Sulphonamide derivatives as chymase inhibitors

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, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, halogen-C1-6-alkoxy, C1-6-alkylsulphonyl, C1-6-alkylthionyl, C1-6-alkylthio group, C1-6-alkylsulphonyl-C1-6-alkyl, C1-6-alkylthionyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl and C1-6-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, C1-6-alkoxy and C1-6-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

 

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

where

A represents 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 ring atoms are C, and one of the carbon atoms of the heterocyclic rings optionally may be replaced by a carbonyl group;

R1and R1'independently represent hydrogen, halogen, nitro, cyano, amino, C1-6alkyl, heteroalkyl,3-7cycloalkyl,2-6alkenylphenol,2-6alkylamino, hydroxyl, C1-6CNS group, -NR'r R", -(C0-6alkylen)-R NR'r" groups where R' and R" are independently selected from the group consisting of hydrogen, C1-6alkyl, heteroalkyl, formyl, C1-6alkylcarboxylic, optionally substituted C3-7cycloalkylcarbonyl, optionally substituted arylcarboxylic, neobyazatel is substituted heteroarylboronic, optionally substituted getrollbackonly, C1-6alkylsulfonyl, optionally substituted C3-7cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroatomcontaining and optionally substituted heterozygosities groups, or -(C0-6alkylene)-OR', where R' represents hydrogen, C1-6alkyl, heteroalkyl, formyl or C1-6alkylcarboxylic group, or R1'is not present, and there is only R1;

R2, R2'and R2"independently represent hydrogen, halogen, cyano, nitro, amino, mono - and di-C1-6alkyl substituted amino, C1-6alkyl, C2-6alkeneamine,2-6alkyline, heteroalkyl, hydroxy or C1-6alkoxy group;

X represents a phenylene, optionally substituted by one, two or three substituents, independently selected from the group consisting of halogen, cyano, nitro, amino, mono - and di-C1-6alkyl substituted amino, C1-6alkyl, C2-6alkenylphenol,2-6alkenylphenol, heteroalkyl, hydroxy, C1-6alkoxy, halogen-C1-6alkyl, halogen, C1-6alkoxy, heteroalkyl, C1-6alkylsulfonyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylsulfonyl-C1-6 alkyl, C1-6alkylsulfonyl-C1-6alkyl, C1-6alkylthio-C1-6alkyl, acyl, formyl, C1-6alkoxycarbonyl, halo, C1-6alkoxycarbonyl, generalclassifiable and generalsearchonline groups;

Y represents an optionally substituted heteroaryl where heteroaryl is a monocyclic aromatic radical containing 6 atoms in the ring containing in the ring one or two heteroatoms, 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 represents 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 obtaining the above mentioned compounds, pharmaceutical preparations which contain such compounds, the use of these compounds for the production of pharmaceutical preparations and method of producing the intermediates.

The compounds of formula (I) inhibit himizu. Chymase is a Serino is th with proteinase expression pattern, strictly limited subpopulation of fat cells (MARTICLEfat cells). Chymase is only activated by the activation and degranulation of mast cells, which limits the activity of the enzyme only MARTICLEpositive tissues. Chymase specifically cleaves a number of pathologically significant substrates (Raymond, W.W., S.W.Ruggles and others; JBC 2003 278(36): 34517-34524), whereby the enzyme can activate angiotensin II, endothelin, TGF-b, IL, SCF (stem cell factor), collagenase and cause the degradation of proteins such as thrombin, FN (fibronectin), APO A1,2 (apoliprotein). This pattern makes himizu an attractive target in allergic, inflammatory and fibrotic diseases. Indeed, a number of successful animal studies with chymase inhibitors have demonstrated efficacy in animals with allergies, injuries of blood vessels 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 H.J 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, occlusal disease and peripheral artery disease, critical limb ischemia (CLI)patients with vulnerable at acclerations plaques, unstable angina, congestive heart failure, the left ventricle hypertrophy, ischemic reperfusion injury, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, wound healing (burns/ulcers in diabetes/CLI).

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

Unless otherwise stated, the following definitions are provided to illustrate and define the meaning and latitude values of the various terms used to describe the invention herein.

The term "halogen" or "halo" represents a fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine.

The term "C1-6alkyl", alone or in combination with other groups, is an unbranched or branched monovalent alkyl radical comprising from one to six carbon atoms. This term can also be illustrated by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. C1-4alkyl is more preferable.

The term "halogen C1-6alkyl", alone or in combination with other groups, represents a C1-6alkyl in which one or more hydrogen atoms replaced with the same or the difference is significant halogen, such as-CH2CL, -CH2CF3, trifluoromethyl. As the halogen, chlorine, bromine or fluorine are preferred, and chlorine or fluorine are preferred.

The term "halogen C1-6alkoxy", alone or in combination with other groups, represents a C1-6alkoxy group in which one or more hydrogen atoms replaced by identical or different Halogens. As the preferred Halogens are chlorine, bromine or fluorine, and chlorine or fluorine are preferred.

The term "acyl", alone or in combination with other groups, represents-CO-C1-6alkyl.

The term "heteroalkyl" represents a C1-6alkyl, substituted by one or more substituents independently selected from the group consisting of nitro, hydroxy, halogen, cyano, C1-6CNS, formyl, C1-6alkylcarboxylic, carboxyl, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylsulfonyl, amino, and mono-and di-C1-6alkyl substituted amino groups. This term can also be illustrated by such radicals as 2-hydroxyethyl, performer.

The term "C3-7cycloalkyl", alone or in combination with other groups, is a saturated monovalent cyclic hydrocarbon radical containing from t the ex to seven carbon atoms in the ring, for example cyclopropyl, cyclobutyl, cyclohexyl.

The term "C1-6alkoxy", alone or in combination with other groups, is a group R'-O-, where R' represents a C1-6alkyl.

The term "C2-6alkenyl", alone or in combination with other groups, is an unbranched or branched hydrocarbon residue containing a double bond, comprising from two to six carbon atoms, such as, for example, ethynyl, 2-propenyl.

The term "C2-6-quinil", alone or in combination with other groups, is an unbranched or branched hydrocarbon residue containing a triple bond, including from two to six carbon atoms, such as, for example, ethinyl, 2-PROPYNYL.

The term "C0-6alkylene" represents a bond or unbranched or branched divalent saturated aliphatic hydrocarbon group containing from 1 to 6 carbon atoms. With0alkylen is a link.

The term "aryl", alone or in combination with other groups, represents phenyl or naftalina group, preferably 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 the ring,where one or two atoms of the ring 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" represents a monocyclic or bicyclic radical, comprising from 5 to 12 atoms in the ring containing at least one aromatic ring containing one, two or three heteroatoms in the ring selected from N, O and S and the remaining ring atoms are C. Preferably, the heteroaryl radical is attached to the connection aromatic ring.

The terms "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocyclyl" and "optionally substituted C3-7cycloalkyl" represent, respectively, aryl, heteroaryl, heterocyclyl and C3-7cycloalkyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, nitro, cyano, amino, C1-6alkyl, C2-6alkenylphenol,2-6alkenylphenol, hydroxy, C1-6alkoxy, heteroalkyl, mono - and di-C1-6alkyl substituted amino, acyl, formyl, generalsearchonline, C1-6alkoxycarbonyl, generalclassifiable and heteroalkyl groups.

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

The compounds of formula (I) can form pharmaceutically acceptable salts attach (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, sulfurous acid and phosphoric acid, or with organic acids, such as methanesulfonate acid, p-toluensulfonate acid, acetic acid, lactic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salt" refers to salts. The compounds of formula (I), which contain a COOH group can also form salts with bases. Examples of such salts are salts of alkali, alkaline earth metal and ammonium salts, such as Na-, K-, CA - and trimethylammonium salt. The term "pharmaceutically acceptable salt" also refers to such salts. Salt accession acid, as described above, are preferred.

The terms "optional" or "optionally" means that the subsequent described event or circumstance may, however, not necessarily, take place, and that the description includes instances where the event or circumstance occurs and instances is when this does not happen. For example, the term "aryl group optionally substituted alkyl group" means that the alkyl group may, however, not necessarily be present, and the description includes situations when the aryl group is substituted by an alkyl group, and a situation where the aryl group is not substituted by an alkyl group.

"Pharmaceutically acceptable excipient" is an excipient that is useful in the manufacture of pharmaceutical compositions, which are completely safe, non-toxic and is not undesirable neither biological, nor with any other point of view, and includes excipients that are acceptable for veterinary use, as well as for pharmaceutical applications for people. The term "pharmaceutically acceptable excipient", as used in the description and claims includes both one and more such auxiliary substances.

Compounds that have the same molecular formula but differ in the nature or sequence of links of their atoms or the arrangement of atoms in space are referred to as "isomers". Isomers that differ in the arrangement of atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other, is called the I "diastereoisomers", and stereoisomers, which are superposition mirror images of each other, are called "enantiomers". If the compound has an asymmetric center, for example, if the carbon atom is linked to four different groups, the formation of a pair of enantiomers. The enantiomers can be characterized by the absolute configuration of the asymmetric center can be described by using R - and S - nomenclature of Cahn, Ingold and Prelog or be characterized by the way in which the molecule rotates the plane of polarized light and designated as programada or levogyrate (i.e., as (+)- or (-)-isomers respectively). Chiral compounds can exist as individual enantiomers or as mixtures. The mixture of enantiomers in equal proportions, is called a "racemic mixture".

The compounds of formula (I) may possess one or more asymmetric centers. If not stated otherwise, the description or the name of the connection in the description and the claims include both individual enantiomers and mixtures thereof, as racemic or not, as well as a separate epimere and mixtures thereof. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the prior art.

Although the definitions of A, R1-R2"X and Y in the broad sense given earlier, for some of the materials are preferred.

I) In the compound of formula (I), And preferably represents a phenyl ring or heteroaryl ring. Heteroaryl ring And is preferably a five-membered ring.

II) In the compound of formula (I),

preferably represents

,or

more preferably

represents a

,or

in which R1and R1'independently represent hydrogen or C1-6alkyl,

even more preferably

represents a

,or

in which R2, R2'and R2"independently represent a hydrogen or halogen.

especially preferably represents

III) In the compound of formula (I), Y is preferably in the para-position in phenylenebis group as X, relative to the-NH-SO2group.

IV) In the compound of formula (I), X preferably represents a phenylene, optionally substituted with one, two the or three substituents, independently selected from the group consisting of halogen, C1-6alkyl, C1-6alkoxy, halo, C1-6alkyl, halo, C1-6alkoxy, C1-6alkylsulfonyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylsulfonyl-C1-6alkyl, C1-6alkylsulfonyl-C1-6alkyl, C1-6alkylthio - C1-6alkyl and C1-6alkoxycarbonyl group; more preferably X represents a phenylene, substituted halo1-6, alkyl or C1-6alkylsulfonyl groups in the ortho-position relative to the-NH-SO2group, even more preferably X represents a phenylene, substituted triptorelin or methylsulfonyl groups in ortho-position to the-NH-SO2group.

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

Bole is preferably Y represents a pyridyl, pyrimidinyl or piperidyl, optionally substituted by one or two substituents, independently selected from the group consisting of halogen, C1-6CNS and C1-6alkoxycarbonyl groups.

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

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

General methods of synthesis

Scheme 1

In figure 1 A, R1-R2"X, Y and Hal are defined previously. R4, R4'and R4"independently represent hydrogen, halogen, cyano, nitro, amino, mono - and di - C1-6alkyl substituted amino group, a C1-6alkyl, C2-6alkenylphenol,2-6alkylamino, heteroalkyl, hydroxy, C1-6alkoxy, halo, C1-6alkyl, halo, C1-6alkoxy, heteroalkyl, C1-6alkylsulfonyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylsulfonyl-C1-6alkyl, C1-6-alkylsulfonyl C1-6alkyl, C1-6alkylthio C1-6alkyl, acyl, formyl, C1-6alkoxycarbonyl, halo, C1-6alkoxycarbonyl is inuu, heteroassociation or generalsearchonline group.

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

Using the compound (II) as an intermediate, the compounds of formula (I) can be obtained by reaction of formation of C-C bond, such as the Suzuki reaction, in which the halide is reacted with appropriately substituted derivatives Bronevoy acid in the presence of a base and a palladium catalyst.

Sulphonylchloride (C) either commercially available or can be synthesized using modern methods of naphthalene, or a bicyclic heteroaromatic link is, or their derivatives. In particular, sulphonylchloride group can be introduced using the reaction of aryl lithium salt with sulfur dioxide and subsequent oxidation/chlorination using, for example, sulfurylchloride 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 the SO3·DMF or SO3·pyridine, followed by chlorination, for example, using thionyl chloride.

Anilines (A) or are commercially available compounds or can be synthesized using modern methods. One option is to enter halogenated compounds (C) in the reaction of formation of C-C bond, such as the Suzuki reaction, in which the halide is reacted with appropriately substituted derivatives Bronevoy acid in the presence of a base and a palladium catalyst. Halogenated derivatives of aniline (C) is either commercially available or can be synthesized using modern methods.

As described above, the compounds of formula (I) are active compounds and inhibit himizu. Therefore, these compounds inhibit the activation of angiotensin II, endothelin, TGFb, IL1, SCF, collagenase and cause degradation of such Belko is, as thrombin, FN, APO A1,2. Therefore, they can be used for the treatment and/or prevention of allergic, inflammatory and/or fibrotic diseases, such as allergies, asthma, occlusal disease peripheral artery 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 diabetes/CLI.

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

The invention also relates to pharmaceutical compositions comprising the above compound and pharmaceutically acceptable auxiliary substance.

The invention also embraces 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, occlusal disease perifer the economic arteries, critical lower 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 diabetes/CLI.

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

The invention is also relative to the tsya the method of production and intermediates for producing compounds of formula (I), and method for producing the intermediates.

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

For chymase was chosen as the substrate containing the peptide of the 4 amino acids AAPF as a standard substrate for chymotrypsinogen connection (succinyl-l-l-RHS-h-[7-amino-4-methylcoumarin]; see Lockhart BE, and others, "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 26 may 2004 as manuscript VA 20040074). The peptide was synthesized with a purity of 95% (Bachem, Bubendorf, Switzerland). Himizu was purified from the fat cells of human skin obtained from Calbiochem (Merck Biosciences, San Diego, California, USA). In the test used is 0.15 M NaCl, 0,05, Tris-HCl, 0.05% of CHAPS (3 -[(3-[cholamidopropyl)-dimethylammonio]-1-propanesulfonate) buffer, 0.1 mg/ml heparin solution (Heparin sodium, Sigma, of the intestinal mucosa of pigs), 0.02 mm solution AAPF-substrate 1 nm solution chymase at pH 7.4. The analysis was carried out in 96-cell plates (Optiplate Packard), in a volume of 0.05 ml at room temperature. Chymase was determined by the initial growth rate of fluorescence at 340/440 nm (excitation/emission) of free 7-amino-4-methylcoumarin, derived from the substrate. Inhibition of enzyme activity ingibiruet what their connections were measured after 30 minutes inactivated with hemati at room temperature in buffer without AAPF-substrate. Then the test was started by addition of the indicated concentrations AAPF-substrate.

IC50 values (palingenia concentration) active compounds of the present invention, preferably comprise from about 1000 to 1 nm, particularly preferably from 30 to 1 nm.

ExampleIC50 (nm)
Example 235
Example 16106
Example 213

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 local administration. They can be used, for example, orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injectable solutions or suspensions, or infusion solutions, or topically, for example in the form of ointments, creams, and oils. Oral introduction is preferred.

Production of pharmaceutical preparations can be effected, as is well known JV is the specialists in a given 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 herbal form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid materials, media, and, if necessary, with the usual pharmaceutical adjuvants.

Suitable materials carriers are not only inorganic materials-media, but also organic materials carriers. So, for example, as materials carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or derivatives thereof, talc, stearic acid and its salts. Suitable materials carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (in the case of soft gelatin capsules as a form of introduction, depending on the nature of the active ingredient, carriers may, however, not be necessary). Suitable materials carriers for the production of syrups and solutions are, for example, water, polyols, saccharose, invert sugar. Suitable materials carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and flora the s oil. Suitable materials carriers for suppositories are, for example, natural or hardened oils (hydrogenated), waxes, fats and semi-liquid or liquid polyols. Suitable materials native to get dosage forms for local injection are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

As pharmaceutical adjuvants can be used conventional stabilizers, preservatives, moisturizing and emulsifying agents that improve the consistency agents, flavoring agents, salts for modifying the osmotic pressure, buffer substances, soljubilizatory, dyes, masking agents and antioxidants.

The dosage of the compounds of formula (I) can vary within wide limits depending on the disease, which will be subject to treatment, age, individual condition of the patient, the mode of administration, and, of course, must be determined individually in each case. For adult patients a daily dose of from 1 to 1000 mg, especially from approximately 1 to 300 mg, depending on the severity of the disease and the precise pharmacokinetic profile, the connection may be entered in one or more of a daytime running the unit dosage forms, for example, from 1 to 3 daily unit dosage forms.

In dosage forms may contain about 1-500 mg, preferably 1-100 mg, of the compounds of formula (I).

Examples

The following examples serve to more detailed illustration of the present invention. They are, however, in no way limit it.

Example 1

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

To a cooled with ice to a 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-sulphonylchloride (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 chromatographically on silica gel using a mixture of heptane/chloroform as eluent to obtain (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (2.35 g) as a colorless solid substance. MS (ISN): 465,9, 468,0 (M-N)-

Example 2

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

A suspension of (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b] thiophene-2-sulfonic acids (0.5 g) and 4-pyridineboronic acid (0,197 g) in 1,2-dimethoxyethane (6 ml), ethanol (2 ml) and 2 M aqueous solution carbon is the sodium (4.0 ml) was degirolami 3-4 times to remove oxygen, and then to the suspension was added tetrakis(triphenylphosphine)palladium (0,065 g). The reaction mixture was stirred at 80°C for 3 hours, was quickly diluted with a mixture of ice/water and extracted with ethyl acetate. The organic layers are washed, dried and concentrated. The residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent, to obtain the specified connection (0.35 g) as a yellowish solid substance. MS (ISP): 467,3 (M+N)+

Example 3

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.12 g) and 2,6-differencein-4-Bronevoy acid (0,063 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0,32 ml) and 2M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (by 0.055 g). The specified connection was received (by 0.055 g) as a brownish solid substances. MS (ISP): 520,2 (M+NH4)+

Example 4

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.12 g) and the guy who rata 3-herperidin-4-Bronevoy 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-pyridine-4-yl)-2-trifluoromethyl-phenyl]-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic

This compound was obtained in analogy to Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.12 g) and 2-herperidin-4-Bronevoy acid (0,072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0,32 ml) and 2M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0,065 g). The indicated compound was obtained (of 0.085 g) as a colourless foam. MS (ISN): 483,4 (M-N)-

Example 6

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.10 g) and 3-pyridineboronic acid (0,052 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0,32 ml) and 2M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0,050 g). The indicated compound was obtained (0,086 g) as colorless solids. MS (ISP): 467,0 (M+N)+

Example 7

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.10 g) and 2-methoxy-5-pyridineboronic acid (0,065 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0,32 ml) and 2M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0,012 g). The indicated compound was obtained (of 0.081 g) as a colorless solid substance. MS (ISP): 497,3 (M+N)+

Example 8

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

This compound was obtained in analogy to Example 2 from(4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.10 g) and pyrimidine-5-Bronevoy acid (0,053 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0,32 ml) and 2M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0,012 g). The indicated compound was obtained (0,045 g) as a colorless solid substance. MS (ISN): 466,1 (M-N)-

Example 9

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

This compound was obtained by analogy with the Use of the Ohm 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.10 g) and 2-methoxy-5-pyrimidinemethanol acid (of 0.066 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 (0,012 g). The indicated compound was obtained (0,064 g) as a colorless solid substance. MS (ISP): 498,4 (M+N)+

Example 10

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.12 g) and 5-herperidin-3-Bronevoy acid (0,072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0,32 ml) and 2M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.015 g). The indicated compound was obtained (0,065 g) as a colorless solid substance. MS (ISP): 485,3 (M+N)+

Example 11

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.12 g) and 2-herperidin-5-Bronevoy acid (0,072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0,32 ml) and 2M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.015 g). The indicated compound was obtained (0,070 g) as a colorless solid the substances. MS (ISP): 485,3 (M+N)+

Example 12

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

To a solution of (4-pyridin-4-yl-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (see example 2, 0.27 g) in chloroform (5.0 ml) was added 85% solution of m-chloroperoxybenzoic acid (of € 0.195 g). The reaction mixture was stirred at room temperature for 4 hours and washed with sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographically on a column of silica gel (10 g) using a mixture of dichloromethane/methanol as eluent to obtain the specified connection (0,065 g) as a yellow foam. MS (ISP): 483,4 (M+H)+

Example 13

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

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

This compound was obtained in analogy to Example 1 from 4-bromo-2-methylsulfonylmethyl-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-sulphonylchloride (1.06 g). The desired compound was obtained (1.3 g) as a brownish solid substances. MS (ISN): 4581, 460,0 (M-N)-

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-methylsulfonylmethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0,23 g) and 4-pyridineboronic acid (0,092 g) in 1,2-dimethoxyethane (10 ml), ethanol (2 ml) and 2M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0,058 g). The indicated compound was obtained (0,153 g) as a brown foam (0,153 g). MS (ISN): 457,2 (M-N)-

Example 14

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

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

To a solution of (4-bromo-2-methylsulfonylmethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0,46 g) (see example 13A) in chloroform (25 ml) was added 85% solution of m-chloroperoxybenzoic acid (0,272 g). The reaction mixture was stirred at room temperature for 18 hours, concentrated, and the crude residue was chromatographically on silica gel, using a mixture of heptane/ethyl acetate as eluent to give the desired compound (0.31 g) as off-white solid. MS (ISN): 473,9, 476,0 (M-N)-

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

This compound was obtained in analogy to Example 2 from (4-bromo-2-methanesulfonamide-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0,238 g) and 4-pyridineboronic acid (0,092 g) in 1,2-dimethoxyethane (10 ml), ethanol (2 ml) and 2M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0,058 g). The indicated compound was obtained (0,077 g) as yellowish foam. MS (ISN): 473,3 (M-N)-

Example 15

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

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

To a solution of (4-bromo-2-methylsulfonylmethyl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0,46 g) (see Example 13A) in chloroform (25 ml) was added 85% solution of m-chloroperoxybenzoic acid (0,272 g). The reaction mixture was stirred at room temperature for 18 hours, concentrated, and the crude residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to give the desired compound (was 0.138 g) as a brownish solid. MS (ISN): 490,0, 492.0 (M-N)-

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

This is the compound was obtained in analogy to Example 2 from (4-bromo-2-methanesulfonamide-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0,123 g) and 4-pyridineboronic 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 yellowish foam. MS (ISN): 489,1 (M-N)-

Example 16

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

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

This compound was obtained in analogy to Example 1 from 4-bromo-2-ethylaniline (CAS: 45762-41-2, 2.0 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonylchloride (0,265 g) in pyridine (2.0 ml), the reaction was conducted for 4 hours. The desired compound was obtained (0.20 g) as a colorless solid substance. MS (ISP): 445,0, 447,0 (M+NH4)+

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

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 acids (0.10 g) and 4-pyridineboronic acid (0,043 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 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+N)+

Example 17

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

This compound was obtained in analogy to Example 1 from 4-bromo-2-(triptoreline)aniline (CAS: 175278-09-8, 2,82 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonylchloride (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 colorless foam. MS (ISP): 501,0, 503,0 (M+NH4)+

Example 18

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

This compound was obtained in analogy to example 2 from (4-bromo-2-triptoreline-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (0.075 g) and 4-pyridineboronic acid (0,029 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 2M aqueous sodium carbonate solution (0.6 ml) with tetrakis(triphenylphosphine)palladium (0,009 g). The specified connection was received (by 0.055 g) as a colorless solid substance. MS (ISP): 483,0 (M+N)+

Example 19

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

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]thiophene-2-sulphonylchloride (0,440 g) and DMAP (0.305 g). The reaction mixture was stirred at room temperature for 16 h, diluted with dichloromethane (12 ml) and was chromatographically on silica gel with use the mixture of heptane/ethyl acetate as eluent to obtain the specified connection (0,205 g) as off-white solid. MS (ISN): 397,1 (M-N)-

Example 20

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

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

1-Bromo-4-chlorobenzene (12,25 g) was added in portions 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 is slowly added to a well stirred mixture of ice water (500 ml)and the mixture continued to stir for 30 minutes. The colorless precipitate was separated by filtration. The wet sediment from the filter was removed using dichloromethane, the mixture is separated from the water, and the organic phase was dried and boiled away until dry (14.1 g). The dry mixture of the 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. To the mixture to maintain the temperature of 20-30°C and a pH of about 9 was added ice and concentrated NaOH. Then the reaction mixture was stirred over night at room temperature and pH 9, was acidified with concentrated HCl to pH 1 and cooled. The precipitate was filtered, washed with cold water and dried over P2O5under high vacuum overnight to obtain a colorless derivative sulfinol acid (10.5 g). This acid is dissolved in DMF (100 ml), to the solution was added methyliodide (13 g), and then potassium carbonate (14.0 g). The reaction mixture was stirred at room temperature overnight and concentrated under high vacuum. To the residue was added water and was extracted with tert-butylmethylamine ether. The organic layers are washed, dried and concentrated. The residue was chromatographically over silica gel using a mixture of cyclohexane/ethyl acetate as eluent to obtain methylsulfonyl derived (9,1 g), which still represented a mixture of 2 isomers. This mixture (9.0 g) was dissolved in dimethoxyethane (400 ml) and ethanol (90 ml), which was replaced by a 2M aqueous solution of sodium carbonate (200 ml). The reaction mixture was degirolami several times and added tetrakis(triphenylphosphine)palladium (3.0 g). The mixture was heated up to 80°C for 16 hours and concentrated until dry. The residue was dissolved in a mixture of dichloromethane / water, was 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 you who akim vacuum. The residue was diluted with a mixture of ice/water and extracted with ethyl acetate. The organic layers are washed, dried and concentrated, and the residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate. Containing compound fraction was evaporated and the residue was led from methanol/ether to obtain the desired compound (5.75 g) as 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 mixture of dioxane/methanol 1:1 (100 ml) was added 2 n HCl (5 ml) and palladium black (1.0 g). The reaction mixture was hydrogenosomal at a pressure of 1.1 bar and room temperature for 18 hours. The catalyst was filtered using a micro filter and washed with methanol. The filtrate was evaporated until dry to obtain the desired compound (1.45 g) as a yellowish solid substance. MS (ISP): 249,1 (M+N)+

d) 2-Methanesulfonyl-4-piperidine-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 hydrogenosomal at a pressure of 1.1 bar and a temperature of 80°C for 8 hours. The reaction mixture was cooled to room temperature, filtered through Mick is filtr, washed with acetic acid and concentrated until dry to obtain the specified connection (0,89 g) as a pale yellow amorphous powder. MS (ISP): 255,4 (M+N)+

e) Tert-butyl ether 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid

To a solution of 2-methanesulfonyl-4-piperidine-4-yl-phenylamine in connection with acetic acid (1.5 g) in dichloromethane (30 ml) was added di-tert-BUTYLCARBAMATE (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 was extracted with dichloromethane. The organic phase was dried and concentrated and the residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain the desired compound (0.64 g) as off-white solid. MS (ISP): 355,1 (M+H)+

f) tert-butyl ether 4-[4-(5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-3-methanesulfonyl-phenyl]-piperidine-1-carboxylic acid

To a cooled ice suspension of sodium hydride (60% to 65% in mineral oil, 0,030 g) in absolute DMSO (3 ml) was added tert-butyl ester 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid (0,106 g). The mixture was stirred at a temperature of 0-5°C for 30 minutes and to the mixture dropwise added races the thief 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonylchloride (0,237 g) in absolute DMSO (1 ml). The reaction mixture was stirred at room temperature for 5 hours, diluted with a mixture of ice/water/1 n HCl and was extracted with ethyl acetate. The organic phase was washed, dried and concentrated, and the residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain (0.025 g) methylbenzo[b]thiophene-2-sulphonylchloride (0,237 g). The desired compound (0.025 g) was obtained as yellowish foam. MS (ISN): 581,3 (M-N)-

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

A solution of tert-butyl ester 4-[4-(5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-3-methanesulfonyl-phenyl]-piperidine-1-carboxylic acid (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. To the mixture was added ether (20 ml), the precipitate was filtered, washed with ether and dried under high vacuum over P2O5to obtain the specified connection (0,020 g) as yellowish powder. MS (ISP): 483,3 (M+N)+

Example 21

(2-methanesulfonyl-4-piperidine-4-yl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic

Hydrochloride (2-methanesulfonyl-4-piperidine-4-yl-phenyl)-amide 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acids (see Example 20g, 6 mg) about hostile through HPLC - column with a mixture of acetonitrile/water/formic acid to obtain the compound (3 mg) as off-white foam. MS (ISP): 483,3 (M+N)+

Example 22

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

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 was chromatographically on silica gel using a mixture of dichloromethane/methanol/ammonia, to obtain said compound (0.025 g) as off-white solid. MS (ISP): 439,1 (M+N)+

Example 23

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

This compound was obtained by analogy with the compound described in Example 20f, 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-sulphonylchloride (0,265 g) in the reaction with sodium hydride (0.10 g), the reaction was carried out at room temperature for 18 hours from the receipt of the indicated compound (0.025 g) as a yellow foam. MS (ISN): 475,0 (M-N)-

Example 24

Tert-butyl ester 4-[3-methanesulfonyl-4-(1-methyl-1H-indole-2-sulfonylamino)-phenyl]-p is peridin-1-carboxylic acid

To a solution of tert-butyl ester 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid (see Example 20E, 0,050 g) in dichloromethane (2.0 ml) was added 1-methyl-1H-indole-2-sulfonyl chloride (0.036 g, Ms. Chan, Ming Fai; Wu, Chengde; Raju, Bore Gowda; Kogan, Timothy; Kois, Adam; Verner, Erik Joel; Castillo, Rosario Silvestre; Yalamorri, Venkatachalapathi; Balaji, Vitukudi Narayanaiyengar, US 5962490) and DMAP (dimethylaminopyridine) (0,021 g). The reaction mixture was stirred at a temperature of 80°C for 18 hours, cooled and directly chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain the specified connection (0,048 g) as yellowish foam. MS (ISN): 546,5 (M-N)-

Example 25

Hydrochloride (2-methanesulfonyl-4-piperidine-4-yl-phenyl)-amide 1-methyl-1H-indole-2-sulfonic

A solution of tert-butyl ester 4-[3-methanesulfonyl-4-(1-methyl-1H-indole-2-sulfonylamino)-phenyl]-piperidine-1-carboxylic acid (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 to the mixture was added ether (20 ml). The precipitate was collected, washed with ether and dried under high vacuum over P2O5with obtaining the specified connection (to 0.032 g) as off-white powder. MS (ISN): KZT 446.4 (M-N)-

Example 26

(2-methanesulfonyl-4-pyridin-4-yl-phenyl)-amide 6-fluoro-naphthas the Lin-2-sulfonic

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, Ms. 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 was directly chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain the specified connection (0,098 g) as a colourless foam. MS (ISP): 457,3 (M+H)+

Example 27

Hydrochloride (4-pyridin-4-yl-phenyl)-amide 1H-indole-2-sulfonic

a) tert-butyl ether 2-(4-pyridin-4-yl-phenylsulfanyl)-indole-1-carboxylic acid

To a solution of (4-pyridin-4-yl)aniline (CAS: 13296-04-3, 0,054 g) and tert-butyl methyl ether 2-chlorosulfonyl-indole-1-carboxylic acid (0,120 g, cf. Shankar, Bandarpalle C.; Gilbert, Eric; Rizvi, Razia K.; Huang, Chunli; Kozlowski, Joseph A.; McCombie, Stuart; Shih, Neng-Yang. WO 2006002133) in 1,2-dichloroethane (5.0 ml) was added DMAP (0,047 g). The reaction mixture was stirred at 50°C for 3 hours and was chromatographically on silica gel using a mixture of dichloromethane/ethyl acetate as eluent to obtain the desired compound (0,070 g) as colorless powder. MS (ISP): 450,4 (M+H)+

(b) hydrochloride (4-pyridin-4-yl-phenyl)-amide 1 H-indole-2-sulfat is slots

To a solution of tert-butyl methyl ether 2-(4-pyridin-4-yl-phenylsulfanyl)-indole-1-carboxylic acid (0,030 g) in ethyl acetate (1.0 ml) was added to 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 P2O5to obtain the compound (0.025 g) as a colorless amorphous powder. MS (ISP): 350,4 (M+H)+

Example 28

Hydrochloride (2-methanesulfonyl-4-piperidine-4-yl-phenyl)-amide 5-fluoro-1-methyl-1H-indole-2-sulfonic

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

To a solution of 1-methyl-5-farindola (CAS: 116176-92-2, 1.98 g) in absolute ether (100 ml) at -78°C. was added dropwise tert-BuLi (1.7 km n solution in pentane, and 12.4 ml). The reaction mixture was stirred at this temperature for 60 minutes, and then over the surface of the solvent missed sulfur dioxide until then, until he stopped exothermic reaction. Then the mixture was stirred for 30 minutes at room temperature and concentrated until dry. The crude residue suspended in dichloromethane (100 ml) and to the mixture was added NCS (K-chlorosuccinimide)(2,94 g). The reaction mixture was stirred at room temperature for 4 hours, diluted with a mixture of ice/snow in the Yes and was extracted with dichloromethane. The organic phase was washed, dried and concentrated. The residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain the desired product (0.405 g) as yellowish solid substance. MS (EI): 247,1 (M)

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

To a solution of tert-butyl ester 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid (see Example 24th, 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 a temperature of 80°C for 72 hours, diluted with dichloromethane (2 ml) and was chromatographically on silica gel using mixtures of dichloromethane/ethyl acetate as eluent to obtain the compound (0.019 g) as off-white foam. MS (ISN): MADE 564.3 (M-N)-

C) hydrochloride (2-methanesulfonyl-4-piperidine-4-phenyl-yl)-amide 5-fluoro-1-methyl-1H-indole-2-sulfonic

A solution of tert-butyl ester 4-[4-(5-fluoro-1-methyl-1H-indole-2-sulfonylamino)-3-phenyl-methanesulfonyl]-piperidine-1-carboxylic acid (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 added ether (20 ml). OS the dock gathered, was washed with ether and dried under high vacuum over P2About5with obtaining the specified connection (0,014 g) as off-white amorphous powder. MS (ISN): 464,0 (M-N)-

Example 29

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

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

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-BUTYLCARBAMATE (as 4.02 g) and DMAP (0,205 g). The reaction mixture was stirred at room temperature for 4 hours, concentrated and the residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain the desired compound (3.15 g) as a colorless solid substance. MS (ISP): 250,1 (M+N)+

b) tert-butyl ether 2-chlorosulfonyl-5-fluoro-3-methyl-indole-1-carboxylic acid

This compound was obtained in analogy to the compound of Example 28a of the tert-butyl ester 5-fluoro-3-methyl-indole-1-carboxylic acid (1.0 g) in a mixture of diethyl ether/THF 1: 2 (15 ml), 1,7 n solution of tert-BuLi (2,85 ml), SO2(gas) and NCS (0,59 g). The indicated compound was obtained (0,80 g) as a colorless solid substance. MS (EI): 347,2, 247,1 (M and M-Sun)

c) tert-BU is silt ester 2-(4-bromo-2-trifluoromethyl-phenylsulfanyl)-5-fluoro-3-methyl-indole-1-carboxylic acid

This compound was obtained in analogy to the compound of Example 1 from tert-butyl ether 2-chlorosulfonyl-5-fluoro-3-methyl-indole-1-carboxylic acid (0.29 grams) and 2-amino-5-bromobenzonitrile (2.0 g) in pyridine (5 ml) by stirring for 7 days at room temperature. The specified connection (0,095 g) was obtained as a colourless foam. MS (ISN); 551,4, 549,3 (M-N)-

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

This compound was obtained in analogy to the compound of Example 2 from tert-butyl ether 2-(4-bromo-2-trifluoromethyl-phenylsulfanyl)-5-fluoro-3-methyl-indole-1-carboxylic acid (to 0.108 g), 4-pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (0.4 ml) and 2 M aqueous sodium carbonate solution (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-N)-

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

This compound was obtained in analogy to the compound of Example 27b of the tert-butyl ester 5-fluoro-3-methyl-2-(4-pyridin-4-yl-2-trifluoromethyl-phenylsulfanyl)-indole-1-carboxylic acid (0,052 g), of 2.5 n HCl/ethyl acetate (10.0 ml). The connection specified level (0.041 g) was is trained as a brown amorphous powder. MS (ISN): 448.4 (M-N)-

Example 30

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

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

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 the suspension is dropwise added itmean (2.85 g) at a temperature of 0-5°Sreaction the 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 phase was washed, dried and concentrated. The crude residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain the desired compound (2.15 g) as a colourless liquid. MS (EI): to 163.1 (M)

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

This compound was obtained in analogy to the compound of Example 28a of 5-fluoro-1,3-dimethyl-1H-indole (1.0 g) in a mixture of diethyl ether/THF 1: 2 (15 ml), 1,7 n solution of tert-BuLi (4,33 ml), SO2(gas) and NCS (0. 90 g). The specified connection (0.27 g) was obtained as yellowish solid substance. MS (ISN): 241,9 (M-F)

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

This compound was obtained in analogy to the compound of Example 1 from 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonyl chloride (0.25 g) and 2-amino-5-bromobenzonitrile (2.3 g) in pyridine (5 ml), the reaction was carried out for 18 hours at 35°C. the Specified connection (0,293 g) was obtained as yellow solid substance. MS (ISN): 551,4, 549,3 (M-N)-

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

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 acids (0,100 g), 4-pyridineboronic acid (0,040 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (1.0 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.025 g). These compounds (0,058 g) was obtained as a brown foam. MS (ISN): 462,4 (M-N)-

Example 31

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

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

To a solution of 3-methyl bromide-5-fermentation (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 within 5 minutes Isopropylamine bromide (1.0 m, 16.6 ml). The reaction mixture was stirred at 50°C for 5 hours, cooled diluted with a mixture of ice/water and a solution of ammonium chloride and was extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated. The residue was chromatographically on silica gel using a mixture of heptane/methylene chloride as eluent to obtain the specified connection (1.35 g) as a yellowish oil. MS (EI): of 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 a mixture of ice/water and extracted with methylene chloride. The organic phase was washed with water and aqueous sodium bicarbonate solution, dried and concentrated. The remains were chromatographically on silica gel using a mixture of heptane/ethyl acetate as eluent to obtain the specified connection (0,49 g) as a colourless oil. MS (EI): 306,8 (M)

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

This compound was obtained similarly to the compound of Example 1 from 5-fluoro-3-isobutyl-benzo[b]thiophene-2-sulfonyl chloride (0,44 g), 2-amino-5-bromobenzonitrile (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 substance. MS (ISN): 5082, 510,3 (M-N)-

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

This compound was obtained in analogy to the compound of Example 2 from (4-bromo-2-trifluoromethyl-phenyl)-amide 5-fluoro-3-isobutyl-benzo[b]thiophene-2-sulfonic acids (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 connection (to 0.47 g) was obtained as yellowish solid substance. MS (ISN): 507,1 (M-N)-

Example

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

ingredientspills
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Hydrated lactose60,0 mg70.0 mg
Povidone K 12.5 mg15,0 mg
Sodium starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(the total mass of the nucleus)120,0 mg350,0 mg
Covering film:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient was sieved and mixed with microcrystalline cellulose and the mixture was granulated with a solution of polyvinylpyrrolidone in water. The obtained granules were mixed with sodium starch glycolate and stearate, spre sofyali obtaining cores weighing 120 or 350 mg, respectively. Cores were covered with a membrane with an aqueous solution/suspension of the above-mentioned cover film.

The example In

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

ingredientsOn capsule
the compound of formula (I)25.0 mg
lactose150,0 mg
corn starch20.0 mg
talc5.0 mg

These components are sifted and mixed, the resulting mixture was filled in capsules 2 sizes.

The example

The solution for injection may have the following composition:

the compound of formula (I)3.0 mg
the polyethylene glycol 400150,0 mg
acetic acidsufficient for pH 5.0
water for injection solutionsto 1.0 ml

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

Example D

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

The capsules composition
the compound of formula (I)5.0 mg
yellow wax8.0 mg
hydrogenated soybean oil8.0 mg
partially hydrogenated vegetable oil34,0 mg
soybean oil110,0 mg
The weight of the components capsules165,0 mg
gelatin capsule
gelatin75,0 mg
glycerol 85%32,0 mg
the Karion 838.0 mg (dry material)
titanium dioxide0.4 mg
yellow iron oxide1.1 mg

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

Example F

The sachet containing the following ingredients can be manufactured in a known manner:

the compound of formula (I)50.0 mg
lactose, fine powder1015,0 mg
microcrystalline cellulose (AVICEL PH 102)1400,0 mg
sodium carboxymethylcellulose14,0 mg
polyvinylpyrrolidone K 3010.0 mg
magnesium stearate10.0 mg
flavorings1.0 mg

The active ingredients are mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylene idona and water. The granules were mixed with magnesium stearate and flavors and the resulting mixture was filled in sachets.

1. The compound of formula (I)
,
where the fragmentrepresents;
X represents a phenylene, optionally substituted by one, two or three substituents, independently selected from the group consisting of halogen, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, halogen-C1-6-alkoxy, C1-6-alkylsulfonyl,1-6-alkylsulfonyl,1-6-allylthiourea,1-6-alkylsulfonyl-C1-6-alkyl, C1-6-alkylsulfonyl - C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl and C1-6-alkoxycarbonyl;
Y represents a pyridyl, pyrimidinyl or piperidyl, which may not necessarily be substituted by one or two substituents, independently selected from the group consisting of halogen, C1-6-alkoxy and C1-6-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-SO2group, if X is fenelonov group.

3. The compound according to claim 1, in which X represents a phenylene, substituted halogen - C1-6-alkyl or C1-6-alkylsulfonyl in ortho-position to the-H,-SO 2group.

4. The compound according to claim 1, in which X represents a phenylene, substituted by trifluoromethyl or methylsulfonyl in ortho-position to the-NH-SO2group.

5. The compound according to claim 1, which represents (4-pyridin-4-yl-2-triptoreline)amide 5-fluoro-3-methylbenzo[b]thiophene-2-sulfonic acids.

6. Pharmaceutical compositions containing a compound according to claim 1 and a pharmaceutically acceptable excipient intended for the treatment, prevention or treatment, and prevention of allergic, inflammatory and/or fibrotic diseases, such as allergies, asthma, occlusal disease peripheral artery 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 diabetes/LI.

7. The compound according to claim 1 for use as therapeutically active substances for the treatment, prevention or treatment, and prevention of allergic, inflammatory and/or fibrotic diseases, such as allergies, asthma, occlusal disease is perifericheskikh arteries, critical lower 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 diabetes/LI.

8. The compound according to claim 1 for use as therapeutically active substances for the treatment and/or prevention of atherothrombosis or asthma.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel amino compound of formula: where X is S or O; R1 and R2 independently denote H or C1-4alkyl, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring; and n equals 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient, and use of the amino compound or pharmaceutically acceptable salt thereof to produce a drug for treating depression.

EFFECT: improved method.

8 cl, 4 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: compound, represented by formula

,

or its pharmaceutically acceptable salt, where Y1 represents nitrogen atom or group, represented by CRA, Y2 represents nitrogen atom or group, represented by CRB, Y3 represents nitrogen atom or group, represented by CRC, RA, RB and RC, which can be similar or different, each represents hydrogen atom, etc. (except in the case, when Y1 is CRA, Y2 is CRB and Y3 is CRC), X represents oxygen atom, etc., R1 represents C1-C6alkyl group, etc., R3 represents optionally substituted phenyl group, etc., R4 represents hydrogen atom, etc., and R5 represents optionally substituted phenyl group, etc.), possesses inhibiting action with respect to S1P binding with its receptor Edg-1(SlP1).

EFFECT: obtaining composition, which can be used as therapeutic medication in case of autoimmune diseases, rheumatoid arthritis, asthma, atopic dermatitis, rejection after organ transplantation, cancer, retinopathy, psoriasis, osteoarthritis or age-related macula lutea degeneration, etc.

13 cl, 9 ex, 1 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to agriculture and specifically to chemical agents for protecting plants based on arylsulphonylurea derivatives, used for weed control in grain and vegetable crops. Disclosed is a method of producing a granular herbicidal preparation which contains water-soluble diethylethanolamine or alkaline salts of arylsulphonylurea of formula: where or n equals 0 or 1; for n-1 Z-CH2; R1-COOCH3; R2-CH3, OCH3, OC2H5; R3-OCH3, NHCH3; R4-H, CH3; X-N, CH; M-(C2H5)2NHC2H4OH, K, Na, involving reaction of the corresponding sulphonylurea and diethylethanolamine or alkali metal hydroxide in an aqueous medium at temperature 25-80°C, adding 3.5-6.5 wt % urea to the reaction product, separating the end product by crystallisation in the presence of 7-30 wt % salting agent to obtain a product in form of a melt which is then extruded at temperature 30-60°C, and subsequently drying the obtained granules.

EFFECT: obtaining chemical agents based on arylsulphonylurea for protecting plants.

4 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I) or to its pharmaceutically acceptable salt: formula (I) wherein; R1 represents hydrogen; R2 represents phenyl, benzothienyl, benzofuranyl or the group -CH2CH2-phenyl; wherein R2 is optionally substituted by 1 or 2 substitutes optionally specified in F, O, Br, I, -CN, -NO2, -OR8, C1-C6alkyl and -N(R9)2; R4 represents phenyl substituted by 1 or 2 substitutes optionally specified in F, CI, Br, I, -CP3, -OH, -OR8 and C1-C6alkyl; each R8 is optionally specified in C1-C6alkyl; and each R9 is optionally specified in H and C1-C6alkyl. The invention also refers to a pharmaceutical composition for activity modulation of depot-controlled calcium channels (SOC-channels) containing such compounds.

EFFECT: there are produced new compounds and based pharmaceutical compositions which can find application in medicine for treating the diseases or conditions, such as rheumatoid arthritis, psoriasis, inflammatory intestinal disease, asthma and multiple sclerosis.

12 cl, 21 dwg, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1,3-disubstituted 4-methyl-1H-pyrrol-2-carboxamides of formula I: wherein the values R1, R2, R3, R4 are presented in cl.1 of the patent claim.

EFFECT: preparing the compounds found to be serotonin-5-HT reuptake inhibitors that enables using them in medicine.

14 cl, 1 dwg

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzimidazole derivatives of general formula I wherein: R1 = CN, halogen or C(=O)CH3; R2 means methyl or H; R3=H or halogen; R4 and R5 independently mean methyl or ethyl, or R4 and R5 together with a carbon atom whereto attached form C3-6cycloalkyl or 5-6-member heterocycloalkyl; R6 and R7 independently mean H, halogen, methyl or ethyl; or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy.

EFFECT: compounds may be used in treating osteoarthritis, chronic tendinitis, pelvic pain and peripheral neuropathy, gastroesophageal reflux disease, irritable bowel syndrome and overactive bladder.

39 cl, 34 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I, as well as to their physiologically acceptable salts wherein: X means NH; R1 means (C1-C6)-alkyl; R2 means OH; R2' means H; R5' means (C1-C6)-alkylene-O-S(O)2-R6; R3, R3', R4, R4' and R5 independently mean H, OH, (C1-C6)-alkylene-O-S(O)p-R6, O-(CH2)m-phenyl; at least one of the radicals R3, R3', R4, R4' and R5 has the value -O-(CH2)m-phenyl; R6 means OH; m=1; p=2.

EFFECT: compounds can find application in medicine, eg as lipid-lowering agents.

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II , where Q is (CR4R5)n3; n1 equals 1 or 2; n2 equals 1 or 2; n3 equals 1; R2 is R2-1 or R2-2 , Ar is phenyl or a heteroaryl ring consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S; X denotes 1-2 substitutes located on Ar, each independently selected from a group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9 and CN; R3-R5 denote H; R8 is H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted with one or more halogens or heteroatom-containing substitutes selected from a group consisting of OR11, NR11R12, CO2R11, CONR11R12, NRnC(=O)Ri2; R9 is H or alkyl; R11-R12 independently denote H, alkyl, pyridinyl or morpholinyl.

EFFECT: compounds are inhibitors of rho-associated protein kinase which can be used in medicine to prevent or treat diseases or conditions associated with cytoskeleton readjustment, specifically treat high intraocular pressure such as primary open angle glaucoma.

10 cl, 3 tbl, 226 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula I: , where values of R1-R4, R7, R8 are given in claim 1. Compounds of formula I exhibit antagonistic activity on MR steroid receptors, which enables their use to produce a pharmaceutical composition and drugs with MR steroid receptor antagonist properties.

EFFECT: improved method.

95 cl, 26 dwg, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of formula I or their pharmaceutically acceptable salts showing activity with respect to HIV reverse transcriptase, as well as to a based pharmaceutical composition (I). In formula I R1 means phenyl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, phenyl or heteroaryl optionally substituted by one-three substitutes independently specified in groups (a)-(r), R2 means -CN, -CH=CHCN or halogen; R3 means hydrogen, halogen, amino group, halogen(C1-C6)alkyl, -CN or methyl; R4 means hydrogen, Br or amino group; R5a and R5b independently mean hydrogen, C1-C6alkyl, C1-C6alkoxy group or halogen; R6a and R6b either independently mean hydrogen, or together mean ethylene; X means NH or O. The groups (a)-(r) are such as presented in the patent claim.

EFFECT: preparing pharmaceutically acceptable salts possessing activity with respect to HIV reverse transcriptase.

17 cl, 42 ex, 6 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a deuterium-enriched α-ketoamide compound of formula wherein: D means a deuterium atom; the values R1-R5 are presented in cl.1 of the patent claim, and to a based pharmaceutical composition.

EFFECT: method improvement.

32 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts possessing the properties of a MMP12 inhibitor, a method for preparing them, an intermediate compound of formula (III), a pharmaceutical composition, a method for preparing it, using the compounds of formula (I) and versions of methods of treating with the use of the compounds of formula (I). The compounds may be used for treating the MMP12-mediated diseases, such as chronic obstructive pulmonary disease. In formula (I) and (III) R1 represents H, CH3, CH3CH2, CF3 or cyclopropyl; and R2 represents H or CH3.

EFFECT: higher clinical effectiveness.

15 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1,3-disubstituted 4-methyl-1H-pyrrol-2-carboxamides of formula I: wherein the values R1, R2, R3, R4 are presented in cl.1 of the patent claim.

EFFECT: preparing the compounds found to be serotonin-5-HT reuptake inhibitors that enables using them in medicine.

14 cl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II , where Q is (CR4R5)n3; n1 equals 1 or 2; n2 equals 1 or 2; n3 equals 1; R2 is R2-1 or R2-2 , Ar is phenyl or a heteroaryl ring consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S; X denotes 1-2 substitutes located on Ar, each independently selected from a group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9 and CN; R3-R5 denote H; R8 is H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted with one or more halogens or heteroatom-containing substitutes selected from a group consisting of OR11, NR11R12, CO2R11, CONR11R12, NRnC(=O)Ri2; R9 is H or alkyl; R11-R12 independently denote H, alkyl, pyridinyl or morpholinyl.

EFFECT: compounds are inhibitors of rho-associated protein kinase which can be used in medicine to prevent or treat diseases or conditions associated with cytoskeleton readjustment, specifically treat high intraocular pressure such as primary open angle glaucoma.

10 cl, 3 tbl, 226 ex

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