EP0891335A1 - Inhibitoren von farnesylprotein-transferase - Google Patents

Inhibitoren von farnesylprotein-transferase

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Publication number
EP0891335A1
EP0891335A1 EP97917759A EP97917759A EP0891335A1 EP 0891335 A1 EP0891335 A1 EP 0891335A1 EP 97917759 A EP97917759 A EP 97917759A EP 97917759 A EP97917759 A EP 97917759A EP 0891335 A1 EP0891335 A1 EP 0891335A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
alkyl
compound
substituted
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Withdrawn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
EP97917759A
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English (en)
French (fr)
Other versions
EP0891335A4 (de
Inventor
John H. Hutchinson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9609334.9A external-priority patent/GB9609334D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0891335A1 publication Critical patent/EP0891335A1/de
Publication of EP0891335A4 publication Critical patent/EP0891335A4/de
Withdrawn legal-status Critical Current

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

Definitions

  • the present invention relates to compounds which inhibit farnesyl protein transferase, a protein which is implicated in the oncogenic pathway mediated by Ras.
  • the Ras proteins (Ha-Ras, Ki4a- Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth
  • 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-teirriinus 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)).
  • q 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen, and t is 0 or 1.
  • the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras, and thus are useful for the treatment of cancer.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • alkyl and the alkyl portion of alkoxy, aralkyl and similar terms, is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, or 1-6 carbon atoms if unspecified.
  • Cycloalkyl means 1- 2 carbocyclic rings which are saturated and contain from 3-10 atoms.
  • Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl and the aryl portion of aralkyl, are intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl elements examples include phenyl, naphthyl,
  • tetrahydronaphthyl indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • a preferred aralkyl group is benzyl.
  • heterocyclyl, heterocycle and heterocyclic mean a 5- to 7-membered monocyclic or 8- to 1 1- membered bicyclic heterocyclic rings, either saturated or unsaturated, aromatic, partially aromatic or non-aromatic, and which consist of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S.
  • it includes any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the ring or ring system may be attached at any heteroatom or carbon atom which results in a stable structure, and may contain 1 -3 carbonyl groups.
  • heterocycles include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl,
  • Heteroaryl is a subset of heterocyclic, and means a monocyclic or bicyclic ring system, with up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples include benzimidazolyl,
  • dihydrobenzothiopyranyl dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,
  • substituted as used in, e.g., with respect to substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl means alkyl, aryl, heterocyclyl and cycloalkyl groups, respectively, having from 1-3 substituents which are selected from: halo, aryl, heterocyclyl, C 1-6 alkyl, C 3- 10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN,
  • R 1a ,R 1 b , R 2 and R 10 are independently selected from: hydrogen, -N(R 8 ) 2 , R 8 C(O)NR 8 - or unsubstituted or substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, -N(R 8 )2, R 8 O- and R 8 C(O)NR 8 -
  • R 3 and R 4 are selected from: hydrogen and C 1 -C 6 alkyl.
  • R 6 represents CN, NO 2 or R 8 O-.
  • R 8 represents H or C 1-6 alkyl
  • R 9 is C 1-6 alkyl
  • a 1 and A 2 are independently selected from: a bond, -C(O)NR 8 -, -NR 8 C(O)-, -O-, -N(R 8 )-, -S(O) 2 N(R 8 )- and- N(R 8 )S(O) 2 -.
  • a 4 represents -C(O)NR 5 - or -NR 5 C(O)-, with R 5 representing H.
  • V is selected from hydrogen, heterocyclyl and aryl. More preferably V is phenyl.
  • W is heterocyclyl selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl. Preferably, m is 0 or 2.
  • n and p are 0, 1, 2 or 3.
  • t is 1.
  • a subset of compounds of the invention is represented by formula la:
  • R 3 , R 4 , A 3 , A 4 , Y, R 8 , R 9 , m, n, p an d r are as originally defined; each R 1 a , R 1b , R 2 and R 10 is independently selected from hydrogen and C 1 -C 6 alkyl; R 5 is selected from the group consisting of: hydrogen and C 1 -C 6 alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C 3 -C 10 cycloalkyl, -N(R 8 ) 2 , -CF 3 , -NO 2 , (R 8 )O-, (R 9 )S(O) m -,
  • heteroatom selected from O, S, and N, and C 2 -C 20 alkenyl provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond and A 2 is S(O) m .
  • a second subset of compounds of the present invention is represented by formula I:
  • R 5 is selected from the group consisting of: hydrogen and C 1 -C 6 alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C 3 -C 10 cycloalkyl, -N(R 8 ) 2 , -CF 3 , -NO 2 , (R 8 )O-, (R 9 )S(O) m -, (R 8 )C(O)NH-, H 2 NC(NH)-, (R 8 )C(O)-, (R 8 )OC(O)-, N 3 , CN and (R 9 )OC(O)NR 8 -; R 6 and R 7 are independently selected from: hydrogen, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perflu
  • W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
  • a third subset of compounds of the invention is represented by formula la:
  • a 3 represents -S-
  • V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C 1 - C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C 2 -C 20 alkenyl, provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O) m ; and
  • W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
  • R 1 a , R 1 b , R 2 , R 10 , A 1 , A 2 , A 4 , Y, R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , m, n, p, q and r are as originally defined;
  • R 7 is selected from: hydrogen and C 1 -C 6 alkyl
  • W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
  • a 4 represents -C(O)NH- or -NHC(O)-; and R 6 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 8 O-, R 8 C(O)NR 8 -, CN, NO 2 , (R S ) 2 N-C(NR 8 )-, R 8 C(O)-,
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the salts are prepared either by ion exchange
  • Schemes 1-2 illustrates the synthesis of one of the preferred embodiments of the instant invention, wherein the variable W is present as a imidazolyl moiety that is substituted with a suitably substituted benzyl group.
  • Substituted protected imidazole alkanols II can be prepared by methods known in the art, such as those described by F. Schneider, Z Physiol Chem., 3:206-210 (1961) and C.P. Stewart, Biochem. Journal, 17: 130-133(1923). Benzylation and deprotection of the imidazole alkanol provides intermediate III which can be oxidized to the corresponding aldehyde IV.
  • the amine VI can be reacted with a variety of other aldehydes, such as IX, as shown in Scheme 7.
  • the product X is first acylated and then can be deprotected to give the instant compound XI.
  • the compound XI is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • Compound XI can further be selectively protected to obtain XII which can subsequently be reductively alkylated with a second aldehyde, such as XIII, to obtain XIV. Removal of the Boc protecting group, and conversion to cyclized products such as the dihydroimidazole XV can be accomplished by literature procedures.
  • the product XVII can first be acylated and the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 9, 10).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXI.
  • 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.
  • Boc protected amino alcohol XIX can also be utilized to synthesize 2-aziridinylmethylamides such as XXIV (Scheme 11).
  • aziridine XXIV The aziridine may be reacted with a nucleophile, such as a thiol, in the presence of base to yield (after deprotection) the ring-opened product XXVI.
  • a nucleophile such as a thiol
  • the 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
  • XXXIV 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.
  • Cancers which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
  • Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e.,
  • NF-1 neurofibromin
  • neu neu
  • scr abl
  • lck lck
  • fyn neurofibromin
  • the compounds of the instant invention inhibit farnesyl- protein transferase and famesylation of the oncogene protein Ras.
  • the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)).
  • Such anti-angiogenic properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • the compounds of this invention are also useful for inhibiting or treating other diseases where Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF- 1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331-1333 (1992).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in
  • the compound is administered, for example, in the form of tablets or capsules, or as a solution or suspension.
  • carriers which are commonly used include lactose and com starch; lubricating agents, such as magnesium stearate, are commonly added.
  • diluents also include lactose and dried com starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • intramuscular For intramuscular,
  • sterile solutions of the active ingredient are usually prepared, the pH of the solution is suitably adjusted and the product is buffered.
  • the total concentration is controlled to render the preparation substantially isotonic.
  • the daily dosage will normally be determined by the prescribing physician, who may vary the dosage according to the age, weight, and response of the individual patient, as well as the severity of the patient's condition.
  • 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.
  • the concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the
  • Step A Preparation of l-pivaloyloxymethyl-3-(4-cyanobenzyl)-4-(2- phthalimidoethyl)imidazolium bromide
  • N ⁇ -Pivaloyloxymethyl-N ⁇ -phthaloylhistamine (4.55 g, 12.8 mmol; prepared as previously described (J. C. Emmett, F. H. Holloway, and J. L. Turner, J. Chem. Soc, Perkin Trans. I, 1341, (1979)) and ⁇ -bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL). The solution was heated at 55°C for 4 h, cooled to room temperature, and filtered to remove the white solid. The acetonitrile (30 mL) was concentrated to 1/2 its volume under reduced pressure and the solution was heated at 55°C overnight.
  • the solution was cooled and filtered to give a white solid.
  • the volume of the filtrate was reduced to 10 mL, the solution was heated at 55°C for 1 hr, then cooled to room temperature, diluted with EtOAc (25 mL) and filtered to obtain additional white solid.
  • the solids were combined, dried, and used without further purification.
  • Step B Preparation of 4-cyanobenzyl-N ⁇ -phthaloylhistamine
  • Step A 2- ⁇ 1-(4-Cyanobenzyl)imidazol-5-ylmethoxyl acetic acid
  • Step B N-3-Chlorophenyl-2-( 2- [1-(4-cyanobenzyl)imidazol-5- yl]ethylamino ⁇ acetamide
  • polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • the cell line used in this assay is a v-ras line derived from either 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 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 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol.
  • Rat 1 cells transformed with either a v-ras, v-raf, or w-mos oncogene is tested.
  • Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
  • Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

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EP97917759A 1996-04-03 1997-03-31 Inhibitoren von farnesylprotein-transferase Withdrawn EP0891335A4 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1479496P 1996-04-03 1996-04-03
US14794P 1996-04-03
GB9609334 1996-05-03
GBGB9609334.9A GB9609334D0 (en) 1996-05-03 1996-05-03 Inhibitors of farnesyl-protein transferase
PCT/US1997/005295 WO1997036877A1 (en) 1996-04-03 1997-03-31 Inhibitors of farnesyl-protein transferase

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EP0891335A1 true EP0891335A1 (de) 1999-01-20
EP0891335A4 EP0891335A4 (de) 2001-08-16

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EP (1) EP0891335A4 (de)
JP (1) JP2000507589A (de)
AU (1) AU707416B2 (de)
CA (1) CA2250460A1 (de)
WO (1) WO1997036877A1 (de)

Families Citing this family (12)

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Publication number Priority date Publication date Assignee Title
ZA981080B (en) * 1997-02-11 1998-08-12 Warner Lambert Co Bicyclic inhibitors of protein farnesyl transferase
HRP990246A2 (en) 1998-08-07 2000-06-30 Du Pont Pharm Co Succinoylamino benzodiazepines as inhibitors of a beta protein production
NZ525513A (en) 1998-08-07 2004-09-24 Pont Pharmaceuticals Du Succinoylamino lactams as inhibitors of Abeta protein production
WO2000038618A2 (en) 1998-12-24 2000-07-06 Du Pont Pharmaceuticals Company SUCCINOYLAMINO BENZODIAZEPINES AS INHIBITORS OF Aβ PROTEIN PRODUCTION
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
CA2387493A1 (en) 1999-10-08 2001-04-19 Lorin Andrew Thompson Amino lactam sulfonamides as inhibitors of a.beta. protein production
WO2001060826A2 (en) 2000-02-17 2001-08-23 Bristol-Myers Squibb Pharma Company SUCCINOYLAMINO CARBOCYCLES AND HETEROCYCLES AS INHIBITORS OF Aβ PROTEIN PRODUCTION
BR0107532A (pt) 2000-04-03 2004-11-03 Bristol Myers Squibb Pharma Co Composto, uso do composto, método para o tratamento de disfunções neurológicas associadas com a produção de b-amilóide, método de inibição da atividade de y-secretase e composição farmacêutica
MXPA02009729A (es) 2000-04-03 2003-03-27 Bristol Myers Squibb Pharma Co Lactamas ciclicas como inhibidores de la produccion de la proteina a-beta.
AU2001257006A1 (en) 2000-04-11 2001-10-23 Du Pont Pharmaceuticals Company Substituted lactams as inhibitors of abeta protein production
BR0106717A (pt) 2000-06-01 2002-04-16 Bristol Myers Squibb Pharma Co Compostos, composição farmacêutica e usos dos compostos de lactama inovadora

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0675112A1 (de) * 1994-03-31 1995-10-04 Bristol-Myers Squibb Company Imidazol-enthaltende Farnesyl-Protein-Transferase-Inhibitoren
WO1996010034A2 (en) * 1994-09-29 1996-04-04 Merck & Co., Inc. Thiol-free inhibitors of farnesyl-protein transferase
WO1996030015A1 (en) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1996030343A1 (en) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1996037204A1 (en) * 1995-05-24 1996-11-28 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036583A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4853383A (en) * 1975-03-03 1989-08-01 Merck & Co., Inc. β-blocking substituted imidazoles
CZ36294A3 (en) * 1991-08-19 1994-07-13 Du Pont Substituted imidazilonone derivatives and pharmaceutical preparations based thereon
US5401851A (en) * 1992-06-03 1995-03-28 Eli Lilly And Company Angiotensin II antagonists
US5534537A (en) * 1995-03-29 1996-07-09 Merck & Co., Inc. Prodrugs of inhibitors of farnesyl-protein transferase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0675112A1 (de) * 1994-03-31 1995-10-04 Bristol-Myers Squibb Company Imidazol-enthaltende Farnesyl-Protein-Transferase-Inhibitoren
WO1996010034A2 (en) * 1994-09-29 1996-04-04 Merck & Co., Inc. Thiol-free inhibitors of farnesyl-protein transferase
WO1996030015A1 (en) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1996030343A1 (en) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1996037204A1 (en) * 1995-05-24 1996-11-28 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036583A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GRAHAM,S.L.: "Inhibitors of protein farnesylation: a new approach to cancer chemotherapy" EXP.OPIN.THER.PATENTS, vol. 5, no. 12, 1995, pages 1269-1285, XP001000610 LONDON *
See also references of WO9736877A1 *

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CA2250460A1 (en) 1997-10-09
WO1997036877A1 (en) 1997-10-09
JP2000507589A (ja) 2000-06-20
AU2600597A (en) 1997-10-22
EP0891335A4 (de) 2001-08-16
AU707416B2 (en) 1999-07-08

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