Patent EA-003860-B1 (EA)
Title: Combinations of protein farnesyltransferase and hmg coa reductase inhibitors and their use to treat cancer
Inventor: LEOPOLD JUDITH
IPC: C07K5/08
Filed: 1999-05-10
Abstract: 1. A pharmaceutical composition of a compound having the formula I wherein R<21> is hydrogen or C1-C6alkyl; R<Q> is n is 0 or 1; A is -COR<A>, -C02R<A'>, -CONHR<A'>, -CSR<A>, -C(S)OR<A'>, -C(S)NHR<A'>, -SO2R<A>, -CONR<A>R<A>, -C(O)SR<A> or -C(S)NR<A>R<A''> ; R<A>, R<A'>, and R<A''> independently are C1-C6alkyl, -(CH2)m-cycloalkyl, -(CH2)m-aryl or -(CH2)m-heteroaryl; each m is independently 0 to 3; R<1>, R<2> and R<4> are independently hydrogen or C<1>-C<6>alkyl; R<3> is C1-C6alkyl, -(CH2)m-(phenyl, substituted with R<B>), -(CH2)m-heteroaryl, -(CH2)m-(heteroaryl substituted with R<B>); wherein m is as it was mentioned above, and t is from 2 to 6; R<B> is -O-phenyl, -O-benzyl, halogen, C1-C6alkyl, hydrogen, -OC1-C6alkyl, -NH2, -NHR<A>, NR<A>R<A'>, -C(O)1-C6alkyl, -C(O)-aryl, -OH, -CF3, -NO2, -C(O)OH, -C(O)OC1-C6alkyl, CN, -OPO3H2, -CH2PO3H2, -C(O)O-aryl, -N3, -CF2CF3, -SO2R<A>, -SO2NR<A>R<A>, -CHO, -OCOCH3, -O-(CH2)m-heteroaryl, C(O)NR<A>R<A>, -NHC(O)R<A>, -O-(CH2)yNR<A>R<A'>, -O-(CH2)m-cycloalkyl, -(CH2)m-cycloalkyl, -O-(CH2)m-aryl, -(CH2)m-aryl or -(CH2)m-heteroaryl; y is 2 or 3; R, R<G>, and R<H> are independently hydrogen, halogen, -OC1-C6alkyl, C1-C6alkyl, -CN, -OPO3H2, -NH-(CO)R<A>, -CH2PO3H2, -O-phenyl, -O-benzyl, NH2, -NHR<A>, -O-(CH2)yNR<A>R<A'>, C(O)C1-C6alkyl, -C(O)-aryl, -OH, -CF3, -N02,-C(O)OH, -C(O)OC1-C6alkyl, -C(O)O-aryl, -N3, -CF2CF3, -SO2R<A>, SO2NR<A>R<A'>, -CHO or -OCOCH3; and R<C>, R<D>, R<E>, and R are independently C1-C6alkyl, hydrogen, -(CH2)m-phenyl, -(CH2)m-OH, -(CH2)m-NH2, and -(CH2)m-cycloalkyl, wherein m was defined above or -CN, or pharmaceutically acceptable salt, ester, amide or prodrugs of each compound thereof and a compound having HMG CoA reductase inhibitory activity selected from the group consisting of lovastatine, provastatine, atorvastatine, velostatine and simvastatine, or pharmaceutically acceptable salt, ester, amide or prodrug thereof. 2. A pharmaceutical composition according to claim 1 comprising a compound of formula I, wherein R<1> is hydrogen, R<2> is hydrogen, R<4> is hydrogen, and R<21> is hydrogen or CH3 and A is or 3. A pharmaceutical composition according to claim 1 comprising a compound of formula I, wherein R<3> is or -CH2-CH(CH3)2, and R<1> is hydrogen, R<2> is hydrogen, R<4> is hydrogen, R<21> is hydrogen or CH3. 4. A pharmaceutical composition according to claim 1 comprising a compound of formula I, wherein R<5> is wherein R is hydrogen, Cl, Br, F or NH2. 5. A pharmaceutical composition according to claim 1 comprising a compound of formula I, wherein R<1> is hydrogen, R<2> is hydrogen, R<4> is hydrogen, R<21> is hydrogen or CH3 and A is or R<3> is wherein R<B> is o-benzyl, -CF3, hydrogen, halogen, C1-C6alkyl, -O-C1-C6alkyl phenyl or -O-(CH2)m-pyridyl, wherein m is 0 to 3; R<5> is R<Q> is or pharmaceutically acceptable salt, ester, amide, and prodrug of a compound thereof. 6. Pharmaceutical composition according to claim 1 comprising at least one of the compounds (S)-[1-[(4-benzyloxy-benzyl)-(phenethyl-carbamoyl-methyl)-carbamoyl]-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-[[2-benzyloxy-ethylcarbamoyl]-methyl]-[[4-chlorobenzyl]-carbamoyl]-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-[(4-benzyloxy-benzyl)-[(2-phenyl-propyl-carbamoyl)-methyl]-carbamoyl]-2-(1H-imidazole-4-yl)-ethyl]carbamic acid benzyl ester; (S)-[1-[(4-benzyloxy-benzyl)-[(2,2-diphenyl-ethylcarbamoyl)-methyl]-carbamoyl]-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{biphenyl-4-ylmethyl-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{biphenyl-4-ylmethyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzylester; (S)-[1-((4-benzyloxy-benzyl)-{[2-(2-fluoro-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-benzyloxy-benzyl)-[(2-pyridin-2-yl-ethylcarbamoyl)- methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-((4-benzyloxy-benzyl)-{[2-(2-bromo-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; 10.(S)-[1-{(4-benzyloxy-benzyl)-[(1-methyl-2-phenyl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole- 4-yl)-ethyl]-carbamic acid benzyl ester; (S)- [1-{(4-benzyloxy-benzyl)-[(2-phenyl-2-pyridin-2-yl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-chloro-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]- carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-benzyloxy-benzyl)-[(2-phenyl-butylcarbamoyl)-methyl]- carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)[1-{(4-fluoro-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(4-methyl-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(4-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-[1-[{[(2-(2-amino-phenyl)-propylcarbamoyl]-methyl}-(4-benzyloxy-benzyl)-carbamoyl]-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-fluoro-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{benzyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; 20.(S)-[1-((4-benzyloxy-benzyl)-{[2-(2-chloro-phenyl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamoyl)-2-(IH-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-benzyloxy-benzyl)-[(2-ethyl-2-phenyl-butylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazoIe-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(2-chloro-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[l-{(4-bromo-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]- carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(3-chloro-benzyl)-[(2-phenyl-propylcarbamoyl)- methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-chloro-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-((4-benzyloxy-benzyl)-{[2-(2-chloro-phenyl)-propylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(2-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{[(2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-4-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(3-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; 30.(S)-(2-(1H-imidazole-4-yl)-1-{[(2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-3-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{naphthalene-1-ylmethyl- [(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-{2-(1H-imidazole-4-yl)-1-[[(2-phenyl-propylcarbamoyl)-methyl]-(4-trifluoromethyl-benzyl)-carbamoyl]-ethyl}-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-pyridin-3-ylmethyl-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-[4- (pyridin-2-ylmethoxy)-benzyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)- [1-{benzyl-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(2-methyl-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(4-methoxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-[1-{(4-benzyloxy-benzyl)-[(2-cyano-2-phenyl-ethylcarbamoyl)- methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{[(2-methyl-2-phenyl- propylcarbamoyl)-methyl]-pyridin-2-ylmethoxy-carbamoyl}-ethyl)-carbamic acid benzyl ester; 40.(S)-(2-(1H-imidazole-4-yl)-1-{(3-methyl-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-[1-{(4-dimethylamino-benzyl)-[(2-phenyl-propylcarbamoyl)- methyl]-carbamoyl}-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-4-ylmethoxy)-benzyl]-carbamoyl}ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-[4-(pyridin-3-ylmethoxy)-benzyl]-carbamoyl}ethyl)-carbamic acid benzyl ester; (2-(1-H-imidazole-4-yl)-1-{isobutyl-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-[1-{(4-benzyloxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-benzyloxy-benzyl)-[(2-hydroxy-2-phenyl-ethylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(4-methoxy-benzyl)-[(2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-[1-((4-benzyloxy-benzyl)-{[2-(2-chloro-phenyl)-ethylcarbamoyl]-methyl}-carbamoyl)-2-(1H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; (S)-[1-{(4-chloro-benzyl)-[1-(2-methyl-2-phenyl-propylcarbamoyl)-ethyl]-carbamoyl}-2-(3H-imidazole-4-yl)-ethyl]-carbamic acid benzyl ester; 50.(S)-2-(1H-imidazole-4-yl)-1-{(4-methyl-benzyl)-[(2-methy2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-imidazole-4-yl)-1-{(2-methoxy-benzyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-ethyl)-carbamic acid benzyl ester; (S)-(2-(1H-