DE102005057408A1 - New sulfamoylsulfonate prodrugs e.g. useful for protecting red blood cells from attack by parasites or for hormone replacement therapy, female fertility control or treating hormone-associated diseases - Google Patents

Abstract

Sulfamoylsulfonate prodrugs (I) are new. Sulfamoylsulfonate prodrugs of formula (I) are new. Drug-O-SO 2-X-SO 2NH 2 (I) X : 1-12C alkanediyl, 1-5C perfluoroalkylene, 3-8C cyloalkanediyl, arylene, heteroalkanediyl, 1-4C alkanediylaryl, (1-4C)alkanediyl(3-8C)cycloalkyl or (3-8C)cycloalkanediyl(1-4C)alkyl; Drug : a pharmaceutical agent capable of forming a sulfonate through an OH group. Independent claims are also included for: (1) pharmaceutical composition comprising a prodrug (I) and another active agent; (2) a process for preparing (I). ACTIVITY : Antiparasitic; Protozoacide; Gynecological; Cytostatic; Antiinflammatory; Antiallergic. MECHANISM OF ACTION : None given.

Description

ein Verfahren zur Herstellung dieser Prodrugs, diese Verbindungen enthaltende pharmazeutische Zusammensetzungen und deren Verwendung zur Herstellung oral verfügbarer Arzneimittel.The invention relates to sulfamoylsulfonate prodrugs of the general formula I

a process for the preparation of these prodrugs, pharmaceutical compositions containing these compounds and their use for the preparation of orally available drugs.

WO 01/91797 discloses steroidal compounds which are bound to erythrocytes via a group - SO ₂ NR ¹ R ² and accumulate there. The concentration ratio of the compounds between erythrocytes and plasma is 10-1000: 1, preferably 30-1000: 1, so that one can speak of a deposit formation in the erythrocytes. Strong binding of the compounds to the erythrocytes avoids metabolism during liver passage. Disadvantageously, despite a reduced metabolization with the indicated dosages no therapeutically relevant drug levels are given. Reasons for this are to be found in an excessive binding to erythrocytes, an enzyme-induced cleavage and in low solubilities.

It It is an object of the invention to provide new prodrugs which are administered orally available are and compared to the prior art even at low dosage ensure a therapy-relevant drug level.

These Task is by Sulfamoylsulfonat prodrugs of the general formula (I) solved, in which a sulfamoyl over a spacer X by means of a sulfonate bond to the releasable Drug is bound.

worin
X eine C_1-12-Alkandiyl-, eine C_pF_2p-Gruppe mit p = 1-5, eine C_3-8-Cycloalkandiyl-, eine Arylen-, eine Heteroalkandiyl-, eine C_1-4-Alkandiylaryl-, eine C_1-4-Alkandiyl-C_3-8-Cycloalkyl- oder C_3-8-Cycloalkandiyl-C_1-4-Alkylgruppe sind, und
Drug ein pharmazeutischer Wirkstoff, der über eine OH-Gruppe ein Sulfonat bilden kann, wie Steroide, Antimalariamittel, Nucleoside, Isoflavonoide, welche gegebenenfalls substituiert sein können.Sulfamoylsulfonate prodrugs of the general formula (I) are

wherein
X is a C _1-12 alkanediyl, a C _p F _2p group with p = 1-5, a C _3-8 cycloalkanediyl, an arylene, a heteroalkanediyl, a C _1-4 alkanediylaryl, C _1-4 alkanediyl C _3-8 cycloalkyl or C _3-8 cycloalkanediyl C _1-4 alkyl group, and
Drug a pharmaceutical agent that can form a sulfonate via an OH group, such as steroids, antimalarials, nucleosides, isoflavonoids, which may optionally be substituted.

The sulfamoyl sulfonate compounds according to the invention bind to erythrocytes, are readily soluble in water and become hydrolytic split without the participation of enzymes.

For the purposes of the present invention, "C _1-12 -alkanediyl group" is understood to mean a doubly bonded, branched or straight-chain alkylene radical having up to 12 carbon atoms which may optionally be substituted, for example by halogen atoms, hydroxyl groups, nitrile groups a methane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6 -diyl, octane-1,8-diyl, undecane-1,11-diyl group.

Among C _p F _2p group where p = 1-5 is meant a branched or straight chain perfluorinated alkyl radical having up to 5 carbon atoms in the sense of the present invention. Examples which may be mentioned are a perfluoropropane-1,3-diyl, perfluorobutane-1,4-diyl, perfluoropentane-1,5-diyl group.

The above-mentioned "C _3-8 -cycloalkanediyl group" means according to the invention a double-bonded, mono- or bicyclic, carbocyclic group having 3 to 8 carbon atoms, which may be optionally substituted by halogen atoms, hydroxy groups, nitrile groups, such as with a cyclobutane-1, 3-diyl, cyclopentane-1,3-diyl or a cyclohexane-1,4-diyl group.

The The above-mentioned "arylene group" means according to the invention a double bonded, aromatic mono- to tricyclic, carbocyclic group with 6 to 15 carbon atoms, optionally with halogen atoms, Substituted hydroxy groups, nitrile groups and alkyl groups such as with an m-phenylene, p-phenylene, phenanthrylene or a naphthalene group.

Of the Heteroarylene each comprises 5-16 ring atoms and contains instead of the carbon one or more, identical or different heteroatoms, such as oxygen, nitrogen or sulfur in the ring. Of the Heteroaryl may be mono-, bi- or tricyclic.

For example may be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, Imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Thiadiazolyl, benzofuranyl, benzothienyl, benzothiazole, benzoxazolyl, Benzimidazolyl, indazolyl, indolyl, isoindolyl, pyridyl, pyridazinyl, Pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl.

A Heteroalkandiyl group in the context of the invention is a two-membered, straight-chain or branched, saturated or unsaturated Heteroalkyl radical each having 1-6 carbon atoms and may instead of the One or more carbon atoms, identical or different heteroatoms, such as oxygen, nitrogen or sulfur, such as a bis-ethyleneoxy radical.

The "C _1-4 -arylalkanediyl group" is an aryl group bonded to a skeleton via a C ₁ -C ₄ -alkanediyl group, where the alkanediyl group may be straight-chain or branched, for example benzyl or phenethylene.

The "C _3-8 cycloalkyl-C _1-4 alkanediyl group" means, for example, cycloalkyl- (CH ₂ ) -, cycloalkyl- (C ₂ H ₄ ) -, cycloalkyl- (C ₃ H ₆ ) -, cycloalkyl- (C ₄ H ₈₎ -, cycloalkyl (C ₅ H ₁₀₎ -. cycloalkyl can thereby be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

A "C _1-4 -alkyl-C _3-8 -cycloalkanediyl group" is to be understood as meaning methylcycloalkanediyl, ethylcycloalkanediyl, propylcycloalkanediyl, butylcycloalkanediyl or pentylcycloalkanediyl.

cycloalkanediyl may be cyclopropane-1,3-diyl, cyclobutane-1,4-diyl, cyclopentane-1,5-diyl, Cyclohexane-1,6-diyl, cycloheptane-1,7-diyl or cyclooctane-1,8-diyl be.

Under The term "halogen atom" is used in the context of understood fluorine, chlorine, bromine or iodine atom, preferred are a fluorine, chlorine, bromine atom.

A pharmaceutically active substance which can form a sulfonate via an OH group means according to the invention the following: steroids: Estrogens, for example estradiol or estriol or androgens, for example testosterone, MENT (7α-methyl-19-nortestosterone), eF-MENT (11-fluoro-7α-methyl-19-nortestosterone), nandrolone, DHT (dihydrotestosterone) or progestagens, for example Norethisterone, dienogest or levonorgestrel corticosteroids, for example cortisol Antimalarials: Quinine, chinchonidine, hydroxychloroquine, primaquine, mefloquine or nucleosides: consisting of a sugar such as ribose or deoxyribose and a base such as adenine, guanine, cytosine, thymine or uracil, furthermore zidovudine, brivudine, indinavir, nelfinavir isoflavonoids: genistein

• 1) 3-Hydroxyestra-1,3,5(10)-trien-17β-yl 3'-sulfamoylphenylsulfonat,
• 2) 3-Acetoxyestra-1,3,5(10)-trien-17β-yl 3'-sulfamoylphenylsulfonat,
• 3) 3-tert-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β-yl 3'-sulfamoyl-phenylsulfonat,
• 4) 3-Hydroxyestra-1,3,5(10)-trien-17β-yl 4'-sulfamoylphenylsulfonat,
• 5) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β-yl 3'-sulfamoylphenylsulfonat,
• 6) 3,16α-Dihydroxyestra-1,3,5(10)-trien-17β-yl 3'-sulfamoylphenylsulfonat,
• 7) 3,17β-Dihydroxyestra-1,3,5(10)-trien-16α-yl 3'-sulfamoylphenylsulfonat,
• 8) 3-Benzoyloxyestra-1,3,5(10)-trien-17β-yl 3'-sulfamoylphenylsulfonat,
• 9) Chinin-3'-sulfamoylphenylsulfonat,
• 10) Cinchonidin-3'-sulfamoylphenylsulfonat,
• 11) Zidovudin-3'-sulfamoylphenylsulfonat,
• 12) 3-Oxoandrost-4-en-17β-yl 3'-sulfamoylphenylsulfonat,
• 13) 3-Oxoandrostan-17β-yl 3'-sulfamoylphenylsulfonat,
• 14) 3-Oxo-7α-methylandrost-4-en-17β-yl 3'-sulfamoylphenylsulfonat,
• 15) 3-Oxoestr-4-en-17β-yl 3'-sulfamoylphenylsulfonat
• 16) Brivudin-3'-sulfamoylphenylsulfonat.

Particularly preferred compounds are listed below:

• 1) 3-hydroxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenyl sulfonate,
• 2) 3-acetoxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenyl sulfonate,
• 3) 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoyl-phenyl sulfonate,
• 4) 3-hydroxyestra-1,3,5 (10) -triene-17β-yl 4'-sulfamoylphenyl sulfonate,
• 5) 2-methoxy-3-hydroxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenyl sulfonate,
• 6) 3,16α-dihydroxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenyl sulfonate,
• 7) 3,17β-dihydroxyestra-1,3,5 (10) -triene-16α-yl 3'-sulfamoylphenyl sulfonate,
• 8) 3-benzoyloxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenyl sulfonate,
• 9) quinine-3'-sulfamoylphenyl sulfonate,
• 10) cinchonidine-3'-sulfamoylphenyl sulfonate,
• 11) zidovudine-3'-sulfamoylphenyl sulfonate,
• 12) 3-oxoandrost-4-en-17β-yl 3'-sulfamoylphenyl sulfonate,
• 13) 3-oxoandrostan-17β-yl 3'-sulfamoylphenyl sulfonate,
• 14) 3-oxo-7α-methylandrost-4-en-17β-yl 3'-sulfamoylphenyl sulfonate,
• 15) 3-oxoestr-4-ene-17β-yl 3'-sulfamoylphenylsulfonate
• 16) Brivudine-3'-sulfamoylphenylsulfonate.

Out the compounds of the invention becomes the therapeutically relevant drug compound by hydrolysis released.

In vitro experiments:

Carbonic anhydrase inhibition

Test principle:

• Literatur: ¹) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).

Photometric determination of the inhibition of human carbonic anhydrase I or II by sulfonamides or sulfamates on microtiter plates by means of the enzymatic conversion of nitrophenyl acetate with a color change from colorless to yellow. Table 1: IC ₅₀ inhibitory values of human carbonic anhydrase I

• References: ¹ ) C. Landolfi, M. Marchetti, G. Ciocci, and C. Milanese, Journal of Pharmacological and Toxicological Methods 38, 169-172 (1997).

It it was found that the sulfamoyl sulfonate prodrugs according to the invention the carbonic anhydrase II surprising good inhibit. Leave it an accumulation of the prodrugs according to the invention in the erythrocytes derived.

Physicochemical data

solubility in water

a) Kinetic measurement:

The Compounds of the invention were as 10 mmol DMSO solution in 0.01 M phosphate buffer solution at pH 7.4 and 25 ° C measured with nephelometry and turbidity. When the turbidity was the solution to be tested dropwise to the buffer solution until a precipitate failed.

By Nephelometry became the precipitate in a dilution series (Compounds of the invention in phosphate buffer solution) detected.

b.) Thermodynamic measurement:

The compounds of the invention in solid form were added to an excess of an aqueous buffer system of different pH. It was stirred for 24 h at 25 ° C. After centrifugation, the solution was analyzed by HPLC (HPLC: column: Xterra MS C18 2.5 μm, 30 × 4.6 mm). Two standard gradient systems were used depending on the compounds to be measured:
acidic gradient: A: water / 0.01% trifluoroacetic acid, B: acetonitrile / 0.01%
Trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
Alkaline gradient: A: water / 0.025% ammonia, B: acetonitrile / 0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B.

Table 2: Water solubility

The Compounds of the invention show a higher solubility compared to sulfamate and carboxylic ester prodrugs, which allows a better absorption in the intestine.

hydrolysis

The Compounds of the invention were called DMSO solution in watery Measure buffers of different pH's at 37 ° C.

The quantification was carried out by HPLC (HPLC column: Xterra MS C18 2.5 μm 4.6 × 30 mm) Depending on the test substances to be measured, the following gradient system was used in HPLC:
acidic gradient: A: water / 0.01% trifluoroacetic acid, B: acetonitrile / 0.01%
Trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
alkaline gradient A: water / 0.025% ammonia, B: acetonitrile / 0.025% ammonia - 0 min 20% B, 0-3 min 80% B, 3-5 min 80% B, 5-6 min 20% B. Quantification took place after 1, 2 and after 24 h.

Stability in artificial Gastric juice:

Solutions of Compounds of the invention were in artificial Gastric juice (aqueous NaCl solution with Pepsin, pH ~ 1.2) at 37 ° C incubated.

The quantification was carried out by HPLC (HPLC column: Xterra MS C18 2.5 μm 4.6 × 30 mm) using a gradient system:
A: water / 0.01% trifluoroacetic acid, B: acetonitrile / 0.01% trifluoroacetic acid - 0 min 5% B, 0-3 min 65% B, 3-5 min 65% B, 5-6 min 5% B
The quantification took place after 0.5, 1, 1.5 and 2 h.

Table 3: Hydrolysis / stability in gastric juice

Carbonsäureester are relatively stable in gastric juice (pH ~ 1) and in the intestine (pH ~ 7.4), but are in the intestinal passage through there existing esterases split. While the passage through the stomach is still almost complete stable prodrug before.

The Cleavage of the carboxylic acid esters thus takes place in the intestinal passage and in the liver.

For sulfonic acid esters No enzymes (esterases) are known. Surprising, therefore, was that the sulfonates are nevertheless cleaved, with a simple hydrolysis takes place. Although a slow hydrolysis already in gastric juice and takes place at pH = 7.4, the sulfonates have sufficient stability, the stomach and to pass the intestine. Esterase cleavage takes place in the intestinal wall not happening. The first-pass effect in the liver is bypassed because the sulfonates over the sulfonamide group are bound to erythrocytes.

The Compounds of the invention of the general formula (I) dependent on from the meaning for "drug" use find for the Treatment and / or prophylaxis of various clinical pictures. For example can the compounds of general formula (I) in the event that "drug" is a steroid such as Androgen or estrogen is included in hormone replacement therapy (HRT) of the woman and the man or in the treatment hormonally induced Diseases of man (prostate, breast, hypogonadism) and women (endometriosis, breast cancer). Farther can the compounds of the invention of general formula (I), wherein "drug" for example for an androgen or estrogen stands, find use for the fertility control with husband or wife.

The Use of other drugs mentioned for "drugs" such as quinine, chinchonidine, hydroxychloroquine, primaquine or mefloquine concerns the treatment of malaria. Compounds of the invention of the general formula (I) wherein "drug" means a cortisol derivative may be used for the treatment and prophylaxis of inflammatory and / or allergic diseases, to influence those by immunosuppressants and / or antiproliferativa are to be used.

Prodrugs according to the invention, where "drug" is a nucleoside (zidovudine, Brivudine, indinavir, nelfinavir) may be used for the treatment of viral diseases (Herpes, HIV) are used.

object of the invention are also the pharmaceutical compositions containing the compounds of the invention of the general formula (I) and, if appropriate, further active substances, for example, progestagens (norethisterone, dienogest, drospirenone, Levonorgestrel), antigestagens (mifepristone, onapristone) and / or Progesterone receptor modulators (mesoprogestins such as asoprisnil).

These Pharmaceutical compositions and drugs are preferred administered orally. They contain in addition to conventional carriers and / or diluents at least one compound of general formula I.

dosage

The Prodrugs according to the invention can be administered orally.

in the general are satisfactory results for both the treatment and / or prophylaxis of said indications or for fertility control to be expected if the dosage is such that after administration of the Prodrugs release a lot of the corresponding drug ("drug"), which corresponds at most to the pharmaceutically used maximum dose of the respective "drug substance".

The Medicaments of the invention are mixed with the usual solid or liquid carriers or diluents and usually used pharmaceutical-technical excipients according to the desired Type of administration with a suitable dosage in a known manner produced. The preferred preparations consist 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 depot forms.

Corresponding tablets can be prepared, for example, by mixing the active compound with known excipients, 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 Mag Nesiumstearat or talc and / or agents for obtaining a depot effect such as carboxyl polymethylene, carboxyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate, are obtained. The tablets can also consist of several layers.

Corresponding can Dragees by coating of cores produced analogously to the tablets with usually used in dragee coatings Agents, for example polyvinylpyrrolidone or shellac, gum arabic, Talc, titanium oxide or sugar. It can also the dragee envelope consist of several layers, the top of the tablets mentioned Excipients can be used.

Solutions or Suspensions with the compounds of general Formula I can additionally taste-improving agents such as saccharin, cyclamate or sugar as well as B. flavorings such as vanillin or orange extract. You can Furthermore Suspension adjuvants such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

The Examples of compounds containing general formula I capsules be prepared by the compounds) of the general Formula I with an inert carrier How to mix milk sugar or sorbitol and encapsulate in gelatine capsules.

The Prodrugs according to the invention can be according to the following Synthesize examples, these serve for the further explanation, without the invention limit.

General synthesis regulations

version 1

Reaction with disulfonyl chlorides

A disulfonic acid chloride of the general formula SO ₂ -X-SO ₂ Cl is dissolved in a base, such as pyridine, under protective gas. To the solution is added the appropriate amount of drug substance. The reaction mixture is stirred until complete. Subsequently, the reaction mixture is concentrated in conc. NH ₃ solution stirred. The precipitate is filtered off, washed with water 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, it is concentrated and chromatographed on silica gel. The corresponding sulfamoylsulfonates are obtained.

Variant 2

Reaction with sulfamoylsulfonic acid halides

A drug substance as defined above is dissolved in a base such as pyridine and an inert solvent such as chloroform under inert gas. While cooling, the appropriate amount of a sulfamoylsulfonic acid halide of the general formula NH ₂ SO ₂ -X-SO ₂ Hal is added to the solution. The reaction mixture is stirred until complete. Subsequently, water is added and optionally acidified with an acid such as 10% HCl. It is extracted with an organic solvent such as ethyl acetate, the organic phase washed and dried with a drying agent such as MgSO ₄ . After filtration, it is concentrated and chromatographed on silica gel. The corresponding sulfamoylsulfonates are obtained.

The corresponding sulfamoylsulfonic acid halides or disulfonic acid chlorides are commercially available or by the methods known in the art.

synthesis Examples

example 1

3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenylsulfonate

1.9 g of 1,3-benzenedisulfonyl chloride are dissolved under argon in 5 ml of pyridine. Subsequently, 1.0 g of 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-17β-ol are added. The reaction mixture is concentrated after 2 h in 25 ml. Stirred in ammonia solution. After 10 min is filtered off with suction, washed with water and dried. The residue is purified by chromatography on silica gel. This gives 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenylsulfonate.
¹ H-NMR (DMSO-D ₆ ): 0.14 (s, 6H, SiMe), 0.77 (s, 3H, 18-Me), 0.93 (s, 9H, t-Bu), 4.43 (t, 1H, 17 -H), 7.68 (s, 2H, NH ₂ ).

Example 2

3-Hydroxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenylsulfonate

300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenyl sulfonate are dissolved in 20 ml of THF. With stirring, 200 mg of tetrabutylammonium fluoride are added at RT. After 1 hour, 20 ml of water are stirred. The substance is extracted with ethyl acetate. The organic phase is washed with saturated NaCl solution, dried over MgSO ₄ , filtered, concentrated and chromatographed on silica gel. 3-Hydroxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenyl sulfonate is obtained.
¹ H-NMR (DMSO-d ₆ ): 0.76 (s, 3H, 18-Me), 4.43 (t, 1H, 17-H), 7.68 (s, 2H, NH ₂ ), 8.98 (s, 1H, 3 -OH).

Example 3

3-Oxo-7α-methylestra-4-en-17β-yl 3'-sulfamoylphenyl sulfonate

1.9 g of 1,3-benzenedisulfonyl chloride are dissolved under argon in 5 ml of pyridine. Subsequently, 1.0 g of MENT are added. The reaction mixture is concentrated after 2 h in 25 ml. Stirred in ammonia solution. After 10 min is filtered off with suction, washed with water and dried. The residue is purified by chromatography on silica gel. 3-Oxo-7α-methylestr-4-en-17β-yl 3'-sulfamoylphenyl sulfonate is obtained.
¹ H-NMR (DMSO-D ₆ ): 0.66 (d, 3H, 7-Me), 4.38 (t, 1H, 17-H), 5.69 (s, 1H, 4-H), 7.67 (s, 2H, NH ₂ ), 7.83-8.28 (m, 4H, H-Ar).

Example 4

3-Oxo-androst-4-en-17β-yl 3'-sulfamoylphenylsulfonate

version 1

2.0 g of 1,3-benzenedisulfonyl chloride under argon in 5.5 ml of pyridine solved. Subsequently 1.0 g of testosterone is added. The reaction mixture is after 2 h in 25 ml conc. ammonia solution stirred. After 10 min is filtered off with suction, washed with water and dried. The residue is purified by chromatography on silica gel. 3-Oxo-androst-4-en-17β-yl 3'-sulfamoylphenyl sulfonate is obtained.

Variant 2

1.0 g of testosterone are dissolved under argon in 5.5 ml of pyridine. Subsequently, 1.8 g of 3-Aminosulfonylphenylsulfonylchlorid are added. The reaction mixture is stirred after 2 h in 25 ml of water and acidified with 10% HCl. After 10 min is filtered off with suction, washed with water and dried. The residue is purified by chromatography on silica gel. 3-Oxo-androst-4-en-17β-yl 3'-sulfamoylphenyl sulfonate is obtained.
¹ H-NMR (DMSO-D ₆ ): 0.78 (s, 3H, 18-Me), 1.11 (s, 3H, 19-Me), 4.34 (t, 1H, 17-H), 5.60 (s, 1H, 4-H), 7.67 (s, 2H, NH ₂ ), 7.83-8.28 (m, 4H, H-Ar).

Example 5

Zidovudine sulfamoylphenylsulfonat

2.0 g of 1,3-benzenedisulfonyl chloride are dissolved under argon in 5.5 ml of pyridine. Subsequently, 1.0 g of zidovudine are added at 0 ° C. The reaction mixture is stirred after 2 h at RT in 25 ml of conc. Given ammonia solution. After stirring for 10 min, it is concentrated to dryness, extracted with EA. The organic phase is concentrated and the residue is purified by chromatography on silica gel. Zidovudine sulfamoyl phenyl sulfonate is obtained.
¹ H-NMR (DMSO-D ₆ ): 1.17 (s, 3H, Me), 2.40 (m, 2H, CH ₂ ), 4.00 (m, 1H, CH), 4.42 (m, 2H, CH ₂ ), 6.09 (m, 1H, CH), 7.40 (s, 1H, CH), 7.66 (s, 2H, NH ₂ ), 7.85-8.30 (3m + s, 5H, 4-H), 11.35 (s, 1H, NH ).

Example 6

Cinchonidine-sulfamoylphenylsulfonat

2.0 g of 1,3-benzenedisulfonyl chloride are dissolved under argon in 5.5 ml of pyridine. Subsequently, 1.0 g of chinchonidine are added at 0 ° C. The reaction mixture is stirred after 2 h at RT in 25 ml of conc. Given ammonia solution. After stirring for 10 min, it is concentrated to dryness, extracted with EA. The organic phase is concentrated and the residue is purified by chromatography on silica gel. Chinchonidin-sulfamoylphenylsulfonate is obtained.
¹ H-NMR (DMSO-D ₆ ): 4.99 (m, 2H, CH = CH ₂ ), 5.94 (m, 1H, CH = CH ₂ ), 7.58 (s, 2H, NH ₂ ).

Claims (21)

Sulfamoylsulfonate prodrugs of the general formula I.

where X is a C _1-12 alkanediyl, a C _p F _2p group with p = 1-5, a C _3-8 cycloalkanediyl, an arylene, a heteroalkanediyl, a C _1-4 alkanediylaryl, , C _1-4 alkanediyl C _3-8 cycloalkyl or C _3-8 cycloalkanediyl C _1-4 alkyl group, and Drug is a pharmaceutically active substance capable of forming a sulfonate through an OH group, such as Steroids, antimalarials, nucleosides, isoflavonoids, which may be optionally substituted. Sulfamoylsulfonate prodrugs according to claim 1, wherein Drug Steroids such as estrogens, for example estradiol or estriol or androgens, for example, testosterone, MENT (7α-methyl-19-nortestosterone), eF-MENT (11-fluoro-7α-methyl-19-nortestosterone), Nandrolone, DHT (dihydrotestosterone) or Progestins, for example Norethisterone, dienogest or levonorgestrel corticoids, for example cortisol Antimalarials, for example, quinine, chinchonidine, Hydroxychloroquine, primaquine, mefloquine or Consisting of nucleosides from a sugar like ribose or deoxyribose and a base like Adenine, guanine, cytosine, thymine or uracil, continue to be zidovudine, Brivudine, indinavir, nelfinavir Isoflavonoids, for example genistein mean. Sulfamoylsulfonate prodrugs according to claim 1, wherein X is a Arylene group is. Sulfamoylsulfonate prodrugs according to claim 3, wherein X is an unsubstituted or chlorine-substituted phenylene, pyridylene or thiophenylene radical is. Sulfamoylsulfonate prodrugs according to claim 3 or 4, namely 1) 3-hydroxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenylsulfonate, 2) 3-acetoxyestra-1,3,5 (10) - trien-17β-yl 3'-sulfamoylphenylsulfonate, 3) 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoyl-phenylsulfonate, 4) 3-hydroxyestra-1,3,5 (10) -triene-17β-yl 4'-sulfamoylphenylsulfonate, 5) 2-methoxy-3-hydroxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenylsulfonate, 6) 3,16α-dihydroxyestra -1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenylsulfonate, 7) 3,17β-dihydroxyestra-1,3,5 (10) -triene-16α-yl 3'-sulfamoylphenylsulfonate, 8) 3 Benzoyloxyestra-1,3,5 (10) -triene-17β-yl 3'-sulfamoylphenylsulfonate, 9) quinine-3'-sulfamoylphenylsulfonate, 10) cinchonidine-3'-sulfamoylphenylsulfonate, 11) zidovudine-3'-sulfamoylphenylsulfonate, 12 ) 3-oxoandrost-4-en-17β-yl 3'-sulfamoylphenylsulfonate, 13) 3-oxoandrostan-17β-yl 3'-sulfamoylphenylsulfonate, 14) 3-oxo-7α-methylandrost-4-en-17β-yl 3'-sulfamoylphenylsulfonate, 15) 3-oxoestr-4-en-17β-yl 3'-sulfamoylphenylsulfonate 16) Brivudine-3'-sulfamoylphenylsulfonate. Compounds according to any one of claims 1, 3 or 4, wherein the Active ingredient an antimalarial drug such as arteether, artemether, artesunate, Chloroquine, pamaquine, pamaquine, pyrethamine, mefloquine, proguanil, Chinchonidine, cinchonine, hydroxychloroquine, pamaquine, prmaquine, Pyrimethamine, quinine or a quinine derivative, such as quinine bisulfate, Quinine carbonate, quinine dihydrobromide, quinine dihydrochloride, quinine ethyl carbonate, Quinine-formate, quinine-gluconate, quinine-hydroiodide, quinine hydrochloride, Quinine salicylate or quinine sulfate. Use of the compounds according to claim 6 for prevention a parasitic attack of erythrocytes. Compounds according to any one of claims 1-7, wherein the therapeutic desirable Effect by release, in particular hydrolytic cleavage of the in the prodrug contained drug or its metabolites takes place. Pharmaceutical composition containing at least a compound of general formula I according to one of claims 1 to 5 and optionally at least one further active ingredient together with pharmaceutically acceptable Auxiliaries and / or carriers. Pharmaceutical composition according to claim 9, wherein the further active ingredient is a steroidal compound. Pharmaceutical composition according to claim 10, the other steroidal compound being a progestin, antigestagen or a progesterone receptor modulator. Pharmaceutical composition according to claim 11, in which the progestagens contained norethisterone, dienogest, drospirenone, Levonorgestrel, Antigestagens Mifepristone, Onapristone and Progesterone Receptor Modulators For example, mesoprogestins such as asoprisnil are. Use of compounds according to one of claims 1 to 8 for the manufacture of a medicament. Use according to claim 13 for the manufacture of a medicament for hormone replacement therapy. Use of compounds according to claim 1-8 for the female Fertility control. Use according to claim 13 for the manufacture of a medicament for therapy and / or prophylaxis of hormonal diseases in men and women. Use according to claim 13 for the manufacture of a medicament for therapy and prophylaxis Endometriosis, breast cancer, prostate cancer or hypogonadism. Use according to claim 13 for the manufacture of a medicament for therapy and / or prophylaxis Diseases that are positive by inhibiting carbohydrate activity be influenced. Use according to claim 13 for the manufacture of a medicament for therapy and / or prophylaxis of inflammatory and / or allergic diseases A process for preparing the sulfamoylsulfonate prodrugs of the general formula (I) according to claim 1 by reacting a corresponding drug "drug" according to claim 1 and 2 with a disulfonic acid chloride SO ₂ -X-SO ₂ Cl in the presence of a base and subsequent treatment with ammonia or by reacting the corresponding drug "drug" according to claim 1 and 2 with a Sulfamoylsulfonsäurehalogenid NH ₂ SO ₂ -X-SO ₂ Cl in the presence of a base. Method according to claim 20, wherein the base is pyridine.