SK59999A3 - Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents - Google Patents

Abstract

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

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to cyclooxygenase-2 inhibitors

The invention relates to the prevention and treatment of angiogenesis. More particularly, the invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof for the prevention and treatment of angiogenesis-related disorders.

BACKGROUND OF THE INVENTION

Prostaglandins play an important role in inflammatory processes, and the inhibition of prostaglandin production, especially the production of PGG2, PGH2 and PGE2, has been a major child of anti-inflammatory drug research. However, conventional non-steroidal anti-inflammatory drugs (NSAID's) that are effective in reducing prostaglandin-induced pain and swelling associated with the inflammatory process are also active in influencing other prostaglandin-regulated processes not related to the inflammatory process. Therefore, the use of high doses of most conventional NSAIDs can cause undesirable side effects, such as life-threatening ulcers, limiting their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which also cause side effects, especially in long-term therapy.

NSAID drugs have been developed to prevent the production of prostaglandins by inhibitors of human arachidonic acid / prostaglandin pathway including the cyclooxygenase (COX) enzyme. The recent discovery of an inducible enzyme associated with inflammation (called cyclooxygenase-2 (COX-2) or prostaglandin G / H synthase Π) provides a viable division of inhibition that more effectively reduces inflammation and provides fewer and less drastic side effects.

Angiogenesis is the formation of new blood vessels in tissues or organs. Under normal conditions, angiogenesis can be monitored for wound healing and embryonic development. Uncontrolled angiogenesis has been associated with neoplastic disease, tumor metastasis, and other angiogenesis-related diseases.

Glucocorticoids, originally developed for their anti-inflammatory effects, have been found to have a wide therapeutic use. For example, many anti-inflammatory steroids inhibit angiogenesis (U.S. Pat. No. S 646 136).

Compounds that selectively inhibit cyclooxygenase-2 have been described in U.S. Patents 5,380,738, 5,344,991, 5,393,790, 5,434,178, 5,474,995, 5,475,018, 5,510,368 and

- WO96 / 06840, WO95 / 21817, WO96 / 03388, WO96 / 03387,

WO96 / 03392, WO96 / 25405, WO96 / 24584, WO96 / 03385, WO96 / 16934, WO95 / 15316, WO94 / 15932, WO94 / 27980, WO95 / 00501, WO94 / 13635, WO94 / 20480, and WO94 / 26731.

[Pyrazol-1-yl] benzenesulfonamides have been described as inhibitors of cyclooxygenase-2 and show promising results in the treatment of inflammation, arthritis, and pain, with minimal side effects in preclinical and clinical trials. Their use in the prevention of colon cancer has been described in U.S. Patent No. 5,466,823. However, their use in the treatment or prevention of angiogenesis-related diseases has not been described.

There are several publications describing the advantages of angiogenesis inhibition. WO Patent Publication No. 96/19469 discloses that COX-2 inhibitors would be useful in the prevention and / or treatment of tumor angiogenesis and diabetic retinopathy.

The invention is directed to the use of cyclooxygenase-2 inhibitors in the treatment and prevention of tumor growth and metastasis that are dependent on angiogenic processes. In addition, the treatment and prevention of non-neoplastic angiogenesis-related disorders such as retinopathy and endometriosis are included.

SUMMARY OF THE INVENTION

The present invention provides a method of treating or preventing angiogenesis-related disorders in a patient in need thereof, the method comprising treating the patient with a therapeutically effective amount of a cyclooxygenase-2 inhibitor or derivative thereof, or a pharmaceutically acceptable salt thereof.

The above method would not only be useful for treating a patient with angiogenesis-related disorders. According to the invention, the compounds of formula I are administered to a patient in need of inhibition of angiogenesis. The method is useful in the treatment of neoplasia, including metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including injury or infection neovascularization, diabetic retinopathy, retrolental fibroplasia, and neovascular glaucoma; ulcerous diseases such as gastric ulcer; pathological but benign conditions, for example, hemangiomas, including invantile hemaginomass, nasopharynx angiofibroma, and avascular bone necrosis; and disorders of the female reproductive system such as endometriosis.

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

The term prevention includes either preventing the onset of clinically evident angiogenesis or preventing the onset of a pre-clinically evident stage of angiogenesis in the subject at risk. Prevention of malignant cell metastasis or arrest or reversal of malignant cell development may also be included in this definition. This includes prophylactic treatment of endangered individuals with developing angiogenesis.

The term therapeutically effective refers to the amount of each agent that causes the disease to improve and the frequency of its occurrence when treated with each agent alone, avoiding the undesirable side effects that usually accompany alternative therapies.

The term patient for treatment refers to any human or animal subject having any of the known angiogenesis related disorders. In prevention methods, we mean patients of any human or animal subject, preferably a human, who is at risk of acquiring an angiogenesis related disorder, such as metastasis. The patient may be at risk due to exposure to carcinogenic agents, may be genetically predisposed to become angiogenesis, and the like. These substances are not only suitable for the treatment of humans, but are also suitable for the veterinary treatment of mammals, including domestic and breeding animals, such as horses, dogs, cats, cows, sheep and pigs. Preferably, the patient is a human.

Inhibitors of the cyclooxygenase pathway in arachidonic acid metabolism used in the prevention and treatment of angiogenesis can inhibit enzyme activity by several mechanisms. For example, inhibitors used in the methods described herein can directly block enzyme activity by acting as a substrate for this enzyme. The use of cyclooxygenase-2 selective inhibitors is very advantageous in that it minimizes stomach side effects that may occur with non-selective NSAIDs, especially where prolonged prophylactic treatment is expected.

The term "cyclooxygenase-2 inhibitor" refers to a compound capable of inhibiting cyclooxygenase-2 without a distinct cyclooxygenase-1 inhibitor. Preferably, these include compounds having an IC 50 of cyclooxygenase-2 of less than 0.2 µΜ, and also have a selectivity ratio of cyclooxygenase-2 inhibition to cyclooxygenase-1 inhibition of at least 50 and more preferably

Even more preferably, the compounds have a cyclooxygenase-1 IC 50 greater than about 1 µΜ, and more preferably greater than 10 µΜ.

The method herein relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in the prevention and treatment of angiogenesis. Preferably, the cyclooxygenase-2 inhibitor is selected from compounds of Formula I

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

wherein R ¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein it is optionally substituted at one of the substitutable positions with one or more groups selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino , alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halogen, alkoxy and alkylthio;

wherein R 2 is methyl or amino; and wherein R 1 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arythioalkyl, aryloxyalkyl, aralkythioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminoalkylcarbonyl, Narylamininocarbonyl, Narylamininocarbonyl, Narylamininocarbonyl arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-Naralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or a pharmaceutically acceptable salt thereof.

A preferred group 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 ¹ is selected from 5- and 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 1 is optionally substituted at one of the substitutable positions with one or more lower alkyl groups, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halogen, lower alkoxy and

-5lower alkylthio; wherein R ² is methyl or amino; and wherein R 3 is selected from hydrido, 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 hydroxylalkyl , lower aralkyl, acyl, phenylcarbonyl, lower alkoxyalkyl, 5 or 6-membered heteroalkyloxy, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower alkylaminoalkyl, phenyloxy, and lower aralkoxy; or a pharmaceutically acceptable salt thereof.

A more preferred group of compounds that inhibit cyclooxygenase-2 consists of compounds of formula I wherein A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and cyclopentenyl; wherein R 6 is selected from pyridyl which is optionally substituted at one of the substitutable positions by one or more methyl groups, and phenyl which is optionally substituted at one of the substitutable positions by one or more groups selected from methyl, ethyl, isopropyl, butyl, tert -butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, N-methylamino, Ν, Ν-dimethylamino, Netylamino, Ν, dip-dipropylamino, butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio; wherein R ² is methyl or amino; and wherein R 1 is a group selected from hydrido, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, kaiboxyethyl, cyanomethyl, fluoro, chloro, bromo, 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, thiazolyl, oxazolyl, furyl, pyrazinyl, hydroxylmethyl, hydroxylmethyl, hydroxylmethyl, hydroxylpropyl, hydroxylpropyl, phenylcarbonyl, methoxymethyl, finylmethyloxy, aminocarbonyl, N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, Ν, Ν-dimethylamino, N-ethylamino, Ν, Ν-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, Ν, Ν-dimethylamine N-methyl-Nethylaminomethyl, benzyloxy, and phenyloxy; or a pharmaceutically acceptable salt thereof.

The group of specific compounds of interest of the general formula I consists of the following compounds and their pharmaceutically acceptable salts:

5- (4-fluorophenyl) -l- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -L-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) -lH-pyrazol-l-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (4-methylphenyl) -lH-pyrazol-l-yl) benzenesulfonamide;

-64- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -lH-pyrazol-l-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -lH-pyrazol-l-yl) benzenesulfonamide; 4- [5- (4-Chloro-phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- (4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide; 4- [5-fenyJ-3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazol-yl] benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-lH-pyrazol-l-yl] benzenesulfonamide;

4- [3- (difluónnetyI) -5- (4-methoxyphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3-cyano-5- (4-fluorophenyl) -lH-pyrazol-l-yl] benzenesulfonamide;

4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [4-chloro-5-phenyl-lH-pyrazol-l-yl] benzenesulfonamide;

4- [5- (4-chlorophenyl) -3- (Hydroxymethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide;

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

2-methyl-6- [l- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -lH-imidazol-2-yl] pyridine; 4- [2- (6-methylpyridin-3-yl) -4- (trifluoromethyl) -lH-imidazol-l-yl] benzenesulfonamide; 2- (3,4-difluorophenyl) -l- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -lH-imidazol; 4- [2- (4-methylphenyl) -4- (trifluoromethyl) -lH-imidazol-l-yl] benzenesulfonamide;

2- (4-chlorophenyl) -l- [4- (methylsulfonyl) phenyl] -4-methyl-lH-imidazole; 2- (4-chlorophenyl) -l- [4- (methylsulphonyl) phenyl] -4-phenyl-lH-imidazole; 2- (4-chlorophenyl) -4- (4-fluorophenyl) -l- [4- (methylsulfonyl) phenyl] -lH-imidazole; 2- (3-fluoro-4-methoxyphenyl) -l- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -lH-imidazole;

1- [4- (methyisulfonyl) 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) -lH-ixnidazol-yl] benzenesulfonamide; 2- (3-fluoro-5-methyl-phenyl) -l- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -lH-imidazole; 4- [2- (3-fluoro-5-methylphenyl) -4- (trifluoromethyl) -lH-imidazol-l-yl] benzenesulfonamide; 2- (3-methyl-phenyl) -l- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-lH-imidazole; 4- [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; l- [4- (methylsulfonyl) phenyl] -2- (3-chlorophenyl) -4-trifluoromethyl-lH-imidazole; 4- [2- (3-chlorophenyl) -4-trifluoromethyl-lH-imidazol-l-yl] benzenesulfonamide;

4- [2-phenyl-4-trifluoromethyl-lH-imidazol-l-yl] benzenesulfonamide;

-4- [2- (4-methoxy-3-chlorophenyl) -4-trifluoromethyl-4-imidazol-1-yl] benzenesulfonamide; l-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl-5- (trifluoromethyl) -lH-pyrazole; 4- [l-ethyl-4- (4-fluorophenyl) -5- (trifluoromethyl) -lH-pyrazol-3-yljbenzénsulfónamid; N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl-5- (trifluoromethyl) -lH-pyrazol-lyljacetamid;

Ethyl [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -lH-pyrazol-l-ylJacetát; 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;

-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-phenyl-isoxazol-4-yl] benzenesulfonamide;

4- [5-difluoromethyl-3-phenyl-isoxazol-4-ylJbenzénsulfónamid;

4- [5-hydroxymethyl-3-phenyl-isoxazol-4-ylJbenzénsulfónamid;

4- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide;

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

[2- (4-fluoro-2-methylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; l- [2- (4-chlorophenyl) cyclopenten-l-YLJ-4- (methylsulfonyl) benzene;

- (2- (2,4-dichlorophenyl) cyclopenten-1-yl) -4- (methylsulfonyl) benzene; 1- [2- (4-trifluoromethylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - (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-dimetylcyklopentén-yl] benzenesulfonamide; l- [2- (4-chlorophenyl) -4,4-dimetylcyklopentén-yl] -4- (methylsulfonyl) benzene;

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

4- [2- (4-fluorophenyl) cyclopenten-l-yljbenzénsulfónamid;

4- [2- (4-chlorophenyl) cyclopenten-l-yl] benzenesulfonamide; l- [2- (4-metóxyfisnyl) cyclopenten-l-yl] -4- (methylsulfinylethoxy) phenyl) benzene;

1- (2- (2,3-difluorophenyl) cyclopenten-l-yl] -4- (methylsulfonyl) benzene;

4- [2- (3-fluoro-4-methoxyphenyl) cyclopenten-l-ylJbenzénsulfónamid;

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

4- [2- (3-chloro-4-fluorophenyl) cyclopenten-l-ylJbenzénsulfónamid;

4- [2- (2-methylpyridin-5-yl) cyclopenten-l-yljbenzénsulfónamid;

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-ethanoic acid; 2- (tert-butyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) fenylJoxazol; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyl-oxazole;

4- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl] oxazole; and 4- [5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide.

The group of specific substances of particular interest of the general formula I is comprised of the following compounds and their pharmaceutically acceptable salts: 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole- l-yl] benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide;

3- [1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl] pyridine; 2-methyl-5- [l- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-lH-imidazol-2-yl] pyridine;

4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; 4- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide; 4- [5-hydroxymethyl-3-phenyl-isoxazol-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] benzenesulfonamide.

Another class of cyclooxygenase-2 inhibitors is selected from compounds of general interest

I of formula Π

II, wherein it is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, alkyloxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl;

wherein it is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen; and wherein it is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic groups; wherein R 6 is optionally substituted at one of the substitutable positions with one or more groups selected from halogen, alkylthio, alkylsulfonyl, cyano,

-9nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino groups; or a pharmaceutically acceptable salt or derivative thereof.

The group of substances of particular interest consists of compounds of the general formula Π wherein R ⁴ is selected from lower haloalkyl groups; wherein R 6 is a hydrido group; and wherein R 1 is selected from phenyl optionally substituted at one of the substitutable positions with one or more groups selected from halogen, lower alkyl and lower alkoxy; or a pharmaceutically acceptable salt or derivative thereof.

The group of specific substances of interest which satisfy the general formula I consists of the following compounds, their derivatives and their pharmaceutically acceptable salts:

4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzénsulfónaiiiid; 4- [5-phenyl-3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; and 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide.

The group of specific substances of increased interest that satisfy Formula I consists of the following compounds and their pharmaceutically acceptable salts or derivatives thereof: 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazole 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 include any compounds that are structurally similar to cycloxygenase-2 inhibitors or that have substantially the same biological activity. For example, these

-10 inhibitors may include, but are not limited to, prodrugs thereof. These compounds can be formed in vivo by a metabolic mechanism.

The term hydrido refers to one hydrogen atom (H). For example, the hydrido group may be attached to an oxygen atom to form a hydroxyl group, or the two hydride groups may be attached to a carbon atom to form a methylene group (-CH 2 -). Where used, either alone or within a term other than haloalkyl, alkylsulfonyl, alkoxyalkyl and hydroxyalkyl, the term alkyl refers to linear or branched groups having from one to twenty carbon atoms, or more preferably, from one to twelve carbon atoms. More preferred alkyl groups are lower alkyls having from one to ten carbon atoms. Most preferred are lower alkyl groups having from one to six carbon atoms. Examples of these groups are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl tert-butyl, pentyl isopentyl, hexyl and the like. The term alkenyl includes linear or branched groups having at least one carbon-carbon double bond and from two to twenty carbon atoms, or more preferably, from two to twelve carbon atoms. More preferred alkenyl groups are lower alkenyl groups having two to six carbon atoms. Examples of alkenyl groups are: ethenyl, propenyl, allyl, propenyl, biitenyl and 4-methylbutenyl. The term alkynyl refers to linear or branched groups having two to twenty carbon atoms, or preferably two to twelve carbon atoms. More preferred alkynyl groups are lower alkynyl groups having two to ten carbon atoms. Most preferred are lower alkynyl groups having two to six carbon atoms. Examples of these groups are propargyl, butynyl and the like. The terms alkenyl, lower alkenyl, include groups having a cis and trans orientation, or alternatively, a Έ and Z orientation. The term cycloalkyl includes saturated kaibocyclic groups having three to twelve carbon atoms. More preferred cycloalkyl groups are lower cycloalkyl groups having three to eight carbon atoms. Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term cycloalkenyl includes partially unsaturated kaibocyclic groups having three to twelve carbon atoms. More preferred cycloalkenyl groups are lower cycloalkenyl groups having four to eight carbon atoms. Examples of such groups are cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. The term halogen means halogens, fluorine, chlorine, bromine or iodine. The term haloalkyl includes groups in which one or more carbon atoms of the alkyl are substituted with halogen as defined above. Specifically, this applies to monohaloalkyl, dihaloalkyl and

-11-polyhaloalkyl groups. For example, a monohaloalkyl group may contain one iodine, bromine, chlorine or fluorine atom. Dihalogen and polyhaloalkyl groups may contain two or more of the same halogenatoms or a combination of different halogen groups. Lower haloalkyl includes groups having 1 to 6 carbon atoms. Examples of haloalkyl groups are: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term hydroxyalkyl refers to linear or branched alkyl groups having from one to ten carbon atoms, any of which may be substituted with one or more hydroxyl groups. More preferred hydroxyalkyl groups are lower hydroxyalkyls having from one to six carbon atoms and one or more hydroxyl groups. Examples of these groups are: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms alkoxy ”and alkyloxy denote linear or branched oxygen-containing groups having from one to ten carbon atoms. More preferred alkoxy groups are lower alkoxy groups having from one to six carbon atoms. Examples of such groups are: methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term alkoxyalkyl refers to alkyl groups having one or more alkoxy groups attached to an alkyl group to form monoalkoxyalkyl and dialkoxyalkyl groups. The alkoxy groups may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to form haloalkoxy groups. More preferred haloalkoxy groups are lower haloalkoxy groups having one to six carbon atoms and one or more halo groups. Examples of such groups are: 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, wherein these rings may be bonded to one another or fused. The term aryl refers to aromatic groups such as phenyl, naphthyl, tetrahydronaflyl, indane and biphenyl. Aryl residues may also be substituted at one of the substitutable positions by one or more substituents independently selected from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halogen, nitro, alkylamino, acyl, cyano, carboxy , aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term heterocyclyl refers to a saturated, partially unsaturated and unsaturated heteroatom containing ring-shaped groups, wherein the heteroatoms may be

-12 taken from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic groups include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3-6 membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (for example, morpholinyl, etc.); saturated 3-6 membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclic groups are dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The term heteroayl refers to unsaturated heterocyclic groups. Examples of unsaturated heterocyclic groups, also called heteroalyl groups, are unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl pyrazinyl, pyridazinyl, triazazolyl (e.g. 4H-1,2, 4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc .; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (for example tetrazolo [1,5-b] pyridazinyl, etc.), etc .; unsaturated 3-6 membered heteromonocyclic groups containing one oxygen atom, for example pyranyl, furyl, etc .; unsaturated 3-6 membered heteromonocyclic groups containing one sulfur atom, for example, thienyl, etc .; unsaturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2 , 5-oxadiazolyl, etc.) etc .; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (for example benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 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 groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (for example benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term also refers to groups wherein heterocyclic groups are fused to aryl groups. Examples of these fused bicyclic groups are benzofuran, benzothiophene and the like. Said heterocyclic groups may have 1 to 3 substituents such as alkyl, hydroxyl, halogen, alkoxy, oxo, amino and alkylamino groups. The term alkylthio refers to groups containing a linear or branched alkyl substituent having from one to ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio

-13 groups are lower alkylthio groups having alkyl groups containing from one to six carbon atoms. Examples of these lower alkylthio groups are: methylthio, ethylthio, propylthio, butylthio and hexylthio. The term alkylthioalkyl ¹ refers to groups containing one alkylthio group bonded via a divalent sulfur atom α to an alkyl group having from one to ten carbon atoms. More preferred alkylthioalkyl groups are lower alkylthioalkyl groups having alkyl groups containing from one to six carbon atoms. An example of such a lower alkylthioalkyl substituent is methylthiomethyl. The term alkylsulfinyl * denotes groups containing a linear or branched alkyl substituent having from one to ten carbon atoms attached to the divalent -S (= O) substituent. More preferred alkylsulfinyl groups are lower alkylsulfinyl groups having alkyl groups containing from one to six carbon atoms. Examples of such lower alkylsulfinyl groups are: methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term sulfonyl, whether used alone or in conjunction with other terms such as alkylsulfonyl, optionally denotes the bivalent groups -SO 2 *. Alkylsulfonyl refers to alkyl groups attached to a sulfonyl group, wherein alkyl is as defined above. More preferred alkylsulfonyl groups are lower alkylsulfonyl groups having one to six carbon atoms. Examples of these lower alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl and propylsulfonyl. The alkylsulfonyl groups may be further substituted with one or more halogen atoms, such as fluoro, chloro or bromo, to form haloalkylsulfonyl groups. The term sulfamyl, aminosulfonyl and sulfonamidyl * denotes NH2O2S-. The term acyl refers to a substituent that results from the removal of hydroxyl from an organic acid. Examples of these acyl substituents are alkanoyl and aroyl. Examples of these lower alkanoyl groups are: formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl. The term carbonyl, either used alone or in conjunction with other terms such as alkoxycarbonyl, means - (C = O) -. The term aroyl refers to an aryl substituent with a carbonyl substituent as defined above. Examples of the aroyl substituent are benzoyl, naphthoyl and the like, and the aryl in said aroyl may be additionally substituted. The terms carboxy or carboxyl, either used alone or together with other terms such as carboxyalkyl, refer to CO 2 H. The term carboxyalkyl * denotes alkyl groups substituted with a carboxy group. More preferably, the lower caiboxyalkyl groups, which denote the lower alkyl groups defined above, may be additionally substituted with halo on the alkyl. Examples of these

The 14-lower carboxyalkyl groups are carboxymethyl, cariboxyethyl and carboxypropyl. The term alkoxycarbonyl refers to a group containing an alkoxy substituent as defined above, attached through an oxygen to the carbonyl group. More preferred are lower alkoxycarbonyl groups with alkyls of 1 to 6 carbons. Examples of these lower alkoxycarbonyl (ester) groups are substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl groups. The terms alkylcarbonyl, arylcarbonyl and aralkylcarbonyl refer to groups containing alkyl, aryl and aralkyl groups as defined above, attached to a carbonyl group. Examples of these groups are substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl groups. The term aralkyl refers to aryl-substituted alkyl groups such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may additionally be substituted by halogen, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term heterocyclylalkyl refers to saturated and partially unsaturated heterocyclyl substituted alkyl groups such as pyrrolidinylmethyl, and heteroaryl substituted alkyl groups such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl and quinolylethyl. The heteroaryl in said heteroaralkyl may additionally be substituted by halogen, alkyl, alkoxy, haloalkyl and haloalkoxy. The term aralkoxy refers to aralkyl groups attached through oxygen to other groups. The term aralkoxyalkyl refers to aralkoxy groups attached through an oxygen to an alkyl group. The term aralkylthio refers to aralkyl groups attached to a sulfur atom. The term aralkylthioalkyl refers to aralkylthio groups bonded via sulfur to an alkyl group. The term aminoalkyl refers to alkyl groups substituted with one or more amino groups. More preferred are lower aminoalkyl groups. Examples of these groups are aminomethyl, aminoethyl and the like. The term alkylamino refers to amino groups which have been substituted with one or two alkyl groups. Preferred are lower N-alkylamino groups having 1 to 6 carbon atoms in the alkyl moiety. Suitable lower alkylamino groups may be mono or dialkylamino groups such as N-methylamino, N-ethylamino, N, N-dimethylamino, Ν, Ν-diethylamino or the like. The term arylamino refers to amino groups which have been substituted with one or two aryl groups such as N-phenylamino. Arylamino groups may be further substituted on the aryl ring. The term aralkylamino refers to aralkyl groups attached through the amino nitrogen to other groups. The terms N-arylaminoalkyl and N-aryl-N-alkyl-aminoalkyl refer to amino groups which have been substituted with one aryl group or one aryl and one alkyl

And having an amino group attached to an alkyl. Examples of such groups are N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term aminocarbonyl refers to an amido group of formula -C (= O) NH 2 - The term alkylaminocarbonyl refers to an aminocarbonyl group which has been substituted with one or two alkyl groups on the nitrogen of the amino group. Preferred are ^N N-alkylaminocarbonyl Ν, Ν-dialkylaminocarbonyl groups. More preferably, the "lower N-alkylaminocarbonyl" is a lower Ν, dia-dialkylaminocarbonyl group having a lower alkyl moiety as defined above. The term alkylaminoalkyl refers to groups having one or more alkyl groups attached to an aminoalkyl group. The term aryloxyalkyl refers to groups having an aryl group attached to an alkyl group via a divalent oxygen atom. The term arylthioalkyl refers to groups having an aryl group attached to an alkyl group via a divalent sulfur atom. The compounds used in the method of the invention may be present in the form of the free bases or their pharmaceutically acceptable acid addition salts. The term pharmaceutically acceptable salts refers to those salts commonly used in the form of alkali metal salts and those which form addition salts of free acids or free bases. The nature of the salt is not critical, provided it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared from an inorganic or organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids may be selected from the group of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids. Examples are: formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic acid almond, embon (pamo), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanil, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicylic, galactaric and galactaric. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) are aluminum, calcium, lithium, magnesium, potassium, sodium and zinc salts or organic salts prepared from N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-glucamine). . All of these salts can be prepared by conventional methods, for example by reacting the corresponding compound of formula I with a suitable acid or base.

-16General synthesis methods

The present invention provides compounds which function as cyclooxygenase2 inhibitors can be synthesized by the following procedures of Schemes I-X, wherein the substituents R 1 -R 3 are as defined for formula I unless otherwise specified.

Scheme I

Synthetic scheme I shows the preparation of cyclooxygenase-2 inhibitors as described in U.S. Patent Nos. 5,521,207 and WQ95 / 15316, which are incorporated by reference and adapted for Formula I. In step 1, ketone 1 is treated with a base, preferably NaOMe. or NaH, and an ester, or equivalent thereof, to give the diketone 2 intermediate (in enol form), which is used without further purification. In step 2, diketone 2 is refluxed in anhydrous protic solvent (absolute ethanol or acetic acid) with salt hydrochloride or free base substituted hydrazine to give a mixture of pyrazoles 3 and 4. Recrystallization or chromatography yields 3 usually as a solid. Similar pyrazoles can be prepared by the methods described in U.S. Pat. Nos. 4,146,721, 5,051,518, 5,134,142 and 4,914,121, which are also incorporated herein by reference.

17Schémall

R ^1ZX 1X1 ^ ^SR2 2) Äco-x *

Scheme Π shows a four step synthesis of the preparation of a cyldooxygenase-2 inhibitor, pyrazoles 8 from ketones S, as described in U.S. Patent No. 5,486,534 (where R ^a is a hydrido or alkyl group). In step 1, ketone 5 is reacted with a base such as lithium bis (triinetylsilyl) amide or lithium diisopropylamide (LDA) to form an anion. In step 2, this anion reacts with an acetylating agent to form diketone 6. In step 3, reacting diketone 6 with hydrazine or substituted hydrazine to form pyrazole 7. In step 4, pyrazole 7 is oxidized by an oxidizing agent such as Oxone® (potassium persulfate), 3 -chloroperoxybenzoic acid (MCPBA) or hydrogen peroxide, to give a mixture of the desired 3 (alkylsulfonyl) phenyl pyrazole 8 and the isomer of the 5- (alkylsulfonyl) phenyl pyrazole. The desired pyrazole 8, usually a white or pale yellow solid, is obtained in pure form either by chromatography or by recrystallization.

Alternatively, diketone 6 can be obtained by reacting ketone 5 with a base, for example sodium hydride, in a solvent, for example dimethylfoimamide, and further reacting with nitrile to form an aminoketone. Treatment of the aminoketone with an acid produces a diketone 6. Similar pyrazoles can be prepared by the methods described in U.S. Patent No. 3,984,431, which is incorporated by reference.

-18Schémam

Cyclooxygenase-2 diaryl / heteroaryl thiophene inhibitors (where T is S, and is alkyl) can be prepared by the methods described in U.S. Patent Nos. 4,427,693, 4,302,461, 4,381,311,4,590,205, and 4,820,827 and PCT documents WO 95/00501 and WO94 / 15932, which are incorporated herein by reference. Similar pyrroles (where T is N), furanones and furans (where T is O) can be prepared by the methods described in PCT documents WO 95/00501 and WO94 / 15932 and in EP799 823.

-19Scheme IV

MCPBA

OH

or ³ -A o

R ^2, S

R ³ COC1 base

TBSO

Cyclooxygenase-2 diaryl / heteroaryl oxazoles inhibitors can be prepared by the methods described in U.S. Patent Nos. 3,743,656, 3,644,499 and 3,647,858, and PCT documents WO 95/00501 and WO94 / 27980, which are incorporated herein by reference. Equivalent oxazole compounds can be prepared by WO96 / 19463 and WO96 / 19462.

-20Scheme V

1) C1SO ₃ H

2) NH ₄ OH

Cyclooxygenase-2 diaryl / heteroaryl isoxazole inhibitors may be prepared by the methods described in U.S. Patent No. 5,633,272, PCT Documents WO92 / 05162, and WO92 / 19604, and European Publication EP 26928, which are incorporated herein by reference. The sulfonamides 24 can be prepared by a two-step synthesis from hydrated isoxazole 23. First, the hydrated isoxazole 23 is treated at 0 ° C with two or three equivalents of chlorosulfonic acid to give the corresponding sulfonyl chloride. In a second step, the sulfonyl chloride so formed is treated with concentrated ammonia to give the sulfonamide derivative 24.

-21Scheme VI

Alkylaluminum reagent -------------------- * · Solvent

n ¹ »

Scheme VI shows a three-step preparation of cyclooxygenase-2 inhibitors, imidazoles 29 of the invention. In step 1, by reaction of substituted nitriles (R 1 CN) 25 s

primary phenylamines 26 in the presence of alkylaluminium reagents such as trimethylaluminum, triethylaluminum, dimethylaluminum chloride, diethylaluminium chloride and in the presence of inert solvents such as toluene, benzene and xylene, amidines 27 are formed. Cl) in the presence of bases such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or protected tertiary amines such as Ν, Ν'-diisopropylethylamine, 4,5 dihydroimidazoles 28 (where R b is alkyl) are formed. Suitable solvents for this reaction are isopropanol, acetone and dimethylformamide. The reaction can be carried out at temperatures from 20 ° C to 90 ° C. In step 3, 4,5-dihydroimidazoles 28 can be dehydrated by the action of an acid catalyst such as 4-toluenesulfonic acid or mineral acids to form

-221,2-disubstituted imidazoles 29 of the invention. Suitable solvents for this dehydration step are, for example, toluene, xylene and benzene. Trifluoroacetic acid can be used as solvent and catalyst for this dehydration step.

In some cases (e.g., where R ³ = methyl or phenyl), intermediate 28 is difficult to isolate. Under the conditions described above, the reaction affords the intended imidazoles directly. .

Similarly, imidazoles can be prepared by attaching a sulfonylphenyl moiety to the 2-position and attaching to the nitrogen atom at the 1-position. WO 93/14082, incorporated herein by reference.

Scheme VII

OTMS

N I

H

The object of the invention, imidazole cyclooxygenase-2,36 inhibitors, can be synthesized according to Scheme VII above. The aldehyde 30 can be converted to the protected cyanohydrin 31 by reaction with a trialkylsilyl cyanide such as trimethylsilyl cyanide (TMSCN), in the presence of a catalyst such as zinc iodide (Zn 12) or potassium cyanide (KCN). Reaction of cyanohydrin 31 with a strong base followed by reaction with benzaldehyde 32 (where R ² is alkyl) followed by treatment with an acid followed by reaction with a base gives benzoin 33. Examples of strong bases suitable for this reaction are lithium diisopropylamide (LDA). and lithiumhexamethyldisilazane. Benzoin 33 can be converted to benzil 34 by reaction with a suitable oxidizing agent such as bismuth or manganese dioxide, or Swem oxidation using dimethylsulfoxide (DMSO) and trifluoroacetic anhydride. Benzil 34 can be obtained directly by reacting the cyanohydrin anion 31 with a substituted benzoic acid halide. Any of compounds 33 and 34 can be used as an intermediate to convert to imidazoles 35 (where R ² is alkyl) by known chemical procedures as described in MR Grimmett, Advances in Imidazole Chemistry in Advances in Heterocydic Chemistry, 12, 104 (1970) . Conversion of 34 to imidazoles 35 is accomplished by reaction with ammonium acetate and a suitable aldehyde (R 2 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 acylation with a suitable acyl group (R ³ CO-) followed by reaction with ammonium hydroxide. It is known that the oxidation of sulfide (where R ² is methyl) to sulfone can be carried out at any time during the synthesis, starting with compounds 35 and ending with oxidation of imidazoles 38, using for example reagents such as hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid (MCPBA) and potassium persulfate (OXONE®).

Diaryl / heteroaryl imidazoles can be prepared by the methods described in U.S. Pat. Nos. 3,707,475.4,686,231.4,503,065.4,472,422, 4,372,964, 4,576,958, 3,901,908, U.S. patent application Ser. No. 08/281,903, European application EP 372 445, and PCT document WO 95/00501, which are incorporated herein by reference.

-24SchemeVUI r ² so

br

ZnCl

1n-BuLi, THF, -78C · ZnCl ₂

Diaryl / heteroaryl cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent No. 5,344,991, and PCT document WO 95/00501, which are incorporated herein by reference.

SchémalX

R1 ^, B (OH) 2

Pd °, PhCH ₃ , c ₂ h ₅ oh, N & 2 CO 3, Δ

Similarly, Synthesis Scheme IX shows a process for preparing 1,2-diabenzene cyclooxygenase-244 inhibitors from 2-bromo-biphenyl intermediates 43 (prepared similarly to that described in the synthesis scheme in m) and suitably substituted phenylboronic acids. Using a coupling procedure similar to that developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)], the intermediates 43 are refluxed with boric acids in toluene / ethanol in the presence of a Pd ° catalyst, e.g., tetrakis (triphenylphosphine) palladium (0), and 2M sodium carbonate to form sodium carbonate. of the corresponding 1,2-diarylbenzene anti-inflammatory agents 44 of the invention. These terphenyl compounds can be prepared by the methods described in PCT Patent Document WO96 / 16934, which is incorporated herein by reference;

Scheme X

with

Diaryl / heteroaryl thiazole inhibitors of cyclooxygenase-2 can be prepared by the methods described in U.S. Patent Nos. 4,051,250, 4,632,930, European Application EP 592,664, and PCT documents WO96 / 03392 and WO 95/00501, which are incorporated herein by reference. Isothiazoles can be prepared as described in PCT document WO 95/00501.

The diaryl / heteroaryl pyridine cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Patent Nos. 5,169,857, 4,011,328, 4,533,666, and WO96 / 24584 and WO96 / 24585, which are incorporated herein by reference.

Biological evaluation Antiangiogenic test

To determine the effect of COX-2 inhibitors on angiogenesis in vivo, selective compounds were tested by a comical microcapsule assay in mice and rats. The mouse comical neovascularization microcapsule model was performed using materials, reagents and procedures as described in Muthukkauppah et al., J. Natl. Cancer Inst. 69: 699-708 (1982). In this assay, a fiber containing basic fibroblast growth factor (FGF) was implanted into the comical supporting connective tissue of the mouse and the newly formed veins were measured by a slit lamp. In this model, COX-2 is extruded into endothelial cells of emerging blood veins. COX-2 inhibitor, 4- [5- (4-chlorophenyl) -

3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide inhibited FGF-induced

I angiogenesis in mice (70-90%) at 6 mg / kg / day.

In the rat microcapsule assay, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazoll-yl] benzenesulfonamide administered only once inhibited FGF-induced angiogenesis (~ 90%).

We also determined the effects of the COX-2 inhibitor (4- [5- (4-chlorophenyl) -3- (difluoromethyl) 1H-pyrazol-1-yl) benzenesulfonamide) on mouse cornea using another angiogenic stimulus, vascular endothelial growth factor (VEGF). In this model, angiogenesis was inhibited (5050%) after administration of the compound at 6 mg / kg.

I I

Metastasis model

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

The invention includes pharmaceutical compositions for treating angiogenic disorders, therapeutically effective amounts of a compound of Formula I in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent (collectively referred to herein as a carrier) and optionally other active ingredients. The active ingredients of the invention may be administered

By any known suitable method, preferably in the form of a pharmaceutical composition acceptable to the method and at a dose effective for the intended treatment. The active agents and compositions can be administered, for example, orally, intravascularly, intraperitoneally, intranasally, intrabronchially, subcutaneously, intramuscularly, or externally (including an aerosol). Following localization of angiogenesis, local administration is preferred over systemic administration. The preparation of medicaments in a lipid vehicle can be used to increase bioavailability.

The compounds of the invention may be administered for the purpose of either prevention or treatment. The methods and compositions used herein can be used alone or in conjunction with known adjunctive therapies to prevent and treat angiogenesis. Alternatively, the methods and compositions described herein can be used as adjunctive therapy. For example, the cyclooxygenase-2 inhibitor may be administered alone or in conjunction with other antineoplastic agents

There are a number of antineoplastic agents available commercially, in clinical trials and in preclinical research that could be selected for the treatment of angiogenesis with combination drug chemotherapy. These antineoplastic agents fall into several main categories: antibiotic-type substances, alkylating agents, antimetabolites, hormonal agents, immunologicals, interphonic-type substances and a variety of diverse substances. Alternatively, other anti-neoplastic agents such as metallomatic protease (MMP) inhibitors may be used, for example MMP-13 inhibitors including batiastate, marimastate, Agouron Pharmaceuticals AG-3340, and Roche RO-32-3555 or avb3 inhibitors.

The first class of antineoplastic agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of antimetabolite-type antineoplastic agents. Suitable antineoplastic agents of the antimetabolite type may be selected from

I of the following groups: 5-FU-fibrinogen, acanthifolinic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrelin Dow DDOS, dideoxyin dosh, dideocinine, dideocin, DMDC, doxifluridine, Wellcome EHNA, Merck & EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrolizine, Lilly LY-188011, Lilly LY-264618, metobenzaprim, methotrexate MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Wamer-Lambert PA PAA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, thiazole

-28Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Tai UFT and uricytin.

A second group of antineoplastic agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of alkylating-type antineoplastic agents. Suitable antineoplastic agents of the alkylating type may be selected from the following group: Shionogi 254-S, aldophosphamide analogs, altretamine, anaxirone, Boehringer Mannheim BBR2207, bestrabucil, budotitan, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinobu-153, Chinobu-153. cisplatin, cyclophosphamide, American Cyanamide CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP (Myr) 2, diphenylspiromustine, diplatin cytostatics, Erba distamycin derivatives, Chugai DWA2114R, elΠ E09 -24517, estramustine phosphate sodium, photemustine, Unimed G-6-M, quinoin GYKI-17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK & F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.

I

A third group of antineoplastic agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from the following group: Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysmin derivative, Ajinomoto AN-201-Π, Ajinomoto AN-3, Nippon Sodium anisycycins, anthracycin, anthracycin -mycm-A, bizukaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin- 1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, Ditrisarubicin D, Shionogubicin B -41, doxorubicin, doxorubicin-fibrinogen, elzamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobatin-900482, grincamycin, herbimycin, idaiubicin, illudins, caseusamycin, kesarirhodins, Kyowa Hakko KM-55 39, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-6149, American Cyanamide LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,

-29mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI Intemational NSC-357704, oxalysin, oxaunomycin, peplomycin, pilatin, pirarubicin, porotramycin, pyrindamycin A, Tobamini RA-I, Tobishi RA-I, risoxin, rhodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparzomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN868A, turpentecin, trazine, tricrosarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024, and zorubicin.

A fourth group of antineoplastic agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of a diverse group of antineoplastic agents selected from the following group: alpha-carotene, alpha-difluoromethylarginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amidine , amphetinil, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, afidicoline glycinate, asparaginase, Avarol, baccharin, batracyline, benfluron, B01ourourourour, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromophosphamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmetizole hydrochloride, Ajinomoto CDAF, chlorosulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Wamer-Lambert -921, Wamer-Lambert CI-937, Wamer-Lambert CI-941, Clanfenur, Claviridenone, ICN Compound 1259, ICN Compound 4711, Contracan, Yakult Honsha CPT11, krisnatol, kuraderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptin, didemnin-B, dihematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-341, Toyo Pharmar DM-341, Toyo Pharmar DM-341 -9693, elliprabin, elliptin acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, 221, homoharingtonine, hydroxyurea, BTG ICRF-187, ilmophosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COON, Kureha Chemical K-AM, MECT Corp KI-8110, Cyanamide L-623 American, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY186641, NCI (US) MAP, marycine, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivine, mitonafide, mopidamole, motretinide, Zenyaku Kogyo MST-16, N (retinoyl) am other acids, Nisshin Flour Milling N-021, N-acylated dehydrolanines,

-30 naphazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, ochizanocin, Akzo Org-10172, pancratistinatin, , Wamer-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhematoporphyrin, polypreic acid, Efamol porphyrin, probiman, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, reteliptin, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK & F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermania, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldion, Suntory SUN 0237, Suntoiy SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin ΙΈΙ-030 , teniposide, taliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, Ukraine, Eastman Kodak USB-006, vinblastine sulphate, vincristine, vindezine, vinestramide, vinorelbine, vintriptol, vinzolidine, witanolides and Yamanouchi YM-534.

• * «

I ·

I i · ¹

Examples of radioprotective agents that can be used in the combination chemotherapy of this invention are: AD-5, adchon, amifostine analogs, detox, dimesna, 1-102, MM-159, Nacylated dehydrolanines, TGF-Genentech, tiprotimod, amifbstin, WR-151327 , FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.

Methods for preparing the antineoplastic agents described above can be found in the literature. For example, methods for preparing doxorubicin are described in U.S. Patent Nos. 3,590,028 and 4,012,448. Methods for preparing metallomatic protease inhibitors are described in EP 780386, WO97 / 20824, WO96 / 15096. Methods for preparing SOD imitations are described in EP 524 101. Methods for preparing 8vb3 inhibitors are described in WO97 / 08174.

In addition, for maximum safety and efficacy, a selective COX-2 inhibitor may be administered in conjunction with other anti-inflammatory agents, including NSAID's, selective COX1 inhibitors, and leukotriene pathway inhibitors, including 5-lipoxygenase inhibitors. Examples of NSAID's are indomethacin, naproxen, ibruprofen, salicylic acid derivatives such as aspirin, diclofenac, ketorolac, piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium, zomepirac, fenoprofen, phenylbutazone, nimesfenbutidolaz, oxyfenbutidola and oxyfenbutidola.

-31Termline adjunctive therapy (or “combination therapy”) in the definition of the use of a cyclooxygenase-2 inhibitor and one or more pharmaceutical agents means administration of each agent in a prescribed dosage regimen, which provides the beneficial effects of that combination of drugs and concurrent administration of these agents. in a simultaneous manner, i.e. in the form of a single preparation having a constant ratio of these active substances, or in the form of several separate preparations containing the individual substances.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably formulated in a dosage form containing a certain amount of active ingredient. Examples of such dosages 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, acacia, corn starch or gelatin; with disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate. The active ingredient can also be administered by injection as a composition in which, for example, saline, glucose or water can be used as a suitable carrier.

For intravenous, intramuscular, subcutaneous or intraperitoneal administration, the agent may be combined with sterile aqueous solutions, which are preferably isotonic with the blood of the recipient. These compositions 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 buffered pH compatible with physiological conditions to form an aqueous solution that can be sterilized. The formulations may be in single or multi-dose containers such as sealed ampoules or vials.

When angiogenesis is localized in the gastrointestinal tract, the substance can be made with an acid-stable and alkali-resistant coating that begins to dissolve at high pH in the small intestine. Formulations enhancing local pharmacological effects and reducing systemic absorption are preferred.

Formulations suitable for parenteral administration include sterile aqueous preparations of the active ingredient which are preferably made isotonic. Formulations for injection may also be prepared by suspending or emulsifying these substances in a non-aqueous solvent such as vegetable oil, synthetic glycerides of aliphatic acids, esters of higher aliphatic acids or propylene glycol.

External formulations include known gels, creams, oils and the like. For aerosol delivery, the substances can be manufactured with known aerosol exipients, such as saline, and administered using commercially available humidifiers. Fatty acid sources can be used to enhance biocompatibility. Aerosol delivery is the preferred method of delivery for epithelial angiogenesis of the lungs in preventive application.

For rectal administration, the active ingredient can be formulated as a suppository using a base that is solid at room temperature and melts or dissolves at body temperature. Commonly used bases are coca butter, glycerinated gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty esters of polyethylene stearate.

The dosage form and amount can be readily estimated by reference to a known treatment or prophylactic regimen. The amount of the therapeutically active agent administered and the dosage regimen for treating the disease with the agents and / or compositions of the invention depends on a number of factors including the age, weight, sex and health of the individual, the severity of the disease, route and frequency of administration and the agent used, the position of angiogenesis, as well as the pharmacological properties of the individual being treated, which can vary greatly. The dose will generally be lower if the substances are administered topically, instead of systemically, and preventively instead of the clinic. The medicines may be administered as needed and at intervals recommended by the attending physician. It will be appreciated that the dosage regimen or therapeutically effective amount of inhibitor administered must be optimized for each individual. The pharmaceutical compositions may contain the active ingredient in the range of from 0.1 to 2000 mg, preferably from 0.5 to 500 mg, and most preferably from 1 to 200 mg. A daily dose of from 0.01 to 100 mg / kg body weight, preferably from 0.1 to 50 mg / kg body weight, will be appropriate. The daily dose may be administered in one to four doses per day.

All documents mentioned herein are incorporated by reference.

Although the present invention is described with respect to a specific embodiment, the details of this embodiment are not to be considered as limiting.

Claims (10)

PATENT CLAIMS Use of a therapeutically effective amount of a cyclooxygenase-2 inhibitor of formula I Wherein A is a substituent selected from oxazolyl, isoxazolyl, thienyl, dihydrophthyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl and pyridyl; wherein rJ is at least one substituent selected from heterocyclyl, C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl and aryl, wherein it is optionally substituted at one of the substitutable positions with one or more groups selected from C ₁ -C ₁₂ alkyl, C 1 -C 4 haloalkyl , cyano, carboxyl, C1-C10-alkoxycarbonyl, hydroxyl, C1-C10-hydroxyalkyl, C1-C10-haloalkoxy, amino, C1-C12-alkylamino, arylamino, nitro, C1-C10-alkoxyalkyl, C1-C10-alkylsulfinyl, halogen, C1-C10 -alkoxy and C 1 -C 10 -alkylthio; wherein R 2 is methyl or amino; and wherein R ³ is selected from hydrido, halogen, C 1 -C 10 -alkyl, C 1 -C 12 -alkenyl, C 2 -C 12 alkynyl, oxo, cyano, carboxyl, C 1 -C 8 -cyanoalkyl, heterocyclyloxy, C 1 -C 10 -alkyloxy, alkylthio, alkylcarbonyl, C ₃ -C ₁₂ -cycloalkyl, aryl, C 1 -C ₁₂ -haloalkyl, heterocyclyl, C 3 -C 12 cycloalkenyl, aryl-C 1 -C 8 alkyl, heterocyclyl-C 1 -C 8 alkyl, acyl, C 1 -C 10 -alkylthio-C 1 -C 8 alkyl, C 1 -C 10 - hydroxyalkyl, C 1 -C 10 -alkoxycarbonyl, arylcarbonyl, aryl-C 1 -C ₁₂ -alkylcarbonyl, aryl-C 2 -C 12 -alkenyl, C 1 -C 10 -alkoxy-C 1 -C ₁₂ -alkyl, arylthio-C 1 -C ₁₀ -alkyl, aryloxy- C 1 -C 10 alkyl, aryl-C 1 -C 10 -alkylthioalkyl, aryl-C 1 -C 10 -alkoxyalkyl, C 1 -C ₁₀ -alkoxyaryl-C 1 -C ₁₀ -alkoxy-C 1 -C ₁₂ alkyl, C 1 -C 10 -alkoxycarbonyl-C 1 -C 10- alkyl, aminocarbonyl, Cl-Cl 2-aminocarbonyl-alkyl, ClCN-alkylaminocarbonyl, N-arylamino carbonyl, N- (Cl-Cl2-alkyl) N-arylaminocarbonyl, C-Cl 2 -alkylaminocarbonyl-C-Cl2-alkyl, C ₂ -karboxyalkyl, Cl-Cl2-alkylamino, Narylamino, N- (aryl-Ci-C ₂ alkyl) amino, N- (Cl-Cl2-alkyl) -N- (aryl-Cl-Cl2-alkyl) amino, N (Cl-Cl2-alkyl) -N-ar ylamino, C-Cu-aminoalkyl, C-Cl2-alkyl amino-C _y Cl 2-alkyl-Narylamino C-Cl2-alkyl, N- (aryl-Ci-C ₂ alkyl) amino-C-C _l2-alkyl, N - (- C 1 -C 12 -alkyl) -N- (arylC 1 -C 12 -alkyl) amino-C 1 -C 12 -alkyl, N- (C 1 -C ₁₂ -alkyl) -N-arylamino-C 1 -C ₁₂ -alkyl, aryloxy , arylC 1 -C 10 -alkoxy, arylthio, aryl-C 1 -C 10 -alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, Cr 1 -34Cn-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N - (- C 1 -C ₁₂ -alkyl) -N-arylaminosulfonyl; or a pharmaceutically acceptable salt thereof; for the preparation of a medicament for treating or preventing a disorder associated with angiogenesis selected from metastasis, ocular neovascularization, retinal neovascularization, diabetic retinopathy, infantile hemangiomase, and disorders of the female reproductive system, in an individual in need of such treatment or prevention. Use according to claim 1, wherein the angiogenesis-related disorder is endometriosis. The use of claim 1, wherein the angiogenesis-related disorder is ocular neovascularization. The use of claim 1, wherein A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, cyclopentenyl, phenyl and pyridyl; wherein is selected from 5- or 6-membered heterocyclyl, C ₂ -C 8 -cycloalkyl, C 1 -C 8 -cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 1 is optionally substituted at one of the substitutable positions, once or by multiple groups selected from C1-C6-alkyl, C1-C6-haloalkyl, cyano, carboxyl, C1-C6-alkoxycarbonyl, hydroxyl, C1-C6-hydroxyalkyl, C1-C6-haloalkoxy, amino, C1-C6-alkylamino, phenylamino, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylsulfinyl, halogen, C 1 -C ₆ -alkoxy and C 1 -C ₆ -alkylthio; wherein R ² is methyl or amino; and wherein R ³ is selected from hydrido, oxo, cyano, carboxyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 carboxyalkyl, C 1 -C 6 cyanoalkyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 3 -C ₈ -cycloalkyl, phenyl, C 1 -C 6 -haloalkyl, 5- or 6-membered heterocyclyl, C 1 -C 6 -hydroxylalkyl, aryl-C 1 -C 6 alkyl, formyl, phenylcarbonyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl 5- or 6-membered heteroaryloxy, aminocarbonyl, C1-C6-alkylaminocarbonyl, C1-C6-alkylamino, C1-C6-aminoalkyl, C1-C6-alkylamino-C1-C6-alkyl, phenyloxy and lower aryl-C1-C6-alkoxy; or a pharmaceutically acceptable salt thereof. The use of claim 4, wherein A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and cyclopentenyl; wherein R 1 is selected from: pyridyl, optionally substituted in one of the substitutable positions with one or more methyl groups and phenyl, optionally substituted in one of the substitutable positions with one or more groups selected from 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, Ν, Ν-dipropylamino, N-butylamino N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentoxy and methylthio; wherein is methyl or amino; and where R? is selected from hydrido, oxo, cyano, caiboxyl, 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, thiazolyl, oxazolyl, furyl, pyrazinyl ,. hydroxylmethyl, hydroxylpropyl, benzyl, formyl, phenylcarbonyl, methoxymethyl, furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl, Ν, Ν-dimethylaminocarbonyl, Ν, Ν-dimethylamino, Nethylamino, Ν, Ν-dipropylamino, N-butylamino, N-methyl ethylamino, aminomethyl, N, N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl benzyloxy and phenyloxy; or a pharmaceutically acceptable salt thereof. Use according to claim 5, wherein the substance is selected from the following compounds and their pharmaceutically acceptable salts: 5- (4-fluorophenyl) -l- [4- (methylsulfonyl) phenyl] -3- (trifluómietyl) pyrazole; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] 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-chloro-phenyl) -3-phenyl-lH-pyrazol-l-yl) benzenesulfonamide; 4- (3,5-bis (4-methoxyphenyl) -lH-pyrazol-l-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (4-methylphenyl) -lH-pyrazol-l-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -lH-pyrazol-l-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -lH-pyrazol-l-yl) benzenesulfonamide; 4- [5- (4-Chloro-phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- (4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yljbenzénsulfónamid; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yljbenzénsulfónamid; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluónnetyl) -5-phenyl-lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [3-cyano-5- (4-fluorophenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -lH-pyrazol-l-yljbenzénsulfónamid; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [4-chloro-5-phenyl-lH-pyrazol-yljbenzénsulfónamid; 4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -lH-pyrazol-l-ylJbenzénsulfónamid; 4- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 2-methyl-4- [1- [4- (methylsulfonyl) phenyl] -4 - (trifluoromethyl) -lH-imidazol-2-ylJpyridín; 2-methyl-6- [l- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -lH-imidazol-2-ylJpyridín; 4- [2- (6-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; 2- (3,4-difluorophenyl) -l- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -lH-imidazole; 4- [2- (4-methylphenyl) -4- (trifluoromethyl) -lH-imidazol-ylJbenzénsulfónamid; 2- (4-chlorophenyl) -l- [4- (methylsulfonyl) phenyl] -4-methyl-lH-imidazole; 2- (4-chlorophenyl) -l- [4- (methylsulfonyl) phenyl-4-phenyl-lH-imidazole; 2- (4-chlorophenyl) -4- (4-fluorophenyl) -l- [4- (methylsulfonyl) phenyl-lH-imidazole; 2- (3-fluoro-4-methoxyphenyl) -l- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -lH-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) -lH-imidazol-l-yl] benzenesulfonamide; 2- (3-fluoro-5-methyl-phenyl) -l- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -lH-imidazole; 4- [2- (3-fluoro-5-methylphenyl) -4- (trifluoromethyl) -lH-imidazol-ylJbenzénsuIfónamid; 2- (3-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole; 4- [2- (3-methylphenyl) -4-trifluoromethyl-lH-imidazol-l-yl] benzenesulfonamide; l- [4- (methylsulfonyl) phenyl-2- (3-chlorophenyl) -4-trifluoromethyl-lH-imidazole; 4- [2- (3-chlorophenyl) -4-trifluoromethyl-lH-imidazol-yljbenzénsulfónamid; 4- [2-phenyl-4-trifluoromethyl-lH-imidazol-yljbenzénsulfónamid; 4- [2- (4-methoxy-3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; l-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -lH-pyrazole; 4- [l-ethyl-4- (4-fluorophenyl) -5- (trifluoromethyl) -lH-pyrazol-3-yljbenzénsulfónamid; N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -lH-pyrazol-lyljacetamid; Elyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -lH-pyrazol-l-ylJacetát; 4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl-l- (2-phenylethyl) -lH-pyrazole; 4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -5- (trifluoromethyl) pyrazole; l-ethyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -lH-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-phenyl-isoxazol-4-yl] benzenesulfonamide; 4- [5-difluoromethyl-3-phenyl-isoxazol-4-ylJbenzénsulfónamid; 4- [5-hydroxymethyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide; -374- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide; l- [2- (4-fluorophenyl) cyclopenten-l-yl] -4- (methylsulfonyl) benzene; l- [2- (4-fluoro-2-methylphenyl) cyclopenten-l-yl] -4- (methylsulfonyl) benzene; l- [2- (4-chlorophenyl) cyclopenten-l-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) 4- [2- (4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide; 1- [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonyl) 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-l-yl] benzenesulfonamide; 4- [2- (2-methylpyridin-5-yl) cyclopenten-l-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] ethanoic acid; 2- (tert-butyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazole; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyl-oxazole; 4- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl] oxazole; and 4- [5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide. Use of a therapeutically effective amount of a compound of Formula II II wherein R ² * is selected from hydrido, C 1 -C 10 -alkyl, haloalkyl, C 1 -C 10 -alkoxycarbonyl, cyano, C 1 -C 12 -cyanoalkyl, carboxyl, aminocarbonyl, C 1 -C 12 alkylaminocarbonyl, C 3 -C 12 -cycloalkylaminocarbonyl, alkylaminocarbonyl, C 1 -C 18 -38alkylaminocarbonyl, C 1 -C 10 -carboxyalkyl, aryl-C 1 -C 10 -alkoxycarbonyl-C 1 -C 10 -alkylaminocarbonyl, C 1 -C 12 -aminocarbonylalkyl, C 1 -C 10 -alkoxycarbonylcyano-C 2 -C 12 -alkenyl and C 1 -C 10 -hydroxyalkyl; wherein R 5 is selected from hydrido, C 1 -C 12 -alkyl, cyano, C 1 -C 10 -hydroxyalkyl, C 3 -C 12 -cycloalkyl, C 1 -C 12 -alkylsulfonyl and halogen; and wherein R ⁶ is selected from aryl-C 2 -C 12 -alkenyl, aryl, C 3 -C 12 -cycloalkyl, C 3 -C 12 cycloalkenyl and heterocyclyl; wherein R ⁴ is optionally substituted at one of the substitutable positions with one or more groups selected from halogen, C 1 -C 10 alkylthio, C 1 -C 12 -alkylsulfonyl, cyano, nitro, C 1 -C 6 haloalkyl, C 1 -C 10 -alkyl, hydroxyl, C 2 -C 10 -alkenyl, C 1 -C 12 -hydroxyalkyl, carboxyl, C 3 -C 12 -cycloalkyl, C 1 -C 10 -alkylamino, di-C 1 -C 12 -alkylamino, alkoxycarbonyl, aminocarbonyl, C 1 -C 10 -alkoxy, haloalkoxy, sulfamyl, heterocyclyl and amino groups, or a pharmaceutically acceptable salt thereof or a derivative. Use according to claim 7, wherein R ⁴ is selected from C 1 -C 6 -haloalkyl; wherein R 8 is hydrido; and wherein R 8 is selected from phenyl optionally substituted at one of the substitutable positions with one or more groups selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 -alkoxy groups; or a pharmaceutically acceptable salt or derivative thereof. The method of claim 8, wherein the agent is selected from the following compounds and pharmaceutically acceptable salts thereof: 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; I * 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methoxyphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -lH-pyrazol-l-yl] benzenesulfonamide; and 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide. The method of claim 9, wherein the agent is selected from the following compounds and pharmaceutically acceptable salts thereof: 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1- yljbenzénsulfónamid; and I 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide.