AU2006319381A1

AU2006319381A1 - Heteroaromatic sulfonamide prodrugs

Info

Publication number: AU2006319381A1
Application number: AU2006319381A
Authority: AU
Inventors: Reinhard Nubbemeyer; Ralf Wyrwa
Original assignee: Bayer Schering Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2005-11-30
Filing date: 2006-11-27
Publication date: 2007-06-07
Also published as: DE102005057421A1; CA2632279A1; ZA200805660B; NO20082916L; CN101321535A; JP2009517425A; ECSP088488A; IL191563A0; EA200801209A1; WO2007062875A1; BRPI0619214A2; EP1959964A1; WO2007062875B1; KR20080074197A

Description

VERIFICATION OF TRANSLATION I, Melissa Stanford, a translator with Chillson Translating Service, 3530 Chas Drive, Hampstead, Maryland, 21074, hereby declare as follows: That I am familiar with the German and English languages; That I am capable of translating from German to English; That the translation attached hereto is a true and accurate translation of German language International Application No. PCT/EP2006/011727 titled, "Heteroaromatic Sulfonamide Prodrugs;" That all statements made herein of my own knowledge are true and that all statements made on information and belief are believed to be true; And further that these statements were made with the knowledge that willful false statements and the like so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code and that such willful false statements may jeopardize the validity of the application or any registration resulting therefrom. By Executed this day of 1 M9 '00 Witness_

_

Heteroaromatic sulphonamide prodrugs The invention relates to sulphonamide prodrugs of the 5 general formula (I), 0

NH

2 Drug ' Group Z ( (lb, in which X is a heteroaromatic, to a process for the preparation of these prodrugs, to pharmaceutical 10 compositions comprising these compounds and to their use for the production of orally available medicaments. From WO 01/91797, steroidal compounds are known which are bonded to erythrocytes via a group -SO 2

NR'R

2 and 15 accumulate there. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000:1, preferentially 30-1000:1, such that we can speak of depot formation in the erythrocytes. Owing to the strong bonding of the compounds to the erythrocytes, 20 metabolization during the liver passage is avoided. Disadvantageously, despite reduced metabolization using the dosages indicated, therapy-relevant active compound levels are not afforded. The reasons for this are to be sought in excessively strong binding to erythrocytes, 25 cleavage induced by enzymes and in low solubilities. It is the object of the invention to make available novel prodrugs which are orally available and in comparison to the prior art guarantee a therapy 30 relevant active compound level even at a low dosage.

- 2 This object is achieved by heterocyclic sulphonamide prodrugs of the general formula (I), in which a sulphamoyl radical is bonded to the drug to be released via a heteroaromatic spacer X by means of a carboxylic 5 acid ester bond, in which 0 04-

NH

2 Drug ' GroupZ (I) 10 X is an unsubstituted or substituted heteroaromatic radical or an alkylheteroaromatic and, Drug is a pharmaceutical active compound which can form a carboxylic acid ester by means of an OH group, such as steroids, anti-malarial agents, 15 nucleosides, isoflavanoids, which can optionally be substituted. The sulphonamide prodrugs according to the invention having a heteroaromatic linker X bind to erythrocytes, 20 are readily water-soluble and are cleaved hydro lytically without the participation of enzymes. In the sense of the invention, a heteroaromatic radical is, for example, thiophene, pyridine, pyrrole, furan or 25 alternatively thiophene, pyridine, pyrrole or furan substituted by C 1

_

4 -alkyl or halogen. For substituted heteroaromatics, 2-bromothiophene, 2-ethylthiophene, N methylpyrrole and 2-bromopyridine may be mentioned. 30 C 1

.

4 -Alkyl is a methyl, ethyl, propyl, butyl or isopropyl group.

- 3 The term "halogen atom" is understood in the context of the present invention as meaning a fluorine, chlorine, bromine or iodine atom; a fluorine, chlorine or bromine atom are preferred. 5 The above term "alkylheteroaromatic" is a hetero aromatic bonded to the ester function via a C1- 3 alkylene radical. Heteroaromatics are the groups named under heteroaromatic radical. 10

C

1 3 -Alkylene radical is a methylene, ethylene or propylene bridge. Preferred heteroaromatics are pyridine and thiophene. 15 Preferred compounds are listed below: 1) 3-hydroxyoestra-l,3,5(10)-trien-17p-yl 6'-sulph amoylnicotinate (1), 2) 3-hydroxyoestra-l,3,5(10)-trien-17B-yl 5'-sulph 20 amoylnicotinate (2), 3) 3-hydroxyoestra-l,3,5(10)-trien-17p-yl 2'-ethyl 5'-sulphamoylthiophene-3'-carboxylate (3), 4) 3-hydroxyoestra-l,3,5(10)-trien-17p-yl 2'-bromo 5'-sulphamoylthiophene-3'-carboxylate (4), 25 5) 3-oxoandrost-4-en-17B-yl 6'-sulphamoylnicotinate (5), 6) 3-oxoandrost-4-en-17p-yl 5'-sulphamoylnicotinate (6), 7) 3-oxoandrost-4-en-17p-yl 2'-ethyl-5'-sulphamoyl 30 thiophene-3'-carboxylate, 8) 3-oxoandrost-4-en-17p-yl 5'-sulphamoylthiophene 3'-carboxylate, 9) 3-hydroxyoestra-l,3,5(10)-trien-17p-yl 5'-sulph amoylthiophene-3'-carboxylate, 35 10) 3-hydroxyoestra-l,3,5(10)-trien-17B-yl 6'-sulph amoylthiophene-3'-carboxylate, 11) 3-oxoandrost-4-en-17P-yl 5'-sulphamoylthiophene 3'-carboxylate, - 4 12) 3-oxo-7a-methylandrost-4-en-17p-yl 5'-sulphamoyl nicotinate, 13) 3-oxo-7a-methylandrost-4-en-17p-yl 6'-sulphamoyl nicotinate, 5 14) 3-oxo-7a-methylandrost-4-en-17B-yl N-ethyl-5' sulphamoylthiophene-3'-carboxylate, 15) 3-hydroxyoestra-l,3,5(10)-trien-17p-yl N-methyl 5'-sulphamoyl-1H-pyrrole-2'-carboxylate. 10 The therapeutically relevant drug compound is released from the compounds according to the invention by hydrolysis. In vitro experiments 15 a) Carboanhydrase inhibition Test principle: Photometric determination of the inhibition of human carboanhydrase I or II by sulphonamides or sulphamates on microtitre plates with the aid of the enzymatic 20 conversion of nitrophenyl acetate with a colour change from colourless to yellow. Table 1: IC 50 inhibitory values of human carboanhydrase I 25 CA II CA I Inhibitor IC 5 0 (nM) ICs 0 (nM) Oestradiol 3-sulphamate 34 157 ± 10.6 3-hydroxyoestra-1,3,5(10) trien-17p-yl 6'- 31 2900 sulphamoylnicotinate (1) 3-hydroxyoestra-1,3,5(10) trien-17p-yl 5'- 160 2100 sulphamoylnicotinate (2) 3-oxoandrost-4-en-17p-yl 5' sulphamoylnicotinate 250 2900 (6) -5 3-oxoandrost-4-en-170-yl 6' sulphamoylnicotinate (5) 41 3200 3-hydroxyoestra-1,3,5(10) trien-17p-yl 2'-ethyl-5' sulphamoylthiophene-3'- 42 3400 carboxylate (3) 3-hydroxyoestra-1,3,5(10) trien-17p-yl 2' -bromo-5' sulphamoylthiophene-3'- 47 3300 carboxylate (4) Acetazolamide 61 1200 (known CA inhibitor) 19001 Literature: 1) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997). 5 It was found that the sulphamoyl prodrugs of the general formula (I) according to the invention inhibit carboanhydrase II surprisingly well. From this, a concentration of the prodrugs according to the 10 invention in the erythrocytes can be derived. b) Blood-plasma concentration ratio - test principle and experimental description: The SO 2

-NH

2 group of the substances according to the 15 invention can lead to a concentration in erythrocytes as a result of binding to carboanhydrases. Test principle: Freshly obtained, heparinized blood from a rat is 20 treated with a defined amount of active compound. The active compound concentration in the plasma obtained therefrom is measured against a calibration curve of plasma which is spiked (with a known active compound concentration). The blood-plasma ratio is calculated 25 from the measured concentration and the theoretical concentration.

-6 Table 2: Blood/plasma ratio of selected prodrugs. Blood/plasma Prodrug ratio Oestradiol 3-sulphamate About 50 3-hydroxyoestra-l,3,5(10)-trien 17P-yl 5'-sulphamoylnicotinate (2) 2 3-oxoandrost-4-en-17p-yl 5' sulphamoylnicotinate 5.7 (6) 3-oxoandrost-4-en-17p-yl 6' sulphamoylnicotinate 3.6 (5) 3-hydroxyoestra-1,3,5(10)-trien 17P-yl 2'-ethyl-5' sulphamoylthiophene-3'- 1.8 carboxylate (3) 3-hydroxyoestra-l,3,5(10)-trien 17A-yl 2'-bromo-5' sulphamoylthiophene-3' - 9.5 carboxylate (4) In contrast to the results published in WO 01/91797, 5 the concentration ratios of the compounds according to the invention between erythrocytes and plasma are not in a range from 10-1000:1, but in the range <10:1. This has shown itself as a crucial disadvantage for achieving therapy-relevant active compound levels. It 10 is possible by the choice of suitable linkers to adjust the optimum blood/plasma ratio for a prodrug compound. These test results open up to the compounds of the general formula (I) according to the invention, 15 depending on the definition of "drug", various possibilities for the treatment and/or prophylaxis of different syndromes. For example, for the case where "drug" is a steroid such as an androgen or oestrogen, - 7 the compounds of the general formula (I) can be used in hormone replacement therapy (HRT) in women and in men or in the treatment of hormonally caused diseases in men (carcinoma of the prostate, mammary carcinoma, 5 hypogonadism) and women (endometriosis, mammary carcinoma). Furthermore, the compounds of the general formula (I) according to the invention, in which "drug" is, for example, an androgen or oestrogen, are used for fertility control in men or women. 10 The use of further active compounds mentioned for "drug" such as quinine, chinchonidine, hydroxychloro quine, primaquine or mefloquine concerns the treatment of malaria. Compounds of the general formula (I) according to the 15 invention in which "drug" is a cortisol derivative can be used for the treatment and prophylaxis of inflammatory and/or allergic diseases which are influenced by immunosuppressives and/or antiproliferatives. 20 Prodrugs according to the invention in which "drug" is a nucleoside (zidovudine, brivudine, indinavir, nelfinavir) can be employed for the treatment of viral diseases (herpes, HIV). 25 The invention moreover relates to the pharmaceutical compositions comprising the compounds of the general formula (I) according to the invention and optionally further active compounds, for example gestagens (norethisterone, dienogest, drospirenone, levo 30 norgestrel), anti-gestagens (mifepristone, onapristone) and/or progesterone receptor modulators (mesoprogestins such as asoprisnil). These pharmaceutical compositions and medicaments are 35 preferably administered orally. In addition to customary vehicles and/or diluents, they contain at least one compound of the general formula I.

- 8 Dosage The prodrugs according to the invention can be administered orally. In general, satisfactory results are to be expected 5 both for the treatment and/or prophylaxis of the indications mentioned or for fertility control if the dosage is carried out such that, after administration of the prodrugs, an amount of corresponding active compound ("drug") is released which maximally 10 corresponds to the highest dose of the respective "drug" substance used pharmaceutically. The medicaments of the invention are prepared in a known manner with a suitable dosage using the customary 15 solid or liquid vehicles or diluents and the pharmaceutical excipients customarily used according to the desired type of administration. The preferred preparations consist in an administration form which is suitable for oral administration. Such administration 20 forms are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or alternatively depot forms. Appropriate tablets can be obtained, for example, by 25 mixing the active compound with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium 30 stearate or talc and/or agents for achieving a depot effect such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of a number of layers. 35 Correspondingly, coated tablets can be prepared by coating cores produced analogously to the tablets with agents customarily used in coated tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, -9 talc, titanium oxide or sugar. Here, the coated tablet shells can also consist of a number of layers, where the excipients mentioned above in the case of the tablets can be used. 5 Solutions or suspensions containing the compounds of the general formula I according to the invention can additionally comprise taste-enhancing agents such as saccharin, cyclamate or sugar and also, for example, 10 flavourings such as vanillin or orange extract. They can moreover comprise suspending excipients such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates. 15 The capsules comprising compounds of the general formula I can, for example, be produced by mixing the compound(s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it (them) in gelatine capsules. 20 The prodrugs according to the invention can be synthesized according to the following examples, these serving for more detailed explanation, without restricting the invention. 25 The corresponding sulphamoylheteroarylcarboxylic acids are commercially obtainable or can be prepared from sulphonic acids or their derivatives by means of methods known to the person skilled in the art. Linkers 30 which are not commercially obtainable can be synthesized as described by way of example below. 6-Sulphamoylnicotinic acid 5 g of 6-thionicotinic acid are dissolved in 41 ml of 35 conc. hydrochloric acid and 9 ml of water. The solution is cooled to 0-50C and chlorine is passed in for 4 h. Subsequently, the reaction solution is added to 100 g of ice, and the precipitated substance is filtered off and added to 100 ml of cold conc. NH 3 solution. After - 10 1 h, the mixture is concentrated to 1/3 and acidified to pH = 3 using HC1. The precipitated substance is filtered off with suction, washed with water and dried. Subsequently, purification is carried out by column 5 chromatography. 6-Sulphamoylnicotinic acid is obtained. 'H-NMR (DMSO-d 6 ): 7.62 (s, 2 H, NH 2 ); 8.03 (m, 1 H, CH); 8.50 (m, 1 H, CH); 9.08 (m, 1 H, CH). 5-Sulphamoylnicotinic acid 10 1.) P-Picoline-5-sulphonic acid 200 ml of oleum (25%) are initially introduced. 97 ml of P-picoline are added dropwise with cooling. 3.12 g of HgSO 4 are added at 40 0 C and the mixture is subsequently heated at 225-2350C for 16 h. About 100 ml 15 of H 2 S0 4 are then distilled off (1600C, 2 mbar). The mixture is then added to 400 g of ice and diluted with 2 1 of water. It is subsequently neutralized using CaCO 3 . The mixture is filtered off from inorganic constituents and the residue is washed with 2 1 of 20 boiling water. The aqueous solution is concentrated and the residue is chromatographed on silica gel. 0 Picoline-5-sulphonic acid is obtained. 1 H-NMR (DMSO-d 6 ): 2.31 (s, 3 H, CH 3 ) ; 7.75 (s, 1 H, CH); 8.36 (s, 1 H, CH); 8.57 (s, 1 H, CH). 25 2.) 5-Sulphamoyl-p-picoline 3.5 g of P-picoline-5-sulphonic acid are mixed together with 6.5 g of PC1s and 2.5 ml of POC1 3 under protective gas and the mixture is heated at 1200C for 3 h. The 30 POC1 3 is distilled off in vacuo and 3 ml of ice water are added with cooling. The mixture is stirred into 150 ml of NH 3 soln. and the solution is concentrated to dryness. The residue is extracted with MeOH and the product obtained after concentration is purified by 35 column chromatography on silica gel. 5-Sulphamoyl-p picoline is obtained. IH-NMR (DMSO-d) : 2.39 (s, 3 H, CH 3 ); 7.56 (s, 2 H,

NH

2 ); 8.00 (s, 1 H, CH); 8.62 (s, 1 H, CH); 8.77 (s, 1 H, CH).

- 11 3.) 5-Sulphamoylnicotinic acid 8.0 g of 5-sulphamoyl-p-picoline are initially introduced in 250 ml of water. After addition of 12.5 g 5 of KMnO 4 , the mixture is warmed to 700C. After decolourization, 12.5 g of KMnO 4 are added again and the mixture is warmed to 70 0 C for 12 h. It is filtered hot and concentrated to about 20 ml. The residue is acidified (pH ~ 2) using 10% strength HC1. The 10 substance crystallized in the cold is filtered off with suction, washed with water and dried. 5-Sulph amoylnicotinic acid is obtained. 1 H-NMR (DMSO-d 6 ): 7.76 (s, 2 H, NH 2 ); 8.62 (m, 1 H, CH); 9.15 (m, 1 H, CH); 9.23 (m, 1 H, CH). 15 Synthesis examples Example 1 3-tert-Butyldimethylsilyloxyoestra-l,3,5(10)-trien 20 17P-yl 6'-sulphamoylnicotinate 0.5 g of 3-tert-butyldimethylsilyloxyoestra-l,3,5(10) trien-17p-ol and 0.5 g of 6-sulphamoylnicotinic acid are dissolved in 7 ml of pyridine under argon. Subsequently, 0.1 g of p-Tos-OH and finally, at 0oC, 25 0.5 g of DCC are added. After 48 h, the reaction mixture is stirred at RT. For work-up, 40 ml of water are added and the mixture is adjusted to pH~6 using 10% strength HC1. The precipitated substance is filtered off, washed with water and dried. It is purified by 30 chromatography on silica gel. 3-tert-Butyldimethyl silyloxyoestra-l,3,5(10)-trien-17p-yl 6'-sulphamoyl nicotinate is obtained. 1 H-NMR (DMSO-ds): 0.16 (s, 6 H, SiMe), 0.938 (s, 9 H, t Bu), 0.944 (s, 3 H, 18-Me), 4.90 (t, 1 H, 17-H), 6.50 35 7.15 (3 m, 3 H, CHAr), 7.69 (s, 2H, NH 2 ), 8.06, 8.55, 9.16 (3 m, 3 H, CHpy). Example 2 - 12 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl 6'-sulphamoyl nicotinate (1) 300 mg of 3-tert-butyldimethylsilyloxyoestra-l,3,5(10) trien-17P-yl 6'-sulphamoylnicotinate are dissolved in 5 20 ml of THF. 250 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 washed with satd. NaCl solution, dried over MgSO 4 , filtered, concentrated and chromatographed on 10 silica gel. 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl 6' sulphamoylnicotinate is obtained. 1 H-NMR (DMSO-ds): 0.94 (s, 3 H, 18-Me), 4.90 (t, 1 H, 17-H) , 6.40-7.15 (3 m, 3 H, CHAr) , 7.69 (s, 2 H, NH 2 ) ; 8.06, 8.55 (2 m, 2 H, CHpy), 9.02 (s, 1 H, 3-OH), 9.17 15 (1 s, 1 H, CHpy) . Example 3 3-tert-Butyldimethylsilyloxyoestra-l,3,5(10)-trien 17P-yl 5'-sulphamoylnicotinate 20 0.55 g of 3-tert-butyldimethylsilyloxyoestra-l,3,5(10) trien-17p-ol and 0.55 g of 5-sulphamoylnicotinic acid are dissolved in 7 ml of pyridine under argon. Subsequently, 0.12 g of p-Tos-OH and finally, at 0oC, 0.55 g of DCC are added. After 48 h, the reaction 25 mixture is stirred at RT. For work-up, 40 ml of water are added and the mixture is adjusted to pH~6 using 10% strength HC1. The precipitated substance is filtered off, washed with water and dried. It is purified by chromatography on silica gel. 3-tert-Butyldimethyl 30 silyloxyoestra-1,3,5(10)-trien-17p-yl 5'-sulphamoyl nicotinate is obtained. 1 H-NMR (DMSO-d 6 ) 0.16 (s, 6 H, SiMe), 0.94 (s, 9 H, t Bu), 0.95 (s, 3 H, 18-Me), 4.92 (t, 1 H, 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, 35 CHpY). Example 4 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl 5'-sulphamoyl nicotinate (2) - 13 250 mg of 3-tert-butyldimethylsilyloxyoestra-l,3,5(10) trien-173-yl 5'-sulphamoylnicotinate are dissolved in 20 ml of THF. 220 mg of TBAF are added with stirring at RT. After 1 hour, 15 ml of water are stirred in. The 5 substance is extracted with ethyl acetate. The organic phase is washed with satd. NaCI solution, dried over MgSO 4 , filtered, concentrated and chromatographed on silica gel. 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl 5' sulphamoylnicotinate is obtained. 10 IH-NMR (DMSO-d 6 ) : 0.94 (s, 3 H, 18-Me), 4.91 (t, 1 H, 17-H), 6.4-7.1 (3 m, 3 H, CHAr), 7.92 (s, 2 H, NH 2 ); 8.61 (s, 1 H, CHp,), 9.00 (s, 1 H, 3-OH), 9.17, 9.26 (2 s, 2 H, CHg,). Example 5 15 3-tert-Butyldimethylsilyloxyoestra-l,3,5(10)-trien 1 7 P-yl 2'-ethyl-5'-sulphamoylthiophene-3'-carboxylate 0.75 g of 3-tert-butyldimethylsilyloxyoestra-1,3,5(10) trien-17B-ol and 0.8 g of 5-(aminosulphonyl)-2-ethyl-3 thiophenecarboxylic acid are dissolved in 10 ml of 20 pyridine under argon. Subsequently, 0.2 g of p-Tos-OH and finally, at 0oC, 0.75 g of DCC are added. After 48 h, the reaction mixture is stirred at RT. For work up, 60 ml of water are added and the mixture is adjusted to pH~6 using 10% strength HC1. The 25 precipitated substance is filtered off, washed with water and dried. It is purified by chromatography on silica gel. 3-tert-Butyldimethylsilyloxyoestra 1,3,5(10)-trien-170-yl 2'-ethyl-5'-sulphamoylthiophene 3'-carboxylate is obtained. 30 'H-NMR (CDC1 3 ): 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 (3 m, 3 H, CHAr), 7.92 (s, 1 H, CHTh). 35 Example 6 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl 2'-ethyl-5' sulphamoylthiophene-3'-carboxylate (3) 440 mg of 3-tert-butyldimethylsilyloxyoestra-l,3,5(10) trien-17P-yl 2'-ethyl-5'-sulphamoylthiophene-3'- - 14 carboxylate are dissolved in 20 ml of THF. 400 mg of TBAF are added with stirring at RT. After 1 hour, 20 ml of water are stirred in. The reaction mixture is concentrated and the precipitated substance is filtered 5 off with suction, washed with water and chromatographed on silica gel. 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl 2'-ethyl-5'-sulphamoylthiophene-3'-carboxylate (3) is obtained. 1H-NMR (DMSO-d 6 ) : 0.89 (s, 3 H, 18-Me), 1.27 (t, 3 H, 10 Et), 3.20 (q, 2 H, Et), 4.79 (t, 1 H, 17-H), 6.35-7.05 (3 m, 3 H, CHAr), 7.72 (s, 1 H, CHTh), 7.76 (s, 2 H,

NH

2 ), 9.01 (s, 1H, 3-OH). 15 Example 7 3-tert-Butyldimethylsilyloxyoestra-1,3,5(10)-trien 17P-yl 2'-bromo-5'-sulphamoylthiophene-3'-carboxylate 0.75 g of 3-tert-butyldimethylsilyloxyoestra-1,3,5(10) trien-17p-ol and 0.8 g of 5-(aminosulphonyl)-2-bromo-3 20 thiophenecarboxylic acid are dissolved in 10 ml of pyridine under argon. Subsequently, 0.2 g of p-Tos-OH and finally, at 0OC, 0.75 g of DCC are added. After 48 h, the reaction mixture is stirred at RT. For work up, 70 ml of water are added and the mixture is 25 adjusted to pH~6 using 10% strength HC1. The precipitated substance is filtered off, washed with water and dried. It is purified by chromatography on silica gel. 3-tert-Butyldimethylsilyloxyoestra 1,3,5(10)-trien-17P-yl 2'-bromo-5'-sulphamoylthiophene 30 3'-carboxylate is obtained. 1 H-NMR (CDC1 3 ): 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, CHAr), 7.85 (s, 1 H, CHTh). 35 Example 8 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl 2'-bromo-5' sulphamoylthiophene-3'-carboxylate (4) - 15 330 mg of 3-tert-butyldimethylsilyloxyoestra-1,3,5(10) trien-17P-yl 2'-bromo-5'-sulphamoylthiophene-3' carboxylate are dissolved in 30 ml of THF. 300 mg of TBAF are added with stirring at RT. After 1 hour, 30 ml 5 of water are stirred in. The reaction mixture is concentrated and the precipitated substance is filtered off with suction, washed with water and chromatographed on silica gel. 3-Hydroxyoestra-1,3,5(10)-trien-17B-yl 2'-bromo-5'-sulphamoylthiophene-3'-carboxylate (4) is 10 obtained. IH-NMR (DMSO-d 6 ): 0.96 (s, 3 H, 18-Me), 4.84 (t, 1 H, 17-H), 6.40-7.15 (3 m, 3 H, CHAr), 7.75 (s, 1 H, CHTh), 8.05 (s, 2 H, NH 2 ), 9.01 (s, 1H, 3-OH). 15 Example 9 3-Oxoandrost-4-en-17p-yl 6'-sulphamoylnicotinate (5) 0.4 g of testosterone is dissolved in 2 ml of pyridine. After addition of 0.4 g of 6-sulphamoylnicotinic acid, 50 mg of p-toluenesulphonic acid and 0.4 g of di 20 cyclohexylcarbodiimide (DCC), the mixture is stirred at room temperature for 72 hours. Subsequently, 10 ml of water are added. The mixture is acidified slightly (pH = 5) using 10% strength HC1. The precipitate is filtered off and washed 2x with satd. NaHCO 3 soln. and 25 water. The dried residue is extracted with ethyl acetate. The organic phase is washed with 10% strength NaHCO 3 solution and satd. NaCl solution, dried over

MGSO

4 , filtered, concentrated and chromatographed on silica gel. 3-Oxoandrost-4-en-17p-yl 6'-sulphamoyl 30 nicotinate (5) is obtained. 1 H-NMR (DMSO-d 6 ): 0.95 (s, 3 H, Me); 1.17 (s, 3 H, Me); 5.64 (s, 1 H, 4-H); 7.68 (s, 2 H, NH 2 ); 8.06, 8.53, 9.15 (3 m, 3 H, CHAr). 35 Example 10 3-Oxoandrost-4-en-17p-yl 5'-sulphamoylnicotinate (6) 0.4 g of testosterone is dissolved in 2 ml of pyridine. After addition of 0.4 g of 5-sulphamoylnicotinic acid, 50 mg of p-toluenesulphonic acid and 0.4 g of di- - 16 cyclohexylcarbodiimide (DCC), the mixture is stirred at room temperature for 72 hours. Subsequently, 10 ml of water are added. The mixture is slightly acidified (pH = 5) using 10% strength HC1. The precipitate is 5 filtered off and washed 2x with satd. NaHCO 3 soln. and water. The dried residue is extracted with ethyl acetate. The organic phase is washed with 10% strength NaHC0 3 solution and satd. NaCl solution, dried over

MGSO

4 , filtered, concentrated and chromatographed on 10 silica gel. 3-Oxoandrost-4-en-17p-yl 5'-sulphamoyl nicotinate (6) is obtained. 'H-NMR (DMSO-d 6 ): 0.96 (s, 3 H, Me); 1.17 (s, 3 H, Me); 5.64 (s, 1 H, 4-H); 7.76 (s, 2 H, NH 2 ); 8.59, 9.17, 9.24 (3 s, 3 H, CHAr) 15 Example 11 3-tert-Butyldimethylsilyloxyoestra-l,3,5(10)-trien 17P-yl N-methyl-5'-sulphamoyl-lH-pyrrole-2'-carboxylate 0.50 g of 3-tert-butyldimethylsilyloxyoestra-l,3,5(10) 20 trien-17p-ol and 0.50 g of N-methyl-5'-sulphamoyl-lH pyrrole-2'-carboxylic acid are dissolved in 7 ml of pyridine under argon. Subsequently, 0.12 g of p-Tos-OH and finally, at 00C, 0.5 g of DCC are added. After 48 h, the reaction mixture is stirred at RT. For work 25 up, 40 ml of water are added and the mixture is adjusted to pH~6 using 10% strength HC1. The precipitated substance is filtered off, washed with water and dried. It is purified by chromatography on silica gel. 3-tert-Butyldimethylsilyloxyoestra 30 1,3,5(10)-trien-17P-yl N-methyl-5'-sulphamoyl-lH pyrrole-2'-carboxylate is obtained. 'H-NMR (CDC1 3 ): 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, 5 H, 35 CHAr) Example 12 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl N-methyl-5' sulphamoyl-lH-pyrrole-2'-carboxylate - 17 300 mg of 3-tert-butyldimethylsilyloxyoestra-1,3,5(10) trien-17B-yl N-methyl-5'-sulphamoyl-1H-pyrrole-2' carboxylate are dissolved in 20 ml of THF. 250 mg of TBAF are added with stirring at RT. After 1 hour, 20 ml 5 of water are stirred in. The reaction mixture is concentrated and the precipitated substance is filtered off with suction, washed with water and chromatographed on silica gel. 3-Hydroxyoestra-l,3,5(10)-trien-17p-yl N-methyl-5'-sulphamoyl-1H-pyrrole-2'-carboxylate is 10 obtained. 1 H-NMR (DMSO-d 6 ): 0.89 (s, 3 H, 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

1. Sulphonamide prodrugs of the general formula I 0 O NH

2 Drug Group Z (U), 5 in which X is an unsubstituted or substituted heteroaromatic radical or an alkylheteroaromatic and, Drug is a pharmaceutical active compound which can form 10 a carboxylic acid ester by means of an OH group, such as steroids, anti-malarial agents, nucleosides, isoflavanoids, which can optionally be substituted. 15 2. Sulphonamide prodrugs according to Claim 1, where X is a pyridine or a thiophene radical.

3. Sulphamoylsulphonate prodrugs according to Claim 1, where 20 Drug is steroids such as oestrogens, for example oestradiol or oestriol or androgens, for example testosterone, MENT (7a-methyl-19-nor testosterone), eF-MENT (11-fluoro-7a-methyl-19 nortestosterone), nandrolone, DHT (dihydro 25 testosterone) or gestagens, for example norethisterone, dienogest or levonorgestrel corticoids, for example cortisol anti-malarial agents, for example quinine, 30 chinchonidine, hydroxychloroquine, primaquine, mefloquine or - 19 nucleosides consisting of a sugar such as ribose or deoxyribose and of a base such as adenine, guanine, cytosine, thymine or uracil, furthermore zidovudine, brivudine, indinavir, nelfinavir 5 isoflavanoids, for example genistein.

4. Sulphamoylsulphonate prodrugs according to Claim 1 or 2, namely 1) 3-hydroxyoestra-1,3,5(10)-trien-17p-yl 6' 10 sulphamoylnicotinate (1), 2) 3-hydroxyoestra-1,3,5(10)-trien-17p-yl 5' sulphamoylnicotinate (2), 3) 3-hydroxyoestra-l,3,5(10)-trien-17p-yl 2' ethyl-5'-sulphamoylthiophene-3'-carboxylate s15 (3), 4) 3-hydroxyoestra-l,3,5(10)-trien-17p-yl 2' bromo-5'-sulphamoylthiophene-3'-carboxylate (4), 5) 3-oxoandrost-4-en-17p-yl 6'-sulphamoyl 20 nicotinate (5), 6) 3-oxoandrost-4-en-17p-yl 5'-sulphamoyl nicotinate (6), 7) 3-oxoandrost-4-en-17p-yl 2'-ethyl-5'-sulph amoylthiophene-3'-carboxylate, 25 8) 3-oxoandrost-4-en-17p-yl 5'-sulph amoylthiophene-3'-carboxylate, 9) 3-hydroxyoestra-l,3,5(10)-trien-17B-yl 5' sulphamoylthiophene-3'-carboxylate, 10)3-hydroxyoestra-l,3,5(10)-trien-17p-yl 6' 30 sulphamoylthiophene-3'-carboxylate, ll)3-oxoandrost-4-en-17B-yl 5'-sulphamoyl thiophene-3'-carboxylate, 12)3-oxo-7a-methylandrost-4-en-17p-yl 5'-sulph amoylnicotinate, 35 13)3-oxo-7a-methylandrost-4-en-17p-yl 6'-sulpha moylnicotinate, 14)3-oxo-7a-methylandrost-4-en-17p-yl N-ethyl-5' sulphamoylthiophene-3'-carboxylate, - 20 15)3-hydroxyoestra-1,3,5(10)-trien-17p-yl N methyl-5'-sulphamoyl-lH-pyrrole-2'-carboxylate.

5. Compounds according to one of Claims 1, 2 or 4, 5 where the active compound is an antimalarial agent such as arteether, artemether, artesunate, chloroquine, pamaquine, primaquine, pyrethamine, mefloquine, proguanil, chinchonidine, cinchonine, hydroxychloroquine, pamaquine, primaquine, 10 pyrimethamine, quinine or a quinine derivative, such as quinine bisulphate, quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethylcarbonate, quinine formate, quinine gluconate, quinine hydroiodide, quinine 15 hydrochloride, quinine salicylate or quinine sulphate.

6. Use of the compounds according to Claim 5 for the prevention of a parasitic attack on erythrocytes. 20

7. Compounds according to one of Claims 1-6, where the therapeutically desired action takes place by release, in particular hydrolytic cleavage, of the active compound contained in the prodrug or its 25 metabolites.

8. Pharmaceutical composition comprising at least one compound of the general formula I according to one of Claims 1 to 4 and optionally at least one 30 further active compound together with pharmaceutically tolerable excipients and/or vehicles.

9. Pharmaceutical composition according to Claim 8, 35 where the further active compound is a steroidal compound.

10. Pharmaceutical composition according to Claim 9, where the further steroidal compound is a - 21 gestagen, anti-gestagen or a progesterone receptor modulator.

11. Pharmaceutical composition according to Claim 10, 5 in which the the gestagens contained are norethisterone, dienogest, drospirenone, levo norgestrel, the anti-gestagens mifepristone, onapristone and progesterone receptor modulators, for example mesoprogestins such as asoprisnil. 10

12. Use of compounds according to one of Claims 1 to 7 for the production of a medicament.

13. Use according to Claim 12 for production of a 15 medicament for hormone replacement therapy.

14. Use of compounds according to Claim 1-7 for female fertility control. 20

15. Use according to Claim 12 for the production of a medicament for the therapy and/or prophylaxis of hormonally caused diseases in men and women.

16. Use according to Claim 12 for the production of a 25 medicament for the therapy and prophylaxis of endometriosis, mammary carcinomas, carcinomas of the prostate or hypogonadism.

17. Use according to Claim 12 for the production of a 30 medicament for the therapy and/or prophylaxis of diseases which can be positively influenced by the inhibition of the carboanhydrase activity.

18. Use according to Claim 12 for the production of a 35 medicament for the therapy and/or prophylaxis of inflammatory and/or allergic diseases.

19. Process for the preparation of the sulphonamide prodrugs of the general formula (I) according to - 22 Claim 1 by reaction of a carboxylic acid NH 2 SO 2 -X COOH of the corresponding heteroaromatic linker in the presence of dicyclohexylcarbodiimide or EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide) 5 optionally using a catalyst, with the appropriate active compound or by coupling of a sulphamoyl carboxylic acid chloride of the corresponding heteroaromatic linker with the appropriate active compound in the presence of a base, preferably 10 pyridine.

20. Process according to Claim 19, where the base is pyridine. 15

21. Process according to Claim 20, where the catalyst is p-toluenesulphonic acid.