Patent IL-102004-A (IL)
Title: Heterocyclic substituted 2-acylamino-5-thiazoles, their preparation and pharmaeutical compositions containing them
IPC: A61P35/00
Filed: 1992-05-26
Abstract: Gastrin and CCK antagonistic 2-aminothiazoles of the formula R1RVS N-ENRIV (I) in which E represents a hydrogen atom or a group -CO-Z; R1 represents a hydrogen atom; a (C1-C4() alkyl group or a phenylalklene group with a (C1-C3) alkyl; an aminoalkylene group of formula -Z1 -NR4R5 in which Z1 represents a (C1-C4) alkylene and R4 and R5 represent, independently, H or a (C1-C4) alkyl or form with the nitrogen atom to which they are attached, a saturated heterocycle such as morpholino, pyrrolidinyl, piperidino, piperazinyl or (C1-C3) 4-alkylpiperazinyl; an optionally esterified carboxyalkylene group of the formula -Z2-COOR6 in which Z2 represents a (C1-C4) alkylene and R6 represents H or a (C1-C6) alkyl; a (C1-C5) cyanoalkylene group; a carbamoylalkylene group of formula -Z3-CONR7R8 in which Z3 represents a (C1-C4) alkylene and R7 and R8 represent, independently, H or a (C1-C4) alkyl, or with N, a heterocycle such as NR4R5; a (C2-C6) hydroxyalkylene group, or a (C1-C10) alkoxyalkylene group; RIV represents a (C3-C7) cycloalkyl group which is unsubstituted or substituted by one or more (C1-C4) alkyl groups; an aromatic group optionally substituted by halogen, (C1-C5) alkyl, and (C1-C3) alkoxy and thioalkoxy groups, nitro and trifluoromethyl groups; a heterocycle containing at least one heteroatom chosen from O, S and N in particular a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl and thiazolyl, which are optionally substituted by a (C1-C3) alkyl group or a halogen atom or (C1-C3) alkoxy or RIV and RV taken together, represent the group: O-(CH2)u- (Xp)np bound through the phenyl carbon in position 4 of the thiazolyl ring and in which u equals 1 to 3, optionally carrying one or more (np) substituents Xp, which are identical or different, chosen from halogen atoms, (C1-C3) alkyl and alkoxy groups, nitro and trifluoromethyl groups, np being equal to 0 to 3; Rv represents a group - (CH2)m-X in which m is 0 to 5 and X represents a halogen atom, preferably a bromine atom, a hydroxyl, a (C3-C7) cycloalkyl, a phenyl which may be substituted by one of the groups chosen from halogen atoms, (C1-C3) alkyl or alkoxy groups, or nitro, amino, hydroxyl or trifluoro-methyl groups; a group chosen from -COOH; -COOX1; -O-COX1; -SCOX1; (O)q -S-X1 with q = 0,1 or 2; -O-COOX1; N-CO-X1 with X3 = H or X3 C1-C3) alkyl; -NH-C-O-X1; -O-C-NH-X1; -NH-C-NHX1 OOW with W = O or S; -NH-C-(CH2)s-COOH O with s = 2, 3, 4 in which X1 represents a (C1-C5) alkyl; a phenyl which may be substituted by one or more groups chosen from halogen atoms, (C1-C3) alkyl or alkoxy groups or nitro, amino, hydroxyl or trifluoromethyl groups; an adamantyl group; a group chosen from -CONX1X2; -NX1X2; in which X1 represents hydrogen, a (C1-C3) alkyl or a phenyl which is unsubstituted or substituted by one or more groups chosen from halogen atoms, (C1-C3) alkyl or alkoxy groups, or nitro, amino, hydroxyl or trifluoromethyl groups and X2 represents a hydrogen atom, a (C1-C3) alkyl, or alternatively, X1 and X2 constitute, with the nitrogen atom to which they are attached, a heterocycle chosen from pyrrolidine or piperidine which is unsubstituted or substituted by an oxo group or by a hydroxyl group, the latter being unsubstituted or substituted by an acyl, or by a -COOX1 or -CONX1X2 group; or alternatively, Rv represents a (C1-C5) alkoxy; a hydroxyl group; a cyclic amine with 5 or 6 members which is unsubstituted or substituted by an oxo group or hydroxyl group; a piperazinyl group which is unsubstituted or N-substituted by a group -COOAlk in which Alk represents a (C1-C5) alkyl; a carboxylic acid group, a group -NX2X4 with X4 = H or X4 - -(CH2)t -X5( with t equal to 2, 3 or 4 and X5 represents -OH, -O-CH-R2, -NHCOR2, -HN-C-NHR2, O in which R2 represents a (C1-C6) alkyl; or a group -NR2R3 with R2 or R3 representing independently H, (C1-C6) alkyl, a phenyl group which is unsubstituted or substituted by one or more substituents chosen from halogen atoms or a (C1-C3) alkyl group or a (C1-C3) alkoxy group, or R2 and R3 constitute, with the nitrogen atom to which they are attached, a heterocycle with 5 or 6 members: Z represents a heterocycle containing one or more heteroatoms chosen from O, S and N, coupled to an aromatic nucleus which may also contain a heteroatom chosen from O, S and N and which may be substituted by one or more groups chosen from halogen atoms, (C1-C3) alkyl and alkoxy groups, or benzyloxy, nitro, amino and trifluoromethyl groups, it being possible for the heteroatom N to be aromatic or in the form of -NH which is unsubstituted or substituted by (C1-C4) alkyl, carboxyalkylene -Z4 -COOR10 in which Z4 represents (C1-C4) alkylene and R10 is H, benzyl or (C1-C6) alkyl; carbamoylalkylene -Z5 -CONR11 in which Z5 represents (C1-C4) alkylene and R11 and R12 represent, independently, H, (C1-C6) alkyl, or form with N a saturated heterocycle such as morpholino or piperidino; acyl COR13 with R13 representing (C1-C4) alkyl or phenyl; alkoxycarbonyl COOR14 with R14 being tert-butyl or benzyl; provided that, when E represents a hydrogen atom, then R1 is also a hydrogen atom and Rv represents a (C1-C5) alkoxy, a piperidine which is unsubstituted or substituted by a 4-hydroxyl, 4-(C1-C3 alkoxy) carbonylpiperazine or a group X1-X2-N-(CH2)mr1- where m is 1 or 2 and X1-X2-N represents a phthalimido or -NH2 group; as well as the addition salts of the compounds of formula (I) with inorganic or organic acids and bases.