Inhibitors of prenyl-protein transferase
First Claim
Patent Images
1. A compound illustrated by the formula I:
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wherein;
R1a and R1b are independently selected from;
a) hydrogen, or b) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)—
NR8—
;
R1 is selected from;
a) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, and b) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R2 is independently selected from;
a) hydrogen, b) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, ClBr, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, and c) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R3 is selected from;
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, (R8)2N—
C—
(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, and c) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
;
R4a and R4b independently are selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, or unsubstituted or substituted aryl;
R4c and R5 independently are selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl,
and —
S(O)2R6, wherein the substituted group is substituted with one or more of;
1) aryl, unsubstituted or substituted with one or two groups selected from;
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) C1-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(O)R6, SO2R6, 5) —
NR6R715) C1-8 alkyl, 16) C1-8 perfluoroalkyl, or 17) halo;
R6, R7 and R7a are independently selected from;
H, C1-4 alkyl, C3-6 cycloalkyl, aryl, C1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;
a) C1-4 alkoxy, b) substituted or unsubstituted aryl, c) halogen, d) HO, g) —
S(O)mR9, or h) N(R8)2;
or R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are bonds;
X1 and X3 are N(H)w;
X2 and X5 are C(H)y;
X4 is selected from;
C(H)y, N(H)w, O, C═
O, S(O)2, and PO(OMe);
u is 0;
V is an aryl, W is an imidazolyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0 1, 2, 3 or 4;
r is independently 0 to 5;
s is 1 or 2;
t is 1;
w is 0 or 1; and
y is 1 or 2;
dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof.
1 Assignment
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Accused Products
Abstract
The present invention is directed to conformationally constrained compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
51 Citations
19 Claims
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1. A compound illustrated by the formula I:
-
wherein; R1a and R1b are independently selected from;
a) hydrogen, or b) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)—
NR8—
;
R1 is selected from;
a) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andb) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R2 is independently selected from;
a) hydrogen, b) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, ClBr, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andc) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R3 is selected from;
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, (R8)2N—
C—
(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andc) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
;
R4a and R4b independently are selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, or unsubstituted or substituted aryl;
R4c and R5 independently are selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl,
and —
S(O)2R6, wherein the substituted group is substituted with one or more of;
1) aryl, unsubstituted or substituted with one or two groups selected from;
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) C1-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(O)R6, SO2R6, 5) —
NR6R715) C1-8 alkyl, 16) C1-8 perfluoroalkyl, or 17) halo;
R6, R7 and R7a are independently selected from;
H, C1-4 alkyl, C3-6 cycloalkyl, aryl, C1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;
a) C1-4 alkoxy, b) substituted or unsubstituted aryl, c) halogen, d) HO, g) —
S(O)mR9, orh) N(R8)2;
orR8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are bonds;
X1 and X3 are N(H)w;
X2 and X5 are C(H)y;
X4 is selected from;
C(H)y, N(H)w, O, C═
O, S(O)2, and PO(OMe);
u is 0;
V is an aryl, W is an imidazolyl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0 1, 2, 3 or 4;
r is independently 0 to 5;
s is 1 or 2;
t is 1;
w is 0 or 1; and
y is 1 or 2;
dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof. - View Dependent Claims (2, 3, 4, 10, 11, 12, 14, 15, 16, 18, 19)
wherein R1a and R1b are independently selected from;
a) hydrogen, or b) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)—
NR8—
;
R1 is selected from;
a) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andb) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R2 is independently selected from;
a) hydrogen, b) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andc) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O()NH—
;
R3 is selected from;
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, (R8)2N—
C—
(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andc) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
;
R4a and R4b independently are selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl;
R5 is selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl,
and S(O)2R6, wherein the substituted group is substituted with one or more of;
1) aryl, unsubstituted or substituted with one or two groups selected from;
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) C1-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(O)R6, SO2R6, 5) —
NR6R715) C1-8 alkyl, 16) C1-8 perfluoroalkyl, or 17) halo;
R6, R7 and R7a are independently selected from;
H, C1-4 alkyl, C3-6 cycloalkyl, aryl, C1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;
a) C1-4 alkoxy, b) substituted or unsubstituted aryl, c) halogen, d) HO, g) —
S(O)mR9, orh) N(R8)2;
orR8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and;
R9 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are bonds;
X1 and X3 are N(H)w;
X2 and X5 are C(H)y;
u is 0;
X4 is selected from;
C(H)y, N(H)w, O, C═
O, S(O)2, and PO(OMe);
V is aryl;
m is 0, 1 or 2;
n is 0, 1, 2, 3 and 4;
p is 0, 1, 2, 3 and 4;
r is independently 0 to 5;
s is 1 or 2;
w is 0 or 1; and
y is 1 or 2;
dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof.
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3. The compound according to claim 1 of the formula III:
-
wherein; R1a and R1b are independently selected from;
a) hydrogen, or b) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)—
NR8—
;
R1 is selected from;
a) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andb) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R2 is independently selected from;
a) hydrogen, b) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andc) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R3 is selected from;
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, (R8)2N—
C—
(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andc) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
;
R4a and R4b independently are selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl;
R5 is selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl,
and —
S(O)2R6, wherein the substituted group is substituted with one or more of;
1) aryl, unsubstituted or substituted with one or two groups selected from;
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) C1-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(O)R6, SO2R6, 5) —
NR6R7,15) C1-8 alkyl, 16) C1-8 perfluoroalkyl, or 17) halo;
R6, R7 and R7a are independently selected from;
H, C1-4 alkyl, C3-6 cycloalkyl, aryl, C1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;
a) C1-4 alkoxy, b) substituted or unsubstituted aryl, c) halogen, d) HO, g) —
S(O)mR9, orh) N(R8)2;
orR8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are bonds;
X1 and X3 are N(H)w;
X2 and X5 are C(H)y;
u is 0;
X4 is selected from;
C(H)y, N(H)w, O, C═
O, S(O)2, and PO(OMe);
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is independently 0 to 5;
s is 1 or 2;
w is 0 or 1; and
y is 1 or 2;
dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof.
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4. The compound according to claim 1 of the formula IV:
-
wherein R1a and R1b are independently selected from;
a) hydrogen, or b) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)—
NR8—
;
R2 is selected from;
a) unsubstituted or substituted aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, R82N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andb) C1-C6 alkyl unsubstituted or substituted by aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NH—
, CN, H2N—
C(NH)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R8OC(O)NH—
;
R3 is selected from;
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, NO2, (R8)2N—
C—
(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
, andc) C1-C6;
alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R8O—
, R9S(O)m—
, R8C(O)NR8—
, CN, (R8)2N—
C(NR8)—
, R8C(O)—
, R8OC(O)—
, N3, —
N(R8)2, or R9OC(O)NR8—
;
R4a and R4b independently are selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted aryl;
R5 is selected from;
H, ═
O, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl,
and —
S(O)2R6, wherein the substituted group is substituted with one or more of;
1) aryl, unsubstituted or substituted with one or two groups selected from;
a) C1-4 alkyl, b) (CH2)pOR6, c) (CH2)pNR6R7, d) halogen, e) C1-4 perfluoroalkyl, 2) C3-6 cycloalkyl, 3) OR6, 4) SR6, S(O)R6, SO2R6, 5) —
NR6R715) C1-8 alkyl, 16) C1-8 perfluoroalkyl, or 17) halo;
R6, R7 and R7a are independently selected from;
H, C1-4 alkyl, C3-6 cycloalkyl, aryl, C1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;
a) C1-4 alkoxy, b) substituted or unsubstituted aryl, c) halogen, d) HO, g) —
S(O)mR9, orh) N(R8)2;
orR8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R9 is independently selected from C1-C6 alkyl and aryl;
A1 and A2 are bonds;
X1 and X3 are NH;
X2 and X5 are CH2;
u is 0;
X4 is selected from;
C(H)y, N(H)w, O, C═
O, S(O)2, and PO(OMe);
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0, 1, 2, 3 or 4;
s is 1 or 2;
u is 0;
w is 0 or 1; and
y is 1 or 2;
dashed lines represent optional double bonds or the pharmaceutically acceptable salts or the optical isomers thereof.
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10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.
-
11. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 2.
-
12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 3.
-
14. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 10.
-
15. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 11.
-
16. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 12.
-
18. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.
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19. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.
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5. A compound selected from:
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4-[5-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-ylmethyl)imidazol-1-ylmethyl]benzonitrile;
4-{5-[4-Oxo-1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-8-ylmethyl]imidazol-1-ylmethyl}benzonitrile;
4-{5-[4-Oxo-1-(4-methylphenyl)-1,3,8-triazaspiro[4.5]dec-8-ylmethyl]imidazol-1-ylmethyl}benzonitrile;
4-{5-[2,4-Dioxo-1-(3-methylphenyl)-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]imidazol-1-ylmethyl}benzonitrile;
4-{5-[2-Oxo-1-(3-methylphenyl)-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]imidazol-1-ylmethyl}benzonitrile;
4-[5-(4-Oxo-3-(3-trifluoromethoxybenzyl)-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-ylmethyl)imidazol-1-ylmethyl]benzonitrile;
4[5-(4-Oxo-3-(2-trifluoromethoxybenzyl)-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-ylmethyl)imidazol-1-ylmethyl]benzonitrile;
or the pharmaceutically acceptable salts thereof. - View Dependent Claims (6, 7, 8, 9, 13, 17)
4-{5-[4-Oxo-1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-8-ylmethyl]imidazol-1-ylmethyl}benzonitrile
or its pharmaceutically acceptable salts.
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7. The compound according to claim 5 which is:
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4-{5-[2-Oxo-1-(3-methylphenyl)-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]imidazol-1-benzonitrile
or its pharmaceutically acceptable salts.
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8. The compound according to claim 5 which is:
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4-{5-(4-Oxo-3-(3-trifluoromethoxybenzyl)-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-ylmethyl)imidazol-1-ylmethyl}benzonitrile
or its pharmaceutically acceptable salts.
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9. The compound according to claim 5 which is:
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4-[5-(4-Oxo-3-(2-trifluoromethoxybenzyl)-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-ylmethyl)imidazol-1-ylmethyl]benzonitrile
or its pharmaceutically acceptable salts.
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13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 5.
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17. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claims 13.
Specification