EP0900081A1 - Inhibiteurs de farnesyl-proteine transferase - Google Patents

Inhibiteurs de farnesyl-proteine transferase

Info

Publication number
EP0900081A1
EP0900081A1 EP97917604A EP97917604A EP0900081A1 EP 0900081 A1 EP0900081 A1 EP 0900081A1 EP 97917604 A EP97917604 A EP 97917604A EP 97917604 A EP97917604 A EP 97917604A EP 0900081 A1 EP0900081 A1 EP 0900081A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
aryl
unsubstituted
cycloalkyl
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Withdrawn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
EP97917604A
Other languages
German (de)
English (en)
Other versions
EP0900081A4 (fr
Inventor
Christopher J. Dinsmore
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9610338.7A external-priority patent/GB9610338D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0900081A1 publication Critical patent/EP0900081A1/fr
Publication of EP0900081A4 publication Critical patent/EP0900081A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • R l a and R ib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, (RlO)2NC(0)-, R l ⁇ 2N-C(NRlO)-, CN, N02, R 10 C(O)-, N3, -N(RlO)2, O ⁇ RH OC(O)NR 10-, c) unsubstituted or substituted C1 -C6 alkyl wherein the substitutent on the substituted -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl°0-, R l lS(0) m -
  • the substituted Cl -8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
  • an unsubstituted or substituted group the group selected from Cl-8 alkyl, C2-8 alkenyl and C2-8 alkynyl; wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cj -4 alkyl, d) halogen,
  • s is 0.
  • the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF-1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331 - 1333 ( 1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
  • Step D Preparation of (S)-6-/?-butyl-l-[l -(4-cyanobenzyl)-5- imidazolylmethyl]-4-(2,3-dimethylphenyl)-2-piperazinone hydrochloride
  • the titled compound is prepared from the product of Step
  • the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %).
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés qui inhibent la farnésyl-protéine transférase (FTase) et la farnésylation de la protéine Ras oncogène. L'invention a en outre pour objet des compositions chimiothérapeutiques contenant les composés de cette invention et des procédés pour inhiber la farnésyl-protéine transférase et la farnésylation de la protéine Ras oncogène.
EP97917604A 1996-04-03 1997-03-27 Inhibiteurs de farnesyl-proteine transferase Withdrawn EP0900081A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1479296P 1996-04-03 1996-04-03
US14792P 1996-04-03
GBGB9610338.7A GB9610338D0 (en) 1996-05-17 1996-05-17 Inhibitors of farnesyl-protein transferase
GB9610338 1996-05-17
PCT/US1997/004750 WO1997036591A1 (fr) 1996-04-03 1997-03-27 Inhibiteurs de farnesyl-proteine transferase

Publications (2)

Publication Number Publication Date
EP0900081A1 true EP0900081A1 (fr) 1999-03-10
EP0900081A4 EP0900081A4 (fr) 2002-01-09

Family

ID=26309349

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97917604A Withdrawn EP0900081A4 (fr) 1996-04-03 1997-03-27 Inhibiteurs de farnesyl-proteine transferase

Country Status (5)

Country Link
EP (1) EP0900081A4 (fr)
JP (1) JP2001518067A (fr)
AU (1) AU707347B2 (fr)
CA (1) CA2250587A1 (fr)
WO (1) WO1997036591A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2336475A1 (fr) 1998-07-02 2000-01-13 Christopher J. Dinsmore Inhibiteurs de prenyl-proteine transferase
SI1940786T1 (sl) 2005-09-16 2010-11-30 Arrow Therapeutics Ltd Bifenilni derivati in njihova uporaba pri zdravljenju hepatitisa C
WO2010114896A1 (fr) 2009-03-31 2010-10-07 Arqule, Inc. Composés indolo-pyridinone substitués
CA2801074A1 (fr) 2010-06-04 2011-12-08 Albany Molecular Research, Inc. Inhibiteurs du transporteur 1 de la glycine, procedes de fabrication associes, et utilisations associees

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA983495A (en) * 1972-10-11 1976-02-10 Gilbert Regnier Procede de preparation de derives du benzodioxole
US4598079A (en) * 1981-08-20 1986-07-01 Cassella Aktiengesellschaft 2-(aryl substitued)piperazinones and nootropic compositions based thereon
WO1993021186A1 (fr) * 1992-04-13 1993-10-28 Fujisawa Pharmaceutical Co., Ltd. 3-pyrrolidinylthio-carbapenemes substitues, utilises comme agents antimicrobiens
WO1995000497A1 (fr) * 1993-06-18 1995-01-05 Merck & Co., Inc. Inhibiteurs de farnesyle-proteine transferase
US5382584A (en) * 1992-07-31 1995-01-17 Bristol-Myers Squibb Company Adenosine re-uptake inhibiting derivatives of diphenyl oxazoles, thiazoles and imidazoles
EP0670314A1 (fr) * 1993-09-22 1995-09-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de la farnesyl-transferase
WO1996030343A1 (fr) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase
WO1996037204A1 (fr) * 1995-05-24 1996-11-28 Merck & Co., Inc. Inhibiteurs de la farnesyle-proteine transferase

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3915981A (en) * 1973-03-16 1975-10-28 Yoshitomi Pharmaceutical 1-{8 2-(2-Chlorobenzoyl)-4-nitrophenyl{9 -2-(diethylaminomethyl)-imidazole
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
US4835154A (en) * 1987-06-01 1989-05-30 Smithkline Beckman Corporation 1-aralykyl-5-piperazinylmethyl-2-mercaptoimidazoles and 2-alkylthioimidazoles and their use as dopamine-βhydroxylase inhibitors
US5219856A (en) * 1992-04-06 1993-06-15 E. I. Du Pont De Nemours And Company Angiotensin-II receptor blocking, heterocycle substituted imidazoles
WO1996016057A1 (fr) * 1994-11-23 1996-05-30 Neurogen Corporation Certains derives d'aminoethyl imidazole et pyrrole substitues en 1; nouveaux ligands specifiques d'un sous-type de recepteur dopaminergique
US5478934A (en) * 1994-11-23 1995-12-26 Yuan; Jun Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA983495A (en) * 1972-10-11 1976-02-10 Gilbert Regnier Procede de preparation de derives du benzodioxole
US4598079A (en) * 1981-08-20 1986-07-01 Cassella Aktiengesellschaft 2-(aryl substitued)piperazinones and nootropic compositions based thereon
WO1993021186A1 (fr) * 1992-04-13 1993-10-28 Fujisawa Pharmaceutical Co., Ltd. 3-pyrrolidinylthio-carbapenemes substitues, utilises comme agents antimicrobiens
US5382584A (en) * 1992-07-31 1995-01-17 Bristol-Myers Squibb Company Adenosine re-uptake inhibiting derivatives of diphenyl oxazoles, thiazoles and imidazoles
WO1995000497A1 (fr) * 1993-06-18 1995-01-05 Merck & Co., Inc. Inhibiteurs de farnesyle-proteine transferase
EP0670314A1 (fr) * 1993-09-22 1995-09-06 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de la farnesyl-transferase
WO1996030343A1 (fr) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase
WO1996037204A1 (fr) * 1995-05-24 1996-11-28 Merck & Co., Inc. Inhibiteurs de la farnesyle-proteine transferase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9736591A1 *

Also Published As

Publication number Publication date
WO1997036591A1 (fr) 1997-10-09
EP0900081A4 (fr) 2002-01-09
CA2250587A1 (fr) 1997-10-09
JP2001518067A (ja) 2001-10-09
AU2587997A (en) 1997-10-22
AU707347B2 (en) 1999-07-08

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