JP2008521805A - β−アドレナリン作用性受容体およびホスホジエステラーゼに対する阻害活性を有する強心性化合物 - Google Patents
β−アドレナリン作用性受容体およびホスホジエステラーゼに対する阻害活性を有する強心性化合物 Download PDFInfo
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- JP2008521805A JP2008521805A JP2007543114A JP2007543114A JP2008521805A JP 2008521805 A JP2008521805 A JP 2008521805A JP 2007543114 A JP2007543114 A JP 2007543114A JP 2007543114 A JP2007543114 A JP 2007543114A JP 2008521805 A JP2008521805 A JP 2008521805A
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- compound
- hydroxy
- chloro
- phenyl
- oxo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 297
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- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 title claims abstract description 21
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- 108010079452 beta Adrenergic Receptors Proteins 0.000 title claims abstract description 19
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- 125000001424 substituent group Chemical group 0.000 claims description 20
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 5
- SFWVFXYXVOWMPL-UHFFFAOYSA-N 3-[3-chloro-4-[2-[4-[(2-hydroxy-3-phenoxypropyl)amino]piperidin-1-yl]-2-oxoethoxy]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C=1C=CC=CC=1OCC(O)CNC(CC1)CCN1C(=O)COC(C(=C1)Cl)=CC=C1C1=NNC(=O)CC1 SFWVFXYXVOWMPL-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
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- 125000003118 aryl group Chemical group 0.000 claims description 3
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
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- 239000012453 solvate Substances 0.000 claims description 3
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 2
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 2
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- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 4
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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| PCT/US2005/040409 WO2006060122A2 (en) | 2004-11-30 | 2005-11-08 | Cardiotonic compounds with inhibitory activity against beta-adrenergic receptors and phosphodiesterase |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012509858A (ja) * | 2008-11-25 | 2012-04-26 | ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 肥大性心筋症治療用のホスホジエステラーゼタイプIII(PDEIII)インヒビターまたはCa2+感作剤 |
| JP2019521964A (ja) * | 2016-05-13 | 2019-08-08 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | アドレナリン受容体調節化合物およびその使用方法 |
| JP2021505598A (ja) * | 2017-12-06 | 2021-02-18 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 心不全およびそれに関連する障害の治療または予防に有用なβ−3アドレナリン受容体のモジュレーター |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102004011512B4 (de) | 2004-03-08 | 2022-01-13 | Boehringer Ingelheim Vetmedica Gmbh | Pharmazeutische Zubereitung enthaltend Pimobendan |
| EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
| GB0415746D0 (en) * | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
| PH12012502411A1 (en) | 2005-05-10 | 2019-07-17 | Intermune Inc | Method of modulating stress-activated protein kinase system |
| WO2007042912A2 (en) * | 2005-10-13 | 2007-04-19 | Orchid Research Laboratories Limited | Heterocyclic compounds as pstat3/il-6 inhibitors |
| CA2658821C (en) | 2006-07-25 | 2014-10-21 | Cephalon, Inc. | Pyridizinone derivatives and uses thereof to treat diseases, disorders and/or conditions that may be mediated or modulated by inhibition of h3 receptors |
| EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
| US20080262226A1 (en) * | 2006-11-07 | 2008-10-23 | Artesian Therapeutics, Inc. | Methods of making compounds having a beta-adrenergic inhibitor and a linker and methods of making compounds having a beta-adrenergic inhibitor, a linker and a phosphodiesterase inhibitor |
| US8304413B2 (en) | 2008-06-03 | 2012-11-06 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| ES2924478T3 (es) | 2012-03-15 | 2022-10-07 | Boehringer Ingelheim Vetmedica Gmbh | Formulación de comprimidos farmacéuticos para el sector médico veterinario, método de producción y uso de los mismos |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| HRP20251029T1 (hr) | 2013-07-19 | 2025-10-24 | Boehringer Ingelheim Vetmedica Gmbh | Konzervirani eterificirani derivati ciklodekstrina koji sadrže tekući vodeni farmaceutski pripravak |
| US12091408B2 (en) * | 2013-08-30 | 2024-09-17 | Uti Limited Partnership | Store overload-induced calcium release inhibitors and methods for producing and using the same |
| PL3106150T3 (pl) | 2013-12-04 | 2022-01-03 | Boehringer Ingelheim Vetmedica Gmbh | Ulepszone kompozycje farmaceutyczne pimobendanu |
| WO2015104602A2 (en) | 2014-01-08 | 2015-07-16 | Wockhardt Limited | A process for the preparation of anagliptin and its intermediates thereof |
| IN2014MU01191A (enExample) | 2014-03-29 | 2015-10-02 | Wockhardt Ltd | |
| RU2692485C2 (ru) | 2014-04-02 | 2019-06-25 | Интермьюн, Инк. | Противофиброзные пиридиноны |
| US10919249B2 (en) | 2016-02-19 | 2021-02-16 | Albert Mardikian | Apparatus for pressing and dehydrating of waste |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
| MA44037B1 (fr) | 2016-06-06 | 2020-03-31 | Arena Pharm Inc | Modulateurs du récepteur adrénergique bêta 3 utile dans le traitement ou la prévention de troubles associés à ceux-ci |
| TN2019000290A1 (en) | 2017-03-20 | 2021-05-07 | Forma Therapeutics Inc | Pyrrolopyrrole compositions as pyruvate kinase (pkr) activators |
| JP7450610B2 (ja) | 2018-09-19 | 2024-03-15 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | ピルビン酸キナーゼrの活性化 |
| BR112021005188A2 (pt) | 2018-09-19 | 2021-06-08 | Forma Therapeutics, Inc. | tratamento de anemia falciforme com um composto de ativação de piruvato cinase r |
| BR112022004715A2 (pt) | 2019-09-19 | 2022-06-14 | Forma Therapeutics Inc | Composições de ativação de piruvato quinase r (pkr) |
| CN111170997A (zh) * | 2019-12-31 | 2020-05-19 | 广州医科大学 | 咔唑类化合物及其制备方法和应用 |
| US12128035B2 (en) | 2021-03-19 | 2024-10-29 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5283382A (en) * | 1975-12-27 | 1977-07-12 | Otsuka Pharmaceut Co Ltd | Synthesis of carbostyril derivatives |
| JPS52108970A (en) * | 1976-03-09 | 1977-09-12 | Boehringer Sohn Ingelheim | Production of novel aminoalkyl heterocyclic compound |
| JPS5368775A (en) * | 1976-10-05 | 1978-06-19 | Boehringer Sohn Ingelheim | 11aryloxyy22mydroxyy33 alkyleneaminopropane |
| JPS54157558A (en) * | 1978-04-13 | 1979-12-12 | Boehringer Mannheim Gmbh | Novel carbazolyll*4**oxyypropanolamine derivative*its manufacture and drug containing it and having vasodilatation and*or betaaacceptor occlusion activity |
| JPS61246162A (ja) * | 1985-02-11 | 1986-11-01 | インペリアル・ケミカル・インダストリ−ズ・ピ−エルシ− | ジヒドロピリジン、その製造法および該化合物を含有する高血圧治療剤 |
| JPS63183568A (ja) * | 1986-09-08 | 1988-07-28 | Teikoku Hormone Mfg Co Ltd | ピリダジノン誘導体 |
| JPH035465A (ja) * | 1989-06-02 | 1991-01-11 | Teikoku Hormone Mfg Co Ltd | 光学活性ピリダジノン誘導体 |
| JPH0386868A (ja) * | 1989-06-19 | 1991-04-11 | Teikoku Hormone Mfg Co Ltd | ピリダジノン化合物 |
| JPH03141264A (ja) * | 1989-08-10 | 1991-06-17 | Glaxo Inc | 強心活性およびベータ遮断活性を有するピリダジノン |
| JPH03178965A (ja) * | 1989-09-22 | 1991-08-02 | Glaxo Inc | 心臓血管障害の治療に有用なピリドンニトリル |
| WO2004050657A2 (en) * | 2002-11-27 | 2004-06-17 | Artesian Therapeutics, Inc. | COMPOUNDS WITH MIXED PDE-INHIBITORY AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE |
| WO2004058726A2 (en) * | 2002-12-23 | 2004-07-15 | Artesian Therapeutics, Inc. | CARDIOTONIC COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST β-ADRENERGIC RECEPTORS AND PHOSPHODIESTERASE |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1488330A (en) * | 1973-12-19 | 1977-10-12 | Smith Kline French Lab | Dihydropyridazinones |
| US4111935A (en) * | 1975-01-02 | 1978-09-05 | Smith Kline & French Laboratories Limited | 3-chloro-6-phenylpyridazine compounds |
| DE3023369A1 (de) * | 1980-06-23 | 1982-01-14 | Boehringer Mannheim Gmbh, 6800 Mannheim | Aryloxypropanolamine, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| GB8323553D0 (en) * | 1983-09-02 | 1983-10-05 | Smith Kline French Lab | Pharmaceutical compositions |
| JPS6193169A (ja) * | 1984-10-12 | 1986-05-12 | Sankyo Co Ltd | ピリダジノン誘導体及びその製法 |
| DE3934436A1 (de) * | 1989-06-01 | 1991-04-18 | Thomae Gmbh Dr K | 2-hydroxy-n-propylamine, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| NZ234087A (en) * | 1989-06-19 | 1991-08-27 | Teikoku Hormone Mfg Co Ltd | 2-(3-aryloxy(2-hydroxy-propylamino))-2-methylpropyl- aminophenyl pyridazine derivatives |
| US5641783A (en) * | 1993-11-12 | 1997-06-24 | Cell Therapeutics, Inc. | Substituted amino alcohol compounds |
| US5827893A (en) * | 1996-03-29 | 1998-10-27 | Lurie; Keith G. | Mechanical and pharmacological therapies to treat cardiac arrest |
| US5905078A (en) * | 1998-06-19 | 1999-05-18 | Orion Corporation | Use of a pyridazinone derivative |
| JP5258763B2 (ja) * | 2007-06-20 | 2013-08-07 | 興和株式会社 | 5−フェニル−3−ピリダジノン誘導体 |
| US8440666B2 (en) * | 2007-10-31 | 2013-05-14 | Nissan Chemical Industries, Ltd. | Pyridazinone compounds and P2X7 receptor inhibitors |
| EP2204366A1 (de) * | 2008-12-19 | 2010-07-07 | Bayer CropScience AG | Herbizid und insektizid wirksame phenylsubstituierte Pyridazinone |
-
2005
- 2005-11-08 EP EP05848640A patent/EP1833480A2/en not_active Withdrawn
- 2005-11-08 WO PCT/US2005/040409 patent/WO2006060122A2/en not_active Ceased
- 2005-11-08 CA CA002588947A patent/CA2588947A1/en not_active Abandoned
- 2005-11-08 US US11/791,894 patent/US20080255134A1/en not_active Abandoned
- 2005-11-08 JP JP2007543114A patent/JP2008521805A/ja active Pending
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5283382A (en) * | 1975-12-27 | 1977-07-12 | Otsuka Pharmaceut Co Ltd | Synthesis of carbostyril derivatives |
| JPS52108970A (en) * | 1976-03-09 | 1977-09-12 | Boehringer Sohn Ingelheim | Production of novel aminoalkyl heterocyclic compound |
| JPS5368775A (en) * | 1976-10-05 | 1978-06-19 | Boehringer Sohn Ingelheim | 11aryloxyy22mydroxyy33 alkyleneaminopropane |
| JPS54157558A (en) * | 1978-04-13 | 1979-12-12 | Boehringer Mannheim Gmbh | Novel carbazolyll*4**oxyypropanolamine derivative*its manufacture and drug containing it and having vasodilatation and*or betaaacceptor occlusion activity |
| JPS61246162A (ja) * | 1985-02-11 | 1986-11-01 | インペリアル・ケミカル・インダストリ−ズ・ピ−エルシ− | ジヒドロピリジン、その製造法および該化合物を含有する高血圧治療剤 |
| JPS63183568A (ja) * | 1986-09-08 | 1988-07-28 | Teikoku Hormone Mfg Co Ltd | ピリダジノン誘導体 |
| JPH035465A (ja) * | 1989-06-02 | 1991-01-11 | Teikoku Hormone Mfg Co Ltd | 光学活性ピリダジノン誘導体 |
| JPH0386868A (ja) * | 1989-06-19 | 1991-04-11 | Teikoku Hormone Mfg Co Ltd | ピリダジノン化合物 |
| JPH03141264A (ja) * | 1989-08-10 | 1991-06-17 | Glaxo Inc | 強心活性およびベータ遮断活性を有するピリダジノン |
| JPH03178965A (ja) * | 1989-09-22 | 1991-08-02 | Glaxo Inc | 心臓血管障害の治療に有用なピリドンニトリル |
| WO2004050657A2 (en) * | 2002-11-27 | 2004-06-17 | Artesian Therapeutics, Inc. | COMPOUNDS WITH MIXED PDE-INHIBITORY AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE |
| WO2004058726A2 (en) * | 2002-12-23 | 2004-07-15 | Artesian Therapeutics, Inc. | CARDIOTONIC COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST β-ADRENERGIC RECEPTORS AND PHOSPHODIESTERASE |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012509858A (ja) * | 2008-11-25 | 2012-04-26 | ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 肥大性心筋症治療用のホスホジエステラーゼタイプIII(PDEIII)インヒビターまたはCa2+感作剤 |
| JP2019521964A (ja) * | 2016-05-13 | 2019-08-08 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | アドレナリン受容体調節化合物およびその使用方法 |
| US11173144B2 (en) | 2016-05-13 | 2021-11-16 | The Board Of Trustees Of The Leland Stanford Junior University | Adrenergic receptor modulating compounds and methods of using the same |
| JP2021505598A (ja) * | 2017-12-06 | 2021-02-18 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 心不全およびそれに関連する障害の治療または予防に有用なβ−3アドレナリン受容体のモジュレーター |
| JP7357617B2 (ja) | 2017-12-06 | 2023-10-06 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 心不全およびそれに関連する障害の治療または予防に有用なβ-3アドレナリン受容体のモジュレーター |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006060122A3 (en) | 2007-03-22 |
| EP1833480A2 (en) | 2007-09-19 |
| WO2006060122A9 (en) | 2006-08-17 |
| WO2006060122A2 (en) | 2006-06-08 |
| CA2588947A1 (en) | 2006-06-08 |
| US20080255134A1 (en) | 2008-10-16 |
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