KR20080072956A - Sulfamoyl sulfonate prodrugs - Google Patents

Abstract

The invention relates to the sulfamoyl sulfonate prodrugs of general formula (I), to a method for producing them, to pharmaceutical compositions containing the same and to their use for producing orally available drugs. The compounds according to the invention bind to carboanhydrases and inhibit these enzymes.

Description

Sulfamoyl sulfonate prodrugs {SULFAMOYL SULFONATE PRODRUGS}

The present invention relates to sulfamoyl sulfonate prodrugs of formula (I), methods for their preparation, pharmaceutical compositions containing them, and their use for preparing orally available medicaments.

From WO 01/91797, steroidal compounds are known which bind to and accumulate to red blood cells via the —SO ₂ NR ¹ R ² group. The concentration ratio of said compound between erythrocytes and plasma is between 10 and 1000: 1, preferably between 30 and 1000: 1, and thus it can be said that depots are formed in erythrocytes. Because of the strong binding of the compound to red blood cells, metabolism is prevented during passage through the liver. Disadvantageously, despite the reduction in metabolism using the indicated dosages, no active ingredient levels associated with the treatment are obtained. The reason for this may be attributed to excessively strong binding to erythrocytes, enzyme-induced cleavage, and low solubility.

It is an object of the present invention to provide novel prodrugs which are orally available and which guarantee the level of active ingredient associated with treatment even at low dosages compared to the prior art.

The object of the present invention is achieved by a sulfamoyl sulfonate prodrug of formula (I), wherein the sulfamoyl radical is bonded to the drug to be released to the sulfonate bond via spacer X.

<Formula I>

In the formula,

X is C _{1 -12-alkanediyl} -, C _p F _2p group (where p is 1 to 5 Im), C _{3 -8-cycloalkyl} alkanediyl -, arylene -, heteroaryl alkanediyl -, C ₁ alkyl group, - ₄ - alkanediyl aryl -, C _{1 -4-alkanediyl} -C _{3 -8-cycloalkyl-or} C _{3 -8-cycloalkyl} -C _{1 -4} alkanediyl

The drug is a pharmaceutically active ingredient, such as a steroid, antimalarial agent, nucleoside or isoflavonoid, which may form a sulfonate through an OH group and may be optionally substituted.

The sulfamoyl sulfonate compounds according to the invention bind to erythrocytes, are soluble in water, and are hydrolytically cleaved without the aid of enzymes.

For the purposes of the present invention, "C _{1 -12} - alkanediyl group" is defined as a straight-containing double bonds has 12 or fewer carbon atoms, linear or branched alkylene radical, which is for example a halogen atom Optionally substituted with hydroxy groups or nitrile groups. Examples include 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- and undecane-1,11-diyl groups may be mentioned.

For the purposes of the present invention, a C _p F _2p group with p of 1 to 5 is defined as a straight or branched perfluorinated alkyl radical having up to 5 carbon atoms. By way of example, mention may be made of perfluoropropane-1,3-diyl-, perfluorobutane-1,4-diyl- and perfluoropentane-1,5-diyl groups.

Referred to above in accordance with the present invention, "C _{3 -8} - cycloalkyl alkanediyl group" which is a halogen atom, means a mono- or bicyclic carbocyclic which containing a double bond having 3 to 8 carbon atoms, Optionally substituted with hydroxy groups and nitrile groups, for example cyclobutane-1,3-diyl-, cyclopentane-1,3-diyl- or cyclohexane-1,4-diyl groups.

The above-mentioned "arylene group" according to the invention means a carbocyclic group which is an aromatic mono- to tricyclic having 6 to 15 carbon atoms and containing a double bond, which is a halogen atom, hydroxy group, nitrile group And alkyl groups, for example m-phenylene-, p-phenylene-, phenanthrylene- or naphthalene groups.

In each case, the heteroarylene radical contains 5 to 16 ring atoms and contains one or more identical or different heteroatoms such as oxygen, nitrogen or sulfur in the ring instead of carbon. Heteroaryl radicals may be mono-, bi- or tricyclic.

For example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzo Thienyl, benzothiazole, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindoleyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl and isoquinolyl May be mentioned.

For the purposes of the present invention, a heteroalkanediyl group is a straight or branched, saturated or unsaturated heteroalkyl radical which in each case has 1 to 6 carbon atoms and contains a double bond, wherein at least one identical or It may contain different heteroatoms such as oxygen, nitrogen or sulfur, for example bis-ethyleneoxy radicals.

"C _{1 -4-aryl} alkanediyl group" alkanediyl group is a straight or branched C ₁ -C ₄ chain which may be - is the aryl group bonded to the skeleton via an alkanediyl. For example, benzyl or phenylene can be mentioned.

"C _{3 -8} - cycloalkyl, -C _{1 -4} - alkanediyl group" is, for example, cycloalkyl - (CH ₂₎ -, cycloalkyl _{- (C 2 H 4) -} , cycloalkyl - (C ₃ H ₆ )-, cycloalkyl- (C ₄ H ₈ )-or cycloalkyl- (C ₅ H ₁₀ )-. In this case, the cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

"C _{1 -4} - alkyl, -C _{3 -8} - cycloalkyl alkanediyl group" methylcyclopentadienyl alkanediyl, ethylcyclohexane alkanediyl, propylcyclopentadienyl alkanediyl, butyl or pentyl cycloalkyl alkanediyl cycloalkanediyl days defined do. In this case, cycloalkanediyl is cyclopropane-1,3-diyl, cyclobutane-1,4-diyl, cyclopentane-1,5-diyl, cyclohexane-1,6-diyl, cycloheptan-1,7 -Diyl or cyclooctane-1,8-diyl.

In the context of the present invention, the term "halogen atom" is defined as a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

For the purposes of the present invention, pharmaceutically active ingredients capable of forming sulfonates via OH groups mean:

Steroids: estrogens such as estradiol or estriol, or androgens such as testosterone, MENT (7α-methyl-19-nortestosterone), eF-MENT (11-fluoro-7α-methyl-19-nor Testosterone), nandrolone, DHT (dihydrotestosterone), or gestagens such as noethysterone, dienogest or levonogestrel, or corticoids such as cortisol

Antimalarial agents: quinine, synconidine, hydroxychloroquine, primaquine, mefloquine; or

Nucleosides: sugars such as ribose or deoxyribose, and bases such as adenine, guanine, cytosine, thymine or uracil, and also zidovudine, brivudine, indinavir and nelpinavir;

Isoflavonoids: Genistein.

Particularly preferred compounds are specified below:

1) 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate,

2) 3-acetoxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate,

3) 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate,

4) 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 4'-sulfamoylphenyl sulfonate,

5) 2-methoxy-3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate,

6) 3,16α-dihydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate,

7) 3,17β-dihydroxyestra-1,3,5 (10) -trien-16α-yl 3'-sulfamoylphenyl sulfonate,

8) 3-benzoyloxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate,

9) quinine-3'-sulfamoylphenyl sulfonate,

10) Cinconidine-3'-sulfamoylphenyl sulfonate,

11) dozibudine-3'-sulfamoylphenyl sulfonate,

12) 3-oxoandro-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate,

13) 3-oxoandrostan-17β-yl 3'-sulfamoylphenyl sulfonate,

14) 3-oxo-7α-methylandrost-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate,

15) 3-oxoest-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate, and

16) Brivudine-3'-sulfamoylphenyl sulfonate.

The therapeutically relevant drug compound is released from the compound according to the invention via hydrolysis.

In vitro  exam:

Carbonic Anhydrase  control

Test principle:

Photometric determination of inhibition of human carbonic anhydrase I or II by sulfonamide or sulfamate on microtiter plates with the aid of enzymatic conversion of nitrophenyl acetate with color change from colorless to yellow.

human Carbonic Anhydrase  Of I IC ₅₀  Suppression value Inhibitor CA II IC ₅₀ (nM) CA I IC ₅₀ (nM) Estradiol-3-sulfate 34 157 ± 10.6 3-oxoandro-4-ene-17β-yl 3'-aminosulfamoylphenyl sulfonate 120 2300 3-oxo-7α-methylandrost-4-ene-17β-yl 3'-aminosulfamoylphenyl sulfonate 120 2300 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'-aminosulfamoylphenyl sulfonate 81 1700 Chidobudine Sulfonate 1100 2900 Acetazolamide (known CA inhibitor) 61 1200 1900 ¹⁾

It has been found that sulfamoyl sulfonate prodrugs according to the invention surprisingly readily inhibit carbonic anhydrase II. The concentration of prodrug according to the invention in erythrocytes can be deduced from above.

Physicochemical Data

Acceptance

a) kinetic measurements:

The compounds according to the invention were measured as 10 mmol DMSO solution in 0.01 M phosphate buffer solution with turbidity and turbidity at pH 7.4 and 25 ° C.

During the cloudy state, the solution to be tested was added dropwise to the buffer solution until the precipitate settled.

Precipitates were detected by serial dilution (compound in phosphate buffer solution according to the invention) by turbidity measurement.

b.) Thermodynamic measurements:

The compound in solid form according to the invention was added to an excess of aqueous buffer system with various pH values. It was stirred at 25 ° C. for 24 hours. After centrifugation, the solution was tested by HPLC (HPLC: Column: Xterra MS C18 2.5 μm, 30 × 4.6 mm). Two standard gradient systems were used based on the compounds to be measured:

Acid gradient: A: water / 0.01% trifluoroacetic acid, B: acetonitrile / 0.01% trifluoroacetic acid-0 min 5% B, 0 to 3 min 65% B, 3 to 5 min 65% B, 5 to 5 6 minutes 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.

Acceptance matter Acceptance Estradiol-3-sulfate 0.15 mg / 100 ml Testosterone propionate Insoluble 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'- sulfamoylphenyl sulfonate 3 mg / l 3-oxoandro-4-ene-17β-yl 3'-sulfamoyl-phenyl sulfonate 5 mg / l 3-oxo-7α-methylandrost-4-ene-17β-yl 3'- sulfamoylphenyl sulfonate About 6 mg / l

The compounds according to the invention show higher solubility compared to sulfamate- and carboxylic ester prodrugs, which allow them to be absorbed better in the intestine.

Hydrolysis

The compounds according to the invention were measured as DMSO solutions in aqueous buffers having various pH values at 37 ° C.

Quantification was performed via HPLC (HPLC column: Xtera MS C18 2.5 μm 4.6 × 30 mm). Based on the test material to be measured, the following gradient system was used for HPLC:

Acid gradient: A: water / 0.01% trifluoroacetic acid, B: acetonitrile / 0.01% trifluoroacetic acid-0 min 5% B, 0 to 3 min 65% B, 3 to 5 min 65% B, 5 to 5 6 minutes 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 was performed after 1 and 2 hours and after 24 hours.

Stability in Artificial Gastric Fluids:

Solutions of the compounds according to the invention were incubated at 37 ° C. in artificial gastric juice (aqueous NaCl solution containing pepsin, about pH 1.2).

Quantification was performed using HPLC (HPLC-Column: Xterra MS C18 2.5 μm 4.6 × 30 mm) using the following gradient system:

A: water / 0.01% trifluoroacetic acid, B: acetonitrile / 0.01% trifluoroacetic acid-0 min 5% B, 0 to 3 min 65% B, 3 to 5 min 65% B, 5 to 6 min 5 % B.

Quantification was performed after 0.5, 1, 1.5 and 2 hours.

Hydrolysis / Stability in Gastric Fluids matter Decomposition (%) pH = 1, 37 ℃ pH = 7.4, 37 ° C 30 minutes 1 hours 2 hours 24 hours 1 hours 2 hours 24 hours 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoyl phenyl sulfonate 4 (pH = 1.2) 7 14 80 6 13 84 3-oxoandro-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate 3 (pH = 1.2) 6 11 78 6 12 75 3-oxo-7α-methylandrost-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate 6 11 71 6 11 70 3-oxoandro-4-ene- 17β-yl n-propionate 0 0 0 0 0 0 0

Carboxylic acid esters are relatively stable in gastric juice (about pH 1) and intestine (about pH 7.4), but are cleaved by the esterase present there through the intestine. However, stable prodrugs are maintained almost completely during passage through the stomach.

Thus, cleavage of the carboxylic acid esters occurs when passing through the intestine and in the liver.

No enzymes (esterases) for sulfonic acid esters are known. It is therefore surprising that the sulfonate is still cleaved by simple hydrolysis. In gastric juice, and when the pH is 7.4, hydrolysis already occurs slowly, but sulfonates have adequate stability to pass through the stomach and intestines. Esterase cleavage does not occur in the intestinal wall. Since the sulfonate is bound to the red blood cells by sulfonamide groups, the first pass effect in the liver is prevented.

Depending on the function of the "drug", the compounds of formula (I) according to the invention can be used for the treatment and / or prevention of various clinical conditions. For example, the compounds of formula (I) can be used in hormone replacement therapy (HRT) in women and men when the “drug” is a steroid, such as androgen or estrogen, or a hormone-induced disease in men (prostate cancer, breast cancer, Hypogonadism) and hormonal induced diseases of women (endometriosis, breast cancer). In addition, the compounds of formula (I) according to the invention in which "drug" means, for example, androgen or estrogen, can be used for regulating fertility in men and women.

The use of additional active ingredients mentioned for "drugs" such as quinine, cinkonidine, hydroxychloroquine, primaquine or mefloquine relates to the treatment of malaria.

The compounds of formula (I) according to the invention wherein the "drug" is a cortisol derivative can be used for the treatment and prevention of inflammatory and / or allergic diseases affected by immunosuppressive and / or antiproliferative agents.

Prodrugs according to the invention wherein the "drug" is nucleoside (zidovudine, brivudine, indinavir, nlpinavir) can be used for the treatment of viral diseases (herpes, HIV).

Also subject to the invention are compounds of the formula I according to the invention and optionally further active ingredients, for example gestagen (norethysterone, dienogest, drospirenone, levonorgestrel), anti- Pharmaceutical compositions containing gestagen (mifepristone, onnapristone) and / or progesterone receptor modulator (mesoprogestin, such as asoprisnil).

The pharmaceutical composition and medicament are preferably administered orally. In addition to the usual vehicles and / or diluents, they contain one or more compounds of formula (I).

administration

Prodrugs according to the invention may be administered orally.

Generally, after administration of a prodrug, the administration is carried out such that the amount of the corresponding active ingredient (“drug”) is released to the maximum that corresponds to the highest dose of each “drug” substance used pharmaceutically. Satisfactory results are expected for both treatment and / or prevention of symptoms or for fertility control.

The medicaments of the present invention are prepared in a known manner at suitable dosages using common solid or liquid vehicles or diluents, and pharmaceutical excipients conventionally employed depending on the desired type of administration. Preferred formulations are in dispersible forms suitable for oral administration. Such dispersible forms are, for example, tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions, or alternatively depot forms.

Suitable tablets are, for example, active ingredients in known excipients, for example inert diluents such as dextrose, sugars, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or Gelatin, lubricants such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of multiple layers.

Accordingly, the coated tablets can be prepared from the cores prepared similarly to tablets with preparations previously used for coating coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. It can be prepared by coating. In this case, the envelope of the coated tablet can also consist of a plurality of layers, wherein the excipients mentioned above for the tablet can be used.

Solutions or suspensions containing a compound of formula (I) according to the invention may additionally contain taste-enhancing agents such as saccharin, cyclates or sugars, and also flavoring agents such as vanilla or orange extracts. They may also contain suspending excipients such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoate.

Capsules containing a compound of formula (I) can be prepared, for example, by mixing the compound (s) of formula (I) with an inert vehicle such as lactose or sorbitol and encapsulating it into a gelatin capsule.

Prodrugs according to the invention can be synthesized according to the following examples, which are used for more detailed description without limiting the invention.

Description of General Synthesis

Variant 1

Reaction with disulfonic acid chloride

Disulfonic acid chloride of formula SO ₂ -X-SO ₂ Cl was dissolved in a base such as pyridine under an inert gas. Corresponding amounts of drug substance were added to the solution. The reaction mixture was stirred until the reaction was complete. Thereafter, the reaction mixture was poured into a concentrated NH ₃ solution and stirred. The precipitate was filtered off, washed with water and dried. The residue was extracted with an organic solvent such as ethyl acetate and the organic phase was washed and dried with a desiccant such as MgSO ₄ . After filtration, it was concentrated by evaporation and purified by chromatography on silica gel. The corresponding sulfamoyl sulfonate was obtained.

Variant 2

Reaction with sulfamoyl sulfonic acid halides

The drug substance as defined above was dissolved in a base such as pyridine and an inert solvent such as chloroform under an inert gas. During cooling, a corresponding amount of sulfamoyl sulfonic acid halide of the formula NH ₂ SO ₂ -X-SO ₂ Hal was added to the solution. The reaction mixture was stirred until the reaction was complete. Thereafter, water was added and it was optionally acidified with an acid such as 10% HCl. It is extracted with an organic solvent such as ethyl acetate and the organic phase is washed and dried with a desiccant such as MgSO ₄ . After filtration, it was concentrated by evaporation and purified by chromatography on silica gel. The corresponding sulfamoyl sulfonate was obtained.

Corresponding sulfamoyl sulfonic acid halides or disulfonic acid chlorides can be purchased commercially or prepared by methods known to those skilled in the art.

synthesis Example

Example  One

3- tert - Butyldimethylsilyloxyestra -1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl Sulfonate

1.9 g of 1,3-benzenedisulfonyl chloride was dissolved in 5 ml of pyridine under argon. Thereafter, 1.0 g of 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -trien-17β-ol was added. After 2 hours, the reaction mixture was poured into 25 ml of concentrated ammonia solution and stirred. After 10 minutes it was aspirated, washed with water and dried. The residue was purified by chromatography on silica gel. 3-tert-Butyldimethylsilyloxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate was obtained.

Example  2

3- Hydroxyestra -1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl Sulfonate

300 mg of 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate was dissolved in 20 ml of THF. While stirring, 200 mg of tetrabutyl ammonium fluoride was added at room temperature. After 1 hour, 20 ml of water was added and stirred. The material was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over MgSO ₄ , filtered, concentrated by evaporation and purified by chromatography on silica gel. 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate was obtained.

Example  3

3-oxo-7α- Methylestra -4-ene-17β-yl 3'- Sulfamoylphenyl Sulfonate

1.9 g of 1,3-benzenedisulfonyl chloride was dissolved in 5 ml of pyridine under argon. Thereafter, 1.0 g of MENT was added. After 2 hours, the reaction mixture was poured into 25 ml of concentrated ammonia solution and stirred. After 10 minutes it was aspirated, washed with water and dried. The residue was purified by chromatography on silica gel. 3-oxo-7α-methylestra-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate was obtained.

Example  4

3-oxo- Androast -4-ene-17β-yl 3'- Sulfamoylphenyl Sulfonate

Variant 1

2.0 g of 1,3-benzenedisulfonyl chloride was dissolved in 5.5 ml of pyridine under argon. Thereafter, 1.0 g of testosterone was added. After 2 hours, the reaction mixture was poured into 25 ml of concentrated ammonia solution and stirred. After 10 minutes it was aspirated, washed with water and dried. The residue was purified by chromatography on silica gel. 3-oxo-androst-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate was obtained.

Variant 2

1.0 g of testosterone was dissolved in 5.5 ml of pyridine under argon. After this, 1.8 g of 3-aminosulfonylphenylsulfonyl chloride was added. After 2 hours, the reaction mixture was stirred in 25 ml of water and acidified with 10% HCl. After 10 minutes it was aspirated, washed with water and dried. The residue was purified by chromatography on silica gel. 3-oxo-androst-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate was obtained.

Example  5

Map Sulfamoylphenyl Sulfonate

2.0 g of 1,3-benzenedisulfonyl chloride was dissolved in 5.5 ml of pyridine under argon. Thereafter, 1.0 g of zidovudine was added at 0 ° C. After stirring for 2 hours at room temperature, the reaction mixture was added to 25 ml of concentrated ammonia solution. After stirring for 10 minutes, it was evaporated to dryness and extracted with EE. The organic phase was concentrated by evaporation and the residue was purified by chromatography on silica gel. Zidobudine-sulfamoylphenyl sulfonate was obtained.

Example  6

Cinconidine-Sulfamoylphenyl Sulfonate

2.0 g of 1,3-benzenedisulfonyl chloride was dissolved in 5.5 ml of pyridine under argon. Thereafter, 1.0 g of cicononidine was added at 0 ° C. After stirring for 2 hours at room temperature, the reaction mixture was added to 25 ml of concentrated ammonia solution. After stirring for 10 minutes, it was evaporated to dryness and extracted with EE. The organic phase was concentrated by evaporation and the residue was purified by chromatography on silica gel. Cinconidine-sulfamoylphenyl sulfonate was obtained.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, certain preferred embodiments herein are to be construed as illustrative only and do not limit the remainder of the disclosure in any way.

In the examples herein, unless otherwise indicated, all temperatures are described without correction in degrees Celsius, and all parts and percentages are by weight.

The examples herein can be repeated with similar results by substituting generic or specifically described reactants and / or manipulating the conditions of the present invention with those used in the above examples.

From the above description, those skilled in the art will be able to readily identify the essential features of the present invention without departing from the spirit and scope of the invention, and to make various changes and modifications of the present invention by adapting to various usages and conditions.

Claims (21)

Sulfamoyl sulfonate prodrugs of formula (I) <Formula I>

In the formula, X is an optionally substituted C ₁ -C ₁₂ -alkanediyl group, a C _p F _2p group where p is 1 to 5, optionally halogen-, hydroxyl- or nitrile-substituted mono- or bicyclic C _3-8 - cycloalkyl alkanediyl group, an optionally halogen-, hydroxyl-, nitrile-and alkyl-substituted mono- to tricyclic C ₆ -C ₁₅ - arylene group, 1 to 6 carbon atoms having a hetero al alkanediyl group one (here being a carbon atom substituted with one or more identical or different hetero atoms), C _{1 -4} - alkanediyl aryl, C _{1 -4} - alkanediyl -C _{3 -8} - cycloalkyl or C _{3 -8} - an alkyl group, - a cycloalkyl alkanediyl -C _{1 -4} Drugs represent pharmaceutically active ingredients such as steroids, antimalarials, nucleosides, isoflavonoids which may form sulfonate groups via OH groups and may be optionally substituted. The method of claim 1 wherein the drug is Steroids such as estrogens such as estradiol or estriol, or androgens such as testosterone, MENT (7α-methyl-19-nortestosterone), eF-MENT (11-fluoro-7α-methyl-19- Nortestosterone), nandrolone, DHT (dihydrotestosterone), or Gestagens such as noethysterone, dienogest or levonorgestrel, or Corticoids, for example cortisol, or Antimalarial agents, for example quinine, synconidine, hydroxychloroquine, primaquine, mefloquine, or Sugars such as ribose or deoxyribose, and bases such as adenine, guanine, cytosine, thymine or uracil, also nucleosides consisting of zidovudine, brivudine, indinavir, nelpinavir, or Sulfamoyl sulfonate prodrugs representing isoflavonoids such as genistein. The sulfamoyl sulfonate prodrug of claim 1, wherein X is an arylene group. The sulfamoyl sulfonate prodrug of claim 3, wherein X is a phenylene, pyridylene or thiophenylene radical which is unsubstituted or substituted with chlorine. The method according to claim 3 or 4, 1) 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate, 2) 3-acetoxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate, 3) 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate, 4) 3-hydroxyestra-1,3,5 (10) -trien-17β-yl 4'-sulfamoylphenyl sulfonate, 5) 2-methoxy-3-hydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate, 6) 3,16α-dihydroxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate, 7) 3,17β-dihydroxyestra-1,3,5 (10) -trien-16α-yl 3'-sulfamoylphenyl sulfonate, 8) 3-benzoyloxyestra-1,3,5 (10) -trien-17β-yl 3'-sulfamoylphenyl sulfonate, 9) quinine-3'-sulfamoylphenyl sulfonate, 10) Cinconidine-3'-sulfamoylphenyl sulfonate, 11) dozibudine-3'-sulfamoylphenyl sulfonate, 12) 3-oxoandro-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate, 13) 3-oxoandrostan-17β-yl 3'-sulfamoylphenyl sulfonate, 14) 3-oxo-7α-methylandrost-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate, 15) 3-oxoest-4-ene-17β-yl 3'-sulfamoylphenyl sulfonate, or 16) Brivudine-3'-sulfamoylphenyl sulfonate Sulfamoyl sulfonate prodrugs. The method according to any one of claims 1, 3 and 4, wherein the active ingredient is an antimalarial agent such as arteether, artemeter, artesunate, chloroquine, permaquine, primaquine, phyretamine, mefloquine, Proguanil, Cinconidine, Cinconin, Hydroxychloroquine, Pharmaquine, Primaquine, Pyrmethamine, Quinine or Quinine Derivatives such as Quinine Bisulfate, Quinine Carbonate, Quinine Dihydrobromide, Quinine Dihydrochloride, Quinine ethylcarbonate, quinine formate, quinine gluconate, quinine hydroiodide, quinine hydrochloride, quinine salicylate or quinine sulfate. Use of a compound according to claim 6 for preventing parasitic infections on red blood cells. 8. A compound according to any one of claims 1 to 7, which achieves a therapeutically desired effect by the release of the active ingredient contained in the prodrug or metabolite thereof, in particular hydrolytic cleavage. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 and optionally at least one further active ingredient together with a pharmaceutically acceptable excipient and / or vehicle. The pharmaceutical composition of claim 9, wherein the additional active ingredient is a steroidal compound. The pharmaceutical composition of claim 10, wherein the additional steroidal compound is a gestagen, anti-gestagen or progesterone receptor modulator. 12. The method of claim 11 wherein the contained gestagen is noethysterone, dienogest, drospirenone or levonorgestrel, the anti-gestagen is mifepristone or onnapristone, the progesterone receptor modulator is mesoprogestin, Pharmaceutical compositions that are for example asoprisnil. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament. Use according to claim 13 for the manufacture of a medicament for hormone replacement therapy. Use of a compound according to any one of claims 1 to 8 for regulating female fertility. Use according to claim 13 for the manufacture of a medicament for the treatment and / or prophylaxis of hormonal induced diseases in men and women. Use according to claim 13 for the manufacture of a medicament for the treatment and prophylaxis of endometriosis, breast cancer, prostate cancer or hypogonadism. Use according to claim 13 for the manufacture of a medicament for the treatment and / or prophylaxis of a disease which may be positively affected by the inhibition of carotenhydrase activity. Use according to claim 13 for the manufacture of a medicament for the treatment and / or prophylaxis of inflammatory and / or allergic diseases. A suitable drug according to claim 1 or 2 is reacted with disulfonyl chloride SO ₂ -X-SO ₂ Cl in the presence of a base and then treated with ammonia, or a suitable drug according to claim 1 or 2 is subjected to a base. A process for preparing the sulfamoyl sulfonate prodrug of formula I according to claim 1 by reacting with sulfamoylsulfonyl halide NH ₂ SO ₂ -X-SO ₂ Cl in the presence of. The method of claim 20, wherein the base is pyridine.