Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor

Abstract

Treatment with a cyclooxygenase-2 inhibitor and a leukotriene A 4 hydrolase inhibitor is described as being useful in reducing recipient rejection of transplanted organs and for treatment of autoimmune diseases.

1 . A method to suppress immune, acute or delayed-type hypersensitivity response in a subject, said method comprising treating the subject with a therapeutically-effective amount of a leukotriene A 4  hydrolase inhibitor and a cyclooxygenase-2 inhibitor selected from the group consisting of 
 5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-thi ophene,    N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide, meloxicam, flosulide and compounds of Formula I                        wherein:    A is a 5- or 6-member ring substituent selected from partially unsaturated or unsaturated heterocyclo and carbocyclic rings;    R 1  is at least one substituent selected from heterocyclo, 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;    R 2  is alkyl or amino; and    R 3  is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclooxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, 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, Narylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-Narylaminosulfonyl;    or a pharmaceutically-acceptable salt thereof.      
     
     
         2 . The method of  claim 1  wherein the leukotriene A 4  hydrolase inhibitor is selected from [4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acetic acid and compounds of Formula II  
         Ar 1 -Q-Ar 2 —Y—R-Z  (II)  
       or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier, 
 wherein Ar 1  is an aryl moiety selected from: 
 (i) phenyl, mono-, di-, or tri-substituted phenyl with the substituents selected from Cl, Br, F, CF 3 , lower alkyl, lower alkoxy, NH 2 , NO 2  and OH;  
 (ii) 2-, 4- or 5-thiazolyl,  
 (iii) 2-, 3- or 4-pyridinyl,  
 (iv) 2- or 3-thienyl, and  
 (v) 2- or 3-furyl;  
 
 wherein Ar 2  is an aryl moiety selected from:  
                     
 wherein Q is selected from: 
 (i) —O—,  
 (ii) —CH 2 —,  
 (iii) —OCH 2 —,  
 (iv) —CH 2 O—,  
 (v) —NH—,  
 (vi) —NHCH 2 —,  
 (vii) —CH 2 NH—,  
 (viii) —CF 2 —,  
 (ix) —CH═CH—,  
 (x) —CH 2 CH 2 —, and  
 (xi) carbon-carbon single bond;  
 
 wherein Y is selected from: 
 (i) —O—,  
 (ii) —S—,  
 (iii) —NH—,  
 (iv) —S(O)—, and  
 (v) —S(O 2 )—;  
 
 wherein R is selected from: 
 (i) linear or branched C 2 -C 6  alkylenyl, and  
 (ii) —C(R 13 ) (R 14 )—(CH 2 ) m —;  
 
 wherein Z is selected from:  
                     (vii) a monocyclic or bicyclic heteroaromatic moiety having at least one heteroatom, wherein the heteroatom is nitrogen, and wherein the monocyclic heteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclic heteroaromatic moiety comprises a fused 9- or 10-membered ring;    
 wherein R 4  and R 5  are independently selected from:  
                     
 wherein R 6  and R 7  are independently H or lower alkyl;  
 wherein R 8  and R 9  are independently selected from  
                     
 wherein R 10  is H, halogen, lower alkyl, lower alkoxy, nitro, or hydroxy, or R 10  taken together with R 13  is an alkylenyl group having one or two carbon atoms;  
 wherein R 11  and R 12  are independently H, halogen, lower alkyl, lower alkoxy, NH 2 , NO 2  or OH;  
 wherein R 13  is H, or lower alkyl, or R 13  taken together with R 10  is an alkylenyl group having one or two carbon atoms;  
 wherein R 14  is H or lower alkyl;  
 wherein R 15  is selected from 
 (i) H,  
 (ii) —OH or ═O,  
 (iii) —(CH 2 ) a COR 18 ,  
 (iv) —(CH 2 ) a CONH(CH 2 ) b CO 2 R 19 , and  
 (v) —NHR 20 ;  
 
 wherein R 16  and R 17  are independently hydrogen, or —(CH 2 ) a COR 18 , provided that at least one of R 16  and R 17  is hydrogen;  
 wherein R 18  is —OR 19 , —NHR 19  or —NHNH 2 ;  
 wherein R 19  is H, lower alkyl or benzyl;  
 wherein R 20  is H, lower alkkyl, benzyl, —COR 19  or —CONH 2 ;  
 wherein X 1  is  
                     
 —S—, or —O—, wherein R 21  is H, lower alkyl, —CONH 2 , —CSNH 2 , —COCH 3  or —SO 2 CH 3 ;  
 wherein a and b are independently integers of from 0 to 5;  
 wherein m is 1, 2 or 3;  
 wherein n is 0, 1, 2 or 3;  
 wherein p is 1 or 2; and  
 wherein q is 1, 2 or 3;  
 provided however that where R is —C(R 13 ) (R 14 )—(CH 2 ) m —, and R 13  taken together with R 10  forms an alkylenyl group having one or two carbon atoms, then —Ar 2 —Y—R— is  
                     
 wherein X is —CH— or —N—; and wherein r is 1 or 2;  
 further provided that wherein Z is  
                     
 and either R 4  or R 5 , or both R 4  and R 5  are —(CH 2 ) a COR 18 , then a is not 0.  
 
     
     
         3 . The method of  claim 1  wherein the cyclooxygenase-2 inhibitor is a compound selected from the group consisting of: 
 3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone;    3-phenyl-4-4-methylsulfonylphenyl-2-(5H)-furanone;    4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;    2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;    4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;    4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;    4-[5-hydroxyethyl-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; 
 or a prodrug of the compound or a pharmaceutically acceptable salt of the compound.  
   
     
     
         4 . A combination comprising a therapeutically-effective amount of a cyclooxygenase-2 inhibitor, a leukotriene A 4  hydrolase inhibitor and an immunosuppressive drug selected from antiproliferative agents, antiinflammatory-acting compounds and inhibitors of leukocyte activation.  
     
     
         5 . The combination of  claim 4  wherein the cyclooxygenase-2 inhibitor is selected from the group consisting of 5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-thiophene, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide, meloxicam, flosulide and compounds of Formula I  
       
         
           
           
               
               
           
         
         wherein A is a 5- or 6-member ring substituent selected from partially unsaturated or unsaturated heterocyclo and carbocyclic rings;  
         wherein R 1  is at least one substituent selected from heterocyclo, 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;  
         wherein R 2  is selected from alkyl, and amino; and  
         wherein R 3  is selected from halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclooxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, 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, Narylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-Narylaminosulfonyl;  
         or a pharmaceutically-acceptable salt or prodrug thereof.  
       
     
     
         6 . The combination of  claim 5  wherein the leukotriene A 4  hydrolase inhibitor is selected from [4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acetic acid and compounds of Formula II  
         Ar 1 -Q-Ar 2 —Y—R-Z  (II)  
       or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier, 
 wherein Ar 1  is an aryl moiety selected from: 
 (i) phenyl, mono-, di-, or tri-substituted phenyl with the substituents selected from Cl, Br, F, CF 3 , lower alkyl, lower alkoxy, NH 2 , NO 2  and OH,  
 (ii) 2-, 4- or 5-thiazolyl,  
 (iii) 2-, 3- or 4-pyridinyl,  
 (iv) 2- or 3-thienyl, and  
 (v) 2- or 3-furyl;  
 wherein Ar 2  is an aryl moiety selected from:  
                     
 wherein Q is selected from:  
 (i) —O—,  
 (ii) —CH 2 —,  
 (iii) —OCH 2 —,  
 (iv) —CH 2 O—,  
 (v) —NH—,  
 (vi) —NHCH 2 —,  
 (vii) —CH 2 NH—,  
 (viii) —CF 2 —,  
 (ix) —CH═CH—,  
 (x) —CH 2 CH 2 —, and  
 (xi) carbon-carbon single bond;  
 wherein Y is selected from 
 (i) —O—,  
 (ii) —S—,  
 (iii) —NH—,  
 (iv) —S(O)—, and  
 (v) —S(O 2 )—;  
 
 wherein R is selected from: 
 (i) linear or branched C 2 -C 6  alkylenyl; and  
 (ii) —C(R 13 ) (R 14 )—(CH 2 ) m —;  
 
 wherein Z is selected from:  
                     
 (vii) a monocyclic or bicyclic heteroaromatic moiety having at least one heteroatom, wherein the heteroatom is nitrogen, and wherein the monocyclic heteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclic heteroaromatic moiety comprises a fused 9- or 10-membered ring;  
 wherein R 4  and R 5  are independently selected from:  
                     
 wherein R 6  and R 7  are independently H or lower alkyl;  
 wherein R 8  and R 9  are independently selected from  
                     
 wherein R 10  is H, halogen, lower alkyl, lower alkoxy, nitro, or hydroxy, or R 10  taken together with R 3  is an alkylenyl group having one or two carbon atoms;  
 wherein R 11  and R 12  are independently H, halogen, lower alkyl, lower alkoxy, NH 2 , NO 2  or OH;  
 wherein R 3  is H, or lower alkyl, or R 13  taken together with R 10  is an alkylenyl group having one or two carbon atoms;  
 wherein R 14  is H or lower alkyl;  
 wherein R 15  is selected from 
 (i) H,  
 (ii) —OH or ═O,  
 (iii) —(CH 2 ) a COR 18 ,  
 (iv) —(CH 2 ) a CONH(CH 2 ) b CO 2 R 19 , and  
 (v) NHR 20 ;  
 
 wherein R 16  and R 17  are independently hydrogen, or —(CH 2 ) a COR 18 , provided that at least one of R 16  and R 17  is hydrogen;  
 wherein R 18  is —OR 19 , —NHR 19  or —NHNH 2 ,  
 wherein R 19  is H, lower alkyl or benzyl;  
 wherein R 20  is H, lower alkyl, benzyl, —COR 19  or —CONH 2 ;  
 wherein X 1  is  
                     
  —S—, or —O—, wherein R 21  is H, lower alkyl, —CONH 2 , —CSNH 2 , —COCH 3  or —SO 2 CH 3 ;  
 wherein a and b are independently integers of from 0 to 5;  
 wherein m is 1, 2 or 3;  
 wherein n is 0, 1, 2 or 3;  
 wherein p is 1 or 2; and  
 wherein q is 1, 2 or 3;  
 provided however that where R is —C(R 13 ) (R 14 )—(CH 2 ) m —, and R 13  taken together with R 0  forms an alkylenyl group having one or two carbon atoms, then —Ar 2 —Y—R— is  
                     
 wherein X is —CH— or —N—; and wherein r is 1 or 2; further provided that wherein Z is  
                     
 and either R 4  or R 5 , or both R 4  and R 1  are —(CH 2 ) a COR 18 , then a is not 0.  
 
 
     
     
         7 . The combination of  claim 6  wherein the leukotriene A 4  hydrolase inhibitor is selected from the group consisting of: 
 (4-[5-(3-phenylpropyl)-2-thienyl]butoxyl)-acetic acid;    ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate;    1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpiperidine;    1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;    3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl [3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl [3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;    3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic acid; and    3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic acid.    
     
     
         8 . The combination of  claim 5  wherein the cyclooxygenase-2 inhibitor is a compound selected from the group consisting of: 
 3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone;    3-phenyl-4-4-methylsulfonylphenyl-2-(5H)-furanone;    4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;    2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;    4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenezulfonamide;    4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;    4-[5-hydroxyethyl-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; 
 or a prodrug of the compound or a pharmaceutically acceptable salt of the compound.  
   
     
     
         9 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a leukotriene A 4  hydrolase inhibitor, a cyclosporin and a cyclooxygenase-2 inhibitor selected from the group consisting of: 
 5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-thi ophene, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide, meloxicam, flosulide and compounds of Formula I                        wherein A is a 5- or 6-member ring substituent selected from partially unsaturated or unsaturated heterocyclo and carbocyclic rings;    wherein R 1  is at least one substituent selected from heterocyclo, 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;    wherein R 2  is selected from alkyl, and amino; and    wherein R 3  is a radical selected from halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclooxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, 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, Narylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-Narylaminosulfonyl;    or a pharmaceutically-acceptable salt or prodrug thereof.      
     
     
         10 . The combination of  claim 6  wherein the immunosuppressant is cyclosporin.  
     
     
         11 . The combination of  claim 6  wherein the immunosuppressant is selected from the group consisting of macrolide lactone, rapamycin, a glucocorticoid, 15-deoxyspergulin and cyclosporin.  
     
     
         12 . The combination of  claim 6  wherein the immunosuppressant is macrolide lactone.  
     
     
         13 . The combination of  claim 6  wherein the immunosuppressant is rapamycin.  
     
     
         14 . The combination of  claim 6  wherein the immunosuppressant is 15-deoxyspergulin.  
     
     
         15 . The combination of  claim 6  wherein the immunosuppressant is a glucocorticoid.  
     
     
         16 . The method of  claim 1 , wherein the cyclooxygenase-2 inhibitor is selected from 5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-thiophene, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide, meloxicam, and flosulide.  
     
     
         17 . The method of  claim 16  wherein the leukotriene A 4  hydrolase inhibitor is selected from the group consisting of: 
 [4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acetic acid;    ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate;    1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpiperidine;    1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;    3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl [3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;    3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic acid; and    3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic acid.    
     
     
         18 . The method of  claim 1 , wherein the leukotriene A 4  hydrolase inhibitor is selected from the group consisting of: 
 [4-[5-(3-phenylpropyl)-2-thienyl]butoxyl]-acetic acid;    ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate;    1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpiperidine;    1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;    3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl [3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;    3-[methyl [3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic acid; and    3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic acid, 
 and the cyclooxygenase-2 inhibitor is selected from the group consisting of:  
   3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone;    3-phenyl-4-4-methylsulfonylphenyl-2-(5H)-furanone;    4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl)pyridine;    2-methyl-5-(1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;    4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;    4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;    4-[5-hydroxyethyl-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.    
     
     
         19 . The method of  claim 18 , wherein the cyclooxygenase-2 inhibitor is 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide and the leukotriene A 4  hydrolase inhibitor is 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid.  
     
     
         20 . The method of  claim 18 , wherein the cyclooxygenase-2 inhibitor is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide and the leukotriene A 4  hydrolase inhibitor is 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid.  
     
     
         21 . The method of  claim 1  wherein the cyclooxygenase-2 selective inhibitor is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.  
     
     
         22 . A combination comprising a therapeutically-effective amount of cyclosporin, a cyclooxygenase-2 inhibitor selected from the group consisting of: 
 3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone;    3-phenyl-4-4-methylsulfonylphenyl-2-(5H)-furanone;    4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;    3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;    2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;    4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;    4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;    4-[5-hydroxyethyl-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; 
 and a leukotriene A 4  hydrolase inhibitor selected from the group consisting of:  
   ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate;    1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-methyl-4-tetrazolylpiperidine;    1-[2-[4-(4-(2-oxazolyl)phenoxy)phenoxy]ethyl]pyrrolidine;    3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl [3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl [3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic acid;    methyl-3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;    3-[methyl [3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;    3-[methyl[3-[4-(4-fluorophenoxy)phenoxy]propyl]amino]propanoic acid; and    3-[methyl[3-[4-(4-biphenyloxy)phenoxy]propyl]amino]propanoic acid.    
     
     
         23 . The combination of  claim 22  wherein the cyclooxygenase-2 selective inhibitor is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.