EP0880320A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase

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Publication number
EP0880320A1
EP0880320A1 EP97904147A EP97904147A EP0880320A1 EP 0880320 A1 EP0880320 A1 EP 0880320A1 EP 97904147 A EP97904147 A EP 97904147A EP 97904147 A EP97904147 A EP 97904147A EP 0880320 A1 EP0880320 A1 EP 0880320A1
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EP
European Patent Office
Prior art keywords
hydrogen
substituted
alkyl
aryl
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97904147A
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German (de)
English (en)
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EP0880320A4 (fr
Inventor
Christopher J. Dinsmore
George D. Hartman
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9605699.9A external-priority patent/GB9605699D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0880320A1 publication Critical patent/EP0880320A1/fr
Publication of EP0880320A4 publication Critical patent/EP0880320A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
  • Mutated ras genes (Ha-ras, Ki4a-r ⁇ 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-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 famesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational famesylation.
  • farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
  • Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al, Cell, 62:81- «8 (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.
  • 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 urea-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 famesyl-protein transferase are illustrated by the formula I:
  • R la, Rib and R2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, R»0-, R9S(0) m -, R S C(0)NR8-, CN, N ⁇ 2, (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, R80-, R9S(0) m -, R8C(0)NR8-, CN, (R8)2N- C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R90C(0)-NR
  • R3 and R4 are independently selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)0-, (R9)S(0)m-, (R 8 )C(0)NH-, H2N- C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN, CF3(CH2)nO-, (R9)0C(0)NR8-, C1-C2O alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R ⁇ a and R5b are independently 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, 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)-, (R8)OC(0)-, N3, CN (R9)0C(0)NR8-;
  • R6 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, perfluoroalkyl, F, Cl, Br, R80-, R s(0) m -, R8C(0)NR8-, CN, N02, R82N-C(NR )-, R8C(0)-,
  • R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
  • R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • 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 A 1 is a bond, n is 0 and A ⁇ 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 Cl-C6 alkyl
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 8 0-, -N(R 8 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8 ⁇ -, or -N(R8)2;
  • R3 and R 4 are independently selected from F, Cl, Br, N(R 8 )2, CF3, N ⁇ 2, (R8)0-, (R9)S(0) m -, (R8)C(0)NH-, H2N-
  • R a and R5b j- e independently 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)-, (R8)0C(0)-, N3, CN (R9)0C(0)NR8- ;
  • R6 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R80-, R8C(0)NR8-, CN, N ⁇ 2, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C 1 -C ⁇ alkyl substituted by C 1 -C6 perfluoroalkyl, R 0-,
  • R ⁇ a is hydrogen or methyl
  • R is independendy selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independendy selected from C1-C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(0) m and V is not hydrogen if A is a bond, n is 0 and A ⁇ 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 R are independently selected from: hydrogen or Cl-C6 alkyl
  • Rib is independendy selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 8 0-, -N(R 8 )2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8 ⁇ -, or -N(R8)2;
  • R 3 and R 4 are independently selected from F, Cl, Br, N(R 8 )2, CF3, N02, (R 8 )0-, (R9)S(0)m-, (R 8 )C(0)NH-, H2N- C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN, (R9)0C(0)NR8-, C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R5a and R ⁇ b are independently 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, N02, (R 8 )0-,
  • R6 is independendy 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, N ⁇ 2, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl substituted by Cl-C ⁇ perfluoroalkyl, R 8 0-,
  • R 7 is selected from: hydrogen and C1-C6 alkyl
  • R8 is independendy selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independendy selected from C1-C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, ) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 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;
  • the inhibitors of famesyl-protein transferase are illustrated by the formula Ic:
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 8 0-, -N(R 8 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R8 ⁇ -, or -N(R8)2;
  • R are independently selected from: hydrogen or Cl-C6 alkyl
  • R3 and R 4 are independendy selected from F, Cl, Br, N(R8)2, CF3, N02, (R8)0-, (R9)S(0)m-, (R 8 )C(0)NH-, H2N- C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN, (R9)OC(0)NR8-, Cl -C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle;
  • R ⁇ and R ⁇ b are independently 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 independendy selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, R8O-, R8C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R90C(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 R90C(0)NR8- ;
  • R is independendy selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • R b is independendy selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 8 0-, -N(R 8 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R O-, or -N(R8)2; R2 are independently selected from: hydrogen or C1-C6 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-, H2N-
  • R5a and R ⁇ b are independently 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, N02, (R 8 )0-, (R9)S(0) ⁇ r, (R 8 )C(0)NH-, H2N-C(NH)-, (R8)C(0)-, (R8)OC(0)-, N3, CN (R9)OC(0)NR8- ;
  • R is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • R9 is independendy selected from C1-C6 alkyl and aryl
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • any variable e.g. aryl, heterocycle, Rl , R ⁇ etc.
  • its definition on each occurence is independent at every other occurence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,
  • heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, 0, 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
  • Rla, Rib and R2 are independendy selected from: hydrogen, -N(R 8 )2, R8C(0)NR8- or C1-C6 alkyl unsubstituted or substituted by -N(R8)2, R S O- or R8C(0)NR8-.
  • R3 and R 4 are independently selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R ⁇ -, R9S(0) m -, CN, N02, R82N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8- and C1-C6 alkyl.
  • R ⁇ a and R ⁇ b are independently selected from hydrogen or C1-C6 alkyl substituted with hydrogen, R9S(0) m -, CF3- or an unsubstituted or substituted aryl group.
  • R6 is selected from: hydrogen, perfluoroalkyl,
  • R 7 is hydrogen or methyl. Most preferably,
  • R 7 is hydrogen.
  • R 8 is selected from H, C1-C6 alkyl and benzyl.
  • 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, pyridyl, furyl and thienyl. Most preferably, Y is phenyl.
  • n, p and r are independendy 0, 1, or 2.
  • t is 1.
  • the pharmaceutically acceptable salts of the compounds of this invention include die 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.
  • -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.
  • 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 1-13, 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 R , R9 and others, depending on the compound of the instant invention that is being synthesized.
  • the variable p' represents p-1.
  • Schemes 1-13 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).
  • Scheme 2 illustrates other methods of preparing amine intermediates.
  • the alkanol II may be converted to the corresponding amine VI via the azide.
  • that reagent may be ring alkylated to provide the intermediate amine VIII.
  • Amines such as those illustrated in Schemes 1 and 2 may be reacted with a suitably substituted isocyanate IX to provide the instant compound X.
  • Compound X can be selectively N-alkylated under standard conditions, such as those illustrated, to provide the instant compound XI.
  • the isocyanate IX can be reacted with a variety of other amines, such as Xfl, as shown in Scheme 8.
  • the product XIII can be deprotected to give the instant compound XIV.
  • the compound XIV is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • Compound XTV can further be selectively protected to obtain XV which can subsequentiy be reductively alkylated with a second aldehyde, such as XVI, to obtain XVII. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XIX can be accomplished by literature procedures.
  • a bis-protected aldehyde XX may be reacted with a suitable Grignard reagent to provide the secondary alcohol XXI. Subsequent protection and reductive deprotection provides the primary alcohol XXII. This alcohol can then be converted to the corresponding amine by the techniques illustrated in Schemes 1-2 above. Amine XXm may then be reacted with isocyanate DC to provide the carbamate XXTV.
  • a fully deprotected amino alcohol XXV ⁇ can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXVIII (Scheme 10), or tertiary amines.
  • the Boc protected amino alcohol XXIX can also be utilized to synthesize 2-aziridinylmethylureas such as XXX (Scheme 11).
  • Treating XXIX with lj'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide can lead to the formation of aziridine XXX.
  • the aziridine can be reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXI.
  • isocyanate DC can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXVII, as shown in Scheme 12.
  • R' is an aryl group
  • XXXVII can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXVIII.
  • the amine protecting group in XXXVII can be removed, and O-alkylated phenolic amines such as IXL produced.
  • Schemes 13 illustrates an alternate preparation of the instant compounds. As shown in Scheme 13, the isocyanate XL is formed first and is then treated with the suitably substituted aniline such as XLI to provide the instant compound X.
  • 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 famesyl- 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 aberrantiy 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 l .FASEB Journal, 2:A3160 (1988)).
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried com starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the 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.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition.
  • FPTase famesyl-protein transferase
  • the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested. 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 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 sufficiendy potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiendy potent inhibitor required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
  • Step 2 Preparation of l-triphenylmethyl-4-(acetoxymethyl)- imidazol (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. HCl soln. (2 x 1 L), sat. aq. NaHC0 3 , and brine, then dried (Na 2 S0 4 ), filtered, and concentrated in vacuo to provide the crude product. The acetate 3 was isolated as a white powder (85.8 g) which was sufficiendy pure for use in the next step.
  • Step 4 Preparation of l-(4-cyanobenzyl)-5-(hydroxymethyl)- imidazole (5)
  • a solution of the acetate 4 (50.4 g) in 1.5 L of 3:1 THF/water at 0 °C was added lithium hydroxide monohydrate (18.9 g).
  • the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCU 3 and brine.
  • the solution was then dried (Na 2 S0 ), filtered, and concentrated in vacuo to provide the crude product (26.2 g) as a pale yellow fluffy solid which was sufficiendy pure for use in the next step without further purification.
  • Step 6 Preparation of l-(4-cyanobenzyl)-5-(n-pentylamino- methvDimidazole (7)
  • Step 7 Preparation of N-(3-chlorophenyl)-N'-[l-(4-cyanobenzyl)-
  • urea 1 (remaining half of crude product prepared above) in 1 mL of dry DMF at 0 °C was added NaH (14 mg, 60% dispersion in mineral oil). After 15 minutes, iodomethane (0.029 mL) was added dropwise. The reaction was stirred at 0 °C for four hours, then poured into EtOAc/hexane (2:1) and water, washed with sat. aq. NaHC ⁇ 3 and brine, dried (Na 2 S0 4 ), filtered, and concentrated in vacuo to provide a purple oil.
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine- ⁇ T-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-famesyl diphosphate ([3HJ-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 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. The compounds of the instant invention described in Examples 1 and 2 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of ⁇ 10 ⁇ M.
  • the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et aL, Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulf oxide, is 0.1%).
  • 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. When the dye front reached the bottom, the gel is fixed, soaked in EnUghtening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.
  • IP buffer 20 nM HEPES, pH 7.5/1 mM EDTA 1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 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

Composés inhibants la farnésyl-protéine transférase (FTase) et la farnésylation du Ras protéique oncogène. L'invention porte en outre sur des compositions chimiothérapeutiques renfermant les composés de cette invention et sur des méthodes d'inhibitions de la farnésyl-protéine transférase et de la farnésylation du Ras protéique oncogène.
EP97904147A 1996-01-30 1997-01-27 Inhibiteurs de la farnesyl-proteine transferase Withdrawn EP0880320A4 (fr)

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US1086096P 1996-01-30 1996-01-30
US10860P 1996-01-30
GBGB9605699.9A GB9605699D0 (en) 1996-03-19 1996-03-19 Inhibitors of farnesyl-protein transferase
GB9605699 1996-03-19
PCT/US1997/001599 WO1997027752A1 (fr) 1996-01-30 1997-01-27 Inhibiteurs de la farnesyl-proteine transferase

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EP1140087A4 (fr) 1998-12-18 2002-04-03 Du Pont Pharm Co N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
EP1158980B1 (fr) 1998-12-18 2005-08-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines utilisees en tant que modulateurs de l'activite des recepteurs des chimiokines
US6331541B1 (en) 1998-12-18 2001-12-18 Soo S. Ko N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6525069B1 (en) 1998-12-18 2003-02-25 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
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AU2001251444A1 (en) 2000-04-10 2001-10-23 Merck And Co., Inc. Inhibitors of prenyl-protein transferase
DE10025782A1 (de) 2000-05-26 2001-12-06 Basf Ag Flüssigkristalline Stoffgemenge
EP1162194A1 (fr) * 2000-06-06 2001-12-12 Aventis Pharma Deutschland GmbH Dérivés de (thio)-urée inhibiteurs du facteur VIIa, procédé de leur préparation et leur utilisation
CA2413245A1 (fr) 2000-06-30 2002-01-10 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloaklyl-piperidines utilises comme modulateurs de l'activite du recepteur de la chimiokine
WO2003024401A2 (fr) 2001-09-18 2003-03-27 Bristol-Myers Squibb Company Piperazinones de modulation de l'activite des recepteurs des chimiokines
TW200409630A (en) 2002-09-12 2004-06-16 Bristol Myers Squibb Co N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6919356B2 (en) 2002-09-26 2005-07-19 Bristol Myers Squibb Company N-substituted heterocyclic amines as modulators of chemokine receptor activity
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WO1997027752A1 (fr) 1997-08-07
AU712504B2 (en) 1999-11-11

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