Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor

• US 6,136,839 A
• Filed: 06/11/1996
• Issued: 10/24/2000
• Est. Priority Date: 06/12/1995
• Status: Expired due to Fees

• Current Assignee: GD Searle LLC (Pfizer Inc.)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Gregory, Susan A, Isakson, Peter C, Anderson, Gary D
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US08/661,660
• Time in Patent Office: 1,596 Days
• Field of Search: 514/406, 514/471
• US Class Current: 514/406
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Combinations of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor are described for treatment of inflammation and inflammation-related disorders.

Claims

1. A combination comprising a therapeutically-effective amount of a 5-lipoxygenase inhibitor and a cyclooxygenase-2 inhibitor selected from compounds of Formula I ##STR12## wherein A is pyrazolyl;

wherein R¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R¹ 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;

wherein R² is methyl or amino; and

wherein R³ 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;

or a pharmaceutically-acceptable salt thereof.

2. The combination of claim 1 wherein the 5-lipoxygenase inhibitor is selected from masoprocol, tenidap, zileuton, Abbott A-76745, N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N'"'"'-hydroxyurea (Abbott A-78773), (R)(+)N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175), Abbott ABT 761, Dainippon AL-3264, Bayer Bay-x-1005, Biofor BF-389, bunaprolast, Ciba-Geigy CGS-25997, Cytomed CMI-392, Cytomed CMI-568, Atlantic Pharmaceutical CT3, Takeda CV-6504, Efamol EF-40, enazadrem phosphate, Leo Denmark ETH-615, flezelastine hydrochloride, flobufen, Merck Frosst L 663536, Merckle ML-3000, linazolast, lonapalene, Mercian MER W8020, N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea (R. W. Johnson Research Institute), ontazolast, 3M Pharmaceuticals R-840, rilopirox, Hoechst Marion Roussel RU54808, Schering Plough SCH 40120, tepoxalin, Tanabe 757, Tanabe 799, Terumo TMK-688, Glaxo Wellcome WILD20, Zeneca ZD-2138, Abbott A-121798, Abbott A 72694, Abbott A-80263, Biofor BF-397, Bristol-Myers Squibb BU-4601A, carbazoycin C, lagunamycin, Wellcome BW-70C, Ciba-Geigy CGS-26529, Warner-Lambert CI 1004, Warner-Lambert PD-136005, Warner-Lambert PD-145246, Eisai E 3040, Fujirebio F-1322, Fisons FPL-64170, Fujisawa FR 110302, Nippon Hypox Hx 0386, Merck &

Co L-699333, Merck Frosst L 739010, Lilly LY-269415, Lilly LY 178002, Meiji Milk MM-7002, Hoechst Roussel P 8892, Hoechst Roussel P 8977, Hoechst Roussel HP977, SmithKline Beecham SB-202235, Green Cross SS-81-OH, Terumo Keio University TMK 685, American Home Products WAY-121520, American Home Products WAY-125007, Zeneca ZD 7717, Zeneca ZM-216800, Zeneca ZM 230487, 1,2-dihydro-n-(2-thiazolyl)-1-oxopyrrolo(3,2,1-kl)phenothiazine-1-carboxamide, Abbott A-65260, Abbott A-69412, Abbott Abbott-63162, American Home Products AHR-5333, Bayer Bay-q-1531, Boehringer Ingelheim BI-L-357, Boehringer Ingelheim BI-L-93BS, Boehringer Ingelheim BIL 226XX, Bristol-Myers Squibb BMY-30094, carbazomycin B, Wellcome BW 4C, Wellcome BW-B218C, Wellcome BW-B70C, Chauvin CBS-1114, Ciba-Geigy CGS-21595, Ciba-Geigy CGS-22745, Ciba-Geigy CGS-23885, Ciba-Geigy CGS 24891, Ciba-Geigy CGS-8515, Chiesi CHF-1909, Warner-Lambert CI-986, Warner-Lambert CI 987, cirsiliol, docebenone, DuPont Merck DuP-654, Eisai E 5110, Eisai E-6080, Green Cross EN-105, enofelast, epocarbazolin-A, eprovafen, evandamine, forsythiaside, Fisons FPL 62064, Glaxo GR-80907, Zeneca ICI-211965, isoflavans, Kyowa Hakko KF-8940, Merck &

Co L-651392, Merck &

Co L-651896, Merck &

Co L-652343, Merck &

Co L-656224, Merck &

Co L-670630, Merck &

Co L-674636, Merck &

Co L-691816, Lilly LY-233569, Lilly LY-280810, Merck &

Co MK-591, Merck &

Co MX-886, nitrosoxacin-A, Ono ONO-5349, Ono ONO-LP-219, Ono ONO-LP-269, Warner-Lambert PD-127443, Purdue Frederick PF-5901, Sandoz QA-208-199, Johnson &

Johnson R-68151, Johnson &

Johnson R-85355, Rhone-Poulenc Rorer Rev-5367, Rhone-Poulenc Rorer RG-5901-A, Rhone-Poulenc Rorer RG-6866, Roussel-Uclaf RU-46057, Searle SC-41661A, Searle SC-45662, Sandoz SDZ-210-610, SmithKline Beecham SK&

F-104351, SmithKline Beecham SK&

F-104493, SmithKline Beecham SK&

F-105809, Synthelabo SL-81-0433, Teijin TEI-8005, Terumo TMK-777, Terumo TMK-781, Terumo TMK-789, Terumo TMK-919, Terumo TMK-992, Teikoku Hormone TZI-2721, Teikoku Hormone TZI-41127, American Home Products WAY-120739, American Home Products WY 47288, American Home Products Wy-48252, American Home Products Wy-50295, and Yoshitomi Y-19432.

3. The combination of claim 2 wherein the 5-lipoxygenase inhibitor is selected from ibudilast, masoprocol, tenidap, zileuton, Abbott A-121798, Abbott A-76745, N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N'"'"'-hydroxyurea (Abbott A-78773), (R)(+)N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175), Abbott ABT 761, Dainippon AL-3264, Bayer Bay-x-1005, Biofor BF-389, bunaprolast, Cytomed CMI-392, Cytomed CMI-568, Atlantic Pharmaceutical CT3, Takeda CV-6504, Ciba-Geigy CGS-26529, Ciba-Geigy CGS-25997, enazadrem phosphate, Eisai E 3040, Leo Denmark ETH-615, flezelastine hydrochloride, flobufen, Fujirebio F-1322, Hoechst Roussel HP977, linazolast, lonapalene, Merck Frosst L 663536, Merck Frosst L 699333, Merckle ML-3000, Mercian MR W8020, N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea (R. W. Johnson Research Institute), ontazolast, Hoechst Roussel P 8892, Hoechst Roussel P 8977, Warner-Lambert PD-145246, Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, Hoechst Marion Roussel RU54808, Schering Plough SCH 40120, Tanabe 757, Tanabe 799, tepoxalin, Terumo TMK-688, Scotia Pharmaceuticals EF-40, Glaxo Wellcome WILD20, Zeneca ZD 7717, and Zeneca ZD-2138.

4. The combination of claim 3 wherein the 5-lipoxygenase inhibitor is selected from ibudilast, masoprocol, tenidap, zileuton, Abbott A-76745, N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N'"'"'-hydroxyurea (Abbott A-78773), (R)(+)N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175), Abbott ABT 761, Bayer Bay-x-1005, Cytomed CMI-392, Ciba-Geigy CGS-26529, Biofor BF-389, Cytomed CMI-392, Eisai E 3040, Scotia Pharmaceuticals EF-40, Leo Denmark ETH-615, flobufen, Fujirebio F-1322, linazolast, lonapalene, Merck Frosst L 699333, Merckle ML-3000, ontazolast, Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, Terumo TMK-688, and Zeneca ZD-2138.

5. The combination of claim 1 wherein A is pyrazolyl;

wherein R¹ is selected from 5- and 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R¹ 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 R² is methyl or amino; and

wherein R³ 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.

6. The combination of claim 5 wherein A is pyrazolyl;

wherein R¹ 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, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio;

wherein R² is methyl or amino; and

wherein R³ is a radical selected from hydrido, oxo, cyano, carboxyl, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, trifluoromethyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoromethyl, difluoropropyl, 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.

7. The combination of claim 6 selected from compounds and their pharmaceutically-acceptable salts, of the group consisting of

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

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

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

8. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a 5-lipoxygenase inhibitor and a cyclooxygenase-2 inhibitor selected from compounds of Formula I ##STR13## wherein A is pyrazolyl;

wherein R¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R¹ 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;

wherein R² is methyl or amino; and

wherein R³ 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;

or a pharmaceutically-acceptable salt thereof.

9. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising co-administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a 5-lipoxygenase inhibitor and a cyclooxygenase-2 inhibitor selected from compounds of Formula I ##STR14## wherein A is pyrazolyl;

wherein R¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R¹ 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;

wherein R² is methyl or amino; and

wherein R³ 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;

or a pharmaceutically-acceptable salt thereof.

10. The method of claim 9 wherein said 5-lipoxygenase inhibitor and said cycloxygenase-2 inhibitor are administered in a sequential manner.

11. The method of claim 9 wherein said 5-lipoxygenase inhibitor and said cycloxygenase-2 inhibitor are administered in a substantially simultaneous manner.

12. The method of claim 9 wherein the 5-lipoxygenase inhibitor is selected from ibudilast, masoprocol, tenidap, zileuton, Abbott A-121798, Abbott A-76745, N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N'"'"'-hydroxyurea (Abbott A-78773), (R)(+)N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175), Abbott ABT 761, Dainippon AL-3264, Bayer Bay-x-1005, Biofor BF-389, bunaprolast, Cytomed CMI-392, Cytomed CMI-568, Atlantic Pharmaceutical CT3, Takeda CV-6504, Ciba-Geigy CGS-26529, Ciba-Geigy CGS-25997, enazadrem phosphate, Eisai E 3040, Leo Denmark ETH-615, flezelastine hydrochloride, flobufen, Fujirebio F-1322, Hoechst Roussel HP977, linazolast, lonapalene, Merck Frosst L 663536, Merck Frosst L 699333, Merckle ML-3000, Mercian MER W8020, N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea (R. W. Johnson Research Institute), ontazolast, Hoechst Roussel P 8892, Hoechst Roussel P 8977, Warner-Lambert PD-145246, Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, Hoechst Marion Roussel RU54808, Schering Plough SCH 40120, Tanabe 757, Tanabe 799, tepoxalin, Terumo TMK-688, Scotia Pharmaceuticals EF-40, Glaxo Wellcome WILD20, Zeneca ZD 7717, and Zeneca ZD-2138.

13. The method of claim 12 wherein the 5-lipoxygenase inhibitor is selected from ibudilast, masoprocol, tenidap, zileuton, Abbott A-76745, N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N'"'"'-hydroxyurea (Abbott A-78773), (R)(+)N'"'"'-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propynyl]-N-hydroxyurea (Abbott A-79175), Abbott ABT 761, Bayer Bay-x-1005, Cytomed CMI-392, Ciba-Geigy CGS-26529, Biofor BF-389, Cytomed CMI-392, Eisai E 3040, Scotia Pharmaceuticals EF-40, Leo Denmark ETH-615, flobufen, Fujirebio F-1322, linazolast, lonapalene, Merck Frosst L 699333, Merckle ML-3000, ontazolast, Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, Terumo TMK-688, and Zeneca ZD-2138.

14. The method of claim 9 wherein A is pyrazolyl wherein R¹ is selected from 5- and 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R¹ 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 R² is methyl or amino; and

wherein R³ 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.

15. The method of claim 14 wherein A is pyrazolyl;

wherein R¹ 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, fluoromethyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio;

wherein R² is methyl or amino; and

wherein R³ 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.

16. The method of claim 9 wherein the condition is inflammation.

17. The method of claim 9 wherein the condition is an inflammation-associated disorder.

18. The method of claim 17 wherein the inflammation-associated disorder is arthritis.

19. The method of claim 9 wherein the subject is susceptible to inflammation.

20. The method of claim 9 wherein the subject is susceptible to an inflammation-associated disorder.

21. The method of claim 20 wherein the subject is susceptible to arthritis.

22. The method of claim 15 selected from compounds, their prodrugs and their pharmaceutically-acceptable salts, of the group consisting of

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

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

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