Patent EA-001863-B1 (EA)
Title: Acryloyl-sbstituted distamycin derivatives, processfor preparing them, and their use as antitumor agents and pharmaceutical compositions
Inventor: COZZI PAOLO
IPC: A61K31/40
Filed: 1997-07-10
Abstract: 1. An acryloyl substituted distamycin derivative of formula:   wherein: n is 2, 3 or 4; R1 and R2 are selected, each independently, from: hydrogen, halogen, and C1-C4 alkyl; R3 is hydrogen or halogen; B is selected from:   wherein R4, R5, R6, R7, and R8 are, each independently, hydrogen or C1-C4 alkyl, with the proviso that at least one of R4, R5 and R6 is C1-C4 alkyl; or pharmaceutically acceptable salts thereof. 2. A compound as defined in claim 1, wherein: n is 3 or 4; R1 and R2 are hydrogen; R3 is chlorine or bromine; B is selected from:   wherein R4, R5, R6, R7, and R8 are, each independently, hydrogen or methyl, with the proviso that at least one of R4, R5 and R6 is methyl; or pharmaceutically acceptable salts thereof. 3. A compound as defined in claim 1, selected from: 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propioncyanamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha. chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propioncyanamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N-methylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N-methylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N'-dimethylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N,N'-dimethylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N,N'-dimethylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamidoxime; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamidoxime; 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine; 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) ethylguanidine; 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) ethylguanidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionitrile; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido) pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.- bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamide; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.- chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propionamide; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) propion-N-methylamide; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methyl-amidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N'-dimethyl-amidine; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime; 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine; and 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(.alpha.-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide; and the pharmaceutically acceptable salts thereof. 4. A process for producing a compound as defined in claim 1 of formula (I) which process comprises: (a) reacting a compound of formula:   wherein: n is 2, 3 or 4; m is 0 or 1; B is selected from:   wherein R4 R5 R6 R7 and R8are, each independently, hydrogen or C1-C4 alkyl, with the proviso that at least one of R4 R5and R6 is C1-C4 alkyl; with a compound of formula:   wherein: R1 and R2 are selected, each independently, from: hydrogen, halogen, and C1-C4 alkyl; R3 is hydrogen or halogen; X is hydroxy or a leaving group; and m has the above reported meanings; in  the presence of a base and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof. 5. A process for producing a compound as defined in claim 1 of formula (I) which process comprises: when B is equal to -C [triple bond] N, reacting a compound of formula:   wherein n, R1, R2, and R3 are as defined above; with succinic anhydride, in the presence of a base and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof. 6. Use of a compound as defined in any one of claims 1 to 3, in the manufacture of a medicament for use in the treatment of cancer. 7. A pharmaceutical composition, which comprises an effective amount of a compound as defined in any one of claims 1 to 3 as an active principle, in association with one or more pharmaceutically acceptable carriers and/or diluents.