FR2689012A1 - Use of aryl compounds in the treatment of cardiovascular conditions. - Google Patents

Use of aryl compounds in the treatment of cardiovascular conditions. Download PDF

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Publication number
FR2689012A1
FR2689012A1 FR9203747A FR9203747A FR2689012A1 FR 2689012 A1 FR2689012 A1 FR 2689012A1 FR 9203747 A FR9203747 A FR 9203747A FR 9203747 A FR9203747 A FR 9203747A FR 2689012 A1 FR2689012 A1 FR 2689012A1
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FR
France
Prior art keywords
group
naphthyl
compound
alkyl
formula
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.)
Pending
Application number
FR9203747A
Other languages
French (fr)
Inventor
Murray Kenneth John
Porter Roderick Alan
Warrington Brian Herbert
Lahouratate Philippe
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.)
Les Laboratoires Beecham SA
SmithKline Beecham Ltd
Original Assignee
Les Laboratoires Beecham SA
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 Les Laboratoires Beecham SA, SmithKline Beecham Ltd filed Critical Les Laboratoires Beecham SA
Priority to FR9203747A priority Critical patent/FR2689012A1/en
Priority to EP93906752A priority patent/EP0632724A1/en
Priority to CA002132981A priority patent/CA2132981A1/en
Priority to PCT/GB1993/000615 priority patent/WO1993019754A1/en
Priority to AU37646/93A priority patent/AU3764693A/en
Priority to JP5517196A priority patent/JPH07508707A/en
Priority to TW082102673A priority patent/TW234086B/zh
Publication of FR2689012A1 publication Critical patent/FR2689012A1/en
Priority to KR1019940703385A priority patent/KR950700736A/en
Pending 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

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

La présente invention concerne l'utilisation de certains dérivés aryliques condensés comme agents lusitropes dans le traitement d'affections cardio-vasculaires où il existe une composante d'insuffisance diastolique. The present invention relates to the use of certain condensed aryl derivatives as lusitropic agents in the treatment of cardiovascular conditions where there is a component of diastolic insufficiency.

Le document WO 91/17987 fait connaître des dérivés aryliques condensés comme agonistes d'une protéine-kinase dépendante de AMP cyclique. WO 91/17987 discloses condensed aryl derivatives as agonists of a cyclic AMP-dependent protein kinase.

On a maintenant découvert que ces dérivés améliorent la relaxation myocardique, c'est-à-dire qu'ils possèdent une activité lusitrope positive, et sont donc utiles dans le traitement d'affections cardio-vasculaires où il existe une composante d'insuffisance diastolique. We have now discovered that these derivatives improve myocardial relaxation, that is to say that they have a positive lusitrope activity, and are therefore useful in the treatment of cardiovascular conditions where there is a component of diastolic insufficiency. .

Ainsi, sous un premier aspect, la présente invention propose l'utilisation d'un composé de formule (1)

Figure img00010001

dans laquelle
A est N ou CH 0
R est OH ou un bioprécurseur de celui-ci
R1 est un groupe 2
R est un groupe P(X)(OH)(OR ), SO2H, SO3H ou 5-tétrazolyle ou un bioprécurseur de celui-ci
3 4
est une liaison simple, CH2, CHF, CF2, CR (OR ),
CO ou C(OR5)(0R6)
R2 est un groupe phényle, cycloalkyle en C3-C5, (cycloalkyle en C3-C5)-(alkyle en C1 -C4) ou alkyle en C1 -C8 facultativement substitué par un groupe alcoxy en C1-C4 ;;
R3 est H, un groupe méthyle ou éthyle
R4 est H ou un groupe alkyle en C1 r
R5 et R6 sont chacun un groupe alkyle en C1 -C3 ou forment ensemble un groupe 1,2-éthanediyle ou un groupe 1 , 3-propanediyle
X est O ou S ; et
Ar est un groupe 1-naphtyle facultativement substitué à la position 4 par un groupe hydroxyle ou alcoxy en C1 -C6, 2-naphtyle facultativement substitué à la position 1 par un groupe hydroxyle ou alcoxy en C1 -C6, 3-phénanthryle, 9-phénanthryle, 2-quinolyle, 4-quinolyle, 3-thianaphtényle ou 2-benzofurannyle, ou d'un sel pharmaceutiquement acceptable de ce composé, dans la fabrication d'un médicament ayant une activité lusitrope positive.Thus, in a first aspect, the present invention proposes the use of a compound of formula (1)
Figure img00010001

in which
A is N or CH 0
R is OH or a bioprecursor thereof
R1 is a group 2
R is a P (X) (OH) (OR), SO2H, SO3H or 5-tetrazolyl group or a bioprecursor thereof
3 4
is a single bond, CH2, CHF, CF2, CR (OR),
CO or C (OR5) (0R6)
R2 is a phenyl, C3-C5 cycloalkyl, (C3-C5 cycloalkyl) - (C1-C4 alkyl) or C1-C8 alkyl optionally substituted by a C1-C4 alkoxy group;
R3 is H, methyl or ethyl
R4 is H or C1-C1 alkyl
R5 and R6 are each a C1-C3 alkyl group or together form a 1,2-ethanediyl group or a 1,3-propanediyl group
X is O or S; and
Ar is a 1-naphthyl group optionally substituted at position 4 by a hydroxyl or C1-C6 alkoxy group, 2-naphthyl optionally substituted at position 1 by a hydroxyl or C1-C6 alkoxy group, 3-phenanthryl, 9- phenanthryl, 2-quinolyl, 4-quinolyl, 3-thianaphthenyl or 2-benzofuranyl, or a pharmaceutically acceptable salt of this compound, in the manufacture of a medicament having positive lusitrope activity.

Sous un deuxième aspect, la présente invention propose un procédé pour améliorer la relaxation myocardique, qui consiste à administrer à un hôte qui en a besoin une quantité efficace d'un composé de formule (1) tel que défini ci-dessus ou d'un sel pharmaceutiquement acceptable de ce composé. In a second aspect, the present invention provides a method for improving myocardial relaxation, which comprises administering to a host in need thereof an effective amount of a compound of formula (1) as defined above or of a pharmaceutically acceptable salt of this compound.

Sous un troisième aspect, la présente invention propose l'utilisation d'un composé de formule (1) tel que défini ci-dessus ou d'un sel pharmaceutiquement acceptable de ce composé, pour traiter une affection cardio-vasculaire où il existe une composante d'insuffisance diastolique, par l'administration à un hôte qui en a besoin d'une quantité efficace d'un tel composé ou sel. Des exemples de ces affections comprennent l'insuffisance cardiaque, l'angine de poitrine, l'hypertension et la myocardiopathie (Kenakin et coll., J. Pharmacol. Exp. Ther. 1991, 257, 1189-1197). In a third aspect, the present invention provides the use of a compound of formula (1) as defined above or of a pharmaceutically acceptable salt of this compound, for treating a cardiovascular disease where there is a component diastolic insufficiency, by administration to a host in need thereof of an effective amount of such a compound or salt. Examples of these conditions include heart failure, angina, hypertension, and cardiomyopathy (Kenakin et al., J. Pharmacol. Exp. Ther. 1991, 257, 1189-1197).

Des exemples de composés de formule (1) et de substituants appropriés sont tels qu'exposés dans le document WO 91/17987. Examples of compounds of formula (1) and of suitable substituents are as set out in document WO 91/17987.

2
De préférence, R1 est P(O) (OH) (OR ) ou un bioprécur- seur de celui-ci comme défini dans le document WO 91/17987.2
Preferably, R1 is P (O) (OH) (OR) or a bioprecursor thereof as defined in document WO 91/17987.

Des composés particuliers de formule (1) com prennent
le pivaloyloxyméthyl [6- (1 -naphtyl ) -2-oxo-1 ,2-dihydro- 3-pyridyl]phosphonate d'éthyle,
la 6-(2-naphtyl)-3-( 5-tétrazolyl) pyridine-i!(lH) -one, et
la 6-[2-(1-pentyloxy)naphtyl]-3-(5-tétrazolyl)- pyridine-2(1H)-one. Specific compounds of formula (1) include
ethyl pivaloyloxymethyl [6- (1-naphthyl) -2-oxo-1,2,2-dihydro-3-pyridyl] phosphonate,
6- (2-naphthyl) -3- (5-tetrazolyl) pyridine-i! (1H) -one, and
6- [2- (1-pentyloxy) naphthyl] -3- (5-tetrazolyl) - pyridine-2 (1H) -one.

Les composés de formule (1) peuvent être préparés et administrés sous forme de compositions pharmaceutiques, comme décrit dans le document WO 91/17987. The compounds of formula (1) can be prepared and administered in the form of pharmaceutical compositions, as described in document WO 91/17987.

L'effet lusitrope positif des composés de formule (1) peut être démontré par la mesure du temps de relaxation du muscle cardiaque dans le ventricule de lapin. The positive lusitrope effect of the compounds of formula (1) can be demonstrated by measuring the relaxation time of the heart muscle in the rabbit ventricle.

Des muscles papillaires du ventricule droit de lapins de Nouvelle-Zélande albinos femelles sont placés dans des bains pour organes normaux contenant une solution de
Krebs oxygénée. Une extrémité du muscle est rattachée à un transducteur isométrique qui permet d'enregistrer la force contractile et sa dérivée première sur des enregistreurs graphiques. Les composés examinés sont ajoutés au bain d'une manière cumulative. Le temps de relaxation est calculé comme le temps compté depuis la tension crête jusqu'au point de demi-relaxation. A des concentrations 30 à 300uM, les composés examinés suivants ont provoqué une diminution de 5 à 25 % du temps de relaxation, ce qui dénote un effet lusitrope positif utile dans le traitement d'affections cardio-vasculaires où il existe une composante d'insuffisance diastolique comme décrit ci-dessus.Papillary muscles of the right ventricle of female albino New Zealand rabbits are placed in normal organ baths containing a solution of
Oxygenated Krebs. One end of the muscle is attached to an isometric transducer which makes it possible to record the contractile force and its first derivative on graphic recorders. The compounds examined are added to the bath in a cumulative manner. The relaxation time is calculated as the time counted from the peak voltage to the half-relaxation point. At concentrations 30 to 300 µM, the following examined compounds caused a reduction of 5 to 25% of the relaxation time, which indicates a positive lusitrope effect useful in the treatment of cardiovascular conditions where there is a component of insufficiency diastolic as described above.

Les composés examinés étaient
le pivaloyloxyméthyl [6- (1 -naphtyl ) -2-oxo-1 , 2-dihydro- 3-pyridyl]phosphonate d'éthyle,
la 6- ( 2-naphtyl ) -3- (5-tétrazolyl )pyridine-2 (1H) -one, et
la 6-[2-(1-pentyloxy)naphtyl]-3-(5-tétrazolyl)pyridine-2(1H)-one. The compounds examined were
ethyl pivaloyloxymethyl [6- (1-naphthyl) -2-oxo-1,2,2-dihydro-3-pyridyl] phosphonate,
6- (2-naphthyl) -3- (5-tetrazolyl) pyridine-2 (1H) -one, and
6- [2- (1-pentyloxy) naphthyl] -3- (5-tetrazolyl) pyridine-2 (1H) -one.

Claims (4)

REVENDICATIONS 1. Utilisation d'.un composé de formule (1)1. Use of a compound of formula (1)
Figure img00040001
Figure img00040001
 dans laquelle in which A est N ou CH; RO est OH ou un bioprécurseur de celui-ci;A is N or CH; RO is OH or a bioprecursor thereof; R1 est un groupe A CO2H, P(X)(OH)(OR2), SO2H, SO3H ou 5tétrazolyle ou un bioprécurseur de celui-ci; AO est une liaison simple, CH2, CHF, CF2, CR3(OR4), CO ou C(OR5)(OR6); R1 is a group A CO2H, P (X) (OH) (OR2), SO2H, SO3H or 5tetrazolyl or a bioprecursor thereof; AO is a single bond, CH2, CHF, CF2, CR3 (OR4), CO or C (OR5) (OR6); R2 est un groupe phényle, cycloalkyle en C3-C5, (cycloal- kyle en C3-C5 ) - ( alkyle en C1-C4) ou alkyle en C1-C8 facultativement substitué par un groupe alcoxy en C1-C4;R2 is phenyl, C3-C5 cycloalkyl, (C3-C5 cycloalkyl) - (C1-C4 alkyl) or C1-C8 alkyl optionally substituted by a C1-C4 alkoxy group; R3 est H, un groupe méthyle ou éthyle;R3 is H, methyl or ethyl; R4 est H ou un groupe alkyle en C1-C3;R4 is H or C1-C3 alkyl; R5 et R6 sont chacun un groupe alkyle en C1-C3 ou forment ensemble un groupe 1,2-éthanediyle ou un groupe 1,3propanediyle;;R5 and R6 are each a C1-C3 alkyl group or together form a 1,2-ethanediyl group or a 1,3propanediyl group; X est O ou S; etX is O or S; and Ar est un groupe l-naphtyle facultativement substitué à la position 4 par un groupe hydroxyle ou alcoxy en C1-C6, 2-naphtyle facultativement substitué à la position 1 par un groupe hydroxyle ou alcoxy en C1-C6, 3-phénanthryle, 9-phénanthryle, 2-quinolyle, 4-quinolyle, 3-thianaphtényle ou 2-benzofurannyle, ou d'un sel pharmaceutiquement acceptable de ce composé, dans la fabrication d'un médicament doué d'activité lusitrope positive. Ar is an l-naphthyl group optionally substituted at position 4 by a hydroxyl or C1-C6 alkoxy group, 2-naphthyl optionally substituted at position 1 by a hydroxyl or C1-C6 alkoxy group, 3-phenanthryl, 9- phenanthryl, 2-quinolyl, 4-quinolyl, 3-thianaphthényle or 2-benzofurannyle, or a pharmaceutically acceptable salt of this compound, in the manufacture of a medicament endowed with positive lusitrope activity. 2. Utilisation d'un composé de formule (1) tel que défini dans la revendication 1 ou d'un sel pharmaceutiquement acceptable de ce composé, pour la fabrication d'un médicament pour le traitement d'une affection cardio-vasculaire où il existe une composante d'insuffisance diastolique. 2. Use of a compound of formula (1) as defined in claim 1 or of a pharmaceutically acceptable salt of this compound, for the manufacture of a medicament for the treatment of a cardiovascular disease where it exists a component of diastolic insufficiency. 3. Utilisation selon l'une des revendications 1 ou 2, caractérisée en ce que R1 est P(O)(OH)(OR2) ou un bioprécurseur de celui-ci. 3. Use according to one of claims 1 or 2, characterized in that R1 is P (O) (OH) (OR2) or a bioprecursor thereof. 4. Utilisation selon l'une quelconque des revendications 1 ou 2, caractérisée en ce que le composé de formule (1) est choisi parmi le pivaloyloxyméthyl [6- ( l-naphtyl ) -2-oxo-1, 2-dihydro-3- pyridylj phosphonate d'éthyle, la 6-(2-naphtyl)-3-(5-tétrazolyl)pyridine-2(1H)-one, et la 6-[2-(1-pentyloxy)naphtyl-3-(5-tétrazolyl)-pyridine- 2(1H)-one.  4. Use according to any one of claims 1 or 2, characterized in that the compound of formula (1) is chosen from pivaloyloxymethyl [6- (l-naphthyl) -2-oxo-1, 2-dihydro-3 - ethyl pyridylj phosphonate, 6- (2-naphthyl) -3- (5-tetrazolyl) pyridine-2 (1H) -one, and 6- [2- (1-pentyloxy) naphthyl-3- (5 -tetrazolyl) -pyridine- 2 (1H) -one.
FR9203747A 1992-03-27 1992-03-27 Use of aryl compounds in the treatment of cardiovascular conditions. Pending FR2689012A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
FR9203747A FR2689012A1 (en) 1992-03-27 1992-03-27 Use of aryl compounds in the treatment of cardiovascular conditions.
EP93906752A EP0632724A1 (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents
CA002132981A CA2132981A1 (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents
PCT/GB1993/000615 WO1993019754A1 (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents
AU37646/93A AU3764693A (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives as lusitropic agents
JP5517196A JPH07508707A (en) 1992-03-27 1993-03-25 Phenol and pyridinol derivatives for lucitropic agents
TW082102673A TW234086B (en) 1992-03-27 1993-04-09
KR1019940703385A KR950700736A (en) 1992-03-27 1994-09-26 Phenolic and pyridinol derivatives as lusitropic agents

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
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
FR2689012A1 true FR2689012A1 (en) 1993-10-01

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FR9203747A Pending FR2689012A1 (en) 1992-03-27 1992-03-27 Use of aryl compounds in the treatment of cardiovascular conditions.

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)

Families Citing this family (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
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

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
CA2081982A1 (en) * 1990-05-21 1991-11-22 Kenneth John Murray Phenol and pyridinol derivatives as pharmaceuticals
CA2091989A1 (en) * 1990-09-28 1992-03-29 Roderick Alan Porter Phenylpyridinol derivatives as medicaments

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JPH07508707A (en) 1995-09-28
TW234086B (en) 1994-11-11
CA2132981A1 (en) 1993-10-14
AU3764693A (en) 1993-11-08
WO1993019754A1 (en) 1993-10-14
KR950700736A (en) 1995-02-20
EP0632724A1 (en) 1995-01-11

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