore also relates to pharmaceutical compositions which contain at least one Δ ¹⁵ -D-homosteroid of the general formula (I), optionally together with pharmaceutically acceptable auxiliaries and carriers, and also the use of these compounds, inter alia, for therapy or for preparation of pharmaceutical preparations, inter alia for the therapy of the aforementioned clinical pictures.

These pharmaceutical compositions and medicaments can be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular application. In addition to the usual carriers and / or diluents, they contain at least one compound of the general formula I. The medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. The preferred preparations are in a dosage form which is suitable for oral administration. Dosage forms of this type are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or even depot forms.

Of course, parenteral preparations such as injection solutions are also suitable. Suppositories and agents for vaginal use may also be mentioned as preparations.

Corresponding tablets can be mixed, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents Achieving a depot effect such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum tarabicum, talc, titanium oxide or sugar. The coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.

Solutions or suspensions with the compounds of general formula I according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z. B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing the compounds of the general formula I can be prepared, for example, by the compound (s) of the general. Formula I mixed with an inert carrier such as milk sugar or sorbitol and encapsulated in gelatin capsules.

Suitable suppositories can be produced, for example, by mixing them with suitable carriers such as neutral fats or polyethylene glycol or their derivatives.

The following examples illustrate the present invention without restricting it.

Example 1 17ass-hydroxy-D-homoestra-4,15-dien-3-one stage 1

3-methoxy-17a-acetoxy-D-homoestra-1, 3.5 (10), 15.17-pentaen 4.0 g 3-methoxy-D-homoestra-1, 3.5 (10), 16-tetraen-17a -One are dissolved in 40 ml of acetic anhydride and 40 ml of isopropenyl acetate. After adding 2.0 g of p-toluenesulfonic acid, the mixture is heated to 80 ° C. for 48 hours. Then with sat. NaHCO ₃ solution neutralized. The substance is extracted with ethyl acetate, the organic phase with sat. Washed NaCl solution, dried over MgSO ₄ , filtered, concentrated and chromatographed on silica gel. 3-Methoxy-17a-acetoxy-D-homoestra-1, 3.5 (10), 15.17-pentaen is obtained.

H-NMR (CDCI ₃ ): 0.96 (s, 3H, H-18), 2.20 (s, 3H, OAc), 3.78 (s, 3H, OCH ₃ ), 5.65-6.05 (m, 3H, H-15, H-16, H-17)

Step 2 3-methoxy-17ass-hydroxy-D-homoestra-1, 3.5 (10), 15-tetraene

6.5 g of 3-methoxy-D-homo-estra-1, 3.5 (10), 15, 17-pentaen-17a-yl acetate are dissolved in 150 ml of methanol and 75 ml of THF. 5.0 g of NaBH are added in portions with stirring at -20 ° C. and the mixture is stirred for 3 hours. The mixture is then concentrated to 1/5 and 250 ml of water are added. Then the remaining organic solvents distilled off. The substance is filtered off, washed with water, dried in vacuo and chromatographed on silica gel. 3-Methoxy-17ass-hydroxy-D-homoestra-1, 3.5 (10), 15-tetraene is obtained.

¹ H-NMR (CDCI ₃ ): 0.81 (s, 3H, H-18), 3.64 (m, 1 H, H-17a), 3.77 (s, 3H, OCH ₃ ), 5.60-5.80 (m, 2H, H-15, H-16)

Step 3 3-methoxy-17ass-hydroxy-D-homoestra-1, 3.5 (10), 15-triene

5.0 g of 3-methoxy-17ass-hydroxy-D-homoestra-2,5 (10), 15-tetraene, dissolved in 35 ml of THF and 15 ml of 1-methoxy-2-propanol, are dissolved in a solution at -70 ° C added dropwise from 100 ml of liquid ammonia, 10 ml of THF and about 0.3 g of sodium. After decolorization, the addition is interrupted and sodium is added again. After the addition of 2.5 g of Na, the reaction is complete. 2.5 ml of isopropanol are added and 8 g of solid NHCl. The ammonia is evaporated with gentle heating. After adding 250 ml of cold water, the steroid is filtered off, washed neutral with water and dried in vacuo. 3-Methoxy-17ass-hydroxy-D-homoestra-1, 3.5 (10), 15-triene is obtained.

Level 4

17aß-hydroxy-D-homoestra-4,15-dien-3-one

4.6 g of 3-methoxy-17ass-hydroxy-D-homoestra-1, 3.5 (10), 15-triene are dissolved in 150 ml of acetone. 8 ml of 5% aqueous hydrochloric acid are added dropwise with stirring at room temperature. After 1h, 50 ml are sat. NaHCO solution and 150 ml of water added. The acetone is then largely distilled off. The substance is filtered off, washed with water, dried in vacuo and chromatographed on silica gel. 17ass-hydroxy-D-homoestra-4,15-dien-3-one is obtained. ¹ H NMR (CDCI ₃ ): 0.84 (s, 3H, H-18), 3.57 (m, 1 H, H-17a), 5.57-5.72 (m, 2H, H-15, H-16), 5.84 (s, 1H, H-4)

Example 2 17ass-hydroxy-D-homoandrost-4,15-dien-3-one step 1

3β-acetoxy-17a-acetoxy-D-homoandrostane-5 ₁ 15.17-triene

6.0 g of 3β-acetoxy-D-homoandrostan-5,16-dien-17a-one are dissolved in 70 ml of acetic anhydride and 70 ml of isopropenyl acetate. After adding 4.0 g of p-toluenesulfonic acid, the mixture is heated to 80 ° C. for 48 hours. Then with sat. NaHCO ₃ solution neutralized. The substance is extracted with ethyl acetate, the organic phase with sat. Washed NaCl solution, dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. 3β-Acetoxy-17a-acetoxy-D-homoandrostane-5,15,17-triene is obtained.

¹ H NMR (CDCI ₃ ): 0.95 (s, 3H, H-18), 1.02 (s, 3H, H-19), 2.04 (s, 3H, OAc), 2.18 (s, 3H, OAc), 4.60 (m, 1 H, H-3), 5.41 (m, 1 H, H-6), 5.60-5.98 (m, 3H, H-15, H-16, H-17)

Level 2

3.beta.-acetoxy-17aß-D-homoandrostan-5,15-dien-hydroxy

5.0 g of 3β, 17a-diacetoxy-D-homoandrost-4,15,17-triene are dissolved in 200 ml of methanol and 150 ml of THF. 5.0 g of NaBH _{4 are} added in portions with stirring at -20 ° C. and the mixture is stirred for 2 hours. Then 100 ml are sat. NH CI solution added. The organic solvents are then distilled off. After adding 250 ml of water, the substance is filtered off, washed with water, dried in vacuo and chromatographed on silica gel. 3β-Acetoxy-17ass-hydroxy-D-homoandrostane-5,15-diene is obtained.

level 3

3β-Acetoxy-D-homoandrostane-5, 15-diene-17ass-tetrahydropyranyl ether 4.25 g of 3ß-acetoxy-17ass-hydroxy-D-homoandrostane-5,15-diene are dissolved in 75 ml of methylene chloride. 7.5 ml. In succession are stirred

Dihydropyran and 500 mg pyridinium tosylate added. After 3 hours with 10% NaHCO ₃ solution and sat. Washed NaCl solution, dried over MgSO ₄ , filtered and concentrated. 3β-Acetoxy-D-homoandrostane-5,15-diene-17ass-tetrahydropyranyl ether is obtained. Level 4

3ß-Hvdroxy-D-homoandrostan-5,15-dien-17ass-tetrahvdropyranylether 5.2 g of 3ß-acetoxy-D-homoandrostane-5,15-dien-17ass-tetrahydropyranylether are dissolved in 175 ml of methanol and 125 ml of THF. 7.5 g of K ₂ CO ₃ and 2.5 ml of water are added with vigorous stirring. After 3.5 hours, the mixture is concentrated to about 1/6.

Then 250 ml of water are added, the substance is filtered off, washed with water and dried in vacuo. 3β-Hydroxy-D-homoandrostane-5, 15-diene-17ass-tetrahydropyranyl ether is obtained.

Level 5

3-Keto-D-homoandrostane-4, 15-diene-17ass-tetrahydropyranyl ether 4.5 g of 3β-hydroxy-D-homoandrostane-5.15-diene-17ass-tetrahydropyranylether are dissolved in 125 ml of toluene under argon. After adding 1.6 g of Al (O-iPr) ₃ , the mixture is heated to 110 ° C. for 2.5 hours. At RT, it is washed twice with 250 ml of 1 M K-Na tartrate solution. The aqueous phases are extracted with ethyl acetate. The united org. Phases are with sat. Washed NaCl solution, dried over MgSO ₄ , filtered and concentrated in vacuo. 3-Keto-D-homoandrostane-4,15-diene-17ass-tetrahydropyranyl ether is obtained.

Level 6

17ass-hydroxy-D-homoandrostan-4, 15-dien-3-one

14 g of crude product of 3-keto-D-homoandrostane-4,15-diene-17ass-tetrahydropyranyl ether are dissolved in 100 ml of acetone. 10 ml of 10% hydrochloric acid are added dropwise at RT.

After 2 hours, 50 ml are sat. NaHCO ₃ solution added. The reaction mixture is concentrated to about 1/3. Then 150 ml of water are added and the precipitated substance is filtered off, washed with water, dried in vacuo and chromatographed on silica gel. 17ass-hydroxy-D-homoandrostan-4,15-dien-3-one is obtained.

¹ H NMR (CDCI ₃ ): 0.82 (s, 3H, H-18), 1.20 (s, 3H, H-19), 3.54 (m, 1 H, H-17a), 5.55-5.67 (m, 2H , H-15, H16), 5.74 (s, 1 H, H-4)

Example 3 17ass-hydroxy-4-chloro-D-homoandrostan-4,15-dien-3-one step 1

17ass-hydroxy-4 £ ,, 5-epoxy-D-homoandrost-15-en-3-one

2.0 g of 17ass hydroxy-D-homoandrost-4,15-dien-3-one are dissolved in 80 ml of methanol and 20 ml of hydrogen peroxide solution (35%) are added at 0 ° C. 4 ml of 10% sodium hydroxide solution are added with stirring and the mixture is stirred for 3 hours. The reaction solution is concentrated to 50 ml, then 50 ml of dichloromethane and 25 ml of water are added and the organic phase is separated off. It is washed with half-concentrated thiosulfate solution, dried and concentrated to dryness. The residue obtained consists of a mixture of 4α, 5α- or 4ß, 5ß-epoxides and is used in the subsequent step without further purification.

Level 2

17ass-hydroxy-4-chloro-D-homoandrostan-4, 15-dien-3-one

1.93 g of epoxy mixture (stage 1) are dissolved in 300 ml of acetone and 17 ml of concentrated hydrochloric acid are added at 0 ° C. After 2 hours, the mixture is neutralized with sodium carbonate solution and the acetone is drawn off. The residue is extracted with dichloromethane. The organic extracts are dried and concentrated. After crystallization from ethyl acetate, 17ass-hydroxy-4-chloro-D-homoandrostan-4,15-dien-3-one is obtained. ¹ H NMR (COCL ₃ ): 0.82 (s, 3H, H-18), 1.25 (s, 3H, H-19), 3.57 (m, 1 H, H-17a), 5.64 (m , 2H, H-15, H-16)

Example 4 17ass-hydroxy-7-methyl-D-homoandrostan-4,15-dien-3-one Step 1 17ass-hydroxy-D-homoandrostane-4,6,15-trien-3-one

2.5 g of 17ass-hydroxy-D-homoandrostan-4,15-dien-3-one is refluxed with 2.5 g of chloranil in 80 ml of tert-butanol for 30 minutes. Allow to cool and evaporate to dryness. The residue is chromatographed on silica gel.

Level 2

17aß-hydroxy-7α-methyl-D-homoandrostan-4,15-dien-3-one

100 ml of THF are added to a solution of methyl magnesium iodide (prepared from 1.75 g of magnesium and 5 ml of methyl iodide in 25 ml of diethyl ether), the mixture is cooled to -5 ° C. and 0.35 g of copper (l) chloride is added. It is cooled to -20 ° C and then a solution of 1.3 g of 17ass-hydroxy-D-homoandrostane-4,6,15-trien-3-one was added dropwise in 20 ml of THF. After 2 hours, pour on ice water / 2N sulfuric acid and extract with 3 times 30 ml of methylene chloride. The organic extract is dried and concentrated. The residue is chromatographed on silica gel. For further purification, the product is recrystallized from ethyl acetate.

¹ H-NMR (CDCI ₃ ): 0.77 (d, J = 7Hz, 3H, H-7Me) 0.83 (s, 3H, H-18), 1.20 (s, 3H, H-19), 3.57 (m, 1 H, H-17a), 5.63 (m, 2H, H-15, H-16), 5.74 (s, 1 H, H-4)

Example 5 17ass-hydroxy-4-chloro-D-homoestra-4,15-dien-3-one

step 1

17ass-hydroxy-4ζ, 5; -epoxy-D-homoestr-15-en-3-one

The preparation is carried out analogously to 17ass-hydroxy-4ξ, 5ξ-epoxy-D-homoandrost-15-en-3-one.

The residue obtained consists of a mixture of 4α, 5 - or 4ß, 5ß-epoxides and is used in the next stage without further purification.

Level 2

17ass-hydroxy-4-chloro-D-homoestra-4, 15-dien-3-one

The preparation is made from 17ass-hydroxy-4-chloro-D-homoandrostan-4,15-dien-3-one analogous to 17ß-hydroxy-17α-trifluoromethyl-4-chloro-androst-4-en-3-one. ¹ H NMR (CDCI3): 0.84 (s, 3H, H-18), 3.57 (m, 1 H, H-17a), 5.58-5.70 (m, 2H, H-15, H-16)

Example 6 17ass-hydroxy-D-homo-5c6-androst-15-en-3-one

step 1

33-17a-Diacetoxy-D-homo-5-androstane-15.17-diene 14.5 g of 3β-acetoxy-D-homoandrostane-5.16-diene-17a-one are dissolved in 200 ml of acetic anhydride and 200 ml of isopropenyl acetate , After adding 5.0 g of p-toluenesulfonic acid, the mixture is heated under reflux for 16 hours. The substance comes with

Extracted ethyl acetate, the organic phase with sat. Washed NaCI solution and dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. 3β-Acetoxy-17a-acetoxy-D-homo-5a-androstane-15,17-diene is obtained. ¹ H-NMR (CDCI ₃ ): 0.82 (s, 3H, H-18), 0.92 (s, 3H, H-19), 2.02 (s, 3H, Oac), 2.17 (s. 3H, = Ac), 4.68 (m, 1H, H-3), 5.60-5.92 (m, 3H, H-15, H-16, H-17)

Level 2

3β-acetoxy-17ass-hydroxy-D-homo-5-androstan-15-ene

8.5 g of 3β, 17a-diacetoxy-D-homo-5α-androstane-15,17-diene are dissolved in 360 ml of methanol and 270 ml of THF. While stirring at -20 ° C., 6.75 g of NaBH _{4 are} added in portions and the mixture is stirred at 0 ° C. for 2 hours. Then 200 ml are sat. NH ₄ CI solution is added and the mixture is stirred at 0 ° C. for 2 hours. Then 200 ml are sat. NH ₄ CI solution added. The organic solvents are then distilled off. After adding 100 ml of water, the substance is filtered off, washed with water, dried in vacuo and chromatographed on silica gel. 3β-Acetoxy-17β-hydroxy-D-homo-5α-androst-15-ene is obtained. ¹ H NMR (CDCL ₃ ): 0.76 (s, 3H, H-18), 0.83 (s, 3H, H- 9), 2.02 (s, 3H, OAc), 3.53 (m, 1 H, 17 aH) , 4.69 (m, 1H, H-3), 5.60-5.65 (m, 2H, H-15, H-16)

Step 3 3ß-acetoxy-D-homo-5α-androst-15-en-17 aß-tetrahydropyranylether

7.60 g of 3β-acetoxy-17-ab-hydroxy-D-homo-5a-androst-15-ene are dissolved in 135 ml of methylene chloride. 13.5 ml of dihydropyran and 900 mg of pyridinium tosylate are added in succession with stirring at RT. After 3 hours with 10% NaHCO ₃ solution and sat. Washed NaCl solution, dried over MgSO ₄ , filtered and concentrated. 3β-Acetoxy-D-homoandrostane-5,15-diene-17ass-tetrahydropyranyl ether is obtained.

Step 4 3ß-Hydroxy-D-homo-5α-androst-15-en-17 aß-tetrahydropyranylether

12.0 g of 3β-acetoxy-D-homo-5α-androst-15-en-17 aß-tetrahydropyranyl ether are dissolved in 150 ml of methanol and 100 ml of THF. 15 g of K ₂ CO ₃ and 5 ml of water are added with vigorous stirring. After 3.5 hours the mixture is concentrated to about 1/6, with Washed water and dried in vacuo. 3β-Hydroxy-D-homo-5α-androst-15-en-17 aß-tetrahydropyranyl ether is obtained.

Step 5 3-Keto-D-homo-5α-androst-15-en-17 aß-tetrahydropyranylether

9.2 g of 3β-hydroxy-D-homo-5α-androst-15-en-17-aß-tetrahydropyranyl ether are dissolved in 200 ml of toluene under argon. After adding 3.0 g of Al (O-iPr) ₃ , the mixture is heated to 110 ° C. for 1.5 hours. At RT, it is washed twice with 250 ml of 1 M K-Na tartrate solution. The aqueous phases are extracted with ethyl acetate. The combined org. Phases are recorded with Washed NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. 3-Keto-D-homo-5α-androst-15-en-17ass-tetrahydropyranyl ether is obtained.

Level 6

17aß-hydroxy-D-homo-5α-androst-15-en-3-one

15.7 g of crude product of 3-keto-D-homo-5α-androst-15-en-17ass-tetrahydropyranyl ether are dissolved in 100 ml of acetone. 10 ml of 10% hydrochloric acid are added dropwise at RT.

After 2 hours, 50 ml are sat. NaHCO ₃ solution added. The reaction mixture is concentrated to about 1/3. Then 150 ml of water are added and the precipitated substance is filtered off, washed with water, in

Dried vacuum and chromatographed on silica gel. 17ass-hydroxy-D-homo-5α-androst-15-en-3-one is obtained.

¹ H NMR (CDCI ₃ ): 0.76 (s, 3H, H-18), 1.02 (s, 3H, H-19), 3.53 (m, 1 H, H-17a), 5.57-5.65 (m , 2H, H-15, H16)

Example 7 2-hydroxymethylene-17ass-hydroxy-D-homo-5α-androst-15-en-3-one

2.1 g 17ass-hydroxy-D-homo-5α-androst-15-en-3-one are placed under protective gas in 80 ml of toluene. Then 2.1 g NaOH and 4.0 ml ethyl formate are added. After 1 h, 2 ml of methanol are added dropwise. 50 ml of water are then added and the mixture is acidified with 5N HCl. It is extracted with ethyl acetate. The org. Phase is washed with NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated. Chromatography is carried out on silica gel. 2-Hydroxymethylene-17-aß-hydroxy-D-homo-5α-androst-15-en-3-one is obtained.

1H NMR (CDCI ₃ ): 0.78 (s, 3H, H-18), 0.79 (s, 3H, H-19), 3.55 (m, 1H, H-17a), 5.55-5.67 (m, 2H, H -15, H16), 8.64 (s, 1 H, = CH (OH)), 14.37 (s, 1 H, = CH (OH))

Claims

claims

1. Δ ¹⁵ -D-homosteroids of the general formula I,

characterized in that and

R ² for a hydroxy group, a group OC (O) -R ²⁰ , OC (O) NH-R ²⁰ or OR ²⁰ , wherein R ^{20 is} a Cι_ι ₂ alkyl group, a C _3-8 cycloalkyl group, an aryl group or an aryl -C _-4 alkyl group, which is optionally substituted, and R ³ represents a hydrogen atom or a Cι _-6 alkyl, vinyl, ethynyl, or C _n F _{2n + 1} - group, with n = 1, 2, 3 and R ⁴ for a hydrogen atom or

R ² represents a hydrogen atom or a Cι _-6 alkyl, vinyl, ethynyl, or C _n F _2n + ι- group, with n = 1, 2, 3,

R ^{3 represents} a hydroxy group, an OC (O) -R ²⁰ , OC (O) NH-R ²⁰ or OR ^{20 group} , where R ^{20 represents} a C _1-12 alkyl group, a C _3-8 cycloalkyl group, an aryl group or represents an aryl-C _-4 -alkyl group which is optionally substituted, and R ^{4 represents} a hydrogen atom or

R ² and R ³ together for an oxygen atom and R ⁴ for a hydrogen atom or R * is a hydroxy group, a group OC (O) -R ^20, OC (O) NH-R ²⁰ or OR ²⁰ wherein R ²⁰ is a Cι.ι ₂ alkyl group, a C _{_3-8} cycloalkyl group, an aryl group or an aryl -C _-4 alkyl group, which is optionally substituted, means, and

R ³ and R ⁴ together form a double bond and

STEROID stand for a steroidal ABC partial ring system of the formulas A, B, C, D, E and F:

B

where in A and C in the 1, 2 position there can be an additional double bond and in B in the 9, 10 position and 11, 12 position there can be one or two additional double bonds, R ^{7 is} a hydrogen atom, a halogen atom, a hydroxyl group or a C. _n F _{2n +} ι- group with n = 1, 2, 3 means

X represents an oxygen atom, two hydrogen atoms or a hydroxyimino group, R ^{8 represents} a hydrogen atom, a methyl or ethyl group, R ^{9 represents} a hydrogen atom or a halogen atom or together with R ^{10 represents} a double bond,

R ^{10 represents} a hydrogen atom, a hydroxyl group, a methyl or ethyl group or together with R ^{9 represents} a double bond, R ^{11 represents} a hydrogen atom, a a nitrile group, one

Hydroxymethylene or formyl group means

R ^{12 represents} a hydrogen atom, a C ₄ alkyl group or a nitrile group,

R ¹¹ and R ^{12 together} with the meanings mentioned above together

Are methylene bridge, R ^{13 is} a hydrogen atom or together with R ^{7 is} a double bond,

R ^{16 represents} a hydrogen atom or together with R ¹³ a double bond,

[3,2c] pyrazole ring and R ^{17 represents} a hydrogen atom or a methyl group,

Y stands for an oxygen or nitrogen atom, the meandering lines on R ⁴ , R ⁷ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ mean that these substituents can be in the α or β position ,

2. Compounds according to claim 1, characterized in that R ^{1 represents} a methyl group or an ethyl group.

3. Compounds according to claim 1 or 2, characterized in that R ^{2 is} a hydroxy group, a formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, [(trans-4-butylcyclohexyl) carbonyl] oxy group, phenylpropionyloxy group, iso-butyryloxy group, heptanyloxy group, undecanyloxy group or Phenylaminocarbonyloxygruppe means.

4. Compounds according to any one of claims 1 to 3, characterized in that R ^{3 represents} a methyl, a trifluoromethyl, an ethyl, a pentafluoroethyl or an ethynyl group.

5. Compounds according to any one of claims 1 to 4, characterized in that R ^{4 represents} a hydrogen atom.

6. Compounds according to any one of claims 1 to 5, characterized in that STEROID stands for a steroidal ring system of partial formula A, wherein R ^{7 is} a hydrogen atom, a chlorine atom, a bromine atom, a hydroxyl group or a trifluoromethyl group, R ^{10 is} a hydrogen atom, a hydroxyl group or one and R ^{9 represent} a hydrogen atom or a fluorine atom and R ^{8 represent} a hydrogen atom or a methyl group.

7. Compounds according to any one of claims 1 to 5, characterized in that STEROID stands for a steroidal ring system of partial formula B, wherein R ^{7 is} a hydrogen atom, a chlorine atom, a bromine atom, a hydroxy group or a trifluoromethyl group and R ^{8 is} a hydrogen atom or a methyl group represent.

8. Compounds according to any one of claims 1 to 5, characterized in that STEROID stands for a steroidal ring system of partial formula C, wherein R ^{7 is} a hydrogen atom, a chlorine atom, a bromine atom or a hydroxy group or a trifluoromethyl group and R ¹¹ and R ¹² each Represents hydrogen atom and that in 1, 2 position is a double bond.

9. Compounds according to any one of claims 1 to 5, characterized in that STEROID stands for a steroidal ring system of partial formula D, wherein R ^{7 is} a hydrogen atom, a chlorine atom, a bromine atom, a hydroxy group or a trifluoromethyl group and R ^{8 is} a hydrogen atom or a methyl group represents, and R ¹³ and R ⁷ together represent a double bond and Y represents an oxygen atom.

10. Compound according to claim 1 to 5, characterized in that STEROID stands for a steroidal ring system of the partial formula E, wherein R ^{8 is} a hydrogen atom or a methyl group, R ^{12 is} a hydrogen atom, R ¹³ and R ^{16 are} each a hydrogen atom or together a double bond, R ^{15 is} a hydroxy group or R ¹⁴ and R ¹⁵ together represent a [3,2c] pyrazole ring.

11. Compounds according to any one of claims 1 to 5, characterized in that STEROID stands for a steroidal ring system of partial formula F, wherein R ^{11 is} a or nitrile group.

12. Compounds according to any one of claims 1 to 11, namely 17ass-hydroxy-D-homo-androstane-4.15-diene-3-one, 17ass, 4-dihydroxy-D-homo-androstane-4.15-diene 3-one, 17ass-hydroxy-4-chloro-D-homo-androstane-4.15-diene-3-one, 17ass-hydroxy-4-bromo-D-homo-androstane-4.15-diene-3- on, 17ass-hydroxy-4-trifluoromethyl-D-homo-androstane-4.15-dien-3-one, 17ass, 11ß-dihydroxy-D-homo-androstane-4.15-dien-3-one, 17ass, 11β-dihydroxy-D-homo-9α-fluoro-androstane-4,15-dien-3-one, 17ass hydroxy-D-homo-androstane-1, 4, 15-trien-3-one, 17ass hydroxy -D-homo-4-chloro-androstan-1, 4.15-trien-3-one, 17ass, 4-dihydroxy-D-homo-androstan-1, 4.15-trien-3-one, 17ass-hydroxy -7α-methyl-D-homo-androstan-1, 4,15-trien-3-one, 17ass-hydroxy-7α-methyl-4-chloro-D-homo-androstan-1, 4,15-trien-3 -on, 17ass-hydroxy-17α-methyl-androstan-4, 15-dien-3-one, 17ass-hydroxy-17aα-trifluoromethyl-7-methyl-androstan-4,15-dien-3-one, 17ass, 4 -Dihydroxy-17aα-trifluoromethyl-androstane-4,15-dien-3-one, 17ass-hydroxy-17aα-trifluoromethyl-4-chloro-androstane-4,15- dien-3-one, 17ass-hydroxy-7α-methyl-D-homo-androstan-4,15-dien-3-one, 17ass-hydroxy-17α-pentafluoroethyl-androstan-4, 15-dien-3-one, 17ass-hydroxy-D-homo-estra-4,15-dien-3-one, 17ass, 4-dihydroxy-D-homo-estra-4,15-dien-3-one, 17ass-hydroxy-4-chloro D-homo-estra-4,15-dien-3-one, 17ass-hydroxy-4-bromo-D-homo-estra-4,15-dien-3-one, 17ass-hydroxy-4-trifluoromethyl -D- homo-estra-4,15-dien-3-one, 17ass-hydroxy-17aα-methyl-D-homo-estra-4,15-dien-3-one, 17ass-hydroxy-17aα-methyl-4-chloro D-homo-estra-4,15-dien-3-one, 17ass-hydroxy-17aα-trifluoromethyl-D-homo-estra-4,15-dien-3-one, 17ass-hydroxy-17aα-pentafluoroethyl-D- homo-estra-4, 15-dien-3-one, 17ass-hydroxy-7-methyl-D-homo-estra-4, 15-dien-3-one, 17ass-hydroxy-7α-methyl-4-chloro D-homo-estra-4,15-dien-3-one, 17ass-hydroxy-D-homo-estra-1, 4,15-trien-3-one, 17ass-hydroxy-D-homo-4-chloro estra-1, 4,15-trien-3-one, 17ass, 4-dihydroxy-D-homo-estra-1, 4,15-trien-3-one, 17ass-hydroxy-7α-methyl-D-homo- estra-, 4, 15-trien-3-one, 17ass-hydroxy-7α-methyl-4-chloro-D-homo-estra-1, 4,15-trien-3-one, 13-ethyl-17ass-hydroxy -D-homo-gon-4,15-dien-3-one, 13-ethyl-17ass-hydroxy-4-chloro-D-homo-gon-4, 15-dien-3 -on, 13-ethyl-17ass-hydroxy-7α-methyl-D-homo-gon-4,15-dien-3-one, 13-ethyl-17ass-hydroxy-17aα-methyl-D-homo-gon-4 , 15-dien-3-one, 13-ethyl-17ass-hydroxy-17aα-methyl-4-chloro-D-homo-gon-4,15-dien-3-one, 13-ethyl-17ass-hydroxy-D -homo-gon-1, 4,15-trien-3-one, 13-ethyl-17ass-hydroxy-4-chloro-D-homo-gon-1, 4, 15-trien-3-one, 13-ethyl -17ass-hydroxy-7α-methyl-D-homo-gon-1, 4,15-trien-3-one, 13-ethyl-17ass-hydroxy-7α-methyl-4-chloro-D-homo-gon-1 , 4,15-trien-3-one, 17ass-hydroxy-D-homo-5α-androst-15-en-3-one, 2-oxa-17ass-hydroxy-D-homo-5α-androst-15-ene -3-one 17ass-hydroxy-D-homo-5α-androstan-1, 15-dien-3-one, or 2-hydroxymethylene-17ass-hydroxy-D-homo-5α-androst-15-en-3-one ,

13. A process for the preparation of compounds according to any one of claims 1 to 12 with the general formula I. and their pharmaceutically acceptable salts, wherein a compound of general formula II

in which R ¹ and STEROID have the meaning given in claims 1 to 12, reacted in the presence of acids with acylating agents to give the dienol acetates and then reduced with reducing agents to give the corresponding 17ass hydroxy-D-homo-Δ ¹⁵ steroids and then the Introduces substituents R ¹ , R ² , R ³ and R ⁴ with the meanings given in claims 1 to 12.

14. The method according to claim 13, wherein the following steroid base bodies are used to prepare the compounds of the general formula II with the partial structures A to F: A: androst-4-en-3,17-dione and dehydroepiandrosterone, B: estrone, 7α-methyltrone, C, D and E: epiandrosterone and F: 5α-androst-2-en-17-one from epiandrosterone.

15. The method according to claim 13 or 14, wherein the functional groups contained in the partial structures of the starting materials for the steroid base bodies A to F are protected.

16. The method according to claim 15, wherein keto groups in the starting materials of substructures A to F are protected as ketals or thioacetals.

17. Pharmaceutical compositions containing at least one compound according to one of claims 1 to 12.

18. Use of the compounds according to one of claims 1 to 12 for the manufacture of medicaments of hormone replacemant therapy in men and women.

19. Use of the compounds according to any one of claims 1 to 12 for the manufacture of medicaments for fertility control in men and women.

20. Uses of the compound according to one of claims 1 to 12 for the manufacture of medicaments for the treatment of hormone-related diseases in men and women.

21. Use of the compounds according to claim 20 for the manufacture of medicaments for the treatment of endometriosis, breast cancer and hypogonadism.