EP0766667A1 - Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant - Google Patents

Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant

Info

Publication number
EP0766667A1
EP0766667A1 EP95925237A EP95925237A EP0766667A1 EP 0766667 A1 EP0766667 A1 EP 0766667A1 EP 95925237 A EP95925237 A EP 95925237A EP 95925237 A EP95925237 A EP 95925237A EP 0766667 A1 EP0766667 A1 EP 0766667A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
oxo
trans
aryl
azetidinyl
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Withdrawn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
EP95925237A
Other languages
German (de)
English (en)
Inventor
Wayne Vaccaro
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 Sharp and Dohme Corp
Original Assignee
Schering Corp
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
Application filed by Schering Corp filed Critical Schering Corp
Publication of EP0766667A1 publication Critical patent/EP0766667A1/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Withdrawn legal-status Critical Current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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the regulation of whole-body cholesterol homeostasis in humans and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing plasma lipoproteins.
  • the liver is the major organ responsible for cholesterol biosynthesis and catabolism and for this reason, it is a prime determinant of plasma cholesterol levels.
  • the liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation.
  • VLDL very low density lipoproteins
  • LDL low density lipoproteins
  • LDL low density lipoproteins
  • Step 2 Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-(3-hydroxy-1-propyl)- phenyl)-3-(3-phenylpropyl)-2-azetidinone:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Agent hypercholestérolémiant d'azétidinone substitué de formule (I) ou d'un sel pharmaceutiquement acceptable où : Ar1 représente aryle ou R3-aryle; Ar2 représente aryl ou R4-aryle; R1 est sélectionné dans le groupe composé de -(CH¿2?)q-, où q est compris entre 2-6; -(CH2)e-Z-(CH2)r-, où Z représente -O-, -C(O)-, phénylène, -NR?10¿- ou -S(O)¿0-2?-, e est compris entre 0-5 et r est compris entre 0-5, à condition que la somme de e et de r soit comprise entre 1-6; -(C2-C6 alcénylène)-; et -(CH2)f-V-(CH2)g-, où V représente C3-C6 cycloalkylène, f est compris entre 1-5 et g est compris entre 0-5, à condition que la somme de f et g soit comprise entre 1-6; R?2¿ représente -(alkylène inférieur)-COR5 ou -(CH=CH)-COR?5; R3 et R4¿ représentent séparément des substituants en position 1-3 sélectionnés à partir d'alkyle inférieur, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH¿2?)1-5OR?6¿, -O(CO)NR?6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO¿2R?9, -COOR6, -CONR6R7, -COR6, -SO¿2NR6R7, S(O)¿0-2R?9, -O(CH¿2?)1-10-COOR?6¿, -O(CH¿2?)1-10CONR?6R7¿, -(alkylène inférieur)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 et halogène; R5 représente -OR ou -NRR?12; R, R6, R7, R8 et R12¿ sont sélectionnés séparément à partir d'hydrogène, alkyle inférieur, et alkyle inférieur à substitution aryle; R9 représente alkyle inférieur, ou alkyle inférieur à substitution aryle; et R10 représente alkyle inférieur, alkyle inférieur aryle ou -C(O)R6; l'invention concerne également une méthode permettant d'abaisser le taux de cholestérol sérique en appliquant un composé, seul ou en combinaison avec un inhibiteur de biosynthèse du cholestérol, ainsi que les compositions pharmaceutiques les contenant.
EP95925237A 1994-06-20 1995-06-15 Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant Withdrawn EP0766667A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US261785 1981-05-08
US26178594A 1994-06-20 1994-06-20
PCT/US1995/007117 WO1995035277A1 (fr) 1994-06-20 1995-06-15 Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant

Publications (1)

Publication Number Publication Date
EP0766667A1 true EP0766667A1 (fr) 1997-04-09

Family

ID=22994864

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95925237A Withdrawn EP0766667A1 (fr) 1994-06-20 1995-06-15 Composes d'azetidinone substitues utilises comme agent hypercholesterolemiant

Country Status (6)

Country Link
EP (1) EP0766667A1 (fr)
JP (1) JPH10501811A (fr)
AU (1) AU2943095A (fr)
CA (1) CA2191455A1 (fr)
MX (1) MX9606319A (fr)
WO (1) WO1995035277A1 (fr)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5633246A (en) * 1994-11-18 1997-05-27 Schering Corporation Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents
IL156552A0 (en) 2000-12-21 2004-01-04 Aventis Pharma Gmbh Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use
IL156548A0 (en) * 2000-12-21 2004-01-04 Aventis Pharma Gmbh Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use
AU2008201609B8 (en) * 2001-01-26 2009-01-08 Organon Llc Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitors(s) and treatments for vascular indications
AU2007201970B2 (en) * 2001-01-26 2008-04-17 Organon Llc Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
CN101297969B (zh) * 2001-01-26 2011-03-09 先灵公司 过氧化物酶体增殖物激活受体(ppar)活化剂和甾醇吸收抑制剂的组合药
AU2006202618B2 (en) * 2001-01-26 2007-04-19 Organon Llc Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
CZ20032031A3 (cs) * 2001-01-26 2003-12-17 Schering Corporation Farmaceutický prostředek
EP1864680A3 (fr) * 2001-01-26 2012-03-28 Schering Corporation Combinaisons d'activateur(s) du récepteur activé de la prolifération des peroxysomes (PPAR) et inhibiteur(s) d'absorption de stérol, et traitements pour les indications vasculaires
AU2006203175B2 (en) * 2001-01-26 2008-07-24 Organon Llc Combinations of peroxisome proliferator-activated receptor (PPAR) activators(s) and sterol absorption inhibitors(s) and treatments for vascular indications
DE60221798T2 (de) * 2001-01-26 2008-06-05 Schering Corp. Kombinationen von gallensäure sequestriermitteln und hemmern der sterol absorption zur behandlung von kardiovaskulären indikationen
US20020183305A1 (en) * 2001-01-26 2002-12-05 Schering Corporation Combinations of nicotinic acid and derivatives thereof and sterol absorption inhibitor(s) and treatments for vascular indications
ES2290562T3 (es) * 2001-01-26 2008-02-16 Schering Corporation Combinaciones del activador del receptor activado por el proliferador de los peroxisomas (ppar) fenofibrato con el inhibidor de la absorcion de esteroles ezetimiba para indicaciones vasculares.
WO2002058734A2 (fr) * 2001-01-26 2002-08-01 Schering Corporation Combinaisons d'inhibiteur(s) d'absorption des sterols et de modificateur(s) sanguin(s) pour le traitement des troubles vasculaires
EP1911462A3 (fr) * 2001-01-26 2011-11-30 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
GB0215579D0 (en) 2002-07-05 2002-08-14 Astrazeneca Ab Chemical compounds
AR040588A1 (es) 2002-07-26 2005-04-13 Schering Corp Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa
US7871998B2 (en) 2003-12-23 2011-01-18 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
SA06270191B1 (ar) 2005-06-22 2010-03-29 استرازينيكا ايه بي مشتقات من 2- أزيتيدينون جديدة باعتبارها مثبطات لامتصاص الكوليسترول لعلاج حالات فرط نسبة الدهون في الدم
TW200806623A (en) * 2005-10-05 2008-02-01 Merck & Co Inc Anti-hypercholesterolemic compounds
TW200811098A (en) 2006-04-27 2008-03-01 Astrazeneca Ab Chemical compounds
JPWO2008108486A1 (ja) 2007-03-06 2010-06-17 帝人ファーマ株式会社 １−ビアリールアゼチジノン誘導体
EP2965752A1 (fr) 2007-12-10 2016-01-13 ratiopharm GmbH Composition pharmaceutique comprenant l'ezetimibe
US9212175B2 (en) 2009-03-06 2015-12-15 Lipideon Biotechnology Ag Pharmaceutical hypocholesterolemic compositions
CN101993403B (zh) 2009-08-11 2012-07-11 浙江海正药业股份有限公司 氮杂环丁酮类化合物及医药应用
WO2015092448A1 (fr) * 2013-12-18 2015-06-25 Rudjer Boskovic Institute Inhibiteurs de l'absorption du cholestérol de type bêta-lactamines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ14294A3 (en) * 1991-07-23 1994-07-13 Schering Corp Substituted beta-lactam compounds usable as hypocholesterol pharmaceutical preparations and process for preparing thereof
US5631365A (en) * 1993-09-21 1997-05-20 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9535277A1 *

Also Published As

Publication number Publication date
CA2191455A1 (fr) 1995-12-28
AU2943095A (en) 1996-01-15
MX9606319A (es) 1997-05-31
WO1995035277A1 (fr) 1995-12-28
JPH10501811A (ja) 1998-02-17

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