CN106794362B - 用于治疗应用的一氧化碳-释放分子及其制备和使用方法 - Google Patents

用于治疗应用的一氧化碳-释放分子及其制备和使用方法 Download PDF

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CN106794362B
CN106794362B CN201580042734.9A CN201580042734A CN106794362B CN 106794362 B CN106794362 B CN 106794362B CN 201580042734 A CN201580042734 A CN 201580042734A CN 106794362 B CN106794362 B CN 106794362B
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aryl
heteroaryl
cycloalkyl
moiety
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CN106794362A (zh
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王炳和
王丹珠
季兴跃
A·德拉加诺夫
戴朝峰
K·达美拉
D·莫林
E·维诺伊斯
郑月钦
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Georgia State University Research Foundation Inc
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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CN201580042734.9A 2014-06-09 2015-06-09 用于治疗应用的一氧化碳-释放分子及其制备和使用方法 Active CN106794362B (zh)

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US201462009451P 2014-06-09 2014-06-09
US62/009,451 2014-06-09
PCT/US2015/034948 WO2015191616A1 (en) 2014-06-09 2015-06-09 Carbon monoxide-releasing molecules for therapeutic applications and methods of making and using thereof

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JP (1) JP6670763B2 (enExample)
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CN106794362B (zh) 2014-06-09 2021-07-06 乔治亚州立大学研究基金会股份有限公司 用于治疗应用的一氧化碳-释放分子及其制备和使用方法
WO2018093924A1 (en) * 2016-11-16 2018-05-24 Georgia State University Research Foundation, Inc. Carbon monoxide-releasing molecules and therapeutic applications thereof
KR102373273B1 (ko) * 2017-04-18 2022-03-15 기초과학연구원 고분자형 젤과 이의 제조방법, 및 이를 포함하는 물품
CN110944629B (zh) * 2017-06-12 2024-04-09 乔治亚州立大学研究基金会股份有限公司 酶触发的一氧化碳释放分子
US20180369278A1 (en) * 2017-06-23 2018-12-27 The Regents Of The University Of Michigan Carbon monoxide-based therapies and implantable devices for the treatment of vascular disease
WO2019032879A1 (en) * 2017-08-09 2019-02-14 Georgia State University Research Foundation, Inc. CARBON MONOXIDE RELEASE MOLECULES DISCHARGED BY PHYSIOLOGICAL STIMULI
WO2019084323A1 (en) * 2017-10-25 2019-05-02 Georgia State University Research Foundation, Inc. CHEMICAL RELEASE SYSTEM DELIVERED BY ENRICHMENT
CN109306049B (zh) * 2018-09-28 2020-12-01 中国热带农业科学院农产品加工研究所 植物油-壳聚糖基可生物降解pua及其制备方法和应用
WO2020081723A1 (en) 2018-10-16 2020-04-23 Georgia State University Research Foundation, Inc. Carbon monoxide prodrugs for the treatment of medical disorders
CN113559071B (zh) * 2021-08-18 2022-12-27 苏州大学 一种co靶向递送系统及其构建方法与应用
EP4275682A1 (en) * 2022-05-12 2023-11-15 Institut National De La Sante Et De La Recherche Medicale - Inserm Carbon monoxide-releasing molecule (corm) or composition thereof for use in the treatment or the prevention of an intestinal dysbiosis in a subject
WO2025090901A1 (en) * 2023-10-26 2025-05-01 Georgia State University Research Foundation, Inc. Ros-activated co prodrugs for cancer treatment

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5670664A (en) * 1995-09-08 1997-09-23 University Of Maryland Biotechnology Institute Photosensitive organic compounds that release carbon monoxide upon illumination

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005519928A (ja) 2002-02-04 2005-07-07 ハース，ベルナー Ｃｏ放出能力を有する化合物の投与によって哺乳動物を治療する方法と、ｃｏ放出能力を有する化合物ならびにその医薬組成物
PT1812031E (pt) 2004-11-01 2015-10-01 Univ California Composições e métodos para modificação de biomoléculas
US8519122B2 (en) 2010-02-12 2013-08-27 The Regents Of The University Of California Compositions and methods for modification of biomolecules
CN106794362B (zh) 2014-06-09 2021-07-06 乔治亚州立大学研究基金会股份有限公司 用于治疗应用的一氧化碳-释放分子及其制备和使用方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5670664A (en) * 1995-09-08 1997-09-23 University Of Maryland Biotechnology Institute Photosensitive organic compounds that release carbon monoxide upon illumination

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A new hypervalent lodine precursor of a highly strained cyclic alkyne. Generation and trapping reactions of bicycle[2.2.1] hept-2-en-5-yne;Tsugio Kitamura，et al.;《Communications》;19991231;第680-681页 *

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US10751344B2 (en) 2020-08-25
JP6670763B2 (ja) 2020-03-25
EP3151919A4 (en) 2018-02-21
US20170128456A1 (en) 2017-05-11
AU2015274767A1 (en) 2017-01-05
EP3151919B1 (en) 2023-08-30
US10300069B2 (en) 2019-05-28
CA2950007A1 (en) 2015-12-17
EP3151919A1 (en) 2017-04-12
AU2015274767B2 (en) 2020-04-16
JP2017528416A (ja) 2017-09-28
KR20170007857A (ko) 2017-01-20
CN106794362A (zh) 2017-05-31
US20190350937A1 (en) 2019-11-21

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