HK1025518B

HK1025518B - Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia

Info

Publication number: HK1025518B
Application number: HK00104885.0A
Authority: HK
Inventors: K‧塞伯特; J‧马斯菲尔雷; G‧B‧戈登
Original assignee: G‧D‧瑟尔公司
Priority date: 1996-10-15
Filing date: 1997-10-14
Publication date: 2008-03-28

Description

Methods of treating and preventing neoplasia using cyclooxygenase-2 inhibitors

no marking

Technical Field

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

Background

Prostaglandins play a major role in the inflammatory process, and the production of prostaglandins, particularly PGG₂，PGH₂And PGE₂Inhibition of production has been a common goal of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (NSAID's) that are effective in reducing prostaglandin-induced pain and swelling associated with inflammatory processes also affect other prostaglandin regulatory processes unrelated to inflammatory processes. Thus, the use of NSAID's, which are most commonly used, in large doses can produce serious side effects, including life-threatening ulcers, and as a result, limit their therapeutic potential. An alternative to NSAID's is the use of corticosteroids, which also have adverse effects, especially in relation to long-term treatment.

NSAID's have been found to inhibit the production of prostaglandins, including Cyclooxygenase (COX), by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway. Recent discovery of an inducible enzyme associated with inflammation, designated "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II", provides a viable inhibition target that is more effective in reducing inflammation and produces fewer, less undesirable side effects.

Compounds that selectively inhibit cyclooxygenase-2 have been described in U.S. Pat. Nos. 5380738, 5344991, 5393790, 5434178, 5474995, 5510368 and WO documents (documents) WO96/06840, WO96/03388, WO96/03387, WO96/25405, WO95/15316, WO94/15932, WO94/27980, WO95/00501, WO94/13635, WO94/20480 and WO 94/26731.

The disease state of a tumor is a serious and often life-threatening disease. These neoplastic diseases, characterized by rapid cell growth, have been the subject of global research efforts directed toward the identification of therapeutic agents that are effective in treating such diseases. An effective therapeutic agent prolongs survival (survivability) of the patient, inhibits rapid proliferation of cell growth associated with the tumor, or causes regression of the tumor. Research in this area has focused primarily on identifying agents that have therapeutic effects in humans and other mammals.

Recently, the presence of COX-2 has been observed in neoplastic diseases. See Masanobu Oshima et al (cell, 87, 803-809(1996)) and Michelle Parret et al (J.En. Oncology, 10, 503-507 (1997)).

[ pyrazol-1-yl ] benzenesulfonamides have been described as cyclooxygenase-2 inhibitors and have shown promise 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 us patent No. 5466823. However, they have not been described previously for the treatment of colon cancer or for the treatment or prevention of other forms of tumor.

The present invention is directed to the use of cyclooxygenase-2 inhibitors for the treatment and prevention of neoplasia. Combination therapy of a selective cyclooxygenase-2 inhibitor and other oncological agents produces a synergistic effect or selectively reduces the toxic side effects associated with chemotherapy by reducing the concentration of the agent causing the side effects required for therapeutic efficacy.

Detailed description of the invention

The present invention provides a method of treating and preventing neoplasia, producing prostaglandins, in a subject in need of such treatment or prevention, comprising treating the subject with a therapeutically effective amount of a cyclooxygenase-2 inhibitor or derivative thereof.

The term "treatment" includes the partial or total inhibition of tumor growth, spread or metastasis, as well as the partial or total destruction of tumor cells.

The term "prevention" includes both prevention of the onset of clinically significant complete tumor formation and prevention of the onset of a preclinically significant stage of tumor formation in at-risk individuals. Prevention of carcinogenesis or prevention or reversal of the process of transformation of precancerous cells into cancerous cells is also encompassed by this definition. The definition also includes prophylactic treatment of those individuals at risk of developing a tumor.

The term "therapeutically effective" means the amount of each agent and the frequency of treatment of each agent itself to achieve the goal of improving the severity of the disease, while avoiding the adverse side effects normally associated with the selected treatment.

The term "subject" for therapeutic purposes includes any human or mammalian subject, preferably a human subject, having any one of the known tumors. For the method of prevention, the subject is any human or animal subject, and preferably a human subject at risk of acquiring epithelial cell-derived neoplasia. The subject may be at risk due to exposure to a carcinogen, a subject having a genetic predisposition to tumor formation, and the like.

The term "neoplasia" includes prostaglandins-producing or cyclooxygenase-expressing neoplasias, including benign and malignant tumors, neoplasms, and polyps.

In the above methods, the prostaglandin-producing tumor includes brain cancer, bone cancer, epithelial cell-derived tumors (epithelial cancers) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, oral cancer, esophageal cancer, small intestine cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and skin cancer, such as squamous cell and basal cell carcinoma, prostate cancer, renal cell carcinoma, and other cancers known to affect epithelial cells throughout the body. Preferably, the tumour is selected from gastrointestinal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancers, such as squamous cell and basal cell carcinomas. COX-2 inhibitors can also be used to treat fibrosis resulting from radiation therapy. The methods can be used to treat subjects with adenomatous polyps, including those with Familial Adenocarcinoma Polyposis (FAP). In addition, the method can be used to prevent polyp formation in patients at risk for FAP.

Inhibitors of the cyclooxygenase pathway in arachidonic acid metabolism can inhibit enzyme activity by a variety of mechanisms in the prevention and treatment of tumors derived from epithelial cells. For example, an inhibitor used in the methods described herein may act as an enzyme to directly block the activity of the enzyme. The use of cyclooxygenase-2 selective inhibitors would be highly advantageous in minimizing gastric side effects that may occur with non-selective NSAID's treatment, especially long-term prophylactic treatment.

The term "cyclooxygenase-2 inhibitor" means a compound that is capable of inhibiting cyclooxygenase-2 without significant inhibition of cyclooxygenase-1. Preferably, it comprises cyclooxygenase-2 IC having less than about 0.2 μ M₅₀And also compounds having a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, more preferably at least 100. More preferably, the compounds have a cyclooxygenase-1 IC of greater than about 1 μ M, and more preferably greater than 10 μ M₅₀. Pyrazoles can be prepared by the methods described in WO95/15316, WO95/15315 and WO 96/03385. Thiophene analogs can be prepared by the methods described in WO95/00501 and WO 94/15932. Oxazoles (oxazoles) can be prepared by the methods described in PCT documents WO95/00501 and WO 94/27980. Isoxazoles can be prepared by the process described in WO 96/25405. Imidazoles can be prepared by the methods described in WO96/03388 and WO 96/03387. Cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Pat. No. 5344991 and WO 95/00501. The triphenyl compounds can be prepared by the methods described in WO 96/16934. Thiazole compounds can be prepared by the methods described in WO 96/03392. Pyridine compounds can be prepared by the methods described in WO96/24584 and WO 96/245785.

The methods provided herein relate to the use of cyclooxygenase-2 inhibitors or derivatives thereof in the prevention and treatment of neoplasia. In a preferred embodiment, the cyclooxygenase-2 compound is selected from a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein A is a substituent selected from the group consisting of partially unsaturated or unsaturated heterocyclic group and partially unsaturated or unsaturated carbocyclic ring;

wherein R is¹Is at least one substituent selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R is¹Optionally substituted at substitutable positions with one or more groups selected from: alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio.

Wherein R is²Is methyl or amino; and R³Is a group selected from: hydrogen (hydrido), halo, alkyl, alkenyl, alkynyl, oxy, cyano, carboxy, cyanoalkyl, heterocyclooxy, alkoxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocycloalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkyloxyalkyl, alkoxyaralkyloxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkoxy-alkyl-N-aralkylamino, N-alkyl-N-aralkylamino, C-alkoxy-alkyl-C-alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl.

Preferred groupCompounds that inhibit cyclooxygenase-2 comprise compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of 5-or 6-membered partially unsaturated heterocyclyl, 5-or 6-membered unsaturated heterocyclyl, 9-or 10-membered unsaturated fused heterocyclyl, lower cycloalkenyl, and phenyl, wherein R is¹Selected from the group consisting of 5-and 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from the group consisting of phenyl, biphenyl and naphthyl, wherein R¹Optionally substituted at substitutable positions with one or more groups selected from: lower alkyl, lower haloalkyl, cyano, carboxy, lower alkoxycarbonyl, hydroxy, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio, wherein R is²Is methyl or amino; and wherein R³Is a group selected from: hydrogen, oxy, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halogen, lower alkyl, lower alkoxy, lower cycloalkyl, phenyl, lower haloalkyl, 5-or 6-membered heterocyclic group, lower hydroxyalkyl, lower aralkyl, acyl, phenylcarbonyl, lower alkoxyalkyl, 5-or 6-membered heteroaryloxy, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower alkylaminoalkyl, phenoxy and lower aralkoxy.

A more preferred class of cyclooxygenase-2 inhibiting compounds comprises compounds of formula I or pharmaceutically acceptable salts thereof, wherein A is selected from the group consisting of oxazolyl, isoxazolyl, furanyl, thienyl, dihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, benzofuranyl, cyclopentenyl, cyclopentadienyl, phenyl, and pyridyl, wherein R is¹A phenyl group selected from pyridyl optionally substituted at substitutable positions with one or more methyl groups, optionally substituted at substitutable positions with one or more groups selected from: methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, carbomethoxy, carboethoxy, hydroxyl, hydroxymethyl, trifluoromethoxy, trifluoromethyl,Amino, N-methylamino, N-dimethylamino, N-ethoxy, N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, N-butoxy, pentyloxy and methylthio, wherein R is methyl, N-propylamino, N-propylamino²Is methyl or amino; and wherein R³Selected from: hydrogen, oxy, 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, pentyloxy, cyclohexyl, phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl, hydroxymethyl, hydroxypropyl, benzyl, formyl, phenylcarbonyl, methoxymethyl, furylmethoxy, aminocarbonyl, N-methylaminocarbonyl, N-dimethylaminocarbonyl, N-dimethylamino, N-ethylamino, N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy and phenoxy.

A particular family of compounds of particular interest in formula I comprises the following compounds and pharmaceutically acceptable salts thereof:

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-tolyl) -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-tolyl) -1H-pyrazol-1-yl) benzenesulfonamide;

4- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -1H-pyrazol-1-yl) benzenesulfonamide;

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

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

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

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

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

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

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

4- [5- (4-tolyl) -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-tolyl) -1H-pyrazol-1-yl ] benzenesulfonamide;

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

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

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

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

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

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

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

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

5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl ] spiro [2, 4] hept-5-ene;

4- [6- (4-fluorophenyl) spiro [2, 4] hept-5-en-5-yl ] benzenesulfonamide;

6- (4-fluorophenyl) -7- [4- (methylsulfonyl) phenyl ] spiro [3, 4] oct-6-ene;

5- (3-chloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl ] spiro [2, 4] hept-5-ene;

4- [6- (3-chloro-4-methoxyphenyl) spiro [2, 4] hept-5-en-5-yl ] benzenesulfonamide;

5- (3, 5-dichloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl ] spiro [2, 4] hept-5-ene;

5- (3-chloro-4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl ] spiro [2, 4] hept-5-ene;

4- [6- (3, 4-dichlorophenyl) spiro [2.4] hept-5-en-5-yl ] benzenesulfonamide;

2- (3-chloro-4-fluorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole;

2- (2-chlorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole;

5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-methylthiazole;

4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole;

4- (4-fluorophenyl) -5- (4-methanesulfonylphenyl) -2- (2-thienyl) thiazole;

4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-benzylaminothiazole;

4- (4-fluorophenyl) -5- (4-methanesulfonylphenyl) -2- (1-propylamino) thiazole;

2- [ (3, 5-dichlorophenoxy) methyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl ] thiazole;

5- (4-fluorophenyl) 4- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole;

1-methanesulfonyl-4- [1, 1-dimethyl-4- (4-fluorophenyl) cyclopenta-2, 4-dien-3-yl ] benzene;

4- [4- (4-fluorophenyl) -1, 1-dimethylcyclopent-2, 4-dien-3-yl ] benzenesulfonamide;

5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl ] spiro [2.4] hepta-4, 6-diene;

4- [6- (4-fluorophenyl) spiro [2.4] hept-4, 6-dien-5-yl ] benzenesulfonamide;

6- (4-fluorophenyl) -2-methoxy-5- [4- (methylsulfonyl) phenyl ] -pyridine-3-carbonitrile;

2-bromo-6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl ] -pyridine-3-carbonitrile;

6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl ] -2-phenyl-pyridine-3-carbonitrile;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4- [2- (3-tolyl) -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-methanesulfonylphenyl) -2-trifluoromethyl-1H-imidazole;

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

5- (4-fluorophenyl) -2-methoxy-4- [4- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridine;

2-ethoxy-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridine;

5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl ] -2- (2-propynyloxy) -6- (trifluoromethyl) pyridine;

2-bromo-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl ] -6- (trifluoromethyl) pyridine;

4- [2- (3-chloro-4-methoxyphenyl) -4, 5-difluorophenyl ] benzenesulfonamide;

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

5-difluoromethyl-4- (4-methanesulfonylphenyl) -3-phenylisoxazole;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl ] oxazol-2-yl ] -2-benzyl-acetic acid ethyl ester;

2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl ] oxazol-2-yl ] acetic acid;

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

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

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

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

A particular class of compounds of more particular interest in formula I includes the following compounds and pharmaceutically acceptable salts thereof:

4- [5- (4-tolyl) -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- [ 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.

A subclass of cyclooxygenase-2 inhibitors is selected from the compounds of WO 95/15316. Preferably, the cyclooxygenase-2 inhibitor is selected from a compound of formula II or a pharmaceutically acceptable salt or derivative thereof:

wherein R is⁴Is lower haloalkyl; wherein R is⁵Is hydrogen; and wherein R⁶Is phenyl optionally substituted in substitutable positions with one or more groups selected from: halo, lower alkylthio, lower alkylsulfonyl, cyano, nitro, lower haloalkyl, lower alkyl, hydroxy, lower alkenyl, lower hydroxyalkyl, carboxy, lower cycloalkyl, lower alkylamino, lower dialkylamino, lower alkoxycarbonyl, aminocarbonyl, lower alkoxy, lower alkoxycarbonyl, amino group,Lower haloalkoxy, sulfamoyl, five or six membered heterocyclic ring and amino.

A particular family of compounds of particular interest in formula II includes the following compounds and pharmaceutically acceptable salts and derivatives thereof:

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

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

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

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

and

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

A particular family of compounds of more particular interest in formula II includes the following compounds and pharmaceutically acceptable salts or derivatives thereof:

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

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

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

Derivatives are meant to include any compound structurally related to the cyclooxygenase-2 inhibitor or having substantially equivalent biological activity. By way of example, such inhibitors may include, but are not limited to, prodrugs thereof.

The compounds used in the process of the invention may be present in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I may be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from the group of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulphonic acids, examples of which are formic, acetic, propionic succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, pamoic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclamic, stearic, algenic, β -hydroxybutyric, salicylic, galactaric and galacturonic acids. Suitable pharmaceutically acceptable base addition salts of the compounds of formula I include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from chloroprocaine (chlorophrocaine), choline, N' -dibenzylethylenediamine, diethanolamine, 1, 2-ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be prepared in a conventional manner by reacting the corresponding compounds of formula I, for example, by reacting an appropriate acid or base with a compound of formula I.

Biological evaluation

The efficacy of cyclooxygenase-2 inhibitors as antitumor agents depends on the following model:

mouse Lewis lung cancer model

Lewis lung carcinoma was implanted subcutaneously in footpads of male C57BL/6 mice. The mice were subsequently treated with 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide. The drug is administered in the drinking water at 6 mg/kg/day. A non-selective COX-1/COX-2 inhibitor indomethacin was also tested in this model. The drug is administered in the drinking water at a maximum tolerated dose of 2mg/kg per day. A total of 10 mice/compound were tested. Tumor volume was measured twice a week with a plethysmometer. The effect of these compounds on tumor growth was examined 32 days after cancer cell injection, as indicated in table 1. The% inhibition value was calculated by calculating the difference in tumor size compared to the control group.

TABLE 1

Tumor volume (32 days)

Therapeutic% inhibition

Vehicle/control 0.00

COX-2 inhibitor 70.86

Indomethacin 62.90

Human prostate cancer cell tumor

Two human prostate cancer cell lines (PC-3 and LN Cap) were obtained (ATCC) to examine the utility of cyclooxygenase-2 inhibitors on inhibiting tumor growth in a model of treatment. In addition, LN CaP cells also secrete Prostate Serum Antigen (PSA) when grown in nude mice.

PC-3

Will be at RPMI1640 PC-3 cells in Medium (10)⁶Cells/0.2 ml 30% matrigel (matrigel)) were injected on the back of nude mice. On day 28, COX-2 inhibitor 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl was administered]Benzenesulfonamide (in water, 20mg/kg per day). After 45 days, PGE was measured₂And TXB₂. COX-2 inhibitors inhibit tumor growth by 55%. PGE in animals treated with COX-2 inhibitors₂And TXB₂The level is reduced by 80-90%.

LNCaP

Similar to the results in PC-3, the COX-2 inhibitor 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide inhibited tumor growth by 55% at 58 days in a drinking water at a dose equivalent to 6mg/kg per day. PSA levels were reduced by about 50% as judged by western blotting.

Others

Cell line: the following cell lines can be used: typical Small Cell Lung Cancer (SCLC) cell lines NCI-H209, NCI-H345 and NCI-H510; variant SCLC cell lines NCI-N417 and NCI-H82; the large cell carcinoma cell line NCI-H1155; adenocarcinoma cell line NCI-H23; and bronchoalveolar carcinoma cell line A549, breast carcinoma cell line MCF-7(American type tissue Culture Rockville MD; ATCC) and colon carcinoma cell lines such as NCI-H630(ATCC), HT29, SW948, HCA-7 and others that can be tested in vivo or in vitro. All cells were able to grow in RPMI-1640 supplemented with 5% Fetal Bovine Serum (FBS), penicillin and streptomycin (Gibco, Grand Island, NY)) and at 5% CO₂Growth was maintained in gas at 37 ℃. All cell lines were free of mycoplasma contamination.

Growth study: improved method of semi-automatic colorimetric analysis (Plemega Cell Titer 96)^®Promega Madison, Wis.), MTT method [ Nakanishi, et al. Exper Call biol.56, 74-85(1988)]It was applied to the determination of cell number based on the reduction of tetrazolium compounds by the determination of tumor cells by a spectrophotometer (540 mm). All analyses were performed in RPMI-1640 medium plus-10 g/ml transferrin, -5 g/ml insulin and selenium (Sigma Chemic)als, st. The concentration of the inoculated cells was 2X 10⁴Cells/well, and cells were grown for 5 days, with each experiment reported as mean optical density to correct for background +/-standard deviation. The cyclooxygenase-2 inhibitor should have activity of inhibiting the growth of cancer cell lines at a dosage of 20 mg/kg.

A mouse bladder cancer model was established using materials, reagents and procedures essentially as described in Gmbs et al [ Anticancer Res.13, 33-36 (1993) ]. The cyclooxygenase-2 inhibitor should be active at a dosage of 20 mg/kg.

A rat breast cancer model was established using materials, reagents and procedures essentially as described by Grubbs et al [ Anticancer Res., 15, 709-16 (1995) ]. The cyclooxygenase-2 inhibitor should be active at a dosage of 20 mg/kg.

A model for cervical and vaginal carcinogenesis was established in mice using materials, reagents and procedures essentially as described in Arbeit et al [ proc.acad.sci.usa., 93, 2930-35 (1996) ]. The cyclooxygenase-2 inhibitor should be active at a dosage of 20 mg/kg.

A colon adenocarcinoma cell model was established using materials, reagents and procedures essentially as described by Shiff et al [ J.Clin. Invest., 96, 491-503 (1995) ]. At a dose of 20mg/kg, the cyclooxygenase-2 inhibitor should be active. See also Masahiko Tsujii et al (Proc. Natl. Acad. Sci. USA 94: 3336-3340, 1997).

In summary, cyclooxygenase-2 inhibitors can reduce tumor growth in several animal cancer models.

Combination therapy of cyclooxygenase-2 and other neoplastic agents

Lewis lung carcinoma cells (2.5X 10) prepared from serous fluid (brei) carried by C57BL/6 mice⁶Cells) was injected subcutaneously into the hind leg of mice, COX-2 inhibitor, 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl]Benzenesulfonamide was administered twice weekly by gavage to two dose groups of 6 and 20mg/kg, 10 mice per group. CyclophosphidoAmine (CTX) was injected into mice at a dose of 50 mg/kg on days 5, 7 and 9 after tumor implantation, and the tumor volume was measured in the study. Animals were sacrificed on day 26 and the results of the trial are summarized in table 2, with the percent inhibition calculated as described above.

TABLE 2

Tumor volume (22 days)

Percentage of therapeutic inhibition

Medium 0

COX-2 inhibitor (6 mg/kg) 0

COX-2 inhibitor (20 mg kg) 54

CTX (50 mg/kg) 57

CTX + COX-2 inhibitor (6 mg kg) 69

CTX + COX-2 inhibitor (20 mg/kg) 77

The results of the experiments indicated that the combination of a COX-2 inhibitor and a cytotoxic agent produces a synergistic effect on their respective ability to inhibit tumor growth.

The active compounds of the invention may be administered by any suitable route known to those skilled in the art, preferably in the form of pharmaceutical compositions adapted to such route, and in dosages as are therapeutically desirable. For example, the active compounds and compositions can be administered orally, intravascularly, intraperitoneally, intranasally, intrabronchially, subcutaneously, intramuscularly, or topically (including by aerosol).

Administration of the present invention may be for either prophylactic or therapeutic purposes. The methods and compositions used herein may be used alone or in combination with additional therapies known to those skilled in the art in the prevention or treatment of tumors. In other words, the methods and compositions described herein can be used as a combination therapy. As an example, the cyclooxygenase-2 inhibitor may be administered alone or in combination with other anti-neoplastic agents or other growth inhibitory agents or other drugs or nutrients.

In commercial applications, a large number of anti-tumor agents are available for clinical evaluation and preclinical development, which can be selected for the treatment of tumors in combination with chemotherapeutic drugs. Such antineoplastic agents fall into several major classes, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, and various other agents. In addition, other antineoplastic agents, such as Metal Matrix Proteases (MMPs), SOD mimics (mimics) or alpha₂β₃Inhibitors may be used alternatively.

A first class of antineoplastic agents that can be used in combination with selective cyclooxygenase-2 inhibitors includes antimetabolite antineoplastic agents. Suitable antimetabolic antineoplastic agents may be selected from the group consisting of 5-Fu-fibrinogen, acanthifolic acid, aminothiadiazole, hemoquinaldium sodium (brequinacridium), 5-fluorouracil, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugate, Lilly DATHF, Merrel DoWDRC, delphine (dezaguanine), dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxylfluorouridine, Wellcome EHNA, Merck & Co. EX-105, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2' -furyl) -5-fluorouracil, Daiichi Seiku pya-152, isopropylolizine, Lizary-188011, Liquidy-264618, Wellloy-264618, NSncinly, NSlllC-3683, methotrexate, NCI NSC-39661, NCI NSC-612567, Warner-LambertPALA, pentostatin, pintrexim, desoxyhelpingmycin (plicamycin), Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, sulfadiazinevine (tiazofurin), Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT, and eugenin (uricysin).

A second class of antineoplastic agents that can be used in combination with selective cyclooxygenase-2 inhibitors includes alkylating antineoplastic agents. Suitable alkylating antineoplastic agents may be selected from Shionogi254-S, aldehyde-phosphoramide analogs, hexamethylmelamine, Anacetron (analitrone), Boehringer Mannheim BBR-2207, benzarbucil, butontin (budotitane), Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, oncoclonine, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cycloplatite, Degussa D-19-384, Suminoto DACHP (Myr)2, Diphenylspiromesine (dihyrylspiromustine), platinum inhibitors, Erba distamycin derivatives, Chugaia DWA-2114R, ITI E09, imustine (elminthine), Erythromycin E-24517, estramustine M, ChinoinGYKI, mechlorethamine, nitrosurea, Nitrospora-1726, Nitrofamide, Nitrospora-M, ChinoinGYKI, Nitrospora phosphate, Nitrospora D-M, ChinoinGYKI, Nitrocarb-D-102, Nitrocarb-D-2, Nitrocarbutin, Nitrocarb D-D, Dibromodulcitol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin (oxaliplatin), Upjohn PCNU, prednimustine, Proter PTT-119, ranitidine, semustine, Smithkline SK & F-101772, Yakult Honsha SN-22, mechlorethamine, Tonabe Seiyaku TA-077, Taromomustine (tauromustine), temozolomide (temozolomide), tyrocirone (teroxirone), tetrachlorohexylplatinamine (tetraplatin), and trimelamol.

A third class of antineoplastic agents that may be used in combination with selective cyclooxygenase-2 inhibitors includes antibiotic antineoplastic agents. Suitable antibiotic antineoplastic agents may be selected from the group consisting of Taiho4181-A, aclacinomycin, dactinomycin, actinolanone, Erbamont ADR-456, Aerolysin derivatives, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda ansamycins, anthracyclines (anthracyclines), azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers Y-27557, Bristol-Myers BMY-28438, bleomycin sulfate, patatin-1, Taiho C-1027, caecimycin, chlomomycin, chromycins, Haemomycin (Hakkomycins A), Hakkowamycin B-3679, Hakkowamycin A-3679, Khakkawa-C-3679, Khakkawa-3688, Khakkawa-C-3679, Khakkawa-C-B, Khakkawa-C-3679, Khakkawa C-B, and Khakkawa C, Shiongi DOB-41, doxorubicin-fibrinogen, elsamicin-A, epirubicin (epirubicin), erbstatin, doxorabicin, esperamicin-AI, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973, fostericin, Fujisawa FR-900482, taxin, gegatin-A, grincamycin, herbimycin, nordaunomycin (idarubicin), selenomycin, kazusamycin, kesarrhodins, Kyowa Hakko KM-5539, KirinBrewer KRN-8602, Kkwa Hakko TK-5432, Ktiokyo TK-5594, Kyowa Hakko TK-61618, Cyrinomycin-494901, Shinylamine K-52, Nippomycin-A (nikonein), Nippomycin-K-S-K-52, Shinylamycin, Shinylosin-K-618, Shinylamycin, Shinylosin-K-S, Shinylamycin, Shinylone K-313, Shinylamycin, Shinyle, Shinylamycin, Shinylone K-5, Shinylanthraquinone, pilatin, doxorubicin pyrane, prothramycin, pyrindamycin A, Tobishi RA-I, rapamycin (rapamycin), rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steganomycin B, Taiho4181-2, talithromycin (talisomycin), TakedaTAN-868A, terpentectin, thrazine, tricozarin A, Upjohn U-73975, Kkwa Hakko-A, Fujisaosin-34028, and yowa-3405, zorubicin, and yowa 25024.

A fourth class of antineoplastic agents which may be used in combination with the selective cyclooxygenase-2 inhibitor includes an additional class of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphetamine, amfenadine, Angiostat, ankinomycin, antineoplast (anti-neoplastone) A10, antineotone A2, antineotone A3, antineotone A5, antineotone AS2-1, Henkel APD, apiicolin glycinate, asparaginase, Avarol, baccharin, bagrocylin, benzoquinone (Wenflorfluron), chloracyl tryptophan, sen-au biur M-15, Bikufane, bri-gordone, Bristo-40481, Velcroothrone BW-10, Velcrofovir, Velcrofone (CDnochromamide), Velcrofone F-773, Velcrofone (CDcoone) A35502, Hakkolone, Hakkoloside D-2, Hakkinolide, Hakk, Chemex CHX-100, Wamer-Lambert CI-921, Wamer-Lambert CI-937, Wamer-Lambert CI-941, Warner-Lambert CI-958, Klanfelu (cranfe), clavidenone, ICN compound 1259, ICN compound4711, Contracan, Yakult Honsha CPT-11. Kreistol (crisnatol), curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABISmallete, triazinylimidazolam, datelliptinium, didemnin-B, dihaematoporphin ether, dihydroperylenequinone, dinaline, distamycin, Toyo pharma DM-341, Toyo pharma DM-75, dAiCHi SeiyakuDN-9693, ellipraline, hydroxycarbazole acetate, Tsumura EPP, ergotamine, etocanoside, itratexate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwardaphanin, Chug GLA-43, Glaxo GR-63178, Vitifen NMF-5, acetylcholine-187, hexadecane HO-221, isochlorosylurea, Correa-36, Correa-Octrex HCI-7, Corynaldine-7, Corynaudi-7, Cy-HCI-H-7, Cy-7, Cyslogan-K-7, Cortina, Cyslogan, Cymbin-R-7, Cymbine, Cymbin-D, Cyno, Cylitha-D, Cylitha-D, Cylitorine, Cylith-III, and Cylith, Leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel DoW MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilino acridine yellow (methylaniloacrine), Molecular Genetics MGI-136, minic ivin, aminonitronapthalene amine, mitoquinone (mitoquinone), moperidine, tolylnonane tetra-amide, Zenyaku Kogyo MST-16, N- (retinyl) amino acids, Nisshin flouring Miln-021, N-acylated-dehydroalanine, naphthoxazone, TaishonNCU-190, thiaurethane pyridazine derivatives, arginine heme, NCI C-145813, NCI C-361456, NCI-361456, NCZ-33, Onclotione C-36, Onclotione-33, Orchii-72, Onci-72, Onclotione-72, Onci-72, Onclothine-MST-136, and Onclotione, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Wamer-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D. brunettone (piroxanthone), polyhalosporin, polyperacid, Efamol porphyrin, prodiamane, procarbazine, proglumide, Invitron protease I, Tobisi RA-700, propyleneimine, Sapporo Breweries RBS, restrictocin-P, Retentin (retelliptine), Retention acid (Retention acid), Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Smithkline SK & F-104864, S-108, Serratine, Sentaphan S, S-94, Suturel-20753, Suturelsp-023, Suturene-S, Suturene-P, Suturelsp-S-32, Suturelstone (Suturelsp-S-94, Suturelstone-S, Suturelstone (Suturen-S-1, Suturelstonine, Suturen-S, Teijin TEI-0303, teniposide, thalistatin, Eastman kodakTJB-29, tocotrienols, Toponin, Teijin TT-82, Kyowa HakkouUCN-01, Kyowa Hakko UCN-1028, Ukrain, Eastman KodakUSB-006, vinblastine sulfate, vincristine, vindesine, vinstramide, vinorelbine, vindoline (vinritol), vinblastine (vinzolidine), withanolides, and Yamanouchi YM-534.

Examples of radioprotectors that may be used in combination with the chemotherapy of this invention are AD-5, adchnon, amifostine analogs, detox, dimesna, I-102, MM-159, N-acylated-dehydroalanine, TGF-Genentech, tilotemod (tiprimiod), amifostine, WR-151327, FUT-187, ketoprofen transdermal, naproxone, superoxide dismutase (Chiron), and superoxide dismutase Enzon.

The above-described preparation methods of antitumor agents can be found in the literature. For example, the preparation of doxorubicin is described in U.S. patent nos. 3590028 and 4012448. Methods for preparing inhibitors of metallomatriptase are described in EP 780386. Methods for preparing SOD mimics are described in EP 524101. Preparation of alpha_vβ₃Methods for inhibitors are described in WO 97/08174.

The term "combination therapy", defined as the use of a cyclooxygenase-2 inhibitor and other agents, is intended to encompass the administration of each agent in a sequential manner in a treatment regimen that provides the beneficial effects of the combination of agents, and is also intended to encompass the co-administration of such agents in a substantially simultaneous manner, such as in a single dosage form having a fixed ratio of such active agents, or in multiple dosage forms with each agent being separate. The invention also includes a pharmaceutical composition for the prevention and treatment of neoplasms comprising a therapeutically effective amount of a compound of formula I in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent (collectively referred to herein as "carrier" material) and other antineoplastic agents or other growth inhibitory agents or other drugs or nutrients.

For oral administration, the pharmaceutical composition may be, for example, a tablet, capsule, suspension or liquid. The pharmaceutical compositions are preferably manufactured in dosage unit form containing the active ingredient in the specified dosage. Examples of such dosage units are capsules, tablets, powders, granules or suspensions, and conventional additives such as lactose, mannitol, cereal starch or potato starch; and binders such as microcrystalline cellulose, cellulose derivatives, acacia, cereal starch or gelatin; and disintegrants, for example cereal starch, potato starch or sodium carboxymethyl cellulose; and lubricating agents such as talc or magnesium stearate. The active ingredient may also be administered by injection, in which case, for example, saline, dextrose or water may be employed as a suitable carrier.

For intravascular, intramuscular, subcutaneous, or intraperitoneal administration, the compounds can be combined with a sterile aqueous solution, preferably one that is isotonic with the blood of the recipient. Such dosage forms may be prepared by dissolving the solid active ingredient in water containing a physiologically compatible substance such as sodium chloride, glycine and the like, and having a buffered pH compatible with the physiological state to produce an aqueous solution, and rendering the solution sterile. The dosage forms may be prepared in unit-dose or multi-dose containers, such as sealed ampoules or vials.

If the tumor is located in the gastrointestinal tract, the compound may be formulated with an acid-stable and base-unstable coating known in the art that begins to dissolve in the high pH small intestine. Formulations that enhance local pharmaceutical effects and reduce systemic uptake are preferred.

Dosage forms suitable for parenteral convenient administration include sterile aqueous preparations of the active compounds, which are preferably made isotonic. Injectable formulations may also be formulated by suspending or emulsifying the compound in a non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, higher aliphatic acid esters, or propylene glycol.

The dosage form for topical use includes known capsules, ointments, oils and the like. For aerosol administration, the compounds may be formulated with known aerosol excipients (exipients), such as saline, and administered using a commercially available nebulizer. Dosage forms derived from fatty acids can be used to enhance biocompatibility. For prophylactic use of lung epithelial tumors, the preferred method of administration is aerosol administration.

For rectal administration, the active ingredient may be formulated as a suppository with a base that is solid at room temperature and melts at body temperature. Commonly used bases include cocoa butter, glycerin-containing gels, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and polyethylene stearate fatty esters.

The dosage form and dosage of the drug can be readily determined by reference to known dosing regimens for tumor treatment or prevention. The therapeutic amount of active compound administered and the dosage regimen for treating a disease with a compound and/or composition of the invention will depend upon a variety of factors including the age, weight, sex and medical condition of the patient, the severity of the disease, the route and frequency of administration, and the particular compound employed, the location of the tumor, and the pharmacokinetic properties of the individual being treated and, therefore, may vary widely. If the compound is administered locally rather than systemically, and for prophylactic rather than therapeutic purposes, the dosage will generally be lower. Such treatment may be administered as often as necessary and at the discretion of the attendant physician. The dosage regimen or therapeutically effective amount of the inhibitor administered will be well understood by those skilled in the art and must be optimal for each individual. The pharmaceutical composition may contain the active ingredient in the range of about 0.1 to 2000mg, preferably in the range of about 0.5 to 500mg, most preferably between about 1 and 200 mg. Suitable daily dosages are from about 0.01 to 100mg per kg body weight, preferably between about 0.1 and about 50mg per kg body weight. The daily dose can be administered in one to four doses per day.

All patents and publications referred to herein are incorporated herein by reference.

While this invention has been described in connection with particular embodiments, the details of these embodiments are not to be considered as limiting.

Claims

1. Use of a compound, or a pharmaceutically acceptable salt or derivative thereof, in the manufacture of a medicament for treating prostaglandin-producing or cyclooxygenase-expressing neoplasia in a subject,

wherein the compound is selected from:

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

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

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

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

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

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

2. The use of claim 1, wherein the compound is 4- [5- (4-tolyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1, wherein said compound is 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

4. The use of claim 1, wherein the compound is 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

5. The use of claim 1, wherein the tumor is selected from the group consisting of colorectal cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, and breast cancer.

6. Use of a compound or a pharmaceutically acceptable salt or derivative thereof in the manufacture of a medicament for preventing neoplasia selected from the group consisting of: bladder cancer, cervical cancer, prostate cancer, lung cancer, and breast cancer,

wherein the compound is selected from:

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

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

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

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

7. The use of claim 6, wherein the compound is 4- [5- (4-tolyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

8. The use of claim 6, wherein the compound is 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

9. The use of claim 6, wherein the compound is 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

10. Use of a cyclooxygenase-2 selective compound and a cytotoxic alkylating antineoplastic agent in the manufacture of a medicament for combination therapy in treating a subject suffering from a prostaglandin-producing or cyclooxygenase-expressing neoplastic disease, wherein the compound is selected from the group consisting of:

4- (3, 5-bis (4-tolyl) -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-tolyl) -1H-pyrazol-1-yl) benzenesulfonamide;

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

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

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

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

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

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

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

5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl ] spiro [2, 4] hept-5-ene;

4- [6- (4-fluorophenyl) spiro [2, 4] hept-5-en-5-yl ] benzenesulfonamide;

6- (4-fluorophenyl) -7- [4- (methylsulfonyl) phenyl ] spiro [3, 4] oct-6-ene;

4- [6- (3, 4-dichlorophenyl) spiro [2.4] hept-5-en-5-yl ] benzenesulfonamide;

2- (2-chlorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazole;

5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-methylthiazole;

4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole;

4- (4-fluorophenyl) -5- (4-methanesulfonylphenyl) -2- (2-thienyl) thiazole;

4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-benzylaminothiazole;

4- (4-fluorophenyl) -5- (4-methanesulfonylphenyl) -2- (1-propylamino) thiazole;

5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethylthiazole;

4- [6- (4-fluorophenyl) spiro [2.4] hept-4, 6-dien-5-yl ] benzenesulfonamide;

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

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

4- [2- (4-tolyl) -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;

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

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

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

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

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

4- [2- (3-chloro-4-methoxyphenyl) -4, 5-difluorophenyl ] benzenesulfonamide;

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

5-difluoromethyl-4- (4-methanesulfonylphenyl) -3-phenylisoxazole;

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

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

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

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

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

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

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

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

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

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

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;

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

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

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

11. The use of claim 10, wherein the compound is selected from the group consisting of the following compounds and their pharmaceutically acceptable salts:

4- [5- (4-tolyl) -3- (trifluoromethyl) -1H-pyrazol-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

12. The use of claim 10, wherein the compound is 4- [5- (4-tolyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide, or a pharmaceutically acceptable salt thereof.