WO1996030015A1 - Inhibiteurs de farnesyl-proteine transferase - Google Patents

Inhibiteurs de farnesyl-proteine transferase Download PDF

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Publication number
WO1996030015A1
WO1996030015A1 PCT/US1996/003980 US9603980W WO9630015A1 WO 1996030015 A1 WO1996030015 A1 WO 1996030015A1 US 9603980 W US9603980 W US 9603980W WO 9630015 A1 WO9630015 A1 WO 9630015A1
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Prior art keywords
independently selected
hydrogen
alkyl
methylthiopropyl
benzamide
Prior art date
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PCT/US1996/003980
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English (en)
Inventor
Terrence M. Ciccarone
Theresa M. Williams
Suzanne C. Mactough
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Merck & Co., Inc.
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Publication date
Priority claimed from US08/412,830 external-priority patent/US5534537A/en
Priority claimed from US08/413,137 external-priority patent/US5578629A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP8529547A priority Critical patent/JPH11503419A/ja
Priority to AU53701/96A priority patent/AU706008B2/en
Priority to EP96910528A priority patent/EP0817630A4/fr
Publication of WO1996030015A1 publication Critical patent/WO1996030015A1/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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton

Definitions

  • Ras protein is 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 signed 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 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 C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (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 farnesylation. Other farnesylated proteins.include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above
  • FPTase farnesyl-protein transferase
  • FPP farnesyl diphosphate
  • Ras protein substrates
  • peptide derived class of inhibitors a subclass of inhibitors has been described which generally comprises cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
  • peptide derived inhibitors which comprises peptidomimetic compounds wherein the central AA portion of the CAAX motif has been replaced by 3-aminobenzoic acid and 3-aminomethylbenzoic acid spacers has recently been described (M. Nigam et al. J. Biol. Chem., 268:20695-20698 (1993), Y. Qian et al. /. Biol.
  • FPTase peptidomimetic inhibitors further lacking a C-terminus peptidyl moiety (wherein the X peptide has been replaced by a non-peptide moiety) have also been recently described (A. Vogt et al. J. BiolChem., 270:660-664 (1995)). All of the
  • the present invention includes substituted
  • aminoalkylbenza ⁇ iide and aminobenzamide analogs which inhibit the farnesyl-protein transferase, chemotherapeutic compositions containing the compounds of this invention, and methods for producing the compounds of this invention. Furthermore these analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid
  • the compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of certain proteins.
  • the farnesyl-protein transferase inhibitors are illustrated by the formula I:
  • R 1a and R 1b are independently selected from: ,
  • R 2a and R 2b are independently selected from: , ,
  • R 3a and R 3b are independently selected from:
  • R 3a and R 3b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 4 and R 5 are independently selected from:
  • R 7 is independently selected from:
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Z is independently H 2 or O
  • R 1a and R 1b are independently selected from: ,
  • R 2a and R 2b are independently selected from:
  • R 3a and R 3b are independently selected from: R 3a and R 3b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ; R 4 and R 5 are independently selected from:
  • R 7 is independently selected from:
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 13 is independently selected from C 1 -C 6 alkyl
  • V is selected from: provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Z is independently H 2 or O
  • R 1a and R 1b are independently selected from:
  • R 2a and R 2b are independently selected from: - , ,
  • R 4 and R 5 are independently selected from:
  • R 7 is independently selected from:
  • R 8 is selected from:
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Z is independently H 2 or O
  • R 1a and R 1b are independently selected from:
  • R 2a and R 2b are independently selected from:
  • R 4 and R 5 are independently selected from: a) hydrogen, and
  • R 7 is independently selected from:
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • V is selected from:
  • V is not hydrogen if A is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ; W is a heterocycle;
  • Z is independently H 2 or O
  • Ras farnesyl transferase inhibitors are illustrated by the Formula la:
  • R 1a is independently selected from: hydrogen or C 1 -C 6 alkyl
  • R 1b is independently selected from:
  • R 2a is selected from:
  • R 2b is hydrogen
  • R 3a and R 3b are independently selected from:
  • R 4 and R 5 are independently selected from: a) hydrogen, and
  • R 7 is independently selected from:
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • Z is independently H 2 or O
  • R 1a is independently selected from: hydrogen or C 1 -C 6 alkyl
  • R 1b is independently selected from:
  • R 2a is selected from:
  • R 2b is hydrogen
  • R 3a and R 3b are independently selected from:
  • R 4 and R 5 are independently selected from:
  • R 7 is independently selected from:
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 13 is independently selected from C 1 -C 6 alkyl
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • Z is independently H 2 or O
  • R 1a is independently selected from: hydrogen or C 1 -C 6 alkyl
  • R 1b is independently selected from:
  • R 2a is selected from:
  • R 2b is hydrogen
  • R 4 and R 5 are independently selected from: a) hydrogen, and
  • R 7 is independently selected from:
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ", W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • R 1a is independently selected from: hydrogen or C 1 -C 6 alkyl
  • R 1b is independently selected from:
  • R 2a is selected from:
  • R 2b is hydrogen
  • R 4 and R 5 are independently selected from: a) hydrogen, and
  • R 7 is independently selected from:
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
  • 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 is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • cycloalkyl is intended to include non-aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds.
  • alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
  • aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11-15 membered tricyclic heterocycle 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. Examples of such heterocyclic elements include, but are not limited to, azepinyl,
  • benzimidazolyl benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, irnidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopi ⁇ erazin
  • substituted aryl substituted heterocycle
  • 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, CF 3 , NH 2 , N(C 1 -C 6 alkyl) 2 , NO 2 , CN, (C 1 -C 6 alkyl)O-, -OH, (C 1 -C 6
  • cyclic moieties are formed.
  • examples of such cyclic moieties include, but are not limited to:
  • cyclic moieties may optionally include a heteroatom(s).
  • heteroatom-containing cyclic moieties include, but are not limited to:
  • 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, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • -N(R 10 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , 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.
  • 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 by reacting the free base with
  • the compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis
  • Reaction Schemes E - M illustrate reactions wherein the non-sulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to an aminomethylbenzamide subunit which may be further elaborated to provide the instant compounds. These reactions may be employed in a linear sequence to provide the
  • Schemes A - D can be reductively alkylated with a variety of aldehydes, such as I, as shown in Reaction Scheme E.
  • the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme E).
  • the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium
  • cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide.
  • the product II can be deprotected to give the final compounds III with trifluoroacetic acid in methylene chloride.
  • the final product III is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine III can further be selectively protected to obtain IV, which can subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.
  • the aminomethylbenzamide subunit can be reductively alkylated with other aldehydes such as 1-trityl-4-carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as VIII (Reaction Scheme F).
  • the trityl protecting group can be removed from VIII to give IX, or alternatively, VIII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X.
  • the aminomethylbenzamide subunit can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XI can be converted to the acetate XIII by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the
  • the aminomethylbenzamide subunit is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XVI in Reaction Scheme H
  • the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes H, I).
  • 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 XX.
  • the fully deprotected amino alcohol XXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme J), or tertiary amines.
  • the Boc protected amino alcohol XVIII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXIII (Reaction Scheme K). Treating XVIII with 1 , 1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXIII . The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXIV .
  • a nucleophile such as a thiol
  • the aminomethylbenzamide subunit can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme L.
  • R 1 is an aryl group
  • XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI.
  • the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced.
  • Reaction Scheme M illustrates a one pot synthesis of an instant compound wherein the N-terminus nitrogen is substituted with two different non-sulfhydryl-containing moieties.
  • aminomethylbenzamide subunit is treated with one equivalent of an appropriate aldehydea and, after the reductive adduct has been formed, the in situ intermediate is treated with an equivalent of a different aldehyde.
  • the -NR 4 R 5 moiety of the compounds of the instant invention may provide advantages over a cysteinyl moiety that is incorporated in other types of molecules that are known to be inhibitors of farnesyl protein transferase.
  • modification of the benzodiazepine compounds described in published PCT application WO 94/26723 with the such -NR 4 R 5 substituents as described herein will provide inhibitors of farnesyl protein transferase of the following formulae A and B:
  • R 4 benz, R 4 'benz R 7 benz and W benz are R 4 , R 4' , R 7 and W respectively as defined in WO 94/26723 and R a and R b are defined as R 4 and R 5 are defined herein respectively.
  • the following combinations of R a and R b are selected for incorporation into the compounds of formulae A and B:
  • benzodiazepine compound would be selected from the following formulae:
  • R and R' are as defined in WO 94/26723 and W' benz is W' as defined in WO 94/26723 and R a and R b are defined as R 4 and R 5 are defined herein respectively.
  • Such benzodiazepine analogs may be synthesized by techniques well known in the art, as well as procedures outlined in WO 94/26723. General methods of synthesis of the benzediazapine analogs of this invention are shown in Schemes N, P and Q. Typically a convergent route is employed, which joins the key intermediate 9 (Scheme N) with suitably functionalized amine and R a and R b
  • the protected amino acid 9 may be prepared from a suitably substituted 2-aminobenzophenone (1).
  • Many 2-aminobenzophenones are known in the art or are available form
  • 3 may be alkylated at N-1 with a variety of other alkylating agents, for instance, esters of substituted or unsubstituted acrylates, 4-bromobutanoates, etc.
  • Branched compounds i.e. R 4benz and/or R 4'benz ⁇ H
  • R 4benz and/or R 4'benz ⁇ H may be prepared by generation of the polyanion of 5 with base and alkylation with an appropriate alkyl halide.
  • the ester of 5 may be cleaved with an acid such as TFA (for the tert-butyl esters) or under mild aqueous base hydrolysis (for other alkyl esters) at temperatures between 0 and 25 °C.
  • the acid 6 is converted to amino acid 8 via reaction of the dianion, generated with at least two equivalents of a strong base with an electrophilic animating agent.
  • 6 may be halogenated and reacted with an amine source such as azide (followed by reduction) or ammonia.
  • 6 is reacted with 4 equivalents of potassium tert-butoxide in glyme at -5 °C for 30 min and treated with 1.1 equivalents of isobutyl nitrite.
  • the resulting oxime 7 can then be reduced to the racemic amino acid 8 using a variety of reductants, preferably hydrogenation at 40 psig in the presence of Ruthenium on carbon or Raney nickel in methanol at 50 to 70 oC for 1-4 days.
  • reductants preferably hydrogenation at 40 psig in the presence of Ruthenium on carbon or Raney nickel in methanol at 50 to 70 oC for 1-4 days.
  • Amino acid 8 is then suitably protected for selective coupling at the carboxyl terminus.
  • 8 can be converted to the N-BOC derivative 9 using standard amino acid protection conditions, preferably, reaction with equimolar amounts of di-tert-butyl dicarbonate and triethyl amine in DMF/ water at ambient temperature.
  • R a ⁇ H 9 can be alkylated at nitrogen with a wide variety of alkylating agents including n-alkyl, branched alkyl, and benzyl, according to the standard procedure of Benoiton, et al., Can.
  • 3 may be directly alkylated with the "top" sidechain in one intact piece, as shown in Scheme Q.
  • Reaction of 3 with an alkyl halide such as a suitably substituted benzyl bromide, alkyl bromide, in the presence of a base, preferably NaH or Cs 2 CO 3 gives 11, which may be processed according to the reactions illustrated in Scheme I to provide the desired FPTase inhibitors.
  • P.G. is a suitably selected protecting group which is utilized if necessary.
  • the compounds of this invention inhibit Ras farnesyl transferase which catalyzes the first step in the post-translational processing of Ras and the biosynthesis of functional Ras protein. These 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, and myeloid leukemias.
  • 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,
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or
  • 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.
  • 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 ad ⁇ iinistration 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 pharmacologically 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.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 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
  • FPTase farnesyl-protein transferase
  • composition to be tested may be divided and the two
  • mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • farnesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
  • the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques.
  • 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 composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficientiy potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficientiy potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • Step B Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-azidomethylbenzamide
  • Step E Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-(4-in ⁇ idazolylmethyl)aminomethylbenzamide dihydrochloride
  • Step F Preparation of N-(1(S)-carboxy-3-methylthiopropyl)-3-(4- imidazolylmethyl)aminomethyl benzamide dihydrochloride
  • Step E The product from Step E (0.030 g, 0.067mmol) was dissolved in 5 mL of methanol and 3 mL of 5% sodium hydroxide and stirred for 1 h under nitrogen.
  • the reaction mixture was injected directiy onto a preparative reverse phase HPLC column with conditions identical as in the preparation of the compound in Step E. Pure fractions were pooled, evaporated in vacuo, and the sample was converted to the hydrochloride salt as before. Lyophillization overnight afforded 0.022 g (0.051 mmol) of the title compound as a solid.
  • Step A Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-[N,N-bis[(1-triphenylmethyl)-4-imidazolylmethyl]- aminomethyl-benzamide
  • Step B Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-[N,N-bis(4-imidazolylmethyl)aminomethyl]benzamide dihydrochloride
  • triethylsilane 0.159 g, 1.36 mmol
  • trifluoroacetic acid 5 mL
  • the 0.1% TFA/water:methanol solution was injected directiy onto a Delta-Pak (C-18, 100 ⁇ , 15 mm, 40mm ⁇ 100mm) preparative HPLC column.
  • the gradient at 40 mL/min was 100% 0.1% TFA/water for 5 min followed by 95% 0.1% TFA/water to 60% 0.1% TFA/water :40% 0.1% TFA/acetonitrile over 40 min.
  • the pure fractions were pooled, evaporated to near dryness, and then taken up in 5 mL of water.
  • the aqueous solution was passed through a 1.2 gm. column of Bio-Rad AG 3-X4 chloride anion exchange resin.
  • Step C Preparation of N-(1(S)-carboxy-3-methylthiopropyl)-3- [N,N-bis(4-imidazolemethyl)aminomethyl]benzamide dihydrochloride
  • the compound from Step B (0.035 g, 0.052 mmol) was dissolved in 5 mL of methanol and 3 mL of 5% sodium hydroxide and stirred for 1 hr under nitrogen.
  • the reaction mixture was injected directly onto a preparative HPLC column with conditions identical as in Step B. Pure fractions were pooled, evaporated, and die sample converted to the hydrochloride salt as before. Lyophilization overnight afforded the title compound as a solid.
  • Step B of Example 1 was used to prepare the title compound.
  • Step C of Example 1 was used to prepare the title compound.
  • Step F Preparation of 3- [(t-butyloxycarbonyl)-N-methylaminomethyl] benzoic acid
  • Step G Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-[(t-butyloxycarbonyl)-N-methylaminomethyl]benzamide
  • hydroxybenzotriazole (0.16 g)
  • EDC (0.19 g
  • N-methylmorpholine (0.40 mL)
  • (S) methione methyl ester hydrochloride (0.203 mg). After stirring for 2 h the solution was concentrated in vacuo and the residue was partitioned with water and ethyl acetate.
  • Step H Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-(N-methylaminomethyl)benzamide trifluoroacetate
  • Step I Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-[(1-triphenylmethyl)-4-imidazolylmethyl-N-methylaminomethyl]benzamide
  • Step J Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 3-[(4-imidazolylmethyl) -N-methyl-minomethyl]benzamide dihydrochloride Starting with the compound from Step I (0.24 g) the method described in Step E of Example 1 was used to prepare the title compound. FAB mas spectrum m/e 391 (m+1).
  • Step K Preparation of N-(1(S)-carboxy-3-methylthio ⁇ ro ⁇ yl)-3-[(4- imidazolemethyl) -N-methyl-aminomethyl]benzamide dihydrochloride
  • Step F of Example 1 Starting with the compound from Step J (0.035 g) the method described in Step F of Example 1 was used to prepare the above title compound. FAB mas spectrum m/e 377 (m+1).
  • Step B Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 4-(t-butyloxycarbonyl)aminobenzamide
  • Step D Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 4-[(1-triphenylmethyl)-4-imidazolylmethyl]- aminobenzamide
  • Step E Preparation of N-(1(S)-carbomethoxy-3-methylthiopropyl)- 4-(4-imidazolylmethyl)aminobenzamide dihydrochloride
  • Step E of Example 1 Starting with the product from Step D (0.24 g) the method described in Step E of Example 1 was used to prepare the title compound. FAB mas spectrum m/e 363 (m+1).
  • Step F Preparation of N-(1(S)-carboxy-3-methylthiopropyl)-4-[(4- imidazolylmethyl)amino]benzamide dihydrochloride
  • Example 5 Using the appropriate starting materials the methods described above for Example 4 were used to prepare Examples 5-7.
  • Step A N-(1(S)-Carbomethoxy-3-methylthiopropyl)-3-[N-(4- imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]- benzamide ditrifluoroacetate
  • N-(1(S)-carbomethoxy-3-methylthiopropyl)-3-aminomethylbenzamide (0.104 g, 0.352 mmol) was dissolved in dichloroethane (5 mL). Cmshed molecular sieves ( 0.209 g) and sodium triacetoxyborohydride (0.186 g, 0.881 mmol). The pH was about 7.5. 4-Nitrobenzaldehyde (0.0533 g, 0.352 mmol) was added plus 0.5 drop of acetic acid to bring the pH to about 7. The reaction was stirred 2 h under nitrogen at 20°C.
  • the cmde product was chromatographed on silica gel with 50% ethyl acetate in hexane. This chromatographed product was dissolved in dichloromethane ( 7 mL); triethylsilane (0.5 mL, 3.13 mmol) was added and then trifluoroacetic acid ( 3.5 mL). After 0.5 h at 20°C, the solvent was evaporated and the residue partitioned between hexane and water.
  • aqueous solution was purified by preparative reverse phase HPLC using a 100 mm Waters PrepPak® reverse phase column (DeltaPakTM C18, 50 ⁇ M, 100 ⁇ ) and pure product isolated by gradient elution using 80% 0.1% trifluoroacetic acid in water (Solvent A) and 20% 0.1% trifluoroacetic acid in
  • Step B Preparation of N-(1(S)-carboxy-3-methylthiopro ⁇ yl)-3-[N- (4-imidazolylymethyl)-N-(4-nitrobenzyl)aminomethyl]- benzamide ditrifluoroacetate
  • Step A The product from Step A ( 0.045 g, 0.0608 mmol) was dissolved in methanol (4 mL) and 0.5 mL of 10% NaOH solution was added to take pH to about 12. Water (4 mL) was added. At 3 h reaction was purified and lyophilized according to the procedure described in Step A to the title compound as a white solid.
  • Step A Preparation of N-(1(S)-carboxymethyl-3-methylthiopropyl)- 3-[N,N-bis-(4-nitrophenylmethyl)] ditrifluoroacetate
  • the cmde product was purified by silica gel chromatography using 40% ethyl acetate in hexane. This product was further purified by preparative reverse phase HPLC using a gradient elution from 85% water, 15% acetonitrile to 20% water over a period of 40 min. (solvents contained 0.1% trifluoroacetic acid).
  • Step B Preparation of N-(1(S)-carboxy-3-methylthiopropyl)-3- [N,N-bis-(4-nitrophenylmethyl)aminomethyl]benzamide ditrifluoroacetate
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2-hydroxy ethyl)
  • HEPMS piperazine-N'-(2-ethane sulfonic acid)
  • pH 7.4 5 mM MgCl 2
  • DTT dithiothreitol
  • 650 nM Ras-CVLS 10 ⁇ g/ml FPTase at 31°C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
  • Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ -plate counter.
  • the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • the compounds of the instant invention were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC 50 of ⁇ 100 ⁇ M.
  • the cell line used in this assay is a v-ras line derived from either Rat1 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%
  • the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400
  • mCi[ 35 S]methionine 1000 Ci/mmol.
  • the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /1mM 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 ⁇ g for 45 min.
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 ⁇ 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 semm) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an

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Abstract

L'invention porte sur des composés peptidomimétiques comportant une fraction aminoalkylbenzamide adéquatement substituée. Ces composés instantanés inhibent la farnésyl-protéine transférase et la farnésylation de certaines protéines. De plus, ces inhibiteurs instantanés de farnésyl-protéine transférase différent de ceux préalablement décrits en ce qu'ils ne présentent pas de fraction thiol. Cette absence de thiol offre des avantages uniques en terme de comportement pharacocinétique amélioré chez l'animal, de prévention des réactions chimiques liées au thiol telles que la rapidité d'auto-oxydation ou la formation de disulfures avec des thiols endogènes, et une toxicité systémique réduite. L'invention porte également sur des compositions chimiothérapeutiques contenant lesdits inhibiteurs de farnésyl-protéine transférase et leurs procédés de production.
PCT/US1996/003980 1995-03-29 1996-03-25 Inhibiteurs de farnesyl-proteine transferase WO1996030015A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8529547A JPH11503419A (ja) 1995-03-29 1996-03-25 ファルネシル−タンパク質トランスフェラーゼ阻害剤
AU53701/96A AU706008B2 (en) 1995-03-29 1996-03-25 Inhibitors of farnesyl-protein transferase
EP96910528A EP0817630A4 (fr) 1995-03-29 1996-03-25 Inhibiteurs de farnesyl-proteine transferase

Applications Claiming Priority (4)

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US08/412,830 US5534537A (en) 1995-03-29 1995-03-29 Prodrugs of inhibitors of farnesyl-protein transferase
US08/412,830 1995-03-29
US08/413,137 1995-03-29
US08/413,137 US5578629A (en) 1995-03-29 1995-03-29 Benzamide-containing inhibitors of farnesyl-protein transferase

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19613691A1 (de) * 1996-04-05 1997-10-09 Boehringer Ingelheim Int Arzneimittel für die Behandlung von Tumorerkrankungen
EP0891352A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP0891335A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de transferase de farnesyl-proteine
FR2766819A1 (fr) * 1997-07-31 1999-02-05 Pf Medicament Nouvelles sulfonamides derivees d'anilines substituees utiles comme medicaments
WO1999020612A1 (fr) * 1997-10-22 1999-04-29 Astrazeneca Uk Limited Derives imidazoles et leur utilisation comme inhibiteurs de la farnesyle-transferase
WO1999020611A1 (fr) * 1997-10-22 1999-04-29 Zeneca Limited Derives d'imidazole et leur utilisation comme inhibiteurs de la farnesyle-proteine transferase
WO2000039716A2 (fr) * 1998-12-23 2000-07-06 Astrazeneca Ab Composes chimiques
US6204293B1 (en) 1995-11-06 2001-03-20 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6221865B1 (en) 1995-11-06 2001-04-24 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
WO2001053274A1 (fr) * 2000-01-21 2001-07-26 Agouron Pharmaceuticals, Inc. Composes amides destinees a inhiber les proteines kinases
US6310095B1 (en) 1995-11-06 2001-10-30 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6693123B2 (en) 1995-11-06 2004-02-17 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US7101897B2 (en) 1999-12-22 2006-09-05 Astrazeneca Ab Farnesyl transferase inhibitors
US7511035B2 (en) 2005-01-25 2009-03-31 Glaxo Group Limited Antibacterial agents
JP2010100619A (ja) * 1997-05-07 2010-05-06 Univ Of Pittsburgh タンパク質イソプレニルトランスフェラーゼの阻害剤

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0944387A1 (fr) * 1996-01-30 1999-09-29 Merck & Co., Inc. Inhibiteurs de la farnesyle transferase

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US5514677A (en) * 1988-11-23 1996-05-07 British Biotech Pharmaceuticals Limited Hydroxamic acid based collagenase inhibitors

Patent Citations (1)

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US5514677A (en) * 1988-11-23 1996-05-07 British Biotech Pharmaceuticals Limited Hydroxamic acid based collagenase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0817630A4 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6693123B2 (en) 1995-11-06 2004-02-17 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6310095B1 (en) 1995-11-06 2001-10-30 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6204293B1 (en) 1995-11-06 2001-03-20 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6221865B1 (en) 1995-11-06 2001-04-24 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
EP0891352A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
EP0891352A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP0891335A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de transferase de farnesyl-proteine
EP0891335A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de transferase de farnesyl-proteine
DE19613691A1 (de) * 1996-04-05 1997-10-09 Boehringer Ingelheim Int Arzneimittel für die Behandlung von Tumorerkrankungen
JP2010100619A (ja) * 1997-05-07 2010-05-06 Univ Of Pittsburgh タンパク質イソプレニルトランスフェラーゼの阻害剤
FR2766819A1 (fr) * 1997-07-31 1999-02-05 Pf Medicament Nouvelles sulfonamides derivees d'anilines substituees utiles comme medicaments
WO1999006376A1 (fr) * 1997-07-31 1999-02-11 Pierre Fabre Medicament Nouvelles sulfonamides derivees d'anilines substituees utiles comme medicaments
WO1999020611A1 (fr) * 1997-10-22 1999-04-29 Zeneca Limited Derives d'imidazole et leur utilisation comme inhibiteurs de la farnesyle-proteine transferase
US6342765B1 (en) 1997-10-22 2002-01-29 Astrazeneca Uk Limited Imidazole derivatives and their use as farnesyl protein transferase inhibitors
US6410539B1 (en) 1997-10-22 2002-06-25 Astrazenca Uk Limited Imidazole derivatives and their use as farnesyl protein transferase inhibitors
WO1999020612A1 (fr) * 1997-10-22 1999-04-29 Astrazeneca Uk Limited Derives imidazoles et leur utilisation comme inhibiteurs de la farnesyle-transferase
WO2000039716A3 (fr) * 1998-12-23 2001-02-22 Astrazeneca Uk Ltd Composes chimiques
US6486156B1 (en) 1998-12-23 2002-11-26 Astrazeneca Ab Chemical compounds
WO2000039716A2 (fr) * 1998-12-23 2000-07-06 Astrazeneca Ab Composes chimiques
US7101897B2 (en) 1999-12-22 2006-09-05 Astrazeneca Ab Farnesyl transferase inhibitors
WO2001053274A1 (fr) * 2000-01-21 2001-07-26 Agouron Pharmaceuticals, Inc. Composes amides destinees a inhiber les proteines kinases
US6635641B2 (en) 2000-01-21 2003-10-21 Agouron Pharmaceuticals, Inc. Amide compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use
US7511035B2 (en) 2005-01-25 2009-03-31 Glaxo Group Limited Antibacterial agents
US7759340B2 (en) 2005-01-25 2010-07-20 Glaxo Group Limited Antibacterial agents

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AU5370196A (en) 1996-10-16
CA2216564A1 (fr) 1996-10-03
EP0817630A4 (fr) 1999-01-27
EP0817630A1 (fr) 1998-01-14
JPH11503419A (ja) 1999-03-26

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