UA70294C2 - Use of cyclooxygenase-2 inhibitors as anti-angiogeuse of cyclooxygenase-2 inhibitors as anti-angiogenic agents nic agents - Google Patents

Abstract

This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating angiogenic disorders.

Description

Description of the invention

This invention relates to the prevention and treatment of angiogenesis. More specifically, this invention relates to the use of inhibitors of cyclooxygenase-2 or its derivatives for the prevention and treatment of disorders associated with the development of blood vessels.

Prostaglandins play a major role in inflammatory processes, and inhibiting the production of prostaglandins, especially the production of ROS, RON, and ROE, was the general goal of the discovery of anti-inflammatory drugs. However, conventional non-steroidal anti-inflammatory drugs (NSAIDs), active 70 in alleviating prostaglandin-induced pain and reducing inflammation-related swelling, also actively affect other processes that are regulated by prostaglandin and are not related to inflammation process. Thus, the use of large doses of most conventional NSAIDs can lead to severe side effects, including life-threatening ulcers, limiting their therapeutic potential.

An alternative to NSAIDs is the use of corticosteroids, which also cause serious adverse effects, 79 especially when long-term therapy is anticipated.

NSAIDs have been found to prevent prostaglandin production by inhibiting enzymes in the human arachidonic acid/prostaglandin metabolic pathway, including the enzyme cyclooxygenase (COX).

The recent discovery of an adaptive inflammation-related enzyme (called "cyclooxygenase-2" or "prostaglandin (Z/H synthase II")) provides an important anti-inflammatory target that more effectively reduces inflammation and causes fewer and less severe side effects .

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

Although glucocorticoids were originally developed for their anti-inflammatory properties, it is now recognized that they (3) have a wide variety of therapeutic uses. For example, many steroids with anti-inflammatory effects inhibit angiogenesis (US Patent No. 5,646,136).

Compounds that selectively suppress cyclooxygenase-2 are described in US Pat.

MO96/03387, U/O96/03392, UUO96/25405, M/O96/24584, M/O96/03385, UMO96/16934, UM/O95/15316, U/O94/15932, Ge")

MO94/27980, UMO95/00501, MU/O94/13635, UU/O94/20480 and M/O94/26731. (Pyrazol-1-yl benzenesulfonamides have been described as inhibitors of cyclooxygenase-2 and during preclinical and clinical trials have shown their promise in the treatment of inflammation, arthritis and in the suppression of pain Ga") with minimal side effects. their use to prevent colon cancer was described in US Patent 32, Mo5,466,823. However, their use for the treatment or prevention of diseases associated with angiogenesis has not been previously described. There are several publications describing suppression of angiogenesis. IN

MO patent publication Mo96/19469 describes that COX-2 inhibitors may be useful for the prevention and/or treatment of tumor angiogenesis and diabetic retinopathy. "

This invention is directed to the use of cyclooxygenase-2 inhibitors for the treatment and prevention of the growth of C 70 tumors and metastases caused by the angiogenesis process. In addition, the treatment and prevention of non-neoplastic disorders associated with angiogenesis, such as retinopathy and endometritis, are also covered.

This invention provides a method of treating or preventing disorders associated with angiogenesis in a human in need of such treatment or prevention, the method includes patients with a therapeutically effective amount of a cyclooxygenase-2 inhibitor, a derivative or a pharmaceutically acceptable salt thereof.

The above method may be useful for the treatment and prevention of disorders associated with, but not limited to, angiogenesis in humans. According to this invention, compounds of Formula av! are prescribed to a patient who needs suppression of the angiogenesis process. This method can be useful for the treatment of neoplasia including metastases; ophthalmic diseases such as corneal transplant rejection, new vessel formation in the eye, retinal new vessel formation, including new vessel formation (Te) 20 caused by injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcer diseases, such as stomach ulcers; pathological but non-malignant

T» diseases such as hemangiomas, including infantile hemangiomas, nasopharyngeal angiofibromas and avascular bone necrosis, as well as disorders of the female reproductive system such as endometritis.

The term "treatment" includes partial or total suppression of angiogenesis, including tumor growth, spread and metastasis, as well as partial or complete destruction of tumor cells.

GF) The term "prevention" includes either the complete prevention of the onset of angiogenesis evident in clinical conditions, or the prevention of the onset of the stage of angiogenesis evident in preclinical conditions in individuals at risk of such a disease. It was also meant that the concept covered by this definition is the prevention of metastases of malignant cells or the stopping of malignant cells or the reduction of their number. This term includes 60 prevention of individuals for whom there is a risk of developing angiogenesis.

The expression "therapeutically effective" is intended to evaluate the amount of each drug that will achieve the goal, improve the patient's condition, and the frequency of administration during treatment with each drug separately, while not showing the harmful side effects that are usually associated with alternative methods of treatment .

For the treatment process, the term "patient" means any patient - human or animal - having any of the 62 known disorders associated with angiogenesis. For methods of prevention, the patient is any human or animal, preferably a human, who is at risk of developing a disorder related to angiogenesis, such as metastasis.

For the patient, there may be a risk caused by the effect of oncogenic substances on him, the presence of a genetic predisposition to angiogenesis, and the like. In addition to being useful in the treatment of humans, these compounds are useful in the treatment of animals, mammals, including domestic and domestic animals such as, but not limited to, horses, dogs, cats, cows, sheep and pigs. It is best if the word "patient" means a person.

Inhibitors of the cyclooxygenase pathway in the metabolism of arachidonic acid, which are used in the prevention and treatment of angiogenesis, can suppress the activity of the enzyme by a number of mechanisms. For example, inhibitors used in the methods described herein can block the activity of an enzyme by acting directly on the enzyme as a substrate. The use of selective cyclooxygenase-2 inhibitors has great advantages in that it can minimize the gastric side effects that can occur with the use of nonselective NSAIDs, especially where prolonged prophylactic treatment is expected.

The term "cyclooxygenase-2 inhibitor" means a compound capable of inhibiting cyclooxygenase-2 without significantly inhibiting cyclooxygenase-1. Most preferably, it includes compounds that have a cyclooxygenase-2 IC of less than about 0.2 µM and also have a selectivity ratio of cyclooxygenase-2 inhibition relative to cyclooxygenase-1 inhibition of at least 50, and more preferably at least 100. Even better. , so that the compounds have a cyclooxygenase-1 IC of greater than about 1 µM, more preferably greater than 10 µM.

The method presented here relates to the use of cyclooxygenase-2 inhibitors or their derivatives in the prevention and treatment of angiogenesis. In a preferred embodiment, the cyclooxygenase-2 inhibitor is selected from the compounds of the formula

E where: A is a substituent selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl, furyl, pyrrolyl, Х pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl and pyridyl; at

IN! - at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, where B is optionally substituted in the substitution position by one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amine, alkylamine, su arylamine, nitro, alkoxyalkyl, alkylsulfinyl, halogen, alkoxy, and alkylthio; 3o B2 - methyl or amine; and in

BZ is a radical selected from hydride, halogen, alkyl, alkenyl, alkynyl, oxy, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl , « дю алкоксикарбонілу, арілкарбонілу аралкілкарбонілу, аралкенілу, алкоксиакілу, арілтіоалкілу, арілоксиалкілу, - аралкілтіоалкілу, аралкоксиалкілу, алкоксиаралкоксиалкілу, алкоксикарбонілалкілу, амінокарбонілу, с амінокарбонілаклкілу, алкіламінокарбонілу, М-аріламінокарбонілу, М-алкіл-М-аріламінокарбонілу, :з» алкіламінокарбонілалкілу, карбоксиалкілу , alkylamine, M-arylamine, M-aralkylamine, M-alkyl-M-aralkylamine,

M-alkyl-M-arylamino, aminoalkyl, alkylaminoalkyl, M-arylaminoalkyl, M-aralkylaminoalkyl, 15 M-alkyl-M-aralkylaminoalkyl, "M-alkyl-M-arylaminoalkyl, aryloxy, aralkyl, arylthio, aralkylthio, -alkylsulfinyl, alkylsulfonyl , aminosulfonyl, alkylaminosulfonyl, M-arylaminosulfonyl, arylsulfonyl, M-alkyl-M-arylaminosulfonyl; or their pharmaceutically acceptable salts. (ав) The best classes of compounds that suppress cyclooxygenase-2 consist of compounds of Formula I, where A is selected from d) oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, cyclopentenyl, phenyl and pyridyl; BK! - selected from 5- and b-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, i, biphenyl and naphthyl, where B ' may be substituted in the position of substitution with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amine, lower alkylamine, phe nylamine, lower alkoxyalkyl, lower alkylsulfinyl, halogen, lower alkoxy and lower alkylthio; where B2 is methyl or amine, and BZ is a radical selected from hydride, oxo, cyano, carboxyl, lower carboxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halogen, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- -th or b-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, im) acyl, phenylcarbonyl, lower alkoxyalkyl, 5- or 6b-membered heteroaryloxy, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamine, lower aminoalkyl, lower alkylaminoalkyl, phenyloxy and lower bo aralcox; or their salts acceptable from the point of view of pharmaceuticals.

Even better classes of compounds that suppress cyclooxygenase-2 consist of compounds of Formula I, where A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, and cyclopentenyl; where V! - selected from pyridyl, optionally substituted in the substitution position with one or more radicals, and phenyl, optionally substituted in the substitution position with one or more radicals, selected from methyl, ethyl, isopropyl, butyl, (eg-butyl, isobutyl, bo pentyl, shexyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amine, M-methylamine, M,M-dimethylamine,

M-ethylamine, M,M-dipropylamine, M-butylamine, M-methyl-M-ethylamine, phenylamine, methoxymethyl, methylsulfinyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, p-butoxy, pentoxy and methylthio; where is B? - methyl or amine; and B is a radical selected from hydride, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, butyl, hexbutyl, isobutyl, pentyl, hexyl, difluoromethyl , trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, methoxy, ethoxy, propoxy, p-butoxy, pentoxy, cyclohexyl, phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl, hydroxylmethyl, hydroxylpropyl, benzyl, formyl, phenylcarbonyl, methoxymethyl , furylmethyloxy, 70 aminocarbonyl, M-methylaminocarbonyl, M,M-dimethylaminocarbonyl, M,M-dimethylamine, M-ethylamine,

M,M-dipropylamine, M-butylamine, M-methyl-M-ethylamine, aminomethyl, M,M-dimethylaminomethyl,

M-methyl-M-ethylaminomethyl, benzyloxy and phenyloxy or their pharmaceutically acceptable salts.

The family of specific compounds of particular interest in Formula I includes the following compounds and their pharmaceutically acceptable salts: 5-(4-fluorophenyl)-1-(4-methylsulfonyl)phenyl|-3-trifluoromethyl)pyrazole; 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl|-1-phenyl-3--trifluoromethyl)pyrazole; 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)/benzenesulfonamide; 4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)/benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)/benzenesulfonamide; 4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5--4chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)/benzenesulfonamide; c 4-15-(4-chlorophenyl)-3-"trifluoromethyl)-1H-pyrazol-1-yl|!senzolesulfonamide; o 4-(b-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl 4-I5-(4-fluorophenyl)-3-"trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; 4-I5-(4-methoxyphenyl)-3-"-"trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; 4-I5-(4-chlorophenyl)-3--difluoromethyl)-1H-pyrazol-1- 4-I(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl|IsSenesolsulfonamide; 4-I4-chloro-5-(4-chlorophenyl)-3- "-trifluoromethyl)-1H-pyrazol-1-yl|Ibenzenesulfonamide; F 4-III--difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl|cSensolsulfonamide; Ge 4-3-difluoromethyl)-5-phenyl-1H-pyrazol-1-yl|Issensolsulfonamide; 4-3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl|isenesolesulfonamide; o 4-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl|Ibenzenesulfonamide; 1-4-3-difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl|Issensolsulfonamide; 4-I5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl|cSensolsulfonamide; 4-(4-Chloro-5phenyl-1H-pyrazol-1-yl|Isenazolesulfonamide; « 4-I5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl|Isenazolesulfonamide; 4-I5- (4-(M,M-dimethylamino)phenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl|cSensolsulfonamide; - c 2-methyl-4-(1-(4-methylsulfonyl)phenyl-4-trifluoromethyl)-1H-imidazol-2-yl|pyridine; and 2-methyl-6-(1-(4-methylsulfonyl)phenyl-4-trifluoromethyl)-1H-imidazol-2-yl|pyridine; "» 4-(2-(6-methylpyridin-3-yl)-4--trifluoromethyl)-1H-imidazol-1-yl|Issensolsulfonamide; 2-(3,4-difluorophenyl)-1-(4-(methylsulfonyl) )phenyl|-4-(trifluoromethyl)-1H-imidazole; 4-(2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl|Issensolsulfonamide; -and 2-(4-chlorophenyl) -1-(4-(methylsulfonyl)phenyl|-4-methyl-1H-imidazole; o 2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl|-4-phenyl-1H-imidazole; 2- (4-chlorophenyl)-4-(4-fluorophenyl)-1-(4-methylsulfonyl)phenyl|-1H-imidazole; co 2-(3-fluoro-4-methoxyphenyl)-1-(4-(methylsulfonyl) phenyl-4-"'trifluoromethyl)-1H-imidazole; so 50 1-(4--("methylsulfonyl)phenyl|-2-phenyl-4-trifluoromethyl-1H-imidazole; 2-(4-methylphenyl)-1- (4-methylsulfonyl)phenyl|-4-trifluoromethyl-1H-imidazole; 2-(33-fluoro-5-methylphenyl)-1-(4-("methylsulfonyl)phenyl|-4-"(trifluoromethyl-1H-imidazole; 4-I(2-(3-fluoro-5-methylphenyl)- 4-(trifluoromethyl)-1H-imidazol-1-yl|Issensolsulfonamide; 2-(3-methylphenyl)-1-(4--methylsulfonyl)phenyl|-4-trifluoromethyl-1H-imidase ol; 4-(2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1yl|Isensolsulfonamide; about 1-(4--"methylsulfonyl)phenyl|-2-(3-chlorophenyl)-4-trifluoromethyl-1H- imidazole; imi) 4-(2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-yl|!senzolesulfonamide; 4-(2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl|Issenzolesulfonamide; 60 4-(2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl|Isensolsulfonamide; 1-allyl-4--4-fluorophenyl)-3-I(4--(methylsulfonyl )phenyl|-5-trifluoromethyl-1H-pyrazole; 4-(/1-ethyl-4-(4-fluorophenyl)-5-trifluoromethyl)-1H-pyrazol-3-yl|I-benzenesulfonamide;

M-phenyl-I4-(4-fluorophenyl)-3-(4-methylsulfone)phenyl|-5-"trifluoromethyl)-1H-pyrazol-1-yl|acetamide; ethylI4-(4-fluorophenyl)-3-I (4--(methylsulfonyl)phenyl|-5-"trifluoromethyl)-1H-pyrazol-1-yl acetate; 65 4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl|-1-(2-phenylethyl)-1H-pyrazole; 4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl| -1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole;

1-ethyl-4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl|-5-trifluoromethyl)-1H-pyrazole; 5-(4-fluorophenyl)-4--4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole; 4-(4-methylsulfonyl)phenyl|-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole; 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole; 4-13-ethyl-5-phenylisoxazol-4-yl|Issensolsulfonamide; 4-(b-difluoromethyl-3-phenylisoxazol-4-yl|Isensolsulfonamide; 4-Ib-hydroxymethyl-3-phenylisoxazol-4-yl|Issensolsulfonamide; 4-(b-methyl-3-phenyl-isoxazol-4-yl| Isensol sulfonamides; 70 1-(2-(4-fluorophenyl)cyclopenten-1-yl|-4--methylsulfonyl)benzene; 1-(2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl|-4- -methylsulfonyl)benzene; 1-(2-(4-chlorophenyl)cyclopenten-1-yl|-4--methylsulfonyl)benzene; 1-(2-(2,4-dichlorophenyl)cyclopenten-1-yl|-4- -methylsulfonyl)benzene; 1--2-(4-trifluoromethylphenyl)cyclopenten-1-yl)|-4-(methylsulfonyl)benzene; 1-(2-(4-methylthiophenyl)cyclopenten-1-yl|-4-( methylsulfonyl)benzene; 1-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl|-4--(methylsulfonyl)benzene; 4-(2-(4-fluorophenyl)-4,4-dimethylcyclopentene -1-yl|Ibsensol sulfonamide; 1-(2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl|-4--(methylsulfonyl)benzene; 4-(2-(4-chlorophenyl)-4, 4-dimethylcyclopenten-1-ylIbsensolsulfonamide; 4-(2-(4-fluorophenyl)|cyclopenten-1-yl|Ibsensolsulfonamide; 4-(2-(4-chlorophenyl)cyclopenten-1-yl|Ibsensolsulfonamide; 1-(2- (4-methoxyphenyl)cyclo penten-1-yl|-4-methylsulfonyl)benzene; 1-2--2,3-difluorophenyl)cyclopenten-1-yl|-4-methylsulfonyl)benzene; 4-(2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl|Ibenzenesulfonamide; ch 1-(2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl|-4--methylsulfonyl)benzene ; 4-(2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl|benzenesulfonamide; and) 4-(2-(2-methylpyridin-5-yl)cyclopenten-1-yl|benzenesulfonamide; ethyl. 2-I4-(4-fluorophenyl)-5-(4--"methylsulfonyl)phenyl|oxazol-2-yl|-2-benzyl-acetate; 2-(4-(4-fluorophenyl)-5-(4- -(methylsulfonyl)phenyl|oxazol-2-yl|acetic acid; "g zo 2-(ep-butyl)-4-(4-fluorophenyl)-5-(4--methylsulfonyl)phenyl|oxazole; 4-(4 -fluorophenyl)-5-(4-(methylsulfonyl)phenyl|-2-phenyloxazole; Me 4-(4-fluorophenyl)-2-methyl-5-I(4--"methylsulfonyl)phenyl|oxazole and c 4-I5 -(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl|cSensolsulfonamide.

The family of specific compounds, even more interesting in Formula I, includes the following compounds and their pharmaceutically acceptable salts: 4-15-(4-chlorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl Sensolsulfonamide; 4-I(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl|Issensolsulfonamide; 4-I5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl) -1H-pyrazol-1-yl|bbenzenesulfonamide; 3-(1--4--"methylsulfonyl)phenyl|-4-trifluoromethyl-1H-imidizal-2-yl|pyridine; « 2-methyl-5-(1-(4-methylsulfonyl)phenyl|-4-trifluoromethyl-1H-imidizal-2-yl|pyridine; with 4-(2-(5-methylpyridin-3-yl)- 4--trifluoromethyl)-1H-imidazol-1-yl|Issensolsulfonamide; 4-(b-methyl-3-phenylisoxazol-4-yl|Issensolsulfonamide; |Isensolsulfonamide; (d-trifluoromethyl-5-(3,4-dichlorophenyl)-4-oxazolyl|Ibenezolsulfonamide; 4-(2-methyl-4-phenyl-5-oxazolyl|Ibenzenesulfonamide and -I 4-I5-(3- fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl|cSensolsulfonamide.

A subclass of cyclooxygenase-2 inhibitors is selected from the compounds of the Formula III

IN

GT" ot vo TE o) era v? and and and , , , and where B is selected from hydride, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, (F) aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,

GI of carboxyalkylaminocarbonyl, carboxyalkyl, armethoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl; in B? is selected from hydride, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen, and 25 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic compounds, wherein 7 may be substituted in the substitution position with one or more radicals selected from halogen, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl. alkylamine, dialkylamine, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkyl, sulfamyl, 65 heterocyclic compounds and amine; or from their pharmaceutically acceptable salts or derivatives.

A class of compounds of particular interest consists of those compounds of Formula II wherein K7 is selected from lower haloalkyl; IN? - hydride and where VU is selected from phenyl, which may be substituted in the substitution position with one or more radicals selected from halogens, lower alkyl and lower alkoxy; or from their pharmaceutically acceptable salts or derivatives.

A family of particular compounds of particular interest in Formula I consists of the following compounds and their pharmaceutically acceptable salts or derivatives: 4-15-(4-chlorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl Sensolsulfonamide; 4-(b-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl|Issensolsulfonamide; 70 4-I5-(4-fluorophenyl)-3-"trifluoromethyl)-1H-pyrazol-1-yl| Isensol sulfonamide; 4-I5-(4-Methoxyphenyl)-3-"-"trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; 4-I5-(4-chlorophenyl)-3-difluoromethyl-1H-pyrazol-1-yl| Isensolsulfonamide; 4-I(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; 4-IZ--difluoromethyl)-5-(4-methylphenyl)-1H-pyrazole -1-yl|cSensolsulfonamide; 4-IZ--difluoromethyl)-5-phenyl-1H-pyrazol-1-yl|IcSensolsulfonamide; 4-IZ-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazole-1 -ylbenzenesulfonamide; 4-13-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-ylbenzenesulfonamide; and 4-15-(3-fluoro-4-methoxyphenyl) -3-"-"trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide.

A family of specific compounds of more interest in Formula I consists of the following compounds and their pharmaceutically acceptable salts or derivatives: 4-I(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl Issensolsulfonamide; 4-I5-(4-chlorophenyl)-3-difluoromethyl)-1H-pyrazol-1-ylIsensolsulfonamide and 4-I5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazole -1-yl|IsSensolsulfonamide.

Derivatives are considered to include any compounds that are structurally related to cyclooxygenase-2 inhibitors, or that have substantially equivalent biological activity. For example, such inhibitors may include, but are not limited to, their prodrugs. Such compounds can be formed in the body, for example, as a result of metabolism.

The term "hydride" means a single atom of hydrogen (H). This hydride radical can be attached, for example, to an oxygen atom, forming a hydroxyl radical, or two hydride radicals can be attached to a carbon atom, forming a methylene radical (-СНо-). Where the term "alkyl" is used alone or in conjunction with other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", it includes F linear or branched radicals having from one to about twenty atoms carbon or, even better, He from one to twelve carbon atoms. Preferred alkyl radicals are "lower alkyl" radicals having from one to about ten carbon atoms. The best radicals are lower alkyl radicals having from about one to about six carbon atoms. Such radicals include, for example, methyl, ethyl, p-propyl, isopropyl, p-butyl, isobutyl, zes-butyl, (ie-butyl, pentyl, iso-amyl, hexyl and the like. The term "alkenyl" includes linear or branched radicals which have at least one carbon-carbon double bond among two to twenty carbon atoms or, even better, have one for two to twelve carbon atoms. The best alkenyl radicals are "lower alkenyl" radicals which have from two to about six carbon atoms. Examples of such radicals are ethenyl, propenyl, allyl, propenyl, butenyl, and -c 4-methylbutenyl. The term "alkynyl" means linear or branched radicals having from two to about twenty carbon atoms or, preferably from two to about twelve carbon atoms. Preferred "alkynyl" radicals are "lower alkynyl" radicals having from two to about ten carbon atoms. Preferred are lower alkynyl radicals having from two to about six carbon atoms. For example such councils potassium are propargyl, butynyl and similar radicals. The terms "alkenyl" and "lower alkenyl" include radicals having "cis" and "trans" orientations, or in other words "CE" and "7" orientations. The term "cycloalkyl" includes saturated carbocyclic radicals having from three to twelve carbon atoms. Preferred cycloalkyl radicals are "lower cycloalkyl" radicals having from three to about eight carbon atoms. Examples of such radicals are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "cycloalkenyl" includes partially unsaturated carbocyclic radicals having from three to twelve carbon atoms Preferred cycloalkenyl radicals are "lower alkenyl" radicals having from four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. The term "halogen" refers to halogens such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" encompasses radicals in which one or more alkyl carbon atoms are substituted with halogen as indicated above. In particular, this concept includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. For example, a monohaloalkyl radical can have an atom of iodine, bromine, chlorine or fluorine in the composition of the radical. Dihalo- and polyhaloalkyl radicals can have two or more atoms of the same halogen or a combination of radicals of different halogens. The term "lower haloalkyl" covers radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, 60 trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The term "hydroxyalkyl" encompasses linear and branched radicals having from one to about ten carbon atoms and any of which may be substituted with one or more hydroxyl radicals. Preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having from one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals 65 include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "Alkoxy" and "Alkyloxy" encompass linear and branched oxygen-containing radicals, each having alkyl moieties,

containing from one to about ten carbon atoms. Preferred alkoxy radicals are "lower alkoxy" radicals having from one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, and i(egi-butoxy). The term "Alkoxyalkyl" encompasses alkyl radicals having one or more Alkoxy radicals bonded to an Alkyl radical to form mono-AlkoxyAlkyl and DiAlkoxyAlkyl radicals . "Alkoxy" radicals may further be substituted with one or more halogen atoms, such as fluorine, chlorine, or bromine, leading to the formation of haloalkyl radicals. Preferred haloalkyl radicals are "lower haloalkyl" radicals having from one to six carbon atoms and one or more halogen radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, 7/0 trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy. The term "aryl," taken alone or in combination, refers to a carbocyclic aromatic system containing one, two, or three rings, and wherein such rings may be linked together as pendants or may be fused.The term "aryl" encompasses aromatic radicals such as pheny l, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted in the substituted position with one or more substituents independently selected from alkyl, alkoxyalkyl, -5 alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, armethoxy, hydroxyl, amine, halogen, nitro, alkylamine, acyl, cyano, carboxyl, aminocarbonyl, alkyloxycarbonyl and aralkylcarbonyl. The term "heterocyclyl" encompasses saturated, partially unsaturated, and unsaturated ring-shaped radicals containing heteroatoms, wherein the heteroatoms may be selected from nitrogen, sulfur, and oxygen.

Examples of saturated heterocyclic radicals include a saturated 3-6 membered heterocyclic group containing 1 to 4 nitrogen atoms (eg, pyrrolidinyl, imidazolidinyl, piperidine, piperazinyl, etc.); a saturated 3-6 membered heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (for example, morpholinyl, etc.); a saturated 3-6 membered heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms (for example, triazolidinyl, etc.). Examples of partially unsaturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The term "heteroaryl" covers unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals, also called "heteroaryl" radicals, include an unsaturated 3-6 membered heterocyclic group containing 1-4 i) nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl, 1H-1,2,Z-triazolyl. o 2H-1,1,2,Z-triazolyl, etc.), tetrazolyl (for example, 1H-tetrazolyl, 2H-tatrazolyl, etc.), etc.; an unsaturated fused heterocyclyl group containing from 71 to 5 nitrogen atoms, for example, indolyl, |isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (for example, tetrazolo|1,5-b|pyridazinyl and etc.), Me) etc.; an unsaturated 3-6 membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furylsu, etc.; an unsaturated 3-6 membered heterocyclic group containing a sulfur atom, for example, thienyl, etc.; an unsaturated 3-6 membered heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example, oxazolyl, o isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, etc.) and etc.; an unsaturated condensed heterocyclyl group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (for example, benzoxazolyl, benzoxadiazolyl, etc.); an unsaturated 3-6 membered heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 5-thiadiazolyl, etc.) etc.;; unsaturated condensed heterocyclic group that "

Contains 1-2 sulfur atoms and 1-3 nitrogen atoms (for example, benzothiazolyl, benzothiadiazolyl, etc.) and the like. This term also covers radicals where heterocyclyl radicals are fused to aryl radicals. . Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Is it indicated? "heterocyclic group" may have 1-3 substituents such as alkyl, hydroxyl, halogen, alkoxy, oxo, amine and alkylamine. The term "alkylthio" covers radicals containing a linear or branched alkyl radical of one to ten carbon atoms attached to a divalent sulfur atom. The best alkylthio radicals are "lower -I alkylthio" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term "alkylthialkyl" includes radicals containing an alkylthio radical bonded by a divalent sulfur atom to an alkyl radical consisting of one to about ten carbon atoms. Preferred alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl. The term "alkylsulfinyl" includes radicals containing a linear or branched alkyl radical of one to ten carbon atoms connected to a divalent radical -5(-0)-. Preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having an alkyl radical of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term "sulfonyl" when used alone or in conjunction with other terms, such as alkylsulfonyl, means (F) respectively divalent radicals -505-. "Alkylsulfonyl" includes alkyl radicals linked to a sulfonyl radical, where alkyl is defined above. Preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having from one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. "Alkylsulfonyl" radicals can further be replaced by one or more halogen atoms, such as fluorine, chlorine or bromine, to give haloalkylsulfonyl radicals. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl" mean

МНХО»5-. The term "acyl" means the radical formed by the residue after the removal of hydroxyl from an organic acid.

Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower 65 alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, trifluoroacetyl. The term "carbonyl" when used alone or in conjunction with other terms,

such as "Alkoxycarbonyl", means -(C-O)-. The term "aroyl" encompasses aryl radicals with carbonyl radicals as defined above. Examples of aroyl include benzoyl, naphthyl and the like and, in addition, the aryl in said aroyl may be substituted. The term "carboxy" or "carboxyl", whether used alone or with other terms such as "carboxyalkyl", means -CO oH. The term "carboxyalkyl" covers substituted alkyl radicals with carboxyl radicals. Preferred are "lower carboxyalkyls" which include lower alkyl radicals as defined above and, in addition, may be optionally substituted with an alkyl radical with a halogen. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term "Alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, 70 linked to a carbonyl radical through an oxygen atom. Preferred are "lower alkoxycarbonyl" radicals with alkyl moieties having from 1 to 6 carbon atoms. Examples of such lower alkoxycarbonyl radicals (ester radicals) include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term "alkylcarbonyl" encompasses radicals having alkyl, aryl, and aralkyl radicals, as defined above, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. The term "aralkyl" encompasses aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl in said aralkyl may, in addition, be substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkyl. The terms benzyl and phenylmethyl are interchangeable.

The term "heterocyclylalkyl" encompasses saturated and partially unsaturated heterocyclyl-substituted alkyl radicals such as pyrrolidinylmethyl and heteroaryl-substituted alkyl radicals such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl and quinolylethyl. Heteroaryl in the specified heteroalkyls may, in addition, be substituted by halogen, alkyl, alkoxy, haloalkyl, and haloalkyl. The term "aralkyl" includes aralkyl radicals connected to other radicals through an oxygen atom. The term "aralkoxyalkyl" covers aralkoxy radicals connected to an alkyl radical by an oxygen atom. The term "aralkylthio" covers aralkyl radicals bonded to a sulfur atom. The term "aralkylthioalkyl" includes aralkylthio radicals bonded to an alkyl radical through a sulfur atom. The term "aminoalkyl" encompasses substituted alkyl radicals with one or more amino radicals. The best are "lower i) aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl and the like. The term "alkylamino" refers to substituted amino groups with one or two alkyl radicals. The "lower" ones are better

M-alkylamino" radicals having alkyl moieties of 1 to 6 atoms. A suitable lower alkylamine may be "g z mono or dialkylamine, such as M-methylamino, M-ethylamino, M,M-diethylamino or the like. The term "arylamino " means substituted amino groups with one or two aryl radicals, such as M-phenylamino. "Arylamino" Me radicals of the aryl ring portion of the radical may be further substituted. The term "aralkylamino" encompasses c aralkyl radicals bonded to other radicals through an amino nitrogen atom. The terms "M-arylaminoalkyl" and "M-aryl-M-alkyl-aminoalkyl" mean substituted amino groups with one aryl radical or one aryl and o

With ONE alkyl radical, respectively, and having an amino group attached to the alkyl radical. Examples of such radicals include M-phenylaminomethyl and M-phenyl-M-methylaminomethyl. The term "aminocarbonyl" means an amide group with the formula -С(-О)МН». The term "alkylaminocarbonyl" means a substituted aminocarbonyl group with one or two alkyl radicals on the amino nitrogen atom. "M-alkylaminocarbonyl" and "M,M-dialkylaminocarbonyl" radicals are best. Even better are the radicals "lower M-alkylaminocarbonyl", "lower "

M,M-dialkylaminocarbonyl" with lower alkyl moieties as defined above. The term "alkylaminoalkyl" includes radicals having one or more alkyl radicals attached to an aminoalkyl radical. The term "aryloxyalkyl" includes radicals having aryl bonded to an alkyl radical through a divalent oxygen atom The term "arylthioalkyl" encompasses radicals having an aryl radical bonded to an alkyl radical through a divalent sulfur atom.

The compounds used in the method of the present invention can be presented in the form of free bases -I or their pharmaceutically acceptable acid addition salts. The term "pharmaceutically acceptable salts" includes salts that are widely used, both alkali metal salts and addition salts of free acids and free bases. The nature of the salts is not critical, provided that they are acceptable from a pharmaceutical point of view. Appropriate

GI pharmaceutically acceptable acid addition salts for compounds of Formula I can be obtained from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids can be selected from the classes of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and 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, methylsulfonyl, 4-hydroxybenzoic, phenylacetic, almond, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic,

F) toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, p-oxybutyric, kosalicylic, galactaric and galacturonic acids. Suitable pharmaceutically acceptable base addition salts for compounds of Formula I include metal salts formed with aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc or organic salts formed with M,M'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (M-methylglucamine) and procat. All these salts can be prepared by conventional means from the corresponding compound of Formula I, for example by reaction of the corresponding acid or base with the compound

Formula I.

GENERAL PROCESSES OF SYNTHESIS

65 Compounds of cyclooxygenase-2 inhibitors of the present invention can be synthesized according to the following processes shown in Schemes 1-X, where substituents 27-83 are as defined for Formula I, above, with the exception of what will be indicated below. 5spete I and SCHEME I

The basis of this o Vase with V write 3 -ssn, V, СОосН, Kk U o 10 1 2 oo

ECON, A 5 MNN, 15 in: 2 (in) in 20 th / more on IF at 3 m Kk - and: 3 se 25 Z sun; ЖЯ о в ви в 30 з ди . F

Synthesis Scheme I shows the preparation of compounds of cyclooxygenase-2 inhibitors covered by Formula I as described in US Pat. No. 5,521,207 and MU/F95/15316, which are incorporated by reference. In step 1, ketone 1 is treated with a base, preferably MaOMe or Mann, and an ester, or ester equivalent, so at 35 to form intermediate diketone 2 (in enol form), which is used without further purification. In step ii-2, the diketone 2 in an anhydrous protective solution such as absolute ethyl alcohol or acetic acid is treated with hydrochloric acid or substituted hydrazine free base at reflux to give a mixture of pyrazoles C and 4. By recrystallization or chromatography, C is obtained as a solid condition

Analogous pyrazoles can be prepared by the method described in US Pat. with c Zzspeshe II

I» SCHEME P z lu Mnryukht il 1 pr chainchh luvyetnh o 2 45 B 2) VSO-X BE - o o 6 ((c) them) VeMNMN. at 50 2 2 t» 5 BE in. Oxidation vi -- o z Y M v 4 A 54 her M. ka t Kk 8 7 60 y nesheya bod y y y

Scheme I shows a four-step process for the formation of cyclooxygenase-2 inhibitors, pyrazoles 8 from ketones 5, as described in US Patent No. 5,486,534 (where BK 2 is hydroxyl or alkyl). In step 1, ketone 5 reacts with a base such as lithium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA) to form an anion. In step 2, the anion reacts with an acetylating reagent to form diketone 6. In step C, the reaction of diketone b 65 with hydrazine or substituted hydrazine gives pyrazole 7. In step 4, pyrazole is oxidized by an oxidizing reagent such as OxonFf (potassium salt of monosulfur acid), with 3-chlorodadebenzoic acid (HNBEC) or hydrogen peroxide, forming a mixture of the desired 3-(alkylsulfonyl)phenylpyrazole 8 and the 5-(alkylsulfonyl)phenylpyrazole isomer. The desired pyrazole 8, of course, is a white or pale yellow solid, obtained in pure form either by chromatography or by recrystallization.

Alternatively, diketone 6 can be obtained from ketone 5 by treatment with a base such as sodium hydride in a solvent such as dimethylformamide and subsequent reaction with a nitrile to form an aminoketone. Treatment of this aminoketone with acid gives the diketone 6. Analogous pyrazoles can be prepared by methods described in US Pat. No. 3,984,431, which is incorporated by reference. I'm in a hurry

For? at 50; board tr I t i m Basis / o o shi yu no ov? o t 9 10 o a 11 se -e Sa, A

Where and call? ach Maov, Ge! (8) 1

IN

Bozi / ov h t Fo di 12.2 s no u on o t 0 o 13 9

CO 5

M se, V t s . "» 50. 50B: -i Kk i

IN

(av) with she

Po) still ------ / t i-o 15

Cyclooxygenase-2 inhibitors, diaryl/heteroaryl thiophenes (where T is 5 and B is alkyl) can be obtained by the methods described in US Patents MoMo 4,427,693, 4,302,461, 4,381,311, 4,590,205 and 4,820,827 and RTS documents 22 MO95/00501 and M/ O94/15932, which are incorporated by reference. Similar pyrroles (where T is M), furanones and furans (where T

Gee! this O) can be prepared by the methods described in RTS documents MUO95/00501 and MUO94/15932 and in EP799.823. ime) 60 b5 sspesheh IU

Scheme of IU vi ki man with She: viye Ge tvvs1 2 otv 8 17 16

MSRVA on tv5Oo 1 1 v nya VE nyu ;

В'оо5 18 2 Во55 о with 18 ksos1

base'

Go) in approx

MN.,.OAs sna t tyu r dulto i ? (in)

V?o25 at 20 V'o,5 « 21

Fo

Cyclooxygenase-2 inhibitors, diaryl/heteroaryl oxazoles, can be obtained by methods described in Patents

US Patent Nos. 3,743,656, 3,644,499 and 3,647,858 and in RTS documents M/0O95/00501 and UUO94/27980, which are incorporated by reference. Equivalent oxazole compounds can be prepared using MUO96/19463 and M/O96/19462. m.

Quickly U

SCHEME U mon Shk vi « 40 . and - with vi 1) 2 va. p-Vagi r: ON -- »(K«AUS:6SYA I I "6 I :- - - - -- Ж -й- ;" 2) (VZs0)250 -I o 22 23 ime) so 1) cС155Н 2) МН.ОН s» o pt eat) in Zh 60 505 МН.

Cyclooxygenase-2 inhibitors, diaryl/heteroaryl isoxazoles, can be prepared by methods described in Pat.

United States No. 5,633,272, in RTS documents UUO92/05162 and MU092/19604 and in European Publication EP 26928, which are incorporated by reference. Sulfonamides 24 can be obtained from hydrated isoxazole 23 in a two-step process. First, the hydrated isoxazole 23 is treated at about 0°C with two or three equivalents of chlorosulfonic acid to form the corresponding sulfonyl chloride. In a second step, the sulfonyl chloride thus obtained is treated with concentrated ammonium to give the sulfonamide derivative 24.

Scheme In the Alkipapuminium we are a vagrant in the spring. In w R r v 7 -6K6- Zh vi chi

EE

Solvent 25 26 27 zo vk g: o. x Alkylation; rya sonova s shchi 6) vi i

Eh Kk ov n i Y du ve Dehydration her SPIRIT and pi en en rn DON" in gi (o) s

Bon? | "in)

her

Bozk, 29 25

Scheme MI shows the three-step preparation of cyclooxygenase-2 inhibitors, imidazoles 29, in this "invention. At stage 1, the reaction of substituted nitriles (B'SM) 25 with primary phenylamines 26 in the presence of - alkylaluminum reagents, such as trimethylaluminum, triethylaluminum, dimethylaluminum chloride, and diethylaluminum chloride, in the presence of an inert solvent such as toluene, benzene, and xylene, leads to "» formation of amidines 27. In stage 2, the reaction of amidine 27 with 2-haloketones (where X is Hg or SI) in the presence of n bases such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or inhibited 15 tertiary amines such as M,M'-diisopropylamine gives 4,5-dihydroimidazoles 28 (where is alkyl). Suitable solvents for this reaction include isopropanol, acetone, and dimethylformamide. The reaction can be carried out at temperatures from about 207C to 90"C. At stage C, 4,5-dihydroimidazoles 28 can be dehydrated in (a) the presence of an acid catalyst, such as 4-toluenesulfonic acid or mineral acids, leading to the formation of 1,2-disubstituted imidazoles 29 of this invention. Suitable solvents for this dehydration step are, for example, toluene, xylene and benzene. At this stage of dehydration, trifluoroacetic acid can be used as a solvent and catalyst.

T» In some cases (for example, when B is methyl or phenyl), the intermediate product 28 cannot be easily soluble. The reaction under the conditions described above proceeds with direct obtaining of the desired imidazoles.

Similarly, imidazoles can be prepared by having sulfonylphenyl moieties attached in the 2-position and B attached to the nitrogen atom in the 1-position. Diaryl/heteroaryl imidazoles can be prepared by methods described in

US Patent 4,822,805, US Application Serial No. 08/282,395 and in RTS Document UM/093/14082, which (F, incorporated by reference. name) 60 b5

Scheme of UP and tsc otnE chy --LMBSN 80 Current capacitor n z o z1 1) Basis o 21 nn 1) Basis

Test 7 ur o EV?

Their

In he 33 7 kto dv? agent o

VE other) z4 s (8) nnusvs, node sno

BV? out there? « (22)

Kk GU p

Z " ben annia rom. 31

What is the oxidization of k o o

I in I vk n n - 35 ze

The subject of the present invention, imidazole compounds 36, cyclooxygenase-2 inhibitors, can be synthesized in accordance with the sequence outlined in Scheme II. Aldehyde ZO can be converted into the protected cyanohydrin 31 by reaction with a trialkylsilyl cyanide such as trimethylsilyl cyanide (TMSC) in the presence of a catalyst such as zinc iodide (Zn) or potassium cyanide (KCM). The reaction of cyanohydrin 31 with a strong base, followed by treatment with benzoic aldehyde 32 (where 2 is alkyl) and the use of both acidic and basic n treatments at the end, in the order indicated, gives benzoin 33. Examples of strong bases for this reaction are lithium diisopropylamide (LDA) and lithium hexamethyldisilazane. Benzoine 33 can be converted to benzyl 34 with a suitable oxidizing agent such as bismuth oxide or manganese dioxide or by Swern oxidation using dimethylsulfoxide (DMSO) and trifluoroacetic anhydride. Benzyl 34 can be obtained av ! directly by the reaction of hydrincyanate anion 31 with a substituted benzoic acid halide. As an intermediate compound t for conversion to imidazoles 35 (where B 2 is alkyl), any of compounds 33 or 34 can be used according to chemical processes known to the skilled person and described M.K. Osgittei in the work (Se) "Successes in heterocyclic chemistry"! in Aimapse ip Neyegosusiis SPetivigu, 12, 104 (1970). Transformation of 34 in

T» of imidazole 35 is carried out by reaction with ammonium acetate and the corresponding aldehyde (B ZSHO) in acetic acid. Benzoin 36 can be converted into imidazoles 38 by reaction with formamide. In addition, benzoin 36 can be converted into imidazoles by first acylation with the corresponding acyl group (B ЗСО-) followed by treatment with ammonium hydroxide. Those skilled in the art should know that the oxidation of the sulfide (where K 2 is methyl) to the sulfone can be carried out at any point in the process, starting with compounds 35 and including the oxidation of imidazoles by 38, using, for example, reagents such as hydrogen peroxide in acetic acid acid, t-chloronadoxybenzoic acid (MHOBC) and potassium salt of monosulfuric acid (Oxonf)).

Diaril/heteroaril Imidazole can be obtained by the ways described in the patents of the United States Momo BO 3,707,475, 4,686,231, 4,503,065, 4,472,422, 4,372,964, 4,576,958, 3,90 which are incorporated by reference. б5 о5спеше UTII

The scheme of MP niyam ve 1-p-vyi, TNE, -789С o 2. F2ps1, 37 38

ВГ в райе

J

VI 39 5ov: 5, sigp C 1i.p-Vai, TNE, -7890 VE V, --KK.-2------ i I « shchi 2. zhps1, Fe vvi em 41 40 s o Vvg doctor « (22)

BV? c and "c) in p i - vv 42 "

Diaryl/heteroaryl cyclopentene inhibitors of cyclooxygenase-2 can be prepared by methods described in US Patent No. 5,344,991 and RTS document M/O95/00501, which are incorporated by reference. . o espete IX 15 Scheme IX still - ; ak vok Ra", RySN 1 s - ' 3 o sonoon, her " t M ve Mvz.soz, A ( vo v"v(OH),-----k is; v v

IS! with

I" В В 44 43

Similarly, the Scheme of Their Synthesis shows the process of obtaining drugs, 1,2-diarylbenzene cyclooxygenase-2 inhibitors 44, from 2-bromo-biphenyl intermediates 43 (obtained similarly to how it is described in

Synthesis schemes of MI) and corresponding substituted phenylboronic acids. Using a coupling process similar to that developed by Zygiki et al. (Zupii. Sottyp., 11, 513 (1981)), intermediates 43 are reacted with boric acids in toluene/ethanol under reflux in the presence of catalyst Ra", e.g., 60 tetrakis(triphenylphosphine)palladium(0) and 2M sodium carbonate, leading to the formation of the corresponding anti-inflammatory drugs of the present invention from 1,2-diarylbenzene 44. Such terphenyl compounds can be prepared by the method described in patent document RTS M/096/16934, which included as a reference b5 is faster than X

Scheme X cats o-a i Zh with SsNasM, ECON is

V o di M 43 46 47

Diaryl/heteroaryl triazole inhibitors of cyclooxygenase-2 can be prepared by methods described in

United States Patent Nos. 4,051,250, 4,632,930, European Application EP 952,664 and RTS documents

MU096/03392 and UMO 95/00501, which are incorporated by reference. Isothiazoles can be prepared as described in PCT document M/O95/00501.

Cyclooxygenase-2 inhibitors from diaryl/heteroaryl pyridine can be obtained by methods described in Pat.

United States Patent Nos. 5,169,857, 4,011,328, 4,533,666 and in M/096/24584 and MUO96/24585, which are incorporated by reference.

Biological assessment

Antiangiogenic tests

To determine the effect of COX-2 inhibitors on angiogenesis, we tested selected compounds in microcavity tests on the corneas of mice and rats. A microcavity model of mouse corneal neovascularization was performed with materials, reagents, and procedures essentially as described by MiipikKashirrai et al. in .). Maya Sapseg Ipvi/.,69, 699-708 (1982). In this study, a bead containing basic fibroblast growth factor (FGF) was implanted into the corneal stroma of a mouse, and the number of new blood vessels formed was measured using a slit lamp. In this model, COX-2 was expressed in endothelial cells of newly formed blood vessels. Inhibitor tsoOg-2, 4-I5-(4-chlorophenyl)-3--difluoromethyl)-1H-pyrazol-1-yl|sensolsulfonamide weakened angiogenesis induced in Me mice by FRF (70-9095) at a dose of mg/kg/day. with

In microcavity tests on rats, 4-15-(4-chlorophenyl)-3--difluoromethyl)-1H-pyrazol-1-yl-Sensolsulfonamide suppressed angiogenesis,

From the Summoned FRF, only once (58090). M

We also determined the effects of the inhibitor tsoOg-2, 4-I5-(4-chlorophenyl)-3--difluoromethyl)-1H-pyrazol-1-yl|cSensolsulfonamide, in the cornea of the mouse eye, when using another substance to stimulate angiogenesis, vascular endothelial growth factor (FERS). In this model, angiogenesis was attenuated (5095) when the compound was given at a dose of bmg/kg. "

Metastasis model - c Tests on lung carcinoma Mygipe I em/iz were performed as described by I. Apdeggop and other ISap. ts Kez., 56, 715 (1996)). In this model, the COX-2 inhibitor is effective in suppressing metastases. "" The present invention encompasses a pharmaceutical composition for the treatment of angiogenesis disorders, comprising a therapeutically effective amount of a compound of Formula I, in association with at least one pharmaceutically acceptable carrier, adjuvant, or blood thinner (collectively referred to herein as a "carrier" " substance) -And, if desired, with other active ingredients. The active compounds of this invention can be administered by any suitable route known to the skilled person, preferably in the form of a pharmaceutical mixture adapted to such a route, and in doses effective for the intended treatment The active compounds and mixture may be administered, for example, orally, intravascularly, intraperitoneally, intranasally, intrabronchially, subcutaneously, intramuscularly, or locally (including by aerosol). If the angiogenesis is localized, local administration is preferred over systemic administration. For placement in linden can be used to increase bioavailability bottom transport

Administration of the drug, which is the subject of the present invention, can be performed either for the purpose of prevention or for the purpose of treatment. The methods and compositions used herein may be used alone or in combination with additional therapies known to those skilled in the art to prevent or treat angiogenesis. Alternatively, the methods and compositions described herein may be used as adjunctive therapy. o For example, a cyclooxygenase-2 inhibitor can be administered alone or in combination with other anticancer drugs or with other growth-suppressing drugs, or with other drugs or foods.

There are a large number of anticancer drugs that are available for commercial use, or are in the stage of clinical evaluation or preclinical development, which can be selected for the treatment of angiogenesis by combining chemotherapy drugs. Such anticancer drugs are divided into several categories, namely: antibiotic-type drugs, alkylating drugs, anti-metabolite drugs, hormonal drugs, immunological drugs, interferon-type drugs, and mixed category drug.

Alternatively, other anticancer drugs can be used, such as metallomatrix protease 65 inhibitors (MMP), such as MMP-13 inhibitors, including batiastat, maristat, Aguron Pharmaceuticals AC-3340 and

Roche KO-32-3555 or sur»z inhibitors.

The first family of anticancer drugs that can be used in combination with a selected inhibitor of cyclooxygenase-2 consists of anticancer drugs of the antimetabolite type. Suitable antitumor drugs can be selected from the group consisting of 5-PO-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, Siba-Geijie SOB-30694, cyclopentyl cytosine, cytrabine phosphate stearate, conjugated cytrabine, Lilly FOATNE, Merrell Dow OOBS, dezaguanine dideoxycytidine, dideoxyguanosine, didox, Yoshitomi OMOS, doxyfluridine, Wellcome ENMA, Merck and Co. EX-015, fasarabine, fluxuridine, fludarabine phosphate, 5-fluorouracil, M-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku PO-152, isopropyl pyrrolizine,

Lilly I M-188011, Lilly I U-264618, metobenzaprim, methoerexit, Wellcome MARE5, norspermidine, MCI MZSO-127716, 70 MCI MZS-264880, MCI M5SOS-39661, MCI MZSO-612567, Warner-Lambert RAGA, pertotreximbert , plicamycin,

Asahi Chemical RI-AS, Takeda TAS-788, thioguanine, thiazofurin, Erbamont TIR, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho CHET and uricitin.

The second family of anticancer drugs that can be used with a selected inhibitor of cyclooxygenase-2 consists of anticancer drugs of the alkylating type. Suitable antitumor drugs of the alkylating /5 type can be selected from the group, which includes Shionogi 2545, analogues of aldo-fosamide, altretamine, anaxiron.

Boehringer Mannheim VVM-2207, bestralucil, budotitan, Wakunaga SA-102, carboplatin, carmustine, Chinoinu-139,

Chinoinu-153, chlorambucil, cispoatin, cyclophosphamide, American Cyanamide SI-286558, Sanofi SU-233, ciplatate, Degusi Yu-19-384, Sumimoto OASNR (Mug)2, diphenylspiromustine, diflatinum cytostatic, derivatives

Erba distamycin, Chugai OMUA-21114K, ITI E09, elumistin, Erbamotn ESE-24517, sodium phosphate estamustine, totemustine, Unimid 5-6-M, Chionion ZUKI17230, nepsuf-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolastol, Nippon Kayaku MK-121, MSI MZSO-264395, MSI MZO-342215, oxaliplatin, Upjohn NSMI, pradnimutin,

Proteru RTT-119, ranimustine, semustine, SmithKline 5KUE-101772, Yakult Honsha 5M-22, spiromus-tyne, Taneib

Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin, and trimelamol.

The third family of anticancer drugs that can be used with a selected cyclooxygenase-2 inhibitor consists of antibiotic-type anticancer drugs. Suitable anticancer drugs of the antibiotic type can be selected from the group, which includes Taiho 4182-A, aclarubicin, actinomycin O, actinoplanon, and)

Erbamont AOK-456, aeroprlysinin derivative, Ajonomoto AM-201-II, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisukaberin, Bristol Miers VI -6859, Bristol Miers VMU-25067, Bristol Miers VMU-25551, Bristol

Mierz VMU-26605, Bristol Mierz VMU27557, Bristol Mierz VMU-28438, bleomycin sulfate, ichiostatin-1, Taiho "g zo C-1027, salichemicin, chromoxymycin, dathymuscin, daunorubicin, Kiova Hakko YuS-102, Kiova Hakko YuS-79, Kiowa

Hakko YuS-88A, Kiowa Hakko YuS-89-A1, Kiowa Hakko YuOS-92-B, ditrisarubicin B, Shionogi OOV-41, doxorubicin, Me) doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamycin-A !, esperemicin-At1b, p

Erbamont ESE-21954, Fuyisawa EK-973, fostriecin, Fuyisawa EK-90482, elidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, cazusumicin, cesarirhodins, Kiowa Hakko KM-5539, Kirin Brewery KAM-8602, o

Kiowa Hakko KT-5432, Kiowa Hakko KT-5594, Kiowa Hakko KT-6149, American Cyanamide II -049194, Meiji Seika ME i- 2303, memogaril, mitomycin, mitoxatron, SmithKline M-TAS, neoenastin, Nippon Kayaku MK-313, Nippon Kayaku

MKT-01, ZKI International MZSO-357704, axalysin, oxaunomycin, peplomycin, pilatin, pyrarubicin, porotramycin, pyrindamycin A, Tobishi KA-Y, rapamycin, rhizoxin, rhodorubicin, sibanomycin, sivenmycin, Sumitomo ZM-5887,

Snow Brand 5M-76, Snow Brand 5M-07, sorangicin-A, sparsomycin SS Farmasuvtikel 55-21020, SS « Pharmasuvtikel Z5-73138, SS Pharmasuvtikel ZZ-98168, steffimicin B, Taiho 4181-2, talisomycin, Takeda sv) TAM-868A, turpentine, trazine, tricrosarin A, Upjohn 0-73975 Kiowa Hakko ShSM-10028A, Fujisawa M/R-3405, . Yoshitomi U-25024 and zurobicin. and?" A fourth family of anticancer drugs that can be used with a selected cyclooxygenase-2 inhibitor is a mixed family of anticancer drugs selected from the group consisting of alpha-carotene, alpha-difluoromethyl, arginine, acitretin, Biotek AO-5, Kyorin ANS- 52, alstonin, amonafid, -I amfetinil, amsacrine, Argiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston AZ, antineoplaston AB, antineoplaston ABZ2-1, Henkel APO, aphidicolin, glycinate, asparaginase, Avarol, baccarin, o batracillin , benfluron, benchotript, Ipsen-Beaufort VIM-23015, bisantren, Bristo-Miers VMU-40481, Vestar kobor-10, bromophosphamide VMUU-502, Welkam VMUU-773, caracemid, carmetizol hydrochloride, Ajinomoto SOABE, 5r Chlorsulfaquinoxalon, Chemes SNH -2053, Chemex SNH-100, Warner Lambert SI-921, Warner Lambert SI-937, ik Warner Lambert SI-941, Warner Lambert SI-958, clanfenur, claviredenone, compound IMS 1259, compound IMS 4711, i» Kontrakan, Yakult Honsha SRT-11, kristanol, kuraderm, cytochalasin B, cytara bin, cytocytin, Mertz 0-609, OAVAZ maleate, dacarbazine, datelliptium, didemnin-B, dichaematoporphyrin ether, dihydrolenperone, dynaline, distamycin, Toyo Pharmar UM-341, Toyo Pharmar UM-75, Daiichi Seiyaku OM-9693, elliprabin, elliptinium , acetate,

Tsumura ERMTS, erogotamine, etoposide, etretinate, fenretinide, Fuyisawa EK-57704, gallium nitrate, genquadafinine,

Chugai IA-43, Glaho (3K-63178, grifolan MME-5M, hexadecylphosphocholine, Green Cross HO-221,

F) homogarringtonine, hydroxyurea, WTO ISKE-187, ilmofosine, isoglutamine, isotretonoin, Otsuka L-36, Ramot K-477, ka Otsuka K-76СООМа, Lurekha Chemical K-AM, MEST Corp K1-8110, Amerken Cyanamide I -623 , leucoregulin, lonidamine,

Lundbeck GO-23-112 Lilly I! M-186641, MCI (05) MAR, maricin, Merrell Dow MOI-27048, Medco MEYUOMK-340, merbarone, derivatives of merocyanide, phenylanilineacridine, Molecular Genetics MoOI-136, minactivin, mitonafid, mopidamole, motretinide, Zenyaku Koyo M5T-16 , M-(retinol)uamino acid, Nisschin Flue Milling M-021,

M-acylated-dehydroalanines, nafazatrol, Taisho TSG-190, nocodazole derivative, Normasang, MCI MZSOS-145813, MCI

MZO-361456, MS! MBOS-604782, MCI M5SOS-95580, octreotide, Ono OMO-112, ohizanocin, Akzo Org-10172, pancratistatin, pazelliptin, Warner-Lambert RO-111707, Warner-Lambert RO-115934, Warner-Lambert 65 RO-131141, Pierre Fabre RE-1001, ISKT peptide O, piroxatron, polyhematoporphyrin, polypreic acid,

Efamol porphyrin, probimin, procarbazine, proglumid, Invitron protease nexin I, Tobishi KA-700, razoxane, Sapporo

Breweriz KV5, restrictin-P, retelliptin, retinoic acid, Ron-Powlens KR-49532, Ron-Powlens KR-56976,

SmithKline ZKYARE-104864, Sumitomo ZM-108, Kurarei BZMAMS5, SiPharm ZR-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmasuvitel 55-554, stripoldinone, stipolashon, Suntory ZOM 0237, Suntory BOM 2071, superoxide dismutase, Toyama T -506, Toyama T-680, taxol, Teijin TEI-0O303, teniposide, taliblastin, Eastman Kodak I5B-006, vinblastine sulfate, vincristine, vindesine, vindestramid, vinorelbine, vintriptol, vinzolidin, withanolides and Yamanouchi UM-534.

Examples of anti-radiation drugs that can be used in combination chemotherapy with this invention: AYU-5, Adchnon, adminfostin analogues, detox, Dimesna, I-102, MM-159, M-acylated dehydroalanines, 70 TOE- Genentech, tiprotimod, amifostine, M/K-151327, ROT-187, ketoprofen transdermal, nabumeton, superoxide dismutase (Chiron) and superoxide dismutase Enzon.

The methods described above for obtaining anticancer drugs can be found in the literature. Methods of obtaining doxorubicin, for example, are described in US Patents Mo4,590,028 and Mo4,012,448. Methods of obtaining metal matrix prosthetic inhibitors are described in EP 780386, UUO97/20824, M/O96/15096. Methods of obtaining 75. ZOB imitators are described in EP 524,101. Methods of obtaining sur" inhibitors are described in UUMO97/08174.

In addition, for maximum safety and efficacy, the selected COX-2 inhibitor can be co-administered with other anti-inflammatory drugs, including NSAIDs, selected COX-1 inhibitors, and leukotriene pathway inhibitors, including 5-lipoxygenase inhibitors. Examples of NSAIDs include indomethacin, naproxen, ibuprofen, salicylic acid derivatives such as aspirin, diclofenac, ketorolac, piroxicam, homomeloxicam, mefenamic acid, sulfindac, tolmetin sodium, zomepirac, fenoprofen, phenylbutazone, oxyphenbutazone, nimesulide, zaltoprofen, and etodolac.

The term "adjuvant therapy" (or "combination therapy") when defining the use of inhibitory drugs against cyclooxygenase-2 and one or more other pharmaceutical drugs will involve the administration of each drug sequentially in such a way as to ensure the therapeutic effects of the combination of peaks, with

It also covers the simultaneous administration of these drugs, without a significant break between their administration, as a single mixture with a fixed ratio of these active drugs, or in several separate mixtures for each drug. at

For oral administration, the pharmaceutical mixture can be, for example, in the form of a tablet, capsule, suspension or liquid. It is better if the pharmaceutical mixture is made in the form of a dosage unit containing a specific 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 or potato starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with o disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose c and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection of a mixture where a suitable carrier can be used, for example, saline, dextrose or water. at

For intravenous, intramuscular, subcutaneous, or intraperitoneal administration, the compound can be mixed with a sterile aqueous solution, with a solution isotonic with the recipient's blood being preferred. Such mixtures can be prepared by dissolving the solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffer pH compatible with physiological conditions, to obtain an aqueous solution, and then sterilize it. Formulations may be supplied in containers containing single or multiple doses, such as sealed ampoules or hermetically sealed 8s vials. and If the angiogenesis is localized in the gastrointestinal tract, the compound may be acid-resistant, "base-resistant" coatings known to medicine, which begin to dissolve at the high pH values that exist in the small intestine. A mixture that enhances local pharmacological effects and reduces systemic absorption is desirable .

Mixtures suitable for parenteral administration usually contain a sterile aqueous solution prepared from the active compound, which is preferably isotonic. Preparations for injections can also be mixed by suspending or emulsifying compounds in a non-aqueous solvent, such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol.

Topical formulations include known gels, creams, oils, and the like. For aerosol administration, the compound can be mixed with known aerosol excipients, such as saline

Ta" and administered using sprayers available on the market. Placement in a fatty acid source can be used to enhance biocompatibility. Aerosol delivery is preferred as a delivery method for epithelial angiogenesis of the lungs, for prophylactic use.

For rectal administration, the active ingredient can be placed in suppositories using bases that are solid at room temperature and melt or soften at body temperature. iF) Bases commonly used include coconut oil, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycol of various molecular weights, and fatty esters of polyethylene stearate.

To learn about the regulation of treatment and prevention from the links, you can easily determine the dosage form and its amount. The amount of therapeutically active compound that is administered and the dosage regimen for the treatment of disease with the compounds and/or mixtures of the present invention depends on many factors, including the patient's age, weight, sex, and health status, the severity of the disease, the route and the frequency of administration and the specific compound used, the site of angiogenesis, and the pharmacokinetic properties of the individual being treated and thus can vary widely. 65 The dosage will, of course, be lower if the compounds are administered locally rather than systemically, and in the prevention of disease as compared to its treatment. Treatment sessions can be performed as often as necessary and for as long as is determined to be necessary by the treating physician. One of the requirements for qualification will be the ability to determine how to optimize the dosage regimen or therapeutically effective amount of inhibitor to be administered for each individual. The pharmaceutical compositions may contain the active ingredient in the range of 0.1 to 2000mg, preferably in the range of about 0.5 to 500mg, and more preferably in the range of about 1 to 200mg. A daily dose of about 0.01-100 Ωg/kg body weight may be suitably taken, preferably between about 0.1 and about 5 Ωg/kg body weight. The daily dose can be administered in one dose or up to four doses per day.

All documents referenced herein are incorporated by reference. 70 Although the present invention is described with respect to a particular implementation, the details of such implementation should not be construed as limiting.

Claims (1)

Formula of the invention 0, i 1. Use of a therapeutically effective amount of cyclooxygenase-2 inhibitor of the formula 1 and / o A 7 dz where: A is a substituent selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl and pyridyl; Go) V! - at least one substituent selected from heterocyclyl, C3-C40-cycloalkyl, C3-C40-cycloalkenyl and aryl, where B is optionally substituted in a position suitable for substitution by one or more radicals selected from C.i-Ci5- alkyl, C.1-Cio-haloalkyl, cyano, carboxyl, C.1-Cio-alkoxycarbonyl, "zo hydroxyl, C.4-C10-hydroxyalkyl, C.C.-Cio-haloalkyl, amine, C.-Ci5-alkylamine, arylamine, nitro, C.1-C-Alkoxyalkyl, C4-C-O-alkylsulfinyl, halogen, C4-C10-Alkoxy and C4-C.10-Alkylthio; Me. B2 - methyl or amine; and BZ is a radical selected from hydride, halogen, C4-C0-alkyl, C0-C1-alkenyl, C0-C1-alkynyl, oxo, cyano, o-carboxyl, C1-C45-cyanoalkyl, heterocyclyloxy, C .--Cio-alkyloxy, C.--Cio-alkylthio, C.4-C.i.5-alkylcarbonyl, C3-C12-cycloalkyl, aryl, C1-C15-haloalkyl, heterocyclyl, C3-C42-cycloalkenyl, aryl-C --C-10-alkyl, ycc heterocyclyl-C1-C25-alkyl, acyl, C1-C10-alkylthio-C4-C10-alkyl, C1-C10-hydroxyalkyl, C.1-Siodo-Alkoxycarbonyl, arylcarbonyl, aryl-C.-C.»-alkylcarbonyl, aryl-C.O.-C.2-alkenyl, C.1-C.O-Alkoxy-C.4-C.425-alkyl, arylthio-C.4-C .45-alkyl, aryloxy-C4-C425-alkyl, " aryl-C.4-C.o-alkylthio-C4-C15-alkyl, aryl-C4-Cio-alkylalkyl, C1-C10-alkoxyaryl-C1-C10 -C4-C.2-alkyl, C1-C10-Alkoxycarbonyl-C1-C.4"-Alkyl, aminocarbonyl, - with C.1-C2-aminocarbonylalkyl, C.-C.5-alkylaminocarbonyl, M-arylaminocarbonyl, "with M-(C4-C2-alkyl)-M-arylaminocarbonyl, C.-C.5-alkylaminocarbonyl-C 1-C. 5-alkyl, C1-C15-carboxyalkyl, C1-C12-alkylamino, M-arylamino, /M-(aryl-C4-C10-alkyl)damino, / M-(C4-C12-alkyl)-M-( aryl-C.4-C"-alkyl)amino, M-(C1-C15-alkyl)-M-arylamino, C.4-C12-aminoalkyl, C4-C4"-alkylamino-C4-C45-alkyl, M -arylamino-C.4-C12-alkyl, M-(aryl-C4-C15-alkyl)amino-C4-C425-alkyl, M-(C4-C1»-alkyl)-M-(aryl-C4-C. 45-alkyl)amino-C4-C15-alkyl, and M-(C41-C4-alkyl)-M-arylamino-C4-C6-alkyl, aryloxy, aryl-C-1-Cio -Alkoxy, arylthio, aryl-C1-C10-alkylthio, alkylsulfinyl, C15-alkylsulfonyl, aminosulfonyl, C1-C2-alkylaminosulfonyl, M-arylaminosulfonyl, arylsulfonyl, M-(C4-C125-alkyl) )-M-arylaminosulfonyl; ko or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of an angiogenesis-related disorder selected from metastases, ocular neovascularization, retinal neovascularization, infantile hemangiomas, and endometriosis, in patients who such treatment or prevention is necessary. 2. Application of cyclooxygenase-2 inhibitor of formula ! according to clause 1, where the disorder associated with angiogenesis is the formation of new vessels in the eye. C. Application of cyclooxygenase-2 inhibitor of formula I according to item 1, where A is selected from oxazolyl, o isoxazolyl, pyrazolyl, imidazolyl, cyclopentenyl, phenyl and pyridyl; B! selected from 5- and 6-membered heterocyclyl, C3-C6-cycloalkyl, C1-C6-cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, where B! where it can additionally be displaced in a position suitable for substitution by one or more radicals selected from C.i.i.-Cvd-alkyl, C.i.-Cv.-haloalkyl, cyano, carboxyl, C.i.-Cv-alkoxycarbonyl, hydroxyl, 60 cC.- C-hydroxyalkyl, C-C-halo-alkoxy, amine, C--C-alkylamine, phenylamine, C--C-alkoxy-C41-C-alkyl, C.-Cv-alkylsulfinyl, halogen, C4-Cv-alkoxy and C.-Cv-alkylthio; where is KB? - methyl or amine, and KZ - a radical selected from hydride, oxo, cyano, carboxyl, C--Cv- alkoxycarbonyl, C41-Cv-carboxyalkyl, C.4-Cv-cyanoalkyl, halogen, C4-Cv-alkyl, Si -C6-alkyloxy, C3-C6-cycloalkyl, phenyl, C1-C6-haloalkyl, 5- or 6-membered heterocyclyl, C4-C6-hydroxyalkyl, aryl-C1-C6-alkyl, formyl, phenylcarbonyl, C.i. -C1-C4-C4-C1-Alkyl, because it is a member of heteroaryloxy, aminocarbonyl, C1-C1-alkylaminocarbonyl, C1-C1-alkylamine, C-C-aminoalkyl, C-C-alkylamino-C1-Cv-alkyl, phenyloxy and aryl-C-C-alkyl; or a pharmaceutically acceptable salt thereof. 4. Application of cyclooxygenase-2 inhibitor of the formula | according to item C, where A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and cyclopentenyl; where BE is selected from pyridyl, which in a position suitable for substitution may be substituted by one or more radicals of methyl and phenyl, which in a position suitable for substitution may be substituted by one or more radicals selected from methyl, ethyl, isopropyl , butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, 70 hydroxymethyl, trifluoromethoxy, amine, M-methylamine, M,M-dimethylamine, M-ethylamine, M,M-dipropylamine, M-butylamine, M-methyl-M-ethylamine, phenylamine, methoxymethyl, methylsulfinyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, p-butoxy, pentoxy and methylthio; where K2 is methyl or amine; and 23 is a radical selected from hydride, oxy, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, 75 pentyl, hexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, methoxy, ethoxy, propoxy, p-butoxy, pentoxy, cyclohexyl, phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl, hydroxymethyl, hydroxylpropyl, benzyl, formyl, phenylcarbonyl, methoxymethyl, furylmethyloxy, aminocarbonyl, M-methylaminocarbonyl, M,M-dimethylaminocarbonyl, M,M-dimethylamine, M-ethylamine, M,M-dipropylamine, M-butylamine, M-methyl-M-ethylamine, aminomethyl, M, M-dimethylaminomethyl, M-methyl-M-ethylaminomethyl, benzyloxy and phenyloxy; or a pharmaceutically acceptable salt thereof. 5. Application of cyclooxygenase-2 inhibitor of formula I! according to point 4, where the compound is selected from the group of compounds and their pharmaceutically acceptable salts, which includes: 5-(4-fluorophenyl)-1-(4-methylsulfonyl)phenyl|-3-trifluoromethyl)pyrazole; c 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl|-1-phenyl-3--trifluoromethyl)pyrazole; o 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)/benzenesulfonamide; 4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)/benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide; 4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; And 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide; F 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide; Ge 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)/benzenesulfonamide; 4-15-(4-chlorophenyl)-3-"trifluoromethyl)-1H-pyrazol-1-yl|!senzolesulfonamide; o 4-(b-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl Issensolsulfonamide; 4-I5-(4-methoxyphenyl)-3-"-"trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; 4-I5-(4-chlorophenyl)-3--difluoromethyl)-1H-pyrazol-1- 4-I(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl|IsSenesolsulfonamide; 4-I4-chloro-5-(4-chlorophenyl)-3- "-trifluoromethyl)-1H-pyrazol-1-yl|Ibenzenesulfonamide; - c 4-3-difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl|cSensolsulfonamide; and 4-3-difluoromethyl)-5-phenyl-1H-pyrazol-1-yl|Issensolsulfonamide; "» 4-13-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl|isenzolsulfonamide; 4-13-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl| Isensolsulfonamide; 4-13--difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl|Isensolsulfonamide; -and 4-(5-(3-fluoro-4-methoxyphenyl)-3 -"-trifluoromethyl)-1H-pyrazol-1-yl|bsSensolsulfonamide; o 4-I4-chloro-5-phenyl-1H-pyrazol-1-yl|Isensolsulfonamide; 4-15-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; co 4-(5-(4--"M,M-dimethylamino)phenyl)-3-"trifluoromethyl)-1H-pyrazol-1-yl|senso sulfonamide; co 50 2-methyl-4-(1-(4- -methylsulfonyl)phenyl|-4-"-trifluoromethyl)-1H-imidazol-2-yl|pyridine; 2-methyl-6-(1-(4-methylsulfonyl)phenyl|-4-"-trifluoromethyl)-1H-imidazol-2-yl|pyridine; chz» 4-(2-(6-methylpyridin-3-yl) )-4--trifluoromethyl)-1H-imidazol-1-yl|Isensolsulfonamide; 2-(3,4-difluorophenyl)-1-(4-(methylsulfonyl)phenyl|-4-(trifluoromethyl)-1H-imidazole; 4 -(2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl|Issensolsulfonamide; 2-(4-chlorophenyl)-1-(4-("methylsulfonyl)phenyl|-4-methyl- 1H-imidazole; 2-(4-chlorophenyl)-1-(4-("methylsulfonyl)phenyl|-4-phenyl-1H-imidazole; o 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1 -(4--methylsulfonyl)phenyl|-1H-imidazole; ime) 2-(33-fluoro-4-methoxyphenyl)-1-(4--methylsulfonyl)phenyl|-4-"-trifluoromethyl)-1H-imidazole; 1-(4--("methylsulfonyl)phenyl|-2-phenyl-4-trifluoromethyl-1H-imidazole; 60 2-(4-methylphenyl)-1-(4--methylsulfonyl)phenyl|-4-trifluoromethyl-1H -imidazole; 4-(2-(3-chloro-4-methylphenyl)-4--trifluoromethyl)-1H-imidazol-1-yl|Issensolsulfonamide; 2-(33-fluoro-5-methylphenyl)-1-(4 --(methylsulfonyl)phenyl|-4-«(trifluoromethyl)-1H-imidazole; 4-I(2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl|Issensolsu lfonamide; 2-(3-methylphenyl)-1-(4-methylsulfonyl)phenyl|-4-trifluoromethyl-1H-imidazole; 65 4-(2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl|I-benzenesulfonamide; 1-(4--"methylsulfonyl)phenyl|-2-(3-chlorophenyl)-4-trifluoromethyl- 1H-imidazole; 4-(2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl|IsSensolsulfonamide; 4-(2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl|IsSensolsulfonamide; 4-(2 -(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl|Isensolsulfonamide; 1-allyl-4--4-fluorophenyl)-3-I(4--(methylsulfonyl)phenyl)|- 5-trifluoromethyl-1H-pyrazole; 4-(/1-ethyl-4-(4-fluorophenyl)-5-trifluoromethyl)-1H-pyrazol-3-yl|I-benzenesulfonamide; M-phenyl-14-(4-fluorophenyl )-3-(4-methylsulfonyl)phenyl|-5-"trifluoromethyl)-1H-pyrazol-1-yl)acetamide; ethyl 4-(4-fluorophenyl)-3-I(4--(methylsulfonyl)phenyl)- 5-"trifluoromethyl)-1H-pyrazol-1-yl acetate; 4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl|-1-(2-phenylethyl)-1H-pyrazole; 70 4-(4 -fluorophenyl)-3-(4-(methylsulfonyl)phenyl|-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole; 1-ethyl-4-(4-fluorophenyl)-3-(4-(methylsulfonyl) phenyl|-5-trifluoromethyl)-1H-pyrazole; 5-(4-fluorophenyl)-4--4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole; 4-(4--methylsulfonyl)phenyl|-5-( 2-thiophenyl)-2-"(trifluoromethyl)-1H-imidazole; 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylase oxazole; 4-13-ethyl-5-phenylisoxazol-4-yl|Issensolsulfonamide; 4-(b-difluoromethyl-3-phenylisoxazol-4-yl|Isensolsulfonamide; 4-Ib-hydroxymethyl-3-phenylisoxazol-4-yl|Issensolsulfonamide; 4-(b-methyl-3-phenylisoxazol-4-yl|Isensolsulfonamide; 1-(2-(4-fluorophenyl)cyclopenten-1-yl|-4-methylsulfonyl)benzene; 1-(2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl|-4-methylsulfonyl) benzene; 1-(2-(4-chlorophenyl)cyclopenten-1-yl|-4--methylsulfonyl)benzene; 1-(2-(2,4-dichlorophenyl)cyclopenten-1-yl|-4--methylsulfonyl) benzene; 1--2-(4-trifluoromethylphenyl)cyclopenten-1-yl|-4-methylsulfonyl)benzene; 1-(2-(4-methylthiophenyl)cyclopenten-1-yl|-4-(methylsulfonyl)benzene; 1-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl|-4--(methylsulfonyl)benzene; 4-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl) |Ibsensol sulfonamide; i) 1-(2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl|-4--(methylsulfonyl)benzene; 4-(2-(4-chlorophenyl)-4,4- dimethylcyclopenten-1-ylIbsensolsulfonamide; 4-(2-(4-fluorophenyl)cyclopenten-1-yl|Ibenzenesulfonamide; "g zo 4-(2-(4-chlorophenyl)cyclopenten-1-yl|Ibsensolsulfonamide; 1-(2- (4-methoxyphenyl)cy clopenten-1-yl|-4-methylsulfonyl)benzene; Me 1-2--2,3-difluorophenyl)cyclopenten-1-yl|-4--methylsulfonyl)benzene; c 4-(2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl|Ibenzenesulfonamide; 1-(2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl|-4--methylsulfonyl)benzene ; o 4-(2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl|benzenesulfonamide; y- 4-(2-(2-methylpyridin-5-yl)cyclopenten-1-yl|benzenesulfonamide; ethyl 2-I4-(4-fluorophenyl)-5-(4-methylsulfonyl)phenyl|oxazol-2-yl|-2-benzyl acetate; 2-(4-(4-fluorophenyl)-5-(4--( methylsulfonyl)phenyl|oxazol-2-yl|acetic acid; 2-(tert-butyl)-4-(4-fluorophenyl)-5-(4--(methylsulfonyl)phenyl|oxazole; « 4-(4-fluorophenyl) -5-(4-(methylsulfonyl)phenyl|-2-phenyloxazole; with c 4-(4-fluorophenyl)-2-methyl-5-I(4--"methylsulfonyl)phenyl|oxazole and . 4-I5-( 3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl-sensol sulfonamide. 6. Use of a therapeutically effective amount of the compound of formula II. ; -sh- і" M ri de B? choose oz hydride, C.-Cio-alkyl, C.-Cio-haloalkyl, C.i-Cio-alkoxycarbonyl, cyano, F) C.-C.»-cyanoalkyl, carboxyl, aminocarbonyl, C1-C12-alkylamines arcarbonyl, C3-C12-cycloalkylaminocarbonyl, co-arylaminocarbonyl, C1-C15-carboxyalkylaminocarbonyl, C1-C15-carboxyalkyl, aryl-C1-C12-alkyloxycarbonyl-C1-C5-alkylaminocarbonyl, C4-C5-aminocarbonylalkyl , because 0 C4-Cio-Alkoxycarbonylcyano-C2-Ci»5-alkenyl and C.4-C.o-hydroxyalkyl; is chosen from hydride, C.1-C.5-alkyl, cyano, C.4-C.10-hydroxyalkyl, C.3-C.42-cycloalkyl, C1-C10-alkylsulfonyl and halogen, and 29 is selected from aryl-C0-C10-alkenyl, aryl, C3-C12-cycloalkyl, C3-C10-cycloalkenyl, and heterocyclic compounds where B may be substituted in position of substitution by one or more radicals selected from halogen, C.4-C.alkylthio, C.4-C.5-alkylsulfonyl, cyano, nitro, C.41-C.40-haloalkyl, C.i.-C.i.5-alkyl, hydroxyl, C0-C0-alkenyl, C4-C10-hydroxyalkyl, carboxyl, C3-C15-cycloalkyl, C41-C1-»-alkylamine, di-C--C15-alkylamino, C.1-Cio-Alkoxycarbonyl, aminocarbonyl, C.--Cio-Alkoxy, C.1-C-o-halo-Alkoxy, sulfamyl, heterocyclic compounds and amine; or a pharmaceutically acceptable salt or derivative thereof for the preparation of a medicament for the treatment of disorders associated with angiogenesis selected from metastasis, neovascularization in the eye, neovascularization in the retina, diabetic retinopathy, infantile hemangiomas, and endometriosis. 7. Application of the compound of formula II according to item 6, where B" is selected from C.--Cv-haloalkyl; B? is a hydride and 5 is selected from phenyl, which can be substituted in a position suitable for substitution by one or more 70 radicals , selected from halogens, C4-C6-alkyl, and C1--C6-alkyl, or a pharmaceutically acceptable salt or derivative thereof. 8. Use of the compound of formula II according to item 7, where the compound is selected from the group of compounds and their pharmaceutically acceptable salts, which includes: 4-15-(4-chlorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl Sensolsulfonamide; 4-(b-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) Sensolsulfonamide; 4-I5-(4-fluorophenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl Isensolsulfonamide; 4-I5-(4-Methoxyphenyl)-3-"-"trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; 4-I5-(4-chlorophenyl)-3-difluoromethyl-1H-pyrazol-1-yl| Isensolsulfonamide; 4-I(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl|Isensolsulfonamide; 4-IZ--difluoromethyl)-5-(4-methylphenyl)-1H-pyrazole -1-yl|cSensolsulfonamide; 4-IZ--difluoromethyl)-5-phenyl-1H-pyrazol-1-yl|IcSensolsulfonamide; 4-IZ-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazole-1 -yl|isenesolesulfonamide; 4-13-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl isenesolesulfonamide and c 4-15-(3-fluoro-4-methoxyphenyl)-3- "-"trifluoromethyl)-1H-pyrazole-1-l-senzolesulfonamide. 9. Application of the compound of formula II according to point 8, where the compound is selected from the group of compounds and their pharmaceutically acceptable salts and 9), which includes: 4-I(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazole -1-yl|Issensolsulfonamide; 4-(5-(4-chlorophenyl)-3--difluoromethyl)-1H-pyrazol-1-yl|ibsensolsulfonamide "I and 4-I5-(3-fluoro-4-methoxyphenyl)- 3--difluoromethyl)-1H-pyrazol-1-yl|cSensolsulfonamide. b c Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2004, M 10, 15.10.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. - shi s;" -I ("c) name) o 50 s" F) name) 60 b5