WO1997036877A1 - Inhibiteurs de transferase de farnesyl-proteine - Google Patents

Inhibiteurs de transferase de farnesyl-proteine Download PDF

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WO1997036877A1
WO1997036877A1 PCT/US1997/005295 US9705295W WO9736877A1 WO 1997036877 A1 WO1997036877 A1 WO 1997036877A1 US 9705295 W US9705295 W US 9705295W WO 9736877 A1 WO9736877 A1 WO 9736877A1
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hydrogen
alkyl
compound
substituted
unsubstituted
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PCT/US1997/005295
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John H. Hutchinson
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Merck & Co., Inc.
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Priority claimed from GBGB9609334.9A external-priority patent/GB9609334D0/en
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Priority to AU26005/97A priority Critical patent/AU707416B2/en
Priority to EP97917759A priority patent/EP0891335A4/fr
Priority to JP9535531A priority patent/JP2000507589A/ja
Publication of WO1997036877A1 publication Critical patent/WO1997036877A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin

Definitions

  • the present invention relates to compounds which inhibit farnesyl protein transferase, a protein which is implicated in the oncogenic pathway mediated by Ras.
  • the Ras proteins (Ha-Ras, Ki4a- Ras, Ki4b-Ras and N-Ras) 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. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • Ras 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. Willumsen, Ann. Rev. Biochem. 62:851- 891 (1993)).
  • Mutated ras genes (Ha-ras, Ki4a-r ⁇ s, 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-teirriinus contains a sequence motif termed a "CAAX” or "Cys-Aaa ⁇ -Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 370:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl -protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C20 isoprenoid, respectively.
  • Ras proteins are known to undergo post-translational famesylation.
  • farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
  • Famesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol Chem., 265: 14701-14704 (1990); Schafer et al, Science, 249: 1133-1139 (1990); Manne et al, Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)).
  • Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • FPTase famesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
  • FPT-ase inhibitors also inhibit the proliferation of vascular smooth muscle cells and are therefore useful in the prevention and treatment of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930).
  • Rla, Rlb p2 an( j RlO are independently selected from the group consisting of: hydrogen, aryl, substituted aryl,C3-Ci ⁇ cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R80-, R9S(0) m -, R8C(0)NR8-, CN, N ⁇ 2, (R8)2NC(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, R9 ⁇ C(0)NR8- and C1-C6 alkyl, unsubstituted or substituted with 1-3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R80-, R9s(0)m-, R8C(0)NR8-, CN, (R8) 2 NC(NR8)-, R8C(0)-, R8 ⁇
  • R3 and R4 are independently selected from the group consisting of: H, F, Cl, Br, -N(R8)2, CF3, N02, R s O-, R9s(0) m -, R8C(0)NH-, H2NC(NH)-, R8C(0)-, R8 ⁇ C(0)-, N3, CN, R9 ⁇ C(0)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
  • a ⁇ is selected from the group consisting of: -C(O)-, -O-, -S(0) m -, -OC(O)-, -C(0)0-, -NR5-, -NR5S(0) m - or S(0) m NR 5 - ;
  • A4 is selected from -0-, -S(0) m -, -NR5-, -NR 5 C(0)-, -C(0)NR 5 -, -OC(O)-, -C(0)0-, -NR5S(0) m - and -S(0) m NR5- ;
  • n 0, 1 or 2;
  • each R5 is independently selected from the group consisting of: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, and C1-C6 alkyl unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, N02, (R 8 )0-, (R9)S(0) m -, (R8)C(0)NH-, H2N-C(NH)-, (R 8 )C(0)-, (R8)OC(0)-, N3, CN (R9)0C(0)NR8- ;
  • R6 and R 7 are independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci -6 perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0)m-, R8C(0)NR8-, CN, N02, (R S )2NC(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, R9 ⁇ C(0)NR8- and C1-C6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R80-, R9S(0)m-, R 8 C(0)NR8-, CN, (R8) 2 NC(NR8)-, R8
  • each R8 is independently selected from hydrogen, C1-C6 alkyl, aryl and aralkyl;
  • each R9 is independently selected from C1-C6 alkyl and aryl;
  • V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A is S(0) m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0) m ;
  • W represents heterocyclyl
  • Y represents aryl
  • each n and p independently represents 0, 1, 2, 3 or 4; q is 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen, and t is 0 or 1.
  • the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras, and thus are useful for the treatment of cancer.
  • 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.
  • alkyl and the alkyl portion of alkoxy, aralkyl and similar terms, is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, or 1-6 carbon atoms if unspecified. Cycloalkyl means 1- 2 carbocyclic rings which are saturated and contain from 3-10 atoms. "Halogen” or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl and the aryl portion of aralkyl, are 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.
  • a preferred aralkyl group is benzyl.
  • heterocyclyl, heterocycle and heterocyclic mean a 5- to 7-membered monocyclic or 8- to 1 1- membered bicyclic heterocyclic rings, either saturated or unsaturated, aromatic, partially aromatic or non-aromatic, and which consist of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S.
  • it includes any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the ring or ring system may be attached at any heteroatom or carbon - 1 -
  • heterocycles 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, morpholin
  • Heteroaryl is a subset of heterocyclic, and means a monocyclic or bicyclic ring system, with 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.
  • Examples include 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, quinazolinyl, quinolinyl, quinoxal
  • substituted as used in, e.g., with respect to substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl means alkyl, aryl, heterocyclyl and cycloalkyl groups, respectively, having from 1-3 substituents which are selected from: halo, aryl, heterocyclyl, Ci-6 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, C 2 -6 alkynyl, R8O-, R9S(0) m -, R8C(0)NR8-, CN, (R8) 2 NC(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R 8 )2 and R9 ⁇ C(0)NR8-.
  • a substituted alkyl group is substituted with a "substituted
  • 1-2 groups are present on substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl, which are selected from: halo, aryl, R O-, CN, R8C(0)- and -N(R 8 ) 2 .
  • Rla ,Rlb, R2 an d RlO are independently selected from: hydrogen, -N(R8)2, R C(0)NR8- or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, -N(R8)2, R80- and R8C(0)NR8-
  • R3 and R 4 are selected from: hydrogen and C1-C6 alkyl.
  • R6 represents CN, NO2 or R 8 0-.
  • R7 represents hydrogen, unsubstituted or substituted C l -C6 alkyl.
  • R 8 represents H or Ci-6 alkyl
  • R9 is Ci-6 alkyl
  • a ⁇ and A ⁇ are independently selected from: a bond, -C(0)NR8-, -NR8C(0)-, -0-, -N(R8)-, -S(0)2N(R8)- and-
  • A3 represents O, S, NR 5 or NR 5 S(0) m , wherein m represents 2 and R5 represents hydrogen.
  • a 4 represents -C(0)NR 5 - or -NR5C(0)-, with R 5 representing H.
  • V is selected from hydrogen, heterocyclyl and aryl. More preferably V is phenyl.
  • W is heterocyclyl selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl. Preferably, m is 0 or 2.
  • n and p are 0, 1, 2 or 3.
  • t is 1.
  • a subset of compounds of the invention is represented by formula la:
  • each Rla , Rib, R2 nd R 10 is independently selected from hydrogen and Cl-C6 alkyl
  • R5 is selected from the group consisting of: hydrogen and
  • Cl-C6 alkyl unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, -N(R8)2, -CF3, -N ⁇ 2, (R 8 )0-, (R9)S(0) m -, (R8)C(0)NH-, H2NC(NH)-, (R 8 )C(0)-, (R8)OC(0)-, N3, CN and (R9)0C(0)NR8- ;
  • R6 and R 7 are independently selected from: hydrogen, Cl- C ⁇ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R80-, R8C(0)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, and C 1 -C ⁇ alkyl substituted by C 1 -C6 perfluoroalkyl, R8O-, R8C(0)NR8-, (R8) 2 N-C(NR8)-, R8C(0)-, R80C(0)-, -N(R8)2 and R9QC(0)NR8- ;
  • V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and C2-C2O alkenyl, provided that V is not hydrogen if A is S(0) m and V is not hydrogen if A* is a bond and A 2 is S(0) m -
  • a second subset of compounds of the present invention is represented by formula I:
  • R3, R 4 , A 3 , A 4 - Y, R8, R9, m, n, p and r are as originally defined;
  • R2 a nd R i0 is independently selected from hydrogen and C1-C6 alkyl
  • R5 is selected from the group consisting of: hydrogen and C1-C6 alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, -N(R8) 2 , -CF3, -N ⁇ 2, (R 8 )0-, (R9)S(0) m -, (R8)C(0)NH-, H2NC(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN and (R9)0C(0)NR8-;
  • R6 and R 7 are independently selected from: hydrogen, Cl- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R80-, R8C(0)NR8-, CN, N ⁇ 2, (R S )2N
  • V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and C2-C2O alkenyl, provided that V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if Al is a bond and A 2 is S(0)m; and
  • W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
  • a third subset of compounds of the invention is represented by formula la:
  • Rla, Ri , R2, RlO, A l, A , A 4 , Y, R , R 4 , R5, R6, R8, R9, m, n, p, q and r are as originally defined;
  • R7 is selected from: hydrogen and -C6 alkyl;
  • a 3 represents -S-
  • V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, Cl C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl,
  • V is not hydrogen if A* is S(0) and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • a fourth subset of compounds of the present invention is represented by formula lb:
  • Rla, Rib, R2, R10, A l, A2, A 4 , Y, R , R 4 , R5, R6, R8 ? R9, m, n, p, q and r are as originally defined;
  • V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if A ⁇ is a bond, n is 0 and A 2 is S(0)m", and
  • W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
  • each Rib and RlO is independently selected from hydrogen and C1-C6 alkyl
  • R3, R4, R8 ; R9 5 mj p ⁇ anc ⁇ q are as originally defined;
  • a 3 represents -O-, -S- or -NH-;
  • a 4 represents -C(0)NH- or -NHC(O)-; and R6 is selected from the group consisting of: hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C ⁇ perfluoroalkyl, F, Cl, R8 ⁇ -, R8C(0)NR8-, CN, N02, (R S )2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8- and Cl-C ⁇ alkyl substituted by Cl-C ⁇ perfluoroalkyl, R ⁇ -, R8C(0)NR8-, (R8)2N-C(NR8)-, R8C(0)-, R8QC(0)-, -N(R8)2 or R9 ⁇ C(0)NR8-.
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
  • the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in Schemes 1-12, 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 R' and R CH2- represent the substituents R8, R9 n d others, depending on the compound of the instant invention that is being synthesized.
  • the variable p' represents p- 1.
  • Schemes 1-2 illustrates the synthesis of one of the preferred embodiments of the instant invention, wherein the variable W is present as a imidazolyl moiety that is substituted with a suitably substituted benzyl group.
  • Substituted protected imidazole alkanols II can be prepared by methods known in the art, such as those described by F. Schneider, Z Physiol Chem., 3:206-210 (1961) and C.P. Stewart, Biochem. Journal, 17: 130-133(1923). Benzylation and deprotection of the imidazole alkanol provides intermediate III which can be oxidized to the corresponding aldehyde IV.
  • the amine VI can be reacted with a variety of other aldehydes, such as IX, as shown in Scheme 7.
  • the product X is first acylated and then can be deprotected to give the instant compound XI.
  • the compound XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • Compound XI can further be selectively protected to obtain XII which can subsequently be reductively alkylated with a second aldehyde, such as XIII, to obtain XIV. Removal of the Boc protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
  • the product XVII can first be acylated and the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 9, 10).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXI.
  • Boc protected amino alcohol XIX can also be utilized to synthesize 2-aziridinylmethylamides such as XXIV (Scheme 11).
  • XXXIV The instant compounds are useful in the treatment of cancer.
  • Cancers which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
  • Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, scr, abl, lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit farnesyl- protein transferase and famesylation of the oncogene protein Ras.
  • the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)).
  • Such anti-angiogenic properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • the compounds of this invention are also useful for inhibiting or treating other diseases where 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 viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331-1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541-545(1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et ⁇ .FASEB Journal, 2: A3160 (1988)).
  • the instant compounds may also be useful for the treatment of fungal infections.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, in the form of a pharmaceutical composition, which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the compounds can be administered orally, topically, rectally, vaginally transdermally or parenterally, including the intravenous, intramuscular, intraperitoneal and subcutaneous routes of administration.
  • the compound is administered, for example, in the form of tablets or capsules, or as a solution or suspension.
  • carriers which are commonly used include lactose and com starch; lubricating agents, such as magnesium stearate, are commonly added.
  • diluents also include lactose and dried com starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, the pH of the solution is suitably adjusted and the product is buffered.
  • the total concentration is controlled to render the preparation substantially isotonic.
  • the compounds of the instant invention may also be co- administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections. If formulated as a fixed dose, such combination products employ a compound of this invention substantially within the dosage range described below and other pharmaceutically active agent(s) typically within the acceptable dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • the daily dosage will normally be determined by the prescribing physician, who may vary the dosage according to the age, weight, and response of the individual patient, as well as the severity of the patient's condition.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg kg of body weight per day.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition.
  • FPTase famesyl-protein transferase
  • the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • Step A Preparation of l-triphenylmethyl-4-(hydroxymethyl)imidazole
  • 4-(hydroxymethyl)imidazole hydrochloride 35.0 g, 260 mmol
  • triethylamine 90.6 mL, 650 mmol
  • a white solid precipitated from the solution.
  • Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water.
  • Step B Preparation of l-triphenylmethyl-4-(acetoxymethyl)imidazole
  • Step C Preparation of l-(4-cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide
  • a solution of the product from Step B (85.8 g, 225 mmol) and ⁇ -bromo- -tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60 °C for 20 hours, during which a pale yellow precipitate formed.
  • the reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt.
  • the filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60 °C for two hours, cooled to room temperature, and filtered again.
  • 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 (50.4 g, 67% yield, 89% purity by HPLC) which was used in the next step without further purification.
  • Step D Preparation of l-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole
  • Nr-Pivaloyloxymethyl-N ⁇ -phthaloylhistamine (4.55 g, 12.8 mmol; prepared as previously described (J. C. Emmett, F. H. Holloway, and J. L. Turner, J. Chem. Soc, Perkin Trans. I, 1341, (1979)) and ⁇ -bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL). The solution was heated at 55°C for 4 h, cooled to room temperature, and filtered to remove the white solid. The acetonitrile (30 mL) was concentrated to 1/2 its volume under reduced pressure and the solution was heated at 55°C overnight.
  • the solution was cooled and filtered to give a white solid.
  • the volume of the filtrate was reduced to 10 mL, the solution was heated at 55°C for 1 hr, then cooled to room temperature, diluted with EtOAc (25 mL) and filtered to obtain additional white solid.
  • the solids were combined, dried, and used without further purification.
  • Step B Preparation of 4-cvar Tavernzyl-N ⁇ -phthaloylhistamine
  • Step A 2- ⁇ l-(4-Cyanobenzyl)imidazol-5-ylmethoxyl acetic acid
  • a solution of 2-bromoacetic acid in THF at room temperature is treated with excess sodium hydride for 15 minutes.
  • l-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole (Example 1) and the mixture is then heated.
  • the mixture is poured into H2 ⁇ and EtOAc, extracted with EtOAc (3X), washed with brine, dried (MgS ⁇ 4), filtered and evaporated to give the desired compound.
  • Step B N-3-Chlorobenzyl-2-( l-(4-cvanobenzyl imidazol-5-ylmethoxy ⁇ acetamide
  • Step B N-3-Chlorophenyl-2-( 2- ⁇ -(4-cvanobenzyl imidazol-5- yllethylamino ⁇ acetamide
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-N'-(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 [ ⁇ HJ-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 ⁇ M Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et aL, Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%).
  • the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 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/l M 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/l M DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF
  • the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA 1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfamesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.
  • IP buffer 20 nM HEPES, pH 7.5/1 mM EDTA 1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl
  • Rat 1 cells transformed with either a v-ras, v-raf, or w-mos oncogene is tested.
  • Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
  • 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.

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Abstract

Cette invention concerne des composés permettant d'inhiber la transférase de farnésyl-protéine (FTase), ainsi que la farnésylation de la protéine oncogène Ras. Cette invention concerne également des compositions chimiothérapeutiques contenant les composés susmentionnés, ainsi que des procédés permettant d'inhiber la transférase de farnésyl-protéine et la farnésylation de la protéine oncogène Ras.
PCT/US1997/005295 1996-04-03 1997-03-31 Inhibiteurs de transferase de farnesyl-proteine WO1997036877A1 (fr)

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AU26005/97A AU707416B2 (en) 1996-04-03 1997-03-31 Inhibitors of farnesyl-protein transferase
EP97917759A EP0891335A4 (fr) 1996-04-03 1997-03-31 Inhibiteurs de transferase de farnesyl-proteine
JP9535531A JP2000507589A (ja) 1996-04-03 1997-03-31 ファルネシル―タンパク質転移酵素の阻害剤

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WO1998034921A1 (fr) * 1997-02-11 1998-08-13 Warner-Lambert Company Inhibiteurs bicycliques de farnesyltransferase de proteine
US6503901B1 (en) 1999-10-08 2003-01-07 Bristol Myers Squibb Pharma Company Amino lactam sulfonamides as inhibitors of Aβ protein production
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US6509333B2 (en) 2000-06-01 2003-01-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
US6713476B2 (en) 2000-04-03 2004-03-30 Dupont Pharmaceuticals Company Substituted cycloalkyls as inhibitors of a beta protein production
US6759404B2 (en) 2000-04-03 2004-07-06 Richard E. Olson Cyclic malonamides as inhibitors of aβ protein production
US6900199B2 (en) 2000-04-11 2005-05-31 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6962913B2 (en) 1998-08-07 2005-11-08 Bristol-Myers Squibb Company Benzo-1,4-diazepin-2-ones as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7304055B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production

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US6133303A (en) * 1997-02-11 2000-10-17 Warner-Lambert Company Bicyclic inhibitors of protein farnesyl transferase
US6265422B1 (en) 1997-02-11 2001-07-24 Warner-Lambert Company Bicyclic inhibitors of protein farnesyl transferase
US6528535B2 (en) 1997-02-11 2003-03-04 Warner-Lambert Company Bicyclic inhibitors of protein farnesyl transferase
WO1998034921A1 (fr) * 1997-02-11 1998-08-13 Warner-Lambert Company Inhibiteurs bicycliques de farnesyltransferase de proteine
US7507815B2 (en) 1998-08-07 2009-03-24 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of a-β protein production
US7304056B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
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US6962913B2 (en) 1998-08-07 2005-11-08 Bristol-Myers Squibb Company Benzo-1,4-diazepin-2-ones as inhibitors of Aβ protein production
US7304055B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7456172B2 (en) 1998-12-24 2008-11-25 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
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US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
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US7112583B2 (en) 1999-09-13 2006-09-26 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
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EP0891335A1 (fr) 1999-01-20
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AU2600597A (en) 1997-10-22
EP0891335A4 (fr) 2001-08-16
AU707416B2 (en) 1999-07-08

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