Patent EA-003510-B1 (EA)
Title: Farnesyl protein transferase inhibitors for treating arthropathies
Inventor: END DAVID WILLIAM
IPC: A61K31/4709
Filed: 1999-06-30
Abstract: 1. Use of at least a farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition for treating arthropathies, 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 following structures 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; R1 is hydrogen, C1-12alkyl, Ar<1>, Ar<2>C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, 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 C1-6alkanediyl, 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, aminoC1-6alkyloxy, 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, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl , C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(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, C1-6alkyloxy-C1-6alkyl, aminocarbonylC1-6alkyl, 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<14>R<15>; R<11> is hydrogen, C1-12alkyl,Ar<1> or Ar<2>C1-6alkyl; R<12> is hydrogen, C1-6alkyl, C1-16alkylcarbonyl, C1-6alkyloxy carbonyl, 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 C<1-6>alkanediyl; R<13> is hydrogen, C2-6alkyl, 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 1 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)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-ethoxy-phenyl)-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 (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof. 9. The use of any one of the preceding claims wherein a therapeutically effective amount of the pharmaceutical composition is administered orally or parenterally. 10. The use of claim 8 wherein the pharmaceutical composition is administered orally in an amount of from 100 to 1,500 mg daily, either as a single dose or subdivided into more than one dose. 11. The use of claim 1 wherein the arthropathy is rheumatoid arthritis, osteoarthritis, juvenile arthritis, polyarthritis, gout, epidemic polyarthritis (Ross River Virus infection), psoriatic arthitis, ankylosing spondylitis, systemic lupus erythematosus, or the arthropathy observed in Felty's syndrome, Reiter's syndrome or Still's syndrome.