EP0632724A1 - Phenol and pyridinol derivatives as lusitropic agents - Google Patents
Phenol and pyridinol derivatives as lusitropic agentsInfo
- 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- Withdrawn
Links
- 230000003295 lusitropic effect Effects 0.000 title claims abstract description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 230000003205 diastolic effect Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 14
- -1 5-tetrazolyl Chemical group 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 230000010117 myocardial relaxation Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- ZBBCZHQAXDJXPG-UHFFFAOYSA-N 6-naphthalen-2-yl-3-(2H-tetrazol-5-yl)-1H-pyridin-2-one Chemical compound C1=C(C=CC2=CC=CC=C12)C1=CC=C(C(N1)=O)C1=NN=NN1 ZBBCZHQAXDJXPG-UHFFFAOYSA-N 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims description 2
- OEFCBKWZTOGVSR-UHFFFAOYSA-N [1-(2,2-dimethylpropanoyloxymethyl)-6-naphthalen-1-yl-2-oxopyridin-3-yl]-ethoxyphosphinic acid Chemical compound CC(C)(C)C(=O)OCN1C(=O)C(P(O)(=O)OCC)=CC=C1C1=CC=CC2=CC=CC=C12 OEFCBKWZTOGVSR-UHFFFAOYSA-N 0.000 claims description 2
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000002708 enhancing effect Effects 0.000 claims description 2
- JYXCYMDNKCNJPR-UHFFFAOYSA-N ethyl 2-methoxy-2-(6-naphthalen-2-yl-2-oxo-1h-pyridin-3-yl)propanoate Chemical compound N1C(=O)C(C(C)(OC)C(=O)OCC)=CC=C1C1=CC=C(C=CC=C2)C2=C1 JYXCYMDNKCNJPR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- XJQFJIRQMZZIOB-UHFFFAOYSA-N 6-(2-pentoxynaphthalen-1-yl)-3-(2H-tetrazol-5-yl)-1H-pyridin-2-one Chemical compound C(CCCC)OC1=C(C2=CC=CC=C2C=C1)C1=CC=C(C(N1)=O)C1=NN=NN1 XJQFJIRQMZZIOB-UHFFFAOYSA-N 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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)
- 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)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9203747 | 1992-03-27 | ||
| FR9203747A FR2689012A1 (fr) | 1992-03-27 | 1992-03-27 | Utilisation de composés aryliques dans le traitement d'affections cardio-vasculaires. |
| PCT/GB1993/000615 WO1993019754A1 (en) | 1992-03-27 | 1993-03-25 | Phenol and pyridinol derivatives as lusitropic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0632724A1 true EP0632724A1 (en) | 1995-01-11 |
Family
ID=9428178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP93906752A Withdrawn EP0632724A1 (en) | 1992-03-27 | 1993-03-25 | Phenol and pyridinol derivatives as lusitropic agents |
Country Status (8)
Families Citing this family (2)
| 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)
| 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 |
| WO1991017987A1 (en) * | 1990-05-21 | 1991-11-28 | Smith Kline & French Laboratories Limited | Phenol and pyridinol derivatives as pharmaceuticals |
| CA2091989A1 (en) * | 1990-09-28 | 1992-03-29 | Roderick Alan Porter | Phenylpyridinol derivatives as medicaments |
-
1992
- 1992-03-27 FR FR9203747A patent/FR2689012A1/fr active Pending
-
1993
- 1993-03-25 CA CA002132981A patent/CA2132981A1/en not_active Abandoned
- 1993-03-25 WO PCT/GB1993/000615 patent/WO1993019754A1/en not_active Application Discontinuation
- 1993-03-25 AU AU37646/93A patent/AU3764693A/en not_active Abandoned
- 1993-03-25 EP EP93906752A patent/EP0632724A1/en not_active Withdrawn
- 1993-03-25 JP JP5517196A patent/JPH07508707A/ja active Pending
- 1993-04-09 TW TW082102673A patent/TW234086B/zh active
-
1994
- 1994-09-26 KR KR1019940703385A patent/KR950700736A/ko not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9319754A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07508707A (ja) | 1995-09-28 |
| AU3764693A (en) | 1993-11-08 |
| KR950700736A (ko) | 1995-02-20 |
| TW234086B (enrdf_load_stackoverflow) | 1994-11-11 |
| CA2132981A1 (en) | 1993-10-14 |
| WO1993019754A1 (en) | 1993-10-14 |
| FR2689012A1 (fr) | 1993-10-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19940826 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE |
|
| GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
| 17Q | First examination report despatched |
Effective date: 19960715 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 19961001 |