BRPI0619214A2 - heteroaromatic sulfonamide prodrugs - Google Patents

Abstract

HETERO-AROMATIC SULPHONAMID PRO-DRUGS. The present invention relates to sulfonamide prodrugs of the general formula (1), with heteroaromatic binding agent, to a process for their preparation, pharmaceutical compositions containing these compounds and to their use for the preparation of oral medications. The compounds according to the invention bind to carboanidrases and inhibit these enzymes.

Description

Descriptive Report of the Invention Patent for "Heteroaromatic Sulfonamide Prodrugs".

The present invention relates to sulfonamide prodrugs of the general formula (I),

<formula> formula see original document page 2 </formula>

wherein X is a heteroaromatic, a process for preparing such prodrugs, pharmaceutical compositions containing such compounds and their use for preparing medicaments for oral application.

From WO 01/91797 are known steroidal compounds which are bound to erythrocytes by means of a group -SOaNR1R2 and concentrate therein. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000: 1, preferably 30-1000: 1, so that it is possible to speak of a deposit formation in the erythrocytes. Due to the strong binding of the compounds to the erythrocytes, metabolism during passage through the liver is avoided. Disadvantageously, despite low metabolism at the indicated dosages, levels of active substance relevant to therapy are not achieved. Reasons for this should be sought in excessively strong erythrocyte binding, enzyme-induced dissociation, and reduced solubilities.

It is the task of the invention to provide new prodrugs which are available for oral application and, in comparison with the state of the art, guarantee a relevant active substance level for therapy even at low dosage.

This task is solved by heterocyclic sulfonamide prodrugs of the general formula (I), wherein a sulfamoyl radical is attached to the drug to be released by a heteroaromatic spacer X via a carboxylic acid ester bond, wherein <formula> formula see original document page 3 </formula>

x is an unsubstituted or substituted heteroaromatic radical or an alkyl heteroaromatic and

drug is a pharmaceutical active substance that through an OH group can form a carboxylic acid ester such as steroids, antimalarial agents, nucleosides, isoflavonoids, which may eventually be substituted.

Sulfonamide prodrugs according to the invention with heteroaromatic X-linker bind to erythrocytes, are well water soluble and are hydrolytically dissociated without enzyme co-action.

In the sense of the invention, a heteroaromatic radical means,

for example thiophene, pyridine, pyrrol, furan or also C 1-4 -alkyl or halogen substituted thiophene, pyridine, pyrrol or furan. For substituted heteroaromatics 2-bromothiophene, 2-ethylthiophene, N-methylpyrrole and 2-bromopyridine are mentioned.

C1-4-alkyl means a methyl, ethyl, propyl, butyl or isopropyl group.

By the term "halogen atom" is meant, within the meaning of the present invention, a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, bromine atom.

The term "heteroaromatic alkyl" above means a heteroaromatic linked by a C1-3-alkyl radical to the ester function. Heteroaromatic means groups designated under a heteroaromatic radical.

C 1-3 alkyl radical means a methylene, ethylene or propylene bridge.

Preferred heteroaromatics are pyridine and thiophene.

Preferred compounds are mentioned below: 1) 3-Hydroxystra-1,3'-3-hydroxystra-1'-sulfamoylnicotinate 6'-sulphamoylnicotinate , 5 (10) -trien-17β-yl (2), 3) 3-hydroxiestras-1,3,5 (10) -trien-17β-yl 2'-ethyl-5'-sulfamoylthiophene-3'-carboxylate (3), 4) 3-Hydroxystra-1,3,5 (10) -trien-17β-yl (4), 5) 6'-sulfamoylnicotinate 2'-bromo-5'-sulfamoylthiophene-3'-carboxylate 3-oxoandrost-4-en-17β-yl (5), 6) 5-oxoandrost-4-en-173-yl (6), 7) 2'-ethyl-5'-sulfamoyl 3-oxoandrost-4-en-17β-yl thiophene-3'-carboxylate, 8) 3-oxoandrost-4-en-17β-yl, 9) 5'-sulfamoylthiophene-5-sulfonylthiophen-3'-carboxylate 3-Hydroxystra-1,3,5 (10) -trien-17β-yl 3 '-carboxylate, 3) 3-hydroxiestras-1'-3,5-10-trien-sulfamoylthiophene-3'-carboxylate -17β-yl, 11) 3-oxoandrost-4-en-17β-yl 5'-sulfamoylthiophene-3'-carboxylate, 12) 3-oxo-7α-methylandrost-4-en-5-sulfamoyl nicotinate 173-yl, 13) 3'-6-sulfamoyl nicotinate -oxo-7α-methylandrost-4-en-17β-yl, 14) 3-oxo-7α-methylandrost-4-en-17β-yl, 15) N-ethyl-5'-sulfamoylthiophene-3'-carboxylate, 15) N 3-Hydroxystra-1,3,5 (10) -trien-17β-β--methyl-5'-sulfamoyl-1H-pyrrol-2'-carboxylate.

The therapeutically relevant drug compound is released from the compound by hydrolysis according to the invention. In vitro experiments:

a) carboanhydrase inhibition

Test Principle:

Photometric determination of inhibition of human carbonidrase I or II by sulfonamides or sulfamates in microtiter plates with the aid of enzymatic conversion of colorless to yellow nitrophenylacetate. Table 1: IC50 human carboanhydrase I inhibition values

<table> table see original document page 5 </column> </row> <table>

Literature: 1) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese1 "Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997)".

Sulfamoyl prodrugs according to the invention of general formula (I) have been found to inhibit carbohydrase II surprisingly well. With this, it is possible to divert a concentration of the prodrugs of the present invention in the erythrocytes.

b) Blood plasma concentration ratio - test principle and experiment description:

The SO2-NH2 group of the substances according to the invention, by binding to carboanhydrases, may lead to a concentration in erythrocytes.

Test Principle:

Freshly collected heparinized blood from a rat is mixed with a defined amount of active substance. The plasma active substance concentration thus obtained is measured on a calibration curve from plasma peaks (with known active substance concentration). The blood-plasma ratio is calculated from the measured concentration and the theoretical concentration.

<table> table see original document page 6 </column> </row> <table>

Contrary to the results published in WO 01/91797, the concentration ratios of the compounds according to the invention between erythrocytes and plasma are not in the range 10 - 1000: 1 but in the range <10: 1. This proved to be a decisive disadvantage for obtaining active substance levels relevant to therapy. By choosing appropriate binding agents it is possible to adjust the optimal blood / plasma ratio for a prodrug compound.

For the compounds according to the invention of the general formula (I), depending on the definition for "drug", these test results open numerous possibilities for the treatment and / or prophylaxis of different morbid conditions. For example, the compounds of general formula (I) may be employed in the case where "drug" is a steroid such as androgen or estrogen, hormone replacement therapy (HRT) in women and men, or treatment of diseases caused by hormone in men (prostate carcinoma, breast carcinoma, hypogonadism) and women (endometriosis, breast carcinoma). In addition, compounds according to the invention of the general formula (I), wherein "drug" represents, for example, androgen or estrogen, may be employed for fertility control in men or women.

The use of other active substances called "drugs" such as quinine, quinconidine, hydroxychloroquine, primaquine or mefloquine refers to the treatment of malaria. Compounds according to the invention of the general formula (I), wherein "drug" means a cortisol derivative, may be employed for the treatment and prophylaxis of inflammatory and / or allergic diseases that may be influenced by immunosuppressive and / or antiproliferative agents. ferative.

Prodrugs according to the invention in which "drug" means a nucleoside (zidovudine, brivudine, indinavir, nelfinavir) may be employed for the treatment of viral diseases (herpes, HIV).

The subject matter of the invention are furthermore pharmaceutical compositions containing the compounds according to the invention of the general formula (I) and possibly other active substances, for example gestagenes (norethystone, dienogest, drospirenone, levonorgestrel), antigestagens ( mifepriston,

onapriston) and / or progesterone receptor modulators (mesoprogestin as asoprisnil).

Such pharmaceutical compositions and medicaments are preferably applied orally. They contain, in addition to usual vehicles and / or diluents, at least one compound of the general formula I. Dosage

The prodrugs according to the invention may be administered orally.

In general, satisfactory results can be expected for both treatment and / or prophylaxis of the above mentioned indications and fertility control when dosing occurs so that after administration of the prodrug an amount of active substance ("drug") is released. ") corresponding to a maximum corresponding to the highest pharmaceutically employed dose of the respective" drug "substance.

The medicaments of the invention are prepared in a known dosage form, with the usual solid or liquid carriers or diluents, and with the customary pharmaceutical-technical auxiliary substances according to the desired application type. Preferred preparations are an appropriate form of administration for oral application. Such administration forms are, for example, tablets, film-coated tablets, tablets, capsules, pills, powders, solutions or suspensions or also depot forms.

Corresponding tablets may be obtained, for example, by mixing the active substance with known auxiliary substances, for example, inert diluents such as dextrose, sugar, sorbite, manita, polyvinylpyrrolidone, distending agents such as cornstarch or alkaline acid. agents, binders such as starches or gelatins, glidants such as magnesium stearate or talc and / or agents for obtaining a depot effect such as carboxylpolymethylene, carboxylmethylcellulose, celluloseacetatophthalate or polyvinyl acetate. The tablets may also consist of several layers.

Correspondingly, dragees may be prepared by coating cores prepared analogously to tablets with agents commonly employed in dragee coating, for example polyvinylpyrrolidone or shellac, gum, talc, titanium oxide or sugar. Here, the coatings of the tablets may also consist of several layers, and the active substances mentioned above may be employed in the tablets.

Solutions or suspensions with the compounds according to the invention of general formula I may additionally contain sweetening agents such as saccharin, cyclamate or sugar as well as flavorings such as vanillin or orange extract. They may further contain suspending agents such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

Compounds of formula I contained in capsules may be prepared, for example, by mixing the compound (s) of formula I with an inert carrier such as lactose or sorbite and encapsulating in gelatin capsules.

The prodrugs according to the invention may be synthesized according to the following examples, which serve to further elucidate the invention without limiting it.

The corresponding sulfamoyl heteroaryl carboxylic acids are commercially obtainable or may be prepared by methods known in the art from sulfonic acids or derivatives thereof. Non-commercially available binding agents may be synthesized as described below by way of example. 6-sulfamoylnicotinic acid

5 g of 6-thionicotinic acid are dissolved in 41 ml of concentrated hydrochloric acid and 9 ml of water. The solution is cooled to 0-5 ° C and introduced over 4 hours by chlorine. Thereafter, the reaction solution is poured into 100 g of ice, the precipitated substance is filtered off and added to 100 ml of cold concentrated NH 3 solution. After one hour, it is concentrated to 1/3 and acidified with HCl to pH = 3. The precipitated substance is filtered off under suction, washed with water and dried. Next, purification by column chromatography is performed. 6-Sulfamoylnicotinic acid is obtained.

1H-NMR (DMSO-d6): 7.62 (s, 2 H, NH 2); 8.03 (m, 1H, CH); 8.50 (m, 1H, CH); 9.08 (m, 1H, CH).

5-Sulfamoylnicotinic Acid

1.) 3-picolin-5-sulfonic acid 200 Ml of oil (25%) is introduced. 97 ml of β-picolino are added by dripping under cooling. 3.12 g of HgSO4 is added at 40 ° C and then heated for 16 hours at 225-235 ° C. About 100 ml H 2 SO 4 are then distilled off (160 ° C, 2 mbar). It is then added to 400 g of ice and diluted with 2 l of water. It is then neutralized with CaCO3. Inorganic components are filtered off and the residue is washed with 2 l of boiling water. The aqueous solution is concentrated and the residue is chromatographed with silica gel. Β-picolin-5-sulfonic acid is obtained.

1H-NMR (DMSO-d6): 2.31 (s, 3 H, CH 3); 7.75 (s, 1H, CH); 8.36 (s, 1H, CH); 8.57 (s, 1H, CH). 2.) 5-sulfamoyl-3-picoline

3.5 G of β-ρϊοοΙίη-δ-ευΙίόηϊοο acid are mixed with 6.5 g of PCI5 and 2.5 ml of POCI3 under inert gas and heated for 3 hours at 120 ° C. POCl 3 is separated by vacuum distillation and 3 ml of ice water under cooling is added. The mixture is stirred in 150 ml NH 3 solution and the solution is concentrated to dryness. It is extracted with MeOH and the product obtained after concentration is purified by silica gel column chromatography. 5-Sulfamoyl-3-picoline is obtained.

1H-NMR (DMSO-d6): 2.39 (s, 3 H, CH 3); 7.56 (s, 2 H, NH 2); 8.00 (s, 1H, CH); 8.62 (s, 1H, CH); 8.77 (s, 1H, CH).

3.) 5-Sulfamoylnicotinic Acid

8.0 g of 5-sulfamoyl-3-picoline is introduced into 250 ml of water. After addition of 12.5 g of KMnO4, it is heated to 70 ° C. After decolouration 12.5 g of It is heated for 12 hours at 70 DEG C. It is hot filtered and concentrated to approximately 20 ml It is acidulated (pH ~ 2) with 10% HCl The cold crystallized substance is filtered off under suction, washed with water and dried 5-sulfamoylnicotinic acid is obtained.

1H-NMR (DMSO-d6): 7.76 (s, 2 H, NH 2); 8.62 (m, 1H, CH); 9.15 (m, 1H, CH); 9.23 (m, 1H, CH). Synthesis Examples Example 1

3-tert-Butyldimethylsilyloxystra-6,5-sulfamoylnicotinate-1,3.5 (10) -trien-17B-yl 0.5 G of 3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-οΙ e 0 0.5 g of 6-sulfamoylnicotinic acid is dissolved in 7 ml of pyridine under argon. Then 0.1 g p-Tos-OH is added and lastly at 0 ° C 0.5 g DCC. The reaction mixture is stirred for 48 hours at room temperature. For processing 40 ml of water are added and adjusted to pH ~ 6 with 10% HCl. The precipitated substance is filtered off, washed with water and dried. It is purified by silica gel chromatography. 3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-yl 6'-sulfamoyl nicotinate is obtained. 1H-NMR (DMSO-d6): 0.16 (s, 6 δ, SiMe), 0.938 (s, 9 δ, t-Bu), 0.944 (s, 3 H, 18-Me), 4.90 (t , 1 δ, 17-H), 6.50-7.15 (3 m, 3 H1 CHAr), 7.69 (s, 2H, NH 2), 8.06, 8.55, 9.16 (3 m , 3H, CHpy).

Example 2

3-Hydroxystra-1,3,5 (10) -trien-173-yl 6'-sulfamoyl nicotinate (1) 300 mg 3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien 6'-sulfamoylnicotinate -17β-yl are dissolved in 20 ml of THF. 250 mg TBAF is added under stirring at room temperature. After one hour, 20 ml of water is introduced. The substance is extracted with acetic ester.

The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered, concentrated and chromatographed on silica gel. 3-Hydroxystra-1,3,5 (10) -trien-17β-yl 6'-sulfamoylnicotinate is obtained. 1H-NMR (DMSO-d6): 0.94 (s, 3 H, 18-Me), 4.90 (t, 1H, 17-H), 6.40-7.15 (3 m, 3 H CH 2) 7.69 (s, 2H, NH 2); 8.06, 8.55 (2 m, 2 H, CHPy), 9.02 (s, 1 H, 3 OH), 9.17 (1 s, 1 H, CHPy).

Example 3

3-tert-Butyldimethylsilyloxystra-5'-sulfamoylnicotinate-1,3.5 (10) -trien-176-yl 0.55 G of 3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-οl and 0 55 g of 5-sulfamoylnicotinic acid are dissolved in 7 ml of pyridine under argon. Then 0.12 g of p-Tos-OH is added and lastly at 0 ° C 0.55 g of DCC. The reaction mixture is stirred for 48 hours at room temperature. For processing 40 ml of water are added and adjusted to pH ~ 6 with 10% HCl. The precipitated substance is filtered off, washed with water and dried. It is purified by silica gel chromatography. 3-tert-Butyldimethyl-silyloxystra-1,3,5 (10) -trien-17β-yl 5'-sulfamoyl nicotinate is obtained.

1H-NMR (DMSO-d6): 0.16 (s, 6 H, SiMe), 0.94 (s, 9 H, t-Bu), 0.95 (s, 3 H, 18-Me), 4 , 92 (t, 1H, 17-H), 6.5-7.2 (3 m, 3 H, CHAr), 7.79 (s, 2 H, NH 2), 8.6-9.3 ( 3 m, 3 H, CHpy).

Example 4

3-Hydroxysteine-5,5-Sulfamoyl nicotinate-3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-5,5-sulfamoyl nicotinate are dissolved in 20 ml of THF 220 mg of TBAF are added under stirring at room temperature After one hour 15 ml of water are introduced The substance is extracted with acetic ester The organic phase is washed with saturated solution of NaCl, dried over MgSO4, filtered, concentrated and chromatographed on silica gel 3-Hydroxystra-1,3,5 (10) -trien-17β-yl 5'-sulfamoylnicotinate is obtained.

1H-NMR (DMSO-d6): 0.94 (s, 3 H, 18-Me), 4.91 (t, 1 H, 17-H), 6.4-7.1 (3 m, 3 H CH 2) 7.92 (s, 2H, NH 2); 8.61 (s, 1H, CHPy), 9.00 (s, 1H, 3-OH), 9.17, 9.26 (2s, 2H, CHpy).

Example 5

3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-yl 2'-ethyl-5'-sulfamoylthiophene-3'-carboxylate

0.75 G of 3-tert-Butyldimethylsilyloxyester-1,3,5 (10) -trien-17β-οΙ and 0.8 g of 5- (aminosulfonyl) -2-ethyl-3-thiophenecarboxylic acid are dissolved in 10 ml of pyridine under argon. Then 0.2 g p-Tos-OH is added and lastly at 0 ° C 0.75 g DCC. The reaction mixture is stirred for 48 hours at room temperature. For processing 60 ml of water are added and adjusted to pH ~ 6 with 10% HCl. The precipitated substance is filtered off, washed with water and dried. It is purified by silica gel chromatography. 3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-yl 2'-ethyl-5'-sulfamoylthiophen-3'-carboxylate is obtained.

1H-NMR (CDCl3): 0.19 (s, 6 H, SiMe), 0.92 (s, 3 H, 18-Me), 0.97 (s, 9 H, t-Bu), 1.34 (t, 3 H, Et), 3.26 (q, 2 H, Et), 4.86 (t, 1 H, 17-H), 5.12 (s, 2 H, NH 2), 6.50 -7.15 (3m, 3H, CHAr), 7.92 (s, 1H, CHrh).

Example 6

3-Hydroxystra-1,3,5 (10) -trien-17B-yl 2'-Ethyl-5'-sulfamoylthiophene-3'-carboxylate (3)

440 mg of 3-tert-Butyldimethylsilyloxyste-1,3,5 (10) -trien-17β-yl 2'-ethyl-5'-sulfamoylthiophene-3'-carboxylate are dissolved in 20 ml of THF. 400 mg TBAF is added under stirring at room temperature. After one hour 20 ml of water is introduced. The reaction mixture is concentrated and the precipitated substance is filtered off under suction, washed with water and chromatographed on silica gel. 3-Hydroxystra-1,3,5 (10) -trien-17β-yl 2'-2'-ethyl-5'-sulfamoylthiophene-3'-carboxylate (3) is obtained. 1H-NMR (DMSO-d6): 0.89 (s, 3 H, 18-Me), 1.27 (t, 3 H, Et), 3.20 (q, 2 H, Et), 4.79 (t, 1 H, 17-H), 6.35-7.05 (3 m, 3 H, CH Ar), 7.72 (s, 1H, CHTh), 7.76 (s, 2 H, NH 2 ), 9.01 (s, 1H, 3-OH).

Example 7

3-tert-Butyldimethylsilyloxiestras-2'-Bromo-5'-sulfamoylthiophene-3'-carboxylate 1.3.5 (10) -trien-17β-yl

0.75 G of 3-tert-Butyldimethylsilyloxyester-1,3,5 (10) -trien-17β-ol and 0.8 g of 5- (aminosulfonyl) -2-bromo-3-thiophenecarboxylic acid are dissolved in 10 ml of pyridine under argon. Then 0.2 g p-Tos-OH is added and lastly at 0 ° C 0.75 g DCC. The reaction mixture is stirred for 48 hours at room temperature. For processing 70 ml of water are added and adjusted to pH ~ 6 with 10% HCl. The precipitated substance is filtered off, washed with water and dried. It is purified by silica gel chromatography. 3-tert-Butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-yl 2'-bromo-5'-sulfamoylthiophene-3'-carboxylate is obtained. 1H-NMR (CDCl3): 0.19 (s, 6 H, SiMe), 0.94 (s, 3 H, 18-Me), 0.97 (s, 9 H, t-Bu), 4.88 (t, 1 H, 17-H), 5.22 (s, 2H, NH 2), 6.50-7.10 (3 m, 3 H, CH Ar), 7.85 (s, 1 H, CHTh) . Example 8

3-Hydroxystra-1,3.5 (1 OVtrien-17β-yl) 2'-Bromo-5'-sulfamoylthiophene-3'-carboxylate (4)

330 mg of 3-tert-Butyldimethylsilyloxyste-1,3,5 (10) -trien-17β-yl 2'-bromo-5'-sulfamoylthiophen-3'-carboxylate are dissolved in 30 ml of THF. Under stirring, 300 mg TBAF is added at room temperature. After one hour 30 ml of water is introduced. The reaction mixture is concentrated and the precipitated substance is filtered off under suction, washed with water and chromatographed on silica gel. 3-Hydroxystra-1,3,5 (10) -trien-17β-yl 2'-bromo-5'-sulfamoylthiophene-3'-carboxylate is obtained (4). 1H-NMR (DMSO-d6): 0.96 (s, 3 H, 18-Me), 4.84 (t, 1H, 17-H), 6.40-7.15 (3 m, 3 H , CHAr), 7.75 (s, 1H, CHTh), 8.05 (s, 2H, NH 2), 9.01 (s, 1H, 3-OH). Example 9

3-Oxoandrost-4-en-17β-yl 6'-sulfamoylnicotinate (5)

0.4 G of testosterone is dissolved in 2 ml of pyridine. After addition of 0.4 g of 6-sulfamoylnicotinic acid, 50 mg of p-toluenesulfonic acid and 0.4 g of di-cyclohexylcarbodiimide (DCC), it is stirred for 72 hours at room temperature. Next, 10 ml of water is added. It is slightly acidified (pH = 5) with 10% HCl. The precipitate is filtered off and washed twice with saturated NaHCO 3 solution and water. The dried residue is extracted with acetic ester. The organic phase is washed with 10% NaHCO3 solution and saturated NaCl solution, dried over MgSO4, filtered, concentrated and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 6'-sulfamoyl nicotinate (5) is obtained.

1H-NMR (DMSO-d6): 0.95 (s, 3 H, Me); 1.17 (s, 3 H, Me); 5.64 (s, 1H, 4-H); 7.68 (s, 2 H, NH 2); 8.06, 8.53, 9.15 (3 m, 3 H, CHAr).

Example 10

3-Oxoandrost-4-en-173-yl 5'-sulfamoylnicotinate (6)

0.4 G of testosterone is dissolved in 2 ml of pyridine. After addition of 0.4 g of 5-sulfamoylnicotinic acid, 50 mg of p-toluenesulfonic acid and 0.4 g of dicyclohexylcarbodiimide (DCC), it is stirred for 72 hours at room temperature. Next, 10 ml of water is added. It is slightly acidified (pH = 5) with 10% HCl. The precipitate is filtered off and washed 2x with saturated NaHCO 3 solution and water. The dried residue is extracted with acetic ester. The organic phase is washed with 10% NaHCO3 solution and saturated NaCl solution, dried over MgSO4, filtered, concentrated and chromatographed on silica gel. 3-Oxoandrost-4-en-17β-yl 5'-sulfamoyl nicotinate is obtained (6).

1H-NMR (DMSO-d6): 0.96 (s, 3 H, Me); 1.17 (s, 3 H, Me); 5.64 (s, 1H, 4-H); 7.76 (s, 2 H, NH 2); 8.59, 9.17, 9.24 (3 s, 3 H, CH "Ar).

Example 11

3-tert-Butyldimethylsilyloxyester-N-methyl-5'-sulfamoyl-1H-pyrrol-2'-carboxylate 1.3.5 (10) -trien-17B-yl

0.50 g of 3-tert-Butyldimethylsilyloxyester-1,3,5 (10) -trien-17β-οl and 0.50 g of N-methyl-5'-sulfamoyl-1H-pyrrol-2'-carboxylic acid are dissolved in 7 ml of pyridine under argon. Then 0.12 g of p-Tos-OH is added and lastly at 0 ° C 0.5 g of DCC. After 48 hours, the reaction mixture is stirred at room temperature. For processing 40 ml of water are added and adjusted to pH ~ 6 with 10% HCl. The precipitated substance is filtered off, washed with water and dried. It is purified by silica gel chromatography. N-Methyl-5'-sulfamoyl-1H-pyrrol-2'-carboxylate of 3-tert-butyldimethylsilyloxystra-1,3,5 (10) -trien-17β-yl is obtained.

1H-NMR (CDCl3): 0.18 (s, 6 H, SiMe), 0.92 (s, 3 H, 18-Me), 0.97 (s, 9 H, t-Bu), 3.95 (s, 3 H, NMe), 4.83 (t, 1 H, 17-H), 4.95 (s, 2 H, NH 2), 6.5-7.3 (5 m, 5H, CHar ).

Example 12

3-Hydroxystra-1,3,5 (10) -trien-17β-yl N-methyl-5'-sulfamoyl-1H-pyrrol-2'-carboxylate

300 mg of 3-tert-Butyldimethylsilyloxyste-1,3,5 (10) -trieri-17β-yl N-methyl-5'-sulfamoyl-1H-pyrrol-2'-carboxylate are dissolved in 20 ml of THF. 250 mg TBAF is added under stirring at room temperature. After one hour, 20 ml of water is introduced. The reaction mixture is concentrated and the precipitated substance is filtered off under suction, washed with water and chromatographed on silica gel. 3-Hydroxystra-1,3,5 (10) -trien-17β-yl N-methyl-5'-sulfamoyl-1H-pyrrol-2'-carboxylate is obtained. 1H-NMR (DMSOd6): 0.89 (s, 3 H1 18-Me), 3.88 (s, 3 H, NMe), 4.76 (t, 1 H, 17-H), 7.12 ( s, 2 H, NH 2), 8.99 (s, 1H, 3-OH).

Claims (21)

1. Sulfonamide prodrugs of the general formula I wherein X is an unsubstituted or substituted heteroaromatic radical or an alkyl and drug heteroaromatic is a pharmaceutical active substance which through an OH group may form an ester of carboxylic acid such as steroids, antimalarial agents, nucleosides, isoflavonoids, which may eventually be substituted. Sulfonamide prodrugs according to claim 1, wherein X is a pyridine radical or a thiophene radical. Sulfamoyl sulfonate prodrugs according to claim 1, wherein drug means steroid such as estrogen, for example estradiol or estriol or androgen, for example testosterone, MENT (7-methyl-19-nortestosterone), eF -MENT (11-Fluoro-7α-methyl-19-nortestosterone, nandrolon, DHT (dihydrotestosterone) or gestagenes, for example, norethistone, dienogest or Ievonorgestrel corticosteroids, for example cortisol antimalarial agents, for example quinine, quinoconidine, hydroxychloroquine, primaquine, mefloquine, or nucleosides consisting of a sugar such as ribose or dosoxyribose and a base such as adenine, guanine, cytosine, thymine or uracil, in addition to zidovudine, brivudine, indinavir, nelfinavir isoflavonoids, for example genistein. 4. Sulfamoylsulfonate prodrugs according to Claims 1 and 2, namely -1) 3-hydroxystra-1,3,5 (10) -trien-17β-yl 6'-sulfamoylnicotinate (1), -2) 3-Hydroxystra-1,3,5 (10) -trien-17β-yl (2) 5'-sulfamoylnicotinate-3'-3'-ethyl-5'-sulfamoylthiophene-3'-carboxylate hydroxystra-1,3,5 (10) -trien-17β-yl (3), -4) 3-hydroxiestra-1,3,5-2'-bromo-5'-sulfamoylthiophene-3'-carboxylate (10) 3-oxoandrost-4-en-17β-yl-5-trien-17β-yl (4), -5) 6'-sulfamoylnicotinate (3), -6) 5-oxoandrost-4-en-17β-5-sulfamoylnicotinate 3-oxoandrost-4-en-17β-yl, -8) 5'-sulfamoylthiophene-3'-carboxylate-6-yl, -7) 2'-ethyl-5'-sulfamoyl-thiophene-3'-carboxylate 3-hydroxiestra-1,3,5 (10) -trien-17β-β, -10) 6'-3-oxoandrost-4-en-17β-yl, -9) 5'-sulfamoylthiophene-3'-carboxylate 3-oxoandrost-4-en-17p-3-hydroxystra-1'-sulfamoylthiophene-3'-carboxylate -sulfamoylthiophen-3'-carboxylate 3-oxo-7α-methylan 5'-sulfamoyl nicotinate drost-4-en-17β-yl, -13) 3-oxo-7α-methyllandrost-4-en-17β-yl, -14) N-ethyl-5'-sulfamoylthiophene-3 '6'-sulfamoyl nicotinate -hydro-7α-methylandrost-4-en-17β-yl, -15) 3-hydroxiestra-1,3,5-N-methyl-5'-sulfamoyl-1 H -pyrrol-2'-carboxylate ( 10) -trien-17β-yl. Compounds according to one of claims 1, 2 or 4, wherein the active substance is an antimalarial agent such as artether, artester, artessunate, chloroquine, paquine, primaquine, pyretamine, mefloquine, proguanyl, chinconidine, cinconine. , hydroxychloroquine, pamaquine, primaquine, pyrimethamine, quinine or a quinine derivative such as quinine bisulfate, quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, quinine formate, quinine gluconate, quinine iodide, quinine hydrochloride, quinine salicylate or quinine sulfate. Use of the compounds as defined in claim 5 for preventing erythrocyte parasite infestation. Compounds according to one of claims 1 - 6, wherein the desired therapeutic effect occurs by the release, particularly hydrolytic dissociation of the active substance contained in the prodrug or its metabolites. Pharmaceutical composition containing at least one compound of the general formula I as defined in one of claims 1 to 4, and possibly at least one other active substance together with pharmaceutically compatible auxiliary agents and / or vehicles. The pharmaceutical composition of claim 8, wherein the other active substance is a steroidal compound. The pharmaceutical composition of claim 9, wherein the other steroidal compound is a gestagen, antistage or progesterone receptor modulator. The pharmaceutical composition according to claim 10, wherein the contained gestagen is norethisterone, dienogest, drospirenone, ivororgestrel; the antigestagen is mifepriston, onapriston and progesterone receptor modulators is, for example, mesoprogestin as asoprisnil. Use of compounds as defined in one of claims 1 to 7 for the preparation of a medicament. Use according to claim 12 for preparing a medicament for hormone replacement therapy. Use of compounds as defined in claims 1 to 7 for controlling female fertility. Use according to claim 12, for the preparation of a medicament for therapy and prophylaxis of hormone diseases in men and women. Use according to claim 12, for the preparation of a medicament for therapy and prophylaxis of endometriosis, breast carcinomas, prostate carcinomas or hypogonadism. Use according to claim 12, for the preparation of a medicament for therapy and / or prophylaxis of diseases which may be positively influenced by inhibition of carboanhydrase activity. Use according to claim 12, for the preparation of a medicament for therapy and / or prophylaxis of inflammatory and / or allergic diseases. A process for preparing sulfonamide prodrugs of the general formula (I) as defined in claim 1 by reacting a carboxylic acid NH 2 SO 2 -X-COOH of the corresponding heteroaromatic binding agent in the presence of dicyclohexylcarbodiimide or EDC (N- ( 3-dimethylaminopropyl) -N'-ethylcarbodiimide) optionally with a catalyst, with the corresponding active substance or by copulation of a corresponding heteroaromatic binding agent sulfamoyl carboxylic acid chloride with the corresponding active substance in the presence of a base, preferably a base pyridine. A process according to claim 19, wherein the base is pyridine. The process according to claim 20, wherein the catalyst is p-toluenesulfonic acid.