EP1747230A1

EP1747230A1 - Aminosulphonyl-or aminosulphonylamino-substituted phenyl esters as estradiol prodrugs

Info

Publication number: EP1747230A1
Application number: EP05747458A
Authority: EP
Inventors: Ralf Wyrwa; Peter Droescher; Sven Ring; Walter Elger; Birgitt Schneider; Alexander Hillisch; Gudrun Reddersen
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 2004-05-21
Filing date: 2005-05-10
Publication date: 2007-01-31
Also published as: UY28909A1; GT200500121A; PA8633701A1; WO2005113574A1; SV2006002121A; AR050335A1; JP2007538025A; DE102004025966A1; TW200613315A; PE20060359A1

Abstract

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

Description

AMINOSULFONYL OR AMINOSULFONYLAMINO SUBSTITUTED PHENYL ESTERS AS ESTRADIOL PRODUCTS

The invention relates to estradiol prodrugs of the general formula I

Group Z (l) a process for their preparation, pharmaceutical compositions containing these compounds and their use for the preparation of medicaments with estrogenic activity. Estrogens play an important role in both sexes in the organism. Estrogens are involved in the formation of gender characteristics in the maturing organism. In both sexes, estrogens control the changes in the organism during sexual maturation, such as the growth spurt and then the stopping of bone growth. In all phases of life, estrogens play a central role in both sexes in bone metabolism ⁽¹⁾ . Their loss leads to the breakdown of bone substance and carries the risk of increased brittleness of the bone.

In women, the estrogens secreted by the ovary dominate in the organism. The placenta produces large amounts of estrogen during pregnancy. In men, estrogens predominantly arise "peripherally" through the aromatization of testosterone or the adrenal androgens in various success organs, such as the CNS, the bones or the intestinal epithelium. This adaptation allows the physiological estrogen effects in men with very low estradiol levels in the blood. In men and women with a genetic defect of the aromatase or the estrogen receptor, the bones are massively disturbed in terms of growth and maintenance ^<2) .

When administered orally, the natural estrogens have a low oral bioavailability ⁽³⁾ . Natural estrogens have been modified to improve oral bioavailability. Conventional chemically modified estrogens with improved Bioavailability, e.g. B. ethinylestradiol, often have another disadvantage, namely a significantly increased estrogen effect in the liver ⁽⁾ .

This hepatic estrogenicity affects a number of functions, such as transport proteins, fat metabolism, blood pressure regulation and coagulation factors ⁽⁵⁾ . The secretion of IGF-I ^{(6), which} is particularly important for the maintenance of muscles and bones, is negatively affected by hepatic estrogen effects ⁽⁷⁾ .

DE 100 27 887.6 A1 discloses steroidally active compounds which are bound to erythrocytes via a group -SO ₂ NR ¹ R ² and accumulate there. The concentration ratio of the connections between erythrocytes and plasma is 10- 1000, preferably 30-1000, so that one can speak of depot formation in the erythrocytes. Due to the strong binding of the compounds to the erythrocytes, metabolism during liver passage is avoided. Disadvantageously, despite a reduced metabolism with the indicated dosages, there are no therapy-relevant active substance levels.

It is an object of the invention to provide new steroidal compounds with an estrogenic effect which are available orally and which, in comparison with the prior art, ensure a therapy-relevant active substance level even at low doses.

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

Group Z (l)

where n is a number 0-4,

R ^{1 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ^{1 represent} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , where R ²⁰ , R ²¹ and R ^{22 are} C _L s-alkyl group, a C _3-8 cycloalkyl group, an aryl group, a C _1-4 alkylene aryl group, a C _1- alkylene C ₃ . _8- cycloalkyl group or C ₃ . _8- Cycloalkylene-C _1- alkyl group and R ^{20 can} also be a hydrogen, or

R ^{2 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ¹ for a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _L s alkyl group, a C _p F _{2p +} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH- R ²¹ , where R ²⁰ , R ²¹ and R ^{22 is} a C _1-5 alkyl group, a C ₃ . ₈ cycloalkyl group, an aryl group, a C _1-4 -Alkylenarylgruppe, a C - alkylene-C _3-8 cycloalkyl group or _{the like} O -β-cycloalkylene-C ^ -alkyl group and R ²⁰ also may mean a hydrogen , or

R ^{3 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH _2l where R ² , R ³ and X, X ¹ for a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a Cι. ₅ -alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , where R ²⁰ , R ²¹ and R ^{22 are} a C _1-5 alkyl group, a C _3-8 cycloalkyl group, an aryl group, a Ci ^ alkylene aryl group, a C _1-4 alkylene C ₃ . _8- cycloalkyl group or C ₃ . _8- Cycloalkylene-C _1- alkyl group and R ^{20 can} also be a hydrogen, and

STEROID stands for a steroidal ABCD ring system of the general sub-formulas (II A), (II B),

in which

R ⁵ , R ⁶ and R ⁸ each represent a hydrogen atom and R ^{7 represents} a hydrogen atom, a methyl or ethyl group or R ⁵ + R ⁶ , R ⁷ + R ⁸ or R ⁶ + R ⁷ together form a double bond,

R ^{9 represents} a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an OC (O) -R ^{20 group} , a methyl or ethyl group,

R ^{10 is} a hydroxyl group, a methoxy group, a tri (Cι.e-alkyl) silyloxy group, a group OC (O) -R ²⁰ , a C _2-5 - heterocycloalkyloxy group or a group Z,

R ^{11 is} a hydrogen or a halogen atom,

R ^{12 is} a hydroxy group, a methoxy group, a alkyl) silyloxy group, a group OC (O) -R ²⁰ , a C ₂ . ₅ - heterocycloalkyloxy group or a group Z,

R ^{14 represents} a hydrogen atom, a methyl group, or an ethyl group

R ^{15 represents} a hydrogen atom, a hydroxy group, a methoxy group, an ethoxy group, a tri (Cι. ₆ -alkyl) silyloxy group, a group OC (O) -R ²⁰ or a C _2-5 heterocycloalkyloxy group,

and their pharmaceutically acceptable salts.

The compounds according to the invention have estrogenic activity.

For the purposes of the present invention, “ds-alkyl group” is understood to mean a branched or straight-chain alkyl radical having 1 to 5 carbon atoms, which can be substituted, for example, by halogen atoms, hydroxyl groups, nitrile groups. Examples include a methyl, ethyl, n Propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl group called.

The aforementioned “C ₃ . ₈ -cycloalkyl group "according to the invention means a mono- or bicyclic group which can be substituted, for example, by halogen atoms, hydroxyl groups, nitrile groups, such as, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a hydroxycyclohexyl group. In the context of the present application, the term “aryl group” is understood to mean a substituted or unsubstituted aryl radical having 6 to 15 carbon atoms, for example a phenyl group, a substituted phenyl group, such as a halophenyl group or a nitrophenyl group, or a naphthyl group.

Under the term "Cι. For the purposes of the present application, -alkylene aryl group "is understood to mean a disubstituted alkyl radical which is substituted by at least one aryl radical. Both radicals together have 7 to 15 carbon atoms, the group being able to carry further substituents, for example a halogen atom. Examples are a benzyl group or a halobenzyl.

Under the term "-C _-4 alkylene-C ₃ . ₈ cycloalkyl group "is meant a disubstituted alkyl radical within the meaning of the present application, at least with a C ₃ H ₈ -.. Is cycloalkyl substituted Both radicals together have 7 to 15 carbon atoms, where may carry the group further substituents such as a halogen atom Examples are a cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl group.

In the context of the present application, the term “Cs-β-cycloalkylene-C ^ alkyl group” is understood to mean a disubstituted C ₃ -C ₈ -cycloalkylene radical which is substituted by at least one C 1 -C -alkyl radical. Both radicals together have 7 to 15 carbon atoms The group may carry further substituents, such as a halogen atom, examples being a propylcyclohexyl or butylcyclohexyl group.

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

The term tri (C _1-6 alkyl) silyloxy group means, for example, a trimethylsilyloxy, a triisopropylsilyloxy, a thexyldimethylsilyloxy or a tert-butyldimethylsilyloxy group.

Under the term “C ₂ . _5- heterocycloalkyloxy group "is understood in the context of the invention to be a C ^ _5- heterocycloalkyloxy group having a nitrogen or oxygen atom as the hetero atom, the C s-heterocycloalkyloxy group being bonded via the oxygen atom in the 2, 3 or 4 position An example of this is the perhydropyranoxy group. In the context of the present invention, the term “halogen atom” is understood to mean a fluorine, chlorine, bromine or iodine atom; preference is given to a fluorine, chlorine or bromine atom.

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

It is preferred that R represents the radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , the radical - SO ₂ NH _{2 being} particularly preferred. The residues mentioned are thus in the m position of the group Z in relation to the ester group via which the group Z is bound to the steroid.

R ¹ preferably denotes a group -SO ₂ NH ₂ , where R ² , R ³ , X ¹ and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl or a methoxy group, or

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

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

R ⁵ , R ⁶ , R ⁷ and R ⁸ are preferably each a hydrogen atom.

R ⁹ and R ¹¹ are preferably and independently of one another a hydrogen atom or a fluorine atom.

R ¹⁰ and R ¹² are preferably a hydroxyl group, a methoxy group, a trimethylsilyloxy, a tert-butyldimethylsilyloxy, a benzoate, acetate, propionate, valerate, butcyclate, cyclopentylpropionate radical or the group Z. Particularly preferred is a hydroxy group.

R ¹⁴ is preferably a hydrogen atom.

R ¹⁵ is preferably a hydrogen atom, a methoxy group or an ethoxy group. The residues R ⁹ in position 11, R ⁷ in position 7, R ¹⁰ in position 17 and R ¹¹ in position 16 can be arranged both in the α and in the β position.

Particularly preferred compounds or estradiol prodrugs are listed below:

1) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoylbenzoate (9),

2) 3-acetoxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoylbenzoate,

3) 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -trien-17ß-yl 3'-sulfamoylbenzoate (10),

4) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2'-chloro-5'-sulfamoylbenzoate (21), 5) 3-hydroxyestra-1, 3,5 (10) -triene- 17β-yl 3'-sulfamoyl-4'-chloro-benzoate (3),

6) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2 ', 4 ^, -dichloro-5'-sulfamoylbenzoate (7),

7) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2'-chloro-4'-fluoro-5'-sulfamoylbenzoate (5),

8) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2'-methoxy-5'-sulfamoylbenzoate (12),

9) 3-tert-Butyldimethylsilyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-methoxy-5'-sulfamoylbenzoate

10) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate (19),

11) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 4'-sulfamoylbenzoate (1),

12) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 3'-sulfamoyl benzoate,

13) 2-methoxy-3-hydroxyestra-1,3,5 (10) -triene-17ß-yl 2'-chloro-5 ^, -sulfamoylbenzoate, 14) 2-methoxy-3-hydroxyestra-1,3,5 ( 10) -triene-17β-yl 3'-sulfamoyl-4'-chloro-benzoate,

15) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2 ', 4'-dichloro-5'-sulfamoyl-benzoate,

16) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2'-chloro-4'-fluoro-5 ^, -sulfamoylbenzoate,

17) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 4'-sulfamoylbenzoate, 18) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene- 17β-yl 4'-sulfamatobenzoate, 19) 3-benzoyloxyestra-1, 3,5 (10) -triene-17ß-yl 3'-sulfamoylbenzoate (14),

20) 17β- (n-pentanoyloxy) estra-1, 3,5 (10) -trien-3-yl 3'-sulfamoylbenzoate (15),

21) 17β-benzoyloxyestra-1, 3,5 (10) -trien-3-yl 3'-sulfamoylbenzoate (16),

22) 17β-hydroxyestra-1, 3,5 (10) -trien-3-yl 4'-sulfamoylbenzoate (17),

23) 17ß-Hydroxyestra-1, 3,5 (10) -trien-3-yl 2 ', 3'-dichloro-5'-sulfamoylbenzoate (24), 24) 17ß-Hydroxyestra-1, 3,5 (10) -trien-3-yl 2'-chloro-4'-fluoro-5'-sulfamoylbenzoate (23),

25) 3-methoxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoylbenzoate (11),

26) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2'-sulfamoylbenzoate (25),

27) 3-benzoyloxyestra-1, 3,5 (10) -triene-17β-yl 2'-sulfamoylbenzoate (26),

28) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 29) Estra-1,3,5 (10) -triene-3,17β-diyl bis (3'-sulfamoylbenzoate) (27) 30) 2-ethoxy -3-hydroxyestra-1,3,5 (10) -triene -17ß-yl 3'-sulfamoylbenzoate, 31) 2-ethoxy -3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2 ^, -chloro-5'-sulfamoylbenzoate, 32) 2-ethoxy -3 -hydroxyestra-1, 3.5 (10) -triene-17ß-yl 3'-sulfamoyl-4'-chloro-benzoate, 33) 2- ethoxy -3-hydroxyestra-1, 3.5 (10) -triene- 17ß-yl 2 ', 4'-dichloro-5'-sulfamoyl-benzoate, 34) 2-ethoxy -3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2'-chloro-4'- fluoro-5'-sulfamoyl benzoate, 35) 2-ethoxy -3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 4'-sulfamoyl benzoate,

36) 2-ethoxy -3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 4'-sulfamatobenzoate,

37) 2-Ethoxy-3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate. 38) 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-chloro-4'-sulfamoylbenzoate (28) 39) 3-hydroxyestra-1, 3,5 (10) - trien-17ß-yl 2'-chloro-4'-sulfamoyl benzoate (29)

For the formation of pharmaceutically acceptable salts of the compounds of the general formula I according to the invention, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids include acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, oxalic acid, Salicylic acid, tartaric acid, citric acid, lactic acid, malic acid, mandelic acid, cinnamic acid and methanesulfonic acid.

The compounds according to the invention have estrogenic activity when administered orally, with hepatic effects, unlike conventional estrogens, being largely avoided. The compounds according to the invention do not themselves bind to the estrogen receptor, rather the therapeutically relevant steroid is released from them by ester cleavage.

/ N-VVO attempts

Surprisingly and unexpectedly, a very strong increase in the “mother estrogen”, for example in compound 9 of estradiol, was found in in vivo experiments in rats for the compounds according to the invention when administered orally, as is not found in other esters, for example of estradiol. The relevance This finding is demonstrated by a strong effect of the substances according to the invention on uterine growth in ovariectomized rats. Test principle and test description:

Adult Wistar rats were used ovariectomized 14 days after this operation to examine the substances according to the invention. Treatment lasted for 3 days (days 1-3), on day 4 after the animals were killed, plasma was obtained for hormone analysis and clinical-chemical determinations and the determination of the uterine weights. In satellite experiments, correspondingly conditioned animals were sacrificed and their blood was taken after a single treatment and at other times (see Table 1 for the determination of estradiol and estrone in plasma).

Table 1

Rise in estradiol (E2) and estrone (E1) levels in the plasma of rats after single oral administration of compounds 9 and compound 1 (0.05 mg / animal): Significantly greater increase in E2 than in E1 to pharmacodynamically relevant values

H compound

1 shows the induction of uterine growth in ovariectomized rats. Treatment is oral from day 1 to day 3, followed by autopsy on day 4. Maximum uterine growth is shown predominantly at 30μg / animal / day. Surprisingly and unexpectedly, z. B. for compound 9 found an increased estrogenic activity on the uterus compared to ethinyl estradiol. When administered orally to ovariectomized rats, substances according to the invention have a significantly stronger effect on the uterus than conventional estrogens.

While ethinylestradiol leads to a significant increase in angiotensinogen even at low doses that are not yet effective on the uterus, no or a significantly smaller change in markers of hepatic estrogen effects was found under doses of substances according to the invention that were fully effective on the uterus.

2 shows estrogenic activity (uterine growth) and liver estrogenicity (marker: angiotensinogen, (angiotensin I is formed by enzymatic conversion from angiotensinogen by adding renin to the sample) of compound 1 in comparison to the standard estrogen ethinyl estradiol (EE) of angiotensin 1 a greater undesirable effect on the liver.

The compound of the invention has a superior effect on uterine growth, but a much less effect on estrogen-modulated liver functions than the EE.

/ N-v / fro-tests

Investigations regarding the binding of the m-substituted compounds 9 and 7 and the p-substituted compound 1 to erythrocytes were also surprising. Weaker bonds were found for the m-substituted derivatives. In contrast, compound 1 shows a very strong bond.

It was unexpected, however, that z. B. the m-substituted compound 9 has a higher oral availability and estrogenicity than the p-substituted compound despite lower binding strength to erytrocytes. The data in Table 2 are intended to illustrate the binding to erythrocytes of selected compounds according to formula I. Table 2

Binding of selected compounds to erythrocytes

test principle

The SO ₂ -NH ₂ group of the substances according to the invention can lead to an accumulation in erythrocytes by binding to carbonic anhydrases. The displacement of estradiol-3-sulfamate from the erythrocyte binding by test substances is measured.

Experimental approach: Human blood is mixed with a mixture of ¹⁴ C-labeled and unlabeled estradiol sulfamate. At the selected working point, the erythrocytes are saturated and the distribution in plasma / erythrocytes is 40:60. A second blood sample is mixed with a mixture of ¹⁴ C-labeled estradiol sulfamate and unlabeled test substance. The relative binding affinity is calculated from the proportion of ¹⁴ C-labeled estradiol sulfamate in the plasma: high proportion = strong displacement of ¹⁴ C-estradiol sulfamate from the erythrocytes by the test substance = high binding affinity of the test substances to the erythrocytes.

test description

Determination of the substance concentration in the erythrocyte / plasma ratio (tracer use):

Fresh blood is incubated with a defined amount of tracer compound from compound 1 or 9. After the erythrocytes have been separated, the measured radioactivity in the erythrocytes is compared to the measured radioactivity in the plasma. Determination of the erythrocyte / plasma ratio (non-radioactive): Freshly obtained, heparinized blood is mixed with a defined amount of test substance. The concentration in the resulting plasma is measured. The erythrocyte / plasma ratio is calculated from the measured concentration of the entire substance in the plasma and the concentration used.

In all cases, binding (inhibition) to the carbonic anhydrase (CA I) found in the erythrocytes was found (Table 3). It is therefore to be expected that the compounds according to the invention also have therapeutically relevant effects as carbonic anhydrase inhibitors. Of importance for the properties as estrogen is the binding to erythrocytes induced by the high affinity for carbonic anhydrases. This binding is essential for a reduced extraction of the orally administered substance during the first passage through the liver. High or lower affinity for the erythrocytic carbonic anhydrases, faster or delayed release from this depot and subsequent hydrolysis determine the therapeutic applicability of the substances according to the invention.

It was unexpectedly found that the compounds according to the invention reach therapeutically relevant levels at lower doses if the binding to the erythrocytes is - unlike what is expected according to DE 100 27 887.6 A1 - less than 10. The compounds according to the invention open up the possibility of achieving higher, short-lasting or uniformly low and longer-lasting hormone levels with the same absolute substance administration. The potency and duration of action are varied and therapy tailored to the individual organism is made possible.

Table 3

IC ₅₀ inhibitory values of human carbonic anhydrase I

Test principle and test description:

Carbonic anhydrases catalyze the CO ₂ hydration.

Experimental approach: A constant CO ₂ flow is passed through a buffer to which carbonic anhydrase I has been added. The measurement parameter is the time required to reduce the pH value within defined limits. This parameter reflects the formation of H ₂ CO ₃ in the medium. IC ₅₀ inhibition values are determined by pipetting test substances into the test batch. In the concentration ranges examined, the test substances cause no or complete inhibition of the enzymes mentioned.

These test results open up the compounds of the general formula (I) or their salts according to the invention in a variety of applications in fertility control and for hormone replacement therapy (HRT) in women or for the treatment of hormone-related diseases in men and women such as endometriosis, breast cancer, prostate cancer and hypogonadism.

The present invention therefore also relates to pharmaceutical compositions which contain at least one compound of the general formula (I) or a corresponding salt, optionally together with at least one further steroidal active ingredient, and optionally pharmaceutically acceptable auxiliaries and excipients. Gestagens, antigestages or mesogestestins may be mentioned as further active substances for combination with the compounds of the general formula (I) according to the invention.

These pharmaceutical compositions and medicaments can preferably be used for oral, but also for rectal, vaginal, subcutaneous, percutaneous, intravenous, transdermal or intramuscular application. In addition to the usual carriers and / or diluents, they contain at least one compound of the general formula I.

The medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. The preferred preparations are in a dosage form which is suitable for oral administration. Such dosage forms are for example tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or even depot forms.

Of course, parenteral preparations such as injection solutions are also suitable. Suppositories and agents for vaginal use may also be mentioned as preparations.

Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve one Depot effects such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

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

Solutions or suspensions with the compounds of general formula I according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z. B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.

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

Suitable suppositories can be produced, for example, by mixing them with suitable carriers such as neutral fats or polyethylene glycol or their derivatives. The compounds according to the invention have estrogenic activity when administered parenterally and orally, and they have pharmacokinetically improved properties over estradiol and 17α-ethinylestradiol (EE), which are based on reduced hepatic extraction and more uniform and longer-lasting blood levels of the released estrogen. The compounds according to the invention also have increased estrogen effects in the uterus compared to estradiol. In humans, unlike oral therapy with estradiol or ethinyl estradiol, the compounds according to the invention should not trigger any appreciable undesirable effects on estrogen-modulated functions in the liver.

The compounds according to the invention are suitable for all forms of estrogen therapy and can be used therapeutically alone or in combination with a progestogen, anti-progestogen or mesoprogestin. They are also suitable for combined oral contraception and analog products for climacteric hormone substitution, as well as for estrogen treatment for prostate cancer.

The substances according to the invention are prodrugs of natural estrogens. The substances according to the invention are preferably used for oral therapy. Compared to their "mother estrogens", the compounds according to the invention have a significantly increased oral bioavailability, an increased systemic, but as a rule reduced hepatic estrogenicity. This dissociation of desired and undesirable hormonal effects simultaneously makes therapeutically more effective and, in comparison to the prior art, more tolerable medicaments allows.

In oral therapy with natural estrogens (estradiol, estradiol valarate, estrone sulfate, conjugated estrogens), but also with that with estradiol sulfamate, high levels of estrone dominate in the blood. In contrast to the cycle, the concentrations of estradiol in the blood are lower than those of estrone. This is disadvantageous because estrone is a much weaker estrogen than estradiol. An advantage of the substances according to the invention compared to the prior art is that the respective “mother estrogen” is preferably released, for example estradiol, equilin or equilenin. The estradiol prodrugs according to the invention can be synthesized according to the following examples, these serving for a more detailed explanation without restricting the invention.

General synthesis instructions

A) Coupling of the steroidal compound with group Z

version 1

Reaction with sulfamoylphenylcarboxylic acids

An estrogen is dissolved in a base such as pyridine. Appropriate amounts of a sulfamoylphenylcarboxylic acid are added to the solution, then an acid such as p-toluenesulfonic acid and finally a carbodiimide such as dicyclohexylcarbodiimide are added. The reaction mixture is stirred until the reaction is complete. Then water is added and acidified with an acid such as 10% HCl. The precipitate is filtered off, washed with water, NaHCO ₃ solution and dried. The residue is extracted with an organic solvent, such as ethyl acetate, the organic phase is washed and dried with a drying agent, such as MgSO ₄ . After filtration, the mixture is concentrated and chromatographed on silica gel. Corresponding estrogen sulfamoyl benzoates are obtained.

Variant 2

Reaction with sulfamoylphenylcarboxylic acid chlorides An estrogen is dissolved in a base such as pyridine. The appropriate amount of a sulfamoylphenylcarboxylic acid chloride is added to the solution. The reaction mixture is stirred until the reaction is complete. Then water is added and acidified with an acid such as 10% HCl. It is extracted with an organic solvent, such as ethyl acetate, the organic phase is washed and dried with a drying agent, such as MgSO ₄ . After filtration, the mixture is concentrated and chromatographed on silica gel. Corresponding estrogen sulfamoyl benzoates are obtained. Variant 3

Reaction with chlorosulfonylphenylcarboxylic acid chlorides

An estrogen is in a base such as e.g. Pyridine and an organic solvent, e.g. Chloroform dissolved and chilled. The appropriate amount of a chlorosulfonylphenylcarboxylic acid chloride is added to the solution. The reaction mixture is stirred at room temperature until the reaction is complete. The reaction mixture is then stirred into concentrated ammonia solution. The mixture is concentrated and mixed with an acid, e.g. Acidified 10% HCL. The precipitate is filtered off, washed with water, dried and chromatographed on silica gel. Corresponding estrogen sulfamoyl benzoates are obtained.

Variant 4

Reaction with 2-sulfophenylcarboxylic acid cyclo-anhydride

An estrogen is dissolved in an organic solvent such as chloroform. After adding 2-sulfophenylcarboxylic acid cyclo-anhydride, the mixture is stirred under an inert gas at elevated temperatures. It is then cooled and a concentrated ammonia solution, such as, for example, methanolic ammonia solution, is added. The solvents are distilled off and the residue is chromatographed on silica gel. To give 2 ^'- Sulfophenylcarboxylic acid ester-Ammoniurnsalze corresponding estrogens, in an organic solvent such as ₃ dissolved under protective gas, for example, CHCI. A corresponding amount of a chlorinating agent, such as PCI ₅ or SOCI _{2, is} added in portions. The reaction mixture is optionally stirred at higher temperatures and then briefly in conc. Given NH ₃ solution. The mixture is concentrated, the precipitated substance is filtered off, washed with water, dried and chromatographed on silica gel. This gives 2 ^{'-Sulfamoylphenylcarbonsäureester} corresponding estrogens.

Variant 5

Conversion to sulfamides (NH ₂ SO ₂ NH-) The conversion to the sulfamides according to the invention is carried out according to methods known to those skilled in the art for their preparation, starting from appropriate amines by means of

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

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

Chem., 1990, 6104.). For example, a corresponding aminobenzoate in an organic solvent such as toluene in the presence of a base such as NEt ₃ with sulfamoyl chloride Temperatures of 20-60 ° C implemented. The reaction mixture is stirred until the reaction is complete. Then water is added, the precipitate is filtered off, washed with water, NaHCO ₃ solution and dried. The substance is purified chromatographically on silica gel. Corresponding estrogen sulfamoylaminobenzoates are obtained.

B) Examples of the synthesis of linkers (Z)

2-Chloro-4-sulfamoylbenzoic acid stage 1

10 g of 2-chloro-toluene-4-sulfonic acid Na salt x H ₂ O are added to 40 ml of thionyl chloride.

After adding 5 ml of DMF, the mixture is boiled under reflux for 6 h. The cold reaction mixture is poured onto 200 g of ice. The precipitated substance is washed with water and dried. 2-Chloro-toluene-4-sulfonic acid chloride is obtained. ¹ H NMR (DMSO-d ₆ ): 2.32 (s, 3H, Me), 7.32-7.58 (m (overlaid), 3H, CH)

Level 2

8 g of 2-chloro-toluene-4-sulfonic acid chloride were dissolved in 25 ml of CHCI ₃ and slowly in 100 ml of conc. NH ₃ solution stirred. After stirring for 10 min at RT, the solution is evaporated in half. The substance is suctioned off, washed with water and dried. 2-Chloro-4-sulfamoyltoluene is obtained. H-NMR (DMSO-d ₆ ): 2.39 (s, 3H, Me), 7.44 (s, 2H, NH ₂ ), 7.55-7.83 (m (superimposed), 3H, CH)

Stage 3 1.67 g of 2-chloro-4-sulfamoyltoluene are placed in 70 ml of water. After adding 5 g

KMnO4 and 0.5 ml sat. NaHCO.sub.3 solution. is heated under reflux for 2 h. After adding 2 ml of MeOH, the resulting manganese dioxide is filtered off and the solution is evaporated in half. To

Acidify with 10% HCI, the solution is cooled for 8 h to complete crystallization.

It is then suctioned off, washed with water and dried. 2-Chloro-4-sulfamoylbenzoic acid is obtained.

¹ H NMR (DMSO-d ₆ ): 7.66 (s, 2H, NH ₂ ), 7.80-8.02 (m (overlaid), 3H, CH), 13.86 (s, 1 H, COOH) example 1

3-Hvdroxyestra-1.3.5 (10) -trien-17ß-yl 4'-sulfamoylbenzoate (1)

Stage 1 3-tert-butyldimethylsilyloxyestra-1.3.5 (1 OVtrien-17ß-yl 4'-sulfamoylbenzoate (2) variant 1

1.0 g of 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-ol is dissolved in 10 ml of pyridine. After adding 1.5 g of p-sulfamoylbenzoic acid, 200 mg of p-toluenesulfonic acid and 1.5 g of dicyclohexylcarbodiimide (DCC), the mixture is stirred at room temperature for 48 hours. Then 20 ml of water and 50 ml of ethyl acetate are added. With 10% HCI it is slightly acidified (pH = 5). The precipitate is filtered off and washed with ethyl acetate. The organic phase is separated off with 10% NaHCO ₃ solution and sat. Washed NaCl solution, dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. 3-tert-Butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 4'-sulfamoyl benzoate is obtained.

Variant 2

1.0 g of 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-ol is dissolved in 10 ml of pyridine. After adding 1.0 g of p-sulfamoylbenzoic acid chloride, the mixture is stirred at room temperature for 2 hours. After adding 20 ml of water, it is slightly acidified with 10% HCl (pH = 5). It is then extracted with ethyl acetate. The organic phase is separated off with 10% NaHCO ₃ solution and with sat. Washed NaCl solution, dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. 3-tert-Butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 4'-sulfamoyl benzoate is obtained.

Level 2

3-Hvdroxyestra-1.3.5 (10) -17ß-yl 4'-sulfamoylbenzoate (1)

500 mg of 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 4'-sulfamoylbenzoate are dissolved in 5 ml of THF. 500 mg of tetrabutylammonium fluoride (TBAF) are added at RT with stirring. After 1 hour, 20 ml of water are added. The substance is extracted with THF. The organic phase is saturated with. Washed NaCl solution, dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. You get 3-

Hydroxyestra-1, 3,5 (10) -17ß-yl 4'-sulfamoyl benzoate.

¹ H NMR (CDCI ₃ ): 0.93 (s, 3H, H-18), 4.86 (m, 1 H, H-17α), 7.56 (s, 2H, NH ₂ ), 9.00 (s, 1 H, OH) ) Example 2

3-Hvdroxyestra-1, 3.5 (10) -trien-17ß-yl 3'-sulfamoyl-4'-chloro-benzoate (3) The substance is prepared analogously to Example 1 according to variant 1, starting from 3-sulfamoyl-4-chloro-benzoic acid obtained via the intermediate 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -triene-17ß-yl 3'-sulfamoyl-4'-chloro-benzoate (4).

¹ H NMR (DMSO-d ₆ ): 0.92 (s, 3H, H-18), 4.87 (m, 1 H, H-17), 7.82 (s, 2H, NH ₂ ), 9.00 (s, 1 H) 3-OH)

Example 3

3-Hvdroxyestra-1.3.5 (10) -trien-17ß-yl 2'-chloro-4'-fluoro-5'-sulfamoylbenzoate (5) The substance is prepared analogously to Example 1 according to variant 1, starting from 2-chloro-4- obtained fluoro-5-sulfamoylbenzoic acid via the intermediate 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-17ß-yl 2'-chloro-4'-fluoro-5'-sulfamoylbenzoate (6). ¹ H NMR (DMSO-d ₆ ): 0.89 (s, 3H, H-18), 4.87 (m, 1 H, H-17), 7.96 (s, 2H, NH ₂ ), 9.02 (s, 1 H , 3-OH)

Example 4

3-Hvdroxyestra-1.3.5 (10) -triene-17ß-yl 2'.4'-dichloro-5'-sulfamoylbenzoate (7)

The substance is prepared analogously to Example 1 according to Variant 1 starting from 2,4-dichloro-5-sulfamoylbenzoic acid via the intermediate 3-tert-Butyldimethylsilyloxyestra- 1, 3,5 (10) -trien-17-yl ^2, 4'- dichloro-5'-sulfamoyl benzoate (8) obtained.

¹ H-NMR (DMSO-de): 0.88 (s, 3H, H-18), 4.87 (m, 1 H, H-17), 7.86 (s, 2H, NH ₂ ), 8.99 (s, 1 H, 3-OH)

Example 5

3-Hvdroxyestra-1.3.5 (10) -trien-17ß-yl 3'-sulfamoylbenzoate (9)

Stufel

3-tert-butyldimethylsilyloxyestra-1.3.5 (10) -trien-17ß-yl 3'-sulfamoylbenzoate (10)

1.0 g of 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-ol is dissolved in 2 ml of pyridine and 2 ml of CHCI ₃ . 1.0 ml of 3- is added to the reaction mixture at -20 ° C. with stirring Chlorosulfonylbenzoic acid chloride added. The mixture is then warmed to RT and stirred for 15 min. The reaction solution is concentrated in 25 ml. Added NH ₃ solution and stirred for 15 min. Then the org. LM distilled off. It is slightly acidified with 10% hydrochloric acid (pH = 5). The precipitated substance is filtered off, washed with 10% NaHCO ₃ solution and water and then dried. 3-tert-Butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 3'-sulfamoyl benzoate is obtained.

¹ H NMR (CDCI ₃ ): 0.19 (s, 6H, Si-Me), 0.98 (s + s (superimposed), 12H, t.-C ₄ H ₉ , H-18), 4.96 (m, 1 H , H-17), 5.08 (s, 2H, NH ₂ )

Level 2

3-Hvdroxyestra-1, 3,5 (10) -17ß-yl 3'-sulfamoylbenzoate (9)

500 mg of 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 3'-sulfamoylbenzoate are dissolved in 10 ml of THF. 500 mg of TBAF are added with stirring at RT. After 1 hour, 40 ml of water are stirred in and then the org. LM distilled off. The substance is filtered off, washed with water, dried and chromatographed on silica gel. 3-Hydroxyestra-1, 3,5 (10) -17ß-yl 3'-sulfamoylbenzoate is obtained. ¹ H NMR (DMSO-d ₆ ): 0.94 (s, 3H, H-18), 4.89 (m, 1H, H-17), 7.55 (s, 2H, NH ₂ ), 9.00 (s, 1 H, 3-OH)

Example 6

3-methoxyestra-1.3.5 (10) -triene-17ß-yl 3'-sulfamoylbenzoate (11)

1.0 g of 3-methoxyestra-1, 3,5 (10) -17ß-ol is dissolved in 2 ml of pyridine and 2 ml of CHCI ₃ . to

The reaction mixture is added at -20 ° C with stirring 1.0 ml of 3-chlorosulfonylbenzoic acid chloride. The mixture is then warmed to RT and stirred for 15 min. The reaction solution is concentrated in 25 ml. Added NH ₃ solution and stirred for a further 15 min. Then the org. LM distilled off. It is slightly acidified with 10% hydrochloric acid (pH = 5). The precipitated substance is filtered off, washed with 10% NaHCO ₃ solution and water, dried and chromatographed on silica gel. 3-Methoxyestra-1, 3,5 (10) -17ß-yl 3'-sulfamoylbenzoate is obtained.

¹ H NMR (CDCI ₃ ): 0.96 (s, 3H, H-18), 3.77 (s, 3H, OMe), 4.96 (m, 1 H, H-17), 5.16 (s, 2H, NH ₂ ) Example 7

3-Hvdroxyestra-1, 3,5 (10) -trien-17ß-yl 2'-methoxy-5'-sulfamoylbenzoate (12) The substance is analogous to Example 1 according to variant 1, starting from 2-methoxy-5-sulfamoylbenzoic acid via the Intermediate 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-methoxy-5'-sulfamoylbenzoate (13) obtained. ¹ H NMR (DMSO-d ₆ ): 0.88 (s, 3H, H-18), 3.91 (s, 3H, OMe), 4.82 (, 1 H, H-17), 7.36 (s, 2H, NH ₂ ), 9.00 (s, 1H, 3-OH)

Example 8

3-Benzoyloxyestra-1.3.5 (10) -trien-17ß-yl 3'-sulfamoylbenzoate (14)

1.0 g of 3-benzoyloxyestra-1, 3,5 (10) -17ß-ol is dissolved in 2 ml of pyridine and 2 ml of CHCI ₃ . 1.0 ml of 3-chlorosulfonylbenzoic acid chloride is added to the reaction mixture at -20 ° C. while stirring. The mixture is then warmed to RT and stirred for 15 min. The reaction solution is concentrated in 30 ml. Added NH ₃ solution and stirred for a further 15 min. Then the org. LM distilled off. It is slightly acidified with 10% hydrochloric acid (pH = 5). The precipitated substance is filtered off, washed with 10% NaHCO ₃ solution and water, dried and chromatographed on silica gel. 3-Methoxyestra-1, 3,5 (10) -17ß-yl 3'-sulfamoylbenzoate is obtained. ¹ H NMR (CDCI3): 0.97 (s, 3H, H-18), 4.91 (m, 1 H, H-17), 7.56 (s, 2H, NH ₂ ).

Example 9

17β- (n-pentanoyloxy) estra-1, 3,5 (10) -trien-3-yl 3'-sulfamoylbenzoate (15) The substance is prepared analogously to Example 9 starting from 3-hydroxyestra-1, 3.5 (10) -17ß-yl valerate. 17β- (n-Pentanoyloxy) estra-1, 3,5 (10) -trien-3-yl 3'-sulfamoyl benzoate is obtained. ¹ H-NMR (CDCI3): 0.81 (s, 3H, H-18), 0.88 (t, 3H, CH ₃ ), 4.64 (m, 1 H, H-17), 7.58 (s, 2H, NH ₂ ) ,

Example 10

17ß-Benzoyloxyestra-1.3.5 (10) -trien-3-yl 3'-sulfamoylbenzoate (16)

The substance is prepared analogously to Example 9 starting from 3-hydroxyestra-1, 3,5 (10) -17ß-yl benzoate. 17β-Benzoyloxyestra-1, 3,5 (10) -trien-3-yl 3'-sulfamoylbenzoate is obtained. ¹ H NMR (CDCI ₃ ): 0.96 (s, 3H, H-18), 4.86 (m, 1 H, H-17), 7.59 (s, 2H, NH ₂ ).

Example 11

17ß-Hvdroxyestra-1.3.5 (10) -trien-3-yl 4'-sulfamoylbenzoate (17)

The substance is analogous to Example 1 according to variant 1, starting from 4-sulfamoylbenzoic acid via the intermediate 17β-tert-butyldimethylsilyloxyestra-

1, 3,5 (10) -triene-17ß-yl 4'-sulfamoylbenzoate (18) obtained. After silyl ether cleavage, one obtains

17β-Hydroxyestra-1, 3,5 (10) -trien-3-yl 4'-sulfamoylbenzoate (17).

Example 12

3-Hvdroxyestra-1.3.5 (10) -trien-17ß-yl 2'.3'-dimethoxy-5'-sulfamoylbenzoate (19) The substance is prepared analogously to Example 1 according to variant 1, starting from 2,3-dimethoxy-5- sulfamoylbenzoic acid obtained via the intermediate 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -trien-17ß-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate (20). ¹ H NMR (DMSO-d ₆ ): 0.87 (s, 3H, H-18), 3.84 (s, 3H, OMe), 3.91 (s, 3H, OMe), 4.82 (, 1 H, H-17) , 7:44 (s, 2H, NH _2), 9:00 (s, 1 H, 3-OH).

Example 13

3-Hvdroxyestra-1, 3,5 (10) -trien-17ß-yl 2'-chloro-5'-sulfamoylbenzoate (21) The substance is analogously to Example 1 according to variant 1, starting from 2-chloro-5-sulfamoylbenzoic acid via the Intermediate 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-chloro-5'-sulfamoylbenzoate (22) obtained.

¹ H NMR (DMSO-d ₆ ): 0.89 (s, 3H, H-18), 4.89 (m, 1 H, H-17), 7.63 (s, 2H, NH ₂ ), 9.02 (s, 1 H) , 3-OH).

Example 14

17ß-Hvdroxyestra-1.3.5 (10) -trien-3-yl 2'-chloro-4'-fluoro-5'-sulfamoylbenzoate (23) 0.65 g of estradiol is dissolved in 7 ml of pyridine. After adding 0.8 g of 2-chloro-4-fluoro-5-sulfamoylbenzoic acid and 0.8 g of dicyclohexylcarbodiimide (DCC), the mixture is stirred at room temperature for 3 hours. It is then acidified with 10% HCl (pH = 2). The precipitate is filtered off and washed with 10% NaHCO ₃ solution and water. The the product obtained is chromatographed on silica gel. 17β-Hydroxyestra-1,3,5 (10) -3-yl 2'-chloro-4'-fluoro-5'-sulfamoylbenzoate (23) is obtained. ¹ H NMR (CD ₃ OD): 0.81 (s, 3H, H-18), 3.67 (m, 1 H, H-7). ¹⁹ F NMR (CD ₃ OD): -102.5 ppm.

Example 15

17ß-Hvdroxyestra-1, 3,5 (10) -trien-3-yl 2'.3'-dichloro-5'-sulfamoylbenzoate (24)

0.4 g of estradiol are dissolved in 7 ml of pyridine. After adding 0.8 g of 2,3-dichloro-5-sulfamoylbenzoic acid and 0.8 g of dicyclohexylcarbodiimide (DCC), the mixture is stirred at room temperature for 1 hour. It is then acidified with 10% HCl (pH = 2) and 8 ml of water are added. The precipitate is filtered off and washed with 10% NaHCO ₃ solution and water. The product obtained is chromatographed on silica gel. 17β-Hydroxyestra-1, 3,5 (10) -3-yl a'.S'-dichloro-δ'-sulfamoylbenzoate (24) is obtained. ¹ H NMR (DMSO-d ₆ ): 0.69 (s, 3H, H-18), 4.51 (m, 1 H, H-17), 7.90 (s, 2H, NH ₂ ).

Example 16

3-Hvdroxyestra-1,3,5 (10) -trien-17ß-yl 2'-sulfamoylbenzoate (25) stage 1

3-Benzoyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-sulfobenzoate ammonium salt 10 g of estradiol-3-benzoate are dissolved in 100 ml of chloroform. After adding 5.0 g of 2-sulfobenzoic acid cyclo-anhydride, the mixture is stirred at 50 ° C. for 12 h. The mixture is then cooled to 10 ° C. and a concentrated methanolic ammonia solution is added. The solvents are distilled off and the residue is chromatographed on silica gel. 3-Benzoyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-sulfobenzoate ammonium salt is obtained. ¹ H NMR (DMSO-d ₆ ): 0.82 (s, 3H, H-18), 4.78 (m, 1 H, H-17), 7.35-8.10 (m (overlaid), 9H, benzoate).

Level 2

3-Benzoyloxyestra-1.3.5 (10) -triene-17β-yl 2'-chlorosulfonyl benzoate

3.0 g of 3-benzoyloxyestra-1, 3,5 (10) -triene-17β-yl 2'-sulfobenzoate ammonium salt are dissolved in 1 ml of DMF and 8 ml of SO ₂ CI ₂ under a protective gas. The reaction mixture is heated under gentle reflux for 4 h. It is then cooled to 0 ° C. and the mixture is opened grated ice. The cold mixture is extracted with ethyl acetate and the organic phase with 5% NaHCO ₃ solution. Washed. After drying over MgSO4, the mixture is filtered and concentrated. This gives 3-benzoyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-chlorosulfonyl benzoate, which can be used without further work-up.

level 3

3-Benzoyloxyestra-1.3.5 (10) -trien-17ß-yl 2'-sulfamoylbenzoate (26)

2.0 g of 3-benzoyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-chlorosulfonylbenzoate are added in 10 ml

CHCI ₃ dissolved and stirred rapidly in 100 ml of 32% ammonia solution. After 10 stirring at room temperature, the organic solvents are distilled off. The fancy

The substance is suctioned off, washed several times with water and dried. 3-Benzoyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-sulfamoylbenzoate (26) is obtained in high purity.

¹ H NMR (DMSO-de): 0.86 (s, 3H, H-18), 4.87 (m, 1 H, H-17), 7.33 (s, 2H, NH ₂ ), 7.55-8.13 (m (superimposed ), 9H, benzoates).

Level 4

3-Hvdroxyestra-1.3.5 (10) -trien-17ß-yl 2'-sulfamoylbenzoate (25)

530 mg of 3-benzoyloxyestra-1,3,5 (10) -trien-17ß-yl 2'-aminosulfonylbenzoate in 90 ml

MeOH solved. 510 mg of Li ₂ CO _{3 are} added. The reaction mixture is stirred at RT for 12 h. After adding 10 ml of water, the mixture is concentrated. The precipitated substance is filtered off, washed with water, dried and chromatographed on silica gel. 3-Hydroxyestra-1, 3,5 (10) -trien-17ß-yl 2'-sulfamoylbenzoate (25) is obtained.

¹ H-NMR (DMSO-d ₆ ): 0.83 (s, 3H, H-18), 4.84 (m, 1 H, H-17), 7.25 (s, 2H, NH ₂ ), 7.60-8.00 (m, 4H, benzoate), 9.00 (s, 1H, 3-OH).

Example 17

Estra-1, 3,5 (10) -triene-3.17ß-diyl bis (3'-sulfamoylbenzoate) (27)

1.0 g of estradiol is dissolved in 4 ml of pyridine. 2.0 ml of 3-chlorosulfonylbenzoic acid chloride are added to the reaction mixture at −20 ° C. with stirring. The mixture is then warmed to RT and stirred for 15 min. The reaction solution is concentrated in 50 ml. Added NH ₃ solution and stirred for 15 min. Then the organic solvents are distilled off. Acidify with 10% hydrochloric acid (pH = 3). The precipitated substance is filtered off, washed with 10% NaHCO ₃ solution and water and then dried. Estra-1,3,5 (10) -triene-3,17β-diyl bis (3'-sulfamoylbenzoate) (27) is obtained. ¹ H NMR (DMSO-d ₆ ): 0.98 (s, 3H, H-18), 4.91 (m, 1 H, H-17), 9.98-7.43 (m, 3H, H-Ar ( Steroid)), 7.65-8.58 (m (overlaid), 8H, H-Ar)).

Example 18

3-tert-Butyldimethylsilyloxyestra-1.3.5 (10) -trien-17ß-yl 2'-chloro-4'-sulfamoylbenzoate (28) 1.0 g of 3-tert-butyldimethylsilyloxyestra-1, 3.5 (10) -17ß -ol is dissolved in 20 ml of pyridine. After adding 1.5 g of 2-chloro-4-sulfamoylbenzoic acid, 250 mg of p-toluenesulfonic acid and 1.5 g of DCC, the mixture is stirred at room temperature for 48 hours. Then 100 ml of water and 30 ml of CHCI _{3 are} added. With 10% HCI it is slightly acidified (pH = 5). The precipitate is filtered off and washed with CHCI ₃ . The organic phase is separated off with 10% NaHCO ₃ solution and sat. Washed NaCl solution, dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. 3-tert-Butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 2'-chloro-4'-sulfamoylbenzoate is obtained.

¹ H NMR (DMSO-d ₆ ): 0.16 (s, 6H, Si-Me), 0.88 (s, 3H, H-18), 0.94 (s, 9H, t.-C ₄ H ₉ ), 4.89 ( t, 1 H, H-17), 7.66 (s, 2H, NH ₂ )

Example 19

3-Hvdroxyestra-1.3.5 (10) -triene-17ß-yl 2'-chloro-4'-sulfamoylbenzoate (29) 300 mg 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 2 '-chlor-4'-sulfamoylbenzoate are dissolved in 25 ml of THF. 180 mg of TBAF are added with stirring at RT. After 1 hour, 20 ml of water are stirred in. The substance is extracted with ethyl acetate. The organic phase is saturated with. Washed NaCl solution, dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. 3-Hydroxyestra-1, 3,5 (10) -17ß-yl 2'-chloro-4'-sulfamoylbenzoate is obtained.

¹ H NMR (DMSO-d ₆ ): 0.87 (s, 3H, H-18), 4.88 (t, 1 H, H-17), 7.66 (s, 2H, NH ₂ ), 9.00 (s, 1 H) , 3-OH) literature

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Claims

claims

1. Estradiol prodrugs of the general formula I

Group Z (I) where n is a number 0-4,

R ^{1 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ^{1 represent} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C _1-5 alkyl group, a C _p F _{2p +} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH- R ²¹ , where R ²⁰ , R ² and R ^{22 are} a C _1-5 alkyl group, a C _3-8 cycloalkyl group, an aryl group, a C alkylene aryl group, a C 1 -C ₃ alkylene group. _8- cycloalkyl group or Cs-s-cycloalkylene-C ^ alkyl group and R ^{20 can} also be a hydrogen, or

R ^{2 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ^{1 represent} a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C ₁ . ₅ -alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH-R ²¹ , where R ²⁰ , R ²¹ and R ^{22 are} a C _1-5 alkyl group, a C ₃ . _8- cycloalkyl group, an aryl group, a C 1-4 alkylene aryl group, a C _1- alkylene C ₃ . _8- cycloalkyl group or Cs-β-cycloalkylene-C ^ alkyl group and R ^{20 can} also be a hydrogen, or R ^{3 is} a radical -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , where R ² , R ³ and X, X ¹ for a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a d- ₅ alkyl group, a C _p F _{2p + 1} group with p = 1-3, a group OC (O) -R ²⁰ , COOR ²⁰ , OR ²⁰ , C (O) NHR ²⁰ or OC (O) NH- R ²¹ , wherein R ²⁰ , R ²¹ and R ^{22 are} a C _1-5 alkyl group, a C _3-8 cycloalkyl group, an aryl group, a C _-4 alkylene aryl group, a C _1- alkylene C ₃ . _8- cycloalkyl group or C ₃ . _8- Cycloalkylene-C _1- alkyl group and R ^{20 can} also be a hydrogen, and

in which

R ⁵ , R ⁶ and R ⁸ each represent a hydrogen atom and R ^{7 represents} a hydrogen atom, a methyl or ethyl group or

R ⁵ + R ⁶ , R ⁷ + R ⁸ or R ⁶ + R ⁷ together are a double bond, a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an OC (O) -R ^{20 group} , a methyl or ethyl group,> 10 one Hydroxyl group, a methoxy group, a tri (C _1-6 alkyl) silyloxy group, an OC (O) -R ^{20 group} , a C _2-5 heterocycloalkyloxy group or a Z group,> 11 a hydrogen or a halogen atom, ι12 a hydroxyl group, a methoxy group, a tri (Cι-C ₆ - alkyl) silyloxy group, a group OC (O) -R ²⁰ , a C _2-5 - heterocycloalkyloxy group or a group Z, j14 a hydrogen atom, a methyl group, or an ethyl group) 15 a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a tri (C _1-6 alkyl) silyloxy group, a group OC (O) -R ²⁰ or a C ₂ . _5- heterocycloalkyloxy group represent

and their pharmaceutically acceptable salts.

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

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

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

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

6. Compounds according to any one of claims 1 to 5, characterized in that R ¹ , R ² , R ³ , unless they represent -SO ₂ NH ₂ or -NHSO ₂ NH ₂ , and X and X ¹ independently of one another for a hydrogen -, Fluorine, chlorine atom, a hydroxy or a methoxy group.

7. Compounds according to any one of claims 1 to 5, characterized in that independently of one another R ⁵ , R ⁶ , R ⁷ and R ⁸ each represent a hydrogen atom, R ^{9 represents} a hydrogen atom or a fluorine atom, R ^{1 represents} a hydrogen atom or a fluorine atom, R. ¹⁰ a hydroxyl group, a methoxy group, a trimethylsilyloxy, a tert-butyldimethylsilyloxy, a benzoate, acetate, propionate, valerate, butcyclate, cyclopentylpropionate radical or a group Z, R ¹² a hydroxyl group, one Methoxy group, a trimethylsilyloxy, a tert-butyldimethylsilyloxy, a benzoate, acetate, propionate, valerate, butcyclate, cyclopentylpropionate radical or a group Z, R ^{14 is} a hydrogen atom and , 15 represent a hydrogen atom, a methoxy group or an ethoxy group.

Compounds according to one of claims 1 to 7,

1) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoylbenzoate (9),

2) 3-acetoxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoylbenzoate,

4) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2'-chloro-5'-sulfamoylbenzoate (21),

5) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoyl-4'-chloro-benzoate (3),

6) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate (7),

7) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2'-chloro-4 ^, -fluoro-5'-sulfamoylbenzoate (5),

9) 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -triene-17ß-yl2'-methoxy-5'-sulfamoylbenzoate,

10) 3-hydroxyestra-1, 3,5 (10) -trien-17-yl ^2,, 3'-dimethoxy-5'-sulfamoyl benzoate (19)

11) 3-hydroxyestra-1,3,5 (10) -triene-17β-yl 4'-sulfamoylbenzoate (1),

12) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 3'-sulfamoyl benzoate,

13) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2'-chloro-5'-sulfamoylbenzoate,

14) 2-methoxy-3-hydroxyestra-1 ^" , 3,5 (10) -triene-17ß-yl 3'-sulfamoyl-4'-chloro-benzoate,

16) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2'-chloro-4'-fluoro-5'-sulfamoyl-benzoate,

17) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 4'-sulfamoylbenzoate,

18) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 4'-sulfamatobenzoate,

19) 3-benzoyloxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoylbenzoate (14),

21) 17β-benzoyloxyestra-1, 3,5 (10) -trien-3-yl 3'-sulfamoylbenzoate (16),

22) 17β-hydroxyestra-1, 3,5 (10) -trien-3-yl 4'-sulfamoylbenzoate (17),

23) 17β-hydroxyestra-1, 3,5 (10) -trien-3-yl 2 ', 3'-dichloro-5'-sulfamoylbenzoate (24),

24) 17β-hydroxyestra-1, 3,5 (10) -trien-3-yl 2'-chloro-4'-fluoro-5'-sulfamoylbenzoate (23),

25) 3-methoxyestra-1, 3,5 (10) -triene-17β-yl 3'-sulfamoylbenzoate 11 (11),

26) 3-hydroxyestra-1, 3,5 (10) -triene-17β-yl 2'-sulfamoylbenzoate,

27) 3-benzoyloxyestra-1, 3,5 (10) -triene-17β-yl 2'-sulfamoyl benzoate, 28) 2-methoxy-3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2 ', 3'-dimethoxy-5'-sulfamoylbenzoate, 29) Estra-1, 3,5 (10) - triene-3,17ß-diyl bis (3'-sulfamoylbenzoate) (27) 30) 2- ethoxy -3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 3'-sulfamoylbenzoate, 31) 2- Ethoxy -3-hydroxyestra-1, 3,5 (10) -triene-17ß-yl 2'-chloro-5'-sulfamoylbenzoate, 32) 2-ethoxy -3-hydroxyestra-1, 3,5 (10) -triene -17ß-yl 3'-sulfamoyl-4'-chloro-benzoate, 33) 2- ethoxy -3-hydroxyestra-1, 3.5 (10) -triene-17ß-yl 2 ', 4'-dichloro-5' -sulfamoyl-benzoate, 34) 2- ethoxy -3-hydroxyestra-1, 3,5 (10) -trien-17ß-yl 2'-chloro-4'-fluoro-5'-sulfamoyl-benzoate, 35) 2- Ethoxy -3-hydroxyestra-1, 3,5 (10) -trien-17ß-yl 4'-sulfamoylbenzoate, 36) 2-ethoxy -3-hydroxyestra-1, 3,5 (10) -trien-17ß-yl 4 '-sulfamatobenzoate, 37) 2-ethoxy-3-hydroxyestra-1, 3,5 (10) -trien-17ß-yl 2', 3'-dimethoxy-5'-sulfamoyl-benzoate. 38) 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -triene-17ß-yl 2'-chloro-4'-sulfamoyl-benzoate (28) 39) 3-hydroxyestra-1, 3.5 (10 ) -triene-17ß-yl 2'-chloro-4'-sulfamoylbenzoate (29)

9. Pharmaceutical compositions containing at least one compound according to one of claims 1 to 8.

10. Pharmaceutical composition according to claim 9, characterized in that at least one further steroidally active compound is contained.

1 1. Pharmaceutical composition according to claim 10, characterized in that the further steroidally active compound is a progestogen, anti-progestogen or mesoprogestin.

12. Use of the compounds according to any one of claims 1 to 8 for the manufacture of medicaments for hormone replacemant therapy in women.

13. Use of the compounds according to one of claims 1 to 8 for fertility control in women.

14. Uses of the compound according to any one of claims 1 to 8 for the manufacture of medicaments for the treatment of hormone-related diseases in men and women.

15. Use according to claim 14 for the manufacture of medicaments for the treatment of endometriosis, breast cancer, prostate cancer and hypogonadism.

16. Use of compounds according to any one of claims 1 to 8 for the manufacture of medicaments for the treatment of diseases which can be influenced positively by inhibiting carbonic anhydrase activity.

17. A process for the preparation of compounds of general formula (I) according to any one of claims 1 to 8

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