CN107250149A - 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 - Google Patents

氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 Download PDF

Info

Publication number
CN107250149A
CN107250149A CN201680010388.0A CN201680010388A CN107250149A CN 107250149 A CN107250149 A CN 107250149A CN 201680010388 A CN201680010388 A CN 201680010388A CN 107250149 A CN107250149 A CN 107250149A
Authority
CN
China
Prior art keywords
compound
pharmaceutical composition
deuterium
acid
gallbladder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201680010388.0A
Other languages
English (en)
Other versions
CN107250149B (zh
Inventor
吕彬华
盛泽林
李成伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Zelgen Biopharmaceutical Co Ltd
Original Assignee
Suzhou Zelgen Biopharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suzhou Zelgen Biopharmaceutical Co Ltd filed Critical Suzhou Zelgen Biopharmaceutical Co Ltd
Publication of CN107250149A publication Critical patent/CN107250149A/zh
Application granted granted Critical
Publication of CN107250149B publication Critical patent/CN107250149B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/007—Steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

本发明涉及氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物。具体地，本发明公开了式(I)所示的氘代鹅去氧胆酸衍生物以及含有该化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物的药物组合物。本发明的上述化合物可用于治疗和/或预防非酒精性脂肪肝炎、非酒精性脂肪肝病、胆结石、原发性胆汁性肝硬化、肝硬化等。

Description

PCT国内申请，说明书已公开。

Claims (10)

  1. PCT国内申请，权利要求书已公开。
CN201680010388.0A 2015-02-16 2016-02-16 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 Active CN107250149B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2015100847385 2015-02-16
CN201510084738.5A CN105985396A (zh) 2015-02-16 2015-02-16 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物
PCT/CN2016/073891 WO2016131414A1 (zh) 2015-02-16 2016-02-16 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物

Publications (2)

Publication Number Publication Date
CN107250149A true CN107250149A (zh) 2017-10-13
CN107250149B CN107250149B (zh) 2020-11-24

Family

ID=56692502

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201510084738.5A Pending CN105985396A (zh) 2015-02-16 2015-02-16 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物
CN201680010388.0A Active CN107250149B (zh) 2015-02-16 2016-02-16 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201510084738.5A Pending CN105985396A (zh) 2015-02-16 2015-02-16 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物

Country Status (11)

Country Link
US (1) US10544185B2 (zh)
EP (1) EP3260463B1 (zh)
JP (1) JP6947644B2 (zh)
KR (1) KR102042112B1 (zh)
CN (2) CN105985396A (zh)
AU (1) AU2016222174B2 (zh)
BR (1) BR112017017529A2 (zh)
CA (1) CA2977109C (zh)
HK (1) HK1248712A1 (zh)
RU (1) RU2712033C2 (zh)
WO (1) WO2016131414A1 (zh)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014169836A1 (en) 2013-04-17 2014-10-23 Sage Therapeutics, Inc. 19-nor neuroactive steroids and methods of use thereof
PL2986624T3 (pl) 2013-04-17 2020-11-16 Sage Therapeutics, Inc. Neuroaktywne steroidy 19-NOR do stosowania w sposobach leczenia
US9512165B2 (en) 2013-04-17 2016-12-06 Sage Therapeutics, Inc. 19-nor C3, 3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof
US9725481B2 (en) 2013-04-17 2017-08-08 Sage Therapeutics, Inc. 19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof
CA2918735C (en) 2013-07-19 2023-08-01 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
EP3035940B1 (en) 2013-08-23 2018-10-17 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
WO2015195962A1 (en) 2014-06-18 2015-12-23 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
NZ769042A (en) 2014-10-16 2023-12-22 Sage Therapeutics Inc Compositions and methods for treating cns disorders
CN117024501A (zh) 2014-10-16 2023-11-10 萨奇治疗股份有限公司 靶向cns障碍的组合物和方法
PT3224269T (pt) 2014-11-27 2020-06-01 Sage Therapeutics Inc Composições e métodos para tratamento de distúrbios do snc
SI3250210T1 (sl) 2015-01-26 2021-07-30 Sage Therapeutics, Inc. Sestavki in metode za zdravljenje CNS motenj
WO2016134301A2 (en) 2015-02-20 2016-08-25 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
CN106008639B (zh) * 2016-03-11 2019-01-08 深圳市塔吉瑞生物医药有限公司 用于预防或治疗fxr-介导疾病的胆烷酸化合物
CN109689673B (zh) 2016-07-11 2023-03-14 萨奇治疗股份有限公司 C17、c20和c21取代的神经活性类固醇及其使用方法
AU2017296295B2 (en) 2016-07-11 2022-02-24 Sage Therapeutics, Inc. C7, C12, and C16 substituted neuroactive steroids and their methods of use
CA3070837A1 (en) * 2017-07-24 2019-01-31 Intercept Pharmaceuticals, Inc. Isotopically labeled bile acid derivatives
KR20200096596A (ko) * 2017-12-08 2020-08-12 세이지 테라퓨틱스, 인크. Cns 장애의 치료를 위한 중수소화 21 -[4-시아노-피라졸-1 -일]-19-노르-프레간-3. 알파-올-20-온 유도체
TW202021595A (zh) 2018-08-10 2020-06-16 德商菲尼克斯製藥股份有限公司 用於預防及治療困難梭狀芽孢桿菌關聯疾病之異石膽酸或異別石膽酸及其氘化衍生物
BR112021024033A2 (pt) 2019-05-31 2022-02-08 Sage Therapeutics Inc Esteroides neuroativos e suas composições
CN112142814B (zh) * 2019-06-26 2021-09-28 江苏吉贝尔药业股份有限公司 牛磺熊去氧胆酸衍生物以及包含其的药物组合物和制剂
MX2022000742A (es) 2019-07-18 2022-02-14 Enyo Pharma Metodo para disminuir los efectos adversos del interferon.
CN112409435B (zh) * 2019-08-23 2023-07-18 深圳云合医药科技合伙企业(有限合伙) 胆汁酸衍生物及其组合物和应用
CN114945361A (zh) 2020-01-15 2022-08-26 法国国家卫生及研究医学协会 Fxr激动剂在治疗丁型肝炎病毒感染中的用途
CN117202905A (zh) 2021-01-14 2023-12-08 埃尼奥制药公司 Fxr激动剂和ifn用于治疗hbv感染的协同效果
CN117320722A (zh) 2021-04-28 2023-12-29 埃尼奥制药公司 使用fxr激动剂作为联合治疗强烈增强tlr3激动剂的作用
KR102490355B1 (ko) * 2021-09-29 2023-01-26 주식회사 에이.비.아이 타우로케노디옥시콜산 함량이 증대된 담즙 추출물을 유효성분으로 포함하는 비만증 예방, 개선 또는 치료용 조성물 및 그의 제조방법
WO2024043842A1 (en) * 2022-08-22 2024-02-29 Pharmactive Ilac Sanayi Ve Ticaret A.S. Pharmaceutical compositions comprising chenodeoxycholic acid (cdca) as active ingredient and other relevant excipients

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072598A1 (en) * 2001-03-12 2002-09-19 Roberto Pellicciari Steroids as agonists for fxr
WO2005082925A2 (en) * 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Novel steroid agonist for fxr
WO2010054158A2 (en) * 2008-11-07 2010-05-14 Auspex Pharmaceuticals, Inc. Steroid modulators of glucocorticoid receptor
WO2013192097A1 (en) * 2012-06-19 2013-12-27 Intercept Pharmaceuticals, Inc. Preparation, uses and solid forms of obeticholic acid

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0751926B1 (en) * 1994-03-25 2007-09-12 Isotechnika,Inc. Enhancement of the efficacy of drugs by deuteration
US6376531B1 (en) * 1998-11-13 2002-04-23 Rupert Charles Bell Method of treatment using deuterium compounds
EP1104760B1 (en) * 1999-12-03 2003-03-12 Pfizer Products Inc. Sulfamoylheteroaryl pyrazole compounds as anti-inflammatory/analgesic agents
WO2010059853A1 (en) * 2008-11-19 2010-05-27 Intercept Pharmaceuticals, Inc. Tgr5 modulators and method of use thereof
EP3150620B1 (en) 2008-11-19 2020-01-08 Intercept Pharmaceuticals, Inc. Tgr5 modulators and methods of use thereof
WO2013037482A1 (en) * 2011-09-15 2013-03-21 Phenex Pharmaceuticals Ag Farnesoid x receptor agonists for cancer treatment and prevention
WO2015061421A1 (en) * 2013-10-22 2015-04-30 Metselex, Inc. Deuterated bile acids

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072598A1 (en) * 2001-03-12 2002-09-19 Roberto Pellicciari Steroids as agonists for fxr
WO2005082925A2 (en) * 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Novel steroid agonist for fxr
WO2010054158A2 (en) * 2008-11-07 2010-05-14 Auspex Pharmaceuticals, Inc. Steroid modulators of glucocorticoid receptor
WO2013192097A1 (en) * 2012-06-19 2013-12-27 Intercept Pharmaceuticals, Inc. Preparation, uses and solid forms of obeticholic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
江文峰 等: "氘代作用在药物研究中的应用", 《齐鲁药事》 *

Also Published As

Publication number Publication date
AU2016222174A1 (en) 2017-09-14
KR20170110723A (ko) 2017-10-11
EP3260463A1 (en) 2017-12-27
CN107250149B (zh) 2020-11-24
RU2712033C2 (ru) 2020-01-24
WO2016131414A1 (zh) 2016-08-25
KR102042112B1 (ko) 2019-11-08
JP2018505220A (ja) 2018-02-22
AU2016222174B2 (en) 2019-04-11
US10544185B2 (en) 2020-01-28
RU2017130849A3 (zh) 2019-03-18
EP3260463B1 (en) 2020-09-02
EP3260463A4 (en) 2018-10-31
BR112017017529A2 (zh) 2018-04-17
HK1248712A1 (zh) 2018-10-19
US20180030083A1 (en) 2018-02-01
CN105985396A (zh) 2016-10-05
CA2977109A1 (en) 2016-08-25
CA2977109C (en) 2020-04-14
RU2017130849A (ru) 2019-03-18
JP6947644B2 (ja) 2021-10-13

Similar Documents

Publication Publication Date Title
CN107250149A (zh) 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物
EP2947070B1 (en) Multi-targeted ubenimex prodrug derivative and preparation method and use thereof
CN111295372B (zh) 硝羟喹啉前药及其用途
US8435962B2 (en) Triacetyl-3-hydroxyphenyladenosine and its use for regulating blood fat
WO2013000286A1 (zh) 蟾毒配基衍生物及其制备方法、包含该衍生物的组合物、及其用途
EP4050008A1 (en) Pyridazinone or pyridazine compound and derivative and pharmaceutical composition thereof
TWI749281B (zh) 肝遞送恩替卡韋前體藥物核苷環磷酸酯化合物及應用
CN101289438B (zh) 3-(3'-羟基)-丁基苯酞酯及其制法和用途
WO2020114495A1 (zh) 二核苷酸化合物及其前体药物
CN110088098A (zh) 喹唑啉酮类parp-1抑制剂及其制备方法、药物组合物和用途
CN103304573B (zh) 石蒜碱类化合物在制备抗肿瘤药物的应用
CN109956986A (zh) 肝递送吉西他滨前体药物核苷环磷酸酯化合物及应用
CN116178350A (zh) 一种天然来源大环内酯衍生物及其制备方法和作为抗肿瘤药物的应用
US10899787B2 (en) Cytarabine prodrug nucleoside cyclic phosphate compound based on liverspecific delivery and use
CN111518157B (zh) 一种雷公藤甲素衍生物及其制备方法和应用
CN113214206B (zh) 橙皮素与甜菜碱共晶物b及制备方法和其组合物与用途
AU2022100062A4 (en) Crystal form for treating liver disease and use thereof
CN116003469B (zh) 嘧啶基抗病毒化合物的制备与使用方法
WO2021033766A1 (ja) ビタミンｄ活性を有するリトコール酸誘導体
CN105949277B (zh) 一种抗肿瘤化合物及其用途
CN108640958A (zh) 异苯并呋喃衍生物、其药物组合物和制剂以及用途

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information

Address after: 215300 Chenfeng Road 209, Yushan Town, Kunshan City, Suzhou City, Jiangsu Province

Applicant after: Suzhou Zehuang Biopharmaceutical Co., Ltd.

Address before: 215300 Chenfeng Road 209, Kunshan City, Suzhou City, Jiangsu Province

Applicant before: Suzhou Zelgen Biopharmaceuticals Co., Ltd.

CB02 Change of applicant information
GR01 Patent grant
GR01 Patent grant