NO327743B1 - Spiro(2H-1-benzopyran-2,4'-piperidin)derivater som glycin-transport-inhibitorer, samt anvendelse derav og farmasoytisk preparat - Google Patents
Spiro(2H-1-benzopyran-2,4'-piperidin)derivater som glycin-transport-inhibitorer, samt anvendelse derav og farmasoytisk preparat Download PDFInfo
- Publication number
- NO327743B1 NO327743B1 NO20022320A NO20022320A NO327743B1 NO 327743 B1 NO327743 B1 NO 327743B1 NO 20022320 A NO20022320 A NO 20022320A NO 20022320 A NO20022320 A NO 20022320A NO 327743 B1 NO327743 B1 NO 327743B1
- Authority
- NO
- Norway
- Prior art keywords
- benzopyran
- piperidine
- spiro
- carboxymethyl
- hydrochloride
- Prior art date
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- KQOCMRACUONAJY-UHFFFAOYSA-N spiro[chromene-2,4'-piperidine] Chemical class C1CNCCC21C=CC1=CC=CC=C1O2 KQOCMRACUONAJY-UHFFFAOYSA-N 0.000 title claims description 20
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 title description 36
- 239000004471 Glycine Substances 0.000 title description 18
- 239000003112 inhibitor Substances 0.000 title 1
- 125000003003 spiro group Chemical group 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
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- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 6
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99309137 | 1999-11-17 | ||
| PCT/EP2000/011351 WO2001036423A1 (en) | 1999-11-17 | 2000-11-13 | Spiro(2h-1-benzopyran-2,4'-piperidine) derivates as glycine transport inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20022320L NO20022320L (no) | 2002-05-15 |
| NO20022320D0 NO20022320D0 (no) | 2002-05-15 |
| NO327743B1 true NO327743B1 (no) | 2009-09-14 |
Family
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Family Applications (1)
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|---|---|---|---|
| NO20022320A NO327743B1 (no) | 1999-11-17 | 2002-05-15 | Spiro(2H-1-benzopyran-2,4'-piperidin)derivater som glycin-transport-inhibitorer, samt anvendelse derav og farmasoytisk preparat |
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|---|---|
| US (2) | US6645973B1 (es) |
| EP (1) | EP1232160B1 (es) |
| JP (1) | JP4825386B2 (es) |
| KR (1) | KR100776226B1 (es) |
| CN (1) | CN1199974C (es) |
| AR (1) | AR026487A1 (es) |
| AT (1) | ATE398622T1 (es) |
| AU (1) | AU779518B2 (es) |
| BR (1) | BR0015586A (es) |
| CA (1) | CA2389491C (es) |
| CO (1) | CO5261618A1 (es) |
| CY (1) | CY1108339T1 (es) |
| CZ (1) | CZ293920B6 (es) |
| DE (1) | DE60039247D1 (es) |
| DK (1) | DK1232160T3 (es) |
| ES (1) | ES2307536T3 (es) |
| HK (1) | HK1047282B (es) |
| HU (1) | HUP0204162A3 (es) |
| IL (2) | IL149286A0 (es) |
| NO (1) | NO327743B1 (es) |
| NZ (1) | NZ518671A (es) |
| PE (1) | PE20010750A1 (es) |
| PL (1) | PL206071B1 (es) |
| PT (1) | PT1232160E (es) |
| RU (1) | RU2250211C2 (es) |
| SK (1) | SK287040B6 (es) |
| TW (1) | TWI243173B (es) |
| WO (1) | WO2001036423A1 (es) |
| ZA (1) | ZA200203320B (es) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI243173B (en) * | 1999-11-17 | 2005-11-11 | Akzo Nobel Nv | Spiro[2H-1-benzopyran-2,4'-piperidine] derivatives |
| FR2842804B1 (fr) * | 2002-07-29 | 2004-09-03 | Sanofi Synthelabo | Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique |
| BRPI0415165A (pt) * | 2003-10-01 | 2007-01-09 | Adolor Corp | composto heterocìclico espirocìclico, composição farmacêutica, método para ligar receptores opióides, métodos para prevenir ou tratar dor, disfunção gastrointestinal, um distúrbio do trato urogenital, um distúrbio imunomodulatório, um distúrbio inflamatório, um distúrbio de função respiratória, ansiedade, distúrbio do humor, um distúrbio relacionado a estresse, distúrbio do sistema nervoso simpático, tosse, e um distúrbio motor, método para tratar uma lesão traumática ao sistema nervoso central, métodos para prevenir ou tratar acidente vascular, arritmia cardìaca, glaucoma, e disfunção sexual, métodos para tratar uma condição selecionada do grupo consistindo de choque, edema cerebral, isquemia cerebral, déficit cerebral após cirurgia cardìaca (bypass) e enxerto, lupus eritematoso sistêmico, doença de hodgkin, doença de sjogren, epilepsia, e rejeição em transplantes de órgão e enxertos de pele, e para tratar dependência de substáncias, métodos para melhorar a sobrevivência de órgãos e células, e cardioproteção após infarto do miocárdio, métodos para reduzir a necessidade de anestesia, para produzir ou manter um estado anestésico, derivado radiomarcado de um composto, derivado isotopicamente marcado de um composto, composto e método de diagnóstico por imagem |
| EP1716147B1 (en) * | 2004-01-08 | 2007-11-14 | F.Hoffmann-La Roche Ag | Diaza-spiropiperidine derivatives as inhibitors of glycine transporter 1 and glycine transporter 2 |
| BRPI0418375A (pt) * | 2004-01-08 | 2007-05-22 | Hoffmann La Roche | derivados de diaza-espiropiperidina |
| CA2609972C (en) * | 2004-03-22 | 2013-05-14 | Apkarian Technologies Llc | Method and compositions for treatment of chronic neuropathic pain |
| US7598261B2 (en) * | 2005-03-31 | 2009-10-06 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
| CN101184749B (zh) * | 2005-03-31 | 2012-12-05 | 阿得罗公司 | 螺环杂环衍生物及其使用方法 |
| US7576207B2 (en) | 2006-04-06 | 2009-08-18 | Adolor Corporation | Spirocyclic heterocyclic derivatives and methods of their use |
| JP2009536175A (ja) * | 2006-05-05 | 2009-10-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 特定の細胞サイクル酵素の阻害剤としてのスピロ−（ｔｈｏ）ベンゾピラン−２，４’−ピペリジン−及びシクロヘキサン誘導体 |
| CN101534819A (zh) * | 2006-09-12 | 2009-09-16 | 阿得罗公司 | 含氮的螺环化合物用于增强认知功能的应用 |
| TWI366565B (en) | 2007-06-06 | 2012-06-21 | Otsuka Pharma Co Ltd | Quinolone compound and pharmaceutical composition |
| KR100888468B1 (ko) * | 2007-08-31 | 2009-03-11 | 한국화학연구원 | 항암활성을 갖는1'-알킬피페리딘-4'-스피로-2-6-(아미도)-2ｈ-벤조피란유도체 |
| WO2009039431A2 (en) * | 2007-09-21 | 2009-03-26 | Neurogen Corporation | Substituted aryl-fused spirocyclic amines |
| EP2380595A1 (en) | 2010-04-19 | 2011-10-26 | Nlife Therapeutics S.L. | Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types |
| TW201643169A (zh) * | 2010-07-09 | 2016-12-16 | 艾伯維股份有限公司 | 作為s1p調節劑的螺-哌啶衍生物 |
| US20170143681A1 (en) | 2015-11-02 | 2017-05-25 | Apkarian Technologies Llc | Methods and compositions for treating pain |
| CN116621187B (zh) * | 2023-07-24 | 2023-09-22 | 江苏泓顺硅基半导体科技有限公司 | 一种用于高温氯化提纯石英砂的设备 |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ243065A (en) * | 1991-06-13 | 1995-07-26 | Lundbeck & Co As H | Piperidine derivatives and pharmaceutical compositions |
| FR2689509B1 (fr) * | 1992-04-01 | 1994-06-03 | Adir | Nouveaux derives spiraniques du 3-amino chromane, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent. |
| DK78692D0 (da) * | 1992-06-12 | 1992-06-12 | Lundbeck & Co As H | Dimere piperidin- og piperazinderivater |
| IL107881A0 (en) * | 1992-12-05 | 1994-04-12 | Fisons Corp | Furanone derivatives and pharmaceutical compositions containing them |
| WO1994018204A1 (en) * | 1993-02-12 | 1994-08-18 | Merck & Co., Inc. | Spiro (2h-1-benzopyran-2, 4' piperidine) class iii antiarrhythmics |
| US5484923A (en) * | 1993-06-10 | 1996-01-16 | Merck & Co., Inc. | Process of making spirocycles and analogs thereof |
| US5439914A (en) * | 1994-02-18 | 1995-08-08 | Merck & Co., Inc. | Spirocycles |
| GB9421003D0 (en) * | 1994-10-18 | 1994-12-07 | Smithkline Beecham Plc | Novel compounds |
| US5654316A (en) * | 1995-06-06 | 1997-08-05 | Schering Corporation | Piperidine derivatives as neurokinin antagonists |
| EP0871440B1 (en) | 1995-12-07 | 2006-03-22 | Daniel C. Javitt | Treatment of negative and cognitive symptoms of schizophrenia with glycine uptake antagonists |
| HUP9600928A3 (en) * | 1996-04-10 | 1999-03-29 | Richter Gedeon Vegyeszet | Use of spiro[2h-1-benzopyran-2,4'-piperidin]-4(3h)-one derivatives for the preparation of pharmaceutical compositions treating dementia, novel derivatives and process for their preparation |
| WO1997045423A1 (en) | 1996-05-31 | 1997-12-04 | Trophix Neuroscience Inc. | Pharmaceutical for treating of neurological and neuropsychiatric disorders |
| WO1997045115A1 (en) | 1996-05-31 | 1997-12-04 | Trophix Pharmaceuticals, Inc. | Pharmaceutical for treatment of neurological and neuropsychiatric disorders |
| US5919653A (en) | 1996-08-20 | 1999-07-06 | Allelix Neuroscience Inc. | Nucleic acids encoding a human glycine transporter |
| AU2030999A (en) | 1998-01-09 | 1999-07-26 | Allelix Neuroscience, Inc. | Glycine transport inhibitors |
| TW555757B (en) | 1998-07-31 | 2003-10-01 | Akzo Nobel Nv | Aminomethylcarboxylic acid derivatives |
| TWI243173B (en) * | 1999-11-17 | 2005-11-11 | Akzo Nobel Nv | Spiro[2H-1-benzopyran-2,4'-piperidine] derivatives |
| CN1249057C (zh) * | 2000-04-27 | 2006-04-05 | 巴斯利尔药物股份公司 | 用作抗菌剂的色烯基甲基嘧啶二胺 |
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2000
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- 2000-11-13 ES ES00977546T patent/ES2307536T3/es not_active Expired - Lifetime
- 2000-11-13 DK DK00977546T patent/DK1232160T3/da active
- 2000-11-13 PT PT00977546T patent/PT1232160E/pt unknown
- 2000-11-13 HU HU0204162A patent/HUP0204162A3/hu unknown
- 2000-11-13 KR KR1020027006305A patent/KR100776226B1/ko not_active IP Right Cessation
- 2000-11-13 SK SK843-2002A patent/SK287040B6/sk not_active IP Right Cessation
- 2000-11-13 IL IL14928600A patent/IL149286A0/xx active IP Right Grant
- 2000-11-13 WO PCT/EP2000/011351 patent/WO2001036423A1/en active Search and Examination
- 2000-11-13 EP EP00977546A patent/EP1232160B1/en not_active Expired - Lifetime
- 2000-11-13 CN CNB008157901A patent/CN1199974C/zh not_active Expired - Fee Related
- 2000-11-13 AT AT00977546T patent/ATE398622T1/de not_active IP Right Cessation
- 2000-11-13 CA CA2389491A patent/CA2389491C/en not_active Expired - Fee Related
- 2000-11-13 PL PL355975A patent/PL206071B1/pl not_active IP Right Cessation
- 2000-11-13 NZ NZ518671A patent/NZ518671A/en unknown
- 2000-11-13 BR BR0015586-1A patent/BR0015586A/pt not_active Application Discontinuation
- 2000-11-13 CZ CZ20021724A patent/CZ293920B6/cs not_active IP Right Cessation
- 2000-11-13 RU RU2002115862/04A patent/RU2250211C2/ru not_active IP Right Cessation
- 2000-11-13 AU AU15219/01A patent/AU779518B2/en not_active Ceased
- 2000-11-13 DE DE60039247T patent/DE60039247D1/de not_active Expired - Lifetime
- 2000-11-13 US US10/130,557 patent/US6645973B1/en not_active Expired - Lifetime
- 2000-11-13 JP JP2001538912A patent/JP4825386B2/ja not_active Expired - Fee Related
- 2000-11-16 AR ARP000106034A patent/AR026487A1/es unknown
- 2000-11-16 PE PE2000001227A patent/PE20010750A1/es not_active Application Discontinuation
- 2000-11-17 CO CO00087799A patent/CO5261618A1/es not_active Application Discontinuation
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2002
- 2002-04-23 IL IL149286A patent/IL149286A/en not_active IP Right Cessation
- 2002-04-25 ZA ZA200203320A patent/ZA200203320B/xx unknown
- 2002-05-15 NO NO20022320A patent/NO327743B1/no not_active IP Right Cessation
- 2002-12-11 HK HK02108962.5A patent/HK1047282B/zh not_active IP Right Cessation
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2003
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