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WO1993019754A1 - Phenol and pyridinol derivatives as lusitropic agents - Google Patents

Phenol and pyridinol derivatives as lusitropic agents Download PDF

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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
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WO
WIPO (PCT)
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.)
Ceased
Application number
PCT/GB1993/000615
Other languages
French (fr)
Inventor
Kenneth John Murray
Roderick Alan Porter
Brian Herbert Warrington
Philippe 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
Priority to JP5517196A priority Critical patent/JPH07508707A/en
Priority to CA002132981A priority patent/CA2132981A1/en
Priority to EP93906752A priority patent/EP0632724A1/en
Publication of WO1993019754A1 publication Critical patent/WO1993019754A1/en
Priority to KR1019940703385A priority patent/KR950700736A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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.

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

Abstract

Fused aryl derivatives are described as lusitropic agents for use in the treatment of cardiovascular disease where there is a component of diastolic failure.

Description

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.
10 It has now been found that these derivatives enhance myocardial relaxation i.e. have positive lusitropic activity and are therefore of use in the treatment of cardiovascular diseases where there is a component of diastolic failure.
Accordingly in a first aspect the present invention provides the use of a compound of the 15 formula (1) :
Figure imgf000003_0001
Formula (1)
20 or a pharmaceutically acceptable salt thereof, wherein :
A is N or CH
25 R0 is OH or a bioprecursor thereof,
R1 is A°CO2H, P(X)(OH)(OR2), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof,
Aθ is a single bond, CH , CHF, CF2, CR3(OR4), CO or C(OR5)(OR6),
30
R is phenyl, C3_5cycloalkyl, C3_5Cycloalkyl-Cι_4alkyl, or C^galkyl optionally substituted by C1.4a.koxy,
R3 is H, methyl or ethyl,
35
R4 is H or Cι_3alkyl,
R5 and R^ are each Cι_3alkyl or together form a 1,2-ethanediyl group or 1,3-propanediyl group,
40
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.
In a second aspect 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.
In a third aspect 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. Examples of such diseases include congestive heart failure, angina, hypenension and cardiomyopathy (Kenakin el al.. J- Pharmacol. Exp. Ther. 1991, 257, 1189-1197).
Examples of compounds of the formula (1) and suitable substituent values are as disclosed in WO 91/17987.
Preferably R1 is P(O)(OH)(OR2) or a bioprecursor thereof as defined in WO 91/17987.
Particular compounds of the formula (1) include :
ethyl pivaloyloxymethyI[6-(l-naphthyl)-2-oxo- l,2-dihydro-3-pyridyI]phosphonate, 6-(2-naphthyl)-3-(5-te-razolyl)pyridin-2(lH)-one, 6-[2-(l-pentyloxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(lH)-one, 4-ethoxy-4-oxo- 1 ,3,4-dioxyphosphono[5,6-b]-7-(l-naphthyl)pyridine, and ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo- l,2-dihydro-3-pyridyl]propionate.
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 μM, 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.
Compounds tested include:
5 ethyl pivaloyloxymethyl[6-(l-naphthyl)-2-oxo- 1 ,2-dihydro-3-pyridyl]phosphonate, 6-(2-naphthyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-[2-(l-pentyloxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(lH)-one, 4-ethoxy-4-oxo-l,3,4-dioxyphosphono[5,6-b]-7-(l-naphthyl)pyridine, and l o ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo- 1 ,2-dihydro-3-pyridyl]propionate.

Claims

Clai s :
1. The use of a compound of the formula (1) :
Figure imgf000006_0001
Formula (1)
or a pharmaceutically acceptable salt thereof, wherein :
A is N or CH
R0 is OH or a bioprecursor thereof,
R1 is A°CO2H, P(X)(OH)(OR2), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof,
Aθ is a single bond, CH2, CHF, CF2, CR3(OR4), CO or C(OR5)(OR6),
R2 is phenyl, C3_5cycloalkyl, C3_5cycloalkyl-Cι_4alkyl, or Ci.galkyl optionally substituted by Cι_4alkoxy,
R3 is H, methyl or ethyl,
R is Hor Cι_3alkyl,
R^ and ^ are each C]_3al_cyl or together form a 1,2-ethanediyl group or 1,3-propanediyl group,
Xis O orS and
Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C^.^alkoxy, 2- naphthyl optionally substituted in the 1-position by hydroxy or C^.^alkoxy, 3-phenanthryl, 9-phenanthryl, 2^uinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl in the manufacture of a medicament having positive lusitropic activity.
2. 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 defined in claim 1 or a pharmaceutically acceptable salt thereof.
3. 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 defined in claim 1 or a pharmaceutically acceptable salt thereof.
4. The use according to any one of claims 1 to 3 wherein R* is 5 P(O)(OH)(OR2) or a bioprecursor thereof.
5. The use according to any one of claims 1 to 3 wherein the compound of the formula (1) is selected from :
l o ethyl pivaloyloxymethyl[6-( 1 -naphthyl)-2-oxo- 1 ,2-dihydro-3-pyridyl]phosphonate, 6-(2-naphthyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6^[2-(l-pentyloxy)naphthyl]-3-(5-tetra_-olyl)pyridin-2(lH)-one, 4-ethoxy-4-oxo-l,3,4-dioxyphosphono[5,6-b]-7-(l-naphthyl)pyridine, and ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo- 1 ,2-dihydro-3-pyridyl]propionate.
PCT/GB1993/000615 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents Ceased WO1993019754A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP5517196A JPH07508707A (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives for lucitropic agents
CA002132981A CA2132981A1 (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents
EP93906752A EP0632724A1 (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents
KR1019940703385A KR950700736A (en) 1992-03-27 1994-09-26 Phenolic and pyridinol derivatives as lusitropic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR92/03747 1992-03-27
FR9203747A FR2689012A1 (en) 1992-03-27 1992-03-27 Use of aryl compounds in the treatment of cardiovascular conditions.

Publications (1)

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

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PCT/GB1993/000615 Ceased WO1993019754A1 (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents

Country Status (8)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2753722A1 (en) * 1996-09-26 1998-03-27 Smithkline Beecham Lab METHOD FOR DETECTING CARDIAC RELAXATION MODULATORS AND MODULATORS THUS OBTAINED

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI486165B (en) 2011-02-15 2015-06-01 Univ China Medical Pharmaceutical compositions and extracts for inhibiting blood vessel stenosis and uses of the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0406958A2 (en) * 1989-07-07 1991-01-09 Janssen Pharmaceutica N.V. Positive inotropic and lusitropic 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one derivatives
WO1991017987A1 (en) * 1990-05-21 1991-11-28 Smith Kline & French Laboratories Limited Phenol and pyridinol derivatives as pharmaceuticals
WO1992006085A1 (en) * 1990-09-28 1992-04-16 Smith Kline & French Laboratories Limited Phenylpyridinol derivatives as medicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0406958A2 (en) * 1989-07-07 1991-01-09 Janssen Pharmaceutica N.V. Positive inotropic and lusitropic 3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-one derivatives
WO1991017987A1 (en) * 1990-05-21 1991-11-28 Smith Kline & French Laboratories Limited Phenol and pyridinol derivatives as pharmaceuticals
WO1992006085A1 (en) * 1990-09-28 1992-04-16 Smith Kline & French Laboratories Limited Phenylpyridinol derivatives as 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 (en) * 1996-09-26 1998-03-27 Smithkline Beecham Lab METHOD FOR DETECTING CARDIAC RELAXATION MODULATORS AND MODULATORS THUS OBTAINED
WO1998013518A1 (en) * 1996-09-26 1998-04-02 Smithkline Beecham Laboratoires Pharmaceutiques Process for detecting modulators of myocardial relaxation

Also Published As

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

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