JP2007538026A - Steroid prodrug with androgenic action - Google Patents

Abstract

The present invention relates to the following general formula (I):
[Wherein the group Z is bound to a steroid], to pharmaceutical compositions containing these compounds, and to their use for the production of pharmaceutical agents having androgenic activity.

Description

The present invention relates to the following general formula (I):

And their use for the production of a pharmaceutical agent having an androgenic action.

Androgens play an important role in organisms in both sexes. They exert their action through nuclear receptors, ie ambalogen receptors. The latter plays a role in many organs and tissues. Androgens are essential for male reproductive function, but this constitutes only a small part of their role in the organism. The latter includes many metabolic functions, skeletal and muscular manifestation and preservation, liver and kidney function, central nervous system (CNS) and skin, and others ⁽¹⁾ .

Androgens regulate many functions of other hormones, especially those of estrogens. Examples of this are estrogenic effects in the uterus and vagina that are antagonized by androgens or regulated in an organ-specific manner. Estrogen / androgen interactions are also very important at the pituitary level and in the liver.
The hormonal properties of androgens (testosterone) can be enhanced, reduced or qualitatively altered in many tissues by enzymatic conversion ⁽²⁾ .

  Due to the aromatization of testosterone, estradiol can be produced in the target organ. The latter very strongly duplicates the effects of testosterone in the central nervous system. In prostate, skin and skin conditions, conversion of testosterone to 5α-dihydrotestosterone (5α-DHT) occurs. This androgen is significantly more potent than testosterone itself. Inhibition of testosterone conversion to 5α-DHT greatly reduces its androgenic action. 5β-lowering results in non-androgenic metabolites.

Androgen (testosterone) is already formed from the fetal testis. This secretion plays an important role in the construction of the male reproductive tract and external gender features with male characteristics. In addition, during the period of intrauterine growth, he experiences male marking of the central nervous system. Also in this process, prenatal differentiation by fetal testicular androgen secretion should play an important role. Differentiation in females of all structures and functions used bisexually first is performed in the absence of androgen or does not work in the case of androgen receptor errors or genetic defects ⁽³⁾ .

After birth, the blood level of testosterone in the body drops to a very low value and then rises again to a high value during adolescence. During this period, they act synergistically on the embryonic epithelium in the testis by gonadotropin hormones. Sex organs prepared under the influence of testosterone in the fetal period are also readily dependent on later life for their function of androgens. However, this is also applicable for a wide range of other organs, tissues and functions that are regulated by androgens or at least are androgen sensitive in both sexes ⁽⁴⁾ .

The skin, hair, and various appendages of the skin, such as sebaceous glands and sweat glands, show this visual expression. Individuals whose androgen receptor is non-functional due to a genetic defect show typical sexual differentiation disorders (the symptoms of “testicular feminization”), and based on the extent of the defect, Little or no growth of hair and pubic hair ⁽⁵⁾ . Their anabolic and other effects on the metabolism associated with complete organisms are another example of the role of androgens outside of the reproductive function. The heavy accumulation in males and the different accumulation and distribution of adipose tissue in males and females are indications and examples of the corresponding androgenic effects. Androgens stimulate the secretion of IGF-1, the most important somatic localization factor in the liver. Fresh erythrocyte formation is also positively influenced by the intervention of the hormone erythropoietin ⁽⁶⁾ . Androgens inhibit mammary gland growth in men.

In women, starting from puberty, androgens are also secreted in physiologically relevant quantities. The adrenal glands, along with androstanedione and dehydroepiandrosterone, secrete two steroids that can be converted to testron and 5α-dihydrotestosterone in organs with corresponding enzymatic properties ⁽⁷⁾ . This transformation should play a particularly major role in the skin. The ovaries secrete androgens, mainly testosterone. Its secretion significantly increases the intermediate cycle and decreases again in the luteal phase. There is no doubt that libido in both sexes is positively affected by androgens ⁽⁸⁾ . In terms of conditions, as is known, adrenal androgens play a major role. In women treated with glucocorticoids, complete adrenal hormone production is suppressed. Depressive mood disorders associated with it can be significantly improved by replacement with dehydroepiandrosterone ⁽⁹⁾ .

  At older ages, testosterone levels in men are significantly reduced on average. In this regard, large individual variability is made at the highest age and consists of normal to excess gonad failure values. Androgen loss is more evident with the age of women. An important andro source declines with the elimination of mature vesicles. Later, the androgenic secretion of the ovarian stroma also declines. With adrenal arrest, adrenal androgen secretion also drops to very low values several years after the onset of menopause.

In both sexes, but older, but also before, under certain conditions, androgen levels that are too low, and their consequences for unhealthy, libido and metabolic function occur. In this regard, somatropin function and anemia, particularly manifested by loss of muscle and bone mass, are affected ⁽¹⁰⁾ . However, results of androgen levels that are too low include depressive mood disorders, libido disorders and low impulses.

In oral treatment of the above disorders, testosterone is well tolerated by the human liver, but should be used at very high doses to achieve therapeutically relevant blood levels. Methyltestosterone and other derivatives have good oral activity, but are associated with poor liver compatibility problems ⁽¹¹⁾ .

A steroidally active compound that binds to and accumulates in erythrocytes through the group —SO ₂ NR ¹ R ² is known from DE 10027887.6A1. The concentration ratio of the compound between erythrocytes and plasma is 10 to 1000, preferably 30 to 1000, so that it is possible to show depot formation in erythrocytes. Due to the strong binding of the compound to red blood cells, metabolism is avoided while passing through the liver. Unfortunately, despite reduced metabolism at the indicated doses, treatment-related active ingredient levels are not obtained.

  It is an object of the present invention to prepare novel steroidal compounds with estrogenic effects that can be used orally and to ensure therapeutically relevant active ingredient levels compared to conventional techniques and even at low doses.

The purpose is to bind the steroid to which the group Z is released, the following general formula (I):

[Wherein n is 0 to 4,
R ¹ is a group —SO ₂ NH ₂ or —NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ¹ are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, C _1-5 — Represents an alkyl group, a CpF _{2p + 1} group (p is 1 to 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 are a C _1-5 -alkyl group, a C _3-8 -cycloalkyl group, an aryl group, a C _1-4 -alkylenearyl group, a C _1-4 -alkylene-C _{A 3-8} -cycloalkyl group or a C _3-8 -cycloalkylene-C _1-4 -alkyl group, and further R ²⁰ may be hydrogen, or

R ² is a group —SO ₂ NH ₂ or —NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ¹ are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, C _1-5 — Represents an alkyl group, a CpF _{2p + 1} group (p is 1 to 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 are a C _1-5 -alkyl group, a C _3-8 -cycloalkyl group, an aryl group, a C _1-4 -alkylenearyl group, a C _1-4 -alkylene-C _{A 3-8} -cycloalkyl group or a C _3-8 -cycloalkylene-C _1-4 -alkyl group, and further R ²⁰ may be hydrogen, or

R ³ is a group —SO ₂ NH ₂ or —NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ¹ are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, C _1-5 — Represents an alkyl group, a CpF _{2p + 1} group (p is 1 to 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 are a C _1-5 -alkyl group, a C _3-8 -cycloalkyl group, an aryl group, a C _1-4 -alkylenearyl group, a C _1-4 -alkylene-C _{A 3-8} -cycloalkyl group or a C _3-8 -cycloalkylene-C _1-4 -alkyl group, and further R ²⁰ may be hydrogen, and
STEROID has the following general formula (AII-CII):

Represents a steroid ring system represented by
Y represents an oxygen atom or a carbon atom,
R ⁴ represents a hydrogen atom, a halogen atom, methyl, trifluoromethyl, hydroxy, tri (C _1-6 -alkyl) silyloxy, C _1-5 -alkoxy or C _2-5 -heterocycloalkyloxy group,
R ⁷ represents a hydrogen atom, a methyl or ethyl group,
R ¹⁰ represents a hydrogen atom, a methyl or ethyl group,

R ¹¹ represents 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 represents a hydrogen atom, a methyl group or an ethyl group,
R ¹³ represents a hydrogen atom, methyl, ethyl, ethynyl, trifluoromethyl or pentafluoroethyl group,
R ¹⁴ represents a hydrogen atom, an OH group, or an oxygen atom bonded through a double bond,
R ¹⁵ represents hydroxy, tri (C _1-6 -alkyl) silyloxy, C _1-5 -alkoxy group, group OC (O) -R ²⁰ or C _2-5 -heterocycloalkyloxy group] Accomplished by steroid prodrugs and their pharmaceutically acceptable salts.

When Y represents a carbon atom, an additional double bond is found in the 1,2-position, or when the group R ¹⁴ is a hydrogen atom or an OH group, it is found in the 2,3-position. Additional double bonds can be found in the 4,5-position.
In the present invention, the “C _1-5 -alkyl group” means a branched or straight-chain alkyl group having 1 to 5 carbon atoms, which can be substituted by, for example, a halogen atom, a hydroxy group or a nitrile group. Defined. By way of example, mention may be made of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl groups.

The term C _1-5 -alkoxy group is defined as a branched or straight chain alkoxy group having 1 to 5 carbon atoms. By way of example, mention may be made of the methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert.-butoxy or n-pentoxy group.
The term tri (C _1-6 -alkyl) silyloxy group is defined, for example, as a trimethylsilyloxy group, triisopropyl, silyloxy group, sexyldimethylsilyloxy group or tert-butyldimethylsilyl group.

According to the present invention, the above-mentioned “C _3-8 -cycloalkyl group” means a monocyclic or bicyclic group which can be substituted by, for example, a halogen atom, a hydroxy group or a nitrile group, such as cyclopropyl, cyclobutyl, etc. , Cyclopentyl, cyclohexyl or hydroxycyclohexyl group.
In this application, the term “aryl group” means a substituted or unsubstituted aryl group having 6 to 15 carbon atoms, such as a phenyl group, a substituted phenyl group, such as a halophenyl group, or Defined as nitrophenyl or naphthyl group.

In the present application, the term “C _1-4 -alkylenearyl group” is defined as a disubstituted alkyl group which is at least substituted by an aryl group. Both groups together have from 7 to 15 carbon atoms so that the groups can carry additional substituents such as halogen atoms. As an example, a benzyl group or a halogen group can be listed.

In this application, the term “C _1-4 -alkylene-C _3-8 -cycloalkyl group” is defined as a disubstituted alkyl group that is at least substituted by a C _3-8 -cycloalkyl group. The Both groups together represent from 7 to 15 carbon atoms, whereby the groups can carry additional substituents such as halogen atoms. By way of example, the cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl groups can be listed.

In this application, the term “C _3-8 -cycloalkylene-C _1-4 -alkyl group” refers to a disubstituted C _{3-8 -cyclo} at least substituted by a C _1-4 -alkyl group. Defined as an alkylene group. Both groups together represent from 7 to 15 carbon atoms, whereby the groups can carry additional substituents, for example halogen atoms. By way of example, a propylcyclohexyl group or a butylcyclohexyl group can be listed.

According to the invention, the term “C _p F _{2p + 1 -group} ” is defined as a perfluorinated alkyl group, for example a trifluoromethyl group and a pentafluoroethyl group.
Within the scope of the present invention, the term “C _2-5 -heterocycloalkyloxy group” is defined as a C _1-5 -heterocycloalkyloxy group having nitrogen or oxygen atoms as heteroatoms, The C _1-5 -heterocycloalkyloxy group is attached through the oxygen atom in the 2-, 3- or 4-position. An example of this is a perhydropyranoxy group.

Within the scope of the present invention, the term “halogen atom” is defined as a fluorine, chlorine, bromine or iodine atom; a fluorine, chlorine or bromine atom is preferred.
The number “n” is preferably 0, 1 and 2, with 0 being particularly preferred.
The group Z is preferably arranged in the 17- and 4-positions, whereby the 17-position is particularly preferred.

Preferably R ¹ represents the group —SO ₂ NH ₂ or —NHSO ₂ NH ₂ , whereby the group —SO ₂ NH ₂ is particularly preferred. Thus, the group is found in the m-position of the group Z with respect to the ester group, through which the group Z is bound to the steroid.
R ¹ preferably denotes the group —SO ₂ NH ₂ , whereby R ² , R ³ , X ¹ and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group, or

R ² preferably denotes the group —SO ₂ NH ₂ , whereby R ¹ , R ³ , X ¹ and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group, or
R ³ preferably denotes the group —SO ₂ NH ₂ , whereby R ¹ , R ² , X ¹ and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group.

Y preferably represents a carbon atom and / or
R ⁴ preferably represents a hydrogen atom, a chlorine atom or a hydroxy group and / or
R ⁷ preferably represents a hydrogen atom or a methyl group and / or
R ¹⁰ preferably represents a hydrogen atom or a methyl group and / or
R ¹¹ preferably represents a hydrogen atom, a fluorine atom or a methyl group and / or
R ¹² preferably represents a hydrogen atom and / or
R ¹³ preferably represents a hydrogen atom or a methyl group and / or
R ¹⁴ preferably represents an oxygen atom and / or
R ¹⁵ preferably represents a hydroxy group or a group OC (O) —R ²⁰ .

Group Z in the 4-, 11- or 17-position, R ⁴ in the ⁴ -position, R ⁷ in the ⁷ -position, R ¹¹ in the ¹¹ -position, R ^{13 in} the 17-position, and the 17-position R ¹⁵ in can be placed in both α- and β-positions as a function of Z or R ¹⁵ .

Particularly preferred steroid prodrugs are shown below:
1) 3-oxo-7α-methylestre-4-en-17β-yl 3'-sulfamoylbenzoate (12),
2) 3-Oxo-7α-methylestre-4-en-17β-yl 4'-sulfamoylbenzoate (11),
3) 3-Oxo-7α-methylestre-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (13),
4) 3-Oxo-7α-methylestre-4-en-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate,
5) 3-oxo-7α-methylestre-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,

6) 3-oxo-7α-methylestre-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate,
7) 3-Oxoestre-4-en-17β-yl 3'-sulfamoylbenzoate (7),
8) 3-Oxoestre-4-en-17β-yl 4'-sulfamoylbenzoate (8),
9) 3-oxoestre-4-en-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate,
10) 3-oxoestre-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate,

11) 3-oxoestre-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,
12) 3-oxoestre-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-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-en-17β-yl 3'-sulfamoylbenzoate (5),
20) 3-Oxoandrost-4-en-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-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,
24) 3-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate,
25) 3-Oxoandrostane-17β-yl 3'-sulfamoylbenzoate (9),

26) 3-Oxoandrostane-17β-yl 4'-sulfamoylbenzoate (10),
27) 3-oxoandrost-4-en-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-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate,

31) 3-Oxo-4-chloro-17α-methylandrost-1,4-dien-17β-yl 3'-sulfamoylbenzoate (16),
32) 3-oxo-4-chloro-17α-methylandrost-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-fluoroestre-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-oxoandrostan-17β-yl 2'hydroxy-5'-sulfamoylbenzoate,

41) 3-oxo-7α-methyl-11 β-fluoroestre-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate,
42) 3-Oxoestre-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate,
43) 3-oxo-7α-methylestre-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-hydroxyestre-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] estre-4-en-4-yl 3'-sulfamoylbenzoate (22),
49) 3-Oxo-17β-hydroxyestre-4-en-4-yl 3'-sulfamoylbenzoate (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, hydrochloric acid, odoric acid, sulfuric acid and phosphoric acid are regarded as inorganic acids and 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, transdermal acid and methanesulfonic acid are considered as organic acids.

  The compounds of the present invention have androgenic activity, whereby a therapeutically relevant steroid is released by esterification of its corresponding compound of formula (I). Therefore, mainly androgens with OH groups, which have higher androgenic activity than compounds with keto groups, are conveniently released.

With respect to known compounds, oral androgen and anti-gonadotropin activities and effects on the liver function of the compounds of the invention were determined by tests on the following animals:
I. Sexually immature castrated male rats,
II. Sexually mature, castrated rats, and
III. Sexually mature male rats that are not gonadally impaired.
The results are illustrated in FIGS.

Study on sexually immature castrated male rats over 8 days (I) :
Surprisingly and unexpectedly, the compound 12 or 18 of the invention of formula (I) on sexually immature castrated male rats showed a strong dose-dependent effect on the growth of the accessory gonadal, For (7α-methyl-19-nortestosterone) MENT, only an insignificant effect was observed. Unexpectedly, the substances of the present invention also show superior anti-gonadotropin activity over that of MENT. However, in contrast to HDL reduction, MENT is more active than the substances of the present invention.

Exam description:
Method: Male rats weighing approximately 45 g are castrated and treated orally with MENT and compounds 12 or 18 of the invention for 7 days. On the 8th day of the test, the animals are sacrificed and the hormonal effects of the test substances are evaluated (growth of paragonads, reduction of gonadotropin hormone in plasma, parameters of liver action: effects on HDL lipoproteins).

Study on sexually mature, castrated male rats over 8 days (II) :
Test (II) was conducted on sexually mature, castrated male rats. Also here, an unexpectedly strong dose-dependent effect on the growth of the paragonads was found with the substances according to the invention, for example compound 12, but only an insignificant effect was observed for MENT. Surprisingly enough, the compounds of the present invention also exhibit superior anti-gonadotropin activity over that of MENT. However, in contrast to the reduction of HDL, MENT is much more active than the substance of the invention in this test (II). After oral administration of a compound of the invention, such as compound 12, a significantly higher level of MENT is achieved in plasma than after administration of MENT itself.

Exam description:
Method: Adult male rats weighing 300 g are castrated and treated orally with MENT and compounds 12 of the invention for 7 days. On day 8 of the study, the animals are sacrificed and the hormonal effects of the test substances are evaluated (growth of paragonads, decreased gonadotropin hormone in plasma, parameters of liver action: effects on HDL lipoprotein, determination of MENT in plasma).

Third study (III) on sexually mature rats, unharmed gonads over 6 weeks :
In a third study (III) on sexually mature rats that were unharmed gonads over a period of 6 weeks, all test substances unexpectedly experienced a major decline in endogenous testosterone during treatment, Only had an unimportant effect on the secondary gonadal. In this case, Compound 12 of the present invention elicited an increase in seminal vesicle and prostate weight in a dose-dependent manner over unimpaired control levels. The corresponding effect did not occur under MENT even at very high doses. The superior anti-gonatotropin effect of Compound 12 of the present invention could also be confirmed. However, in contrast to the reduction in HDL, MENT is much more effective than the substances of the present invention. Compound 5 of the present invention is distinguished by particularly small changes in liver parameters.

Exam description:
Method: Adult male rats weighing about 300 g are treated orally with MENT and compounds 12 or 5 of the present invention for 6 weeks. At the end of the test, the animals are killed and the hormonal effects of the test substances are evaluated (testis and paragonad weight, during the test, gonadotropin hormone and testosterone reduction in plasma, liver action parameters: effects on HDL riboprotein) .

  The androgenic sulfamoylbenzoate of the present invention is clearly superior to its corresponding androgen in terms of oral androgenic and anti-gonadotropin activity, as shown in Test (I-III). The effect on liver function is clearly superior to the therapeutically desired androgenic effect.

Red blood cell binding studies :
In addition, Compound 5 or 12 of the present invention and Compound 1 or 11 of the present invention were studied for binding to erythrocytes.
For m-substituted compounds, significantly weaker binding to erythrocytes is detected. However, 4'-sulfamoyl benzoate shows strong binding.

  However, in this case, for example, m-substituted compound 12 is not expected to show higher activity in the Hershberger test compared to p-substituted compound 11 despite the low binding strength to erythrocytes. The data in Table 1 shows the binding of selected compounds of formula (I) to erythrocytes.

Test principle and test description:
The SO ₂ —NH ₂ group of the substances of the invention can lead to enrichment in erythrocytes by binding to carboanhydrase. The displacement of estradiol-3-sulfamate from red blood cell binding by the test substance is measured.

Test preparation: Human blood is mixed with a mixture of ¹⁴ C-labeled and unlabeled estradiol sulfamate. Red blood cells are saturated at the selected point of action and the distribution in plasma / red blood cells is 40:60. A second blood sample is mixed with a mixture of ¹⁴ C-labeled estradiol sulfamate and unlabeled test substance. Relative binding affinity is calculated from the percentage of ¹⁴ C-labeled estradiol sulfamate in plasma as follows: higher percentage = strong displacement of ¹⁴ C-estradiol sulfamate from red blood cells by the test substance = High binding affinity of test substance to erythrocytes.

Determination of red blood cell / plasma distribution ratio:
Freshly obtained, heparinized plasma is mixed with a defined amount of test substance. The concentration in the resulting plasma is measured. The red blood cell / plasma ratio is calculated from the measured concentration of total substance measurement in plasma and the concentration used.

  Surprisingly enough, in all cases, binding to carboanhydrase (CAI) found in erythrocytes is found (Table 2). Accordingly, the compounds of the present invention are also expected to have therapeutically relevant effects as carboanhydrase inhibitors. Binding to erythrocytes, induced by high affinity for carboanhydrase, is important for its estrogenic nature. This binding is essential for the reduced extraction of orally administered substance in the first liver passage. High or low affinity for erythroid carboanhydrase, early or delayed release from this depot, and subsequent hydrolysis determine the therapeutic utility of the substances of the invention.

  Unexpectedly, the compounds of the present invention may reach therapeutically relevant levels at low doses when the red blood cell / substance concentration ratio in plasma is 10 or less, unlike that predicted according to DE10027887.6A1. It was found. The compounds of the present invention open the possibility that higher, short duration or equally low and long lasting hormonal levels can be achieved with the same absolute amount of substance administered. As a result, the activity intensity and duration of action varies and allows treatments adapted to individual organisms.

Test principle and test description:
Carboanhydrase catalyzes CO ₂ hydrate.
Test preparation: A constant flow of CO ₂ is directed by a buffer mixed with carboanhydrase I. The time required to lower the pH within defined limits is a measurement parameter. This parameter affects the formation of H ₂ CO ₃ in the medium. IC ₅₀ inhibition values are determined by the test substance pipetted into the test preparation. In the concentration range tested, the test substance does not cause inhibition to complete the inhibition of the enzyme.

  In vivo studies (Studies I-III) and potential test results shown for variations in the activity intensity and duration of the action of treatments adapted to individual organisms have been shown to be feasible in childbirth restriction and hormone exchange therapy (HRT) in men and women. ), And opens many potential applications for the treatment of hormonally induced diseases in men and women.

  Accordingly, the subject of the invention also comprises at least one compound of general formula (I) or the corresponding salt, and optionally another steroid active ingredient, and optionally pharmaceutically compatible adjuvants and vehicles. It is a pharmaceutical composition. Preferred active ingredients for this are GnRH analogues, gestagens, antigestagens or glucocorticoids.

  These pharmaceutical compositions and pharmaceutical agents can preferably be used for oral administration, rectal, vaginal, subcutaneous, dermal, intravenous, buccal, transdermal or intramuscular administration. In addition to commonly used vehicles and / or diluents, they contain at least one compound of general formula I or a salt thereof.

The pharmaceutical agents of the present invention are produced by commonly used solid or liquid vehicles or diluents and commonly used pharmaceutical-technical adjuvants that correspond to the desired type of administration at an appropriate dose by known means. . Preferred preparations exist in a form for dispersion that is suitable for oral administration. Such forms for dispersion are for example tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions, or else depot forms.
Of course, parenteral preparations such as injectable solutions are also conceivable. In addition, for example, suppositories, and agents for vaginal administration may also be mentioned as preparations.

  Corresponding tablets, for example, contain the active ingredient in a base adjuvant such as an inert diluent such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, a binder such as starch or gelatin, a lubricant such as It is obtained by mixing with magnesium stearate or talc and / or an agent for achieving the depot effect, for example carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. A tablet can also consist of several layers.

  Coated cores produced similar to tablets with agents commonly used for tablet coating, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide, or sugar, result in coated tablets. be able to. In this case, the coated tablet shell can also consist of several layers, whereby the adjuvants mentioned above in the tablets can be used.

Solutions or suspensions comprising a compound of general formula I according to the invention may contain additional taste-improving agents such as saccharin, cyclamate or sugar, and flavor substances such as vanilla or orange extract. In addition, they can contain suspending adjuvants such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
Capsules containing a compound of general formula I can be produced, for example, by mixing a compound of general formula I with an inert vehicle such as lactose or sorbitol and encapsulating in a gelatin capsule.

Suitable suppositories can be made, for example, by mixing with vehicles provided for this purpose, such as neutral fats or polyethylene glycols or derivatives thereof.
The compounds of the present invention are steroid prodrugs and have androgenic activity. The compounds of the invention are particularly suitable for oral administration. A therapeutically suitable steroid is released from the compound of the invention or a salt thereof by ester separation.

The compounds of the present invention are distinguished by weak erythrocyte binding associated with good androgenic activity. In this case, the factors used as a reference for binding or concentration in erythrocytes are known from DE 10027887.6A1 and in the compounds according to the invention not more than 10.
The compounds of the present invention allow the therapeutic administration of androgenic active compounds in the form of oral therapy, and for this type of therapy due to the poor bioavailability of eg testosterone, 5α-DHT or MENT. Not appropriate for that.

The compounds of the present invention are suitable for replacement therapy, particularly GnRH-analogues, gestagens or other therapies resulting in suppression of endogenous androgen secretion in combination with antigonadotropic and contraceptive methods in men It is.
The compounds of the present invention are also suitable for replacement therapy in combination with glucocorticoids or other therapies that result in suppression of adrenal androgen secretion.
The compounds of the invention are also suitable for replacement therapy in women, especially after an age-specific decrease in ovarian and adrenal androgen secretion.

  Liver compatibility problems are minimized by the compounds of the present invention. With respect to conventional orally administered androgens, especially C-17 alkylated androgens, the liver is known to be very stressed. Androgens contained in the compounds of the present invention do not stress the liver after their release.

  The oral bioavailability of contained androgens is enhanced by the compounds of the present invention. Therefore, the total amount of hormones that have an effect on the organism is reduced. Hormonal action on the liver in the first pathway is reduced. In this regard, the known adverse effects of oral androgen treatment on lipid metabolism (lowering of HPL cholesterol, increased risk of atherogenesis) and other liver secretion products are reduced.

Androgens differ in their hormonal range of action and thus in their suitability for various therapeutic requirements. The compounds of the present invention enable the possibility of androgen therapy that differentiates by the choice of included androgens.
The following examples are used to illustrate the invention in more detail, but are not intended to limit the invention.

General synthesis teaching:
For the production of androgens based on the general formula (AII-CII), known steroid precursors can be used. The following steroid precursors can be used:
Testosterone, dihydrotestosterone, 19-nortestosterone, 7α-methyl-19-nortestosterone, 7α-methyl-11β-fluoro-19-nortestosterone and 3,3-dimethoxy-estro-5 (10) -17-one (DD79 -213049), epiandrosterone, 5α-androst-2-en-17-one (US-A-3,098,951) from epiandrosterone, 7α-methyl-11β-methyl-19-nortestosterone, 7α- Methyl-11β-methyltestosterone, oxandrolone, oral-turinabol, 17α-methyltestosterone, and the like.

  The functional group contained in the starting material for the steroid precursor can optionally be protected according to methods known to those skilled in the art or can be converted to the corresponding functional group. Thus, the keto group in the starting material can be protected as a ketal or thioketal according to methods known to those skilled in the art. The 17-keto compound can be reduced to the hydroxy compound according to methods known to those skilled in the art.

(A) Coupling of steroid compound to group Z:
Variant 1:
Reaction with sulfamoylphenylcarboxylic acid:
Androgen is dissolved in a base such as pyridine. A corresponding amount of sulfamoylphenyl carboxylic acid is added to the solution, then an acid, such as p-toluenesulfonic acid, and finally a carbodiimide, such as dicyclohexylcarbodiimide. The reaction mixture is stirred until the reaction is complete. Then water is added and it is acidified with an acid such as 10% HCl. The precipitate is filtered, washed with water and sodium bicarbonate solution and dried. The residue is extracted with an organic solvent, such as ethyl acetate, the organic phase is washed and dried with a desiccant, such as magnesium sulfate. After filtration, it is concentrated by evaporation and chromatographed on silica gel. The corresponding estrogen sulfamoyl benzoate is obtained.

Variant 2:
Reaction with sulfamoylphenylcarboxylic acid chloride:
Estrogens are dissolved in a base such as pyridine. A corresponding amount of sulfamoylphenylcarboxylic acid chloride is added to the solution. The reaction mixture is stirred until the reaction is complete. Then water is added and it is acidified with an acid such as 10% HCl. It is extracted with an organic solvent such as ethyl acetate, the organic phase is washed and dried with a desiccant such as magnesium sulfate. After filtration, it is concentrated by evaporation and chromatographed on silica gel. The corresponding estrogen sulfamoyl benzoate is obtained.

Variant 3:
Reaction with chlorosulfamoylphenylcarboxylic acid chloride:
Estrogens are dissolved in a base such as pyridine and an organic solvent such as chloroform and cooled. A corresponding amount of chlorosulfonylphenyl carboxylic acid chloride is added to the solution. The reaction mixture is stirred until the reaction is complete. The reaction mixture is then stirred in concentrated ammonia solution. The mixture is concentrated by evaporation and acidified with an acid such as 10% HCl. The precipitate is aspirated, washed with water, dried and chromatographed on silica gel. The corresponding estrogen sulfamoyl benzoate is obtained.

Variant 4:
Reaction with 2-sulfophenylcarboxylic acid-cyclo-anhydride:
Estrogens are dissolved in an organic solvent such as chloroform. After the addition of 2-sulfophenylcarboxylic acid-cyclo-anhydride, it is stirred at elevated temperature under cover gas. It is then cooled and mixed with a concentrated ammonia solution, such as a methanolic ammonia solution. The solution is evaporated and the residue is chromatographed on silica gel. The corresponding 2′-sulfophenylcarboxylic acid ester-ammonium salt of estrogen is obtained which is dissolved in an organic solvent, for example CHCl ₃ under a cover gas. Corresponding amounts of chlorinating agent, for example PCl ₅ or SOCl _2, are added in portions. The reaction mixture is optionally stirred at an elevated temperature and then added to the concentrated NH ₃ solution. The mixture is concentrated by evaporation, the precipitated material is filtered, washed with water, dried and chromatographed on silica gel. The corresponding 2′-sulfamoylphenyl carboxylic acid ester of estrogen is obtained.

Variant 5:
Reaction to form sulfamide (NH ₂ SO ₂ NH-):
The reaction to form the sulfamides of the invention is carried out with sulfamide, sulfamoyl chloride or aminosulfonyl isocyanate starting from the corresponding amine according to methods known to those skilled in the art for their production (PO Burke et al. , J. Chem. Soc. Perk. Trans 2, 1984, 1851; M. Preiss et al. Chem. Ber., 1978, 1915; CH. Lee et al., J. Org. Chem., 1990, 6104.).

For example, the corresponding aminobenzoate in an organic solvent such as toluene is reacted with the base sulfamoyl in the presence of a base such as NEt ₃ at a temperature of 20-60 ° C. The reaction mixture is stirred until the reaction is complete. Then water is added and the precipitate is filtered, washed with water and sodium bicarbonate solution and dried. The material is purified by chromatography on silica gel. The corresponding estrogen sulfamoylaminobenzoate is obtained.

B) Synthesis of group (Z) :
2-Chloro-4-sulfamoylbenzoic acid :
Stage 1 :
10 g of 2-chloro-toluene-4-sulfonic acid-Na-salt xH ₂ O is added to 40 ml of thionyl chloride. After the addition of 5 ml DMF, it is refluxed for 6 hours. The cold reaction mixture is added to 200 g of ice. The precipitated material is washed with water and dried. 2-Chloro-toluene-4-sulfonic acid chloride is obtained.
¹ H-NMR (DMSO-d ₆ ): 2.32 (s, 3H1 Me), 7.32-7.58 (m (overlap), 3H, CH).

Stage 2 :
8 g of 2-chloro-toluene-4-sulfonic acid chloride is dissolved in 25 ml of CHCl ₃ and stirred slowly into 100 ml of concentrated NH ₃ solution. After 10 minutes of stirring at room temperature, the solution is concentrated by evaporation to half its original volume. The material is aspirated, washed with water and dried. 2-Chloro-4-sulfamoyltoluene is obtained.
¹ H-NMR (DMSO-d ₆ ): 2.39 (s, 3H, Me), 7.44 (s, 2H, NH2), 7.55-7.83 (m (overlap), 3H, CH).

Stage 3 :
1.67 g of 2-chloro-4-sulfamoyltoluene is introduced into 70 ml of water. After the addition of 5 g KMnO ₄ and 0.5 ml saturated sodium bicarbonate solution, it is refluxed for 2 hours. After the addition of 2 ml of MeOH, the manganese dioxide produced is filtered and the solution is concentrated by evaporation to half its original volume. After acidification with 10% HCl, the solution is cooled for 8 hours until crystallization is complete. It is then aspirated, washed with water and dried. 2-Chloro-4-sulfamoylbenzoic acid is obtained.
¹ H-NMR (DMSO-d ₆ ): 7.66 (s, 2H, NH2), 7.80-8.02 (m (overlap), 3H, CH), 13.86 (s, 1 H1 COOH).

5-sulfamoylisophthalic acid :
Stage 1 :
20 g of 5-sulfoisophthalic acid-Na-salt is added to 500 g of ice and the precipitated material is sucked off, washed with water and dried. 5-Chlorosulfonylisophthalic acid dichloride is obtained.
¹ H-NMR (CDCI ₃ ): 8.98 (s, 2H, H-4,6), 9.11 (s, 1 H, H-2).

Stage 2 :
10 g of 5-chlorosulfonylisophthalic acid dichloride is mixed little by little into 150 ml of NH ₃ solution. The solution is concentrated by evaporation and the precipitated material is filtered, 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).

Stage 3 :
1 g of 5-sulfamoylisophthalic acid diamide is suspended in 20 ml of 1,4-dioxane. 5 ml of 10% HCl is added and the reaction mixture is heated to about 90 ° C. for 3 hours. The reaction mixture is then evaporated 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 is dissolved in 100 ml of saturated ammonia solution. The solution is concentrated by evaporation and the salt is dried over P ₂ O ₅ . 5 g of salt is dissolved in 20 ml of SOCl ₂ . 0.3 ml of DMF is added to the reaction mixture and refluxed for 2 hours. It is cooled, toluene is added for crystallization and it is filtered. The product is washed with toluene and dried. 4-Chlorosulfonylbenzoic acid chloride is obtained which is used for further reactions.

Example 1: 3-Oxoandrost-4-en-17β-yl 4′-sulfamoylbenzoate (1) :
Variant 1 :
1.0 g testosterone is dissolved in 10 ml pyridine. After the addition of 1.5 g p-sulfamoylbenzoic acid, 200 mg p-toluenesulfonic acid and 1.5 g dicyclohexylcarbodiimide (DCC), it is stirred for 48 hours at room temperature. Next, 20 ml of water is added. It is slightly acidified with 10% HCl (pH = 5). The precipitate is filtered and washed twice with saturated sodium bicarbonate and water. The dried residue is extracted with ethyl acetate. The organic phase is washed with 10% sodium hydrogen carbonate solution and saturated NaCl solution, dried over magnesium sulfate, filtered, concentrated by evaporation and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 4′-sulfamoylbenzoate (1) is obtained.

Variant 2 :
1.0 g testosterone is dissolved in 10 ml pyridine. After the addition of 1.0 g p-sulfamoyl benzoic acid chloride, it is stirred for 2 hours at room temperature. Then after addition of 20 ml of water it is acidified slightly with 10% HCl (pH = 5). It is then extracted with ethyl acetate. The organic phase is separated by 10% sodium hydrogen carbonate solution and washed with saturated NaCl solution, dried over magnesium sulfate, filtered, concentrated by evaporation and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 4′-sulfamoylbenzoate (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-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate (2) :
Said material is obtained according to variant 1, analogously to example 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, 3 H, H-19), 4.82 (m, 1 H, H-17α), 5.64 (s, 1 H, H-4), 7.88 (s, 2H, NH ₂ ), 8.02 (s, 1 H, H-Ar), 8.37 (s, 1H1 H-Ar).

Example 3: 3-oxoandrost-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (3) :
Said material is obtained according to variant 1, starting from 2-chloro-5-sulfamoylbenzoic acid and testosterone, analogous to example 1.
¹ H-NMR (DMSO-d ₆ ): 0.90 (s, 3H, H-18), 1.16 (s, 3 H, H-19), 4.77 (m, 1 H, H-17α), 5.64 (S, 1 H, H-4), 7.56 (s, 2H, NH2), 7.75-8.80 (m, 3H, H-Ar).

Example 4: 3-oxoandrost-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate (4) :
The material is obtained according to variant 1, analogously to example 1, starting from 2-methoxy-5-sulfamoylbenzoic acid and testosterone.
¹ H-NMR (DMSO-d ₆ ): 0.90 (s, 3H, H-18), 1.16 (s, 3 H, H-19), 4.74 (m, 1 H, H-17α), 5.64 (s, 1H, H-4), 7.33 (m, 1 H, 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'-sulfamoylbenzoate (5) :
1.0 g testosterone is dissolved in 2 ml pyridine and 2 ml CHCl ₃ . 1.0 ml of 3-chlorosulfonylbenzoic acid chloride is added to the reaction mixture at −20 ° C. with stirring. It is then heated to room temperature and stirred for 15 minutes. The reaction solution is added to 25 ml concentrated NH ₃ solution and stirred for 15 minutes. Next, the organic mobile solvent is distilled. It is slightly acidified with 10% hydrochloric acid (pH = 5). The precipitated material is aspirated, washed with 10% sodium hydrogen carbonate solution and water, dried and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 3′-sulfamoylbenzoate (5) is obtained.
¹ H-NMR (CDCI ₃ ): 0.98 (s, 3H, H-18), 1.21 (s, 3 H, H-19), 4.88 (m, 1H, H-17α), 5.28 (s, 2H, NH ₂ ), 5.74 (s, 1 H, H-4), 7.33 (m, 1 H, H-Ar) 1 7.60-8.60 (m, 4H, H-Ar).

Example 6: 3-oxoandrost-4-en-17β-yl 2'-sulfamoylbenzoate (6) :
Stage 1 :
3-Oxoandrost-4-en-17β-yl 2′-sulfobenzoate-ammonium salt :
Dissolve 2.5 g of testosterone in 10 ml of chloroform. After adding 3.5 g of 2-sulfobenzoic acid-cyclo-anhydride, it is stirred for 12 hours at 50 ° C. under cover gas. It is then cooled to 0 ° C. and mixed with concentrated methanolic ammonia solution. The solvent is distilled 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, 3 H, H-19), 4.67 (m, 1H, H-17α), 5.63 (s, 1 H, H-4), 7.33 (m, 1H, H-Ar), 7.18-7.75 (m, 4H, H-Ar).

Stage 2 :
3-Oxoandrost-4-en-17β-yl 2'-sulfamoylbenzoate (6) :
3.95 g of 3-oxoandrost-4-en-17β-yl 2′-sulfamoylbenzoate ammonium salt is dissolved in 160 ml of CHCl ₃ under Gabergas. 6.0 g of PCl ₅ is added in portions within 1 hour. The reaction mixture is stirred at room temperature for 12 hours and then added to 600 ml of concentrated NH ₃ solution. The mixture is concentrated by evaporation, the precipitated material is filtered, washed with water, dried and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 2′-sulfamoylbenzoate (6) is obtained.
¹ H-NMR (CDCI ₃ ): 0.94 (s, 3H, H-18), 1.20 (s, 3 H, H-19), 4.90 (m, 1H, H-17α), 5.73 (s, 1 H, H-4), 5.80 (s, 2H, NH ₂ ), 7.58-8.15 (m, 4H1 H-Ar).

Example 7: 3-oxoestre-4-en-17β-yl 3'-sulfamoylbenzoate (7) :
The material is obtained analogously to Example 5 starting from nandrolone, 3-chlorosulfonylbenzoic acid chloride 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-Oxoestre-4-en-17β-yl 4'-sulfamoylbenzoate (8) :
The material 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, 1 H, H-17α), 5.74 (s, 1H1 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 material is obtained analogously to Example 5, starting from 17β-hydroxy-5α-androstan-3-one, 3-chlorosulfonylbenzoic acid chloride 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 , NH2), 7.68-8.38 (m, 4H, H-Ar).

Example 10: 3-Oxoandrostane-17β-yl 4'-sulfamoylbenzoate (10) :
The material 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, NH2), 7.90-8.13 (m, 4H, H-Ar).

Example 11: 3-oxo-7α-methylestre-4-en-17β-yl 4'-sulfamoylbenzoate (11) :
The material is obtained analogously to example 1, variant 1, starting from 17β-hydroxy-7α-methylestr-3-en-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, 1 H, 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-methylestre-4-en-17β-yl 3′-sulfamoylbenzoate (12) :
The material is obtained analogously to Example 5, starting from 17β-hydroxy-7α-methylestr-3-en-one (MENT), chlorosulfamoyl benzoic acid chloride and ammonia.
¹ H-NMR (DMSO-d ₆ ): 0.75 (d, 3H, 7α-Me), 0.98 (s, 3H, H-19), 4.83 (m, 1H1 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-methylestre-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (13) :
The material is obtained analogously to Example 1, variant 1, starting from 17β-hydroxy-7α-methylestr-3-en-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, 1 H, H-17α), 5.72 (s, 1 H, H-4), 7.60 (s, 2H, NH ₂ ), 7.75-8.18 (m, 4H1 H-Ar).

Example 14: 3-oxoandrost-4-en-17β-yl 4'-sulfamoylphenylpropionate (14) :
The material is obtained analogously to Example 1, variant 1, starting from 3- (p-sulfamoylphenyl) propionic acid and testosterone.
¹ H-NMR (DMSO-d ⁶ ): 0.74 (s, 3H1 CH ₃ ), 1.14 (s, 3 H, CH ₃ ), 2.66 (t, 2 H1 CH ₂ ), 2.92 (t. 2H1 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 material is obtained analogously to Example 5, starting from 17β-hydroxy-7α-androst-1-en-3-one, 3-chlorosulfamoylbenzoic 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, 1 H, H-2), 7.21 (s, 1 H, 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'-sulfamoylbenzoate (16) :
The material is analogous to Example 5, starting from 4-chloro-17α-methyl-17β-hydroxyandrost-1,4-dien-3-one, 3-chlorosulfamoylbenzoic acid chloride and ammonia. Get.
^{1 H-NMR (DMSO-d} 6): 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, 2H1 NH ₂ ), 7.70-8.38 (m, 4H, H-Ar).

Example 17: 3-oxo-7α-methyl-11β-fluoroestre-4-en-17β-yl 3'-sulfamoylbenzoate (17) :
Said material is analogous to Example 5, variant 3, starting from 17β-hydroxy-7α-methyl-11β-fluoro-estr-4-en-3-one, 3-chlorosulfonylbenzoic acid chloride and ammonia. Get.
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, 1 H1 H-4), 7.55 (s, 2H1 NH ₂ ), 7.70-8.38 (m, 4H, H-Ar).

Example 18: 3-Oxoandrost-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate (18) :
The material is obtained analogously to Example 1, 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, 1 H1 H-17α), 5.64 (S1 1 H1 H -4), 7.14 (m, 1 H1 H-Ar) 1 7.36 (s, 2H1 NH 2), 7.90- 8.2 (m, 2H1 H-Ar) 1 1 1.03 (s, 1 H, OH).

Example 19: 3-oxo-4-chloroandrost-4-en-17β-yl 3'-sulfamoylbenzoate (19) :
The material is obtained analogously to Example 5, variant 3, starting from 3-oxo-4-chloro-17β-hydroxy-androst-4-ene and 3-chlorosulfonylbenzoic acid chloride and ammonia.
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, 1H1 H-Ar).

Example 20: 3-Oxo-4-chloroandrosta-1,4-dien-17β-yl 3'-sulfamoylbenzoate (20) :
The material is obtained analogously to Example 5, variant 3, starting from 3-oxo-4-chloro-17β-hydroxyandrost-1,4-diene and 3-chlorosulfonylbenzoic acid chloride and ammonia. .
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-hydroxyestre-4-en-4-yl 3'-sulfamoylbenzoate (21) :
Step 1: 4-Texyldimethylsilyloxy-17β-acetoxyestr-4-en-3-one :
5.9 g of 4-hydroxy-17β-acetoxyestr-4-en-3-one is reacted in 58 ml of DMF with 12 g of imidazole and 15 ml of texyldimethylsilyl chloride at 35 ° C. for 2 hours. 500 ml of water is added to the reaction solution. It is then extracted with ethyl acetate, dried over magnesium sulphate and concentrated by evaporation. The product is purified by chromatography on silica gel. 4-Texyldimethylsilyloxy-17β-acetoxyestr-4-en-3-one is obtained.
¹ H-NMR (CDCI ₃ ): 0.14 (s, 6H, SiMe), 0.65-0.88 (m (upper), 15H, Thexyl, H-18), 2.04 (s, 3H, OAc), 4.60 (m, 1 H, H-17α).

Step 2: 4-Texyldimethylsilyloxy-17β-hydroxyestr-4-en-3-one :
2 g of 4-Texyldimethylsilyloxy-17β-acetoxyestr-4-en-3-one is dissolved in 50 ml of methanol. After adding 2 g of K ₂ CO ₃ and 2 ml of water, it is stirred at 30 ° C. for 2 hours. 100 ml of water is added to the reaction solution and the methanol is evaporated to a very high degree. It is then extracted with ethyl acetate, dried over magnesium sulphate and concentrated by evaporation. The product is purified by chromatography on silica gel. 4-Dexyldimethylsilyloxy-17β-hydroxyestr-4-en-3-one is obtained.

Step 3: 4-Texyldimethylsilyloxy-17β-[(perhydropyran-2-yl) oxy] estol-9-en-3-one :
1 g 4-Texyldimethylsilyloxy-17β-hydroxyestr-4-en-3-one is reacted with 1.8 ml dihydropyran and 80 ml pyridinium tosylate in 16 ml CH ₂ Cl ₂ for 2 hours. . 10 ml of saturated Na ₂ CO ₃ solution is added to the reaction solution. It is then extracted with CH ₂ Cl ₂ , dried over magnesium sulphate and concentrated by evaporation. The product is purified by chromatography on silica gel. 4-Texyldimethylsilyloxy-17β-[(perhydropyran-2-yl) oxy] estol-9-en-3-one is obtained.

Step 4: 4-Hydroxy-17β-[(perhydropyran-2-yl) oxy] estr-4-en-3-one :
1 g 4-Texyldimethylsilyloxy-17β-[(perhydropyran-2-yl) oxy] estol-9-en-3-one is reacted with 300 mg TBAF in 20 ml THF for 2 hours. 10 ml of saturated Na ₂ CO ₃ solution is added to the reaction solution. It is then extracted with ethyl acetate, dried over magnesium sulphate and concentrated by evaporation. The product is purified by chromatography on silica gel. 4-Hydroxy-17β-[(perhydropyran-2-yl) oxy] estr-4-en-3-one is obtained.

Step 5: 3-Oxo-17β-[(perhydropyran-2-yl) oxy] estre-4-en-4-yl 3′-sulfamoylbenzoate (22) :
The material is prepared according to variant 3, analogously to example 5, and 4-hydroxy-17β-[(perhydropyran-2-yl) oxy] est-4-en-3-one and 3-chlorosulfonylbenzoic acid chloride. Get started from.

Step 6: 3-Oxo-17β-hydroxyestre-4-en-4-yl 3′-sulfamoylbenzoate (21) :
500 mg of 3-oxo-17β-[(perhydropyran-2-yl) oxy] estre-4-en-4-yl 3′-sulfamoylbenzoate is dissolved in 25 ml of acetone and 3 ml of 10% HCl Allow the reaction to proceed for 1 hour at room temperature. 10 ml of saturated sodium carbonate solution is added to the reaction solution. The acetone is then distilled and extracted with ethyl acetate, dried over magnesium sulphate and concentrated by evaporation. The product is purified by chromatography on silica gel. 3-Oxo-17β-hydroxyestre-4-en-4-yl 3′-sulfamoylbenzoate (21) is obtained.
¹ H-NMR (DMSO-D ₆ ): 0.71 (s. 3H, H-18), 3.46 (m, 1 H, H-17α), 4.50 (d, 1 H, 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 testosterone is dissolved in 20 ml pyridine. After the addition of 1.5 g 2-chloro-4-sulfamoylbenzoic acid, 250 mg p-toluenesulfonic acid and 1.5 g DCC, it is stirred for 48 hours at room temperature. Then 100 ml water and 30 ml CHCl ₃ are added. It is slightly acidified with 10% HCl (pH = 5). The precipitate is filtered and rewashed with CHCl ₃ . The organic phase is separated by 10% sodium hydrogen carbonate solution and washed with saturated NaCl solution, dried over magnesium sulfate, filtered, concentrated by evaporation and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 2′-chloro-4′-sulfamoylbenzoate is obtained.
¹ H-NMR (DMSO-d ₆ ): 0.89 (s, 3H1 H-18), 1.16 (s, 3H, H-19), 4.80 (t, 1H, H-17), 5.64 (s, 1 H, HC =), 7.64 (s, 2H1 NH 2).

Example 23: 3-oxoandrost-4-en-17β-yl 3'-carboxy5'-sulfamoylbenzoate (24) :
1.0 g testosterone is dissolved in 3.5 ml pyridine. After the addition of 1.1 g 5-sulfamoylphthalic acid and 880 ml EDC, it is stirred for 48 hours at room temperature. Next, 10 ml of water is added. It is acidified with 10% HCl. The precipitate is then filtered, washed with water and dried. It is chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 3′-carboxy 5′-sulfamoylbenzoate is obtained.
¹ H-NMR (DMSO-d ₆ ): 0.96 (s, 3H1 H-18), 1.17 (s, 3H1 H-19), 4.84 (t, 1H, H-17), 5.64 (s, 1 H, HC =), 7.62 (s, 2H, NH2), 7.72, 8.45 (2H, NH2).

Example 24: 3-oxoandrost-4-en-17β-yl 3'-carbamido-5'-sulfamoylbenzoate (25) :
1.0 g testosterone is dissolved in 3.5 ml pyridine. After the addition of 1.1 g 5-sulfamoylphthalic acid monoamide and 880 ml EDC, it is stirred for 48 hours at room temperature. Next, 10 ml of water is added. It is acidified with 10% HCl. The precipitate is then filtered, washed with water and dried. It is chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 3′-carbamido-5′-sulfamoylbenzoate is obtained.
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).

Reference :
(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. 2nd 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 Ia differenciation sexuelle de l'embryon de lapin: III.RoIe des gonades foetales dans Ia differenciation sexuelle somatique. Arch Anat micr Morph exp; 36, 271-315; 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.

(4) Liu PY and Handelsman DJ (1990) Androgen therapy in non-gonadal disease.In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2nd 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. 2nd Edition (1998), Springer, Berlin Heidelberg, Chapter 2, 33- 106.
(6) Cardim HJP, Lopes CMC, Giannella-Neto D, da 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. 2πd 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. 2πd 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) ArIt 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) Uu PY and Handelsman DJ (1990) Androgen therapy in non-gonadal disease.In: Nieschlag E and Behre HM (eds) Testosterone: Action, Deficiency, Substitution. 2nd 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. 2nd 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, 169-172 (1997).

FIG. 1 shows the growth of the accessory gland (prostate) / Hershberger test / Test I FIG. 2 shows the rLH content / test I in serum. FIG. 3 shows HDL-cholesterol content / test I in plasma. FIG. 4 shows the growth of the accessory gland (prostate) / Hershberger test / Trial II. FIG. 5 shows the rLH content in serum / Test II. FIG. 6 shows the HDL-cholesterol content in plasma / Test II.

FIG. 7 shows the MENT content in serum / Test II. FIG. 8 shows the growth of the accessory gland (prostate) / Hershberger test / Trial III. FIG. 9 shows the rLH content in serum / Test III. FIG. 10 shows testosterone content / test III in serum. FIG. 11 shows HDL-cholesterol content in serum / Test III.

Claims (17)

The following general formula (I):

[Wherein n is 0 to 4,
R ¹ is a group —SO ₂ NH ₂ or —NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ¹ are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, C _1-5 — Represents an alkyl group, a CpF _{2p + 1} group (p is 1 to 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 are a C _1-5 -alkyl group, a C _3-8 -cycloalkyl group, an aryl group, a C _1-4 -alkylenearyl group, a C _1-4 -alkylene-C _{A 3-8} -cycloalkyl group or a C _3-8 -cycloalkylene-C _1-4 -alkyl group, and further R ²⁰ may be hydrogen, or
R ² is a group —SO ₂ NH ₂ or —NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ¹ are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, C _1-5 — Represents an alkyl group, a CpF _{2p + 1} group (p is 1 to 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 are a C _1-5 -alkyl group, a C _3-8 -cycloalkyl group, an aryl group, a C _1-4 -alkylenearyl group, a C _1-4 -alkylene-C _{A 3-8} -cycloalkyl group or a C _3-8 -cycloalkylene-C _1-4 -alkyl group, and further R ²⁰ may be hydrogen, or
R ³ is a group —SO ₂ NH ₂ or —NHSO ₂ NH ₂ , wherein R ² , R ³ and X, X ¹ are a hydrogen atom, a halogen atom, a nitrile group, a nitro group, C _1-5 — Represents an alkyl group, a CpF _{2p + 1} group (p is 1 to 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 are a C _1-5 -alkyl group, a C _3-8 -cycloalkyl group, an aryl group, a C _1-4 -alkylenearyl group, a C _1-4 -alkylene-C _{A 3-8} -cycloalkyl group or a C _3-8 -cycloalkylene-C _1-4 -alkyl group, and further R ²⁰ may be hydrogen, and
STEROID has the following general formula (AII-CII):

Represents a steroid ring system represented by
Y represents an oxygen atom or a carbon atom,
R ⁴ represents a hydrogen atom, a halogen atom, methyl, trifluoromethyl, hydroxy, tri (C _1-6 -alkyl) silyloxy, C _1-5 -alkoxy or C _2-5 -heterocycloalkyloxy group,
R ⁷ represents a hydrogen atom, a methyl or ethyl group,
R ¹⁰ represents a hydrogen atom, a methyl or ethyl group,
R ¹¹ represents 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 represents a hydrogen atom, a methyl group or an ethyl group,
R ¹³ represents a hydrogen atom, methyl, ethyl, ethynyl, trifluoromethyl or pentafluoroethyl group,
R ¹⁴ represents a hydrogen atom, an OH group, or an oxygen atom bonded through a double bond,
R ¹⁵ represents hydroxy, tri (C _1-6 -alkyl) silyloxy, C _1-5 -alkoxy group, group OC (O) —R ²⁰ or C _2-5 -heterocycloalkyloxy group,
Here additional double bonds can be found in the 4,5-position, and when Y represents a carbon atom, an additional double bond is found in the 1,2-position or the group R ¹⁴ is If it is a hydrogen atom or an OH group, it is found in the 2,3-position]
And pharmaceutically acceptable salts thereof.   2. A compound according to claim 1 characterized in that n is 0, 1 or 2. The compound according to claim 1 or 2, wherein R ¹ represents a group -SO ₂ NH ₂ or -NHSO ₂ NH ₂ . R ¹ is The compound of claim 3, wherein represents a group -SO ₂ NH _2. R ^1, either R ² or R ³ is A compound according to claim 1 or 2, wherein represents a group -SO ₂ NH _2. R ¹ , R ² , R ³ (when the latter does not represent —SO ₂ NH ₂ or —NHSO ₂ NH ₂ ), and X and X ¹ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, The compound according to any one of claims 1 to 5, which represents a hydroxy group or a methoxy group.   7. A compound according to any one of claims 1 to 6, wherein STEROID represents a steroid ring system for the general partial formulas AII and BII. Independent of each other,
Y represents a carbon atom and / or
R ⁴ represents a hydrogen atom, a chlorine atom or a hydroxy group, and / or
R ⁷ represents a hydrogen atom or a methyl group and / or
R ¹⁰ represents a hydrogen atom or a methyl group, and / or
R ¹¹ represents a hydrogen atom, a fluorine atom or a methyl group, and / or
R ¹² represents a hydrogen atom and / or
R ¹³ represents a hydrogen atom or a methyl group, and / or
R ¹⁴ represents an oxygen atom and / or
R ¹⁵ is a hydroxy group or a group OC (O) -R ^20, any one compound according to claims 1-7. 1) 3-oxo-7α-methylestre-4-en-17β-yl 3'-sulfamoylbenzoate (12),
2) 3-Oxo-7α-methylestre-4-en-17β-yl 4'-sulfamoylbenzoate (11),
3) 3-Oxo-7α-methylestre-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate (13),
4) 3-Oxo-7α-methylestre-4-en-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate,
5) 3-oxo-7α-methylestre-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,
6) 3-oxo-7α-methylestre-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate,
7) 3-Oxoestre-4-en-17β-yl 3'-sulfamoylbenzoate (7),
8) 3-Oxoestre-4-en-17β-yl 4'-sulfamoylbenzoate (8),
9) 3-oxoestre-4-en-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate,
10) 3-oxoestre-4-en-17β-yl 2'-chloro-5'-sulfamoylbenzoate,
11) 3-oxoestre-4-en-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,
12) 3-oxoestre-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-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-en-17β-yl 3'-sulfamoylbenzoate (5),
20) 3-Oxoandrost-4-en-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-17β-yl 2'-methoxy-5'-sulfamoylbenzoate,
24) 3-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate,
25) 3-Oxoandrostane-17β-yl 3'-sulfamoylbenzoate (9),
26) 3-Oxoandrostane-17β-yl 4'-sulfamoylbenzoate (10),
27) 3-oxoandrost-4-en-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-oxoandrost-4-en-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate,
31) 3-Oxo-4-chloro-17α-methylandrost-1,4-dien-17β-yl 3'-sulfamoylbenzoate (16),
32) 3-oxo-4-chloro-17α-methylandrost-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-fluoroestre-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-11 β-fluoroestre-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate,
42) 3-Oxoestre-4-en-17β-yl 2'-hydroxy-5'-sulfamoylbenzoate,
43) 3-oxo-7α-methylestre-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-hydroxyestre-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] estre-4-en-4-yl 3'-sulfamoylbenzoate (22),
49) 3-Oxo-17β-hydroxyestre-4-en-4-yl 3'-sulfamoylbenzoate (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),
The compound according to any one of claims 1 to 8.   10. A pharmaceutical composition comprising at least one compound according to any one of claims 1-9.   11. A pharmaceutical composition according to claim 10 comprising at least one additional steroidally active compound.   12. The pharmaceutical composition of claim 11, wherein the additional steroidally active compound is a glucocorticoid, gestagen, or GnRH analog.   Use of a compound according to any one of claims 1 to 9 for the manufacture of a pharmaceutical agent for hormone exchange / replacement therapy in men and women.   Use of a compound according to any one of claims 1 to 9 for birth control in men and women.   Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of hormone-induced diseases in men and women.   Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for treating a disease that can be positively influenced by inhibition of carboanhydrase activity. The following general formula (I) according to any one of claims 1 to 9:

A method comprising the reaction of sulfamoylphenylcarboxylic acid or a derivative thereof together with estrogen, or the reaction of sulfamide, sulfamoyl chloride or aminosulfonyl isocyanate with a corresponding compound.

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