Sulphonilecarbomide acid

 

(57) Abstract:

The invention relates to sulphonilecarbomide acids of the formula

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and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

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where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-; In means (CH2)mwhere m means n is compound I from compound similar structures, which instead of

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has

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where R8means1-C6-alkyl, phenyl. 2 S. and 2 C.p. f-crystals, 2 tab.

The invention relates to new sulphonilecarbomide acids, method for their production and their use as pharmaceuticals.

In the application for the European patent 0606046, international application 95/35276 and international application 96/27583 describes arylsulfonamides acids and their action as inhibitors of matrix metalloproteinases. Special arylsulfonamides acids serve as intermediates for obtaining thrombin inhibitors (European patent 0468231) and inhibitors of aldose-reductase (European patent 0305947). In the application for the European patent 0757037 also describes the effect of derivative sulfonilmocevinnah acids as inhibitors of metalloproteinases.

Next, arylsulfonyl group is suitable as an effective protective group of the amine function aminocarbonyl acid [R. Roemmele, H. Rapoport, J. Org. Chem., 53, 2367-2371 (1988)].

In the quest to find effective compounds for the treatment of diseases of the connective tissue at the present time found that the proposed sulfone the increase is attributed to inhibition stromelysin (matrix metalloproteinase 3) and neutrophiles collagenase (MMP-8), both enzyme largely participate in the destruction of the most important components of cartilage tissue [A. J. Fosang, etc., J. Clin. Invest., 98, 2292-2299 (1996)].

Therefore, the invention relates to the compound of formula (I):

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and/or a stereoisomeric form of the compounds of formula (I), and/or physiologically acceptable salts of the compounds of formula (I), and

R1means:

1. phenyl;

2. phenyl, one - or twofold substituted: (2.1) a linear, cyclic or branched (C1-C6)-alkyl, (2.2) hydroxyl, (2.3) group (C1-C6)-alkyl-C(O)-O-, (2.4) group (C1-C6)-alkyl-O-, (2.5) group (C1-C6)-alkyl-O-(C1-C4)-alkyl-O-, (2.6) halogen, (2.7) trifluoromethyl, (2.8) cyano, (2.9) nitrogroup, (2.10) group BUT-C(O)-, (2.11) group (C1-C6)-alkyl-O-C(O)-, (2.12) methylenecyclopropane, (2.13) the group R4-(R5)N-C(O)- or (2.14) the group R4-(R5)N-; or

3. heteroaromatic residue of the following groups (3.1)-(3.15), which is unsubstituted or substituted as described in the PP (2.1)-(2.14) as the residue (3.1) pyrrole, (3.2) pyrazole, (3.3) imidazole, (3.4) triazole, (3.5) thiophene, (3.6) thiazole, (3.7) oxazole, (3.8) isoxazol, (3.9) pyridine, (3.10) pyrimidine, (3.11) indole. (3.12) benzothiophene, (3 is suspended or different and mean:

1. a hydrogen atom;

2. (C1-C6)-alkyl-;

3. HO-C(O)-(C1-C6)-alkyl-;

4. phenyl-(CH2)n- where phenyl unsubstituted or once or twice substituted as described in the PP (2.1)-(2.14), or substituted-NH-C(O)-(C1-C3)-alkyl and where n denotes the integer zero, 1 or 2; or

5. picolyl or

R4and R5together with the amino group, which is the Deputy cycle, form a 4-7-membered cycle, where one of the carbon atoms replaced by-O-, -S - or-NH -, or two adjacent carbon atom 4-7-membered cycle are part of the benzyl residue;

R3means:

1. a hydrogen atom;

2. (C1-C10)-alkyl-, where the alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl;

3. (C2-C10)-alkenyl-where alkenyl is linear or branched;

4. R2-O- (C1-C6)-alkyl-;

5. R2-S (O)n-(C1-C6)-alkyl-, and n have the above meaning;

6. R2-S(O)(=NH)-(C1-C6)-alkyl-;

7. a group of the formula

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where n denotes an integer zero, 1 or 2 and W means nitrogen atom, oxygen or sulfur;

8. phenyl-(CH2)m-, where m indicates an integer zero, 1, 2, 3, 4,�ukratko substituted: (8.1) as described in paras. (2.1)-(2.14), (8.2) -O-(CH2)m-phenyl, where phenyl unsubstituted or one - or twofold substituted as described in paras. (2.1)-(2.14) and m means an integer zero, 1, 2, 3, 4, 5 or 6 (8.3) -C(O)-(CH2)m-phenyl, where phenyl is specified in paragraph (8.2) value;

9. heteroaryl-(CH2)m- where heteroaryl is specified in paras. (3.1)-(3.15) the value of m has the above meaning and/or one atom of hydrogen,- (CH2)m-chain replaced by hydroxyl and heteroaryl unsubstituted or one - or twofold substituted: (9.1) as described in PP (2.1)-(2.14) or (9.2) the group-CH(O)-, (9.3) -SO2-phenyl, where phenyl unsubstituted or is specified in p. p. (8.2) or (8.3) (9.4) -O-(CH2)m-phenyl;

10. -(CH2)m-P(O)(OH)-(C1-C3)-alkyl, where m has the above meaning; or

11. R6-C(O)-(C1-C6)-alkyl-, where

R6means:

1. a hydrogen atom;

2. (C1-C6)-alkyl-, where the alkyl is a linear, branched or cyclic;

3. phenyl, where phenyl unsubstituted or substituted as described in paragraphs. (2.1)-(2.14);

4. heteroaryl where heteroaryl is specified in paras. (3.1)-(3.15) the value and/or substituted as described in the PP (2.1)-(2.14) or substituted by a group -(C1-C4)-alkyl-COOH;

5. hydroxyl;

8. heteroaryl-(CH2)m-NH-, where heteroaryl is specified in paras. (3.1)-(3.15) the value and/or substituted as described in paras. (2.1)-(2.14) and m has the above meaning;

9. R4-(R5)N-NH-, where R4and R5have the above meanings; or

10. HO-C(O)-CH(R3)-NH-, where R3has the above meaning; or

R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula (II):

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where g denotes the integer zero, 1, 2 or 3 and/or one of the carbon atoms in the cycle replaced by-O-, -S - or -(R7)N-, where R7means:

1. a hydrogen atom;

2. (C1-C6)-alkyl;

3. phenyl, where phenyl unsubstituted or substituted as described in paragraphs. (2.1)-(2.14);

4. benzyl, where the benzyl unsubstituted or substituted as described in paragraphs. (2.1)-(2.14);

5. R2N-C(=NH)-, and R2has the above meaning;

and/or the carbon atoms in the cycle of partial formulas (II) one - or multi-substituted (C1-C6)-alkyl, phenyl, phenyl group-(CH2)mor hydroxyl;

And means:

a) covalent bond;

b) -O-;

in) -CH=CH - or

g) -C=C-;

In means:

(a) -(CH2)mwhere m has the above meaning;

oxygen or sulfur atom.

Preferred is a compound of formula (I), where R1means:

1. phenyl or

2. phenyl, substituted once: (2.1) (C1-C6)-alkyl, where alkyl is a linear, cyclic or branched, (2.2) hydroxyl, (2.3) group (C1-C6)-alkyl-C(O)-O-, (2.4) group (C1-C6)-alkyl-O-, (2.5) group (C1-C6)-alkyl-O-(C1-C4)-alkyl-O-, (2.6) halogen, (2.7) trifluoromethyl or (2.8) the group R4-(R5)N-;

R2, R4and R5are the same or different and mean:

1. a hydrogen atom or

2. (C1-C6)-alkyl-;

R3means:

1. (C1-C10)-alkyl-, where the alkyl is a linear, branched or cyclic and/or where one carbon atom alkyl residue substituted by hydroxyl;

2. R2-S(O)n-(C1-C6)-alkyl-, where R2means (C1-C6)-alkyl - or phenyl-(CH2)nand n means an integer of zero or 1;

3. phenyl-(CH2)m- where phenyl unsubstituted or one - or twofold substituted as described in the PP (2.1)-(2.14) and/or one atom of hydrogen,- (CH2)m-chain replaced by hydroxyl and m means an integer of 1, 2, 3, 4 or 5;

4. heteroaryl-(CH2)m- where gin the hydrogen atom is -(CH2)m-chain replaced by hydroxyl and m means an integer of 1, 2, 3 or 4; or

5. R6-C(O)-(C1-C6)-alkyl-, where R6means:

1. hydroxyl;

2. R2O-, where R2has the above meaning;

3. R4-(R5)N-, where R4and R5have the above meanings; or

4. R4and R5together with the amino group, which is the Deputy cycle, form a 5-6-membered cycle, where one of the carbon atoms replaced by-O-, -S - or-NH -, or two adjacent carbon atom 5-6-membered cycle are part of the benzyl residue;

5. R2and R3together form a cycle with a carboxyl group as a substituent of partial formula (II), where n means an integer of 1 or 2 and/or one of the carbon atoms in the cycle replaced by-O - or -(R7)N -, and R7means:

1. a hydrogen atom;

2. (C1-C6)-alkyl;

3. phenyl, where phenyl unsubstituted or substituted as described in the PP (2.1)-(2.14);

4. benzyl, where the benzyl unsubstituted or substituted as described in the PP (2.1)-(2.14); or

5. R2N-C(=NH)-, where R2has the above meaning;

and/or the carbon atoms in the cycle of partial formula (II) may be substituted once by phenyl or hydroxyl;

And oznachaet the number zero, 1 or 2; or

b) -O-(CH2)p- where R indicates an integer of 1 or 2; and

X is-CH=CH-.

Especially preferred is the compound of formula (I), where R1means:

1. phenyl or

2. phenyl, substituted once (2.1) halogen, in particular chlorine or fluorine, (2.2) the group R4-(R5)N-, and R4and R5are the same or different and mean (2.2.1) (C1-C3)-alkyl or (2.2.2) R4and R5together with the amino group, which is the Deputy cycle, form a 5-6-membered cycle, and if necessary, one of the C-atoms replaced by-O - or-N-;

R2means a hydrogen atom;

R3means:

1. heteroaryl-(CH2)m- where heteroaryl is specified in p. p. (3.5), (3.11) or (3.13) the value and heteroaryl unsubstituted or once substituted as described in the PP (2.1)-(2.14) and m means an integer of 1 or 2; or

2. R6-C(O)-(C2-C3)-alkyl, where R6means:

1. hydroxyl;

2. R2-O-, where R2has the above meaning; or

3. R4-(R5)N-, where R4and R5are the same or different and mean:

(3.1) a hydrogen atom;

(3.2) (C1-C3)-alkyl-;

(3.3) phenyl-(CH2) is zero, 1 or 2;

(3.4) R4and R5together with the amino group, which is the Deputy cycle, form a 5-6-membered cycle, and if necessary, one of the C-atoms replaced by-O - or-NH-, or form indolinyl residue; or

(3.5) HO-C(O)-CH(R3)-NH-, where R3has the above meaning;

And means covalent bond;

In means a group -(CH2)o- which means zero, and

X is-CH=CH-.

Under the expression "R4and R5together with the amino group, which is the Deputy cycle, form a 4-7-membered cycle and/or one of the carbon atoms replaced by-O-, -S - or-NH -," see remnants derived, for example, azetidine, pyrrole, pyrroline, pyridine, azepine, piperidine, oxazole, isoxazol, imidazole, indoline, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine or pyrazine. The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "alkyl" or "alkenyl" understand hydrocarbon residues, carbon chain which is linear or branched. Cyclic alkyl residues are, for example, 3-6-membered monocycle as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Further, the alkyl residues may also contain double bonds.

The invention further relates to a method for obtaining compounds of formula (I) and/or stereoisomeric forms of the compounds of formula (I), and/or physiologically acceptable salts of the compounds of formula (I), which differs in that

a) aminocarbonyl acid of formula (III):

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where R2and R3have the above for formula (I) values, enter into interaction with the derived sulfonic acids of the formula (IV):

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where R1, A and b have the above for formula (I) values and Y means a halogen atom, imidazolyl or8where R8means a hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl, which is unsubstituted or may be substituted,

in the presence of a base or, if necessary, in the presence of dehydrating means of obtaining the compounds of formula (I) or

b) ester aminocarbonyl acid of formula (V):

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where R2, R3and R8have the above significance, enter into interaction with the derived sulfonic acids of the formula (IV) under the above conditions to obtain compounds of formula (VI):

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and the compound of formula (VI) by removal of residue R8, preferably in the presence of base or acid, is converted into a compound of formula (I); lippy E is converted into a compound of formula (VIII):

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the compound of formula (VIII) with a derivative of sulphonic acids of the formula (IV) under the above conditions translate into a compound of formula (IX):

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and then the compound of formula (IX) by removal of the protective group E and remainder R8using suitable for the cleavage reagent is transferred to a compound of formula (I); or

g) obtained by the variants of the method (a), (b) or (C) a compound of formula (I), which is based on its chemical structure is in enantiomeric forms, separated into individual enantiomers by salt formation with acids or bases in the form of individual enantiomers, chromatography on chiral stationary phases or derivatization using chiral compounds in individual enantiomeric forms such as amino acids, separation of the resulting diastereomers and removal of the chiral auxiliary groups; or

d) obtained by the variants of the method (a), (b) or (C) a compound of formula (I) or isolated in free form or in the presence of acidic or basic groups converted into a physiologically acceptable salt.

As a suitable protective group E is preferably used conventional in the chemistry of peptides N-protective is renisexyboy (Fmoc), allyloxycarbonyl (Aloc), or aminokislotnogo type, in particular formyl, acetyl or TRIFLUOROACETYL, and alkyl type, for example benzyl.

As compounds of the formula (III) in which R2means a hydrogen atom and R3means a typical remnant natural amino acids, preferably using glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid. Natural, however, synthetic amino acids contain functional groups as amino, hydroxyl, carboxyl, mercaptopropyl, guanidyl, imidazolyl or indolyl, in the side chain R3this group can also be protected.

In the case of the imidazole residue in R3for example, used for education sulfonamida derived sulfonic acids of the formula (IV) is used as a protective group of the imidazole nitrogen, which again can be split in particular in the presence of bases like sodium hydroxide solution.

To obtain the compounds of formula (I) in which R2and R3together form a cycle of partial structure (II), as the original Azin-2-carboxylic acid and hexahydropyridine-3-carboxylic acid, and in particular the nitrogen in position 4 of the piperazine-2-carboxylic acid can be substituted by a protective group Z, for example by benzyloxycarbonyl or tert.-butyloxycarbonyl, as described in the variant of the method), or by using a remainder R7.

As the original products to obtain derivatives of sulfonic acids of the formula (IV) are preferably sulfonic acids or their salts of the formula (X), such as:

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and R9means described in p. p. (2.1)-(2.14) residue.

To obtain arylsulfonyl formula (Ha) and (b) preferably used is described in the manual Houben-Weil "Methods of organic chemistry", volume 9, S. 450-546, methods of sulfonation with concentrated sulfuric acid, optionally in the presence of a catalyst, sulfur trioxide or its adducts or halogenocarboxylic as chlorosulfonic acid. Especially in the case of simple diphenyl ether of the formula (b) using concentrated sulfuric acid and acetic anhydride as solvent [see C. M. Suter, J. Am. Chem. Soc., 53, 1114 (1931)] or carry out the transformation with excess chlorosulfonic acid [J. P. Bassin, R. Cremlyn and F. Swinbourne, Phosphorus, Sulfur and Silicon, 72, 157 (1992)]. Sulfarsenides with sulfites, as sodium sulfite or ammonium sulfite, aqueous or aqueous-alcoholic solution, and the interaction can be accelerated in the presence of tetraalkylammonium salts, as tetrabutylammonium.

As derivatives of sulfonic acids of the formula (IV) are used in particular acid chlorides of sulfonic acids. To obtain the corresponding sulfonic acids, also in the form of their salts, as salts of sodium, ammonium or pyridinium, in a known manner enter into interaction with pentachloride phosphorus or thionyl chloride without solvent or in the presence of a solvent, such as oxytrichloride phosphorus, or an inert solvent like dichloromethane, cyclohexane or chloroform, at temperatures of reaction from the 20oC to the boiling point of the used reaction medium.

The interaction of derivatives of sulfonic acids of the formula (IV) with the amino acid of formula (III), (V) or (VII) according to the options method a), b) or C) preferably proceeds by reacting the Schotten's-Baumann. As the bases are suitable especially hydroxides of alkaline metals such as sodium hydroxide, however, acetates, bicarbonates, carbonates of alkali metals and amines. The interaction is carried out in water or miscible or Nestora reaction is maintained from -10oWith up to 50oC. In the case when the reaction is carried out in anhydrous medium, used primarily tetrahydrofuran or dichloromethane, acetonitrile or dioxane in the presence of a base, such as triethylamine, N-methylmorpholine, N-ethyl - or diisopropylethylamine, possibly in the presence of N,N-dimethylaminopyridine as a catalyst.

In another embodiment, aminocarbonyl acid of formula (III), (IV) or (VII) first using cilleruelo funds as bis-trimethylsilyltrifluoroacetamide (BSTFA), you can translate in their Siciliano form and then enter into interaction with derivatives of sulfonic acids with formation of compounds of formula (I).

Physiologically acceptable salts capable of salt formation of compounds of formula (I), including their stereoisomeric forms, get in a known manner. Carboxylic acids with basic reagents, as hydroxides, carbonates, bicarbonates, alcoholate, and also ammonia or with organic bases, such as trimethyl - or triethylamine, ethanolamine or triethanolamine, or with basic amino acids, such as lysine, ornithine or arginine, form stable alkali metal salts, alkaline earth metal or optionally substituted salt ü stable salt accession acids. For this purpose use as inorganic and organic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, benzosulfimide, n-toluensulfonate, 4-bromobenzonitrile, cyclohexanedicarboxylate, triftormetilfullerenov, acetic acid, oxalic acid, tartaric acid, succinic acid or triperoxonane acid.

The invention relates also to a medicinal product, characterized in that it contains an effective amount of at least one of the compounds of formula (I) and/or physiologically acceptable salts of the compounds of formula (I), and/or optionally stereoisomeric form of the compounds of formula (I) together with a pharmaceutically suitable and physiologically acceptable carrier, additive and/or other biologically active and auxiliary substances.

Based on the pharmacological properties of the proposed compound suitable for the prevention and treatment of all diseases, in the course of which involved enhanced activity destroys the matrix (intercellular substance of a tissue metalloproteinases. Such diseases include degenerative joint disease, as osteoar is uridine meniscus or kneecap or torn ligaments. Further, they include connective tissue disease, as collagenoses, periodontal disease, impaired wound healing and chronic diseases of the musculoskeletal system as inflammatory, due to immunological or metabolic acute and chronic arthritides, arthropathies, myalgias and disturbances of bone metabolism. Further, the compounds of formula (I) are suitable for the treatment of ulceration, atherosclerosis and stenosis. Further, the compounds of formula (I) are suitable for the treatment of inflammation, cancer, education, tumor metastasis, cachexia, anorexia and septic shock.

Offer medicines administered orally or parenterally. It is also possible rectal or transdermal administration.

The invention relates also to a method for producing a medicinal product, which is characterized in that at least one compound of formula (I) with pharmaceutically suitable and physiologically acceptable carrier and optionally other suitable biologically active substances, additives or auxiliary substances transferred in a suitable form for the application.

Suitable solid or galenovye forms of the compositions are, for example, g, drops or solutions for injection, and preparations with prolonged release of biologically active substances, upon receipt of which use conventional tools, as media, parafora, binder, means for coating, contributing to the swelling means giving lubricity (tablets) of the substance or lubricants, flavorings, sweeteners and agents of dissolution. As commonly used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oil, as fish oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and one - or polyhydric alcohols as glycerol.

Preferably the pharmaceutical drugs and get injected in the form of single doses, with each dose as an active integral part contains a certain number of compounds of formula (I). In the case of a solid single doses as tablets, capsules medicine tablets or suppositories, this quantity may be up to about Erno 300 mg, however, preferably about 10-100 mg.

For the treatment of adult patients weighing approximately 70 kg, depending on the activity of the compounds of formula (I), shows a daily dose of about 20-1000 mg of biologically active substances, preferably about 100-500 mg Under certain circumstances, however, you can also enter a higher or lower daily doses. The daily dose can be administered by a single dose single dose or several smaller doses, and by repeated introduction of fractional doses at certain intervals of time.

1H-NMR spectra are removed on the device company Varian 200 MHz, as a rule, when using tetramethylsilane (TMS) as an internal standard at room temperature. In each case specify the used solvents. The target products are typically characterized using mass spectroscopy techniques [fast atom bombardment (FAB) ionization electron spray (ESI)]. Temperature data are given in degrees Celsius, RT means room temperature (22-26oC). Used abbreviations are either explained or correspond to the generally accepted.

Example 1: N-(phenoxymethl mixed with 50 ml of 1 N. the sodium hydroxide solution and 50 ml of tetrahydrofuran. At a temperature of 5oWith and with stirring was added dropwise a solution of 16 g (59.5 mmol) of acid chloride of phenoxybenzenesulfonyl in 50 ml of tetrahydrofuran, and after adding half the number of the reaction mixture is mixed with 7.1 g (54,9 mmol) diisopropylethylamine. After stirring over night with 2 N. hydrochloric acid to establish a pH of 5.5 and repeatedly extracted with glacial acetic acid. The combined organic phase after drying over sodium sulfate filtered and evaporated under reduced pressure. Recrystallization from a mixture of glacial acetic acid with petroleum ether gives the above connection. Yield: 18.3 g (73% of theory); so pl.=134oC.

1H-NMR-spectrum (hexadeuterated dimethyl sulfoxide): 1,6-of 1.85 (m, 2H); 3,2 is-3.45 (m, 3H); 3.75 to 3,95 (m, 1H); of 7.0 to 8.1 (m, N).

Example 2: (2R)-1-(4-chlorophenylsulfonyl)-4-CIS - hydroxyproline [get on the variant of method (a)]

2 g (15,2 mmol) of D-CIS-hydroxyproline dissolved in anhydrous acetonitrile and together with 12.1 ml (46,7 mmol; 3,1 equivalent) batrineteasinguratatea (BSTFA) for two hours refluxed. Then mixed with a solution of 4.4 g (15,2 mm and under reflux. Roll a dense white precipitate of O-similarvideo N-sulfonated compounds. After cooling the suspension and complete deposition of this sediment is separated and well dried under reduced pressure. The yield of the reaction is quantitative. For desirelove 100 mg O-similarvideo connection handle 10 ml of methanol (Meon) and with 10 ml of 1 N. hydrochloric acid with the addition of 100 mg of potassium fluoride is stirred for two hours at room temperature. After the extraction of the precipitate and drying under reduced pressure to obtain the above product. Yield: 61 mg (84% of theory).

1H-NMR-spectrum (hexadeuterated dimethyl sulfoxide): 1,8-2,2 (m, 2H); 3.15 in (m, 1H); 3,3 (DD, 2H); 4.0 a (m, 1H); 4,3 (DD, 1H); 7,6;7,8 (2D, 4H); and 7.9 (s, 4H).

Example 29: (R)-N-(4-chlorophenylsulfonyl)tryptophan [get option method b)]

a). Methyl ester of (R)-N-(4-chlorophenylsulfonyl)tryptophan

to 5.1 g (20 mmol) of methyl ester hydrochloride D-tryptophan suspended in 50 ml of anhydrous acetonitrile, mixed with 2 g (20 mmol) of triethylamine and stirred at room temperature. After adding 6.2 ml (24 mmol) of BSTFA is stirred for two hours at a temperature of 80oWith, then was added dropwise a solution of 5.75 g (20 mmol) of CHL is their two hours at a temperature of 80oC. After cooling to room temperature, to the reaction mixture with stirring, add 100 ml of 1 N. hydrochloric acid, and falls crystalline precipitate. Recrystallization from a mixture of methanol with water gives the above methyl ester. Yield: 6.8 g (92% of theory); so pl. =189oC.

b). (R)-N - (4-chlorophenylsulfonyl)tryptophan

2,34 (5 mmol) videolounge difficult methyl ester are dissolved in 30 ml of methanol and after adding 10 ml of 1 n sodium hydroxide solution is stirred for 6 hours at a temperature of 40oC. Acidification of the solution with 1 N. hydrochloric acid to pH 6 gives the above carboxylic acid in crystalline form. Yield: 1.8 g (81% of theory); so pl.=138-140oC.

1H-NMR-spectrum (hexadeuterated dimethyl sulfoxide): 2,8 of 2.92 (m, 1H); 3,0-of 3.12 (m, 1H); 3,83-of 3.97 (m, 1H); 6,85 one-7.8 (m, 13H); and 8.3 (d, 1H); is 10.75 (s, 1H); and 12.4 (s, 1H).

The compounds specified in the examples, which are given in table 1, receive according to the methods of examples 1, 2 and 29.

The drugs examples

The receipt and determination of the enzymatic activity of the catalytic domains of human stromelysin and neutrophiles collagenase

Both enzyme - stromelysin (MMP-3) and neutrophiles to or action inhibitor of the enzyme 70 μl of buffer solution of the enzyme with 10 ál of 10% (by volume) aqueous solution of dimethyl sulfoxide, which optionally contains an inhibitor of the enzyme, incubated for 15 minutes. After adding 10 μl of 10% (by volume) aqueous solution of dimethyl sulfoxide, which contains 1 mmol/l substrate, for an enzymatic reaction observed by fluorescence spectroscopy (328 nm (ex)/393 nm (em)).

Enzymatic activity get in the form of increase in extinction / minute. Listed in the table 2 values IR50defined as the concentration of inhibitor that results in each case to a 50% increase inhibition of the enzyme.

Buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) and 0.1 mol/l Tris/Hcl; 0.1 mol/l NaCI; 0.01 mol/l CaCl2and 0.1 mol/l of piperazine-N,N'-bis[2-econsultancy] (pH 6.5).

The enzyme solution contains 5 mg/ml of one of the received Ye and other domains of the enzyme. The substrate solution contains 1 mmol/l fluorogenic substrate (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2', 4'-dinitrophenyl)-L-2,3 - diaminopropionic-l-AGD-NH2(Bachem, Heidelberg, Germany).

1. Sulphonilecarbomide acid of the formula (I)

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and/or a stereoisomeric form of the compounds of formula (I) and/or a physiologically acceptable salt of the compounds of formula (I),

where R1tila; group (C1-C6)-alkyl-O-C(O)-; methylendioxy; group R4-(R5)N-; heteroaromatic residue, which is a triazole, thiophene, pyridine;

R2means a hydrogen atom, (C1-C6)-alkyl;

R4and R5are the same or different and mean a hydrogen atom, (C1-C6)-alkyl;

R3means a hydrogen atom; (C1-C10) alkyl-, where the alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl; (C2-C10)-alkenyl-where alkenyl is linear or branched; R2-S(O)n-(C1-C6)-alkyl-, and n means an integer zero, 1 or 2; R2-S(O)(= NH)-(C1-C6)-alkyl-; a group of the formula

< / BR>
where n means zero, W stands for a sulfur atom; phenyl - (CH2)m- where m means 0, 1, 2 or 3 and/or one atom of hydrogen, - (CH2)m-chain substituted by hydroxyl and phenyl unsubstituted or one - or twofold substituted by a group (C1-C6)-alkyl-O, trifluoromethyl; -O-(CH2)m-phenyl, where phenyl unsubstituted or one - or twofold substituted by a group R4-(R5)N -, and m means 0, 1, 2, 3, 4, 5 or 6; -C(O)-(CH2)m-phenyl, where phenyl unsubstituted or mono - or twice will znachit the imidazole, thiophene, indole or benzothiophene, m have the above significance and/or one atom of hydrogen,- (CH2)-chains substituted by hydroxyl; -(CH2)m-P(O)(OH)-(C1-C3)-alkyl, where m has the above meaning;

or R2and R3together form a cycle with a carboxyl group as a substituent cycle chastenay formula (II)

< / BR>
where r is 0, 1, 2 or 3 and/or one of the carbon atoms in the cycle replaced by-O-,

and/or the carbon atom in the cycle of partial formula (II) once substituted by phenyl;

And means covalent bond; -O-;

In means (CH2)mwhere m denotes zero;

X is the group-CH= CH - or a sulfur atom.

2. The compound of formula (I) under item 1, wherein R1means phenyl, phenyl, once substituted by a group (C1-C6)-alkyl-O, a halogen trifluoromethyl group, R4-(R5)N-; R2means a hydrogen atom, (C1-C6)-alkyl; R4and R5are the same or different and mean a hydrogen atom, (C1-C6)-alkyl; R3means (C1-C10)-alkyl-, where the alkyl is a linear, branched or cyclic and/or where one carbon atom alkyl residue substituted by hydroxyl; R2-S(O)n)m- where m is 1, 2 or 3 and/or one atom of hydrogen,- (CH2)m-chain substituted by hydroxyl and phenyl unsubstituted or one - or twofold substituted by a group (C1-C6)-alkyl-O, trifluoromethyl; heteroaryl-(CH2)mwhere heteroaryl means imidazole, thiophene or indole, m is 1, 2 or 3, and/or one atom of hydrogen,- (CH2)-chains substituted by hydroxyl; R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula (II), where r is 1 or 2 and/or one of the carbon atoms in the cycle are replaced by-O-, and/or the carbon atom in the cycle of partial formula (II) once substituted by phenyl; a represents a covalent bond, -O-; In means (CH2)mwhere m denotes zero; x is the group-CH= CH-.

3. The compound of formula (I) under item 1, wherein R1means phenyl, phenyl, substituted once by halogen, in particular chlorine or fluorine, R4-(R5)N-; R2means a hydrogen atom; R4and R5are the same or different and mean (C1-C3)-alkyl; R3means heteroaryl-(CH2)mwhere heteroaryl means thiophene or indole, m denotes 1 or 2; a represents a covalent bond; means (of Sanovich acids of the formula (VI)

< / BR>
and/or a stereoisomeric form of the compounds of formula (VI) and/or a physiologically acceptable salt of the compounds of formula (VI), and R1AND, X, R2and R3have the meanings specified for compounds of formula (I) under item 1, R8denotes a hydrogen atom, (C1-C6)-alkyl or phenyl.

 

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