EP1019391A1 - Inhibiteurs de la prenyl-proteine transferase - Google Patents

Inhibiteurs de la prenyl-proteine transferase

Info

Publication number
EP1019391A1
EP1019391A1 EP98952003A EP98952003A EP1019391A1 EP 1019391 A1 EP1019391 A1 EP 1019391A1 EP 98952003 A EP98952003 A EP 98952003A EP 98952003 A EP98952003 A EP 98952003A EP 1019391 A1 EP1019391 A1 EP 1019391A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
rlo
unsubstituted
nrl0
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.)
Withdrawn
Application number
EP98952003A
Other languages
German (de)
English (en)
Inventor
S. Jane Desolms
Anthony W. Shaw
William C. Lumma, Jr.
John T. Sisko
Thomas J. Tucker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9807948.6A external-priority patent/GB9807948D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1019391A1 publication Critical patent/EP1019391A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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-r ⁇ s, Ki4a-ras, 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-Aaal-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 farnesyl-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 farnesyla- tion.
  • Other 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 structure and function in addition to those listed above.
  • Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl 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, 87:1541-1545 (1990)).
  • FPTase farnesyl-protein transferase
  • FPP farnesyl diphosphate
  • Ras protein substrates
  • Bisubstrate inhibitors and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described.
  • 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 farnesyl-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.
  • farnesyl-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 H7-112930).
  • an object of this invention to develop low molecular weight compounds that will inhibit a prenyl-protein transferase and thus, the post-translational prenylation 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 bicyclic compounds which inhibit a prenyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these prenyl transferase inhibitors and methods for their production.
  • the compounds of this invention are useful in the inhibition of prenyl-protein transferases and the prenylation of the oncogene protein Ras.
  • the inhibitors of prenyl-protein transferase are illustrated by the formula A:
  • Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from
  • Rl and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, RlOO-, RUS(0) m -, R 10 C(O)NRl0-, Rl lC(0)0-, (R10) 2 NC(OK R 10 2N-C(NRlO)-, CN, N02, R!0C(O)-, N3, -N(RlO)2, or RHOC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
  • R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R 6a , R6b ? R6C ? R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R 1 1 S(0) m NR 10 -, N3, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, RHS(0)m-, R ⁇ C ⁇ NRiO-, (RlO) 2 NC(0)-,
  • R7 is 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,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -,
  • R9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br,
  • RH ⁇ C(O)NRl0- and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -, R 10 C(O)NRl0-,
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • RU is independently selected from C1-C6 alkyl and aryl
  • Rl2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • Rl3 is selected from hydrogen, C1-C6 alkyl, cyano, C1-C6 alkylsulfonyl and C1-C6 acyl;
  • A3 is selected from: -CH2-, -CH 2 CH 2 -, -C ⁇ C-, O, -N(R10)-, S(0) m , -C(O)NR!0-, -NRIOC(O)-, - CH2C(0)NRlO-, - CH2NRlOC(0)- , -C(0)NRlOCH2-, -NRl0C(O)CH2-, -CH2O-, -CH2N(RlO)-, -CH2S(0) m -, -OCH2-, -N(RlO)CH2- and -S(0) m CH2-;
  • 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 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
  • inhibitors of prenyl-protein transferase are illustrated by the formula A:
  • Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to
  • Rl and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RHS(0) m -, R10C(O)NR10-, RHC(0)0-, (RlO)2NC(0)-, R10 N-C(NR10)-, CN, N ⁇ 2, R10C(O)-, N3, -N(RlO)2, or RH ⁇ C(O)NRl0-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent 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-, R 10 C(O)NRl0-,
  • R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R10 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO)2, and R ⁇ OC(O)-NRl0-;
  • R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C alkenyl,
  • R7 is 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,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Ri lS(0) m -, Rl0C(O)NRl0-, (RlO) 2 NC(0)-, (Rl0) 2 NS(O)2-, R ⁇ S(O) m NRl0-, Rl0 2 N-C(NRlO)-, CN, N ⁇ 2, R 10 C(O)-, N3, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) Cl-C alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C
  • R9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIOO-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, Rl ⁇ 2N-C(NRlO)-, CN, N ⁇ 2, R 10 C(O)-, N3, -N(RlO) 2 , or
  • RlO is independently selected from hydrogen, C1-C alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Ri 1 is independently selected from C1-C6 alkyl and aryl
  • Ri 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
  • Rl3 is selected from hydrogen, Cl-C6 alkyl, cyano, C1-C alkylsulfonyl and C1-C6 acyl;
  • A3 is selected from: -CH2-, O, -N(R10)-, S(0) m , -C(O)NRl0-, -NRiOC(O)-, - CH2C(0)NRlO-, - CH2NRlOC(0)- , -C(O)NRl0cH2-, -NRlOC(0)CH2-, -CH2O-, -CH2N(RlO)-, CH2S(0) m -, -OCH2-, -N(RlO)CH2- and -S(0) m CH2-;
  • 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)m;
  • W is a heterocycle
  • Y is selected from: phenyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, piperazinyl and tetrahydrothienyl;
  • Rl is independently selected from: hydrogen, C3-C10 cycloalkyl, RlOO-, -N(RlO)2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R ⁇ O-, -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO- and -N(RlO) 2;
  • R3, R4 and R ⁇ are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-,
  • R 6a , R6b ? R6C ? R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0) m -, R10C(O)NR10-, (R10) 2 NC(O)-, (Rl0)2NS(O)2-, Rl lS(O) m NRl0-, R10 2 N-C(NR10)-, CN, N02, Rl°C(0)-, N3, -N(RlO)2, or RH ⁇ C(O)NRl0-, c) unsubstituted C 1 -C6 alkyl ; d) substituted C1-C6 alkyl
  • R7 is 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,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, (RlO) 2 NC(0)-, CN, N02, (R1°)2N-C(NR10)-, R10C(O)-, (Rl0)2NS(O)2-, Rl lS(O) m NRl0-, -N(RlO) , or
  • Rl l ⁇ C(O)NRl0- and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (RlO) 2 N-C(NRlO)-, RlOC(O)-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
  • Rl lOC(O)NRl0- and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-,
  • R O is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
  • A3 is selected from: -CH2-, O, -N(R10)-, S(0) m , -C(O)NRl0-, -NRlOC(O)-, -CH2C(0)NRlO-, -CH2NRlOC(0)-, -C(0)NRlOCH2-, -NRl0C(O)CH2-, -CH20-, -CH2N(RlO)-, -CH2S(0) m -, -OCH2-, -N(RlO)CH2- and -S(0) m CH2-;
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0) and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(0)m * >
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
  • Y is selected from: phenyl, cyclohexyl and pyridyl;
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl, Rl°0-, -N(RlO)2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(RlO)2,
  • C2-C6 alkenyl c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO- and -N(RlO)2;
  • R3 and R4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C 2 -C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-,
  • R 6a , R b ? R6C 5 R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, (RlO) 2 NC(0)-, (Rl0)2NS(O)2-, R 1 lS(O) m NRl0-, CN,
  • Rl lOC(O)NRl0- and c) C 1 -C6 alkyl substituted by C l -C6 perfluoroalkyl, R 1 0 O-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, (Rl0)2NS(O)2-, Rl lS(O) m NRl0-, Rl0c(O)-, -N(RlO) 2 , or
  • R9 and R9b are independently hydrogen, C1-C alkyl, trifluoromethyl and halogen;
  • RIO is independently selected from hydrogen, C1-C alkyl, benzyl, 2,2,2-trif uoroethyl and aryl;
  • RU is independently selected from C1-C6 alkyl and aryl
  • R 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • A3 is selected from: -CH2-, O, -N(R10)-, - C(O)NRl0-, -C(0)NRlOCH2-, -CH2C(O)NRl0-, -CH2O-, -OCH2- or S(0) m ;
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with 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 Al is a bond, n is 0 and A 2 is S(0)m;
  • Y is selected from: phenyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thiazolyl, isothiazolyl, tetrahydrofuryl, piperdinyl, thiazolidinyl, piperazinyl and tetrahydrothiophenyl;
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl, Rl°0-, -N(R1°)2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(RlO)2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO- and -N(RlO) 2 ;
  • R3 and R4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C perfluoroalkyl, R12O, Rl lS(0)
  • R10 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO)2, and R11OC(O)-NR10- ;
  • R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, (RlO)2NC(0 , RHS(O)2NR10-, (Rl0) 2 NS(O)2-, CN, N ⁇ 2, (RlO)2N-C(NRlO)-, RlOC(O)-, -N(RlO)2, or
  • Rl l ⁇ C(O)NRl0- and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOo-, Rl0c(O)NRl0-, (RlO) 2 NC(0)-, Rl lS(0)2NRlO-, (Rl0)2NS(O)2-, (R1°)2N-C(NR1 )-, R10C(O)-, -N(RlO)2, or Rl 10C(0)NR10-;
  • R9 and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
  • RlO is independently selected from hydrogen, C1-C alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • RU is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • A3 is selected from: -CH2-, O, -N(R10)- or S(0) m ;
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, 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, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(0) m ;
  • the inhibitors of prenyl-protein transferase are illustrated by the formula D:
  • f(s) are independently N, and the remaining f s are independently CH;
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(R10)2, F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, Rl°0-, or -N(RlO) 2 ;
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, halogen, -C6 perfluoroalkyl, Rl 2 0-,
  • RHOC(O)NR10- c) unsubstituted C1-C alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
  • R4 is selected from H, halogen, C1-C6 alkyl and CF3;
  • R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, Rl 0-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, (RlO)2NC(0)-, CN, N02, (R1°)2N-C(NR10)-, RlOC(O)-, -N(RlO)2, or RHOC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-, Rl0C(O)NRl0-, (RlO) 2 NC(0)-, (RlO)2N-C(NRlO)-, RlOC(O)-, -N(RlO)2, or RHOC(O)NR10-;
  • R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl
  • RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C perfluoroalkyl,
  • Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
  • A3 is selected from: -CH2-, O, -N(R10)- or S(0) m ;
  • n is 0 or 1; provided that n is not 0 if Al is a bond, O,
  • the inhibitors of prenyl-protein transferase are illustrated by the formula E:
  • Q is selected from from 0- 1 of f(s) are independently N, and the remaining f s are independently CH;
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl, Rl°0-, -N(R1°) 2 , F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(RlO)2, F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RlOO-, or -N(RlO) 2 ;
  • R is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
  • R4 is selected from H, halogen, C1-C6 alkyl and CF3;
  • R6a, R6b 9 R6C 5 R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C perfluoroalkyl,
  • R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, (Rl0)2NC(O)-, CN, N02, (Rl°)2N-C(NRlO)-, Rl ⁇ c( ⁇ )-, -N(RlO)2, or RHOC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (R10) NC(O)-, (R10)2N-C(NR10)-, R10C(O)-, -N(RlO)2, O ⁇ RHOC(O)NR10- ;
  • R9 and R9b are independently hydrogen, ethyl, cyclopropyl or methyl
  • RIO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen, Cl-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
  • Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
  • A3 is selected from: -CH2-, O, -N(R10)- or S(0) m ;
  • inhibitors of prenyl-protein transferase are illustrated by the formula F:
  • f(s) are independently N, and the remaining f s are independently CH;
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RlOO-, -N(RlO) 2 or
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
  • R4 is selected from H, halogen, CH3 and CF3;
  • R8 is independently selected from: -CN, Cl, -N ⁇ 2, C1-C6 alkoxy, and 2,2,2-trifluoroethoxy;
  • R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trif uoroethyl and aryl;
  • RU is independently selected from C1-C alkyl and aryl
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
  • A is selected from: -CH2-, O, -N(R10)- or S(0) m ;
  • the inhibitors of prenyl-protein transferase are illustrated by the formula G:
  • f(s) are independently N, and the remaining f s are independently CH;
  • Rl is selected from: hydrogen, C3-C10 cycloalkyl, Rl°0-, -N(R1°)2, F or C1-C6 alkyl;
  • R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, Rl°0-,
  • R3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-, Rl lS(0)m-, R 10 C(O)NRl0-, (RlO) 2 NC(0)-, R10 2 N-C(NR10)-, CN, N ⁇ 2, Rl°C(0)-, N3, -N(RlO) 2 , or RH ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycl
  • R4 is selected from H, halogen, CH3 and CF3;
  • R 6 , R6b ? R C, R6d an d R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12Q-, Rl lS(0)m-, R 10 C(O)NRl0-, (R10) 2 NC(0)-, Rl ⁇ 2N-C(NRlO)-, CN, N02, Rl°C(0)-, N3, -N(RlO) 2 , or RH ⁇ C(O)NRl0-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted
  • R8 is independently selected from: -CN, Cl, -N ⁇ 2, C1-C alkoxy, and 2,2,2-trif uoroethoxy;
  • R a and R b are independently hydrogen, ethyl, cyclopropyl or methyl;
  • RIO is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • RU is independently selected from Cl-C6 alkyl and aryl
  • R 2 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(0) m ;
  • A3 is selected from: -CH2-, O, -N(R10)- or S(0) m ;
  • n 0 or 1
  • 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 and the alkyl portion of aralkyl and similar terms, 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.
  • cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
  • Alkynyl groups include those groups having the specified number of carbon atoms and having one triple bond. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
  • Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
  • carbocyclic ring is intended to mean any stable monocyclic carbon ring of the designated ring atoms, which can either be aromatic or non-aromatic.
  • aryl and the aryl portion of aroyl and aralkyl, 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
  • 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 hetero- cyclic 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 is intended to mean a substituted Cl-8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R3, R4 ? R5 a nd R6a-e 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 substituents in addition to the point of attachment to the rest of the compound. Lines drawn into the ring systems from substituents (such as from R3, R4, Q etc.) means that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms.
  • Y represents a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein Y is attached to A3 through a carbon atom and includes the following ring systems:
  • Y is the moiety designated by the following structure
  • the Y is selected from phenyl and pyridyl.
  • fused ring moieties may be further substituted by the remaining R6a R6b ? R6C, R6d and/or R6e a s defined hereinabove.
  • Rl and R 2 are independently selected from: hydrogen, RHC(0)0-, -N(R10) 2 , R10C(O)NR10-, RIOO- or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(RlO) , RlOO- and R10C(O)NR10-.
  • R3 is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, R i2 0-,
  • CN N02, Rl°C(0)- or -N(RlO)2, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl 2 0-, Rl lS(0)m-, R 10 C(O)NRl0_, (RlO) 2 NC(0)-,
  • R10 2 N-C(NR10)-, CN, RlOC(O)-, N3, -N(RlO)2, and R! 1OC(O)-NR10-.
  • R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C1-C6 alkyl.
  • R ⁇ is hydrogen.
  • R6 , R6b, R6C ? R6d an d R6e are independently selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, Rl 2 0-, R n S(0)m-, CN, N02, Rl°C(0)- or -N(RlO) 2 , c) unsubstituted C1-C alkyl; and d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, C3-C10 cycloalkyl, Rl 2 0-, RHS(0) m -,
  • R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 perfluoroalkyl, C1-C6 alkoxy
  • RlO is selected from H, C1-C6 alkyl and benzyl.
  • Al and A 2 are independently selected from: a bond, -C(O)NRl0-, -NRIOC(O)-, O, -N(R10)-, -S(0)2N(RlO)- and
  • A3 is selected from-CH2-, O, -N(R10)-, -C(O)NRl0-, -C(0)NRlOCH2-, - CH2C(0)NRlO-, -CH2O-, -OCH2- or S(0)m- Most preferably, A 3 is selected from: -C(0)NRl°-, -C(0)NRlOCH2-, -OCH2-, O or S(0) m .
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
  • n and r are independently 0, 1, or 2.
  • s is 0.
  • t is 1.
  • any substituent or variable e.g., Rl, R2, R9, n, etc.
  • -N(RlO)2 represents -NHH, -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 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, palmoic, 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. Generally, 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 1-19, 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.
  • Substituents R3, R6 and R as shown in the Schemes, represent the substituents R 3 , R4, R5 ? R6a, R6b ? R6C ? R6d ⁇ R6e and R ; although only one such R3, R6 or R is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heterocyclic moieties contain multiple substituents.
  • Schemes 1-19 The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures.
  • Schemes 1-9 illustrate synthesis of the instant bicyclic compounds which inco ⁇ orate a preferred benzylimidazolyl sidechain.
  • a bicyclic intermediate that is not commercially available may be synthesized by methods known in the art.
  • a suitably substituted halogenated picoline may be synthesized by methods known in the art.
  • This intermediate 4 may then be coupled under vigorous conditions to a carbocyclic/ heterocyclic ring having a nucleophilic heteroatom to provide a compound of the instant invention 5.
  • Scheme 2 illustrates an analogous synthesis of an isomeric intermediate 8 starting from a suitably substituted picoline 6.
  • a suitably substituted pyridinonyl alcohol 10 may be synthesized starting from the corresponding isonicotinate 9 according to procedures described by Boekelhiede and Lehn (J. Org. Chem., 26:428-430 (1961)). The alcohol is then protected and alkylated with a suitably substituted benzyl halide, to provide the intermediate bicyclic alcohol. The intermediate alcohol 3 may converted to the corresponding bromide 11. The bromide 11 may be coupled to a suitably substituted benzylimidazolyl 3 to provide, after deprotection, the instant compound 12.
  • Scheme 4 illustrates synthesis of an instant compound wherein a non-hydrogen R b is inco ⁇ orated in the instant compound.
  • Scheme 5 illustrates synthesis of instant compounds that inco ⁇ orate a preferred imidazolyl moiety connected to the biscyclic portion of the instant compounds via an alkyl amino, sulfonamide or amide linker.
  • the 4-aminoalkylimidazole 15, wherein the primary amine is protected as the phthalimide is selectively alkylated then deprotected to provide the amine 16.
  • the amine 16 may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown.
  • Compounds of the instant invention wherein the Al(CRl2)nA 2 (CRl2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 6.
  • the suitably substituted phenol 17 may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole 18.
  • the intermediate 19 can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
  • Scheme 8 illustrates inco ⁇ oration of an acetyl moiety as the (CR 2 2)pX(CR 2)p linker of the instant compounds.
  • the suitably substituted acetyl pyridine 23 is brominated to provide intermediate 24.
  • Reaction with the imidazolyl reagent 5 provides, after deprotection and further functionalization, the instant compound 25.
  • Scheme 9 illustrates a synthetic route to the instant compounds wherein the heterocyclic-linker-cyclic moiety is first formed and then couple to the preferred imidazolyl moiety.
  • sealed tube H-A 3 OH, SH, NH 2
  • the intermediates whose synthesis are illustrated in the above Schemes, and other pyridinonecarbocyclic and pyridinone-heterocyclic intermediates obtained commercially or readily synthesized can be coupled with a variety of aldehydes.
  • 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.
  • a suitably substituted bromopyridine is lithiated and is reacted with an aldehyde to provide the C-alkylated instant compound 27.
  • Compound 27 can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound 28.
  • the compound 28 may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine 28 can further be selectively protected to obtain 29, which can subsequently be reductively alkylated with a second aldehyde to obtain compound 30. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole 31 can be accomplished by literature procedures.
  • the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 11, 12).
  • 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 alkyl lithium reagents, to obtain secondary alcohols such as 34.
  • the fully deprotected amino alcohol 35 can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as 36 (Scheme 12), or tertiary amines.
  • the Boc protected amino alcohol 33 can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as 37 (Scheme 13). Treating 33 with lj'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine 37. The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product 38.
  • the arylpyridinone reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as 40, as shown in Scheme 14.
  • R' is an aryl group
  • 40 can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce 41. Alternatively, the amine protecting group in 40 can be removed, and O-alkylated phenolic amines such as 42 produced.
  • Schemes 15-18 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that inco ⁇ orate other heterocyclic moieties for variable W are also well known in the art.
  • Scheme 19 illustrates preparation of substituted aldehydes which inco ⁇ orate the benzylimidazolyl sidechain. As set forth in Scheme 19, these aldehydes can be reductively aminated with various amines to give the instant compounds.
  • the compounds of the invention are selective inhibitors of farnesyl-protein transferase.
  • a compound is considered a selective inhibitor of farnesyl- protein transferase, for example, when its in vitro farnesyl-protein transferase inhibitory activity, as assessed by the assay described in Example 17, is at least 100 times greater than the in vitro activity of the same compound against geranylgeranyl-protein transferase-type I in the assay described in Example 19.
  • a selective compound exhibits at least 1000 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition.
  • the compounds of the invention are dual inhibitors of farnesyl-protein transferase and geranylgeranyl-protein transferase type I.
  • Such a dual inhibitor will exhibit certain characteristics when assessed in in vitro assays, which are dependent on the type of assay employed.
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 12 ⁇ M against K4B-Ras dependent activation of MAP kinases in cells. More preferably, the dual inhibitor compound has an in vitro inhibitory activity (IC50) against K4B-Ras dependent activation of MAP kinases in cells which is more than about 5 times lower than the inhibitory activity (IC50) against Myr-Ras dependent activation of MAP kinases in cells. Also more preferably, in a SEAP assay, the dual inhibitor compound has an inhibitory activity (IC50) that is less than about 10 nM against H-Ras dependent activation of MAP kinases in cells.
  • IC50 in vitro inhibitory activity
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 5 ⁇ M against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAXG motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion.
  • IC50 in vitro inhibitory activity
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 1 ⁇ M against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAXG motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion.
  • IC50 in vitro inhibitory activity
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) in the in vitro assay as described in Example 17 that is less than about 1 ⁇ M against transfer of a farnesyl residue to a protein or peptide substrate, comprising a CAAXF motif, by farnesyl-protein transferase.
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about lOOnM against transfer of a farnesyl residue to a protein or peptide substrate, comprising a CAAX ⁇ 7 motif, by farnesyl-protein transferase. Also preferably, the dual inhibitor compound has an in vitro inhibitory activity (IC50) in the in vitro assay as described in Example 20, that is less than about 100 nM against the anchorage independent growth of H-ras-transformed mammalian fibroblasts.
  • IC50 in vitro inhibitory activity
  • the protein or peptide substrate utilized in the instant assay may inco ⁇ orate any CAAX motif that is geranylgeranylated by GGTase-I.
  • CAAX will refer to such motifs that may be geranylgeranylated by GGTase-I. It is understood that some of the "CAAX " containing protein or peptide substrates may also be farnesylated by farnesyl-protein transferase. In particular such
  • CAAX motifs include (the corresponding human protein is in parentheses): CVIM (K4B-Ras) (SEQ.ID.NO.: 1), CVLL (mutated H- Ras) (SEQ.ID.NO.: 2), CVVM (N-Ras) (SEQ.ID.NO.: 3), CUM (K4A- Ras) (SEQ.ID.NO.: 4), CLLL (Rap-IA) (SEQ.ID.NO.: 5), CQLL (Rap- IB) (SEQ.ID.NO.: 6), CSIM (SEQ.ID.NO.: 7), CAIM (SEQ.ID.NO.: 8), CKVL (SEQ.ID.NO.: 9) and CLIM (PFX) (SEQ.ID.NO.: 10).
  • the CAAX motif is CVIM.
  • CAAX is used to designate a protein or peptide substrate that inco ⁇ orates four amino acid
  • CAAX motifs include (the corresponding human protein is in parentheses): CVLS (H-ras) (SEQ.ID.NO.: 11), CVIM (K4B-Ras) (SEQ.ID.NO.: 1) and CVVM (N-Ras) (SEQ.ID.NO.: 3).
  • 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, src, abl, lck, fyn) or by other mechanisms.
  • NF-1 neurofibromin
  • neu src
  • abl abl
  • lck lck
  • the compounds of the instant invention inhibit prenyl- protein transferase and the prenylation 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 vision deficit 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. Schaffher et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
  • the instant compounds may also be useful for the treatment of fungal infections.
  • the instant compounds may also be useful as inhibitors of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, 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.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl- cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha- tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this pu ⁇ ose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula A may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed. (For pu ⁇ oses of this application, topical application shall include mouth washes and gargles.)
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • 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, sex 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 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 compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the instant farnesyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that such a combination of antineoplastic agent and inhibitor of farnesyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery.
  • antineoplastic agent examples include, in general, microtubule-stabilizing agents (such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), epothilone A, epothilone B, desoxy epothilone A, desoxy epothilone B or their derivatives); microtubule-disruptor agents; alkylating agents, anti- metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • microtubule-stabilizing agents such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), epothilone A, epothilone B, desoxy epothilone A, desoxy
  • Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins.
  • Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-f ⁇ uorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.
  • antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • the preferred class of antineoplastic agents is the taxanes and the preferred antineoplastic agent is paclitaxel.
  • Radiation therapy including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with the instant inhibitor of farnesyl-protein transferase alone to treat cancer. Additionally, compounds of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on October 23, 1997, and herein inco ⁇ orated by reference. The instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • the instant compounds may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity.
  • the instant compounds may also be co-administered with compounds that are selective inhibitors of geranylgeranyl protein transferase or farnesyl-protein transferase.
  • such administration can be orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration. It is preferred that such administration be orally. It is more preferred that such administration be orally and simultaneously.
  • the protein substrate-competitive inhibitor and farnesyl pyrophosphate-competitive inhibitor are administered sequentially, the administration of each can be by the same method or by different methods.
  • the instant compounds may also be useful in combination with an integrin antagonist for the treatment of cancer, as described in U.S. Ser. No. 09/055,487, filed April 6, 1998, which is inco ⁇ orated herein by reference.
  • an integrin antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an integrin(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells.
  • the term refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the v ⁇ 5 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the v ⁇ 3 integrin and the ⁇ v ⁇ 5 integrin, or which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ v ⁇ 6, ⁇ v ⁇ 8, l ⁇ l, ⁇ 2 ⁇ l, ⁇ 5 ⁇ l, ⁇ 6 ⁇ l and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3, v ⁇ 5, ⁇ v ⁇ 6, v ⁇ 8, ⁇ l ⁇ l, ⁇ 2 ⁇ l, ⁇ 5 ⁇ l, ⁇ 6 ⁇ l and ⁇ 6 ⁇ 4 integrins.
  • the instant compounds may also be useful with other agents that inhibit angiogenisis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin.
  • the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restenosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
  • combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
  • FPTase farnesyl-protein transferase
  • 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 farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • farnesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
  • the chemical content of the assay mixtures may be determined by well known immuno- logical, radiochemical or chromatographic techniques.
  • the compounds of the instant invention are 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 farnesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl 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 1 1 -Trityl-4- (4-cy anobenzy Dimidazole
  • Step 2 2-bromo-5-bromomethyl pyridine To a flask was charged 2-bromo-5-methylpyridine
  • Step 3 5-(4-Cyanobenzyl)-l-(2-bromopyrid-5-ylmethyl)imidazole To a flask was charged 1-trityl -4-p-cyanobenzyl imidazole
  • Step 4 5-(4' -cyanobenzyl)- 1 - [2-(3 " methylphenylthio)pyrid-5- ylmethyDimidazole
  • Step 2 5-(4' -Cyanobenzyl)- l-(2-bromo-4-pyridylmethyl)imidazole Following the procedure in Example 1 , Step 2 the product was obtained from 2-bromo-4-methylpyridine. FAB-MS: calc: 249 found: 250. H-NMR (CDC1 3 ): 4.4ppm (s, 2H); 7.2ppm (d, IH); 7.5ppm (s, IH); 8.4ppm (d, IH).
  • Step 4 5-(4' -cyanobenzyl)- 1 - [2-(3 " methylphenylthio)4- pyridylmethyDlimidazole
  • Step 1 2- cyclohexylamino-5-pyridine carboxylic acid
  • Step 3 5-(4' -cyanobenzyl)- 1 -[2-(cyclohexylamino)pyrid-5-yl- methyDlimidazole hydrochloride
  • Example 1 The product of Example 1 was oxidized with 1.1 equivalent of 3-chloroperbenzoic acid in THF at -60° to room temperature. Preparative HPLC followed by lyophilization from dioxane HCI gave pure title compound.
  • Nr-Pivaloyloxymethyl-N ⁇ -phthaloylhistamine (4.55 g, 12.8 mmol) prepared as previously described (J. C. Emmett, F. H. Hollo way, and J. L. Turner, J. Chem. Soc, Perkin Trans. 1, 1341, (1979)) and ⁇ -Bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL) and 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 2- [N-( 1 -(4' -Cyanobenzyl)- 1 H-imidazol-5- ylethyDcarbamoyll -6-(3-trifluoromethylphenoxy)pyridine 6-(3-Trifluoromethylphenoxy)pyridine-2-carboxylic acid (0.05 g, 0.146 mmol) was dissolved in DMF (2 mL) and treated with EDC (0.0338 g, 0.176 mmol), HOBT (0.0238 g, 0.176 mmol), 4-cyanobenzyl histamine (0.0399 g, 0.176 mmol) and N- methylmo ⁇ holine (0.048 mL, 0.438 mmol) and stirred at ambient temperature for 18 hr. Purification of the crude reaction by preparative RP HPLC on a Vydac column gave the title compound. Anal, calcd for C26H20N5O2F 3 - 1.35 CF 3 C0 2 H -0.5
  • 3-carboxylic acid (0.10 g, 0.335 mmol) was dissolved in DMF (10 mL) and treated with EDC (0.077 g, 0.402 mmol), HOBT (0.054 g, 0.402 mmol), 4-cyanobenzyl histamine (0.079 g, 0.352 mmol) and NMM (0.11 mL, 1.00 mmol) and stirred at ambient temperature for 18 hr.
  • the reaction mixture was concentrated to remove the DMF, then partitioned between EtOAc and aq saturated NaHC0 3 solution, the organic layer separated, washed with brine and dried (MgS0 4 ).
  • Step B Mono methyl ester of 4-ethoxy-2.6-pyridine dicarboxylate
  • the diethyl ester 0.300 g, 1.12 mmol
  • LiOH 0.052 g, 1.23 mmol
  • H 2 0/CH 3 OH 24 mL
  • the title compound was obtained after preparative RP HPLC.
  • Step C 4-Ethoxy-6-methoxycarbonyl-pyridine-2-carboxylic acid
  • Step D 4-Ethoxy-6-carboxyl-pyridine-2-carboxylic acid ⁇ 2-[3-(4- cyanobenzyl)-3H-imidazol-4-yll -ethyl ⁇ -amide 4-Ethoxy-6-methoxycarbonyl-pyridine-2-carboxylic acid
  • Step E 6-[N-(3-Chlorobenzyl) carbamoyl]- 4-ethoxy-pyridine-2- carboxylic acid ⁇ 2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]- ethyll -amide
  • Step A 4-(3-Chlorobenzyloxy)- pyridine-2.6- dicarboxylic acid
  • Step B Dimethyl 4-(3-Chlorobenzyloxy) - pyridine-2,6- dicarboxylate
  • Step C Mono methyl ester of 4-(3-Chlorobenzyloxy)- pyridine-
  • Step D 4-(3-Chlorobenzyloxy)- 6-methoxycarbonyl- pyridine-2- carboxylic acid ⁇ 2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]- ethyl ⁇ -amide
  • Step A l-Triphenylmethyl-4-(hydroxymethyl)-imidazole
  • Step B l-Triphenylmethyl-4-(acetoxymethyl)-imidazole
  • Step C 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 l-(4-Cyanobenzyl)-5-(hydroxymethyl)-imidazole
  • Step E l-(4-Cyanobenzyl)-5-imidazolecarboxaldehyde
  • the crude oil was redissolved in ethyl acetate and was washed twice with 20% aq. NaOH solution. The organic layer was dried over anhydrous MgS0 4 and was filtered and concentrated to give a yellow oil. The oil was purified by gravity column chromatography over silica gel with 4: 1 hexanes/ethyl acetate. Suspected product fractions were combined and concentrated in vacuo to give the product as a yellow oil. The oil was dissolved in 2 mL of 10% aq. sulfuric acid, and the solution heated at 100°C for 18 hours. The reaction was cooled and basified to pH 11 with concentrated NH 4 OH solution, and extracted twice with ethyl acetate.
  • Step G l-(4-Cyanobenzyl)imidazole-5-[6-(3- chlorophenoxy)pyridin-2-yl1methanamide
  • Step A 2- Amino-6-( 1 -phenylethyn-2-yl)pyridine
  • Step B 1 -(4-Cyanobenzyl)imidazole-5- [6-( 1 -phenylethyn-2- yl)pyridin-2-yllmethanamine
  • Step A 2-Amino-6-(1.2.3.4-tetrahydronaphthyloxy-6-yl)pyridine
  • Step B l-(4-Cyanobenzyl)imidazole-5-[6-(l,2,3,4- tetrahydronaphthyloxy-6-yl)pyridin-2-yl]methanamine
  • Step G Via a procedure identical to that described in Example 13, Step G from 132 mg (0.62 mmol) of aldehyde (from Example 13, Step E) and 148 mg (0.62 mmol) of 2-amino-6-( 1,2,3,4- tetrahydronaphthyloxy-6-yl)pyridine (from Step A) was obtained the desired product as a clear oil.
  • 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 sulf oxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of inco ⁇ oration of radioactivity in the presence of the test compound when compared to the amount of inco ⁇ oration in the absence of the test compound.
  • DMSO dimethyl sulf oxide
  • 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 nM 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 sulf oxide, 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 farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl 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
  • the modified geranylgeranyl-protein transferase inhibition assay is carried out at room temperature.
  • a typical reaction contains (in a final volume of 50 ⁇ L): [ 3 H]geranylgeranyl diphosphate, biotinylated Ras peptide, 50 mM HEPES, pH 7.5, a modulating anion (for example 10 mM glycerophosphate or 5mM ATP), 5 mM MgCl 2 , 10 ⁇ M ZnCl 2 ,
  • the GGTase-type I enzyme employed in the assay is prepared as described in U.S. Pat. No. 5,470,832, inco ⁇ orated by reference.
  • the Ras peptide is derived from the K4B-Ras protein and has the following sequence: biotinyl- GKKKKKKSKTKCVIM (single amino acid code) (SEQ.ID.NO.: 13).
  • Reactions are initiated by the addition of GGTase and stopped at timed intervals (typically 15 min) by the addition of 200 ⁇ L of a 3 mg/mL suspension of streptavidin SPA beads (Scintillation Proximity Assay beads, Amersham) in 0.2 M sodium phosphate, pH 4, containing 50 mM EDTA, and 0.5% BSA. The quenched reactions are allowed to stand for 2 hours before analysis on a Packard TopCount scintillation counter. For inhibition studies, assays are run as described above, except inhibitors are prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 25 -fold into the enzyme assay mixture. IC 50 values are determined with Ras peptide near KM concentrations. Enzyme and nonsaturating substrate conditions for inhibitor IC 50 determinations are as follows: 75 pM GGTase-I, 1.6 ⁇ M Ras peptide, 100 nM geranylgeranyl diphosphate.
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 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 serum) 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.
  • the SEAP reporter plasmid, pDSElOO was constructed by ligating a restriction fragment containing the SEAP coding sequence into the plasmid pCMV-RE-AKI.
  • the SEAP gene is derived from the plasmid pSEAP2-Basic (Clontech, Palo Alto, CA).
  • the plasmid pCMV-RE-AKI was constructed by Deborah Jones (Merck) and contains 5 sequential copies of the 'dyad symmetry response element' cloned upstream of a 'CAT-TATA' sequence derived from the cytomegalovirus immediate early promoter.
  • the plasmid also contains a bovine growth hormone poly-A sequence.
  • the plasmid, pDSElOO was constructed as follows. A restriction fragment encoding the SEAP coding sequence was cut out of the plasmid pSEAP2-Basic using the restriction enzymes EcoRl and Hpal. The ends of the linear DNA fragments were filled in with the Klenow fragment of E. coli DNA Polymerase I. The 'blunt ended' DNA containing the SEAP gene was isolated by electrophoresing the digest in an agarose gel and cutting out the 1694 base pair fragment. The vector plasmid pCMV-RE-AKI was linearized with the restriction enzyme Bgl- II and the ends filled in with Klenow DNA Polymerase I.
  • the SEAP DNA fragment was blunt end ligated into the pCMV-RE-AKI vector and the ligation products were transformed into DH5-alpha E. coli cells (Gibco-BRL). Transformants were screened for the proper insert and then mapped for restriction fragment orientation. Properly oriented recombinant constructs were sequenced across the cloning junctions to verify the correct sequence. The resulting plasmid contains the SEAP coding sequence downstream of the DSE and CAT-TATA promoter elements and upstream of the BGH poly-A sequence.
  • a DNA fragment containing viral-H-r ⁇ s can be PCRed from plasmid "H-l” (Ellis R. et al. J. Virol. 36, 408, 1980) using the following oligos.
  • Sense strand
  • the sense strand oligo also optimizes the 'Kozak' translation initiation sequence immediately 5' to the ATG start site.
  • cysteine 186 would be mutated to a serine by substituting a G residue for a C residue in the C-terminal antisense oligo.
  • the PCR primer oligos introduce an Xhol site at the 5' end and a Xbal site at the 3 'end.
  • the Xhol-Xbal fragment can be ligated into the mammalian expression plasmid pCI (Promega) cut with Xhol and Xbal. This results in a plasmid in which the recombinant myr- viral-H-ras gene is constitutively transcribed from the CMV promoter of the pCI vector.
  • a viral-H-r ⁇ s clone with a C-terminal sequence encoding the amino acids CVLL can be cloned from the plasmid "H-l" (Ellis R. et al. J. Virol. 36, 408, 1980) by PCR using the following oligos.
  • the sense strand oligo optimizes the 'Kozak' sequence and adds an Xhol site.
  • the antisense strand mutates serine 189 to leucine and adds an Xbal site.
  • the PCR fragment can be trimmed with Xhol and Xbal and ligated into the Xhol-Xbal cut vector pCI (Promega). This results in a plasmid in which the mutated viral-H-ras-CVLL gene is constitutively transcribed from the CMV promoter of the pCI vector.
  • the human c-H-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers.
  • Antisense strand
  • the primers will amplify a c-H-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an EcoRl site at the N-terminus and a Sal I stite at the C-terminal end.
  • the c-H-ras fragment can be ligated ligated into an EcoRl -Sal I cut mutagenesis vector p Alter- 1 (Promega). Mutation of glutamine-61 to a leucine can be accomplished using the manufacturer' s protocols and the following oligonucleotide:
  • the mutated c-H-ras-Leu61 can be excised from the p Alter- 1 vector, using EcoRI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with EcoRI and Sal I.
  • the new recombinant plasmid will constitutively transcribe c-H-ras-Leu61 from the CMV promoter of the pCI vector.
  • the human c-N-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers.
  • Antisense strand
  • the primers will amplify a c-N-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-terminal end.
  • the c-N-ras fragment can be ligated into an EcoRI -Sal I cut mutagenesis vector p Alter- 1 (Promega). Mutation of glycine-12 to a valine can be accomplished using the manufacturer's protocols and the following oligonucleotide:
  • the mutated c-N-ras-Val-12 can be excised from the p Alter- 1 vector, using EcoRI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with EcoRI and Sal I.
  • the new recombinant plasmid will constitutively transcribe c-N-ras-Val-12 from the CMV promoter of the pCI vector.
  • the human c-K-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers.
  • Antisense strand
  • the primers will amplify a c-K-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, a Kpnl site at the N-terminus and a Sal I stite at the C-terminal end.
  • the c-K-ras fragment can be ligated into a Kpnl -Sal I cut mutagenesis vector p Alter- 1 (Promega). Mutation of cysteine- 12 to a valine can be accomplished using the manufacturer's protocols and the following oligonucleotide:
  • the mutated c-K-ras-Val-12 can be excised from the pAlter-1 vector, using Kpnl and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with Kpnl and Sal I.
  • the new recombinant plasmid will constitutively transcribe c-K-ras-Val-12 from the CMV promoter of the pCI vector.
  • the cells are washed with PBS and trypsinized with 1ml of 0.05% trypsin.
  • the 1 ml of trypsinized cells is diluted into 10ml of phenol red free DMEM + 0.2% charcoal stripped calf serum + IX (Pen/Strep, Glutamine and NEAA ).
  • Transfected cells are plated in a 96 well microtiter plate (lOO ⁇ l/well) to which drug, diluted in media, has already been added in a volume of lOO ⁇ l. The final volume per well is 200 ⁇ l with each drug concentration repeated in triplicate over a range of half-log steps.
  • Incubation of cells and drugs is for 36 hrs at 37° under C02- At the end of the incubation period, cells are examined microscopically for evidence of cell distress.
  • lOO ⁇ l of media containing the secreted alkaline phosphatase is removed from each well and transferred to a microtube array for heat treatment at 65°C for 1 hr to inactivate endogenous alkaline phosphatases (but not the heat stable secreted phosphatase).
  • the heat treated media is assayed for alkaline phosphatase by a luminescence assay using the luminescence reagent CSPD® (Tropix, Bedford, Mass.).
  • a volume of 50 ⁇ l media is combinRased with 200 ⁇ l of CSPD cocktail and incubated for 60 minutes at room temperature. Luminesence is monitored using an ML2200 microplate luminometer (Dynatech). Luminescence reflects the level of activation of the fos reporter construct stimulated by the transiently expressed protein.
  • Assay Buffer Add 0.05M Na 2 C0 3 to 0.05M NaHCO, to obtain pH 9.5. Make ImM in MgCl 2
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 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 serum) 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention porte sur des composés inhibiteurs de la prényl-protéine transférase (FTase), sur la prénylation de la protéine oncogène Ras, sur des compositions chimiothérapeutiques contenant les composés de l'invention, et sur des procédés d'inhibition de la prényl-protéine transférase et de prénylation de la protéine oncogène Ras.
EP98952003A 1997-10-02 1998-10-01 Inhibiteurs de la prenyl-proteine transferase Withdrawn EP1019391A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US6087197P 1997-10-02 1997-10-02
US60871P 1997-10-02
GBGB9807948.6A GB9807948D0 (en) 1998-04-14 1998-04-14 Inhibitors of farnesyl-protein transferase
GB9807948 1998-04-14
PCT/US1998/020525 WO1999018096A1 (fr) 1997-10-02 1998-10-01 Inhibiteurs de la prenyl-proteine transferase

Publications (1)

Publication Number Publication Date
EP1019391A1 true EP1019391A1 (fr) 2000-07-19

Family

ID=26313473

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98952003A Withdrawn EP1019391A1 (fr) 1997-10-02 1998-10-01 Inhibiteurs de la prenyl-proteine transferase

Country Status (4)

Country Link
EP (1) EP1019391A1 (fr)
JP (1) JP2001519345A (fr)
AU (1) AU9781098A (fr)
WO (1) WO1999018096A1 (fr)

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9828511D0 (en) 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
GB9919778D0 (en) 1999-08-21 1999-10-27 Zeneca Ltd Chemical compounds
GB0004888D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004887D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004890D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004886D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0007371D0 (en) 2000-03-28 2000-05-17 Astrazeneca Uk Ltd Chemical compounds
GB0016877D0 (en) 2000-07-11 2000-08-30 Astrazeneca Ab Chemical compounds
GB0021726D0 (en) 2000-09-05 2000-10-18 Astrazeneca Ab Chemical compounds
WO2002036587A2 (fr) 2000-11-01 2002-05-10 Cor Therapeutics, Inc. Composes heterocycliques azotes et procede de fabrication de ces composes et de leurs intermediaires
US7211595B2 (en) 2000-11-30 2007-05-01 Abbott Laboratories Farnesyltransferase inhibitors
DK1357111T3 (da) 2000-12-28 2009-11-02 Shionogi & Co 2-pyridonderivater med affinitet for cannabinoid type 2-receptor
GB0103926D0 (en) 2001-02-17 2001-04-04 Astrazeneca Ab Chemical compounds
GB0113041D0 (en) 2001-05-30 2001-07-18 Astrazeneca Ab Chemical compounds
GB0205688D0 (en) 2002-03-09 2002-04-24 Astrazeneca Ab Chemical compounds
EP1490354A1 (fr) 2002-03-09 2004-12-29 Astrazeneca AB Derives de la pyrimidine substituee par 4-imidazolyle presentant une activite d'inhibition de cdk
GB0205690D0 (en) 2002-03-09 2002-04-24 Astrazeneca Ab Chemical compounds
GB0205693D0 (en) 2002-03-09 2002-04-24 Astrazeneca Ab Chemical compounds
GB0311274D0 (en) 2003-05-16 2003-06-18 Astrazeneca Ab Chemical compounds
GB0311276D0 (en) 2003-05-16 2003-06-18 Astrazeneca Ab Chemical compounds
TW200528101A (en) 2004-02-03 2005-09-01 Astrazeneca Ab Chemical compounds
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
BRPI0616722A2 (pt) 2005-09-30 2012-12-25 Astrazeneca Ab composto ou um sal farmaceuticamente aceitÁvel ou um Éster hidrolisÁvel in vivo do mesmo, processo para preparar o mesmo, composiÇço farmacÊutica, uso de um composto ou um sal farmaceuticamente aceitÁvel ou um Éster hidrolisÁvel in vivo do mesmo, e, mÉtodos para produzir um efeito anti-proliferaÇço celular e um efeito inibidor cdk2, para tratar cÂncer, e para tratar doenÇas
BRPI0620066A2 (pt) * 2005-12-20 2011-11-01 Novartis Ag derivados de ácido nicotìnico como moduladores do receptor de glutamato metabotrópico, processo para preparação dos mesmos, composição farmacêutica e uso dos referidos derivados
AR059898A1 (es) 2006-03-15 2008-05-07 Janssen Pharmaceutica Nv Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2
UA93548C2 (uk) 2006-05-05 2011-02-25 Айерем Елелсі Сполуки та композиції як модулятори хеджхогівського сигнального шляху
ES2431466T3 (es) 2006-06-30 2013-11-26 Sunesis Pharmaceuticals, Inc. Inhibidores de piridinonil pdk1
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
BRPI0816767B8 (pt) 2007-09-14 2021-05-25 Addex Pharmaceuticals Sa composto 4-fenil-3,4,5,6-tetra-hidro-2h,1'h-[1,4']bipiridi¬nil-2'-onas 1',3'-dissubstituídas, composição farmacêutica e uso dos mesmos
AU2009289784B2 (en) 2008-09-02 2012-03-22 Addex Pharma S.A. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
WO2010060589A1 (fr) 2008-11-28 2010-06-03 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. Dérivés d'indole et de benzoxazine comme modulateurs des récepteurs métabotropiques au glutamate
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
MY161325A (en) 2009-05-12 2017-04-14 Janssen Pharmaceuticals Inc 1, 2, 4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders
AU2011328203B2 (en) 2010-11-08 2015-03-19 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
PL2649069T3 (pl) 2010-11-08 2016-01-29 Janssen Pharmaceuticals Inc Pochodne 1,2,4-triazolo[4,3-a]pirydyny i ich zastosowanie jako dodatnich allosterycznych modulatorów receptorów mGluR2
CN103261195B (zh) 2010-11-08 2015-09-02 杨森制药公司 1,2,4-三唑并[4,3-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途
GB201104153D0 (en) 2011-03-11 2011-04-27 Glaxo Group Ltd Novel compounds
JO3368B1 (ar) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2
JO3367B1 (ar) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2
UA121965C2 (uk) 2014-01-21 2020-08-25 Янссен Фармацевтика Нв Комбінації, які містять позитивні алостеричні модулятори або ортостеричні агоністи метаботропного глутаматергічного рецептора 2 підтипу, та їх застосування
KR102461134B1 (ko) 2014-01-21 2022-10-28 얀센 파마슈티카 엔.브이. 대사 조절형 글루탐산 작동성 수용체 제2아형의 양성 알로스테릭 조절제 또는 오르토스테릭 작동제를 포함하는 조합 및 그 용도
GB201514021D0 (en) 2015-08-07 2015-09-23 Arner Elias Set Jeno Novel Pyridines and their use in the treatment of cancer
TW201718581A (zh) 2015-10-19 2017-06-01 英塞特公司 作為免疫調節劑之雜環化合物
LT3377488T (lt) 2015-11-19 2023-01-10 Incyte Corporation Heterocikliniai junginiai, kaip imunomoduliatoriai
SI3394033T1 (sl) 2015-12-22 2021-03-31 Incyte Corporation Heterociklične spojine kot imunomodulatorji
MA44860A (fr) 2016-05-06 2019-03-13 Incyte Holdings Corp Composés hétérocycliques utilisés comme immunomodulateurs
WO2017205464A1 (fr) 2016-05-26 2017-11-30 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
EP4137489A1 (fr) 2016-06-20 2023-02-22 Incyte Corporation Composés hétérocycliques en tant qu'immunomodulateurs
WO2018013789A1 (fr) 2016-07-14 2018-01-18 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
EP3504198B1 (fr) 2016-08-29 2023-01-25 Incyte Corporation Composés hétérocycliques utilisés comme immunomodulateurs
ES2874756T3 (es) 2016-12-22 2021-11-05 Incyte Corp Derivados de triazolo[1,5-A]piridina como inmunomoduladores
MX2019007416A (es) 2016-12-22 2019-12-11 Incyte Corp Derivados de benzooxazol como inmunomoduladores.
US20180179179A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds as immunomodulators
TWI798192B (zh) 2016-12-22 2023-04-11 美商英塞特公司 免疫調節劑化合物及使用方法
BR112019016233A2 (pt) 2017-02-07 2020-04-07 Oblique Therapeutics Ab piridinas substituídas com heterociclilsulfonila e uso das mesmas no tratamento de câncer
EP3580215A1 (fr) 2017-02-07 2019-12-18 Oblique Therapeutics AB Pyridines à substitution hétéroarylsulfonyle et leur utilisation dans le traitement du cancer
US11208384B2 (en) 2017-02-07 2021-12-28 Oblique Therapeutics Ab Sulfinylpyridines and their use in the treatment of cancer
RU2019128063A (ru) 2017-02-07 2021-03-09 Облик Терапьютикс Аб Углеводородсульфонилзамещенные пиридины и их применение при лечении рака
ES2940750T3 (es) 2018-03-30 2023-05-11 Incyte Corp Compuestos heterocíclicos como inmunomoduladores
HRP20230306T1 (hr) 2018-05-11 2023-05-12 Incyte Corporation Derivati tetrahidro-imidazo[4,5-c]piridina kao pd-l1 imunomodulatori
CA3150434A1 (fr) 2019-08-09 2021-02-18 Incyte Corporation Sels d'un inhibiteur de pd-1/pd-l1
TW202126652A (zh) 2019-09-30 2021-07-16 美商英塞特公司 作為免疫調節劑之吡啶并［３，２—ｄ］嘧啶化合物
KR20220101664A (ko) 2019-11-11 2022-07-19 인사이트 코포레이션 Pd-1/pd-l1 억제제의 염 및 결정질 형태
WO2022031736A1 (fr) 2020-08-04 2022-02-10 Nura Bio, Inc. Dérivés de pyridine substitués utiles comme inhibiteurs de sarm1
EP4214197A1 (fr) 2020-09-16 2023-07-26 Nura Bio, Inc. Dérivés de pyridine substitués utiles comme inhibiteurs de sarm1
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
WO2022099018A1 (fr) 2020-11-06 2022-05-12 Incyte Corporation Procédé de préparation d'un inhibiteur de pd-1/pd-l1
TW202313009A (zh) 2021-07-28 2023-04-01 美商努拉生物科技公司 作為sarm1抑制劑之經取代的吡啶衍生物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5652257A (en) * 1994-09-29 1997-07-29 Merck & Co., Inc. Heterocycle-containing inhibitors of farnesyl-protein transferase
US5585359A (en) * 1994-09-29 1996-12-17 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5624936A (en) * 1995-03-29 1997-04-29 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5627202A (en) * 1995-03-29 1997-05-06 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9918096A1 *

Also Published As

Publication number Publication date
AU9781098A (en) 1999-04-27
JP2001519345A (ja) 2001-10-23
WO1999018096A1 (fr) 1999-04-15

Similar Documents

Publication Publication Date Title
EP1019391A1 (fr) Inhibiteurs de la prenyl-proteine transferase
US5977134A (en) Inhibitors of farnesyl-protein transferase
US5859012A (en) Inhibitors of farnesyl-protein transferase
US5919785A (en) Inhibitors of farnesyl-protein transferase
US5854264A (en) Inhibitors of farnesyl-protein transferase
US6093737A (en) Inhibitors of farnesyl-protein transferase
US5932590A (en) Inhibitors of farnesyl-protein transferase
US6103723A (en) Inhibitors of farnesyl-protein transferase
US6054466A (en) Inhibitors of farnesyl-protein transferase
CA2276081A1 (fr) Inhibiteurs de farnesyl-proteine transferase
US5885995A (en) Inhibitors of farnesyl-protein transferase
US5859015A (en) N-heterocyclic piperazinyl and H-heterocyclic piperazinonyl inhibitors of farnesyl-protein transferase
WO2000051614A1 (fr) Inhibiteurs de prenyl-proteine transferases
WO2000051611A1 (fr) Inhibiteurs de la prenyle-proteine transferase
CA2250353A1 (fr) Inhibiteurs de la farnesyl-proteine transferase
EP1091736A1 (fr) Inhibiteurs de prenyl-proteine transferase
US5972966A (en) Inhibitors of farnesyl-protein transferase
US6015817A (en) Inhibitors of farnesyl-protein transferase
WO2001060458A2 (fr) Inhibiteurs de la prenyl-proteine transferase
WO1997036593A1 (fr) Inhibiteurs de la farnesyle-proteine transferase
US6127390A (en) Inhibitors of prenyl-protein transferase
AU715604B2 (en) Inhibitors of farnesyl-protein transferase
CA2311921A1 (fr) Inhibiteurs de la transferase de la farnesyl-proteine
JP2002542155A (ja) プレニル蛋白トランスフェラーゼの阻害剤
US5972942A (en) Inhibitors of farnesyl-protein transferase

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000502

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20000502;LT PAYMENT 20000502;LV PAYMENT 20000502;MK PAYMENT 20000502;RO PAYMENT 20000502;SI PAYMENT 20000502

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020503