WO2005113575A1

WO2005113575A1 - Steroid prodrugs with androgenic effect

Info

Publication number: WO2005113575A1
Application number: PCT/EP2005/005256
Authority: WO
Inventors: Ralf Dr. Wyrwa; Peter Dr. Droescher; Sven Dr. Ring; Walter Dr. Elger; Birgitt Schneider; Alexander Dr. Hillisch; Gudrun Reddersen
Original assignee: Schering Aktiengesellschaft
Priority date: 2004-05-21
Filing date: 2005-05-10
Publication date: 2005-12-01
Also published as: ZA200610769B; DE102004025986A1; MXPA06013469A; AU2005245568A1; CA2564963A1; ECSP067028A; CR8785A; UY28911A1; SV2006002123A; BRPI0510136A; EP1747229A1; CN1993375A; NO20065885L; GT200500122A; JP2007538026A; TW200613317A; EA200602049A1; PE20060271A1; IL179293A0; AR049547A1

Abstract

The invention relates to steroid prodrugs with androgenic effect of general formula (I), in which the group Z is bonded to the steroid, pharmaceutical compositions comprising said compounds and the use thereof for the production of medicaments with androgenic effect.

Description

Steroid prodrugs with androgenic effects

The invention relates to steroid prodrugs of the general formula (I)

Group Z (I)

Process for their preparation, pharmaceutical compositions containing them and their use for the production of medicaments with androgenic action.

Androgens play an important role in the organism in both sexes. They exert their effect via a nuclear receptor, the androgen receptor. This plays a role in many organs and tissues. Androgens are essential for male reproductive function, but this only accounts for a small segment of their role in the organism. This includes many metabolic functions, manifestation and maintenance of the skeletal system and the musculature, functions of the liver and kidney, the CNS and the skin, etc. ⁽¹⁾ .

Androgens modulate a number of functions of other hormones, particularly those of estrogens. Examples include estrogen effects in the uterus and vagina, which are antagonized by orrogens or organ-specific modulated. Estrogen / androgen interactions are also of great importance at the pituitary level and in the liver.

The hormonal properties of androgens (testosterone) may be enhanced, attenuated or qualitatively altered in some tissues by enzymatic transformations ^<2) .

The aromatization of testosterone can produce estradiol in target organs. The latter is likely to strongly overshadow the effect of testosterone in the CNS. In the prostate, the skin and skin appendages, a conversion of testosterone into 5α- Dihydrotetosterone (5α-DHT) instead. This androgen is much more potent than testosterone itself. Inhibition of the conversion of testosterone into 5α-DHT severely weakens its androgen action. 5β reduction results in non-androgenic metabolites.

Androgens (testosterone) are already made by the fetal testis. This secretion plays an important role in the development of male sexual routes and male-dominated external sexual characteristics. Also, the central nervous system undergoes a masculine imprint in the phase of intrauterine development. Also in this process, the prenatal sexual differentiation through the androgen secretion of the fetal testicles may play an important role. A female differentiation of all initially bisexual structures and functions takes place when no androgens are present or by the absence or a genetic defect of the androgen receptor is not effective

After birth, the blood levels of testosterone in boys fall to very low levels, and then rise again during sexual maturity to high levels. In this phase they act in the testes on the germinal epithelium in a synergism with the gonadotropic hormones. The sexual organs created under the influence of testosterone in the fetal phase are also dependent on androgens in later life for their function. However, this also applies to a wide range of other organs, tissues and functions, which are controlled by androgens in both sexes or are at least androgen-sensitive ⁽⁴⁾ .

This is especially true for the skin, hair and various appendages of the skin, such as sebaceous and sweat glands. Individuals whose androgen receptor by a genetic

Defective is not functional, have typical disorders of sexual differentiation

(Syndrome of so-called "testicular feminization") and develop, depending on

Extent of defect, little or no axillary and pubic hair ⁽⁵⁾ . Another one

Examples of the role of androgens outside the immediate reproductive functions are their anabolic effects and other metabolic effects on the whole organism. The stronger expression of the musculature in the male sex and the different conditioning and distribution of adipose tissue in the male and female sex are expressions and examples of corresponding androgen effects.

Androgens stimulate the secretion of IGF-1, the most important somatotropic factor in the liver. The formation of new red blood cells is also mediated by the hormone

Erythropoietin positively influenced

, Androgens suppress the growth of mammary glands in men. Beginning with puberty, androgens are also secreted in physiologically relevant amounts in the female sex. The adrenal glands secrete two steroids, androstenedione and dehydroepiandrosterone, which can be converted into testosterone and 5α-dihydrotestosterone in organs with the appropriate enzyme content ' ⁷ '. This transformation is likely to play a major role in the skin. The ovaries secrete androgens, predominantly testosterone. Its secretion increases significantly towards the middle of the cycle to drop again in the luteal phase. There can be no doubt that libido is positively affected by androgens in both sexes ⁽⁸⁾ . Adrenal androgens have been shown to play a major role in well-being. In women treated with glucocorticoids, all adrenal hormone production is suppressed. This is accompanied by depressive moods, which can be significantly improved by substitution treatment with dehydroepiandrosterone ⁽⁹⁾ .

In older age, the testosterone levels in men fall significantly on average. There is a large individual variation from normal to very high hypogonadal values even in the highest age. Even more pronounced is the loss of androgens in women aged. With the elimination of maturing follicles, an important source of androgens dries up. Later, the androgen secretion of the ovarian stroma subsides. With adrenopause, adrenal androgen secretion falls to very low levels a few years after the onset of menopause.

In both genders, in older age, but under special circumstances even before, too low androgen levels and their consequences for mood, libido and metabolic functions can occur. In particular somatotropic functions are affected, which manifest themselves by loss of muscle and bone mass and anemia ⁰⁰ *. The consequences of low androgen levels, however, also include depressive moods, libido disorders and lack of drive.

Testosterone is well tolerated in oral therapy of the aforementioned disorders of the human liver, but must be used in extremely high dosages to achieve therapeutically relevant blood levels. Methyltestosterone and other derivatives have better oral efficacy but are associated with the problem of poor liver tolerance ⁰¹ '. DE 100 27 887.6 A1 discloses steroidally active compounds which are bound to erythrocytes via the group -SO ₂ NR ¹ R ² and are enriched there. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000, preferably 30-1000, so that one can speak of a deposit formation in the erythrocytes. Strong binding of the compounds to the erythrocytes avoids metabolism during liver passage. Disadvantageously, despite a reduced metabolization with the indicated dosages no therapeutically relevant drug levels are given.

It is an object of the invention to provide new steroidal compounds with androgenic action, which are available orally and in comparison to the prior art, even at low dosage ensure a drug-relevant drug levels.

This object is achieved by steroid prodrugs of the general formula (I) in which a group Z is bound to the steroid to be released,

Group Z

(I)

wherein n is a number 0 - 4, R ^{1 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ^{1 is} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH R ²¹ is where R ²⁰ , R ² and R ^{22 are} C _1-5 alkyl, C _3-8 cycloalkyl, aryl, C _1-4 alkylene, C _1-4 alkylene Cycloalkyl group or C ₃ . ₈ -cycloalkylene-C _1-4 -alkyl group and R ^{20 can} also denote a hydrogen, or R ^{2 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ^{1 is} a Hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , wherein R, R and R is a C _1-5 Alkyl group, a C _3-8 cycloalkyl group, an aryl group, a d ^ -Alkylenarylgruppe, a C ^ alkylene-Q ^ -cycloalkyl or Cs-α-cycloalkylene-C ^ alkyl group and R ^{20 is} also a hydrogen or a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ^{1 represent} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 -alkyl group, a C _p F _{2p +} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , wherein R ²⁰ , R ²¹ and R ²² is a Cι _-5 alkyl group, a C _3-8 cycloalkyl group, an aryl group, a C _1- -Alkylenarylgruppe, a Cι ^ alkylene-C. ₃ ₈ -cycloalkyl group or C _3-8 -cycloalkylene-C _1-4 -alkyl group and also R ^{20 can} also denote a hydrogen, and

STEROID for a steroidal ring system according to the general formulas (All - CM) is:

All Bll

CM in which

Y is an oxygen or a carbon atom,

R ⁴ is a hydrogen atom, a halogen atom, a methyl, trifluoromethyl, hydroxy, tri (Cι _-β alkyl) silyloxy, Cι. _5- alkoxy- or a C _2-5 -heterocycloalkyloxy group, R ^{7 is} a hydrogen atom, a methyl or ethyl group,

R ^{10 is} a hydrogen atom, a methyl or ethyl group,

R ^{11 is} halogen, hydrogen, hydroxy, methoxy, OC (O) -R ²⁰ , methyl or ethyl, R ^{12 is} hydrogen, methyl or ethyl, R ^{13 is} hydrogen, Ethyl, ethynyl, trifluoromethyl, pentafluoroethyl group R ^{14 is} a hydrogen atom, an OH group or an oxygen atom bonded via a double bond, R ^{15 is} a hydroxy, tri (C _1-6 -alkyl) silyloxy, C _{1 5} alkoxy group, a group OC (O) -R ²⁰ or a C _2-5 heterocycloalkyloxy group, and their pharmaceutically acceptable salts.

When Y is a carbon atom, additional double bonds may be in 1,2-positions or, when the radical R ^{14 is} a hydrogen atom or an OH group, in the 2,3-positions. An additional double bond may also be in 4,5 positions.

The term "C _1-5 alkyl" is meant a branched or straight chain alkyl group having 1 to 5 carbon atoms in the sense of the present invention, which, for example, by halogen atoms, nitrile group may be substituted hydroxy groups. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl group called.

The term C _L s -alkoxy group is understood to mean a branched or straight-chain alkoxy radical having 1-5 carbon atoms. As Beispie its a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy or n-pentoxy called.

The term tri (C 1 -C 4) -alkyl) silyloxy group is understood as meaning, for example, a trimethylsilyloxy, a triisopropylsilyloxy, a thexyldimethylsilyloxy or a tert-butyldimethylsilyloxy group. The above-mentioned "C ₃ . ₈ -cycloalkyl "means according to the invention a mono- or bicyclic group which may be substituted for example by halogen atoms, hydroxyl groups, nitrile groups, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a hydroxycyclohexyl group.

For the purposes of the present application, the term "aryl group" is understood to mean a substituted or unsubstituted aryl radical having 6 to 15 carbon atoms, for example a phenyl group, a substituted phenyl group, such as a halophenyl group or a nitrophenyl group, a diphenyl group or a naphthyl group.

For the purposes of the present application, the term "C _1-4 -alkylene-aryl group" is understood to mean a disubstituted alkyl radical which is at least substituted by an aryl radical, both radicals having from 7 to 15 carbon atoms, where the group carries further substituents, for example a halogen atom Examples are a benzyl group or a halobenzyl group.

The term "d ^ alkylene-Ca-a-cycloalkyl group" is a disubstituted alkyl radical is understood within the meaning of the present application, at least with a C ₃ H ₈ -.. Cycloalkyl group is substituted, both radicals together have 7 to 15 carbon atoms, wherein the group may carry further substituents such as, for example, a halogen atom, examples being a cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl group.

For the purposes of the present application, the term "C _3-8 -cycloalkylene-C _1-4 -alkyl group" is understood as meaning a disubstituted C 3-β-cycloalkyl radical which is substituted by at least one C _1-4 -alkyl radical 7 to 15 carbon atoms, which group may carry further substituents such as a halogen atom, for example, a propylcyclohexyl or butylcyclohexyl group.

The term "C _p F _{2p + 1} group" in the present invention means a perfluorinated alkyl radical, such as, for example, a trifluoromethyl and pentafluoroethyl radical.

The term "C _2-5 -Heterocycloalkyloxy-group" means a C, _2- ₅ understood -Heterocycloalkyloxy group with a nitrogen or oxygen atom as a hetero atom in the invention, wherein the binding of the Cι. ₅ -Heterocycloalkyloxy group on the Oxygen atom in 2, 3 or 4. An example of this is the perhydropyranoxy group. In the context of the present invention, the term "halogen atom" is understood to mean a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

The number "n" is preferably 0, 1 and 2 and more preferably 0.

Preferably, the group Z is located in the 17- and 4-position, with the 17-position being particularly preferred.

It is preferred that R ¹ represents the residue -SO ₂ NH ₂ or -NHSO ₂ NH _2, where the radical - SO ₂ NH _{2 is} particularly preferred. Mentioned radicals are thus in the m-position of the group Z in relation to the ester group, via which the group Z is bound to the steroid.

R ¹ preferably represents a group -SO ₂ NH ₂ , wherein R ² , R ³ , X ¹ and X are preferably each a hydrogen, fluorine, chlorine atom, a hydroxy or a methoxy group, or

R ² is preferably a group -SO ₂ NH ₂ , wherein R ¹ , R ³ , X ¹ and X are preferably each a hydrogen, fluorine, chlorine atom, a hydroxy or a methoxy group, or

R ³ is preferably a group -SO ₂ NH ₂ , wherein R ¹ , R ² , X ¹ and X are preferably each a hydrogen, fluorine, chlorine atom, a hydroxy or a methoxy group.

Y is preferably a carbon atom.

R ⁴ is preferably a hydrogen atom, a chlorine atom or a hydroxy group.

R ⁷ is preferably a hydrogen atom or a methyl group.

R ¹⁰ is preferably a hydrogen atom or a methyl group.

R ¹¹ is preferably a hydrogen atom, a fluorine atom or a methyl group.

R ¹² is preferably a hydrogen atom.

R ³ is preferably a hydrogen atom or a methyl group. R is preferably an oxygen atom.

R ¹⁵ is preferably a hydroxy group or a group OC (O) -R ^: ₂ o

The radicals Z in position 4, 1 1 or 17, R ⁴ in position 4, R ⁷ in position 7, R ¹¹ in position 1 1, R ¹³ in position 17, depending on Z or R ¹⁵ , and R ¹⁵ in Position 17 can be arranged in both α and β positions.

Particularly preferred steroid prodrugs are listed below: 1) 3-oxo-7α-methylestr-4-en-17β-yl 3'-sulfamoylbenzoate (12), 2) 3-oxo-7α-methylestr-4-ene-17β- yl 4'-sulphamoylbenzoate (11), 3) 3-oxo-7α-methylestr-4-ene-17β-yl 2'-chloro-5'-sulphamoylbenzoate (13), 4) 3-oxo-7α-methylestrol 4-ene-17 (3-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate, 5) 3-oxo-7α-methylestr-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate, 6 ) 3-oxo-7α-methylestr-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulphamoylbenzoate, 7) 3-oxoestr-4-en-17β-yl 3'-sulphamoylbenzoate (7), 8) 3-oxoestr-4-en-17β-yl 4'-sulfamoylbenzoate (8), 9) 3-oxoestr-4-en-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate, 10) 3 Oxoestr-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate, 1 1) 3-oxoestr-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate, 12) 3-oxoestrone 4-en-17β-yl 2 ', 3'-dimethoxy-5 ^, -sulfamoylbenzoate, 13) 3-oxo-7α-methylandrost-4-en-17β-yl 3'-sulfamoylbenzoate, 14) 3-oxo-7α -methylandrost-4-en-17β-yl 4-sulfamoylbenzoate, 15) 3-oxo-7α-methylandrost-4-en-17β-y l 2'-chloro-5'-sulfamoyl benzoate, 6) 3-oxo-7α-methylandrost-4-en-17-yl ^2, ^{4'-dichloro-5,} -sulfamoylbenzoat, 17) 3-oxo-7α-methylandrost 4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate, 18) 3-oxo-7α-methylandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 19) 3-oxoandrost-4-en-17β-yl 3'-sulfamoylbenzoate (5), 20) 3-oxoandrost-4-en-17β-yl 4'-sulfamoylbenzoate (1), 21) 3-oxoandrost-4-ene 17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate, 22) 3-oxoandrost-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate, 23) 3-oxoandrost-4-ene-17β -yl 2'-methoxy-5'-sulfamoylbenzoate, 24) 3-oxoandrost-4-en-17ß-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 25) 3-oxoandrostan-17ß-yl 3'- sulphamoylbenzoate (9), 26) 3-oxoandrostan-17β-yl 4'-sulphamoylbenzoate (10), 27 3-Oxoandrost-4-en-17β-yl 2 ', 4'-dichloro-5'-sulphamoylbenzoate (2), 28 3-Oxoandrost-4-en-17β-yl 2'-chloro-5'-sulphamoylbenzoate ( 3), 29 3-oxoandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate (4), 30 3-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5' sulfamoyl benzoate, 31 3-oxo-4-chloro-17α-methylandrosta-1, 4-dien-17β-yl 3'-sulfamoylbenzoate (16), 32 3-oxo-4-chloro-17α-methylandrosta-1, 4- dien-17β-yl 4'-sulfamoylbenzoate, 33 androst-2-en-17β-yl 3'-sulfamoylbenzoate, 34 3-oxoandrost-4-en-17β-yl 2'-sulfamoylbenzoate (6), 35 androst-2-one en-17β-yl 4'-sulfamoylbenzoate, 36 3-oxo-7α-methyl-11β-fluorostr-4-en-17β-yl 3'-sulfamoylbenzoate (17), 37 3-oxoandrost-4-en-17β-yl 4'-sulfamoylphenylpropionate (14), 38 3-oxo-5α-androst-1-en-17β-yl 3'-sulfamoylbenzoate (15). 39 3-oxoandrost-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate (18), 40 3-oxoandrostane-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate, 41 3-oxo-7α-methyl -11β-fluoroestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate, 42 3-oxoestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate, 43 3-oxo-4-ol 7α-methylestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate, 44 3-oxo-4-chloroandrost-4-en-17β-yl 3'-sulfamoylbenzoate (19), 45 3-oxo 4-chlorandrosta-1, 4-dien-17β-yl 3'-sulfamoylbenzoate (20), 46 3-Oxo-4-hydroxyestr-4-en-17β-yl 3'-sulfamoylbenzoate, 47 3-Oxo-4-hydroxyandrost 4-en-17β-yl 3-sulfamoylbenzoate, 48 3-oxo-l 7β - [(perhydropyran-2-yl) oxy] estr-4-en-4-yl 3'-sulfamoylbenzoate (22), 49 3- oxo-l 7ß- hydroxyestr-4-en-4-yl 3 ^{'-sulfamoylbenzoat} (21). 50 3-Oxoandrost-4-en-17β-yl 2'-chloro-4'-sulfamoylbenzoate (23) 51 3-Oxoandrost-4-en-17β-yl 3'-carboxy-5'-sulfamoylbenzoate (24) 52 3 -Oxoandrost-4-en-17β-yl 3'-carbamido-5'-sulfamoylbenzoate (25)

For the formation of pharmaceutically acceptable salts of the compounds of general formula (I) according to the invention come as inorganic acids, inter alia hydrochloric, hydrobromic, sulfuric and phosphoric acid, and as organic acids, inter alia, 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 into consideration. The compounds of the invention have androgenic activity, wherein the therapeutically relevant steroids are released by ester cleavage of the corresponding compound of formula (I). Thus, it is advantageous to release predominantly androgens having an OH group which have a higher androgenic activity than the compounds having a keto group.

Through experiments

I non-sexed castrated male rats,

II sexually mature castrated rats and III gonadal intact adult sexually mature rats, the oral androgenic and antigonadalotropic activity and the influence on the liver function of the compounds of the invention in relation to known compounds was determined.

The results are shown graphically in FIGS. 1 to 11. Show it:

1 the growth of the accessory sexual glands (prostate) Hershberger test / experiment I,

FIG. 2 shows the rLH content in serum / sample I, FIG. 33 shows the HDL-cholesterol content in plasma / sample I, FIG.

4 the growth of the accessory sexual glands (prostate) Hershberger test / experiment II)

5 shows the rLH content in serum / experiment II,

FIG. 6 shows the HDL-cholesterol content in plasma / experiment II, FIG. 7 shows the MENT content in serum / experiment II, FIG.

8 shows the growth of the accessory sexual glands (prostate) Hershberger test / experiment III,

9 shows the rLH content in serum / experiment III,

Fig. 10 the testosterone content in the serum / Experiment III and FFiiqg .. 1111 the HDL cholesterol content in the serum / Experiment III.

Experiment (I) on non-mature castrated male rats over 8 days

Surprisingly and unexpectedly, the compounds 12 and 18 according to the invention in a test (I) on sexually immature castrated male rats show a dose-dependent strong effect on the growth of accessory sex glands, whereas for (7α-)

Methyl-19-nortestosterone) MENT only marginal effects were observed. Unexpectedly The inventive substances also show a MENT superior antigonadotrophic activity. With regard to the lowering of HDL but MENT is more effective than the substances of the invention.

test description

Method: Male rats weighing approximately 45 g of body weight are castrated and treated orally with MENT and compounds 12 and 18 according to the invention for 7 days. On the 8th day of the experiment, the animals are killed and the hormonal effects of the test substances are evaluated (growth of accessory sexual glands, reduction of gonadotropic hormones in plasma, parameters of hepatic effects: effects on HDL-lipoproteins).

Experiment (II) on sexually mature castrated male rats over 8 days trial (II) was performed on sexually mature castrated male rats. Again, with the substances according to the invention, such as e.g. Compound 12 unexpectedly potent, dose-dependent effects on the growth of accessory gonads were found, while only marginal effects were observed for MENT. Surprisingly, the compounds according to the invention also show a MENT superior antigonadotrophic activity here. With regard to the lowering of HDL, however, (II) MENT is also more effective than the substances according to the invention in this experiment. After oral administration of compounds of the invention, e.g. Compound 12 has significantly higher levels of MENT in the plasma than after administration of MENT itself.

test description

Method: Adult male rats of about 300 g body weight are castrated and treated orally with MENT and compound 12 according to the invention for 7 days. On the 8th day of the experiment, the animals are killed and the hormonal effects of the test substances are evaluated (growth of accessory sexual glands, reduction of gonadotropic hormones in plasma, parameters of hepatic effects: effects on HDL-lipoproteins, determination of MENT in plasma).

Experiment (III) on gonadally intact adult sexually mature rats over 6 weeks In the third trial (III) on gonadally intact adult sexually mature rats for 6 weeks, all the test substances had only marginal effects on accessory sex glands, although it unexpectedly became severe during treatment Waste of endogenous testosterone had come. The compound 12 of the invention induced a dose-dependent increase in the weights of the seminal vesicle and prostate beyond the level of intact controls. Under MENT a corresponding effect did not occur even at extremely high dosage. A superiority of the compound 12 according to the invention could also be ensured with respect to antigonadotropic effects. With regard to lowering of HDL but MENT is more effective than the substances of the invention. The ^'compound 5 according to the invention is distinguished by particularly low hepatic parameters changes.

test description

Method: Adult male rats of more than 300 g body weight are treated orally with MENT and the compounds 12 and 5 according to the invention for 6 weeks. At the end of the experiment, the animals are killed and the hormonal effects of the test substances are evaluated (weight of the testes and accessory sexual glands, reduction of gonadotropic hormones and plasma testosterone during the course of the experiment, parameters of hepatic effects: effects on HDL lipoproteins).

The sulfamoyl benzoates of the androgens according to the invention are clearly superior to the corresponding androgens in terms of oral androgenic and antigonadotropic activity, as could be demonstrated in experiments (I-III). In contrast to the therapeutically desired androgenic effects, effects that reflect the influence on liver functions are clearly reduced.

Examination of erythrocyte binding

The compounds 5 and 12 according to the invention and the compounds 1 and 11 according to the invention were also investigated for binding to erythrocytes.

For the m-substituted compounds significantly weaker bonds to the erythrocytes could be detected. In contrast, the 4'-sulfamoyl benzoates show stronger binding.

However, it was unexpected that, for example, the m-substituted compound 12 has a higher activity in the Hershberger test compared to the p-substituted compound 11 despite lower binding strength to the erythrocytes. The data in Table 1 are intended to illustrate the binding to erythrocytes of selected compounds of Formula (I). Table 1

Binding of selected compounds to erythrocytes and specific erytrocyte / plasma ratio

Test principle and test description:

The SO ₂ -NH ₂ - group of the compounds of the invention can by binding to

Carbonic anhydrases lead to an accumulation in erythrocytes. The displacement of estradiol-3-sulfamate from the erythrocyte binding by test substances is measured. Experimental approach: Human blood is treated with a mixture of ¹⁴ C-labeled and unlabeled estradiol sulfamate. At the selected operating point the erythrocytes are saturated. The distribution in plasma / erythrocytes is 40:60. A second blood sample is spiked with a mixture of ¹⁴ C-labeled estradiol sulfamate and unlabeled test substance. The relative binding affinity is calculated from the proportion of ¹⁴ C-labeled estradiol sulfamate in plasma: high proportion = strong displacement of ¹⁴ C-estradiol sulfamate from the erythrocytes by the test substance = high binding affinity of the test substances to the erythrocytes. Determination of the erythrocyte / plasma distribution ratio

Freshly collected, heparinized blood is mixed with a defined amount of test substance. The concentration in the plasma obtained is measured. The erythrocyte / plasma distribution ratio is calculated from the measured concentration of the total substance in the plasma and the concentration used.

Surprisingly, however, a binding to the carboanhydrase (CA I) located in the erythrocytes could still be shown in all cases (Table 2). It is therefore to be expected that the substances according to the invention also have therapeutically relevant effects as carbonic anhydrase inhibitors. Of importance for the properties as androgen is the binding to erythrocytes induced by the affinity for carbonic anhydrases. This binding is essential for a reduced extraction of the orally administered substance in the first passage of the liver. High or low affinity for the erythrocytic carbonic anhydrases, faster or delayed release from this depot and subsequent hydrolysis determine the therapeutic substitutability of the compounds of the invention.

Unexpectedly, it has been found that the compounds according to the invention achieve therapeutically relevant levels at lower dosages, if the ratio of the loading of the erythrocytes / substance in the plasma - unlike that expected according to DE 100 27 887.6 A1 - is less than 10. The compounds according to the invention open up the possibility of achieving higher, short-lasting or uniformly low and longer-lasting hormone levels with the same absolute substance administration. As a result, the strength and duration of action are varied and a therapy tailored to the individual organism is made possible.

Table 2

ICso inhibition of human carbonic anhydrase

Principle of the test and experimental description Carbonic anhydrases catalyze the CO ₂ hydrogenation.

Experimental approach: A buffer, which was mixed with carbonic anhydrase I, a constant flow of CO _{2 is} passed. Measurement parameter is the time required to lower the pH within defined limits. This parameter reflects the formation of H ₂ CO ₃ in the medium. IC ₅₀ inhibition values are determined by pipetting test substances to the experimental batch. In the concentration ranges examined, the test substances cause no to complete inhibition of said enzymes.

The test results of the in vivo experiments (Experiments I - III) and the possibilities of varying the potency and duration of action for a therapy tailored to the individual organism open up a wide range of possible applications for fertility control and hormone replacement therapy (HRT) in men and women as well as the treatment Hormonal disorders in men and women.

The present invention therefore also pharmaceutical compositions containing at least one compound of general formula (I) or a corresponding salt, optionally together with another steroidal drug and with pharmaceutically acceptable excipients and carriers. Preferred active ingredients are GnRH analogues, progestins, antigestagens and glucocorticoids.

These pharmaceutical compositions and pharmaceutical compositions may preferably be used for oral, but also for rectal, vaginal, subcutaneous, percutaneous, intravenous, buccal, transdermal or intramuscular administration. In addition to conventional carriers and / or diluents they contain at least one compound of the general formula (I) or its salt.

The pharmaceutical compositions of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical excipients according to the desired mode of administration with a suitable dosage. The preferred formulations consist of a dosage form which is suitable for oral administration. Such dosage forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms. Of course, parenteral preparations such as injection solutions come into consideration. Further examples of preparations which may be mentioned are suppositories and vaginal administration agents.

Corresponding tablets, for example, by mixing the active ingredient with known excipients, 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 to achieve a Depot effect such as carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, are obtained. The tablets can also consist of several layers.

Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. In this case, the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.

Solutions or suspensions with the compounds of the general formula (I) according to the invention may additionally contain taste-improving agents such as saccharin, cyclamate or sugar as well as e.g. Flavorings such as vanillin or orange extract contain. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

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

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

The compounds of the invention are steroid prodrugs and have androgenic activity. The compounds of the invention are particularly suitable for oral administration. The therapeutically relevant steroid is released from the compound according to the invention or its salt by ester cleavage. The compounds according to the invention are characterized by a weak erythrocyte binding combined with a good androgenic activity. The factor which serves as a measure of the binding or accumulation in the erythrocytes is known from DE 100 27 887.6 A1 and is less than 10 in the compounds according to the invention.

The compounds of the invention allow the therapeutic use of the androgen-active compound in the form of an oral therapy, which are not suitable for this form of therapy due to low oral bioavailability, e.g. those of testosterone, 5α-DHT or MENT.

The compounds of the present invention are useful for replacement therapy, especially for replacement therapy in combination with antigonadotropic and antifertile strategies in males in conjunction with a GnRH analog, a progestin, or other therapies that suppress endogenous androgen secretion.

The compounds according to the invention are also suitable for the replacement therapy in combination with glucocorticoids or other therapies which lead to the suppression of adrenal androgen secretion.

The compounds of the invention are also suitable for the replacement therapy in women, especially after a age-typical decline in ovarian and adrenal androgen secretion.

The compounds of the invention minimize liver compatibility problems. For conventional, orally administered androgens, especially for C-17 alkylated androgens, it is known that the liver is heavily loaded. The androgens contained in the compounds of the invention do not burden the liver after their release.

The compounds according to the invention increase the oral bioavailability of the androgen contained. The entire amount of hormone acting on the organism is therefore reduced. The hormonal effect on the liver at the first passage is reduced. This reduces known adverse effects of oral androgen therapy on lipid metabolism (lowering HDL cholesterol, increasing atherogenic risk) and other hepatic secretory products. Androgens differ in their hormonal action spectra and thus in their suitability for various therapeutic requirements. The compounds according to the invention make it possible to select differentiated androgen therapy by selecting the androgen contained.

The following examples serve to illustrate the invention without limiting it thereto.

General Synthesis Instructions

For the preparation of the general formula (All-Cll) underlying androgens can be used to known steroid body. The following basic steroid bodies can be used, for example: testosterone, dihydrotestosterone, 19-nortestosterone, 7α-methyl-19-nortestosterone, 7α-methyl-11β-fluoro-19-nortestosterone and 3,3-dimethoxy-estr-5 (10) -17- on (DD 79-213049), epiandrosterone, 5α-androst-2-en-17-one from epiandrosterone (US-A-3,098,851), 7α-methyl-11β-methyl-19-nortestosterone, 7α-methyl-11β-methyltestosterone , Oxandrolone, Oral Turinabol, 17α-Methyltestosterone etc.

The functional groups contained in the starting materials for the basic steroid body may optionally be protected by methods known to those skilled in the art or converted into corresponding functional groups. Thus, keto groups in the starting materials can be protected as ketals or thiocetals by methods known to those skilled in the art. 17-keto compounds can be reduced to hydroxyl compounds by methods known to those skilled in the art.

A) Coupling of the steroidal compound with the group Z variant 1

Reaction with sulfamoylphenylcarboxylic acids

An androgen is dissolved in a base such as pyridine. To the solution are added appropriate amounts of a sulfamoylphenylcarboxylic acid, then an acid such as p-toluenesulfonic acid and finally a carbodiimide such as dicyclohexylcarbodiimide are added. The reaction mixture is stirred until complete. Subsequently, water is added and acidified with an acid such as 10% HCl. The precipitate is filtered off, washed with water, NaHCO ₃ solution and dried. The residue is extracted with an organic solvent such as ethyl acetate, the organic phase is washed and dried with a drying agent such as MgSO 4. After filtration, it is concentrated and chromatographed on silica gel. Are obtained corresponding Androgensulfamoylbenzoate. Variant 2

Reaction with sulfamoylphenylcarboxylic acid chlorides

An androgen is dissolved in a base such as pyridine. To the solution is added the appropriate amount of a sulfamoylphenyl carboxylic acid chloride. The reaction mixture is stirred until complete. Subsequently, water is added and acidified with an acid such as 10% HCl. It is extracted with an organic solvent such as ethyl acetate, the organic phase washed and dried with a drying agent such as MgSO ₄ . After filtration, it is concentrated and chromatographed on silica gel. Are obtained corresponding Androgensulfamoylbenzoate.

Variant 3

Reaction with Chlorsulfonylphenylcarbonsäurechloriden

An androgen is in a base, such. Pyridine and an organic solvent, e.g. Chloroform dissolved and cooled. To the solution is added the appropriate amount of a Chlorsulfonylphenylcarbonsäurechlorides. The reaction mixture is stirred until complete reaction at room temperature. Subsequently, the reaction mixture is stirred into concentrated ammonia solution. The mixture is concentrated and acidified with an acid, e.g. 10% HCL acidified. The precipitate is filtered off, washed with water, dried and chromatographed on silica gel. Are obtained corresponding Androgensulfamoylbenzoate.

Variant 4

Reaction with 2-sulfophenylcarboxylic acid cyclo-anhydride An androgen is dissolved in an organic solvent such as chloroform. After addition of 2-sulfophenylcarboxylic acid cyclo-anhydride is stirred under inert gas at elevated temperatures. It is then cooled and treated with a concentrated ammonia solution such as methanolic ammonia solution. The solvents are distilled off and the residue is chromatographed on silica gel. This gives 2-Sulfophenylcarbonsäureester ammonium salts of corresponding androgens, which are dissolved in an organic solvent such as CHCl ₃ under inert gas. Portionwise, an appropriate amount of a chlorinating agent, such as PCI ₅ or SOCI _{2 is} added. The reaction mixture is optionally stirred at higher temperatures and then briefly in concentrated. NH ₃ solution given. The mixture is concentrated, the precipitated substance is filtered off, washed with water, dried and chromatographed on silica gel. This gives 2 ^{'-Surfamoylphenylcarbonsäureester} corresponding androgens. Variant 5

Reaction to sulfamides (NH ₂ S0 ₂ NH-)

The conversion to the sulfamides according to the invention is carried out by methods known to those skilled in the art for their preparation starting from corresponding amines by means

Sulfamide, sulfamoyl chloride or aminosulfonyl isocyanate (P.O. Burke et al., J. Chem. Soc.

Perk. Trans 2, 1984, 1851; M. Preiss et al. Chem. Ber., 1978, 1915; C.-H. Lee et al., J. Org.

Chem., 1990, 6104.).

For example, a corresponding aminobenzoate in an organic solvent such as toluene in the presence of a base such as NEt ₃ with sulfamoyl chloride at

Temperatures of 20-60 ° C implemented. The reaction mixture is until complete

Reaction stirred. Then water is added, the precipitate filtered off with

Washed water, NaHCO ₃ solution and dried. The substance is purified by chromatography on silica gel. Corresponding androgensulfamoylaminobenzoates are obtained.

B) Synthesis of the group Z 2-chloro-4-sulfamoylbenzoic acid stage 1

10 g of 2-chloro-toluene-4-sulfonic acid-Na-SalzxH ₂ O are added in 40 ml of thionyl chloride. After addition of 5 ml of DMF is refluxed for 6 h. The cold reaction mixture is added to 200 g of ice. The precipitated substance is washed with water and dried. This gives 2-chloro-toluene-4-sulfonic acid chloride. ¹ H-NMR (DMSO-de): 2.32 (s, 3H, Me), 7.32-7.58 (m (superimposed), 3H, CH)

Level 2

8 g of 2-chloro-toluene-4-sulfonic acid chloride were dissolved in 25 ml of CHCl ₃ and slowly poured into 100 ml of conc. Stirred NH ₃ solution. After stirring for 10 min at RT, the solution is concentrated by half. The substance is filtered off with suction, washed with water and dried. 2-Chloro-4-sulfamoyltoluene is obtained.

¹ H-NMR (DMSO-dβ): 2.39 (s, 3H, Me), 7.44 (s, 2H, NH ₂ ), 7.55-7.83 (m (superimposed), 3H, CH)

Stage 3 1.67 g of 2-chloro-4-sulfamoyltoluene are initially charged in 70 ml of water. After addition of 5 g of KMnO and 0.5 ml of sat. NaHCO ₃ sol. is heated under reflux for 2 h. After addition of 2 ml of MeOH, resulting manganese dioxide is filtered off and the solution in half concentrated. After acidification with 10% HCl, the solution is cold for 8 h for complete crystallization. It is then filtered off with suction, washed with water and dried. 2-Chloro-4-sulfamoylbenzoic acid is obtained. ¹ H-NMR (DMSO-d ₆ ): 7.66 (s, 2H, NH ₂ ), 7.80-8.02 (m (superimposed), 3H, CH), 13.86 (s, 1H, COOH)

5-sulfamoylisophthalic acid Step 1 20 g of 5-sulfoisophthalic acid Na salt are boiled in 80 ml of thionyl chloride with the addition of 5 ml of DMF for 5 h. The cold reaction mixture is added to 500 g of ice and the precipitated substance is filtered off with suction, washed with water and dried. 5-Chlorosulfonylisophthalic acid dichloride is obtained. ¹ H-NMR (CDCl ₃ ): 8.98 (s, 2H, H-4,6), 9.11 (s, 1 H, H-2)

Level 2

10 g of 5-chlorosulfonylisophthaloyl chloride are stirred in small portions in 150 ml of NH ₃ solution. The solution is concentrated, the precipitated substance is filtered off, washed with water and dried. 5-sulfamoylisophthalic acid diamide is obtained. ¹ H-NMR (DMSO-d ₆ ): 7.51, 7.67, 8.22 (6H, NH ₂ ), 8.43 (s, 2H, H-4,6), 8.53 (s, 1H, H-2)

level 3

1 g of 5-sulfamoylisophthalic acid diamide are suspended in 20 ml of 1,4-dioxane. 5 ml of 10% HCl are added and the reaction mixture is heated to about 90 ^{C for} 3 h. Subsequently, the reaction mixture is concentrated to dryness. The residue is chromatographed on silica gel. 5-sulfamoylisophthalic acid monoamide and 5-sulfamoylisophthalic acid are obtained.

4-Chlorosulfonylbenzoic acid chloride 15 g of 4-sulfonobenzoic acid K salt are added in 100 ml of sat. Dissolved ammonia solution. The solution is concentrated and the salt is dried over P ₂ O ₅ . 5 g of the salt are dissolved in 20 ml of SOCl ₂ . 0.3 ml of DMF are added to the reaction mixture and heated under reflux for 2 h. It is allowed to cool, toluene is added to crystallize and filtered off. The product is washed with toluene and dried. 4-chlorosulfonylbenzoic acid chloride is obtained, which is used for further reactions. Svnthesebeispiele

Example 1 3-Oxoandrost-4-en-17β-yl 4'-sulfamoylbenzoate (1)

version 1

1.0 g of testosterone is dissolved in 10 ml of pyridine. After addition of 1.5 g of p-

Sulfamoylbenzoic acid, 200 mg of p-toluenesulfonic acid and 1.5 g of dicyclohexylcarbodiimide (DCC) are stirred for 48 hours at room temperature. Subsequently, 20 ml of water are added. It is slightly acidified with 10% HCl (pH = 5). The precipitate is filtered off and washed 2x with sat. NaHCO ₃ sol. and water washed. The dried residue is extracted with ethyl acetate. The organic phase is washed with 10% NaHCO ₃ solution and sat. NaCl solution, dried over MgSO4, filtered, concentrated and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 4'-sulphamoylbenzoate (1) is obtained.

Variant 2

1.0 g of testosterone is dissolved in 10 ml of pyridine. After addition of 1.0 g of p-sulfamoylbenzoic acid chloride is stirred for 2 hours at room temperature. After addition of 20 ml of water is slightly acidified with 10% HCl (pH = 5). It is then extracted with ethyl acetate. The organic phase is separated off with 10% NaHCO ₃ solution and with sat. NaCl solution, dried over MgSO ₄ , filtered, concentrated and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 4'-sulphamoylbenzoate (1) is obtained.

¹ H-NMR (DMSO-d _6): 0.95 (s, 3H, H-18), 1.17 (s, 3 H, H-19), 4.80 (m, 1H, H-17α), 5.64 (s, 1 H, H-4), 7.56 (s, 2H, NH ₂ ), 7.92-8.15 (m, 4H, Ar).

Example 2

3-Oxoandrostan-17ß-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate (2) The substance is obtained analogously to Example 1 according to variant 1, starting from 2,4-dichloro-5-sulfamoylbenzoic acid and testosterone. ¹ H-NMR (DMSO-d ₆ ): 0.90 (s, 3H, H-18), 1.16 (s, 3H, H-19), 4.82 (m, 1H, H-17α), 5.64 (s, 1 H, H-4), 7.88 (s, 2H, NH ₂ ), 8.02 (s, 1H, H-Ar), 8.37 (s, 1H, H-Ar). Example 3

3-Oxoandrost-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (3)

The substance is obtained analogously to Example 1 according to variant 1, starting from 2-chloro-5-sulfamoylbenzoic acid and testosterone. ¹ H-NMR (DMSO-d ₆ ): 0.90 (s, 3H, H-18), 1.16 (s, 3H, H-19), 4.77 (m, 1H, H-17α), 5.64 (s, 1 H, H-4), 7.56 (s, 2H, NH ₂ ), 7.75-8.80 (m, 3H, H-Ar).

Example 4

3-Oxoandrost-4-en-17ß-yl 2'-methoxy-5'-sulfamoylbenzoate (4) The substance is obtained analogously to Example 1 according to variant 1, starting from 2-methoxy-5-sulfamoylbenzoic acid and testosterone.

¹ H-NMR (DMSO-de): 0.90 (s, 3H, H-18), 1.16 (s, 3H, H-19), 4.74 (m, 1H, H-17α), 5.64 (s, 1H , H-4), 7.33 (m, 1H, H-Ar), 7.35 (s, 2H, NH ₂ ), 7.92-8.07 (m, 2H, H-Ar).

Example 5

3-Oxoandrost-4-en-17β-yl 3'-sulphamoylbenzoate (5)

1.0 g of testosterone is dissolved in 2 ml of pyridine and 2 ml of CHCl ₃ . The reaction mixture is at

-20 ° C with stirring 1.0 ml of 3-Chlorsulfonylbenzoesäurechlorid added. The mixture is then warmed to RT and stirred for 15 min. The reaction solution is concentrated in 25 ml. NH ₃ solution and stirred for 15 min. Then the org. Distilled off LM. It is slightly acidified with 10% hydrochloric acid (pH = 5). The precipitated substance is filtered off, washed with 10% NaHCO ₃ solution and water, dried and chromatographed on silica gel. 3-Oxoandrost-4-en-17ß-yl 3'-sulphamoylbenzoate (5) is obtained. ¹ H-NMR (CDCl ₃ ): 0.98 (s, 3H, H-18), 1.21 (s, 3H, H-19), 4.88 (m, 1H, H-17α), 5.28 (s, 2H, NH ₂ ), 5.74 (s, 1H, H-4), 7.33 (m, 1H, H-Ar), 7.60-8.60 (m, 4H, H-Ar).

Example 6 3-Oxoandrost-4-en-17β-yl 2'-sulfamoylbenzoate (6)

step 1

3-Oxoandrost-4-en-17ß-yl 2'-sulfobenzoate ammonium salt

2.5 g of testosterone are dissolved in 10 ml of chloroform. After adding 3.5 g of 2-

Sulfobenzoic acid-cyclo-anhydride is stirred under inert gas at 50 ° C for 12 h. It is then cooled to 0 ° C and with a concentrated methanolic

Ammonia solution added. The solvents are distilled off and the residue on Silica gel chromatographed. 3-Oxoandrost-4-en-17ß-yl is obtained 2'-sulfobenzoat-

Ammonium salt.

¹ H-NMR (DMSO-de): 0.81 (s, 3H, H-18), 1.15 (s, 3H, H-19), 4.67 (m, 1H, H-17α), 5.63 (s, 1H , H-4), 7.33 (m, 1H, H-Ar), 7.18-7.75 (m, 4H, H-Ar).

Level 2

3-Oxoandrost-4-en-17β-yl 2'-sulphamoylbenzoate (6)

3.95 g of 3-oxoandrost-4-en-17ß-yl 2'-sulfobenzoate ammonium salt are dissolved in 160 ml of CHCl ₃ under inert gas. Portions of 6.0 g of PCI _{5 are added} within 1 h. The reaction mixture is stirred for 12 h at RT and then concentrated in 600 ml. NH ₃ solution given. The mixture is concentrated, the precipitated substance is filtered off, washed with water, dried and chromatographed on silica gel. 3-oxoandrost-4-ene is obtained

17β-yl 2'-sulfamoylbenzoate (6).

¹ H-NMR (CDCl ₃ ): 0.94 (s, 3H, H-18), 1.20 (s, 3H, H-19), 4.90 (m, 1H, H-17α), 5.73 (s, 1H, H-4), 5.80 (s, 2H, NH ₂ ), 7.58-8.15 (m, 4H, H-Ar).

Example 7

3-oxoestr-4-en-17β-yl 3'-sulfamoylbenzoate (7)

The substance is obtained analogously to Example 5, starting from nandrolone, 3-Chlorsulfonylbenzoesäurechlorid and ammonia.

¹ H-NMR (DMSO-d _6): 0.98 (s, 3H, H-19), 4.82 (m, 1H, H-17α), 5.74 (s, 1 H, H-4), 7:54 (s, 2H , NH ₂ ), 7.68-8.38 (m, 4H, H-Ar).

Example 8 3-Oxoestr-4-en-17β-yl 4'-sulfamoylbenzoate (8)

The substance is analogously to Example 1 variant 1 starting from nandrolone and p-

Obtained sulfamoylbenzoic acid.

¹ H-NMR (DMSO-d _6): 0.97 (s, 3H, H-19), 4.80 (m, 1 H, H-17α), 5.74 (s, 1H, H-4), 7:57 (s, 2H , NH ₂ ), 7.92-8.15 (m, 4H, H-Ar).

Example 9

3-oxoandrostane-17β-yl 3'-sulfamoylbenzoate (9)

The substance is prepared analogously to Example 5, starting from 17ß-hydroxy-5α-androstan-3-one, 3

Chlorsulfonylbenzoesäurechlorid and ammonia. ¹ H-NMR (DMSO-d _6): 0.92 (s, 3H, H-18), 1.00 (s, 3H, H-19), 4.79 (m, 1 H, H-17α), 7:54 (s, 2H , NH ₂ ), 7.68-8.38 (m, 4H, H-Ar). Example 10

3-oxoandrostane-17β-yl 4'-sulfamoylbenzoate (10)

The substance is obtained analogously to Example 1 variant 1, starting from 17ß-hydroxy-5α-androstan- 3-one and p-sulfamoylbenzoic acid. ¹ H-NMR (DMSO-de): 0.92 (s, 3H, H-18), 0.99 (s, 3H, H-19), 4.78 (m, 1H, H-17α), 7.56 (s, 2H, NH ₂ ), 7.90-8.13 (m, 4H, H-Ar).

Example 11

3-oxo-7α-methylestr-4-en-17β-yl 4'-sulfamoylbenzoate (11) The substance is prepared analogously to Example 1 variant 1 starting from 17β-hydroxy-7α-methylestr-4-en-3-one (MENT) and p-sulfamoylbenzoic acid.

¹ H-NMR (DMSO-d ₆ ): 0.75 (d, 3H, 7α-Me), 0.98 (s, 3H, H-19), 4.82 (m, 1H, H-17α), 5.72 (s, 1 H, H-4), 7.55 (s, 2H, NH ₂ ), 7.92-8.15 (m, 4H, H-Ar).

Example 12

3-oxo-7α-methylestr-4-en-17β-yl 3'-sulfamoylbenzoate (12)

The substance is analogously to Example 5, starting from 17ß-hydroxy-7α-methylestr-4-en-3-one

(MENT), Chlorsulfonylbenzoesäurechlorid and ammonia.

¹ H-NMR (DMSO-de): 0.75 (d, 3H, 7α-Me), 0.98 (s, 3H, H-19), 4.83 (m, 1H, H-17α), 5.74 (s, 1 H, H-4), 7.57 (s, 2H, NH ₂ ), 7.68-8.38 (m, 4H, H-Ar).

Example 13

3-oxo-7α-methylestr-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (13)

The substance is obtained analogously to Example 1 variant 1 starting from 17ß-hydroxy-7α-methyl-4-en-3-one (MENT) and 2-chloro-5-sulfamoylbenzoesäure.

¹ H-NMR (DMSO-d ₆ ): 0.74 (d, 3H, 7α-CH ₃ ), 0.93 (s, 3H, H-19), 4.84 (m, 1 H, H-17α), 5.72 (s, 1 H, H-4), 7.60 (s, 2H, NH ₂ ), 7.75-8.18 (m, 4H, H-Ar).

Example 14 3-Oxoandrost-4-en-17β-yl 4'-sulfamoylphenylpropionate (14)

The substance is analogously to Example 1 according to variant 1, starting from 3- (p-

Sulfamoylphenyl) propionic acid and testosterone.

¹ H-NMR (DMSO-d _6): 0.74 (s, 3H, CH _3), 1.14 (s, 3 H, _CH3), 2.66 (t, 2 H, CH _2), 2.92 (t, 2H, CH ₂ ), 4.50 (m, 1H, H-17α), 5.62 (s, 1H, H-4), 7.28 (s, 2H, NH ₂ ), 7.37-7.72 (m, 4H, H-Ar). Example 15

3-oxo-5α-androst-1-en-17β-yl 3'-sulfamoylbenzoate (15)

The substance is obtained analogously to Example 5 starting from 17β-hydroxy-5α-androst-1-en-3-one, 3-chlorosulfonylbenzoic acid chloride and ammonia. ¹ H-NMR (DMSO-d _6): 0.94 (s, 3H, H-18), 0.99 (s, 3 H, H-19), 4.82 (m, 1 H, H-17α), 5.74 (s, 1H, H-2), 7.21 (s, 1H, H-1), 7.54 (s, 2H, NH ₂ ), 7.70-8.38 (m, 4H, H-Ar).

Example 16 3-Oxo-4-chloro-17α-methylandrosta-1,4-dien-17β-yl 3'-sulfamatobenzoate (16) = sulfamoylbenzoate (16)

The substance is obtained analogously to Example 5, starting from 4-chloro-17α-methyl-17ß-hydroxyandrosta-1, 4-dien-3-one, 3-Chlorsulfonylbenzoesäurechlorid and ammonia. ¹ H-NMR (DMSO-de): 1:02 (s, 3H, H-18), 1.31 (s, 3 H, H-19), 1:48 (s, 3 H, CH ₃ - 17α), 6.30 (d, 1 H, H-2), 7.31 (d, 1 H, H-1), 7.53 (s, 2H, NH ₂ ), 7.70-8.38 (m, 4H, H-Ar).

Example 17 3-Oxo-7α-methyl-11.beta.-fluoro-estr-4-en-17-yl 3 ^{'-sulfamoylbenzoat} (18)

The substance is obtained according to variant 3 analogously to Example 5 starting from 17ß-hydroxy-7α-methyl-11ß-fluoro-estr-4-en-3-one, 3-Chlorsulfonylbenzoesäurechlorid and ammonia. ¹ H-NMR (DMSO-d _6): 0.77 (d, 3H, 7α-Me), 1:07 (s, 3H, H-18), 4.85 (m, 1 H, H-17α), 5.78 (s, 1H , H-4), 7.55 (s, 2H, NH ₂ ), 7.70-8.38 (m, 4H, H-Ar).

Example 18

3-Oxoandrost-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate (18)

The substance is obtained analogously to Example 1 according to variant 1, starting from 2-hydroxy-5-sulfamoylbenzoic acid and testosterone. ¹ H-NMR (DMSO-d ₆ ): 0.94 (s, 3H, H-18), 1.17 (s, 3H, H-19), 4.81 (m, 1H, H-17α), 5.64 (s, 1 H, H-4), 7.14 (m, 1H, H-Ar), 7.36 (s, 2H, NH ₂ ), 7.90-8.2 (m, 2H, H-Ar), 11.03 (s, 1H, OH ). Example 19

3-Oxo-4-chlorandrost-4-en-17β-yl 3'sulfamoylbenzoate (19)

The substance is obtained analogously to Example 5 according to variant 3, starting from 3-oxo-4-chloro-17ß- hydroxyandrost-4-ene and 3-Chlorsulfonylbenzoesäurechlorid.

¹ H-NMR (DMSO-de): 0.95 (s, 3H, H-18), 1.23 (s, 3H, H-19), 4.81 (, 1H, H-17α), 7.55 (s, 2H, NH ₂ ), 7.75 (m, 1H, H-Ar), 8.05-8.28 (m, 2H, H-Ar), 8.38 (s, 1H, H-Ar)

Example 20

3-Oxo-4-chlorandrosta-1,4-dien-17β-yl 3'-sulfamoylbenzoate (20)

The substance is obtained analogously to Example 5 according to variant 3, starting from 3-oxo-4-chloro-17ß- hydroxyandrosta-1, 4-diene and 3-Chlorsulfonylbenzoesäurechlorid. ¹ H-NMR (DMSO-de): 4.81 (m, 1H, H-17α), 7.55 (s, 2H, NH ₂ ), 7.75 (m, 1H, H-Ar), 8.05-8.28 (m, 2H, H-Ar), 8.38 (s, 1H, H-Ar).

Example 21

3-oxo-17β-hydroxyestr-4-en-yl 3'-sulfamoylbenzoate (21)

Step 1: 4-Thexyldimethylsilyloxy-17β-acetoxyestr-4-en-3-one

5.9 g of 4-hydroxy-17ß-acetoxyestr-4-en-3-one are reacted in 58 ml of DMF with 12 g of imidazole and 15 ml of Thexyldimethylsilylchlorid 2h at 35 ° C. To the reaction solution 500 ml

Given water. It is then extracted with ethyl acetate, dried with MgSO ₄ and concentrated. The product is purified by chromatography on silica gel. You get 4-

Thexyldimethylsilyloxy-17-acetoxyestr-4-en-3-one.

¹ H NMR (CDCl ₃ ): 0.14 (s, 6H, SiMe), 0.65-0.88 (m (sup.), 15H, thexyl, H-18), 2.04 (s, 3H, OAc), 4.60 (m, 1H, H-17α).

Step 2: 4-Thexyldimethylsilyloxy-17β-hydroxyestr-4-en-3-one

2 g of 4-thexyldimethylsilyloxy-17β-acetoxyestr-4-en-3-one are dissolved in 50 ml of MeOH. After addition of 2 g K ₂ CO ₃ and 2 ml of water is stirred at 30 ° C for 2 h. 100 ml of water are added to the reaction solution and most of the MeOH is distilled off. It is then extracted with ethyl acetate, dried with MgSO 4 and concentrated. The product is purified by chromatography on silica gel. 4-Thexyldimethylsilyloxy-17β-hydroxyestr-4-en-3-one is obtained. Step 3: 4-Thexyldimethylsilyloxy-17β-rperhv-pyran-2-yl) oxylestr-4-en-3-one 1 g of 4-thexyldimethylsilyloxy-17β-hydroxyestr-4-en-3-one is taken up in 16 ml of CH ₂ Cl ₂ 1.8 ml of dihydropyran and 80 mg of pyridinium tosylate 2h reacted. To the reaction solution, 10 ml of sat. Added Na ₂ CO ₃ solution. The mixture is then extracted with CH ₂ CI _2, dried with MgSO ₄ and concentrated. The product is purified by chromatography on silica gel. 4-Thexyldimethylsilyloxy-17β- [perhydropyran-2-yl) oxy] estr-4-en-3-one is obtained.

Step 4: 4-Hydroxy-17β-fpervovy-pyran-2-yl) oxylestr-4-en-3-one

1 g of 4-thexyldimethylsilyloxy-17β- [perhydropyran-2-yl) oxy] estr-4-en-3-one is reacted in 20 ml of THF with 300 mg of TBAF for 1 h at RT. To the reaction solution, 10 ml of water are added. It is then extracted with ethyl acetate, dried with MgSO ₄ and concentrated. The product is purified by chromatography on silica gel. 4-Hydroxy-17ß- [perhydropyran-2-yl) oxy] ester-4-en-3-one is obtained.

Step 5: 3-Oxo-17β-fibrethoxy-2-yl) oxylestr-4-en-4-yl 3'-sulfamoylbenzoate (22)

The substance is obtained analogously to Example 5 according to variant 3, starting from 4-hydroxy-17ß- [perhydropyran-2-yl) oxy] estr-4-en-3-one and 3-Chlorsulfonylbenzoesäurechlorid.

Step 6: 3-Oxo-17β-hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoate (21) 500 mg 3-oxo-17β- [perhydropyran-2-yl) oxy] estr-4-ene-4 yl 3 ^' -sulfamoylbenzoate are dissolved in 25 ml of acetone and reacted with 3 ml of 10% HCl for 1 h at RT. To the reaction solution, 10 ml of sat. Added Na ₂ CO ₃ solution. Subsequently, acetone is distilled off and extracted with ethyl acetate, dried with MgSO ₄ and concentrated. The product is purified by chromatography on silica gel. This gives 3-oxo-l 7ß-hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoate (21).

1 H-NMR (DMSO-De): 0.71 (see 3H, H-18), 3.46 (m, 1H, H-17α), 4.50 (d, 1H, 4-OH), 7.57 (s, 2H , NH ₂ ) 7.75-8.44 (m, 4H, H-Ar).

Example 22

3-Oxoandrost-4-en-17β-yl 2'-chloro-4'-sulfamoylbenzoate (23)

1.0 g of testosterone is dissolved in 20 ml of pyridine. After addition of 1.5 g of 2-chloro-4-sulfamoylbenzoic acid, 250 mg of p-toluenesulfonic acid and 1.5 g of DCC is stirred for 48 hours at room temperature. Subsequently, 100 ml of water and 30 ml of CHCl _{3 are} added. It is slightly acidified with 10% HCl (pH = 5). The precipitate is filtered off and washed with CHCl ₃ . The organic phase is separated off with 10% NaHCO ₃ solution and sat. NaCl solution, dried over MgSO ₄ , filtered, concentrated and chromatographed on silica gel. 3-Oxoandrost-4-ene-17β-yl 2'-chloro-4'-sulphamoylbenzoate is obtained.

¹ H-NMR (DMSO-de): 0.89 (s, 3H, H-18), 1.16 (s, 3H, H-19), 4.80 (t, 1H, H-17), 5.64 (s, 1H, HC =), 7.64 (s, 2H, NH ₂ )

Example 23

3-oxoandrost-4-en-17β-yl 3'-carboxy-5'-sulfamoylbenzoate (24) 1.0 g of testosterone is dissolved in 3.5 ml of pyridine. After addition of 1.1 g of 5-sulfamoylisophthalic acid and 880 mg EDC is stirred for 48 hours at room temperature. Subsequently, 10 ml of water are added. It is acidified with 10% HCl. The precipitate is filtered off, washed with water and dried. On silica gel is chromatographed. 3-Oxoandrost-4-en-17ß-yl 3'-carboxy-4'-sulphamoylbenzoate is obtained.

¹ H-NMR (DMSO-de): 0.96 (s, 3H, H-18), 1.17 (s, 3H, H-19), 4.84 (t, 1H, H-17), 5.64 (s, 1H, HC =), 7.62 (s, 2H, NH ₂ ), 7.72, 8.45 (2H, NH ₂ )

Example 24

3-Oxoandrost-4-en-17β-yl 3'-carbamido-5'-sulfamoylbenzoate (25)

1.0 g of testosterone is dissolved in 3.5 ml of pyridine. After adding 1.1 g of 5-

Sulfamoylisophthalic acid monoamide and 880 mg EDC are added for 48 hours

Room temperature stirred. Subsequently, 10 ml of water are added. It is acidified with 10% HCl. The precipitate is filtered off, washed with water and dried. On silica gel is chromatographed. 3-oxoandrost-4-en-17ß-yl is obtained

3'-carbamido-4'-sulfamoyl benzoate.

¹ H-NMR (DMSO-d ₆ ): 0.95 (s, 3H, H-18), 1.17 (s, 3H, H-19), 4.83 (t, 1H, H-17), 5.64 (s, 1H, HC =), 7.55 (s, 2H, NH ₂ ), 8.35-8.64 (3s, 3H, CH) literature

(1) Moordian AD, Morley JE and Korenman SG (1987) Biological actions of androgens. Endocr. Rev. 8, 1-27. (2) Rommerts FFG (1990) Testosterone: An overview of biosynthesis, transport, metabolism and nongenomic actions. In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 1, 1-31; Wilson JD, Griffin JE, Russell DW (1993) Steroid 5α-reductase 2 deficiency. Endocr. Rev. 14, 577-93. (3) Jost A (1946) Recherches sur la differenciation sexual de Tembryon de lapin: III. Role of the gonades foetales dans la differenciation sexual somatique. Arch Anat micr Morph exp; 36, 271-315; Neumann F, Berswordt-Wallrabe R, Elger W, Steinbeck H, Hahn JD, et al. (1970) Aspects of androgen-dependent events as studied by antiandrogens. Recent Prog. Horm. Res. 26, 337-410; Neumann F, Elger W, Kramer M (1966) Development of a vagina in male rats by inhibiting androgen receptors with anti-androgen during the critical phase of organogenesis. Endocrinology 78 (3), 628-32.

(4) Liu PY and Handelsman DJ (1990) androgen therapy in non-gonadal disease. In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 17, 473-512.

(5) Quigley CA (1990) The androgen receptor: Physiology and pathophysiology. In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 2, 33-106.

(6) Cardim HJP, Lopes CMC, Giannella-Neto D, as Fonseca AM and Pinotti JA (2001), The insulin-like growth factor-l system and hormone replacement therapy. Fertility and Sterility 75 (2), 282-7; Liu PY and Handelsman DJ (1990) androgen therapy in non-gonadal disease. In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2 ^πd Edition (1998), Springer, Berlin Heidelberg, Chapter 17, 473-512. (7) Rommerts FFG (1990) Testosterone: An overview of biosynthesis, transport, metabolism and nongenomic actions. In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2 ^πd Edition (1998), Springer, Berlin Heidelberg, Chapter 1, 1-31.

(8) Moordian AD, Morley JE and Korenman SG (1987) Biological actions of androgens. Endocr. Rev. 8, 1-27. (9) Arlt W, Callies F and Allolio B (2000), DHEA replacement in women with adrenal 1 insufficiency - pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition. Endocr. Res. 26 (4), 505-11.

(10) Liu PY and Handelsman DJ (1990) Androgen therapy in non-gonadal disease. In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 17, 473-512.

(11) Nieschlag E and Behre HM (1990) Pharmacology and clinical uses of testosterone. In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 10, 293-328. (12) C. Ladolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 69-172 (1997).

Claims

claims

1. Steroid Prodrugs of the General Formula (I)

wherein n is a number 0 - 4, R ^{1 is} -SO ₂ NH ₂ or -NHSO ₂ NH _2l wherein R ² , R ³ and X, X ^{1 is} hydrogen, halogen, nitrile, nitro, C _1-5 alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH R ²¹ is wherein R ²⁰ , R ²¹ and R ^{22 are} C _1-5 alkyl, C _3-8 cycloalkyl, aryl, C _1-4 alkylene, C _1-4 alkylene ₃ -a-cycloalkyl group or C _3-8 -cycloalkylene-C _1-4 -alkyl group and R ^{20 can} also denote a hydrogen, or R ^{2 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ^{1 represents} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , wherein R ²⁰ , R ²¹ and R ^{22 is} a C _1-5 alkyl group, a C ₃ , ₈ -cycloalkyl group, an aryl group, a

group, or C ₃ .s-cycloalkylene-C _1-4 -alkyl group and R ²⁰ also may be a hydrogen, or R ³ is -SO ₂ NH ₂ or -NHSO ₂ NH _2, wherein R ^2, R ³ and X , X ^{1 represents} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 alkyl group, a C _p F _{2p +} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , where R ²⁰ , R ²¹ and R ^{22 are} a C _1-5 -alkyl group, a C _3-8 -cycloalkyl group, an aryl group, a C _1- alkylenearyl group, a C _1-4 -alkylene-C _3-8 -cycloalkyl- and R ^{20 can} furthermore denote a hydrogen, and. a C ₃ -Cycloalkylene-C _1-4 -alkyl group

All Bll

CM wherein Y is an oxygen or a carbon atom, R ^{4 is} a hydrogen atom, a halogen atom, a methyl, trifluoromethyl, hydroxy, tri (C _1-6 alkyl) silyloxy, C _1-5 alkoxy or a C _2-5- heterocycloalkyloxy group, R ^{7 is} a hydrogen atom, a methyl or ethyl group, _R 10 is a hydrogen atom, a methyl or ethyl group, R ^{11 is} a halogen atom, a hydrogen atom, a hydroxy group, a methoxy group, a group OC (O) R ^{20 is} a methyl or ethyl group, R ^{12 is} a hydrogen atom, a methyl group or an ethyl group, c.13 is a hydrogen atom, a methyl, ethyl, ethynyl, trifluoromethyl, pentafluoroethyl group R ^{14 is} a hydrogen atom, an OH group or an oxygen atom bonded via a double bond, R ^{15 is} a hydroxy, tri (C _1-6 -alkyl) silyloxy, C _1-5 -alkoxy group, an OC (O) -R group ²⁰ or a C _2-5 heterocycloalkyloxy group, where an additional double bond may be in the 4,5-position, and when Y is a carbon atom, additional double bonds may be in the 1, 2-position or when the radical R ^{14 is} a hydrogen atom or an OH group located at the 2,3-position, and pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1, characterized in that n is 0, 1 or 2.

3. Compounds according to any one of claims 1 or 2, characterized in that R ^{1 represents} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ .

4. Compounds according to claim 3, characterized in that R ^{1 represents} a group -SO ₂ NH ₂ .

5. Compounds according to claim 1 or 2, characterized in that either R ¹ , R ² or R ^{3 represents} a group -SO ₂ NH ₂ .

6. Compounds according to one of claims 1 to 5, characterized in that R ¹ , R ² , R ³ , provided that they are not -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , and X and X ¹ independently of one another are hydrogen , Fluorine, chlorine, hydroxy or methoxy.

7. Compounds according to one of claims 1 to 6, characterized in that STEROID stands for a steroidal ring system of the general part formulas All and Bll.

8. Compounds according to any one of claims 1 to 7, characterized in that independently of one another Y is a carbon atom and / or R ^{4 is} a hydrogen atom, a chlorine atom or a hydroxy group and / or R ^{7 is} a hydrogen atom or a methyl group and / or R ^{10 is} a hydrogen atom or a methyl group and / or R ^{1 is} a hydrogen atom, a fluorine atom or a methyl group and / or R ^{12 is} a hydrogen atom and / or

R ^{13 is} a hydrogen atom or a methyl group,

R ^{14 is} an oxygen atom and / or

R ^{15 represents} a hydroxy group or a group OC (O) -R ²⁰ .

Compounds according to one of claims 1 to 8, namely

1) 3-oxo-7α-methylestr-4-en-17β-yl 3'-sulphamoylbenzoate (12),

2) 3-oxo-7α-methylestr-4-en-17β-yl 4'-sulfamoylbenzoate (11),

3) 3-oxo-7α-methylestr-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (13),

4) 3-oxo-7α-methylestr-4-en-17β-yl 2 ', 4'-dichloro-5'-sulphamoylbenzoate,

5) 3-oxo-7α-methylestr-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,

6) 3-oxo-7α-methylestr-4-en-17-yl ^2,, 3'-dimethoxy-5'-sulfamoyl benzoate,

7) 3-oxoestr-4-en-17β-yl 3'-sulfamoylbenzoate (7),

8) 3-oxoestr-4-en-17β-yl 4'-sulfamoylbenzoate (8),

9) 3-oxoestr-4-en-17β-yl 2 ', 4'-dichloro-5'-sulphamoylbenzoate,

10 3-oxoestr-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate, 11 3-oxoestr-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate, 12 3-oxoestr-4 -en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 13 3-oxo-7α-methylandrost-4-en-17β-yl 3'-sulfamoylbenzoate, 14 3-oxo-7α-methylandrost-4 -en-17β-yl 4'-sulfamoylbenzoate, 15 3-oxo-7α-methylandrost-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate, 16 3-oxo-7α-methylandrost-4-ene 17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate, 17 3-oxo-7α-methylandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate, 18 3-oxo-7α- methylandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 19 3-oxoandrost-4-en-17β-yl 3'-sulfamoylbenzoate (5), 20 3-oxoandrost-4-ene -17β-yl 4'-sulfamoylbenzoate (1), 21 3-oxoandrost-4-en-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate, 22 3-oxoandrost-4-en-17β-yl 2 '-chloro-5'-sulfamoylbenzoate, 23 3-oxoandrost-4-en-17ß-yl 2'-methoxy-5'-sulfamoylbenzoate, 24 3-oxoandrost-4-en-17ß-yl 2', 3'-dimethoxy 5'-sulphamoylbenzoate, 25 3-oxoandrostane-17ß-y l 3'-sulphamoylbenzoate (9), 26 3-oxoandrostan-17β-yl 4'-sulphamoylbenzoate (10), 27 3-oxoandrost-4-en-17β-yl 2 ', 4'-dichloro-5'-sulphamoylbenzoate ( 2), 28 3-Oxoandrost-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (3), 29 3-Oxoandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate ( 4), 30 3-oxoandrost-4-en-17ß-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 31 3-Oxo-4-chloro-17α-methylandrosta-1, 4-dien-17β-yl 3'-sulfamoylbenzoate (16), 32 3-Oxo-4-chloro-17α-methylandrosta-1,4-diene-17β - yl 4'-sulphamoylbenzoate, 33 androst-2-en-17ß-yl 3'-sulphamoylbenzoate, 34 3-oxoandrost-4-en-17ß-yl 2'-sulphamoylbenzoate (6), 35 androst-2-ene-17ß - yl 4'-sulphamoylbenzoate, 36 3-oxo-7α-methyl-11β-fluorostr-4-en-17β-yl 3'-sulphamoylbenzoate (17), 37 3-oxoandrost-4-en-17β-yl 4 ' -sulfamoylphenylpropionate (14), 38 3-oxo-5α-androst-1-en-17β-yl 3'-sulfamoylbenzoate (15), 39 3-oxoandrost-4-en-17β-yl 2'-hydroxy-5 ' sulfamoylbenzoate (18), 40 3-oxoandrostane-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate, 41 3-oxo-7α-methyl-11β-fluorostr-4-en-17β-yl 2'-hydroxy-5 ' -sulfamoylbenzoate, 42 3-oxoestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate, 43 3-oxo-7α-methylestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate , 44 3-Oxo-4-chloroandrost-4-en-17β-yl 3'-sulphamoylbenzoate (19), 45 3-Oxo-4-chloro-androsta-1,4-dien-17β-yl 3'-sulphamoylbenzoate (20) , 46 3-Oxo-4-hydrox yestr-4-en-17β-yl 3'-sulfamoylbenzoate, 47 3-oxo-4-hydroxyandrost-4-en-17β-yl 3'-sulfamoylbenzoate, 48 3-oxo-l 7β - [(perhydropyran-2-yl ) oxy] estr-4-en-4-yl 3 ^{'-sulfamoylbenzoat} (22), 49 3-oxo-l 7ß- hydroxyestr-4-en-4-yl ^3' -sulfamoylbenzoat (21). 50 3-Oxoandrost-4-en-17β-yl 2'-chloro-4'-sulfamoylbenzoate (23) 53 3-Oxoandrost-4-en-17β-yl 3'-carboxy-5'-sulfamoylbenzoate (24) 54 3 -Oxoandrost-4-en-17β-yl 3'-carbamido-5'-sulfamoylbenzoate (25)

10. Pharmaceutical compositions containing at least one compound according to any one of claims 1 to 9.

1 1. A pharmaceutical composition according to claim 10, characterized in that at least one further steroidal active compound is included.

12. A pharmaceutical composition according to claim 1 1, characterized in that the further steroidal active compound is a glucocorticoid, a progestin or a GnRH analogue.

13. Use of the compounds according to one of claims 1 to 9 for the preparation of medicaments for hormone replacemant therapy / replacement therapy in men and women.

14. Use of the compounds according to one of claims 1 to for the fertility control in men and women.

15. Use of the compounds according to one of claims 1 to 9 for the preparation of medicaments for the treatment of hormone-related diseases in men and women.

16. Use of the compounds according to any one of claims 1 to 9 for the preparation of medicaments for the treatment of diseases that can be positively influenced by the inhibition of the Carboanhydraseaktivität.

17. A process for the preparation of compounds of general formula (I) according to any one of claims 1 to 9

Group Z (I) by reacting androgens with sulfamoylphenylcarboxylic acid or its derivatives or by reacting corresponding compounds with sulfamide, sulfamoyl chloride or aminosulfonyl isocyanate.