UA120353C2 - Модулятори натрієвого каналу для лікування болю і діабету - Google Patents
Модулятори натрієвого каналу для лікування болю і діабету Download PDFInfo
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- UA120353C2 UA120353C2 UAA201603676A UAA201603676A UA120353C2 UA 120353 C2 UA120353 C2 UA 120353C2 UA A201603676 A UAA201603676 A UA A201603676A UA A201603676 A UAA201603676 A UA A201603676A UA 120353 C2 UA120353 C2 UA 120353C2
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- Prior art keywords
- chloro
- propyl
- fluoro
- thiazol
- formula
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
- C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361876046P | 2013-09-10 | 2013-09-10 | |
| PCT/US2014/054764 WO2015038533A2 (en) | 2013-09-10 | 2014-09-09 | Sodium channel modulators for the treatment of pain and diabetes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| UA120353C2 true UA120353C2 (uk) | 2019-11-25 |
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Family Applications (1)
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| UAA201603676A UA120353C2 (uk) | 2013-09-10 | 2014-09-09 | Модулятори натрієвого каналу для лікування болю і діабету |
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| Country | Link |
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| US (2) | US20160221974A1 (enExample) |
| EP (1) | EP3043787B1 (enExample) |
| JP (1) | JP6445565B2 (enExample) |
| KR (1) | KR20160054570A (enExample) |
| CN (1) | CN105611923B (enExample) |
| AU (1) | AU2014318979B2 (enExample) |
| BR (1) | BR112016005271A2 (enExample) |
| CA (1) | CA2922851C (enExample) |
| ES (1) | ES2687598T3 (enExample) |
| IL (1) | IL244506B (enExample) |
| MX (1) | MX2016002881A (enExample) |
| MY (1) | MY181928A (enExample) |
| PH (1) | PH12016500296A1 (enExample) |
| RU (1) | RU2016113156A (enExample) |
| SG (2) | SG10201805552PA (enExample) |
| UA (1) | UA120353C2 (enExample) |
| WO (1) | WO2015038533A2 (enExample) |
| ZA (1) | ZA201702410B (enExample) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2968234B1 (en) | 2013-03-15 | 2018-06-27 | Chromocell Corporation | Sodium channel modulators for the treatment of pain |
| JP6445565B2 (ja) | 2013-09-10 | 2018-12-26 | クロモセル コーポレイション | とう痛及び糖尿病の治療用ナトリウムチャネル調節物質 |
| JP2017527573A (ja) * | 2014-09-09 | 2017-09-21 | クロモセル コーポレーション | 糖尿病の治療用の選択的ＮａＶ１．７阻害剤 |
| WO2017106226A1 (en) | 2015-12-18 | 2017-06-22 | Merck Sharp & Dohme Corp. | Hydroxyalkylamine- and hydroxycycloalkylamine-substituted diamine-arylsulfonamide compounds with selective activity in voltage-gated sodium channels |
| JP6938545B2 (ja) | 2016-05-20 | 2021-09-22 | ゼノン・ファーマシューティカルズ・インコーポレイテッドＸｅｎｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | ベンゼンスルホンアミド化合物および治療剤としてのそれらの使用 |
| CN105924670A (zh) * | 2016-06-02 | 2016-09-07 | 扬州兰都塑料科技有限公司 | 一种电力电缆用耐磨剂 |
| CN105924843A (zh) * | 2016-06-02 | 2016-09-07 | 扬州兰都塑料科技有限公司 | 一种耐刮擦的电力电缆 |
| CN106084535A (zh) * | 2016-06-02 | 2016-11-09 | 扬州兰都塑料科技有限公司 | 一种耐刮擦的电力电缆的制备方法 |
| KR20190086772A (ko) | 2016-12-09 | 2019-07-23 | 제논 파마슈티칼스 인크. | 벤젠술폰아미드 화합물 및 치료제로서의 그의 용도 |
| CN106892845B (zh) * | 2017-02-28 | 2018-10-30 | 四川同晟生物医药有限公司 | 一种2,4-二氨基丁酸衍生物及其制备方法 |
| WO2019200369A1 (en) * | 2018-04-13 | 2019-10-17 | Chromocell Corporation | Compounds and methods of using compounds for the prevention or treatment of peripheral nerve damage |
| WO2019217822A1 (en) * | 2018-05-11 | 2019-11-14 | Chromocell Corporation | Compounds and methods of using compounds for the prevention or treatment of inflammatory conditions |
| UA127024C2 (uk) | 2018-06-13 | 2023-03-15 | Ксенон Фармасьютікалз Інк. | Бензолсульфонамідні сполуки та їх застосування як терапевтичних агентів |
| EP3844150A1 (en) | 2018-08-31 | 2021-07-07 | Xenon Pharmaceuticals Inc. | Heteroaryl-substituted sulfonamide compounds and their use as therapeutic agents |
| CA3104913A1 (en) | 2018-08-31 | 2020-03-05 | Xenon Pharmaceuticals Inc. | Heteroaryl-substituted sulfonamide compounds and their use as sodium channel inhibitors |
| CN113527281B (zh) * | 2020-04-20 | 2023-12-22 | 昆山彭济凯丰生物科技有限公司 | 杂环化合物及其制备方法和应用 |
Family Cites Families (30)
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|---|---|---|---|---|
| US5356897A (en) | 1991-09-09 | 1994-10-18 | Fujisawa Pharmaceutical Co., Ltd. | 3-(heteroaryl)-pyrazololi[1,5-a]pyrimidines |
| JP2004527508A (ja) * | 2001-03-14 | 2004-09-09 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 鎮痛剤としての置換されたピラゾロ−及びチアゾロピリミジン類 |
| US7659082B2 (en) | 2002-02-19 | 2010-02-09 | Xenon Pharmaceuticals Inc. | Methods for identifying analgesic agents |
| EP2471533A1 (en) | 2002-06-27 | 2012-07-04 | Novo Nordisk A/S | Aryl carbonyl derivatives as therapeutic agents |
| GB0324792D0 (en) | 2003-10-23 | 2003-11-26 | Sterix Ltd | Compound |
| US7449477B2 (en) | 2003-11-25 | 2008-11-11 | Eli Lilly And Company | 7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (protein kinase B) |
| CA2564355C (en) | 2004-05-07 | 2012-07-03 | Amgen Inc. | Protein kinase modulators and method of use |
| BRPI0513717A (pt) * | 2004-07-23 | 2008-05-13 | Pfizer | derivados de piridina |
| CA2584413A1 (en) | 2004-10-29 | 2006-05-04 | Astrazeneca Ab | Novel sulphonamide derivatives as glucocorticoid receptor modulators for the treatment of inflammatory diseases |
| EP2386539B1 (en) * | 2005-12-23 | 2016-07-20 | Zealand Pharma A/S | 4-Aminoproline derivatives useful as lysine mimetics |
| TW200838539A (en) * | 2007-02-05 | 2008-10-01 | Xenon Pharmaceuticals Inc | Pyridopyrimidinone compounds useful in treating sodium channel-mediated diseases or conditions |
| WO2009012241A1 (en) | 2007-07-13 | 2009-01-22 | Icagen, Inc. | Sodium channel inhibitors |
| EP2173743A2 (en) | 2007-07-13 | 2010-04-14 | Icagen, Inc. | Sodium channel inhibitors |
| CN102348697B (zh) | 2009-01-12 | 2014-12-10 | 辉瑞股份有限公司 | 磺酰胺衍生物 |
| MX2011012712A (es) | 2009-05-29 | 2012-01-30 | Raqualia Pharma Inc | Derivados de carboxamida sustituidos con arilo como bloqueadores del canal de calcio o sodio. |
| JP2013525368A (ja) | 2010-04-23 | 2013-06-20 | キネタ・インコーポレイテツド | 抗ウイルス性化合物 |
| ES2526675T3 (es) | 2010-07-09 | 2015-01-14 | Pfizer Limited | N-sulfonilbenzamidas como inhibidores de los canales de sodio dependientes de voltaje |
| EP2590972B1 (en) | 2010-07-09 | 2015-01-21 | Pfizer Limited | N-sulfonylbenzamides as inhibitors of voltage-gated sodium channels |
| EP2590951B1 (en) * | 2010-07-09 | 2015-01-07 | Pfizer Limited | Benzenesulfonamides useful as sodium channel inhibitors |
| WO2012007883A1 (en) | 2010-07-12 | 2012-01-19 | Pfizer Limited | Sulfonamide derivatives as nav1.7 inhibitors for the treatment of pain |
| KR20140009311A (ko) | 2011-01-18 | 2014-01-22 | 암젠 인크 | Nav1.7 넉아웃 마우스 및 이의 용도 |
| TW201837023A (zh) * | 2011-07-01 | 2018-10-16 | 美商基利科學股份有限公司 | 作為離子通道調節劑之稠合雜環化合物 |
| WO2013025883A1 (en) | 2011-08-17 | 2013-02-21 | Amgen Inc. | Heteroaryl sodium channel inhibitors |
| AU2012312266A1 (en) * | 2011-09-21 | 2013-05-02 | Gilead Sciences, Inc. | Sodium channel blockers reduce glucagon secretion |
| WO2013064984A1 (en) | 2011-10-31 | 2013-05-10 | Xenon Pharmaceuticals Inc. | Biaryl ether sulfonamides and their use as therapeutic agents |
| WO2014078479A2 (en) | 2012-11-14 | 2014-05-22 | The Board Of Regents Of The University Of Texas System | INHIBITION OF HIF-2α HETERODIMERIZATION WITH HIF1β (ARNT) |
| EP2968234B1 (en) * | 2013-03-15 | 2018-06-27 | Chromocell Corporation | Sodium channel modulators for the treatment of pain |
| RS60953B1 (sr) | 2013-09-09 | 2020-11-30 | Peloton Therapeutics Inc | Aril etri i njihove upotrebe |
| JP6445565B2 (ja) | 2013-09-10 | 2018-12-26 | クロモセル コーポレイション | とう痛及び糖尿病の治療用ナトリウムチャネル調節物質 |
| JP2017527573A (ja) * | 2014-09-09 | 2017-09-21 | クロモセル コーポレーション | 糖尿病の治療用の選択的ＮａＶ１．７阻害剤 |
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2016
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2017
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Also Published As
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| AU2014318979B2 (en) | 2019-03-28 |
| JP6445565B2 (ja) | 2018-12-26 |
| RU2016113156A (ru) | 2017-10-16 |
| PH12016500296A1 (en) | 2016-05-16 |
| IL244506A0 (en) | 2016-04-21 |
| EP3043787A2 (en) | 2016-07-20 |
| WO2015038533A3 (en) | 2015-10-29 |
| MY181928A (en) | 2021-01-14 |
| CA2922851A1 (en) | 2015-03-19 |
| CA2922851C (en) | 2023-03-14 |
| SG11201601367QA (en) | 2016-03-30 |
| KR20160054570A (ko) | 2016-05-16 |
| CN105611923B (zh) | 2019-08-23 |
| EP3043787A4 (en) | 2017-02-01 |
| AU2014318979A1 (en) | 2016-03-03 |
| MX2016002881A (es) | 2016-04-21 |
| SG10201805552PA (en) | 2018-08-30 |
| US20160130239A1 (en) | 2016-05-12 |
| RU2016113156A3 (enExample) | 2018-07-02 |
| US9458118B2 (en) | 2016-10-04 |
| ES2687598T3 (es) | 2018-10-26 |
| IL244506B (en) | 2020-02-27 |
| BR112016005271A2 (pt) | 2020-05-12 |
| JP2016532716A (ja) | 2016-10-20 |
| CN105611923A (zh) | 2016-05-25 |
| ZA201702410B (en) | 2019-06-26 |
| EP3043787B1 (en) | 2018-09-05 |
| US20160221974A1 (en) | 2016-08-04 |
| WO2015038533A2 (en) | 2015-03-19 |
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