Inhibitors of farnesyl-protein transferase

• US 5,817,678 A
• Filed: 11/15/1996
• Issued: 10/06/1998
• Est. Priority Date: 11/22/1995
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Graham, Samuel L., Shaw, Anthony W., deSolms, S. Jane, Ciccarone, Terrence M., Kim, Byeong M.
• Primary Examiner(s): FAN, JANE T
• Application Number:
  US08/749,254
• Time in Patent Office: 690 Days
• Field of Search: 546/210, 514/326
• US Class Current: 514/326
• CPC Class Codes: C07D 233/24 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

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.

Claims

1. A compound which inhibits farnesyl-protein transferase of the formula A:

##STR65## wherein;

R^1a, R^1b and R^1c are independently selected from;

a) hydrogen,

b) unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)--NR⁸ --;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted aryl, ##STR66## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR67##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl;

R³ is selected from;

H;

##STR68## R⁴ is independently selected from;

a) hydrogen,

b) unsubstituted or substituted aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, R⁸₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(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, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NH--, CN, H₂ N--C(NH)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁸ OC(O)NH--;

R⁵ is independently selected from;

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C--(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, C_1-4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) substituted or unsubstituted aryl,

c) halogen,

d) HO, ##STR69## or h) N(R⁸)₂ ;

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;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, unsubstituted or substituted aryl, substituted aroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR70## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, --NR⁸ C(O)--, O, --N(R⁸)--, --S(O)₂ N(R⁸)--, --N(R⁸)S(O)₂ --, or S(O)_m ;

V is phenyl;

W is imidazolyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m --, --NR¹⁰ --, O or --C(═

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;

s is 1 or 2;

t is 1; and

or an optical isomer or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which inhibits farnesyl-protein transferase, of the formula A:

##STR71## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl,

R⁸ O--, --N(R⁸)₂, F or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) unsubstituted or substituted aryl, C₃ -C₆ cycloalkyl, R⁸ O--, --N(R⁸)₂ or C₂ -C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by unsubstituted or substituted aryl, C₃ -C₆ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

a) C_1-8 alkyl, unsubstituted or substituted with one or more of;

1) aryl, unsubstituted or substituted with;

i) C_1-4 alkyl,

ii) (CH₂)_p OR⁶,

iii) (CH₂)_p NR⁶ R⁷,

iv) halogen,

v) C_1-4 perfluoroalkyl,

2) OR⁶,

3) SR⁶, SO₂ R⁶, or ##STR72## c) aryl, unsubstituted or substituted with one or more of;

     1) C_1-8 alkyl,

2) C_1-8 perfluoroalkyl,

3) OR⁶,

4) SR⁶, SO₂ R⁶, or

5) ##STR73## d) --SO₂ R⁶ ;

R³ is selected from;

H;

##STR74## R⁴ is independently selected from;

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R⁵ is selected from;

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁹ S(O)_m --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl;

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;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, unsubstituted or substituted aryl, substituted aroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR75## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)--, or S(O)_m ;

V is phenyl;

W is imidazolyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 1, 2 or 3;

q is 0 or 1;

r is 0 to 5;

s is 1 or 2; and

t is 1;

or an optical isomer or pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, which inhibits farnesyl-protein transferase, of the formula B:

##STR76## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl,

R⁸ O--, --N(R⁸)₂, F or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

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, R⁸ O-- and --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted aryl, ##STR77## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR78##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl;

R³ is selected from;

H;

##STR79## R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, C₁ -C₆ alkyl, cyclopropyl, trifluoromethyl and halogen;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, unsubstituted or substituted aryl, substituted aroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR80## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)--, or S(O)_m ;

V is phenyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

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 or 1; and

r is 0 to 5;

or an optical isomer or pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, which inhibits farnesyl-protein transferase, of the formula C:

##STR81## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

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, R⁸ O-- and --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted aryl, ##STR82## and --S(O)₂ R⁶, wherein the substituted group is substituted with one or more of;

1) aryl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR83##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl;

R³ is selected from;

H;

##STR84## R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, C₁ -C₆ alkyl, cyclopropyl, trifluoromethyl and halogen;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, unsubstituted or substituted C_3-6 cycloalkyl, unsubstituted or substituted aryl, substituted aroyl, substituted arylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR85## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)--, or S(O)_m ;

V is phenyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR⁸ -- or O;

q is 0 or 1; and

r is 0 to 5;

or an optical isomer or pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, which inhibits farnesyl-protein transferase, of the formula D:

##STR86## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR87## wherein the substituted group is substituted with one or more of;

     1) aryl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR88##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl;

R³ is selected from;

H;

##STR89## R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR90## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ is selected from;

a bond, --C(O)--, O, --N(R⁸)--, or S(O)_m ;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

n is 0 or 1;

provided that n is not 0 if A¹ is a bond, O, --N(R⁸)--, or S(O)_m ;

m is 0, 1 or 2;

p is 0, 1, 2, 3 or 4; and

q is 0 or 1;

or an optical isomer or pharmaceutically acceptable salt thereof.

6. The compound according to claim 4, which inhibits farnesyl-protein transferase, of the formula E:

##STR91## wherein;

R^1a and R^1c are independently selected from;

hydrogen, R⁸ O--, --N(R⁸)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂, F or C₂ -C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR92## wherein the substituted group is substituted with one or more of;

     1) aryl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR93##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl;

R³ is selected from;

H;

##STR94## R⁴ is independently selected from;

a) hydrogen,

b) aryl, substituted aryl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --;

R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR95## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

n is 0 or 1;

m is 0, 1 or 2;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR⁸ -- or O; and

q is 0 or 1;

or an optical isomer or pharmaceutically acceptable salt thereof.

7. The compound according to claim 5, which inhibits farnesyl-protein transferase, of the formula F:

##STR96## wherein;

R^1a and R^1c are independently selected from;

hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, --N(R⁸)₂ or F,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR97## wherein the substituted group is substituted with one or more of;

     1) aryl, unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR98##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl;

R³ is selected from;

H;

##STR99## R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR100## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

m is 0, 1 or 2;

p is 0, 1, 2, 3 or 4; and

q is 0 or 1;

or an optical isomer or pharmaceutically acceptable salt thereof.

8. The compound according to claim 6, which inhibits farnesyl-protein transferase, of the formula G:

##STR101## wherein;

R^1a and R^1c are independently selected from;

hydrogen, R⁸ O--, --N(R⁸)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl or C₃ -C₁₀ cycloalkyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R⁸ O--, or --N(R⁸)₂ ;

R² is selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted aryl, ##STR102## wherein the substituted group is substituted with one or more of;

     1) aryl or unsubstituted or substituted with one or two groups selected from;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) C_1-4 perfluoroalkyl,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR⁶, S(O)R⁶, SO₂ R⁶, ##STR103##

     15) C_1-8 alkyl, or

     16) C_1-8 perfluoroalkyl;

R³ is selected from;

H;

##STR104## R^5a and R^5b are independently hydrogen, ethyl, cyclopropyl or methyl;

R⁶, R⁷ and R^7a are independently selected from;

H;

C_1-4 alkyl, C_3-6 cycloalkyl, aryl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) halogen, or

c) substituted or unsubstituted aryl;

R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl, benzyl and aryl;

R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹⁰ is selected from;

H;

R⁸ C(O)--;

R⁹ S(O)_m --;

unsubstituted or substituted C_1-4 alkyl, wherein the substituted alkyl group is substituted with one or two substituents selected from;

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR105## h) N(R⁸)₂, or i) C_3-6 cycloalkyl;

A¹ is selected from;

a bond, --C(O)--, O, --N(R⁸)--, or S(O)_m ;

X is a bond, --C(═

O)NR¹⁰ --, --NR¹⁰ C(═

O)--, --S(O)_m -- or --NR¹⁰ --;

m is 0, 1 or 2;

n is 0 or 1;

p is 1, 2 or 3; and

q is 0 or 1;

or an optical isomer or pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.

19. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 5.

20. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 6.

22. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.

23. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A compound which inhibits farnesyl-protein transferase which is:

1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Phenethyl-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(1-Naphthylmethyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Benzyl-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Methyl-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Indanyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Diphenylethyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Phenylpropyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Methylpropyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Phenethyl-cis-3-carboxyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Phenethyl-cis-3- N-(benzyl)carbamyl!-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Phenethyl-cis-3- N-(cyclopropyl)carbamyl!-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Phenethyl-cis-3- N-(t-butyl)carbamyl!-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2,2-Diphenylethyl)-cis-3- N-(t-butyl)carbamyl!-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

N- 1-Phenethyl-cis-5-(N'"'"'-(4-cyanobenzyl-1-imidazol-5-ylethyl)carbamyl)piperidine-3-carbonyl!methionine methyl ester

N- 1-Phenethyl-cis-5-(N'"'"'-(4-cyanobenzyl-1-imidazol-5-ylethyl)carbamyl)piperidine-3-carbonyl!methionine

1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl)amino!piperidine

1-Phenethyl-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl)amino!piperidine

1-Diphenylacetyl-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(t-Butoxycarbonyl)-trans-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!-piperidine

1-(2,2-Diphenylethyl)-3- N-1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylacetyl)amino!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylpropionyl)amino!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylcarbonyl)amino!piperidine

1-(Phenylacetyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Diphenylacetyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Chlorobenzoyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-(3-Chlorophenyl)-2-phenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Dibenzylsuberylmethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-(3-Methylphenyl)-2-phenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-(3-Trifluoromethylphenyl)-2-phenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-(2-Chlorophenyl)-2-phenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-(4-Chlorophenyl)-2-phenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-(3-Aminomethylphenyl)-2-phenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Phenethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Phenethyl)-3-(R)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Phenylpropyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Benzyl)-3- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Chlorobenzyl)-3- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Chlorobenzyl)-3- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Chlorobenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2,2-Diphenyl-2-hydroxyethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Methoxybenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3,5-Dichlorobenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Trifluoromethoxybenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2,5-Dimethylbenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Trifluoromethylbenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Bromobenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Methylbenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1-H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Isobutyl-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2-Methyl-2-phenylethyl)-3- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-2-methyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-methoxybenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Diphenylmethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Methoxyphenethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(1-Naphthylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Chlorophenethyl)-3(S)- N-1-(4-cyanobenzy)1-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(α

-Methylbenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Diphenylmethyl)-3(S)- N-(1-(4-cyanobenzyl)-2-methyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(α

-Toluenesulfonyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Benzenesulfonyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(1-Naphthylenesulfonyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Chlorobenzenesulfonyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3,5-Dichlorobenzenesulfonyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(α

-Toluenesulfonyl)-3-(R)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(α

-Toluenesulfonyl)-cis-3-methoxycarbonyl-5- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Methanesulfonyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Diphenylcarbamoyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(Phenylcarbamoyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-Phenyl-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(3-Methylphenyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- 2-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)ethylthiomethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)ethylsulfonylmethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)-N-methyl-carbamoyl!piperidine

1-(3-Bromobenzyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl) N-methyl-carbamoyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)aminomethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)-N-acetyl-aminomethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-2-methyl-1H-imidazol-5-ylethyl)-N-acetyl-aminomethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)-N-cyclopropylmethyl-aminomethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- N-(2-methyl-1H-imidazol-4-ylethyl)-N-(4-cyanobenzoyl)aminomethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- 5-(4-cyanobenzyl)-1H-imidazol-1-ylmethyl!piperidine

1-(2,2-Diphenylethyl)-3(S)- 5-(4-cyanobenzyl)-1H-imidazol-1-ylethylcarbamoyl!piperdine

or an optical isomer or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 which is:

N- 1-Phenethyl-5-(N'"'"'-(4-cyanobenzyl-1-imidazole-5-ethyl)carbamyl)piperidine-3-carbonyl!methionine ##STR106## or an optical isomer or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 9 which is:

1-(2-Diphenylethyl)-3-methoxycarbonyl-5- N-(4-cyanobenzyl-1-imidazole-5-ethyl)carbamyl!piperidine ##STR107## or an optical isomer or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 9 which is:

1-(2,2-Diphenylethyl)-cis-3- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine ##STR108## or an optical isomer or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 9 which is:

1-(3-Chlorobenzyl)-3- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine ##STR109## or an optical isomer or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 9 which is:

1-(Diphenylmethyl)-3(S)- N-(1-(4-cyanobenzyl)-2-methyl-1H-imidazol-5-ylethyl)carbamoyl!piperidine ##STR110## or an optical isomer or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 9 which is:

1-(3-Methylphenyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine ##STR111## or an optical isomer or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 9 which is:

1-(2,2-Diphenylethyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)-N-acetyl-aminomethyl!piperidine ##STR112## or an optical isomer or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 9 which is:

1-(Benzenesulfonyl)-3(S)- N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl!piperidine ##STR113## or an optical isomer or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 9.