2-cyclooxygenase inhibitors as antiangiogenic agents

FIELD: medicine, in particular angiogenesis prophylaxis and treatment.

SUBSTANCE: invention relates to 2-cyclooxygenase inhibitors selected from group containing 4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazole-1-yl] benzenesulfonamide; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl] benzenesulfonamide; 4-[5-methyl-3-phenyloxazole-4-yl] benzenesulfonamide or pharmaceutically acceptable salts thereof and pharmaceutical composition containing the same in therapeutically effective amount. Said composition are useful in treatment and/or prophylaxis of angiogenesis disorders such as metastasis, eye angiogenesis, diabetic retinopathy, etc. in subjects are needed in such treatment and/or prophylaxis.

EFFECT: new pharmaceuticals for angiogenesis treatment and/or prophylaxis.

5 cl

 

Description

This invention relates to the field of prevention and treatment of angiogenesis. More specifically, this invention relates to the use of inhibitors of cyclooxygenase-2 or a derivative thereof for the prevention and treatment of disorders associated with angiogenesis.

Background of invention

Prostaglandins play a major role in the process of inflammation, and inhibition of production of prostaglandins, especially the production of PGG2, PGH2and PGE2it was a common goal in the field of open anti-inflammatory drugs. However, conventional non-steroidal anti-inflammatory drugs (NSAID's)that are active at lower induced prostaglandin pain and swelling associated with inflammation, is also active in influencing others, regulated by prostaglandins processes not associated with inflammation. Thus, the use of high doses of conventional NSAID's can cause serious side effects, including life-threatening ulcers that limit their therapeutic potential. Alternative NSAID's is the use of corticosteroids, which also cause serious adverse effects, especially when long-term therapy.

It was found that NSAID's prevent the production of prostaglandins put the m inhibition of enzymes in the pathway arachidonic acid/prostaglandin person, including the enzyme cyclooxygenase (SOH). The recent discovery of the inducible enzyme associated with inflammation (called cyclooxygenase-2 (SOH-2)" or "prostaglandin G/H synthase II"), provides a viable object of inhibition, which more effectively reduces inflammation and causes smaller and less drastic side effects.

Angiogenesis is the development of new blood vessels in a tissue or organ. Under normal conditions the development of blood vessels observed during wound healing and embryonic development. Uncontrolled development of blood vessels associated with tumor disease, metastasis of tumors and other diseases associated with angiogenesis.

Although glucocorticoids were originally developed because of their anti-inflammatory properties, now found that they have a wide variety of therapeutic applications. For example, many steroids having anti-inflammatory activity inhibit the development of blood vessels (U.S. patent No. 5646136).

Compounds that selectively inhibit cyclooxygenase-2, have been described in U.S. patents 5380738, 5344991, 5393790, 5434178, 5474995, 5475018, 5510368 and in WO 96/06840, WO 95/21817, WO 96/03388, WO 96/03387, WO 96/03392, WO 96/25405, WO 96/24584, WO 96/03385, WO 96/16934, WO 95/15316, WO 94/15932, WO 94/27980, WO 95/00501, WO 94/13635, WO 94/20480 and WO 94/26731.

[Pyrazole-1-yl]bansilal Hamidi have been described as inhibitors of cyclooxygenase-2 and gave hope in the treatment of inflammation, arthritis and pain with minimal side effects in preclinical and clinical trials. Their use for the prevention of colon cancer has been described in U.S. patent No. 5466823. However, their use for the treatment or prevention of diseases associated with angiogenesis, has not previously been described.

There were several publications that describe the benefit of inhibiting angiogenesis. In the published international patent application WO No. 96/19469 describes inhibitors SOH-2, which can be used for the prevention and/or treatment of tumor angiogenesis and diabetic retinopathy.

This invention relates to the use of inhibitors of cyclooxygenase-2 for the treatment and prevention of tumor growth and metastasis, which depend on the process of angiogenesis. It also enables treatment and prevention of non-tumor-related angiogenesis disorders, such as retinopathy and endometriosis.

Detailed description of the invention

This invention provides a method of treatment or prevention of disorders in a subject in need of such treatment or prevention, the method includes treating a subject a therapeutically effective amount of an inhibitor of cyclooxygenase-2 or its derivative or pharmaceutically acceptable salt.

The above method can be used, but not limited to, for Les the program associated with angiogenesis disorders in the subject. In accordance with this, invention compounds of the formula I is administered to a subject in need of inhibition of angiogenesis. The method can be used for the treatment of neoplasia, including metastasis; ophthalmological conditions such as corneal rejection of the transplant, the eye formation of new blood vessels, retinal formation of new blood vessels, including the formation of new blood vessels after injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant conditions such as hemangiomas, including infantile hemangioma, angiofibroma of the nasal part of the pharynx and avascular necrosis of bone; and abnormalities in the reproductive systems of women, such as endometriosis.

The term "treatment" includes partial or total inhibition of angiogenesis, including tumor growth, proliferation or metastasis, as well as partial or full destruction of tumor cells.

The term "prevention" includes either preventing the beginning of clinically apparent development of angiogenesis in General, or the prevention of early preclinical obvious stage of development of angiogenesis in individuals with risk of such development. This definition is intended to include prevention of metastasis of malignant what's cells or stop or reverse the development of progression of malignant cells. This definition includes prophylactic treatment when the risk of the development of angiogenesis.

The phrase "therapeutically effective" is intended to determine the amount of each agent which will achieve the goal of improvement in disease severity and the incidence of disease during the treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

The term "subject" for purposes of treatment includes any entity, person or animal that has any one of the well-known relating to the development of angiogenesis disorders. For methods of prevention, the subject is any subject, person, or animal, preferably human, which has the risk of getting related to the development of angiogenesis disorders, such as metastasis. The subject may have the risk of such disorders due to exposure to carcinogenic agents, being genetically predisposed to angiogenesis, and the like. In addition, they can be used for treatment of humans, these compounds can also be used in veterinary medicine for treatment of animals, including Pets and farm animals, such as, but not limited to, horses, dogs, cats, cows, sheep and pigs. The subject preferably is a human.

Inhibitors path cyclohexen the threat in arachidonic acid metabolism, used for the prevention and treatment of developmental angiogenesis, inhibit enzyme activity by different mechanisms. As an example, the inhibitors used in the methods described herein may block the activity of the enzyme directly by acting as a substrate for the enzyme. The use of selective inhibitors of cyclooxygenase-2 is very advantageous in that they minimize the gastrointestinal side effects that can occur when using non-selective NSAID'C, especially when it is assumed prolonged prophylactic treatment.

The term "inhibitor of cyclooxygenase-2" means a compound capable to inhibit cyclooxygenase-2 without significant inhibition of cyclooxygenase-1. Preferably, it includes compounds that have the IC50cyclooxygenase-2 is lower than about 0.2 μm, and also have a selectivity ratio of inhibition of cyclooxygenase-2 by inhibition of cyclooxygenase-1 at least 50 and more preferably at least 100. Even more preferably, the compounds have the IC50Cox-1 more than about 1 μm, and more preferably, greater than 10 microns.

The proposed method relates to the use of inhibitors of cyclooxygenase-2, or derivatives thereof for the treatment and prevention of the development of angiogenesis. In preferably the x variants inhibitor of cyclooxygenase-2 are selected from compounds of the formula I

where a represents a Deputy selected from oxazolyl, isoxazolyl, teinila, dihydrofurane, furil, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazoline, cyclopentenyl, phenyl and pyridyl;

where R1represents at least one Deputy, selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, where R1optionally substituted in can replace the position by one or more radicals selected from alkyl, halogenoalkane, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, halogenoalkane, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfonyl, halogen, alkoxy, alkylthio;

where R2is methyl or amino;

where R3represents a radical selected from the group comprising hydrogen, halogen, alkyl, alkenyl, quinil, oxo, cyano, carboxyl, cianelli, heterocyclics, alkyloxy, alkylthio, alkylsulphonyl, cycloalkyl, aryl, halogenated, heterocyclyl, cycloalkenyl, aralkyl, geterotsiklicheskikh, acyl, alkylthiomethyl, hydroxyalkyl, alkoxycarbonyl, arylcarbamoyl, aralkylamines, aralkyl, alkoxyalkyl, alltoall, aryloxyalkyl, aralkylated, alcoxialchil, alkoxylalkyl, alkoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, alkylaminocarbonyl, N-Allam noncarbonyl, N-alkyl-N-allumination, alkylaminocarbonyl, carboxyethyl, alkylamino, N-arylamino, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-arylamino, aminoalkyl, acylaminoalkyl, N-alluminati, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-alluminati, aryloxy, Alcoxy, aaltio, Uralkali, alkylsulfanyl, alkylsulfonyl, aminosulfonyl, alkylaminocarbonyl, N-arylamination, arylsulfonyl, N-alkyl-N-arylamination; or their pharmaceutically acceptable salt.

A preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of formula I, where a is chosen from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, cyclopentenyl, phenyl and pyridyl; where R is selected from 5 - or 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, where R1optionally substituted in can replace the position by one or more radicals selected from lower alkyl, lower halogenoalkane, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower halogenoalkane, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfonyl, halogen, lower alkoxy and lower alkylthio; where R2represents methyl or amino, and R3not only is no radical, selected from the group comprising hydrogen, oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower cianelli, halogen, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower halogenated, 5 - or 6-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, acyl, phenylcarbinol, lower alkoxyalkyl, 5 - or 6-membered, heteroaromatic, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower acylaminoalkyl, phenyloxy and lower Alcoxy; or their pharmaceutically acceptable salts.

A more preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of formula I, where a is chosen from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and cyclopentyl, where R1choose from pyridyl, optionally substituted in can replace the position of one or more methyl radicals, and phenyl, optionally substituted in can replace the position by one or more radicals selected from the group comprising methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vermeil, deformity, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, etoxycarbonyl, hydroxyl, hydroxymethyl, triptoreline, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N N-methyl-N-ethylamino phenylamino, methoxymethyl, methylsulfonyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentox and methylthio; R2represents methyl or amino, and R3represents a radical selected from the group comprising hydrogen, oxo, cyano, carboxyl, methoxycarbonyl, etoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, deformity, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, defloratin, direcror, methoxy, ethoxy, propoxy, n-butoxy, pentox, cyclohexyl, phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl, hydroxymethyl, hydroxypropyl, benzyl, formyl, phenylcarbinol, methoxymethyl, fullmetaljacket, aminocarbonyl, N-methylaminomethyl, N,N-dimethylaminoethyl, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy, phenyloxy; or their pharmaceutically acceptable salts.

Family specific, particularly interesting compounds of formula I consists of the following compounds and their pharmaceutically acceptable salts, including

5-(4-forfinal)-1-[4-(methylsulphonyl)phenyl]-3-(trifluoromethyl)pyrazole;

4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-1-phenyl-3-(trifluoromethyl) pyrazole;

4-(5-(4-chlorophenyl)-3-(4-methoxy who enyl)-1H-pyrazole-1-yl)benzosulfimide;

4-(3,5-bis(4-were)-1H-pyrazole-1-yl)benzosulfimide;

4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazole-1-yl)benzosulfimide;

4-(3,5-bis(4-methoxyphenyl)-1H-pyrazole-1-yl)benzosulfimide;

4-(5-(4-chlorophenyl)-3-(4-were)-1H-pyrazole-1-yl)benzosulfimide;

4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazole-1-yl)benzosulfimide;

4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazole-1-yl)benzosulfimide;

4-(4-chloro-3,5-diphenyl-1H-pyrazole-1-yl)benzosulfimide;

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1˜Il]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(4-were)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-cyano-5-(4-forfinal)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(Tr is permitil)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

2-methyl-4-[1-[4-(methylsulphonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-methyl-6-[1-[4-(methylsulphonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

2-(3,4-differenl)-1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

4-[2-(4-were)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

2-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]-4-methyl-1H-imidazole;

2-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]-4-phenyl-1H-imidazole;

2-(4-chlorophenyl)-4-(4-forfinal)-1-[4-(methylsulphonyl)phenyl]-1H-imidazole;

2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulphonyl)phenyl-4-(trifluoromethyl)-1H-imidazole;

1-[4-(methylsulphonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;

2-(4-were)-1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

4-[2-(3-chloro-4-were)-4-(trifluoromethyl)-1H-imidazol-1-yl] benzosulfimide;

2-(3-fluoro-5-were)-1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

4-[2-(3-fluoro-5-were)-4-(trifluoromethyl)-1H-imidazol-1-yl] benzosulfimide;

2-(3-were)-1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

4-[2-(3-meth is fenil)-4-trifluoromethyl-1H-imidazol-1-yl]benzosulfimide;

1-[4-(methylsulphonyl)phenyl)-2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazole;

4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzosulfimide;

4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzosulfimide;

4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzosulfimide;

1-allyl-4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

4-[1-ethyl-4-(4-forfinal)-5-(trifluoromethyl)-1H-pyrazole-3-yl]benzosulfimide;

N-phenyl-[4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl]ndimethylacetamide;

ethyl-[4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole-1-yl]acetate;

4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-1-(2-phenylethyl)-1H-pyrazole;

4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-1-(2-phenylethyl)-

5-(trifluoromethyl)pyrazole;

1-ethyl-4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

5-(4-forfinal)-4-(4-methylsulfinylphenyl)-2-trifluoromethyl-1H-imidazole;

4-[4-(methylsulphonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;

5-deformity-4-(4-methylsulfinylphenyl)-3-phenylisoxazol;

4-[3-ethyl-5-phenylisoxazol-4-yl]benzosulfimide;

4-[5-deformity-3-phenylisoxazol-4-yl]benzosulfimide;

4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzosulfimide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide;

1-[2-(4-forfinal)cyclopenten-1-yl]-4-(METI sulfonyl)benzene;

1-[2-(4-fluoro-2-were)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)-benzene;

1-[2-(4-triptoreline)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)-benzene;

1-[2-(4-forfinal)-4,4-dimethylcyclopentene-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(4-forfinal)-4,4-dimethylcyclopentene-1-yl]benzosulfimide;

1-[2-(4-chlorophenyl)-4,4-dimethylcyclopentene-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(4-chlorophenyl)-4,4-dimethylcyclopentene-1-yl]benzosulfimide;

4-[2-(4-forfinal)cyclopenten-1-yl]benzosulfimide;

4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzosulfimide;

1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulphonyl)-benzene;

1-[2-(2,3-differenl)cyclopenten-1-yl]-4-(methylsulphonyl)-benzene;

4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzosulfimide;

1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(3-chloro-4-forfinal)cyclopenten-1-yl]benzosulfimide;

4-[2-(2-methylpyridin-5-yl)cyclopentan-1-yl]benzosulfimide;

ethyl-2-[4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]oxazol-2-yl]-2-benzoylacetate;

2-[4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]oxazol-2-yl]acetic acid;

2-(tert-butyl)-4-(4-forfinal)-5-[4-(methylsulphonyl)FeNi is]-oxazol;

4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-2-phenyloxazol;

4-(4-forfinal)-2-methyl-5-[4-(methylsulphonyl)phenyl]oxazol;

4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]-benzosulfimide.

Family specific, particularly interesting compounds of formula I consists of a group comprising the following compounds and their pharmaceutically acceptable salts:

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

3-[1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

2-methyl-5-[1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide;

4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzosulfimide;

[2-trifluoromethyl-5-(3,4-differenl)-4-oxazolyl]benzosulfimide;

4-[2-methyl-4-phenyl-5-oxazolyl]benzosulfimide;

and

4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]-benzosulfimide.

A subclass of inhibitors of cyclooxygenase-2 are selected from compounds of the formula II

where R4selected from hydrogen, alkyl, halogenoalkane, alkoxycarbonyl, cyano of cyanoalanine, carboxyl of aminocarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl, arylenecarborane, carboxymethylaminomethyl, carboxyethyl, alcoxycarboxylates, aminocarbonylmethyl, alkoxycarbonylmethyl and hydroxyalkyl;

where R5selected from hydrogen, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen and

where R6choose from aralkyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic radicals; where R4optionally substituted in can replace the position by one or more radicals selected from halogen, alkylthio, alkylsulfonyl, cyano, nitro, halogenoalkane, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, halogenoalkane, sulfamyl, heterocyclic radicals, and amino;

or their pharmaceutically acceptable salts or derivatives thereof.

The class of compounds of particular interest consists of those compounds of formula II, where R4choose from lower halogenoalkane; where R5represents hydrogen; where R6selected from phenyl, optionally substituted in can replace the position by one or more radicals selected from halogen, lower alkyl and lower alkoxy; or pharmaceutically acceptable the salts or derivatives thereof.

The collection is particularly interesting, specific compounds of formula I consists of compounds, their derivatives and pharmaceutically acceptable salts, comprising;

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(4-were)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide.

Family is more especially interesting, specific compounds within formula I consists of a group comprising the following compounds and their pharmaceutically acceptable salts or derivatives:

4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide and

4-[5-(3-fluoro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-and the] benzosulfimide.

It is assumed that the derivatives include any compounds that are structurally related to inhibitors of cyclooxygenase-2 or which have essentially equivalent biological activity. As an example, such inhibitors may include, but are not limited to, their prodrugs. Such compounds can be formed in vivo, e.g., by metabolic mechanisms.

The term "hydrogen" means one atom of hydrogen (H). This hydrogen radical may be attached, for example, the oxygen atom with the formation of hydroxyl radical, or two hydrogen radicals can be joined to the carbon atom with the formation of a methylene (-CH2-) radical. The term "alkyl" in cases where it is applied either separately or in other terms, such as "halogenated", "alkylsulfonyl", "alkoxyalkyl and hydroxyalkyl"includes linear or branched radicals having from one to twenty carbon atoms or, preferably, from one to twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to ten carbon atoms. Most preferred are lower alkyl radicals having from one to six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The term "alkenyl" includes linear or branched radicals having at least one carbon-carbon double bond and containing from two to twenty carbon atoms or, preferably, from two to twelve carbon atoms. More preferred alkenylamine radicals are "lower alkeneamine" radicals having two to six carbon atoms. Examples alkenyl radicals include ethynyl, propenyl, allyl, propenyl, butenyl and 4-methylbutanal. The term "quinil" means a linear or branched radicals having from two to twenty carbon atoms or, preferably, from two to twelve carbon atoms. More preferred alkenylamine radicals are "lower alkyline" radicals having two to ten carbon atoms. Most preferred are lower alkyline radicals having from two to six carbon atoms. Examples of such radicals include propargyl, butynyl and the like. The terms "alkenyl", "lower alkenyl" include radicals having orientation "CIS" and "TRANS" or, alternatively, the orientation of the "E" and "Z". The term "cycloalkyl" includes saturated carbocyclic radicals having three to twelve carbon atoms. More prefer the elegance cycloalkyl radicals are "lower cycloalkyl" radicals, having from three to eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkenyl" includes partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkyl" radicals having from four to eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. The term "halogen" means a halogen, such as fluorine, chlorine, bromine or iodine. The term "halogenated" includes radicals where any one or more of the carbon atoms of the alkyl substituted by halogen, as defined above. Specifically, included monohalogenated, dihalogenoalkane and POLYHALOGENATED radicals. Monologically radical as one example, can have either iodine, bromine, chlorine or fluorine atom in the radical. Dihalogen or POLYHALOGENATED radicals may have two or more identical halogen atoms, or a combination of different halogen radicals. "Lower halogenated" includes radicals having 1-6 carbon atoms. Examples halogenating radicals include vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoro is l, diperchlorate, dichloromethyl, defloratin, direcror, dichlorethyl and dichloropropyl. The term "hydroxyalkyl" includes linear or branched alkyl radicals having from one to ten carbon atoms, any of which may be substituted by one or more hydroxyl radicals. Preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkyloxy" include linear or branched oxycodonesee radicals, each of which has an alkyl portion containing from one to ten carbon atoms. More preferred alkoxyalkyl are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" includes alkyl radicals having one or more alkoxyalkyl attached to the alkyl radical to form monoatomically and dialkoxybenzene radicals. "Alkoxy" radicals may be further substituted by one or more atoms and halogen, such as fluorine, chlorine or bromine, forming halogenoacetyl. More preferred halogenoacetyl represent "lower halogenoalkane" radicals having one to six carbon atoms and one or more of the radicals halogen. Examples of such radicals include formatosi, chloromethoxy, triptoreline, triptoreline, floratone, forproperty. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be connected together by way of lateral substitution or which may be condensed. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indan and biphenyl. Aryl part can be substituted in can replace the position by one or more substituents selected independently from the group comprising alkyl, alkoxyalkyl, acylaminoalkyl, carboxyethyl, alkoxycarbonylmethyl, aminocarbonyl, alkoxy, Alcoxy, hydroxyl, amino, halogen, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and arelaxation. The term "heterocyclyl" includes saturated, partially unsaturated and unsaturated heteroaromatics cyclic radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen is. Examples of saturated heterocyclic radicals include saturated 3-6 membered heterogenities group containing 1 to 4 nitrogen atoms (for example, pyrrolidinyl, imidazolidinyl, piperidine, piperazinil and so on), saturated 3-6 membered heterogenities group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl and so on), saturated 3-6 membered heterogenities group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atoms (e.g., diazolidinyl and so on). Examples of partially unsaturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazolo. The term "heteroaryl" includes unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals, also called "heteroaryl" radicals, include unsaturated 3-6 membered heterogenities group containing 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and so on), tetrazolyl (for example, 1H-tetrazolyl 2N-tetrazolyl and so on and so forth, unsaturated condensed heterocyclic group containing from 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzamides is poured, chenail, ethanolic, indazoles, benzotriazolyl, tetrachloropyridine (for example, tetrazolo[1,5-b]pyridazinyl and so on and so forth, unsaturated 3-6 membered heterogenities group containing an oxygen atom, for example, pyranyl, furyl and the like; unsaturated 3-6 membered heterogenities group containing a sulfur atom, such as thienyl and so forth, unsaturated 3-6 membered heterogenities group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and so on and so forth; unsaturated condensed heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazole, etc.); unsaturated 3-6 membered heterogenities group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl (for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and so on and so forth, unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazole and so on), and the like. The term also includes radicals where heterocyclic radicals are fused with aryl radicals. Examples of such condensed illecebra radicals include benzofuran, benzothiophen and the like. Mentioned "heterocyclic group" may have 1 to 3 substituents such as alkyl, hydroxyl, halogen, alkoxy, oxo, amino, alkylamino. The term "alkylthio" includes radicals containing a linear or branched alkyl radical containing from one to ten carbon atoms, connected to a divalent sulfur atom. The preferred alkilirovannami are "lower alkylthio" radicals having alkyl radicals containing from one to six carbon atoms. Examples of such lower alkylthiomethyl are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term "alkylthiomethyl" includes radicals containing alkylthiomethyl, linked through a divalent sulfur atom with an alkyl radical containing from one to ten carbon atoms. More preferred alkylthiophene radicals are "lower alkylthiomethyl" radicals having alkyl radicals containing from one to six carbon atoms. Examples of such lower alkylthiomethyl radicals include methylthiomethyl. The term "alkylsulfonyl" includes radicals containing a linear or branched alkyl radical containing from one to ten carbon atoms, coupled with the divalent radical-S(=O)-. More preferred alcalali silnymi radicals are "lower alkylsulfonyl" radicals, having alkyl radicals containing from one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfonyl and exisulind. The term "sulfonyl" regardless of use whether its alone or with other terms such as alkylsulfonyl, denotes, respectively divalent radicals-SO2-. "Alkylsulfonyl" includes alkyl radicals, United with sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulphonyl, ethylsulfonyl and propylsulfonyl. "Alkylsulfonyl" radicals may be further substituted by one or more halogen atoms, for example fluorine, chlorine or bromine, forming galogenzameshchennye radicals. The terms "sulfamyl", "aminosulfonyl" and "sulfonamides" mean NH2O2S-. The term "acyl" means a radical formed by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alcoholnye and aroline radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, about Ionel, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, TRIFLUOROACETYL. The term "carbonyl", regardless of use whether its alone or with other terms, such as "alkoxycarbonyl" means -(C=O)-. The term "aroyl" includes aryl radicals with carbonyl radical, as defined above. Examples of Arola include benzoyl, naphtol and the like and aryl in the specified arole may be optionally substituted. The terms "carboxy" or "carboxyl", regardless of use whether alone or with other terms, such as "carboxylic"mean-CO2H. the Term "carboxylic" includes alkyl radicals, substituted by carboxylation. More preferred are "lower carboxyacid", which include lower alkyl radicals, as defined above, and may be additionally substituted in the alkyl moiety by halogen. Examples of such lower carboxialkilnuyu radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term "alkoxycarbonyl" means a radical containing alkoxyalkyl, as defined above connected through an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals with alkyl parts, having from 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ether radicals include substituted or unsubstituted methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxybenzoyl. The terms "alkylaryl", "arylcarbamoyl and aralkylamines" include radicals having alkyl, aryl and Aracely radicals, as defined above, connected to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbamyl, ethylcarboxyl, phenylcarbinol and benzylcarbamoyl. The term "aralkyl" includes aryl-substituted alkyl radicals, such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylether. Aryl in the specified aralkyl may be optionally substituted with halogen, alkyl, alkoxy, halogenation, halogenoalkane. Terms benzyl and phenylethyl interchangeable. The term "geterotsiklicheskikh" includes alkyl radicals, substituted saturated and partially unsaturated heterocyclyl, such as pyrrolidinyl, and alkyl radicals, substituted by heteroaryl, such as pyridylmethyl, chenailler, thienylmethyl, purolater and hemolysates. Heteroaryl in the specified heteroaryl may be optionally substituted with halogen, alkyl, alcokey, halogenation, halogenoalkane. The term "arakaki includes kalkilya radicals connected via an oxygen atom to other radicals. The term "alcoxialchil" includes alcoxides, United cher is C the oxygen atom with an alkyl radical. The term "Uralkali includes kalkilya radicals connected to the sulfur atom. The term "Uralkaliy" includes aracytidine connected via a sulfur atom to an alkyl radical. The term "aminoalkyl" includes alkyl radicals, substituted by one or more amino groups. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl and the like. The term "alkylamino" means an amino group which is substituted by one or two alkyl radicals. Preferred are "lower N-alkylamino" radicals having alkyl portion containing from 1 to 6 carbon atoms. Suitable lower alkylamino may be mono - or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term "arylamino" means an amino group which is substituted by one or two aryl radicals, such as N-phenylamino. "Arylamino" radicals may be further substituted by anilino-ring portion of the radical. The term "aralkylamines includes kalkilya radicals connected via a nitrogen atom of an amino group other radicals. The terms "N-alluminati" and "N-aryl-N-acylaminoalkyl" means an amino group which is substituted by one aryl radical or one aryl and one alkyl is s ' radical, respectively, and having the amino group connected to an alkyl radical. Examples of such radicals include N-phenyliminomethyl and N-phenyl-N-methylaminomethyl. The term "aminocarbonyl" means aminogroup formula-C(=O)NH2. The term "alkylaminocarbonyl" means aminocarbonyl group, which is substituted by one or two alkyl radicals on the nitrogen atom of the amino group. Preferred are N-alkylaminocarbonyl" and "N,N-dialkylaminoalkyl" radicals. More preferred are "lower N-alkylaminocarbonyl", "lower N,N-dialkylaminoalkyl" radicals with the lower alkyl parts, as defined above. The term "acylaminoalkyl" includes radicals having one or more alkyl radicals, with the United aminoalkyl radical. The term "aryloxyalkyl" includes radicals having aryl radical, coupled with an alkyl radical through a divalent sulfur atom.

The compounds used in the methods of this invention can be present in the form of free bases or pharmaceutically acceptable acid additive salts. The term "pharmaceutically acceptable salt" includes salts, commonly used for the formation of salts of alkali metals and for the formation of additive salts of free acids or free bases. The nature and uncritical, provided that it is pharmaceutically acceptable. Suitable pharmaceutical acceptable acid additive salts of compounds of formula I can be obtained from inorganic acids or organic acids. Examples of such inorganic acids are hydrochloric, Hydrobromic, itestosterone, nitric, carbonic, sulfuric and phosphoric acid. Suitable organic acids can be selected from classes of aliphatic, cycloaliphatic, aromatic, alifaticheskih and heterocyclic carboxylic and organic sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, Anthranilic, musilova (methanesulfonate), 4-hydroxybenzoic, phenylacetic, almond, albanova (amoeba), methansulfonate, econsultancy, benzolsulfonat, Pantothenic, 2-hydroxyethanesulfonic, toluensulfonate, sulfanilic, cyclohexanesulfonyl, stearic, Allenova, β-hydroxybutiric, salicylic, galactosemia and galacturonic acid. Suitable pharmaceutically acceptable basic additive salts of compounds of formula I include salts of metals derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be obtained by using common methods from the corresponding compounds of formula I by reaction, for example, the appropriate acid or base with the compound of the formula I.

GENERAL SYNTHETIC METHODS

Compounds of the invention are inhibitors of cyclooxygenase-2 can be synthesized in accordance with the following procedures of schemes I-X, where the substituents R1-R3such as defined above for formula I, except that it further notes.

SCHEME I

In synthetic scheme I shows the formation of compounds which are inhibitors of cyclooxygenase-2, covered by formula I, as described in U.S. patent No. 5521207 and WO 95/15316, which are included as references. In stage 1, the ketone 1 is treated with a base, preferably NaOMe or NaH, and complex ester or the equivalent of ether for the formation of the intermediate diketone 2 (in the form of enol), which is used without further purification. In stage 2 diketone 2 in anhydrous proton solvent such as absolute ethanol or acetic acid, treated with cleaners containing hydrochloride salt or the free base substituted hydras is on while boiling under reflux, receiving a mixture of pyrazoles 3 and 4. Recrystallization or chromatography gives compound 3 is usually in the form of a solid product. These pyrazoles can be obtained by methods described in U.S. patent No. 4146721, 5051518, 5134142 and 4914121, which are also included as references.

SCHEME II

In scheme II is composed of four stages in the methods of education are inhibitors of cyclooxygenase-2 pyrazoles 8, as described in U.S. patent No. 5486534 (where Rarepresents hydrogen or alkyl) ketones 5. In stage 1 to give ketone to react with a base, such as bis (gramatically)amide lithium or diisopropylamide lithium (LDA) with the formation of the anion. In stage 2 the anion reacts with azetiliruet reagent to obtain diketone 6. At stage 3 the reaction of diketone 6 with hydrazine or substituted hydrazine gives the pyrazole 7. In stage 4 of the pyrazole 7 oxidized oxidizing agent, such as Oxone®(peroxymonosulfate potassium), 3-chloroperbenzoic acid (MSRA) or hydrogen peroxide, receiving a mixture of the target 3-(alkylsulfonyl)phenylpyrazole 8 and its isomer, 5-(alkylsulfonyl)phenylpyrazole. Target pyrazole 8, usually white or pale yellow solid product is obtained in pure form either by chromatography or by recrystallization.

Alternatively, the ketone 6 can be obtained from the ketone 5 treatment the second base, such as sodium hydride, in a solvent such as dimethylformamide, and further reaction with a nitrile to form aminoketone. Processing aminoketone acid gives the diketone 6. Similar pyrazoles can be obtained by methods described in U.S. patent No. 3984431, which is included as a reference.

SCHEME III

Are inhibitors of cyclooxygenase-2 diaryl/heterogeneity (where T represents S and Rbis alkyl) can be obtained by methods described in U.S. patent No. 4427693, 4302461, 4381311, 4590205 and 4820827 and PCT documents WO 95/00501 and WO 94/15932, which are included as references.

Similar pyrrole (where T is N), furanones and furans (where T is O) can be obtained by methods described in PCT documents WO 95/00501 and WO 94/15932 and in the European patent EP 799823.

SCHEME IV

Are inhibitors of cyclooxygenase-2 diaryl/heteroepitaxial can be obtained by methods described in U.S. patent No. 3743656, 3644499 and 3647858 and PCT documents WO 95/00501 and WO 94/27980, which are included as references. Equivalent connection oxazole can be obtained by methods described in WO 96/19463 and WO 96/19462.

SCHEME V

Are inhibitors of cyclooxygenase-2 diaryl/heteroepitaxial you can get the way the mi, described in U.S. patent No. 5633272, PCT documents WO 92/05162 and WO 92/19604 and European publication EP 26928, which are included as references. Sulfonamides 24 can be obtained from hydrated isoxazol 23 two-stage methodology. First hydrated isoxazol 23 is treated at about 0°With two or three equivalents of chlorosulfonic acid with the formation of the corresponding sulphonylchloride. In the second stage thus formed sulphonylchloride treated with concentrated ammonia, getting derived sulfonamida 24.

SCHEME VI

In scheme VI illustrates a three-stage receive are inhibitors of cyclooxygenase-2 imidazoles 29 of the present invention. In stage 1, the reaction of the substituted NITRILES (R1CN) 25 primary phenylamine 26 in the presence of alkyl aluminum reagents such as trimethylaluminum, triethylaluminum, dimethylammoniumchloride, diethylaluminium, in the presence of inert solvents, such as toluene, benzene and xylene, gives amidine 27. In stage 2 the reaction of amidine 27 with 2 halogenatom (where X is Br or Cl) in the presence of bases, such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or employed tertiary amines, such as N,N'-diisopropylethylamine gives 4,5-dihydroimidazole 28 (where Rb is alkyl). Some of the suitable solvents for this reaction are isopropanol, acetone and dimethylformamide. The reaction can be conducted at temperatures from about 20°to 90°C. stage 3 4,5-dihydroimidazole 28 can be degidratiruth in the presence of an acid catalyst, such as 4-toluensulfonate acid or mineral acid, with the formation of 1,2-disubstituted imidazoles 29 of the present invention. Suitable solvents for this stage of dehydration are, for example, toluene, xylene and benzene. Triperoxonane acid can be used as a solvent and catalyst for this stage of dehydration.

In some cases (for example, where R3represents methyl or phenyl), the intermediate product 28 can be difficult allocated by the product. The reaction conditions described above, flows, giving directly the target imidazoles.

Similarly you can get the imidazoles having sulfonylamino part, attached in position 2, and R1attached at the nitrogen atom in position 1. Diaryl/heteroaromatic can be obtained by methods described in U.S. patent No. 4822805, in the application for U.S. patent No. 08/282395 and document PCT WO 93/14082, which are included as references.

SCHEME VII

Are inhibitors of cycloate is easy-2 connections imidazole 36 of the present invention can be synthesized in accordance with the sequence shown in scheme VII. Aldehyde 30 can be turned into a protected cyanohydrin 31 by reaction with trialkylsilanes, such as trimethylsilylacetamide (TMSCN)in the presence of a catalyst, such as iodide of zinc (ZnI2) or potassium cyanide (KCN). The reaction cyanohydrin 31 with a strong base followed by treatment with benzaldehyde 32 (where R2is alkyl) and the use of treatments such as acid and base, in this order when selected gives benzoin 33. Examples of strong bases suitable for this reaction are diisopropylamide lithium (LDA) and hexamethyldisilazane lithium. Benzoin 33 can be converted into benzyl 34 by reaction with a suitable oxidizing agent such as bismuth oxide or manganese dioxide, or oxidation by Turn using dimethyl sulfoxide (DMSO) and triperoxonane anhydride. Benzyl 34 can be obtained directly by reaction of the anion of cyanohydrin 31 with galogenangidridy substituted benzoic acid. Any of compounds 33 and 34 can be used as intermediates for conversion to imidazoles 35 (where R2is alkyl) in accordance with chemical techniques known to experts in this field and described .R.Grimmet, "Advances in Imidasole Chemistry" in Advances in Heterocyclic Chemistry, 12, 104 (1970). Turning 34 in the imidazoles 35 can be carried out by reaction with ammonium acetate and approach Asim aldehyde (R 3CHO) in acetic acid. Benzoin 36 can be turned into a imidazoles 38 by reaction with formamide. In addition, benzoin 36 can be turned into a imidazoles first by acylation of the appropriate acyl group (R3CO-) and then by treatment with ammonium hydroxide. Specialists in this area must recognize that the oxidation of sulfide (where R2is methyl) in sulfon can be performed at any point along the path of synthesis, starting with the connection 35 and includes oxidation of imidazoles 38 using, for example, such compounds as hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid (MSRA) and peroxymonosulfate potassium (OXONE®).

Diaryl/heteroaromatic can be obtained by methods described in U.S. patents№№3707475, 4686231, 4503065, 4472422, 4372964, 4576958, 3901908, the application for U.S. patent No. 08/281903, European publication EP 372445 and document PCT About 95/00501, which are included as references.

SCHEME VIII

Are inhibitors of cyclooxygenase-2 diaryl/heteroalicyclic can be obtained by methods described in U.S. patent No. 5344991 and document PCT WO 95/00501, which are included as references.

SCHEME IX

Similarly, in the synthetic scheme IX illustrates the methods of production are inhibitors cyclooxygenase 1,2-Derevenskov 44 of the intermediate products, 2-bromobiphenyl 43 (obtained similarly to the receipt described in synthetic scheme VIII) and the appropriate substituted phenylboronic acids. Using combination techniques, similar to the method developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)], intermediate products 43 is subjected to reaction with baronowie acids in a mixture of toluene/ethanol by boiling under reflux in the presence of Pd catalyst°for example tetrakis(triphenylphosphine)-palladium(0), and 2 M sodium carbonate, receiving anti-inflammatory drugs which 1,2-diaryentry 44 of the present invention. Such compounds terphenyl can be obtained by methods described in the patent document PCT WO 96/16934, which is included as a reference.

SCHEME X

Diaryl/heteroaromatics, are inhibitors of cyclooxygenase-2, can be obtained by methods described in U.S. patent No. 4051250, 4632930, the application for the European patent EP 592664 and PCT documents WO 96/03392 and WO 95/00501, which are included as references. Isothiazole can be obtained, as described in document PCT WO 5/00501.

Diaryl/heteroarylboronic, are inhibitors of cyclooxygenase-2, can be obtained by methods described in U.S. patent No. 5169857, 4011328, 4533666 and WO 96/24584 and WO 96/24585, which are included as references.

Biological assessment

Antiangiogenic analysis of the Sabbath.

To determine the effect of inhibitors SOH-2 on angiogenesis in vivo, we have tested the selective connection in the analysis of corneal Microterminal mice and rats. The formation of new blood vessels in a model of corneal Microterminal performed with materials, reagents and procedures essentially as described Muthukkauppah., J. Natl. Cancer Inst., 69, 699-708 (1982). In this analysis the sediment after centrifugation, containing basic fibroblast growth factor (FGF), implanted in the corneal stroma of the mouse and newly formed blood vessels was measured using a slit lamp. In this model, we have expressed SOH-2 in endothelial cells of newly developed blood vessels. Inhibitor SOH-2, 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide, inhibited FGF-induced development of blood vessels in mouse (70-90%) at a dose of 6 mg/kg/day.

In the analysis Microterminal rats 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide this only once, inhibited FGF-induced development of blood vessels (˜90%).

We have also determined the effect of the inhibitor SOH-2, 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide, in the mouse cornea using a different angiogenic stimulus, vascular endothelial growth factor (VEGF). In this model, the development of angiogenesis was ingibirovalo (˜50%), when Obedinenie was given at a dose of 6 MGK.

Model metastases

Analysis of carcinoma of the lung of mice Lewis performed as described I. Andersen et al [Can. Res., 56, 715 (1996)]. Inhibitor SOH-2 is effective in the inhibition of metastasis in this model.

This invention provides a pharmaceutical composition for the treatment of angiogenic disorders, comprising a therapeutically effective amount of the compounds of formula I in Association with at least one pharmaceutically acceptable carrier, adjuvant or diluent (collectively referred to here as the materials-"carrier") and, if desired, other active ingredients. The active compounds of this invention can be entered by any suitable, well-known experts in this field, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the intended treatment. Active compounds and compositions can be entered, for example, oral, vnutrisosudisto, intraperitoneally, intranasally, vnutribronhialno, subcutaneously, intramuscularly, or locally (including aerosol). If the localized angiogenesis, preferably local introduction, and not the system introduction. To increase the biological availability, you can use ready preparative form in the liquid filler.

Introduction according to the present invention can be designed for the purpose or prevention, is for treatment. Methods and compositions used herein can be used separately or in conjunction with additional therapies known to specialists in this area, for the prevention or treatment of the development of blood vessels. Alternatively, the methods and compositions described herein can be used as an additional therapeutic measures. As an example, the inhibitor of cyclooxygenase-2 can be entered separately or in combination with other anticancer drugs or any abscopal other growth media or other drugs or nutrients.

There are a large number of anticancer agents that are available for commercial use, for clinical examination and pre-clinical development, which can be selected to ensure the development of blood vessels combinational drug therapy. Such antineoplastic agents match several main categories, namely tools antibiotic type, alkylating agents, antimetabolites means, hormonal means, immunological tools, tools such as interferon and the category of mixed agents. Alternatively, you can use other antitumor agents, such as inhibitors metallating proteases (MMP), such as inhibitors of MMP-13, including Batista, Marie is astatine, Agouron Pharmaceuticals AG-3340 and Roche, RO-32-3555, or inhibitors of avβ3.

The first family of anticancer agents that can be used in combination with a selective inhibitor of cyclooxygenase-2 consists of anticancer agents type of antimetabolite. Suitable antimetabolite antineoplastic agents can be selected from the group consisting of 5FU-fibrinogen, centifolias acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentylamine, literalinteger, conjugates of cytarabine, Lilly DATHF, Merrel Dow DDFC, deazaguanine, dideoxycytidine, dideoxyinosine, deocsa, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck and Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furandi)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrazine, Lilly LY-188011, Lilly LY-264618, metabasepath, methotrexate, Wellcome MZPES, nonspermicidal, NSC NCI-127716, NSC NCI-264880, NSC NCI-39661, NSC NCI-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, Tg, tesofensine, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, inhibitors tyrosylprotein, Taiho UFT and writiting.

The second family of anticancer agents that can be used in combination with a selective inhibitor of cyclooxygenase-2 consists of alkylating anticancer agents type. Fit protivoopujoleve the s means alkylating type can be selected from the group consisting of Shionogi 254-S, analogues of aldophosphamide, altretamine, anxiron, Boehringer Mannheim BBR-2207, astroballe, budotitane, Wakunaga CA-102, carboplatin, carmustine, chinoin-139, chinoin-153, hlorambuzila, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, ciputat, Degussa P-19-384, Sumimoto DACHP(Myr)2, diphenylpyraline, diplotene cytotoxic derivatives distamycin Erba, Chugai DWA-2114R, ITI E09, elastin, Erbamont FCE-24517, estramustine sodium, fotemustine, Unimed G-6-M, chinoin GYKI-17230, gasulla, ifosfamide, iproplatin lomustina, mafosfamide, mitolactol, Nippon Kayaku NK-121, NSC NCI-264395, NCI 342215, oxaliplatin, decision Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiramycin, Tanabe Seiyaku TA-077, tauromachine, temosolomida, taraxerone, tetraploidy and timelabel.

The third family of anticancer agents that can be used in combination with a selective inhibitor of cyclooxygenase-2 consists of anticancer agents type of antibiotics. Suitable antineoplastic agents type of antibiotic can be selected from the group consisting of Taiho-4181-A, aclarubicin, actinomycin D, actinoplanes, Abbamonte ADR-456, derived aeroplysinin, Ajinomoto AN-201-II, Ajinomoto AN-3, anisomycin Nippon Soda, anthracycline, sinomenine, boukabara, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calicheamicin, chromogenicity, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, dirithromycin, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, alcomicin-a, epirubicin, erbstein, zorubicin, espiramicina-A1, espiramicina-Alb, Abbamonte FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, Helicobacter, gregarina, grancanaria, herbimycin, idarubitsina, illumines, kasugamycin, nezariadena, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mi-oxanthrone, SmithKline M-TAG, Newington, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxylipin, oxaprotiline, peplomycin, Palatine, pirarubicin, portraiting, peringamala A, Tobishi RA-I, rapamycin, rhizoxin, adorabella, sirenomelia, sevenmile, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sarangiran-a, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin, Taiho 4181-2, talisayan, Takeda TAN-868A, Carpentaria, Traina, Tricreatine A decision Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

The fourth family of anticancer agents that can be used in combination with a selective inhibitor of cyclooxygenase-2 consists of anticancer agents mixed family selected from the group consisting of al is of carotene, alpha deformalisation, azitretina, Biotec AD-5, kyorin ANS-52, alstonia, amonafide, ampline, amsacrine, angiostatin, Antinomian, antineoplaston a10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, epidemological, asparaginase, avarol, Bukharin, brazilin, enflurane, benzodepa, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, brontophobia, Wellcome BW-502, Wellcome BW-773, caracemide, Carmelita hydrochloride, Ajinomoto CDAF, chlorosulfonation, Chemes CHX-2053, Chemes CHX-100, Warner-Lambert CI - 921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, centenera, clairedelune, connection ICN 1259, connection ICN 4711, kontrakan, Yakult Honsha CPT-11, krishnalila, curaderm, cytochalasin, tsitarabina, Cicolina, Merz D-609, DABIS maleate, dacarbazine, dateoption, didemnin-In, simple ester dihematoporphyrin, dihydroindolone, dinamina, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, ethipramine, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, phenetidine, Fujisawa FR-57704, gallium nitrate, genkwanin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine. Green Cross HO-221, homoharringtonine, hydroxyacetone, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM PLACES Corp KI-8110, American Cyanamid L-623, laborelena, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, maritina, Merrel Dow MDL-27048, Medco MER-340, barbarona, derivatives of merocyanine, methylenedianiline, Molekular Genetics MGI-136, inactivity, mitonafide, methadone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinol)amino acids, Nisshin Flour Milling N-021 N-acylated dehydroalanine, nafazatrom, Taisho NCU-190, derived nocodazole, Normosang, NSC NCI-145813, NSC NCI -361456, NSC NCI-604782, NSC NCI-95580, octreotide, Ono ONO-112, opisaniya, Akzo Org-10172, pancratistatin, patellifera, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre D-1001, peptide ICRT D, piroxantrone, polyhemoglobin, polyprenol acid, porphyrin of Efamol, broumana, procarbazine, proglumide, protease Environ nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-R, realitiy, retinoic acid, Rhone-Poulenc Rp-49532, Rhone-Poulenc RP-56976, SmithKline SKK&F 104864, Sumitomo SM-108, Kuraray SNANCS, SeaPharm SP-10094, spatola, derived spirocyclopropane, spirogermanium, Unimed, SS Pharmaceutical SS-554, lipoldino, stipoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, Taxol, Teijin TEI-0303, teniposide, calibratin, Eastman Kodak TJB-29, tocotrienols, Topolino, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, Ukraine, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, fenestrated, vinorelbine, ventricosa, ventricina, withanolides and Yama-nouchi YM-534.

Examples of radioprotective agents that can be used in combination chemotherapy of the present invention, are AD-5, ADHD is h, analogues of amifostine, detox, dimesna, 1-102, MM-159, N-acylated dehydroalanine, TGF-Genentech, ciprocinol, amifostine, WR-151327, FUT-187, percutaneous Ketoprofen, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.

Methods of obtaining anticancer agents described above can be found in the literature. Methods for producing doxorubicin, for example, described in U.S. patent No. 3590028 and N-4012448. Ways of getting inhibitors Metallostroy protease are described in European patent 780386, WO 97/20824, WO 96/15096. Ways of getting SOD mimetics are described in European patent 524101. Ways of getting inhibitors αvβ3described in WO 97/08174.

In addition, for maximum safety and efficacy of a selective inhibitor SOH-2 can be introduced in combination with other anti-inflammatory drugs, including NSAID's, selective inhibitors of MOR-1 and inhibitors of the pathway leukotrienes, including inhibitors of 5-lipoxygenase. Examples NSAID's include indomethacin, naproxen, ibuprofen, salicylic acid derivatives such as aspirin, diclofenac, Ketorolac, piroxicam, meloxicam, mefenamico acid, sulindac, tolmetin sodium, zomepirac, fenoprofen, phenylbutazone, oxyphenbutazone, nimesulid, zaltoprofen and etodolac.

The phrase "ancillary activity" (or "combination therapy") in the definition of IP is the use of tools inhibition of cyclooxygenase-2 and one or more other pharmaceutical agents designed to allow the introduction of each tool in a consistent way according to the scheme, which will provide beneficial effects of the combination of drugs, and is intended to enable conscientious introduction of these tools essentially simultaneous manner, such as one prepared preparative shape having installed the ratio of these active agents or in multiple, separate ready preparative forms for each tool.

For oral administration the pharmaceutical composition may be in the form of, for example, tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of dosage units containing a certain amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules, or suspensions with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, Arabian gum, corn starch or gelatin; (C dezinfeciruyuhimi agents such as corn starch, potato starch or sodium carboxymethyl cellulose and with lubricating agents such as talc or magnesium stearate. The active ingredient can also enter by injection in the form of a composition, where as a suitable carrier can be used, for example, the physical is the logical solution, dextrose or water.

For intravenous, intramuscular, subcutaneous or intraperitoneal administration of the compound can be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient. These are ready preparative forms can be obtained by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to obtain an aqueous solution and make the solution sterile. Ready preparative forms may be present in the containers for one or more doses, such as sealed ampoules or vials.

If angiogenesis is localized in the gastrointestinal tract, the connection can be made with resistant to the action of acids and resistant to the action of bases coatings known in this field, which begin to dissolve in the small intestine at high pH value. Preferred are ready preparative form, which increases local pharmacological effect and reduces systemic absorption.

The finished formulation suitable for parenteral administration typically comprise a sterile aqueous preparation of active compound, which, preferably, do isotone the poor. Injectable preparations may be produced by suspendirovanie or emulsification of compounds in non-aqueous solvent, such as vegetable oil, synthetic aliphatic acids glycerides, esters of higher aliphatic acids or propylene glycol.

Ready preparative forms for local use include known gels, creams, oils and the like. For aerosol delivery connection can be made with known aerosol fillers, such as saline, and administered using commercially available dispensers. Ready preparative form in the source of fatty acids can be used to improve biocompatibility. Aerosol delivery is a preferred method of delivery for use for the prevention of epithelial lung angiogenesis.

For rectal injection of the active ingredient can be manufactured as suppositories using frameworks that are solid at room temperature and melt or dissolve at body temperature. Commonly used bases include cocoa butter, glitserinovoye gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights and fatty esters (esters of fatty acids) and polyethyleneimine.

Dosage form and quantity can be easily installed n is the known drug regimens or prevention. The amount of therapeutically active compound that is administered, and the regimen of medicines for the treatment of painful conditions compounds and/or compositions of this treatment depends on various factors, including age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration and specific applicable connections, angiogenesis, and pharmacokinetic properties of the person being treated, and, thus, can vary within wide limits. The dose should usually be lower when the compound is administered locally rather than systemically, and for prevention, not treatment. Such therapy can be performed as often as necessary, and during the period of time that the attending physician deems it necessary. The person skilled in the art should recognize that the regimen of a drug or therapeutically effective amount of an inhibitor that is administered, it may be necessary to optimize for each person. The pharmaceutical compositions may contain the active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably about 1 to 200 mg May be appropriate daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg of body weight. The daily dose can be administered is from one to four doses per day.

All the documents mentioned here are included as references.

Although this invention has been described with reference to a specific variant implementation, the details of these options should not be construed as limitations.

1. The use of a therapeutically effective amount of angiogenic inhibitors of cyclooxygenase-2, selected from the group consisting of 4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazole-1-yl] benzosulfimide, 4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide, 4-[5-methyl-3-phenylisoxazol-4-yl] benzosulfimide, or their pharmaceutically acceptable salts for obtaining a medicinal product for treatment or prevention related to angiogenesis disorders, selected from a metastasis, eye of the formation of new blood vessels, retinal formation of new blood vessels, diabetic retinopathy, infant hemangiomas and disorders of the reproductive system in women, the subject in need of such treatment or prevention.

2. The use according to claim 1, where related to angiogenesis infringement is endometriosis.

3. The use according to claim 1, where related to angiogenesis violation of the eye is the formation of new blood vessels.

4. The use according to claim 1, where the antiangiogenic compound is 4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide or his farm is citiesi acceptable salt.

5. The use according to claim 1, where the antiangiogenic compound is 4-[5-methyl-3-phenyl-4-isoxazolyl] benzosulfimide or its pharmaceutically acceptable salt.

6. The use according to claim 1, where the antiangiogenic compound is 4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazole-1-yl] benzosulfimide or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: oncology.

SUBSTANCE: invention is directed, in particular, to treatment of patients with Ewing's sarcoma and osteogenic sarcoma at different stages of malignant process. Method comprises chemotherapy and beam therapy. Samples of venous blood are taken from children in age of 5 to 12 years in amounts not larger than 5% of the total volume of circulating blood per 1 introduced dose of chemical preparation and, from adolescents and young persons, in amount of 200 ml. Then 4 courses of polychemotherapy are fulfilled with autoblood according to standard treatment schemes for given diseases, taking into account stages of disease, in recommended doses. Between 2nd and 3rd chemotherapy courses, radiotherapy is fulfilled on metastatic focuses in lungs. After 4 courses of induction autohemo-chemotherapy, local therapy on the primary focus (radiotherapy and/or surgical treatment) is fulfilled and also radiotherapy on metastatic focuses in other bones, after which follows consolidation involving chemical preparation of the second line.

EFFECT: improved remote results of treatment , suppressed metastatic focuses, reduced tumor dimensions, and weakened toxic manifestations of therapy.

2 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention proposes applying bis-phosphonic acids (bis-phosphonates) for the embolic treatment of angiogenesis and corresponding methods for prophylaxis or treatment of angiogenesis by embolization. Invention provides suppression of growth, invasion or metastasis of tumors, treatment of angiogenesis in myocardium ischemia, rheumatic arthritis, osteoarthritis by embolization of newly formed vessels in intra-arterial route of administration of bis-phosphonate (for example, pamidronic acid or zoledronate).

EFFECT: valuable medicinal properties of medicine agents.

10 cl, 3 dwg, 7 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of patients with disseminated forms of prostate cancer. Method involves administration of navelbine in the dose 30 mg/m2 on the background of anti-androgenic therapy. The course time in navelbine administration is 4 weeks and from 7-th day after the last injection of navelbine method involves administration of strontium-89 chloride in the dose 4 mKi (150 MBk), once time per 3 months, two injections. For patients with the amount of osseous metastases above 6 the dose of strontium-89 chloride is 8 mKi per one administration (300 MBk). In further courses of systemic therapy are repeated in 3 months, not early. Method shows the optimal regimen set in administration of preparations and provides the maximal effect of navelbine on osseous metastases followed by damaging effect of strontium-89 chloride on blood vessels of tumor and its cells and the absence of the potentiation toxicity on the hemopoiesis system.

EFFECT: improved and enhanced effectiveness of treatment.

3 dwg, 2 ex

FIELD: medical engineering.

SUBSTANCE: method involves exposing an intraocular neoplasm after vitrectomy and retinotomy, smoothening retina with perfluororganic compound later substituted with silicon oil. After having removed the neoplasm, intravenous 10% Perfluorane emulsion transfusion is carried out at a rate of 60 drops per 1 min in the amount of 80-100 ml. Next to it, photosensitizer is intravenously drop-by-drop introduced into cubital vein of the same arm. Laser irradiation of blood is carried out with power of 20-50 mW through laser light guide set in advance into cubital vein of the other arm in 5-15 min after starting introducing Perfluorane. When applying 0.1-1% water solution of Khlorine as photosensitizer at a dose of 0.2-0.5 mg/kg, irradiation is carried out at wavelength of 630-633 nm during 10-45 min. The treatment is administered twice with 5 days long pause.

EFFECT: enhanced effectiveness of treatment; reduced risk of tumor cells dissemination and metastases formation.

3 cl

FIELD: medicine.

SUBSTANCE: after keeping during pharmaceutically acceptable period oxaliplatinum is placed in transparent, colorless and residue-free solution at concentration of, at least, 7 mg/ml, and a solvent contains sufficient quantity of, at least, one hydroxylated derivative chosen among of 1.2-propandiol, glycerol, maltite, saccharose and inositol. The innovation describes the way to obtain such a preparation. The preparation is stable during pharmaceutically acceptable period of time, that is it remains transparent, colorless and free of any residue within the range of 2-30 C that could be available during its transportation, storage and/or any handling.

EFFECT: higher efficiency of application.

14 cl, 6 ex, 4 tbl

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: method involves applying surgical intervention and antitumor therapy. After having removed a part or the whole lung, mediastinum is opened by cutting out horseshoe-shaped or rectangular flap of mediastinal pleura and carrying out lymphodissection. Then, hemostatic sponge is placed in mediastinum. The sponge is impregnated with antitumor chemotherapeutical preparations in intraoperative mode. Pleura is sutured above the sponge. Another hemostatic sponge impregnated with cytostatic preparations in intraoperative mode is attached to visceral pleura of interlobular sulcus.

EFFECT: prolonged chemotherapeutical preparations delivery to malignant neoplasm foci or subclinical metastases.

The invention relates to medicine, namely to chemoradiation treatment of bone metastases

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with conservative treatment of corneal, retinal and optic nerve's diseases. It includes depositing in ocular tissues of medicinal preparation upon cellular mass. For this purpose it is necessary to apply erythrocytic mass isolated out of a patient to saturate it with medicinal preparation at the ratio of 1:1 due to incubating this mixture at 22-25° C for 20 min. The mixture should be injected into ocular tissues at the nearest distance against pathological focus once/5 d. In case of corneal lesions erythrocytic mass-based preparation should be injected under bulbar conjunctiva perilimbically at the quantity of 0.2-0.3 ml, and at retinal lesions and those of patient's optic nerve - parabulbarly and retrobulbarly at the quantity of 1.0 ml, moreover, medicinal preparation should be chosen out of the following group of solutions: 0.3% gentamicin, or 0.25% derinate, or 1% emoxipine, or 4% taufone. The method is low invasive, of lower immunoreactivity and enables to shorten the terms for inactivation of erythrocytes saturated with medicinal preparation by depositing it at maximal distance against pathological focus.

EFFECT: higher efficiency.

2 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: medicine, ophthalmology, pediatrics.

SUBSTANCE: method involves irrigation therapy (IT) by retrobulbar catheterization. Before carrying out IT the preparation "Ginkgo biloba" in capsules and age dosage and nasal drops "Semaks" by 1-2 drops for 1 month is prescribed to patient. Then in IT is carried out for 10 days in hospital by administration of cerebrolysin, riboflavin, agapurin, taufon and emoxipine in the dose 0.4 ml of each of them. Preparations are administrated successively, by fractional doses with interval for 2 h in combination with laser-pleoptic treatment at wavelength 0.63 mcm using device "SPEKL" for 10 min, by one procedure per a day for 10 days. After treatment in hospital glutamine and lecithin is prescribed by ambulatory treatment in age doses for 1 month. Method provides the prolonged remission of disease and reduced hospital period due to the complex effect of indicated curative factors on metabolism normalization in nervous cells, their resistance to stress injures, improvement of regenerative and microcirculating processes in eye tissues, frequency-contrast characterization of visual analyzer.

EFFECT: improved treatment method.

1 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves intravenous administration of metypred in every other day being in the 1-st and 3-d days the dose is by 500.0 mg, in 5-th and 7-th day - by 250.0 mg, and in 9-th and 10-th day - by 125 mg. In onset of metypred administration dexamethasone in the dose 1.0 ml is administrated by retrobulbar route every day for 10 days. Also, method involves pterygopalatine blockade including dexamethasone, ketorol, emoxipine, lidocaine, dalargin in doses 1.0; 1.0; 1.0; 2.0 ml and 0.001 g every day for 5 days and then 3 blockades in every other day, one blockade per a day. Method expands assortment of therapeutic approaches in treatment of acute optical neuritis in patients with cerebrospinal sclerosis.

EFFECT: improved and enhanced treatment method.

1 tbl, 1 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: one should introduce Botulotoxin A-based Disport preparation into extra-ocular ipsilateral muscle being an antagonist of a paralyzed extra-ocular muscle at the dosage of 10-120 U to be injected into middle part of muscular bursa by leaving about 5 mm , not less against the site of its fixation to sclera. Moreover, additionally, one should inject the preparation suggested either into one or several muscles being contralateral synergists of paralyzed muscles, moreover, one should apply by 10% preparation less into those muscles which are ipsilateral antagonists in comparison with contralateral synergistic ones. The method provides stimulation of afferent nervous impulsation of paralyzed muscle that prevents its hypotrophy.

EFFECT: higher efficiency of therapy.

3 dwg, 3 ex, 12 tbl

FIELD: medicine, ophthalmology, pharmacology, pharmacy.

SUBSTANCE: invention proposes a new agent for applying in therapy of inflammatory diseases of eye anterior site, namely, the silver-containing preparation "Argogel" "Argogel" represents argovite dispersion in polyethylene oxide gel. The preparation shows an antibacterial and virucidal effect and gel base shows additional keratoplastic effect. Invention can be used in therapy of conjunctivitis and retina suppurative ulcers.

EFFECT: valuable medicinal properties of agent.

4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: composition contains cellulose derivatives, glycosaminoglycanes, oligosaccharides, novocain or mercain (both as local anestetics), non-steroidal anti-inflammatory agent, adrenalin, glycerol, and purified water at specified proportions of components.

EFFECT: achieved protection of cornea against mechanical damage due to prevented access of air bubbles and blood under lens, best visualization of fundus of eye, and reduced operation time.

2 ex

FIELD: medical engineering.

SUBSTANCE: viscoelastic has 1.5-2.5% of methylcellulose with 0.02-0.05% thymolol maleate solution and 0.0005-0.001% benzalconium chloride solution as stabilizer being added.

EFFECT: prolonged action; avoided additional drug therapy application.

FIELD: medicine, ophthalmology.

SUBSTANCE: the suggested composition includes an antibacterial chemotherapeutic preparation, plant and/or animal phospholipids, sodium chloride, monosodium phosphate, disubstituted sodium phosphate and purified water at certain quantitative ratio of components, weight%. The innovation provides prolonged antiphlogistic action onto inflammatory focus.

EFFECT: higher efficiency of application.

5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): that are useful as antagonists of prostaglandin IP (I2 or PGI2). Invention proposes compound of the formula (I) wherein each R1, R2 and R3 means independently in each case aryl or heteroaryl; R4 means -COOH or tetrazolyl; A, B, m, p, q, n and r are determined in the invention description. Also, invention relates to separated isomers, racemic or nonracemic mixtures of isomers and to their pharmaceutically acceptable salts or solvates also. Also, invention relates to pharmaceutical compositions comprising indicated compounds, to a method for their preparing and using as therapeutic agents. Invention provides the development of pharmaceutical composition possessing property of antagonists of IP wherein antagonists of these receptors can prevent states associated with excessive bleeding, for example, (but not only) hemophilia and hemorrhage and relieve septic shock-associated hypotension and diminish formation of edemas.

EFFECT: valuable medicinal properties of compounds.

28 cl, 15 sch, 29 ex

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