AR052900A1 - DERIVATIVES OF TIAZOL, A METHOD FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE IN THE PREPARATION OF MEDICINES FOR THE TREATMENT OF DISEASES MEDIATED BY ECE-1 - Google Patents

Abstract

A process for its preparation; pharmaceutical compositions containing them; and its use in chronic pulmonary obstruction therapy. Claim 1: A compound characterized in that it responds to formula (1), wherein: R1 is optionally substituted aryl or optionally substituted heteroaryl; R2 is cyano, CF3, halogen or XR7; R3 is optionally substituted aryl, optionally substituted heteroaryl or C3-7 cycloalkyl [optionally substituted with halogen or C1-4 alkyl]; A is NR4 or CR5R6; R4, R5 and R6 independently represent each other hydrogen or C1-4 alkyl or C3-7 cycloalkyl [optionally substituted with halogen or C1-4 alkyl]; X is a single bond, C1-6 alkylene [optionally substituted with halogen], C2-6 alkenylene [optionally substituted with halogen], C2-6 alkynylene [optionally substituted with halogen], S (O) n, NR8C (O), C (O) NR9, NR10, C (O), OC (O), C (O) O, C1-4alkylene, S1 (O) C1-4 alkylene, NR11C (O) C1-4 alkylene, C (O) NR12 alkyleneC1- 4, NR13 C1-4 alkylene, C (O) C1-4 alkylene, OC (O) C1-4 alkylene, C1 (O) C1-4 alkylene, C1-4 alkylene, C1-4S alkylene (O) n, C1-4NR14C alkylene (O), C1 alkylene -4C (O) NR15, C1-4 alkylene16, C1-4C alkylene (O), C1-4OC alkylene (O), C1-4 alkyleneC1-4 alkylene, C1-4S alkylene (O) C1-4 alkylene, C1-4 alkylene (O) C1-4 alkylene , C1-4C alkylene (O) NR18C1-4 alkylene, C1-4 alkyleneC1-4 alkylene, C1-4C alkylene (O) C1-4 alkylene, C1-4OC alkylene (O) C1-4 alkylene or C1-4C alkylene (O) C1-4 alkylene; R7 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, C3-7 cycloalkyl [optionally substituted with halogen or C1-4 alkyl], an aliphatic heterocyclyl ring of 4 to 8 members [optionally substituted with halogen or C1-4 alkyl], OR20, NR21R22, C (O) R23, CO2R24, OC (O) R25, C (O) NR26R27, S (O) nR28, SO2NR29R30, NR32C (O) R33, NR34C (O) OR35, phenoxy [optionally substituted with halogen , cyano CF3 or C1-4 alkyl] or heteroaryloxy [optionally substituted with halogen, cyano, CF3 or C1-4 alkyl]; R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R32, R33, R34 and R35 are independently hydrogen C1-6 alkyl [optionally substituted with halogen]; the aryl and heteroaryl portions are optionally independently substituted with one or more of halogen, cyano, nitro, OC (O) NR36R37, NR38R39, NR40C (O) R41, NR42C (O) NR43R44, S (O) 2NR45R46, NR47S ( O) 2R48, C (O) NR49R50, CO2R51, NR52CO2R53, S (O) nR54, OS (O) 2R55, C1-6 alkyl [optionally monosubstituted with S (O) 2R56, C (O) NR57R58 or NR31R62], C (O) R59, NR60C (O) R61, C2-6 alkenylene [optionally substituted with phenyl or heteroaryl], C2-6 alkynylene [optionally substituted with phenyl or heteroaryl], C3-7 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxyC1 -6, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, phenylC1-4 alkylene, phenoxy, phenylthio, phenylS (O), phenylS (O) 2, phenylC1-4alkoxy, heteroaryl, heteroarylC1-4alkyl, heteroaryloxy, heteroarylC 1-4 alkoxy or a 4 to 8 membered aliphatic heterocyclic ring [optionally substituted with halogen or C 1-4 alkyl]; wherein any of the immediately preceding phenyl and heteroaryl moieties are optionally substituted with halogen, nitro, NH2, NHC1-4alkyl, N (C1-4alkyl) 2, C1-4alkyl, S (O) C1-4alkyl, S (O) 2C1alkyl -4, S (O) 2NH2, S (O) 2NH1-4alkyl, S (O) 2N (C1-4alkyl) 2, cyano, C1-4alkyl, C1-4alkoxy, C (O) NH2, C ( O) NH1-4alkyl, C (O) N (C1-4alkyl) 2, CO2H, CO2C1-4alkyl, NHC (O) C1-4alkyl, NHS (O) 2C1-4alkyl, C (O) C1-4alkyl, CF3 or OCF3; R31, R36, R37, R38, R39, R40, R41, R42, R44, R45, R46, R47, R49, R50, R51, R52, R53, R57, R58, R59, R60, R61 and R62 are, independently , hydrogen C1-6 alkyl [optionally substituted with halogen, C3-6 cycloalkyl or phenyl {optionally substituted with halogen or C1-4 alkyl]]; CH2-C2-6 alkenyl, phenyl [in turn optionally substituted with halogen, nitro, NH2, NH1-4alkyl, N (C1-4alkyl) 2, C1-4alkyl, S (O) C1-4alkyl, S (O) 2C1-4alkyl , S (O) 2NH2, S (O) 2NH1-4alkyl, S (O) 2N (C1-4alkyl) 2, cyano, C1-4alkyl, C1-4alkoxy, C (O) NH2, C (O) NH1-4alkyl, C (O) N (C1-4alkyl) 2, CO2H, CO2C1-4alkyl, NHC (O) C1-4alkyl, NHS (O) 2C1-4alkyl, C (O) C1-4alkyl, CF3 or OCF3 ] or heteroaryl [in turn optionally substituted with halogen, nitro, NH2, NH1-4alkyl, N (C1-4alkyl) 2, C1-4alkyl, S (O) C1-4alkyl, S (O) 2C1-4alkyl, S (O) 2NH2, S (O) 2NH1-4alkyl, S (O) 2N (C1-4alkyl) 2, cyano, C1-4alkyl, C1-4alkoxy, C (O) NH2, C (O) NHalkylC1- 4, C (O) N (C1-4alkyl) 2, CO2H, CO2C1-4alkyl, NHC (O) C1-4alkyl, NHS (O) 2C1-4alkyl, C (O) C1-4alkyl, CF3 or OCF3]; R48, R54, R55 and R56 are, independently, C1-6 alkyl [optionally substituted with halogen, C3-6 cycloalkyl or phenyl {optionally substituted with halogen or C1-4 alkyl}], CH2alkenylC2-6, phenyl [a optionally substituted with halogen, nitro, NH2, NH1-4alkyl, N (C1-4alkyl) 2, C1-4alkyl, S (O) C1-4alkyl, S (O) 2C1-4alkyl, S (O) 2NH2, S (O) 2N C1-4alkyl, S (O) 2N (C1-4alkyl) 2, cyano, C1-4alkyl, C1-4alkoxy, C (O) NH2, C (O) NH1-4alkyl, C (O ) N (C1-4 alkyl) 2, CO2H, CO2 C1-4 alkyl, NHC (O) C1-4 alkyl, NHS (O) 2 C1-4 alkyl, C (O) C1-4 alkyl, CF3 or OCF3] or heteroaryl [in turn] optionally substituted with halogen, nitro, NH2, NH1-4alkyl, N (C1-4alkyl) 2, C1-4alkyl, S (O) C1-4alkyl, S (O) 2C1-4alkyl, S (O) 2NH2, S ( O) 2N C1-4alkyl, S (O) 2N (C1-4alkyl) 2, cyano, C1-4alkyl, C1-4alkoxy, C (O) NH2, C (O) NHC1-4alkyl, C (O) N (C1-4 alkyl) 2, CO2H, CO2 C1-4alkyl, NHC (O) C1-4alkyl, NHS (O) 2C1-4alkyl, C (O) C1-4alkyl, CF3 or OCF3]; and n is 0.1 or 2; or a salt acceptable for pharmaceutical use thereof. Claim 12: A process for the preparation of a compound of formula (1) according to claim 1, or a salt acceptable for pharmaceutical use thereof, characterized in that it comprises: a) when A is CRR5R6 coupling a compound of formula (2 ), with a compound of formula (3); b) when A is NH reacting a compound of formula (4), with a compound of formula (3) as defined in a) in the presence of a phosphoryl azide; or c) when A is NH reacting a compound of formula (5), with a compound of formula (3) as defined in a); od) when A is NR4 to react a compound of formula (6), with a compound of formula (7), and optionally after a), b), c) or d) carry out one or more of the following steps: convert the compound to another compound of the present; or form an acceptable salt for pharmaceutical use of the compound.