Patent IL-112249-A (IL)
Title: Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
IPC: C07D239/00
Filed: 1995-01-04
Abstract: A pharmaceutical composition adapted for administration as an inhibitor of the epidermal growth factor receptor family of tyrosine kinases, comprising a therapeutically effective amount of a compound of the formula 2933 י' בכסלו התשס" ב - November 25, 2001 or a pharmaceutical salt or hydrate thereof, in admixture with a pharmaceutically acceptable excipient, diluent or carrier: X= O, S or NH; n = 0, 1, 2; R1 = H or alkyl (1-4 carbon atoms); if n = 2, R1 can be independently H or alkyl (1-4 carbon atoms) on either linking carbon atom; R2 is alkyl (1-4 carbon atoms), cycloalkyl (3-8 carbon atoms), alkoxy (1-4 carbon atoms), cycloalkoxy (3-8 carbon atoms), halo (fluoro, chloro, bromo, iodo), perfluoroalkyl (1-4 carbon atoms), hydroxy, acyloxy of the formula -O-C(O)R where R is alkyl of 1-4 carbon atoms or cycloalkyl of 3-8 carbon atoms, amino, mono or dialkylamino (1-4 carbon atoms in each alkyl group), mono or dicycloalkylamino (3-8 carbon atoms in each ring), hydroxymethyl, acyl of the formula -C(O)R, cyano, alkylthio (1-4 carbon atoms), alkylsulfinyl (1-4 carbon atoms), alkylsulfonyl (1-4 carbon atoms), cycloalkylthio (3-8 carbon atoms), cycloalkylsulfinyl (3-8 carbon atoms), cycloalkylsulfonyl, (3-8 carbon atoms), sulfamoyl, mono or dialkylsulfamoyl (1-4 carbon atoms in each alkyl group), mono or dicycloalkylsulfamoyl (3-8 carbon atoms in each ring), mercapto, carboxy, carbamoyl (-C(O)-NH2), mono or dialkylcarbamoyl (1-4 carbon atoms in each alkyl group), mono or 2934 י' בכסלו התשס" ב - November 25, 2001 dicycloalkylcarbamoyl (3-8 carbon atoms in each ring), alkoxycarbonyl (1-4 carbon atoms in the alkyl moiety), cycloalkoxycarbonyl (3-8 carbon atoms in the ring), alkenyl (2-4 carbon atoms), cycloalkenyl (4-8 carbon atoms), alkynyl (2-4 carbon atoms), or two R2 taken together on contiguous carbon atoms can form a carbocyclic ring of 5-7 members; m=0-3, wherein Ar is phenyl, thienyl, furanyl, pyrrolyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl; at least one of A-E cannot be carbon, unless R3 and R4 taken together form an aromatic or heteroaromatic ring, as defined below; any one of the A-E can be N with proviso that if R3 and R4 are either a lone pair on N or H, then n=0 or 1; both B and E can be N, with the following provisos: the other two atoms of B-C in that ring are C, R3 is not H, and n is 0 or 1; any two contiguous positions in A-E can be a single heteroatom, N, O or S, wherein one of the two remaining named positions of A-E must be C(H), and the other can be C(H) or N, resulting in a 5 membered fused ring; R3 and R4 are independently H, alkyl (1-4 carbon atoms), cycloalkyl (3-8 carbon atoms), alkoxy (1-4 carbon atoms), cycloalkoxy (3-8 carbon atoms, hydroxy, acyloxy (1-4 carbon atoms), amino, mono or dialkylamino (1-4 carbon atoms), mono or dicycloalkylamino (3-8 carbon atoms), carbonato (-OC(O)OR), where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8 carbon atoms), mono or dialkyl substituted ureido, thioureido, or N- or O-linked urethano (1-4 carbon atoms in each alkyl group), alkylthio (1-4 carbon atoms) or cycloalkylthio (3-8 carbon atoms), mercapto, alkenyl (2-4 carbon atoms), hydrazino, N(-lower alkylhydrazino (1-4 carbon atoms), acylamino (1-4 carbon atoms), hydroxylamino, O-alkylhydroxylamino (1-4 carbon atoms), or taken together can be methylene-, ethylene -or propylenedioxy, or taken together form a fused pyrrolidine, tetrahydrofuran, piperidine, piperazine, morpholine or thiomorpholine ring, or taken together form a further aromatic ring selected from the group consisting of phenyl, furan, thiophene, pyrazole, isoxazole, isothiazole, pyrrole, oxazole, imidazole and thiazole, optionally substituted with 1-3 of the R2 substituents; if B and D are C, A and E can be N, provided that at least one of R3 and R4 is lower alkoxy, or the two taken together form an aromatic ring sele