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US 5,491,164 AGranted
Inhibitors of farnesyl-protein transferase
AssigneeMerck & Co., Inc.
InventorsS. Jane deSolms, Samuel J. Graham
Life of this patent
Estimating the term…
Abstract
The present invention comprises dipeptide analogs that inhibit the farnesylation of Ras. These farnesyl-protein transferase inhibitors are characterized by the inclusion of a cyclic amine in the backbone of the dipeptide. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
Claims18
A compound which inhibits Ras farnesyl-transferase having the formula I:
- ##STR13## wherein:
- R.sup.1 is selected from:
- a) hydrogen,
- b) R.sup.5 S(O).sub.2 --, R.sup.5 C(O)--, (R.sup.5).sub.2 NC(O)-- or R.sup.6 OC(O)--, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R.sup.5 O--, R.sup.5 S(O).sub.m --, R.sup.5 C(O)NR.sup.5 --, CN, (R.sup.5).sub.2 N--C(NR.sup.5)--, R.sup.5 C(O)--, R.sup.5 OC(O)--, N.sub.3, --N(R.sup.5).sub.2, or R.sup.6 OC(O)NR.sup.5 --;
- R.sup.2a and R.sup.2b are independently selected from:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R.sup.5 O--, R.sup.5 S(O).sub.m --, R.sup.5 C(O)NR.sup.5 --, CN, (R.sup.5).sub.2 N--C(NR.sup.5)--, R.sup.5 C(O)--, R.sup.5 OC(O)--, N.sub.3, --N(R.sup.5).sub.2, or R.sup.6 OC(O)NR.sup.5 --, and
- c) aryl, heterocycle, cycloalkyl, alkenyl, R.sup.5 O--, R.sup.5 S(O).sub.m --, R.sup.5 C(O)NR.sup.5 --, CN, NO.sub.2, (R.sup.5).sub.2 N--C(NR.sup.5)--, R.sup.5 C(O)--, R.sup.5 OC(O)--, N.sub.3, --N(R.sup.5).sub.2, or R.sup.6 OC(O)NR.sup.5 --,
- R.sup.3 is selected from:
- a) unsubstituted or substituted aryl,
- b) unsubstituted or substituted heterocycle,
- c) unsubstituted or substituted cycloalkyl, and
- d) C.sub.1 -C.sub.6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
- X-Y is ##STR14## R.sup.4a is selected from a) hydrogen,
- b) unsubstituted or substituted aryl,
- c) unsubstituted or substituted heterocycle,
- d) unsubstituted or substituted cycloalkyl, and
- e) C.sub.1 -C.sub.6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
- R.sup.4b is selected from
- a) hydrogen,
- b) unsubstituted or substituted aryl,
- c) unsubstituted or substituted heterocycle,
- d) unsubstituted or substituted cycloalkyl,
- e) C.sub.1 -C.sub.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.sub.1 -C.sub.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.sub.1 -C.sub.6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
- R.sup.5 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl and aryl;
- R.sup.6 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
- Z is H.sub.2 ;
- m is 0, 1 or 2, provided that m is 0 when R.sup.5 =hydrogen;
- n is 0, 1, 2, 3 or 4;
- and
- t is 3;
- or a pharmaceutically acceptable salt thereof.
32 more elements
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-dichlorobenzamid e
- N-[2(R)-Amino-3-mercaptopropyl]-D-3-trans-ethylproline-2,3-dichlorobenzamid e
- 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.
10 more elements
Dependencies are inferred from the claim text.