Inhibitors of farnesyl-protein transferase

Claim 2

A compound of the formula I: ##STR46## or a pharmaceutically acceptable salt or disulfide thereof; wherein: R 1 and R 2 are independently selected from H, C 1-4 alkyl, C 1-4 aralkyl, --S(O) m --R 6 and ##STR47## R 3 and R 4 are independently selected from: H; C 1-8 alkyl, alkenyl, alkynyl, or ##STR48## unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a. C 1-4 alkyl, b. (CH 2 ) t OR 6 , c. (CH 2 ) t NR 6 R 7 , or d. halogen, 2) C 3-6 cycloalkyl, 3) OR 6 , 4) SR 6 , S(O)T 6 , SO 2 R 6 , ##STR49## R 5 is hydrogen; R 6 , R 7 and R 8 are independently selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR50## wherein R 6 and R 7 may be joined in a ring, and R 7 and R 8 may be joined in a ring; R 9 is C 1-4 alkyl or aralkyl; m is 0, 1 or 2; t is1 to 4; X is 0 or H 2 ; and Y is substituted or unsubstituted nitrogen containing C 4 -C 9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle and wherein the substituent is selected from C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR51## provided that Y is not ##STR52##

Claim 3

A prodrug compound of the formula I: ##STR53## or a pharmaceutically acceptable salt or disulfide thereof; wherein: R 1 and R 2 are independently selected from H, C 1-4 alkyl, C 1-4 aralkyl, --S(O) m --R 6 and ##STR54## R 3 and R 4 are independently selected from; H; C 1-8 alkyl, alkenyl, alkynyl, ##STR55## or unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH 2 ) t OR 6 , c) (CH 2 ) t NR 6 R 7 , d) halogen, 2) C 3-6 Cycloalkyl, 3) OR 6 , 4) SR 6 ,S(O)R 6 ,SO 2 R 6 , ##STR56## R 5 is C 1-8 alkyl, C 3-6 cycloalkyl, heterocycle or aryl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR57## provided that Y is not ##STR58##

Claim 4

A prodrug compound of the formula I: ##STR53## or a pharmaceutically acceptable salt or disulfide thereof; wherein: R 1 and R 2 are independently selected from H, C 1-4 alkyl, C 1-4 aralkyl, --S(O) m --R 6 and ##STR54## R 3 and R 4 are independently selected from; H; C 1-8 alkyl, alkenyl, alkynyl, ##STR55## or unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH 2 ) t OR 6 , c) (CH 2 ) t NR 6 R 7 , d) halogen, 2) C 3-6 Cycloalkyl, 3) OR 6 , 4) SR 6 ,S(O)R 6 ,SO 2 R 6 , ##STR56## R 5 is C 1-8 alkyl, C 3-6 cycloalkyl, heterocycle or aryl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR57## provided that Y is not ##STR58##

Claim 5

The compound according to claim 1 having the formula I: ##STR59## or a pharmaceutically acceptable salt or disulfide thereof; wherein: R 1 and R 2 are independently selected from H and C 1-4 alkyl; R 3 and R 4 are independently selected from: H; C 1-8 alkyl, alkenyl, alkynyl, or ##STR60## unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH 2 ) t OR 6 , c) (CH 2 ) t NR 6 R 7 , d) halogen, 2) C 3-6 cycloalkyl, 3) OR 6 , 4) SR 6 ,S(O)R 6 ,SO 2 R 6 , R 5 is hydrogen; R 6 , R 7 and R 8 are independently selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a ) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR61## wherein R 6 and R 7 may be joined in a ring, and R 7 and R 8 may be joined in a ring; R 9 is C 1-4 alkyl or aralkyl; m is 0, 1 or 2; t is 1 to 4; X is H 2 ; and Y is substituted or unsubstituted ring system selected from the following ##STR62## and wherein the substituent is selected from C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, said substituent which is unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR63##

Claim 6

The prodrug compound according to claim 2 having the formula I: ##STR64## or a pharmaceutically acceptable salt or disulfide thereof; wherein: R 1 and R 2 are independently selected from H and C 1-4 alkyl; R 3 and R 4 are independently selected from: H; C 1-8 alkyl, alkenyl, alkynyl, or ##STR65## unsubstituted or substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) C 1-4 alkyl, b) (CH 2 ) t OR 6 , c) (CH 2 ) t NR 6 R 7 , d) halogen, 2) C 3-6 cycloalkyl, 3) OR 6 , 4) SR 6 ,S(O)R 6 , SO 2 R 6 , R 5 is C 1-8 alkyl, C 3-6 cycloalkyl, heterocycle or aryl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen; d) HO, ##STR66## R 6 , R 7 and R 8 are independently selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR67## wherein R 6 and R 7 may be joined in a ring, and R 7 and R 8 may be joined in a ring; R 9 is C 1-4 alkyl or aralkyl; m is 0, 1 or 2; t is 1 to 4; X is H 2 ; and Y is substituted or unsubstituted ring system selected from the following ##STR68## wherein the substituent is selected from C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl,said substituent which is unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, ##STR69##

Claim 7

A compound or prodrug compound which is selected from: N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine methyl ester (Compound 3) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine (Compound 4) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine methyl ester (Compound 5) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine (Compound 6) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-cis-3-ethyl-prolyl-methionine methyl ester (compound 7) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-cis-3-ethyl-prolyl-methionine (Compound 8) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone methyl ester (Compound 9) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl ]-prolyl-methionine sulfone (Compound 10) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-methionine methyl ester (Compound 11 ) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-methionine (Compound 12) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-homoserine (Compound 16) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-homoserine (Compound 18) N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-prolyl-homserine (Compound 20) N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-2(S)-pipecolyl-homserine (Compound 22) N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine methyl ester (Compound 23) N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine (Compound 24) N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone methyl ester (Compound 25) and N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone (Compound 26) or a pharmaceutically acceptable salt or disulfide thereof.

Claim 8

A compound or prodrug compound which is selected from: N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine methyl ester (Compound 3) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine (Compound 4) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine methyl ester (Compound 5) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine (Compound 6) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-cis-3-ethyl-prolyl-methionine methyl ester (compound 7) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-cis-3-ethyl-prolyl-methionine (Compound 8) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone methyl ester (Compound 9) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl ]-prolyl-methionine sulfone (Compound 10) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-methionine methyl ester (Compound 11 ) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-methionine (Compound 12) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-prolyl-homoserine (Compound 16) N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-2(S)-pipecolyl-homoserine (Compound 18) N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-prolyl-homserine (Compound 20) N-[2(R)-amino-3-mercaptopropyl]-isoleucyl-2(S)-pipecolyl-homserine (Compound 22) N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine methyl ester (Compound 23) N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine (Compound 24) N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone methyl ester (Compound 25) and N-[2(S)-(2(R)-amino-3-(mercaptopropyl)methylamino)-3(S)-methylpentyl]-prolyl-methionine sulfone (Compound 26) or a pharmaceutically acceptable salt or disulfide thereof.

Claim 9

The compound according to claim 1 which is: N-[N'-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4 -tetrahydro-3(S)-isoquinolinecarboxyl]-homoserine (Compound 14) ##STR70##

Claim 10

The compound according to claim 1 which is: N-[N'-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4 -tetrahydro-3(S)-isoquinolinecarboxyl]-methionine (Compound 2) ##STR71##

Claim 11

The prodrug compound according to claim 2 which is: N-[N'-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-1,2,3,4 -tetrahydro-3(S)-isoquinolinecarboxyl]-methionine methyl ester (Compound 1) ##STR72##

Claim 12

The compound according to claim 1 which is: N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-trans-3-ethyl-prolyl-methionine (Compound 6) ##STR73##

Claim 13

The prodrug compound according to claim 0 which is: N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3-methylpentyl]-trans-3-ethyl-prolyl-methionine methyl ester (Compound 5) ##STR74##

Claim 14

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

Claim 15

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 3.

Claim 16

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