Patent EA-002273-B1 (EA)
Title: Distamycin derivatives, process for preparing them, and their use as antitumor agents
Inventor: COZZI PAOLO
IPC: A61P35/00
Filed: 1997-04-24
Abstract: 1. A compound of formula (I):   wherein: n is 2, 3 or 4; R0 is C1-C4 alkyl or C1-C3 haloalkyl; R1 and R2, which may be the same or different, are each selected from hydrogen, C1-C4 alkyl optionally substituted by one or more fluorine atoms, and C1-C4 alkoxy; X is a halogen atom; B is selected from:   wherein R3, R4, R5, R6, R7, R8, and R9, which may be the same or different, are each hydrogen or C1-C4 alkyl, and m is 0, 1 or 2; or pharmaceutically acceptable salt thereof. 2. A compound according to Claim 1, wherein: n is 3; X is chloro or bromo; R0 is ethyl, propyl, 2-chloroethyl when X is chloro, or 2-bromoethyl when X is bromo; R1 and R2, which may be the same or different, are each hydrogen, -CH3, -OCH3, or-CF3; B is selected from:   wherein R3, R4, R5, R6, R7, R8, and R9, which may be the same or different, are each hydrogen or methyl, and m is 0 or 1. 3. A compound according to Claim 1, selected from: 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine; 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N'-dimethylamidine; 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocynnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime; 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine; 2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine; 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; 3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; and the pharmaceutically acceptable salts thereof. 4. A process for preparing a compound as claimed in Claim 1, which process comprises: when B is different from  reacting a compound of formula:   wherein n is 2, 3 or 4, B is selected from the group of formulae:   wherein R3, R4, R5, R6, R7, R8, and R9, which may be the same or different, are each hydrogen or C1-C4 alkyl, and m is 0, 1 or 2; with a compound of formula   wherein R0 is C1-C4-alkyl or C1-C3-haloalkyl; R1 and R2, which may be the same or different, are each selected from: hydrogen, C1-C4-alkyl optionally substituted by one or more fluorine atoms, and C1-C4-alkoxy; X is a halogen atom; and Y is hydroxy or a leaving group; so obtaining the corresponding compound of formula (I). 5. Use of a compound as defined in Claim 1, as a therapeutic agent for treating human or animal. 6. Use as defined in Claim 5 of a compound according to Claim 1 as an antitumor agent. 7. Use of a compound as defined in Claim 1 for manufacture of medicine used in method for treating cancer. 8. A pharmaceutical composition comprising as an active principle a compound according to Claim 1, in association with one or more pharmaceutically acceptable carriers and/or diluents.