Inhibitors of farnesyl-protein transferase
First Claim
Patent Images
1. A compound which inhibits Ras farnesyl-transferase having the Formula XVI:
- ##STR18## wherein;
R2 and R3 are independently selected from;
a) a side chain of a naturally occurring amino acid,b) an oxidized form of a side chain of a naturally occurring amino acid which is;
i) methionine, sulfoxide, orii) methionine sulfone, andc) substituted or unsubstituted C1 -C20 alkyl, substituted or unsubstituted C2 -C20 alkenyl, substituted or unsubstituted C3 -C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group,wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3,-- N(R10)2, R11 OC(O)NR10 -- and C1 -C20 alkyl, andd) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl;
orR2 and R3 are combined to form --(CH2)s --;
R4 and R5 are independently selected from;
a) hydrogen,b) C1 -C6 alkyl unsubstituted or substituted by C2 -C20 alkenyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, N3, (R10)2 N-- C(NR10)--, R10 C(O)--, --N(R10)2, or R10 OC((O)NR10 --,c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, halogen, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C(NR10)--, R10 (O)--, N3,-- N(R10)2, or R11 OC(O)NR10 --, andd) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3 -C10 cycloalkyl;
R6 is selected from;
a) hydrogen,b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S (O)m --, R10 C(O)NR10 --, CN, NO2, R102 N--C(NR10)--, R10 C(O)--, N3, --N(R10)2, (R12)2 NC(O)-- or R11 OC(O)NR10 --, andc) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 C(O)--, N3, --N(R10)2, or R10 OC(O)NH--;
R7 is independently selected froma) hydrogen,b) unsubstituted or substituted aryl,c) unsubstituted or substituted heterocycle,d) unsubstituted or substituted C3 -C10 cycloalkyl, ande) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl;
R8 is selected from;
a) hydrogen,b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, --S(O)2 NR102, CN, NO2, R102 N-- C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, andc) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 OC(O)--, R10 OC(O)--, N3, --N(R10)2, or R10 OC(O)NH--;
R10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl;
R11 is independently selected from C1 -C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1 -C6 alkyl and aryl, or (R12)2 forms --(CH2)s --;
A1 and A2 are independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)2 N(R7)--, --N(R7)S(O)2 --, or S(O)m ;
A3 is independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)N(R7)--, --N(R7)S(O)2 --, or S(O)m ;
A4 is selected from;
a bond, O, --N(R7)-- or S,V is aryl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 4 or 5; and
provided heterocycle is not tetrazolyl; and
substituted aryl is an aryl group which is substituted with 1 or 2 substitutents selected from F, Cl, Br, CF3, NH2, N(C1 -C6 alkyl)2, NO2, CN, (C1 -C6 alkyl)O--, --OH, (C1 -C6 alkyl)S(O)m --, (C1 -C6 alkyl)C(O)NH--, H2 N--C(NH)--, (C1 -C6 alkyl)C(O)--, (C1 -C6 alkyl)OC(O)--, N3, (C1 -C6 alkyl)OC(O)NH-- and C1 -C20 alkyl;
or a pharmaceutically acceptable salt thereof.
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Accused Products
Abstract
The present invention comprises low molecular weight peptidyl compounds that inhibit the farnesyl-protein transferase. Furthermore, these compounds differ from the mono- or dipeptidyl analogs previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
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Citations
21 Claims
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1. A compound which inhibits Ras farnesyl-transferase having the Formula XVI:
- ##STR18## wherein;
R2 and R3 are independently selected from;a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is; i) methionine, sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1 -C20 alkyl, substituted or unsubstituted C2 -C20 alkenyl, substituted or unsubstituted C3 -C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3,-- N(R10)2, R11 OC(O)NR10 -- and C1 -C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl;
orR2 and R3 are combined to form --(CH2)s --; R4 and R5 are independently selected from; a) hydrogen, b) C1 -C6 alkyl unsubstituted or substituted by C2 -C20 alkenyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, N3, (R10)2 N-- C(NR10)--, R10 C(O)--, --N(R10)2, or R10 OC((O)NR10 --, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, halogen, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C(NR10)--, R10 (O)--, N3,-- N(R10)2, or R11 OC(O)NR10 --, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3 -C10 cycloalkyl; R6 is selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S (O)m --, R10 C(O)NR10 --, CN, NO2, R102 N--C(NR10)--, R10 C(O)--, N3, --N(R10)2, (R12)2 NC(O)-- or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 C(O)--, N3, --N(R10)2, or R10 OC(O)NH--; R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3 -C10 cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl; R8 is selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, --S(O)2 NR102, CN, NO2, R102 N-- C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 OC(O)--, R10 OC(O)--, N3, --N(R10)2, or R10 OC(O)NH--; R10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl; R11 is independently selected from C1 -C6 alkyl and aryl; R12 is independently selected from hydrogen, C1 -C6 alkyl and aryl, or (R12)2 forms --(CH2)s --; A1 and A2 are independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)2 N(R7)--, --N(R7)S(O)2 --, or S(O)m ;A3 is independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)N(R7)--, --N(R7)S(O)2 --, or S(O)m ;A4 is selected from;
a bond, O, --N(R7)-- or S,V is aryl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; and provided heterocycle is not tetrazolyl; and substituted aryl is an aryl group which is substituted with 1 or 2 substitutents selected from F, Cl, Br, CF3, NH2, N(C1 -C6 alkyl)2, NO2, CN, (C1 -C6 alkyl)O--, --OH, (C1 -C6 alkyl)S(O)m --, (C1 -C6 alkyl)C(O)NH--, H2 N--C(NH)--, (C1 -C6 alkyl)C(O)--, (C1 -C6 alkyl)OC(O)--, N3, (C1 -C6 alkyl)OC(O)NH-- and C1 -C20 alkyl; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (15, 17, 19, 21)
- ##STR18## wherein;
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2. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound which inhibits Ras farnesyl-transferase having the Formula I:
- ##STR19## wherein;
R1a is independently selected from;a) hydrogen, b) aryl, heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O)m, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C(NR10)--, R10 OC(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)--NR10 --; R1b is independently selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O)m --, CN, NO2, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)-- or N3, c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O)m --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)-- or N3 ; R2 and R3 are independently selected, from; a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is; i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1 -C20 alkyl, substituted or unsubstituted C2 -C20 alkenyl, substituted or unsubstituted C3 -C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, R11 OC(O)NR10 -- and C1 -C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl;
orR2 and R3 are combined to form --(CH2)s --; R4 and R5 are independently selected from; a) hydrogen, b) C1 -C6 alkyl unsubstituted or substituted by C2 -C20 alkenyl, R10 O--, R10 S(O)m --, R10 C(O)NR10 --, CN, N3, (R10)2 N-- C(NR10)--, R10 C(O)--, --N(R10)2, or R11 OC(O)NR10 --, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, halogen, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C(NR10)--, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3 -C10 cycloalkyl; R6 is selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, R102 N--C(R10)--, R10 C(O)--, N3, --N(R10)2, (R12)2 NC(O)-- or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(H)--, R10 C(O)--, N3, --N(R10)2, or R10 OC(O)NH--; R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3 -C10 cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl; R8 is selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, --S(O)2 NR102, CN, NO2, R102 N-- C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, C, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R10 OC(O)NH--; R9 is selected from; a) hydrogen, b) C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C-- (NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --; R10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl; R11 is independently selected from C1 -C6 alkyl and aryl; R12 is independently selected from hydrogen, C1 -C6 alkyl and aryl, or (R12)2 forms --(CH2)s --; A1 and A2 are independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)2 N(R7)--, --N(R7)S(O)2 --, or S(O)m ;A3 is independently selected from;
a bond, --CH═
CH--, --C.tbd.C--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)2 N(R7)--, --N(R7)S(O)2 --, or S(O)m ;A4 is selected from;
a bond, O, --N(R7)-- or S,V is selected from; a) hydrogen, b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) 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 imidazolyl; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; and provided heterocycle is not tetrazolyl; and substituted aryl is an aryl group which is substituted with 1 or 2 substitutents selected from F, Cl, Br, CF3, NH2, N(C1 -C6 alkyl)2, NO2, CN, (C1 -C6 alkyl)O--, --OH, (C1 -C6 alkyl)S(O)m --, (C1 -C6 alkyl)C(O)NH--, H2 N--C(NH)--, (C1 -C6 alkyl)C(O)--, (C1 -C6 alkyl)OC(O)--, N3, (C1 -C6 alkyl)OC(O)NH-- and C1 -C20 alkyl; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (3)
- ##STR19## wherein;
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4. A method of treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of a pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound which inhibits Ras farnesyl-transferase having the Formula I:
- ##STR21## wherein;
R1a is independently selected from;a) hydrogen, b) aryl, heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O)m --, R10 C(O))NR10 --, CN, NO2, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)--NR10 --; R1b is independently selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O))m --, CN, NO2, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)-- or N3, c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, R10 O--, R11 S(O)m --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)-- or N3 ; R2 and R3 are independently selected from; a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is; i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1 -C20 alkyl, substituted or unsubstituted C2 -C20 alkenyl, substituted or unsubstituted C3 -C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R10)2, NO2, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, R11 OC(O)NR10 -- and C1 -C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl;
orR2 and R3 are combined to for, --(CH2)s --; R4 and R5 are independently selected from; a) hydrogen, b) C1 -C6 alkyl unsubstituted or substituted by C2 -C20 alkenyl, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, N3, (R10)2 N-- C(NR10)--, R10 C(O)--, --N(R10)2, or R11 OC(O)NR10 --, c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, halogen, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C(NR10)--, R10 C(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3 -C10 cycloalkyl; R6 is selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, R102 N--C(NR10)--, R10 C(O)--, N3, --N(R10)2, (R12)2 NC(O)-- or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(H)--, R10 C(O)--, N3, --N(R10)2, or R10 OC(O)NH--; R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3 -C10 cycloalkyl, and e) C1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3 -C10 cycloalkyl; R8 is selected from; a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C1 -C20 perfluoroalkyl, allyloxy, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, --S(O)2 NR102, CN, NO2, R102 N-- C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3 -C10 cycloalkyl, C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NH--, CN, H2 N--C(NH)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R10 OC(O)NH--; R9 is selected from; a) hydrogen, b) C2 -C20 alkenyl, C2 -C20 alkynyl, C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, NO2, (R10)2 N--C-- (NR10)--, R10 C(O), R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --, and c) C1 -C6 alkyl unsubstituted or substituted by C2 -C20 perfluoroalkyl, F, Cl, Br, R10 O--, R11 S(O)m --, R10 C(O)NR10 --, CN, (R10)2 N--C(NR10)--, R10 C(O)--, R10 OC(O)--, N3, --N(R10)2, or R11 OC(O)NR10 --; R10 is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl; R11 is independently selected from C1 -C6 alkyl and aryl; R12 is independently selected from hydrogen, C1 -C6 alkyl and aryl, or (R12)2 forms --(CH2)s --; A1 and A2 are independently selected from;
a bond, --C═
CH--, --C.tbd.C--, --C(O)--, --C(O)NR7 --, --NR7 C(O)--, O, --N(R7)--, --S(O)2 N(R7)--, --N(R7)S(O)2 --, or S(O)m ;A3 is independently selected from a bond, --CH═
CH--, --C.tbd.C--, --C(O)NR7 --, NR7 C(O)--, O, --N(R7)--, --S(O)2 N(R7)--, --N(R7)S(O)2 --, or S(O)m ;A4 is selected from;
a bond, O, --N(R7)-- or S,V is selected from; a) hydrogen, b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) 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 imidazolyl; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; and provided heterocycle is not tetrazolyl; and substituted aryl is an aryl group which is substituted with 1 or 2 substitutents selected from F, Cl, Br, CF3, NH2, N(C1 -C6 alkyl)2, NO2, CN, (C1 -C6 alkyl)O--, --OH, (C1 -C6 alkyl)S(O)m --, (C1 -C6 alkyl)C(O)NH--, H2 N--C(NH)--, (C1 -C6 alkyl)C(O)--, (C1 -C6 alkyl)OC(O)--, N3, (C1 -C6 alkyl)OC(O)NH-- and C1 -C20 alkyl; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (5)
- ##STR21## wherein;
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6. A compound which inhibits farnesyl-protein transferase which is:
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N-Allyloxycarbonyl-N-naphth-1-ylmethyl-2(S)-{1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-Naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl pentanamine N-Methoxycarbonyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl pentanamine N-Acetyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-Propionyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-Methylsulfonyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-Ethylsulfonyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-Methylaminocarbonyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-Propyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-3-Chlorobenzyl-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine N-(2-Imidazolylmethyl)-N-naphth-1-ylmethyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methylpentanamine 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-(t-butoxycarbonyl)amino-N-(naphth-1-ylmethyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-(t-butoxycarbonyl)amino-N-methyl-N-benzyl propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-(t-butoxycarbonyl)amino-N-(2-methylbenzyl) propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-(t-butoxycarbonyl)amino-N-(3-methylbenzyl) propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-amino-N-(naphth-1-ylmethyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-amino-N-methyl-N-benzyl propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-amino-N-(2-methylbenzyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-amino-N-(3-methylbenzyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-acetylamino-N-(3-methylbenzyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-acetylamino-N-(naphth-1-ylmethyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-(2-methylpropionyl)amino-N-(naphth-1-ylmethyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-(phenylacetyl)amino-N-(naphth-1-ylmethyl)propionamide 2(RS)-{ 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!acetyl}amino-3-(phenylacetyl)amino-N-methyl-N-benzyl) propionamide 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!-N-butylacetamide 1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl)!-N-methyl-N-(3,3-diphenylpropyl)acetamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(t-butoxycarbonyl)amino-N-methyl-N-benzyl propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(t-butoxycarbonyl)amino-N-(3-methylbenzyl) propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(t-butoxycarbonyl)amino-N-(naphth-1-ylmethyl) propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-amino-N-methyl-N-benzyl-propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-amino-N-(3-methylbenzyl) propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-amino-N-(naphth-1-ylmethyl) propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(phenylacetyl)amino-N-methyl-N-benzyl) propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(acetyl)amino-N-(naphth-1-ylmethyl)propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(2-methylpropionyl)amino-N-(naphth-1-ylmethyl) propionamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(2-methylpropionyl)amino-N-(naphth-1-ylmethyl) propionamide N- 2(S)-( 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetylamino)-3(S)-methylpentyl!-N-(1-naphthylmethyl)glycine isopropylamide N- 2(S)-( 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetylamino)-3(S)-methylpentyl!-N-(1-naphthylmethyl)glycine piperidinylamide 2(RS)-{ 1-(4-Cyanobenzyl)-1H-imidazol-5-yl!acetyl}amino-3-(t-butoxycarbonyl)amino-N-methyl-N-(naphth-1-ylmethyl) propionamide N-Allyloxycarbonyl-2(S)-{(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl-pentanamine 2(S)-{(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl-N-(naphth-2-ylsulfonyl)-pentanamine N-Acetyl-N-2-chlorobenzyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl-pentanamine N-Acetyl-N-3-chlorobenzyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl-pentanamine N-Acetyl-N-4-chlorobenzyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl-pentanamine N-Acetyl-N-2,3-dichlorobenzyl-2(S)-{(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl-pentanamine N-Allyloxycarbonyl-N-naphth-1-ylmethyl-2(S)-{2(R,S)-methyl-2-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl}amino-3(S)-methyl-pentanamine N-t-Butoxycarbonylaminoacetyl-N-naphth-1-ylmethyl-2(S)-{1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl}amino-3(S)-methylpentanamine N-Aminoacetyl-N-naphth-1-ylmethyl-2(S)-{1-(4-cyanobenzyl)-1-imidazol-5-ylacetyl}amino-3(S)-methylpentanamine (S)-2- (1-(4-cyanobenzyl)-5-imidazolylmethyl)amino!-1- N-(2,3-dimethylphenyl)acetamido!hexane (S)-2- N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(methyl)amino!-1- N-(2,3-dimethylphenyl)acetamido!hexane N- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-N'"'"'-(3-chlorophenyl)ethylenediamine 1-(4-Cyanobenzyl)-5- N-(3-phenylpropyl)aminomethyl!imidazole or (S)-2- (1-(4-Cyanobenzyl)-5-imidazolylmethyl)amino!-N-(benzyloxycarbonyl)-N-(3-chlorobenzyl)-4-(methanesulfonyl)butanamine or a pharmaceutically acceptable salt or optical isomer thereof. - View Dependent Claims (7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20)
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Specification
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Current AssigneeMerck & Co., Inc.
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Original AssigneeMerck & Co., Inc.
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InventorsBergman, Jeffrey M., Williams, Theresa M., Anthony, Neville J., Gomez, Robert P., MacTough, Suzanne C., Solinsky, Kelly M., Dinsmore, Chrisopher J.
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Primary Examiner(s)Ivy, C. Warren
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Assistant Examiner(s)DAHLEN, GARTH
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Application NumberUS08/652,055Time in Patent Office733 DaysField of Search548/338.1, 548/203, 548/312.7, 548/314.7, 514/307, 514/314, 514/326, 514/341, 514/397, 514/399, 546/146, 546/175, 546/210, 546/274.7US Class Current514/399CPC Class CodesC07D 233/64 with substituted hydrocarbo...C07D 401/14 containing three or more he...
