TW202227421A - Glp-1r促效劑的晶型及其用途 - Google Patents
Glp-1r促效劑的晶型及其用途 Download PDFInfo
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Abstract
Description
本申請要求2020年10月14日申請之第PCT/CN2020/120814號國際專利申請的優先權益。前述申請的全部內容以引用的方式併入本文中。
GLP-1係一種由腸內L細胞在攝入食物後分泌之30個胺基酸長度之腸促胰素激素。GLP-1已被證明以生理及葡萄糖依賴性方式刺激胰島素分泌、降低升糖素分泌、抑制胃排空、降低食欲及刺激β細胞之增殖。在非臨床實驗中,GLP-1藉由刺激對葡萄糖依賴性胰島素分泌重要之基因轉錄及促進β細胞新生以促進持續之β細胞能力(Meier等人,Biodrugs.17(2):93-102,2013)。
在健康的個體中,GLP-1藉由刺激胰臟之葡萄糖依賴性胰島素分泌,從而使周邊葡萄糖吸收增加而在調節餐後血糖含量方面發揮重要作用。GLP-1復抑制升糖素分泌,導致肝臟葡萄糖的排出量減少。此外,GLP-1延遲胃排空並減慢小腸蠕動而延遲食物吸收。在患有T2DM的人
中,GLP-1餐後上升係不存在或降低(Vilsboll等人,Diabetes.50:609-613,2001)。
Hoist(Physiol.Rev.87:1409,2007)及Meier(Nat.Rev.Endocrinol.8:728,2012)描述GLP-1受體促效劑,如GLP-1、利拉鲁肽(liraglutide)及exendin-4,有3個主要的藥理活性,藉由降低空腹及餐後葡萄糖(FPG及PPG)來改善T2DM患者的血糖控制:(i)增加葡萄糖依賴性胰島素分泌(經改善之第一及第二階段),(ii)在高血糖條件下之升糖素抑制活性,(iii)延遲胃排空率引起的膳食衍生葡萄糖之吸收延遲。
國際專利申請第PCT/CN2020/084203號(其全部內容以引用的方式併入本文中做為參考資料)揭露高效的GLP-1促效劑,該案所揭露之其中一種促效劑(本文內稱“化合物A”)之結構如下所示:
化合物A之化學名稱為(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯並[d]咪唑-6-羧酸。
藥物活性劑(例如化合物A)的成功開發通常需要鑑定一種固體形式,該固體形式具有在合成後易於分離和純化的特性,適用於大規模生產,可以長時間儲存且具備最低限度的水分吸收、分解或轉化成其他固體形式,其適合於配製並且在施用於受試者後可以容易地吸收(例如,可溶於水和胃液)。
現已發現化合物A游離酸的三種新晶型能在良好制定的條件下獲得,以提供所需晶型(參見實施例2和5-7)。這四種形式皆具有高熔點。其中,化合物A游離酸的晶型I有輕微吸濕性,在60℃/封蓋與40℃/75%RH(開蓋)下具備12天的物理與化學穩定性。
於一態樣中,本揭露提供化合物A游離酸之晶型I。
於另一態樣中,本揭露提供化合物A游離酸之晶型II。
於另一態樣中,本揭露提供化合物A游離酸之晶型III。
於另一態樣中,本揭露提供化合物A游離酸之晶型IV。
於另一態樣中,本揭露提供包含化合物A游離酸之晶型I(或化合物A游離酸之晶型II或化合物A游離酸之晶型III)的藥物組合物及其藥學上可接受之載劑。
本揭露提供一種治療心臟代謝和相關疾病的方法,將本文所述之結晶型(I、II、III或IV型)或相應的藥物組合物以一治療有效量施用於需要此治療的受試者。
本揭露亦提供所揭露結晶型(I、II、III或IV型)或包含其之藥物組合物於上述任何方法中的用途。於一實施態樣中,所提供為結晶型(I、II、III或IV型)或包含其之藥物組合物於本文所述任何方法中的用途。於另一實施態樣中,所提供為結晶型(I、II、III或IV型)或包含其之藥物組合物於本文所述任何方法中的製藥用途。
本揭露亦提供製備化合物A及其結晶型(I、II、III或IV型)的方法。
應理解,本揭露之任一實施態樣,包括僅描述於實例或請求項中,或僅於說明書一段落中出現之實施態樣,皆能與本揭露之一或多個附加實施態樣組合,此組合所延伸之範圍不被予以否定或視為不妥。
圖1展示化合物A游離酸之晶型I的X射線粉末繞射(XRPD)圖。
圖2展示化合物A游離酸之晶型I的熱重分析(TGA)熱分析圖和差示掃描量熱分析(DSC)熱分析圖。
圖3展示化合物A游離酸之晶型I的動態蒸汽吸附(DVS)結果。
圖4展示化合物A游離酸之晶型II的X射線粉末繞射(XRPD)圖。
圖5展示化合物A游離酸之晶型II的熱重分析(TGA)熱譜圖和差示掃描量熱分析(DSC)熱譜圖。
圖6展示化合物A游離酸之晶型III的X射線粉末繞射(XRPD)圖。
圖7展示化合物A游離酸之晶型III的熱重分析(TGA)熱譜圖和差示掃描量熱分析(DSC)熱譜圖。
圖8展示化合物A游離酸之晶型IV的X射線粉末繞射(XRPD)圖。
圖9展示化合物A游離酸之晶型IV的差示掃描量熱分析(DSC)熱譜圖。
圖10展示化合物A游離酸之晶型IV的熱重分析(TGA)熱譜圖。
本揭露關於化合物A游離酸的新穎結晶型態。
「水合物型式」意旨化合物A游離酸之結晶型式,其中水與化合物A游離酸以化學計量比(例如,化合物A:水的莫耳比為1:1、1:1.5或1:2)作為固體或晶體的組成部分。
「非水合物型式」意旨結晶型中水與化合物A游離酸間不具有化學計量比,且水大致上(如藉由卡爾費修分析(Karl Fischer analysis)測定小於10%重量比例)不以固體形式存在。本發明揭露之新固體型態包括水合物與非水合物形式。
如本文所用,術語「結晶型」意旨具有結晶結構之固體,其中的個別分子具有高度均勻的規則三維構型。
本揭露的化合物A游離酸之晶型能為單結晶型或由不同單結晶型所組成之混合物。單結晶型指該化合物A游離酸為一單結晶或為個別具有相同晶型的結晶所組成的多結晶。
如本文所述化合物A游離酸之晶型,其至少具有一定重量百分比的化合物A游離酸為單結晶型,具體重量百分比包括85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、
99%、99.5%、99.9%,或基於化合物A游離酸重量之重量百分比70%至75%、75%至80%、80%至85%、85%至90%、90%至95%、95%至100%、70%至80%、80%至90%、90%至100%為單結晶型。應理解,這些值和範圍之間的所有值和範圍均意涵蓋於本揭露。
當結晶化合物A游離酸以一指定百分比定義為化合物A游離酸之特定晶型時,其餘部分則由非晶型及/或不同於所指定的一種或多種特定晶型所組成。單結晶型的實例包括由本文所述一或多種性質所定性的化合物A游離酸之I型、化合物A游離酸之II型、化合物A游離酸之III型及化合物A游離酸之IV型。
化合物A具有手性中心。本文所述化合物A游離酸之結晶型相比於其他立體異構物具有至少80%、90%、99%、或99.9%重量純度比(即該立體異構物之重量除以所有立體異構物重量之比例)。
定性化合物A游離酸之結晶I型
於一實施態樣中,1:1化合物A游離酸為單結晶型I型,其由X射線粉末繞射圖譜定性為包含2θ=11.4°、12.7°、18.1°、及18.3°±0.2的特徵峰。於另一實施態樣中,I型由X射線粉末繞射圖譜定性為進一步包含一或多個2θ=4.9°、11.8°、及21.5°±0.2的特徵峰。然於另一實施態樣中,I型由X射線粉末繞射圖譜定性為進一步包含一或多個2θ=15.8°、18.8°、及23.0°±0.2的特徵峰。然於另一實施態樣中,I型由X射線粉末繞射圖譜定性為包含2θ=4.9°、11.4°、11.8°、12.7°、15.8°、18.1°、18.3°、18.8°、21.5°、及23.0°±0.2的特徵峰。然於另一實施態樣中,I型由X射線粉末繞射圖譜定性為大致上與圖1相似。
於另一實施態樣中,化合物A游離酸I型由差示掃描量熱分析(DSC)峰值的相轉變溫度定性為200±3℃(如199.7℃)。
定性化合物A游離酸之結晶II型
於一實施態樣中,1:1化合物A游離酸為單結晶型II型,其由X射線粉末繞射圖譜定性為包含2θ=11.4°、12.0°、12.9°、18.6°、及20.4°±0.2的特徵峰。於另一實施態樣中,II型由X射線粉末繞射圖譜定性為進一步包含2θ=25.9°±0.2的特徵峰。於另一實施態樣中,II型由X射線粉末繞射圖譜定性為進一步包含一或多個2θ=4.9°、7.7°、15.8°、及25.9°±0.2的特徵峰。然於另一實施態樣中,II型由X射線粉末繞射圖譜定性為包含2θ=4.9°、7.7°、11.4°、12.0°、12.9°、15.8°、18.6°、20.4°、及25.9°±0.2的特徵峰。於另一實施態樣中,II型由X射線粉末繞射圖譜定性為不包含2θ=18.1°±0.2的特徵峰。於另一實施態樣中,II型由X射線粉末繞射圖譜定性為不包含2θ=21.5°±0.2的特徵峰。然於另一實施態樣中,II型由X射線粉末繞射圖譜定性為大致上與圖4相似。
於另一實施態樣中,化合物A游離酸II型由差示掃描量熱分析(DSC)峰值的相轉變溫度定性為205±3℃(如204.6℃)。
定性化合物A游離酸之結晶III型
於一實施態樣中,1:1化合物A游離酸為單結晶型III型,其由X射線粉末繞射圖譜定性為包含2θ=9.8°、13.3°、17.3°、及18.1°±0.2的特徵峰。於另一實施態樣中,III型由X射線粉末繞射圖譜定性為進一步包含2θ=11.7°、14.2°、24.7°、26.3°、及27.7°±0.2的特徵峰。然於另一實施態樣中,III型由X射線粉末繞射圖譜定性為包含2θ=9.8°、
11.7°、13.3°、14.2°、17.3°、18.1°、24.7°、26.3°、及27.7°±0.2的特徵峰。然於另一實施態樣中,III型為水合物,其化合物A與水之比例為介於1:1及1:2之間(如1:1.5)。然於另一實施態樣中,III型由X射線粉末繞射圖譜定性為大致上與圖6相似。
於另一實施態樣中,化合物A游離酸III型由差示掃描量熱分析(DSC)峰值的相轉變溫度定性為204±3℃(如204.4℃)。
定性化合物A游離酸之結晶IV型
於一實施態樣中,1:1化合物A游離酸為單結晶型IV型,其由X射線粉末繞射圖譜定性為包含2θ=10.8°、11.8°、13.2°、17.8°、18.6°、及19.7°±0.2的特徵峰。於另一實施態樣中,IV型由X射線粉末繞射圖譜定性為進一步包含一或多個2θ=10.8°、11.8°、13.2°、17.8°、18.6°、19.7°、22.9°、及26.6°±0.2的特徵峰。然於另一實施態樣中,IV型由X射線粉末繞射圖譜定性為包含2θ=10.8°、11.8°、13.2°、17.8°、18.6°、19.7°、22.9°、26.6°、28.2°、及28.4°±0.2的特徵峰。然於另一實施態樣中,IV型為水合物。然於另一實施態樣中,IV型由X射線粉末繞射圖譜定性為大致上與圖8相似。
於另一實施態樣中,化合物A游離酸IV型由差示掃描量熱分析(DSC)峰值的相轉變溫度定性為196±3℃(如196.8℃)。
為晶體學領域中習知,對於任何給定的晶型,其角峰位置可能會因溫度變化、樣品位移、及是否存在內標等因素而略有變化。於本揭露中,角峰位置的變化在2θ中為±0.2。此外,給定晶型的相對峰強度可能
因XRPD分析樣品製備中微晶尺寸和非隨機微晶取向的差異而變化。於領域中周知,此可變性將解釋上述因素,而不會妨礙對晶型的明確鑑定。
藥物組合物
於另一實施態樣中,本揭露為藥物組合物。此藥物組合物包含本文所述化合物A游離酸之結晶型及其藥學上可接受的載劑,並亦能包含其他藥理活性物質。
如本文所用,術語「藥學上可接受的載劑」包括包括生理相容的任何及所有溶劑、分散介質、塗層、抗菌劑和抗真菌劑、等滲劑和吸收延遲劑等。藥學上可接受的載劑之實例包括水、鹽水、磷酸鹽緩衝鹽水、葡萄糖、甘油、乙醇中的一或多種及其組合,且於組合物中能包括等滲劑,如糖、氯化鈉或多元醇(如甘露醇或山梨醇)。藥學上可接受的物質,如潤濕劑或少量輔助物質(如潤濕劑或乳化劑、防腐劑或緩衝劑),能提高抗體或抗體部分的保存期限或有效性。
本揭露之組合物能為多種形式,包括如液體、半固體及固體劑型,例如液體溶液(如可注射或可輸注溶液)、分散劑或懸浮劑、片劑、丸劑、粉劑、脂質體和栓劑。劑型視給藥的傾向模式與治療的應用而定。
典型的組合物為可注射或可輸注溶液的形式,如與通常用於人類被動免疫中佐以抗體的組合物所類似的組合物。給藥模式之一種為腸胃外(如靜脈內、皮下、腹膜內、肌肉內)。於另一實施態樣中,該抗體係藉由靜脈輸注或注射給藥。然於另一實施態樣中,該抗體係通過肌內或皮下注射給藥。
固體劑型的口服給藥能例如存在於離散單元中,例如硬膠囊或軟膠囊、丸劑、扁囊劑、錠劑或片劑,每個單元含有預定量的至少一種本揭露之化合物。於另一實施態樣中,口服給藥能是粉末或顆粒形式。於另一實施態樣中,口服劑型為舌下給藥,如錠劑。於固體劑型中,上述任一形式的化合物通常與一或多種佐劑組合。如膠囊或片劑能含有控釋製劑。在膠囊、片劑和丸劑的情況下,劑型亦能包含緩衝劑或能製備有腸溶衣。
於另一實施態樣中,口服給藥能是液體劑型。口服液體劑型包括如藥學上可接受的乳化劑、溶液、懸浮液、糖漿和含有本領域常用之惰性稀釋劑(如水)的酏劑。此類組合物亦能包含佐劑,例如潤濕劑、乳化劑、懸浮劑、調味劑(例如甜味劑)及/或加香劑。
於另一實施態樣中,本揭露包含腸胃外給藥劑型。
「腸胃外給藥」包括如皮下注射、靜脈注射、腹腔注射、肌肉注射、胸骨內註射和輸液。可注射製劑(即無菌可注射水性或油性懸浮液)能根據已知技術使用合適的分散劑、潤濕劑及/或懸浮劑配製。
於另一實施態樣中,本揭露包含外用劑型。
「外用給藥」包括如經皮給藥(如通過經皮貼劑或離子電滲裝置)、眼內給藥、或鼻內或吸入給藥。用於外用給藥的組合物亦包括如外用凝膠劑、噴霧劑、軟膏劑和乳膏劑。外用製劑能包括增強活性成分通過皮膚或其他受影響區域的吸收或滲透的化合物。當本揭露之化合物通過經皮裝置給藥時,將使用貯水和多孔膜類型或固體基質種類的貼劑完成給藥。典型的配方包括凝膠、水凝膠、洗劑、溶液、霜劑、軟膏、粉劑、敷料、泡沫、薄膜、皮膚貼劑、晶片、植入物、海綿、纖維、繃帶和微乳液,亦能使
用脂質體。典型的載劑包括酒精、水、礦物油、液體礦脂、白礦脂、甘油、聚乙二醇和丙二醇,亦能結合滲透促進劑於其中--參見,例如,芬寧和摩根,藥物科學雜誌。科學,88:955-958,1999。(Finnin and Morgan,J.Pharm.Sci.,88:955-958,1999.)
適用於眼部的外用給藥配方包含如滴眼劑,其中本揭露之化合物溶解或懸浮於合適的載劑中。適用於眼部或耳部給藥的典型配方能為微粉化懸浮液或等滲、pH調節的無菌鹽水中的溶液之滴劑形式。適用於眼部和耳部給藥的其他配方包括軟膏、可生物降解的(即可吸收凝膠海綿、膠原蛋白)和不可生物降解的(即矽樹脂)植入物、晶片、晶狀體及微粒或囊泡系統,例如類脂質體或脂質體。聚合物如交聯聚丙烯酸、聚乙烯醇、透明質酸、纖維素聚合物(如羥丙基甲基纖維素、羥乙基纖維素或甲基纖維素)、或雜多醣聚合物(如結冷膠)能與防腐劑(如苯扎氯銨)結合。此類配方亦能通過離子電滲療法遞送。
對於鼻內給藥或通過吸入給藥,本揭露之化合物以溶液或懸浮液形式從患者擠壓或泵送的泵噴霧容器中方便地遞送,或者自加壓容器或霧化器中使用適合的推進劑作為氣霧劑噴霧呈現。適用於鼻內給藥的配方通常以乾粉形式給藥(單獨作為混合物(如與乳糖乾混)或作為混合組分顆粒(如與磷脂(如磷脂醯膽鹼)混合))自乾粉吸入器或作為來自加壓容器、泵、噴霧器、霧化器(較佳為使用電流體動力學產生細霧的霧化器)或霧化器的氣溶膠噴霧,其中包含或不包含適合推進劑(如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷)的使用。對於鼻內使用,該粉末能包含生物黏附劑,如殼聚醣或環糊精。
於另一實施態樣中,本揭露包含直腸劑型。此類直腸劑型能例如為栓劑。可可脂為一種傳統的栓劑基質,但能酌情使用各種替代品。
其他製藥領域中習知的載劑材料及給藥模式亦能使用。本揭露之藥物組合物能藉由任何藥劑學中所周知的技術製備,如有效的配方與給藥的程序。
上述關於有效配方和給藥程序的考量為本領域所周知且描述於標準教科書中。藥物配方見於例如胡佛,約翰E.,雷明頓製藥科學,麥克出版公司.,賓夕法尼亞州伊斯頓,1975中;利伯曼等人.,編輯.,藥物劑型,馬塞爾.德克爾,紐約,N.Y.,1980;和Kibbe等人,編輯,藥用輔料手冊(第3版),美國製藥協會,華盛頓,1999年。(Hoover,John E.,Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pa.,1975;Liberman et al.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980;and Kibbe et al.,Eds.,Handbook of Pharmaceutical Excipients(3rd Ed.),American Pharmaceutical Association,Washington,1999.)
治療方法
「受試者」為哺乳動物,較佳為人類,但亦能為需要獸醫治療的動物,例如伴生動物(例如狗、貓等)、農場動物(例如牛、羊、豬)、馬等)和實驗室動物(例如大鼠、小鼠、豚鼠等)。
以有效量的本揭露之化合物對受試者的「治療」方案能包括單次給藥、或可選地包含一系列應用。治療期的長短取決於多種因素,例如疾病的嚴重程度、受試者的年齡、本揭露之化合物的濃度和活性,或上
述之組合。應理解,用於治療或預防之化合物的有效劑量能在特定治療或預防方案的過程中增加或減少。藉由本領域習知的標準診斷測定能顯見劑量的變化。在某些情況下,可能需要長期給藥。
於一態樣中,本揭露提供如本文所述化合物A游離酸之結晶型,用以預防及/或治療如本文討論的心臟代謝和相關疾病,包括T2DM、糖尿病前期、NASH和心血管疾病。
於另一態樣中,本揭露提供一種於需此預防及/或治療的受試者中以GLP-1R促效劑治療疾病或病症的方法,包含給藥予該受試者一治療有效量的如本文所述化合物A游離酸之結晶型。
於另一態樣中,本揭露提供如本文所述化合物A游離酸之結晶型於以GLP-1R促效劑治療疾病或病症的藥物製造用途。
於另一態樣中,本揭露提供如本文所述化合物A游離酸之結晶型於以GLP-1R促效劑治療疾病或病症的用途。
於另一態樣中,本揭露提供一種以GLP-1R促效劑治療疾病或病症的藥物組合物,其包含本文所述化合物A游離酸之結晶型。
本揭露亦提供一種包含本文所述化合物A游離酸之晶型的藥物組合物於治療及/或預防本文所述心臟代謝和相關疾病,包括T2DM、糖尿病前期、NASH和心血管疾病的用途。
於另一態樣中,本發明提供本文所述化合物A游離酸之結晶型於治療及/或預防心臟代謝和相關疾病的用途,該疾病包括糖尿病(T1D及/或T2DM,包括糖尿病前期)、特發性T1D(1b型)、成人潛伏性自身免疫性糖尿病(LADA)、早發性T2DM(EOD)、青年期非典型糖尿病(YOAD)、
成熟期糖尿病(MODY)、營養不良相關的糖尿病、妊娠期糖尿病、高血糖、胰島素抵抗、肝胰島素抵抗、糖耐量受損、糖尿病神經病變、糖尿病腎病、腎臟疾病(如急性腎病、腎小管功能障礙、近端小管)、糖尿病視網膜病變、脂肪細胞功能障礙、內臟脂肪沉積、睡眠呼吸暫停、肥胖(包括下丘腦肥胖和單基因肥胖)和相關合併症(如骨關節炎和尿失禁)、飲食失調(包括暴食綜合徵、神經性貪食症和綜合徵性肥胖,如Prader-Willi和Bardet-Biedl綜合徵),使用其他藥物(如使用類固醇和抗精神病藥)導致體重增加,糖分過多血脂異常(包括高脂血症、高甘油三酯血症、總膽固醇升高、高低密度脂蛋白膽固醇和低高密度脂蛋白膽固醇)、高胰島素血症、NAFLD(包括脂肪變性、NASH、纖維化、肝硬化和肝細胞癌等相關疾病)、心血管疾病、動脈粥樣硬化(包括冠狀動脈疾病)、外周血管疾病、高血壓、內皮功能障礙、血管順應性受損、充血性心力衰竭、心肌梗塞(如壞死和凋亡)、中風、出血性中風、缺血性中風、外傷性腦損傷、肺動脈高壓、血管成形術後再狹窄、間歇性跛行、餐後脂血症、代謝性酸中毒、酮症、關節炎、骨質疏鬆症、帕金森病、左心室肥厚、外周動脈疾病、黃斑變性、白內障、腎小球硬化、慢性腎功能衰竭、代謝綜合徵、X綜合徵、經前期綜合徵、心絞痛、血栓形成、動脈粥樣硬化、短暫性腦缺血發作、血管再狹窄、葡萄糖代謝受損、空腹血糖受損、高尿酸血症、痛風、勃起功能障礙、皮膚和結締組織疾病、銀屑病、足部潰瘍、潰瘍性結腸炎、高載脂蛋白B脂蛋白血症、阿爾茨海默病、精神分裂症、認知障礙、炎症性腸病、短腸綜合徵、克羅恩病、結腸炎、腸易激綜合徵、預防或多囊卵巢綜合徵的治療我和成癮的治療(如酒精及/或藥物濫用)。
於某些實施態樣中,該疾病或病症為肥胖、飲食失調、使用其他藥物導致體重增加、過度渴望糖分和血脂異常。
於某些實施態樣中,該疾病或病症為肥胖。
於某些實施態樣中,該疾病或病症為糖尿病前期。
於某些實施態樣中,該疾病或病症為T2DM。
於某些實施態樣中,該疾病或病症為NASH。
於某些實施態樣中,該疾病或病症為NAFLD。
於某些實施態樣中,該疾病或病症為心臟代謝疾病,如高血壓。
於另一態樣中,本揭露提供一種增強或刺激GLP-1R介導cAMP信號傳導的方法,其中β-抑制蛋白/抑制蛋白-2的募集較少。該方法包括以上述任何式(如式I、II-A、III-A、及IV-A)之化合物、或其溶劑化物或水合物進行給藥。此係部分基於本揭露之令人驚訝的發現,即與天然GLP-1R配體GLP-1相比,本揭露之化合物雖為GLP-1R介導cAMP訊號的完全促效劑,但也是β-抑制蛋白募集活化GLP-1R的部分促效劑,因本揭露之化合物對活化GLP-1R所需的最大β-抑制蛋白募集低於GLP-1的最大β-抑制蛋白募集。此類用於cAMP信號傳導的GLP-1R部分及/或偏向促效劑能提供更持續的cAMP信號傳導活性,從而獲得更好的功效和較低的副作用。
因此,本揭露之方法能有利地用於治療本文所述的任何疾病或病症,例如II型糖尿病(T2D)和相關疾病。
於某些實施態樣中,該治療引起血糖益處而不伴隨胃腸副作用如噁心、嘔吐或腹瀉的增加或至少減少其增加。於某些實施態樣中,與具有正常或增強的β-抑制蛋白募集(如GLP-1的β-抑制蛋白募集)的對照治療相比,該治療具有更大的耐受性。
給藥與劑量
本揭露之化合物通常以有效治療本文所述病症的量給藥。
本揭露之化合物係經任何合適的途徑以適於此類途徑的藥物組合物形式給藥,且以對預期治療有效的劑量施用。本揭露之化合物能以口服、直腸、陰道、腸胃外或外用給藥。
本揭露之化合物能經口服給藥。口服給藥能包括吞嚥,從而使化合物進入胃腸道,或能採用口腔或舌下給藥,從而使化合物直接從口腔進入血流中。
於另一實施態樣中,本揭露之化合物亦能直接給藥至血流、肌肉、或內臟中。腸胃外給藥的合適方式包括靜脈內、動脈內、腹膜內、鞘內、心室內、尿道內、胸骨內、顱內、肌肉內和皮下。適用於腸胃外給藥的裝置包括針(包括微針)注射器、無針注射器和輸液技術。
於另一實施態樣中,本揭露之化合物亦能經外用給藥至皮膚或黏膜,即經皮給藥。於另一實施態樣中,本揭露之化合物亦能經鼻內或吸入給藥。於另一實施態樣中,本揭露之化合物能經直腸或陰道給藥。於另一實施態樣中,本揭露之化合物亦能直接給藥至眼或耳。
本揭露之化合物及/或包含所述化合物之組合物的劑量方案係基於多項因素考量,包括病人的類型、年齡、體重、性別和醫療狀況;
病情的嚴重程度;給藥途徑;以及所用特定化合物的活性。因此,劑量方案能有很大的變化。於一實施態樣中,本揭露之化合物的總日劑量通常為約0.001至約100mg/kg(即本揭露之化合物mg/kg體重)以治療本文所述的指定病症。於另一實施態樣中,本揭露之化合物的總日劑量為約0.01至約30mg/kg,且於另一個實施態樣中,約0.03至約10mg/kg,且於另一個實施態樣中,約0.1至約3mg/kg。本揭露之化合物於一天內重複多次的給藥(通常不超過4次)並不少見。通常視需要能以每日多劑量增加總日劑量。於某些實施態樣中,該患者為人類,如患有本文別處所描述可治療疾病適應症或病症之一的人。
對於口服給藥,該組成物能以包含0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、30.0、50.0、75.0、100、125、150、175、200、250及500毫克對症調整的有效成分以片劑形式對該患者給藥。通常藥劑含有約0.01mg至約500mg的有效成分,或於另一實施態樣中,約1mg至約100mg的有效成分。於靜脈注射時,恆定速率輸液的劑量範圍能自約0.01至約10mg/kg/分鐘。
根據本揭露之合適的受試者或患者包括哺乳動物受試者,包括人類或非人類哺乳動物,例如靈長類動物、囓齒動物(小鼠、大鼠、倉鼠、兔子等)。於一實施態樣中,人類為合適的受試者。人類受試者能為任何性別並且處於任何發展階段。於某些實施態樣中,該人類是小於18歲、15歲或14歲左右、12歲、10歲或小於5歲的兒童。
共同給藥
本揭露之化合物能單獨、或與其他治療藥物組合使用。本揭露提供本文定義之任何用途、方法或組合物,其中上述任一實施態樣或任一式之化合物或該化合物藥學上可接受的溶劑化物與本文討論之一或多個其他治療藥物組合使用。
兩種或更多種化合物之「組合」的給藥意旨所有化合物在足夠接近的時間內施用,使每種化合物能在相同的時間範圍內產生生物學效應。一種藥劑的存在可能會改變其他化合物的生物學效應。兩種或更多種化合物可以同時或順序給藥。此外,同時給藥能通過在給藥前混合化合物或通過在相同時間點但在相同或不同的部位給藥化合物作為分開的劑型來實施。
術語「同時給藥」及「共同給藥」意旨該化合物以組合的方式給藥。
於另一實施態樣中,本揭露提供包括以本揭露之化合物與一或多種其他藥物組合給藥的治療方法,其中該一或多種其他藥物能選自本文討論之藥物。
於一實施態樣中,本揭露之化合物係與抗糖尿病劑,包括但不限於雙胍(例如二甲雙胍)、磺醯脲類(例如甲苯磺丁脲、格列本脲、格列齊特、氯丙醯胺、妥拉唑胺、乙醯己胺、格列吡嗪、格列美脲或格列吡嗪)、噻唑烷二酮(例如吡格列酮)或洛格列酮)、格列扎(例如沙格列汀、阿格列扎、莫拉格列扎或特格列扎)、格列奈(例如那格列奈、瑞格列奈)、二肽基肽酶4(DPP-4)抑制劑(例如,西格列汀、維格列汀、沙格列汀、利格列汀、格列汀、阿格列汀、替格列汀、阿格列汀、曲格列汀、度格列汀或奧格列汀)、
格列酮(例如,吡格列酮、羅格列酮、巴拉格列酮、利沃格列酮或洛格列酮)、鈉-葡萄糖連接的轉運蛋白2抑制劑(如恩格列淨、卡納格列淨、達格列淨、伊格列淨、托格列淨、舍格列淨、依碳酸鹽(etabonate)、依碳酸瑞格列淨(remogliflozin etabonate)、或埃格列淨)、SGLTL1抑制劑、GPR40促效劑(FFAR1/FFA1促效劑(如法斯利方(fasiglifam)))、葡萄糖依賴性促胰島素肽(GIP)及其類似物、α葡萄糖苷酶抑制劑(例如伏格列波糖、阿卡波糖或米格列醇),或胰島素或胰島素類似物,包括具體命名的藥劑和藥學上可接受的所述藥劑的鹽及該藥劑及鹽之藥學上可接受的溶劑化物。
於另一實施態樣中,本揭露之化合物係與抗肥胖劑一起給藥,包括但不限於肽YY或其類似物、神經肽Y受體2(NPYR2)促效劑、NPYR1或NPYR5拮抗劑、大麻素受體1(CB1R)拮抗劑、脂肪酶抑製劑(如奧利司他)、人胰島肽(HIP)、黑皮質素受體4促效劑(如塞美拉肽)、黑色素濃縮激素受體1拮抗劑、法尼醇X受體(FXR)促效劑(如奧貝膽酸)、唑尼沙胺、芬特明(單獨或與托吡酯組合)、去甲腎上腺素/多巴胺再攝取抑制劑(如安非他酮)、阿片受體拮抗劑(如納曲酮)、去甲腎上腺素/多巴胺再攝取抑制劑和阿片受體拮抗劑的組合(如安非他酮和納曲酮的組合)、GDF-15類似物、西布曲明、縮膽囊素促效劑、胰淀素及其類似物(如普蘭林肽)、瘦素及其類似物(如甲氨蝶呤)、5-羥色胺能藥物(如氯卡色林),甲硫氨酸氨肽酶2(MetAP2)抑制劑(如,貝洛拉尼布或ZGN-1061)、苯地美曲嗪、二乙基丙酸、苯苯丙胺、SGLT2抑制劑(如恩格列淨、卡納格列淨、達格列淨、伊格列淨、伊格列淨(Ipragliflozin)、托格列淨、依碳酸沙格列淨(remogliflozin)、依碳酸瑞格列淨(etabonate)或依格列淨(ertugliflozin))、SGLTL1抑製劑、
SGLT2/SGLT1雙重抑製劑、成纖維細胞生長因子受體(FGFR)調節劑、AMP活化蛋白激酶(AMPK)活化劑、生物素、MAS受體調節劑或胰高血糖素受體促效劑(單獨或與另一GLP-1R促效劑組合,例如利拉魯肽、艾塞那肽、度拉魯肽、阿必魯肽、利西拉來或司美魯肽),包括具體命名的藥劑和藥學上可接受的所述藥劑的鹽及該藥劑及鹽之藥學上可接受的溶劑化物。
於另一實施態樣中,本揭露之化合物係與藥劑一同治療NASH,包括但不限於PF-05221304、FXR促效劑(如奧貝膽酸)、PPAR α/δ促效劑(如依拉非坦(elafibranor))、合成脂肪酸-膽汁酸偶聯物(如阿拉克爾(aramchol))、半胱天冬酶抑制劑(如恩利卡生(emricasan))、抗賴氨醯氧化酶同源物2(LOXL2)單克隆抗體(如辛圖珠單抗)、半乳糖凝集素3抑制劑(如GR-MD-02)、MAPK5抑制劑(如GS-4997)、趨化因子受體2的雙重拮抗劑(CCR2)和CCR5(如,森尼維若)、成纖維細胞生長因子21(FGF21)激動劑(如BMS-986036)、白三烯D4(LTD4)受體拮抗劑(例如替普魯司特)、菸酸類似物(如ARI 3037MO)、ASBT抑制劑(例如,沃利巴特(volixibat))、乙醯輔酶A羧化酶(ACC)抑制劑(例如NDI 010976)、酮己糖激酶(KHK)抑制劑、二醯基甘油醯基轉移酶2(DGAT2)抑制劑、CB1受體拮抗劑、抗CB1R抗體,或細胞凋亡信號調節激酶1(ASK1)抑制劑,包括具體命名的藥劑和藥學上可接受的所述藥劑的鹽及該藥劑及鹽之藥學上可接受的溶劑化物。
本揭露之此些藥劑及化合物能與藥學上可接受之載體結合,如生理食鹽水、林格氏液、葡萄糖溶液等及其類似物。具體的給藥方案(即劑量、時間和重複次數),將取決於特定個體和該個體的病史。
可接受的載劑、賦形劑、或穩定劑為其所用劑量與濃度對接受者為無害的。該劑亦能包含緩衝劑,如磷酸鹽、檸檬酸鹽和其他有機酸;鹽類,如氯化鈉;抗氧化劑,包括抗壞血酸和蛋氨酸;防腐劑(如十八烷基二甲基芐基氯化銨;六甲銨氯化物;苯扎氯銨、芐索氯銨;苯酚、丁醇或苯甲醇;對羥基苯甲酸烷基酯,如對羥基苯甲酸甲酯或丙酯;鄰苯二酚;間苯二酚;環己醇;3-戊醇;和間甲酚);低分子量(少於約10個殘基)的多肽;蛋白質,如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,如聚乙烯吡咯烷酮;胺基酸,例如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸;單醣、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑如EDTA;蔗糖、甘露糖醇、海藻糖或山梨糖醇等醣類;形成鹽的反離子,如鈉;金屬複合物(如,鋅-蛋白質複合物);及/或非離子表面活性劑,例如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。含有本揭露之此些藥劑及/或化合物的脂質體係通過本領域習知的方法製備,例如美國專利案第4,485,045和4,544,545號中所述的方法。具有延長循環時間的脂質體公開於美國專利案第5,013,556號中。特別有用的脂質體能通過反相蒸發法用脂質組合物產生,該脂質組合物包含磷脂醯膽鹼、膽固醇和PEG衍生的磷脂醯乙醇胺(PEG-PE)。脂質體通過限定孔徑的過濾器擠出,以產生具有所需直徑的脂質體。
本揭露之此些藥劑及/或化合物亦能包裹於例如,藉由凝聚技術或界面聚合的微膠囊中,如羥甲基纖維素或明膠微膠囊和聚(甲基丙烯酸甲酯)微膠囊,分別包裹在膠體藥物遞送系統(如脂質體、白蛋白微球、微乳液、納米顆粒和納米膠囊)或於粗滴乳液中。此類技術見於雷明頓,學科學
與實踐,第20版.,麥克出版公司(2000)(Remington,The Science and Practice of Pharmacy,20th Ed.,Mack Publishing(2000))。
本揭露亦能用於緩釋製劑。緩釋製劑的合適實例包括含有上述任一式之化合物的固體疏水聚合物之半透性基質,該基質為成型製品的形式(如薄膜或微膠囊)。緩釋基質的實例包括聚酯、水凝膠(如聚(2-羥乙基甲基丙烯酸酯)或聚(乙烯醇))、聚丙交酯(美國專利號3,773,919)、L-麩胺酸和7-乙基-L-麩胺酸、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-乙醇酸共聚物,例如用於LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林組成的可注射微球)、乙酸異丁酸蔗糖酯和聚-D-(-)-3-羥基丁酸。
用於靜脈內給藥的配方須為無菌。此易於藉由如通過滅菌過濾膜來完成。本揭露之化合物通常置於具有無菌揭入口的容器內,如具有可被皮下注射針頭刺破之塞子的靜脈溶液袋或小瓶。
適宜的乳劑能使用市售的脂肪乳液製備,例如IntralipidTM、LiposynTM、InfonutrolTM、LipofundinTM和LipiphysanTM。活性成分能溶解於預先混合的乳液組合物中,或溶解在油(如,大豆油、紅花油、棉籽油、芝麻油、玉米油或杏仁油)及與磷脂(例如,雞蛋磷脂、大豆磷脂或大豆卵磷脂)混合時形成的乳液及水。應理解,其他成分亦能添加於其中(如甘油或葡萄糖)以調節乳劑的張力。適宜之乳劑通常含有高達20%的油,如介於5%和20%之間。脂肪乳劑能包含0.1至1.0μm之間的脂肪滴,具體為0.1至0.5μm之間,且具有5.5至8.0範圍內的pH值。
乳劑組合物能藉由混合本揭露之化合物與IntralipidTM或其組分(大豆油、磷脂蛋白、甘油、及水)製得。
用於吸入或吹入的組合物包括藥學上可接受之水性或有機溶劑或其混合物中的溶液和懸浮液,及粉末。液體或固體組合物能含有上述適宜的藥學上可接受的賦形劑。於一些實施態樣中,該組合物通過口腔或鼻呼吸途徑施用以獲得局部或全身性作用。組合物於較佳無菌之藥學上可接受的溶劑中能通過氣體的使用進行霧化。霧化溶液能直接自霧化裝置吸入,或霧化裝置能連接到面罩、帳篷或間歇性正壓呼吸機。溶液、懸浮液或粉末組合物能較佳地經口或鼻自以適當方式遞送配方的裝置給藥。
試劑組
本發明之另一態樣提供包含上述化合物A游離酸之晶型或包含上述化合物A游離酸之晶型的藥物組合物的試劑組。試劑組能除了包含上述任一式之化合物、本揭露之化合物、或其藥物組合物外,另包含診斷或治療藥劑。試劑組還可以包括用於診斷或治療方法的說明。於一些實施態樣中,該試劑組包括上述任一式之化合物、或其藥物組合物及診斷藥劑。於其他實施態樣中,該試劑組包括上述任一式之化合物、或其藥物組合物。
然於另一實施態樣中,本揭露包含適宜實施本文所述治療方法的試劑組。於一實施態樣中,該試劑組包含足量的一或多種本揭露之化合物的第一劑型,以實現本揭露之方法。於另一實施態樣中,該試劑組包含足量的一或多種本揭露之化合物以實現本揭露之方法,及用於劑量之容器。
製備
上述任一式之化合物能藉由如下之通常或特定的方法使用有機化學合成中的通常知識所製得。此類通常知識能見於標準參考書目如
綜合有機化學,編輯。巴頓和奧利斯,愛思唯爾(Comprehensive Organic Chemistry,Ed.Barton and Ollis,Elsevier);綜合或綜合有機轉化:官能團製備指南,拉洛克,約翰威立(Comprehensive Organic Transformations:A Guide to Functional Group Preparations,Larock,John Wiley and Sons);及有機合成方法綱要,卷。一至十二(由威立-跨科學出版)(Compendium of Organic Synthetic Methods,Vol.I-XII(published by Wiley-Interscience))。本文所用之起始材料為市面上可取得或藉由領域中習知的常規方法製得。
於上述任一式之化合物的製備中,需注意本文所述之某些製備方法可能需要末端官能性的保護(如上述任一式前驅物的一級胺、二級胺、羧基)。此保護之需求視該製備方法的末端官能性與機制而定。此保護之需求易藉由領域中通常知識者所決定。此類保護/去保護方法的使用亦為領域中習知。保護基及其用途的通常敘述參見格林,有機合成中的保護基,約翰威立,紐約,1991.(Greene,Protective Groups in Organic Synthesis,John Wiley & Sons,New York,1991.)
舉例而言,某些含有一級胺或羧酸官能性的化合物若處於未保護狀態則可能干擾分子中其他位置的反應。據此,此類官能性能藉由適宜之保護基保護,並能於後續步驟中將該保護基移除。用於保護胺及羧酸的適宜保護基包括常見於肽合成的那些(如用於胺之N-第三丁氧基羰基(Boc)、芐氧基羰基(Cbz)和9-芴基亞甲氧基羰基(Fmoc),及用於羧酸之低級烷基酯或芐酯),該保護基於所述條件下通常不具化學活性,且能在不化學性製換上述任一式化合物中其他官能性的情況下被移除。
下面所述的方案旨在提供本揭露之化合物於製備中所採用方法的通常描述。本揭露之一些化合物能含有具有立體化學名稱(R)或(S)的單個或多個手性中心。為本領域技術人員所顯見,無論材料為對映體富集(enantioenriched)或外消旋,所有合成轉化皆能以類似的方式實施。此外,對所欲光學活性材料的拆分能利用諸如本文和化學文獻中描述的公知方法於序列中任何所欲的點上進行。
經由本文所述方法製得的胺化合物能在適合的鹼(如K2CO3、Et3N、NaH或LiHMDS的存在下於極性非質子溶劑(如但不限於DMF、DMAc、DMSO或NMP中,以受保護的2-溴乙酸進行烷基化而交付化合物。標準酯水解則能提供酸。如果Pg2為第三丁基,則能使用標準酸性去保護方法,如TFA/DCM、HCl/1,4-二噁烷、HCl/EtOAc或其他合適的條件來傳遞酸。
溶劑的縮寫如下表所示
分析條件
X射線粉末繞射(XRPD)
XRPD圖譜為X-射線繞射儀(PANalytical Empyrean)所鑑定。該系統配備PIXcel1D偵測器。樣品於2θ位置以0.013°步長自3至40掃描°。管電壓及電流分別為45KV與40mA。
差示掃描量熱分析(DSC)
DSC係經Discovery DSC 250(TA Instruments,US)進行。樣品置於鋁製針孔密封盤中並準確紀錄該樣品重量。而後該樣品以10℃/分鐘之速率自25℃加熱至最終溫度。
熱重分析(TGA)
TGA由Discovery TGA 55(TA Instruments,US)實施。樣品置於歸零後鋁盤內、自動秤重並送入TGA爐內。該樣品以10℃/分鐘之速率自室溫加熱至最終溫度(無設置重量穩定程式且封蓋並留一針孔)。
動態蒸汽吸附(DVS)
水分吸收/去吸收資料係於Vsorp動態水分吸收分析儀(ProUmid GmbH & Co.KG,德國)上蒐集。樣品置於歸零後之樣品室中並自動秤重。
偏光顯微鏡(PLM)
光學顯微鏡係使用偏光顯微鏡ECLIPSE LV100POL(Nikon,JPN)。
1
H-核磁共振光譜(
1
H-NMR)
1H-NMR係使用Bruker AVANCE III HD 300/400配備自動取樣器(Sample Xpress 60)執行。
高效液相層析(HPLC)
HPLC係以Agilent HPLC 1260系列設備執行。穩定性與溶解性之HPLC方法如下表所示。
穩定性與溶解性測試之HPLC方法
實例1. 合成(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯並[d]咪唑-6-羧酸(化合物A)
製備方法A
步驟1.
在0-10℃下,向2-(4-溴-2-氟-苯基)乙腈(2.0g,9.34mmol)於MeOH(2.7mL)中的攪拌溶液加入DCM(10mL)。將反應混合物在0-10℃攪拌並加入草醯二氯(9.49g,74.75mmol,6.50mL)2h,藉TLC判斷反應完成後,直接真空乾燥得到粗產物甲基2-(4-溴-2-氟-苯基)乙亞胺酯(methyl 2-(4-bromo-2-fluoro-phenyl)ethanimidate,2.2g,1.43mmol,15.3%產率)。LCMS:[M+H]+=246;HPLC滯留時間(0.01% TFA)=1.14分鐘。
步驟2.
將2-(4-溴-2-氟-苯基)乙亞氨酸甲酯(4.5g,3.11mmol)在MeOH(20mL)中的混合物於室溫N2保護下攪拌24小時,待LCMS指示反應完成。將反應混合物通過帶有PE的矽藻土墊過濾。真空乾燥後得到粗
產物。加入PE,濾出固體得到濾液。重複幾次直到沒有固體。獲得產物4-溴-2-氟-1-(2,2,2-三甲氧基乙基)苯(4.0g,2.87mmol,92.2%產率),為無色液體。HPLC滯留時間(0.01% TFA)=1.89分鐘。
步驟3.
將4-溴-2-氟-1-(2,2,2-三甲氧基乙基)苯(2.10g,7.16mmol)、4-胺基-3-[[(2S)-氧雜環丁烷-2-基]甲基胺基]苯甲酸第三丁酯(1.00克,3.59mmol)、4-甲基苯磺酸(185.6毫克,1.08mmol)之混合物的CH3CN(10mL)溶液於60℃、N2保護下攪拌2小時,直至LCMS指示反應完成。將反應混合物通過帶有EtOAc的矽藻土墊過濾,並真空濃縮結合的有機層,通過矽膠色譜法(己烷/EtOAc=8:1)純化,得到所需淡黃色固體之產物(S)-2-(4-溴-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯並[d]咪唑-6-羧酸第三丁酯(1.13g,2.38mmol,66.2%產率)。LCMS:[M+H]+=475;HPLC滯留時間(10mM NH4HCO3)=2.05分鐘。
步驟4.
向(S)-2-(4-溴-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯並[d]咪唑-6-羧酸第三丁酯(21.0g,44.18mmol)在1,4-二噁烷(30mL)中的懸浮液加入4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1,3,2-二氧硼烷(13.46g,53.01mmol)、環戊基(二苯基)膦二氯鈀鐵(9.70g,13.25mmol)和乙酸鉀(8.67g,88.36mmol,5.52mL)。將混合物於N2、100℃下攪拌2小時。通過LCMS判斷反應完成後,該反應混合物直接用於下一步。LCMS:[M+H]+=523.0;HPLC滯留時間(10mM NH4HCO3)=2.17分鐘。
步驟5.
將第三丁基(S)-2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)芐基)-1-(氧雜環丁烷-2-基甲基))-1H-苯並[d]咪唑-6-羧酸酯(80.0mg,52.07μmol)、2-溴-6-[(4-氯-2-氟-苯基)甲氧基]吡啶(24.7mg,78.10μmol)、碳酸二銫(50.9mg,156.20μmol)和環戊基(二苯基)膦二氯鈀鐵(3.81mg,5.21μmol)之混合物的1,4-二噁烷(8mL)H2O(1mL)溶液於N2、90℃下攪拌3小時。直至LCMS指示反應完成後,將反應混合物通過帶有DCM的矽藻土墊過濾。真空濃縮結合的有機層以得到所需的淡黃色固體粗產物第三丁基(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯並[d]咪唑-6-羧酸酯(40mg,18.98μmol,36.5%產率)。LCMS:[M+H]+=632;HPLC滯留時間(0.01% TFA)=1.90分鐘。
步驟6.
將第三丁基(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯並[d]咪唑-6-羧酸酯(40mg,63.28μmol)與2,2,2-三氟乙酸(36.08mg,316.41μmol,24.38μL)之混合物的DCM(8mL)溶液於室溫、N2下攪拌2小時,直至LCMS指示反應完成,將反應混合物通過帶有EtOAc的矽藻土墊過濾並真空濃縮結合的有機層。反應完成後,得到所需淺白色固體產物(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯並[d]咪唑-6-羧酸(4.1mg,7.12μmol,11.3%產率)。LCMS:[M+H]+=575.8;HPLC滯留時間(10mM NH4HCO3)=1.65分鐘。
1H NMR(400MHz,DMSO-d6)δ 8.25-8.24(brs,1H),7.96-7.75(m,4H),7.69-7.57(m,3H),7.50(dd,J=10.0,1H)),7.43(t,J=8.1Hz,1H),7.32(dd,J=8.2,1.8Hz,1H),6.88(d,J=8.2Hz,1H),5.52(s,2H),5.04(d,J=7.2Hz,1H),4.73(dd,J=15.5,7.0Hz,1H),4.60(d,J=13.0Hz,1H),4.54-4.46(m,2H),4.37(ddd,J=18.5,11.9,11.3Hz,2H),2.70(dd,J=12.1,6.1Hz,1H),2.41-2.29(m,1H)。
製備方法B
步驟1:
在5℃下,向2-(4-溴-2-氟-苯基)乙酸(100g,429.12mmol)的甲醇(300mL)溶液中加入硫酸(11.5mL,純度98%)。將該溶液加熱回流8小時。將該混合物冷卻至室溫,並於40℃、減壓下濃縮至無明顯餾出物,用EA(500mL)進行稀釋,並以水(200mL)洗滌兩次及以飽和NaHCO3溶液
洗滌以完全中和H2SO4。結合的有機物用鹽水洗滌並用Na2SO4和MgSO4乾燥。該有機層無需進一步純化而通過矽膠短墊過濾並濃縮結合的有機濾液以獲得所需的酯(104g,98.1%)。
1H NMR(400MHz,CDCl3)δ 7.30-7.25(m,2H),7.20(t,1H),3.70(s,3H),3.63(s,1 H)。
步驟2:
向三頸瓶中依次加入2-(4-溴-2-氟-苯基)乙酸甲酯(150g,607.14mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1,3,2-二氧硼烷(185.01g,728.57mmol)、乙酸鉀(119.17g,1.21mol)和環戊基(二苯基)膦;二氯鈀;鐵(6.66g,9.11mmol)。將該瓶抽真空並用N2充氣兩次。加入1,4-二噁烷(750mL),將混合物抽真空並用N2充氣一次後於100℃下加熱2小時。將反應混合物冷卻至室溫並通過矽藻土墊過濾,而後在35℃下真空濃縮至無明顯餾出物。殘餘物使用PE/EA=4/1(600mL/150mL)稀釋並通過矽膠墊(200目)過濾且使用PE/EA=4/1(360mL/90mL)洗滌。將濾液濃縮至無明顯餾出物,即得到粗產物Bpin酯(按純度計算為158.9g,產率89%),其無需進一步純化而能直接使用。
LCMS:[M+H]+=294.9
步驟3:
向(4-氯-2-氟-苯基)甲醇(100g,622.77mmol)(1.0eq)、2-溴-6-氟-吡啶(109.60g,622.77mmol,64.09mL)的THF(500mL)溶液於N2保護、25±5℃下加入氫氧化鈉(32.38g,809.60mmol,15.20mL)。將混合物攪拌16小時。向該系統添加HOAc(0.3eq)0.5h。向該系統添加
DMF(500mL)並於40℃真空下濃縮至無明顯餾出物。向該系統加入水(500mL)、過濾、以水(300mL)洗滌濾餅、並收集該濾餅。於45±5℃下真空乾燥該濾餅16小時後獲得呈灰白色至白色固體的產物(182.3g,92.5%)。
LCMS:[M+H]+=317.6
步驟4:
向三頸瓶中依次加入2-溴-6-[(4-氯-2-氟-苯基)甲氧基]吡啶(171.0g,0.54mol)、碳酸二銫(352.1g,1.1mol)和環戊基(二苯基)膦;二氯鈀;鐵(3.95克,5.4mmol)。將該瓶抽真空並用N2充氣兩次。分次加入上述製得的Bpin酯於1,4-二噁烷(780mL)和水(195mL)中的溶液,將混合物抽真空並用N2充氣一次,而後於90℃下加熱3小時。冷卻反應混合物至室溫並通過矽藻土墊過濾。所得混合物以EtOAc(3×1000mL)進行萃取。
將合併的有機相以鹽水(400mL)洗滌,經無水Na2SO4乾燥並過濾。於真空下除去揮發物後,將殘餘物以PE/EA=3/1(600mL/200mL)稀釋與通過矽膠墊(2W,200目)過濾,並用PE/EA=4/1(800mL/200mL)洗滌。將濾液濃縮以獲得用於進一步純化的粗酯。
LCMS:[M+H]+=403.7
步驟5:
向2-[4-[6-[(4-氯-2-氟-苯基)甲氧基]-2-吡啶基]-2-氟-苯基]乙酸甲酯(150g,371.47mmol)的THF/EtOH=900mL/300mL攪拌溶液中逐滴加入氫氧化鈉(29.72g,742.93mmol)於水(300mL)中的溶液並保持溫度於25℃。將反應混合物在25℃下攪拌2小時,而後於25℃用HOAc(42.5mL)的水(300mL)溶液處理。將所得懸浮液濃縮至無明顯蒸餾物。過濾白
色固體、以水(2×600mL)洗滌並用DMF/水=1/1(450mL/450mL)製成漿液,得到所需的酸(137.5g,94.8%)。
LCMS:[M+H]+=389.7
步驟6:
向2-[4-[6-[(4-氯-2-氟-苯基)甲氧基]-2-吡啶基]-2-氟-苯基]乙酸(117.8g,272.00mmol)、甲基4-胺基-3-[[(2S)-氧雜環丁烷-2-基]甲基胺基]苯甲酸酯(67.65g,272.00mmol)和苯並三唑-1-基氧基(三吡咯烷-1-基)磷鎓;六氟磷酸鹽(162.78g,312.80mmol)的DCM(590mL)攪拌懸浮液於10℃下加入N-乙基-N-異丙基-丙-2-胺(52.73g,408.00mmol,71.06mL)的DCM(120mL)溶液。將反應混合物逐漸升溫至25℃並攪拌12小時,而後以5%Na HCO3水溶液(480mL)淬滅並攪拌2小時。有機相以鹽水(240mL)洗滌、以無水Na2SO4乾燥和過濾。將濾液通過矽膠墊(200目)、用PE/EA=2/1(200mL/100mL)洗滌並真空濃縮。殘餘物以PE/EA=3/1(300mL/100mL)製成漿液並過濾以獲得胺化產物(165.4g,90.0%)。
LCMS:[M+H]+=607.7
步驟7:
將甲基4-[[2-[4-[6-[(4-氯-2-氟-苯基)甲氧基]-2-吡啶基]-2-氟-苯基]乙醯基]胺基]-3-[將[(2S)-氧雜環丁烷-2-基]甲基胺基]苯甲酸酯(15.8g,25.99mmol)的二噁烷(75mL)懸浮液加熱至60℃以取得溶液。於60℃下向該溶液中加入乙酸(7.80g,129.93mmol,7.43mL)的二噁烷(15mL)溶液。將所得溶液於60℃下加熱24小時,而後將其冷卻至25℃並以5% NaHCO3水溶液(218mL)淬滅。將所得沉澱物於二噁烷/水系統中漿
化4小時,過濾得到粗環化產物。自78℃冷卻至25℃後,該粗產物於EtOAc/PE=1/2(50mL/100mL)中重新結晶並取得純產物(14.6g,95.2%)。
LCMS:[M+H]+=589.7
步驟8:
向攪拌的甲基2-[[4-[6-[(4-氯-2-氟-苯基)甲氧基]-2-吡啶基]-2-氟-苯基]甲基]-3-[[(2S))-氧雜環丁烷-2-基]甲基]苯並咪唑-5-羧酸酯(20g,33.90mmol)的THF/MeOH=120mL/40mL溶液中逐滴加入氫氧化鈉的水溶液(40mL)並保持溫度於22℃。將反應混合物在22℃下攪拌12小時,而後於22℃以HOAc(7.9mL)的水(40mL,2V)溶液處理。過濾所得白色固體,將其用水(2×100mL)洗滌並以THF/水=2/1(200mL/100mL)進行結晶,得到所需酸化合物A(19.0g,97.3%)。將化合物A在丙酮中於22℃漿化48小時、過濾、而後於45±5℃下真空乾燥48小時,得到化合物A的I型。
LCMS:[M+H]+=575.7
1H NMR(400MHz,DMSO-d6)δ 8.23(brs,1H),7.96-7.75(m,4H),7.76-7.56(m,3H),7.50(dd,1H),7.42(t,1H)7.31(dd,1H),6.87(d,1H),5.51(s,2H),5.04(d,1H),4.71(dd,1H),4.58(d,1H),4.56-4.45(m,2H),4.42-4.35(m,2H),2.71-2.66(m,1H),2.39-2.36(m,1 H)。
實例2. 化合物A游離酸之晶型I的製備和定性
2.1.1 製備方法1
將約300mg化合物A之游離酸(無定形)加入到12mL丙酮中以形成懸浮液。於~20℃下,將該懸浮液於20mL小瓶中持續攪拌~40
小時(磁力攪拌)。通過過濾收集固體並於40℃下真空乾燥4小時。獲得約250mg的游離酸晶型I。
2.1.2 製備方法2
將約20mg化合物A之游離酸(無定形)加入到1mL溶劑(丙酮、甲苯、乙醇或甲基第三丁基醚)中製成懸浮液。於~20℃下,將該懸浮液持續攪拌3天(磁力攪拌)。通過過濾收集固體樣品並獲得晶型I。
2.1.3 製備方法3
將約20mg化合物A之游離酸(無定形)加入到0.5mL甲乙酮中製成懸浮液。於~22℃下,將該懸浮液持續攪拌1週(磁力攪拌)。通過過濾收集固體樣品並獲得晶型I。
2.1.4 製備方法4
將約20mg化合物A之游離酸(無定形)加入到0.5mL的2-甲基四氫呋喃中製成懸浮液。於~22℃下,將該懸浮液持續攪拌1週(磁力攪拌)。通過過濾收集固體樣品並獲得晶型I。
2.1.5 製備方法5
將約20mg化合物A之游離酸(無定形)加入到0.5mL IPA中製成懸浮液。於~50℃下,將該懸浮液持續攪拌1週(磁力攪拌)。通過過濾收集固體樣品並獲得晶型I。
2.2 定性
自製備方法1所得產物係藉由XRPD(圖1)、TGA、DSC(圖2)、DVS(圖3)和1H-NMR進行定性。
游離酸晶型I顯示為無水物。於1H-NMR中未檢測出有機溶劑。TGA於150℃前未顯示出顯著的重量損失。DSC於200℃處顯示出與樣品熔化相關的一個吸熱峰。DVS數據(圖3)顯示自0到80% RH及自0.6%到90% RH間約有0.3%的重量變化,顯示游離酸晶型I具輕微吸濕性。於DVS測試後游離酸晶型I的結晶型維持不變。游離酸晶型I的定性結果總結於表1中。XRPD峰值總結於表2中。
實例3. 化合物A之游離酸晶型I的溶解性測量
游離酸晶型I在生物相關介質(模擬胃液(SGF)、禁食狀態模擬腸液(FaSSIF)和進食狀態模擬腸液(FeSSIF))中的溶解性於37℃下高達
24小時。稱取約15mg樣品放入樣品瓶中並加入5.0mL生物相關培養基製成懸浮液。使用QQMSC-100振盪器將所有製備的懸浮液於37℃下以600rpm的速度振盪。於0.5、2及24小時時,分別取1000μL左右的懸浮液過濾及稀釋,而後以HPLC分析濾液以測試溶解性。測量濾液的pH值,並通過XRPD分析濾餅。
游離酸晶型I不溶於SGF中。溶解性研究顯示,在0.5小時時,FaSSIF和FeSSIF中游離酸的濃度分別為~5和10μg/mL。溶解性研究後,游離酸晶型I的XRPD圖譜未改變。研究結果總結於表3中。
實例4. 化合物A之游離酸晶型I的固體穩定性研究
將約25mg游離酸晶型I置於60℃/封蓋及40℃/75% RH(開蓋)條件下長達12天。於第0天和第7天時,將樣品溶解在稀釋劑中以製備0.5mg/mL溶液用以HPLC純度分析。於第12天通過XRPD分析固體樣品以檢查結晶型。
結果總結於表4中。游離酸晶型I於60℃/封蓋及40℃/75% RH下,於12天中保持物理與化學穩定性。
實例5. 化合物A之游離酸晶型II的製備和定性
5.1.1 製備方法1
將約20mg化合物A之游離酸(無定形)加入到1mL乙腈中製成懸浮液。於~20℃下,將該懸浮液持續攪拌3天。通過過濾收集固體樣品並獲得晶型II。
5.1.2 製備方法2
將約20mg化合物A之游離酸(無定形)加入到0.5mL乙酸異丙酯中製成懸浮液。於~50℃下,將該懸浮液持續攪拌1週。通過過濾收集固體樣品並獲得晶型II。
5.2 定性
所得產物通過XRPD(圖4)、TGA、DSC(圖5)、DVS和1H-NMR定性。
游離酸晶型II顯示為無水物。於100℃前幾乎沒有重量損失。於~205℃處偵測到與樣品熔化相關的吸熱峰。XRPD峰值總結於表5中。
實例6. 化合物A之游離酸晶型III的製備和定性
6.1.1 製備方法1
將約20mg化合物A之游離酸(無定形)加入到1mL甲醇中製成懸浮液。於~20℃下,將該懸浮液持續攪拌3天。通過過濾收集固體樣品並獲得晶型III。
6.1.2 製備方法2
將約20mg化合物A之游離酸(無定形)加入到1mL水中製成懸浮液。於~20℃下,將該懸浮液持續攪拌3天。通過過濾收集固體樣品並獲得晶型III。
6.1.3 製備方法3
將約20mg化合物A之游離酸晶型I溶解於0.2mLDMF中以獲得澄清溶液。經過濾後將該藥物溶液逐滴加入1mL水中。通過過濾收集固體樣品並獲得晶型III。
6.2 定性
所得產物通過XRPD(圖6)、TGA、DSC(圖7)和1H-NMR定性。
游離酸晶型III顯示為一種水合物。NMR僅檢測到0.1% MeOH;於130℃(約1.6eq.H2O)前,可能因脫水造成重量損失約4.9%。
於DSC曲線中觀察到多處熱事件(thermal events)。於~160℃偵測到一處放熱峰,接續偵測到一處吸熱峰,指出加熱時發生了相變化。XRPD峰值總結於表6中。
實例7. 化合物A之游離酸晶形IV的製備和定性
7.1 製備方法
將約30mg化合物A之游離酸I型加入0.4mL EA中以製成懸浮液。於~50℃下,將該懸浮液持續攪拌5天。通過過濾收集固體樣品並獲得晶型IV。
7.2 定性
所得產物通過XRPD(圖8)、DSC(圖9)、TGA(圖10)和1H-NMR定性。
游離酸晶型IV顯示為無水物。1H-NMR中未檢測到有機溶劑。於150℃前,TGA未顯示出顯著的重量損失。DSC於196.8℃處顯示一個與樣品熔化相關的吸熱峰。XRPD峰值總結於表7中。
Claims (21)
- 如請求項1所述的晶型I,其中所述X射線粉末繞射圖譜進一步包含2θ=4.9°、11.8°、和21.5°±0.2的一個或多個峰。
- 如請求項1或2所述的晶型I,其中所述X射線粉末繞射圖譜進一步包含2θ=15.8°、18.8°、和23.0°±0.2的一個或多個峰。
- 如請求項1所述的晶型I,其中所述X射線粉末繞射圖譜包含2θ=4.9°、11.4°、11.8°、12.7°、15.8°、18.1°、18.3°、18.8°、21.5°和23.0°±0.2的峰。
- 如請求項1至4中任一項所述的晶型I,其特徵在於,該晶型I的差示掃描量熱分析(DSC)峰值的相轉變溫度為200±3℃。
- 如請求項1至5中任一項所述的晶型I,其中至少90%重量百分比的化合物A為晶型I。
- 如請求項7所述的晶型II,其中所述X-射線粉末繞射圖譜不包含在2θ=18.1°及/或21.5°±0.2的峰。
- 如請求項7或8所述的晶型II,其中所述X-射線粉末繞射圖譜進一步包含2θ=4.9°、7.7°、15.8°、和25.9°±0.2的一個或多個峰。
- 如請求項7至9中任一項所述的晶型II,其特徵在於,該晶型II之X射線粉末繞射圖譜包含2θ=4.9°、7.7°、11.4°、12.0°、12.9°、15.8°、18.6°、20.4°、和25.9°±0.2的峰。
- 如請求項7至10中任一項所述的晶型II,其特徵在於,該晶型II的差示掃描量熱分析(DSC)峰值的相轉變溫度為205±3℃。
- 如請求項7至11中任一項所述的II型晶型,其中至少90%重量百分比的化合物A為晶型II。
- 如請求項13所述的晶型III,其中所述X-射線粉末繞射圖譜進一步包含2θ=11.7°、14.2°、24.7°、26.3和27.7°±0.2的一個或多個峰。
- 如請求項13所述的晶型III,其特徵在於,該晶型III之X射線粉末繞射圖譜包含2θ=9.8°、11.7°、13.3°、14.2°、17.3°、18.1°、24.7°、26.3°、和27.7°±0.2的峰。
- 如請求項13至15中任一項所述的晶型III,其特徵在於,該晶型III的差示掃描量熱分析(DSC)峰值的相轉變溫度為204±3℃。
- 如請求項13至16中任一項所述的晶型III,其中該晶型III為水合物。
- 如請求項13至17中任一項所述的晶型III,其中至少90%重量百分比的化合物A為晶型III。
- 一種藥物組合物,其包含請求項1至18中任一項的化合物A之晶型及藥學上可接受的載劑。
- 一種治療或預防疾病或病症的方法,該方法包含向需要治療的受試者施用治療有效量的請求項1至18中任一項的化合物A之晶型或其藥物組合物,其中該疾病或病症為T1D、T2DM、糖尿病前期、特發性T1D、LADA、EOD、YOAD、MODY、營養不良相關的糖尿病、妊娠期糖尿病、高血糖、胰島素抵抗、肝胰島素抵抗、糖耐量受損、糖尿病神經病變、糖尿病腎病、腎臟疾病、糖尿病視網膜病變、脂肪細胞功能障礙、內臟脂肪沉積、睡眠呼吸暫停、肥胖、飲食失調、使用其他藥物導致體重增加、過度渴望糖分、血脂異常、高胰島素血症、NAFLD、NASH、纖維化、肝硬化、肝細胞癌、心血管疾病、動脈粥樣硬化、冠狀動脈疾病、外周血管疾病、高血壓、內皮功能障礙、血管順應性受損、充血性心力衰竭、心肌梗塞、中風、出血性中風、缺血性中風、創傷性腦損傷、肺動脈高壓、 血管成形術後再狹窄、間歇性跛行、餐後脂血症、代謝性酸中毒、酮症、關節炎、骨質疏鬆症、帕金森病、左心室肥大、外周動脈疾病、黃斑變性、白內障、腎小球硬化、慢性腎功能衰竭、代謝綜合徵、X綜合徵、經前期綜合徵、心絞痛、血栓形成、動脈粥樣硬化、短暫性腦缺血發作、血管再狹窄、葡萄糖代謝受損、空腹血糖受損情況、高尿酸血症、痛風、勃起功能障礙、皮膚和結締組織疾病、銀屑病、足部潰瘍、潰瘍性結腸炎、高載脂蛋白B脂蛋白血症、阿茲海默症、精神分裂症、認知障礙、炎症性腸病、短腸綜合徵、克羅恩病、結腸炎、腸易激綜合徵、多囊卵巢綜合症或成癮。
- 一種治療有效量之請求項1至18中任一項的化合物A之晶型或其藥物組合物於製備用於治療有需要的受試者之疾病或病症的藥物中之用途,其中所述疾病或病症為T1D、T2DM、糖尿病前期、特發性T1D、LADA、EOD、YOAD、MODY、營養不良相關的糖尿病、妊娠期糖尿病、高血糖、胰島素抵抗、肝胰島素抵抗、糖耐量受損、糖尿病神經病變、糖尿病腎病、腎臟疾病、糖尿病視網膜病變、脂肪細胞功能障礙、內臟脂肪沉積、睡眠呼吸暫停、肥胖、飲食失調、使用其他藥物導致體重增加、過度渴望糖分、血脂異常、高胰島素血症、NAFLD、NASH、纖維化、肝硬化、肝細胞癌、心血管疾病、動脈粥樣硬化、冠狀動脈疾病、外周血管疾病、高血壓、內皮功能障礙、血管順應性受損、充血性心力衰竭、心肌梗塞、中風、出血性中風、缺血性中風、創傷性腦損傷、肺動脈高壓、血管成形術後再狹窄、間歇性跛行、餐後脂血症、代謝性酸中毒、酮症、關節炎、骨質疏鬆症、帕金森病、左心室肥大、外周動脈疾病、黃斑變性、白內障、腎小球硬化、慢性腎功能衰竭、代謝綜合徵、X綜合徵、經前期綜 合徵、心絞痛、血栓形成、動脈粥樣硬化、短暫性腦缺血發作、血管再狹窄、葡萄糖代謝受損、空腹血糖受損情況、高尿酸血症、痛風、勃起功能障礙、皮膚和結締組織疾病、銀屑病、足部潰瘍、潰瘍性結腸炎、高載脂蛋白B脂蛋白血症、阿茲海默症、精神分裂症、認知障礙、炎症性腸病、短腸綜合徵、克羅恩病、結腸炎、腸易激綜合徵、多囊卵巢綜合症或成癮。
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US12024507B2 (en) | 2021-10-25 | 2024-07-02 | Terns Pharmaceuticals, Inc. | Compounds as GLP-1R agonists |
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