EP0632724A1 - Derives de phenol et de pyridinol utilises comme agents lusitropes - Google Patents

Derives de phenol et de pyridinol utilises comme agents lusitropes

Info

Publication number
EP0632724A1
EP0632724A1 EP93906752A EP93906752A EP0632724A1 EP 0632724 A1 EP0632724 A1 EP 0632724A1 EP 93906752 A EP93906752 A EP 93906752A EP 93906752 A EP93906752 A EP 93906752A EP 0632724 A1 EP0632724 A1 EP 0632724A1
Authority
EP
European Patent Office
Prior art keywords
naphthyl
formula
compound
oxo
ethyl
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Withdrawn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
EP93906752A
Other languages
German (de)
English (en)
Inventor
Kenneth John Murray
Roderick Alan Porter
Brian Herbert Warrington
P Smithkline Beecham Lab.Pharmac. Lahouratate
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.)
SmithKline Beecham Laboratoires Pharmaceutiques
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Laboratoires Pharmaceutiques
SmithKline Beecham Ltd
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 SmithKline Beecham Laboratoires Pharmaceutiques, SmithKline Beecham Ltd filed Critical SmithKline Beecham Laboratoires Pharmaceutiques
Publication of EP0632724A1 publication Critical patent/EP0632724A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • Phenol and pyridi nol derivatives as l usitropic agents Phenol and pyridi nol derivatives as l usitropic agents.
  • the present invention relates to the use of certain fused aryl derivatives as lusitropic agents 5 in the treatment of cardiovascular diseases where there is a component of diastolic failure.
  • WO 91/17987 discloses fused aryl derivatives as agonists of a cyclic AMP-dependent protein kinase.
  • the present invention provides the use of a compound of the 15 formula (1) :
  • A is N or CH
  • 25 R0 is OH or a bioprecursor thereof
  • R 1 is A°CO2H, P(X)(OH)(OR 2 ), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof,
  • a ⁇ is a single bond, CH , CHF, CF 2 , CR 3 (OR 4 ), CO or C(OR 5 )(OR 6 ),
  • R is phenyl, C3_5cycloalkyl, C3_5Cycloalkyl-C ⁇ _4alkyl, or C ⁇ galkyl optionally substituted by C1.4a.koxy,
  • R3 is H, methyl or ethyl
  • R 4 is H or C ⁇ _3alkyl
  • R5 and R ⁇ are each C ⁇ _3alkyl or together form a 1,2-ethanediyl group or 1,3-propanediyl group,
  • X is O or S and Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C ⁇ galkoxy, 2- naphthyl optionally substituted in the 1-position by hydroxy or C ⁇ . ⁇ alkoxy, 3-phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl in the manufacture of a medicament having positive lusitropic activity.
  • the present invention provides a method of enhancing myocardial relaxation which comprises administering to a host in need thereof an effective amount of a compound of formula (1) as hereinbefore defined or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating cardiovascular disease where there is a component of diastolic failure which comprises administering to a host in need thereof an effective amount of a compound of formula (1) as hereinbefore defined or a pharmaceutically acceptable salt thereof.
  • diseases include congestive heart failure, angina, hypenension and cardiomyopathy (Kenakin el al.. J- Pharmacol. Exp. Ther. 1991, 257, 1189-1197).
  • R 1 is P(O)(OH)(OR 2 ) or a bioprecursor thereof as defined in WO 91/17987.
  • Particular compounds of the formula (1) include :
  • Compounds of the formula (1) can be prepared and administered as pharmaceutical compositions as described in WO 91/17987.
  • the positive lusitropic effect of the compounds of the foimula (1) can be demonstrated by measurement of cardiac muscle relaxation time in rabbit ventricle.
  • Papillary muscles from the right ventricle of female Albino New Zealand rabbits were mounted in standard organ baths containing oxygenated Krebs solution.
  • One end of the muscle was connected to an isometric transducer which allowed recording of contractile force and its first derivative on chartrecorders.
  • Test compounds were added to the bath in a cumulative manner. Relaxation time was calculated as the time taken from peak tension to the point of half relaxation. At concentrations of 30-300 ⁇ M, and stimulation rates at 0.5, 1 or 2 Hz, the following test compounds caused a 5-30% decrease in the relaxation time indicating a positive lusitropic effect of use in the treatment of cardiovascular diseases where there is a component of diastolic failure as hereinbefore described.

Landscapes

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

Abstract

L'invention se rapporte à des dérivés d'aryle fusionnés utilisés comme agents lusitropes dans le traitement des maladies cardiovasculaires dans le cas où l'une des causes est l'insuffisance diastolique
EP93906752A 1992-03-27 1993-03-25 Derives de phenol et de pyridinol utilises comme agents lusitropes Withdrawn EP0632724A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9203747A FR2689012A1 (fr) 1992-03-27 1992-03-27 Utilisation de composés aryliques dans le traitement d'affections cardio-vasculaires.
FR9203747 1992-03-27
PCT/GB1993/000615 WO1993019754A1 (fr) 1992-03-27 1993-03-25 Derives de phenol et de pyridinol utilises comme agents lusitropes

Publications (1)

Publication Number Publication Date
EP0632724A1 true EP0632724A1 (fr) 1995-01-11

Family

ID=9428178

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93906752A Withdrawn EP0632724A1 (fr) 1992-03-27 1993-03-25 Derives de phenol et de pyridinol utilises comme agents lusitropes

Country Status (8)

Country Link
EP (1) EP0632724A1 (fr)
JP (1) JPH07508707A (fr)
KR (1) KR950700736A (fr)
AU (1) AU3764693A (fr)
CA (1) CA2132981A1 (fr)
FR (1) FR2689012A1 (fr)
TW (1) TW234086B (fr)
WO (1) WO1993019754A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2753722A1 (fr) * 1996-09-26 1998-03-27 Smithkline Beecham Lab Procede de detection de modulateurs de relaxation cardiaque et modulateurs ainsi obtenus
TWI486165B (zh) 2011-02-15 2015-06-01 Univ China Medical 用於抑制血管狹窄之醫藥組合物及萃取物與該等之應用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ234186A (en) * 1989-07-07 1991-10-25 Janssen Pharmaceutica Nv Imidazo quinazolin-one derivatives and pharmaceutical compositions
PT97722A (pt) * 1990-05-21 1992-02-28 Smith Kline French Lab Processo de preparacao de derivados de aril fenol/piridinol condesados e de composicoes farmaceuticas que os contem
JPH06501254A (ja) * 1990-09-28 1994-02-10 スミス・クライン・アンド・フレンチ・ラボラトリース・リミテッド 医薬用フェニルピリジノール誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9319754A1 *

Also Published As

Publication number Publication date
TW234086B (fr) 1994-11-11
JPH07508707A (ja) 1995-09-28
AU3764693A (en) 1993-11-08
FR2689012A1 (fr) 1993-10-01
WO1993019754A1 (fr) 1993-10-14
CA2132981A1 (fr) 1993-10-14
KR950700736A (ko) 1995-02-20

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