Patent ID: 6407140
Filing Date: 2002-06-18
Classification: A61K,A61P

Abstract:
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 A4 hydrolase inhibitor and a cyclooxygenase-2 inhibitor compound, wherein said leukotriene A4 hydrolase inhibitor is selected from compounds of Formula IIAr1â€”Qâ€”Ar2â€”Yâ€”Râ€”Zâ€ƒâ€ƒ(II) wherein Ar1 is a moiety selected from: (i) phenyl, mono-, di-, or tri-substituted phenyl with the substituents selected from Cl, Br, F, CF3, lower alkyl, lower alkoxy, NH2, NO2 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) â€”Oâ€”, (ii) â€”CH2â€”, (iii) â€”OCH2â€”, (iv) â€”CH2Oâ€”, (v) â€”NHâ€”; (vi) â€”NHCH2â€”, (vii) â€”CH2NHâ€”, (viii) â€”CF2â€”, (ix) â€”CH&boxH;CHâ€”, (x) â€”CH2CH2â€”, and (xi) carbon-carbon single bond; wherein Y is selected from: (i) â€”Oâ€”, (ii) â€”Sâ€”, (iii) â€”NHâ€”, (iv) â€”S(O)â€”, and wherein R is selected from: (i) linear or branched C2-C6 alkylenyl; and (ii) â€”C(R13) (R14)â€”(CH2)mâ€”; wherein Z is selected from: (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 R4 and R5 are independently selected from: (i) H, (ii) lower alkyl or allyl, (iii) benzyl, (iv) â€”(CH2)aCOR18, (v) â€ƒand (vi) â€”(CH2)aâ€”OH; wherein R6 and R7 are independently H or lower alkyl; wherein R8 and R9 are independently selected from wherein R10 is H, halogen, lower alkyl, lower alkoxy, nitro, or hydroxy, or R10 taken together with R13 is an alkylenyl group having one or two carbon atoms; wherein R11 and R12 are independently H, halogen, lower alkyl, lower alkoxy, NH2, NO2 or OH; wherein R13 is H, or lower alkyl, or R13 taken together with R10 is an alkylenyl group having one or two carbon atoms; wherein R14 is H or lower alkyl; wherein R15 is selected from (i) H, (ii) â€”OH or &boxH;O, (iii) â€”(CH2 )aCOR18 (iv) â€”(CH2)aCONH(CH2)bCO2R19, and (v) â€”NHR20; wherein R16 and R17 are independently hydrogen, or â€”(CH2)aCOR18 , provided that at least one of R16 and R17 is hydrogen; wherein R18 is â€”OR19, â€”NHR19 or â€”NHNH2; wherein R19 is H, lower alkyl or benzyl; wherein R20 is H, lower alkyl, benzyl, â€”COR19 or â€”CONH2; wherein X1 is â€ƒâ€”Sâ€”, or â€”Oâ€”, wherein R21 is H, lower alkyl, â€”CONH2, â€”CSNH2, â€”COCH3 or â€”SO2CH3; 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 â€”C(R13) (R14)â€”CH2)mâ€”, and R13 taken together with R10 forms an alkylenyl group having one or two carbon atoms, then â€”Ar2â€”Yâ€”Râ€” is wherein X is â€”CHâ€”or â€”Nâ€”; and wherein r is 1 or 2; further provided that wherein Z is â€ƒand either R4 or R5, or both R4 and R5 are â€”(CH2)aCOR18, then a is not 0; and wherein said cyclooxygenase-2 inhibitor compound is selected from compounds of Formula I wherein A is pyrazolyl; wherein R1 is at least one substituent selected from heterocyclo, 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 selected from alkyl, and amino; and wherein R3 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.