TWI673284B - 包含非結晶狀歐貝提膽酸之醫藥組成物 - Google Patents
包含非結晶狀歐貝提膽酸之醫藥組成物 Download PDFInfo
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- TWI673284B TWI673284B TW102121547A TW102121547A TWI673284B TW I673284 B TWI673284 B TW I673284B TW 102121547 A TW102121547 A TW 102121547A TW 102121547 A TW102121547 A TW 102121547A TW I673284 B TWI673284 B TW I673284B
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- Prior art keywords
- acid
- obeticholic acid
- hydroxy
- specific example
- keto
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- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 title claims abstract description 514
- 229960001601 obeticholic acid Drugs 0.000 title claims abstract description 411
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- 238000000034 method Methods 0.000 claims abstract description 161
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 153
- 150000004702 methyl esters Chemical class 0.000 claims description 150
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 124
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- 239000000243 solution Substances 0.000 claims description 73
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 44
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 37
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- 229960001091 chenodeoxycholic acid Drugs 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
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- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims description 25
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- 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
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- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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- C—CHEMISTRY; METALLURGY
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- 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
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ATE303399T1 (de) | 2001-03-12 | 2005-09-15 | Intercept Pharmaceuticals Inc | Steroide als agonisten für fxr |
| WO2011140441A2 (en) | 2010-05-06 | 2011-11-10 | Children's Hospital Medical Center | Methods and systems for converting precursor cells into intestinal tissues through directed differentiation |
| EP2545964A1 (en) | 2011-07-13 | 2013-01-16 | Phenex Pharmaceuticals AG | Novel FXR (NR1H4) binding and activity modulating compounds |
| EA201990211A1 (ru) | 2012-06-19 | 2019-06-28 | Интерсепт Фармасьютикалз, Инк. | Получение, применение и твердые формы обетихолевой кислоты |
| US9982008B2 (en) | 2012-06-19 | 2018-05-29 | Intercept Pharmaceuticals, Inc. | Preparation and uses of obeticholic acid |
| KR102106186B1 (ko) * | 2012-11-28 | 2020-05-04 | 인터셉트 파마슈티컬즈, 인크. | 폐 질환의 치료 |
| US9814733B2 (en) * | 2012-12-31 | 2017-11-14 | A,arin Pharmaceuticals Ireland Limited | Compositions comprising EPA and obeticholic acid and methods of use thereof |
| ES2998982T3 (en) | 2013-04-17 | 2025-02-24 | Sage Therapeutics Inc | 19-nor neuroactive steroids for inducing sedation |
| WO2014169831A1 (en) | 2013-04-17 | 2014-10-23 | Sage Therapeutics, Inc. | 19-nor c3,3-disubstituted c21-c-bound heteroaryl steroids and methods of use thereof |
| US20160068563A1 (en) | 2013-04-17 | 2016-03-10 | Boyd L. Harrison | 19-nor neuroactive steroids and methods of use thereof |
| 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 |
| PT3021852T (pt) | 2013-07-19 | 2021-04-21 | Sage Therapeutics Inc | Esteroides neuroativos, composições e utilizações das mesmas |
| CN105579043B (zh) | 2013-08-23 | 2021-09-14 | 萨奇治疗股份有限公司 | 神经活性类固醇、组合物和其用途 |
| ES2860423T3 (es) | 2014-05-28 | 2021-10-05 | Childrens Hospital Med Ct | Métodos y sistemas para convertir células precursoras en tejidos gástricos mediante diferenciación dirigida |
| RS64050B1 (sr) | 2014-05-29 | 2023-04-28 | Bar Pharmaceuticals S R L | Derivati holana za upotrebu u lečenju i/ili prevenciji fxr i tgr5/gpbar1 posredovanih bolesti |
| WO2015195962A1 (en) | 2014-06-18 | 2015-12-23 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
| CN106459136B (zh) * | 2014-09-28 | 2018-06-26 | 江苏盛迪医药有限公司 | 一种奥贝胆酸的制备方法 |
| WO2016061527A1 (en) | 2014-10-16 | 2016-04-21 | Sage Therapeutics, Inc. | Compositions and methods for treating cns disorders |
| RS60642B1 (sr) | 2014-10-16 | 2020-09-30 | Sage Therapeutics Inc | Kompozicije i postupci za lečenje poremećaja cns-a |
| WO2016061464A1 (en) | 2014-10-17 | 2016-04-21 | Children's Hospital Center, D/B/A Cincinnati Children's Hospital Medical Center | In vivo model of human small intetine using pluripotent stem cells and methods of making and using same |
| KR20170094184A (ko) | 2014-11-06 | 2017-08-17 | 이난타 파마슈티칼스, 인코포레이티드 | Fxr/tgr5 작용제로서의 담즙산 유사체 및 이의 이용 방법 |
| PL3221332T3 (pl) | 2014-11-19 | 2019-10-31 | Nzp Uk Ltd | Steroidy, 5.beta.-6-alkilo-7-hydroksy-3-ony jako związki pośrednie do wytwarzania steroidowych modulatorów fxr |
| BR112017010319B1 (pt) | 2014-11-19 | 2023-04-11 | NZP UK Limited | Esteroides 6-alquil-7-hidróxi-4-en-3-ona e processo para a preparação dos mesmos |
| WO2016079520A1 (en) | 2014-11-19 | 2016-05-26 | Dextra Laboratories Limited | 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal fxr modulators |
| DK3221333T3 (da) | 2014-11-19 | 2019-09-30 | Nzp Uk Ltd | 6-alfa-alkyl-3,7-dionsteroider som mellemprodukter til fremstilling af steroide FXR-modulatorer |
| US10208081B2 (en) | 2014-11-26 | 2019-02-19 | Enanta Pharmaceuticals, Inc. | Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof |
| WO2016086115A1 (en) | 2014-11-26 | 2016-06-02 | Enanta Pharmaceuticals, Inc. | Tetrazole derivatives of bile acids as fxr/tgr5 agonists and methods of use thereof |
| KR20170099909A (ko) | 2014-11-26 | 2017-09-01 | 이난타 파마슈티칼스, 인코포레이티드 | Fxr/tgr5 작용제로서의 담즙산 유사체 및 이의 이용 방법 |
| HUE049014T2 (hu) | 2014-11-27 | 2020-09-28 | Sage Therapeutics Inc | Készítmények és módszerek a központi idegrendszer rendellenességeinek kezelésére |
| CN105777835B (zh) * | 2014-12-25 | 2020-02-14 | 重庆药友制药有限责任公司 | 一种制备鹅去氧胆酸类似物的方法 |
| CN105801653B (zh) * | 2014-12-30 | 2018-04-17 | 苏州晶云药物科技有限公司 | 奥贝胆酸的晶型a及其制备方法 |
| CN105859814A (zh) * | 2015-01-23 | 2016-08-17 | 江苏奥赛康药业股份有限公司 | 一种奥贝胆酸化合物及其药物组合物 |
| SI3250210T1 (sl) | 2015-01-26 | 2021-07-30 | Sage Therapeutics, Inc. | Sestavki in metode za zdravljenje CNS motenj |
| EA036404B1 (ru) | 2015-02-06 | 2020-11-06 | Интерсепт Фармасьютикалз, Инк. | Фармацевтические композиции для комбинированной терапии |
| SG11201706089RA (en) | 2015-02-11 | 2017-09-28 | Enanta Pharm Inc | Bile acid analogs as fxr/tgr5 agonists and methods of use thereof |
| CN105985395A (zh) * | 2015-02-13 | 2016-10-05 | 江苏奥赛康药业股份有限公司 | 一种奥贝胆酸化合物及含有该化合物的药物组合物 |
| CN105985396A (zh) * | 2015-02-16 | 2016-10-05 | 苏州泽璟生物制药有限公司 | 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 |
| WO2016134301A2 (en) | 2015-02-20 | 2016-08-25 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
| HK1243646A1 (zh) * | 2015-03-09 | 2018-07-20 | 英特塞普特医药品公司 | 用於调节骨密度的方法 |
| PT3277286T (pt) | 2015-03-31 | 2021-07-01 | Enanta Pharm Inc | Derivados de ácidos biliares como agonistas de fxr/tgr5 e métodos de utilização destes |
| PE20180034A1 (es) | 2015-04-07 | 2018-01-09 | Intercept Pharmaceuticals Inc | Composiciones farmaceuticas para terapias combinadas |
| CN105777836A (zh) * | 2015-04-09 | 2016-07-20 | 厦门蔚扬药业有限公司 | 奥贝胆酸的多晶型物及其制备方法 |
| WO2016168553A1 (en) * | 2015-04-17 | 2016-10-20 | Concert Pharmaceuticals, Inc. | Deuterated obeticholic acid |
| PE20180690A1 (es) * | 2015-04-27 | 2018-04-23 | Intercept Pharmaceuticals Inc | Composiciones de acido obeticolico y metodos de uso |
| CN106290594B (zh) * | 2015-05-27 | 2020-07-17 | 中美华世通生物医药科技（武汉）有限公司 | 测定奥贝胆酸片溶出含量的方法 |
| CN105294801A (zh) * | 2015-07-02 | 2016-02-03 | 扬子江药业集团南京海陵药业有限公司 | 6-乙基鹅去氧胆酸异构体的合成及其分离测定方法 |
| CZ2015504A3 (cs) | 2015-07-16 | 2017-01-25 | Zentiva, K.S. | Krystalické formy obeticholové kyseliny |
| EP3124080A1 (en) * | 2015-07-28 | 2017-02-01 | Merz Pharma GmbH & Co. KGaA | Semisynthetic bile acids for injection lipolysis |
| CN105085597B (zh) * | 2015-08-28 | 2017-03-29 | 成都百裕制药股份有限公司 | 一种无定型奥贝胆酸的制备方法 |
| CN106478756A (zh) * | 2015-09-02 | 2017-03-08 | 中美华世通生物医药科技（武汉）有限公司 | Oca-e单晶及其制备方法和用途 |
| WO2017053428A1 (en) * | 2015-09-21 | 2017-03-30 | Intercept Pharmaceuticals, Inc. | Methods of promoting hepatic regeneration |
| KR20180052756A (ko) | 2015-09-24 | 2018-05-18 | 인터셉트 파마슈티컬즈, 인크. | 담즙산 유도체 제조를 위한 방법 및 중간체 |
| EP3359160B1 (en) | 2015-10-07 | 2021-08-25 | Intercept Pharmaceuticals, Inc. | Farnesoid x receptor modulators |
| CN106589039B (zh) * | 2015-10-15 | 2019-12-17 | 苏州朗科生物技术股份有限公司 | 一种奥贝胆酸的制备方法及相关化合物 |
| CN106589038A (zh) * | 2015-10-15 | 2017-04-26 | 重庆医药工业研究院有限责任公司 | 一种制备3α,7α-二羟基-6α-乙基-5β-胆烷酸的方法 |
| CN106632564B (zh) * | 2015-10-30 | 2021-04-13 | 苏州泽璟生物制药股份有限公司 | 奥贝胆酸盐及其无定形物和药物组合物 |
| CN106668027A (zh) * | 2015-11-05 | 2017-05-17 | 中美华世通生物医药科技（武汉）有限公司 | 奥贝胆酸药物组合物及其制备方法 |
| HK1254055A1 (zh) * | 2015-11-06 | 2019-07-12 | 英特塞普特医药品公司 | 制备奥贝胆酸及其衍生物的方法 |
| CN106749466B (zh) * | 2015-11-23 | 2019-05-21 | 南京济群医药科技股份有限公司 | 一种高纯度奥贝胆酸的制备方法 |
| CN105315320B (zh) * | 2015-11-30 | 2017-03-08 | 山东省药学科学院 | 一种制备奥贝胆酸的方法 |
| CN106810586A (zh) * | 2015-12-01 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | 奥贝胆酸晶型ⅱ及其制备方法和用途 |
| CN106810587A (zh) * | 2015-12-01 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | 制备无定型奥贝胆酸的方法 |
| CN106822005A (zh) * | 2015-12-03 | 2017-06-13 | 江苏先声药业有限公司 | 奥贝胆酸组合物及其制备方法 |
| CN106854229A (zh) * | 2015-12-08 | 2017-06-16 | 陈剑 | 一类脂肪酸盐,其制备及其在医药上的应用 |
| CN105481925B (zh) * | 2015-12-17 | 2018-06-22 | 南京济群医药科技股份有限公司 | 一种奥贝胆酸及其中间体的制备方法 |
| CA3009149A1 (en) * | 2015-12-22 | 2017-06-29 | Intercept Pharmaceuticals, Inc. | Polymorphic crystalline forms of obeticholic acid |
| CN105399793A (zh) * | 2015-12-24 | 2016-03-16 | 北京康立生医药技术开发有限公司 | 一种胆烷酸的制备方法 |
| CN106916195A (zh) * | 2015-12-25 | 2017-07-04 | 中美华世通生物医药科技（武汉）有限公司 | 奥贝胆酸中间体的纯化方法 |
| WO2017115324A1 (en) | 2016-01-01 | 2017-07-06 | Lupin Limited | Solid forms of obeticholic acid and processes thereof |
| CN105646633B (zh) * | 2016-01-22 | 2020-05-26 | 南京长澳医药科技有限公司 | 一种制备奥贝胆酸1型的方法 |
| CN105566429B (zh) * | 2016-01-22 | 2020-12-01 | 南京长澳医药科技有限公司 | 一种奥贝胆酸1型的制备方法 |
| CN105646634A (zh) * | 2016-01-29 | 2016-06-08 | 中国药科大学 | 奥贝胆酸杂质的制备方法 |
| WO2017133360A1 (zh) * | 2016-02-02 | 2017-08-10 | 深圳市塔吉瑞生物医药有限公司 | 一种甾体类化合物及包含该化合物的组合物及其用途 |
| DK3411031T3 (da) * | 2016-02-04 | 2024-10-21 | Cindome Pharma Inc | Deutererede domperidonpræparater og fremgangsmåder til terapi af lidelser |
| US11168107B2 (en) | 2016-02-10 | 2021-11-09 | Dr. Reddy's Laboratories Limited | Amine salt of obeticholic acid |
| US10364267B2 (en) | 2016-02-23 | 2019-07-30 | Enanta Pharmaceuticals, Inc. | Deuterated bile acid derivatives as FXR/TGR5 agonists and methods of use thereof |
| WO2017147137A1 (en) | 2016-02-23 | 2017-08-31 | Enanta Pharmaceuticals, Inc. | Benzoic acid derivatives of bile acid as fxr/tgr5 agonists and methods of use thereof |
| WO2017147174A1 (en) | 2016-02-23 | 2017-08-31 | Enanta Pharmaceuticals, Inc. | Heteroaryl containing bile acid analogs as fxr/tgr5 agonists and methods of use thereof |
| CN107126419B (zh) * | 2016-02-26 | 2020-06-19 | 石药集团中诺药业（石家庄）有限公司 | 一种奥贝胆酸片剂及其制备方法 |
| 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 |
| CN105541953B (zh) * | 2016-03-15 | 2017-11-21 | 成都市新功生物科技有限公司 | 一种高纯度奥贝胆酸的重结晶纯化方法 |
| CN107188917A (zh) * | 2016-03-15 | 2017-09-22 | 正大天晴药业集团股份有限公司 | 奥贝胆酸盐及其药物组合物 |
| CN109152840A (zh) * | 2016-03-28 | 2019-01-04 | 英特塞普特医药品公司 | 通过结合fxr激动剂和arb获得的药物 |
| US11161871B2 (en) | 2016-03-31 | 2021-11-02 | Jiangsu Hengrui Medicine Co., Ltd. | Crystalline form of obeticholic acid and preparation method therefor |
| JPWO2017170858A1 (ja) * | 2016-03-31 | 2019-02-14 | インターセプト ファーマシューティカルズ， インコーポレイテッド | 溶出性に優れた経口製剤 |
| KR20180125573A (ko) | 2016-03-31 | 2018-11-23 | 인터셉트 파마슈티컬즈, 인크. | 유효 성분의 화학적 안정성이 뛰어난 필름 코팅정 |
| EP3228306A1 (en) | 2016-04-04 | 2017-10-11 | ratiopharm GmbH | Complex compound comprising obeticholic acid and cyclodextrin and pharmaceutical formulation comprising the complex compound |
| US10752654B2 (en) | 2016-04-04 | 2020-08-25 | Dipharma Francis S.R.L. | Method for preparing a farnesoid X receptor agonist |
| TW201738254A (zh) * | 2016-04-19 | 2017-11-01 | 英特賽普醫藥品公司 | 奧貝膽酸及其衍生物之製備方法 |
| JP6963882B2 (ja) | 2016-05-05 | 2021-11-10 | チルドレンズ ホスピタル メディカル センター | 胃底部組織のインビトロでの製造のための方法及び当該方法と関連した組成物 |
| CN105859817A (zh) * | 2016-05-09 | 2016-08-17 | 成都宇西医药技术有限公司 | 一种制备3α-羟基-6-乙烯基-7-酮基-5β-胆烷酸的方法 |
| GB201608776D0 (en) | 2016-05-18 | 2016-06-29 | Dextra Lab Ltd | Methods and compounds |
| GB201608777D0 (en) | 2016-05-18 | 2016-06-29 | Dextra Lab Ltd | Compounds |
| CN107400154A (zh) * | 2016-05-18 | 2017-11-28 | 北京凯因科技股份有限公司 | 一种制备3α,7α-二-羟基-6α-乙基-5β-胆烷酸的方法 |
| CN106046094A (zh) * | 2016-05-30 | 2016-10-26 | 福建广生堂药业股份有限公司 | 一种奥贝胆酸二聚体杂质及其制备方法 |
| CN105859818A (zh) * | 2016-05-31 | 2016-08-17 | 四川瑞希康生物医药有限公司 | 一种奥贝胆酸α晶型及其制备方法、药物组合物和用途 |
| EP3464316A4 (en) | 2016-06-01 | 2020-02-19 | Dr. Reddy's Laboratories Ltd. | PROCESS FOR THE PREPARATION OF OBETICHOLIC ACID |
| CN105997909A (zh) * | 2016-06-02 | 2016-10-12 | 中国药科大学 | 一种奥贝胆酸口崩片及其制备方法 |
| JP6678779B2 (ja) | 2016-06-13 | 2020-04-08 | ギリアード サイエンシーズ， インコーポレイテッド | Ｆｘｒ（ｎｒ１ｈ４）調節化合物 |
| CA3252823A1 (en) | 2016-06-13 | 2025-02-25 | Gilead Sciences, Inc. | Fxr (nr1h4) modulating compounds |
| CN106083971B (zh) * | 2016-06-17 | 2017-11-14 | 苏州敬业医药化工有限公司 | 一种(E)‑3α‑羟基‑6‑亚乙基‑7‑酮‑5β‑胆烷‑24‑酸的制备方法 |
| CZ2016385A3 (cs) | 2016-06-28 | 2018-01-10 | Zentiva, K.S. | Způsoby přípravy intermediátů pro syntézu Obeticholové kyseliny |
| CN107540720B (zh) * | 2016-06-29 | 2021-03-02 | 常州市第四制药厂有限公司 | 3α,7α-二羟基-6α-乙基-5β-胆烷酸晶型H及其制备方法和应用 |
| NZ749664A (en) | 2016-07-11 | 2025-08-29 | Sage Therapeutics Inc | C17, c20, and c21 substituted neuroactive steroids and their methods of use |
| AU2017296295B2 (en) | 2016-07-11 | 2022-02-24 | Sage Therapeutics, Inc. | C7, C12, and C16 substituted neuroactive steroids and their methods of use |
| CN107648190B (zh) * | 2016-07-26 | 2021-04-27 | 海南先声药业有限公司 | 奥贝胆酸组合物及其制备方法 |
| CN106279331B (zh) * | 2016-07-27 | 2019-06-14 | 宋火良 | 胆酸类肝病治疗药物 |
| CN107674106B (zh) * | 2016-08-01 | 2021-06-22 | 华北制药集团新药研究开发有限责任公司 | 一种奥贝胆酸二聚体的制备方法 |
| CN106279335A (zh) * | 2016-08-12 | 2017-01-04 | 齐鲁制药有限公司 | 一种制备奥贝胆酸及其中间体的方法 |
| EP3287467A1 (en) | 2016-08-22 | 2018-02-28 | ratiopharm GmbH | Preparation of obeticholic acid comprising continuous flow process steps |
| CN107793463A (zh) * | 2016-08-29 | 2018-03-13 | 鲁南制药集团股份有限公司 | 一种3α‑羟基‑6α‑乙基‑7‑酮‑5β‑胆‑24‑酸的制备方法 |
| CN107778339A (zh) * | 2016-08-29 | 2018-03-09 | 鲁南制药集团股份有限公司 | 一种无定型奥贝胆酸的制备方法 |
| EP3293196A1 (en) | 2016-09-09 | 2018-03-14 | Hexal AG | Process for purifying obeticholic acid |
| CN106478757B (zh) * | 2016-09-27 | 2019-01-18 | 华南理工大学 | 一种3α,7α-二羟基-6α-乙基胆烷酸的制备方法 |
| CN109963567A (zh) * | 2016-09-30 | 2019-07-02 | 英特塞普特医药品公司 | 胆汁酸衍生物的结晶形式 |
| CN107976506B (zh) * | 2016-10-25 | 2020-05-12 | 成都弘达药业有限公司 | 一种奥贝胆酸有关物质的检测方法 |
| EP3534907A4 (en) * | 2016-11-04 | 2020-06-24 | Children's Hospital Medical Center | COMPOSITIONS AND METHODS FOR TREATING HEPATIC DISEASE |
| WO2018102418A1 (en) * | 2016-11-29 | 2018-06-07 | Enanta Pharmaceuticals, Inc. | Process for preparation of sulfonylurea bile acid derivatives |
| EP3548507A4 (en) | 2016-12-05 | 2020-07-15 | Children's Hospital Medical Center | COLON ORGANOIDS AND PROCESSES FOR THE PREPARATION AND USE THEREOF |
| JP6840853B2 (ja) * | 2016-12-09 | 2021-03-10 | カディラ・ヘルスケア・リミテッド | 原発性胆汁性胆管炎の治療 |
| CN108614038B (zh) * | 2016-12-13 | 2022-05-17 | 亚宝药业集团股份有限公司 | 一种测定奥贝胆酸原料药有关物质的方法 |
| CN106749472B (zh) * | 2016-12-30 | 2019-02-22 | 江苏开元医药化工有限公司 | 一种3α-羟基-6α-乙基-7-酮-5β-胆烷-24-酸的制备方法 |
| CN106645497A (zh) * | 2017-01-03 | 2017-05-10 | 山东省药学科学院 | 一种奥贝胆酸及其制剂中有关物质的检测方法 |
| MX2019008510A (es) | 2017-01-18 | 2019-11-11 | Tremco Inc | Compuesto de union estructural. |
| US10472386B2 (en) | 2017-02-14 | 2019-11-12 | Enanta Pharmaceuticals, Inc. | Bile acid derivatives as FXR agonists and methods of use thereof |
| CN106892954B (zh) * | 2017-02-23 | 2019-04-30 | 广州隽沐生物科技有限公司 | 奥贝胆酸的制备工艺 |
| MX2019010640A (es) * | 2017-03-08 | 2019-11-28 | Intercept Pharmaceuticals Inc | Formas cristalinas de acido obeticolico. |
| PT4122464T (pt) | 2017-03-28 | 2024-06-27 | Gilead Sciences Inc | Combinações terapêuticas para o tratamento de doenças do fígado |
| CN108659086A (zh) * | 2017-03-29 | 2018-10-16 | 杭州源昶医药科技有限公司 | 一种奥贝胆酸的合成方法 |
| WO2018187804A1 (en) | 2017-04-07 | 2018-10-11 | Enanta Pharmaceuticals, Inc. | Process for preparation of sulfonyl carbamate bile acid derivatives |
| EP3609997A4 (en) | 2017-04-14 | 2021-03-03 | Children's Hospital Medical Center | COMPOSITIONS OF STEM CELLS FROM MULTIPLE DONOR CELLS AND THEIR PREPARATION PROCEDURES |
| CN106986910A (zh) * | 2017-04-19 | 2017-07-28 | 成都百特万合医药科技有限公司 | 奥贝胆酸中间体的制备方法 |
| CN110799519B (zh) * | 2017-04-20 | 2023-02-28 | 大雄Bio株式会社 | 利用连续流动反应的胆汁酸衍生物的制备方法 |
| WO2018211413A1 (en) * | 2017-05-15 | 2018-11-22 | Dr. Reddy’S Laboratories Limited | Solid forms of obeticholic acid and process for preparation |
| CZ2017298A3 (cs) | 2017-05-26 | 2018-12-05 | Zentiva, K.S. | Amorfní formy obeticholové kyseliny |
| CN107286160A (zh) * | 2017-06-05 | 2017-10-24 | 毛佳婧 | 一种抗肝炎药物的哌啶并吡啶并吡唑‑锌配合物的制备方法 |
| KR20240125702A (ko) | 2017-06-30 | 2024-08-19 | 신돔 파마, 인크. | 중수소화 돔페리돈 조성물, 방법, 및 제조 |
| US12478612B2 (en) | 2017-06-30 | 2025-11-25 | Cindome Pharma, Inc. | Deuterated domperidone compositions, methods, and preparation |
| CN109280071A (zh) * | 2017-07-19 | 2019-01-29 | 东莞东阳光药物研发有限公司 | 奥贝胆酸的晶型及其制备方法 |
| CN111050772A (zh) | 2017-07-24 | 2020-04-21 | 英特塞普特医药品公司 | 同位素标记的胆汁酸衍生物 |
| JP6937893B2 (ja) | 2017-08-03 | 2021-09-22 | メディトックス インク． | 胆汁酸類を製造するための方法 |
| CN107383139A (zh) * | 2017-08-09 | 2017-11-24 | 杭州和泽医药科技有限公司 | 一种3α‑羟基‑7‑氧代‑5β‑胆烷酸新衍生物制备奥贝胆酸的方法 |
| CN109485687A (zh) * | 2017-09-12 | 2019-03-19 | 成都弘达药业有限公司 | 奥贝胆酸的晶型j及其制备方法 |
| CA3077442A1 (en) | 2017-10-10 | 2019-04-18 | Children's Hospital Medical Center | Esophageal tissue and/or organoid compositions and methods of making same |
| US10611793B1 (en) | 2017-11-27 | 2020-04-07 | Teva Czech Industries S.R.O. | Solid state forms of obeticholic acid salts |
| WO2019106043A1 (en) | 2017-11-29 | 2019-06-06 | Hexal Ag | Pharmaceutical composition comprising obeticholic acid |
| EP4484440A3 (en) | 2017-12-08 | 2025-03-26 | Sage Therapeutics, Inc. | Deuterated 21 -[4-cyano-pyrazol-1 -yl]-19-nor-pregan-3. alpha-ol-20-one derivatives for treating cns disorders |
| WO2019126626A1 (en) | 2017-12-21 | 2019-06-27 | Children's Hospital Medical Center | Digitalized human organoids and methods of using same |
| US11434256B2 (en) | 2018-01-25 | 2022-09-06 | Msn Laboratories Private Limited, R&D Center | Process for the preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid |
| CN108440629A (zh) * | 2018-03-16 | 2018-08-24 | 丽珠集团新北江制药股份有限公司 | 一种制备奥贝胆酸中间体及奥贝胆酸的方法 |
| WO2019197962A1 (en) * | 2018-04-09 | 2019-10-17 | Biophore India Pharmaceuticals Pvt. Ltd | Crystalline forms of (3α, 5β, 6α, 7α)-6-ethyl-3, 7-dihydroxycholan-24-oic acid (obeticholic acid) and processes thereof |
| CN110655550A (zh) * | 2018-06-29 | 2020-01-07 | 江苏海悦康医药科技有限公司 | (E)-3α-羟基-6-亚乙基-7-氧代-5β-胆甾烷-24-酸的制备方法 |
| CN108794558B (zh) * | 2018-07-03 | 2020-05-22 | 丽珠集团新北江制药股份有限公司 | 一种反应条件温和的奥贝胆酸制备方法 |
| SG11202100533VA (en) | 2018-07-26 | 2021-02-25 | Childrens Hospital Med Ct | Hepato-biliary-pancreatic tissues and methods of making same |
| GB201812382D0 (en) | 2018-07-30 | 2018-09-12 | Nzp Uk Ltd | Compounds |
| WO2020039449A1 (en) | 2018-08-24 | 2020-02-27 | Solara Active Pharma Sciences Limited | An improved process for the preparation of obeticholic acid and intermediates used in the process thereof |
| CA3112026A1 (en) | 2018-09-12 | 2020-03-19 | Children's Hospital Medical Center | Organoid compositions for the production of hematopoietic stem cells and derivatives thereof |
| MX2021005316A (es) * | 2018-11-08 | 2021-09-10 | Intercept Pharmaceuticals Inc | Métodos de uso del ácido obeticólico. |
| CN109535217B (zh) * | 2018-11-13 | 2020-04-14 | 丽珠集团新北江制药股份有限公司 | 一种奥贝胆酸的精制方法 |
| SG11202107434PA (en) | 2019-01-15 | 2021-08-30 | Gilead Sciences Inc | Fxr (nr1h4) modulating compounds |
| CN118388473A (zh) | 2019-02-19 | 2024-07-26 | 吉利德科学公司 | Fxr激动剂的固体形式 |
| WO2020243590A1 (en) | 2019-05-30 | 2020-12-03 | Intercept Pharmaceuticals, Inc. | Pharmaceutical compositions comprising a fxr agonist and a fibrate for use in the treatment of cholestatic liver disease |
| US12497597B2 (en) | 2019-05-31 | 2025-12-16 | Children's Hospital Medical Center | Methods of generating and expanding hematopoietic stem cells |
| KR20220016098A (ko) | 2019-05-31 | 2022-02-08 | 세이지 테라퓨틱스, 인크. | 신경활성 스테로이드 및 이의 조성물 |
| WO2021029656A1 (ko) * | 2019-08-14 | 2021-02-18 | 주식회사 바이오톡스텍 | 하이드로퀴논 유도체, 및 오베티콜릭산을 포함하는 비알콜성 지방간염의 예방 또는 치료용 약학조성물 |
| CN112824425B (zh) * | 2019-11-21 | 2023-10-03 | 成都西岭源药业有限公司 | 一种6-位烯基取代胆酸化合物及其制备方法和应用 |
| US20230201222A1 (en) * | 2020-05-13 | 2023-06-29 | Children's Hospital Medical Center | Alleviation of liver injury by activating the signaling pathway mediated by farnesoid x receptor |
| WO2022051321A1 (en) | 2020-09-03 | 2022-03-10 | Coherus Biosciences, Inc. | Fixed dose combinations of chs-131 and a fxr agonist |
| KR102526452B1 (ko) * | 2020-10-28 | 2023-04-27 | (주)델로 | 관절 구조를 포함하는 토이 로봇 |
| CN114644670A (zh) * | 2020-12-17 | 2022-06-21 | 四川弘远药业有限公司 | 奥贝胆酸和对氨基苯甲酸的共晶及其制备方法 |
| CN114236027B (zh) * | 2021-12-22 | 2024-01-12 | 中山百灵生物技术股份有限公司 | 一种(E)-6-亚乙基-3α-羟基-7-酮基-5β-胆甾烷-24-酸的检测方法 |
| US12343351B2 (en) | 2022-03-25 | 2025-07-01 | Rutgers, The State University Of New Jersey | Pulmonary function treatment |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102121547A (zh) * | 2010-12-23 | 2011-07-13 | 拉卡萨安吉拉股份有限公司 | 用于管道接头的衬套和采用该衬套的管道接头 |
Family Cites Families (69)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072695A (en) * | 1972-09-21 | 1978-02-07 | Intellectual Property Development Corporation | 3α,7α-Dihydroxy-cholanic acid derivatives |
| IT1137459B (it) * | 1981-04-14 | 1986-09-10 | Erregierre Spa | Prodesso per la preparazione di acido ursodeossicolico ad alta purezza |
| EP0101554B1 (en) | 1982-07-29 | 1986-10-15 | Lehner A.G. | New derivatives of biliary acids, process for the production thereof and pharmaceutical compositions containing the same |
| IT1206112B (it) | 1983-04-29 | 1989-04-14 | Lehner Ag | Nuovi derivati di acidi biliari, procedimento per la loro preparazione e relative composizioni farmaceutiche. |
| IT1212835B (it) | 1983-08-18 | 1989-11-30 | Lehner Ag | Derivati di acidi biliari, procedimento per la loro preparazione e relative composizioni farmaceutiche. |
| US4892868A (en) | 1984-08-17 | 1990-01-09 | Gipharmex, S.P.A. | Derivatives of biliary acids, process for the production thereof and corresponding pharmaceutical compositions |
| IT1196377B (it) | 1984-12-21 | 1988-11-16 | Lehner Ag | Derivati di acidi biliari,procedimento per la loro preparazione e relative composizioni farmaceutiche |
| US5023252A (en) | 1985-12-04 | 1991-06-11 | Conrex Pharmaceutical Corporation | Transdermal and trans-membrane delivery of drugs |
| IT1223313B (it) | 1987-10-20 | 1990-09-19 | Gipharmex Spa | Derivati di acidi biliari loro preparazione e composizioni farmaceutiche che li contengono |
| JPH0320265A (ja) * | 1989-02-10 | 1991-01-29 | Meiji Seika Kaisha Ltd | アミノチアゾール酢酸誘導体並びにその製造法 |
| US5175320A (en) | 1989-04-17 | 1992-12-29 | Giuliani S.P.A. | Fluorinated bile acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
| IT1229570B (it) | 1989-04-17 | 1991-09-04 | Giuliani Spa | Derivati fluorurati di acidi biliari, loro preparazione e composizioni farmaceutiche che li contengono. |
| DE69018592T2 (de) | 1989-12-13 | 1995-10-05 | Mitsubishi Chem Corp | Pyrazolylacrylsäure-Derivate, verwendbar als systemische Fungiziden in Pflanzen- und Materialschutz. |
| WO1997028149A1 (en) | 1996-02-02 | 1997-08-07 | Merck & Co., Inc. | Method for raising hdl cholesterol levels |
| GB9604242D0 (en) | 1996-02-28 | 1996-05-01 | Glaxo Wellcome Inc | Chemical compounds |
| GB9606805D0 (en) | 1996-03-30 | 1996-06-05 | Glaxo Wellcome Inc | Medicaments |
| AU3552697A (en) | 1996-07-12 | 1998-02-09 | Smithkline Beecham Plc | Novel treatment of leptine resistance |
| JP3600713B2 (ja) | 1997-08-06 | 2004-12-15 | 東京応化工業株式会社 | ポジ型ホトレジスト組成物 |
| US6008237A (en) | 1997-12-19 | 1999-12-28 | Merck & Co., Inc. | Arylthiazolidinedione derivatives |
| AU759255B2 (en) | 1998-01-29 | 2003-04-10 | Amgen, Inc. | PPAR-gamma modulators |
| JP3146187B2 (ja) * | 1998-06-26 | 2001-03-12 | 高砂香料工業株式会社 | ジホスフィンオキシドの新規な製造方法 |
| EP1137940A4 (en) | 1998-10-23 | 2004-06-02 | Glaxo Group Ltd | METHOD FOR IDENTIFYING LIGANDS OF NUCLEAR RECEPTORS |
| WO2000037077A1 (en) | 1998-12-23 | 2000-06-29 | Glaxo Group Limited | Assays for ligands for nuclear receptors |
| AU2409600A (en) | 1999-01-07 | 2000-07-24 | Tularik Inc. | Fxr receptor-mediated modulation of cholesterol metabolism |
| US20020132223A1 (en) | 1999-03-26 | 2002-09-19 | City Of Hope | Methods for modulating activity of the FXR nuclear receptor |
| EP1473042B1 (en) | 1999-03-26 | 2006-06-21 | City of Hope | Screening for FXR receptor modulators |
| ATE274921T1 (de) | 1999-03-26 | 2004-09-15 | Hope City | Verfahren zur selektion von fxr- rezeptormodulatoren |
| HK1047705A1 (zh) | 1999-06-11 | 2003-03-07 | Allergan, Inc. | 用於调节fxr受体活性的方法 |
| US6906057B1 (en) | 1999-06-11 | 2005-06-14 | Allergan, Inc. | Methods for modulating FXR receptor activity |
| US6559188B1 (en) | 1999-09-17 | 2003-05-06 | Novartis Ag | Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes |
| AU1215701A (en) | 1999-10-22 | 2001-05-08 | Merck & Co., Inc. | Pharmaceuticals for treating obesity |
| US6627636B2 (en) | 2000-06-15 | 2003-09-30 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
| US6777446B2 (en) | 2000-09-05 | 2004-08-17 | Tularik, Inc. | FXR modulators |
| US20020119958A1 (en) | 2001-02-13 | 2002-08-29 | Shinichiro Tojo | Therapeutic agent for hyperlipidemia |
| ATE303399T1 (de) | 2001-03-12 | 2005-09-15 | Intercept Pharmaceuticals Inc | Steroide als agonisten für fxr |
| US7354726B2 (en) | 2001-04-12 | 2008-04-08 | Takeda Pharmaceutical Company Limited | Screening method |
| WO2003015777A1 (en) | 2001-08-13 | 2003-02-27 | Lion Bioscience Ag | Nr1h4 nuclear receptor binding compounds |
| EP1285914B1 (en) | 2001-08-13 | 2007-12-19 | PheneX Pharmaceuticals AG | Nr1h4 nuclear receptor binding compounds |
| WO2003016280A1 (en) | 2001-08-13 | 2003-02-27 | Lion Bioscience Ag | Nr1h4 nuclear receptor binding compounds |
| US7112340B2 (en) * | 2001-10-19 | 2006-09-26 | Baxter International Inc. | Compositions of and method for preparing stable particles in a frozen aqueous matrix |
| HRP20040510A2 (en) | 2001-11-14 | 2005-08-31 | Teva Pharmaceutical Industries Ltd. | Amorphous and crystalline forms of losartan potassium and process for their preparation |
| US20030144360A1 (en) | 2001-11-19 | 2003-07-31 | Allergan Sales, Inc. | Composition and method for modulating BAR/FXR receptor activity |
| WO2003080803A2 (en) | 2002-03-21 | 2003-10-02 | Smithkline Beecham Corporation | Methods of using farnesoid x receptor (fxr) agonists |
| WO2003086303A2 (en) | 2002-04-12 | 2003-10-23 | The University Of Chicago | Farnesoid x-activated receptor agonists |
| US6987121B2 (en) | 2002-04-25 | 2006-01-17 | Smithkline Beecham Corporation | Compositions and methods for hepatoprotection and treatment of cholestasis |
| ITMI20021532A1 (it) | 2002-07-12 | 2004-01-12 | Roberto Pellicciari | Composti chimici |
| JP2006515838A (ja) | 2002-11-22 | 2006-06-08 | スミスクライン ビーチャム コーポレーション | ファルネソイドｘ受容体アゴニスト |
| EP1696910A4 (en) | 2003-09-26 | 2009-12-09 | Smithkline Beecham Corp | COMPOSITIONS AND METHOD FOR THE TREATMENT OF FIBROSIS |
| EP1568706A1 (en) | 2004-02-26 | 2005-08-31 | Intercept Pharmaceuticals, Inc. | Novel steroid agonist for FXR |
| AR048918A1 (es) * | 2004-03-11 | 2006-06-14 | Fresenius Kabi De Gmbh | Conjugados de almidon de hidroxietilo y eritropoyetina |
| DK2712617T3 (en) | 2004-03-12 | 2017-02-13 | Intercept Pharmaceuticals Inc | Treatment of fibrosis with Fxr ligands. |
| AU2005272916A1 (en) * | 2004-08-10 | 2006-02-23 | Exelixis, Inc. | Heterocyclic compounds as pharmaceutical agents |
| US20060252670A1 (en) * | 2004-10-14 | 2006-11-09 | Intercept Pharmaceuticals Inc. | Method of reducing drug-induced adverse side effects in a patient |
| AU2006239811B2 (en) | 2005-04-25 | 2012-02-02 | Enterin, Inc. | Polymorphic and amorphous salt forms of squalamine dilactate |
| ITMI20050912A1 (it) * | 2005-05-19 | 2006-11-20 | Erregierre Spa | Processo di preparazione di acidi 3-a-ya(b)-diidrossi-6-a(b)-alchil-5b-colanici |
| JP2007077123A (ja) | 2005-09-16 | 2007-03-29 | Shiono Chemical Co Ltd | 非晶質セフジニル、その製造方法およびこれを含有する経口投与用医薬組成物 |
| ES2523591T3 (es) | 2006-06-27 | 2014-11-27 | Intercept Pharmaceuticals Inc. | Derivados de ácidos biliares como ligandos de FXR para la prevención o el tratamiento de enfermedades o estados mediados por FXR |
| EP1894924A1 (en) * | 2006-08-29 | 2008-03-05 | Phenex Pharmaceuticals AG | Heterocyclic FXR binding compounds |
| CL2007003035A1 (es) * | 2006-10-24 | 2008-05-16 | Smithkline Beechman Corp | Compuestos derivados de isoxazol sustituidos, agonistas de receptores farnesoid x; procedimiento de preparacion; composicion farmaceutica que lo comprende; y uso del compuesto en el tratamiento de la obesidad, diabetes mellitus, fibrosis en organos, |
| WO2008091540A2 (en) | 2007-01-19 | 2008-07-31 | Intercept Pharmaceuticals, Inc. | 23-substituted bile acids as tgr5 modulators and methods of use thereof |
| EP1947108A1 (en) | 2007-01-19 | 2008-07-23 | Intercept Pharmaceuticals, Inc. | TGR5 modulators and methods of use thereof |
| US8338628B2 (en) | 2007-08-28 | 2012-12-25 | City Of Hope | Method of synthesizing alkylated bile acid derivatives |
| AU2008323017B2 (en) * | 2007-11-15 | 2012-12-20 | F. Hoffmann-La Roche Ag | Methyl-benzimidazole derivatives |
| WO2010014836A2 (en) | 2008-07-30 | 2010-02-04 | Intercept Pharmaceuticals, Inc. | Tgr5 modulators and methods of use thereof |
| WO2010039529A2 (en) * | 2008-09-23 | 2010-04-08 | Resolvyx Pharmaceuticals, Inc. | Compositions and methods for the treament of inflammatory disease |
| DK2376519T3 (da) | 2008-11-19 | 2014-02-03 | Intercept Pharmaceuticals Inc | TGR5-modulatorer og fremgangsmåde til anvendelse deraf |
| JP5909774B2 (ja) | 2009-08-25 | 2016-04-27 | クィン ビル セラピューティクス インコーポレイテッド | 胆道疾患を治療するためのポリヒドロキシル化胆汁酸 |
| CN102372757B (zh) | 2011-10-31 | 2013-01-16 | 安徽科宝生物工程有限公司 | 酯化法制备猪胆汁中鹅去氧胆酸的方法 |
| EA201990211A1 (ru) | 2012-06-19 | 2019-06-28 | Интерсепт Фармасьютикалз, Инк. | Получение, применение и твердые формы обетихолевой кислоты |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102121547A (zh) * | 2010-12-23 | 2011-07-13 | 拉卡萨安吉拉股份有限公司 | 用于管道接头的衬套和采用该衬套的管道接头 |
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