Claims
- 1. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein:One of a, b, c and d represents N or NR9 wherein R9 is O−, —CH3 or —(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2; or each of a, b, c, and d are independently selected from CR1 or CR2; each R1 and each R2 is independently selected from H, halo, —CF3, —OR10, —COR10, —SR10, —S(O)tR11 (wherein t is 0, 1 or 2), —SCN, —N(R10)2, —NR10R11, —NO2, —OC(O)R10, —CO2R10, —OCO2R11, —CN, —NHC(O)R10, —NHSO2R10, —CONHR10, —CONHCH2CH2OH, —NR10COOR11, —SR11C(O)OR11, —SR11N(R75)2 wherein each R75 is independently selected from H and —C(O)OR11, 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, —OR10 or —CO2R10; R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III); R5, R6, R7 and R8 each independently represents H, —CF3, —COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR10, —SR10, —S(O)tR11, —NR10COOR11, —N(R10)2, —NO2, —COR10, —OCOR10, —OCO2R11, —CO2R10, OPO3R10, or R5 is combined with R6 to represent ═O or ═S and/or R7 is combined with R8 to represent ═O or ═S; R10 represents H, alkyl, aryl, or aralkyl; R11 represents alkyl or aryl; X represents N and the optional bond (represented by the dotted line) to carbon 11 is absent; 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 —R10, halo, —OR11, —OCO2R11 or —OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, —(OR11)2; H and halo, dihalo, alkyl and H, (alkyl)2, —H and —OC(O)R10, H and —OR10, ═O, aryl and H, ═NOR10 or —O—(CH2)p—O— wherein p is 2, 3 or 4; and W represents a group selected from the group consisting of: wherein: R12 is selected from the group consisting of: (a) H; (b) alkyl; (c) aralkyl; and (d) heteroarylalkyl; R13 and R14 are each independently selected from the group consisting of: (a) H; (b) —C(O)OR16 wherein R16 represents alkyl, aralkyl, and heteroaralkyl; (c) —SO2R17 wherein R17 is selected from the group consisting of: NH2, —N(alkyl)2 wherein each alkyl is the same or different, alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; (d) —C(O)R18 wherein R18 is selected from the group consisting of: aryl, alkyl, aralkyl, heteroaryl, and heteroaralkyl; (e) C1-6 alkyl; (f) alkaryl; and (g) C3-6 cycloalkyl; r is 0, 1 or 2; s represents 1, 2, 3, 4, or 5, and each Y for each —CY2— group is independently selected from H or —OH, provided that both Y substituents of each —CY2— group are not —OH, and provided that for the —CY2— group alpha to the nitrogen both Y substituents are H, such that the group forms a 3, 4, 5, 6, or 7 membered ring; v is 0, 1 or 2; R15 is selected from the group consisting of: (a) heteroaryl; (b) a group selected from: (5) —CH(OCH2CH3)2, (6) —OH, and (7) —CN; and (c) heterocycloalkyl selected from the group consisting of: z is 0, 1, 2, 3, 4, or 5 wherein each —CH2— group is optionally substituted with a —OH group; R22 represents a group selected from: (5) alkyl, (6) —OR23 wherein R23 is selected from the group consisting of: alkyl, aryl and H, and wherein R24 and R25 are independently selected from the group consisting of: —NH2, alkoxy, —OH, —CH2CO2H, —OCH2Ph, —CH(OCH3)CH(CH3)2, alkyl, aryl, H, aralkyl, and heteroaralkyl; or R24 and R25 taken together form a carbon chain having 4 or 5 (—CH2—) groups such that R24 and R25 taken together with the nitrogen to which they are bound form a 5 or 6 membered heterocycloalkyl ring.
- 2. The compound of claim 1 wherein R2 is H; R1 is selected from the group consisting of: Br and Cl; R3 is selected from the group consisting of: Br and Cl; R4 is selected from the group consisting of: H, Br and Cl; R5, R6, R7 and R8 are H; A and B are each H2; and the optional bond between C5 and C6 is absent.
- 3. The compound of claim 2 wherein R4 is H.
- 4. The compound of claim 2 wherein R4 is selected from the group consisting of: Cl or Br.
- 5. The compound of claim 4 wherein W is selected from the group consisting of:(A) wherein: (1) s is 1, 2, 3, 4 or 5; and (2) R13 is selected from the group consisting of: (a) H and —C(O)OR16 wherein R16 is alkyl; (B) wherein: (1) v is 0; (2) R12 is H; and (3) R15 is selected from the group consisting of: and —OH, —CN; (C) wherein: (1) v is 1 or 2; (2) R12 is H; and (3) R15 is heterocycloalkyl; (D) wherein: (1) z is 0; (2) R22 is —NR24R25; and (3) R24 and R25 are independently selected from: H, —NH2, alkyl, alkoxy, —OH, —CH2CO2H, or —OCH2C6H5; and (E) wherein: (1) z is 1, 2, 3, 4 or 5; (2) R22 is selected from: —OR23, —ONa, —OLi, alkyl, —NR24R25 or (3) R23 is alkyl; and (4) R24 and R25 are independently selected from H, —CH(OCH3)CH(CH3)2,
- 6. The compound of claim 1 selected from: wherein R1, R3 and R4 are each independently selected from halo; and A, B, X and W are as defined in claim 1.
- 7. The compound of claim 6 wherein R1 is selected from the group consisting of: Br and Cl; R3 and R4 are independently selected from the group consisting of: Br and Cl; A and B are each H2; and the optional bond between C5 and C6 is absent.
- 8. The compound of claim 7 wherein R1 is Br; R3 is Cl; and R4 is Br.
- 9. The compound of claim 8 wherein W is selected from the group consisting of:(A) wherein: (1) s is 1, 2, 3, 4 or 5; and (2) R13 is selected from the group consisting of: (a) H and —C(O)OR16 wherein R16 is alkyl; (B) wherein: (1) v is 0; (2) R12 is H; and (3) R15 is selected from the group consisting of: and —OH, —CN; (C) wherein: (1) v is 1 or 2; (2) R12 is H; and (3) R15 is heterocycloalkyl; (D) wherein: (1) z is 0; (2) R22 is —NR24R25; and (3) R24 and R25 are independently selected from: H, —NH2, alkyl, alkoxy, —OH, —CH2CO2H, or —OCH2C6H5; and (E) wherein: (1) z is 1, 2, 3, 4 or 5; (2) R22 is selected from: —OR23, —ONa, —OLi, alkyl, —NR24R25 or (3) R23 is alkyl; and (4) R24 and R25 are independently selected from H, —CH(OCH3)CH(CH3)2,
- 10. A method of treating tumor cells, 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 or colon tumors cells, in a human by inhibition of farnesyl protein transferase comprising administering to a human in need thereof the compound of claim 1 in an amount that inhibits farnesyl protein transferase.
- 11. A method of inhibiting farnesyl protein transferase in a human comprising the administration of the compound of claim 1 to a human in need thereof in an amount that inhibits farnesyl protein transferase.
- 12. A pharmaceutical composition comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier.
REFERENCE TO RELATED APPLICATIONS
This application is a divisional of application Ser. No. 09/417,885 filed Oct. 14, 1999 now U.S. Pat. No. 6,228,856 which is a divisional of application Ser. No. 08/927,731 filed Sep. 11, 1997 now U.S. Pat. No. 6,030,982 which claims the benefit of U.S. Provisional Application Ser. No. 60/025,249 filed Sep. 13, 1996 U.S. Provisional Application Ser. No. 60/050,009 filed Jun. 17, 1997.
US Referenced Citations (3)
Non-Patent Literature Citations (1)
Entry |
Khosravi-Far R et al. Cell Growth & Differentiation. 3, 461-468 (1992). |
Provisional Applications (2)
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Number |
Date |
Country |
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60/025249 |
Sep 1996 |
US |
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60/050009 |
Jun 1997 |
US |