RU2312857C2 - Фосфатные производные фтороксиндолов и способ лечения с их использованием - Google Patents
Фосфатные производные фтороксиндолов и способ лечения с их использованием Download PDFInfo
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- RU2312857C2 RU2312857C2 RU2004131201/04A RU2004131201A RU2312857C2 RU 2312857 C2 RU2312857 C2 RU 2312857C2 RU 2004131201/04 A RU2004131201/04 A RU 2004131201/04A RU 2004131201 A RU2004131201 A RU 2004131201A RU 2312857 C2 RU2312857 C2 RU 2312857C2
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- Russia
- Prior art keywords
- methoxyphenyl
- fluoro
- chloro
- trifluoromethyl
- oxo
- Prior art date
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- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
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- HGJMXJABQKRULV-UHFFFAOYSA-K tetrabutylazanium;phosphate Chemical compound [O-]P([O-])([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC HGJMXJABQKRULV-UHFFFAOYSA-K 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Psychiatry (AREA)
- Gynecology & Obstetrics (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36601002P | 2002-03-20 | 2002-03-20 | |
| US60/366,010 | 2002-03-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2004131201A RU2004131201A (ru) | 2005-05-10 |
| RU2312857C2 true RU2312857C2 (ru) | 2007-12-20 |
Family
ID=28454740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2004131201/04A RU2312857C2 (ru) | 2002-03-20 | 2003-03-20 | Фосфатные производные фтороксиндолов и способ лечения с их использованием |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6930100B2 (https=) |
| EP (1) | EP1485085A4 (https=) |
| JP (1) | JP4359150B2 (https=) |
| KR (1) | KR100951499B1 (https=) |
| CN (1) | CN100384820C (https=) |
| BR (1) | BR0308737A (https=) |
| CA (1) | CA2479256A1 (https=) |
| CO (1) | CO5611143A2 (https=) |
| GE (1) | GEP20074230B (https=) |
| HR (1) | HRP20040853A2 (https=) |
| IL (2) | IL164022A0 (https=) |
| IS (1) | IS7456A (https=) |
| MX (1) | MXPA04008999A (https=) |
| NO (1) | NO20044442L (https=) |
| NZ (1) | NZ535365A (https=) |
| PL (1) | PL372413A1 (https=) |
| RS (1) | RS81904A (https=) |
| RU (1) | RU2312857C2 (https=) |
| UA (1) | UA77296C2 (https=) |
| WO (1) | WO2003080047A1 (https=) |
| ZA (1) | ZA200407337B (https=) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
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| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| ES2445208T3 (es) | 2002-07-29 | 2014-02-28 | Rigel Pharmaceuticals, Inc. | Compuestos de 2,4-pirimidindiamina para uso en métodos para tratar o prevenir enfermedades autoinmunitarias |
| US6916937B2 (en) * | 2003-02-03 | 2005-07-12 | Bristol-Myers Squibb Company | Carbohydrate prodrugs of fluorooxindoles |
| BRPI0413018B8 (pt) | 2003-07-30 | 2021-05-25 | Rigel Pharmaceuticals Inc | composto, e, uso de um composto |
| US7169803B2 (en) * | 2004-03-15 | 2007-01-30 | Bristol-Myers Squibb Company | N-substituted prodrugs of fluorooxindoles |
| US7253167B2 (en) | 2004-06-30 | 2007-08-07 | Bristol-Myers Squibb Company | Tricyclic-heteroaryl compounds useful as kinase inhibitors |
| DE602006010979D1 (de) | 2005-01-19 | 2010-01-21 | Rigel Pharmaceuticals Inc | Prodrugs aus 2,4-pyrimidindiamin-verbindungen und ihre verwendungen |
| US8227455B2 (en) | 2005-04-18 | 2012-07-24 | Rigel Pharmaceuticals, Inc. | Methods of treating cell proliferative disorders |
| JP4981673B2 (ja) * | 2005-09-13 | 2012-07-25 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 安定性が改善されたクロロメチルフォスフェイト誘導体を含む組成物およびその製造方法 |
| TWI385169B (zh) | 2005-10-31 | 2013-02-11 | Eisai R&D Man Co Ltd | 經雜環取代之吡啶衍生物及含有彼之抗真菌劑 |
| TW200841879A (en) * | 2007-04-27 | 2008-11-01 | Eisai R&D Man Co Ltd | Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same |
| US8513287B2 (en) * | 2007-12-27 | 2013-08-20 | Eisai R&D Management Co., Ltd. | Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same |
| AU2009212514A1 (en) * | 2008-02-05 | 2009-08-13 | Merck Sharp & Dohme Corp. | Prodrugs of CGRP receptor antagonist |
| US8188119B2 (en) * | 2008-10-24 | 2012-05-29 | Eisai R&D Management Co., Ltd | Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same |
| CA2937222C (en) * | 2009-06-25 | 2019-06-04 | Alkermes Pharma Ireland Limited | Prodrugs of nh-acidic compounds |
| LT2445502T (lt) | 2009-06-25 | 2017-09-25 | Alkermes Pharma Ireland Limited | Heterocikliniai junginiai, skirti neurologinių ir fiziologinių susirgimų gydymui |
| AU2011270701B2 (en) | 2010-06-24 | 2015-05-14 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
| KR101974793B1 (ko) | 2015-07-06 | 2019-05-02 | 길리애드 사이언시즈, 인코포레이티드 | Cot 조정제 및 그의 사용 방법 |
| KR20200121800A (ko) | 2018-01-05 | 2020-10-26 | 싸이브렉사 1, 인크. | 산성 또는 저산소성 질환에 걸린 조직에 관련된 질환의 치료를 위한 화합물, 조성물 및 방법 |
| EP3761983A1 (en) | 2018-03-05 | 2021-01-13 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
| ES2975753T3 (es) * | 2018-03-05 | 2024-07-12 | Teon Therapeutics Inc | Antagonistas del receptor de adenosina y usos de los mismos |
| TWI770527B (zh) | 2019-06-14 | 2022-07-11 | 美商基利科學股份有限公司 | Cot 調節劑及其使用方法 |
| TW202116356A (zh) | 2019-07-10 | 2021-05-01 | 美商斯布雷克薩三號公司 | 作為治療劑之微管靶向藥劑之肽結合物 |
| CN114341162B (zh) | 2019-07-10 | 2025-10-17 | 赛博克萨2公司 | 作为治疗剂的细胞毒素的肽缀合物 |
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| EP3912625A1 (en) | 2020-05-20 | 2021-11-24 | Kaerus Bioscience Limited | Novel maxi-k potassium channel openers for the treatment of fragile x associated disorders |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5187173A (en) * | 1991-12-27 | 1993-02-16 | Sterling Winthrop Inc. | 2-saccharinylmethyl and 4,5,6,7-tetrahydro-2-saccharinylmethyl phosphates, phosphonates and phosphinates useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
| SU749063A1 (ru) * | 1979-01-29 | 1996-09-10 | Военно-медицинская академия им.С.М.Кирова | 3-(4-карбэтокси)-фенилимино-2-оксоиндолин, повышающий устойчивость организма к повторной черепно-мозговой травме |
| US5602169A (en) * | 1995-06-07 | 1997-02-11 | Bristol-Myers Squibb Company | 3-substituted oxindole derivatives as potassium channel modulators |
| US5939405A (en) * | 1998-01-29 | 1999-08-17 | Bristol-Myers Squibb Company | Phosphate derivatives of diaryl 1,3,4-oxadiazolone |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5234947A (en) | 1991-11-07 | 1993-08-10 | New York University | Potassium channel activating compounds and methods of use thereof |
| KR20010033811A (ko) | 1997-12-31 | 2001-04-25 | 토마스 안 빅토리아 | 2차 및 3차 아민을 함유하는 약제의 물에 용해가능한프로드럭 및 그것의 제조방법 |
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2003
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- 2003-03-20 NZ NZ535365A patent/NZ535365A/en not_active IP Right Cessation
- 2003-03-20 UA UA20041109513A patent/UA77296C2/uk unknown
- 2003-03-20 CA CA002479256A patent/CA2479256A1/en not_active Abandoned
- 2003-03-20 BR BR0308737-9A patent/BR0308737A/pt not_active IP Right Cessation
- 2003-03-20 IL IL16402203A patent/IL164022A0/xx active IP Right Grant
- 2003-03-20 RU RU2004131201/04A patent/RU2312857C2/ru not_active IP Right Cessation
- 2003-03-20 GE GEAP8458A patent/GEP20074230B/en unknown
- 2003-03-20 RS YUP-819/04A patent/RS81904A/sr unknown
- 2003-03-20 MX MXPA04008999A patent/MXPA04008999A/es active IP Right Grant
- 2003-03-20 JP JP2003577875A patent/JP4359150B2/ja not_active Expired - Fee Related
- 2003-03-20 EP EP03711659A patent/EP1485085A4/en not_active Withdrawn
- 2003-03-20 US US10/393,031 patent/US6930100B2/en not_active Expired - Lifetime
- 2003-03-20 KR KR1020047014626A patent/KR100951499B1/ko not_active Expired - Fee Related
- 2003-03-20 PL PL03372413A patent/PL372413A1/xx not_active Application Discontinuation
- 2003-03-20 WO PCT/US2003/008613 patent/WO2003080047A1/en not_active Ceased
- 2003-03-20 CN CNB038109778A patent/CN100384820C/zh not_active Expired - Fee Related
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2004
- 2004-09-12 IL IL164022A patent/IL164022A/en not_active IP Right Cessation
- 2004-09-13 ZA ZA200407337A patent/ZA200407337B/en unknown
- 2004-09-17 IS IS7456A patent/IS7456A/is unknown
- 2004-09-20 CO CO04093294A patent/CO5611143A2/es not_active Application Discontinuation
- 2004-10-19 NO NO20044442A patent/NO20044442L/no not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU749063A1 (ru) * | 1979-01-29 | 1996-09-10 | Военно-медицинская академия им.С.М.Кирова | 3-(4-карбэтокси)-фенилимино-2-оксоиндолин, повышающий устойчивость организма к повторной черепно-мозговой травме |
| US5187173A (en) * | 1991-12-27 | 1993-02-16 | Sterling Winthrop Inc. | 2-saccharinylmethyl and 4,5,6,7-tetrahydro-2-saccharinylmethyl phosphates, phosphonates and phosphinates useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
| US5602169A (en) * | 1995-06-07 | 1997-02-11 | Bristol-Myers Squibb Company | 3-substituted oxindole derivatives as potassium channel modulators |
| RU2165925C2 (ru) * | 1995-06-07 | 2001-04-27 | Бристоль Мейерз Сквибб Компани | 3-замещенные оксиндольные производные в качестве модуляторов калийных каналов, фармацевтическая композиция, способ лечения |
| US5939405A (en) * | 1998-01-29 | 1999-08-17 | Bristol-Myers Squibb Company | Phosphate derivatives of diaryl 1,3,4-oxadiazolone |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1485085A4 (en) | 2007-03-14 |
| PL372413A1 (en) | 2005-07-25 |
| RU2004131201A (ru) | 2005-05-10 |
| BR0308737A (pt) | 2005-01-11 |
| NO20044442L (no) | 2004-10-19 |
| US6930100B2 (en) | 2005-08-16 |
| IL164022A (en) | 2008-04-13 |
| HRP20040853A2 (en) | 2004-12-31 |
| CO5611143A2 (es) | 2006-02-28 |
| IS7456A (is) | 2004-09-17 |
| UA77296C2 (en) | 2006-11-15 |
| CN1652769A (zh) | 2005-08-10 |
| AU2003215017A1 (en) | 2003-10-08 |
| JP2005526097A (ja) | 2005-09-02 |
| JP4359150B2 (ja) | 2009-11-04 |
| GEP20074230B (en) | 2007-11-12 |
| CA2479256A1 (en) | 2003-10-02 |
| KR100951499B1 (ko) | 2010-04-07 |
| RS81904A (sr) | 2007-02-05 |
| MXPA04008999A (es) | 2004-12-07 |
| CN100384820C (zh) | 2008-04-30 |
| EP1485085A1 (en) | 2004-12-15 |
| US20030195169A1 (en) | 2003-10-16 |
| NZ535365A (en) | 2006-07-28 |
| KR20040106293A (ko) | 2004-12-17 |
| IL164022A0 (en) | 2005-12-18 |
| ZA200407337B (en) | 2006-02-22 |
| WO2003080047A1 (en) | 2003-10-02 |
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