CZ176899A3 - Use of cyclooxygenase-2 inhibitors as anti-angiogenic substances - Google Patents

Abstract

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

Description

also desire cyclooxygenase-2 inhibitors as anti-angiogenic agents

Technical field

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 in 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, particularly the production of PGG2, PGH2 and PGE2, has been a major objective of anti-inflammatory drug research. However, conventional non-steroidal anti-inflammatory drugs (NSATD's) that are effective in reducing prostaglandin-induced pain and inflammation-related edema 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 unwanted 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 prodrugs have been developed 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 inflammatory enzyme (called cyclooxygenase-2 (COX-2) or prostaglandin G / H synthase II) provides a viable target of inhibition that more effectively reduces inflammation and provides less and less drastic side effects.

Angiogenesis is the formation of new blood vessels in tissues or organs. Under normal conditions, angiogenesis can be monitored in 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. Patent No. 5,646,136).

Compounds that selectively inhibit cyclooxygenase-2 have been described in U.S. Pat. Nos. 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. Pat. 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 inhibiting angiogenesis. 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, it is encompassed by the treatment and prevention of non-neoplastic angiogenesis-related disorders such as retinopathy and endometriosis.

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 be useful not only 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 would be useful in treating neoplasia, including metastasis; ophthalmic conditions, such as corneal graft rejection, ocular neovascularization, retinal neovascularization including post-injury or infection neovascularization, diabetic retinopathy, retrolental fibroplasia, and neovascular glaucoma; ulcerous diseases such as gastric ulcer; pathological but non-malignant conditions, for example hemangiomas, including invantile hemaginomas, nasopharynx angiofibroma, and avascular bone necrosis; and disorders of the female reproductive system, for example 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.

Φ φ φ · · · · φ φ · · · · · · φ

ΦΦ V φφ ΒΦ

The term prevention includes either preventing the onset of clinically evident angiogenesis or preventing the onset of a preclinically 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 a patient of any human or animal subject, preferably a human, who is at risk of acquiring some angiogenesis-related disorder, such as metastasis. The patient may be at risk due to exposure to carcinogenic substances, 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 so that they function as a substrate for this enzyme. The use of cyclooxygenase-2 selective inhibitors is very advantageous in that it minimizes the 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 appreciably inhibiting cyclooxygenase-1. Preferably, these include compounds having an IC 50 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 at least 100. More preferably, the compounds have an IC 50 cyclooxygenase- 1 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 6 is methyl or amino; and wherein R 3 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl 1, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxy alkyl, aralkylthio alkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, Narylaminocarbonylcarbonyl, Narylaminocarbonylcarbonyl, Narylaminocarbonylcarbonyl, , carboxyalkyl, alkylamino, N-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, alkylsulfonyl, 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 it is optionally substituted at one of the substitutable positions with one or more groups 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; wherein R 6 is methyl or amino; and wherein R 1 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 heteroaryloxy, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower alkylaminoalkyl, phenyloxy, and lower aralkoxy; or a pharmaceutically acceptable salt thereof.

ΦΦΦΦ · · · · · · ·

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, Arc -butyl. isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, bydroxymethyl, trifluoromethoxy, amino, N-methylamino, Ν, Ν-dimethylamino, N-ethylamino, Ν, dip-dipropylamino N-butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio; wherein R 6 is methyl or amino; and wherein R 6 is a group selected from hydrido, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, 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, hydroxylpropyl, benzyl, hydroxylpropyl, phenylcarbonyl, methoxymethyl, furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, Ν, Ν-dimethylamino, N-ethylamino, Ν, Ν-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, Ν, Ν- dimethylaminomethyl, 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) -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) -4-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-4-pyrazol-1-yl) benzenesulfonamide

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

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

4- [5- (4-Fluorophenyl) -3- (trifluoromethyl) -4-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;

0 * 0 0 «0« 00 * «0 0 0« * 0 0000 »» 0 0 0 0 0 »0000 0» 0 »0 00

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) -4-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 _J N-dimethylamino) phenyl) -3- (trifluoromethyl) -lH-pyrazol-l-yl] benzenesulfonamide;

2-methyl-4- [1- [4- (methylsulfanyl) 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;

[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;

-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;

• 44 44 4 4 4 · 4

4 4 4 4 4 444 444 · 4 4 φ 4 4

444 444 Mi 44 44

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

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

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

[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;

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

1- [2- (4-Trifluoromethylphenyl) cycloperiten-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;

- [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;

- [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;

[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] ethanoic 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; and

4- [5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide,

A group of specific substances of particular interest which are of the general formula I consists of 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] benzenesulfonamide.

Another class of cyclooxygenase-2 inhibitors is selected from compounds of Formula II

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

wherein R 5 is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen; and wherein R 6 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic groups; wherein it is optionally substituted at one of the substitutable positions with one or more groups selected from halogen, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy , sulfamyl, heterocyclic groups and amino groups; or a pharmaceutically acceptable salt or derivative thereof.

A group of substances of particular interest consists of compounds of formula (II) wherein R 1 is selected from lower haloalkyl; wherein the group is hydrido; and wherein R 6 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.

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

• · ··

Β Β

Β Β

ΒΒΒ ΒΒΒ

ΒΒ «« «Β

ΒΒΒ ΒΒΒ ΒΒΒ • Β

ΒΒ ΒΒ

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;

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

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

AND

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

The group of specific substances of increased interest which satisfy formula I consists of 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 include any compounds that are structurally similar to cycloxygenase-2 inhibitors or that have substantially the same biological activity. For example, these 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 another term such as haloalkyl. alkylsulfonyl, alkoxyalkyl and hydroxyalkyl, refers to alkyl 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. Disadvantages are lower alkyl groups having from one to six carbon atoms. Examples of such 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.

4. · 4 4 * 44 4> 4 · ♦ · · 4 4 4

The carbon-carbon double bond and from two to twenty carbon atoms, or better, 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, butenyl 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 such 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 carbocyclic 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 carbocyclic 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 of the carbon atoms of the alkyl is substituted with a halogen as defined above. Specifically, this applies to monohaloalkyl, dihaloalkyl and 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 halo atoms or a combination of different halo groups. Lower haloalkyl includes groups having 1 to 6 carbon atoms. Examples of haloalkyl groups are: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 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 such 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. The alkoxy groups having from one to six carbon atoms. Examples of these 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 the rings may be bonded to one another or fused. The term aryl refers to aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl residues may also be substituted at one of the substitutable positions with 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 selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic groups include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (eg, 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 heteroaryl refers to unsaturated heterocyclic groups. Examples of unsaturated heterocyclic groups, also called heteroaryl groups, are unsaturated 3-6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1, 2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. ΙΗ-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 to 6-membered • Ί ··· • ·, ·! 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 (for example 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 3-6 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 such 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 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 refers to groups containing one alkylthio group bonded via a divalent sulfur atom 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 refers to 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, denotes optionally the divalent 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 such 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 sulfamyr, aminosulfonyl and sulfonamidyl refers to NH2O2S-. The term acyl refers to a substituent that results from the removal of hydroxyl from an organic acid. Examples of such acyl substituents are alkanoyl and aroyl. Examples of these lower alkanoyl groups are: form 1, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl. The term carbonyl, either used alone or in conjunction with other terms such as alkoxycarbonyl, denotes - (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 additionally be 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 refers to alkyl groups substituted with a carboxy group. More preferred are lower carboxyalkyl groups which denote lower alkyl groups as defined above and may additionally be substituted with halogen on alkyl. Examples of such lower carboxyalkyl groups are carboxymethyl, carboxyethyl and carboxypropyl. The term alkoxycarbonyl refers to a group containing an alkoxy substituent as defined above, attached through an oxygen to a carbonyl group. More preferred are lower alkoxycarbonyl groups with alkyls having 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 with halogen, alkyl, alkoxy, haloalkyl and haloalkoxy. The term aralkoxy refers to aralkyl groups attached via oxygen to other groups. The term aralkoxyalkyl refers to aralkoxy groups attached via oxygen to an alkyl group. The term aralkylthio refers to aralkyl groups attached to a sulfur atom.

999

9 9 9 9 9 9 <B. B. B.

Β · · · Β Β

ΒΒ ΒΒΒ! BBt · Β Β

The term aralkylthioalkyl refers to aralkylthio groups attached through a 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 such groups are aminomethyl, aminoethyl and the like. The term alkylamino refers to amino groups which have been substituted with one or two alkyl groups. Lower Nalkylamino groups having 1 to 6 carbon atoms in the alkyl portion are preferred. 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 nitrogen of an amino group 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 group and which have 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 the 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-alkylaminocarbonyl N, N-dialkylaminocarbonyl groups. More preferred are lower N-alkylaminocarbonyl lower N, N dialkylammocarbonyl groups with 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 process of the invention may be present in the form of the free bases or of 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 acids: formic, acetic, 444. »» «

AAA ···

AND

AAAA Propionic, Amber, Glycolic, Gluconic, Milk, Apple, Wine, Lemon, Ascorbic, Glucuron, Maleic, Fumaric, Pyruvic, Aspartic, Glutamic, Benzoic, Anthranilic, Mesyl, 4-hydroxybenzoic, Phenylacetic, Almond, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanil, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicylic, galactaric and galacturonic. 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-methylglucamine) ) and procaine. 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.

«Φ .:

Φ Φ ΦΦΦ * • • • r r,,,,,,, «φ · φ · · φ · φ φ «'φ φ φ φ Φ'

General methods of synthesis

The present invention provides compounds which function as cyclooxygenase-2 inhibitors can be synthesized by the following Scheme I-X procedures wherein the substituents R 1 -R 1 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. Pat. No. 5,521,207 and WQ95 / 15316, incorporated herein 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 form the diketone 2 intermediate (enol). form), which was used without further purification. In step 2, diketone 2 is refluxed in anhydrous protic solvent (absolute ethanol or acetic acid) with salt hydrochloride or a free base of 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.

• 999 «

9 9 9 9 9 9

9 9 9 ·

9 9 '9 9 9l 9.9 9 t * 9 9

9 «9 i

Scheme II

7

Scheme II shows a four-step synthesis of the preparation of a cyclooxygenase-2 inhibitor, pyrazoles 8 from ketones 5 as described in US 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 (trimethylsilyl) amide or lithium diisopropylamide (LDA) to form anions. 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 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 such as dimethylformamide, and further reacting with the nitrile to form an aminoketone. Treatment of the aminoketone with an acid gives a diketone 6. Similar pyrazoles can be prepared by the methods described in U.S. Pat. No. 3,984,431, which is incorporated herein by reference.

· 4

F '4 4 4 4

4 * 4,444 ·

4 ·

Scheme lil

Cyclooxygenase-2 diaryl / heteroaryl thiophenes inhibitors (wherein T is S, and is alkyl) can be prepared by the methods described in U.S. Pat. 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.

»· 0 0 • 0 0 0

000 4 · 0

0

00 *

Scheme IV in * at • 000

000 000 • 0 00

R ³ COC1 base

Cyclooxygenase-2 diaryl / heteroaryl oxazoles inhibitors may be prepared by the methods described in U.S. Pat. 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.

• ·

Scheme V

1) ₃ hours

2) NH ₄ OH

Cyclooxygenase-2 diaryl / heteroaryl isoxazole inhibitors may be prepared according to the procedures described in United States No. 5,633,272, PCT documents WO92 / 05162, and WO92 / 19604, and European Publication EP 26928, which are incorporated herein by reference. 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 form a sulfonamide derivative

24.

• · ♦ · · · · · · ···

Scheme VI

RjCN + YO- alkylaln mim agent - Solvent NH "AND J 25 26 F

Alkylation; base

Scheme VI shows a three-step preparation of cyclooxygenase-2 inhibitors of imidazoles 29 of the invention. In step 1, reaction of substituted nitriles (R 4 CN) 25 with primary phenylamines 26 in the presence of alkylaluminum reagents such as trimethylaluminum, triethylaluminum, dimethylaluminum chloride, diethylaluminum chloride and in the presence of inert solvents such as toluene, benzene and xylene give amidines 27. 2, the reaction of amidine 27 with 2-haloketones (where X is Br or 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 yields 4.5 dihydroimidazoles 28 (wherein R 1 is alkyl). 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, the 4,5-dihydroimidazoles 28 can be dehydrated by the action of an acid catalyst such as 4-toluenesulfonic acid or a mineral acid to give 1,2-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.

• ··· • * »4 • 4 · 4 *« · ·· <

«3 ·« ··

In some cases (eg, where - methyl or phenyl), intermediate 28 is difficult to isolate. Under the conditions described above, the reaction provides the intended imidazoles directly.

Similarly, imidazoles can be prepared by linking the sulfonylphenyl residue to position 2 and R 1 to the nitrogen atom at position 1. Diaryl / heteroaryl imidazoles can be prepared by the methods described in U.S. Pat. No. 4,822,805, U.S. Pat. application Serial No. 08 / 282,395 and PCT document WO 93/14082, which are incorporated herein by reference.

Scheme VII «OTMS

TMSCN

-► r ¹ I CN

The subject invention, imidazole cyclooxygenase-2,36 inhibitors, can be synthesized according to Scheme VII. Aldehyde 30 can be converted to protected cyanohydrin • H

ΦΦΦ ·· »· * ΦΦΦ 4

Φ

Reak reak 4 by reaction with a trialkylsilyl cyanide such as trimethylsilyl cyanide (TMSCN) in the presence of a catalyst such as zinc iodide (Znl 2) or potassium cyanide (KCN). Reaction of cyanohydrin 31 with a strong base followed by reaction with benzaldehyde 32 (where 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 for conversion to imidazoles 35 (where R 1 is alkyl) by known chemical procedures as described in MR Grimmett, Advances in Imidazole Chemistry in Advances in Heterocyclic Chemistry, 12, 104 (1970) . Conversion of 34 to imidazoles 35 is accomplished by treatment 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 2 CO-) followed by reaction with ammonium hydroxide. It is known that the oxidation of sulfide (where R 6 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, agents such as hydrogen peroxide in acetic acid, n-chloroperoxybenzoic acid (MCPBA) and potassium petoxosulfate (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; application Serial No. 08 / 281,903 European publication EP 372,445, and PCT document WO 95/00501, which are incorporated herein by reference.

• • φ * φ φ φ φ φ φ φ

Scheme VIII

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

Similarly, Synthesis Scheme IX shows a process for preparing 1,2-diarylbenzene cyclooxygenase-2.44 inhibitors from 2-bromobiphenyl intermediates 43 (prepared similarly to that described in Synthesis Scheme VIII) and suitably substituted phenylboronic acids. Using a coupling procedure similar to that developed by Suzuki et al. [Synth. Commun., 11, 513 (1981)], 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 compounds 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

Diaryl / heteroaryl thiazole cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Pat. No. 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.

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

• ΦΦ Φ φ Φ Φ Β

ΦΦΦ · Φ φ Φ Φ · · Φ Φ · · Φφφ Φφφ • ΦΦΦ Φ Φ

Φ ΦΦ »··« φ

Biological evaluation

Antiangiogenic test

To determine the effect of COX-2 inhibitors on angiogenesis in vivo, we tested selective compounds by a comical microcapsule assay in mice and rats. The mouse comeal neovascularization microcapsule model was performed using materials, reagents and procedures as described in Muthukkauppah et al., J. Natl. Cancer Itis, 69, 699-708 (1982). In this assay, the pellet containing the basic fibroblast growth factor (FGF) was implanted in the mouse's supporting fibrous 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. The COX-2 inhibitor, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide inhibited FGF-induced angiogenesis in mice (70-90%) at 6 mg / kg / day.

In the rat microcapsule assay, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-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 the mouse cornea using another angiogenic stimulus, vascular endothelial growth factor (VEGF) . In this model, angiogenesis was inhibited (-50%) after administration of the compound at 6 mg / kg.

Metastasis model

The mouse 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 route, preferably in the form of a pharmaceutical composition acceptable for the route 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 aerosol). After localization of angiogenesis it is preferred

Φ · · φ ·

Podání ΦΦΦ ΦΦΦ · · · · * ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ ΦΦΦ podání ΦΦΦ podání ΦΦΦ ΦΦΦ podání ΦΦΦ podání podání ΦΦΦ ΦΦΦ podání podání podání podání podání podání podání podání podání ΦΦΦ podání podání podání podání podání podání podání podání podání podání podání podání The preparation of medicaments in a lipid vehicle can be used to increase bioavailability.

The compounds of the invention may be administered for 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 or other growth inhibitory agents or other drugs or nutrients.

There are a number of antineoplastic agents available commercially, in clinical evaluation and in preclinical research that could be selected for the treatment of angiogenesis with combination drug chemotherapy. These antineoplastic agents fall into several major categories: antibiotic-type substances, alkylating agents, antimetabolites, hormonal agents, immunological agents, mterferon type agents, and a variety of diverse categories. Alternatively, other antineoplastic agents such as metallomatic protease inhibitors (MMPs) may be used, for example MMP-13 inhibitors including batiastat, marimastat, Agouron Pharmaceuticals AG-3340, and Roche RO-32-3555 or D _V D3 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 antimetabolite-type antineoplastic agents may be selected from the following group: 5-FUfibrinogen, acanthifoliic acid, aminothiadiazole, brequinar sodium, carmofur, CibaGeigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly dideoxyguide, Lilly DATHINCIN, didox, Yoshtomi DMDC, doxifluridine, Wellcome EHNA, Merck & EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyaku FO152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, thiazofurine, Erbamontine , trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricytin.

A second class of antineoplastic agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from the following group: Shionogi 254-S, aldophosphamide analogs, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitan, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,

9 9 ««

9 ·· 999

9 9 9

9, 9 And 9

9 9. 9 * 9 «99 ·· · · 99 chlorambucil, 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 DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, photemustm, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafol amide, , NipponKayakuNK-121, NCINSC-264395, NCINSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT119, ranimustine, semustine ,. SmithKline SK & F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.

A third class of antineoplastic agents that can be used in combination with a selective cyclooxygenase-2 inhibitor consists of antibiotic-type antineoplastic agents. Suitable antineoplastic antibiotics may be selected from the following group: Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azine -A, bisucaberine, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY28438, 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 B, Shionogi D41 , doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa F-900482, glidatinactin, Herbimycin, Idarubicin, Illudins, Kazusamycin, Kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery K RN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-6149, American Cyanamide LLD49194, Meiji Seika ME 2303, Menogaril, Mitomycin, Mitoxantrone, SmithKline M-TAG, Neoenactin, Nippon Kayaku NK-313 Nippon Kayaku NKT-01, SRI International NSC357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rhodorubicin, sibanomicin, SN-SNOM-58, Sumitomo-SN70, Sumitomo , Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmacutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024, and zorubicin.

V 4 ··· ♦ »t * ······ 4 ·» 44 44

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, amonaphide, amphethinil, amsacrine, Angiostat, ankinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, afidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, beniptluron, benfluren, benfluren 23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromophosphamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorosulfaquinoxalon, Chemes CHX-2053, Chemex CHX-100, Warner- Lambert CI-921, Warner-Lambert CI941, Warner-Lambert CI-958, Canciridenone, ICN Compound 1259, ICN Compound 4711, Contracan, Yakult Honsha CPT-11, Crisnatol, c uraderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Dai-Pharmar DM69, Dai-Pharmar DM-75 , elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, NMF-5N grifolan, Hexadecylfos, HO, , hydroxyurea, BTG ICRF-187, Ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COON, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamide L-623, leukoregulin, lonidamine Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycine, Merrel Dow MDL-27048, MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivine, mitonafide, mitochidone , mopidamole, motretinide, Zenyaku Kogyo MST-16, N- (retmoyl) amino acid, Nisshin Fl our Milling N-021, N-acylated dehydroalanines, naphazatrome, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, ochizanocin, Akzo Org-10172, pancratistatin, pazelliptin, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhematoporphyrin, polypreic acid, Efamol poririn, probiman, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptin, 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, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldion, Suntory SUN 0237, Suntory

A A »

A A ·

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A A A

AA A

A A

A A A

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AAA AAA

A A

A A

AA A A

SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, Taxol, Teijin TEI-0303, Teniposide, Thaliblastine, Eastman Kodak TJB-29, Tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UC -1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534.

and

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 dehydroalanines, TGF-Genentech, tiprotimod, amifostine, 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 US Patent Nos. 3,590,028 and 4,012,448. Methods for preparing metalloprotein 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 Π _ν Π3 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 COX-1 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, phenoprofen, phenylbutazone, oxyfenbide azon, nimesulbutazone, nimesulbutazone, nimesulbutazone, nimesulbutazone, nimesulbide;

The term adjunctive therapy (or "combination therapy") in the definition of the use of a cyclooxygenase-2 inhibitor and one or more pharmaceutical agents means administering each agent in the manner prescribed by the dosage regimen, providing the beneficial effects of the combination, and co-administering the 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 a plurality of separate preparations containing 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 a binder such as crystalline cellulose, 444 444 444 444 444 444 444 444 cellulose, acacia, corn starch or gelatin; disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition in which, for example, saline, glucose or water may be used as a suitable carrier.

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

When angiogenesis is located 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. Preference is given to formulations enhancing local pharmacological effects and reducing systemic absorption.

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 the substances in a non-aqueous solvent, such as a vegetable oil, synthetic glycerides of aliphatic acids, esters of higher aliphatic acids, or propylene glycol.

Formulations for external use 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 nebulizers. Fatty acid sources can be used to enhance biocompatibility. Aerosol delivery is the preferred delivery method for epithelial lung angiogenesis 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 medical condition of the individual, the severity of the disease, the method and the condition. , The frequency of administration and the agent used, the location of angiogenesis, as well as the pharmacokinetic properties of the individual being treated, which may vary widely. The dose will generally be lower if the substances are administered topically instead of systematically, and preventively instead of medically. Drugs may be administered as needed and at intervals recommended by the attending physician. Obviously, 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 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 construed as limiting.

•.

Toto 'toto to a a a a a a a a a a

1768-99 (revised version claims for reconnaissance)

Claims (10)

PATENT CLAIMS Use of a therapeutically effective amount of a cyclooxygenase-2 inhibitor of the formula I wherein A is a substituent selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl, turyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl and pyridyl; wherein R ¹ is at least one substituent selected from heterocyclyl, C 3 -C 12 cycloalkyl, C 1 -C 6 -cycloalkenyl and aryl, wherein R ¹ is optionally substituted at one of the substitutable positions with one or more groups selected from C 1 -C ₁₂ -alkyl, C1-C10-haloalkyl, cyano, carboxyl, C1-C10-alkoxycarbonyl, hydroxyl, C1-C10-hydroxyalkyl, C1-C10-haloalkoxy, amino, C1-C12-alkylamino, arylamino, nitro, C1-C10-alkoxyalkyl, C 1 -C 10 -alkylsulfinyl, halogen, C 1 -C 10 -alkoxy and C 1 -C 10 -alkylthio; wherein R 6 is methyl or amino; and wherein selected from hydrido, halogen, C ₁ -C ₆ -alkyl, C ₂ -C ₁₂ -alkenyl, C ₂ -C ₁₂ alkynyl, oxo, cyano, carboxyl, C 1 -C 12 -cyanoalkyl, heterocyclyloxy, C 1 -C 10 -alkyloxy, alkylthio, alkylcarbonyl, C3-CI2-cycloalkyl, aryl, C-Cl2 haloalkyl, heterocyclyl, C 3 -C 12 cycloalkenyl, aryl-Ci-Ci2-alkyl, heterocyclyl-Ci-Cl2-alkyl, acyl, Ci-Ci ₀ -alkylthio- C 1 -C ₁₂ 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 ₁₂ -alkyl, aryloxy-C 1 -C ₁₂ -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 | ₂ alkyl, _{Ci-Cio-alkoxycarbonyl-Ci-Ci2-alkyl,} amino-carbonyl, C ₂ -C -aminokarbonylalkyl, Cr Cl2-alkylaminocarbonyl, N-arylamino carbonyl, N- _(Ci-Ci2 alkyl) -N -arylaminocarbonyl, C 1 -C 12 -alkylaminocarbonyl-C 1 -C ₁₂ -alkyl, C 1 -C ₁₂ -alkyl; ₂ -carboxyalkyl, C 1 -C 1 _2- alkylamino, N-arylamino, N- (aryl-C 1 -C ₁₂ -alkyl) -amino, N- (C 1 -C ₁₂ -alkyl) -N- (aryl-C 1 -C ₁₂ -alkyl) amino, N- (C _r C ₁₂ -alkyl) N-arylamino, C-Cl2 aminoalkyl, Cl-Cn-alkylamino-Ci-Cn-alkyl, _{N-arylamino-C-Ci2-alkyl,} N- (aryl- C 1 -C 1 ₂ alkyl) amino-C j -C 1 ₂ alkyl, N - (- Ci-C] ₂ alkyl) -N- (aryl-C 1 1 -C 1 ₂ alkyl) amino-C 1 C | _2- alkyl, N- (C 1 -C ₁₂ -alkyl) -N-arylamino-C 1 -C ₁₂ -alkyl, aryloxy, aryl-C 1 -C 10 -alkoxy, arylthio, aryl-C 1 -C 10 -alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, C 1 -C 4 -alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N - (- C 1 -C ₁₂ -alkyl) -N-arylaminosulfonyl; or a pharmaceutically acceptable salt thereof; '»Φ φ φ φ φ φ I I I I I I I I I 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 hemangiomas 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. Use according to 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 it 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 with one or more groups selected from C 1 -C 4 -alkyl. _Ci-C6 haloalkyl, cyano, carboxyl, _Ci-C6 alkoxycarbonyl, hydroxy, CrCe-hydroxyalkyl, _Ci-C6 haloalkoxy, amino, C Cňalkylamino, phenylamino, Ci-CU-alkoxy-Ci-CU-alkyl, C 1 -C 6 -alkylsulfinyl, halogen, C 1 -C 6, alkoxy and C 1 -C 6 -alkylthio; wherein R 1 is methyl or amino; and wherein 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 1 -C ₆ -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 8 -alkoxy-C 1 -C 6 -alkyl, 5- or 6-membered heteroaryloxy, aminocarbonyl, Ci-Ce-alkylaminocarbonyl, _Ci-C6 alkylamino, Ci-Ce aminoalkyl, Ci-Cg-alkylamino-Ci-Cealkyl, phenyloxy, and lower arybC _[--Cn -alkoxy; or a pharmaceutically acceptable salt thereof. Use according to claim 4, wherein A is selected from oxazolyl, isoxazolyl, pyrazolyl, imidazolyl and cyclopentenyl; wherein R 1 is selected from: pyridyl, optionally substituted at one of the substitutable positions with one or more methyl groups, and phenyl, optionally substituted at 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, Ν, Ν-dimethylamino, N-ethylamino, Ν, dip-dipropylamino, N butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentoxy and methylthio; wherein R 6 is methyl or amino; and wherein R 1 is selected from hydrido, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, tert-butyl, 4 • ··· 4 · 4 4 4J '4 4' · * 4j 4 4 · «····· # · 4 '4 4 4 ·. ·· 4 4 • 44 445 44 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, N, N-dimethylaminocarbonyl, Ν, Ν-dimethylamino, N-ethylamino, Ν, Ν-dipropylamino, N-butylamino, N-methyl- N-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) -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) -4-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-4-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; • ι · v v * 9 ·· »! · ·.. · · · • · ♦ · · 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) -4-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-phenylisoxazo-4-yl] benzenesulfonamide; 4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; 4- [5-methyl-3-phenyl-isoxazol-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-Chloro-phenyl) -cyclopenten-1-yl] -4- (methylsulfonyl) -benzene; 1- [2- (2,4-dichlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; • • »tt 9« «» »» - »-» 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; _t 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] ethanoic 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; and 4- [5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide. Use of a therapeutically effective amount of a compound of formula (I) wherein ie is selected from hydrido, C 1 -C 12 -alkyl, haloalkyl, C 1 -C 10 alkoxycarbonyl, cyano, C 1 -C 12 -cyanoalkyl, carboxyl, aminocarbonyl, C 1 -C 12 alkylaminocarbonyl, Ca-C 1-4C-cycloalkylaminocarbonyl, arylaminocarbonyl, C1-C12-carboxyalkylaminocarbonyl, C1-C12-carboxyalkyl, aryl-C1-C10-alkoxycarbonyl-C1-C12-alkylaminocarbonyl, C1-C12-aminocarbonylalkyl, C1-C10-alkoxycarbonylkyano-C2-C12-carboxyalkyl; _2- alkenyl and C 1 -C 6 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 • * 0 « JC 0 · • 0 0 * 0 00 «• · 0 · ·; Wherein R ₆ is selected from aryl-C ₂ -C | _2- alkenyl, aryl, C 3 -C ₁₂ -cycloalkyl, C ₃ -C ₁₂ cycloalkenyl and heterocyclyl; wherein R 1 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 ₁₂ -haloalkyl, C 1 -C 12 -alkyl, hydroxyl, C 2 -C ₂ -alkenyI, Cr C | ₂ -hydroxyalkyl, carboxyl, C ₃ -C 12 -cycloalkyl, C 1 -C ₁₂ -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 or derivative thereof. The use of claim 7, wherein R 1 is selected from C 1 -C ₆ -haloalkyl; wherein R 8 is hydrido; and wherein R 6 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) -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-Hyl] 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; and 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl] benzenesulfonamide. ¹ 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-yl] benzenesulfonamide; and 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide.