JP2007538027A - Estriol and Estetrol prodrugs - Google Patents

Abstract

The present invention relates to the following general formula (I):
[Wherein the group Y is bound to a steroid]. The invention further relates to methods for their production, pharmaceutical compositions comprising these compounds, and their use for the production of pharmaceutical agents having an estrogenic effect.

Description

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

  And estetrol prodrugs represented by the formula, methods for their production, pharmaceutical compositions containing these compounds, and their use for the production of pharmaceutical agents having an estrogenic action.

  Estrogens regulate many functions on the cell surface. They play a central role in reproductive organ function in both sexes. Furthermore, estrogen action in the central nervous system plays an important role for monitoring CNS (central nervous system) mechanism, behavioral regulation, and pituitary gonadotropin secretion. Other pituitary hormones are also regulated by estrogens.

Their action is mediated by at least two known receptors ERα and ERβ expressed in very different concentrations in intact organisms, ie even outside the reproductive organs ⁽¹⁾ .
In women, estrogens secreted by the ovary survive in the organism and are thereby fully concentrated in the secretion of estradiol. In pregnancy, the placenta forms a large amount of estrogen, which causes a very large amount of estriol to be secreted especially in the later stages of pregnancy ⁽²⁾ .

  In men, estrogens are produced mainly "peripherally" by aromatization of testosterone or adrenal androgens in various effector organs, such as the CNS, bone, adipose tissue or intestine. This organ-selective match allows a physiological estrogen effect in men at very low estradiol levels in the blood.

Loss of estrogens or their destroyed formation (aromatase deficiency or inhibition) is achieved by the destruction of a wide range of organs and metabolic functions ⁽³⁾ . This range includes disruption or loss of reproductive function, disruption in carbohydrate and lipid metabolism, mainly also skeletal disorders ⁽⁴⁾ . In young people, abnormalities in linear growth dominate; at later ages, changes in bone density dominate. Loss of bone mass (osteoporosis) is the most risk of estrogen deficiency after the end of linear growth because it is achieved by increased brittleness of the bone and sometimes causes illness in older age ⁽⁵⁾ .

In women, estrogens have important circulatory functions. In the early menopause, their effects are essential factors for the low risk in women with respect to cardiovascular morbidity and mortality. Loss of estrogens results in unfavorable changes in lipoprotein and endothelial function with respect to the prevention of vessel dilation and aggregation ⁽⁶⁾ .
Urogenital function is also estrogen-regulated. The construction and regeneration of epithelial cells and muscles in the urethra and bladder are positively influenced by estrogens ⁽⁷⁾ .

  The use of estrogen has a fixed position in gynecological treatment. This includes use in hormonal contraceptives and various forms of estrogen replacement therapy. Hormonal contraceptives inhibit ovulation and thus ovarian secretion of estrogen and progesterone. At the same time, they are replaced by endogenous hormones in the genital tract and whole organisms. Their most important function in the uterus, in this context, is the stabilization of the uterine mucosa to achieve good menstrual regulation.

  In therapeutic applications, estrogen can be applied orally and parenterally. For oral treatment, natural estrogens such as estradiol or derivatives thereof such as estradiol valerate are used. Estrogen mixtures obtained from pregnant women's urine, so-called conjugated estrogens, play a major role in oral estrogen therapy. The latter represents sulfates from estrone and from estrogens (equilin and echilenin) that are typical in horses. After ingestion by the organism, they are hydrolyzed; in this regard, the therapeutically relevant “mother estrogen” is released. These estrogens dominate all forms of postmenopausal replacement therapy. However, despite certain oral bioavailability, they do not play any role for hormonal contraception. The essential reason for this is the inappropriate regulation of uterine bleeding by natural estrogens and their derivatives (esters), corresponding to the prior art.

Hormonal contraception is completely governed by ethinyl estradiol. The basis for poor menstrual regulation by estradiol versus ethinyl estradiol is the metabolism of estradiol in the endometrium by simultaneous application of gestagen. The enzyme 17β-hydroxysteroid dehydrogenase (17βHSD) is induced in the human endometrium by progesterone and gestagens ⁽⁸⁾ . Estradiol converts the latter to the weaker estrogen estrone. In the case of ethinylestradiol, the corresponding oxidation step is not possible. This also applies for the substances according to the invention. Estriol and estetrol are not metabolized by 17βHSD in the endometrium.

An essential feature of conventional estrogen therapy is the need for a much higher dose than that required for parenteral application. This is why oral estrogen treatment or treatment has other metabolic effects other than simultaneous parenteral treatment or treatment, even when natural estrogen is actually used ⁽⁹⁾ . However, ethinyl estradiol has a particularly strong liver estrogenicity because it is inactivated only with a time delay in the liver ⁽¹⁰⁾ . Estrogen-sensitive liver function is involved in the renin-angiotensinogen-aldosterone system and thus blood pressure regulation ⁽¹¹⁾ . For muscle and skeletal systems, a decrease in liver IGF-I synthesis is undesirable ⁽¹²⁾ . There are many other liver functions that are also deflected by estrogens.

In the case of estradiol, often 40 times higher doses are used for oral treatment than in therapeutically equivalent transdermal therapy. Therefore, the high doses required for oral therapy are the strong in the liver, after absorption, the total dose administered first enters the portal vein and thereby metabolizes most of the substance Has the disadvantage of an estrogen effect ⁽¹³⁾ .

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 Y 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

で表されるステロイドABCD−環系を表し、 STEROID has the following general formula (IIA)-(IID):

A steroid ABCD-ring system represented by

Here, R ⁴ , R ¹⁶ and R ¹⁷ are a hydroxy group, a tri (C ₁ -C ₆ -alkyl) silyloxy group, a group OC (O) -R ²⁰ , a C _2-5 -heterocycloalkyloxy group, or Represents the group Y, and
R ¹⁵ represents a hydrogen atom, a hydroxy group, a tri (C ₁ -C ₆ -alkyl) silyloxy group, a group OC (O) —R ²⁰ , a C _2-5 -heterocycloalkyloxy group, or a group Y]
And estriol prodrugs, and pharmaceutically acceptable salts thereof.

The compounds of the present invention have estrogenic activity.
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.

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.
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.

Within the scope of the present invention, the term “C _2-5 -heterocycloalkyloxy group” is defined as a C _2-5 -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.
STEROID preferably represents a steroid ABCD-ring system of the partial general formulas IIB and IIC.
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 Y with respect to the ester group, through which the group Z is attached 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.

R ⁴ , R ¹⁶ and R ¹⁷ are preferably in each case and independently of one another, a hydroxy group, a trimethylsilyloxy group, a tert-butyldimethylsilyloxy group, a benzoate group, an acetate group, a propylnate group, a valerate group, It is a butocyclate group or a cyclopentylpropionate group, where a hydroxy group is particularly preferred.
R ¹⁵ is preferably a hydrogen atom.
The groups R ¹⁵ , R ¹⁶ and R ¹⁷ can be placed in the α-position and the β-position.

Particularly preferred compounds or estriol or estetrol prodrugs are shown below:
1) 3,16α-Dihydroxyestradi-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate (7),
2) 3,16α-Dihydroxyestradi-1,3,5 (10) -trien-17β-yl 4'-sulfamoylbenzoate (1),
3) 3-tert.-Butyldimethylsilyloxy-16α-hydroxyestradi-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate,
4) 3-tert.-butyldimethylsilyloxy-16α-hydroxyestradi-1,3,5 (10) -trien-17β-yl 4'-sulfamoylbenzoate,
5) 3,17β-dihydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate (10),
6) 3,17β-Dihydroxyestradi-1,3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate (4),

7) 3-tert.-Butyldimethylsilyloxy-17β-hydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate,
8) 3-tert.-butyldimethylsilyloxy-17β-hydroxyestradi-1, 3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate,
9) 3,16α-dihydroxyestradi-1,3,5 (10) -trien-17β-yl 2'-chloro-5'-sulfamoylbenzoate,
10) 16α, l7β-dihydroxyestradi-1,3,5 (10) -trien-3-yl 4'-sulfamoylbenzoate (13),
11) 3,15α, 16α-trihydroxyestradi-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate,
12) 3,15α, 16α-Trihydroxyestradi-1,3,5 (10) -trien-17β-yl 4'-sulfamoylbenzoate,

13) 3,15α, 17β-Trihydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate,
14) 3,15α, 17β-trihydroxyestradi-1,3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate,
15) 3,16α, 17β-trihydroxyestradi-1,3,5 (10) -trien-15α-yl 3'-sulfamoylbenzoate,
16) 3,16α, 17β-trihydroxyestradi-1,3,5 (10) -trien-15α-yl 4'-sulfamoylbenzoate,
17) 15α, 16α, 17β-Trihydroxyestradi-1,3,5 (10) -trien-3yl 3'-sulfamoylbenzoate,
18) 15α, 16α, 17β-Trihydroxyestradi-1,3,5 (10) -trien-3yl 4′-sulfamoylbenzoate.

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 estrogenic activity when administered orally, thereby avoiding a very high liver effect other than that of conventional estrogens. The compounds of the present invention do not bind themselves to the estrogen receptor, but rather the therapeutically relevant steroid is released, the latter by esterification.

In vivo testing :
Exam I:
Surprisingly and unexpectedly, higher estrogenic activity and oral bioavailability are due to m-substituted compound 7 than to m-substituted compound 10 or p-substituted compound 1. In the case of oral administration, it is achieved in in vivo experiments in rats.
Table 1 shows estrogenic activity in the case of oral administration and liver toxicity (liver effect) based on data of selected compounds in in vivo studies with rats.

Test principle and test description :
Adult Wistar rats are ovariectomized and tested after a 14 day waiting period. The animals are then treated for 3 days (Days 1 to 3) and then killed (Day 4). Next, organ weights are determined, and estrogen-modulated factors of liver secretion in serum, where there is an increase in angiotensinogen and a decrease in total and HDL cholesterol in rats.

  When increased uterine weight is taken as an indicator of systemic estrogenic effects, it is clear that even at very high doses, estriol does not cause a doubling of uterine weight. For the substances in Table 1 according to the present invention, the fraction of the treated dose for estriol is sufficient to induce a corresponding degree of uterine growth. Unlike in the uterus, the estrogenic effect in the liver appeared very clearly with the treatment of underivatized estriol. In absolute terms, hepatic estrogenicity was not reduced compressively by the substances of the invention compared to estriol, but a therapeutically relevant effect can be achieved in the uterus for lower doses .

  The action of estriol in the rat liver, which is stronger compared to estradiol, affects the reduced oxidation of the 17β-OH function of this estrogen and inactivation in the rat due to the presence of the 16α-OH group. Compared to other natural estrogens (estradiol), the unreduced estrogenic effect in the uterus is particularly when 17β-hydroxysteroid dehydrogenase in the uterus is enhanced by gestagen and estradiol is quickly separated in the uterine mucosa. Has a negative effect.

Test II :
Surprisingly enough, it was now possible to determine that estriol and its corresponding compounds of the invention are capable of preventing the weakening of the estrogen effect in the uterus by gestagens.

Test principle and test description :
Mature guinea pigs were ovariectomized and treated for 7 days with a large dose range of estradiol or estriol two weeks after this surgery. Selected doses of estrogen were administered by subcutaneous injection in an oily solution (a) alone and (b) in combination with fully gestogenically active 3.0 mg progesterone / animal / day. The effect of this treatment on the reproductive organs increased on the 8th test day.

1 and 2, the various interactions of estradiol and estriol with progesterone in the vagina and uterus of ovariectomized guinea pigs are shown on treatment days 1-7 and autopsy day 8.
In this case, progesterone weakens the uterine tropic action of estradiol, but the action of its corresponding estriol is enhanced.

  In the case of estradiol and estriol, corresponding interactions occur. Thus, this is also surprising since estriol is generally seen as a substantially weak estrogen. Progesterone weakens the uterine tropic effect of estradiol, whereas its corresponding effect of estriol at all doses of estriol treated is clearly enhanced. The observed interaction is specific for the uterus. The increase in vaginal weight by estriol is not enhanced or enhanced to the same extent as by progesterone; the inhibitory effect of progesterone is outstanding.

  For this reason, the compounds of the present invention are superior to estradiol in terms of their ability to progress under co-treatment with estrogen and to prevent intramenstrual menstrual bleeding. In humans, estriol is inactivated in the liver very quickly by conjugation (glucoronidation, sulfation), so the deviation of estrogen-regulated liver function is very high in humans, unlike in rats It does not occur under oral doses of estriol. Thus, the substances of the invention can be used in humans, unlike estradiol and ethinylestradiol, at doses that act uterotropically without the undesirable effects in the liver to be tolerated.

In vitro test :
Test I:
Studies on the binding of m-substituted compounds 7 and 10 to erythrocytes were also surprising. For m-substituted compounds, very weak binding was detected.
However, in this case, surprisingly, m-substituted compounds have various oral availability and estrogenicity, despite low binding strength to erythrocytes. The data in Table 2 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.

Exam II :
Surprisingly enough, in all cases, binding to carboanhydrase (CAI) found in erythrocytes has been found (Table 3). 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. Thus, 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. In this case, a treatment adapted to the individual organism is made possible.

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.

These test results are many possibilities for the compounds of general formula (I) according to the invention for birth control in women and for hormone replacement therapy (HRT) or for the treatment of cancer, eg prostate cancer Open application.
The substances of the present invention achieve menstrual regulation with natural hormones and at the same time avoid dangerous liver estrogenic effects because they occur typically and particularly strongly under non-natural ethinylestradiol and other estrogens. Is appropriate.

Prevention of the corresponding first course interaction is another object of the substance of the invention. The latter can pass through the liver for the most part and also in an inactive form. They are applied at lower doses to achieve the desired systemic estrogenic effect than their “maternal estrogens” and thus have less undesirable effects in the liver.
The substances according to the invention are preferably used for oral therapy. Compared to their mother estrogens, the compounds of the present invention have clearly increased oral bioavailability, increased systemicity, but reduced liver estrogenicity.

This dissociation of desired and undesired hormonal effects at the same time enables more therapeutically effective and more compatible pharmaceutical agents compared to conventional techniques.
In the case of oral treatment with natural estrogens (estradiol, estradiol valerate, estrone sulfate, conjugated estrogens), but also in the case of oral treatment with estradiol sulfamate, high levels of estrone are predominant in the blood. This is an important departure from the menstrual rate, where the concentration of estradiol in the blood is higher than that of estr. This is therefore disadvantageous because estrone is a lower effective estrogen than estradiol.

  Thus, a particular advantage of the compounds of the invention compared to the prior art is the release according to the invention of the mother estrogens which are not oxidized in the individual case, preferably in the case of estriol and estetrol. This contributes to the desired high systemic estrogenicity of the substances of the invention. Furthermore, in the case of organ-selective enhanced estrogenicity, it is known that inappropriate metabolism of those estrogens in the uterus is advantageous.

  The compounds of the present invention have estrogenic activity when administered parenterally and orally, thereby reducing liver effects compared to isotropic doses of estriol with respect to action on the uterus. Oxidation at the 17-position to weak estrone derivatives is avoided. In this regard, some desired estrogenic action in their effector organs with respect to estrogen is absolutely or relatively enhanced compared to estradiol, where enzyme supplementation helps with inactivation of estradiol. This can be applied to the estrogenic effect in the human uterus, especially when the estrogenic effect is greatly reduced under progesterone or gestagen excellence.

Estriol can also induce estrogenic effects in the uterus under these conditions. The substances according to the invention are therefore particularly suitable for use with estrogen, for example as so-called “combined oral contraceptives” or gestagen-containing HRT products, for the control of uterine bleeding behavior.
Undesirable effects on the uterus (proliferation) and liver (aggregation factor or angiotensinogen) comprising a compound of general formula (I) according to the invention at a very low dose, for example 0.05-1 mg / day po A pharmaceutical agent for ERT (estrogen replacement therapy) that does not exert the target.

  Also of interest are pharmaceutical agents for ERT comprising the general formula (I) of the invention or a salt thereof in combination with gestagen at very low doses, eg 0.05-3 mg / day p.o. The gestagen can be progesterone, norethisterone, dienogest, cyproterone acetate, chlormadinone acetate, drospirenone, medroxyprogesterone acetate, levonorgestrel, guestden or other gestagens suitable for HRT. This can be used for conventional therapies and doses, such as “continuous combinations”, or for variations of interrupted and continuous administration.

  A medical for contraception comprising the general formula (I) of the present invention or a salt thereof in combination with gestagen in a common therapy as an oral contraceptive at a very low dose, eg 0.05-3 mg / day po Drugs are also subjects.

These pharmaceutical compositions and pharmaceutical agents can preferably be used for oral administration, rectal, vaginal, subcutaneous, dermal, intravenous, 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 estriol and estetrol prodrugs of the present invention can be synthesized according to the following examples, which are used to illustrate the present invention in more detail and are not intended to limit the present invention.

General synthesis teaching :
For the production of compounds of general formula IIA-D, known steroid parent substances can be used. The following steroidal parent substances can be used: esterone, estriol and esterol. The functional group can optionally be protected according to methods known to those skilled in the art or can be converted to the corresponding functional group. Thus, keto groups can be reduced to hydroxy compounds and converted to enone and enol compounds according to methods known to those skilled in the art. Double bonds can be converted to dihydroxy compounds according to methods known to those skilled in the art.

(A) Coupling of steroid compound to group Z:
Variant 1: Reaction with sulfamoylphenylcarboxylic acid :
Estrogens are 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 chlorosulfonylphenylcarboxylic 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 5 ml of DMF and boiled with 80 ml of thionyl chloride for 5 hours. The cooled reaction mixture is added to 500 g of ice and the precipitated material is aspirated, 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 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 :
Stage 1 :
3,16α-Dihydroxyestradi 1,3,5 (10) -trien-17β-yl 4'-sulfamoylbenzoate (1) :
450 mg of 3,16α-di (tert-butyldimethylsilyloxy) estradi-1,3,5 (10) -17β-ol is dissolved in 7 ml of pyridine. After the addition of 1.0 g p-sulfamoylbenzoic acid, 120 mg p-toluenesulfonic acid and 1.0 g dicyclohexylcarbodiimide (DCC), it is stirred at room temperature for 48 hours. Then 20 ml of water and 50 ml of ethyl acetate are added. It is slightly acidified with 10% HCl (pH = 5). The precipitate is filtered and rewashed with ethyl acetate.
The organic phase is separated by 10% sodium bicarbonate solution and washed with saturated NaCl solution, dried over magnesium sulfate, filtered, concentrated by evaporation and chromatographed on silica gel. 3,16α-di (tert-butyldimethylsilyloxy) estra-1,3,5 (10) -trien-17β-yl 4′-sulfamoylbenzoate (2) is obtained.
¹ H-NMR (CDCI ₃ ): 0.04 (s, 6H, 2SiMe), 0.22 (s, 6H, 2SiMe), 0.87 (s, 9H, tert.-C ₄ H ₉ ), 0.93 (s, 3H, H- 18), 1.01 (s, 9H, tert.-C ₄ H ₉ ), 4.51 (m, 1 H, H-16), 5.04 (s, 2H, NH ₂ ), 5.17 (m, 1 H, H-17 ).

Stage 2 :
3-Hydroxy-16α-tert-butyldimethylsilyloxyestradi-1,3,5 (10) -17β-yl 4'-sulfamoylbenzoate (3) :
450 mg of 3,16α-di (tert-butyldimethylsilyloxy) estradial-1,3,5 (10) -17β-yl 4′-sulfamoylbenzoate is dissolved in 10 ml of THF. While stirring, 300 mg TBAF is added at room temperature. After 1 hour, 40 ml of water is added and then the organic mobile solvent is distilled. The material is filtered, washed with water, dried and chromatographed on silica gel. 3-hydroxy-16α-tert-butyldimethylsilyloxyestradi-1,3,5 (10) trien-17β-yl 4′-sulfamoylbenzoate is obtained.

Stage 3 :
3,16α-Dihydroxyestradi-1,3,5 (10) -17β-yl 4'-sulfamoylbenzoate (1) :
600 mg of 3-hydroxy-16α-tert. -Butyldimethylsilyloxyestradi-1,3,5 (10) -17β-yl 4'-sulfamoylbenzoate is dissolved in 30 ml of THF. While stirring, 1.5 ml HCl (32%) is added at room temperature. After 2 hours, 20 ml of saturated NaHCO ₃ solution is stirred and then the organic mobile solvent is distilled. The material is filtered, washed with water, dried and chromatographed on silica gel. 3,16α-dihydroxyestradi-1,3,5 (10) -trien-17β-yl 4′-sulfamoylbenzoate is obtained.
¹ H-NMR (DMSO-d ₆ ): 0.85 (s, 3H, H-18), 4.32 (m, 1H, H-16) 4.92 (d, 1H, H-17), 5.04 (m, 1 H, 16-OH), 7.57 (m, 2H, NH ₂ ), 8.99 (s, 1 H, 3-OH).

Example 2: 3,17β-dihydroxyestradi-1,3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate (4) :
Said material was converted to the intermediate products 3,17β-di (tert-butyldimethylsilyloxy) estradia-1,3,5 (10) -trien-16α-yl 4′-sulfamoylbenzoate (5) and 3-hydroxy -17β-tert. -Butyldimethylsilyloxyestradi-1,3,5 (10) -16α-yl 4'-sulfamoylbenzoate (6) gives 3,17β-di (tert-butyldimethylsilyloxy) estradial-1,3, It is obtained analogously to Example 1, starting from 5 (10) -trien-16α-ol.

3,17β-di (tert-butyldimethylsilyloxy) estradi-1,3,5 (10) -trien-16α-yl 4′-sulfamoylbenzoate (5):
¹ H-NMR (CDCI ₃ ): -0.04 (s, 3H, SiMe), 0.09 (s, 3H, SiMe) 1 0.18 (s, 6H1 2SiMe), 0.86 (s, 9H, tert.-C4H9), 0.87 ( s, 3H, H-18), 0.97 (S, 9H, tert.-C ₄ H ₉ ), 3.94 (d, 1H, H-17), 5.09 (s, 2H, NH ₂ ), 5.18 (m, 1 H, H-16).

3,17β-Dihydroxyestradi-1,3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate (4):
¹ H-NMR (DMSO-d ₆ ): 0.78 (s, 3H, H-18), 3.81 (d, 1H, H-17) 5.09 (m, 1 H1 H-16), 5.20 (m, 1H, 17 -OH), 7.55 (m, 2H1 NH 2), 9.00 (s, 1 H, 3-OH).

Example 3: 3,16α-dihydroxyestradi-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate (7) :
Stage 1 :
3,16α-di (tert-butyldimethylsilyloxy) oestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate (8) :
1.5 g of 3,16α-di (tert-butyldimethylsilyloxy) estradi-1,3,5 (10) -17β-ol is dissolved in 3 ml of pyridine and 3 ml of CHCl ₃ . 1.5 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 and then dried. 3,16α-di (tert-butyldimethylsilyloxy) estradia-1,3,5 (10) -17β-yl 3′-sulfamoylbenzoate is obtained.
¹ H-NMR (CDCI ₃ ): -0.03 (s, 3H1 SiMe), 0.02 (s, 3H, SiMe) 1 0.18 (s, 6H, 2SiMe), 0.84 (s, 9H, tert.-C ₄ H ₉ ) , 0.89 (s, 3H, H-18), 0.97 (s, 9H1 tert.-C ₄ H ₉ ), 4.48 (m, 1 H, H-16), 4.71 (s, 2H, NH ₂ ), 5.12 ( m, 1 H. H-17).

Stage 2 :
3-hydroxy-16α-tert-butyldimethylsilyloxyestradi-1,3,5 (10) -17β-yl 3′-sulfamoylbenzoate (9) :
500 mg of 3,16α-di (tert-butyldimethylsilyloxy) estradi-1,3,5 (10) -17β-yl 3′-sulfamoylbenzoate is dissolved in 10 ml of THF. While stirring, 500 mg TBAF is added at room temperature. After 1 hour, 40 ml of water is stirred and then the organic mobile solvent is distilled. The material is filtered, washed with water, dried and chromatographed on silica gel. 3-Hydroxy-16α-tert-butyldimethylsilyloxyestradi-1,3,5 (10) -17β-yl 3′-sulfamoylbenzoate is obtained.

Stage 3 :
3,16α-dihydroxyestradi-1,3,5 (10) -17β-yl 3′-sulfamoylbenzoate (7) :
850 mg of 3-hydroxy-16α-tert-butyldimethylsilyloxyestradi-1,3,5 (10) -17β-yl 3′-sulfamoylbenzoate is dissolved in 35 ml of THF. While stirring, 1.5 ml HCl (32%) is added at room temperature. After 2 hours, 20 ml of saturated NaHCO ₃ solution is stirred and then the organic mobile solvent is distilled. The material is filtered, washed with water, dried and chromatographed on silica gel. 3,16α-Dihydroxyestradi-1,3,5 (10) -17β-yl 3′-sulfamoylbenzoate is obtained.
¹ H-NMR (DMSO-d ₆ ): 0.86 (s, 3H, H-18), 4.32 (m, 1 H, H-16) 4.94 (d, 1H, H-17), 5.07 (d, 1H, 16-OH), 7.56 (m, 2H, NH ₂ ), 9.00 (s, 1 H, 3-OH).

Example 4: 3,17β-dihydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate (10)
Said substance was converted to the intermediate products 3,17β-di (tert-butyldimethylsilyloxy) estradia-1,3,5 (10) -trien-16α-yl 3′-sulfamoylbenzoate (11) and 3-hydroxy -17β-tert. -Butyldimethylsilyloxyestradi-1,3,5 (10) -trien-16α-yl 3′-sulfamoylbenzoate (12) gives 3,17β-di (tert-butyldimethylsilyloxy) estradi-1, It is obtained analogously to Example 3, starting from 3,5 (10) -trien-16α-ol (12).

3,17β-Di (tert-butyldimethylsilyloxy) estradia-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate (11):
¹ H-NMR (CDCI ₃ ): -0.03 (s, 3H, SiMe), 0.09 (s, 3H, SiMe), 0.18 (s, 6H, 2SiMe), 0.86 (s, 9H, tert.-C ₄ H ₉ ), 0.87 (s, 3H, H-18), 0.97 (s, 9H, tert.-C ₄ H ₉ ), 3.95 (d, 1 H, H-17), 5.02 (s, 2H, NH ₂ ), 5.20 (m, 1 H, H-16).

3,17β-Dihydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate (10):
¹ H-NMR (DMSO-d ₆ ): 0.79 (s, 3H, H-18), 3.82 (m, 1H, H-17) 5.09 (m, 1 H, H-16), 5.20 (d, 1H, 17-OH), 7.55 (m, 2H, NH ₂ ), 8.99 (s, 1 H, 3-OH).

Example 5: 16α, l7β-dihydroxyestradi-1,3,5 (10) -trien-3-yl 4'-sulfamoylbenzoate (13)
0.4 g estriol is dissolved in 7 ml pyridine. After adding 0.8 g 4-sulfamoylbenzoic acid and 0.8 g dicyclohexylcarbodiimide (DCC), it is stirred for 1 hour at room temperature. It is then acidified with 10% HCl (pH = 2) and 8 ml of water is added. The precipitate is filtered and washed with 10% sodium bicarbonate solution and water. The resulting product is chromatographed on silica gel. 16α, l7β-dihydroxyastra-1,3,5 (10) -trien-3-yl 4′-sulfamoylbenzoate is obtained.
¹ H-NMR (DMSO-d ₆ ): 0.69 (s, 3H, H-18), 3.32 (m, 1 H, H-17), 3.85 (m, 1 H, H-16), 7.62 (s, 2H1 NH ₂ ).

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In FIG. 1, the various interactions of estradiol and estriol with progesterone in the vagina and uterus of ovariectomized guinea pigs are shown on treatment days 1-7 and autopsy day 8. In FIG. 2, the various interactions of estradiol and estriol with progesterone in the vagina and uterus of ovariectomized guinea pigs are shown on treatment days 1-7 and autopsy day 8.

Claims (19)

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 (IIA)-(IID):

A steroid ABCD-ring system represented by
Here, R ⁴ , R ¹⁶ and R ¹⁷ are a hydroxy group, a tri (C ₁ -C ₆ -alkyl) silyloxy group, a group OC (O) -R ²⁰ , a C _2-5 -heterocycloalkyloxy group, or Represents the group Y, and
R ¹⁵ represents a hydrogen atom, a hydroxy group, a tri (C ₁ -C ₆ -alkyl) silyloxy group, a group OC (O) —R ²⁰ , a C _2-5 -heterocycloalkyloxy group, or a group Y]
And estriol prodrugs represented by the formula: 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. R ⁴ , R ¹⁶ and R ¹⁷ are in each case and independently of one another, a hydroxy, trimethylsilyloxy, tert-butyldimethylsilyloxy, benzoate, acetate, propionate, valerate, butoxylate, or cyclopentylpropionate group or group It represents Y, and the compound of any one of claims 1 to 6, R ¹⁵ represents a hydrogen atom.   8. A compound according to any one of claims 1 to 7, wherein STEROID represents a steroid ABCD-ring system of the partial general formulas IIB and IIC. 1) 3,16α-Dihydroxyestradi-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate (7),
2) 3,16α-Dihydroxyestradi-1,3,5 (10) -trien-17β-yl 4'-sulfamoylbenzoate (1),
3) 3-tert.-Butyldimethylsilyloxy-16α-hydroxyestradi-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate,
4) 3-tert.-butyldimethylsilyloxy-16α-hydroxyestradi-1,3,5 (10) -trien-17β-yl 4'-sulfamoylbenzoate,
5) 3,17β-Dihydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate (10),
6) 3,17β-Dihydroxyestradi-1,3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate (4),
7) 3-tert.-Butyldimethylsilyloxy-17β-hydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate,
8) 3-tert.-butyldimethylsilyloxy-17β-hydroxyestradi-1, 3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate,
9) 3,16α-dihydroxyestradi-1,3,5 (10) -trien-17β-yl 2'-chloro-5'-sulfamoylbenzoate,
10) 16α, l7β-dihydroxyestradi-1,3,5 (10) -trien-3-yl 4'-sulfamoylbenzoate (13),
11) 3,15α, 16α-trihydroxyestradi-1,3,5 (10) -trien-17β-yl 3'-sulfamoylbenzoate,
12) 3,15α, 16α-Trihydroxyestradi-1,3,5 (10) -trien-17β-yl 4'-sulfamoylbenzoate,
13) 3,15α, 17β-Trihydroxyestradi-1,3,5 (10) -trien-16α-yl 3'-sulfamoylbenzoate,
14) 3,15α, 17β-trihydroxyestradi-1,3,5 (10) -trien-16α-yl 4'-sulfamoylbenzoate,
15) 3,16α, 17β-trihydroxyestradi-1,3,5 (10) -trien-15α-yl 3'-sulfamoylbenzoate,
16) 3,16α, 17β-trihydroxyestradi-1,3,5 (10) -trien-15α-yl 4'-sulfamoylbenzoate,
17) 15α, 16α, 17β-Trihydroxyestradi-1,3,5 (10) -trien-3yl 3'-sulfamoylbenzoate,
18) 15α, 16α, 17β-trihydroxyestradi-1, 3,5 (10) -trien-3-yl 4'-sulfamoylbenzoate,
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 gestagen.   13. The pharmaceutical composition according to claim 12, wherein the gestagen is selected from the following group: progesterone, norethisterone, dienogest, cyproterone acetate, chlormadinone acetate, drospirenone, medroxy, progesterone acetate, levonorgestrel and guestden.   Use of a compound according to any one of claims 1 to 9 for the manufacture of a pharmaceutical agent for estrogen replacement therapy in women.   Use of a compound according to any one of claims 1 to 9 for birth control in 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.   17. Use according to claim 16 for the manufacture of a medicament for treating endometriosis, breast cancer, prostate cancer and reproductive dysfunction.   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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