Inhibitors of farnesyl-protein transferase

• US 5,856,326 A
• Filed: 03/01/1996
• Issued: 01/05/1999
• Est. Priority Date: 03/29/1995
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Dinsmore, Christopher J., Williams, Theresa M., Hartman, George D., Anthony, Neville J., Gomez, Robert P., Ciccarone, Terrence M.
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US08/600,728
• Time in Patent Office: 1,040 Days
• Field of Search: 544/370, 514/252
• US Class Current: 514/254.05
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/192 from aromatic carboxylic acids
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 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 which is:

5(S)-n-Butyl-1-(2,3-dimethylphenyl)-4-(4-imidazolylmethyl)-piperazin-2-one

5(S)-n-Butyl-4- 1-(4-cyanobenzyl)imidazol-5-ylmethyl!-1-(2,3-dimethylphenyl)piperazin-2-one

4- 1-(4-Cyanobenzyl)imidazol-5-ylmethyl!-1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one

(S)-1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-5- 2-(methanesulfonyl)ethyl!-2-piperazinone

(S)-1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-5- 2-(ethanesulfonyl)ethyl!-2-piperazinone

(R)-1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-5- 2-(ethanesulfonyl)methyl!-2-piperazinone

(S)-1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-5- N-ethyl-2-acetamido!-2-piperazinone

(±

)-5-(2-Butynyl)-1-(3-chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-2-piperazinone

1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-2-piperazinone

5(S)-Butyl-4- 1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl!-1-(2,3-dimethylphenyl)-piperazin-2-one

4- 1-(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl!-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one

5(S)-n-Butyl-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-1-(2-methylphenyl)piperazin-2-one

4- 1-(4-Cyanobenzyl)-5-imidazolylmethyl!-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-one

4- 5-(4-Cyanobenzyl)-1-imidazolylethyl!-1-(3-chlorophenyl)piperazin-2-one

or a pharmaceutically acceptable salt or optical isomer thereof.

2. The compound according to claim 1 which is:

5(S)-n-Butyl-4- 1-(4-cyanobenzyl)imidazol-5-ylmethyl!-1-(2,3-dimethylphenyl)piperazin-2-one ##STR101## or a pharmnaceutically acceptable salt or optical isomer thereof.

3. The compound according to claim 1 which is:

4- 1-(4-Cyanobenzyl)imidazol-5-ylmethyl!-1-(2,3-dimethylphenyl)-5(S)-(2-methoxyethyl)piperazin-2-one ##STR102## or a pharmaceutically acceptable salt or optical isomer thereof.

4. The compound according to claim 1 which is:

5(S)-n-Butyl-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-1-(2-methylphenyl)piperazin-2-one ##STR103## or a pharmaceutically acceptable salt or optical isomer thereof.

5. The compound according to claim 1 which is:

(S)-1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-5- 2-(methanesulfonyl)ethyl!-2-piperazinone ##STR104## or a pharmaceutically acceptable salt or optical isomer thereof.

6. The compound according to claim 1 which is:

(S)-1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-5- 2-(ethanesulfonyl)ethyl!-2-piperazinone ##STR105## or a pharmaceutically acceptable salt or optical isomer thereof.

7. The compound according to claim 1 which is:

(S)-1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolylmethyl!-5- 2-(ethanesulfonyl)methyl!-2-piperazinone ##STR106## or a pharmaceutically acceptable salt or optical isomer thereof.

8. The compound according to claim 1 which is:

1-(3-Chlorophenyl)-4- 1-(4-cyanobenzyl)-5-imidazolyl-methyl!-2-piperazinone ##STR107## or a pharmaceutically acceptable salt or optical isomer thereof.

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

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

##STR108## wherein;

R^1a and R^1b 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 -, CN(R¹⁰)₂ NC(O)--, R¹⁰₂ N-C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ -,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent on the substituted C₁ -C₆ alkyl is selected from aryl, cyanophenyl, 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)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ -;

R² and R³ are independently selected from;

H;

unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted C_2-8

alkynyl, unsubstituted or substituted aryl, ##STR109## wherein the substituted group is substituted with one or more of;

     1) aryl, unsubstituted or substituted with;

a) C_1-4 alkyl,

b) (CH₂)_p OR⁶,

c) (CH₂)_p NR⁶ R⁷,

d) halogen,

e) CN,

2) C_3-6 cycloalkyl,

3) OR⁶,

4) SR^6a, S(O)R^6a, SO₂ R^6a, ##STR110## R⁴ is selected from H and CH₃ ; and

any two of R², R³ and R⁴ are optionally attached to the same carbon atom;

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

H;

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

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR111## f) --SO, or g) N(R¹⁰)₂ ;

R^6a is selected from;

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

a) C_1-4 alkoxy,

b) aryl,

c) halogen,

d) HO, ##STR112## f) --SO, or g) N(R¹⁰)₂ ;

R⁸ is independently selected from;

a) hydrogen,

b) 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)--, R¹⁰ OC(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 akynyl, 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)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from;

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_m -, R¹⁰₂ N-C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃ or R¹¹ OC(O)NR¹⁰ -, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_m -, R¹⁰₂ N-C(NR¹⁰)--, CN, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃ 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;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)-- or O;

G is O;

V is phenyl or naphthyl;

W is imidazolyl;

X is --CH₂ -, --C(═

O)--, or --S(═

O)_m -;

Z is a unsubstituted or substituted group selected from phenyl, benzyl, naphthyl and naphthylmethyl, wherein the substituted group is substituted with one or more of the following;

1) C_1-4 alkyl, unsubstituted or substituted with;

a) C_1-4 alkoxy,

b) NR⁶ R⁷,

c) C_3-6 cycloalkyl,

d) aryl,

e) HO,

f) --S(O)_m R^6a, or

g) --C(O)NR⁶ R⁷,

2) aryl,

3) halogen,

4) OR⁶,

5) NR⁶ R⁷,

6) CN,

7) NO₂,

8) CF₃ ;

9) --S(O)_m R^6a,

10) --C(O)NR⁶ R⁷, or

11) C₃ -C₆ cycloalkyl;

aryl is independently selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl;

m is 0, 1 or 2;

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

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

q is 1 or 2;

r is 0 to 5;

s is 0;

t is 1; and

u is 4 or 5;

or an optical isomer or pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 of the formula B:

##STR113## wherein;

R^1a is independently selected from;

hydrogen or C₁ -C₆ alkyl;

R^1b is independently selected from;

a) hydrogen,

b) aryl, cycloalkyl, R¹⁰ O-, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substitutent on the substituted C₁ -C₆ alkyl is selected from aryl, cyanophenyl, cycloalkyl, alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ;

R³ and R⁴ are independently selected from H and CH₃ ;

R² is H;

##STR114## C_1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of;

1) aryl,

2) OR⁶,

3) SR^6a, SO₂ R^6a, or ##STR115## and any two of R², R³ and R⁴ are optionally attached to the same carbon atom;

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

H;

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

a) C_1-4 alkoxy,

b) halogen, or

c) aryl;

R^6a is selected from;

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

a) C_1-4 alkoxy,

b) halogen, or

c) aryl;

R⁸ is independently selected from;

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ -, CN, NO₂, (R¹⁰)₂ N-C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ -, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ -, (R¹⁰)₂ N-C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ -;

R⁹ is selected from;

hydrogen or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from;

a bond, --CH═

CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ -, O, --N(R¹⁰)--, or S(O)_m ;

V is phenyl;

G is O;

W is imidazolyl;

X is --CH₂ - or --C(═

O)--;

Z is phenyl or naphthyl, unsubstituted or substituted with one or two of the following;

1) C_1-4 alkyl, unubstituted or substituted with;

a) C_1-4 alkoxy,

b) NR⁶ R⁷,

c) C_3-6 cycloalkyl,

d) aryl,

e) HO,

f) --S(O)_m R⁶, or

g) --C(O)NR⁶ R⁷,

2) aryl,

3) halogen,

4) OR⁶,

5) NR⁶ R⁷,

6) CN,

7) NO₂,

8) CF₃ ;

9) --S(O)_m R⁶,

10) --C(O)NR⁶ R⁷, or

11) C₃ -C₆ cycloalkyl;

aryl is independently selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl;

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 to 5;

s is 0;

t is 1; and

u is 4 or 5;

or pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 10.

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

space="preserve" listing-type="tabular"> TABLE 3______________________________________ ##STR116## Y______________________________________ 3-SO.sub.2 Me 3-OCF.sub.3______________________________________

space="preserve" listing-type="tabular"> TABLE 4______________________________________ ##STR117## X Y______________________________________ CH.sub.2 OCH.sub.2 Ph CF.sub.3 CH.sub.2 SO.sub.2 Et CF.sub.3 CH.sub.2 SO.sub.2 Ph CF.sub.3 CH.sub.2 SO.sub.2 Me Cl CH.sub.2 SO.sub.2 Et Cl CONHMe CF.sub.3 CONHEt CF.sub.3 CH.sub.2 SO.sub.2 Ph Cl CONHMe Cl CONHEt Cl CONHc-Pr Cl CONHc-Pr CF.sub.3 NHCOMe Cl CONHMe.sub.2 CF.sub.3 SO.sub.2 Et Cl CH.sub.2 SMe Cl (±

) C.tbd.CMe Cl______________________________________

space="preserve" listing-type="tabular"> TABLE 5______________________________________ ##STR118## X Y______________________________________ CH.sub.2 CH.sub.2 H CH.sub.2 CO H CH.sub.2 H CH.sub.2 3-Cl CH.sub.2 CH.sub.2 CO 3-Cl CH.sub.2 2,3-Cl.sub.2 CH.sub.2 2-Br CH.sub.2 3-CF.sub.3 CH.sub.2 4-Cl CH.sub.2 CO 3-Cl CH.sub.2 3-F CH.sub.2 3-Br______________________________________

space="preserve" listing-type="tabular"> TABLE 6______________________________________ ##STR119##X Y Z______________________________________4-CN CH.sub.2 5-CH.sub.2 CH.sub.2 CO3-CN CH.sub.2 5-CH.sub.22-CN CH.sub.2 5-CH.sub.24-CN CH.sub.2 4-CH.sub.2 CH.sub.2 CO4-CN (CH.sub.2).sub.2 4-CH.sub.2 CH.sub.2 CO______________________________________

space="preserve" listing-type="tabular"> TABLE 7______________________________________ ##STR120## X Y______________________________________ 4-Me CH.sub.2 CH.sub.2 SO.sub.2 Me 4-Me H 2-Me H______________________________________

space="preserve" listing-type="tabular"> TABLE 8______________________________________ ##STR121## Y______________________________________ 3-CF.sub.3 3-CH.sub.3 2,3-(CH.sub.2).sub.4 3-OCH.sub.3 3-Cl 2-CH.sub.3, 3-Cl H 3-F______________________________________

space="preserve" listing-type="tabular"> TABLE 9______________________________________ ##STR122## R______________________________________ CH.sub.2 CH.sub.2 OCH.sub.2 CF.sub.3 ##STR123## CH.sub.2 CH.sub.2 N.sub.3 CH.sub.2 CH.sub.2 NHCOCH.sub.3 CH.sub.2 CH.sub.2 NHCOC.sub.2 H.sub.5 CH.sub.2 CH.sub.2 SO.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 SCH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 S(O)CH(CH.sub.3).sub.2______________________________________

space="preserve" listing-type="tabular"> TABLE 10______________________________________ ##STR124##______________________________________ ##STR125## ##STR126## ##STR127## ##STR128## ##STR129## ##STR130##______________________________________

space="preserve" listing-type="tabular"> TABLE 11______________________________________ ##STR131##R Y______________________________________ ##STR132## Cl ##STR133## F ##STR134## Cl______________________________________

space="preserve" listing-type="tabular"> TABLE 12______________________________________ ##STR135##______________________________________ ##STR136##______________________________________

space="preserve" listing-type="tabular"> TABLE 13______________________________________ ##STR137##______________________________________ ##STR138## ##STR139## ##STR140##______________________________________

space="preserve" listing-type="tabular"> TABLE 14______________________________________ ##STR141##R.sup.1 R.sup.2______________________________________ ##STR142## CH.sub.2 CH.sub.2 F______________________________________

space="preserve" listing-type="tabular"> TABLE 15______________________________________ ##STR143##R Y______________________________________ ##STR144## 2,3-(CH.sub.2).sub.4 ##STR145## 2-CH.sub.3, 3-Cl ##STR146## 3-Cl______________________________________

space="preserve" listing-type="tabular"> TABLE 17______________________________________ ##STR147##______________________________________

space="preserve" listing-type="tabular"> TABLE 18______________________________________ ##STR148##or ##STR149##______________________________________

or a pharmaceutically acceptable salt or optical isomer thereof.