FIELD OF THE INVENTION

[0002] This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to co-administration of an inhibitor of cyclooxygenase-2 and a leukotriene B ₄ receptor antagonist for treating inflammation and inflammation-related disorders, such as arthritis.

BACKGROUND OF THE INVENTION

[0003] Prostaglandins play a major role in the inflammation process, and the inhibition of prostaglandin production, especially production of PGG ₂ , PGH ₂ and PGE ₂ , has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.

[0004] Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”) provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.

[0005] In another portion of the arachidonic acid pathway, physiologically active leukotrienes, such as leukotriene B ₄ (LTB ₄ ), leukotriene C ₄ (LTC ₄ ) and leukotriene D ₄ (LTD ₄ ) and other metabolites, are produced by the 5-lipoxygenase-mediated (5-LO) oxidation of arachidonic acid. These leukotrienes have been implicated in various inflammation-related disorders and allergic diseases, and thus compounds which inhibit leukotriene A ₄ conversion to leukotriene B ₄ , such as compounds which inhibit leukotriene A ₄ hydrolase are useful in the treatment of disease states in which leukotrienes play an important role.

[0006] It is believed that selective inhibitors of cyclooxygenase-2 and of leukotriene A ₄ hydrolase, which affect the two enzymes at low concentrations, will decrease the incidence and severity more completely. These compositions also will beneficially affect the damage caused by the various inflammatory diseases and inflammation-related disorders mediated by cyclooxygenase-2 and leukotriene A ₄ hydrolase. These compositions also will not have the level of gastrointestinal side effects commonly associated with traditional NSAIDs.

[0007] Compounds which selectively inhibit cyclooxygenase-2 have been described in U.S. Pat. Nos. 5,380,738, 5,344,991, 5,393,790, 5,466,823, 5,434,178, 5,474,995, 5, 510,368 and WO documents W096/06840, WO96/03388, WO96/03387, WO95/15316, WO94/15932, WO94/27980, WO95/00501, WO94/13635, WO94/20480, and WO94/26731.

[0008] Compounds which affect leukotriene B ₄ have been described. U.S. Pat. No. 5,384,318 describes substituted sulfonamides for the treatment of asthma. U.S. Pat. No. 5,246,965 describes aryl ethers as leukotriene B ₄ receptor antagonists.

[0009] Combined therapies of NSAIDs and other reagents are known in the art. Brooks and Karl describe the treatment of hay fever with combined antihistamines and a cyclooxygenase-inhibiting drug (flurbiprofen) (J. Allergy Clin. Immunol., 81, 110 (1988)). J. Basmajian (Spine, 14, 438 (1989)) describes the combination of the analgesic diflunisal and an antispasm agent in the treatment of back pain. V. Fossaluzza and S. DeVita describe the combined therapy of ibuprofen and an antispasm agent to reduce morning stiffness associated with primary fibromyaglia syndrome (Int. J. Clin. Pharm. Res., XII, 99 (1992)). R. Greenwald et al. (J. Rheumatol., 19, 927 (1992)) report the combination of tetracycline and the NSAID flurbiprofen ameliorates the tissue damage associated with rheumatoid arthritis.

[0010] Combination analgesics have been reported (W. Beaver, Am. J. Med., 77, 38 (1984)) although such combinations do not substantially reduce adverse effects.

[0011] The combination of NSAIDs and steroids have been described. A combination of indomethacin, steroid and lipopolysaccharide has been reported for the treatment of spinal injury (L. Guth et al., Proc. Natl. Acad. Sci. USA, 91, 12308 (1994)). G. Hughes et al. describe combinations of corticosteroids with NSAIDs for the treatment of sunburn (Dermatology, 184, 54 (1992)). C. Stewart et al. (Clin. Pharmacol. Ther., 47, 540 (1990)) describe the combination of naproxen and methotrexate as safe, although concurrent administrations of methotrexate with other NSAIDs have been reported to be toxic and sometimes fatal. A combination of a dual 5-lipoxygenase/cyclooxygenase inhibitor with a glucocorticoid is described for the treatment of skin disorders (K. Tramposch, Inflammation, 17, 531 (1993)). Combinations of NSAIDs and steroids should be used in the treatment of scleritis only if patients are not responsive to any other treatment (S. Lightman and P. Watson, Am. J. Ophthalmol., 108, 95 (1989)).

[0012] Combinations of cyclooxygenase inhibitors, lipoxygenase inhibitors, collagenase inhibitors and cytotoxic agents have been used in the treatment of non-small-cell lung cancers (B. Teicher et al., Cancer. Chemother. Pharmacol., 33, 515 (1994)).

[0013] Combinations of naproxen with other NSAIDs have been described in the treatment of arthritis. R. Willikens and E. Segre (Arthritis Rheum., 19, 677 (1976)) describe the combination of aspirin and naproxen as being more effective than aspirin alone for the treatment of rheumatoid arthritis. Naproxen and acetaminophen together were described for treating the pain associated with arthritis (P. Seideman et al., Acta Orthop. Scand., 64, 285 (1993)). However, combinations of naproxen with indomethacin or ibuprofen offer no advantage in the treatment of arthritis [M. Seifert and C. Engler (Curr. Med. Res. Opin., 7, 38 (1980))]. European patent document EP485,111, published May 13, 1992, describes the synergistic combination of lipoxygenase inhibitors and NSAID's for the treatment of inflammatory disease.

[0014] There have been no reported combinations of a cyclooxygenase-2 selective inhibitor and a leukotriene B ₄ receptor antagonist.

DESCRIPTION OF THE INVENTION

[0015] The invention involves a method of treating a subject having inflammation or an inflammation-related disorder with a combination comprising a therapeutically-effective amount of a cyclooxygenase-2 inhibitor and a leukotriene B ₄ receptor antagonist.

[0016] In addition, the invention describes a combination comprising a therapeutically-effective amount of a leukotriene B ₄ receptor antagonist and a cyclooxygenase-2 inhibitor selected from Taisho NS-398, meloxicam, floculide, Merck MK-966, Merck L-752,860 and compounds of Formula I 1

[0017] wherein

[0018] A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;

[0019] wherein R ¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R ¹ is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

[0020] wherein R ² is methyl or amino; and

[0021] wherein R ³ is a radical selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl;

[0022] or a pharmaceutically-acceptable salt thereof.

[0023] Combinations of the invention would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, combinations of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such combinations of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns and dermatitis. Combinations of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention or treatment of cancer, such as colorectal cancer. Combinations of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and of acute injury to the eye tissue. The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders such as cortical dementias including Alzheimer's disease. The combinations of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. As inhibitors of 5-lipoxygenase, these compositions would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and central nervous system damage resulting from stroke, ischemia and trauma.

[0024] Besides being useful for human treatment, these compounds are also useful for treatment of mammals, including horses, dogs, cats, rats, mice, sheep, pigs, etc.

[0025] The term “cyclooxygenase-2 inhibitor” embraces compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably, the compounds have a cyclooxygenase-2 IC ₅₀ of less than about 0.5 μM, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC ₅₀ of greater than about 1 μm and more preferably of greater than 20 μM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.

[0026] The term “leukotriene B ₄ receptor antagonist” embraces compounds which selectively antagonize a leukotriene B ₄ receptor with an IC ₅₀ of less than about 10 μM. More preferably, the leukotriene B ₄ receptor antagonists have an IC ₅₀ of less than about 1 μM.

[0027] The phrases “combination therapy”, “co-administration” or “co-therapy”, in defining use of a cyclooxygenase-2 inhibitor agent and a leukotriene B ₄ receptor antagonist agent, are intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.

[0028] The phrase “therapeutically-effective”, is intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in inflammation severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

[0029] Preferred leukotriene B ₄ receptor antagonists include Bayer Bay-x-1005, Ciba-Geigy CGS-25019C, ebselen, Leo Denmark ETH-615, Lilly LY-293111, Ono ONO-4057, Terumo TMK-688, Boehringer Ingleheim BI-RM-270, Lilly LY 213024, Lilly LY 264086, Lilly LY 292728, Ono ONO LB457, Pfizer 105696, Perdue Frederick PF 10042, Rhone-Poulenc Rorer RP 66153, SmithKline Beecham SB-201146, SmithKline Beecham SB-201993, Searle SC-53228, Sumitamo SM 15178, American Home Products WAY 121006, Bayer Bay-o-8276, calcitriol, Warner-Lambert CI-987, Merck and Co. L-651392, Lilly LY 210073, Lilly LY 223982, Lilly LY 233569, Lilly LY-255283, Merck and Co. MK-591, Merck and Co. MK-886, Ono ONO-LB-448, Purdue Frederick PF-5901, Rhone-Poulenc Rorer RG 14893, Rhone-Poulenc Rorer RP 66364, Rhone-Poulenc Rorer RP 69698, Searle SC-41930, Searle SC-50505, Searle SC-51146, SmithKline Beecham SK&F-104493, and Teijin TEI-1338.

[0030] More preferred leukotriene B ₄ receptor antagonists include Bayer Bay-x-1005, Ciba-Geigy CGS-25019C, ebselen, Leo Denmark ETH-615, Lilly LY-293111, Ono ONO-4057, Terumo TMK-688, Boehringer Ingleheim BI-RM-270, Lilly LY 213024, Lilly LY 264086, Lilly LY 292728, Ono ONO LB457, Pfizer 105696, Perdue Frederick PF 10042, Rhone-Poulenc Rorer RP 66153, SmithKline Beecham SB-201146, SmithKline Beecham SB-201993, Searle SC-53228, Sumitamo SM 15178, and American Home Products WAY 121006.

[0031] Even more preferred leukotriene B ₄ receptor antagonists include Bayer Bay-x-1005, Ciba-Geigy CGS-25019C, ebselen, Leo Denmark ETH-615, Lilly LY-293111, Ono ONO-4057, and Terumo TMK-688.

[0032] A preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is selected from 5- or 6-member partially unsaturated heterocyclyl, 5- or 6-member unsaturated heterocyclyl, 9- or 10-member unsaturated condensed heterocyclyl, lower cycloalkenyl and phenyl; wherein R ¹ is selected from 5- and 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R ¹ is optionally substituted at a substitutable position with one or more radicals selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; wherein R ² is methyl or amino; and wherein R ³ is a radical selected from hydrido, oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halo, 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.

[0033] A more preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of Formula I wherein A is selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, benzofuryl, cyclopentenyl, cyclopentadienyl, phenyl, and pyridyl; wherein R ¹ is selected from pyridyl optionally substituted at a substitutable position with one or more methyl radicals, and phenyl optionally substituted at a substitutable position with one or more radicals selected from methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl, trifluoromethoxy, hydroxyl, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio; wherein R ² is methyl or amino; and wherein R ³ is a radical 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, hydroxylpropyl, benzyl, formyl, phenylcarbonyl, methoxymethyl, furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy, and phenyloxy; or a pharmaceutically-acceptable salt thereof.

[0034] A family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:

[0035] 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoro methyl)pyrazole;

[0036] 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-( trifluoromethyl)pyrazole;

[0037] 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)be nzenesulfonamide

[0038] 4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamid e;

[0039] 4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfon amide;

[0040] 4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonami de;

[0041] 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)ben zenesulfonamide;

[0042] 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benz enesulfonamide;

[0043] 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl )benzenesulfonamide;

[0044] 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide

[0045] 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be nzenesulfonamide;

[0046] 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfo namide;

[0047] 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be nzenesulfonamide;

[0048] 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]b enzenesulfonamide;

[0049] 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]ben zenesulfonamide;

[0050] 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be nzenesulfonamide;

[0051] 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazo l-1-yl]benzenesulfonamide;

[0052] 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]ben zenesulfonamide;

[0053] 4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfon amide;

[0054] 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]be nzenesulfonamide;

[0055] 4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfona mide;

[0056] 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazo l-1-yl]benzenesulfonamide;

[0057] 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyraz ol-1-yl]benzenesulfonamide;

[0058] 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

[0059] 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benz enesulfonamide;

[0060] 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-py razol-1-yl]benzenesulfonamide;

[0061] 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hep t-5-ene;

[0062] 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfona mide;

[0063] 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct -6-ene;

[0064] 5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spi ro[2.4]hept-5-ene;

[0065] 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benz enesulfonamide;

[0066] 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl ]spiro[2.4]hept-5-ene;

[0067] 5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spir o[2.4]hept-5-ene;

[0068] 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesul fonamide;

[0069] 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsu lfonylphenyl)thiazole;

[0070] 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphe nyl)thiazole;

[0071] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazo le;

[0072] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromet hylthiazole;

[0073] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)t hiazole;

[0074] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminot hiazole;

[0075] 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylami no)thiazole;

[0076] 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-4-(meth ylsulfonyl)phenyl]thiazole;

[0077] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromet hylthiazole;

[0078] 1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopent a-2,4-dien-3-yl]benzene;

[0079] 4-[(4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide;

[0080] 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hep ta-4,6-diene;

[0081] 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesu lfonamide;

[0082] 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-py ridine-3-carbonitrile;

[0083] 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyri dine-3-carbonitrile;

[0084] 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl] -2-phenyl-pyridine-3-carbonitrile;

[0085] 4-[2-(4--methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol -1-yl]benzenesulfonamide;

[0086] 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol- 1-yl]benzenesulfonamide;

[0087] 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol- 1-yl]benzenesulfonamide;

[0088] 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imida zol-2-yl]pyridine;

[0089] 2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidaz ol-2-yl]pyridine;

[0090] 2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)- 1H-imidazol-2-yl]pyridine;

[0091] 2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)- 1H-imidazol-2-yl]pyridine;

[0092] 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol- 1-yl]benzenesulfonamide;

[0093] 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifl uoromethyl)-1H-imidazole;

[0094] 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]b enzenesulfonamide;

[0095] 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl] -4-methyl-1H-imidazole;

[0096] 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl] -4-phenyl-1H-imidazole;

[0097] 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)p henyl]-1H-imidazole;

[0098] 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-( trifluoromethyl)-1H-imidazole;

[0099] 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-i midazole;

[0100] 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluorom ethyl-1H-imidazole;

[0101] 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidaz ol-1-yl]benzenesulfonamide;

[0102] 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-( trifluoromethyl)-1H-imidazole;

[0103] 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidaz ol-1-yl]benzenesulfonamide;

[0104] 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluorom ethyl-1H-imidazole;

[0105] 4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]ben zenesulfonamide;

[0106] 1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluorom ethyl-1H-imidazole;

[0107] 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]ben zenesulfonamide;

[0108] 4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfon amide;

[0109] 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazo l-1-yl]benzenesulfonamide;

[0110] 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(t rifluoromethyl)-1H-pyrazole;

[0111] 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol -3-yl]benzenesulfonamide;

[0112] N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-( trifluoromethyl)-1H-pyrazol-1-yl]acetamide;

[0113] ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl-5-(trifluoro methyl)-1H-pyrazol-1-yl]acetate;

[0114] 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenyle thyl)-1H-pyrazole;

[0115] 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenyle thyl)-5-(trifluoromethyl)pyrazole;

[0116] 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(t rifluoromethyl)-1H-pyrazole;

[0117] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromet hyl-1H-imidazole;

[0118] 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluorome thyl)-1H-imidazole;

[0119] 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine;

[0120] 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-( trifluoromethyl)pyridine;

[0121] 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propyny loxy)-6-(trifluoromethyl)pyridine;

[0122] 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(t rifluoromethyl)pyridine;

[0123] 4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesu lfonamide;

[0124] 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene; 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazol e;

[0125] 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide ;

[0126] 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

[0127] 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)ben zene;

[0128] 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsul fonyl)benzene;

[0129] 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)ben zene;

[0130] 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl )benzene;

[0131] 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsul fonyl)benzene;

[0132] 1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl )benzene;

[0133] 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl-4-(methyl sulfonyl)benzene;

[0134] 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesu lfonamide;

[0135] 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl] -4-(methylsulfonyl)benzene;

[0136] 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesu lfonamide;

[0137] 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;

[0138] 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;

[0139] 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)be nzene;

[0140] 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl-4-(methylsulfonyl) benzene;

[0141] 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfo namide;

[0142] 1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsu lfonyl)benzene;

[0143] 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfon amide;

[0144] 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonami de;

[0145] ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-2-benzyl-acetate;

[0146] 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-y l]acetic acid;

[0147] 2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny l]oxazole;

[0148] 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxaz ole;

[0149] 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxaz ole; and

[0150] 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl ]benzenesulfonamide.

[0151] A family of specific compounds of more particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:

[0152] 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]be nzenesulfonamide;

[0153] 4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben zenesulfonamide;

[0154] 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazo l-1l-yl]benzenesulfonamide;

[0155] 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazo l-2-yl]pyridine;

[0156] 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2-yl]pyridine;

[0157] 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol- 1-yl]benzenesulfonamide;

[0158] 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

[0159] [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzene sulfonamide;

[0160] 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; and 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl ]benzenesulfonamide.

[0161] The term “hydrido” denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (—CH ₂ —) radical. Where used, either alone or within other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and “hydroxyalkyl”, the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term “alkenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term “alkynyl” denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like. The terms “alkenyl”, “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. The term “cycloalkyl” embraces saturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkenyl” embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. The term “halo” means halogens such as fluorine, chlorine, bromine or iodine. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. “Lower haloalkyl” embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term “hydroxyalkyl” embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms “alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are “lower haloalkoxy” radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl”, embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term “heterocyclo” embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclo radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclo radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The term “heteroaryl” embraces unsaturated heterocyclo radicals. Examples of unsaturated heterocyclo radicals, also termed “heteroaryl” radicals include unsaturated 3 to 6 membered heteromonocyclic group 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. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclo group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclo group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclo group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term also embraces radicals where heterocyclo radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclo group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term “alkylthioalkyl” embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are “lower alkylthioalkyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl. The term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S(═O)— radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO ₂ —. “Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals. The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” denote NH ₂ O ₂ S—. The term “acyl” denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl. The term “carbonyl”, whether used alone or with other terms, such as “alkoxycarbonyl”, denotes —(C═O)—. The term “aroyl” embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted. The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO ₂ H. The term “carboxyalkyl” embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term “alkoxycarbonyl” means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl porions having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The terms “alkylcarbonyl”, “arylcarbonyl” and “aralkylcarbonyl” include radicals having alkyl, aryl and aralkyl radicals, as defined above, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. The term “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term “heterocycloalkyl” embraces saturated and partially unsaturated heterocyclo-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term “aralkoxy” embraces aralkyl radicals attached through an oxygen atom to other radicals. The term “aralkoxyalkyl”, embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical. The term “aralkylthio” embraces aralkyl radicals attached to a sulfur atom. The term “aralkylthioalkyl” embraces aralkylthio radicals attached through a sulfur atom to an alkyl radical. The term “aminoalkyl” embraces alkyl radicals substituted with one or more amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term “alkylamino” denotes amino groups which have been substituted with one or two alkyl radicals. Preferred are “lower N-alkylamino” radicals having alkyl portions having 1 to 6 carbon atoms. Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term “arylamino” denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The “arylamino” radicals may be further substituted on the aryl ring portion of the radical. The term “aralkylamino” embraces aralkyl radicals attached through an amino nitrogen atom to other radicals. The terms “N-arylaminoalkyl” and “N-aryl-N-alkyl-aminoalkyl” denote amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term “aminocarbonyl” denotes an amide group of the formula —C(═O)NH ₂ . The term “alkylaminocarbonyl” denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” “lower N,N-dialkylaminocarbonyl” radicals with lower alkyl portions as defined above. The term “alkylaminoalkyl” embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical. The term “aryloxyalkyl” embraces radicals having an aryl radical attached to an alkyl radical through a divalent oxygen atom. The term “arylthioalkyl” embraces radicals having an aryl radical attached to an alkyl radical through a divalent sulfur atom.

[0162] The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a leukotriene B ₄ receptor antagonist and of a cyclooxygenase-2 inhibitor compound in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.

[0163] The present invention also comprises a method of treating inflammation or inflammation-associated disorders in a subject, the method comprising administering to the subject having or susceptible to such inflammation or disorder a therapeutically-effective amount of a leukotriene B ₄ receptor antagonist and of a cyclooxygenase-2 inhibitor. The method of the present invention also includes prophylactic or chronic treatment, especially in the case of arthritis and other inflammatory conditions which can lead to deterioration in the joints.

[0164] Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces 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 compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclo, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.

General Synthetic Procedures

[0165] The cyclooxygenase-2 inhibitor compounds of the invention can be synthesized according to the following procedures of Schemes I-X, wherein the R ¹ -R ³ substituents are as defined for Formula I, above, except where further noted. 2

[0166] Synthetic Scheme I shows the preparation of cyclooxygenase-2 inhibitor compounds, as described in U.S. Pat. No. 5,466,823, which is incorporated by reference, embraced by Formula I where R is Ar or Z (as defined in Scheme I), and R ^a is a radical defined above for the substituents optionally substituted on A. In step 1, ketone 1 is treated with a base, preferably NaOMe or NaH, and an ester, or ester equivalent, to form the intermediate diketone 2 (in the enol form) which is used without further purification. In step 2, diketone 2 in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the hydrochloride salt or the free base of a substituted hydrazine at reflux to afford a mixture of pyrazoles 3 and 4. Recrystallization or chromatography affords 3 usually as a solid. Similar pyrazoles can be prepared by methods described in U.S. Pat. Nos. 4,146,721, 5,051,518,.5,134,142 and 4,914,121 which also are incorporated by reference. 3

[0167] Scheme II shows the four step procedure for forming cyclooxygenase-2 inhibitor pyrazoles 8 as described in U.S. Pat. No. 5,486,534 (where R ^a is alkyl) from ketones 5. In step 1, ketone 5 is reacted with a base, such as lithium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA) to form the anion. In step 2, the anion is reacted with an acetylating reagent to provide diketone 6. In step 3, the reaction of diketone 6 with hydrazine or a substituted hydrazine, gives pyrazole 7. In step 4, the pyrazole 7 is oxidized with an oxidizing reagent, such as Oxone® (potassium peroxymonosulfate), 3-chloroperbenzoic acid (MCPBA) or hydrogen peroxide, to give a mixture of the desired 3-(alkylsulfonyl)phenyl-pyrazole 8 and the 5-(alkylsulfonyl)phenyl-pyrazole isomer. The desired pyrazole 8, usually a white or pale yellow solid, is obtained in pure form either by chromatography or recrystallization.

[0168] Alternatively, diketone 6 can be formed from ketone 5 by treatment with a base, such as sodium hydride, in a solvent, such as dimethylformamide, and further reacting with a nitrile to form an aminoketone. Treatment of the aminoketone with acid forms the diketone 6. Similar pyrazoles can be prepared by methods described in U.S. Pat. No. 3,984,431 which is incorporated by reference. 4

[0169] Cyclooxygenase-2 inhibitor diaryl/heteroaryl thiophenes (where T is S, and R ^b 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 by reference. Similar pyrroles (where T is N), furanones and furans (where T is O) can be prepared by methods described in PCT documents WO 95/00501 and WO94/15932. 5

[0170] Cyclooxygenase-2 inhibitor diaryl/heteroaryl oxazoles can 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 by reference. 6

[0171] Cyclooxygenase-2 inhibitor diaryl/heteroaryl isoxazoles can be prepared by the methods described in U.S. application Ser. No. 08/387,680, PCT documents WO92/05162, and WO92/19604, and European Publication EP 26928 which are incorporated by reference. Sulfonamides 24 can be formed from the hydrated isoxazole 23 in a two step procedure. First, hydrated isoxazole 23 is treated at about 0° C. with two or three equivalents of chlorosulfonic acid to form the corresponding sulfonyl chloride. In step two, the sulfonyl chloride thus formed is treated with concentrated ammonia to provide the sulfonamide derivative 24. 7

[0172] Scheme VI shows the three step preparation of the cyclooxygenase-2 inhibitor imidazoles 29 of the present invention. In step 1, the reaction of substituted nitrites (R ¹ CN) 25 with primary phenylamines 26 in the presence of alkylaluminum reagents such as trimethylaluminum, triethylaluminum, dimethylaluminum chloride, diethylaluminum chloride in the presence of inert solvents such as toluene, benzene, and xylene, gives amidines 27. In step 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 hindered tertiary amines such as N,N′-diisopropylethylamine, gives the 4,5-dihydroimidazoles 28 (where R ^b is alkyl). Some of the suitable solvents for this reaction are isopropanol, acetone and dimethylformamide. The reaction may be carried out at temperatures of about 20° C. to about 90° C. In step 3, the 4,5-dihydroimidazoles 28 may be dehydrated in the presence of an acid catalyst such as 4-toluenesulfonic acid or mineral acids to form the 1,2-disubstituted imidazoles 29 of the invention. Suitable solvents for this dehydration step are e.g., toluene, xylene and benzene. Trifluoroacetic acid can be used as solvent and catalyst for this dehydration step.

[0173] In some cases (e.g., where YR=methyl or phenyl) the intermediate 28 may not be readily isolable. The reaction, under the conditions described above, proceeds to give the targeted imidazoles directly.

[0174] Similarly, imidazoles can be prepared having the sulfonylphenyl moiety attached at position 2 and R ¹ attached at the nitrogen atom at position 1. Diaryl/heteroaryl imidazoles can be prepared by the methods described in U.S. Pat. No. 4,822,805, PCT document WO 96/03388 and PCT document WO 93/14082, which are incorporated by reference. 8

[0175] The subject imidazole cyclooxygenase-2 inhibitor compounds 36 of this invention may be synthesized according to the sequence outlined in Scheme VII. Aldehyde 30 may be converted to the protected cyanohydrin 31 by reaction with a trialkylsilyl cyanide, such as trimethylsilyl cyanide (TMSCN) in the presence of a catalyst such as zinc iodide (ZnI ₂ ) or potassium cyanide (KCN). Reaction of cyanohydrin 31 with a strong base followed by treatment with benzaldehyde 32 (where R ² is alkyl) and using both acid and base treatments, in that order, on workup gives benzoin 33. Examples of strong bases suitable for this reaction are lithium diisopropylamide (LDA) and lithium hexamethyldisilazane. Benzoin 33 may be converted to benzil 34 by reaction with a suitable oxidizing agent, such as bismuth oxide or manganese dioxide, or by a Swern oxidation using dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride. Benzil 34 may be obtained directly by reaction of the anion of cyanohydrin 31 with a substituted benzoic acid halide. Any of compounds 33 and 34 may be used as intermediates for conversion to imidazoles 35 (where R ² is alkyl) according to chemical procedures known by those skilled in the art and described by M. R. Grimmett, “Advances in Imidazole Chemistry” in Advances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of 34 to imidazoles 35 is carried out by reaction with ammonium acetate and an appropriate aldehyde (RYCHO) in acetic acid. Benzoin 36 may be converted to imidazoles 38 by reaction with formamide. In addition, benzoin 36 may be converted to imidazoles by first acylating with an appropriate acyl group (RYCO-) and then treating with ammonium hydroxide. Those skilled in the art will recognize that the oxidation of the sulfide (where R ² is methyl) to the sulfone may be carried out at any point along the way beginning with compounds 35, and including oxidation of imidazoles 38, using, for examples, reagents such as hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid (MCPBA) and potassium peroxymonosulfate (OXONE®).

[0176] 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, PCT document WO 96/03387, European publication EP 372,445, and PCT document WO 95/00501, which are incorporated by reference. 9

[0177] 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 by reference. 10

[0178] Similarly, Synthetic Scheme IX shows the procedure for the preparation of 1,2-diarylbenzene cyclooxygenase-2 inhibitor agents 44 from 2-bromo-biphenyl intermediates 43 (prepared similar to that described in Synthetic Scheme VIII) and the appropriate substituted phenylboronic acids. Using a coupling procedure similar to the one developed by Suzuki et al. [ Synth. Commun., 11, 513 (1981)], intermediates 43 are reacted with the boronic acids in toluene/ethanol at reflux in the presence of a Pd ^o catalyst, e.g., tetrakis(triphenylphosphine) palladium(0), and 2M sodium carbonate to give the corresponding 1,2-diarylbenzene antiinflammatory agents 44 of this invention. Such terphenyl compounds can be prepared by the methods described in U.S. application Ser. No. 08/346,433, which is incorporated by reference. 11

[0179] Diaryl/heteroaryl thiazole cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Pat. Nos. 4,051,250, 4,632,930, PCT document WO 96/03392, European Application EP 592,664, and PCT document WO 95/00501, which are incorporated 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, U.S. application Ser. Nos. 08/386,843 and 08/387,150 which are incorporated by reference. Diaryl/heteroaryl benzofuran derivatives can be prepared by the methods described in U.S. application Ser. Nos. 08/541,850 and 08/540,522 which are incorporated by reference.

[0180] The following examples contain detailed descriptions of the methods of preparation of combinations with compounds of Formula I. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.

Biological Evaluation

[0181] A combination therapy of a cyclooxygenase-2 inhibitor and a leukotriene B ₄ receptor antagonist could be evaluated as described in the following tests.