EP0877610A1 - Inhibiteurs de farnesyl-proteine transferase - Google Patents

Inhibiteurs de farnesyl-proteine transferase

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Publication number
EP0877610A1
EP0877610A1 EP97907546A EP97907546A EP0877610A1 EP 0877610 A1 EP0877610 A1 EP 0877610A1 EP 97907546 A EP97907546 A EP 97907546A EP 97907546 A EP97907546 A EP 97907546A EP 0877610 A1 EP0877610 A1 EP 0877610A1
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EP
European Patent Office
Prior art keywords
substituted
alkyl
aryl
unsubstituted
hydrogen
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Withdrawn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
EP97907546A
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German (de)
English (en)
Other versions
EP0877610A4 (fr
Inventor
Christopher J. Dinsmore
George D. Hartman
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
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Merck and Co Inc
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Publication date
Priority claimed from GBGB9607124.6A external-priority patent/GB9607124D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0877610A1 publication Critical patent/EP0877610A1/fr
Publication of EP0877610A4 publication Critical patent/EP0877610A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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

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-ra.s, Ki4b-r ⁇ .s 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 box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 570:583-586 (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 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.
  • 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, (52:81-88 (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, 57:7541-7545 (1990)).
  • Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • direct inhibition of famesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
  • FPTase famesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al, Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
  • deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
  • famesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and thereapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930).
  • an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit famesyl-protein transferase and thus, the post-translational famesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.
  • the present invention comprises small molecule peptidomimetic amide-containing compounds which inhibit the famesyl- protein transferase.
  • the instant compounds lack a thiol moiety and thus offer unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity.
  • the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula I:
  • R la, Rib an d R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R80-, R9S(0) m -, R 8 C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R90C(0)NR8-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O-, R9s(0) m -, R8C(0)NR8-, CN, (R8)2N- C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R
  • R 3 and R 4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)0-, (R9)S(0) m -, (R8)C(0)NH-, H2N- C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN, CF3(CH2) n O-, (R9)OC(0)NR8-, C1-C2O alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R5 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstit
  • R6 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-
  • R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0)m-, R8c(0)NR8-, CN, N ⁇ 2, (R8)2N-C-(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R90C(0)NR8-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0)m-, R S C(0)NR8-, CN, (R8)2N- C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R90C(0)NR8-; R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independently selected from Cl-C6 alkyl and aryl
  • RIO and Rl 1 are independently selected from: H; O or
  • Rl2 is H, Cl-ClO alkyl, substituted or unsubstituted aryl or Cl-
  • a 3 is selected from: -NR5- or a bond
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-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 aryl or heteroaryl
  • n 0, 1, 2, 3 or 4
  • p 0, 1, 2, 3 or 4
  • r 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ;
  • Rla and R2 are independently selected from: hydrogen or C1-C alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R80-, -N(R8)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R80-, or -N(R8)2;
  • R3 and R 4 are independently selected from F, Cl, Br, N(R 8 )2, CF3, N02, (R8)0-, (R9)S(0)m-, (R 8 )C(0)NH-, H2N- C(NH)-, (R8)C(0)-, (R8)0C(0)-, N3, CN, (R9)OC(0)NR8-, C 1 -C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R5 is selected from: a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, N ⁇ 2, (R 8 )0-,
  • R6 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, R 0-, R8C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R ⁇ C(O)-, R80C(0)-, -N(R8) 2 , or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R80-,
  • R ⁇ is hydrogen or methyl;
  • R is independently selected from hydrogen, Cl-C6 alkyl, benzyl and aryl;
  • R9 is independently selected from Cl-C6 alkyl and aryl
  • RlO and RU are independently selected from: H; O or
  • Rl2 is H, Cl-ClO alkyl and substituted or unsubstituted aryl
  • A is selected from: -NR5- or a bond
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that 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 ;
  • n 0, 1, 2, 3 or 4
  • p 0, 1 , 2, 3 or 4
  • r 0 to 5, provided that r is 0 when V is hydrogen
  • Rla and R2 are independently selected from: hydrogen or C1-C alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 0-, -N(R8)2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R80-, or -N(R8)2;
  • R3 and R 4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R 8 )0-, (R9)S(0)m-, (R8)C(0)NH-, H2N- C(NH)-, (R8)C(0)-, (R8)0C(0)-, N 3 , CN, (R9)OC(0)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R5 is selected from: a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R 8 )2, CF3, N02, (R 8 )0-, (R9)S(0)m-, (R8)C(0)NH-, H2N-C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN (R9)OC(0)NR8-;
  • R ⁇ is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C l -C6 perfluoroalkyl, F, Cl, R s O-, R8C(0)NR 8 -, CN, NO2, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C 1 -C6 alkyl substituted by C l -C6 perfluoroalkyl, R80-, R8C(0)NR8-, (R8)2N-C(NR8)-, R8 O)-, R8 ⁇ C(0)-, -N(R8)2, or R90C(0)NR8- ;
  • R7 is selected from: hydrogen and C1-C6 alkyl
  • R is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl; NR 8
  • R 0 and RU are independently selected from: H; O or
  • Cl-5 alkyl unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl, 2) heterocycle,
  • R is Cl-ClO alkyl and substituted or unsubstituted aryl
  • a 3 is selected from: -NR ⁇ - or a bond
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided diat 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 is S(0)m;
  • W is a heterocycle selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 1 ;
  • the inhibitors of famesyl-protein transferase are illustrated by the formula Ic:
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R8 ⁇ -, -N(R8)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R Q-, or -N(R8)2;
  • R2 are independently selected from: hydrogen or C1-C alkyl
  • R3 and R 4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)0-, (R9)S(0)m-, (R8)C(0)NH-, H 2 N- C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN, (R9)OC(0)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R5 is selected from: a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R 8 )2, CF3, N ⁇ 2, (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 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, R80-, R8C(0)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8C(0)-, R8oC(0)-, -N(R8) 2 , or
  • R9 ⁇ C(0)NR8- and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R80-, R8C(0)NR8-, (R8) 2 N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9QC(0)NR8-;
  • R is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independently selected from Cl-C ⁇ alkyl and aryl
  • R 10 and RU are independently selected from: H; O 0 r
  • R 2 is Cl-Cio alkyl and substituted or unsubstituted aryl
  • p 0, 1, 2, 3 or 4;
  • Rib is independendy selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R8 ⁇ -, -N(R8)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8 ⁇ -, or -N(R8)2;
  • R2 are independently selected from: hydrogen or Cl-C6 alkyl
  • R3 and R 4 are independently selected from F, Cl, Br, N(R 8 )2, CF3, N02, (R8)0-, (R9)S(0)m-, (R8)C(0)NH-, H 2 N- C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN, (R9)OC(0)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R5 is selected from: a) hydrogen, and b) C1-C6 alkyl substituted with hydrogen or a group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C3-C10 cycloalkyl, N(R8)2, CF3, N ⁇ 2, (R 8 )0-, (R9)S(0)m-, (R8)C(0)NH-, H2N-C(NH)-, (R8)C(0)-,
  • R is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • R O and Rl 1 are independently selected from: H; O or
  • Rl2 is Cl-ClO alkyl and substituted or unsubstituted aryl
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • any variable e.g. aryl, heterocycle, Rla, R2 etc.
  • its definition on each occurence is independent at every other occurence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazo
  • 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
  • substituted aryl As used herein, the terms “substituted aryl”, “substituted heterocycle” and “substituted cycloalkyl” are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2, N ⁇ 2, CN, (C1-C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0)m-, (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(0)NH- and C1-C20 alkyl.
  • Rla, Rib and R2 are independently selected from: hydrogen, -N(R 8 )2, R S C(0)NR8- Q r C1-C6 alkyl unsubstituted or substituted by -N(R8)2, R80- or R8C(0)NR8-.
  • R3 and R4 are independently selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R8O-, R S(0) m -, CN, NO2,
  • R5 is selected from hydrogen or C1-C6 alkyl substituted with hydrogen, R9S(0) ⁇ , CF3- or an unsubstituted or substituted aryl group.
  • R6 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0) m -, CN, N ⁇ 2, R 2N-C(NR8)-, R8C(0)-, R80C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8- and C1-C6 alkyl.
  • R? is hydrogen.
  • R is selected from H, C1-C6 alkyl and benzyl.
  • R9 is selected from C1-C6 alkyl.
  • RlO and R is selected from H, C1-C6 alkyl and benzyl.
  • Rl2 is selected from C1 -C6 alkyl. More preferably Rl2 is methyl.
  • Al and A are independently selected from: a bond, -C(0)NR8-, -NR8c(0)-, O, -N(R8)-, -S(0)2N(R8)- and-
  • V is selected from hydrogen, heterocycle and aryl. Most preferably, V is phenyl.
  • Y is selected from phenyl, furyl, thienyl and pyridyl. Most preferably, Y is phenyl.
  • n, p and r are independently 0, 1, or 2.
  • 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.
  • any substituent or variable e.g., Rla, Z, n, etc.
  • -N(R8)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
  • the pharmaceutically acceptable salts of the compounds of this invention 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 die 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- as shown in the Schemes, represent the substituents R , R and others, depending on the compound of the instant invention that is being synthesized.
  • the variable p' represents p-1.
  • Schemes 1-2 illustrates the syntiiesis 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,
  • the aldehyde whose synthesis is illustrated in Scheme 1 may be reacted witii a suitably substituted diamine VI, which was prepared from the aniline V as shown in Scheme 2, to provide the intermediate compound VII.
  • Compound VII can be selectively N- acylated under standard conditions, such as those illustrated, to provide the instant compound VIII.
  • the analogous reaction directed towards compounds wherein A ⁇ is a bond is illustrated in Scheme 2a.
  • Schemes 3-6 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 syntiietic strategies for preparing alkanols tiiat incorporate other heterocyclic moieties for variable W are also well known in die art.
  • the diamine 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 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.
  • the fully deprotected amino alcohol XXII can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXIII (Scheme 10), or tertiary amines.
  • the Boc protected amino alcohol XIX can also be utilized to synthesize 2-aziridinylmethylamides such as XXIV (Scheme 11). Treating XIX with 1 , 1 '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide leads to the formation of aziridine XXIV. The aziridine may be reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXVI.
  • a nucleophile such as a thiol
  • die diamine VI can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXII, as shown in Scheme 12.
  • Intermediate XXXII is first acylated before it is further elaborated.
  • R' is an aryl group
  • XXXIII can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXIV.
  • the amine protecting group in XXXIII can be removed, and O-alkylated phenolic amines such as XXXV produced.
  • the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
  • Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras formation (i.e., neurofibromen (NF-1), neu, scr, abl, lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit farnesyl- protein transferase and the famesylation of the oncogene protein Ras.
  • the instant compounds may also inhibit tumor angiogenisis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenisis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF- 1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1:541-545(1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142: 1051-1060 (1993) and B. Cowley, Jr. et a FASEB Journal, 2:A3160 (1988)).
  • the compounds of mis invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • 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 present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents.
  • Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacolo ⁇ gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
  • 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 farnesyl-protein transferase (FPTase) in a composition.
  • FPTase farnesyl-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 die amine terminus) and farnesyl 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 me 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. It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quantitating the enzyme.
  • 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 fa esyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at d e 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 1 Preparation of l-triphenylmethyl-4-(hydroxymethyl)- imidazole (2)
  • Step 2 Preparation of l-triphenylmethyl-4-(acetoxymethyl)- imidazole (3)
  • Alcohol 2 (prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 L), 5% aq. HCI soln. (2 x 1 L), sat. aq. NaHC ⁇ 3 , and brine, then dried (Na 2 S ⁇ 4 ), filtered, and concentrated in vacuo to provide the crude product. The acetate 3 was isolated as a white powder which was sufficiently pure for use in the next step.
  • Step 3 Preparation of l-(4-cyanobenzyl)-5-(acetoxymethyl)- imidazole hvdrobromide (4)
  • a solution of 3 (85.8 g) and oc-bromo-/?-tolunitrile (50.1 g) 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.
  • Step 5 Preparation of l-(4-cyanobenzyl)-5-imidazole- carboxaldehyde (6)
  • the amine hydrochloride 7 (978 mg) was partitioned between dilute aqueous NaHC0 3 solution and methylene chloride. The aqueous layer was washed with three portions of CH 2 CI 2 , and die combined organics were dried (Na 2 S ⁇ 4 ), filtered, and concentrated in vacuo to provide the free amine. To a solution of the amine in 11 mL of 1,2-dichloroethane at 0 °C was added 4 A powdered molecular sieves (2 g), followed by sodium triacetoxyborohydride (3.04 g). The aldehyde 6 (1.21 g) was added, and the reaction was stirred at 0 °C.
  • Step 8 Preparation of N-[l -(4-cyanobenzyl)-5-imidazolylmethyl]-
  • Step 2 Preparation of N-[ ⁇ -(4-cyanobenzyl)-5-i ⁇ nidazolylmethyl]-
  • 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 [ ⁇ Hj-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
  • Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ - plate counter.
  • the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in die 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. The compound of die instant invention described hereinabove in Example 1 was tested for inhibitory activity against human FPTase by the assay described above and was found to have IC50 of ⁇ 10 ⁇ M.
  • 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 R___a_ch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%).
  • the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35s]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the ly sates 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.
  • 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 eitiier 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 die 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

Composés qui inhibent la farnésyl-protéine transférase (Ttase) et la farnésylation de la protéine oncogène Ras. La présente invention concerne en outre des compositions chimiothérapeutiques contenant lesdits composés et des procédés permettant d'inhiber la farnésyl-protéine transférase et la farnésylation de la protéine oncogène Ras.
EP97907546A 1996-01-30 1997-01-27 Inhibiteurs de farnesyl-proteine transferase Withdrawn EP0877610A4 (fr)

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US1108196P 1996-01-30 1996-01-30
US11081P 1996-01-30
GBGB9607124.6A GB9607124D0 (en) 1996-04-04 1996-04-04 Inhibitors of farnesyl-protein transferase
GB9607124 1996-04-04
PCT/US1997/001455 WO1997027853A1 (fr) 1996-01-30 1997-01-27 Inhibiteurs de farnesyl-proteine transferase

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CA2243507A1 (fr) * 1996-01-30 1997-08-07 Christopher J. Dinsmore Inhibiteurs de la farnesyl-proteine transferase
WO2000001382A1 (fr) 1998-07-02 2000-01-13 Merck & Co., Inc. Inhibiteurs de prenyl-proteine transferase
WO2000001701A1 (fr) 1998-07-02 2000-01-13 Merck & Co., Inc. Inhibiteurs de prenyl-proteine transferase
US7049324B1 (en) 1999-11-15 2006-05-23 Ashis Kumar Saha Triazoles as farnesyl transferase inhibitors
AU779426B2 (en) 1999-11-15 2005-01-27 Janssen Pharmaceutica N.V. Triazoles as farnesyl transferase inhibitors
US6380228B1 (en) 2000-04-10 2002-04-30 Merck & Co., Inc. Inhibitors of prenyl-protein transferase

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US4749713A (en) * 1986-03-07 1988-06-07 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
US5571792A (en) * 1994-06-30 1996-11-05 Warner-Lambert Company Histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase
US5534537A (en) * 1995-03-29 1996-07-09 Merck & Co., Inc. Prodrugs of inhibitors of farnesyl-protein transferase
US5578629A (en) * 1995-03-29 1996-11-26 Merck & Co., Inc. Benzamide-containing inhibitors of farnesyl-protein transferase

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