Patent EA-000710-B1 (EA)
Title: Farnesyl protein transerase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivatives
Inventor: VENER MARC GASTON
IPC: A61P43/00
Filed: 1996-10-16
Abstract: 1. A compound of formula (I)   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>, Ar2<2>C1-6alkyl, quinolinyl-C1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6 alkyl, C1-6alkyloxy-C1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl, or a radical of formula -Alk<1>-C(=O)-R<9>, -Alk<1>-S(O)-R<9> or -Alk<1>-S(O)2-R<9>, wherein Alk<1> is C1-6 alkanediyl, R<9> is hydroxy, C1-6 alkyl, C1-6 alkyloxy, amino, C1-8 alkylamino or C1-8 alkylamino substituted with C1-6 alkyloxycarbonyl; R<2>, R<3> and R<16> each independetly are hydrogen, hydroxy, halo, cyano, C1-6 alkyl, C1-6 alkyloxy, hydroxy C1-6 alkyloxy, C1-6 alkyloxy, C1-6 alkyloxy, aminoC1-6 alkyloxy, mono- or di(C1-6alkyl)amino C1-6alkyloxy, Ar<1>, Ar<2>C1-6 alkyl, Ar<2>oxy, Ar<2>-C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6 alkenyl, 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>, C1-6 alkyl, hydroxyC1-6 alkyl, C1-6 alkyloxyC1-6 alkyl, C1-6alkyloxy, C1-6 alkylthio, amino, hydroxycarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkyl S(O)C1-6 alkyl or C1-6 alkyl S(O)2 C1-6 alkyl; R<6> and R<7> each independently are hydrogen, halo, cyano, C1-6 alkyl, C1-6 alkyloxy, Ar<2> oxy, trihalomethyl, C1-6 alkylthio, di(C1-6 alkyl)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, aminocarbonylC1-6alkyl, or a radical of formula -O-R<10> (b-l), -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<14>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 residue of natural amino acid, Ar<1>carbonyl, Ar<2>C1-6alkylcarbonyl,  aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, 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. A compound as claimed in claim 1 wherein X is oxygen. 3. A compound as claimed in claims 1 or 2 wherein the dotted line represents a bond. 4. A compound as claimed in claims 1, 2 or 3 wherein R<1> is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl or mono- or di(C1-6alkyl)aminoC1-6alkyl. 5. A compound as claimed in any of claims 1 to 4 wherein R<3> is hydrogen and R<2> is halo, C1-6alkyl, C2--6alkenyl, C1-6alkyloxy, trihalomethoxy or hydroxyC1-6alkyloxy. 6. A compound as claimed in any of claims 1 to 5 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. A compound as claimed in 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)hydroxy(1-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. A compound as claimed in claim 7 wherein the compound is  (B)-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 pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claims 1 to 8. 10. A process of preparing a pharmaceutical composition as claimed in claim 9 characterized in that a therapeutically effective amount of a compound as claimed in any one of claims 1 to 8 is intimately mixed with a pharmaceutically acceptable carrier. 11. A compound as claimed in any of claims 1 to 8 for use as a medicine. 12. A compound of formula (XII) wherein the radicals R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<16> R<17>, R<18> and R<19> are as defined in claim 1; a stereoisomeric form or a pharmaceutically acceptable acid or base addition salt form thereof.   13. A compound of formula (VI) wherein the radicals R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<16> R<17>, R<18> and R<19> are as defined in claim 1; a stereoisomeric form or a pharmaceutically acceptable acid or base addition salt form thereof.   14. A process for preparing a compound of general formula (I) as claimed in claim 1, characterized by  a) hydrolysing an intermediate ether of formula (II), wherein R is C1-6alkyl in an aqueous acid solution, preferably an aqueous solution hydrochloric acid, yielding a compound of formula (I-a) wherein R<1> is hydrogen; and optionally transforming the compound of formula (I-a) wherein R<1> is hydrogen into a compound of formula (I-a), wherein R<1> is as defined in claim 1, except hydrogen.   15. A process of claim 14, wherein the acid is a hydrochloric acid. 16. A process for preparing a compound of general formula (I), wherein reacting an intermediate ketone of formula (III) with a intermediate of formula (IV-a), wherein P is an optional protective group which is removed after the addition reaction, in the presence of a suitable strong base in an appropriate solvent, yielding a compound of formula (I-b);   17. A process for preparing a compound of general formula (I) as claimed in claim 1, wherein reacting an intermediate of formula (XXI) with an intermediate of formula (IV-a), wherein P is an optional protective group which is removed after the addition reaction, with subsequent treatment with an acid such as, e.g. TiCl3 in the presence of water, and reacting the thus formed intermediate (XXIII) with a suitable reagent such as, e.g. R<17>CH2COCl or R<17>CH2COOC2H5, optionally followed by treatment with a base such as, e.g. potassium tert-butoxide, yielding a compound of formula (I-b-l).     18. A process for preparing a compound of general formula (I) as claimed in claim 1, wherein reacting an intermediate of formula (XIII), wherein W is an appropriate leaving group with a reagent of formula (XIV) in an appropriate solvent, yielding a compound of formula (I-g);   wherein the substituents R<1> to R<16> are as defined in claim 1. 19. A process for preparing a compound of general formula (I) as claimed in claim 1, wherein convening compounds of formula (I) into each other; or if desired; a compound of formula (I) into a pharmaceutically acceptable acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/or preparing stereochemically isomeric forms thereof.