WO1993019754A1 - Derives de phenol et de pyridinol utilises comme agents lusitropes - Google Patents

Derives de phenol et de pyridinol utilises comme agents lusitropes Download PDF

Info

Publication number
WO1993019754A1
WO1993019754A1 PCT/GB1993/000615 GB9300615W WO9319754A1 WO 1993019754 A1 WO1993019754 A1 WO 1993019754A1 GB 9300615 W GB9300615 W GB 9300615W WO 9319754 A1 WO9319754 A1 WO 9319754A1
Authority
WO
WIPO (PCT)
Prior art keywords
naphthyl
formula
compound
oxo
ethyl
Prior art date
Application number
PCT/GB1993/000615
Other languages
English (en)
Inventor
Kenneth John Murray
Roderick Alan Porter
Brian Herbert Warrington
Philippe Lahouratate
Original Assignee
Smithkline Beecham Plc
Smithkline Beecham Laboratoires Pharmaceutiques
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 Plc, Smithkline Beecham Laboratoires Pharmaceutiques filed Critical Smithkline Beecham Plc
Priority to EP93906752A priority Critical patent/EP0632724A1/fr
Priority to JP5517196A priority patent/JPH07508707A/ja
Priority to CA002132981A priority patent/CA2132981A1/fr
Publication of WO1993019754A1 publication Critical patent/WO1993019754A1/fr
Priority to KR1019940703385A priority patent/KR950700736A/ko

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)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (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
PCT/GB1993/000615 1992-03-27 1993-03-25 Derives de phenol et de pyridinol utilises comme agents lusitropes WO1993019754A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93906752A EP0632724A1 (fr) 1992-03-27 1993-03-25 Derives de phenol et de pyridinol utilises comme agents lusitropes
JP5517196A JPH07508707A (ja) 1992-03-27 1993-03-25 ルシトロピック剤用フェノールおよびピリジノール誘導体
CA002132981A CA2132981A1 (fr) 1992-03-27 1993-03-25 Derives phenol et pyridinol utilises comme agents lusitropiques
KR1019940703385A KR950700736A (ko) 1992-03-27 1994-09-26 루시트로픽제로서 페놀 및 피리디놀 유도체(Phenol and pyridinol derivatives as lusitropic agents)

Applications Claiming Priority (2)

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.
FR92/03747 1992-03-27

Publications (1)

Publication Number Publication Date
WO1993019754A1 true WO1993019754A1 (fr) 1993-10-14

Family

ID=9428178

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000615 WO1993019754A1 (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)

Cited By (1)

* 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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0406958A2 (fr) * 1989-07-07 1991-01-09 Janssen Pharmaceutica N.V. Dérivés de la 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one lisitropiques et inotropiques positives
WO1991017987A1 (fr) * 1990-05-21 1991-11-28 Smith Kline & French Laboratories Limited Derives de phenol et de pyridinol comme agents pharmaceutiques
WO1992006085A1 (fr) * 1990-09-28 1992-04-16 Smith Kline & French Laboratories Limited Derives de phenylpyridinol utilises comme medicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0406958A2 (fr) * 1989-07-07 1991-01-09 Janssen Pharmaceutica N.V. Dérivés de la 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one lisitropiques et inotropiques positives
WO1991017987A1 (fr) * 1990-05-21 1991-11-28 Smith Kline & French Laboratories Limited Derives de phenol et de pyridinol comme agents pharmaceutiques
WO1992006085A1 (fr) * 1990-09-28 1992-04-16 Smith Kline & French Laboratories Limited Derives de phenylpyridinol utilises comme medicaments

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY vol. 33, no. 6, June 1990, pages 1735 - 1741 COATES, W.J. ET AL '1,4-BIS(3-OXO-2,3-DIHY DROPYRIDAZIN-6-YL)BENZENE ANALOGUES: POTENT PHOSPHODIESTERASE INHIBITORS AND INODILATORS.' *
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS vol. 257, no. 3, June 1991, pages 1189 - 1197 KENAKIN T.P. ET AL 'THE RELATIVE EFFICIENCY OF BETA ADRENOCEPTOR COUPLING TO MYOCARDIAL INOTROPY AND DIASTOLIC RELAXATION: ORGAN-SELECTIVE TREATMENT FOR DIASTOLIC DYSFUNCTION' cited in the application *

Cited By (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
WO1998013518A1 (fr) * 1996-09-26 1998-04-02 Smithkline Beecham Laboratoires Pharmaceutiques Procede pour detecter des modulateurs de la relaxation myocardique

Also Published As

Publication number Publication date
AU3764693A (en) 1993-11-08
CA2132981A1 (fr) 1993-10-14
JPH07508707A (ja) 1995-09-28
TW234086B (fr) 1994-11-11
EP0632724A1 (fr) 1995-01-11
KR950700736A (ko) 1995-02-20
FR2689012A1 (fr) 1993-10-01

Similar Documents

Publication Publication Date Title
CN103443079B (zh) 可用作抗菌剂的氟吡啶酮衍生物
US5583122A (en) Pharmaceutical compositions containing geminal diphosphonates
US3261859A (en) Basically substituted phenyl acetonitrile compounds
DE68911742T2 (de) Substituierte flavonoide Verbindungen, ihre Salze, ihre Herstellung und die enthaltende Arnzeizusammensetzungen.
JP6173393B2 (ja) 変異ｃｆｔｒタンパク質の修飾因子としての化合物
JP2003525303A (ja) 心臓保護ホスホン酸塩およびマロン酸塩
JPH11508576A (ja) 化合物およびこれを含有する医薬組成物
WO1991011994A1 (fr) Inhibiteur de la formation de lipoproteines denaturees de faible densite
JP2007517837A5 (fr)
US4535073A (en) Antihypertensive phosphono derivatives of hantzsch dihydropyridines
SK81099A3 (en) Aminoalkylphosphonic acid drivatives, process for their preparation, pharmaceutical composition containing the same and their use
JP4163007B2 (ja) カルバ環状ホスファチジン酸誘導体を含む癌転移抑制剤
KR20010070962A (ko) 유기 인 화합물 및 이의 용도
TWI223651B (en) Phosphonic acid derivatives having inhibitory activity against carboxypeptidase B
JP2702419B2 (ja) ジホスホン酸化合物
WO1993019754A1 (fr) Derives de phenol et de pyridinol utilises comme agents lusitropes
EP0016310A1 (fr) Composés monophosphonates, procédé pour leur préparation et compositions pharmaceutiques les contenant
JPS63239290A (ja) 新規の二環式ジホスホネート化合物、医薬組成物、および異常なカルシウムおよびホスフェート代謝の治療法
RU2004117595A (ru) Производные пиридина в качестве лигандов рецептора nmda
EP0996439B1 (fr) Beta-alcoxyacrylates contre la malaria
JPH10500977A (ja) ピリジルビスホスホン酸エステルよりなる治療用活性薬剤
BRPI1007902B1 (pt) Compostos de fenilmidazol
US20040110757A1 (en) Flt-1 ligands and their uses in the treatment of diseases regulatable by angiogenesis
PT86168B (pt) Processo para a preparacao de acidos fosfonicos insaturados e de seus derivados
CN105517996A (zh) 治疗活性化合物及其使用方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR NZ US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1993906752

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1994 307601

Country of ref document: US

Date of ref document: 19940916

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2132981

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 1993906752

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1993906752

Country of ref document: EP