Derivative, containing condensed ring structure, and its application in medicine

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds, represented by formula (I) , where X1 and X2 independently represent CH or N; ring U represents benzene ring, pyrazole ring, 1,2,4-oxadiazole ring, 1,2,4-thiadiazole ring, isothiazole ring, oxazole ring, pyridine ring, thiazole ring or thiophene ring, m represents integer number, which has values from 0 to 1; n represents integer number, which has values from 0 to 3; R1 represents hydroxygroup or C1-6 alkyl; R2 represents any of (1)-(3): (1) halogen atom; (2) hydroxygroup; (3) C1-6 alkyl or C1-6 alkoxy, each of which can independently contain any group, selected from group of substituents α; group of substituents α includes fluorine atom and hydroxygroup, or its pharmaceutically acceptable salt. Invention also relates to pharmaceutical composition, possessing inhibiting activity with respect to xanthenes oxidase, including formula (I) compound or its pharmaceutically acceptable salt as active ingredient.

EFFECT: derivative, which contains condensed ring structure, intended as means for prevention and treatment of disease, associated with abnormal level of uric acid in serum.

15 cl, 11 tbl, 126 ex

 

The scope of the invention

The present invention relates to containing condensed ring derivatives, useful as pharmaceuticals.

More specifically, the present invention relates to containing condensed ring derivatives having inhibitory activity against xanthine oxidase and which is useful as a means for the prevention or treatment of diseases associated with abnormal levels of uric acid in serum, or their prodrugs, or pharmaceutically acceptable salts.

Background of the invention

Uric acid is the end product of purine metabolism in humans. Many mammals, unlike humans, uric acid then decomposes under the action of urotoxicity (uricase) in the liver to allantoin that is excreted through the kidneys. In humans, the major route of excretion of uric acid are the kidneys, where approximately two-thirds of uric acid excreted in the urine. The remainder excreted in the feces. When there is excessive production or decreased excretion of uric acid, this causes hyperuricemia. The hyperuricemia is divided into type with excessive production of uric acid, the type with insufficient excretion of uric acid and mixed type. This classification hyperwrt the MIA is clinically important. With the aim of reducing adverse effects of therapeutic agents, therapeutic agents are selected in accordance with each class (for example, see non-patent document 1).

When hyperuricemia with excessive production of uric acid urinary excretion of uric acid increases, and when the urinary excretion of uric acid is further increased when using tools that promote the excretion of uric acid may develop such complications as urinary concretions. Therefore, in principle, allopurinol, an inhibitor of the production of uric acid (or sometimes referred to as inhibitor of the synthesis of uric acid, hereinafter referred to in this application is listed as "inhibitor of the production of uric acid), used in the type of excessive production of uric acid.

Uric acid is formed from purine substances that have nutritional origin, and are synthesized endogenously, ultimately, by oxidation of xanthine by xanthine oxidase. Allopurinol developed as an inhibitor of xanthine oxidase, and this is the only inhibitor of the production of uric acid, used in medical practice. However, although allopurinol reportedly is effective in hyperuricemia and various diseases that it causes, it was also reported about severe adverse effects, such as Sindh is ω poisoning (allergic anghit), the syndrome of Stevens-Johnson, exfoliative dermatitis, aplastic anemia, liver dysfunction and the like (for example, see non-patent document 2). As one of the reasons it was stated that allopurinol has a structure similar to nucleic acids, and inhibits the path of pyrimidine metabolism (for example, see non-patent document 3).

On the other hand, when the type of hyperuricemia with insufficient excretion of uric acid excretion of uric acid Senegalese. It was reported that when using allopurinol, which is metabolized in oxipurinol, accretively through the kidneys via the same mechanism as uric acid excretion oxipurinol also decreases, and it increases the number of cases of disorders of the liver (for example, see non-patent document 4). Therefore, in principle, contribute to the excretion of uric acid, such as probenecid, benzbromarone and the like, used in the type of disease with insufficient excretion of uric acid. These funds, promote the excretion of uric acid, however, also have side effects such as gastrointestinal disorders, the formation of urinary stones or similar. In particular, it is known that benzbromarone can cause fulminant hepatitis in the case of idiosyncratic patients (for example, see not-atentie documents 5 and 6).

Thus, consider that currently exist inhibitor of the production of uric acid, as well as a means of facilitating the excretion of uric acid, is limited in application to patients or have severe side effects. Therefore, the development of easy-to-use tools for the treatment of hyperuricemia or similar diseases is desirable.

Uric acid is excreted mainly by the kidneys, and the dynamics of lithate kidney hitherto explored in some experiments using membrane vesicles brush edges (BBMV)prepared from cortical substance of the kidney (for example, see non-patent documents 7 and 8). It is known that in humans, uric acid passes through the renal glomeruli freely, and there are mechanisms of reabsorption and secretion of uric acid in the proximal tubules (for example, see non-patent document 9).

In recent years there has been identified a gene (SLC22A12), encoding the mount of lithate in the human kidney (for example, see non-patent document 10). Mount encoded by this gene (mount of lithate 1, in the present application is further specified as "URAT1"), is a 12-transmembrane-type molecule, belonging to the family instead. URAT1 mRNA specifically expressed in the kidney, and the localization of URAT1 on the apical side of the proximal tubules were observed on cf who see the fabric of the human kidney. In the experiment using the expression system of xenopus oocytes was shown the absorption of uric acid via URAT1. In addition, it was shown that the absorption of uric acid is transported by sharing with organic anions, such as lactic acid, perintalmanna acid (PZA), nicotinic acid and the like, and the absorption of uric acid via URAT1 inhibited the means for facilitating the excretion of uric acid, probenecid and benzbromarone. Thus, as expected on the basis of the experiment using membrane vesicles, there are serious grounds to assume that URAT1 is lithate/anyone-exchanger. It has been shown that URAT1 is a mount, which plays an important role in the reabsorption of uric acid in the kidneys (for example, see non-patent document 10).

In addition, the relationship between URAT1 and diseases becomes clear. Idiopathic renal hypouricemia is a disease in which the excretion of uric acid is increased due to the anomalous dynamics of lithate in the kidneys, and the level of uric acid in the serum becomes low. It is known that this disease is often associated with urinary concrements or acute renal failure after exercise. URAT1 was identified as the gene responsible for renal g is morikami (for example, see non-patent document 10). It also gives a strong basis for assuming that URAT1 is responsible for controlling the level of uric acid in the blood.

Therefore, a substance having inhibitory activity against URAT1 is useful as a drug for treatment and prevention of diseases associated with high levels of uric acid in the blood, such as hyperuricemia, gouty site, gouty arthritis, renal disorder associated with hyperuricemia, urinary concretions or similar.

There were reports that in the treatment of hyperuricemia combination of allopurinol as an inhibitor of the production of uric acid and tools that promote the excretion of uric acid, decreased the level of uric acid in serum is much stronger than allopurinol separately (for example, see non-patent documents 11 and 12). Therefore, when treatment is only one of the existing tools cannot provide a sufficient effect, a higher therapeutic effect can be expected when using the combined use of an inhibitor of production of uric acid and tools that promote the excretion of uric acid. In addition, as for the type of hyperuricemia with insufficient excretion of uric acid, believe that, because the urinary excretion of uric acid can the t to decrease with decrease in blood levels of uric acid, the risk of the formation of urinary calculus, which is the result of monotherapy using tools that promote the excretion of uric acid, can be reduced. In addition, with regard hyperuricemia mixed type, the highest expected therapeutic effect. Thus, it is expected that the tool, as having inhibitory activity against the production of uric acid and the activity of excretion of uric acid, will be extremely useful agent for the prevention or treatment of hyperuricemia or similar diseases.

As compounds with as inhibitory activity against xanthine oxidase, and inhibitory activity against URAT1, known Morin, which is the natural product (see non-patent document 13). Furthermore, as compounds with activity excretion of uric acid, a known compound berelovich or girilovich esters (see Patent document 1).

The quality of the connection, where the condensed ring structure linked to aromatic ring containing carboxypropyl known, for example, naphthalene derivative, has a therapeutic effect against HIV (see Patent document 2), a quinoline derivative having an antihypertensive effect (see Patent documents is 3) and the like. However, these compounds have structures other than containing condensed ring structure derived by the present invention. In addition, in this reference document says nothing and there is no assumption that containing condensed ring structure derived by the present invention has inhibitory activity against xanthine oxidase and is useful for prevention or treatment of diseases associated with abnormal levels of uric acid in serum, such as gout, hyperuricemia or similar.

Patent document 1: Patent publication Japan No. 2000-001431

Patent document 2: international publication number WO95/33754, brochure

Patent document 3: European patent publication No. 0569013, description

Non-patent document 1: Atsuo Taniguchi and 1 person, Modern Physician, 2004, Vol.24, No.8, pp.1309-1312

Non-patent document 2: Kazuhide Ogino and 2 persons, Nihon Rinsho (Japan Clinical), 2003, Vol.61, Extra edition 1, pp.197-201

Non-patent document 3: Hideki Horiuchi and 6 persons, Life Science, 2000, Vol.66, No.21, pp.2051-2070

Non-patent document 4: Hisashi Yamanaka and 2 persons, Konyosankessyo to Tsufu (Hyperuricemia and gout), issued by Medical Review Co., 1994, Vol.2, No.1, pp.103-111

Non-patent document 5: Robert A Terkeltaub, N. Engl. J. Med., 2003, Vol.349, pp.1647-1655

Non-patent document 6: Ming-Han H. Lee and 3 persons, Drug. Safety, 2008, Vol.31, pp.643-665

Non-patent document 7: Francoise Roch-Ramel and 2 persons, Am. J. Physiol., 1994, Vol.266 (Renl Fluid Electrolyte Physiol., Vol.35), F797-F805

Non-patent document 8: Francoise Roch-Ramel and 2 persons, J. Pharmacol. Exp. Ther. 1997, Vol.280, pp.839-845

Non-patent document 9: Gim Gee Teng and 2 persons, Drugs, 2006, Vol.66, pp. 1547-1563

Non-patent document 10: Atsushi Enomoto and 18 persons, Nature, 2002, Vol.417, pp.447-452

Non-patent document 11: Takahashi S and 5 persons, Ann. Rheum. Dis., 2003, Vol.62, pp.572-575

Non-patent document 12: M. D. Feher and 4 persons, Rheumatology, 2003, Vol.42, pp.321-325

Non-patent document 13: Zhifeng Yu and 2 persons, J. Pharmacol. Exp. Ther., 2006, Vol.316, pp.169-175

The disclosure of the present invention

The problem to which the present invention is directed

The present invention is intended to provide a means, which has inhibitory activity against the production of uric acid for the prevention or treatment of diseases associated with abnormal levels of uric acid in serum.

Means of solving the problem

The authors of the present invention have conducted extensive studies to solve this problem. As a result, it was found that containing condensed ring structure derivatives represented by the following formula (I)exhibit an excellent inhibitory activity against xanthine oxidase and significantly lowers the levels of uric acid in serum, and therefore they may represent a new tool for the prevention or treatment of diseases associated with anomals the m level of uric acid in serum, what was the basis of the present invention.

Thus, the present invention relates to:

[1] containing condensed ring structure derivative represented by the formula (I):

,

where

X1and X2independently represent CH or N;

ring U represents C6aryl or 5 - or 6-membered heteroaryl;

m is an integer having a value of from 0 to 2;

n is an integer having a value of from 0 to 3;

R1represents a hydroxy-group, halogen atom, amino or C1-6alkyl, and when m is set to 2, two R1not necessarily, are different from each other;

R2represents any of the(1)-(11):

(1) a halogen atom;

(2) the hydroxy-group;

(3) cyano;

(4) nitro;

(5) carboxy;

(6) carbarnoyl;

(7) amino;

(8) C1-6alkyl, C2-6alkenyl or C1-6alkoxy, each of which can independently contain any (preferably 1-3) a group selected from the group of substituents α;

(9) C2-6quinil, C1-6alkylsulfonyl, mono(di)C1-6alkylsulfonyl, C2-7acyl, C1-6alkoxycarbonyl, C1-6alkoxycarbonyl, mono(di)C1-6alkylamino, mono(di)C1-6alkoxy, C1-6alkylamino, C1-6alkoxy, C1-6alkyl(C1-6lcil)amino, C2-7acylamino, C1-6alkoxycarbonyl, C1-6alkoxycarbonyl(C1-6alkyl)amino, mono(di)C1-6allylcarbamate, mono(di)C1-6alkoxy, C1-6allylcarbamate, C1-6alkoxy, C1-6alkyl(C1-6alkyl)carbarnoyl, mono(di) C1-6alkylaminocarbonyl, C1-6alkylsulfonyl or C1-6alkylthio, each of which can independently contain any 1-3 groups selected from a fluorine atom, hydroxy-group and amino;

(10) C3-8cycloalkyl, 3-8-membered heteroseksualci, C5-8cycloalkenyl or 5-8-membered geteroseksualen, each of which independently may contain any 1-3 groups selected from a fluorine atom, hydroxy-group, amino, oxo, C1-6of alkyl, C1-6alkoxy, C1-6alkoxy, C1-6of alkyl, carboxy, C2-7acyl, C1-6alkoxycarbonyl, carbamoyl, mono(di) C1-6allylcarbamate, mono(di) C1-6alkoxy, C1-6allylcarbamate and C1-6alkoxy, C1-6alkyl(C1-6alkyl)carbamoyl;

(11)6aryl, C6aryloxy,6arylcarbamoyl, 5 or 6-membered heteroaryl, 5 - or 6-membered, heteroaromatic, 5 - or 6-membered heteroarylboronic,6arylamino,6aryl(C1-6alkyl)amino, 5 - or 6-membered, heteroarenes or 5 - or 6-membered heteroaryl(C1-6alkyl)amino, each of which can independently from erati any 1-3 groups selected from halogen atom, hydroxy-group, amino, cyano, nitro, C1-6of alkyl, C1-6alkoxy, C1-6alkoxy, C1-6of alkyl, carboxy, C2-7acyl, C1-6alkoxycarbonyl, carbamoyl, mono(di) C1-6allylcarbamate, mono(di) C1-6alkylamino, mono(di) C1-6alkoxy, C1-6alkylamino, C1-6alkoxy, C1-6alkyl(C1-6alkyl)amino, C1-6alkoxycarbonyl, mono(di) C1-6alkoxy, C1-6allylcarbamate and C1-6alkoxy, C1-6alkyl(C1-6alkyl)carbamoyl; and when n has the value 2 or 3, these R2not necessarily, are different from each other, and when there are two R2associated with the neighboring atoms, and independently represents a C1-6alkyl or C1-6alkoxy, each of which may contain C1-6alkoxy, these two R2not necessarily form a 5-8-membered ring together with the atoms to which they are linked;

the group of substituents α includes a fluorine atom; a hydroxy-group; amino; carboxy; C1-6alkoxy, mono(di)C1-6alkylamino, mono(di)C1-6alkoxy, C1-6alkylamino, C1-6alkoxy, C1-6alkyl(C1-6alkyl)amino, C1-6alkoxycarbonyl, C2-7acyl, C1-6alkoxycarbonyl, mono(di)C1-6allylcarbamate, mono(di)C1-6alkoxy, C1-6allylcarbamate, C1-6ALCO is C C 1-6alkyl(C1-6alkyl)carbarnoyl, C1-6alkylsulfonyl, C2-7acylamino and C1-6alkoxycarbonyl, each of which can contain any 1-3 groups selected from a fluorine atom, hydroxy-group and amino; C3-8cycloalkyl and 3-8-membered heteroseksualci, each of which can independently contain any 1-3 groups selected from a fluorine atom, hydroxy-group, amino, oxo, C1-6of alkyl, C1-6alkoxy, C1-6alkoxy, C1-6of alkyl, carboxy, C2-7acyl, C1-6alkoxycarbonyl, carbamoyl, mono(di) C1-6allylcarbamate, mono(di) C1-6alkoxy, C1-6allylcarbamate and C1-6alkoxy, C1-6alkyl(C1-6alkyl)carbamoyl; and (C6aryl and 5 - or 6-membered heteroaryl, each of which can independently contain any 1-3 groups selected from a halogen atom, hydroxy-group, amino, cyano, nitro, C1-6of alkyl, C1-6alkoxy, C1-6alkoxy, C1-6of alkyl, carboxy, C2-7acyl, C1-6alkoxycarbonyl, carbamoyl, mono(di) C1-6allylcarbamate, mono(di) C1-6alkylamino, mono(di) C1-6alkoxy, C1-6alkylamino, C1-6alkoxy, C1-6alkyl(C1-6alkyl)amino, C1-6alkoxycarbonyl, mono(di) C1-6alkoxy, C1-6allylcarbamate and C1-6alkoxy, C1-6alkyl(C1-6alkyl)carbamoyl, ilego the prodrug, or its pharmaceutically acceptable salt;

[2] containing condensed ring structure derived as described above in paragraph [1], where X1represents CH, or its prodrug, or pharmaceutically acceptable salt;

[3] containing condensed ring structure derived as described above in paragraph [1] or [2], where X2represents CH, or its prodrug, or pharmaceutically acceptable salt;

[4] containing condensed ring structure derived, as described in any of paragraphs [1]-[3], where the ring U represents a benzene ring, pyridine ring, thiazole ring, a pyrazol ring or thiophene ring, or its prodrug, or pharmaceutically acceptable salt;

[5] containing condensed ring structure derived as described above in paragraph [4], where m is 0 or m is 1 and ring U represents any one of rings represented by the following formula:

in this formula, R1arepresents a hydroxy-group, amino or C1-6alkyl; A is a link to a condensed ring; and a represents a bond with the carboxy; respectively, or its prodrug, or pharmaceutically acceptable salt;

[6] containing condensers is nnow ring structure derived, described above in paragraph [5], where the ring U represents a thiazole ring, or its prodrug, or pharmaceutically acceptable salt;

[7] containing condensed ring structure derived as described above in paragraph [5], where the ring U represents a pyridine ring, or its prodrug, or pharmaceutically acceptable salt;

[8] containing condensed ring structure derived as described above in paragraph [6], where R1arepresents a methyl group; n is 0, or n has a value of 1-3, and R2represents a halogen atom, a hydroxy-group or C1-6alkyl, which may contain 1-3 fluorine atom, or its prodrug, or pharmaceutically acceptable salt;

[9] containing condensed ring structure derived as described above in paragraph [7], where m is 0; or m is 1, R1arepresents a hydroxy-group, and R2represents a halogen atom, a hydroxy-group or C1-6alkyl, which may contain 1-3 fluorine atom, or its prodrug, or pharmaceutically acceptable salt;

[10] containing condensed ring structure derived as described above in any one of items [1]to[7], where n is 0, or n has a value of 1-3, and R2represents a halogen atom, a guide is oxygraph or C 1-6alkyl or C1-6alkoxy, each of which can independently contain any 1-3 groups selected from a fluorine atom, hydroxy-group and amino, or its prodrug, or pharmaceutically acceptable salt;

[11] containing condensed ring structure derived as described above in paragraph [10], where n is 0, or n has a value of 1-3, and R2represents a halogen atom, or a C1-6alkyl or C1-6alkoxy, each of which can independently contain any 1-3 groups selected from a fluorine atom, hydroxy-group and amino; and ring U represents a thiazole ring or a pyridine ring, or its prodrug, or pharmaceutically acceptable salt;

[12] containing condensed ring structure derived as described above in any one of items [1]to[11], where m is 0, or its prodrug, or pharmaceutically acceptable salt;

[13] containing condensed ring structure derived as described above in any one of items [1]to[12], where n is 0, or its prodrug, or pharmaceutically acceptable salt;

[14] containing condensed ring structure derived as described above in paragraph [10], where n has a value of 1-3, and R2represents a fluorine atom, or its prodrug, or pharmaceutically acceptable Sol is;

[15] containing condensed ring structure derived as described above in paragraph [11]represented by the formula (Ib):

,

where R21represents a hydrogen atom, fluorine atom or methyl group; R22represents a hydrogen atom or a fluorine atom; R23represents a hydrogen atom, fluorine atom or methyl group; R24represents a hydrogen atom or a fluorine atom; and R11represents a hydrogen atom or a methyl group, or its prodrug, or pharmaceutically acceptable salt;

[16] containing condensed ring structure derived as described above in any one of items [1]to[15], which is an inhibitor of xanthine oxidase, or its prodrug, or pharmaceutically acceptable salt;

[17] a pharmaceutical composition comprising as an active ingredient soderjashie condensed ring structure derived as described above in any one of items [1]to[15], or its prodrug, or pharmaceutically acceptable salt;

[18] the pharmaceutical composition described above in paragraph [17], which is an agent for the prevention or treatment of a disease selected from the group including hyperuricemia, gouty site, gouty arthritis, renal disorder, linked to the OU with hyperuricemia, and urinary concretions;

[19] the pharmaceutical composition described above in paragraph [18], which is an agent for the prevention or treatment of hyperuricemia;

[20] the pharmaceutical composition described above in paragraph [17], which is a medicine to lower uric acid levels in the plasma;

[21] the pharmaceutical composition described above in paragraph [17], which is an inhibitor of the production of uric acid; and the like

In the present invention each term has the following meaning, unless otherwise indicated.

The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

The term "C1-6alkyl" means a linear or branched alkyl group containing 1-6 carbon atoms, and as an illustration, you can specify, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

The term "C1-6alkylene" means a divalent group formed of the above C1-6the alkyl.

The term "C2-6alkenyl" means a linear or branched alkenylphenol group containing 2-6 carbon atoms, and as an illustration, you can specify vinyl, allyl, 1-propenyl, Isopropenyl and the like.

The term "C2-6quinil" means a linear or branched alkylamino group containing 2-6 carbon atoms, and as the illustration, you can specify ethinyl, 2-PROPYNYL and the like.

The term"C1-6alkoxy" means a linear or branched alkoxygroup containing 1-6 carbon atoms, and as an illustration, you can specify methoxy, ethoxy, propoxy, isopropoxy and the like.

The term "C1-6alkoxycarbonyl" means a group represented by formula (C1-6alkoxy)-C(O)-, and as an illustration, you can specify methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and the like.

The termC1-6alkoxycarbonyl” means a group represented by formula (C1-6alkoxy)-C(O)O-.

The term "C1-6alkoxy, C1-6alkyl" means the above C1-6alkyl, substituted the above C1-6alkoxy.

The term "C1-6alkylsulfonyl" means a group represented by formula (C1-6alkyl)-SO2and as an illustration, you can specify methylsulphonyl, ethylsulfonyl and the like.

The term "C1-6alkylsulfonyl" means a group represented by formula (C1-6alkyl)-SO2NH-, and as an illustration, you can specify methylsulfonylamino, ethylsulfonyl and the like.

The term "mono(di)C1-6alkylsulfonyl" means sulfamoyl group, mono - or di-substituted by the above C1-6the alkyl.

The term "C2-7acyl" means a group represented by the formula C 1-6alkyl)-C(O)-, and as an illustration, you can specify acetyl, propionyl, butyryl, isobutyryl, pivaloyl and the like.

The term "C1-6alkylthio" means a group represented by formula (C1-6alkyl)-S-.

The term "mono(di)C1-6alkylamino" means an amino group mono - or di-substituted by the above C1-6the alkyl, the term "mono(di)C1-6alkoxy, C1-6alkylamino" means an amino group mono - or di-substituted by the above C1-6alkoxy, C1-6the alkyl, and the term "C1-6alkoxy, C1-6alkyl(C1-6alkyl)amino" means an amino group substituted with the above C1-6alkoxy, C1-6the alkyl and the above C1-6the alkyl.

The term "C2-7acylamino" means a group represented by formula (C1-6alkyl)-C(O)NH-.

The term "C1-6alkoxycarbonyl" means an amino group substituted with the above C1-6alkoxycarbonyl, and the term “C1-6alkoxycarbonyl(C1-6alkyl)amino”means an amino group substituted with the above C1-6alkoxycarbonyl and above C1-6the alkyl.

The term "mono(di)C1-6alkylaminocarbonyl" means a group represented by formula (mono(di)C1-6alkylamino)-C(O)NH-.

The term "mono(di)C1-6allylcarbamate" means karbamoilnuyu group, mono - or di-substituted specified the above C 1-6the alkyl, the term "mono(di)C1-6alkoxy, C1-6allylcarbamate" means karbamoilnuyu group, mono - or di-substituted by the above C1-6alkoxy, C1-6the alkyl, and the term "C1-6alkoxy, C1-6alkyl(C1-6alkyl)carbarnoyl" means carbamoyl group substituted by the above C1-6alkoxy, C1-6the alkyl and the above C1-6the alkyl. These substituents may be different from each other in the case of di-substitution.

The term "C3-8cycloalkyl" means a 3-8-membered saturated cyclic hydrocarbon group, and as an illustration, you can specify cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term "C5-8cycloalkenyl" means a 5-8-membered cycloalkenyl group, and as an illustration, you can specify cyclopropyl, cyclobutyl, cyclopentenyl and the like.

The term “3-8-membered heteroseksualci” means a 3-8-membered geterotsyklicescoe group containing 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, in the ring, and as an illustration, you can specify aziridine, azetidine, morpholine, 2-morpholinyl, thiomorpholine, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinil, 1-pyrrolyl, tetrahydrofuryl, tetrahydropyranyl and the like.

The term “5-8-membered geteroseksualen” means a 5-8 member is nnow geterotsyklicescoe group, containing any 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, in the ring, and as an illustration, you can specify 2,3-dihydrofuran, 2,5-dihydrofuran, 3,4-dihydro-2H-Piran and the like.

The term "C6aryl" means phenyl.

The term "C6aryloxy" means a group represented by formula (C6aryl)-O-, and as an illustration, you can specify phenyloxy and the like.

The term "C6arylcarbamoyl" means a group represented by formula (C6aryl)-C(O)-, and as an illustration, you can specify the benzoyl and the like.

The term "C6arylamino" means a group represented by formula (C6aryl)-NH-.

The term "C6aryl(C1-6alkyl)amino" means an amino group substituted with the above With6the aryl and the above C1-6the alkyl.

The term "5 - or 6-membered heteroaryl" means 5 - or 6-membered aromatic heterocyclic group containing any 1-4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, in the ring, and as an illustration, you can specify thiazolyl, oxazolyl, isothiazolin, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furutani and the like.

The term "5 - or 6-membered, heteroaromatic" means a group, before the purposes of the formula (5 - or 6-membered heteroaryl)-O-.

The term "5 - or 6-membered heteroarylboronic" means a group represented by the formula (5 - or 6-membered heteroaryl)-C(O)-.

The term "5 - or 6-membered, heteroarenes" means a group represented by the formula (5 - or 6-membered heteroaryl)-NH-.

The term "5 - or 6-membered heteroaryl(C1-6alkyl)amino" means an amino group substituted with the above 5 - or 6-membered heteroaryl and above C1-6the alkyl.

Containing condensed ring structure derivative represented by the formula (I)according to the present invention can be obtained, for example, by the method described below, or a similar method or by the method described in the literature, or similar method, etc. in Addition, when necessary, the protective group, procedures for the introduction and removal of such groups can be performed optionally in combination in accordance with the General method.

Each reaction also optional, can be performed using a reaction vessel with increased resistance to pressure.

[Method of synthesis of 1]

In this formula Llrepresents a removable group such as chlorine atom, bromine atom, iodine atom, triftormetilfullerenov or the like, Rarepresents a hydrogen atom or a C1-6alkyl, provided that two Ramay be the b differ from each other or both R acan connect together to form a ring, and X1X2, ring U, m, n, R1and R2have the meanings given above.

Method 1

Containing condensed ring structure derived (I) of the present invention can also be obtained through the implementation of the combinations according to the method of Suzuki-Miyaura compounds (2) and compound (3) in an inert solvent, in the presence of base and palladium catalyst and, optionally, removal of the protective group. As the inert solvent can be noted in the illustration, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol, N,N-dimethylformamide, N-organic, dimethylsulfoxide, water, a solvent which is a mixture of the above, and the like. As a basis you can specify as an illustration, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, ethoxide sodium, sodium methoxide, potassium fluoride, cesium fluoride, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and the like. As the palladium catalyst can be specified as an illustration of tetrakis(triphenylphosphine)palladium, dichloro-bis(triphenylphosphine)palladium, 1,1'-bi is(diphenylphosphino)ferrocene-paradigalla and the like. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

From containing condensed ring structure derivatives represented by the formula (I)according to the present invention, the compound (Ia), where X1and X2represent CH, can also be obtained, for example, by the method of synthesis of 2.

[Method of synthesis of 2]

In this formula L1, Ra, ring U, m, n, R1and R2have the meanings given above.

Method 2

Containing condensed ring structure derivative (Ia) of the present invention can also be obtained through the implementation of combination reaction according to the method of Suzuki-Miyaura compounds (4) and compound (5) in a manner analogous to method 1 and, optionally, removal of the protective group.

Method 3

The compound (4)used in the above-described Method 2 can also be obtained by interaction of the corresponding compound (2A) with an appropriate reagent based Bronevoy acid, in an inert solvent, in the presence of a base and a palladium catalyst, in the presence or in the absence of ligand. As a researcher who is named as the inert solvent can be noted in the illustration, benzene, toluene, xylene, N,N-dimethylformamide, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N -, an organic solvent which is a mixture of the above, and the like. As a basis you can specify as an illustration of the triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium acetate, and the like. As the palladium catalyst can be noted in the illustration, palladium acetate, tetrakis(triphenylphosphine)palladium, dichloro-bis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene-paradigalla and the like. As a ligand can be specified as an illustration bis(diphenylphosphino)ferrocene, tricyclohexylphosphine, 2-(dicyclohexylphosphino)biphenyl and the like. As a reagent based on Bronevoy acid can be noted in the illustration, pinacolborane, catecholborane, bis(pinacolato)LIBOR and the like. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

In Method 3, when L1represents a bromine atom or an iodine atom, the Compound (4) can be obtained by processing the compound (2a) ORGANOMETALLIC reagent and implementation of its interaction with borate ether complex in an inert solvent. As the inert solvent can be noted in the illustration, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, benzene, toluene, hexane, a solvent which is a mixture of the above, and the like. As the ORGANOMETALLIC reagent can be specified as an illustration of isopropylacrylamide, phenylaniline, n-utility, second-utility, tert-utility and the like. As baronetage of ester can be specified as an illustration of trimethylboron, triethylborane, triisopropylsilyl, tributyrate, triisopropylsilyl, Tris(trimethylsilyl)borate and the like. The reaction temperature is usually in the range from -78°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

Of the compounds represented by Compound (2), Compound (2b), where X1and X2represent CH, and L1represents a chlorine atom, a bromine atom or an iodine atom, can also be obtained, for example, a method for the synthesis of 3.

[Method of synthesis of 3]

In this formula L2represents a chlorine atom, a bromine atom or an iodine atom, n and R2have the meanings given above.

Method 4

With the unification of (7) can be obtained subjecting the Compound (6) and ammonia the amidation reaction, optionally, using an additive such as 1-hydroxybenzotriazole or the like, in an inert solvent, in the presence of a condensing agent, in the presence or in the absence of base. As the inert solvent can be noted in the illustration, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, a solvent which is a mixture of the above, and the like. As the condensing agent can be specified as an illustration, acetic anhydride, thionyl chloride, oxalicacid, N,N'-carbonyldiimidazole, N,N-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylamine and cleaners containing hydrochloride salt, diphenylphosphoryl and the like. As a basis you can specify as an illustration of the triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine and the like. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

Method 5

The compound (2b) can be obtained by treating compound (7) in an inert solvent in the presence of the agent money is gratzii, in the presence or in the absence of base. As the inert solvent can be noted in the illustration, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, a solvent which is a mixture of the above, and the like. As a dehydration agent, you can specify as an illustration of acetic anhydride, triperoxonane anhydride, thionyl chloride, phosphorylchloride, methanesulfonamido, p-toluensulfonate, N,N'-dicyclohexylcarbodiimide, diphosphocholine, triphosgene and the like. As a basis you can specify as an illustration of the triethylamine, N,N'-diisopropylethylamine, pyridine, 2,6-lutidine and the like. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

Also the above Compound (Ia) of the present invention can also be obtained, for example, by the method of synthesis of 4.

[Method of synthesis of 4]

In this formula L1, ring U, m, n, R1and R2have the meanings given above.

Method 6

Containing condensed to iceway structure derivative (Ia) of the present invention can also be obtained by interaction of the Compound (8) with a cyanation reagent in an inert solvent, in the presence or in the absence of base, in the presence or in the absence of a palladium catalyst, and, optionally, removal of the protective group. As the inert solvent can be noted in the illustration, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, butanol, ethylene glycol, N,N-dimethylformamide, N,N-dimethylacetamide, N-organic, dimethylsulfoxide, hexamethylphosphoramide, water, a solvent which is a mixture of the above, and the like. As a basis you can specify as an illustration, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, ethoxide sodium, sodium methoxide, potassium fluoride, cesium fluoride, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diaza-bicyclo[5,4,0]-7-undecene and the like. As the palladium catalyst can be specified as an illustration of tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride, palladium acetate, triptorelin palladium and the like. As a cyanation reagent can be noted in the illustration, the copper cyanide, sodium cyanide, potassium cyanide, hydrogen cyanide zinc, trimethylsilylacetamide, ferrocyanide of potassium and the like. The reaction temperature is usually náchod is carried out in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

In the Compound (8), the Compound (8a), where L1represents a chlorine atom, a bromine atom or an iodine atom, the ring U represents a thiazole ring, m is 1, and R1represents a C1-6alkyl, can also be obtained, for example, by the method of synthesis 5.

[Method of synthesis of 5]

In this formula, R1brepresents a C1-6alkyl, L2n and R2have the meanings given above.

Method 7

The compound (10) can also be obtained by reacting Compound (9) with thioacetamide in an inert solvent in acid conditions. As the inert solvent can be noted in the illustration, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N-organic, benzene, toluene, xylene, solvent composed of a mixture of the above, and the like. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

Method 8

The is a group of (8a) can also be obtained by reacting Compound (10) with a derivative of 2-chloro-3-oxomalonate acid in an inert solvent and, optionally, removal of the protective group. As the inert solvent can be noted in the illustration, methanol, ethanol, n-butanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, benzene, toluene and the like. The temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

In the Compound (8), the Compound (8b), where the ring U represents a thiazole ring, m is 1, R1represents a C1-6alkyl and L2is triftormetilfullerenov, can also be obtained, for example, by the method of synthesis 6.

[Method of synthesis of 6]

In this formula, Rbrepresents a C1-6alkyl, R1bn and R2have the meanings given above.

Method 9

The compound (12) can also be obtained by subjecting the Compound (11) condensation reagent Horner-Wadsworth-Emmons, such as 1-ethyl-4-tert-butyl-2-diethylphosphonoacetate or similar, and then removing the protective group, or by subjecting the Compound (11) condensation with diethylamine in an inert solvent, in the presence of a base. As the inert solvent can be specified in the when asked illustration benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N-organic, methanol, ethanol, a solvent which is a mixture of the above, and the like. As a basis you can specify as an illustration, sodium hydride, tert-piperonyl potassium, sodium methoxide, ethoxide sodium and the like. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

Method 10

The compound (13) can also be obtained by reacting Compound (12) in a suitable solvent in the presence of a dehydration agent, or in a solvent such as an acid anhydride, in the presence or in the absence of the base, and, optionally, with further hydrolizate. As a suitable solvent can be specified as an illustration, for example, acetic acid, sulfuric acid, phosphoric acid, tetrahydrofuran, N,N-dimethylformamide, N-organic, benzene, toluene, xylene, 1,4-dioxane, water, a solvent which is a mixture of the above, and the like. As a dehydration agent, you can specify as an illustration of acetic anhydride, triperoxonane anger is d, methylchloroform, ethylchloride and the like. As a solvent, selected from acid anhydride, you can specify as an illustration of acetic anhydride, triperoxonane anhydride and the like. As a basis you can specify as an illustration, sodium acetate, potassium acetate and the like. The reaction temperature generally ranges from room temperature to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature, or similar settings. As the inert solvent used in the hydrolysis, can be noted in the illustration, methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, N-organic, dimethoxyethane, water and a solvent which is a mixture of the above. As the base used in the hydrolysis, can be noted in the illustration, sodium hydroxide, potassium hydroxide and lithium hydroxide. The reaction temperature generally ranges from room temperature to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

Method 11

the Compound (14) can also be obtained, subjecting the Compound (13) cyanidation method similar to those described above in Methods 4 and 5.

Way 12

The compound (15) can also be obtained by reacting Compound (14) in a manner analogous to that described above in Methods 7 and 8.

Way 13

The compound (8b) can be obtained by reacting Compound (15) with triftormetilfullerenov anhydride in an inert solvent, in the presence of a base. As the inert solvent can be noted in the illustration, dichloromethane, dichloroethane, chloroform, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N-organic, benzene, toluene, xylene, 1,4-dioxane and the like. As a basis you can specify as an illustration of the triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5,4,0]-7-undecene and the like. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent, and the reaction time is usually from 30 minutes to 7 days, varying depending on the source material, solvent and reaction temperature or similar parameters.

As protective groups for use in the present invention can use various protective groups, which are usually used in organic reactions. For example, as protective groups for the hydroxy-group, in addition to p-methoxybenzyloxy the group, you can specify as an illustration, benzyl group, methoxymethyl group, acetyl group, pivaloyloxy group, benzoyloxy group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, allyl group and the like, and when two of the hydroxy-group are adjacent, you can specify to illustrate isopropylidene group, cyclopentadienyl group, cyclohexylidene group and the like. As protective groups for the thiol group can be specified as an illustration of the p-methoxybenzyloxy group, benzyl group, acetyl group, pivaloyloxy group, benzoyloxy group, benzyloxycarbonyl group and the like. As protective groups for the amino group can be specified as an illustration benzyloxycarbonyloxy group, tert-butoxycarbonyl group, benzyl group, p-methoxybenzyloxy group, trifluoracetyl group, acetyl group, palolo group and the like. As protective groups for carboxypropyl you can specify as an illustration of C1-6alkyl group, benzyl group, tert-butyldimethylsilyloxy group, allyl group and the like.

The compound represented by formula (I)according to the present invention can be isolated or purified by traditional methods of selection, such as fractional recrystallization, clean the ka by chromatography, by solvent extraction, solid-phase extraction and the like.

Containing condensed ring structure derivative represented by the formula (I)according to the present invention can be converted into its pharmaceutically acceptable salts in the usual way. As such a salt can be specified as an illustration of an acid additive salt with inorganic acid, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid and the like, an acid additive salt with organic acid such as formic acid, acetic acid, methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, coal acid, benzoic acid, glutamic acid, aspartic acid and the like, inorganic salt such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, lithium salt, an aluminium salt and the like, a salt with organic amine, such as N-methyl-D-glucamine, N,N'-dibenziletilendiaminom, 2-aminoethanol, Tris(hydroxymethyl)aminomethane, arginine, lysine, piperazine, choline, is ethylamin, 4-vinylcyclohexane and the like.

From containing condensed ring structure derivatives represented by the formula (I)according to the present invention, in the compound containing an unsaturated bond, there are two geometric isomer, compound CIS (Z) form and connection of the TRANS (E) form. In the present invention it is possible to use any compounds and their mixture can also be used.

From containing condensed ring structure derivatives represented by the formula (I)according to the present invention, in the compound containing a chiral carbon atom, the present connection R configuration and the connection's configuration for each chiral carbon. In the present invention can use any of the optical isomers and a mixture of optical isomers can also be used.

In containing condensed ring structure derivatives represented by the formula (I)according to the present invention can be some of the tautomers, the compounds of the present invention also include these tautomers.

In the present invention, the term "prodrug" means a compound, which should be converted into the compound represented by formula (I)in the body. The prodrug of the compound represented by formula (I)according to the present invention can be obtained by introducing suitable for the coming group, forming a prodrug, in any one or more groups selected from a hydroxy-group, amino group, carboxypropyl and other groups that can form a prodrug of the compound represented by formula (I), using the appropriate reagent to obtain prodrugs, such as a halide compound or the like, in the usual way, with subsequent appropriate selection and purification in the usual way, as is necessary in a particular case. Cm. Gekkan-Yakuji iyakuhin tekiseisiyou no tameno rinsyou yakubutsudoutai (monthly pharmaceutical, clinical pharmacokinetics for the proper use of pharmaceutical products), 2000,3. extra edition, Vol.42, No.4, pp.669-707, and New Drug delivery system, published by CMC Co., Ltd., 2000,1,31., pp.67-173. As a group forming a prodrug used in the hydroxy-group or amino group, as an illustration, you can specify, for example, C1-6alkyl-CO-, such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl and the like; C6aryl-CO-, such as benzoyl and the like; C1-6alkyl-O-C1-6alkylene-CO-; C1-6alkyl-OCO-C1-6alkylene-CO; C1-6alkyl-OCO-, such as methyloxycarbonyl, ethoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, tert-butyloxycarbonyl and the like; C1-6alkyl-O-C1-6alkylene-OCO-; C1-6alkyl-COO-C1-6alkylene, such as acetoacetyl, pivaloyloxymethyl, 1-(atomic charges)ethyl, 1-(pivaloyloxy)ethyl and the like; C1-6alkyl-OCOO-C1-6 alkylene, such as methoxycarbonylmethyl, 1-(methoxycarbonylamino)ethyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl, tert-butyloxycarbonyl, 1-(tert-butyloxycarbonyl)ethyl and the like; C3-8cycloalkyl-OCOO-C1-6alkylene, such as cyclohexyloxycarbonyloxy, 1-(cyclohexyloxycarbonyl)ethyl and the like; ester or amide with an amino acid such as glycine and the like; and so on

As a group forming a prodrug used in carboxypropyl, as an illustration, you can specify, for example, C1-6alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like; C1-6alkyl-COO-C1-6alkylene, such as pivaloyloxymethyl, acetoacetyl, 1-(pivaloyloxy)ethyl, 1-(atomic charges)ethyl and the like; C1-6alkyl-OCOO-C1-6alkylene, such as ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl, tert-butyloxycarbonyl, 1-(tert-butyloxycarbonyl)ethyl and the like; C3-8cycloalkyl-OCOO-C1-6alkylene, such as cyclohexyloxycarbonyl, 1-(cyclohexyloxycarbonyl)ethyl and the like; and so on

In the present invention, the pharmaceutically acceptable salt includes her MES with pharmacy is is automatic acceptable solvent, such as water, ethanol or the like.

The pharmaceutical composition of the present invention is useful as a means for prevention or treatment of diseases associated with high levels of uric acid in the blood, such as hyperuricemia, gouty site, gouty arthritis, renal disorder associated with hyperuricemia, urinary concretions or similar, especially for hyperuricemia.

For practical use of the pharmaceutical compositions of the present invention for the prevention or treatment of a dose of a compound represented by the formula (I), or its prodrug, or pharmaceutically acceptable salt as the active ingredient is appropriately determined depending on age, sex, body mass index, degree of disorder and treatment of each patient and the like, for example, it is approximately in the range from 1 to 2000 mg per day per adult human in the case of oral administration, the daily dose can be divided and put in the form of one or several doses per day.

For practical use of the pharmaceutical compositions of the present invention for the prevention or treatment use of various dosage forms for oral or parenteral, depending on their applications, for example, preferred are compositions for peroral the aqueous introduction, such as powders, fine granules, granules, tablets, capsules, dry syrups or similar.

These pharmaceutical compositions can be obtained depending on their preparations, optionally, by mixing with an appropriate pharmaceutical additive such as excipients, disintegrating agents, binders, lubricants and the like, in accordance with conventional pharmaceutical methods, and formulating the mixture in accordance with conventional methods.

For example, the powders can be formulated, if desired, by thoroughly mixing the active ingredient with suitable excipients, lubricating agents and the like. For example, tablets can be formulated by tabletting of the active ingredient with suitable excipients, disintegrating agents, binders, lubricating agents and the like in accordance with conventional ways, then, if it is desirable to apply a suitable coating to obtain film-coated tablets, tablets, sugar coated tablets with intersolubility coating and the like. For example, capsules can be formulated by thoroughly mixing the active ingredient with suitable excipients, lubricating agents and the like, or by formulating fine granules, according the traditional methods, and fill them suitable capsules. In addition, in the case of such drugs for oral administration, it can also be formulated with obtaining compositions quick release or slow release, depending on the methods of prevention or treatment.

The compound represented by formula (I)according to the present invention or its prodrug, or pharmaceutically acceptable salt can also be used in conjunction with any other drug for the treatment of hyperuricemia or the medicinal product for the treatment of gout. As a drug for the treatment of hyperuricemia, which can be used in the present invention, as an illustration, you can specify, for example, podslushivaet urine, such as sodium bicarbonate, potassium citrate, sodium citrate and the like. In addition, as a drug for the treatment of gout as an illustration, you can specify the colchicine or nonsteroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, Ketoprofen, etoricoxib, tenoxicam and the like, and steroids and similar tools. In the present invention the active ingredient of the present invention can also be used in combination with at least one of these Lekarstvo what x means, and a pharmaceutical composition comprising a combination of at least one of these drugs include any drug, including not only a single drug with the active ingredient of the present invention, but also a combination drug consisting of a pharmaceutical composition comprising the active ingredient of the present invention, and separately obtained pharmaceutical composition for simultaneous administration or administration with different dosing intervals. In addition, when used in combination with any drug, other than the active ingredient of the present invention, a dose containing condensed ring structure derived by the present invention can be reduced depending on the dose of the other drug used in combination as required for this specific case, it is possible to achieve a favorable effect, a greater than additive effect in preventing or treating the above diseases, or you can avoid or reduce the adverse effects of the other drugs used in combination.

The effect of the present invention

Containing condensed ring structure derivative represented by the formula (I)according to the present invention have the proven excellent inhibitory activity against xanthine oxidase and suppress production of uric acid. In addition, the preferred compound of the present invention can also exhibit excellent inhibitory activity against URAT1 and increase the excretion of uric acid. Therefore containing condensed ring structure derivative represented by the formula (I)according to the present invention or its prodrug, or their pharmaceutically acceptable salts can significantly suppress the increase in levels of uric acid in serum and are useful as a means for prevention or treatment of diseases associated with abnormal levels of uric acid in serum, such as hyperuricemia or similar.

Best mode for carrying out the present invention

The present invention is hereinafter illustrated in more detail below by Reference Examples, Examples, and sample tests. However, the present invention is not limited to them.

Reference Example 1

3 does not depend-1-carbonitrile

To a solution of 3 does not depend-1-carboxylic acid (0,30 g) in tetrahydrofuran (3 ml) was added 1,1'-carbonyldiimidazole (0,29 g) under ice cooling and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added ammonia water (1.0 ml, 28% aqueous solution) and the mixture was stirred at room temperature for 4 hours. The reaction to the offer was concentrated under reduced pressure. To the residue was added water and the mixture was stirred at room temperature for 15 minutes. The precipitated solid was collected by filtration. The obtained solid substance was washed with water and 1 mol/l hydrochloric acid and dried to obtain amide 3 does not depend-1-carboxylic acid (0.28 g).

To a solution of the obtained compound (0.27 g) in dichloromethane (5 ml) was added triethylamine (0,44 g) and triperoxonane anhydride (0,47 g) under ice cooling and the mixture was stirred at room temperature for 6 hours. To the reaction mixture were added methanol and the mixture was concentrated under reduced pressure. The obtained solid substance was collected by filtration, washed with water and n-hexane and dried to obtain specified in the connection header (0,22 g).

Reference Example 2

4-Cyano-2-naphthaleneboronic acid

To a solution of 3 does not depend-1-carbonitrile (0,69 g) and triisopropylsilane (0,89 g) in tetrahydrofuran (10 ml) was added n-utility (1.6 ml, 2,63 mol/l solution in heptane) at -78°C in argon atmosphere. After heating to room temperature, the mixture was stirred at room temperature overnight. To the reaction mixture were added saturated aqueous solution of ammonium chloride at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of chloride of shumilkin) and saturated saline solution, was dried over magnesium sulfate and concentrated. The residue is suspended in n-hexane and the solid collected by filtration. The obtained solid is suspended in water. The suspension was acidified with hydrochloric acid and the mixture was stirred for 30 minutes. The solid is collected by filtration, washed with water and dried under reduced pressure to obtain specified in the connection header (0,49 g).

Reference Example 3

2-Chlorhydrin-4-carbonitril

Specified in the title compound was obtained by a method similar to that described in Reference Example 1, using 2-chlorhydrin-4-carboxylic acid instead of 3 does not depend-1-carboxylic acid.

Reference Example 4

Ethyl ester of 2-(4-does not depend-2-yl)-4-methylthiazole-5-carboxylic acid

To a solution of 4-does not depend-2-carbonitrile (0,57 g) in N,N-dimethylformamide (4 ml) and the solution of 4 mol/l HC1 in 1,4-dioxane (4 ml) was added thioacetamide (1.1 g) at room temperature and the reaction mixture was stirred at 70°C during the night. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel with getting 4 does not depend-2-thioamide group by forming (0,48 g). To a suspension of e is th connection (0,48 g) in ethanol (6 ml) was added ethyl 2-chloro-acetoacetate (0,59 g) and the mixture was stirred at 65°C for 24 hours. After cooling to room temperature the precipitated solid was collected by filtration, washed with ethanol and dried to obtain specified in the connection header (0,41 g).

Reference Example 5

4-Hydroxy-6-methylnaphthalene-2-carboxylic acid

To a solution of 4-methylbenzaldehyde (0,70 g) and dimethylsuccinic (0.95 g) in tetrahydrofuran (15 ml) was added tert-piperonyl potassium (0.73 g) at room temperature and the reaction mixture was stirred over night. To the reaction mixture were added water and diethyl ether, and two layers were separated. The aqueous layer was acidified with 1 mol/l hydrochloric acid and the resulting mixture was extracted with diethyl ether. This organic layer was washed with a saturated aqueous solution of sodium carbonate. The aqueous layer was acidified with 1 mol/l hydrochloric acid and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate and concentrated. To the residue was added acetic acid (5 ml), acetic anhydride (5 ml) and sodium acetate (3.0 g) and the mixture was heated at the boiling point under reflux for 6 hours. After cooling to room temperature the reaction mixture was poured into water. The resulting mixture was extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium bicarbonate and who has koncentrirebuli. To the obtained residue were added methanol (20 ml) and 1 mol/l aqueous sodium hydroxide solution (20 ml) and the mixture was heated at the boiling point under reflux for 5 hours. After cooling the reaction mixture to room temperature, the methanol was removed under reduced pressure. The resulting solution was acidified with 2 mol/l hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated to obtain specified in the title compound (0.20 g).

Reference Example 6

4-Hydroxy-6-methylnaphthalene-2-carbonitril

Specified in the title compound was obtained by a method similar to that described in Reference Example 1 using 4-hydroxy-6-methylnaphthalene-2-carboxylic acid (0.20 g) instead of 3 does not depend-1-carboxylic acid.

Reference Example 7

Ethyl ester of 2-(4-hydroxy-6-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid

Specified in the title compound was obtained by a method similar to that described in Reference Example 4, using 4-hydroxy-6-methylnaphthalene-2-carbonitrile instead of 4 does not depend-2-carbonitrile.

Reference Example 8

Ethyl ester of 2-(6-chloro-4-hydroxynaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid

Specified in the title compound was obtained by the method of analogues of the figures described in Reference Example 4, using 6-chloro-4-hydroxynaphthalene-2-carbonitrile instead of 4 does not depend-2-carbonitrile.

Reference Example 9

8-Bromo-4-hydroxy-7-methylnaphthalene-2-carboxylic acid

Specified in the title compound was obtained by a method similar to that described in Reference Example 5, using the appropriate source materials.

Reference Example 10

4-Hydroxy-7-methylnaphthalene-2-carboxylic acid

To a solution of 8-bromo-4-hydroxy-7-methylnaphthalene-2-carboxylic acid (0.45 g) in ethanol (8 ml) was added palladium on carbon (180 mg) in 3 portions and the mixture was stirred at room temperature for 2 days in an atmosphere of hydrogen. The insoluble substance was removed by filtration through a layer of celite and the filtrate was concentrated to obtain specified in the title compound (0.32 g).

Reference Example 11

Ethyl ester of 2-(4-hydroxy-7-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid

Specified in the title compound was obtained by a method similar to that described in Reference Example 8, using the appropriate source materials.

Reference Example 12

Methyl ester of 4-acetoxy-8-bromo-5-fornatale-2-carboxylic acid

To a solution of dimethylsuccinic (4.6 g) in toluene (3.5 ml) was added sodium methoxide (28% solution in methanol, to 2.9 ml) at room temperature and the mixture was stirred at 70°C in the atmosphere is fere argon. To this reaction mixture was added dropwise a solution of 2-bromo-5-forventelige (3.0 g) in toluene (6.5 ml) and the mixture was stirred at 85°C for 5 hours. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether and the mixture was poured into water. The aqueous layer was separated and the organic layer was washed with water. The combined aqueous layer was acidified with 2 mol/l hydrochloric acid and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. To the residue was added acetic anhydride (10 ml) and sodium acetate (3.7 g) and the mixture was stirred at 140°C during the night. After cooling the reaction mixture to room temperature, to the mixture was added toluene (20 ml) and the mixture was concentrated under reduced pressure. To the residue was added 2 mol/l hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to obtain specified in the connection header.

Reference Example 13

Methyl ester of 4-acetoxy-5-fornatale-2-carboxylic acid

To a solution of methyl who Fira 4-acetoxy-8-bromo-5-fornatale-2-carboxylic acid (2.0 g) and triethylamine (0,72 g) in ethyl acetate (60 ml) was added palladium on carbon (600 mg) at room temperature and the mixture was stirred for 1 hour at the same temperature in an atmosphere of hydrogen. The insoluble substance was removed by filtration through a layer of celite and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to obtain specified in the connection header.

Reference Example 14

4-Hydroxynaphthalene-2-carbonitril

Specified in the title compound was obtained by a method similar to that described in Reference Example 6, using the appropriate source materials.

Reference Example 15

Ethyl ester of 3-(4-hydroxynaphthalene-2-yl)-[1,2,4]oxadiazol-5-carboxylic acid

A mixed solution of 4-hydroxynaphthalene-2-carbonitrile (0.34 g), hydroxylamine hydrochloride (0.14 g) and potassium carbonate (0,30 g) in tert-butyl alcohol (4.5 ml) and water (0.5 ml) was stirred at 80°C for 6 hours. To the reaction mixture was added hydroxylamine hydrochloride (0.14 g) and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: dichloromethane/methanol). This compound (0,22 g) was dissolved in dichloromethane (5.3 ml). To the mixture was added ETHYLACETYLENE (0.35 ml) and pyridine (0,52 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution were added water and the organic layer was washed with water and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate) to obtain the specified title compound (0.15 g).

Reference Example 16

Ethyl ester of 3-(4-does not depend-2-yl)-[1,2,4]thiadiazole-5-carboxylic acid

To a solution of amide 4 does not depend-2-carboxylic acid (1.10 g) in toluene (11,0 ml) was added chlorocarbonylsulfenyl (0,73 ml) and the mixture was stirred at 100°C for 18 hours. To the reaction solution was added water (50 ml). The precipitated solid was collected by filtration and washed with water and hexane to obtain 5-(4-does not depend-2-yl)-[1,3,4]oxadiazol-2-she (1.13 g). This compound (1.12 g) was dissolved in dichlorobenzene (18 ml). To the solution was added achilleifolia (1,42 ml) and the mixture was stirred at 160°C for 22 hours. To the mixture was added water (30 ml) at room temperature and the resulting mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane/ethylacetate) what rucenim specified in the connection header (1,21 g).

Reference Example 17

Ethyl ester of 3-(4-does not depend-2-yl)isothiazol-5-carboxylic acid

To a solution of amide 4 does not depend-2-carboxylic acid (1.10 g) in toluene (11,0 ml) was added chlorocarbonylsulfenyl (0,73 ml) and the mixture was stirred at 100°C for 18 hours. To the reaction solution was added water (50 ml) and the precipitated solid substance was collected by filtration. The obtained solid substance was washed with water and hexane to obtain 5-(4-does not depend-2-yl)-[1,3,4]oxadiazol-2-she (1.13 g). This compound (1.13 g) was dissolved in dichlorobenzene (18 ml). To the solution was added ethylpropyl (1,52 ml) and the mixture was stirred at 160°C for 18 hours. The reaction solution was purified column chromatography on silica gel (eluent: hexane/ethyl acetate) to obtain the specified title compound (0.66 g).

Reference Example 18

4-Cyanonaphthalene-2-carboxylic acid

To a solution of ethyl ester of 4-hydroxynaphthalene-2-carboxylic acid (2.16 g) and pyridine (1.60 ml) in dichloromethane (100 ml) was added triftormetilfullerenov anhydride (2.5 ml) under ice cooling and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution were added water (30 ml) and the resulting mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated is under reduced pressure. The residue was dissolved in N-organic (33 ml). To the solution was added cyanide zinc (1,41g) and tetrakis(triphenylphosphine)palladium (0,58 g) and the resulting mixture was stirred at 110°C for 40 minutes. After cooling the reaction mixture to room temperature, to the reaction solution was added water (50 ml) and dichloromethane (50 ml). The insoluble substance was removed by filtration through a layer of celite. The aqueous layer was separated and the organic layer was filtered through a gel aminopropyl-silica (eluent: dichloromethane). The organic layer was concentrated under reduced pressure. To the residue was added ethyl acetate (20 ml) and the mixture was washed with water (30 ml, 5 times). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the ethyl ester of 4-cyanonaphthalene-2-carboxylic acid (2.25 g). To a mixed solution of this compound (0.45 g) in tetrahydrofuran (10 ml), ethanol (5.0 ml) and water (5.0 ml) was added lithium hydroxide monohydrate (0.25 g) and the mixture was stirred for 1 hour. To the reaction solution were added water (20 ml) and the resulting mixture was washed with diethyl ether. To the aqueous layer was added 1 mol/l hydrochloric acid (3.3 ml) and the precipitated solid substance was collected by filtration. Received from the solid substance was dried under reduced pressure at 50°C with obtaining specified in the connection header (0,37 g).

Reference Example 19

Methyl ester of 2-(4-cyanonaphthalene-2-yl)-4-methoxazole-5-carboxylic acid

To a solution of 4-cyanonaphthalene-2-carboxylic acid (0,37 g) in dichloromethane (20 ml) was added dimethylformamide (5 drops) and oxaliplatin (0.5 ml) under ice cooling and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. To the residue was added toluene (10 ml) and the mixture was concentrated under reduced pressure. To a solution of the hydrochloride of the ethyl ester of 2-aminopropionic acid (0.29 grams) and triethylamine (0,66 ml) in dichloromethane (10 ml) was added dropwise the resulting residue under ice cooling and the mixture was stirred at room temperature for 30 minutes. To the mixture was added water and 1 mol/l hydrochloric acid (1,56 ml). The aqueous layer was separated and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate) to obtain ethyl 2-[(4-cyanonaphthalene-2-carbonyl)amino]propionate (0,43 g). To a solution of this compound (0,43 g) in tetrahydrofuran (10 ml) was added 1 mol/l aqueous sodium hydroxide solution (3.8 ml) and the mixture paramesh the Wali for 30 minutes. To the mixture was added 1 mol/l hydrochloric acid (4.4 ml) under ice cooling and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2-[(4-cyanonaphthalene-2-carbonyl)amino]propionic acid (0.39 g). To a solution of this compound (0.39 g) in dichloromethane (7.0 ml) was added dimethylformamide (2 drops) and oxaliplatin (1,26 ml) and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. To the residue was added toluene (10 ml) and the mixture was concentrated under reduced pressure. After dissolving the obtained residue in dichloromethane (7.0 ml) to the mixture was added triethylamine (0.31 in ml) and methanol (1.0 ml) under cooling with ice. The mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate) to obtain specified in the connection header (0,045 g).

Reference Example 20

Methyl ester of 4-acetoxy-8-bromo-5,6-defernatly-2-carboxylic acid

Specified in the title compound was obtained by a method similar to that described in Reference Example 12, using 2-bromo-4,5-diferentialglea instead of 2-bromo-5-forventelige.

Seloc the first Example 21

5-fluoro-2-iodine-3-methylbenzaldehyde

To a solution of methyl ester of 5-fluoro-2-iodine-3-methylbenzoic acid (11.2 g) in dichloromethane (80 ml) was added dropwise over 25 minutes diisobutylaluminium (113 ml of 1.02 mol/l solution in hexane) at -78°C and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dropwise methanol (10 ml) at the same temperature and the mixture was stirred for 10 minutes. To the reaction mixture were added saturated aqueous solution of tartrate of potassium-sodium tetrahydrate (300 ml) under ice cooling and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to obtain (5-fluoro-2-iodine-3-were)methanol (7,15 g). To a suspension of the obtained compound (7,15 g) in chloroform (53 ml) and acetone (5.2 ml) was added manganese dioxide and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated. The residue was purified column chromatography on silica gel (eluent: ethyl acetate/n-hexane = 0-15%) to obtain the specified title compound (3.54 in).

Reference Example 22

Methyl ester of 4-acetoxy-5-fluoro-8-iodine-7-m is trafton-2-carboxylic acid

Specified in the title compound was obtained by a method similar to that described in Reference Example 12, using 5-fluoro-2-iodine-3-methylbenzaldehyde instead of 2-bromo-5-forventelige.

Reference Examples 23-24

Methyl ester of 4-acetoxy-5,6-defernatly-2-carboxylic acid

Methyl ester of 4-acetoxy-5-fluoro-7-methylnaphthalene-2-carboxylic acid

Specified in the title compounds were obtained by the method similar to that described in Reference Example 13, using the appropriate starting materials.

Reference Examples 25-43

Compounds of Reference Examples 25-43 got a way similar to that described in Reference Example 6, using the appropriate starting materials.

Reference Examples 44-62

Compounds of Reference Examples 44-62 got a way similar to that described in Reference Example 7, using the appropriate starting materials.

Reference Example 63

Ethyl ester of 2-(4-hydroxynaphthalene-2-yl)thiazole-5-carboxylic acid

Specified in the title compound was obtained by a method similar to that described in Reference Example 7, using ethyl 2-chloro-oxopropionate instead of ethyl 2-chloro-acetoacetate.

Reference Examples 64-75

Compounds of Reference Examples 64-75 got a way similar to that described in Reference Example 63, using suitable the x of the original substances.

Example 1

2-(4-Cyanonaphthalene-2-yl)isonicotinate acid

To a suspension of 4-cyano-2-naphthaleneboronic acid (0.10 g), ethyl ester 2-bromoisonicotinic acid (0.12 g) and cesium fluoride (0.09 g) in dimethoxyethane (6 ml) was added tetrakis(triphenylphosphine)palladium (0.06 g) and the mixture was stirred at 150°C for 40 minutes using a microwave reactor (Biotage). The reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 100/0-66/34) to give the ethyl ester of 2-(4-cyanonaphthalene-2-yl)isonicotinic acid (0.14 g). To a solution of this compound (0.14 g) in a mixed solvent consisting of tetrahydrofuran (4 ml), ethanol (1 ml) and water (1 ml)was added lithium hydroxide monohydrate (to 0.060 g) and the mixture was stirred at room temperature overnight. To the reaction mixture was added acetic acid (0,27 ml). The precipitated solid was collected by filtration and washed with water and n-hexane. The solid was dried under reduced pressure to obtain specified in the connection header (0,098 g).

Example 2

2-(4-Cyanonaphthalene-2-yl)-5-hydroxyisoquinoline acid

Ethyl ester of 2-(4-cyanonaphthalene-2-yl)-5-ethoxymethyleneamino acid (0.12 g) was obtained in a manner similar to described in the Example 1, using the ethyl ester of 2-bromo-5-ethoxymethyleneamino acid instead of the ethyl ester of 2-bromoisonicotinic acid. To a mixed solution of this compound in tetrahydrofuran (4 ml), ethanol (1 ml) and water (1 ml) was added lithium hydroxide monohydrate (0,043 g) and the mixture was stirred at room temperature overnight. To this reaction mixture was added 2 mol/l hydrochloric acid (1 ml) and the mixture was stirred at 50°C for 8 hours. After cooling the reaction mixture to room temperature the precipitated solid was collected by filtration and dried under reduced pressure to obtain specified in the connection header (0,087 g).

Example 3

1-(4-Cyanonaphthalene-2-yl)-1H-pyrazole-3-carboxylic acid

A suspension of ethyl ester 1H-pyrazole-3-carboxylic acid (0.1 g), 3-does not depend-1-carbonitrile (0.17 g), copper iodide (0,0068 g), (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine (0,010 g) and potassium carbonate (0.21 g) in toluene (3 ml) was stirred at 90°C during the night. After cooling to room temperature, to the reaction mixture were added ethyl acetate. The resulting mixture was filtered through a layer of celite. The residue was purified column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 100/0-66/34) to give the ethyl ester of 1-(4-cyanonaphthalene-2-yl)-1H-pyrazole-3-carboxylic acid (0,040 g). To a solution of this connection is s (0,040 g) in a mixed solvent, consisting of tetrahydrofuran (0.2 ml), ethanol (0,08 ml) and water (0,08 ml), was added lithium hydroxide monohydrate (0,017 g) and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/l hydrochloric acid (0.35 ml). The precipitated solid was collected by filtration, washed with water and n-hexane and dried under reduced pressure to obtain specified in the connection header (0,026 g).

Example 4

4-(4-Cyanonaphthalene-2-yl)benzoic acid

4-Methoxycarbonylpropionyl acid (0,039 g), 3-does not depend-1-carbonitrile (0.05 g), tetrakis(triphenylphosphine)palladium (0,012 g) and cesium carbonate (0.11 g) suspended in a mixed solvent consisting of N,N-dimethylformamide (3 ml) and water (1 ml)and the resulting mixture was stirred at 150°C for 40 minutes using a microwave reactor (Biotage). The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 100/0-66/34) to give the methyl ester of 4-(4-cyanonaphthalene-2-yl)benzoic acid (0.025 g).

Specified in the header connection (0,020 g) was obtained by a method similar to that described in Example 3 using methyl ester of 4-(4-cyanonaphthalene-2-yl)benzoic sour the s instead of the ethyl ester of 1-(4-cyanonaphthalene-2-yl)-1H-pyrazole-3-carboxylic acid.

Example 5

4-(4-Cyanohydrin-2-yl)benzoic acid

2-Chlorhydrin-4-carbonitrile (0.20 g), 4-methoxycarbonylpropionyl acid (0.21 g), tetrakis(triphenylphosphine)palladium (0,061 g) and sodium carbonate (0,22 g) suspended in a mixed solvent consisting of dimethoxyethane (2 ml) and water (0.5 ml)and the resulting mixture was stirred at 150°C for 30 minutes using a microwave reactor (Biotage). To the reaction mixture were added ethyl acetate and the reaction mixture was filtered through a layer of celite. The filtrate was poured into water and the organic layer was washed with water and saturated salt solution. The organic layer was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 100/0-66/34) to give the methyl ester of 4-(4-cyanonaphthalene-2-yl)benzoic acid (0.12 g). To a solution of this compound (0.12 g) in a mixed solvent consisting of tetrahydrofuran (2 ml), ethanol (1 ml) and water (1 ml)was added lithium hydroxide monohydrate (0.14 g) and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/l hydrochloric acid (0.35 ml). The precipitated solid was collected by filtration, washed with methanol and dried under reduced pressure to obtain specified in the connection header (0,024 g).

Example 6

4-(4-CYANOGEN the Lin-2-yl)-2-hydroxy-benzoic acid

2-Chlorhydrin-4-carbonitrile (0.15 g), methyl ester 2-methoxyethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzoic acid (0.26 g), tetrakis(triphenylphosphine)palladium (0,045 g) and sodium carbonate (0.16 g) suspended in a mixed solvent consisting of dimethoxyethane (2 ml) and water (0.5 ml)and the resulting mixture was stirred at 150°C for 30 minutes using a microwave reactor (Biotage). To the reaction mixture were added ethyl acetate and the mixture was filtered through a layer of celite. The filtrate was poured into water. The organic layer was washed with water and saturated saline and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 100/0-66/34) to give the methyl ester of 4-(4-cyanohydrin-2-yl)-2-hydroxy-benzoic acid (0.1 g). To a mixed solution of this compound (0.1 g) in tetrahydrofuran (4 ml), ethanol (1 ml) and water (1 ml) was added lithium hydroxide monohydrate (to 0.060 g) and the mixture was stirred at room temperature overnight. To this reaction mixture was added 2 mol/l hydrochloric acid (2.8 ml) and the mixture was stirred at 50°C for 10 hours. After cooling the reaction mixture to room temperature the precipitated solid was collected by filtration and dried under reduced pressure to obtain specified in the connection header(0,068 g).

Example 7

2-(4-Cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid

A suspension of ethyl ester of 2-(4-does not depend-2-yl)-4-methylthiazole-5-carboxylic acid (0,050 g), cyanide zinc (0,031 g) and tetrakis(triphenylphosphine)palladium (0.015 g) in N-organic (2 ml) was stirred at 150°C for 50 minutes using a microwave reactor (Biotage). To the reaction mixture were added water (15 ml) and the precipitated solid substance was collected by filtration and washed with water and n-hexane to obtain ethyl ester 2-(4-cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid (0,042 g).

Specified in the title compound (0.035 g) was obtained by a method similar to that described in Example 6, using the ethyl ester of 2-(4-cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid instead of methyl ester of 4-(4-cyanohydrin-2-yl)-2-hydroxy-benzoic acid.

Example 8

2-(4-Cyano-6-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid

To a suspension of ethyl ester of 2-(4-hydroxy-6-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid (0,030 g) in dichloromethane (2 ml) was added pyridine (0,058 g) and triftormetilfullerenov anhydride (0.10 g) at room temperature and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol/l hydrochloric acid (4 ml) and the resulting mixture was extracted with diethyl ether. The organic layer is washed and water and a saturated saline solution and dried over magnesium sulfate to obtain ethyl ester 4-methyl-2-(6-methyl-4-triftoratsetilatsetonom-2-yl)thiazole-5-carboxylic acid. To a solution of the obtained compound in N-added organic cyanide zinc (0,043 g) and tetrakis(triphenylphosphine)palladium (0,021 g) at room temperature and the mixture was stirred at 150°C for 40 minutes using a microwave reactor (Biotage). To the reaction mixture were added water and the precipitated solid substance was collected by filtration. This solid is washed with water and purified column chromatography on gel aminopropyl-silica (eluent: ethyl acetate) to give the ethyl ester of 2-(4-cyano-6-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid (0,022 g). To a mixed solution of this compound (0,022 g) in tetrahydrofuran (2 ml), ethanol (0.5 ml) and water (0.5 ml) was added lithium hydroxide monohydrate (0.008 g) and the mixture was stirred at room temperature overnight. To this reaction mixture was added water (2 ml) and the resulting mixture was extracted with diethyl ether. To the aqueous layer was added 1 mol/l hydrochloric acid (2 ml) and the resulting mixture was extracted with ethyl acetate (8 ml). The organic layer was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (0,012 g).

Examples 9-10

Compounds of Examples 9-10 were obtained by the method similar to that described in Example 8, using the appropriate source in the substances.

Examples 11-44

Connection Examples 11-44 got a way similar to that described in Example 8, using the appropriate starting materials.

Examples 45-46

Connection Examples 45-46 got a way similar to that described in Example 7 using the appropriate starting materials.

Example 47

2-(4-Cyanonaphthalene-2-yl)-4-methoxazole-5-carboxylic acid

To a mixed solution of methyl ester of 2-(4-cyanonaphthalene-2-yl)-4-methoxazole-5-carboxylic acid (0,045 g) in tetrahydrofuran (1.5 ml), ethanol (0.8 ml) and water (0.8 ml) was added lithium hydroxide monohydrate (0.02 g) and the mixture was stirred for 30 minutes. To the reaction solution were added water and the resulting mixture was washed with diethyl ether. To the aqueous layer was added 1 mol/l hydrochloric acid (0.5 ml). The precipitated solid was collected by filtration and dried under reduced pressure to obtain specified in the connection header (0,028 g).

Example 48

2-(4-Cyano-8-fluoro-7-hydroxynaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid

To a suspension of 2-(4-cyano-8-fluoro-7-methoxynaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid (0,22 g) in dichloromethane (1 ml) was added tribromide boron (1 mol/l solution in dichloromethane, 128 ml) under cooling in a bath of methanol-ice and the mixture was stirred at room temperature for 30 minutes, with subsequent paramashiva is receiving with heating at 40°C for 2.5 hours. After cooling to room temperature, to the mixture was added 1 mol/l hydrochloric acid. The precipitated crystalline substance was collected by filtration and dried under reduced pressure at 50°C with obtaining specified in the connection header (0,018 g).

Example 49

2-(4-Cyano-7-hydroxynaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid

To a suspension of ethyl ester of 2-(7-benzyloxy-4-cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid (0.27 g) in tetrahydrofuran (20 ml) was added palladium on carbon (100 mg) at room temperature and the mixture was stirred at the same temperature for 1.5 hours in an atmosphere of hydrogen. The mixture was stirred at 50°C during the night. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure. The residue is suspended in ethyl acetate and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 95/5-40/60) to give the ethyl ester of 2-(4-cyano-7-hydroxynaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid (0,067 g). Specified in the header of the connection is 0.019 g) was obtained by removal of protection for this connection (0,030 g) by the method similar to that described in Example 47.

In Tables 1-10 presents the chemical structures of the above compounds Ssy is full of Examples 25-75 and chemical structure and data 1H-NMR of the compounds of Examples 1-49.

The abbreviations in these Tables: "Ref. Approx. No.", "PR. No.", "structure" and "Rest.",indicate the number of the Reference Example, Example, the chemical structure and the solvent for measurement1H-NMR, respectively.

[Table 1]
Ref. Approx. No.Struct.Ref. Approx. No.Struct.Ref. Approx. No.Struct.Ref. Approx. No.Struct.
25262728
29303132
33343536
37383940
414243

[Table 2]
Ref. Approx. No.Struct.Ref. Approx. No.Struct.
44 52
4553
4654
4755
4856
4957
5058
5159

[Table 3]
Ref. Approx. No.Struct.Ref. Approx. No.Struct.
6068
6169
6270
6371
6472
6573
66 74
6775

7,80 at 8.60 (6H, m), 8,48 (2H, d, J=8,2 Hz), of 8.92(1H, s)
[Table 4]
Approx. No.Struct.1H-NMR δ ppm
(DMSO-d6)
17,75-of 7.95 (3H, m), 8,10-of 8.15 (1H, m), with 8.33 (1H, d, J=8,2 Hz), 8,60-8,65 (1H, m), 8,90-9,00 (2H, m), 9,15-9,20 (1H, m)
27,70-a 7.85 (2H, m), 8,10-of 8.15 (1H, m), 8,20-8,30 (1H, m), to 8.41 (1H, s), 8,54 (1H, s), 8,83 (1H, d, J=1,8 Hz), 8,95-9,05 (1H, m)
37,75-of 7.90 (2H, m), 8,10-8,30 (3H, m), 8,83 (1H, d, J=2.3 Hz), cent to 8.85-8,95 (1H, m), 9.28 are(1H, s), 12,81 (1H, user. C)
47,75-of 7.90 (2H, m), 8,00-8,30 (6H, m)8,64 (1H, d, J=1.9 Hz), 8,75-8,80 (1H, m)
5
6the 7.85-with 8.05 (5H, m), 8,10-of 8.15 (1H, m), 8,25-8,30 (1H, m), 8,89 (1H, s), 11,38 (1H, user. C)
7by 2.73 (3H, s), 7,75-of 8.00 (2H, m), 8,16 (1H, d, J=8,3 Hz), with 8.33 (1H, d, J=8,2 Hz), 8,68 (1H, d, J=1.7 Hz), 8,95-9,05 (1H,m), 13,55 (1H, user. C)

[Table 5]
Approx. No.Struct.1H-NMR δ ppm
(DMSO-d6)
82,60 (31-1, s)of 2.72 (3H, s), to 7.64 (1H, DD, J=8,3 Hz, 1.3 Hz), to $ 7.91 (1H, s), to 8.20 (1H, d, J=8,3 Hz), 8,59 (1H, d, J=1.7 Hz), cent to 8.85-8,95 (1H, m), 13,50 (1H, user. C)
9of 2.54 (3H, s), a 2.71 (3H, s), 7,72 (1H, DD, J=8.6 Hz, 1.2 Hz), 7.95 is-8,10 (2H, m), 8,54 (1H, d, J=1,8 Hz), 8,75 cent to 8.85 (1H, m)
10by 2.73 (3H, s), a 7.85 (1H, m), 8,08 (1H, s)of 8.37 (1H, d, J=8,8 Hz), 8,70 is 8.75 (1H, m), of 9.02 (1H, s)13,59 (1H, user. C)

[Table 6]
Approx. No.Struct.1H-NMR δ ppm
(DMSO-d6)
11of 2.54 (3H, s), of 2.72 (3H, s), was 2.76 (3H, s)to 7.50 (1H, s), to 7.77 (1H, s), 8,55-8,65 (1H, m), 8,75 cent to 8.85 (1H, m), 13,52 (1H, user. C)
12by 2.73 (3H, s), 7,65-of 7.90 (1H, m), 8,05-8,35 (2H, m), 8,55-8,80 (1H, m), cent to 8.85-9,10 (1H, m)to 13.6 (1H, user. C)
13to 2.74 (3H, s), 7,60 to 7.75 (1H, m), 7,80-8,10 (2H, m), 8,70 cent to 8.85 (1H, m), of 8.90 (1H, s), 13,60 (1H, user. C)
14of 2.72 (3H, s), of 4.05 (3H, s), a 7.85-of 8.00 (2H, m), 8,50 at 8.60 (1H, m), 8,70-8,80 (1H, m), 13,57 (1H, user. C)
15of 2.72 (3H, s), 2,96 (3H, s), 7,45-of 7.55 (1H, m), 7,60-the 7.65 (1H, m), 8,65 (1H, d, J=1.9 Hz), 8,82 (1H, d, J=1.9 Hz), of 13.58 (1H, user. C)
16of 2.72 (3H, s), 2,77 (3H, s), 7,60-the 7.65 (1H, m), 7,70-7,80 (1H, m), of 7.90-8,00 (1H, m), 8,55-8,65 (1H, m), 8,75 cent to 8.85 (1H, m), 13,55 (1H, user. C)
17/td> by 2.73 (3H, s), 7,75-a 7.85 (1H, m), a 7.85-of 7.95 (1H, m), 8,65-to 8.70 (1H, m), 8,80 cent to 8.85 (1H, m), of 13.58 (1H, user. C)
18of 2.72 (3H, s), 7,75-of 7.90 (1H, m), 7,95-8,10 (1H, m), 8,60-8,65 (1H, m), 8,95-9,00 (1H, m), 13,62 (1H, user. C)

[Table 7]
Approx. No.Struct.1H-NMR δ ppm
(DMSO-d6)
19of 2.72 (3H, s), the 7.65 to 7.75 (1H, m), 7,80-of 7.95 (1H, m), 8,75-of 8.90 (2H, m), of 13.58 (1H, user. C)
20by 2.73 (3H, s), was 4.02 (3H, s), 7,20-7,30 (1H, m), 7,50-of 7.60 (1H, m), at 8.60 (1H, d, J=1,8 Hz), 8,77 (1H, d, J=1,8 Hz), 13,59 (1H, user. C)
21by 2.73 (3H, s), 8,05-to 8.20 (1H, m), 8,70-8,80 (1H, m), 8,80-of 8.90 (1H, m), 13,65 (1H,user. C)
22by 2.73 (3H, s), 7,60-of 7.70 (1H, m), 7,70-7,80 (1H, m), 8,10-to 8.20 (1H, m), 8,66 (1H,s), 9,01 (1H,s)13,59 (1H, user. C)
23by 2.73 (3H, s), 7,70-a 7.85 (2H, m), 8,40-and 8.50 (1H, m), 8,70 is 8.75 (1H, m), 9,00-9,10 (1H,m), 13.56MHz (1H, user. C)
24of 2.72 (3H, s), was 4.02 (3H, s), 7,81 (1H, d, J=11.5 Hz), 8,02 (1H, d, J=8.5 Hz), 8,50-8,55 (1H, m), cent to 8.85-8,95 (1H, m), 13,54 (1H, user. C)
25a 2.71 (3H, s), 4,10 (3H, s), 7,45-of 7.55 (1H, m), 8,15-to 8.20 (1H, m), 8,55 at 8.60 (1H, m), 8,80-of 8.90 (1H, m), 13,53 (1H, user. C)
26of 2.72 (3H, s), to 3.02 (3H, s), 7,55-the 7.65 (1H, m), of 7.90-8,00 (1H, m), 8,50-8,55 (1H, m), cent to 8.85-of 8.90 (1H,m), 13,55 (1H, user. C)

[Table 8]
Approx. No.Struct.1H-NMR δ ppm
(DMSO-d6)
27of 2.72 (3H, s), 8,00-8,10 (1H, m), 8,40-and 8.50 (1H, m), 8,65 is 8.75 (1H, m), 8,95-9,00 (1H, m), 13,59(1H, user. C)
28of 2.72 (3H, s), of 3.94 (3H, s), 7,50-of 7.55 (1H, m), 7,75-7,80 (1H, m), 8,00-8,10 1H, m), 8,45-and 8.50 (1H, m), cent to 8.85-of 8.90 (1H, m), 13,55 (1H, user. C)
292,52 (3H, s), of 2.72 (3H, s), 7,50-of 7.60 (1H, m), to $ 7.91 (1H, s), 8,50 at 8.60 (1H, m), 8,80-of 8.90 (1H, m), of 13.58 (1H, user. C)
302,69 (3H, s), a 7.85-of 7.95 (1H, m), 8,15-of 8.25 (1H, m), 8,60-8,65 (1H, m), 8,90-8,95(11-1, m), 13,57 (1H, user. C)
317,70-of 8.00 (2H, m), 8,05-to 8.45 (2H, m), charged 8.52 (1H, s), 8,60 cent to 8.85 (1H, m), 8,90 is 9.15 (1H, m), 13,50-14,00 (1H, m)
327,60-8,15 (3H, m), 8,40 at 8.60 (1H, m), 8,75-9,05 (2H, m), of 13.58 (1H, user. C)
334,06 (3H, s), of 7.90-with 8.05 (2H, m), 8,53 (1H, s), 8,63 (1H, d, J=1,8 Hz), 8,80 cent to 8.85 (1H, m), 13,79 (1H, user. C)
34of 2.97 (3H, s), 7,45-of 7.70 (2H, m), charged 8.52 (1H, s), 8,72 (1H, d, J=1.9 Hz), 8,89 (1H, d, J=1.9 Hz), 13,80 (1H, user. C)

[Table 9]
Approx. No.Struct. 1H-NMR δ ppm
(DMSO-d6)
357,75-a 7.85 (1H, m), a 7.85-of 7.95 (1H, m), charged 8.52 (1H, s), 8,70 is 8.75 (1H, m), 8,80-of 8.90 (1H, m), 13,80(1H, user. C)
367,80-of 7.95 (1H, m), 8,00-8,10 (1H, m), 8,55 (1H, s), 8,65 is 8.75 (1H, m), 9,00-9,10 (1H,m), at 13.84 (1H, user. C)
377,70-7,80 (1H, m), 7,80-of 7.95 (1H, m), charged 8.52 (1H, s), cent to 8.85-8,95 (2H, m), 13,83 (1H, user. C)
38as 4.02 (3H, s), 7,20-7,30 (1H, m), 7,50-of 7.60 (1H, m), 8,53 (1H, s), 8,65 (1H, d, J=1.7 Hz), 8,82 (1H, d, J=1.7 Hz), 13,81 (1H, user. C)
398,05-to 8.20 (1H, m), 8,56 (1H, s), 8,75 cent to 8.85 (1H, m), 8,90-8,95 (1H, m), 13,87 (1H,user. C)
407,60 is 7.85 (2H, m), 8,16 (1H, d, J=8,2 Hz), 8,53 (1H, s)8,71 (1H, s), 9,07 (1H,s), 13,80 (1H, user. C)
414.09 to (3H, s), 7,40-7,50 (1H, m), 8,05-of 8.15 (1H, m), to 8.45 (1H, s), 8,55 at 8.60 (1H, m), 8,80 cent to 8.85 (1H, m), 13,73 (1H, user. C)
42totaling 3.04 (3H, s), 7,60-of 7.70 (1H, m), 7.95 is-with 8.05 (1H, m), 8,53 (1H, s), at 8.60 (1H, d, J=2.0 Hz), 8,97 (1H, d, J=2.0 Hz), 13,78 (1H, user. C)

[Table 10]
Approx. No.Struct.(rest.)1H-NMR δ ppm
43(DMSO-d6) to 2.54 (3H, s), 7,50-the 7.65 (1H, m), 7,94 (1H,s), 8,53 (1H, s), 8,60-8,65 (1H, m), 8,90-9,00 (1H, m)13,82 (1H, user. C)
44(CDCl3) 7,70-of 7.95 (2H, m), 7,95-8,10 (2H, m), 8,25-8,35 (1H, m), 8,46 (1H, s)
45(DMSO-d6) 7,70-of 8.00 (2H, m), 8,10-to 8.45 (2H, m), 8,75 cent to 8.85 (1H, m)to 9.15 (1H, s)
46(DMSO-d6) 7,70-of 7.95 (2H, m), 8,05-8,30 (2H, m), to 8.70 (1H, s), 8,80-of 8.90 (1H,m), 9,10 (1H, s)
47(DMF-d7) to 2.75 (3H, s), 7,95-8,30 (2H, m), 8,35-to 8.70 (2H, m), 8,75 cent to 8.85 (1H, m), 9,25 (1, C)
48(DMSO-d6) 2,73 (3H, s), 7,55-the 7.65 (1H, m), 7,86 (1H, d, 9.1 Hz), 8,49 (1H, d, J=1.6 Hz), 8,70 is 8.75 (1H, m), 10,88 (1H,s), 13.56MHz (1H, user. C)
49(DMSO-d6) of 2.72 (3H, s), 7,40-of 7.55 (2H, m), 7.95 is-with 8.05 (1H, m), 8,35-to 8.40 (1H, m), 8,70-8,80 (1H, m), 10,48 (1H, s), 13,53 (1H, user. C)

The test example 1

Inhibitory activity against xanthine oxidase

(1) preparation of the test compounds

Test compounds were dissolved in DMSO (Wako) at a concentration of 40 mm and then diluted to the desired concentrations of phosphate-buffered saline (PBS).

(2) Method of measurement

The xanthine oxidase (from bovine milk, Sigma) was obtained with the use of a phosphate buffer saline (PBS) at a 0.02 units/ml, and then the solution was added to 96-well tablets at 50 μl/well. Also added test compounds diluted in PBS, 50 μl/well. Xanthine (Wako) at 200 μm prepared with PBS was added at 100 μl/well and the reaction mixture was measured for 10 minutes at room temperature. Spectral absorption capacity at 290 nm was measured using a reader for microplates SpectraMax Plus 384 (Molecular evice). Spectral absorption capacity without xanthine is 0%, and a control without test compounds is 100%. Expected concentration of the test compounds, which achieved 50% inhibition (IC50) (Table 11). Ave. No. in the table indicates the number of the example.

[Table 11]
Ave. No.123456789
IR50(nm)1113382081871126
Ave. No.1213152231
IR50(nm) 48772

The test example 2

Inhibitory activity against transport of uric acid using cells expressing human URAT1

(1) Obtaining cells, unstable expressing human URAT1

A full-sized human cDNA URAT1 (NCBI access Number NM_144585) was subclinically the expression vector, rdnk (Invitrogen). The vector expressing human URAT1 was transfusional in COS7 cells (RIKEN CELL BANK RCB0539) using Lipofectamine 2000 (Invitrogen). COS7 cells were sown in a coated collagen 24-hole plates (Japan Becton Dickinson) at 90-95% of confluently and cultured in D-MEM culture medium (Invitrogen)containing 10% fetal bovine serum (Sanko Junyaku), for 2 hours at 37°C in 5% CO2. For 1 wells, 2 ál of Lipofectamine 2000 was diluted in 50 ál of OPTI-MEM (Invitrogen) and allowed to stand at room temperature for 7 minutes (hereinafter indicated as Lipo2000-OPTI). For 1 wells, 0.8 µg of vector expressing human URAT1, was diluted in 50 ál of OPTI-MEM (Invitrogen) and was carefully combined with Lipo2000-OPTI. After maturation at room temperature for 25 minutes, the mixture was added to COS7 cells at 100 μl/well. In addition, COS7 cells were cultured during 2 days at 37°C in 5% CO 2and used to measure inhibitory activity against absorption.

(2) Obtaining test compounds

Test compounds were dissolved in DMSO (Wako) at a concentration of 10 mm and then diluted to a concentration of 2 times greater than the desired concentration, buffer for pre-treatment (125 mm sodium gluconate, 4.8 mm potassium gluconate, 1.2 mm of potassium dihydrophosphate, 1.2 mm magnesium sulfate, 1.3 mm calcium gluconate, 5.6 mm glucose, 25 mm Hepes, pH 7,4). Buffer for pre-treatment without the test compounds used for control. In addition, an equal volume of buffer for pre-treatment, containing14C-labeled uric acid (American Radiolabeled Chemicals, Inc.), added to test compounds and control and, as a result, received buffer for analysis, including 20 μm uric acid.

(3) measurement Method

All testing was performed on a hot plate at 37°C. the Buffer for pre-treatment and buffer for analysis were incubated at 37°C and then used for analysis. The medium was removed from the tablets and was added to 700 μl of the buffer for pre-treatment and the cells were pre-incubated for 10 minutes. After repeating this stage buffer for pre-treatment was removed and added to the buffer for analysis by 400 µl/well. The reaction of the acquisitions carried out during the course the e 5 minutes. After stopping the reaction buffer for analysis were rapidly removed and cells were washed twice by adding ice buffer for pre-treatment at 1.2 ml/well. Then the cells were literally by adding 0,2n sodium hydroxide solution at 300 μl/well. Lysed solution was transferred into a Picoplate (PerkinElmer) was added Microscinti 40 (PerkinElmer) at 600 μl/well. After mixing radioactivity was counted using a liquid scintillation counter (PerkinElmer). Radioactivity in COS7 cells not transfected with the vector expressing human URAT1, was also calculated in the same conditions that were used for control. In addition, the percentage of inhibition for the tested compounds was calculated according to the formula described below. As a result, it was shown that all the Examples 2, 6, 7, 12, 13, 15, 22 and 31 have more than 80% inhibition at a concentration of 100 ám.

The percentage of inhibition (%) = [1-(B-C)/(A-C)] X 100

A: Radioactivity in control

B: Radioactivity in the case of adding the test compounds

C: Radioactivity in COS7 cells not transfected with the vector expressing human URAT1

Industrial applicability

Containing condensed ring structure derivative represented by the formula (I)according to the present invention or their prodrugs, or headlamp is asepticheski acceptable salts exhibit excellent inhibitory activity against xanthine oxidase and therefore can exhibit inhibitory activity against the production of uric acid and reduce the level of uric acid in the blood. Therefore, the present invention can provide an agent for the prevention or treatment of hyperuricemia, gouty site, gouty arthritis, renal disorder associated with hyperuricemia, urinary concretions or similar

1. Containing condensed ring structure derivative represented by the formula (I):

where
X1and X2independently represent CH or N;
ring U represents a benzene ring, a pyrazol ring, 1,2,4-oxadiazole ring, 1,2,4-thiadiazole ring, isothiazol ring, oxazoline ring, pyridine ring, thiazole ring or a thiophene ring.
m is an integer having a value from 0 to 1;
n is an integer having a value of from 0 to 3;
R1represents a hydroxy-group or C1-6alkyl;
R2represents any one of (1)to(3):
(1) a halogen atom;
(2) a hydroxy-group;
(3) C1-6alkyl or C1-6alkoxy, each of which can independently be any group selected from the group of substituents α;
the group of substituents α includes a fluorine atom and a hydroxy-group, or its pharmaceutically acceptable salt.

2. Containing condensed ring structure derived according to claim 1, where X1represents CH, or it is farmacevtichesky acceptable salt.

3. Containing condensed ring structure derived according to claim 1 or 2, where X2represents CH, or its pharmaceutically acceptable salt.

4. Containing condensed ring structure derived according to any one of claims 1 to 3, where m is 0 or m is 1 and ring U represents any one of rings represented by the following formula:

in the presented formulas, R1Arepresents a hydroxy-group, or C1-6alkyl; a represents a link to a condensed ring; and a represents a bond with the carboxy; respectively, or its pharmaceutically acceptable salt.

5. Containing condensed ring structure derived according to claim 4, where the ring U represents a thiazole ring, or its pharmaceutically acceptable salt.

6. Containing condensed ring structure derived according to claim 4, where the ring U represents a pyridine ring, or its pharmaceutically acceptable salt.

7. Containing condensed ring structure derived according to claim 5, where R1arepresents a methyl group; n is 0, or n has a value of 1-3, and R2represents a halogen atom, a hydroxy-group or C1-6alkyl, which may contain 1-3 fluorine atom, or its pharmaceutically acceptable salt.

8. Containing condensed ring structure derived according to claim 6, where m is 0; or m is 1, R1arepresents a hydroxy-group, and R2represents a halogen atom, a hydroxy-group or C1-6alkyl, which may contain 1-3 fluorine atom, or its pharmaceutically acceptable salt.

9. Containing condensed ring structure derived according to any one of claims 1 to 8, where m is 0, or its pharmaceutically acceptable salt.

10. Containing condensed ring structure derived according to any one of claims 1 to 9, where n is 0, or its pharmaceutically acceptable salt.

11. Containing condensed ring structure derived according to any one of claims 1 to 6, where n has a value of 1-3, and R2represents a fluorine atom, or its pharmaceutically acceptable salt.

12. Containing condensed ring structure derived according to any one of claims 1 to 6 represented by the formula:

where R21represents a hydrogen atom, fluorine atom or methyl group; R22represents a hydrogen atom or a fluorine atom; R23represents a hydrogen atom, fluorine atom or methyl group; R24represents a hydrogen atom or a fluorine atom; and R11represents a hydrogen atom or a methyl group, or f is rmaceuticals acceptable salt.

13. Containing condensed ring structure derived according to claim 1, which is selected from the group consisting of
2-(4-cyanonaphthalene-2-yl)-5-hydroxyisoquinoline acid,
2-(4-cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-7-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-7-fornatale-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-8-fornatale-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-8-fluoro-5-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-8-fluoro-7-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-5,7-defernatly-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-6,8-defernatly-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-5,7,8-tripterygion-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-5-fornatale-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-6-fornatale-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-7-fluoro-5-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-6,7-defernatly-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-5-fluoro-7-methylnaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyano-5,6-defernatly-2-yl)-4-methylthiazole-5-carboxylic acid,
2-(4-cyanonaphthalene-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-8-fornatale-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-8-fluoro-5-methylnaphthalene-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-8-fluoro-7-methylnaphthalene-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-5,7-defernatly-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-6,8-defernatly-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-5,7,8-tripterygion-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-5-fornatale-2-yl)-thiazole-5-carboxylic acid,
2-(4-cyano-7-fluoro-5-methylnaphthalene-2-yl)-thiazole-5-carboxylic acid, and
2-(4-cyano-5-fluoro-7-methylnaphthalene-2-yl)-thiazole-5-carboxylic acids or their pharmaceutically acceptable salts.

14. Pharmaceutical composition having inhibitory activity against xanthine oxidase, comprising as active ingredient a condensed ring derivative according to claims 1-13, or its pharmaceutically acceptable salt.

15. The pharmaceutical composition according to 14, which is an agent for the prevention or treatment of a disease selected from the group including hyperuricemia, gouty site, gouty arthritis, renal disorder associated with hyperuricemia, urinary concretions.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole derivatives of general formula wherein R1, R2, R3 can be identical or different independently means hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, heteroaralkyl (wherein 5- or 6-member N-, O- or S-heteroaromatic cycle), cycloalkyl, 2,2,6,6-tetramethyl-piperidin-4-yl, and also R1+R2 can mean heterocycle specified in optionally substituted pyrrolidine, piperidine, azepane, piperazine, morpholine wherein optional substitutes can be hydroxyl, cyanogroup, halogens, alkyls, lower alkoxy groups, lower alkothio groups, trihalogen methyl, sulphamide, optionally substituted amino groups (amino, dimethyl amino, diethyl amino) provided R1=H, R2 is different from hydrogen or methyl.

EFFECT: there are produced new compounds which can find application in medicine as the substances possessing neuromodulatory activity.

2 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel compounds of formula (I), where R1 represents hydroxymethyl; R2 is selected from -C(O)NR4R5; HET-1 represents 5- or 6-member heteroaryl ring, bound by atom C; R3 represents halogeno; R4 and R5 together with nitrogen atom, to which they are bound, can form heterocyclyl ring system, as it is defined for HET-3; HET-3 represents possibly substituted azetidinyl; m equals 1; n equals 0, 1 or 2; or their pharmaceutically acceptable salt, which can be applied as glucokinase (GLK) activators or active ingredient of pharmaceutical compositions, also described are methods of obtaining them.

EFFECT: creation of novel compounds applied as glucokinase (GLK) activators in treatment of diabetes.

13 cl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns improved method of obtaining 3,5-diamino-1,2,4-thiadizol applied in synthesis of medicines, macroheterocyclic compounds, bioactive substances etc. Invention claims method of obtaining 3,5-diamino-1,2,4-thiadizol by reaction of 2-imino-4-thiobiuret with equimolecular quantity of hydrogen peroxide of 26-35% concentration in boiling alcohol for 20-30 minutes.

EFFECT: increased output to by 86% of target product with melting temperature of 172-174°C and reduced general process duration from 60 to 2 hours.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel derivatives of 1,2,4-thiadiazole-2-il formula (I), , where R1, R2 and R4 present the radicals containing cyclic fragments, R3 designates hydrogen, alkyl, alkenyl or alkinyl that can be used as the agonists and antagonists of melanokortin receptors. Also, in this invention, the pharmaceutical composition, which shows the activity of modulator of melanokortin receptors, and the method of its preparation, are described. The purpose of this invention is to obtain the pharmaceutical compositions, which contain the therapeutically effective amount of compounds, as well as the pharmaceutically acceptable carrier, which are administered to the subject that suffers the melanokortin-mediated diseases, from the group with metabolic disturbances, abnormalities related to CNS and dermatologic abnormalities.

EFFECT: compounds can be used in treatment of CNS and dermatologic diseases.

21 cl, 13 ex, 13 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method which involves reacting a compound of formula (1), where: R1 is a hydrogen atom or a halogen atom; R2 is a hydrogen atom, a cyano group, a nitro group, a halogen atom, a formyl group or a halomethyl group; A is a hydrogen atom, C1-C8 alkyl group, C3-C6 cycloalkyl group, a phenyl group, a fluorine atom (only when X denotes a bond), a protective group for a hydroxyl group (only when X denotes an oxygen atom), where A can be substituted with 1 to 3 substitutes, such a substitute representing a group selected from a group consisting of a halogen atom, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 alkylthio group, C3-C6 cycloalkyl group, phenyl group, phenoxy group and pyridyl group; X is a bond (only when A is a phenyl group or a fluorine atom) or an oxygen atom; and Y is a leaving group and a compound of formula (2): H is a hydrogen atom; R3 is COOR3a or COR3b; R3a is a hydrogen atom, C1-C4 alkyl group or protective ester group for the carboxyl group; R3b is an amide protective group for the carboxyl group, a protective group which forms an amide with a neighbouring carbonyl group; R4 is a hydrogen atom, a halogen atom or a C1-C4 alkyl group; in the presence of a transition metal compound, selected from a group consisting of zero valence palladium and a salt of mon- and divalent palladium and (ii) a phophinic ligand capable of coordinating the transition metal compound to obtain a phenyl-substituted heterocyclic derivative of formula (3), where: A, X, R1 and R2 are as defined in formula (1); R3 and R4 are as defined in formula (2).

EFFECT: method of producing a phenyl-substituted heterocyclic derivative with fewer steps, high output and at a low cost.

17 cl, 11 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound selected from a group consisting of: 4-[(2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-[(5-chlor-2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2S)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-{[(6-{[(2S)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl] (pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor- 2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl] benzoic acid, 4-[(2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl] benzoic acid, 4-{[(6-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid and 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, or a pharmaceutically acceptable salt thereof. These compounds have an EP1 receptor antagonist effect and may be used for treating the dysfunction pollakiuria.

EFFECT: preparing the sulfonamide compounds with a strong EP1 receptor antagonist effect.

23 cl, 24 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns a EP2 agonist which exhibits the EP3 agonist action, and induce a neurotising and/or protective effect and thereby is effective as a therapeutic agent for a peripheral nerve disease, such as lower and upper motor neuron disorder, nerve root disease, plexopathy, brachial plexus compression syndrome, peripheral neuropathy, neurofibromatosis and nervomuscular conduction disease.

EFFECT: EP2 agonist which exhibits the EP3 agonist action; it is a safe and effective neurotisation and/or protection agent which has an insignificant impact on the cardiovascular system.

13 cl, 36 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: described is 2-alkyl-cycloalk(en)yl-carboxamides of formula

, in which X, s, R1 , L, R2 and A assume values given in the formula of invention, a method of producing said compounds, an agent and use of said compounds against unwanted microorganisms.

EFFECT: higher activity compared to existing compounds, low toxicity and high toleration by plants.

6 cl, 8 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) , in which Ar is furanyl, thiophenyl, thiazolyl, pyridinyl; R1 is independently chosen from a group consisting of hydrogen, lower alkyl, lower alkoxy, halogen and nitro; R2 is independently chosen from a group consisting of hydrogen and halogen; R4 is hydroxyl or residue of pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid or 1-aminocyclopentane carboxylic acid, bonded through a nitrogen atom of an amino acid residue; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; p is 0, and s is 0, or to their pharmaceutically acceptable salts, under the condition that, the compound is not S-1- [5-(biphenyl-4-yloxymethyl)furan-2-carbonyl]pyrrolidin-2-carboxylic acid, 5-(biphenyl-4-yloxymethyl)furan-2-carboxylic acid, 3-(biphenyl-4-yloxymethyl)benzoic acid, 2-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-4-yloxymethyl)benzoic acid, 5-(biphenyl-4-yloxymethyl)thiophene-2-carboxylic acid. Invention also relates to a pharmaceutical composition based on formula (I) compounds, which stimulates glycogen synthase activity.

EFFECT: wider range of use of the compounds.

27 cl, 34 ex, 8 dwg

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method which involves reacting a compound of formula (1), where: R1 is a hydrogen atom or a halogen atom; R2 is a hydrogen atom, a cyano group, a nitro group, a halogen atom, a formyl group or a halomethyl group; A is a hydrogen atom, C1-C8 alkyl group, C3-C6 cycloalkyl group, a phenyl group, a fluorine atom (only when X denotes a bond), a protective group for a hydroxyl group (only when X denotes an oxygen atom), where A can be substituted with 1 to 3 substitutes, such a substitute representing a group selected from a group consisting of a halogen atom, C1-C4 alkyl group, C1-C4 alkoxy group, C1-C4 alkylthio group, C3-C6 cycloalkyl group, phenyl group, phenoxy group and pyridyl group; X is a bond (only when A is a phenyl group or a fluorine atom) or an oxygen atom; and Y is a leaving group and a compound of formula (2): H is a hydrogen atom; R3 is COOR3a or COR3b; R3a is a hydrogen atom, C1-C4 alkyl group or protective ester group for the carboxyl group; R3b is an amide protective group for the carboxyl group, a protective group which forms an amide with a neighbouring carbonyl group; R4 is a hydrogen atom, a halogen atom or a C1-C4 alkyl group; in the presence of a transition metal compound, selected from a group consisting of zero valence palladium and a salt of mon- and divalent palladium and (ii) a phophinic ligand capable of coordinating the transition metal compound to obtain a phenyl-substituted heterocyclic derivative of formula (3), where: A, X, R1 and R2 are as defined in formula (1); R3 and R4 are as defined in formula (2).

EFFECT: method of producing a phenyl-substituted heterocyclic derivative with fewer steps, high output and at a low cost.

17 cl, 11 tbl, 15 ex

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