DE102004025986A1 - Steroid prodrugs with androgenic effects - Google Patents

Abstract

The present invention relates to steroid prodrugs with androgenic activity of the general formula (I) in which the group Z is bound to the steroid, DOLLAR F1 pharmaceutical compositions containing these compounds, as well as their use for the production of medicaments with androgenic action.

Description

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

method for their preparation, these compounds containing pharmaceutical Compositions and their use for the preparation of medicaments with androgenic effect.

androgens play an important role in the organism in both sexes. They unfold their effect a nuclear Receptor, the androgen receptor. This plays in many organs and tissues play a role. Androgens are essential for the male Reproduction function, but this makes only a small segment their role in the organism. This includes many metabolic functions, shaping and maintenance of the skeletal system and musculature, functions of Liver and kidney, CNS and skin u. a. m. (Moordian AD, Morley JE and Korenman SG (1987) Biological actions of androgens. Endocr. Rev. 8, 1-27)

androgens modulate a number of functions of other hormones, in particular those of the estrogens. Examples of this are estrogen effects in the uterus and vagina, which are antagonized by androgens or organ specific be modulated. Estrogen / -Androgeninteraktionen are also on pituitary Level and in the liver of great Importance.

The hormonal properties of androgens (testosterone) can be enhanced, attenuated or qualitatively altered in some tissues by enzymatic transformations. (Romnierts FFG (1990) Testosterone: An overview of biosynthesis, transport, metabolism and nongenomic actions. In: Nieschlag E and Behre HM (eds) Testosterone. Action, Deficiency, substituting 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).

By The aromatization of testosterone may be in target organs estradiol arise. The latter is likely the Effect of testosterone in the CNS very much overlap. In the prostate, The skin and skin appendages undergo a conversion of testosterone in 5α-dihydrotetosterone (5α-DHT) instead of. This androgen is much more potent than testosterone itself. Inhibition of the conversion of testosterone into 5α-DHT weakens its androgen action very strong. A 5β reduction leads to not androgenic metabolites.

androgens (Testosterone) are already formed by the fetal testis. These Secretion plays an important role in male education Sexual routes and male embossed external sex characteristics. The central nervous system also experiences the phase of intrauterine Developing a male Embossing. Also in this process is likely the prenatal Sexual differentiation through the androgen secretion of the fetal testicles play an important role. A female differentiation of all first bisexual structures and functions take place when no androgens are present or by the absence or one genetic defect of the androgen receptor do not take effect. (Jost A (1946) Recherches sur la differenciation sexual de l'embryon 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 an anti-androgen during the critical phase of organogenesis. Endocrinology 78 (3), 628-32)

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 on the testicles the germinal epithelium in 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 that are controlled by androgens in both sexes or are at least androgen-sensitive. (Liu PY and Handelsman DJ (1990) androgen therapy in non-gonadal disease. In: Nieschlag E and Behre HM (eds) Testosterone. Action, Deficiency, substituting 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 17, 473-512)

This is especially true for the skin, hair and various appendages of the skin, such as sebaceous and sweat glands. Individuals whose androgen receptor is nonfunctional due to a genetic defect have typical sexual differentiation disorders (so-called "testicular feminization" syndrome) and develop little or no axillary and pubic hair, depending on the extent of the defect (Quigley CA (1990) ) The androgen receptor. Physiology and pathophysiology In: Nieschlag e and Behre HM (eds) Testosterone. Action, Deficiency, substituting 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 2, 33-106) another example. Their role in androgens outside of immediate reproductive functions is their anabolic effects and other metabolic effects on the whole organism.The greater expression of male musculature and the differential attachment and distribution of adipose tissue in males and females are both expressions and examples Androgen effects androgens stimu liberate the secretion of IGF-1, the main somatotropic factor in the liver. The formation of new red blood cells is also positively influenced by the mediation of the hormone erythropoietin. (Cardim HJP, Lopes CMC, Giannella-Neto D, as Fonseca AM and Pinotti JA (2001), The insulin-like growth factor 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, substituting 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 17, 473-512 ) Androgens suppress the growth of mammary glands in men.

In the female sex, androgens are also secreted in physiologically relevant amounts starting with puberty. The adrenals secrete two steroids, androstenedione and dehydroepiandrosterone, which can be converted into testosterone and 5α-dihydrotestosterone in organs with the appropriate enzyme content. (Rommerts FFG (1990) Testosterone: An overview of biosynthesis, transport, metabolism and nongenomic actions. In: Nieschlag E and Behre HM (eds) Testosterone. Action, Deficiency, substituting 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 1, 1-31) This transformation may be particularly important in the skin. The ovata 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. (Moordian AD, Morley JE and Korenman SG (1987) Biological actions of androgens, Endocr. Rev. 8, 1-27) 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 a substitution treatment with dehydroepiandrosterone. (Arlt W, Callies F and Allolio B (2000), DHEA replacement in women with adrenal 1 insufficiency - pharmacokinetics, bioconversion and clinical effects on wellbeing, sexuality and cognition.) Endocr. Res. 26 (4), 505-11)

in the higher Age of testosterone levels in men fall significantly on average from. There is a big one here individual variation of normal even in the highest age up to strongly hypogonadal values. Even more pronounced the loss of androgens in old age in women. With the elimination of maturing follicles dries up an important source of androgens. Later, androgen secretion also subsides of the ovarian stroma. With the adrenopause falls a few years after admission Menopause also adrenal androgen secretion to very low Values.

In both sexes, in older age, but under special circumstances even before, too low androgen levels and their consequences for the mood, libido and metabolic functions can occur. In particular, somatotropic functions are affected, which manifest themselves through loss of muscle and bone mass and anemia. (Liu PY and Handelsman DJ (1990) androgen therapy in non-gonadal disease. In: Nieschlag E and Behre HM (eds) Testosterone. Action, Deficiency, substituting 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 17, 473-512) The consequences of low androgen levels 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 therapeutically relevant blood levels to reach. Methyltestosterone and other derivatives have better oral efficacy, but are associated with the problem of poor liver tolerance. (Nieschlag E and Behre HM (1990) Pharmacology and clinical uses of testosterone. In: Nieschlag E and Behre HM (eds) Testosterone. Action, Deficiency, substituting 2 ^nd Edition (1998), Springer, Berlin Heidelberg, Chapter 10, 293 -328)

From the DE 27 887.6 A1 Steroidally active compounds are known which are bound via the group -SO ₂ NR ¹ R ² to erythrocytes and accumulate 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 Object of the invention, new steroidal compounds with androgenic To provide effect that are available orally and in comparison to the prior art, even at low dosage a treatment-relevant Ensure active ingredient levels.

worin n eine Zahl 0–4,
R¹ ein Rest -SO₂NH₂ oder -NHSO₂NH₂,
wobei R², R³ und X, X¹ für ein Wasserstoffatom, ein Halogenatom, eine Nitrilgruppe, eine Nitrogruppe, eine Hydroxygruppe, eine C_1-5-Alkylgruppe, eine CpF_2p+1-Gruppe mit p=1-3, eine Gruppe OC(O)-R²⁰, OC(O)NH-R²¹ oder OR²² steht;
wobei R²⁰, R²¹ und R²² eine C_1-5-Alkylgruppe, eine C_3-8-Cycloalkylgruppe, eine Arylgruppe, eine C_1-4-Alkylidenarylgruppe, eine C_1-4-Alkyliden-C_3-8-Cycloalkylgruppe oder C_3-8-Cycloalkyliden-C_1-4-Alkylgruppe sind, oder
R² ein Rest -SO₂NH₂ oder -NHSO₂NH₂,
wobei R¹, R³ und X, X¹ für ein Wasserstoffatom, ein Halogenatom, eine Nitrilgruppe, eine Nitrogruppe, eine Hydroxygruppe, eine C_1-5-Alkylgruppe, CpF_2p+1-Gruppe mit p=1-3, eine Gruppe OC(O)-R²⁰, OC(O)NH-R²¹ oder OR²² steht,
wobei R²⁰, R²¹ und R²² eine C_1-5-Alkylgruppe, eine C_3-8-Cycloalkylgruppe, eine Arylgruppe, eine C_1-4-Alkylidenarylgruppe, eine C_1-4-Alkyliden-C_3-8-Cycloalkylgruppe oder C_3-8-Cycloalkyliden-C_1-4-Alkylgruppe sind, oder
R³ ein Rest -SO₂NH₂ oder -NHSO₂NH₂,
wobei R¹, R² und X, X¹ für ein Wasserstoffatom, ein Halogenatom, eine Nitrilgruppe, eine Nitrogruppe, eine Hydroxygruppe, eine C_1-5-Alkylgruppe, C_pF_2p+1-Gruppe mit p=1-3, eine Gruppe OC(O)-R²⁰, OC(O)NH-R²¹ oder OR²² steht,
wobei R²⁰, R²¹ und R²² eine C_1-5-Alkylgruppe, eine C_3-8-Cycloalkylgruppe, eine Arylgruppe, eine C_1-4-Alkylidenarylgruppe, eine C_1-4-Alkyliden-C_3-8-Cycloalkylgruppe oder C_3-8-Cycloalkyliden-C_1-4-Alkylgruppe sind, und
STEROID für ein steroidales Ringsystem gemäß der allgemeinen Formeln (AII–CII) steht:

wobei
Y ein Sauerstoff oder ein Kohlenstoffatom,
R⁴ ein Wasserstoffatom, ein Halogenatom, eine Methyl-, Trifluormethyl-, Hydroxy-, Tri(C_1-6-alkyl)silyloxy-, C_1-5-Alkoxy- oder eine C_2-5-Heterocycloalkyloxy-Gruppe;
R⁷ ein Wasserstoffatom, eine Methyl- oder Ethylgruppe,
R¹⁰ ein Wasserstoffatom, eine Methyl- oder Ethylgruppe,
R¹¹ ein Halogenatom, ein Wasserstoffatom, eine Hydroxygruppe, eine Methoxygruppe, eine Gruppe OC(O)-R²⁰, eine Methyl- oder Ethylgruppe,
R¹² ein Wasserstoffatom, eine Methylgruppe oder eine Ethylgruppe,
R¹³ ein Wasserstoffatom, eine Methyl-, Ethyl-, Ethinyl-, Trifluormetyl-, Pentafluorethylgruppe
R¹⁴ ein Wasserstoffatom oder ein über eine Doppelbindung gebundenes Sauerstoffatom,
R¹⁵ eine Hydroxy-, Tri(C_1-6-alkyl)silyloxy-, C_1-5-Alkoxygruppe, eine Gruppe OC(O)-R²⁰ oder eine C_2-5-Heterocycloalkyloxy-Gruppe darstellen,
und ihre pharmazeutisch annehmbaren Salze.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,

where 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 represent} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a hydroxy group, a C _1-5 alkyl group, a CpF _{2p + 1} group with p = 1-3 Group OC (O) -R ²⁰ , OC (O) NH-R ²¹ or OR ²² ;
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 C _1-4 -Alkylidenarylgruppe, a C _1-4 alkylidene-C _3-8 cycloalkyl or C _3-8 cycloalkylidene-C _1-4 alkyl group, or
R ^{2 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ ,
wherein R ¹ , R ³ and X, X ^{1 represent} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a hydroxy group, a C _1-5 alkyl group, CpF _{2p + 1} group where p = 1-3, a group OC (O) -R ²⁰ , OC (O) NH-R ²¹ or OR ²² ,
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 C _1-4 -Alkylidenarylgruppe, a C _1-4 alkylidene-C _3-8 cycloalkyl or C _3-8 cycloalkylidene-C _1-4 alkyl group, or
R ^{3 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ ,
wherein R ¹ , R ² and X, X ^{1 represent} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a hydroxy group, a C _1-5 alkyl group, C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , OC (O) NH-R ²¹ or OR ²² ,
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 C _1-4 -Alkylidenarylgruppe, a C _1-4 alkylidene-C _3-8 cycloalkyl or C _3-8 cycloalkylidene-C _1-4 alkyl group, and
STEROID for a steroidal ring system according to the general formulas (AII-CII) is:

in which
Y is an oxygen or a carbon atom,
R ^{4 represents} a hydrogen atom, a halogen atom, a methyl, trifluoromethyl, hydroxy, tri (C _1-6 alkyl) silyloxy, C _1-5 alkoxy or 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} a hydrogen atom, a methyl group or an ethyl group,
R ^{13 is} a hydrogen atom, a methyl, ethyl, ethynyl, trifluoromethyl, pentafluoroethyl group
R ^{14 is} a hydrogen atom or an oxygen atom bonded via a double bond,
R ^{15 represents} 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 can be in the 1,2-positions or, when the radical R ^{14 is} hydrogen, in the 2,3-positions. An additional double bond may also be in 4,5 positions.

For the purposes of the present invention, "C _1-5 -alkyl group" is understood as meaning a branched or straight-chain alkyl radical having 1 to 5 carbon atoms, which may be substituted by halogen atoms, hydroxyl groups, nitrile groups, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl group called.

The term C _1-5 -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 _1-6 -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 group" means according to the present invention a mono- or bicyclic group which may be substituted by, for example, halogen atoms, hydroxy groups, nitrile groups, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or hydroxycyclohexyl group.

Under The term "aryl group" is used in the sense of present application 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 Understood.

For the purposes of the present application, the term "C _1-4 -alkylidenaryl group" is to be understood as meaning an alkyl radical which is substituted by an aryl radical and together have 7 to 15 carbon atoms, it being possible for the group to carry further substituents, for example a halogen atom Benzyl group or a halobenzyl group.

For the purposes of the present application, the term "C _1-4 -alkylidene-C _3-8 -cycloalkyl group" is to be understood as meaning an alkyl radical which is substituted by a C _3-8 -cycloalkyl radical and together have from 4 to 15 carbon atoms, the group being further Substituents such as a halogen atom, examples being cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

For the purposes of the present application, the term "C _3-8 -cycloalkylidene-C _1-4 -alkyl group" is understood to mean a C _3-8 -cycloalkylidene radical which is substituted by a C _1-4 -alkyl radical and together have from 4 to 15 carbon atoms wherein the group may carry further substituents such as, for example, a halogen atom, examples being a propylcyclohexyl or butylcyclohexyl group.

The term "CpF _{2p + 1} group" is understood in accordance with the present invention, a perfluorinated alkyl radical, such as a trifluoromethyl and Pentafluorethylrest.

For the purposes of the invention, the term "C _2-5 -heterocycloalkyloxy group" is understood as meaning a C _2-5 -heterocycloalkyloxy group having a nitrogen or oxygen atom as heteroatom, the bond of the C _1-5 -heterocycloalkyloxy group being understood via the Oxygen atom in 2, 3 or 4. An example of this is the perhydropyranoxy group.

Under The term "halogen atom" is used in the context of understood fluorine, chlorine, bromine or iodine atom, preferred are a fluorine, chlorine or bromine atom.

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

preferably, the group Z is arranged in 17- and 4-position, whereby the 17-position is particularly preferred.

It is preferred that R ^{1 represents} the radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , with the radical -SO ₂ NH _{2 being} 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 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 ¹³ is preferably a hydrogen atom or a methyl group.
R ¹⁴ is preferably an oxygen atom.
R ¹⁵ is preferably a hydroxy group or a group OC (O) -R ²⁰ .

The radicals Z in position 4, 11 or 17, R ⁴ in position 4, R ⁷ in position 7, R ¹¹ in position 11, R ¹³ in position 17, depending on Z or R ¹⁵ , and R ¹⁵ in position 17 may be located in both the α and β positions.

• 1) 3-Oxo-7α-methylestr-4-en-17β-yl 3'-sulfamoylbenzoat (12),
• 2) 3-Oxo-7α-methylestr-4-en-17β-yl 4'-sulfamoylbenzoat (11),
• 3) 3-Oxo-7α-methylestr-4-en-17β-yl 2'-chlor-5'-sulfamoylbenzoat (13),
• 4) 3-Oxo-7α-methylestr-4-en-17β-yl 2',4'-dichlor-5'-sulfamoylbenzoat,
• 5) 3-Oxo-7α-methylestr-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoat,
• 6) 3-Oxo-7α-methylestr-4-en-17β-yl 2',3'-dimethoxy-5'-sulfamoylbenzoat,
• 7) 3-Oxoestr-4-en-17β-yl 3'-sulfamoylbenzoat (7),
• 8) 3-Oxoestr-4-en-17β-yl 4'-sulfamoylbenzoat (8),
• 9) 3-Oxoestr-4-en-17β-yl 2',4'-dichlor-5'-sulfamoylbenzoat,
• 10) 3-Oxoestr-4-en-17β-yl 2'-chlor-5'-sulfamoylbenzoat,
• 11) 3-Oxoestr-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoat,
• 12) 3-Oxoestr-4-en-17β-yl 2',3'-dimethoxy-5'-sulfamoylbenzoat,
• 13) 3-Oxo-7α-methylandrost-4-en-17β-yl 3'-sulfamoylbenzoat,
• 14) 3-Oxo-7α-methylandrost-4-en-17β-yl 4'-sulfamoylbenzoat,
• 15) 3-Oxo-7α-methylandrost-4-en-17β-yl 2'-chlor-5'-sulfamoylbenzoat,
• 16) 3-Oxo-7α-methylandrost-4-en-17β-yl 2',4'-dichlor-5'-sulfamoylbenzoat,
• 17) 3-Oxo-7α-methylandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoat,
• 18) 3-Oxo-7α-methylandrost-4-en-17β-yl 2',3'-dimethoxy-5'-sulfamoylbenzoat,
• 19) 3-Oxoandrost-4-en-17β-yl 3'-sulfamoylbenzoat (5),
• 20) 3-Oxoandrost-4-en-17β-yl 4'-sulfamoylbenzoat (1),
• 21) 3-Oxoandrost-4-en-17β-yl 2',4'-dichlor-5'-sulfamoylbenzoat,
• 22) 3-Oxoandrost-4-en-17β-yl 2'-chlor-5'-sulfamoylbenzoat,
• 23) 3-Oxoandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoat,
• 24) 3-Oxoandrost-4-en-17β-yl 2',3'-dimethoxy-5'-sulfamoylbenzoat,
• 25) 3-Oxoandrostan-17β-yl 3'-sulfamoylbenzoat (9),
• 26) 3-Oxoandrostan-17β-yl 4'-sulfamoylbenzoat (10),
• 27) 3-Oxoandrost-4-en-17β-yl 2',4'-dichlor-5'-sulfamoylbenzoat (2),
• 28) 3-Oxoandrost-4-en-17β-yl 2'-chlor-5'-sulfamoylbenzoat (3),
• 29) 3-Oxoandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoat (4),
• 30) 3-Oxoandrost-4-en-17β-yl 2',3'-dimethoxy-5'-sulfamoylbenzoat,
• 31) 3-Oxo-4-chlor-17α-methylandrosta-1,4-dien-17β-yl 3'-sulfamoylbenzoat (16),
• 32) 3-Oxo-4-chlor-17α-methylandrosta-1,4-dien-17β-yl 4'-sulfamoylbenzoat,
• 33) Androst-2-en-17β-yl 3'-sulfamoylbenzoat,
• 34) 3-Oxoandrost-4-en-17β-yl 2'-sulfamoylbenzoat (6),
• 35) Androst-2-en-17β-yl 4'-sulfamoylbenzoat,
• 36) 3-Oxo-7α-methyl-11β-fluorestr-4-en-17β-yl 3'-sulfamoylbenzoat (17),
• 37) 3-Oxoandrost-4-en-17β-yl 4'-sulfamoyiphenylpropionat (14),
• 38) 3-Oxo-5α-androst-1-en-17β-yl 3'-sulfamoylbenzoat (15),
• 39) 3-Oxoandrost-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoat (18),
• 40) 3-Oxoandrostan-17β-yl 2'hydroxy-5'-sulfamoylbenzoat,
• 41) 3-Oxo-7α-methyl-11β-fluorestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoat,
• 42) 3-Oxoestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoat,
• 43) 3-Oxo-7α-methylestr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoat,
• 44) 3-Oxo-4-chlorandrost-4-en-17β-yl 3'-sulfamoylbenzoat (19),
• 45) 3-Oxo-4-chlorandrosta-1,4-dien-17β-yl 3'-sulfamoylbenzoat (20),
• 46) 3-Oxo-4-hydroxyestr-4-en-17β-yl 3'-sulfamoylbenzoat,
• 47) 3-Oxo-4-hydroxyandrost-4-en-17β-yl 3'-sulfamoylbenzoat,
• 48) 3-Oxo-17β-[(perhydropyran-2-yl)oxy]estr-4-en-4-yl 3'-sulfamoylbenzoat (22),
• 49) 3-Oxo-17β-hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoat (21).

Particularly preferred steroid prodrugs are listed below:

• 1) 3-oxo-7α-methylestr-4-en-17β-yl 3'-sulphamoylbenzoate (12),
• 2) 3-oxo-7α-methylestr-4-en-17β-yl 4'-sulphamoylbenzoate (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'-sulfamoylbenzoate,
• 5) 3-oxo-7α-methylestr-4-en-17β-yl 2'-methoxy-5'-sulphamoylbenzoate,
• 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'-sulphamoylbenzoate,
• 10) 3-oxoestr-4-ene-17β-yl 2'-chloro-5'-sulfamoylbenzoate,
• 11) 3-oxoestr-4-ene-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,
• 12) 3-oxoestr-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulphamoylbenzoate,
• 13) 3-oxo-7α-methylandrost-4-en-17β-yl 3'-sulfamoylbenzoate,
• 14) 3-oxo-7α-methylandrost-4-en-17β-yl 4'-sulphamoylbenzoate,
• 15) 3-oxo-7α-methylandrost-4-en-17β-yl 2'-chloro-5'-sulphamoylbenzoate,
• 16) 3-oxo-7α-methylandrost-4-en-17β-yl 2 ', 4'-dichloro-5'-sulphamoylbenzoate,
• 17) 3-oxo-7α-methylandrost-4-en-17β-yl 2'-methoxy-5'-sulphamoylbenzoate,
• 18) 3-oxo-7α-methylandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulphamoylbenzoate,
• 19) 3-oxoandrost-4-en-17β-yl 3'-sulphamoylbenzoate (5),
• 20) 3-oxoandrost-4-en-17β-yl 4'-sulphamoylbenzoate (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-17β-yl 2'-methoxy-5'-sulphamoylbenzoate,
• 24) 3-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulphamoylbenzoate,
• 25) 3-oxoandrostan-17β-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'-sulfamoylbenzoate (3),
• 29) 3-oxoandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate (4),
• 30) 3-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulphamoylbenzoate,
• 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-en-17β-yl 4'-sulfamoylbenzoate,
• 36) 3-oxo-7α-methyl-11β-fluorestr-4-en-17β-yl 3'-sulfamoylbenzoate (17),
• 37) 3-oxoandrost-4-en-17β-yl 4'-sulfamoyl-phenylpropionate (14),
• 38) 3-oxo-5α-androst-1-en-17β-yl 3'-sulphamoylbenzoate (15),
• 39) 3-oxoandrost-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate (18),
• 40) 3-oxoandrostan-17β-yl 2'-hydroxy-5'-sulphamoylbenzoate,
• 41) 3-oxo-7α-methyl-11β-fluorostr-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate,
• 42) 3-oxoestr-4-ene-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate,
• 43) 3-oxo-7α-methylestr-4-en-17β-yl 2'-hydroxy-5'-sulphamoylbenzoate,
• 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-17β - [(perhydropyran-2-yl) oxy] estr-4-en-4-yl 3'-sulfamoylbenzoate (22),
• 49) 3-oxo-17β-hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoate (21).

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 in Be costume.

The Compounds of the invention have androgenic activity, wherein the therapeutically relevant steroids by ester cleavage the corresponding compound of formula (I) are released. This advantageously becomes predominant Androgens are released with an OH group that has a higher androgenic activity as the compounds having a keto group.

• I nicht geschlechtsreifen kastrierten männlichen Ratten,
• II geschlechtsreifen kastrierten Ratten und
• III gonadal intakten adulten geschlechtsreifen Ratten

wurde die orale androgene und antigonadalotrope Aktivität sowie die Beeinflussung. der Leberfunktion der erfindungsgemäßen Verbindungen in Relation zu bekannten Verbindungen ermittelt.Through experiments

• I non-sexed castrated male rats,
• II sexually mature castrated rats and
• III gonadally intact adult sexually mature rats

was the oral androgenic and antigonadalotropic activity as well as the influence. the liver function of the compounds of the invention in relation to known compounds.

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

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

2 the rLH content in serum / experiment I,

3 the HDL-cholesterol content in plasma / experiment I,

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

5 the rLH content in the serum / experiment II,

6 the HDL-cholesterol content in the plasma / experiment II,

7 the MENT content in the serum / trial II,

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

9 the rLH content in serum / experiment III,

10 the testosterone content in the serum / trial III and

11 the serum HDL cholesterol content / Experiment III.

attempt (I) Untreated castrated male rats over 8 days Surprising and unexpectedly the compounds of the invention show 12 and 18, respectively in a trial (I) of non-sexually mature castrated males Rats dose-dependent strong effects on the growth of accessory gonads while (7α-methyl-19-nortestosterone) MENT only marginal effects were observed. Show unexpectedly the substances according to the invention also a MENT superior antigonadotropic activity. Regarding the Lowering HDL is MENT stronger effective as the substances of the invention.

test description

Method: male Rats weighing approximately 45 g are castrated and over 7 Days with MENT and compounds of the invention 12 or 18 treated orally. On the 8th day of the experiment the animals are killed and evaluated the hormonal effects of the test substances (growth the accessory sexual glands, Reduction of gonadotropic hormones in plasma, parameters hepatic Effects: effects on HDL lipoproteins).

Experiment (II) on sexually mature castrated male Rats over 8 days

Experiment (II) was performed on sexually mature castrated male rats. Again, with the substances according to the invention, such as, for example, compound 12, it was possible to find unexpectedly strong, dose-dependent effects on the growth of accessory sexual glands, whereas only marginal effects were observed for MENT. Surprisingly, the compounds according to the invention also show here a MENT superior antigonadotrophic activity. 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 according to the invention, such as, for example, of compound 12, significantly higher levels of MENT are achieved in plasma than after administration of MENT itself.

test description

Method: Adult male Rats, of about 300 g body weight are castrated and over 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 evaluated the test substances (growth of the accessory sex glands, lowering of gonadotropic hormones in plasma, parameters of hepatic effects: Effects on HDL-lipoproteins, determination of MENT in plasma).

Experiment (III) on gonadal intact adult sexually mature rats over 6 weeks

In the third trial (III) of gonadal intact adult sexual maturity Rats over For 6 weeks all test substances had only marginal effects on accessory Gonads, although it unexpectedly becomes a strong in the course of treatment Waste of endogenous testosterone had come. The induced inventive compound 12 dose-dependent an increase in the weights of seminal vesicle and prostate over the Level of intact controls. Under MENT entered a corresponding Effect does not occur even at extremely high dosage. A superiority the compound of the invention 12 could also be secured with respect to antigonadotropic effects. In terms of Lowering HDL is MENT stronger effective as the substances of the invention. The compound of the invention 5 is characterized by particularly small changes in hepatic parameters out.

test description

Method: Adult male Rats, from over 300 g body weight be over 6 weeks with MENT and the compounds 12 and 5 according to the invention treated orally. At the end of the experiment the animals are killed and evaluated the hormonal effects of the test substances (weight of the Testes and accessory gonads, lowering gonadotropic Hormones and testosterone in plasma during the course of the experiment, parameters hepatic effects: effects on HDL lipoproteins).

The Sulfamoylbenzoates according to the invention the androgens are, as could be shown in the experiments (I-III), the corresponding androgens in terms of oral androgenic and antigonadotropic activity clearly superior. Across from the therapeutically desired androgenic effects occur effects that affect the liver functions reflect, clearly back.

examination the erythrocyte binding

The Compounds of the invention 5 or 12 and the compounds 1 and 11 according to the invention were also examined for binding to erythrocytes.

For the m-substituted Compounds were able to demonstrate significantly weaker bonds to the erythrocytes become. In contrast, the 4'-sulfamoyl benzoates a stronger one Binding.

Unexpectedly, however, was 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 according to the invention can lead to an accumulation in erythrocytes by binding to carbonic anhydrases. 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 the plasma: high proportion = strong displacement of ¹⁴ C-estradiol sulfamate from the erythrocytes by the test substance = high binding affinity.

determination of the red blood cell / plasma distribution ratio Freshly recovered, heparinized blood is administered with a defined amount of test substance added. The concentration in the plasma obtained is measured. The erythrocyte / plasma distribution ratio is calculated from the measured concentration of total substance in the plasma and the concentration used.

Surprised could still in all cases a bond to the carbonic anhydrase found in the erythrocytes (CA I) (Table 2). It is therefore to be expected that the substances according to the invention Also as carbohydrate inhibitors have therapeutically relevant effects. Of importance to the Properties as androgen is due to the affinity to carbonic anhydrases induced binding to erythrocytes. This bond is essential for one reduced extraction of the orally administered substance at the first liver passage. High or low affinity to the erythrocytic Carbonic anhydrases, faster or delayed release from this Depot and subsequent hydrolysis determine the therapeutic applicability the compounds of the invention.

Unexpectedly, it has been found that the compounds according to the invention achieve therapeutically relevant levels at lower dosages when the ratio of the loading of the erythrocytes / substance in the plasma is different from that after DE 100 27 887.6 A1 to expect - less than 10. By means of the compounds according to the invention, it is possible to achieve higher short duration or even lower 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: IC ₅₀ inhibitory values of human carbonic anhydrase I

Test principle and test 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 in vivo experiments (experiments I-III) and the indicated options for variation of potency and duration of action for a tailored to the individual organism therapy open up a variety of applications for the birth control and hormone replacement therapy (HRT) in men and women as well as the treatment Hormonal disorders in men and women.

object The present invention therefore also relates to pharmaceutical compositions which at least one compound of general formula (I) or a corresponding Salt, optionally together with pharmaceutically acceptable Auxiliaries and carriers contain.

These Pharmaceutical compositions and drugs may preferably for oral, but also rectal, vaginal, subcutaneous, percutaneous, intravenous, buccal, transdermal or intramuscular administration become. They contain besides usual Carrier- and / or diluents at least one compound of general formula (I) or their Salt.

The Medicaments of the invention are mixed with the usual solid or liquid carriers or diluents and usually used pharmaceutical-technical excipients according to the desired Type of administration with a suitable dosage in a known manner produced. The preferred preparations consist in a dosage form, which is suitable for oral administration. Such dosage forms are for example tablets, film-coated tablets, dragees, capsules, Pills, powders, solutions or Suspensions or depot forms.

Of course, come also parenteral preparations such as injection solutions into consideration. Farther Examples of preparations include suppositories and agents called for vaginal application.

Appropriate Tablets can for example, by mixing the active ingredient with known excipients, for example, inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants like cornstarch or alginic acid, Binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or Means for obtaining a depot effect such as carboxyl polymethylene, Carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, to be obtained. The tablets can also consist of several layers.

Corresponding can Dragees by coating of cores produced analogously to the tablets with usually used in dragee coatings Agents, for example polyvinylpyrrolidone or shellac, gum arabic, Talc, titanium oxide or sugar. It can also the dragee envelope consist of several layers, the top of the tablets mentioned Excipients can be used.

Solutions or Suspensions with the compounds of general Formula (I) can additionally taste-improving agents such as saccharin, cyclamate or sugar as well as e.g. Flavorings such as vanillin or orange extract contain. You can Furthermore Suspension adjuvants such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

The Examples of capsules containing compounds of the general formula (I) can be be prepared by the compounds) of the general Formula (I) with an inert carrier How to mix milk sugar or sorbitol and encapsulate in gelatine capsules.

suitable Suppositories can be, for example, by mixing with designated carriers as neutral fats or polyethylene glycol or their derivatives.

The Compounds of the invention are steroid prodrugs and have androgenic activity. The compounds of the invention are especially suitable for oral application. The therapeutic relevant steroid is from the compound of the invention or its salt released by ester cleavage.

The compounds according to the invention are characterized by a weak erythrocyte binding combined with a good androgenic activity. The factor that serves as a measure of the binding or accumulation in the erythrocytes, is from the DE 100 27 887.6 A1 is known and is less than 10 in the compounds of the invention.

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

The Compounds of the invention are suitable for Substitution therapy, especially for substitution therapy in combination with antigonadotropic and antifertile strategies in the man in connection with a GnRH analogue, a progestin or other therapies used to suppress endogenous androgen secretion to lead.

The Compounds of the invention are also suitable for the replacement therapy in combination with glucocorticoids or Other therapies used to suppress adrenal androgen secretion to lead.

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

By the compounds of the invention Become problems of liver tolerance minimized. For conventional, orally administered androgens, especially for C-17 alkylated androgens, It is known that the liver is heavily loaded. The in the compounds of the invention contained androgens burden after its release the liver Not.

By the compounds of the invention is the oral bioavailability of the contained androgen increases. The entire amount of hormone acting on the organism therefore becomes reduced. The hormonal effect on the liver at the first passage is reduced. This will be known unfavorable effects of oral androgen therapy on the lipid metabolism (lowering HDL cholesterol, increasing the atherogenic risk) and other hepatic secretion products.

androgens differ in their hormonal action spectra and thus in their suitability for different therapeutic requirements. The compounds of the invention allow it by selecting the androgen contained a differentiating androgen therapy to enable.

The The following examples serve to explain the invention in more detail, without to restrict it to it.

General synthesis regulations

For the preparation of the general formula (II) underlying androgens can be used 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-one ( DD 79213049 ), Epiandrosterone, 5α-androst-2-en-17-one from epiandrosterone (US Pat. No. 3,098,851), 7α-methyl-11β-methyl-19-nortestosterone, 7α-methyl-11β-methyltestosterone, oxandrolone, Oral-Turinabol , 17α-Methyltestosterone etc.

The in the starting materials for the steroidal bodies functional groups may be present after the Be protected professional known methods or in corresponding functional groups are converted. So can keto groups in the starting materials as ketals or thiocetals according to methods known in the art protected become. 17-keto compounds can reduced by methods known in the art to hydroxyl compounds become.

Synthesis instructions for Preparation of compounds of general formula (I)

version 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 dissolved in a base such as pyridine and an organic solvent such as chloroform 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 such as 10% HCl. The precipitate is sucked off, with Washed 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. 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 PCl ₅ or SOCl _{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. 2'-Sulfamoylphenylcarbonsäureester corresponding androgens.

Variant 5

Reaction to sulfamides (NH ₂ SO ₂ NH-)

The Reaction to the sulfamides according to the invention takes place according to methods known to the person skilled in the art for their preparation starting from corresponding amines by means of 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 is reacted 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. The reaction mixture is stirred until complete. Then water is added, the precipitate is filtered off, washed with water, NaHCO ₃ solution and dried. The substance is purified by chromatography on silica gel. Corresponding androgensulfamoylaminobenzoates are obtained.

synthesis Examples

example 1

3-Oxoandrost-4-en-17β-yl 4'-sulphamoylbenzoate (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) is stirred for 48 hours at room temperature. Subsequently, 20 ml of water are added. It is acidified slightly with 10% HCl (pH = 5). The precipitate is filtered off and washed 2 × 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 MgSO ₄ , 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-sulfamoylbenzoyl 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, 1H , H-4), 7.56 (s, 2H, NH ₂ ), 7.92-8.15 (m, 4H, Ar).

Example 2

3-Oxoandrostan-17β-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, 1H, 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, 1H, H-4), 7.56 (s, 2H, NH ₂ ), 7.75-8.80 (m, 3H, H-Ar).

Example 4

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

The substance is analogous to Example 1 according to variant 1, starting from 2-methoxy-5-sulfamoylbenzoesäure and testosterone. receive.
¹ H-NMR (DMSO-d ₆ ): 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 . To the reaction mixture is added at -20 ° C with stirring 1.0 ml of 3-Chlorsulfonylbenzoesäurechlorid. 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-17β-yl 3'-sulphamoylbenzoate (5) is obtained.
¹ H-NMR _(CDCl3): 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-ene-17R-yl 2'-sulfamoyl benzoate (6)

step 1

3-oxoandrost-4-en-17β-yl 2'-sulfobenzoate ammonium salt

2.5 g of testosterone are dissolved in 10 ml of chloroform. After addition of 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 treated with a concentrated methanolic ammonia solution. The solvents are distilled off and the residue is chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 2'-sulfobenzoate ammonium salt is obtained.
¹ H-NMR (DMSO-d ₆ ): 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-17β-yl 2'-sulfobenzoate ammonium salt are dissolved in 160 ml of CHCl ₃ under protective gas. Portions of 6.0 g of PCl _{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-en-17β-yl 2'-sulphamoylbenzoate (6) is obtained.
¹ H-NMR _(CDCl3): 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-ene-17R-yl 3'-sulfamoyl benzoate (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, 1H, 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 (8th)

The substance is obtained analogously to Example 1 variant 1 starting from nandrolone and p-sulfamoylbenzoic acid.
¹ H-NMR (DMSO-d ₆ ): 0.97 (s, 3H, H-19), 4.80 (m, 1H, 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-Oxoandrostan-17β-yl 3'-sulphamoylbenzoate (9)

The substance is obtained analogously to Example 5 starting from 17β-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, 1H, H-17α), 7.54 (s, 2H, NH ₂ ), 7.68-8.38 (m, 4H, H-Ar).

Example 10

3-Oxoandrostan-17β-yl 14'-sulphamoylbenzoate (10)

The substance is obtained analogously to Example 1 variant 1 starting from 17β-hydroxy-5α-androstan-3-one and p-sulfamoylbenzoic acid. ¹ H-NMR (DMSO-d ₆ ): 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 obtained 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, 1H, 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 obtained analogously to Example 5 starting from 17β-hydroxy-7α-methylestr-4-en-3-one (MENT), Chlorsulfonylbenzoesäurechlorid and ammonia.
¹ H-NMR (DMSO-d ₆ ): 0.75 (d, 3H, 7α-Me), 0.98 (s, 3H, H-19), 4.83 (m, 1H, H-17α), 5.74 (s, 1H, 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'-sulphamoylbenzoate (13)

The substance is obtained analogously to Example 1 variant 1 starting from 17β-hydroxy-7α-methylestr-4-en-3-one (MENT) and 2-chloro-5-sulfamoylbenzoic acid.
¹ H-NMR (DMSO-d ₆ ): 0.74 (d, 3H, 7α-CH ₃ ), 0.93 (s, 3H, H-19), 4.84 (m, 1H, H-17α), 5.72 (s, 1H , 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 obtained 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, 3H, CH _3), 2.66 (t, 2H, 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-Chlorsulfonylbenzoesäurechlorid and ammonia.
¹ H-NMR (DMSO-d ₆ ): 0.94 (s, 3H, H-18), 0.99 (s, 3H, H-19), 4.82 (m, 1H, 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) = sulfamoyl benzoate (16)

The substance is obtained analogously to Example 5, starting from 4-chloro-17α-methyl-17β-hydroxyandrosta-1,4-dien-3-one, 3-Chlorsulfonylbenzoesäurechlorid and ammonia.
¹ H-NMR (DMSO-d _6): 1:02 (s, 3H, H-18), 1.31 (s, 3H, H-19), 1:48 (s, 3H, CH ₃ -17α), 6.30 (d, 1H , H-2), 7.31 (d, 1H, H-1), 7.53 (s, 2H, NH ₂ ), 7.70-8.38 (m, 4H, H-Ar).

Example 17

3-Oxo-7α-methyl-11β-fluoro-estr-4-en-17β-yl 3'-sulfamoylbenzoate (18)

The substance is obtained according to variant 3 analogously to Example 5, starting from 17β-hydroxy-7α-methyl-11β-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, 1H, 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'-sulphamoylbenzoate (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, 1H, 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-chloroandrost-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-17β-hydroxyandrost-4-ene and 3-Chlorsulfonylbenzoesäurechlorid.
¹ H-NMR (DMSO-d ₆ ): 0.95 (s, 3H, H-18), 1.23 (s, 3H, H-19), 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 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-17β-hydroxyandrosta-1,4-diene and 3-Chlorsulfonylbenzoesäurechlorid.
¹ H-NMR (DMSO-d ₆ ): 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'-sulfamoyl benzoate (21)

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

5.9 g of 4-hydroxy-17β-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. 500 ml of water are added to the reaction solution. 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-acetoxyestr-4-en-3-one is obtained.
¹ H-NMR _(CDCl3): 0:14 (s, 6H, SiMe), 0.65-0.88 (. M (überlg), 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- [perhydropyran-2-yl) oxy] estr-4-en-3-one

1 g of 4-thexyldimethylsilyloxy-17β-hydroxyestr-4-en-3-one is reacted in 16 ml of CH ₂ Cl ₂ with 1.8 ml of dihydropyran and 80 mg of pyridinium tosylate 2 h. To the reaction solution, 10 ml of sat. Added Na ₂ CO ₃ solution. It is then extracted with CH ₂ Cl 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- [perhydropyran-2-yl) oxy] estr-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-17β- [perhydropyran-2-yl) oxy] ester-4-en-3-one is obtained.

Step 5: 3-Oxo-17β- [perhydropyran-2-yl) oxy] estr-4-en-4-yl 3'-sulfamoyl benzoate (22)

The substance is analogously to Example 5 according to variant 3, starting from 4-hydroxy-17β- [perhydropy ran-2-yl) oxy] estr-4-en-3-one and 3-chlorosulfonylbenzoic acid chloride.

Step 6: 3-oxo-17β-hydroxyestr-4-en-4-yl 3'-sulfamoyl benzoate (21)

500 mg of 3-oxo-17β- [perhydropyran-2-yl) oxy] estr-4-en-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. 3-Oxo-17β-hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoates (21) are obtained.
¹ H-NMR (DMSO-D ₆ ): 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).

Claims (17)

Steroid prodrugs of the general formula (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 hydroxy group , a C _1-5 alkyl group, a CpF _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , OC (O) NH-R ²¹ or OR ²² , 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 C _1-4 -Alkylidenarylgruppe, a C _1-4 alkylidene-C _3-8 cycloalkyl or C _{3- 8 cycloalkylidene-C1-4} alkyl group, or R ² is a group -SO ₂ NH ₂ or -NHSO ₂ NH _2, wherein R ^1, R ³ and X, X ¹ represents a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a hydroxy group, a C _1-5 alkyl group, a CaF _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , OC (O) NH-R ²¹ or OR ²² in which 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 _1-4 -alkylidenaryl group, a C _1-4 -alkylidene-C _3-8 - Cycloalky lgruppe or _{C3-8 cycloalkylidene-C1-4} alkyl group, or R ³ is -SO ₂ NH ₂ or -NHSO ₂ NH _2, wherein R ^1, R ² and X, X ¹ represents a hydrogen atom, a Halogen atom, a nitrile group, a nitro group, a hydroxy group, a C _1-5 alkyl group, a CpF _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , OC (O) NH-R ²¹ or oR ^22, where R ^20, R ²¹ and R ²² is a C _1-5 alkyl group, a C _3-8 cycloalkyl group, an aryl group, a C _1-4 -Alkylidenarylgruppe, a C _1-4 alkylidene C _3-8 -cycloalkyl group or C _3-8 -cycloalkylidene-C _1-4 -alkyl group, and STEROID for a steroidal ring system according to the general formulas (AII-CII):

where 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 , a methyl or ethyl group, R ^{12 is} a hydrogen atom, a methyl group or an ethyl group, R ^{13 is} a hydrogen atom, a methyl, ethyl, ethynyl, trifluoromethyl, pentafluoroethyl group R ^{14 is} a hydrogen atom or an oxygen atom bonded via a double bond, R ^{15 represents} 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, wherein an additional Double bond can be in the 4,5-position, and when Y is a carbon atom, z additional double bonds in the 1,2-position or when the radical R ^{14 is} a hydrogen atom, in the 2,3-position, and their pharmaceutically acceptable salts. Compounds according to claim 1, characterized that n is 0, 1 or 2. Compounds according to one of claims 1 or 2, characterized in that R ^{1 represents} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ . Compounds according to claim 3, characterized in that R ^{1 represents} a group -SO ₂ NH ₂ . Compounds according to claim 1 or 2, characterized in that either R ¹ , R ² or R ^{3 is} a Group -SO ₂ NH ₂ represents. Compounds according to one of claims 1 to 5, characterized in that R ¹ , R ² , R ³ , if these are not -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , and X and X ¹ independently of one another for a hydrogen, Fluorine, chlorine, hydroxy or methoxy. Compounds according to one of Claims 1 to 6, characterized that STEROID for a steroidal ring system of general subformulae AII and BII stands. Compounds according to 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 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 or R ^{11 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 is} a hydroxy group or a group OC (O) -R ²⁰ represent _: Compounds according to any 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-ene-17β -yl 4'-sulphamoylbenzoate (11), 3) 3-oxo-7α-methylestr-4-en-17β-yl 2'-chloro-5'-sulphamoylbenzoate (13), 4) 3-oxo-7α-- methylestr-4-en-17β-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'-sulfamoylbenzoate, 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'-sulfamoylbenzoate, 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'-sulfamoy benzoate, 16) 3-oxo-7α-methylandrost-4-en-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-ene-17β -yl 3'-sulphamoylbenzoate (5), 20) 3-oxoandrost-4-en-17β-yl 4'-sulphamoylbenzoate (1), 21) 3-oxoandrost-4-en-17β-yl 2 ', 4'- dichloro-5'-sulphamoylbenzoate, 22) 3-oxoandrost-4-en-17β-yl 2'-chloro-5'-sulphamoylbenzoate, 23) 3-oxoandrost-4-en-17β-yl 2'-methoxy-5 ' -sulfamoylbenzoate, 24) 3-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 25) 3-oxoandrostan-17β-yl 3'-sulfamoylbenzoate (9), 26) 3- Oxoandrostan-17β-yl 4'-sulfamoylbenzoate (10), 27) 3-oxoandrost-4-ene-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate (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-oxoandrostic acid 4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 31) 3-oxo-4-chloro-17α-methyl landrosta-1,4-dien-17β-yl 3'-sulfamoylbenzoate (16), 32) 3-oxo-4-chloro-17α-methylandrosta-1,4-diene-17β-yl 4'-sulfamoylbenzoate, 33) Androst -2-en-17β-yl 3'-sulphamoylbenzoate, 34) 3-oxoandrost-4-ene-17βyl 2'-sulphamoylbenzoate (6), 35) androst-2-ene-17β-yl 4'-sulphamoylbenzoate, 36) 3-oxo-7α-methyl-11β-fluorestr-4-en-17β-yl 3'-sulfamoylbenzoate (17), 37) 3-oxoandrost-4-en-17β-yl 4'-sulfamoylphenylpropionate (14), 38) 3-oxo-5-androst-1-en-17β-yl 3'-sulphamoylbenzoate (15), 39) 3-oxoandrost-4-en-17β-yl 2'-hydroxy-5'-sulphamoylbenzoate (18), 40) 3-oxoandrostan-17β-yl 2'-hydroxy-5'-sulphamoylbenzoate, 41) 3-oxo 7α-methyl-11β-fluorestr-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'-sulfamoylbenzoate (19), 45 ) 3-Oxo-4-chloroandrosta-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-17β - [(perhydropyran-2-yl) oxy] estr-4-en-4-yl 3'-sulfamoylbenzoate (22), 49) 3-oxo-17β-hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoate (21). Pharmaceutical compositions at least one A compound according to any one of the claims Containing 1 to 9. Pharmaceutical composition according to claim 10, characterized in that at least one further steroidal effective Connection is included. Pharmaceutical composition according to claim 11, characterized in that the further steroidal active compound a glucocorticoid, a progestin or a GnRH analogue. Use of the compounds according to one of claims 1 to 9 for the preparation of medicines for hormone replacemant therapy / subtitution therapy with husband and wife. Use of the compounds according to one of claims 1 to 9 for the production of medicines for fertility control in men and women. Use of the compounds according to one of claims 1 to 9 for the preparation of medicaments for the treatment of hormone-related Illnesses in man and woman. Use of the compounds according to one of claims 1 to 9 for the preparation of medicaments for the treatment of diseases, which are positive by the inhibition of carbonic anhydrase activity be influenced. Process for the preparation of compounds of general formula (I) according to one of Claims 1 to 9

by reacting androgens with sulfamoylphenylcarboxylic acid or its derivatives or by reacting corresponding compounds with sulfamide, sulfamoyl chloride or aminosulfonyl isocyanate.