RU2268716C2 - 2-cyclooxygenase inhibitors as antiangiogenic agents - Google Patents

Abstract

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

Description

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

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process, and inhibition of prostaglandin production, especially the production of PGG ₂ , PGH ₂ and PGE ₂ , was a common goal in the field of discovery of anti-inflammatory drugs. However, conventional non-steroidal anti-inflammatory drugs (NSAID's), which are active in reducing prostaglandin-induced pain and swelling associated with the inflammation process, are also active in other prostaglandin-controlled processes that are not associated with the inflammation process. Thus, the use of high doses of conventional NSAIDs can cause serious side effects, including life-threatening ulcers, which limit their therapeutic potential. NSAID's alternative is to use corticosteroids, which also cause a serious negative effect, especially when long-term therapy is taking place.

NSAID's have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid / prostaglandin pathway, including the cyclooxygenase (COX) enzyme. The recent discovery of an inducible inflammation-related enzyme (termed “cyclooxygenase-2 (COX-2)” or “prostaglandin G / H synthase II”) provides a viable inhibition target that reduces inflammation more effectively and causes less and less potent side effects. .

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

Despite the fact that glucocorticoids were originally developed due to their anti-inflammatory properties, it has now been discovered that they have a wide variety of therapeutic applications. For example, many steroids with anti-inflammatory activity inhibit the development of blood vessels (US patent No. 56646136).

Compounds that selectively inhibit cyclooxygenase-2 have been described in US 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.

[Pyrazol-1-yl] benzenesulfonamides have been described as cyclooxygenase-2 inhibitors and have shown promise in treating 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 US patent No. 5466823. However, their use for the treatment or prevention of diseases associated with angiogenesis has not been previously described.

There have been several publications describing the benefits of inhibiting angiogenesis. The publication of international patent application WO No. 96/19469 describes COX-2 inhibitors that can be used to prevent and / or treat tumor angiogenesis and diabetic retinopathy.

This invention relates to the use of cyclooxygenase-2 inhibitors for the treatment and prevention of tumor growth and metastasis, which are dependent on the process of angiogenesis. In addition, treatment and prevention of non-cancerous, angiogenesis-related disorders such as retinopathy and endometriosis are also included.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for treating or preventing disorders in a subject in need of such treatment or prophylaxis, the method comprising treating the subject with a therapeutically effective amount of a cyclooxygenase-2 inhibitor or derivative or pharmaceutically acceptable salt thereof.

The above method can be used, but not limited to, for the treatment of disorders associated with angiogenesis in a subject. In accordance with this invention, compounds of formula I are administered to a subject in need of inhibiting angiogenesis. The method can be used to treat neoplasia, including metastasis; ophthalmic conditions such as corneal transplant rejection, ocular vascular formation, retinal vascular formation, including vascular formation after damage or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; peptic ulcers, such as a stomach ulcer; pathological, but non-cancerous conditions, such as hemangiomas, including infant hemangiomas, pharyngeal angiofibroma and avascular necrosis of the bone; and disorders in the reproductive system in women, such as endometriosis.

The term “treatment” includes partial or complete inhibition of angiogenesis, including tumor growth, spread or metastasis, as well as partial or complete destruction of tumor cells.

The term “prophylaxis” includes either the prophylaxis of the onset of the clinically obvious development of angiogenesis in general, or the prophylaxis of the onset of the preclinically obvious stage of development of angiogenesis in individuals at risk of such development. This definition is also intended to include the prevention of metastasis of malignant cells or stopping or reverse development of the progression of malignant cells. This definition includes prophylactic treatment at the risk of developing angiogenesis.

The phrase “therapeutically effective” is intended to determine the amount of each agent that will achieve the goal of improving the severity of the disease and the incidence of the disease during treatment with each agent by itself, while avoiding the negative side effect typically associated with alternative therapies.

The term “subject” for the purpose of treatment includes any subject, human or animal that has any one of the known disorders related to the development of angiogenesis. For prophylactic methods, the subject is any subject, person or animal, preferably a person who is at risk of developing an angiogenesis-related disorder, such as metastasis. A subject may be at risk of such a disorder due to exposure to carcinogenic agents, being genetically predisposed to angiogenesis, and the like. In addition to being used to treat humans, these compounds can also be used in veterinary medicine to treat animals, including domestic animals and farm animals such as, but not limited to, horses, dogs, cats, cows, sheep and pigs. The subject is preferably a human.

Inhibitors of the cyclooxygenase pathway in arachidonic acid metabolism, used to prevent and treat the development of angiogenesis, can inhibit enzyme activity through various mechanisms. As an example, the inhibitors used in the methods described herein can block the activity of the enzyme directly by acting as a substrate for the enzyme. The use of selective cyclooxygenase-2 inhibitors is very beneficial in that they minimize the gastric side effect that can occur when using non-selective NSAIDs, especially when prolonged prophylactic treatment is contemplated.

The term “cyclooxygenase-2 inhibitor” means a compound capable of inhibiting cyclooxygenase-2 without significant inhibition of cyclooxygenase-1. Preferably, it includes compounds that have an IC _{50 of} cyclooxygenase-2 lower than about 0.2 μM, and also have a selectivity ratio of cyclooxygenase-2 inhibition to cyclooxygenase-1 inhibition of at least 50, and more preferably at least 100. Even more preferably, the compounds have an IC _{50 of} cyclooxygenase-1 greater than about 1 μM, and more preferably more than 10 μM.

The proposed method relates to the use of cyclooxygenase-2 inhibitors or their derivatives for the prevention and treatment of the development of angiogenesis. In preferred embodiments, the cyclooxygenase-2 inhibitor is selected from compounds of formula I

where A represents a substituent selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl and pyridyl;

where R ¹ represents at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, where R ^{1 is} optionally substituted at the position to be replaced by one or more radicals selected from alkyl, halogenated, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halogen, alkoxy and alkylthio;

where R ² represents methyl or amino;

where R ³ represents a radical selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, arylalkyl , acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxy aralkoxyalkyl, alkoxycarbonylalkylalkyl, okarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylamino-sulfonyl, N-aryl, aryl, alkyl arylaminosulfonyl; or their pharmaceutically acceptable salts.

A preferred class of compounds that inhibit cyclooxygenase-2 consists of compounds of formula I, wherein A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, cyclopentenyl, phenyl and pyridyl; wherein R is selected from 5- or 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, where R ^{1 is} optionally substituted at the position-replaceable one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halogen, lower alkoxy and lower alkylthio; where R ² represents methyl or amino and where R ³ represents a radical selected from the group consisting of hydrogen, oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halogen, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, acyl, phenylcarbonyl, lower alkoxyalkyl, 5- or 6-membered heteroaryloxy, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower alkylamino th aralkoxy; or their pharmaceutically acceptable salts.

A more preferred class of compounds that inhibit cyclooxygenase-2 consists of compounds of formula I, wherein A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and cyclopentyl, where R ^{1 is} selected from pyridyl optionally substituted at the position of one or more methyl radicals, and phenyl optionally substituted at the position to be substituted by one or more radicals selected from the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-dipropylamino, N-butylamino, N-methyl-N- ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentoxy and methylthio; where R ² represents methyl or amino and where R ³ represents a radical selected from the group consisting of hydrogen, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl , butyl, tert-butyl, isobutyl, pentyl, hexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, cyclohexyl, phenyl, pyridyl, thienyl, thienazyl, thienazole , pyrazinyl, hydroxymethyl, hydroxypropyl, bin silt, formyl, phenylcarbonyl, methoxymethyl, furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-dimethylamino, N-ethylamino, N, N-dipropylamino, N-butylamino, N-methyl-N-ethylamino aminomethyl, N, N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy and phenyloxy; or their pharmaceutically acceptable salts.

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

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- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -1H-pyrazol-1-yl) benzenesulfonamide;

4- (4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide;

4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1 ~ yl] benzenesulfonamide;

4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [4-chloro-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

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

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;

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

2- (3,4-difluorophenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazole;

4- [2- (4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;

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

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

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

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

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

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

4- [2- (3-chloro-4-methylphenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide;

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

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

2- (3-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole;

4- [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide;

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

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

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

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

1-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazole;

4- [1-ethyl-4- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl] benzenesulfonamide;

N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetamide;

ethyl [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-pyrazol-1-yl] acetate;

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

4- [5-difluoromethyl-3-phenylisoxazol-4-yl] benzenesulfonamide;

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

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

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] benzenesulfonamide;

1- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) benzene;

4- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide;

4- [2- (4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide;

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

1- [2- (4-methoxyphenyl) cyclopenten-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] benzenesulfonamide;

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

4- [2- (3-chloro-4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide;

4- [2- (2-methylpyridin-5-yl) cyclopenten-1-yl] benzenesulfonamide;

ethyl 2- [4- (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;

4- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl] oxazole;

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

The family of 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-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

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

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

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

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

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

[2-trifluoromethyl-5- (3,4-difluorophenyl) -4-oxazolyl] benzenesulfonamide;

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

and

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

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

wherein R ⁴ is selected from hydrogen, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, tsikloalkilaminokarbonila, arylaminocarbonyl, karboksialkilaminokarbonila, carboxyalkyl, aralkoksikarbonilalkilaminokarbonila, aminocarbonylalkyl, alkoksikarboniltsianoalkenila and hydroxyalkyl;

where R ⁵ selected from hydrogen, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen and

where R ^{6 is} selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and a heterocyclic radical; where R ^{4 is} optionally substituted in position to be substituted by one or more radicals selected from halogen, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl haloalkoxy, sulfamyl, heterocyclic radical and amino;

or their pharmaceutically acceptable salts or derivatives.

A class of compounds of particular interest consists of those compounds of formula II wherein R ^{4 is} selected from lower haloalkyl; where R ⁵ represents hydrogen; where R ^{6 is} selected from phenyl optionally substituted in a position to be substituted by one or more radicals selected from halogen, lower alkyl and lower alkoxy; or their pharmaceutically acceptable salts or derivatives.

A family of particularly interesting, specific compounds of formula I consists of compounds, their derivatives and pharmaceutically acceptable salts, including;

4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5- (4-methylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfamide.

The family of more particularly interesting, specific compounds within the formula I consists of a group comprising the following compounds and their pharmaceutically acceptable salts or derivatives:

4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide;

4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide and

4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide.

Derivatives are intended to include any compounds that are structurally related to cyclooxygenase-2 inhibitors or that have substantially equivalent biological activity. By way of example, such inhibitors may include, but are not limited to, their prodrugs. Such compounds can be formed in vivo, for example, by metabolic mechanisms.

The term "hydrogen" means one atom of hydrogen (H). This hydrogen radical can be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydrogen radicals can be attached to a carbon atom to form a methylene (—CH ₂ -) radical. The term “alkyl” when used either singly or in other terms, such as “haloalkyl”, “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 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 alkenyl radicals are "lower alkenyl" radicals having two to six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkynyl" means linear or branched radicals having from two to twenty carbon atoms, or, preferably, from two to twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having from two to ten carbon atoms. Most preferred are lower alkynyl 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 the orientations “cis” and “trans” or, alternatively, the orientations “E” and “Z”. The term “cycloalkyl” includes saturated carbocyclic radicals having from three to twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkenyl” includes partially unsaturated carbocyclic radicals having from three to twelve carbon atoms. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. The term “halogen” means halogens such as fluoro, chloro, bromo or iodo. The term “haloalkyl” includes radicals where any one or more carbon atoms of alkyl are substituted with halogen, as defined above. Specifically, monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are included. The monohaloalkyl radical as one example may have either iodine, bromine, chlorine, or a fluorine atom in the radical. The dihalo or polyhaloalkyl 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 of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl 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. More 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 oxo radicals, each of which has alkyl moieties containing from one to ten carbon atoms. More preferred alkoxy radicals 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 alkoxy radicals attached to an alkyl radical so as to form monoalkoxyalkyl and dialkoxyalkyl radicals. “Alkoxy” radicals may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to form haloalkoxy radicals. More preferred haloalkoxy radicals are “lower haloalkoxy” radicals having one to six carbon atoms and one or more halogen radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, where such rings can be linked together by a side-substitution method or can be condensed. The term “aryl” includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The aryl moieties may also be substituted in position-capable position with one or more substituents independently selected from the group consisting of alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halogen, nitro, alkylamino, acyl , carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term “heterocyclyl” includes saturated, partially unsaturated and unsaturated heteroatom-containing cyclic radicals, where heteroatoms can be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include a saturated 3-6 membered heteromonocyclic group containing from 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidine, piperazinyl and so on), a saturated 3-6 membered heteromonocyclic group containing 1 or 2 atoms oxygen and from 1 to 3 nitrogen atoms (for example, morpholinyl and so on), a saturated 3-6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and from 1 to 3 nitrogen atoms (for example, thiazolidinyl and so on). Examples of partially unsaturated heterocyclic radicals include dihydrothiophene, dihydropiran, dihydrofuran and dihydrothiazole. The term “heteroaryl” includes unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals, also called “heteroaryl” radicals, include an unsaturated 3-6 membered heteromonocyclic group containing from 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triid e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and so on), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl and so on ) and so on, an unsaturated condensed heterocyclic group containing from 1 to 5 nitrogen atoms, e.g. mer indolyl, isoindolyl, indolisinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (for example, tetrazolo [1,5-b] pyridazinyl and so on) and so on, an unsaturated 3-6 membered atomic oxygen group for example, pyranyl, furyl, and so on; unsaturated 3-6 membered heteromonocyclic group containing a sulfur atom, for example thienyl and so on, unsaturated 3-6 membered heteromonocyclic group containing 1 or 2 oxygen atoms and from 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 on; unsaturated condensed heterocyclic group containing 1 or 2 oxygen atoms and from 1 to 3 nitrogen atoms (for example, benzoxazolyl, benzoxadiazolyl and so on); unsaturated 3-6 membered heteromonocyclic group containing 1 or 2 sulfur atoms and from 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2, 5-thiadiazolyl and so on) and so on, an unsaturated condensed heterocyclic group containing 1 or 2 sulfur atoms and from 1 to 3 nitrogen atoms (for example, benzothiazolyl, benzothiadiazolyl and so on) and the like. The term also includes radicals where heterocyclic radicals are fused to aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene and the like. The specified "heterocyclic group" may have from 1 to 3 substituents, such as alkyl, hydroxyl, halogen, alkoxy, oxo, amino and 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. More preferred alkylthio radicals are “lower alkylthio” radicals having alkyl radicals containing one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term “alkylthioalkyl” includes radicals containing an alkylthio radical connected through a divalent sulfur atom to an alkyl radical containing from one to ten carbon atoms. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having alkyl radicals containing from 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 containing from one to ten carbon atoms connected to the divalent radical —S (= O) -. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl” radicals having alkyl radicals containing one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term “sulfonyl”, whether used alone or with other terms, such as alkylsulfonyl, means, respectively, divalent radicals —SO ₂ -. “Alkylsulfonyl” includes alkyl radicals joined to a sulfonyl radical, wherein alkyl is defined as described above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. "Alkylsulfonyl" radicals can be further substituted with one or more halogen atoms, for example fluorine, chlorine or bromine, to form halogenated alkylsulfonyl radicals. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl" mean NH ₂ O ₂ S-. The term “acyl” means a radical formed by the residue after removal of the hydroxyl from the organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl. The term carbonyl, whether used alone or with other terms, such as alkoxycarbonyl, means - (C = O) -. The term "aroyl" includes aryl radicals with a carbonyl radical, as defined above. Examples of aroyl include benzoyl, naphthoyl and the like, and the aryl in said aroyl may be further substituted. The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, mean —CO ₂ H. The term “carboxyalkyl” includes alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyls,” which include lower alkyl radicals as defined above, and may be further substituted in the alkyl radical with 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, linked through an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals with alkyl moieties having from 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ether) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" include 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” includes aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl in said aralkyl may be further substituted with halogen, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are used interchangeably. The term “heterocyclylalkyl” includes alkyl radicals substituted with saturated and partially unsaturated heterocyclyl, such as pyrrolidinylmethyl, and alkyl radicals substituted with heteroaryl, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl and quinolylethyl. The heteroaryl in said heteroalkyl may be further substituted with halogen, alkyl, alkoxy, haloalkyl and haloalkoxy. The term “aralkoxy” includes aralkyl radicals linked through an oxygen atom to other radicals. The term “aralkoxyalkyl” includes aralkoxy radicals linked through an oxygen atom to an alkyl radical. The term “aralkylthio” includes aralkyl radicals attached to a sulfur atom. The term “aralkylthioalkyl” includes aralkylthio radicals bonded through a sulfur atom to an alkyl radical. The term “aminoalkyl” includes alkyl radicals substituted with 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 amino groups which are substituted with one or two alkyl radicals. Preferred are “lower N-alkylamino” radicals having alkyl moieties 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 amino groups that are substituted with one or two aryl radicals, such as N-phenylamino. “Arylamino” radicals may be further substituted on the aryl-ring part of the radical. The term “aralkylamino” includes aralkyl radicals linked through a nitrogen atom of an amino group to other radicals. The terms “N-arylaminoalkyl” and “N-aryl-N-alkylaminoalkyl” mean amino groups which are substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having an amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term “aminocarbonyl” means an amido group of the formula —C (═O) NH ₂ . The term “alkylaminocarbonyl” means an aminocarbonyl group which is substituted with one or two alkyl radicals on the nitrogen atom of the amino group. Preferred are “N-alkylaminocarbonyl” and “N, N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl”, “lower N, N-dialkylaminocarbonyl” radicals 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 an aryl radical attached to an alkyl radical via a divalent sulfur atom.

The compounds used in the methods of this invention may be present in the form of free bases or their pharmaceutically acceptable acid addition salts. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form additive salts of free acids or free bases. The nature of the salt is non-critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I can be prepared from an inorganic acid or from an organic acid. 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 and heterocyclic carboxylic and sulfonic organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, malic, , fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic (methanesulfonic), 4-hydroxybenzoic, phenylacetic, almond, embonic (pamay vaya), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of formula I include metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts derived from N, N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, ethylenediamine meglumine (N-methylglucamine) and procaine. All of these salts can be prepared by conventional methods from the corresponding compound of formula I by reaction, for example, a suitable acid or base with a compound of formula I.

GENERAL SYNTHETIC METHODS

Compounds of the invention which are cyclooxygenase-2 inhibitors can be synthesized in accordance with the following procedures of Schemes IX, where R ¹ -R ³ substituents are as defined above for formula I, except as further noted.

DIAGRAM I

Synthetic Scheme I shows the preparation of cyclooxygenase-2 inhibitor compounds encompassed by Formula I as described in US Pat. No. 5,521,207 and WO 95/15316, which are incorporated by reference. In step 1, ketone 1 is treated with a base, preferably NaOMe or NaH, and an ester or equivalent of ether to form intermediate diketone 2 (in the form of enol), which is used without further purification. In step 2, diketone 2 in an anhydrous proton solvent such as absolute ethanol or acetic acid is treated with the hydrochloride salt or the free base of substituted hydrazine under reflux to give a mixture of pyrazoles 3 and 4. Recrystallization or chromatography gives compound 3, usually in the form of a solid product . Such pyrazoles can be obtained by the methods described in US patent No. 4146721, 5051518, 5134142 and 4914121, which are also included by reference.

DIAGRAM II

Scheme II shows a four-stage procedure for the formation of cyclooxygenase-2 inhibitors of pyrazoles 8, as described in US Pat. No. 5,448,634 (where R ^a is hydrogen or alkyl) from ketones 5. In step 1, the ketone is allowed to react with a base such as bis (grimethylsilyl) lithium amide or lithium diisopropylamide (LDA) to form an anion. In step 2, the anion reacts with an acetylating reagent to produce diketone 6. In step 3, the reaction of diketone 6 with hydrazine or substituted hydrazine gives pyrazole 7. In step 4, pyrazole 7 is oxidized with an oxidizing reagent such as Oxone ^® (potassium peroxymonosulfate), 3-chloroperbenzoic acid (MCPBA) or hydrogen peroxide to obtain a mixture of the desired 3- (alkylsulfonyl) phenylpyrazole 8 and its isomer, 5- (alkylsulfonyl) phenylpyrazole. The desired pyrazole 8, usually a white or pale yellow solid, is obtained in pure form either by chromatography or by recrystallization.

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

DIAGRAM III

Cyclooxygenase-2 inhibitors of diaryl / heteroarylthiophenes (where T represents S and R ^b represents alkyl) can be obtained by the methods described in US patent No. 4427693, 4302461, 4381311, 4590205 and 4820827 and PCT documents WO 95/00501 and WO 94/15932 which are included as a reference.

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

DIAGRAM IV

Cyclooxygenase-2 inhibitors diaryl / heteroaryloxazoles can be prepared by methods described in US Pat. Nos. 3,743,656, 3,644,499 and 3,647,858 and PCT Documents WO 95/00501 and WO 94/27980, which are incorporated by reference. Equivalent oxazole compounds can be prepared by the methods described in WO 96/19463 and WO 96/19462.

DIAGRAM V

Cyclooxygenase-2 inhibitors of diaryl / heteroaryl isoxazoles can be prepared by the methods described in US Pat. No. 5,663,272, PCT documents WO 92/05162 and WO 92/19604 and European publication EP 26928, which are incorporated by reference. Sulfonamides 24 can be obtained from hydrated isoxazole 23 by a two-step procedure. First, 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 formed is treated with concentrated ammonia to give the sulfonamide derivative 24.

DIAGRAM VI

Scheme VI demonstrates a three-step preparation of cyclooxygenase-2 inhibitors of imidazoles 29 of the present invention. In step 1, the reaction of substituted nitriles (R ¹ CN) 25 with primary phenylamines 26 in the presence of alkyl aluminum reagents such as trimethyl aluminum, triethyl aluminum, dimethyl aluminum chloride, diethyl aluminum chloride, in the presence of inert solvents such as toluene, benzene and xylene gives amidines 27. On stage 2 the reaction of amidine 27 with 2-halogen-ketones (where X represents Br or Cl) in the presence of bases such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or hindered tertiary amines such as N, N'-diisopropylethyl n, gives 4,5-dihydroimidazoles 28 (where R ^b represents alkyl). Some of the suitable solvents for this reaction are isopropanol, acetone and dimethylformamide. The reaction can be carried out at temperatures from about 20 ° C to about 90 ° C. In step 3, 4,5-dihydroimidazoles 28 can be dehydrated in the presence of an acid catalyst, such as 4-toluenesulfonic acid or mineral acids, to form the 1,2-disubstituted imidazoles 29 of the present invention. Suitable solvents for this dehydration step are, for example, toluene, xylene and benzene. Trifluoroacetic acid can be used as a solvent and catalyst for this dehydration step.

In some cases (for example, where R ³ is methyl or phenyl), intermediate 28 may be a difficult to isolate product. The reaction under the conditions described above proceeds, giving directly the desired imidazoles.

Similarly, you can get imidazoles having a sulfonylphenyl moiety attached at position 2, and R ¹ attached to the nitrogen atom at position 1. Diaryl / heteroaryl imidazoles can be obtained by the methods described in US patent No. 4822805 in US patent application No. 08 / 282395 and PCT document WO 93/14082, which are incorporated by reference.

DIAGRAM VII

Cyclooxygenase-2 inhibitors of the imidazole 36 compound of the present invention can be synthesized in accordance with the sequence shown in Scheme VII. Aldehyde 30 can be converted to protected cyanohydrin 31 by reaction with a trialkylsilyl cyanide such as trimethylsilyl cyanide (TMSCN), in the presence of a catalyst such as zinc iodide (ZnI ₂ ) or potassium cyanide (KCN). The reaction of cyanohydrin 31 with a strong base followed by treatment with benzaldehyde 32 (where R ² is alkyl) and using treatments with both acid and base gives benzoin 33 in this order during isolation. Examples of strong bases suitable for this reaction are lithium diisopropylamide ( LDA) and lithium hexamethyldisilazane. Benzoin 33 can be converted to benzyl 34 by reaction with a suitable oxidizing agent, such as bismuth oxide or manganese dioxide, or Swern oxidation using dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride. Benzyl 34 can be prepared directly by reacting the anion of cyanohydrin 31 with a substituted benzoic acid halide. Any of compounds 33 and 34 can be used as intermediates for conversion to imidazoles 35 (where R ² is alkyl) in accordance with chemical methods known to those skilled in the art and described by M. R. Grimmet, "Advances in Imidasole Chemistry" in Advances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of 34 to imidazoles 35 can be carried out by reaction with ammonium acetate and a suitable aldehyde (R ³ CHO) in acetic acid. Benzoin 36 can be converted to imidazoles 38 by reaction with formamide. In addition, benzoin 36 can be converted to imidazoles by first acylating with a suitable acyl group (R ³ CO-) and then treating with ammonium hydroxide. Specialists in this field should recognize that the oxidation of sulfide (where R ² is methyl) to sulfone can be carried out at any point along the synthesis pathway starting from compound 35 and including the oxidation of imidazoles 38 using, for example, reagents such as hydrogen peroxide in acetic acid acid, m-chloroperoxybenzoic acid (MCPBA) and potassium peroxymonosulfate (OXONE ^® ).

Diaryl / heteroaryl imidazoles can be prepared by methods described in US Pat. Nos. 3,707,475, 4,686,231, 4,504,065, 4,472,422, 4,372,964, 4,576,958, 3,901,908, US Patent Application No. 08/281903, European Publication EP 372445 and PCT Document O 95/00501, which are incorporated as a reference.

SCHEME VIII

Cyclooxygenase-2 inhibitors of diaryl / heteroarylcyclopentenes can be prepared by the methods described in US Pat. No. 5,344,991 and PCT Document WO 95/00501, which are incorporated by reference.

DIAGRAM IX

Similarly, Synthetic Scheme IX demonstrates the preparation of cyclooxygenase-2 inhibitors 1,2-diarylbenzenes 44 from intermediates, 2-bromobiphenyls 43 (prepared analogously to the preparation described in synthetic Scheme VIII) and suitable substituted phenylboronic acids. Using a coupling technique similar to that developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)], intermediates 43 are reacted with boronic acids in a toluene / ethanol mixture under reflux in the presence of a Pd ° catalyst, for example tetrakis (triphenylphosphine) palladium (0), and 2 M carbonate sodium, obtaining being anti-inflammatory drugs 1,2-diarylbenzenes 44 of the present invention. Such terphenyl compounds can be prepared by the methods described in PCT patent document WO 96/16934, which is incorporated by reference.

DIAGRAM X

Diaryl / heteroarylthiazoles, which are cyclooxygenase-2 inhibitors, can be obtained by the methods described in US Patent Nos. 4,051,250, 4,632,930, European Patent Application EP 592664 and PCT Documents WO 96/03392 and WO 95/00501, which are incorporated by reference. Isothiazoles can be prepared as described in PCT document WO 5/00501.

Diaryl / heteroarylpyridines, which are cyclooxygenase-2 inhibitors, can be prepared by methods described in US Pat. Nos. 5,169,857, 4,011,328, 4,533,666 and WO 96/24584 and WO 96/24585, which are incorporated by reference.

Biological assessment

Antiangiogenic analysis

To determine the effect of COX-2 inhibitors on in vivo angiogenesis, we tested selective compounds in the analysis of corneal micro-pockets of mice and rats. The formation of new vessels in the model of corneal micro-pockets was carried out with materials, reagents and methods, essentially as described by Muthukkauppah., J. Natl. Cancer Inst. 69, 699-708 (1982). In this assay, a centrifuged pellet containing the main fibroblast growth factor (FGF) was implanted into the corneal stroma of the mouse and the newly formed vessels were measured using a slit lamp. In this model, we expressed COX-2 in the endothelial cells of newly developed blood vessels. COX-2, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfamide inhibitor, inhibited FGF-induced development of blood vessels in mice (70-90%) at a dose of 6 mg / kg / day.

In rat micro pockets analysis, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzene sulfamide, given only once, inhibited FGF-induced development of blood vessels (~ 90%).

We also determined the effect of the COX-2, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzene sulfamide inhibitor in the mouse cornea using another angiogenic stimulus, vascular endothelial growth factor (VEGF). In this model, the development of angiogenesis was inhibited (~ 50%) when the compound was given at a dose of 6 mgk.

Metastasis model

Lewis mouse lung carcinoma analysis is performed as described by I. Andersen et al [Can. Res., 56, 715 (1996)]. The COX-2 inhibitor is effective in inhibiting metastasis in this model.

The present invention provides a pharmaceutical composition for the treatment of angiogenic disorders, comprising a therapeutically effective amount of a compound of formula I in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent (collectively referred to as “carrier” materials) and, if necessary, other active ingredients . The active compounds of this invention can be administered by any suitable route known to those skilled in the art, preferably in the form of a pharmaceutical composition adapted for such a route and in a dose effective for the intended treatment. The active compounds and composition can be administered, for example, orally, intravascularly, intraperitoneally, intranasally, intrabronchially, subcutaneously, intramuscularly or locally (including aerosol). If angiogenesis is localized, local administration rather than systemic administration is preferred. To increase the bioavailability, you can use the finished formulation in a liquid filler.

The introduction of the present invention may be intended for either prophylaxis or treatment. The methods and compositions used herein can be used alone or in combination with additional therapies known to those skilled in the art for the prevention or treatment of blood vessel development. Alternatively, the methods and compositions described herein can be used as an additional therapeutic measure. By way of example, a cyclooxygenase-2 inhibitor may be administered alone or in combination with other antitumor agents or other growth inhibitory agents or other drugs or nutrients.

There are a large number of antitumor agents available for commercial use, for clinical examination and preclinical development, which can be selected for the treatment of blood vessel development with combination drug chemotherapy. Such antitumor agents correspond to several main categories, namely antibiotic-type agents, alkylating agents, antimetabolic agents, hormonal agents, immunological agents, interferon-type agents, and mixed agent categories. Alternatively, other antitumor agents, such as metal matrix protease inhibitors (MMPs), such as MMP-13 inhibitors, including bathiostat, marimastat, Agouron Pharmaceuticals AG-3340 and Roche RO-32-3555, or a _v β ₃ inhibitors, can be used.

The first family of antitumor agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of antitumor agents such as antimetabolites. Suitable antimetabolic antitumor agents can be selected from the group consisting of 5FU-fibrinogen, acanthifolic acid, aminothiadiazole, sodium brequinar, karmofur, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate D-aminofluoride, DFC dideoxyguanosine, didox, Yoshitomi DMDC, doxyfluridine, Wellcome EHNA, Merck and Co. EX-015, phasarabine, phloxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolisin, Lilly LY-188011, Lilly LY-264618, methoben, metoben, metoben, methoben, metoben, methoben, methoben, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, pyritrexime, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, tiogani thiofu , Erbamont TIF, trimethrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricitin.

The second family of antitumor agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of an alkylating type antitumor agent. Suitable alkylating type antitumor agents can be selected from the group consisting of Shionogi 254-S, aldophosphamide, altretamine, anaxiron, Boehringer Mannheim BBR-2207, bestrabucil, budotitan, Wakunaga CA-102, carboplatin, carmustine, quinine-139 , chlorambucil, cisplatin, cyclophosphamide, American cyanamide CL-286558, sanofi CY-233, ciplate, Degussa P-19-384, Sumimoto DACHP (Myr) 2, diphenylspiramustine, diplatin cytostatic, Erbam dystamycin derivatives, ChugRai ITA-2109, DWA-DWA-I , elmustine, Erbamont FCE-24517, sodium estramustine phosphate, fotemustine, Unimed G-6-M, hino on GYKI-17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI 342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119Kline, & ranim , Yakult Honsha SN-22, spiramustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxiron, tetraplatin and trimelamol.

A third family of antitumor agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of antitumor agents such as antibiotics. Suitable antitumor agents such as antibiotics can be selected from the group consisting of Taiho-4181-A, aclarubicin, actinomycin D, actinoplanon, Erbamont ADR-456, aerosilizin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nipponoda anisomycin anisomycin , azinomucin-A, bisucaberin, Bristol-Myers BMY-25055, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemicin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-b, In, Shionogi DOB-41, before xorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamycin-A1, esperamycin-Alb, erbamont FCE-21954, Fujisawa FK-973, fostricin, Fujinacin, fjocin ginacin, , idarubicin, illudin, casuzamycin, caesarrodin, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, ME menogaril, mitomycin, myotoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatine, pyrarubicin, porotram ina, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rhodorubicin, sibanomycin, syvenmicin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, turpentine, trazine, tricrosarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yosh Y-25024 and zorubicin.

The fourth family of antitumor agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of a mixed family of antitumor agents selected from the group consisting of alpha-carotene, alpha-difluoromethylarginine, acitretin, AD-5 biotech, ANS-52 kiorin, alstonine, Amonafide, Amphetinyl, Amsacrine, Angiostat, Ankinomycin, Antineoplaston A10, Antineoplaston A2, Antineoplaston A3, Antineoplaston A5, Antineoplaston AS2-1, Henkel APD, Afidicolinglicinat, Asparaginase, Avarol, Bakharin, Ba tracilin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisanthrene, Bristo-Myers BMY-40481, Vestar boron-10, bromophosphamide, Wellcome BW-502, Wellcome BW-773, caratsemide, carmethysole hydrochloride, Ajinomoto CD CHX-2053, Chemes CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN 1259 connection, ICN 4711 connection, contract , Yakult Honsha CPT-11, Crisnatolum, Curaderm, Cytochalazine B, Cytarabine, Cytocytin, Merz D-609, DABIS Maleate, Dacarbazine, Datelliptinum, Didemnin-B, Diheimatoporphyrin Ether, Dihydrolenperone, Dyne, Dyne, Dyne Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabine, elliptinum acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, phenretinide, Fujisawa FR-57704, gallium nitrate, genquadaphne, 43 Chugax GLA -63178, grifolan NMF-5N, hexadecylphosphocholine. Green Cross HO-221, homogarringtonin, hydroxyurea, BTG ICRF-187, ilmofosin, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MEST Corp KI-8110, American Cyan L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, maricin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, derivatives of merocyanine, methylanilinoacridine, Molekular Genetics MGI- 136, minactivine, mitonafide, mitochidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N- (retinoyl) amino acids, Nisshin Flour Milling N-021, N-acylated dehydroalanines, naphazatrom, Taisho NCU-190, nocodazole derivative, NC, Normosang NSC-145813, NCI NSC -361456, NCI NSC-60 4782, NCI NSC-95580, ostreotide, Ono ONO-112, ochisanocin, Akzo Org-10172, pankratistatin, pazelliptin, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE- 1001, ICRT D peptide, pyroxantrone, polyhymatoporphyrin, polypreinic acid, Efamol porphyrin, probiman, procarbazine, proglumide, Invitron nexin I protease, Tobishi RA-700, razoxan, Sapporo Breweries RBS, restrictin-R, retelliptin, retinoic acid, retinoic acid, retinoic acid Rp-49532, Rhone-Poulenc RP-56976, SmithKline SKK & F-104864, Sumitomo SM-108, Kuraray SNANCS, SeaPharm SP-10094, Spatol, Spirocyclopropane Derivatives, Spiro Germania, Unimed, SS Pharmaceutical SS-554, Stripoldinone, STI half-dione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, Taxola, Teijin TEI-0303, teniposide, taliblastin, Eastman Kodak TJB-29, tocotrienol, topostin, Teijin TT-82 H, Kyow UCN-01, Kyowa Hakko UCN-1028, Ukraine, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vinriptriptol, vinzolidine, vitanolides and Yama-nouchi YM-534.

Examples of radioprotective agents that can be used in combination chemotherapy of the present invention are AD-5, adhnon, analogs of amifostine, detox, dimezna, 1-102, MM-159, N-acylated dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR- 151327, FUT-187, transdermal ketoprofen, nabumeton, superoxide dismutase (Chiron) and superoxide dismutase Enzon.

Methods for preparing the antitumor agents described above can be found in the literature. Methods for producing doxorubicin, for example, are described in US patent No. 3590028 and N-4012448. Methods for producing metallo-matrix protease inhibitors are described in European Patent 780386, WO 97/20824, WO 96/15096. Methods for producing SOD mimetics are described in European Patent 524101. Methods for producing α _v β ₃ inhibitors are described in WO 97/08174.

In addition, for maximum safety and efficacy, a COX-2 selective inhibitor can be administered in combination with other anti-inflammatory drugs, including NSAID's, COX-1 selective inhibitors, and leukotriene pathway inhibitors, including 5-lipoxygenase inhibitors. Examples of NSAID's include indomethacin, naproxen, ibruprofen, salicylic acid derivatives such as aspirin, diclofenac, ketorolac, piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium, zomepirac, phenoprofen, phenylbutazone, oxyftenbutazone, zlipodophenbutenzole, nimetolbutazone, zolipenoptenebenzene, nimetolbutazone, zoliphenbutazone, zolipenoptenebenzene.

The phrase “complementary therapeutic measure” (or “combination therapy”) in determining the use of a cyclooxygenase-2 inhibitor and one or more other pharmaceutical agents is intended to include the administration of each drug in a sequential manner according to a scheme that will provide the beneficial effect of the combination of drugs, and also to enable the co-administration of these funds essentially simultaneously, for example, in the form of a single finished formulation having fief ratio of these active agents or in multiple, separate formulations for each agent.

For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, suspensions or liquids. 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, gum arabic, corn starch or gelatins; with disintegrating agents such as corn starch, potato starch or sodium carboxymethyl cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection in the form of a composition where, for example, saline, dextrose or water can be used as a suitable carrier.

For intravenous, intramuscular, subcutaneous or intraperitoneal administration, the compound can be combined with a sterile aqueous solution, which is preferably isotonic with the blood of the recipient. Such formulations can be prepared by dissolving a solid active ingredient in water containing physiologically compatible substances, such as sodium chloride, glycine and the like, and having a pH buffered pH compatible with physiological conditions to produce an aqueous solution and converting this solution to sterile. Finished formulations may be present in containers for one or more doses, such as sealed ampoules or vials.

If angiogenesis is localized in the gastrointestinal tract, the compound can be made with acid resistant and base unstable coatings known in the art that begin to dissolve in the small intestine at a high pH. A formulation is preferred that enhances local pharmacological effects and reduces systemic absorption.

Formulations suitable for parenteral administration usually include a sterile aqueous preparation of the active compound, which is preferably made isotonic. Injectable preparations can also be prepared by suspending or emulsifying the compounds in a non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, higher aliphatic acid esters or propylene glycol.

Formulations for topical use include known gels, creams, oils, and the like. For aerosol delivery, the compounds can be formulated with known aerosol excipients, such as saline, and administered using commercially available nebulizers. The formulation in a fatty acid source can be used to enhance biocompatibility. Aerosol delivery is a preferred delivery method for use in preventing epithelial angiogenesis of the lungs.

For rectal administration, the active ingredient can be formulated as suppositories using bases that are solid at room temperature and melt or dissolve at body temperature. Commonly used bases include cocoa butter, glycerinated gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights and fatty esters (fatty acid esters) and polyethylene stearate.

The dosage form and quantity can be easily determined based on known drug regimens or prophylaxis regimens. The amount of therapeutically active compound that is administered and the dosage regimen for treating a disease state with the compounds and / or compositions of this treatment depend on various factors, including the age, weight, gender and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular used compounds, places of angiogenesis, as well as pharmacokinetic properties of the person who is being treated, and thus can vary within wide limits. The dose should usually be lower if the compounds are administered locally, and not systemically, and for prophylaxis, and not for treatment. Such therapy can be carried out as often as necessary, and during the period of time that the attending physician considers necessary. One of skill in the art will recognize that a dosage regimen or therapeutically effective amount of an inhibitor that is administered may need to be optimized 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. A daily dose of about 0.01 to 100 mg / kg body weight may be suitable, preferably between about 0.1 and about 50 mg / kg body weight. The daily dose can be administered in the form of one to four doses per day.

All documents mentioned herein are incorporated by reference.

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

Claims (6)

1. The use of a therapeutically effective amount of an antiangiogenic cyclooxygenase-2 inhibitor selected from the group consisting of 4- [5- (4-chlorophenyl) -3-phenyl-1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4 -methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide, or their pharmaceutically acceptable salts for the manufacture of a medicament for treatment or prevention related to angiogenesis of a disorder selected from metastasis, ocular formation of new vessels, retinal images Nia neovascularization, diabetic retinopathy, infantile hemangiomas, and disorders of the reproductive system in women, a subject in need of such treatment or prevention. 2. The use according to claim 1, where the violation related to angiogenesis is endometriosis. 3. The use according to claim 1, where the violation related to angiogenesis is the ocular formation of new vessels. 4. The use according to claim 1, wherein the antiangiogenic compound is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof. 5. The use according to claim 1, where the antiangiogenic compound is 4- [5-methyl-3-phenyl-4-isoxazolyl] benzenesulfonamide or a pharmaceutically acceptable salt thereof. 6. The use according to claim 1, where the antiangiogenic compound is 4- [5- (4-chlorophenyl) -3-phenyl-1H-pyrazol-1-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof.