TW202402287A - 包含喹諾酮類化合物的腸易激綜合症用醫藥組成物 - Google Patents
包含喹諾酮類化合物的腸易激綜合症用醫藥組成物 Download PDFInfo
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Abstract
本發明關於包含喹諾酮類化合物的腸易激綜合症用醫藥組成物,尤其關於該喹諾酮類化合物,特別是1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥理學上可接受的鹽、水合物、溶劑化物或氘化物用於預防或治療人或動物的腸易激綜合症的用途。
Description
本發明關於醫學領域,特別關於一種用於預防或治療腸易激綜合症的藥物,該藥物含有低吸收性喹諾酮類化合物或該化合物的藥理學上可接受的鹽作為活性成分。
腸易激綜合症(IBS)是一種功能性胃腸道病症,其症狀包括與大便形式或頻率變化相關、但與用目前的常規診斷工具可檢測到的結構或生化異常無關的腹痛。在任一時間點,該疾患影響了5%至10%在其它方面健康的個體,並且在大多數人中有復發和緩解的過程。根據羅馬分類,IBS可分類為四類:腹瀉型(IBS-D)、便秘型(IBS-C)、混合型(IBS-M)和未知型(IBS-U)。在中國,IBS人群在1.4%至11.5%的範圍內,大多數是以腹瀉型為主型(IBS-D)。只有25%的患者會到醫院尋求治療。
目前還沒有治癒IBS的方法。治療的主要內容包括對患者進行病情、飲食改變、可溶性纖維和抗痙攣藥物的教育。其它治療往往適用於症狀嚴重的人,並且包括中樞神經調節劑、腸道促分泌劑、作用於阿片類受體或5-HT受
體的藥物,或吸收最少的抗生素,以及心理療法。例如,三環類抗抑鬱藥在治療IBS-D方面是有效的,儘管存在一些副作用,如睡眠、便秘、口渴等。同樣,5HT拮抗劑也適用於本領域(非專利文獻1:Ford等人,Functional Gastrointestinal Disorders.2020,396,1675-1688)。然而,即便使用了這些藥物,也不期望完全治療IBS-D,因此需要開發一種比現有藥物更有效的藥物。
專利文獻1(WO2013/029548)揭露對生活在腸道中的艱難梭菌(Clostridium difficile)表現出抗細菌活性的特異性喹諾酮類抗微生物劑。
本發明的主要目的是提供一種治療和/或預防腸易激綜合症(IBS),尤其是IBS-D的新型藥物,它比現有藥物更有效。
本發明人進行了廣泛的研究,然後發現已知的喹諾酮類抗微生物劑1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸可以改善受約束大鼠的排便數量,降低尿液和血清中的組織胺水平,並改善內臟超敏反應,這些都是腸易激綜合症的標誌,該喹諾酮類抗微生物劑可有效治療腸易激綜合症。基於這些新的發現,完成了本發明。
發明概述
本發明提供了喹諾酮類化合物用於預防或治療IBS,尤其是IBS-D的用途,如下面的第1項至第11項所述。
第1項. 一種用於治療和/或預防IBS的藥物,該藥物包含1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物作為活性成分。
第2項. 根據第1項所述的藥物,其中該代謝物是(2S,3S,4S,5R,6R)-6-((7-胺基-5-氰基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羰基)側氧)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸、7-(6-胺基-5-胺基甲醯基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羧酸或7-(6-胺基-5-氰基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羧酸乙酯。
第3項. 根據第1項或第2項所述的藥物,該藥物用於口服施用。
第4項. 根據第1項至第3項中任一項所述的藥物,其中該活性成分的日劑量是7.5mg至24000mg。
第5項. 根據第1項至第4項中任一項所述的藥物,其中IBS是IBS-D。
第6項. 一種治療和/或預防IBS的方法,該方法包括將治療有效量的1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物作為活性成分施用於有需要的患者。
第7項. 根據第6項所述的方法,其中IBS是IBS-D。
第8項. 1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物在製造用於治療和/或預防IBS的藥物中的用途。
第9項. 根據第8項所述的用途,其中IBS是IBS-D。
第10項. 1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物,用於治療和/或預防IBS。
第11項. 根據第10項所述的1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物,其中IBS是IBS-D。
圖1示出了化合物OPS-2071對約束應激RS-IBS模型中的大鼠的體重的影響。
圖2示出了化合物OPS-2071對RS-IBS模型中的大鼠的體重變化(BWC)%的影響。
圖3示出了化合物OPS-2071對RS-IBS模型中的大鼠在2小時/天期間的排便的影響。
圖4示出了第3天,即化合物治療前一天記錄的對照組和RS組之間的RS-IBS模型中內臟運動反應。
圖5示出了在RS-IBS模型中第7天化合物OPS-2071對結直腸擴張的內臟運動反應(mmHg)的影響。
圖6示出了在RS-IBS模型中第7天化合物OPS-2071對尿液中組織胺水平的影響。
本發明化合物1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸具有式(1)的結構,作為化合物2-18在WO2013/029548中公開,並且可根據WO2013/029548合成。
本發明化合物還可以包括該化合物的前體或代謝物,例如(2S,3S,4S,5R,6R)-6-((7-胺基-5-氰基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-碳基)側氧)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸、7-(6-胺基-5-胺基甲醯基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羧酸和7-(6-胺基-5-氰基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羧酸乙酯,它們分別具有下列式(2)至式(4)的結構:
本發明化合物可以為水合物和/或溶劑化物的形式,因此本發明化合物還包括其水合物和/或溶劑化物。此外,任一個或多個1H原子被2H(D)原子替代的本發明化合物也落在本發明的範圍內。在本發明化合物或其藥學上可接受的鹽的晶體中可能存在多晶型(polymorphism),因此這種晶體多晶型也在本發明的範圍內。
“藥學上可接受的鹽”包括酸加成鹽,即與無機酸形成的鹽,如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、高氯酸鹽和磷酸鹽;與有機酸形成的鹽如草酸鹽、丙二酸鹽、馬來酸鹽、富馬酸鹽、乳酸鹽、蘋果酸鹽、檸檬酸鹽、酒石酸鹽、苯甲酸鹽、三氟乙酸鹽、乙酸鹽、甲磺酸鹽、甲苯磺酸鹽和三氟甲磺酸鹽;以及與胺基酸形成的鹽如谷胺酸鹽和天冬胺酸鹽;以及作為與鹼形成的鹽的鹼金屬鹽如鈉鹽和鉀鹽;鹼土金屬鹽如鈣鹽;和銨鹽。
本發明的化合物及其醫藥組成物通常以常用藥物製劑的形式使用。該藥物製劑可以與常規藥學上可接受的稀釋劑或載體,如填料、填充劑、黏結劑、潤濕劑、崩解劑、表面活性劑和潤滑劑混合來製備。該藥物製劑包括適合於治療該疾病的各種製劑,例如,片劑、丸劑、粉劑、溶液劑、混懸劑、乳劑、顆粒劑、膠囊、栓劑、注射劑如溶液劑和混懸劑等。在製備片劑時,可以使用任何常規載體,例如,賦形劑如乳糖、白糖、氯化鈉、葡萄糖、尿素、澱粉、碳酸鈣、高嶺土、結晶纖維素和矽酸鹽,黏結劑如水、乙醇、丙醇、單糖漿、葡萄糖溶液、澱粉溶液、明膠溶液、接甲基纖維素、蟲膠、甲基纖維素、磷酸鉀和聚乙烯吡咯烷酮,崩解劑如乾澱粉、海藻酸鈉、瓊脂粉、褐藻澱粉、碳酸氫鈉、碳酸鈣、聚氧乙烯山梨醇酐脂肪酸酯、月桂基硫酸鈉、硬脂酸單甘油酯、澱粉和乳糖,崩解抑制劑如白糖、硬脂、可可脂和氫化油,吸收促進劑如季銨鹽和月桂基硫酸
鈉,潤濕劑如甘油和澱粉,吸附劑如澱粉、乳糖、高嶺土、膨潤土和膠體矽酸鹽,潤滑劑如純化的滑石、硬脂酸酯、硼酸粉和聚乙二醇等。該片劑還可以用常規包衣劑包衣,例如,可以是糖包衣片劑、明膠包衣片劑、腸溶包衣片劑、膜包衣片劑或者雙層或多層片劑的形式。在製備丸劑時,可以使用常規載體,包括賦形劑如葡萄糖、乳糖、澱粉、可可脂、氫化植物油、高嶺土和滑石,黏結劑如阿拉伯膠粉、黃芪膠粉、明膠和乙醇,崩解劑如褐藻澱粉和瓊脂等。在製備栓劑時,可以使用常規載體,例如聚乙二醇、可可脂、高級醇、高級醇酯、明膠和半合成甘油酯。在製備注射劑時,對化合物的溶液劑、乳劑或混懸劑進行滅菌並較佳與體液等滲。這些溶液劑、乳劑和混懸劑是藉由將活性化合物與常規稀釋劑如水、乳酸水溶液、乙醇、丙二醇、乙氧基化異硬脂醇、聚氧基化異硬脂醇或聚氧乙烯山梨醇酐脂肪酸酯混合來製備。該製劑還可以與氯化鈉、葡萄糖或甘油以足以使其與體液等滲的量結合。該製劑還可以併入常規增溶劑、緩衝劑、麻醉劑,還可以併入著色劑、防腐劑、芳香劑、調味劑、甜味劑和其它藥物。糊劑、乳膏或凝膠形式的製劑可以藉由使用如白凡士林、石蠟、甘油、纖維素衍生物、聚乙二醇、矽酮、膨潤土等稀釋劑來製備。當活性成分化合物在注射劑中沉澱時,可以根據需要向注射劑中加入酸,例如甲磺酸、丙酸、鹽酸、琥珀酸或乳酸來保持注射劑為穩定溶液形式。
本發明化合物可以以任何量包含在製劑中,並且以製劑的總重量計,含量通常為1重量%至70重量%。
本發明的醫藥組成物可以用任何方法施用。可以根據製劑形式、患者的年齡和性別、疾病的嚴重程度等來選擇合適的施用方法。例如,片劑、丸劑、溶液劑、混懸劑、乳劑、顆粒劑和膠囊以口服途徑施用。在注射劑的情況下,
它以單一形式或與輔助液體如葡萄糖或胺基溶液一起經靜脈內施用。注射劑還可以以肌肉內、皮內、皮下或腹膜內途徑施用。栓劑以直腸內途徑施用。
本發明組成物的劑量可以根據施用方法、患者的年齡和性別、疾病的嚴重程度等而變化。例如,在口服施用的情況下,通常可以以每千克人或哺乳動物體重約0.125mg至約400mg,較佳約0.25mg至約200mg,更佳約0.5mg至約100mg,甚至更佳約1mg至約50mg的劑量分一份至若干份施用。例如,人用日劑量包括約7.5mg至約24000mg,較佳約15mg至約12000mg,更佳約30mg至約6000mg,甚至更佳約60mg至約3000mg。
藉由以下實施例、實驗例和製備例來說明本發明。應理解,本發明不限於這些實施例、實驗例或製備例,並且可以在不脫離本發明的範圍和精神的情況下進行各種變化和修改。
下列實施例所使用的約束應激(RS)模型是用於檢測藥物對IBS的療效的常用模型,最早由Williams等人,Gatroenterology 1988,94:611提出。RS模型表現出了對腸道輸送的抑制和排便數量的增加而不形成潰瘍,因此被視為模擬IBS,後者顯示出與結構或生化異常無關的腸道病症。如今,廣泛使用改進的約束應激模型,如先前在Wang等人,Int.J.Gastroenterol.Disord.Ther.2017,4:131中所述。涉及內臟超敏反應和組織胺的參考文獻有例如Christine West,Karen-Anne McVey Neufeld,Animal models of visceral pain and the role of the microbiome,Neurobiotogy of Pain 10(2021)100064;Giada De PalmaChiko ShimboriDavid E.ReedYang YuVirginia RabbiaJun LuNestor Jimenez-VargasJessica SessenweinCintya Lopez-LopezMarc PigrauJosue Jaramillo-PolancoYong ZhangLauren BaergAhmad ManzarJulien PujoXiaopeng BaiMaria Ines Pinto-SanchezAlberto CamineroKaren
MadsenMichael G.SuretteMichael BeyakAlan E.LomaxElena F.VerduStephen M.CollinsStephen J.VannerPremysl Bercik,Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice,Sci.Transl.Med.,14(655),eabj1895。
實驗例
下面參考實施例詳細說明本發明,然而,本發明不應局限於此。如下所示得到本文使用的本發明化合物(下文簡稱為“測試物質”)和參考藥物。
測試物質
1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸,稱為OPS-2071:從大塚製藥有限公司(Otsuka Pharmaceutical Co.,Ltd.)合成得到。
實驗例1:測試物質對約束應激(RS)模型中大鼠糞便量的影響
動物:
雄性斯潑累格-多雷(SD)大鼠體重200-250g,購自北京查爾斯河實驗室(Charles River Laboratories Beijing),並飼養在OSRI的SPF級動物設施中的獨立通氣籠(IVC)中,每籠3隻大鼠。所有動物都保持12小時光/暗循環,並自由獲取齧齒動物用食物和水。所有動物研究程序都按照動物福利法規進行,並得到了OSRI機構動物護理和使用委員會(IACUC)批准。
試劑 :
阿拉伯膠(AG)購自Sigma。
測試方法:
SD大鼠按體重隨機分為3組,每組6隻大鼠,如表1所示。每天上午將大鼠(來自第2組和第3組)送到塑料圓筒中進行2小時約束,連續10天(D1至D10)。對照組(第1組)的大鼠在整個實驗中都待在各自的籠中,不受干擾。反復RS模型化3天後,從D4至D10,第2組和第3組的大鼠分別在上午(上午約束前4小時)用媒劑(5%AG)和測試物質(2.5mg/kg)處理,連續7天。糞粒排出量用於估計作為驗證指標的遠端結腸運動(Hong S等人,Gut 2009,58:202-210)。在2小時約束期內,收集大鼠的糞粒排出量並計數,對照組大鼠在相同的2小時模擬觀察期內同樣如此。
結果
每日觀察大鼠行為,所有指標均正常。如圖1和圖2所示,藉由OPS-2071治療,改善了由約束應激引起的體重下降。每天2小時RS模型化持續10天,減緩了在非RS對照大鼠中觀察到的體重增加(第2組對比第1組)。然而,2.5mg/kg OPS-2071治療持續7天有助於在一定程度上緩解這種影響(3第組對比第2組)。
從治療開始後3天(施加RS後6天)開始監測食物攝取。在RS對照組中觀察到OPS-2071治療對食欲下降有保護作用(第3組對比第2組)。
在施加約束應激後觀察排便數量的變化。應激導致RS組的糞粒排出量增加(第2組對比第1組)。在第4天,測試組用2.5mg/kg OPS-2071治療,觀察到糞粒排出量減少(第3組對比第2組),如圖3所示。
實驗例2:評價OPS-2071在約束應激(RS)模型中在內臟敏感性和組織胺水平方面的功效
大鼠RS模型的建立
每天將斯潑累格-多雷大鼠送至塑料圓筒內進行120分鐘約束,連續10天。在對照組中,大鼠在整個實驗中都待在各自的籠中,不受干擾。
第3天和第7天對結直腸擴張的內臟運動反應
結腸擴張:將聚乙烯球囊(長3cm,最大直徑1.5cm)固定到與血壓計連接的管子上以用於進行結腸擴張。將球囊潤滑並放入大鼠的遠端結腸中,使球囊尖端距離肛門近端2cm。使用血壓計擴張裝置,將大鼠約束在塑料容器中並允許在測試前適應10分鐘。大鼠接受結腸階段性擴張(0-100mmHg,以5mmHg增量遞增),直到睾丸、尾部或腹部肌肉組織出現首次收縮。由三名獨立的觀察者進行這項可視化觀察。內臟疼痛閾值指標被定義為如前所述的首次傷害反應(T.J.Ness;G.F.Gebhart,“Colorectal distension as a noxious visceral stimulus:physiologic and pharmacologic characterization of pseudaffective reflexes in the rat”,Brain Research,第450卷,第1-2期,第153-169頁,1998年5月21日;Wesselmann,U.;Lai,J.,“Mechanisums of referred visceral pain:uterine inflammation in the adult virgin rat results in neurogenic plasma extravasation in the skin”,Pain第73卷,第3期,第309-317頁,1997)。考慮到本研究中使用了快速擴張方案,未測量結腸順應性。
以5分鐘刺激間間隔,重複結腸擴張三次,並記錄每一隻大鼠在傷害閾值下的平均壓力。
治療
OPS-2071(2071):在5%AG(阿拉伯膠)中製備,每週一次,阿拉伯膠購自從SIGMA購買的阿拉伯膠樹(CAT號:G9752-500G),治療從第4天至第7天開始,如表2所示。
取樣
第7天的尿液收集:
在約束後每天收集尿樣。將塑料盤至於約束管下方並收集尿樣。將尿樣立即轉移到管內並在-80℃儲存直到進一步分析。用組織胺ELISA試劑盒(CAT號:D751012,BBI),根據製造商的說明書如下測量組織胺。
程序:
1.提前計算出所需的板數,在測試前30分鐘取出試劑盒,使它恢復到室溫。
2.向每一個反應孔加入50μL標準工作液和測試樣品。標準物需要重新鑽孔。立即向每一個反應孔加入50uL生物素標記的組織胺抗體工作液,將板密封,並在37℃孵育45分鐘。
3.洗滌:丟棄液體並將其甩乾。向每一個反應孔中加入350μL洗滌液,浸泡1-2分鐘,將其甩乾並重複4次。
4.向每一個反應孔中加入100μL HRP標記的鏈黴親和素工作液,將板密封並在37℃孵育30分鐘。
5.洗滌:向每一個反應孔中加入300μL洗滌液,並以30秒間隔乾燥該液體。重複4次。
6.向每一個反應孔中加入90μL顯色劑(避光劑),板密封後在37℃避光顯色15分鐘。
7.向每一個反應孔中加入50μL終止溶液,立即用酶標儀在450nmm長下測量OD值(在5分鐘內)。
8.利用酶標儀在450nm波長下測量OD值。
9.以標準物質的濃度為橫坐標,以吸光度為縱坐標,繪製標準曲線。
10.藉由雙尾T-檢驗(第3天的內臟敏感性)或使用Dunnett’s多比較單因素方差分析ANAOV計算統計學顯著性。P<0.05視為統計學顯著。
結果:
圖4至圖5示出了結直腸擴張的內臟運動反應(mmHg),其中圖4示出了第3天,即化合物治療前一天記錄的對照組和RS組之間的內臟運動反應;圖5示出了第7天的內臟運動反應。
如圖4所示,第3天,RS組大鼠的內臟敏感性與對照組相比有所增加(內臟敏感性水平顯示出顯著差異(p<0.01)-對照組對比RS組)。
如圖5所示,在第7天觀察到接受2.5mg/kg OPS-2071的治療組的內臟敏感性下降(即,給與OPS-2071後4天;內臟敏感性水平顯示出顯著差異(p<0.05)-2.5mg/kg組對比RS組)。
圖6示出了藉由ELISA定量的尿液中的組織胺水平,示出了第7天,即OPS-2071化合物治療後4天尿液中的尿液組織胺水平。
如圖6所示,第7天,RS組大鼠的尿液組織胺水平高於對照組,而在2.5mg/kg化合物治療組中觀察的尿液組織胺水平降低(在對照組和RS組之間的尿液組織胺水平示出了高的顯著差異(p<0.01);在2.5mg/kg組和RS組之間的尿液組織胺水平示出了高的顯著的差異(p<0.01))。
Claims (11)
- 一種用於治療和/或預防腸易激綜合症(IBS)的藥物,該藥物包含1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物作為活性成分。
- 如請求項1所述的藥物,其中該代謝物是(2S,3S,4S,5R,6R)-6-((7-胺基-5-氰基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羰基)側氧)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸、7-(6-胺基-5-胺基甲醯基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羧酸或7-(6-胺基-5-氰基吡啶-3-基)-1-環丙基-6-氟-8-甲基-4-側氧-1,4-二氫喹啉-3-羧酸乙酯。
- 如請求項1或2所述的藥物,其中該藥物用於口服施用。
- 如請求項1至3中任一項所述的藥物,其中該活性成分的日劑量是7.5mg至24000mg。
- 如請求項1至4中任一項所述的藥物,其中IBS是IBS-D。
- 一種治療和/或預防IBS的方法,該方法包括將治療有效量的1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物作為活性成分施用於有需要的患者。
- 如請求項6所述的方法,其中IBS是IBS-D。
- 一種1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物在製造用於治療和/或預防IBS的藥物中的用途。
- 如請求項8所述的用途,其中IBS是IBS-D。
- 一種1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物,用於治療和/或預防IBS。
- 如請求項10所述的1-環丙基-6-氟-1,4-二氫-8-甲基-7-(2-胺基-3-氰基-5-吡啶基)-4-側氧-3-喹啉-羧酸或其藥學上可接受的鹽、前體或代謝物、水合物、溶劑化物或氘化物,其中IBS是IBS-D。
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JP2023012557A (ja) * | 2020-02-10 | 2023-01-26 | 大塚製薬株式会社 | 新規肝性脳症治療剤 |
JP2023012559A (ja) * | 2020-02-10 | 2023-01-26 | 大塚製薬株式会社 | 新規炎症性疾患治療剤 |
JP2023012558A (ja) * | 2020-02-10 | 2023-01-26 | 大塚製薬株式会社 | 腸内細菌叢構成比率調整剤 |
-
2023
- 2023-07-11 TW TW112125862A patent/TW202402287A/zh unknown
- 2023-07-11 WO PCT/CN2023/106675 patent/WO2024012421A1/en unknown
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WO2024012421A1 (en) | 2024-01-18 |
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