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.

What is claimed is:  
     
         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 Dupont Dup 697, Taisho NS-398, 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, 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 method of  claim 1  wherein said leukotriene A 4  hydrolase inhibitor and said cycloxygenase-2 inhibitor are administered in a sequential manner.  
     
     
         3 . The method of  claim 1  wherein said leukotriene A 4  hydrolase inhibitor and said cycloxygenase-2 inhibitor are administered in a substantially simultaneous manner.  
     
     
         4 . The method of  claim 1  wherein the leukotriene A 4  hydrolase inhibitor is selected from Rhone-Poulenc Rorer RP-64966 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 Ar2 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:  
                     
  and  
 (viii) 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: 
 (i) H,  
 (ii) lower alkyl or allyl,  
 (iii) benzyl,  
 (iv) —(CH 2)a COR 18 ,  
                     
  and  
 (vi) —(CH 2 ) a —OH;  
 
 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 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 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.  
 
     
     
         5 . The method of  claim 4  wherein the leukotriene A 4  hydrolase inhibitor is selected from compounds of Formula II wherein Ar 1 —Q—Ar 2 —Y— is  
       
         
           
           
               
               
           
         
       
       wherein Q is —O—, —CH 2 —, —CF 2 —or —CH 2 O—; and R 11  and R 22  are independently H, lower alkyl, lower alkoxy, halogen, NH 2  or NO 2 .  
     
     
         6 . The method of  claim 4  wherein the leukotriene A 4  hydrolase inhibitor is selected from compounds of Formula II wherein Ar 1 —Q—Ar 2 —Y— is  
       
         
           
           
               
               
           
         
       
       wherein X 2  is —S—, or —CH═N—; and wherein Q is —CH 2 —, —CF 2 —, —O— or —CH 2 O—.  
     
     
         7 . The combination of  claim 4  wherein the leukotriene A 4  hydrolase inhibitor is selected from compounds, their prodrugs and their pharmaceutically-acceptable salts, of 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.  
 
     
     
         8 . The method of  claim 1  wherein A is selected from oxazolyl, isoxazolyl, dihydrofuryl, imidazolyl, and pyrazolyl; wherein R 1  is selected from 5- and 6-membered heterocyclo, 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, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; wherein R 2  is amino; and wherein R 3  is a radical selected from oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halo, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, 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.  
     
     
         9 . The method of  claim 8  wherein A is selected from oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl; wherein R 1  is phenyl optionally substituted at a substitutable position with one or more radicals selected from methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio; wherein R 2  is amino; and wherein R 3  is a radical selected from oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, 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.  
     
     
         10 . The method of  claim 9  wherein the cyclooxygenase-2 inhibitor is selected from compounds, their prodrugs and their pharmaceutically-acceptable salts, of 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.  
 
     
     
         11 . 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.  
     
     
         12 . The combination of  claim 11  wherein the cyclooxygenase-2 inhibitor is selected from Dupont Dup-697, Taisho NS-398, 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, 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.  
       
     
     
         13 . The combination of  claim 12  wherein the leukotriene A 4  hydrolase inhibitor is selected from Rhone-Poulenc Rorer RP-64966 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 in 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:  
                     
  and 
 (viii) 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: 
 (i) H,  
 (ii) lower alkyl or allyl,  
 (iii) benzyl,  
 (iv) —(CH 2)   a COR 18 ,  
                     
 
  and 
 (vi) —(CH 2 ) a —OH;  
 
 wherein R 6  and R 7  are independently H or lower alkyl;  
 wherein R 8  and R 9  are independently selected from 
 (i) H  
 (ii) —OH, ═O or —(CH 2 ) a —OH,  
 (iii) —(CH 2 ) a COR 18    
 
  and 
 (iv) —(CH 2 ) a CONH(CH 2 ) b CO 2 R 19 ,  
 (v) —NHR 20 ,  
                     
 
 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 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 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.  
 
     
     
         14 . The combination of  claim 13  wherein the leukotriene A 4  hydrolase inhibitor is selected from wherein the leukotriene A 4  hydrolase inhibitor is selected from Rhone-Poulenc Rorer RP-64966, 
 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)phenoxylpropyl]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.  
 
     
     
         15 . The combination of  claim 12  wherein A is selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl, and pyridyl; wherein R 1  is selected from 5- and 6-membered heterocyclo, 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, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; wherein R 2  is selected from lower alkyl and amino; and wherein R 3  is a radical selected from halo, lower alkyl, oxo, cyano, carboxyl, lower cyanoalkyl, heteroaryloxy, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lower hydroxylalkyl, lower aralkyl, acyl, phenylcarbonyl, lower alkoxyalkyl, heteroaryloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, aminoalkyl, alkylaminoalkyl, aryloxy, and aralkoxy; or a pharmaceutically-acceptable salt thereof.  
     
     
         16 . The combination of  claim 15  wherein A is selected from oxazolyl, isoxazolyl, dihydrofuryl, imidazolyl, and pyrazolyl; wherein R 1  is selected from 5- and 6-membered heterocyclo, 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, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; wherein R 2  is amino; and wherein R 3  is a radical selected from oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halo, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, 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.  
     
     
         17 . The combination of  claim 16  wherein A is selected from oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl; wherein R 1  is phenyl optionally substituted at a substitutable position with one or more radicals selected from methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio; wherein R 2  is amino; and wherein R 3  is a radical selected from oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, 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.  
     
     
         18 . The combination of  claim 17  wherein the cyclooxygenase-2 inhibitor is selected from compounds, their prodrugs and their pharmaceutically-acceptable salts, of 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 composition of  claim 11  wherein the leukocyte activation inhibitor is a cyclosporin.  
     
     
         20 . The composition of  claim 19  wherein the cyclosporin is cyclosporin A.  
     
     
         21 . 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 Dupont Dup 697, Taisho NS-398, 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, 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.  
       
     
     
         22 . The method of  claim 1  further characterized by suppressing immune response in a subject susceptible to or afflicted with rejection of an organ transplanted to said subject; graft versus host disease; an autoimmune disease, an inflammatory disease, or a condition with underlying autoimmune or inflammatory reactivities or responses; an allergy; asthma; airway hypersensitivity; septic shock; myesthemia gravis; autoimmune thyroiditis; Grave's disease; autoimmune hemolytic anemia; autoimmune thromboeytopenia purpura; mixed connective tissue disease; idiopathic Addison's disease; Sjogren's syndrome; urticaria; an acute hypersensitivity response or a delayed hypersensitivity response; Goodpasture's syndrome; hemolytic anemia; contact dermatitis; granuloma; antibody-induced thrombocytopenia; hypersensitivity pneumonitis; glomerulonephritis; thyroiditis; encephalomyelitis; or meningitis.