Inhibitors of farnesyl-protein transferase
First Claim
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1. A compound which inhibits farnesyl-protein transferase of the formula A:
- ##STR24## wherein;
one of the f(s) is N, and the remaining f'"'"'s are CR6 ;
R1a and R1b are independently selected from;
a) hydrogen,b) aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, R11 C(O)O--, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --,c) unsubstituted or substituted C1 -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, and R11 OC(O)--NR10 --;
R2, R3, R4 and R5 are independently selected from;
a) hydrogen,b) unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, halogen, C1 -C6 perfluoroalkyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R11 C(O)O--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --,c) unsubstituted C1 -C6 alkyl,d) substituted C1 -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, and R11 OC(O)--NR10 --;
each R6 is independently selected from;
a) hydrogen,b) unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, halogen, C1 -C6 perfluoroalkyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R11 C(O)O--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --,c) unsubstituted C1 -C6 alkyl,d) substituted C1 -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, and R11 OC(O)--NR10 --;
R7 is selected from;
H;
C1-4 alkyl, C3-6 cycloalkyl, aryl, aroyl, arylsulfonyl, unsubstituted or substituted with;
a) C1-4 alkoxy,b) aryl,c) halogen,d) HO, ##STR25## f) --SO2 R11, g) N(R10)2 orh) C1-4 perfluoroalkyl;
R8 is independently selected from;
a) hydrogen,b) aryl, substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, andc) C1 -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, or R10 OC(O)NH--;
R9 is independently selected from;
a) hydrogen,b) C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, Br, R11 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, andc) C1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --;
R10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1 -C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1 -C6 alkyl, C1 -C6 aralkyl, C1 -C6 substituted aralkyl, aryl, substituted aryl, C1 -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR10 --, --NR10 C(O)--, O, --N(R10)--, --S(O)2 N(R10)--, --N(R10)S(O)2 -- or S(O)m ;
V is selected from;
a) hydrogen,b) aryl,c) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, andd) C2 -C20 alkenyl,provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m ;
W is a imidazolyl;
X is a bond, --CH═
CH--, O, --C(═
O)--, --C(O)NR7 --, --NR7 C(O)--, --C(O)O--, --OC(O)--, --C(O)NR7 C(O)--, --NR7 --, --S(O)2 N(R10)--, --N(R10)S(O)2 -- or --S(═
O)m --;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
t is 1;
or a pharmaceutically acceptable salt thereof.
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Abstract
The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
141 Citations
15 Claims
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1. A compound which inhibits farnesyl-protein transferase of the formula A:
- ##STR24## wherein;
one of the f(s) is N, and the remaining f'"'"'s are CR6 ;R1a and R1b are independently selected from; a) hydrogen, b) aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, R11 C(O)O--, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, c) unsubstituted or substituted C1 -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, and R11 OC(O)--NR10 --; R2, R3, R4 and R5 are independently selected from; a) hydrogen, b) unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, halogen, C1 -C6 perfluoroalkyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R11 C(O)O--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, c) unsubstituted C1 -C6 alkyl, d) substituted C1 -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, and R11 OC(O)--NR10 --; each R6 is independently selected from; a) hydrogen, b) unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, halogen, C1 -C6 perfluoroalkyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R11 C(O)O--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, c) unsubstituted C1 -C6 alkyl, d) substituted C1 -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, R12 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, and R11 OC(O)--NR10 --; R7 is selected from;
H;
C1-4 alkyl, C3-6 cycloalkyl, aryl, aroyl, arylsulfonyl, unsubstituted or substituted with;a) C1-4 alkoxy, b) aryl, c) halogen, d) HO, ##STR25## f) --SO2 R11, g) N(R10)2 or h) C1-4 perfluoroalkyl; R8 is independently selected from; a) hydrogen, b) aryl, substituted aryl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, C3 -C10 cycloalkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, or R10 OC(O)NH--; R9 is independently selected from; a) hydrogen, b) C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, Br, R11 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, NO2, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, (R10)2 NC(O)--, R102 N--C(NR10)--, CN, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --; R10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R11 is independently selected from C1 -C6 alkyl and aryl; R12 is independently selected from hydrogen, C1 -C6 alkyl, C1 -C6 aralkyl, C1 -C6 substituted aralkyl, aryl, substituted aryl, C1 -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A1 and A2 are independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR10 --, --NR10 C(O)--, O, --N(R10)--, --S(O)2 N(R10)--, --N(R10)S(O)2 -- or S(O)m ;V is selected from; a) hydrogen, b) aryl, c) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2 -C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m ; W is a imidazolyl; X is a bond, --CH═
CH--, O, --C(═
O)--, --C(O)NR7 --, --NR7 C(O)--, --C(O)O--, --OC(O)--, --C(O)NR7 C(O)--, --NR7 --, --S(O)2 N(R10)--, --N(R10)S(O)2 -- or --S(═
O)m --;m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 1; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 15)
- ##STR24## wherein;
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9. The compound which is:
1-(4- Pyrid-2-yl!phenylmethyl)-5-(4-cyanobenzyl)imidazole ##STR34## or a pharmaceutically acceptable salt thereof. - View Dependent Claims (13)
Specification
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Current AssigneeMerck Sharp & Dohme Corporation (Merck & Co., Inc.)
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Original AssigneeMerck & Co., Inc.
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InventorsAnthony, Neville J., Gomez, Robert P.
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Primary Examiner(s)FAN, JANE T
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Application NumberUS08/826,251Time in Patent Office642 DaysField of Search546/272.7, 546/274.4, 546/274.7, 546/275.1, 514/341US Class Current514/341CPC Class CodesC07D 401/10 linked by a carbon chain co...C07D 403/10 linked by a carbon chain co...
