Patent EA-003877-B1 (EA)
Title: Farnesyl protein transferase inhibitors with in vitro radiosensitizing properties
Inventor: VAN GINCKEL ROBERT FRANCISCUS
IPC: A61P43/00
Filed: 1999-06-30
Abstract: 1. Use of at least a farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition having radiosensitizing properties for administration before, during or after irradiation of a tumor for treating cancer in vivo, wherein said farnesyl protein transferase inhibitor is a compound of formula (I), or a compound of formula (II) or (III) which is metabolized in vivo to a compound of formula (I), said compounds being represent by a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; R<1> is hydrogen, C1-12alkyl, Ar<1>, Ar<2>C1-6alkyl, quinolinylC1-6alkyl, pyridyl-C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)-aminoC1-6alkyl, aminoC1-6alkyl, S(O)2-R<9> wherein Alk1 is C1-6alkanediyl, R<9> is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl; R<2>, R<3> and R<16> each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, amino-C1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar<1>, Ar<2>C1-6alkyl, Ar<2>oxy, Ar<2>C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R<2> and R<3> taken together may form a bivalent radical of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); R<4> and R<5> each independently are hydrogen, halo, Ar<1>, C1-6alkyl, hydroxy-C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkyl S(O)2C1-6alkyl; R<6> and R<7> each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar<2>oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or when on adjacent positions R<6> and R<7> taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2); R<8> is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)-aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, amino-carbonylC1-6alkyl, or a radical of formula -O-R<10> (b-1), -S-R<10> (b-2), -N-R<11>R<12> (b-3), wherein R<10> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar<1>, Ar<2>C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, a radical or formula -Alk<2>-OR<13> or -Alk<2>-NR<1>R<15>; R<11> is hydrogen, C1-12alkyl, Ar<1> or Ar<2>C1-6alkyl; R<12> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar<1>, Ar<2>C1-6alkyl, C1-6alkylcarbonylC1-6alkyl, a natural amino acid, Ar<1>carbonyl, Ar<2>C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxy-C1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical of formula -Alk<2>-OR<13> or -Alk<2>-NR<14>R<15>; wherein Alk<2> is C1-6alkanediyl; R<13> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar<1> or Ar<2>C1-6alkyl; R<14> is hydrogen, C1-6alkyl, Ar<1> or Ar<2>C1-6alkyl; R<15> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar<1> or Ar<2>C1-6alkyl; R<17> is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar<1>; R<18> is hydrogen, C1-6alkyl, C1-6alkyloxy or halo; R<19> is hydrogen or C1-6alkyl; Ar<1> is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo; and Ar<2> is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo. 2. The use of claim 1 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein X is oxygen. 3. The use of claim 1 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein the dotted line represents a bond. 4. The use of claim 1 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R<1> is hydrogen, C1-6alkyl, C1-6alkyloxy-C1-6alkyl or mono- or di(C1-6alkyl)aminoC1-6alkyl. 5. The use of claim 1 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R<3> is hydrogen and R<2> is halo, C1-6alkyl, C2-6alkenyl, C1-6alkyloxy, trihalomethoxy or hydroxyC1-6alkyloxy. 6. The use of claim 2 wherein said farnesyl protein transferase inhibitor is a compound of formula (I) and wherein R<8> is hydrogen, hydroxy, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, imidazolyl, or a radical of formula -NR<11>R<12> wherein R<11> is hydrogen or C1-12alkyl and R<12> is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, or a radical of formula -Alk<2>-OR<13> wherein R<13> is hydrogen or C1-6alkyl. 7. The use of claim 1 wherein the compound is 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)-methyl]-1-methyl-2(1H)-quinolinone, 6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone; 6-[(4-chlorophenyl)hydroxyl1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxy-phenyl)-1-methyl-2(1H)-quinolinone; 6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone monohydrochloride monohydrate; 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone, and 6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salts thereof. 8. The use of claim 1 wherein the compound is (+)-(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof. 9. A method of cancer therapy for a host harboring a tumor comprising the steps of: - administering a radiation-sensitizing effective amount of a farnesyl protein transferase inhibitor of formulae (I), (II) and (III) according to claim 1 before, during or after - administering radiation to said host in the proximity to the tumor. 10. A method of claim 9 wherein a therapeutically effective amount of the pharmaceutical composition is administered orally, parenterally, rectally or topically. 11. The method of claim 9 wherein the pharmaceutical composition is administered orally in an amount of from 10 to 1500 mg/m<2> daily, either as a single dose or subdivided into more than one dose. 12. The method of claim 9 wherein the irradiation is ionizing irradiation. 13. The method of claim 9The use of claim 1 wherein the irradiation of the tumor is external or internal. 14. The method of claim 9 wherein the administration of the pharmaceutical composition commences up to one month before the irradiation of the tumor. 15. The use of claim 9 wherein the irradiation of the tumor is fractionated and the administration of the pharmaceutical composition is maintained in the interval between the first and the last irradiation session.