RS20060104A - Delta 15-d-homosteroids having an androgenic effect - Google Patents

Abstract

The invention relates to 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

A<15->D- Homosteroids of androgenic action

The invention relates to A<15->D- Homosteroids in general

the procedure for obtaining them, pharmaceutical compositions containing these compounds as well as their application for obtaining drugs with androgenic action.

A15-D- Homosteroids of the ester or androstane series are not known so far. However, they are known from US-PS 4, 155,918 as well as Avery et al., Steroids, 1990, vol.55, S. 59 - 64) A<16->D- Homosteroids possessing androgenic as well as antigonadotropic activity.

The task of the proposed invention is to make available further androgenic-active compounds as well as to achieve some technically simple and efficient procedure for their production.

This task is solved by A<15->D- Homosteroids of the general formula I,

in which

R<1> stands for one C M -alkyl group

and

R<2> stands for a hydroxy group, one group OC(0)-R<20>, OC(0)NH-R<20>

or OR<20>, where R<20> represents a C1-12-alkyl group, a C3-3-cycloalkyl group, an aryl group or an aryl-C1-C1-alkyl group, which

is substituted in the given listen,

R<3> stands for a hydrogen atom or a C1-4 alkyl-, vinyl-, ethynyl- group

CnF2rH-rgnipu, for n=l, 2, 3 und

R<4>stands for a hydrogen atom

or

R stands for a hydrogen atom or a C1-6-alkyl-, vinyl-, ethynyl- or

CnF2n+i-group, for n=1, 2,3,

R<3> stands for a hydroxy group, a group OC(0)-R<20>, OC(0)NH-Rzu or ORzu, where R means a C1-12-3 alkyl group, a C3-cycloalkyl group, an aryl group or an aryl-C1-alkyl group, which

is substituted in this case, a

R<4>stands for a hydrogen atom

or

R 2 and • R 3 together stand for one oxygen atom a

R4 stands for a hydrogen atom.

or

R stands for one hydroxyl group, some group OC(0)-R<20>,

OC(0)NH-R<20>or OR<20>, where R<20> denotes a CH2-alkyl group, a C1-cycloalkyl group, an aryl group or an aryl-C1-4-alkyl group, which is substituted in the given case, and

R<3> and R<4> together form a double bond

and

STEROID stands for the steroid part of the ring system of formulas

A, B, C, D, E and F:

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

R<7> means a hydrogen atom, a halogen atom, one hydroxyl group or some CnF2n+i -group with n = 1,2,3,

X means an oxygen atom, two hydrogen atoms or a hydroxylamine group

R Q means one hydrogen atom, one methyl or ethyl group,

R<9> means one hydrogen atom or halogen atom or together with R<10> stands for one double bond,,

R<10> means one hydrogen atom, one hydroxyl group, one methyl-or

ethyl group or together with R<9> stands for one double bond,

R11 means one hydrogen atom, one Ci-4-alkyl group, one nitrile group, hydroxymethylene- or formyl group,

R means one hydrogen atom, one Ci.4-alkyl group or one nitrile group, R<n>and R<12>mean<p>in addition to the previously mentioned meanings, together a methylene bridge,

R means one hydrogen atom or together with R one double bond,

R 16 means one hydrogen atom or together with R 13 one double bond,

R1<5>means one hydroxyl group, R<14>and R<15>stand for one hydrogen atom or together for one double bond, one [2,3c]oxadiazole ring, one [3,2c]isoxazole ring or one [3,2c]pyrazole ring R means one hydrogen atom or one methyl group,

Y stands for an oxygen or nitrogen atom,

where the spiral lines on R<4>, R<7>, R<8>, R<1>1, R12, R13, R14 and R<15> mean that these substituents can be a- or B-positioned

and pharmaceutically acceptable salts thereof.

The compounds according to the invention possess androgenic activity.

CM-Alkyl group is a branched or straight-chain alkyl residue, which is primarily formed by some methyl-, ethyl-, n-propyl-, i-propyl-, n-butyl-, i-butyl-

or tert.-butyl group.

C1-4-alkyl group is a branched or straight-chain alkyl residue, which is primarily formed 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.

The C^-alkyl group is a branched or straight-chain alkyl residue, which is primarily formed 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-dimethyl-butyl group, an octyl-, by a nonyl-, decyl- or undecyl group.

The C3-g-cycloalkyl group is primarily 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 with preferably 6 to 15 carbon atoms, such as a phenyl group, a substituted phenyl group, such as a halogenophenyl group or a nitrophenyl group or a naphthyl group.

The term aryl-Ci-4-alkyl group should primarily mean an alkyl residue, substituted by an aryl residue, which together have primarily 7 to 15 carbon atoms, whereby the aryl residue and/or alkyl residue may carry further substituents, such as primarily one halogen atom, one hydroxy-one methoxy or nitrile group. Particularly suitable aryl radicals are a free or aromatically substituted benzyl group, such as a benzyl group or some halobenzyl group.

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

If STEROID stands for the steroid ring system of part of the formula A, R means primarily one hydrogen atom, one chlorine atom, one bromine atom, one hydroxyl group or one trifluoromethyl group, R<10> primarily one hydrogen atom, one hydroxyl group, or one methyl group, R<9> primarily one hydrogen atom or fluorine atom, R8 primarily one hydrogen atom or a methyl group, whereby the methyl group is particularly favorable.

If STEROID stands for the steroid ring system of part of the formula B, R means primarily one hydrogen atom, one chlorine atom, one bromine atom, one hydroxyl group or one trifluoromethyl group, and R<8> primarily one hydrogen atom or a methyl group, whereby the methyl group is particularly favorable.

If STEROID stands for the steroid ring system of part of the formula C, R means primarily one hydrogen atom, one chlorine atom, one bromine atom, one hydroxyl group or one trifluoromethyl group and R 11 , R 12 primarily one hydrogen atom. A double bond in the 1,2 position is preferred. H or CH3 is equally preferred for R.

If STEROID stands for the steroid ring system of part of the formula D, R means primarily one hydrogen atom, one chlorine atom, one bromine atom, one hydroxyl group or one trifluoromethyl group and R<8>primarily one hydrogen atom or methyl group, whereby the methyl group is particularly favorable, and R13 and R mean primarily together one double bond and Y means primarily one oxygen atom.

If STEROID stands for the steroid ring system of part of the formula E, R<8>means primarily one hydrogen atom or one methyl group, wherein the methyl group is particularly favorable, R stands primarily for one hydrogen atom, R 13 and R 16 st<o>stands primarily for one hydrogen atom or together for one double bond, R<15>stands always primarily for one hydroxyl group or R<14>and R<15>stand primarily together for one ring [3,2c]pyrazole.

If STEROID stands for the steroidal ring system of part of the formula F, R 11 means preferably a C 1-4 -alkyl group or a nitrile group.

R<1> means primarily one methyl group or one ethyl group, whereby the methyl group is particularly favorable.

R<2>means primarily one hydroxyl group, one formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, [(trans-4-butylcyclohexyl)carbonyl]oxy group, phenylpropionyloxy group, iso-butyryloxy group, heptanyloxy group, undecanyloxy group or fem-aminocarbonyloxy group, whereby the hydroxy group is particularly favorable.

R means preferably one methyl-, one trifluoromethyl-, one ethyl-, one pentafluoroethyl- or one ethynyl group, whereby methyl-, ethyl-, trifluoromethyl and pentafluoromethyl groups are particularly advantageous.

R<4> means primarily one hydrogen atom.

Particularly favorable A<15->D-Homosteroids are listed in the following:

1) 17aB-Hydroxy-D-homo-androstan-4,15-dien-3-one,

2) 17aB,4-Dihydroxy-D-homo-androstan-4,1 5-dien-3-one,

3) 17aB-Hydroxy-4-chloro-D-homo-androstan-4,15-dien-3-one,

4) 17aB-Hydroxy-4-bromo-D-homo-androstane-4,15-dien-3-one,

5) 17aB-Hydroxy-4-trifluoromethyl-D-homo-androstan-4,15-dien-3-one,

6) 17aB,ll B-Dihydroxy-D-homo-androstan-4,15-dien-3-one,

7) 17aB, 11B-Dihydroxy-D-homo-9a-fluoro-androstan-4,15-dien-3-one,

8) 17aB-Hydroxy-D-homo-androstan-1,4,15-trien-3-one,

9) 17aB-Hydroxy-D-homo-4-chloro-androstan-1,4,15-trien-3-one,

10) 17aB,4-Dihydroxy-D-homo-androstan-1,4,15-trien-3-one,

11) 17aB-Hydroxy-7a-methyl-D-homo-androstan-1,4,15-trien-3-one,

12) 17aB-Hydroxy-7a-methyl-4-chloro-D-homo-androstan-1,4,15-trien-3-one,

13) 17aB-Hydroxy-17a-methyl-androstan-4,15-dien-3-one,

14) 17aB-Hydroxy-17aa-trifluoromethyl-7a-methyl-androstan-4,15-dien-3-one, 15) 17aB,4-Dihydroxy-17aa-trifluoromethyl-androstan-4,15-dien-3-one, 16) 17aB-Hydroxy-17aa-trifluoromethyl-4-chloro-androstan-4,15-dien-3-one - he

17) 17aB-Hydroxy-7a-methyl-D-homo-androstan-4,15-dien-3-one,

18) 17afl-Hydroxy-17a-pentafluoroethyl-androstan-4,15-dien-3-one,

19) 17aB-Hydroxy-D-homo-estra-4,15-dien-3-one,

20) 17α,4-Dihydroxy-D-homo-estra-4,15-dien-3-one,

21) 17a6-Hydroxy-4-chloro-D-homo-estra-4,15-dien-3-one,

22) 17aB-Hydroxy-4-bromo-D-homo-estra-4,15-dien-3-one,

23) 17aB-Hydroxy-4-trifluoromethyl-D-homo-estra-4,15-dien-3-one,

24) 17aB-Hydroxy-17aa-methyl-D-homo-estra-4,15-dien-3-one,

25) 17aB-Hydroxy-17aa-methyl-4-chloro-D-homo-estra-4,15-dien-3-one, 26) 17aB-Hydroxy-17aa-trifluoromethyl-D-homo-estra-4,15-dien-3-one, 27) 17aB-Hydroxy-17aa-pentafluoroethyl-D-homo-estra-4,15-dien-3-one,

28) 17aB-Hydroxy-7a-methyl-D-homo-estra-4,15-dien-3-one,

29) 17aB-Hydroxy-7a-methyl-4-chloro-D-homo-estra-4,15-dien-3-one,

3 0) 17aB-Hydroxy-D-homo-estra-1,4,15-trien-3-one,

31) 17aB-Hydroxy-D-homo-4-chloro-estra-1,4,15-trien-3-one,

32) 17aB,4-Dihydroxy-D-homo-estra-1,4,15-trien-3-one,

33) 17aB-Hydroxy-7a-methyl-D-homo-estra-1,4,15-trien-3-one,

34) 17α-Hydroxy-7α-methyl-4-chloro-D-homo-estra-1,4,15-trien-3-one,

35) 13-Ethyl-17α-hydroxy-D-homo-gona-4,15-dien-3-one,

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

37) 13-Ethyl-17aB-hydroxy-7a-methyl-D-homo-gona-4,15-dien-3-one,

38) 13-Ethyl-17aB-hydroxy-17aa-methyl-D-homo-gona-4,15-dien-3-one, 39) 13-Ethyl-17aB-hydroxy-17aa-methyl-4-chloro-D-homo-gona-4,15-dien-3-one,

40) 13-Ethyl-17aB-hydroxy-D-homo-gona-1,4,15-trien-3-one,

41) 13-Ethyl-17aB-hydroxy-4-chloro-D-homo-gona-1,4,15-trien-3-one,

42) 13-Ethyl-17aB-hydroxy-7a-methyl-D-homo-gona-1,4,15-trien-3-one, 43) 13-Ethyl-17aB-hydroxy-7a-methyl-4-chloro-D-homo-gona-1,4,15-trien-3-one,

44) 17α-Hydroxy-D-homo-5a-androst-15-en-3-one,

45) 2-Oxa-17aB-hydroxy-D-homo-5a-androst-15-en-3-one

46) 17aB-Hydroxy-D-homo-5a-androstan-1,15-dien-3-one,

47) 2-Hydroxymethylene-17aB-hydroxy-D-homo-5a-androst-15-en-3-one,

A further object of the invention is a technically simple and effective procedure for obtaining A<15->D-homosteroids of the general formula (I).

Accordingly, known compounds of the general formula (II) react in a known manner (M. A. Avery et al., Steroids, 1990, 55, 59 - 64; A. Furst et al., 1976, US 3,984,476.) in which R<1> and STEROID, have the aforementioned meaning, in the presence of acids, such as p-toluenesulfonic acid, with acylating agents such as for example isopropenylacetate (Hosoda, H. etal., Chem. Phar. Buli., 23, 1975, 3141-3145), acetic anhydride (Rasmusson, G.H., Arth, G.E., Steroids, 22, 1973, 107-111) or others, into dienolacetates and then reduced with reducing agents* such as NaBHt, into the corresponding 17aB-Hydroxy-D-homo-A<15>-steroids.

To obtain compounds of the general formula (II) with part of the structure A to F, the known basic skeletons of steroids can be used.

The following basic steroid skeletons can be used for example:

For the basic skeleton of steroids A: Androst-4-ene-3,17-dione and Dehydroepiandrosterone.

For the basic skeleton of steroid B: Estrone, 7a-methylestrone.

For the basic skeleton of steroids C, D respectively. E: Epiandrosterone.

For the basic steroid skeleton F: 5a-Androst-2-en-17-onizeepiandrosterone (US-A-3,098,851).

The functional groups contained in the structural components of the starting materials for the basic steroid skeletons A to F can be protected according to methods known to the skilled person.

Keto groups in the starting material of the basic steroid skeletons A to F can thus be protected as ketals or thioacetals according to methods known to the expert.

The introduction of the substituents R<7> to R<15> into the structural parts A to F can follow both before and after the incorporation of the D-Homo-A<15->cycle according to methods known to the expert.

In order to obtain pharmaceutically acceptable salts of compounds according to the invention of the general formula I, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as organic acids besides 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, can be considered as inorganic acids. cinnamic acid and methanesulfonic acid.

The compounds according to the invention possess androgenic activity, as presented in Table 1 below:

17aB-Hydroxy-7a-methyl-D-homoestra-4,16-dien-3-one is described as an androgen with antigonadotropic properties in Steroids, 1990, 55, 59-64. However, 17α13-Hydroxy-7α-methyl-D-homoestra-4,16-dien-3-one shows only a low receptor binding affinity to the androgen prescription of 2% (Reference DHT= 100%).

Completely unexpectedly and surprisingly, the A<15->D-Homo-steroids according to the invention show a significantly higher binding affinity to the androgen prescription. They bind A<15->D-Homo-compounds compared to 17aB-Hydroxy-7a-methyl-D-homoestra-4,16-dien-3-one (Steroids 1990, 55, 59-64) with >12% (reference DHT=100%) to the androgen receptor. Thus, it becomes close to another mediation of androgenic affinity in the A<15->D-Homo-steroid according to the invention than in the literature known 17aB-Hydroxy-7a-methyl-D-homoestra-4,16-dien-3-one (Steroids, 1990, 55, 59-64).

These test results open up diverse possibilities for the compounds according to the invention for the control of fertility in men and women, Hormone Replacement Therapy (HRT) in men and women, such as endometriosis, mammary carcinoma or hypogonadism.

The subject of the proposed invention is therefore also pharmaceutical compositions containing at least one A,<5->D-Homosteroid of the general formula (I), in this case together with pharmaceutically acceptable auxiliary and carrier substances, as well as the application of these compounds, among other things, for therapy, i.e., the production of pharmaceutical preparations, among other things, for the treatment of the above-mentioned diseases.

These pharmaceutical compositions and drugs may be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. They contain, in addition to the usual carriers and/or diluents, at least one compound of general formula I.

The means for the treatment of the invention are produced in a known manner with the usual solid or liquid carrier substances or diluents and with the usual pharmaceutical-technical auxiliary substances applied in the usual way, according to the method of application, in a suitable dosage. Preferred preparations consist of a single dosage form suitable for oral administration. Such administration forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, but also depot forms.

Of course, parenteral preparations such as injection solutions also come into consideration. Furthermore, they should also be listed as preparations, for example, also suppositories and means for vaginal administration.

Suitable tablets can be obtained by mixing the active substance with known excipients, for example inert diluting agents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc and/or depot effect agents such as carboxyl polymethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets can also consist of several layers.

Dragees can be produced by coating the cores produced analogously to tablets with, in the usual manner for coating dragees, applied agents, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. At the same time, the coating of the dragee can also consist of several layers, in which case the auxiliary substances mentioned above can be applied.

Solutions or suspensions with compounds according to the invention of general formula I

they may additionally contain flavor enhancers such as saccharin, cyclamate or sugar, as well as, for example, aromatic substances such as vanillin or orange extract. They may also contain auxiliaries

suspending agents such as sodium carboxymethylcellulose or preserving agents such as p-hydroxybenzoate.

Capsules containing compounds of general formula I can for example be produced by mixing the compound(s) of general formula I with an inert carrier such as lactose or sorbitol and encapsulating in gelatin capsules.

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

The following examples illustrate the proposed invention without limiting it thereto.

Example 1

17afi- FIhydroxy- D- homoestra- 4, 15- diene- 3- one

Level 1

3- Methoxy- 17a- acetoxy- D- homoestra- 1, 3, 500), 15, 17- pentaene

4.0 g of 3-Methoxy-D-homoestra-1,3,5(10),16-tetraen-17a-one was dissolved in 40 ml of acetic anhydride and 40 ml of isopropenyl acetate. after the addition of 2.0 g of p-toluenesulfonic acid, it is heated to 80°C for 48 hours. It is then neutralized with saturated NaHCO3 solution. The substance is extracted with ethyl acetate, the organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered, evaporated and chromatographed on silica gel. 3-Methoxy-17a-acetoxy-D-homoestra-1,3,5(10), 15,17-pentaene is obtained.

1H-NMR (CDCl3): 0.96 (s, 3H, H-18), 2.20 (s, 3H, OAc), 3.78 (s, 3H, OCH3), 5.65-6.05 (m, 3H, H-15, H-16, H-17)

Level 2

3-Methoxy-17aif-hydroxy-D-homoestral, 3, 5(10), 15-tetraene

6.5 g of 3-Metokai-D-homc-estra-1,3,5(10),15,17-pentaen-17a-yl-acetate were dissolved in 150 ml of methanol and 75 ml of THF. With stirring at -20°C, 5.0 g of NaBHip is added in portions and further stirred for 3 hours. It is then reduced to 1/5 and 250 ml of water is added to it. Then, the remains of the organic solvent are distilled off. The substance is filtered off, washed with water, dried in a vacuum and chromatographed on silica gel. 3-Methoxy-17αB-hydroxy-D-homoestra-1,3,5(10),15-tetraene is obtained.

1H-NMR (CDCl3): 0.81 (s, 3H, H-18), 3.64 (m, 1H, H-17a), 3.77 (s, 3H, OCH3), 5.60-5.80 (m, 2H, H-15.H-16)

Level 3

3- Methoxy- 17ai3- hydroxy- D- homoestra- 1, 3, 5( 10), 15- triene

5.0 g of 3-Methoxy-17α-hydroxy-D-homoester-2,5(10),15-tetraene, dissolved in 35 ml of THF and 15 ml of l-Methoxy-2-propanol, is added dropwise at - 70°C to a solution of 100 ml of liquid ammonia, 10 ml of THF and ca. 0.3 g of sodium. After decolorization, the addition is stopped and sodium is added again. After adding 2.5 g of Na, the reaction is complete. 2.5 ml of isopropanol and 8 g of solid NH 4 Cl are added.

With gentle heating, the ammonia evaporates. After adding 250 ml of cold water, the steroid is filtered, washed neutrally with water and dried in a vacuum. 3-Methoxy-17aB-hydroxy-D-homoester-1,3,5(10), 15-triene is obtained.

Level 4

17aJ3- Hydroxy- D- homoestra- 4. 15- diene- 3- one

4.6 g of 3-Metolcsi-17al-hiaVoxy-D-homoestra-1,3,5(10),15-triene were dissolved in 150 ml of acetone. With stirring at room temperature, 8 ml of 5% soda is added

acid. After 1 h, 50 ml of saturated NaHCO3 solution and 150 ml of water are added. After that, most of the acetone is distilled off. The substance is filtered off, washed with water, dried in a vacuum and chromatographed on silica gel. 17aB-Hydroxy-D-homoestra-4,15-dien-3-one is obtained.

^-NMR (CDCl3): 0.84 (s, 3H, H-18), 3.57 (m, IH, H-17a), 5.57-5.72 (m, 2H, H-15, H-16), 5.84 (s, IH, H-4)

Example 2

2 17aB- Hydroxy- D- homoandrost- 4, 15- diene- 3- one

Level 1

3 fi- Acetoxy- 17a- acetoxy- D- homoandrostane- 5, 15, 17- triene

6.0 g of 3B-Acetoxy-D-homoandrostan-5,16-dien-17a-one was dissolved in 70 ml of acetic anhydride and 70 ml of isopropenyl acetate. After adding 4.0 g of p-toluenesulfonic acid, it is heated for 48 hours at 80°C. After that, it is neutralized with saturated NaHC03 solution. The substance is extracted with ethyl acetate, the organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered, evaporated and chromatographed on silica gel. 3B-Acetoxy-17a-acetoxy-D-homoandrostane-5,15,17-triene is obtained.

1H-NMR (CDCl3): 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, IH, H-3), 5.41 (m, IH, H-6), 5.60-5.98

(m,3H,H-15,H-16,H-17)

Level 2

3B- Acetoxy- 17aB- hydroxy- D- homoandrostane- 5, 15-diene

5.0 g of 3B,17a-Diacetoxy-D-homoandrost-4,15,17-triene was dissolved in 200 ml of methanol and 150 ml of THF. With stirring at -20°C, 5.0 g of NaBFLj is added in portions and further stirred for 2 hours. Then 100 ml of saturated NH4Cl solution was added. Then the organic solvent is distilled off. 250 per supplement

ml of water, the substance is filtered, washed with water, dried in a vacuum and chromatographed on silica gel. 3B-Acetoxy-17aB-hydroxy-D-homoandrostane-5,15-diene is obtained.

Level 3

3B- Acetoxy- D- homoandrostane- 5, 15- diene- 17aB- tetrahydropyrani Lethar

4.25 g of 3B-Acetoxy-17aB-hydroxy-D-homoandrostane-5,15-diene was dissolved in 75 ml of methylene chloride. With stirring, 75 ml of dihydropyran and 500 mg of pyridinium tosylate are added one after the other at room temperature. After 3 hours, it is washed with a 10% solution of NaHCl>3 and a saturated solution of NaCl, dried over MgSO4, filtered and evaporated. 3B-Acetoxy-D-homoandrostane-5,15-diene-17aB-tetrahydropyranylether is obtained.

Level 4

3fi-Hydroxy^i- D- homoandrostane- 5, 15- diene-- 17aB- tetrahydropyranyl ether

5.2 g of 3B-Acetoxy-D-homoandrostane-5,15-diene-17aB-tetrahydropyranylether were dissolved in 175 ml of methanol and 125 ml of THF. With vigorous stirring, 7.5 g of K2CO3 and 2.5 ml of water are added. After 3.5 hours it evaporates to about 1/6. Then 250 ml of water is added, the substance is filtered, washed with water and dried in a vacuum. 3B-Hydroxy-D-homoandrostane-5,15-diene-17aB-tetrahydropyranyl ether is obtained.

Level 5

3- Keto- D- homoandrostane- 4, 15- diene- 17 aphi- tetrahydropyranylether

4.5 g of 3B-Hydroxy-D-homoandrostane-5,15-diene-17aB-tetrahydropyranylether were dissolved under argon in 125 ml of toluene. After the addition of 1.6 g of Al(0-iPr)3, it is heated for 2.5 hours at 110°C. At room temperature, it is washed twice with 250 ml of 1 M solution of K-Na-tartrate. The aqueous phases are extracted with ethyl acetate. The combined organic phases are washed with saturated NaCl solution and dried

over MgSO4, filter and evaporate in vacuo. 3-Keto-D-homoandrostane-4,15-diene-17aJ3-tetrahydropyranyl ether was obtained.

Level 6

17aB- Hydroxy- D- homoandrostane- 4, 15- diene- 3- one

14 g of crude product 3-Keto-D-homoandrostane-4,1 5-diene-17aB-tetrahydropyranylether were dissolved in 100 ml of acetone. 10 ml of 10% hydrochloric acid is added dropwise at room temperature. After 2 hours, 50 ml of saturated NaHCO3 solution is added. The reaction mixture was evaporated at ca. 1/3. Then 150 ml of water is added and the precipitated substance is filtered off, washed with water, dried in a vacuum and chromatographed on silica gel. 17aB-Hydroxy-D-homoandrostan-4,15-dien-3-one is obtained.

'H-NMR (ĆDC13): 0.82 (s, 3H, H-18), 1.20 (s, 3H, H-19), 3.54 (m, IH, H-17a), 5.55-5.67 (m, 2H, H-15, H16), 5.74 (s, IH, H-4)

Example 3

17afi- Hydroxy- 4- chloro- D- homoandrostane- 4, 15- diene- 3- one

Level 1

17afi- Hydroxy- 4C5C- epoxv- D- homoandrost- l 5- en- 3- one

2.0 g of 17aB-Hydroxy-D-homoandrost-4,15-dien-3-one was dissolved in 80 ml of methanol and mixed with 20 ml of hydrogen peroxide solution (35%) at 0°C. With stirring, add 4 ml of 10% sodium hydroxide solution and continue stirring for 3 hours. The reaction solution is evaporated to 50 ml, then mixed with 50 ml of dichloromethane and 250 ml of water, and the organic phase is separated. It is washed with semi-concentrated thiosulfate solution, dried and evaporated to dryness. The resulting residue consists of a mixture of 4a,5a- or 4J3,5B-epoxide and is used without further purification in the next step.

Level 2

17aB- Hydroxy- 4- chloro- D- homoandrostane- 4, 15- diene- 3- one

1.93 g of the epoxy mixture (step 1) was dissolved in 300 ml of acetone and mixed with 17 ml of concentrated hydrochloric acid at 0°C. After 2 hours, it is neutralized with soda solution and acetone is removed by distillation. The residue is extracted with dichloromethane. The organic extracts are dried and evaporated. After crystallization from ethyl acetate, 17aB-Hydroxy-4-chloro-D-homoandrostan-4,15-dien-3-one is obtained.

1H-NMR (COCl3): 0.82 (s, 3H, H-18), 1.25 (s, 3H, H-19), 3.57 (m, 1H, H-17a), 5.64 (m, 2H, H-15, H-16)

Example 4

17afi- Hydroxy- 7a- methyl- D- homoandrostane- 4, 15- diene- 3- one

Level 1

17afl- Hydroxy- D- homoandrostane- 4, 6, 15- trien- 3- one

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

Level 2

17afi- Hydroxy- 7a- methyl- D- homoandrostane- 4, 15- diene- 3- one

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

1H-NMR (CDCl3): 0.77 (d, J=7Hz, 3H, H-7Me) 0.83 (s, 3H, H-18), 1.20 (s, 3H, H-19), 3.57 (m, IH, H-17a), 5.63 (m, 2H, H-15, H-16), 5.74

(s,1H, H-4)

Example 5

5 17afi- Hydroxy- 4- chloro- D- homoestra- 4, 15 - diene- 3 - one

Level 1

17afi- Hydroxy- 4C5C- epoxy- D- homoestrone- 15- en- 3- one

Obtaining follows analogously to 17al3-Hydroxy-4^5^-epoxy-D-homoandrost-15-en-3-one. The resulting residue consists of a mixture of 4a,5a- or 4/3,513-epoxide and is used without further purification in the next step.

Level 2

17al3- Hydroxy- 4- chloro- D- homoestra- 4. 15- diene- 3- one

Obtaining follows from 17aB-Hydroxy-4-chloro-D-homoandrostan-4,15-dien-3-one analogous to 1713-Hydroxy-17a-trifluoromethyl-4-chloro-androst-4-en-3-one.

1H-NMR (CDCl 3 ): 0.84 (s, 3H, H-18), 3.57 (m, 1H, H-17a), 5.58-5.70

(m,2H, H-15, H-16)

Example 6

17afi- Hydroxy- D- homo- 5a- androst- l 5- en- 3- one

Level 1

3 [ 3- 17a- Diacetoxy- D- homo- 5 a- androstane- 15, 17- diene

14.5 g of 313-Acetoxy-D-homoandrostan-5,16-dien-17a-one was dissolved in 200 ml of acetic anhydride and 200 ml of isopropenyl acetate. After the addition of 5.0 g of p-toluenesulfonic acid, it is heated for 16 hours on a reflux condenser. The substance is extracted with ethyl acetate, the organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered, evaporated and

chromatographed on silica gel. 313-Acetoxy-17a-acetoxy-D-homo-5a-androstane-15,17-diene is obtained.

1H-NMR (CDCl3): 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, IH, H-3), 5.60-5.92 (m, 3H, H-15, H-16, H-17)

Level 2

3fi- Acetoxy- 17afi- hydroxy- D- homo- 5a- androstane- 15-ene

8.5 g of 3B,17a-Diacetoxy-D-homo-5a-androstane-15,17-diene were dissolved in 360 ml of methanol and 270 ml of THF. With stirring, add 6.75 g of NaBHtpa in portions at - 20°C and stir for 2 hours at 0°C. Then 200 ml of saturated NH4Cl solution is added. After that, the organic solvents are distilled off. After adding 100 ml of water, the substance is filtered, washed with water, dried in a vacuum and chromatographed on silica gel. 3B-Acetoxy-17aB-hydroxy-D-homo-5a-androst-15-ene is obtained.

1H-NMR (CDCl3): 0.76 (s, 3H, H-18), 0.83 (s, 3H, H-19), 2.02 (s, 3H, OAc), 3.53 (m, 1H, 17 a-H), 4.69 (m, IH, H-3), 5.60-5.65 (m, 2H, H-15, H-16)

Level 3

3fi- Acetoxy- D- homo- 5a- androst- 15- en- 17 afl- tetrahydropyranylether

7.60 g of 3B-Acetoxy-17-ab-hydroxy-D-homo-5a-androst-15-ene were dissolved in 135 ml of methylene chloride. With stirring, 13.5 ml of dihydropyran and 900 mg of pyridinium tosylate are added one after the other at room temperature. After three hours, it is washed with a 10% solution of NaHCO3 and diluted with NaCl solution, dried over MgSO4, filtered and evaporated. 313-Acetoxy-D-homoandrostane-5,15-diene-17aB-tetrahydropyranyl ether is obtained.

Level 4

3 B- Hydroxy- D- homo- 5 a- androst- 15- en- 17 aB- tetrahydropyranylether

12.0 g of 3B-Acetoxy-D-homo-5a-androst-15-ene-17aB-tetrahydropyranylether was dissolved in 150 ml of methanol and 100 ml of THF. 15 g of K2CO3 and 5 ml of water are added with vigorous stirring. After 3.5 hours, it is evaporated to about 1/6, washed with water and dried in a vacuum. 3B-Hydroxy-D-homo-5a-androst-15-ene-17aB-tetrahydropyranylether is obtained.

Level 5

3- Keto- D- homo- 5a- androst- 15- en- 17 aB- tetrahvdropvran<y>lether

9.2 g of 3B-Hydroxy-D-homo-5a-androst-15-ene-17-aB-tetrahydropyranylether were dissolved under argon in 200 ml of toluene. After adding 3.0 g of Al(0-iPr)3, it is heated for 1.5 hours at 110°C. At room temperature, it is washed twice with 250 ml IM solution of K-Na-tartrate. The aqueous phases are extracted with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over MgSO 4 , filtered and evaporated in vacuo. 3-Keto-D-homo-5a-androst-15-ene-17aB-tetrahydropyranyl ether is obtained.

Level 6

17aB- Hydroxy- D- homo- 5a- androst- 15- en- 3 - one

15.7 g of the crude product 3-Keto-D-homo-5a-androst-15-ene-17aB-tetrahydropyranylated were dissolved in 100 ml of acetone. 10 ml of 10% hydrochloric acid is added dropwise at room temperature. After 2 hours, 50 ml of saturated NaHCO3 solution was added. The reaction mixture was evaporated at ca. 1/3. Then 150 ml of water is added and the precipitated substance is filtered off, washed with water, dried in a vacuum and chromatographed on silica gel. 17aB-Hydroxy-D-homo-5a-androst-15-en-3-one is obtained.

1H-NMR (CDCl3): 0.76 (s, 3H, H-18), 1.02 (s, 3H, H-19), 3.53 (m, 1H, H-17a), 5.57-5.65(m, 2H, H-15, H16)

Example 7

2- Hydroxymethylene-l 7aB- hydroxy- D- homo- 5a-androst- 15-en- 3-one

2.1 g of 17aB-Hydroxy-D-homo-5a-androst-15-en-3-one was placed under a protective gas in 80 ml of toluene. After that, 2.1 g of NaOH and 4.0 ml of formic acid ethyl ester were added. After 1 hour, add 2 ml of methanol. After that, add 50 ml of water and acidify with 5n HCl. It is extracted with ethyl acetate. The organic phase is washed with NaHCO 3 solution, dried over MgSO 4 , filtered and evaporated. It is chromatographed on silica gel. 2-Hydroxymethylene-17-aB-hydroxy-D-homo-5a-androst-15-en-3-one is obtained.

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

=CH(OH))

Claims (21)

1. A<15->D- Homosteroids of general formula I, indicated by what R<1> stands for one C1-C4 alkyl group a R<2> stands for a hydroxy group, one group OC(0)-R<20>, OC(0)NH-R<20> or OR20, where R<20> denotes a C1-n-alkyl group, a C3-g-cycloalkyl group, an aryl group or an aryl-C1-alkyl group, which is substituted in the given sequence, R<3> stands for a hydrogen atom or a C1-4 alkyl-, vinyl-, ethynyl- group CnF2n+rgroup, for n=l, 2.3 und R<4> stands for hydrogen atom or R stands for a hydrogen atom or a C1-6-alkyl-, vinyl-, ethynyl- or CnF2n+i-group, for n=l, 2,3, R<3> stands for a hydroxy group, some group OC(0)-R<20>, OC(0)NH- R<20> or OR<20>, where R<20> means some C1-12-alkyl group, some C3-cycloalkyl group, some aryl group or some aryl-C1-6-alkyl group, which in the given case is substituted, and R<4> stands for hydrogen atom or R<2> and R<3> together stand for one oxygen atom and R<4> stands for a hydrogen atom or R<2> is also for one hydroxyl group some group OC(0)-R<20>, OC(0)NH-R<20> or OR<20>, where R<20> represents a C 1-4 alkyl group, a C 3-cycloalkyl group, an aryl group or an aryl-C 1-4 alkyl group, which is in this case substituted, and R<3> and R<4> together form a double bond a STEROID stands for the steroid part of the ring system of formulas A, B, C, D, E and F: where A and C can have one additional double bond in position 1,2 and B has one or two additional double bonds in position 9,10 and 11,12, R means a hydrogen atom, a halogen atom, one hydroxyl group or some C„F2n+rgroup san = 1, 2, 3, X means an oxygen atom, two hydrogen atoms or a hydroxylamine group, R 8 means one hydrogen atom, one methyl or ethyl group, R<9> means one hydrogen atom or halogen atom or together with R<10> stands for one double bond,, R<10> means one hydrogen atom, one hydroxyl group, one methyl- or ethyl group or together with R stands for one double bond, R<11> means one hydrogen atom, one C1-4-alkyl group, one nitrile group, hydroxymethylene- or forml group, R 12 means ■ j• one hydrogen atom, one Ci.4-alkyl*l<g>ru<pu>or one nitrile group, R 11 and R 12 mean, in addition to the previously mentioned meanings, together a methylene bridge, R 13 means * one hydrogen atom or together with R 7 one double bond, 16"* 13 R means one hydrogen atom or together with R one double bond, R<15>means one hydroxyl group, R14 and R<15>stand<e><z>a one hydrogen atom or one double bond, one [2,3c]oxadiazole ring, one [3,2c]isoxazole ring or one [3,2c]pyrazole ring R 17 means • one hydrogen atom or one methyl group, Y stands for an oxygen or nitrogen atom, wherein the spiral lines on R<4>,<R7>,<R8,>R<11>, R<12>, R<13>,R14 and R<15>mean that these substituents can be a- or 6-positioned. 2. Compounds according to claim 1, indicated by the fact that R stands for a methyl group or one ethyl group. 3. Compounds according to claim 1 or 2, indicated by what R 2 means * one hydroxy• group, one formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, [(trans-4-butylcyclohexyl)carbonyl]-oxygroup, phenylpropionyloxy group, iso-butyryloxy group, heptanyloxy group, undecanyloxy group or phenylaminocarbonyloxy group. 4. Compounds according to one of claims 1 to 3, indicated by what R<3> means one methyl, one trifluoromethyl-, one ethyl-, one pentafluoroethyl- or one ethynyl group. 5. Compounds according to one of claims 1 to 4 characterized in that, R<4> means one hydrogen atom. 6. Compounds according to one of claims 1 to 5, characterized in that STEROID stands for the steroid ring system of part of the formula A, where R<7>represents one hydrogen atom, one chlorine atom, one bromine atom, one hydroxyl group, or a trifluoromethyl group, R<10>one hydrogen atom, one hydroxyl group or one methyl group, and R<9>one hydrogen atom or one fluorine atom and R o one hydrogen atom or a methyl group. 7. Compounds according to one of claims 1 to 5, characterized in that STEROID stands for the steroidal ring system of part B, where R represents one hydrogen atom, one chlorine atom, one a bromine atom, one hydroxyl group, or one trifluoromethyl group and R8 one hydrogen atom or one methyl group. 8. Compounds according to one of claims 1 to 5, characterized in that STEROID stands for the steroid ring system of part of the formula C, where R7 is one hydrogen atom, one chlorine atom, one bromine atom or one hydroxyl group or one trifluoromethyl group and R<11> as well as R<12> each represents one hydrogen atom and which is in position 1, 2 a double bond. 9. Compounds according to one of claims 1 to 5, characterized in that STEROID stands for the steroid ring system of part of the formula D, where R<7>represents one hydrogen atom, one chlorine atom, one bromine atom, one hydroxyl group, or one trifluoromethyl group and R one hydrogen atom or one methyl group, and R and R<d>together one double bond and Y one oxygen atom. 10. Compounds according to one of claims 1 to 5, characterized in that STEROID stands for the steroid ring system part of the formula E, where R<8>represents one hydrogen atom or one methyl group, R<12>one hydrogen atom, R13 and R<16>each one hydrogen atom or together one double bond, R15 one hydroxyl group or R<14>and R15 together one pyrazoline ring[3,2c]. 11. Compounds according to one of claims 1 to 5, characterized in that STEROID stands for the steroid ring system of part of the formula F, where R<11> represents a C1-4-alkyl group or a nitrile group. 12. Compounds according to one of claims 1 to 11, namely 17aB-Hydroxy-D-homo-androstane-4,15-dien-3-one, 17aB,4-Dihydroxy-D-homo-androstane-4,15-dien-3-one, . 17aB-Hydroxy-4-chloro-D-homo-androstan-4,15-dien-3-one, 17aB-Hydroxy-4-bromo-D-homo-androstan-4,15-dien-3-one, 17aB-Hydroxy-4-trifluoromethyl-D-homo-androstan-4,15-dien-3-one, 17aB,l 1 B-Dihydroxy-D-homo-androstan-4,15-dien-3-one, 17aB, 1 lB-Dihydroxy-D-homo-9a-fluoro-androstan-4,15-dien-3-one, 17aB-Hydroxy-D-homo-androstan-1,4,15-trien-3-one, 17aB-Hydroxy-D-homo-4-chloro-androstane-1,4,15-trien-3-one, 17aB,4-Dihydroxy-D-homo-androstan-1,4,15-trien-3-one, 17aB-Hydroxy-7a-methyl-D-homo-androstan-l ,4,15-trien-3-one, 17aB-Hydroxy-7a-methyl-4-chloro-D-homo-androstan-l ,4,15-trien-3-one, 17aB-Hydroxy-17a-methyl-androstan-4,15-dien-3-one, 17aB-Hydroxy-17aa-trifluoromethyl-7a-methyl-androstan-4,15-dien-3-one, 17aB,4-Dihydroxy-17aa-trifluoromethyl-androstan-4,15-dien-3-one, 17aB-Hydroxy-17aa-trifluoromethyl-4-chloro-androstan-4,15-dien-3-one, 17aB-Hydroxy-7a-methyl-D-homo-androstan-4,15-dien-3-one, 17aB-Hydroxy-17a-pentafluoroethyl-androstan-4,15-dien-3-one, 17aB-Hydroxy-D-homo-estra-4,15-dien-3-one, 17aB,4-Dihydroxy-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-4-chloro-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-4-bromo-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-4-trifluoromethyl -D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-17aa-methyl-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-17aa-methyl-4-chloro-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-17aa-trifluoromethyl-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-17aa-pentafluoroethyl-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-7a-methyl-D-homo-estra-4,15-dien-3-one, • 17aB-Hydroxy-7a-methyl-4-chloro-D-homo-estra-4,15-dien-3-one, 17aB-Hydroxy-D-homo-estra-1,4,15-trien-3-one, 17aB-Hydroxy-D-homo-4-chloro-estra-1,4,15-trien-3-one, 17aB,4-Dihydroxy-D-homo-estra-l ,4,15-trien-3-one, 17aB-Hydroxy-7a-methyl-D-homo-estra-l ,4,15-trien-3-one, 17aB-Hydroxy-7a-methyl-4-chloro-D-homo-estra-1,4,15-trien-3-one, 13-Ethyl-17aB-hydroxy-D-homo-gona-4,15-dien-3-one, 13-Ethyl-17aB-hydroxy-4-chloro-D-homo-gona-4,15-dien-3-one, 13-Ethyl-17aB-hydroxy-7a-methyl-D-homo-gona-4,15-dien-3-one, 13-Ethyl-17aB-hydroxy-l 7aa-methyl-D-homo-gona-4,15-dien-3-one, 13 -Ethyl-17aB-hydroxy-17aa-methyl-4-chloro-D-homo-gona-4,15 -dien-3-one, 13 -Ethyl-17aB-hydroxy-D-homo-gona-1,4,15 -trien-3 -one, 13-Ethyl-17aB-hydroxy-4-chloro-D-homo-gona-1,4,15-trien-3-one, 13-Ethyl-1 7aB-hydroxy-7a-methyl-D-homo-gona-1,4,15-trien-3-one, 13-Ethyl-17aB-hydroxy-7a-methyl-4-chloro-D-homo-gona-1,4,15-trien-3-one, 17aB-Hydroxy-D-homo-5a-androst-15-en-3-one, 2-Oxa-17aB-hydroxy-D-homo-5a-androst-15-en-3-one 17aB-Hydroxy-D-homo-5a-androstan-1,15 -dien-3 -one, or 2-Hydroxymethylene-17aB-hydroxy-D-homo-5a-androst-15-en-3-one. 13. Process for obtaining a compound according to one of claims 1 to 12 with the general formula I and their pharmaceutically acceptable salts, wherein the compound of general formula II in which R<1> and STEROID have the meanings specified in claims 1 to 12, react in the presence of acids with acylating agents to form dienolacetates, and then reduce with reducing agents to the corresponding 17aB-Hydroxy-D-homo-A<15->Steroids and then introduce the substituents R<1>, R<2>, R<3> and R<4> with the meanings specified in claims 1 to 12. 14. The method according to claim 13, wherein the following steroid basic schemes are used to obtain compounds of the general formula II with parts of the structure A to F A: Androst-4-ene-3,17-dione and dehydroepiandrosterone, B: Estrone, 7a-methylestrone, C, D and E: Epiandrosterone and F: 5a-Androst-2-en-17-one from epiandrosterone. 15. The method according to claim 13 or 14, wherein the functional groups contained in the parts of the structure of the starting materials for the basic steroid skeletons A to F are protected. 16. The method according to claim 15, wherein the keto groups in the starting materials of parts of the structure 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 compound according to one of claims 1 to 12 for the production of hormone replacement therapy drugs in men and women. 19. Use of the compound according to one of claims 1 to 12 for the production of drugs for male and female fertility control. 20. Application of the compound according to one of claims 1 to 12 for the production of drugs for the treatment of hormonally conditioned diseases in men and women. 21. Application of the compound according to claim 20 for the production of drugs for the treatment of endometriosis, mammacarcinoma and hypogonadism.