EP0897303A1 - Inhibitors of farnesyl-protein transferase - Google Patents

Inhibitors of farnesyl-protein transferase

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Publication number
EP0897303A1
EP0897303A1 EP97916942A EP97916942A EP0897303A1 EP 0897303 A1 EP0897303 A1 EP 0897303A1 EP 97916942 A EP97916942 A EP 97916942A EP 97916942 A EP97916942 A EP 97916942A EP 0897303 A1 EP0897303 A1 EP 0897303A1
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European Patent Office
Prior art keywords
substituted
alkyl
aryl
unsubstituted
heterocycle
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EP97916942A
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German (de)
English (en)
French (fr)
Other versions
EP0897303A4 (enrdf_load_stackoverflow
Inventor
Samuel L. Graham
Theresa M. Williams
John S. Wai
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9609667.2A external-priority patent/GB9609667D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0897303A1 publication Critical patent/EP0897303A1/en
Publication of EP0897303A4 publication Critical patent/EP0897303A4/xx
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
  • Mutated ras genes (Ha-ras, Ki4a-r ⁇ , Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
  • Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
  • the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa ⁇ Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 370:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational famesylation.
  • famesylated proteins include the Ras-related GTP -binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.
  • Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al., Cell, 62:81 -88 (1990); Schaber et al, J. Biol. Chem., 265: 14701-14704 (1990); Schafer et al, Science, 249: 1 133-1 139 (1990); Manne et al, Proc. Natl. Acad. Sci USA , 87:1541 -7545 ( 1990)).
  • Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • direct inhibition of famesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
  • FPTase famesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
  • deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
  • famesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 1 12930).
  • an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit famesyl-protein transferase and thus, the post-translational famesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.
  • the present invention comprises peptidomimetic piperidinone-containing compounds which inhibit the famesyl-protein transferase.
  • the instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity.
  • chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production are illustrated by the formulae A, B and C:
  • the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras.
  • the inhibitors of famesyl-protein transferase are illustrated by the formula A:
  • Rl a and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, RlOo-, Rl lS(0) m -, R1 C(O)NR10., (RlO) 2 N- C(O)-, CN, N ⁇ 2, (R 10) 2 N-C(NR 10)_, RlOc(O)-, N3,
  • R 1 ⁇ (0) 0! -, Rl0c(O)NRl0., (Rl 0) 2N .
  • R2 and R3 are independently selected from: H; unsubstituted or substituted Ci-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
  • halogen e) CN, f) aryl or heteroaryl, g) perfluoro-C 1 -4 alkyl, h) SR°a, S(0)R6a, S ⁇ 2R 6a ,
  • R2 and R3 are attached to the same C atom and are combined to form (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO). ;
  • R4 and R ⁇ are independently selected from H and CH3;
  • R6, R7 and R?a are independently selected from: H; Ci-4 alkyl, C3- cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl and heteroaryl sulfonyl, unsubstituted or substituted with: a) Ci -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R6 and R ⁇ may be joined in a ring;
  • R7 and R ⁇ a may be joined in a ring;
  • R6 is selected from: Ci -4 alkyl, C3-6 cycloalkyl, heterocycle and aryl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIOO-, Rl lS(0) m -, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, R 10 2 N-C(NR 10)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, or R 1 10C(0)NR1 _, a nd c) C1 -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, Rl o-, Rl lS(0) m -, R10C(O)NR10_, (Rl0)2NC(O)-, R l ⁇ 2N-C(NR lO)_, CN, R lOC(O)-, N3, -N(R 10)2, or R 1 1 OC
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1 -C6 alkyl and aryl
  • G 1 and G 2 are independently oxygen or absent, provided that at least one of G 1 and G 2 is oxygen;
  • G3 is oxygen or H2;
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1 -C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0) ;
  • W is a heterocycle
  • Y is unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
  • Rla and R ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, RlOO-, Rl lS(0) m -, R! C(O)NR 10-, CN(Rl ) 2 NC(0)-, R10 2 N-C(NR 10)-, CN, NO2,
  • R 2 and R3 are independently selected from: H; unsubstituted or substituted Ci -8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
  • halogen e) CN, f) aryl or heteroaryl, g) perfluoro-C l -4 alkyl, h) SR 6a , S(0)R6a, S ⁇ 2R 6a ,
  • R 2 and R ⁇ are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(CORlO)- ;
  • R4 is selected from H and CH3;
  • R 2 , R-* and R4 are optionally attached to the same carbon atom;
  • R6, R7 and R are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl and heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, 11
  • R6 and R7 may be joined in a ring; R and R7 may be joined in a ring;
  • R oa is selected from: Cl -4 alkyl, C3-6 cycloalkyl, heterocycle and aryl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRlO)-, CN, N ⁇ 2, Rl°C(0)-, N3, -N(RlO)2, or Rl 10C(0)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R ⁇ O-, R 1 ⁇ (OW, Rl0C(O)NH
  • R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, RllS(0) m -, R 10 C(O)NRl0-, (Rl0) 2 NC(O)-, Rl0 2 N-
  • Rl is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl;
  • G 1 and G 2 are independently oxygen or absent provided that at least one of G! and G 2 is oxygen;
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • W is a heterocycle
  • Z is selected from: 1) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl -4 alkyl, unsubstituted or substituted with: C l -4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(0) m R°a, 0 r -C(0)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) N ⁇ 2, h) CF3; i) -S(0) m R6a, j) -C(0)NR6R7, or k) C3-C6 cycloalkyl; and 2) unsubstituted C1
  • C3-C6 cycloalkyl is substituted with one or two of the following: a) Cl-4 alkoxy, b) NR6R7 ? c) C3-6 cycloalkyl, d) -NR6C(0)R7, e) HO, f) -S(0) m R6a, g) halogen, or h) perfluoroalkyl;
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R lOo-, R l lS(0) m -, Rl0c(O)NRl0-, (Rl0)2NC(O)-, R!0 2 N-C(NR 10)-, CN, N ⁇ 2, R 10 C(O)-, RlO ⁇ C(O)-, N3, -N(R l )2, or RHOC(0)NR 10-, and c) unsubstituted or substituted C1-C6 alkyl wherein the substitutent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R lOO-, R
  • R 2 and R3 are independently selected from: H; unsubstituted or substituted Cl -8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
  • halogen e) CN, f) aryl or heteroaryl, g) perfluoro-Cl-4 alkyl, h) SR6a S(0)R6a, S ⁇ 2R 6a ,
  • R 2 and R3 are attached to the same C atom and are combined to form - (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR 10 )- ;
  • R 4 is selected from H and CH3;
  • R 2 , R3 and R4 are optionally attached to the same carbon atom;
  • R°, R7 and R7a are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl and heteroarylsulfonyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R6 and R7 may be joined in a ring; R7 and R7 may be joined in a ring;
  • R6 is selected from: Cl-4 alkyl, C3-6 cycloalkyl, heterocycle and aryl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0)m-,
  • Rl lS(0) ⁇ r Rl°C(0)NH-, (Rl0) 2 NC(O)-, Rl0 2 N- C(NRlO)-, CN, Rl0c(O)-, N3, -N(RlO) 2 , or Rl0 ⁇ C(O)NH-;
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RllS(0)m-, R 10 C(O)NRl0-, (Rl0) 2 NC(O)-, Rl0 2 N-C(NRl )-, CN, NO2, RlOC(O)-, N3, -N(RlO) 2 , or RllOC(O)NRl0-,and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, R10C(O)NR 1 -, (RlO) 2 NC(0)-, Rl ⁇ 2N-C(NRlO)-, CN, Rl°C(0)-, N3, -N(R 10 )2, or Rl 10C(0)NR10- ;
  • RI is independently selected from hydrogen, Cl -C6 alkyl, benzyl and aryl;
  • R 1 is independently selected from C1-C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1 -C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0) m ;
  • W is a heterocycle
  • Z is selected from: 1 ) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, he teroary Imethy 1, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl -4 alkyl, unsubstituted or substituted with:
  • C3-C6 cycloalkyl is substituted with one or two of the following: a) Cl -4 alkoxy, b) NR6R7 ? c) C3-6 cycloalkyl, d) -NR6C(0)R7, e) HO, f) -S(0) m R6a, g) halogen, or h) perfluoroalkyl;
  • q is 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 1 ; t is 0 or 1 ; and u is 4 or 5;
  • the inhibitors of famesyl-protein transferase are illustrated by the formula B:
  • Rl is independently selected from: hydrogen and C l -C6 alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R1°)2 or C2-C6 alkenyl, and c) unsubstituted or substituted C l -C6 alkyl wherein the substitutent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, Rl°0- and -N(RlO) 2 ;
  • R3 and R ⁇ are independently selected from H and CH3; ⁇ .NR 6 R 7
  • R 2 is H; or Ci-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R6, R7 and R7a are independently selected from:
  • R6 i selected from:
  • R8 is independently selected from: a) hydrogen, b) C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perfluoroalkyl, F, Cl, Rl O-, R 10C(O)NR 10-, CN, NO2, (RlO) 2 N-C(NRlO)-, RlOc(O)-, -N(RlO) 2 , or R 1 1 OC(O)NR 10-, and c) C l -C6 alkyl substituted by C l -C6 perfluoroalkyl, R 1 ⁇ -, Rl0C(O)NRl0-, (R10) 2 N-C(NR 10)-, RlOc(O)-, -N(RlO)2, or Rl 10C(0)NR10-;
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, Rl0c(O)NR l0-, CN, N ⁇ 2, (RlO) 2 N-C(NR lO)-, RlOc(O)-, -N(RlO) 2 , or Rl lOC(O)NR l0-, and c) C 1 -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, Rl l S(0) m -, R !0C(O)NR 10-, CN, (RlO) N-C(NRlO)-, R lOC(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl0-;
  • RlO is independently selected from hydrogen, C1-C alkyl, benzyl and aryl;
  • Rl 1 is independently selected from Cl -C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • Gl is absent; G 2 is oxygen;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl;
  • Z is selected from:
  • a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroary Imethy 1, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl -4 alkyl, unsubstituted or substituted with: Cl -4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(0) m R6a, or -C(0)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) N02, h) CF3; i) -S(0)mR 6a , j) -C(0)NR6R7, or k) C3-C6 cycloalkyl; and
  • n 0, 1 or 2;
  • P is 0, 1 , 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is O or 1; t is 0 or 1 ; and u is 4 or 5;
  • Rla is selected from: hydrogen and C1-C6 alkyl
  • Rlb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R1 °)2 or C2-C6 alkenyl, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R OO-, or -N(RlO)2;
  • R3 and R4 independently selected from H and CH3;
  • R 2 is selected from H; O and Ci-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R 2 , R3 and R4 are optionally attached to the same carbon atom;
  • R6 and R7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl and heterocycle, unsubstituted or substituted with: a) Cl -4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R6a is selected from:
  • R& is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Rl O-, R10C(O)NR10-, CN, N ⁇ 2,
  • R9a i hydrogen or methyl
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1 -C6 alkyl and aryl
  • Z is selected from:
  • a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl -4 alkyl, unsubstituted or substituted with: Cl-4 alkoxy, NR6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(0) m R6a, 0 r -C(0)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) N02, h) CF3; i) -S(0) m R6a, j) -C(0)NR6R7, or k) C3-C6 cycloalkyl; and
  • the inhibitors of famesyl-protein transferase are illustrated by the formula E:
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R1°)2 or C2-C6 alkenyl, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 O-, or -N(R 10 )2;
  • R3 and R4 independently selected from H and CH3;
  • R 2 is selected from H; O and C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl,
  • R 2 , R3 and R4 are optionally attached to the same carbon atom;
  • R6 and R7 are independently selected from:
  • R6a is selected from: Cl -4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R ⁇ is independently selected from: a) hydrogen, b) Ci -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -Co perfluoroalkyl, F, Cl, RlOO-, Rl0c(O)NRl0-, CN, NO2, (R lO) 2 N-C(NRlO)-, RlOc(O)-, -N(R lO) 2 , or
  • Rl lOC(O)NRl0- and c) Cl -C ⁇ alkyl substituted by Cl -C ⁇ perfluoroalkyl, R O-, Rl0C(O)NRl0-, (R10) 2 N-C(NR 10)_, RlOc(O)-, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0- ;
  • RlO is independently selected from hydrogen, C1 -C6 alkyl, benzyl and aryl;
  • R! 1 is independently selected from Cl -C6 alkyl and aryl;
  • Z is selected from:
  • a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl-4 alkyl, unsubstituted or substituted with:
  • C3-C6 cycloalkyl is substituted with one or two of the following: a) Cl-4 alkoxy, b) NR°R7, c) C3-6 cycloalkyl, d) -NR6C(0)R7, e) HO, f) -S(0)mR 6a , g) halogen, or h) perfluoroalkyl;
  • the inhibitors of famesyl-protein transferase are illustrated by the formula F:
  • Ri is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(Rl°)2 or C2-C6 alkenyl, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R l°0-, or -N(R 1°)2;
  • R3 and R4 independently selected from H and CH3;
  • R 2 is selected from H; O and C 1 -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1 ) aryl,
  • R 2 , R3 and R 4 are optionally attached to the same carbon atom;
  • R6 and R7 are independently selected from:
  • R6a is selected from: Cl -4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl -4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C alkyl and aryl
  • Z is selected from:
  • a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl -4 alkyl, unsubstituted or substituted with:
  • Examples of the compounds of this invention are as follows: 4-[5-(4-Cyanobenzyl)imidazol-l -ylmethyl]-l -phenyl-2-piperidinone
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • any variable e.g. aryl, heterocycle, Rl , R 2 etc.
  • its definition on each occurence is independent at every other occurence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,
  • heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
  • heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolin
  • the substituted group intended to mean a substituted Cl-8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R 2 and R ⁇ are selected.
  • the substituted Cl-8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
  • substituted aryl includes moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
  • such substitutents are selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl -C6 alkyl)2, N02, CN, (C1 -C6 alkyl)0-, -OH, (C1 -C6 alkyl)S(0) m -, (C1 -C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1 -C6 alkyl)C(O)-, (C 1-C6 alkyl)OC(O)-, N3,( -C6 alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.
  • R 2 and R3 are combined to form - (CH2)u -, cyclic moieties are formed. Examples of such
  • cyclic moieties may optionally include a heteroatom (s).
  • heteroatom-containing cyclic moieties include, but are not limited to:
  • substituents Gl and/or G 2 are "absent," the ring carbons to which Gl and/or G 2 are attached are understood to be substituted with two hydrogen atoms and are considered substitutable ring carbon atoms, and are therefore optionally substituted with a substituent selected from R 2 , R 3 , R4 and R ⁇ .
  • Rla and Ri are independently selected from: hydrogen, -N(Rl°)2, R!0C(O)NR 10- or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(RlO)2, Rl O- and Rl0C(O)NRl0-.
  • R 2 is selected from: H, ⁇ * ⁇ , ⁇ ° H6 ,
  • R3 is selected from: hydrogen and C1 -C6 alkyl.
  • R4 is hydrogen
  • R6, R7 and R7a j s selected from: hydrogen, unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R6a is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R9 is hydrogen or methyl.
  • R a is hydrogen.
  • Rl is selected from H, Cl-C ⁇ alkyl and benzyl.
  • a l and A 2 are independently selected from: a bond, -C(0)NRl _, -NRIOC(O)-, O, -N(R10)-, -S(0)2N(R10). and-
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • Y is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. More preferably, Y is unsubstituted or substituted phenyl.
  • Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl, unsubstituted or substituted thienyl, unsubstituted or substituted C l -C6 alkyl and unsubstituted or substituted C3-C6 cycloalkyl. More preferably, Z is unsubstituted or substituted phenyl.
  • W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
  • Gl is oxygen and G 2 is absent.
  • G 2 is oxygen and Gl is absent.
  • Gl is oxygen and G 2 is absent.
  • n and r are independently 0, 1 , or 2.
  • p is 1 , 2 or 3.
  • s is 0.
  • t is 1.
  • V - A 1 (CR 1 a 2 ) n A 2 (CR 1 a 2 ) n is selected from:
  • any substituent or variable e.g., Rla, R9, n , etc.
  • -N(RlO)2 represents -NH2, -NHCH3, -NHC2H5, etc.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
  • the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-14, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
  • the piperidone nitrogen may be arylated by employing a triaryl bismuth - copper coupling.
  • the resulting diester Va can then be converted to the acid Via and the aldehyde Vila by procedures well known in the art.
  • Scheme 3 illustrates the analogous preparation of the piperidone having an alkyl substitutent on the ring nitrogen.
  • the aldehyde intermediates VII can undergo a Wittig coupling with a protected imidazole to provide compound IX, which can then be catalytically reduced to the intermediate X (Scheme 4).
  • Intermediate X can be deprotected to provide the instant compound XI or it can be further alkylated to eventually provide the instant compound XII.
  • Scheme 4a Synthesis of compounds of the invention that have an alternate connectivity of the piperidinon-4-ylethyl to the preferred imidazolyl moiety is illustrated in Scheme 4a.
  • the Scheme illustrates use of a suitably substituted protected piperidine XIII, which is either commercially avaiable or may be prepared by techniques known in the art, as the precursor to the 2-piperidinone XV.
  • the nitrogen of intermediate XV may then be functionalized and the suitably substituted imidazolyl moiety inco ⁇ orated via nucleophilic displacement.
  • Schemes 4b and 4c illustrate syntheses of suitably substituted homologous 4-hydroxymethyl 2-piperidinones, that may be utilized in the reactions illustrated in Scheme 4a, starting with commercially available materials.
  • Schemes 4d and 4e illustrate alternate syntheses of the homologous piperidinon-4-ylmethyl-l -imidazolyl compounds starting with the previously described intermediate IV.
  • Scheme 5 illustrates the preparation of the instant compound wherein the linker between the piperidone and the heterocyclic substitutent is a carbonyl.
  • the protected imidazolyl Grignard XVI is reacted with the key intermediate VII to provide the secondary alcohol, which can be oxidized and alkylated as illustrated above to provide the instant compound XVII.
  • Scheme 6 illustrates the analogous synthesis of the instant compound XVIII wherein the heterocyclic moity is linked to the piperidone carbon by an acetyl linker.
  • the carboxylic acid VI can be converted to the phosphonium salt XIX which can then be coupled to a variety of aldehydes, such as XX, as shown in Scheme 7.
  • the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69- 75), from the appropriate amino acid.
  • the coupling reaction provides the unsaturated intermediate, which is catalytically reduced to the bisprotected diamine XXI.
  • the product XXI can be deprotected to give the instant compound XXII with trifluoroacetic acid in methylene chloride.
  • the final product XXII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV.
  • Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures. If the phosphonium XIX is coupled with with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 8, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 8, 9).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX.
  • organometallic reagents such as Grignard reagents
  • the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 9), or tertiary amines.
  • the Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperidones such as XXXII (Scheme 10).
  • the phosphonium XVm can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIII.
  • R' is an aryl group
  • catalytic hydrogenation of XXXIII also unmasks the phenol, and the amine group is then deprotected with acid to produce XXXV.
  • XXXV is an O-alkylated phenolic amines.
  • the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
  • Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, scr, abl , lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit famesyl- protein transferase and the famesylation of the oncogene protein Ras.
  • the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF-1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331 - 1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et &LFASEB Journal, 2:A3160 (1988)).
  • the instant compounds may also be useful for the treatment of fungal infections.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried co starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the compounds of the instant invention may also be co- administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney disease, infections of hepatitis delta and related vimses and fungal infections.
  • compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacolo- gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's blood-stream by local bolus injection.
  • composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition.
  • FPTase famesyl-protein transferase
  • the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • Step A l-Phenyl-2-piperidinone-4,4-dicarboxylic acid diethyl ester
  • 2-Piperidinone-4,4-dicarboxylic acid diethyl ester prepared as described in US 4,870,173, is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20°C in dichloromethane (60 mL). The reaction mixture was adsorbed onto silica gel and chromatographed to provide the title compound.
  • Step B l-Phenyl-2-piperidinone-4-carboxylic acid ethyl ester
  • Step C 1 -Pheny l-2-piperidinone-4-carboxylic acid
  • Step D 4-Hvdroxymethyl- 1 -phenyl-2-piperidinone
  • Step E l -Trityl-4-(4-cvanobenzyP-imidazole.
  • Step F 4-[5-(4-Cyanobenzyl)imidazol- 1 -y lmethyl]- 1 -phenyl-2- piperidinone hydrochloride
  • Step A l -fer/-Butoxycarbonyl-4-hydroxyethylpiperidine
  • Step B 4-(2-AcetoxyethyD- 1 -tert-butox vcarbony lpiperidine
  • methylene chloride 50 mL
  • pyridine 5.8 mL, 72.27 mmol
  • acetic anhydride added (3.3 mL, 34.68 mmol).
  • the reaction was stirred overnight at room temperature.
  • Saturated sodium bicarbonate solution was added, and the layers separated.
  • the organic phase was washed with 10% aqueous hydrogen chloride, saturated sodium bicarbonate solution, and saturated brine.
  • the organic phase was dried over magnesium sulfate.
  • the title compound was obtained as an oil.
  • Step C 4-(2- AcetoxyethyP- 1 -tgrt-butoxycarbonylpiperidin-2-one
  • ethyl acetate 5 mL
  • a solution of sodium periodate in water (0.5 g in 5 mL) and ruthenium tetroxide (13 mg, 0.10 mmol) was added, and the heterogeneous reaction stirred vigorously overnight at room temperature.
  • An additional portion of sodium periodate in water was added (0.5 g in 5 mL) and the reaction stirred overnight.
  • the reaction was quenched with 10% sodium thiosulfate, and filtered through celite. The phases were separated, and the organic phase dried over magnesium sulfate. Filtration and evaporation gave the title compound.
  • Step E 4-(2- Acetoxyethyl - 1 -phenylpiperidin-2-one
  • the product from Step D is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20°C in dichloromethane (60 mL).
  • the reaction mixture is adsorbed onto silica gel and chromatographed to provide the title compound.
  • Step F 4-(2-Hydroxyethyl)- 1 -phenylpiperidin-2-one
  • Step E The product from Step E is hydrolyzed according to the procedure described in Example 1 , Step C, giving the title compound.
  • Step G 4-[2- ⁇ 5-(4-Cyanobenzyl)imidazol- 1 -yl ⁇ ethyl]-l - phenylpiperidin-2-one hydrochloride
  • Step F The product from Step F ( 1 eq) and the product from Example 1 , Step E (1 eq) were dissolved in methylene chloride containing diisopropylethylamine , cooled to -78°C under argon and treated with trifluoromethane sulfonic anhydride as described in Example 1 , Step F. After methanolysis, the title compound was isolated by chromatography on silica gel.
  • Step A l-PhenyI-2-piperidinone-4,4-dicarboxylic acid diethyl ester
  • 2-Piperidinone-4,4-dicarboxylic acid diethyl ester prepared as described in US 4,870,173, is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20°C in dichloromethane (60 mL). The reaction mixture is adsorbed onto silica gel and chromatographed to provide the title compound.
  • Step B 1 -Phenyl-2-piperidinone-4.4-dicarhoxylic acid
  • the product from Step A is dissolved in methanol and 5% aqueous sodium hydroxide added.
  • 6 N aqueous hydrochloric acid is added to obtain pH 1, and the solution extracted with ethyl acetate.
  • the organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound.
  • Step C 1 -Phenyl-2-piperidinone-4-carboxylic acid
  • step B The product from step B is dissolved in toluene and refluxed for 6 h. The reaction is cooled and concentrated to provide the title compound.
  • Step D l-Phenyl-2-piperidinone-4-carboxylic acid methyl ester
  • the product from Step C is dissolved in 10 % methanol in toluene, and trimethylsilyldiazomethane added. The reaction is quenched with acetic acid and concentrated. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound.
  • Step E 4-Formyl- 1 -phenyl-2-piperidinone
  • Step D The product from Step D is dissolved in THF and cooled to -78°C under nitrogen. A solution of diisobutylaluminum hydride ( 1 eq.) in toluene is added dropwise. After 30 min, the reaction is quenched with saturated sodium potassium tartrate solution. The mixture is extracted with ethyl acetate, and the organic phase washed with saturated brine, and dried over MgS ⁇ 4. Filtration and concentration provides the title compound
  • Step F 4-Hydroxymethy 1- 1 -tripheny lmethylimidazole
  • Step G 4-Chloromethyl-l-triphenylmethylimidazole
  • Step H 4-Diethylphosphonomethyl- 1 -triphenylmethy limidazole
  • the product from Step G is dissolved in acetonitrile and cooled to 0°C.
  • Triethyl phosphite (1 equivalent) and sodium iodide (1 equivalent) were added, and the reaction stirred at room temperature ovemight.
  • the reaction is quenched with ammonium chloride, and extracted with ethyl acetate.
  • the organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.
  • Step I 4-[2- ⁇ 1 -(Triphenylmethy l)-4-imidazolyl Jethenyl]- 1 -phenyl- 2-piperidinone
  • Step I The product from Step I is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.
  • Step K 4-[2- ⁇ l-(4-Cyanobenzyl)-5-imidazolyl ⁇ ethyl]- 1-pheny 1-2- piperidinone hydrochloride
  • the product from Step J is dissolved in acetonitrile and reacted with 4-cyanobenzylbromide (1 equivalent) at room temperature ovemight.
  • the reaction is concentrated in vacuo, and the residue dissolved in methanol.
  • the methanol solution is refluxed for 3 h and then concentrated.
  • the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution.
  • the organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated.
  • the title compound is obtained after purification by silica gel chromatography, and conversion to the hydrochloride salt.
  • Step A ( ⁇ )cis- and ( ⁇ )tra -3-Methyl-l-phenyl-4-[2- ⁇ 1 - triphenylmethyl)-4-imidazolyl lethyl1-2-piperidinone 4-[2- ⁇ l-(Triphenylmethyl)-4-imidazolyI ⁇ ethyI]-l -phenyl-2- piperidinone in THF is added to a solution of 1 eq lithium hexamethyldisilylazide in THF at -78°C, under argon. The reaction is stirred for 30 min, and 1 eq methyl iodide is added.
  • the reaction is warmed to room temperature, quenched with saturated ammonium sulfate solution, and extracted with ethyl acetate. The organic phase is washed with saturated brine and dried over magnesium sulfate. The crude products are purified by columnm chromatography and provide the title compounds.
  • Step B ( ⁇ )cis- and ( ⁇ )trans-4-[2- ⁇ l -(4-Cyanobenzyl)-5- imidazoly 1 ⁇ ethyl]-3-methyl- 1 -phenyl-2-piperidinone hydrochloride
  • Step A N-Methyl N-methoxy l -phenyl-2-piperidinone-4- carboxamide l-Phenyl-2-piperidinone-4-carboxylic acid is stirred with 1 eq N,0-dimethylhydroxylamine hydrochloride, 1.1 eq EDC • HCl, 1 eq hydroxybenzotriazole in DMF at pH 7 ovemight.
  • the reaction is poured into water and extracted with ethyl acetate.
  • the organic phase is dried over magnesium sulfate, filtered and concentrated, and provides the title compound.
  • Step B 1 -Phenyl-4-[l-tripheny Imethy 1-4-imidazolyl ⁇ carbonyl] -2- piperidinone hydrochloride
  • 1-Tripheny Imethy limidazole-4-magnesium iodide in methylene chloride is prepared as described by R.M. Turner, S.D. Lindell and S.V. Ley in J. Org. Chem., 1991, 56, 5739-5740, and is added to 1 eq of N-methyl N-methoxy 1 -phenyl-2-piperidinone-4- carboxamide in dichloromethane under argon at -78°C.
  • Step C 4-[2- ⁇ 1 -(4-Cyanobenzyl)-5-imidazolyl ⁇ carbonyl]- 1 -pheny 1-
  • the title compound is prepared according to the procedure described in Example 3, Step K, except using the product from Step B in place of 4-[2- ⁇ l-(triphenylmethyl)-4-imidazolyl ⁇ ethyl] -1 -pheny 1-2- piperidinone.
  • the title compound is obtained after purification by silica gel chromatography, and conversion to the hydrochloride salt.
  • the reaction mixture was stirred at room temp, ovemight.
  • the product mixture was concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate.
  • the organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum.
  • the residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound as clear colorless oil, which was stored under argon at -10 °C.
  • Step B Preparation of Ethyl N-tert-butoxycarbonyl-3-oxo-4-(3- methy benzyl)piperidine-4-carboxylate
  • Step D Preparation of Ethyl l-[3-(4-cyanobenzyl)-3H-imidazol-4- ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4- carboxylate trifluoroacetate salt
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM V-(2- hydroxy ethyl) piperazine-/V"-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [ H] -famesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
  • Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ - plate counter.
  • the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • Human FPTase was prepared as described by Omer et al.,
  • the compounds of the instant invention described in the above Examples are tested for inhibitory activity against human FPTase by the assay described above.
  • the compound of the instant invention described in Examples 1 and 6 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of 10 ⁇ M.
  • the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%).
  • the cells After 4 hours at 37 °C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min.
  • 1 ml lysis buffer 1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF
  • the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfamesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.
  • IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x IO 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine semm) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
  • the cells are fed twice weekly with 0.5 ml of medium A containing 0.1 % methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

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US6015817A (en) * 1996-12-05 2000-01-18 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
JP2002511054A (ja) * 1996-12-30 2002-04-09 メルク エンド カンパニー インコーポレーテッド ファルネシル蛋白トランスフェラーゼ阻害薬
AU1612099A (en) * 1997-12-04 1999-06-16 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1999037304A1 (en) * 1998-01-27 1999-07-29 Aventis Pharmaceuticals Products Inc. SUBSTITUTED OXOAZAHETEROCYCLYL FACTOR Xa INHIBITORS
FR2819509B1 (fr) * 2001-01-18 2004-04-16 Servier Lab Nouveaux composes cycloheptene, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2819512B1 (fr) * 2001-01-18 2003-02-21 Servier Lab Nouveaux composes cyclo[d] azepane, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2819510B1 (fr) * 2001-01-18 2003-10-31 Servier Lab Nouveaux composes cyclo[c] azepane, leur procede de preparation et les compositions pharmaceutiques qui le contiennent
FR2819511A1 (fr) * 2001-01-18 2002-07-19 Servier Lab Nouveaux composes azepane, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2003018554A1 (en) * 2001-08-24 2003-03-06 Wyeth Holdings Corporation 3-substituted-3-(substitutedsulfonyl or sulfanyl)pyrrolidine-2,5-diones useful for inhibition of farnesyl-protein transferase
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
GB0611907D0 (en) 2006-06-15 2006-07-26 Glaxo Group Ltd Compounds
JP5486928B2 (ja) 2007-02-26 2014-05-07 ヴァイティー ファーマシューティカルズ，インコーポレイテッド １１β−ヒドロキシステロイドデヒドロゲナーゼ１のサイクリックウレアおよびカルバメートインヒビター
AR069207A1 (es) 2007-11-07 2010-01-06 Vitae Pharmaceuticals Inc Ureas ciclicas como inhibidores de la 11 beta - hidroxi-esteroide deshidrogenasa 1
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JP5860042B2 (ja) 2010-06-16 2016-02-16 ヴァイティー ファーマシューティカルズ，インコーポレイテッド 置換５、６及び７員複素環、そのような化合物を含有する医薬及びそれらの使用
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