Inhibitors of farnesyl-protein transferase

Claim 2

A compound which inhibits Ras farnesyl-transferase having the formula I: ##STR13## wherein: R 1 is selected from: a) hydrogen, b) R 5 S(O) 2 --, R 5 C(O)--, (R 5 ) 2 NC(O)-- or R 6 OC(O)--, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --; R 2a and R 2b are independently selected from: a) hydrogen, b) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, and c) aryl, heterocycle, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, NO 2 , (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, R 3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted heterocycle, c) unsubstituted or substituted cycloalkyl, and d) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; X-Y is ##STR14## R 4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; R 5 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl; R 6 is independently selected from C 1 -C 6 alkyl and aryl; Z is H 2 ; m is 0, 1 or 2, provided that m is 0 when R 5 =hydrogen; n is 0, 1, 2, 3 or 4; and t is 3; or a pharmaceutically acceptable salt thereof.

Claim 3

The compound according to claim 1 having a structure of the formula I: ##STR15## wherein: R 1 is selected from: a) hydrogen, b) R 5 S(O) 2 --, R 5 C(O)--, (R 5 ) 2 NC(O)-- or R 6 OC(O)--, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --; R 2a and R 2b are independently selected from: a) hydrogen, b) C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, and c) aryl, heterocycle, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, NO 2 , (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, R 3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted heterocycle, c) unsubstituted or substituted cycloalkyl, and d) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; X-Y is ##STR16## R 4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R 5 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl; R 6 is independently selected from C 1 -C 6 alkyl and aryl; Z is H 2 ; m is 0, 1 or 2, provided that m is 0 when R 5 =hydrogen; n is 0, 1, 2, 3 or 4; and t is 3; or a pharmaceutically acceptable salt thereof.

Claim 4

The compound according to claim 1 which inhibits Ras farnesyl-transferase having the formula I: ##STR17## wherein: R 1 is selected from: a) hydrogen, b) R 5 S(O) 2 --, R 5 C(O)--, (R 5 ) 2 NC(O)-- or R 6 OC(O)--, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, alkynyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --; R 2a and R 2b are independently selected from: a) hydrogen, b) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, and c) aryl, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, NO 2 , (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, R 3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted cycloalkyl, and c) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl; X-Y is ##STR18## R 4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted cycloalkyl, and d) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl; R 4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted cycloalkyl, d) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl, e) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl, and f) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl; R 5 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl; R 6 is independently selected from C 1 -C 6 alkyl and aryl; Z is H 2 ; m is 0, 1 or 2, provided that m is 0 when R 5 =hydrogen; n is 0, 1, 2, 3 or 4; and t is 3; or a pharmaceutically acceptable salt thereof.

Claim 5

The compound according to claim 3 having a structure of the formula I: ##STR19## wherein: R 1 is selected from: a) hydrogen, b) R 5 S(O) 2 --, R 5 C(O)--, (R 5 ) 2 NC(O)-- or R 6 OC(O)--, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, alkynyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --; R 2a and R 2b are independently selected from: a) hydrogen, b) C 1 -C 6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, and c) aryl, cycloalkyl, alkenyl, R 5 O--, R 5 S(O) m --, R 5 C(O)NR 5 --, CN, NO 2 , (R 5 ) 2 N--C(NR 5 )--, R 5 C(O)--, R 5 OC(O)--, N 3 , --N(R 5 ) 2 , or R 6 OC(O)NR 5 --, R 3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted cycloalkyl, and c) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl and cycloakyl; X-Y is ##STR20## R 4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted cycloalkyl, and d) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl; R 4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted cycloalkyl, d) C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl, e) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl and cycloalkyl; R 5 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl; R 6 is independently selected from C 1 -C 6 alkyl and aryl; Z is H 2 ; m is 0, 1 or 2, provided that m is 0 when R 5 =hydrogen; n is 0, 1, 2, 3 or 4; and t is 3; or a pharmaceutically acceptable salt thereof.

Claim 6

A compound which inhibits farnesyl-protein transferase which is: N-[2(R)-Amino-3-mercaptopropyl]-L-proline-2,3-dichlorobenzylamide N-[2(R)-Amino-3-mercaptopropyl]-L-proline-1-naphthylmethyl amide N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-D-3-trans-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-L-3-cis-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-D-3-cis-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-1-naphthylmethyl amide N-[2(R)-Amino-3-mercaptopropyl]-D-3-trans-ethylproline-1-naphthylmethyl amide N-[2(R)-Amino-3-mercaptopropyl]-L-proline-2,3-dimethylphenyl amide N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-2,3-dimethylphenyl amide; or N-[2(R)-Amino-3-mercaptopropyl]-D-3-transoethylproline-2,3-dimethylphenyl amide or a pharmaceutically acceptable salt thereof.

Claim 7

A compound which inhibits farnesyl-protein transferase which is: N-[2(R)-Amino-3-mercaptopropyl]-L-proline-2,3-dichlorobenzylamide N-[2(R)-Amino-3-mercaptopropyl]-L-proline-1-naphthylmethyl amide N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-D-3-trans-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-L-3-cis-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-D-3-cis-ethylproline-2,3-dichlorobenzamide N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-1-naphthylmethyl amide N-[2(R)-Amino-3-mercaptopropyl]-D-3-trans-ethylproline-1-naphthylmethyl amide N-[2(R)-Amino-3-mercaptopropyl]-L-proline-2,3-dimethylphenyl amide N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-2,3-dimethylphenyl amide; or N-[2(R)-Amino-3-mercaptopropyl]-D-3-transoethylproline-2,3-dimethylphenyl amide or a pharmaceutically acceptable salt thereof.

Claim 8

The compound according to claim 5 which inhibits farnesyl-protein transferase which is: N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-2,3-dichlorobenzamide ##STR21## or a pharmaceutically acceptable salt thereof.

Claim 9

The compound according to claim 5 which inhibits farnesyl-protein transferase which is: N-[2(R)-Amino-3-mercaptopropyl]-L-3-cis-ethylproline-2,3-dichlorobenzamide ##STR22## or a pharmaceutically acceptable salt thereof.

Claim 10

The compound according to claim 5 which inhibits farnesyl-protein transferase which is: N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-1-naphthylmethyl amide ##STR23## or a pharmaceutically acceptable salt thereof.

Claim 11

The compound according to claim 5 which inhibits farnesyl-protein transferase which is: N-[2(R)-Amino-3-mercaptopropyl]-L-3-trans-ethylproline-2,3-dimethylphenyl amide ##STR24## or a pharmaceutically acceptable salt thereof.

Claim 12

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

Claim 13

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 2.

Claim 14

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

Claim 15

A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 10.

Claim 16

A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 11.

Claim 17

A method for inhibiting farnesylation of Ras protein which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 12.

Claim 18

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 10.

Claim 19

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 11.

Claim 20

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 12.