Claims
- 1. A compound of the formula: ##STR146## or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR.sup.9 wherein R.sup.9 is O.sup.-, --CH3 or --(CH.sub.2).sub.n CO.sub.2 H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR.sup.1 or CR.sup.2 ;
- each R.sup.1 and each R.sup.2 is independently selected from H, halo, --CF.sub.3, --OR.sup.10, --COR.sup.10, --SR.sup.10, --S(O).sub.t R.sup.11 (wherein t is 0, 1 or 2), --SCN, --N(R.sup.10).sub.2, --NR.sup.10 R.sup.11, --NO.sub.2, --OC(O)R.sup.10, --CO.sub.2 R.sup.10, --OCO.sub.2 R.sup.11, --CN, --NHC(O)R.sup.10, --NHSO.sub.2 R.sup.10, --CONHR.sup.10, --CONHCH.sub.2 CH.sub.2 OH, --NR.sup.10 COOR.sup.11, ##STR147## --SR.sup.11 C(O)OR.sup.11, --SR.sup.11 N(R.sup.75).sub.2 wherein each R.sup.75 is independently selected from H and --C(O)OR.sup.11, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, --OR.sup.10 or --CO.sub.2 R.sup.10 ;
- R.sup.3 and R.sup.4 are the same or different and each independently represents H, any of the substituents of R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 taken together represent a saturated or unsaturated C.sub.5 -C.sub.7 fused ring to the benzene ring (Ring III);
- R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently represents H, --CF.sub.3, --COR.sup.10, alkyl or aryl, said alkyl or aryl optionally being substituted with --OR.sup.10, --SR.sup.10, --S(O).sub.t R.sup.11, --NR.sup.10 COOR.sup.11, --N(R.sup.10).sub.2, --NO.sub.2, --COR.sup.10, --OCOR.sup.10, --OCO.sub.2 R.sup.11, --CO.sub.2 R.sup.10, OPO.sub.3 R.sup.10 or R.sup.5 is combined with R.sup.6 to represent .dbd.O or .dbd.S and/or R.sup.7 is combined with R.sup.8 to represent .dbd.O or .dbd.S;
- R.sup.10 represents H, alkyl, aryl, or aralkyl;
- R.sup.11 represents alkyl or aryl;
- X represents CH or C, which C contain a double bond (represented by the dotted line) to carbon atom 11;
- the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent --R.sup.10, halo, --OR.sup.11, --OCO.sub.2 R.sup.11 or --OC(O)R.sup.10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H.sub.2, --(OR.sup.11 ).sub.2 ; H and halo, dihalo, alkyl and H, (alkyl).sub.2, --H and --OC(O)R.sup.10, H and --OR.sup.10, .dbd.O, aryl and H, .dbd.NOR.sup.10 or --O--(CH.sub.2).sub.p --O-- wherein p is 2, 3 or 4; and
- W represents a group selected from: ##STR148## wherein: R.sup.12 is selected from the group consisting of: (1) H; (2) alkyl; (3) aryl; (4) arylalkyl;
- R.sup.13 is selected from the group consisting of: (1) H; (2) alkyl; (3) alkoxy; (4) heterocycloalkyl; (5) aryl; and (5) aralkyl;
- R.sup.14 is selected from the group consisting of: (1) H; (2) alkyl; (3) aryl; and (4) heteroaryl;
- ring ##STR149## represents a heterocycloalkyl ring wherein Y represents the remainder of the ring, said remainder comprising carbon atoms and optionally a hetero atom selected from the group consisting of: NH, NR.sup.15, O and S, and said remainder optionally having an aryl ring fused thereto;
- R.sup.15 represents --C(O)OR.sup.16 ; and
- R.sup.16 represents alkyl.
- 2. The compound of claim 1 wherein R.sup.2 is H; R.sup.1 is selected from the group consisting of: Br and Cl; R.sup.3 is selected from the group consisting of: Br and Cl; R.sup.4 is selected from the group consisting of: H, Br and Cl; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are H; A and B are each H.sub.2 ; and the optional bond between C5 and C6 is absent.
- 3. The compound of claim 2 wherein R.sup.4 is H.
- 4. The compound of claim 2 wherein R.sup.4 is selected from the group consisting of: Cl or Br.
- 5. The compound of claim 4 wherein X is CH.
- 6. The compound of claim 4 wherein W is selected from the group consisting of:
- (A) ##STR150## wherein: (1) R.sup.12 is selected from the group consisting of: H, alkyl and aralkyl; and
- (2) R.sup.13 is selected from the group consisting of: H, alkyl, alkoxy, aralkyl, and heterocycloalkyl;
- (B) ##STR151## wherein the heterocycloalkyl ring ##STR152## is selected from the group consisting of: ##STR153## and (C) ##STR154## wherein R.sup.14 is H or alkyl.
- 7. The compound of claim 6 wherein X is CH.
- 8. The compound of claim 7 wherein R.sup.12 is selected from: H, methyl, ethyl or benzyl; R.sup.13 is selected from: H, methyl, ethyl, methoxy, benzyl, or ##STR155## and R.sup.14 represents H or --C(CH.sub.3).
- 9. The compound of claim 1 selected from: ##STR156## wherein R.sup.1, R.sup.3 and R.sup.4 are each independently selected from halo; and A, B, X and W are as defined in claim 1.
- 10. The compound of claim 9 wherein R.sup.1 is selected from the group consisting of: Br and Cl; R.sup.3 and R.sup.4 are independently selected from the group consiting of: Br and Cl; A and B are each H.sub.2 ; and the optional bond between C5 and C6 is absent.
- 11. The compound of claim 10 wherein R.sup.1 is Br; and R.sup.3 is Cl; and R.sup.4 is Br.
- 12. The compound of claim 11 wherein X is CH.
- 13. The compound of claim 11 wherein W is selected from the group consisting of:
- (A) ##STR157## wherein: (1) R.sup.12 is selected from the group consisting of: H, alkyl and aralkyl; and
- (2) R13 is selected from the group consisting of: H, alkyl, alkoxy, aralkyl, and heterocycloalkyl;
- (B) ##STR158## wherein the heterocycloalkyl ring ##STR159## is selected from the group consisting of: ##STR160## and (C) ##STR161## wherein R.sup.14 is H or alkyl.
- 14. The compound of claim 13 wherein X is CH.
- 15. The compound of claim 14 wherein R.sup.12 is selected from: H, methyl, ethyl or benzyl; R.sup.13 is selected from: H, methyl, ethyl, methoxy, benzyl, or ##STR162## and R.sup.14 represents H or --C(CH.sub.3).
- 16. The compound of claim 14 wherein said compound is a compound of the formula: ##STR163## .
- 17. A compound selected from the group consisting of: ##STR164## .
- 18. A compound selected from the group consisting of: ##STR165## .
- 19. A compound selected from the group consisting of: ##STR166## .
- 20. A method of treating tumor cells in a human by inhibition of farnesyl protein transferase wherein the cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells or prostate tumor cells comprising administering to the human in need thereof a farnesyl protein transferase inhibiting amount of a compound of claim 1.
- 21. A method of inhibiting farnesyl protein transferase in a human comprising the administration to the human in need thereof a farnesyl protein transferase inhibiting amount of the compound of claim 1.
- 22. A pharmaceutical composition comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier.
- 23. A method of treating tumor cells in a human by inhibition of farnesyl protein transferase wherein the cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells or prostate tumor cells comprising administering to the human in need thereof a farnesyl protein transferase inhibiting effective amount of a compound of claim 17.
- 24. A method of inhibiting farnesyl protein transferase in a human comprising the administration to the human in need thereof a farnesyl protein transferase inhibiting amount of the compound of claim 17.
- 25. A pharmaceutical composition comprising an effective amount of compound of claim 17 in combination with a pharmaceutically acceptable carrier.
- 26. A method of treating tumor cells in a human by inhibition of farnesyl protein transferase wherein the cells treated are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells or prostate tumor cells comprising administering to the human in need thereof a farnesyl protein transferase inhibiting effective amount of a compound of claim 18.
- 27. A method of inhibiting farnesyl protein transferase in a human comprising the administration to the human in need thereof a farnesyl protein transferase inhibiting amount of the compound of claim 18.
- 28. A pharmaceutical composition comprising an effective amount of compound of claim 18 in combination with a pharmaceutically acceptable carrier.
- 29. A method of treating tumor cells in a human by inhibition of farnesyl protein transferase wherein the cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells or prostate tumor cells comprising administering to the human in need thereof a farnesyl protein transferase inhibiting amount of a compound of claim 19.
- 30. A method of inhibiting farnesyl protein transferase in a human comprising the administration to the human in need thereof a farnesyl protein transferase inhibiting amount of the compound of claim 19.
- 31. A pharmaceutical composition comprising an effective amount of compound of claim 19 in combination with a pharmaceutically acceptable carrier.
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Ser. No. 60/026,114 filed Sep. 13, 1996, and U.S. Provisional Application Ser. No. 60/050,009 filed Jun. 17, 1997.
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