RU2471783C2 - Sulphonamide derivatives as chymase inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new sulphonamide derivatives of formula

wherein fragment

represents fragment

and wherein X represents phenylene optionally substituted by one, two or three substitutes optionally specified in a group consisting of halogen, C_1-6-alkyl, C_1-6-alkoxy, halogen-C_1-6-alkyl, halogen-C_1-6-alkoxy, C_1-6-alkylsulphonyl, C_1-6-alkylthionyl, C_1-6-alkylthio group, C_1-6-alkylsulphonyl-C_1-6-alkyl, C_1-6-alkylthionyl-C_1-6-alkyl, C_1-6-alkylthio-C_1-6-alkyl and C_1-6-alkoxycarbonyl; Y represents pyridyl, pyrimidinyl or piperidyl which may be optionally substituted by one or two substitutes optionally specified in a group consisting of halogen, C_1-6-alkoxy and C_1-6-alkoxycarbonyl; or to its pharmaceutically acceptable salts. The sulphonamide derivatives of formula (I) represent chymase inhibitors and are applicable for preparing a pharmaceutical composition.

EFFECT: sulphonamide derivatives of formula (I) as chymase inhibitors.

8 cl, 36 ex

Description

The invention relates to new sulfonamide derivatives of the formula (I),

Where

A is a phenyl ring, or a heteroaryl ring, which is a monocyclic aromatic ring of 5 or 6 atoms, containing one or two heteroatoms selected from N, O and S, and the remaining ring atoms are C, or a heterocyclic ring, which is a non-aromatic monocyclic ring of 5 or 6 atoms, containing one or two heteroatoms selected from N and S (O) _n (where n is an integer from 0 to 2), and the remaining atoms of the ring are C, and one of the carbon heterocyclic ring atoms may optionally be replaced by a carbonyl group;

R ¹ and R ^{1 '} independently represent hydrogen, halogen, nitro, cyano, amino, C _1-6 alkyl, heteroalkyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxyl, C _{1- 6} alkoxy groups, -NR'R ", - (C _0-6 alkylene) -NR'R""groups, where R 'and R" are independently selected from the group consisting of hydrogen, C _1-6 alkyl, heteroalkyl , formyl, C _1-6 alkylcarbonyl, optionally substituted C _3-7 cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heter ocyclocarbonyl, C _1-6 alkylsulfonyl, optionally substituted C _3-7 cycloalkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl and optionally substituted heterocyclicsulfonyl groups, or - (C _0-6 alkylene) -OR ', where R' represents hydrogen, C _1-6 alkyl, heteroalkyl, formyl or C _1-6 alkylcarbonyl groups, or R ^{1 'is} not present, but only R ^{1 is} present;

R ² , R ^{2 '} and R ^2'' independently represent hydrogen, halogen, cyano, nitro, amino, mono and di-C _1-6 alkyl substituted amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroalkyl, hydroxy or C _1-6 alkoxy groups;

X is phenylene optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano, nitro, amino, mono and di-C _1-6 alkyl, substituted amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, heteroalkyl, hydroxy, C _1-6 alkoxy, halo-C _1-6 alkyl, halogen C _1-6 alkoxy, heteroalkyloxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl-C _1-6 alkyl, C _1-6 alkylsulfinyl-C _1-6 alkyl, C _1-6 alkylthio-C _1-6 alkyl, acyl, formyl, C _1-6 alkoxic arbonyl, halo C _1-6 alkoxycarbonyl, heteroalkyloxycarbonyl and heteroalkylcarbonyl groups;

Y is an optionally substituted heteroaryl, where heteroaryl is a monocyclic aromatic radical containing 6 atoms in the ring, containing one or two heteroatoms in the ring selected from N (O) _n (where n is 0 or 1), O and S, and the remaining ring atoms are C, or

optionally substituted heterocyclyl, where heterocyclyl is a non-aromatic monocyclic radical containing six atoms in the ring, containing in the ring one or two heteroatoms selected from N, O, or S (O) _n (where n is an integer from 0 to 2) and the remaining ring atoms are C;

as well as prodrugs and their pharmaceutically acceptable salts.

In addition, the invention relates to a method and intermediates for the preparation of the above compounds, pharmaceutical preparations that contain such compounds, the use of these compounds for the manufacture of pharmaceutical preparations, as well as a method for the preparation of intermediates.

The compounds of formula (I) inhibit chymase. Chymase is a serine proteinase with an expression pattern strictly limited to a mast cell subpopulation (M _CT mast cells). Chymase is activated only when mast cells are activated and degranulated, which limits the activity of the enzyme to only M _CT positive tissues. Chymase specifically cleaves a number of pathologically significant substrates (Raymond, WW, SWRuggles et al .; JBC 2003 278 (36): 34517-34524), whereby this enzyme can activate angiotensin II, endothelin, TGF-b, IL1, SCF (stem factor cells), collagenase and cause degradation of proteins such as thrombin, FN (fibronectin), APO A1,2 (apoliprotein). This pattern makes chymase an attractive target for allergic, inflammatory, and fibrotic diseases. Indeed, a number of successful studies in animals with chymase inhibitors have shown efficacy in animals with allergies, vascular injuries, and atherosclerosis (Doggrell SA, Wanstall JC Can J Physiol Pharmacol. February 2005; 83 (2): 123-30; Lindstedt KA, Kovanen PT Curr Opin Lipidol. October 2004; 15 (5): 567-73; Reed CE, Kita HJ Allergy Clin Immunol. November 2004; 114 (5): 997-1008; Takai S, et al. Eur J Pharmacol, October 2004 6; 501 (1-3): 1-8; Takai S, et al, Trends Pharmacol Sci. October 2004; 25 (10): 518-22; Takai S, Miyazaki M. Curr Vasc Pharmacol. June 2003; l (2): 217-24).

Thus, inhibition of chymase is a useful mechanism for allergies, asthma, occlusive peripheral artery disease, critical limb ischemia (CLI), the treatment of patients with vulnerable atherosclerotic plaques, unstable angina pectoris, congestive heart failure, left ventricular hypertrophy, ischemic reperfusion injury, cardi restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, wound healing (burns / ulcers in patients with Sakha diabetes mellitus / CLI).

The present invention provides novel compounds of formula (I) as chymase inhibitors.

Unless otherwise specified, the following definitions are provided to illustrate and determine the meaning and breadth of the meanings of various terms used to describe the invention in this document.

The term “halogen” or “halo” is fluoro, chloro, bromo and iodo, preferably fluoro, chloro.

The term “C _1-6 alkyl”, alone or in combination with other groups, is an unbranched or branched monovalent alkyl radical containing from one to six carbon atoms. This term can also be illustrated by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. C _1-4 alkyl is more preferred.

The term “halogen C _1-6 alkyl”, alone or in combination with other groups, is C _1-6 alkyl in which one or more hydrogen atoms are replaced by the same or different halogens, such as —CH ₂ Cl, —CH ₂ CF ₃ , trifluoromethyl. As halogens, chlorine, bromine or fluorine are preferred, and chlorine or fluorine are more preferred.

The term “C _1-6 alkoxy halogen”, alone or in combination with other groups, is a C _1-6 alkoxy group in which one or more hydrogen atoms are replaced by the same or different halogens. As halogens, chlorine, bromine or fluorine are preferred, and chlorine or fluorine are more preferred.

The term “acyl”, alone or in combination with other groups, is —CO — C _1-6 alkyl.

The term “heteroalkyl” is C _1-6 alkyl substituted with one or more substituents independently selected from the group consisting of nitro, hydroxy, halogen, cyano, C _1-6 alkoxy, formyl, C _1-6 alkylcarbonyl, carboxyl, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, amino, and mono- and di-C _1-6 alkyl substituted amino groups. This term can also be illustrated by radicals such as 2-hydroxyethyl, perfluoromethyl.

The term “C _3-7 cycloalkyl”, alone or in combination with other groups, is a saturated monovalent cyclic hydrocarbon radical containing from three to seven carbon atoms in the ring, for example cyclopropyl, cyclobutyl, cyclohexyl.

The term "C _1-6 alkoxy", alone or in combination with other groups, represents an R'-O- group, where R 'is C _1-6 alkyl.

The term “C _2-6 alkenyl”, alone or in combination with other groups, is a straight or branched hydrocarbon residue containing a double bond comprising from two to six carbon atoms, such as, for example, ethenyl, 2-propenyl.

The term “C _2-6 alkynyl”, alone or in combination with other groups, represents a straight or branched hydrocarbon residue containing a triple bond comprising from two to six carbon atoms, such as, for example, ethynyl, 2-propynyl.

The term “C _0-6 alkylene” is a bond, or an unbranched or branched divalent saturated aliphatic hydrocarbon group comprising from 1 to 6 carbon atoms. C ₀ alkylene is a bond.

The term "aryl", alone or in combination with other groups, represents a phenyl or naphthyl group, preferably a phenyl group.

The term “heterocyclyl”, alone or in combination with other groups, is a non-aromatic mono- or bicyclic radical containing from three to eight atoms in a ring, where one or two ring atoms are heteroatoms selected from N, O, or S ( O) _n (where n is an integer from 0 to 2), and the remaining ring atoms are C.

The term “heteroaryl” is a monocyclic or bicyclic radical containing from 5 to 12 atoms in a ring, containing at least one aromatic ring containing one, two or three heteroatoms in a ring selected from N, O and S, and the remaining ring atoms are C. Preferably, the heteroaryl radical is attached to the compound on an aromatic ring.

The terms “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted heterocyclyl” and “optionally substituted C _3-7 cycloalkyl” are respectively aryl, heteroaryl, heterocyclyl and C _3-7 cycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, cyano, amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, hydroxy, C _1-6 alkoxy, heteroalkyloxy, mono and di C _1-6 alkyl substituted amino, acyl, formyl, heteroal kilkarbonyl, C _1-6 alkoxycarbonyl, heteroalkyloxycarbonyl and heteroalkyl groups.

Preferred radicals for the chemical groups defined above are given in the examples.

The compounds of formula (I) can form pharmaceutically acceptable addition salts (with acid). Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulphurous acid and phosphoric acid, or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salt" refers to such salts. Compounds of formula (I) in which a COOH group is present can also form salts with bases. Examples of such salts are alkali metal, alkaline earth metal salts and ammonium salts, such as, for example, Na-, K-, Ca- and trimethylammonium salts. The term "pharmaceutically acceptable salt" also refers to such salts. Acid addition salts as described above are preferred.

The terms “optional” or “optionally” mean that the subsequent described phenomenon or circumstance may, however, not necessarily occur, and that the description includes instances where the phenomenon or circumstance occurs and instances where this does not occur. For example, the term “optionally substituted aryl group with an aryl group” means that an alkyl group may, however, not necessarily be present, and this description includes a situation where the aryl group is substituted by an alkyl group, and a situation where the aryl group is not substituted by an alkyl group.

A “pharmaceutically acceptable excipient” is an excipient that is useful in the manufacture of a pharmaceutical composition that is completely safe, non-toxic and not biologically or otherwise undesirable, and includes excipients that are acceptable to the veterinary application, as well as for pharmaceutical use for humans. The term "pharmaceutically acceptable excipient", as used in the description and claims, includes both one or more such excipients.

Compounds that have the same molecular formula, but differ in nature or in the sequence of bonds of their atoms, or in the arrangement of atoms in space, are called “isomers”. Isomers that differ in the arrangement of atoms in space are called “stereoisomers”. Stereoisomers that are not mirror images of one another are called “diastereomers”, and stereoisomers that are non-superposition mirror images of one another are called “enantiomers”. If the compound has an asymmetric center, for example, if the carbon atom is bonded to four different groups, a pair of enantiomers can form. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described using the R- and S- nomenclature of Kahn, Ingold and Prelog, or characterized by how the molecules rotate the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., as (+) - or (-) - isomers, respectively). Chiral compounds may exist as single enantiomers or as mixtures. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

Compounds of formula (I) may possess one or more asymmetric centers. Unless otherwise indicated, the description or name of a particular compound in the description and claims includes both both individual enantiomers and mixtures thereof, whether racemic or not, as well as individual epimers and mixtures thereof. Methods for determining stereochemistry and separation of stereoisomers are well known in the art.

Although the definitions of A, R ¹ -R ^{2 ″} , X, and Y are broadly given previously, certain radicals are preferred.

I) In the compound of formula (I), A is preferably a phenyl ring or heteroaryl ring. The heteroaryl ring A is also preferably a five-membered ring.

II) In the compound of formula (I),

preferably represents

,

или

,

or

more preferably

represents

,

или

,

or

in which R ¹ and R ^{1 '} independently represent hydrogen or C _1-6 alkyl,

even more preferably

represents

,

или

,

or

in which R ² , R ^{2 '} and R ^{2 "} independently represent hydrogen or halogen.

 particularly preferably

III) In the compound of formula (I), Y is preferably in the para position in the phenylene group as X, with respect to the —NH — SO ₂ group.

IV) In the compound of formula (I), X is preferably phenylene optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl-C _1-6 alkyl, C _1-6 alkylsulfinyl-C _1-6 alkyl C _1-6 alkylthio-C _1-6 alkyl and C _1-6 alkoxycarbonyl groups; more preferably X is phenylene substituted with a halo of C _1-6 , alkyl or C _1-6 alkylsulfonyl groups in the ortho position with respect to the —NH — SO ₂ group, even more preferably X is phenylene substituted with trifluoromethyl or methylsulfonyl groups in the ortho position relative to the —NH — SO ₂ group.

V) In the compound of formula (I), Y is preferably an optionally substituted heteroaryl, where heteroaryl is a monocyclic aromatic radical containing 6 atoms in the ring, containing one or two nitrogen atoms in the ring, and the remaining atoms of the ring are C, or optionally substituted heterocyclyl, where heterocyclyl is a non-aromatic cyclic mono radical containing 6 atoms in the ring, containing one or two nitrogen atoms in the ring, and the remaining atoms of the ring are C.

More preferably, Y is pyridyl, pyrimidinyl or piperidyl optionally substituted with one or two substituents independently selected from the group consisting of halogen, C _1-6 alkoxy and C _1-6 alkoxycarbonyl groups.

VI) Preferably, the compound of the invention is a compound of formula (I), which is 5-fluoro-3-methyl-benzo [b] thiophen-2- (4-pyridin-4-yl-2-trifluoromethyl-phenyl) -amide sulfonic acids.

Compounds of the present invention can be obtained, for example, using the general methods of synthesis described below.

General synthesis methods

Scheme 1

In Scheme 1, A, R ¹ -R ^{2 ″} , X, Y, and Hal are defined previously. R ⁴ , R ^{4 '} and R ^4'' independently represent hydrogen, halogen, cyano, nitro, amino, mono and di C _1-6 alkyl substituted amino groups, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, heteroalkyl, hydroxy, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, heteroalkyloxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylthio , C _1-6 alkylsulfonyl-C _1-6 alkyl, C _1-6 -alkylsulfinyl C _1-6 alkyl, C _1-6 alkylthio C _1-6 alkyl, acyl, formyl, C _1-6 alkoxycarbonyl, halo C _{1- 6} alkoxycarbonyl, or geteroalkiloksikarbonilnuyu geteroalkilk rbonilnuyu group.

The compounds of formulas (I) and (II) were predominantly prepared by the reaction of sulfonyl chloride (B) with an amine (A) or with aniline (C) in the presence of a base. The base is preferably sodium hydride or an amine selected from the group consisting of pyridine, picoline, triethylamine, diethylamine, 4-N-dimethylaminopyridine diisopropylethylamine. The most preferred amines are pyridine and N, N-dimethylaminopyridine (DMAP). Aprotic solvents are preferred, preferably selected from acetonitrile, dioxane, methylene chloride, tetrahydrofuran, toluene, dimethoxyethane, N, N-dimethylacetamide, dimethyl sulfoxide, dimethylformamide, and combinations thereof. Preferably, the temperature is in the range from 0 ° C to 100 ° C.

Using compound (II) as an intermediate, compounds of formula (I) can be prepared using C — C bond formation reactions, such as the Suzuki reaction, in which the halide reacts with a suitably substituted boronic acid derivative in the presence of a base and a palladium catalyst.

Sulfonyl chlorides (B) are either commercially available or can be synthesized using modern methods from naphthalene, or bicyclic heteroaromatic compounds, or their derivatives. In particular, the sulfonyl chloride group can be introduced using the reaction of an aryl lithium salt with sulfur dioxide and subsequent oxidation / chlorination using, for example, sulfuryl chloride or N-chlorosuccinimide. Alternatively, the activated position of the aromatic ring can react with chlorosulfonic acid or with a complex of sulfur trioxide, such as SO ₃ · DMF or SO ₃ · pyridine, followed by chlorination, for example, with thionyl chloride.

Anilines (A) are either commercially available compounds, or can be synthesized using modern methods. One option is to introduce halogenated compounds (C) into a C — C bond formation reaction, such as the Suzuki reaction, in which the halide reacts with a suitably substituted boronic acid derivative in the presence of a base and a palladium catalyst. Halogenated derivatives of aniline (C) are either commercially available or can be synthesized using modern methods.

As described above, the compounds of formula (I) are active compounds and inhibit chymase. Therefore, these compounds prevent the activation of angiotensin II, endothelin, TGFb, IL1, SCF, collagenase and cause the degradation of proteins such as thrombin, FN, APO A1,2. Therefore, they can be used to treat and / or prevent allergic, inflammatory and / or fibrotic diseases, such as allergies, asthma, peripheral arterial occlusive disease, critical limb ischemia (CLI), patients with vulnerable atherosclerotic plaques, unstable angina, congestive heart failure , left ventricular hypertrophy, ischemic reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, pain Hb Crohn's disease, atherothrombosis and / or burns / ulcers in patients with diabetes / CLI.

Prevention and / or treatment of allergic, inflammatory or fibrotic diseases, especially atherothrombosis or asthma, are preferred applications.

The invention also relates to a pharmaceutical composition comprising the compound described above, as well as a pharmaceutically acceptable excipient.

The invention also encompasses compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and / or prevention of allergic, inflammatory and / or fibrotic diseases, such as allergies, asthma, peripheral arterial occlusive disease, critical limb ischemia (CLI), patients with vulnerable atherosclerotic plaques, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemic reperfu Ion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, atherothrombosis and / or burns / ulcers in patients with diabetes / CLI.

The invention also relates to the use of the compounds described above for the manufacture of drugs for the therapeutic and / or prophylactic treatment of allergic, inflammatory and / or fibrotic diseases, especially for the therapeutic and / or prophylactic treatment of allergies, asthma, peripheral arterial occlusive disease, critical ischemia limbs (CLI), patients with vulnerable atherosclerotic plaques, unstable angina pectoris, congestive heart failure, lion hypertrophy third ventricle, ischemic reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, atherothrombosis and / or burns / ulcers in patients with diabetes / CLI. Such drugs include compounds as described above.

The invention also relates to a preparation method and intermediates for preparing compounds of formula (I), as well as a method for preparing intermediates.

Inhibition of chymase by the compounds of the present invention can be demonstrated using a peptide substrate, as described herein below.

For the chymase, a substrate containing a peptide of 4 amino acids AAPF was selected as the standard substrate for the chemotrypsin-like compound (succinyl-Ala-Ala-Pro-Phe- [7-amino-4-methylcoumarin]; see Lockhart BE, et al., " Recombinant human mast-cell chymase: an improved procedure for expression in Pichia pastoris and purification of the highly active enzyme. "Biotechnol Appl Biochem., Published as immediate publication on May 26, 2004 in the form of manuscript BA 20040074). The peptide was synthesized with a purity of 95% (Bachem, Bubendorf, Switzerland). The chymase was purified from human skin mast cells obtained from Calbiochem (Merck Biosciences, San Diego, California, USA). The test used 0.15 M NaCl, 0.05, Tris-HCl, 0.05% CHAPS (3 - [(3- [cholamidopropyl) dimethylammonium] -1-propanesulfonate) buffer, 0.1 mg / ml heparin solution (Heparin sodium, Sigma, from pig intestinal mucosa), 0.02 mM AAPF substrate solution, 1 nM chymase solution at pH 7.4. The analysis was performed in 96-well plates (Optiplate Packard), in a volume of 0.05 ml at room temperature. The activity of chymase was determined by the initial growth rate of fluorescence at 340/440 nm (excitation / radiation) of free 7-amino-4-methylcoumarin, cleaved from the substrate. Inhibition of enzyme activity by inhibitory compounds was measured after 30 minutes of pre-incubation with chymase at room temperature in a buffer without an AAPF substrate. Then the test was started by adding the indicated concentration of the AAPF substrate.

IC50 values (semi-inhibitory concentration) of the active compounds of the present invention are preferably from about 1000 to 1 nM, particularly preferably from 30 to 1 nM.

Example IC50 (nM) Example 2 35 Example 16 106 Example 21 3

The compounds of formula (I) and / or their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be used, for example, orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, for example in the form of suppositories, parenterally, for example in the form of injectable solutions, or suspensions, or infusion solutions, or topically, for example in the form of ointments, creams and oils. Oral administration is preferred.

The manufacture of pharmaceutical preparations can be carried out, as is known to specialists in this field of technology, by introducing the described compounds of formula (I) and / or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, in a galenic form together with suitable, non-toxic, inert , therapeutically compatible solid or liquid carrier materials, and, if necessary, with conventional pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. For example, lactose, corn starch or derivatives thereof, talc, stearic acid and its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (in the case of soft gelatine capsules as an administration form, carriers may, however, not be required, depending on the nature of the active ingredient). Suitable carrier materials for the production of syrups and solutions are, for example, water, polyols, sucrose, invert sugar. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerin and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils (hydrogenated), waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for the preparation of topical dosage forms are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

As pharmaceutical adjuvants, conventional stabilizers, preservatives, moisturizing and emulsifying agents, consistency improving agents, flavoring agents, salts for varying the osmotic pressure, buffering agents, solubilizers, colorants, masking agents and antioxidants can be used.

The dosage of the compounds of formula (I) can vary widely depending on the diseases to be treated, age, individual condition of the patient, mode of administration, and, of course, must be determined individually in each case. For adult patients, the daily dose is from 1 to 1000 mg, especially from about 1 to 300 mg. Depending on the severity of the disease and the exact pharmacokinetic profile, the compound may be administered in one or more daily unit dosage forms, for example, from 1 to 3 daily unit dosage forms.

Dosage forms may contain about 1-500 mg, preferably 1-100 mg, of a compound of formula (I).

Examples

The following examples serve to illustrate the present invention in more detail. They, however, in no way limit it.

Example 1

5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (4-bromo-2-trifluoromethyl-phenyl) -amide

To an ice-cooled solution of 4-bromo-2- (trifluoromethyl) benzamine (CAS 445-02-3, 18 g) in pyridine (25 ml) was added 5-fluoro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (CAS: 404964-34-7, 2.0 g). The reaction mixture was stirred at room temperature for 72 hours, concentrated in vacuo, and the residue was chromatographed on silica gel using heptane / chloroform as an eluent to give (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3- methyl benzo [b] thiophene-2-sulfonic acid (2.35 g) as a colorless solid. MS (ISN): 465.9, 468.0 (M-H) ^-

Example 2

(4-Pyridin-4-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

Suspension of (4-bromo-2-trifluoromethyl-phenyl) -amide of 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.5 g) and 4-pyridineboronic acid (0.197 g) in 1.2 -dimethoxyethane (6 ml), ethanol (2 ml) and a 2 M aqueous solution of sodium carbonate (4.0 ml) were degassed 3-4 times to remove oxygen, and then tetrakis (triphenylphosphine) palladium (0.065 g) was added to the suspension. The reaction mixture was stirred at 80 ° C for 3 hours, quickly diluted with ice / water and extracted with ethyl acetate. The organic layers were washed, dried and concentrated. The residue was chromatographed on silica gel using heptane / ethyl acetate as eluent to afford the title compound (0.35 g) as a yellowish solid. MS (ISP): 467.3 (M + H) ⁺

Example 3

[4- (2,6-difluoro-pyridin-4-yl) -2-trifluoromethyl-phenyl] -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acids

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.12 g) and 2.6 -difluoropyridin-4-boronic acid (0.063 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and a 2M aqueous solution of sodium carbonate (1.0 ml) with tetrakis (triphenylphosphine) palladium (0.055 g). The indicated compound was obtained (0.055 g) as a brownish solid. MS (ISP): 520.2 (M + NH4) ⁺

Example 4

[4- (3-fluoro-pyridin-4-yl) -2-trifluoromethyl-phenyl] -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.12 g) and 3- hydrate fluoropyridin-4-boronic acid (0.061 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and 2M aqueous sodium carbonate solution (1.0 ml) with tetrakis (triphenylphosphine) palladium ( 0.050 g). The indicated compound was obtained (0.025 g) as a yellowish foam. MS (ISP): 485.3 (M + H) ⁺

Example 5

[4- (2-fluoro-pyridin-4-yl) -2-trifluoromethyl-phenyl] -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.12 g) and 2-fluoropyridine -4-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and 2M aqueous sodium carbonate solution (1.0 ml) with tetrakis (triphenylphosphine) palladium (0.065 d). The indicated compound was obtained (0.085 g) as a colorless foam. MS (ISN): 483.4 (M-H) ^-

Example 6

(4-pyridin-3-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.10 g) and 3-pyridinboronic acid (0.052 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and a 2M aqueous solution of sodium carbonate (0.8 ml) with tetrakis (triphenylphosphine) palladium (0.050 g). The title compound was obtained (0.086 g) as a colorless solid. MS (ISP): 467.0 (M + H) ⁺

Example 7

[4- (6-methoxy-pyridin-3-yl) -2-trifluoromethyl-phenyl] -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.10 g) and 2-methoxy -5-pyridineboronic acid (0.065 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and 2M aqueous sodium carbonate solution (0.8 ml) with tetrakis (triphenylphosphine) palladium (0.012 d). The specified compound was obtained (0.081 g) as a colorless solid. MS (ISP): 497.3 (M + H) ⁺

Example 8

(4-pyrimidin-5-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.10 g) and pyrimidine-5 -boronic acid (0.053 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and 2M aqueous sodium carbonate solution (0.8 ml) with tetrakis (triphenylphosphine) palladium (0.012 g) . The specified compound was obtained (0.045 g) as a colorless solid. MS (ISN): 466.1 (M-H) ^-

Example 9

[4- (2-methoxy-pyrimidin-5-yl) -2-trifluoromethyl-phenyl] -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.10 g) and 2-methoxy -5-pyrimidine boronic acid (0.066 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and a 2M aqueous solution of sodium carbonate (1.0 ml) with tetrakis (triphenylphosphine) palladium (0.012 d). The title compound was obtained (0.064 g) as a colorless solid. MS (ISP): 498.4 (M + H) ⁺

Example 10

[4- (5-Fluoro-pyridin-3-yl) -2-trifluoromethyl-phenyl] -amide of 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.12 g) and 5-fluoropyridine -3-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and 2M aqueous sodium carbonate solution (1.0 ml) with tetrakis (triphenylphosphine) palladium (0.015 d). The specified compound was obtained (0.065 g) as a colorless solid. MS (ISP): 485.3 (M + H) ⁺

Example 11

[4- (6-fluoro-pyridin-3-yl) -2-trifluoromethyl-phenyl] -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.12 g) and 2-fluoropyridine -5-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.32 ml) and 2M aqueous sodium carbonate (1.0 ml) with tetrakis (triphenylphosphine) palladium (0.015 d). The specified compound was obtained (0.070 g) as a colorless solid. MS (ISP): 485.3 (M + H) ⁺

Example 12

[4- (1-hydroxy-pyridin-4-yl) -2-trifluoromethyl-phenyl] -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

To a solution of (4-pyridin-4-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid (see Example 2, 0.27 g) in chloroform ( 5.0 ml) 85% m-chloroperoxybenzoic acid solution (0.195 g) was added. The reaction mixture was stirred at room temperature for 4 hours and washed with sodium bicarbonate solution. The organic phases were dried over magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column (10 g) using a dichloromethane / methanol mixture as eluent to give the title compound (0.065 g) as a yellow foam. MS (ISP): 483.4 (M + H) ⁺

Example 13

(2-methylsulfanylmethyl-4-pyridin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

a) (4-bromo-2-methylsulfanylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 1 of 4-bromo-2-methylsulfanylmethyl-phenylamine (Allen, David George; Eldred, Colin David; Judkins, Brian David; Mitchell, William Leonard, WO 9749699, 4.6 g) and 5 -fluoro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (1.06 g). The desired compound was obtained (1.3 g) as a brownish solid. MS (ISN): 458.1, 460.0 (M-H) ^-

b) (2-methylsulfanylmethyl-4-pyridin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-methylsulfanylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.23 g) and 4-pyridinorone acid (0.092 g) in 1,2-dimethoxyethane (10 ml), ethanol (2 ml) and a 2M aqueous solution of sodium carbonate (2 ml) with tetrakis (triphenylphosphine) palladium (0.058 g). The title compound was obtained (0.153 g) as a brown foam (0.153 g). MS (ISN): 457.2 (M-H) ^-

Example 14

(2-methanesulfinylmethyl-4-pyridin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

a) (4-bromo-2-methanesulfinylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

To a solution of (4-bromo-2-methylsulfanylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.46 g) (see example 13a) in chloroform (25 ml) 85% m-chloroperoxybenzoic acid solution (0.272 g) was added. The reaction mixture was stirred at room temperature for 18 hours, concentrated, and the crude residue was chromatographed on silica gel using heptane / ethyl acetate as eluent to give the desired compound (0.31 g) as an off-white solid. MS (ISN): 473.9, 476.0 (M-H) ^-

b) (4-bromo-2-methanesulfinylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-methanesulfinylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.238 g) and 4-pyridinboronic acid ( 0.092 g) in 1,2-dimethoxyethane (10 ml), ethanol (2 ml) and a 2M aqueous solution of sodium carbonate (2 ml) with tetrakis (triphenylphosphine) palladium (0.058 g). The title compound was obtained (0.077 g) as a yellowish foam. MS (ISN): 473.3 (M-H) ^-

Example 15

(2-methanesulfonylmethyl-4-pyridin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

a) (4-bromo-2-methanesulfonylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [B] thiophene-2-sulfonic acid

To a solution of (4-bromo-2-methylsulfanylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.46 g) (see Example 13a) in chloroform (25 ml) 85% m-chloroperoxybenzoic acid solution (0.272 g) was added. The reaction mixture was stirred at room temperature for 18 hours, concentrated, and the crude residue was chromatographed on silica gel using heptane / ethyl acetate as eluent to give the desired compound (0.138 g) as a brownish solid. MS (ISN): 490.0, 492.0 (M-H) ^-

b) (2-methanesulfonylmethyl-4-pyridin-4-phenyl-yl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

This compound was obtained by analogy with Example 2 from (4-bromo-2-methanesulfinylmethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.123 g) and 4-pyridinboronic acid ( 0.0462 g) in 1,2-dimethoxyethane (5 ml), ethanol (1 ml) and 2M aqueous sodium carbonate solution (2 ml) with tetrakis (triphenylphosphine) palladium (0.035 g). The indicated compound was obtained (0.029 g) as a yellowish foam. MS (ISN): 489.1 (M-H) ^-

Example 16

(2-ethyl-4-pyridin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

a) (4-bromo-2-ethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid

This compound was obtained by analogy with Example 1 from 4-bromo-2-ethylaniline (CAS: 45762-41-2, 2.0 g) and 5-fluoro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (0.265 g ) in pyridine (2.0 ml), the reaction was carried out for 4 hours. The desired compound was obtained (0.20 g) as a colorless solid. MS (ISP): 445.0, 447.0 (M + NH4) ⁺

b) (2-ethyl-4-pyridin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

This product was obtained by analogy with Example 2 from (4-bromo-2-ethyl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.10 g) and 4-pyridineboronic acid (0.043 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.25 ml) and a 2M aqueous solution of sodium carbonate (0.9 ml) with tetrakis (triphenylphosphine) palladium (0.013 g). The indicated compound was obtained (0.025 g) as a yellowish foam. MS (ISP): 427.3 (M + H) ⁺

Example 17

5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (4-bromo-2-trifluoromethoxy-phenyl) -amide

This compound was prepared by analogy with Example 1 from 4-bromo-2- (trifluoromethoxy) aniline (CAS: 175278-09-8, 2.82 g) and 5-fluoro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (0.265 g) in pyridine (2.0 ml), the reaction was carried out for 18 hours. The desired compound was obtained (0.12 g) as a colorless foam. MS (ISP): 501.0, 503.0 (M + NH4) ⁺

Example 18

(4-pyridin-4-yl-2-trifluoromethoxy-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

This compound was obtained by analogy with example 2 from (4-bromo-2-trifluoromethoxy-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (0.075 g) and 4-pyridineboronic acid ( 0.029 g) in 1,2-dimethoxyethane (1.5 ml), ethyl alcohol (0.25 ml) and 2M aqueous sodium carbonate solution (0.6 ml) with tetrakis (triphenylphosphine) palladium (0.009 g). The indicated compound was obtained (0.055 g) as a colorless solid. MS (ISP): 483.0 (M + H) ⁺

Example 19

5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid (4-pyridin-4-yl-phenyl) -amide

To a solution of (4-pyridin-4-yl) aniline (CAS: 13296-04-3, 0.290 g) in dichloromethane (12.0 ml) was added 5-fluoro-3-methylbenzo [b] thiophen-2-sulfonyl chloride (0.440 d) and DMAP (0.305 g). The reaction mixture was stirred at room temperature for 16 hours, diluted with dichloromethane (12 ml) and chromatographed on silica gel using heptane / ethyl acetate as eluent to give the title compound (0.205 g) as an off-white solid. MS (ISN): 397.1 (M-H) ^-

Example 20

(2-methanesulfonyl-4-piperidin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid hydrochloride

a) 4- (4-chloro-3-methanesulfonyl-phenyl) -pyridine

1-Bromo-4-chlorobenzene (12.25 g) was added portionwise to chlorosulfonic acid (56 g) at 5-10 ° C. The resulting mixture was heated to 130 ° C for 16 hours. After cooling, the reaction mixture was slowly added to a well-mixed ice-water mixture (500 ml), and the mixture was continued to stir for the next 30 minutes. The colorless precipitate was separated by filtration. The wet cake was removed with dichloromethane, the mixture was separated from water, and the organic phases were dried and evaporated to dryness (14.1 g). A dry mixture of 2 isomers was dissolved in THF (20 ml) and added to a solution of sodium sulfite (15.3 g) in water (100 ml). The reaction was exothermic and was accompanied by a decrease in pH. Ice and concentrated NaOH were added to the mixture to maintain a temperature of 20-30 ° C. and a pH of about 9. Then the reaction mixture was stirred overnight at room temperature and pH 9, acidified with concentrated HCl to pH 1 and cooled. The precipitate was filtered off, washed with cold water and dried over P ₂ O ₅ under high vacuum overnight to give a colorless sulfinic acid derivative (10.5 g). This acid was dissolved in DMF (100 ml), methyl iodide (13 g) was added to the solution, followed by potassium carbonate (14.0 g). The reaction mixture was stirred at room temperature overnight and concentrated under high vacuum. Water was added to the residue and extracted with tert-butyl methyl ether. The organic layers were washed, dried and concentrated. The residue was chromatographed over silica gel using a cyclohexane / ethyl acetate mixture as eluent to give the methylsulfonyl derivative (9.1 g), which was still a mixture of 2 isomers. This mixture (9.0 g) was dissolved in dimethoxyethane (400 ml) and ethanol (90 ml), which were replaced with 2M aqueous sodium carbonate (200 ml). The reaction mixture was degassed several times and tetrakis (triphenylphosphine) palladium (3.0 g) was added. The mixture was heated to 80 ° C. for 16 hours and concentrated to dryness. The residue was dissolved in dichloromethane / water, extracted, dried and concentrated. The solid residue was dissolved in ether, filtered, washed and dried to obtain the desired compound (5.54 g) as off-white crystals. MS (EI): 267.1 (M)

b) Benzyl- (2-methanesulfonyl-4-pyridin-4-yl-phenyl) -amine

A suspension of 4- (4-chloro-3-methanesulfonyl-phenyl) -pyridine (5.5 g) in benzylamine (23 ml) was heated at 160 ° C. for 4 hours, then concentrated under high vacuum. The residue was diluted with ice / water and extracted with ethyl acetate. The organic layers were washed, dried and concentrated, and the residue was chromatographed on silica gel using heptane / ethyl acetate. The fractions containing the compound were evaporated and the residue was crystallized from methanol / ether to give the desired compound (5.75 g) as an off-white solid. MS (ISP): 339.1 (M + H) ⁺

c) 2-Methanesulfonyl-4-pyridin-4-yl-phenylamine

To a solution of benzyl- (2-methanesulfonyl-4-pyridin-4-yl-phenyl) -amine (2.0 g) in a 1: 1 dioxane / methanol mixture (100 ml) was added 2 n HCl (5 ml) and palladium black (1.0 g). The reaction mixture was hydrogenated at a pressure of 1.1 bar and room temperature for 18 hours. The catalyst was filtered off with a microfilter and washed with methanol. The filtrate was evaporated to dryness to give the desired compound (1.45 g) as a yellowish solid. MS (ISP): 249.1 (M + H) ⁺

d) 2-methanesulfonyl-4-piperidin-4-yl-phenylamine; compound with acetic acid

A suspension of 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (0.70 g) and platinum oxide (0.70 g) in acetic acid (15 ml) was hydrogenated at a pressure of 1.1 bar and a temperature of 80 ° C for 8 ocloc'k. The reaction mixture was cooled to room temperature, filtered through a microfilter, washed with acetic acid and concentrated to dryness to give the title compound (0.89 g) as a pale yellow amorphous powder. MS (ISP): 255.4 (M + H) ⁺

e) 4- (4-amino-3-methanesulfonyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester

To a solution of 2-methanesulfonyl-4-piperidin-4-yl-phenylamine in combination with acetic acid (1.5 g) in dichloromethane (30 ml) was added di-tert-butyl carbonate (1.15 g) and a saturated aqueous solution of sodium carbonate (10 ml). The reaction mixture was stirred at room temperature for 3 hours and extracted with dichloromethane. The organic phases were dried and concentrated, and the residue was chromatographed on silica gel using heptane / ethyl acetate as eluent to give the desired compound (0.64 g) as an off-white solid. MS (ISP): 355.1 (M + H) ⁺

f) 4- [4- (5-Fluoro-3-methyl-benzo [b] thiophen-2-sulfonylamino) -3-methanesulfonyl-phenyl] -piperidine-1-carboxylic acid tert-butyl ester

To ice-cooled suspension of sodium hydride (60-65% in mineral oil, 0.030 g) in absolute DMSO (3 ml) was added 4- (4-amino-3-methanesulfonyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (0.106 g). The mixture was stirred at 0-5 ° C. for 30 minutes, and a solution of 5-fluoro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (0.237 g) in absolute DMSO (1 ml) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 5 hours, diluted with ice / water / 1 N HCl and extracted with ethyl acetate. The organic phases were washed, dried and concentrated, and the residue was chromatographed on silica gel using heptane / ethyl acetate as an eluent to give (0.025 g) methylbenzo [b] thiophene-2-sulfonyl chloride (0.237 g). The desired compound (0.025 g) was obtained as a yellowish foam. MS (ISN): 581.3 (M-H) ^-

g) 5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonic acid (2-methanesulfonyl-4-piperidin-4-yl-phenyl) -amide hydrochloride

Solution of 4- [4- (5-fluoro-3-methyl-benzo [b] thiophene-2-sulfonylamino) -3-methanesulfonyl-phenyl] piperidine-1-carboxylic acid tert-butyl ester (0.025 g) in ethyl acetate ( 1 ml) was treated with a mixture of 2.5 n HCl / ethyl acetate (2 ml). The reaction mixture was stirred at room temperature for 2 hours. Ether (20 ml) was added to the mixture, the precipitate was filtered off, washed with ether and dried under high vacuum over P ₂ O ₅ to give the title compound (0.020 g) as a yellowish powder. MS (ISP): 483.3 (M + H) ⁺

Example 21

(2-methanesulfonyl-4-piperidin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

5-Fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid hydrochloride of (2-methanesulfonyl-4-piperidin-4-yl-phenyl) -amide (see Example 20g, 6 mg) was passed through an HPLC column with a mixture of acetonitrile / water / formic acid to obtain the specified compound (3 mg) as an off-white foam. MS (ISP): 483.3 (M + H) ⁺

Example 22

(2-methanesulfonyl-4-pyridin-4-yl-phenyl) -amide naphthalene-2-sulfonic acid

To a solution of 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (see Example 20c, 0.046 g) in pyridine (0.5 ml) was added naphthalene-2-sulfochloride (0.051 g). The reaction mixture was stirred at 70 ° C for 6 hours, diluted with dichloromethane and chromatographed on silica gel using a dichloromethane / methanol / ammonia mixture to give the title compound (0.025 g) as an off-white solid. MS (ISP): 439.1 (M + H) ⁺

Example 23

(2-methanesulfonyl-4-pyridin-4-yl-phenyl) -amide 5-fluoro-3-methyl-benzo [b] thiophen-2-sulfonic acid

This compound was prepared by analogy with the compound described in Example 20f from 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (see Example 20c, 0.27 g) in tetrahydrofuran (10 ml) and 5-fluoro- 3-methylbenzo [b] thiophene-2-sulfonyl chloride (0.265 g) in a reaction with sodium hydride (0.10 g), the reaction was carried out at room temperature for 18 hours to obtain the indicated compound (0.025 g) as a yellow foam. MS (ISN): 475.0 (M-H) ^-

Example 24

4- [3-Methanesulfonyl-4- (1-methyl-1H-indole-2-sulfonylamino) phenyl] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (4-amino-3-methanesulfonyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (see Example 20f, 0.050 g) in dichloromethane (2.0 ml) was added 1-methyl-1H- indole-2-sulfonyl chloride (0.036 g, cf. Chan, Ming Fai; Wu, Chengde; Raju, Bore Gowda; Kogan, Timothy; Kois, Adam; Verner, Erik Joel; Castillo, Rosario Silvestre; Yalamorri, Venkatachalapathi; Balaji, Vitukudi Narayanaiyengar, US 5,962,490) and DMAP (dimethylaminopyridine) (0.021 g). The reaction mixture was stirred at 80 ° C for 18 hours, cooled and directly chromatographed on silica gel using heptane / ethyl acetate as eluent to give the title compound (0.048 g) as a yellowish foam. MS (ISN): 546.5 (M-H) ^-

Example 25

1-Methyl-1H-indole-2-sulfonic acid hydrochloride of (2-methanesulfonyl-4-piperidin-4-yl-phenyl) -amide

A solution of 4- [3-methanesulfonyl-4- (1-methyl-1H-indole-2-sulfonylamino) phenyl] piperidine-1-carboxylic acid tert-butyl ester (0.038 g) was treated with a mixture of 2.5 n HCl / ethyl acetate (2.5 ml). The reaction mixture was stirred at room temperature for 2 hours, then ether (20 ml) was added to the mixture. The precipitate was collected, washed with ether and dried under high vacuum over P ₂ O ₅ to give the title compound (0.032 g) as an off-white powder. MS (ISN): 446.4 (M-H) ^-

Example 26

(2-methanesulfonyl-4-pyridin-4-yl-phenyl) -amide 6-fluoro-naphthalene-2-sulfonic acid

To a solution of 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (see Example 20c, 0.27 g) and 6-fluoro-naphthalene-2-sulfonyl chloride (0.148 g, cf. Brown, George Robert; Stokes, Elaine Sophie Elisabeth; Waterson, David; Wood, Robin. WO 9706802) in dichloromethane (1.0 ml) was added DMAP (0.037 g). The reaction mixture was stirred at room temperature for 2 hours and directly chromatographed on silica gel using heptane / ethyl acetate as eluent to give the title compound (0.098 g) as a colorless foam. MS (ISP): 457.3 (M + H) ⁺

Example 27

(4-Pyridin-4-yl-phenyl) -amide 1H-indol-2-sulfonic acid hydrochloride

a) 2- (4-Pyridin-4-yl-phenylsulfamoyl) -indole-1-carboxylic acid tert-butyl ester

To a solution of (4-pyridin-4-yl) aniline (CAS: 13296-04-3, 0.054 g) and 2-chlorosulfonyl-indole-1-carboxylic acid tert-butyl ester (0.120 g, compare Shankar, Bandarpalle B. ; Gilbert, Eric; Rizvi, Razia K .; Huang, Chunli; Kozlowski, Joseph A .; McCombie, Stuart; Shih, Neng-Yang. WO 2006002133) in 1,2-dichloroethane (5.0 ml) added DMAP (0.047) d). The reaction mixture was stirred at 50 ° C. for 3 hours and chromatographed on silica gel using dichloromethane / ethyl acetate as eluent to give the desired compound (0.070 g) as a colorless powder. MS (ISP): 450.4 (M + H) ⁺

b) (4-Pyridin-4-yl-phenyl) -amide 1 H-indole-2-sulfonic acid hydrochloride

To a solution of 2- (4-pyridin-4-yl-phenylsulfamoyl) -indole-1-carboxylic acid tert-butyl ester (0.030 g) in ethyl acetate (1.0 ml) was added a mixture of 3.5 n HCl / ethyl acetate (2, 0 ml). The reaction mixture was stirred at 45 ° C for 8 hours, then diluted with ether (40 ml). The precipitate was collected, washed with ether and dried under high vacuum over P ₂ O ₅ to give the title compound (0.025 g) as a colorless amorphous powder. MS (ISP): 350.4 (M + H) ⁺

Example 28

5-Fluoro-1-methyl-1H-indole-2-sulfonic acid hydrochloride of (2-methanesulfonyl-4-piperidin-4-yl-phenyl) -amide

a) 5-fluoro-1-methyl-1H-indole-2-sulfonyl chloride

To a solution of 1-methyl-5-fluorindole (CAS: 116176-92-2, 1.98 g) in absolute ether (100 ml) at -78 ° C was added dropwise tert-BuLi (1.7 N solution in pentane, 12.4 ml). The reaction mixture was stirred at this temperature for 60 minutes, and then sulfur dioxide was passed over the surface of the solvent until the exothermic reaction ceased. The mixture was then stirred for another 30 minutes at room temperature and concentrated to dryness. The crude residue was suspended in dichloromethane (100 ml) and NCS (K-chlorosuccinimide) (2.94 g) was added to the mixture. The reaction mixture was stirred at room temperature for 4 hours, diluted with ice / water and extracted with dichloromethane. The organic phases were washed, dried and concentrated. The residue was chromatographed on silica gel using heptane / ethyl acetate as eluent to give the desired product (0.405 g) as a yellowish solid. MS (EI): 247.1 (M)

b) 4- [4- (5-Fluoro-1-methyl-1H-indole-2-sulfonylamino) -3-phenyl-methanesulfonyl] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (4-amino-3-methanesulfonyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (see Example 24e, 0.048 g) in 1,2-dichloroethane (3.0 ml) was added 5- fluoro-1-methyl-1H-indole-2-sulfonyl chloride (0.035 g) and DMAP (0.025 g). The reaction mixture was stirred at 80 ° C. for 72 hours, diluted with dichloromethane (2 ml) and chromatographed on silica gel using dichloromethane / ethyl acetate as eluent to give the title compound (0.019 g) as an off-white foam. MS (ISN): 564.3 (M-H) ^-

c) 5-fluoro-1-methyl-1H-indole-2-sulfonic acid hydrochloride of (2-methanesulfonyl-4-piperidin-4-phenyl-yl) -amide

A solution of 4- [4- (5-fluoro-1-methyl-1H-indole-2-sulfonylamino) -3-phenylmethanesulfonyl] piperidine-1-carboxylic acid tert-butyl ester (0.019 g) was treated with 2.5 n HCl / ethyl acetate (2.5 ml). The reaction mixture was stirred at room temperature for 3 hours, then ether (20 ml) was added. The precipitate was collected, washed with ether and dried under high vacuum over P ₂ O ₅ to give the title compound (0.014 g) as an off-white amorphous powder. MS (ISN): 464.0 (M-H) ^-

Example 29

(4-Pyridin-4-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-methyl-1H-indole-2-sulfonic acid hydrochloride

a) 5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester

To a solution of 5-fluoro-3-methyl-indole (CAS: 392-13-2, 2.5 g) in THF (tetrahydrofuran) (25 ml) at a temperature of 0-5 ° C was added di-tert-butyl dicarbonate (4, 02 g) and DMAP (0.205 g). The reaction mixture was stirred at room temperature for 4 hours, concentrated and the residue was chromatographed on silica gel using heptane / ethyl acetate as eluent to give the desired compound (3.15 g) as a colorless solid. MS (ISP): 250.1 (M + H) ⁺

b) 2-Chlorosulfonyl-5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester

This compound was obtained by analogy with the compound of Example 28a from 5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (1.0 g) in a diethyl ether / THF 1: 2 mixture (15 ml), 1 , 7 N solution of tert-BuLi (2.85 ml), SO ₂ (gas) and NCS (0.59 g). The title compound was obtained (0.80 g) as a colorless solid. MS (EI): 347.2, 247.1 (M and M-Boc)

c) 2- (4-Bromo-2-trifluoromethyl-phenylsulfamoyl) -5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester

This compound was obtained by analogy with the compound of Example 1 from 2-chlorosulfonyl-5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (0.29 g) and 2-amino-5-bromobenzotrifluoride (2, 0 g) in pyridine (5 ml) by stirring for 7 days at room temperature. The indicated compound (0.095 g) was obtained as a colorless foam. MS (ISN); 551.4, 549.3 (M-H) ^-

d) 5-fluoro-3-methyl-2- (4-pyridin-4-yl-2-trifluoromethyl-phenylsulfamoyl) -indole-1-carboxylic acid tert-butyl ester

This compound was prepared by analogy with the compound of Example 2 from 2- (4-bromo-2-trifluoromethyl-phenylsulfamoyl) -5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (0.108 g), 4- pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (0.4 ml) and a 2 M aqueous solution of sodium carbonate (0.8 ml) with tetrakis (triphenylphosphine) palladium (0.023 g). The desired compound (0.058 g) was obtained as a brown foam. MS (ISN): 548.3 (M-H) ^-

e) 5-fluoro-3-methyl-1H-indole-2-sulfonic acid (4-pyridin-4-yl-2-trifluoromethyl-phenyl) -amide hydrochloride

This compound was prepared by analogy with the compound of Example 27b from 5-fluoro-3-methyl-2- (4-pyridin-4-yl-2-trifluoromethyl-phenylsulfamoyl) -indole-1-carboxylic acid tert-butyl ester (0.052 g ), 2.5 n HCl / ethyl acetate (10.0 ml). The indicated compound (0.041 g) was obtained as a brown amorphous powder. MS (ISN): 448.4 (M-H) ^-

Example 30

(4-pyridin-4-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonic acid

a) 5-fluoro-1,3-dimethyl-1H-indole

To a solution of 5-fluoro-3-methyl-indole (CAS: 392-13-2, 2.5 g) in DMF (20 ml) was added potassium hydroxide (1.41 g). The suspension was stirred at room temperature for 1 hour and iodomethane (2.85 g) was added dropwise to the suspension at a temperature of 0-5 ° C. The reaction mixture was stirred at room temperature for 18 hours and concentrated under high vacuum. The residue was diluted with water and extracted with ethyl acetate. The organic phases were washed, dried and concentrated. The crude residue was chromatographed on silica gel using heptane / ethyl acetate as eluent to give the desired compound (2.15 g) as a colorless liquid. MS (EI): 163.1 (M)

b) 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonyl chloride

This compound was prepared by analogy with the compound of Example 28a from 5-fluoro-1,3-dimethyl-1H-indole (1.0 g) in a diethyl ether / THF 1: 2 mixture (15 ml), a 1.7 n solution of tert BuLi (4.33 ml), SO ₂ (gas) and NCS (0. 90 g). The specified compound (0.27 g) was obtained as a yellowish solid. MS (ISN): 241.9 (MF)

c) (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonic acid

This compound was obtained by analogy with the compound of Example 1 from 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonyl chloride (0.25 g) and 2-amino-5-bromobenzotrifluoride (2.3 g) in pyridine (5 ml), the reaction was carried out for 18 hours at a temperature of 35 ° C. The specified compound (0.293 g) was obtained as a yellow solid. MS (ISN): 551.4, 549.3 (M-H) ^-

d) (4-pyridin-4-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonic acid

This product was obtained by analogy with the compound of Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonic acid (0.100 g), 4-pyridinboronic acid (0.040 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (1.0 ml) and a 2 M aqueous solution of sodium carbonate (1.0 ml) with tetrakis (triphenylphosphine) palladium (0.025 g). These compounds (0.058 g) were obtained as a brown foam. MS (ISN): 462.4 (M-H) ^-

Example 31

(4-pyridin-4-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-isobutyl-benzo [b] thiophen-2-sulfonic acid

a) 5-fluoro-3-isobutyl-benzo [b] thiophene

To a solution of 3-bromomethyl-5-fluorobenzothiophene (2.0 g; see Raga, Manuel; Palacin, Celia; Castello, Josep Maria; Ortiz, Jose A .; Cuberes, Maria Rosa; Moreno-Manas, Marcial, Eur. J Med. Chem. (1986), 21 (4), 329-32) in THF (30 ml) was added isopropyl magnesium bromide (1.0 m, 16.6 ml) over 5 minutes. The reaction mixture was stirred at 50 ° C. for 5 hours, cooled, diluted with ice / water and a solution of ammonium chloride, and extracted with ethyl acetate. The organic phases were washed with water, dried and concentrated. The residue was chromatographed on silica gel using heptane / methylene chloride as eluent to afford the title compound (1.35 g) as a yellowish oil. MS (EI): 208.3 (M)

b) 5-fluoro-3-isobutyl-benzo [b] thiophene-2-sulfonyl chloride

To a solution of 5-fluoro-3-isobutyl-benzo [b] thiophene (0.55 g) in chloroform (10 ml) was added chlorosulfonic acid (1.54 g) and the resulting mixture was stirred at room temperature for 3 hours, diluted with the mixture. ice / water and was extracted with methylene chloride. The organic phases were washed with water and an aqueous solution of sodium bicarbonate, dried and concentrated. The residues were chromatographed on silica gel using heptane / ethyl acetate as eluent to afford the title compound (0.49 g) as a colorless oil. MS (EI): 306.8 (M)

c) 5-fluoro-3-isobutyl-benzo [b] thiophene-2-sulfonic acid (4-bromo-2-trifluoromethyl-phenyl) -amide

This compound was obtained analogously to the compound of Example 1 from 5-fluoro-3-isobutyl-benzo [b] thiophen-2-sulfonyl chloride (0.44 g), 2-amino-5-bromobenzotrifluoride (3.44 g) in pyridine ( 5 ml), the reaction was carried out for 18 hours at room temperature. The desired compound (0.24 g) was obtained as a colorless solid. MS (ISN): 508.2, 510.3 (M-H) ^-

d) (4-pyridin-4-yl-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-isobutyl-benzo [b] thiophen-2-sulfonic acid

This compound was obtained by analogy with the compound of Example 2 from (4-bromo-2-trifluoromethyl-phenyl) -amide 5-fluoro-3-isobutyl-benzo [b] thiophen-2-sulfonic acid (0.10 g) and 4- pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (7 ml), ethanol (1 ml) and 2 M sodium carbonate solution (2.0 ml) with tetrakis (triphenylphosphine) palladium (0.027 g). The specified compound (0.47 g) was obtained as a yellowish solid. MS (ISN): 507.1 (M-H) ^-

Example A

Coated tablets containing the following ingredients can be made by known methods:

Ingredients per pill Core: The compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Hydrated lactose 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium Starch Glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4,5 mg (total mass of the core) 120.0 mg 350.0 mg Coating Film: Hydroxypropyl methylcellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron Oxide (Yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg

The active ingredient was sieved and mixed with microcrystalline cellulose and the mixture was granulated with a solution of polyvinylpyrrolidone in water. The granules obtained were mixed with sodium starch with glycolate and magnesium stearate and compressed to obtain nuclei weighing 120 or 350 mg, respectively. The cores were coated with an aqueous solution / suspension of the aforementioned coating film.

Example B

Capsules containing the following ingredients can be made by known methods:

Ingredients Per capsule compound of formula (I) 25.0 mg lactose 150.0 mg corn starch 20.0 mg talc 5.0 mg

These components were sieved and mixed, the resulting mixture filled 2 size capsules.

Example C

The injection may have the following composition:

compound of formula (I) 3.0 mg polyethylene glycol 400 150.0 mg acetic acid enough for pH 5.0 water for injection up to 1.0 ml

The active substance was dissolved in a mixture of polyethylene glycol 400 and water for injection (part of the water). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding a residual amount of water. The solution was filtered and filled with ampoules with an acceptable excess and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be made by known methods:

Capsule composition compound of formula (I) 5.0 mg yellow wax 8.0 mg hydrogenated soybean oil 8.0 mg partially hydrogenated vegetable oils 34.0 mg soybean oil 110.0 mg Weight of capsule components 165.0 mg gelatin capsule gelatin 75.0 mg glycerol 85% 32.0 mg karion 83 8.0 mg (dry material) titanium dioxide 0.4 mg yellow iron oxide 1.1 mg

The active ingredient was dissolved in a warm melt of other ingredients, and soft gelatin capsules of appropriate sizes were filled in the resulting mixture. Filled soft gelatin capsules were processed by known methods.

Example E

Sachets containing the following ingredients can be made in a known manner:

compound of formula (I) 50.0 mg lactose, fine powder 1015.0 mg microcrystalline cellulose (AVICEL PH 102) 1400.0 mg sodium carboxymethyl cellulose 14.0 mg polyvinylpyrrolidone K 30 10.0 mg magnesium stearate 10.0 mg flavoring additives 1.0 mg

The active ingredients were mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone and water. The granulate was mixed with magnesium stearate and flavors, and the resulting mixture was filled in a sachet.

Claims (8)

1. The compound of formula (I)

,
where is the fragment

represents

;
X is phenylene optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halogen C _{1 -6-} alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylsulfinyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl-C _1-6 alkyl, C _1-6 alkylsulfinyl-C _{1- 6-} alkyl, C _1-6 -alkylthio-C _1-6 -alkyl and C _1-6 -alkoxycarbonyl;
Y represents pyridyl, pyrimidinyl or piperidyl, which optionally can be substituted with one or two substituents independently selected from the group consisting of halogen, C _1-6 alkoxy and C _1-6 alkoxycarbonyl;
and its pharmaceutically acceptable salts. 2. The compound according to claim 1, in which Y is in the para position relative to the —NH — SO ₂ group, if X is a phenylene group. 3. The compound according to claim 1, in which X is phenylene substituted by halogen-C _1-6 -alkyl or C _1-6 -alkylsulfonyl in the ortho position relative to the -NH-SO ₂ -group. 4. The compound according to claim 1, in which X is phenylene substituted with trifluoromethyl or methylsulfonyl in the ortho position relative to the —NH — SO ₂ group. 5. The compound according to claim 1, which is (4-pyridin-4-yl-2-trifluoromethylphenyl) amide 5-fluoro-3-methylbenzo [b] thiophene-2-sulfonic acid. 6. Pharmaceutical compositions containing the compound according to claim 1 and a pharmaceutically acceptable excipient intended for the treatment, prophylaxis or treatment and prevention of allergic, inflammatory and / or fibrotic diseases, such as allergies, asthma, peripheral arterial occlusive disease, critical limb ischemia (CLI), patients with vulnerable atherosclerotic plaques, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemic reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, atherothrombosis and / or burns / ulcers in patients with diabetes mellitus / CLI. 7. The compound according to claim 1 for use as therapeutically active substances for the treatment, prophylaxis or treatment, and the prevention of allergic, inflammatory and / or fibrotic diseases, such as allergies, asthma, peripheral arterial occlusive disease, critical limb ischemia (CLI ), patients with vulnerable atherosclerotic plaques, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemic reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatism offensive arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, atherothrombosis and / or burns / ulcers in patients with diabetes mellitus / CLI. 8. The compound according to claim 1 for use as therapeutically active substances for the treatment and / or prevention of atherothrombosis or asthma.