4-Amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivs., particularly I [X = CH or N; R = H, alkylthio, aminoalkylthio; R1 = NH-cyclopropyl, NHPr, NHBu, NEt2, NHCH2CH2OEt, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, NH-cyclohexyl, hexahydroazepin-1-yl, NHCH2Ph, NHCH2CH2Ph (others unclaimed); R2 = H, C6H4R3; R3 = H, halo, alkyl; R4 = CH2CH(R5)C6H4R3 or CH:CHC6H4R3; R5 = Cl, Br, OH], are described. I are inhibitors of cell proliferation in A431, 8701-BC, and leukemia cell lines, and are thus potential antitumor and antileukemic agents. Approx. 50 compds. I were tested in bioassays, and preparatory data for most of the compds. is given. For instance, Et 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylate was thioacylated with benzoyl isothiocyanate (93%), cyclized with aq. NaOH (80%), S-methylated with MeI (72%), and chlorinated at both the ring and sidechain with POCl3 and DMF (Vilsmeier complex) (65%), to give the chloride intermediate II. Reaction of II with PhCH2NH2 in PhMe at room temp. for 24 h gave 81% invention compd. III. This compd. inhibited Src phosphorylation with almost the same efficacy as PP2. In regard to antiproliferative activity toward A431 cells, 11 compds. including III had IC50 values comparable to or better than PP2. Compds. I showed no cytotoxicity toward tested cell lines at 10 nM to 10 μM when evaluated by trypan blue exclusion.
4-Amino-substituted derivatives of pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine and their preparation, pharmaceutical composistion and use antitumor and antileukemic agents
BONDAVALLI, FRANCESCO;BRUNO, OLGA;SCHENONE, SILVIA;
2004-01-01
Abstract
4-Amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivs., particularly I [X = CH or N; R = H, alkylthio, aminoalkylthio; R1 = NH-cyclopropyl, NHPr, NHBu, NEt2, NHCH2CH2OEt, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, NH-cyclohexyl, hexahydroazepin-1-yl, NHCH2Ph, NHCH2CH2Ph (others unclaimed); R2 = H, C6H4R3; R3 = H, halo, alkyl; R4 = CH2CH(R5)C6H4R3 or CH:CHC6H4R3; R5 = Cl, Br, OH], are described. I are inhibitors of cell proliferation in A431, 8701-BC, and leukemia cell lines, and are thus potential antitumor and antileukemic agents. Approx. 50 compds. I were tested in bioassays, and preparatory data for most of the compds. is given. For instance, Et 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylate was thioacylated with benzoyl isothiocyanate (93%), cyclized with aq. NaOH (80%), S-methylated with MeI (72%), and chlorinated at both the ring and sidechain with POCl3 and DMF (Vilsmeier complex) (65%), to give the chloride intermediate II. Reaction of II with PhCH2NH2 in PhMe at room temp. for 24 h gave 81% invention compd. III. This compd. inhibited Src phosphorylation with almost the same efficacy as PP2. In regard to antiproliferative activity toward A431 cells, 11 compds. including III had IC50 values comparable to or better than PP2. Compds. I showed no cytotoxicity toward tested cell lines at 10 nM to 10 μM when evaluated by trypan blue exclusion.
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