EP0891360A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase

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Publication number
EP0891360A1
EP0891360A1 EP97917738A EP97917738A EP0891360A1 EP 0891360 A1 EP0891360 A1 EP 0891360A1 EP 97917738 A EP97917738 A EP 97917738A EP 97917738 A EP97917738 A EP 97917738A EP 0891360 A1 EP0891360 A1 EP 0891360A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
aryl
cycloalkyl
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP97917738A
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German (de)
English (en)
Other versions
EP0891360A4 (fr
Inventor
Christopher J. Dinsmore
Theresa M. Williams
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9609666.4A external-priority patent/GB9609666D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0891360A1 publication Critical patent/EP0891360A1/fr
Publication of EP0891360A4 publication Critical patent/EP0891360A4/fr
Withdrawn legal-status Critical Current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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • A61P31/12—Antivirals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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, K 4a-ras, K ⁇ 4b-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 constitutive ly 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 3/0:583-586 (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.
  • farnesylated 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 farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown stmcture 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: 1133-1139 (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 altemate 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: 1934-1931 (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 piperazine-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 further contained in this invention.
  • 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, R lOO-, R l l S(0) m -, R 10C(O)NR 10-, CN(RlO)2NC(0)-, R 10 2 N-C(NR 10)-, CN, N ⁇ 2, R lOc(O)-, N3, -N(RlO)2, or Rl l ⁇ C(O)NR l0-, c) unsubstituted or substituted C 1 -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, RlOO-, Rl lS(0)m
  • R2 and R ⁇ 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-C 1 -4 alkyl, h) SR6 , S(0)R6a, S ⁇ 2R 6a ,
  • R3 and R5 are selected from H and CH3;
  • R2 and R3 or R4 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 -10 -N ⁇ OR ⁇ O)- ;
  • R6, R7 and R ⁇ a are independently selected from: H; Cl -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, 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 R ⁇ a m ay be joined in a ring;
  • R6a is selected from: C] -4 alkyl, C3-6 cycloalkyl, heterocycle, 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-C 10 cycloalkyl, C2-C6 alkenyl, C2-
  • R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl*>0-, R 1 lS(0)m-, R 10 C(O)NRl0-, (Rl0) 2 NC(O)-, RIO2N- C(NRlO)-, CN, N02, R 10 C(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 -, R!0C(O)NR10-, (Rl ) 2 NC(O)-, Rl ⁇ 2N-C(NRlO)-, CN, RlOC(O)-, N3, -N(Rl )2, or Rl l ⁇ C(O)NRl0- ;
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 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-C20 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:
  • a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) C l -4 alkyl, unsubstituted or substituted with:
  • R la is independently selected from: hydrogen or C1 -C6 alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(R lO) or C2-C6 alkenyl, c) unsubstituted or substituted Ci -C ⁇ alkyl wherein the substitutent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R lOO- and -N(RlO) 2;
  • R3 and R ⁇ are independently selected from H and CH3;
  • R2 and R ⁇ are independently selected from H; O or Cl -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R°, R7 and R ⁇ are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl -4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R6a i selected from: Cl-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, NO2,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, RlOO-, RllS(0) m -, R!0C(O)NR10-, CN, NO2,
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from Cl-C ⁇ 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 A l is a bond, n is 0 and A 2 is S(0)
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
  • Y is a bond or -CH2-
  • Z is selected from:
  • a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, 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, NR 6 R 7 , C3-6 cycloalkyl, aryl, heterocycle, HO, -S(0) m R 6a , or -C(0)NR6R7, b) aryl or heterocycle, c) halogen, d) OR6, e) NR6R7, f) CN, g) N ⁇ 2, h) CF3; i) -S(0) m R 6a , j) -C(0)NR6R7, or k) C3-C6 cycloalkyl; or 2) unsubstituted C1-C6 alkyl, substitute
  • Rla is selected from: hydrogen or C1-C6 alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(Rl°)2 or C2-C6 alkenyl, c) C1-C alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
  • R3 and R ⁇ are independently selected from H and CH3;
  • R2 and R4 are independently selected from H; O or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R6 and R 7 are independently selected from: a) hydrogen, b) Cl -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N02, (R10) 2 N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, -N(RlO)2, or R1IOC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-,
  • R ⁇ i selected from: Cl-4 alkyl or C3-6 cycloalkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle;
  • R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N02, (R!0)2N-C(NR10)-, RlOC(O)-, -N(RlO)2, or
  • R11OC(O)NR10- and c) C1-C6 alkyl substituted by Cl-C ⁇ perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOC(O)-, -N(RlO)2, O ⁇ RHOC(O)NR10-;
  • R ⁇ is 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
  • 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) Cl -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 A ⁇ is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2
  • Z is selected from: 1 ) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, 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 6a , or -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; or 2) unsubstituted C1
  • the inhibitors of famesyl-protein transferase are illustrated by the formula C:
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(Rl°)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RI ⁇ O-, or -N(R 0)2;
  • R3 and R ⁇ are independently selected from H and CH3;
  • R and R4 are independently selected from H; O or Ci-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R6 and R 7 are independently selected from: a) hydrogen, b) C l -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N02,
  • R8 is independently selected from: a) hydrogen, b) Cl -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, NO2, (RlO)2N-C(NR O)-, Rl°C(0)-, -N(RlO)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by Cj-C ⁇ perfluoroalkyl, Rl°0-, R!0C(O)NR1°-, (RlO)2N-C(NRlO)-, RlOC(O)-,
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from Cl -C alkyl and aryl
  • Z is selected from:
  • a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, 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, R6R7, C3-6 cycloalkyl, aryl, heterocycle, HO, -S(0) m R 6a , or -C(0)NR6R7 5
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 ⁇ -, -N(R 1 °)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(Rl )2;
  • R2 and R ⁇ are independently selected from: hydrogen or Cl-C6 alkyl
  • R3 and R ⁇ are hydrogen
  • R6 and R 7 are independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C ⁇ perfluoroalkyl, F, Cl, Rl O-, R!0C(O)NR10-, CN, N ⁇ 2, (R10) 2 N-C(NR10)-, RlOc(O)-, Rl ⁇ C(O)-, -N(Rl )2, or Rll ⁇ C(O)NRl0-,and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10 , RlOc(O)-,
  • R 10 ⁇ C(O)-, -N(R 10)2, or R 11 OC(0)NR 1 . ;
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl;
  • 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, R l , R2 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.
  • 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 1 1- 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 stmcture.
  • 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 -8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R and R3 are selected.
  • R° As used herein in the definition of R°, R oa , R7 an d R7a ? 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.
  • such substitutents are selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl -C6 alkyl)2, N ⁇ 2, 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)-, (C1 -C6 alkyl)OC(O)-, N3,(Cl -C6 alkyl)OC(0)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1 -C2O alkyl.
  • R2 and R3 are combined to form - (CH2)u -» cyclic moieties are formed
  • cyclic moieties may optionally include a heteroatom(s).
  • heteroatom-containing cyclic moieties include, but are not limited to:
  • Rla and R ib are independently selected from: hydrogen, -N(R 10 )2, R l0C(O)NR l0- 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, R I ⁇ - and Rl°C(O)NRl0-.
  • R is selected from: H, ⁇ 1R 6 R 7 _ ⁇ -OR 6
  • R3 is selected from: hydrogen and Cl -C6 alkyl.
  • R4 and R ⁇ are hydrogen.
  • R6, R7 and R 7a is selected from: hydrogen, unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R6a i unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R°- is hydrogen or methyl.
  • R a is hydrogen.
  • R IO is selected from H, C1 -C6 alkyl and benzyl.
  • Al and A2 are independently selected from: a bond, -C(0)NR lO-, -NR IOC(O)-, O, -N(R 10)-, -S(0)2N(R 10). and-
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • Y is a bond or -CH2-. More preferably, Y is -CH2-.
  • Z 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, Z is unsubstituted or substituted phenyl.
  • W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrohdinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
  • n and r are independently 0, 1 , or 2.
  • p is 1 , 2 or 3.
  • s is 0.
  • t is 1.
  • -N(R lO)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that 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 - 15, 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.
  • Substituent R as shown in the Schemes, represents the substituents R2, R3, R4 ⁇ d R5; however the point of attachment to the ring is illustrative only and is not meant to be limiting.
  • Schemes 1 -15 The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part.
  • Scheme 1 for example, the synthesis of 3-substituted-2- piperidone is outlined.
  • a suitably substituted 2-hydroxynicotinic acid I may be catalytically hydrogenated to provide the 2-piperidone II.
  • This intermediate may be coupled to a suitably substituted aryl moiety to provide the key intermediate III.
  • the ester of compound III can be saponified and the acid can be reacted with an amine such as IV to provide the instant compound V.
  • intermediate III can be deprotonated and reacted with an electrophile, such as VI, to provide the instant compound VII.
  • Compound VII can also be decarboxylated to provide the instant compound VIII.
  • Similar coupling to an aryl moiety, deprotonation and alkylation can be performed on a pyrrolidinone, as shown in Scheme 3, to provide the instant compound IX.
  • Scheme 3a illustrates an alternative synthesis of the pyrrolidinone compounds of the instant invention.
  • a suitably substituted 4-halobutanoyl chloride may be cyclized with an amine in a two step procedure and then selectively functionalized adjacent to the carbonyl to provide the instant compound having a preferred arylmethylimidazolyl moiety.
  • Scheme 3c illustrates preparation of the instant compounds wherein Y is S.
  • the suitably substituted thiomo ⁇ holinone may be selectively alkylated with reagents illustrated in Scheme 3 and hereinbelow and may also be oxidized subsequent to the alkylation as shown in the scheme.
  • Preparation of a thiomo ⁇ holinone intermediate having a substituent in the 5-position is illustrated in Scheme 3d.
  • Scheme 4 illustrates preparation of the instant copounds wherein the linker X is an amine.
  • the amine intermediate X may be alkylated with a suitably substituted electrophile.
  • the amine intermediate X can be reductively alkylated with a variety of aldehydes, such as XI.
  • 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 (Scheme 3).
  • the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroe thane, methanol or dimethylformamide.
  • the product XII can be deprotected to give the final compounds XIII with trifluoroacetic acid in methylene chloride.
  • the final product XIII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine XIII can further be selectively protected to obtain XIV, which can subsequently be reductively alkylated with a second aldehyde to obtain XV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XVI can be accomplished by literature procedures.
  • the piperidone intermediate X can be reductively alkylated with other aldehydes such as l -trityl-4-imidazolyl- carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products such as XVII (Scheme 6).
  • the trityl protecting group can be removed from XVII to give XVIII, or alternatively, XVII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XIX.
  • the intermediate X can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XX can be converted to the acetate XXI by standard procedures, as shown in Scheme 7, and XXI can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XXII.
  • Hydrolysis and reaction with intermediate X in the presence of condensing reagents such as l -(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
  • Scheme 7a illustrates the preparation of a suitably substituted benzylimidazolyl aldehyde intermediate whch may be reacted with the piperazinone and thiomo ⁇ holinone intermediates whose syntheses is described in Schemes 3b-3d (Scheme 7a and 7b).
  • 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.
  • 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-aziridinylmethylpiperazines such as XXXII (Scheme 10). Treating XXVII with l ,l '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIII.
  • a nucleophile such as a thiol
  • intermediate X can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIX, as shown in Scheme 1 1.
  • R' is an aryl group
  • XXXIX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XL. Altematively, the amine protecting group in XXXIX can be removed, and O-alkylated phenolic amines such as XLI produced.
  • 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 alFASEB 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 co starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried com 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 viruses 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 fa esyl 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 4-Cvanobenzyl-N ⁇ .-phthaloylhistamine
  • N ⁇ -Pivaloyloxymethyl-N ⁇ -phthaloylhistamine (4.55 g, 12.8 mmol) was prepared as previously described (J. C. Emmett, F. H. Holloway, and J. L. Turner, J. Chem. Soc, Perkin Trans. 1 , 1341 , (1979)).
  • ⁇ -Bromo-p-tolunitrile (3.77 g, 1 .2 mmol) was dissolved in acetonitrile (70 mL). The solution was heated at 55°C for 4 h, cooled to room temperature, and filtered to remove the white solid. The acetonitrile (30 mL) was concentrated to 1/2 its volume under reduced pressure and the solution was heated at 55°C overnight.
  • Step B 4-Cvanobenzyl histamine 4-Cyanobenzyl-N ⁇ -phthaloylhistamine (1.64 g, 4.61 mmol), and hydrazine (1.46 mL, 46.1 mmol) were dissolved in absolute ethanol (70 mL). The solution was concentrated after 1 hr and filtered to remove a white precipitate which was washed several times with ethanol. The filtrate was concentrated and the residue was chromatographed (silica gel, 10:90: 1 MeOH/CH2Cl2/NH4 ⁇ H) to give the title compound.
  • Step C 3-Carbethoxy- 1 -phenyl-2-piperidinone
  • Step D 3-Carboxy- 1 -pheny 1-2-piperidinone
  • Step E N-[2- ⁇ l -(4-Cyanobenzyl)-5-imidazolyl ⁇ ethyl]-3- carbamoyl- 1 -phenyl-2-piperidinone hydrochloride
  • Step D 4-(3-Hydroxy- 1 -propyl)-3-( 1 -triphenylmethyl-4- imidazolvDpropionate
  • Step E 1 -Pheny 1-2-piperdinone
  • Step F 3-[3- ⁇ l -triphenylmethyl-4-imidazolyl ⁇ - l -propyl]- l -phenyl- 2-piperidinone hydrochloride
  • a solution of 1 -phenyl-2-piperidinone from Step F in THF is added to a solution of one equivalent of LDA in THF at -78°C, and stirred for 30 min.
  • a solution of 4-(3-hydroxy-l-propyl)-3-( l - triphenylmethyl-4-imidazolyl)propionate in methylene chloride is cooled to -78°C under nitrogen.
  • One equivalent of ⁇ -butyl lithium followed by one equivalent of triflic anhydride is added, the reaction stirred for 10 min, then added to the LDA/l -phenyl-2-piperidinone solution.
  • the reaction is warmed to room temperature, and quenched with saturated ammonium chloride.
  • the reaction is then partitioned between ethyl acetate and saturated brine.
  • the organic phase is dried over magnesium sulfate, filtered and concentrated.
  • the title compound is isolated by chromatography on silica gel.
  • Step G 3-[3- ⁇ l-(4-Cyanobenzyl)-5-imidazolyl ⁇ -l-propyl]-l- phenyl-2-piperidinone hydrochloride
  • the product from Step F is dissolved in acetonitrile and one equivalent of 4-cyanobenzylbromide added.
  • the reaction is stirred at room temperature overnight, concentrated, and taken up in methanol.
  • the methanol solution is refluxed for 3 h, concentrated, and partitioned between ethyl acetate and saturated sodium bicarbonate solution.
  • the organic phase is washed with saturated brine and dried over magnesium sulfate.
  • the title compound is obtained after chromatography on silica gel, and conversion to the dihydrochloride salt.
  • Step A 1 -Phenyl-2-pyrrolidinone
  • the title compound is prepared according to the procedure described in Example 2, Step E, except using 2-pyrrolidinone in place of valerolactam.
  • the cmde product is purified by column chromatography.
  • Step B 3-[3- ⁇ l -triphenylmethyl-4-imidazolyl ⁇ -l -propyl]-l -phenyl- 2-pyrrolidinone
  • the title compound is prepared according to the procedure described in Example 2, Step F, except using 1 -phenyl-2-pyrrolidinone in place of 1 -phenyl-2-piperdinone.
  • the title compound is isolated by chromatography on silica gel.
  • Step C 3-[3- ⁇ l -(4-Cyanobenzyl)-5-imidazolyl ⁇ - l-propyl]- l - phenyl-2-pyrrolidinone hydrochloride
  • the title compound is prepared according to the procedure described in Example 2, Step G except using 3-[3- ⁇ l-triphenylmethyl-4- imidazolyl ⁇ -l -propyl]-l -phenyl-2-pyrrolidinone in place of 3-[3- ⁇ 1- triphenylmethyl-4-imidazolyl ⁇ -l -propyl]-l -phenyl-2-piperidinone.
  • the title compound is obtained after chromatography on silica gel, and conversion to the hydrochloride salt.
  • Step A 4-Carbomethoxy- 1 -pheny 1-2-pyrrolidinone
  • Step B 4-Hydroxymethy 1- 1 -phenyl-2-pyrrolidinone
  • Step C 4-Methoxymethyl- 1 -phenyl-2-pyrrolidinone
  • Step D ( ⁇ )cis- and ( ⁇ )/r ⁇ /2s-4-Methoxymethyl-l-phenyl-3-[3- ⁇ 1 -t riphenylmethyl-4-imidazolyl ⁇ - 1 -propyl]-2- pyrrolidinone
  • the title compound is prepared according to the procedure described in Example 2, Step F, except using 4-methoxymethyl-l - phenyl-2-pyrroIidinone in place of l-phenyl-2-piperdinone.
  • the title compounds are isolated by chromatography on silica gel.
  • Step E ( ⁇ )cis- and ( ⁇ )trans-3-[3- ⁇ 1 -(4-Cyanobenzyl)-5- imidazolyl ⁇ - 1 -propyl ]-4-methoxymethy 1- 1 -pheny 1-2- pyrrolidinone hydrochloride
  • the title compound is prepared according to the procedure described in Example 2, Step G except using cis -and trans-4- methoxymethyl- 1 -pheny l-3-[3- ⁇ 1 -triphenylmethyl-4-imidazolyl ⁇ - 1 - propyl]-2-pyrrolidinone_in place of 3-f3- ⁇ l -triphenylmethyl-4- imidazolyl ⁇ -l -propyl]- 1 -pheny 1-2-piperidinone.
  • the title compounds are separated by preparative HPLC and converted to their hydrochloride salts.
  • Step B 1 -Phenyl-2-pyrrolidinone
  • THF 157 mL
  • sodium hydride 50% dispersion in oil
  • the reaction was stirred at room temperature overnight.
  • An additional portion of sodium hydride was added (1 g) and the reaction continued to stir for 3 h.
  • the reaction was diluted with ethyl acetate and poured into 10% aqueous hydrogen chloride.
  • the organic phase was washed with saturated brine, and dried over sodium sulfate. Concentration in vacuo afforded the title compound.
  • Step C 3-(f-ButylcarboxymethyD- 1 -phenyl-2-pyrrolidinone
  • Step D 3-(2-CarboxymethyP- 1 -pheny 1-2-pyrrolidinone
  • Step E 3-(2-HvdroxyethvD- 1 -phenyl-2-pyrrolidinone
  • Step G 3-[2- ⁇ 5-(4-Cyanobenzyl)- 1 -imidazolyl ⁇ - 1 -ethyl]- 1 -phenyl-
  • Step B 1 -Benzy l-3-[2- ⁇ 5-(4-cyanobenzy 1)- 1 -imidazolyl ⁇ - 1 -ethy 1] - 2-pyrrolidinone hydrochloride
  • Step A Preparation of l -triphenylmethyl-4-(hydroxymethyl)- imidazole
  • Step B Preparation of l -triphenylmethyl-4-(acetoxymethyl)- imidazole
  • Step C Preparation of l-(4-cyanobenzyl)-5-(acetoxymethyl)- imidazole hydrobromide
  • the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 °C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60 °C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
  • Step D Preparation of l-(4-cyanobenzyl)-5-(hydroxymethyl)- imidazole
  • Step E Preparation of l-(4-cyanobenzyl)-5-imidazole- carboxaldehyde
  • Step F Preparation of N-(3-chlorophenyl)ethylenediamine hydrochloride To a solution of 3-chloroaniline (30.0 mL, 284 mmol) in 500 mL of dichloromethane at 0 °C was added dropwise a solution of 4 N HCI in 1 ,4-dioxane (80 mL, 320 mmol HCI). The solution was warmed to room temperature, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2- oxazolidinone (24.6 g, 282 mmol) was heated under nitrogen atmosphere at 160 °C for 10 hours, during which the solids melted, and gas evolution was observed.
  • Step G Preparation of /V-( / ⁇ -butoxycarbonyl)-/V'-(3- chlorophenyDethylenediamine
  • the amine hydrochloride from Step F (ca. 282 mmol, cmde material prepared above) was taken up in 500 mL of THF and 500 mL of sat. aq. NaHC ⁇ 3 soln., cooled to 0 °C, and ⁇ i-tert- butylpyrocarbonate (61.6 g, 282 mmol) was added. After 30 h, the reaction was poured into EtOAc, washed with water and brine, dried (Na2S ⁇ 4), filtered, and concentrated in vacuo to provide the titled carbamate as a brown oil which was used in the next step without further purification.
  • Step H Preparation of ⁇ H2-(f -butoxycarbamoyl)ethyl]-/V-(3- chloropheny 1 )-2-chloroacetami de
  • Step I Preparation of 4-(/crt-butoxycarbonyl)- 1 -(3- chlorophenvl)-2-piperazinone
  • Step J Preparation of ( ⁇ )-4-(r -butoxy carbonyl)- 1 -(3- chloropheny)-3-[ 1 -(1 -(4-cyanobenzyl)-5-imidazolyl)- 1 -
  • the solution was dried (Na2S04), filtered, and concentrated in vacuo to provide the cmde product.
  • the product was purified by flash chromatography on silica gel (3-6% MeOH/CH2C12) to provide 60 mg of the titled product as a 9: 1 mixture of diastereomers.
  • Step K Preparation of ( ⁇ )- l -(3-chloropheny)-3-[ l -(l -(4- cyanobenzy l)-5-imidazolyl)- 1 -(hydroxy )methyl]-2- piperazinone hydrochloride
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-/V'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl 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.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 ⁇ M Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • 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 mCif35s]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 farnesylated 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 10 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 se m) 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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Abstract

La présente invention concerne des composés qui inhibent la farnésyl-protéine transérase (FTase) et farnésylation de la protéine oncogène Ras. L'invention concerne, en outre, des compositions chimiothérapeutiques contenant les composés de cette invention et des méthodes pour inhiber la farnésyl-protéine transférase et la farnésylation de la protéine oncogène Ras.
EP97917738A 1996-04-03 1997-03-27 Inhibiteurs de la farnesyl-proteine transferase Withdrawn EP0891360A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1479896P 1996-04-03 1996-04-03
US14798P 1996-04-03
GBGB9609666.4A GB9609666D0 (en) 1996-05-09 1996-05-09 Inhibitors of farnesyl-protein transferase
GB9609666 1996-05-09
PCT/US1997/005235 WO1997036900A1 (fr) 1996-04-03 1997-03-27 Inhibiteurs de la farnesyl-proteine transferase

Publications (2)

Publication Number Publication Date
EP0891360A1 true EP0891360A1 (fr) 1999-01-20
EP0891360A4 EP0891360A4 (fr) 2002-05-15

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EP97917738A Withdrawn EP0891360A4 (fr) 1996-04-03 1997-03-27 Inhibiteurs de la farnesyl-proteine transferase

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EP (1) EP0891360A4 (fr)
JP (1) JP2000507585A (fr)
AU (1) AU715603B2 (fr)
CA (1) CA2250353A1 (fr)
WO (1) WO1997036900A1 (fr)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972966A (en) * 1996-12-05 1999-10-26 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
CA2311921A1 (fr) * 1997-12-04 1999-06-10 Merck & Co., Inc. Inhibiteurs de la transferase de la farnesyl-proteine
US6436960B1 (en) * 1998-02-02 2002-08-20 Lg Chemical Ltd. Farnesyl transferase inhibitors having a piperidine structure and process for preparation thereof
KR100388790B1 (ko) * 1998-03-06 2003-10-04 주식회사 엘지생명과학 파네실전이효소저해제로서유용한피리딘-2-온유도체
HRP990246A2 (en) 1998-08-07 2000-06-30 Du Pont Pharm Co Succinoylamino benzodiazepines as inhibitors of a beta protein production
NZ509241A (en) 1998-08-07 2003-08-29 Du Pont Pharm Co Succinoylamino lactams as inhibitors of alpha-beta protein production
IL142816A0 (en) 1998-12-24 2002-03-10 Du Pont Pharm Co SUCCINOYLAMINO BENZODIAZEPINES AS INHIBITORS OF Aβ PROTEIN PRODUCTION
CA2361848A1 (fr) * 1999-04-02 2000-10-12 Dupont Pharmaceuticals Company Nouveaux inhibiteurs de lactame de metalloproteases matricielles, de tnf-alpha, et de l'aggrecanase
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
EP1218377A1 (fr) 1999-10-08 2002-07-03 Bristol-Myers Squibb Pharma Company AMINO SULFONAMIDES DE LACTAME UTILISES COMME INHIBITEURS DE LA PRODUCTION DE PROTEINE A$g(b)
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
US6495540B2 (en) 2000-03-28 2002-12-17 Bristol - Myers Squibb Pharma Company Lactams as inhibitors of A-β protein production
BR0107532A (pt) 2000-04-03 2004-11-03 Bristol Myers Squibb Pharma Co Composto, uso do composto, método para o tratamento de disfunções neurológicas associadas com a produção de b-amilóide, método de inibição da atividade de y-secretase e composição farmacêutica
CA2403550A1 (fr) 2000-04-03 2001-10-11 Hong Liu Lactames cycliques utiles en tant qu'inhibiteurs de la production de proteine a-beta
US6632812B2 (en) 2000-04-11 2003-10-14 Dupont Pharmaceuticals Company Substituted lactams as inhibitors of Aβ protein production
BR0106717A (pt) 2000-06-01 2002-04-16 Bristol Myers Squibb Pharma Co Compostos, composição farmacêutica e usos dos compostos de lactama inovadora
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
TW200307667A (en) 2002-05-06 2003-12-16 Bristol Myers Squibb Co Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
WO2004101523A1 (fr) * 2003-05-17 2004-11-25 Korea Research Institute Of Bioscience And Biotechnology Nouveaux composes 2-oxo-heterocycliques et compositions pharmaceutiques contenant ces composes
ATE531693T1 (de) * 2003-05-17 2011-11-15 Korea Res Inst Of Bioscience Neue heterozyklische 2-oxo-verbindungen und pharmazeutische zusammensetzungen, die diese enthalten
JP4799408B2 (ja) * 2003-07-15 2011-10-26 コリア リサーチ インスティテュート オブ バイオサイエンス アンド バイオテクノロジー 新規な２−オキソ複素環化合物およびそれを含有する薬剤組成物の使用
US20070123508A1 (en) * 2005-05-27 2007-05-31 Roger Olsson PAR2-modulating compounds and their use
AU2010256360A1 (en) 2009-06-05 2012-01-12 Astrazeneca Ab Aminopyrrolidinone derivatives and uses thereof
WO2015130958A1 (fr) * 2014-02-26 2015-09-03 Howard University Utilisation de dérivés de 5-oxopyrrolidine comme inhibiteurs de l'intégrase du vih

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0236940A2 (fr) * 1986-03-07 1987-09-16 Ciba-Geigy Ag Tolunitriles substitués en position 1 par des hétérocycles
WO1993012108A1 (fr) * 1991-12-18 1993-06-24 Schering Corporation Imidazolyle ou imidazoylalkyle substitue par un azote a quatre ou cinq membres contenant un compose heterocyclique
WO1993012107A1 (fr) * 1991-12-18 1993-06-24 Schering Corporation Imidazoylalkyle substitue par un cycle heterocyclique contenant de l'azote a six elements

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL69407A (en) * 1982-08-23 1987-10-20 Warner Lambert Co 2(1h)-pyridinones,their preparation and pharmaceutical compositions containing them
DE3336024A1 (de) * 1983-10-04 1985-04-18 Boehringer Ingelheim KG, 6507 Ingelheim 4-amino-l-benzyl-pyrrolidinone und ihre saeureadditionssalze, verfahren zu ihrer herstellung und arzneimittel
DE3433953A1 (de) * 1984-09-15 1986-03-27 A. Nattermann & Cie GmbH, 5000 Köln Neue, eine imidazol-gruppe enthaltende 3,4-dihydro-2(1h)-pyridone und2(1h)-pyridone, verfahren zu ihrer herstellung und diese enthaltende arzneimittel
US5015653A (en) * 1989-07-10 1991-05-14 Hoffmann-La Roche Inc. [(5-oxo)-2-pyrrolidinyl)methyl]cyclohexaneacetamides, compositions and use
US5264449A (en) * 1989-11-13 1993-11-23 Allergan, Inc. N-substituted derivatives of 3R,4R-ethyl-[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidinone
US5055467A (en) * 1989-11-13 1991-10-08 Allergan, Inc. Pharmaceutical epinephrine-pilocarpine compounds
TW218017B (fr) * 1992-04-28 1993-12-21 Takeda Pharm Industry Co Ltd

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0236940A2 (fr) * 1986-03-07 1987-09-16 Ciba-Geigy Ag Tolunitriles substitués en position 1 par des hétérocycles
WO1993012108A1 (fr) * 1991-12-18 1993-06-24 Schering Corporation Imidazolyle ou imidazoylalkyle substitue par un azote a quatre ou cinq membres contenant un compose heterocyclique
WO1993012107A1 (fr) * 1991-12-18 1993-06-24 Schering Corporation Imidazoylalkyle substitue par un cycle heterocyclique contenant de l'azote a six elements

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9736900A1 *

Also Published As

Publication number Publication date
EP0891360A4 (fr) 2002-05-15
AU715603B2 (en) 2000-02-03
CA2250353A1 (fr) 1997-10-09
WO1997036900A1 (fr) 1997-10-09
JP2000507585A (ja) 2000-06-20
AU2598897A (en) 1997-10-22

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