IT1276170B1 - New quinoline 4-carboxamide derivatives - have NK3 and/or NK2 binding activity, useful for treating respiratory, inflammatory gastrointestinal, renal and CNS disorders - Google Patents

Abstract

Quinoline 4-carboxamide derivatives of formula (I) and their salts and solvates are new. Ar = optionally substituted aryl or 5-7C cycloalkadienyl or an optionally substituted single or fused ring hetero-aromatic group; R = 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkylalkyl, optionally substituted Ph or Ph(1-6C alkyl), an optionally substituted 5-membered heteroaromatic ring containing up to four heteroatoms N or O, hydroxy(1-6C alkyl), amino(1-6C alkyl), 1-6C alkylaminoalkyl, di(1-6C alkyl)aminoalkyl, 1-6C acylaminoalkyl, 1-6C alkoxyalkyl, 1-6C alkylcarbonyl, carboxy, 1-6C alkoxycarbonyl, 1-6C alkoxycarbonyl-(1-6C alkyl), aminocarbonyl, 1-6C alkylaminocarbonyl, di(1-6C alkyl)-aminocarbonyl, halo(1-6C alkyl), or (CH2)p; p = 2 or 3 such that, taken with a C atom from Ar, a ring is formed; R1 = H or up to four of 1-6C alkyl, 1-6C alkenyl, aryl, 1-6C alkoxy, OH, halo, NO2, CN, carboxy, carboxamido, sulphonamido, 1-6C alkoxycarbonyl, CF3, acyloxy, phthalimido, NH2 or mono- or di-(1-6C alkyl)amino; R2 = O(CH2)nX or NHCONHY; X = alkyl (optionally substituted with one or two groups OH or NH2), carboxy, CN, 1-6C alkoxycarbonyl, aminocarbonyl, mono- or di-(1-6C alkyl)aminocarbonyl, amino(1-6C alkyl)aminocarbonyl or mono- or di(1-6C alkyl)amino(1-6C alkyl)aminocarbonyl; or X = NX1X2 or a C-linked single or fused ring heterocyclic group where any ring is an optionally unsaturated 5- to 6-membered ring containing 1 or 2 N atoms and optionally 1 or 2 additional heteroatoms N or O and where 1 or 2 ring atoms are optionally substituted with 1-6C alkyl, OH, NH2, mono- or bis-(1-6C alkyl)amino or oxo; X1, X2 = H, carboxyalkylcarbonyl, alkoxycarbonyl-alkylcarbonyl, alkylcarbonyl, arylcarbonyl, heteroaryl-carbonyl, aryl-(1-6C alkyl)carbonyl, heteroaryl(1-6C alkyl)carbonyl, amino-carbonyl, mono- or bis(1-6C alkyl)aminocarbonyl, amino(1-6C alkyl)carbonyl, mono- or bis(1-6C alkyl)amino(1-6C alkyl)carbonyl, a group COTCOT1 or a 5-9-membered single or fused-ring cycloalkyl group containing 1 or 2 N atoms and optionally containing 1 or 2 additional heteroatoms N or O, and where 1 or 2 of the ring atoms are optionally substituted with 1-6C alkyl and the ring is optionally fused to a benzene ring; (all aryl or heteroaryl groups are optionally substituted with up to 2 of OH, 1-6C alkoxy, hydroxy(1-6C alkyl), amino(1-6C alkyl), mono- or bis(1-6C alkyl)amino, mono- or bis(1-6C alkyl)amino(1-6C alkyl), amino(1-6C alkoxy), mono or bis(1-6C alkyl)amino(1-6C alkoxy), carboxy, 1-6C alkylcarbonyl, 1-6C alkoxycarbonyl, carboxy(1-6C alkyl), carboxy(1-6C alkoxy) and 1-6C alkylcarbonyl(1-6C alkoxy); any alkyl groups of hetero(1-6C alkyl) or aryl(1-6C alkyl) groups is optionally substituted with amino or mono- or bis(1-6C alkyl)amino; n = 0-7, provided that when X = NX1X2, n = 2-7 and X1 and X2 are not both H; R3 = 1-6C alkyl, 3-7C cycloalkyl, 4-7C cycloalkylalkyl; or optionally substituted aryl or single or fused ring aromatic heterocyclic group; T = 1-6C alkylene or 2-6C alkenylene; T1 = OH or 1-6C alkoxy; Y = 1-6C alkyl, aryl, aryl(1-3C alkyl) or (CH2)p'X3; p' = 1-4; X3 = carboxy, 1-6C alkoxycarbonyl or CONH(CH2)qNX4X5; q = 2-4; and X4, X5 = H, 1-6C alkyl or 1-6C alkylcarbonyl. Also claimed is a combined NK2/NK3 antagonist (A), having NK2/NK3 binding affinity ratio of 0.005-20 (preferably 0.1-10) or having equal binding affinities.