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US 6,103,723 AGranted
Inhibitors of farnesyl-protein transferase
AssigneeMerck & Co., Inc.
InventorsJeffrey M. Bergman, Christopher J. Dinsmore, Samuel L. Graham
Life of this patent
Estimating the term…
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.
Claims34
A compound which inhibits farnesyl-protein transferase of the formula A:
- ##STR37## wherein:
- R.sup.1a and R.sup.1b are independently selected from:
- a) hydrogen,
- b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN(R.sup.10).sub.2 NC(O)--, (R.sup.10).sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
- c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, CN, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
- R.sup.2 and R.sup.3 are independently selected from:
- H, unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, ##STR38## wherein the substituted group is substituted with one or more of:
- 1) aryl or heterocycle, unsubstituted or substituted with:
- a) C.sub.1-4 alkyl,
- b) (CH.sub.2).sub.p OR.sup.4,
- c) (CH.sub.2).sub.p NR.sup.4 R.sup.6,
- d) halogen,
- e) CN,
- 2) C.sub.3-6 cycloalkyl,
- 3) OR.sup.4,
- 4) SR.sup.5, S(O)R.sup.5, SO.sub.2 R.sup.5,
- 5) --NR.sup.4 R.sup.6, ##STR39## 15) N.sub.3, or 16) F;
- or
- R.sup.2 and R.sup.3 are attached to the same C atom and are combined to form --(CH.sub.2).sub.u -- wherein one of the carbon atoms is optionally replaced by a moiety selected from:
- O, S(O).sub.m, --NC(O)--, and --N(COR.sup.10)--;
- and
- R.sup.2 and R.sup.3 are optionally attached to the same carbon atom;
- R.sup.4 and R.sup.6 are independently selected from:
- H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl or heterocycle,
- c) halogen,
- d) HO,
- e) ##STR40## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
- or
- R.sup.4 and R.sup.6 may be joined in a ring;
- R.sup.5 is selected from:
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl or heterocycle,
- c) halogen,
- d) HO
- e) ##STR41## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
- R.sup.8 is independently selected from:
- a) hydrogen,
- b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, (R10).sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.10 OC(O)NH--;
- R.sup.9 is selected from:
- a) hydrogen,
- b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
- R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.14 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and unsubstituted or substituted aryl;
- A.sup.1 and A.sup.2 are independently selected from:
- a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
- A.sup.3 is selected from:
- a) a bond,
- b) unsubstituted or substituted aryl, and
- c) unsubstituted or substituted heteroaryl;
- G.sup.1 and G.sup.2 are independently selected from:
- O or H.sub.2 ;
- V is selected from:
- a) hydrogen,
- b) heterocycle,
- c) aryl,
- d) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and
- e) C.sub.2 -C.sub.20 alkenyl,
- provided that V is not hydrogen if A.sup.1 is S(O).sub.m and V is not hydrogen if A.sup.1 is a bond, n is 0 and A.sup.2 is S(O).sub.m ;
- W is a heterocycle;
- X is selected from a bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m ;
- Y is selected from:
- a bond, --CH.dbd.CH--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
- Z is selected from:
- 1) an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, unsubstituted or substituted aryl, heterocycle, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
- b) aryl or heterocycle,
- c) halogen,
- d) OR.sup.4,
- e) NR.sup.4 R.sup.6,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3,
- i) --S(O).sub.m R.sup.5,
- j) --C(O)NR.sup.4 R.sup.6, or
- k) C.sub.3 -C.sub.6 cycloalkyl;
- or
- 2) an unsubstituted or substituted group selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted group is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.4 R.sup.6,
- c) C.sub.3-6 cycloalkyl
- d) --NR.sup.4 C(O)R.sup.6,
- e) HO,
- f) --S(O).sub.m R.sup.5,
- g) halogen, or
- h) perfluoroalkyl;
- 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, 1, 2, 3, 4 or 5;
- provided that r is 0 when V is hydrogen;
- t is 0 or 1;
- and
- u is 4 or 5;
- or the pharmaceutically acceptable salts thereof.
98 more elements
A compound which inhibits farnesyl-protein transferase of the formula B:
- ##STR42## wherein:
- R.sup.1a and R.sup.1b are independently selected from:
- a) hydrogen,
- b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN(R.sup.10).sub.2 NC(O)--, (R.sup.10).sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
- c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, CN, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
- R.sup.2 and R.sup.3 are independently selected from:
- H, unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, ##STR43## wherein the substituted group is substituted with one or more of:
- 1) aryl or heterocycle, unsubstituted or substituted with:
- a) C.sub.1-4 alkyl,
- b) (CH.sub.2).sub.p OR.sup.4,
- c) (CH.sub.2).sub.p NR.sup.4 R.sup.6,
- d) halogen,
- e) CN,
- 2) C.sub.3-6 cycloalkyl,
- 3) OR.sup.4,
- 4) SR.sup.5, S(O)R.sup.5, SO.sub.2 R.sup.5,
- 5) --NR.sup.4 R.sup.6, ##STR44## 15) N.sub.3, or 16) F;
- or
- R.sup.2 and R.sup.3 are attached to the same C atom and are combined to form --(CH.sub.2).sub.u -- wherein one of the carbon atoms is optionally replaced by a moiety selected from:
- O, S(O).sub.m, --NC(O)--, and --N(COR.sup.10)--;
- and
- R.sup.2 and R.sup.3 are optionally attached to the same carbon atom;
- R.sup.4 and R.sup.6 are independently selected from:
- H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl or heterocycle,
- c) halogen,
- d) HO
- e) ##STR45## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
- or
- R.sup.4 and R.sup.6 may be joined in a ring;
- R.sup.5 is selected from:
- C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl or heterocycle,
- c) halogen,
- d) HO,
- e) ##STR46## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
- R.sup.8 is independently selected from:
- a) hydrogen,
- b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 OC(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, (R10).sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.10 OC(O)NH--;
- R.sup.9 is selected from:
- a) hydrogen,
- b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
- R.sup.10 is independently selected from hydrogen, C.sub.1 --C.sub.14 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and unsubstituted or substituted aryl;
- A.sup.1 and A.sup.2 are independently selected from:
- a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
- A.sup.3 is selected from:
- a) a bond,
- b) unsubstituted or substituted aryl, or
- c) unsubstituted or substituted heteroaryl;
- G.sup.1 and G.sup.2 are independently sele(:ted from:
- O or H.sub.2 ;
- V is selected from:
- a) hydrogen,
- b) heterocycle,
- c) aryl,
- d) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and
- e) C.sub.2 -C.sub.20 alkenyl,
- provided that V is not hydrogen if A.sup.1 is S(O).sub.m and V is not hydrogen if A.sup.1 is a bond, n is 0 and A.sup.2 is S(O).sub.m ;
- W is a heterocycle;
- X is selected from a bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m ;
- Y is selected from:
- a bond, --CH.dbd.CH--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
- Z is selected from:
- 1) an unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, unsubstituted or substituted aryl, heterocycle, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
- b) aryl or heterocycle,
- c) halogen,
- d) OR.sup.4,
- e) NR.sup.4 R.sup.6,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3,
- i) --S(O).sub.m R.sup.5,
- j) --C(O)NR.sup.4 R.sup.6, or
- k) C.sub.3 -C.sub.6 cycloalkyl;
- or
- 2) an unsubstituted or substituted group selected from C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted group is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.4 R.sup.6,
- c) C.sub.3-6 cycloalkyl
- d) --NR.sup.4 C(O)R.sup.6,
- e) HO,
- f) --S(O).sub.m R.sup.5,
- g) halogen, or
- h) perfluoroalkyl;
- 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, 1, 2, 3, 4, or 5;
- provided that r is 0 when V is hydrogen;
- t is 0 or 1;
- and
- u is 4 or 5;
- or the pharmaceutically acceptable salts thereof.
98 more elements
A compound which inhibits farnesyl-protein transferase which is:
- 1(R),5(S)-3-[(3-trifluoromethyl)phenyl]-8-[(4-cyanobenzyl)-5-imidazolylmeth yl]-3,8-diaza-2-oxobicyclo[3.2.1]octane
- (.+-.)-9-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-b-benzo-1,9-diaza-4-oxa-12- oxobicyclo[6.3.1]dodecane
- (.+-.)-9-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1,9-diaza-b,e-dibenzo-4-oxa -12-oxobicyclo[6.3.1]dodecane
- (.+-.)-9-[1-(4-cyanobenzyl)-5-imidazolylcarbonyl]-1,9-diaza-b,e-dibenzo-4-o xa-bicyclo[6.3.1]dodecane
- or a pharmaceutically acceptable salt or optical isomer thereof.
2 more elements
Dependencies are inferred from the claim text.