TWI805699B - 甲基內醯胺環化合物及其用途 - Google Patents
甲基內醯胺環化合物及其用途 Download PDFInfo
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- TWI805699B TWI805699B TW108106807A TW108106807A TWI805699B TW I805699 B TWI805699 B TW I805699B TW 108106807 A TW108106807 A TW 108106807A TW 108106807 A TW108106807 A TW 108106807A TW I805699 B TWI805699 B TW I805699B
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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Abstract
本發明之目的在於提供一種具有SGLT1抑制活性,可用來作為醫藥之甲基內醯胺環化合物或其製藥上所容許的鹽及含有其等之醫藥組成物以及其等之醫藥用途。本發明提供一種式[I]之化合物或其製藥上所容許之鹽及含有其等之醫藥組成物以及其等的醫藥用途。
Description
本發明係關於一種具有SGLT1抑制活性之甲基內醯胺環化合物或其製藥上所容許的鹽、含有其等之醫藥組成物、以及其等之醫藥用途。
已知SGLT1(Na+-葡萄糖共輸送載體1、Sodium-Glucose Cotransporter 1)係負責大部分小腸中之葡萄糖及半乳糖之吸收,據報告人類SGLT1之缺損患者係葡萄糖及半乳糖之吸收會不良。再者,確認出糖尿病患者係小腸SGLT1之表現會增加,並認為糖尿病患者中之糖吸收的亢進係起因於該小腸SGLT1之高表現者。
從此等之見識,SGLT1抑制劑係可期待藉由抑制來自小腸之糖的吸收而使血糖值正常化,並認為係在附隨糖尿病及高血糖而引起之糖尿病性併發症上顯示效果者。又,認為藉由抑制糖流入於體內,係在肥胖症上亦顯示效果者(非專利文獻1及2)。
一般名稱伏格列波糖(Voglibose)係通過日本國藥事法14條規定之醫藥品等製造販賣認可之醫藥品(認可編號:21600AMZ00368等)。 伏格列波糖係抑制從存在於腸管黏膜之二糖類分解成單糖類的角色的二糖類水解酵素(α-葡萄糖苷酶),藉由抑制或遲延糖質在腸管的消化及吸收,改善飯後高血糖。已知該藥理效果在抑制耐糖能異常之2型糖尿病的併發症上為有效。
從此等之見識,認為藉由SGLT1抑制劑抑制來自小腸之糖的吸收,並改善飯後高血糖,在抑制耐糖能異常之2型糖尿病的併發症上為有效。
SGLT1係被認為在心肌細胞表現。已知在心肌細胞之葡萄糖的攝入通常係GLUT1(Glucose Transporter Type1)及GLUT4(Glucose Transporter Type4)擔任,且SGLT1之參與較小。然而,經導入家族性肥大型心肌症(糖原蓄積性之心肌症)的原因基因之PRKAG2(AMPK(AMP-Activated Protein Kinase)的γ(gamma)2次單元)的突變基因之小鼠或進行心肌缺血處置之小鼠的心肌而誘導SGLT1之表現,據報告在此等之病態中SGLT1有助於對心肌細胞之葡萄糖攝入。認為藉由SGLT1所攝入之葡萄糖係在心肌細胞內過剩地蓄積或代謝,並對細胞造成障礙。據報告實際上前者之模型係藉由非選擇性的SGLT抑制劑之根皮苷(phlorhizin)的處置,抑制在心肌之糖原的蓄積。
從此等之見識,認為SGLT1抑制劑係藉由抑制對心肌細胞內之過剩葡萄糖的攝入,而在肥大型心肌症及缺血性心疾病上顯示效果(非專利文獻3及4)。
在癌細胞中,SGLT1係藉由上皮增殖因子接受體(Epidermal Growth Factor Receptor、於眾多癌細胞所看到之表面蛋白質)而安定化。對癌細胞之榮養供給係與葡萄糖、乳酸、胺基酸等之轉運子相關,尤其有關葡萄糖之輸送,已知SGLT1及GLUT1對癌細胞不絕地供給葡萄糖。長期不供給葡萄糖時,則細胞經由自食作用而破壞。
從此等之見識,認為SGLT1抑制劑係抑制對癌細胞之葡萄糖的供給,而顯示抗癌作用者(非專利文獻5及6)。
食事中之糖質係在消化管內被分解成單糖,在消化管上部被吸收,故不會有較多之糖到達下部消化管。但,服用延遲或抑制糖吸收之藥劑,或大量攝取難消化性之多糖類時,未消化之糖會滯留於下部消化管,滯留於下部消化管之未消化的糖會引起滲透壓性之下痢。
SGLT1抑制劑係藉由抑制糖吸收,而使下部消化管內之單糖量增加。因此,認為SGLT1抑制劑係在便秘上顯示效果者。
所謂糖尿病係胰島素之作用不足,為血糖值變高之病症,持續性的高血糖係可能引起糖尿病性併發症(例如已知為細小血管症之網膜症、腎症及神經障礙、以及已知為大血管症之腦血管障礙、缺血性心疾病及下肢閉塞性動脈硬化症)。伴隨血糖值變高之其他疾病亦可例舉肥胖症。
認為糖尿病係存在1型及2型糖尿病,1型糖尿病係分泌胰島素之胰臟β細胞被破壞,胰島素作用變成不充分而病發,並認為2型糖尿病係包含胰島素分泌降低或胰島素阻抗性之複數基因上加上過食、運動不足、肥胖、壓力等環境因子及年齡增長而病發。糖尿病之診斷係可使用依據血糖值而分類之3種型(正常型、邊界型、糖尿病型)。確認出以下之(1)至(4):
(1)早朝空腹時血糖值126mg/dL以上
(2)在75gOGTT(經口葡萄糖負荷試驗)為2小時值200mg/dL以上
(3)随時血糖值200mg/dL以上
(4)HbA1cg6.5%以上之任一者經確認時係判定為糖尿病型,有糖尿病或糖尿病之疑慮(非專利文獻7)。
在上述(2)所使用之OGTT係診斷糖尿病之手段之一。一般,在人類絕食之後,服用含有75g葡萄糖之溶液,從葡萄糖服用至一定時間後之血糖值若為200mg/dL以上,則診斷為糖尿病(非專利文獻7)。因而,認為OGTT係糖尿病診斷之指標,可使在OGTT中受到葡萄糖負荷之被檢體的血糖值降低之化合物係對糖尿病顯示效果者。
[非專利文獻1] Am J Physiol Gastrointest Liver Physiol. 2002; 282(2): G241-8
[非專利文獻2] Nature. 1991; 350(6316): 354-6
[非專利文獻3] J Mol Cell Cardiol. 2010; 49(4):683-92
[非專利文獻4] Cardiovasc Res. 2009; 84(1): 111-8
[非專利文獻5] Cancer Cell. 2008, 13: 385-93
[非專利文獻6] Pharmacol Ther. 2009, 121: 29-40
[非專利文獻7] 糖尿病治療導引2016-2017
提供一種具有SGLT1抑制活性,且可用來作為醫藥之甲基內醯胺環化合物或其製藥上所容許的鹽及含有其等之醫藥組成物以及其等之醫藥用途。
本發明人等係累積專心研究之結果,發現某特定之甲基內醯胺環化合物,終於完成本發明。
亦即,在某態樣中,可提供一種式[I]之化合物或其製藥上所容許之鹽及其醫藥用途。
式[I]之化合物或其製藥上所容許之鹽因具有SGLT1抑制活性,故在藉由SGLT1活性之調節可期待改善之各種疾病或狀態之治療及/或預防上為有用。式[I]之化合物或其製藥上所容許之鹽係在因血糖值變高所引起之各種疾病或狀態之治療及/或預防上亦為有用。
第1圖係表示實施例1之化合物(以下稱為「化合物1」)與介質相較,係使OGTT葡萄糖負荷之SD鼠的血糖值明顯地降低。
第2圖係表示在經投與之化合物中,與介質相較,僅化合物1使OGTT葡萄糖負荷之SD鼠的血糖值明顯地降低。
本發明係包含以下例示之具體的態樣。
項1.式[I]之化合物或其製藥上所容許之鹽。
項2.一種醫藥組成物,係包含項1所述之化合物或其製藥上所容許的鹽、及製藥上所容許之載體。
項3.一種SGLT1抑制劑,係包含項1所述之化合物或其製藥上所容許的鹽。
項4.一種糖尿病之治療劑或預防劑,係包含項1所述之化合物或其製藥上所容許的鹽。
項5.如項4所述之治療劑或預防劑,其中,糖尿病為2型糖尿病。
項6.一種抑制SGLT1之方法,係將治療上有效量之項1所述之化合物或其製藥上所容許的鹽投與至哺乳動物。
項7.一種治療或預防糖尿病之方法,係將治療上有效量之項1所述之化合物或其製藥上所容許的鹽投與至哺乳動物。
項8.如項7所述之方法,其中,糖尿病為2型糖尿病。
項9.一種項1所述之化合物或其製藥上所容許的鹽的使用,係用以製造SGLT1抑制劑。
項10.一種鹽項1所述之化合物或其製藥上所容許的鹽的使用,係用以製造糖尿病之治療劑或預防劑。
項11.如項10所述之使用,其中,糖尿病為2型糖尿病。
項12.如項1所述之化合物或其製藥上所容許之鹽,係用以使用於SGLT1之抑制。
項13.如項1所述之化合物或其製藥上所容許之鹽,係使用於糖尿病之治療或預防。
項14.如項13所述之化合物或其製藥上所容許之鹽,其中,糖尿病為2型糖尿病。
項15.一種商業包裝體,係包含:項2所述之醫藥組成物、及記載可將該醫藥組成物使用或應使用於糖尿病之治療及/或預防有關該醫藥組成物之記載物。
項16.一種套件,係包含:項2所述之醫藥組成物;及記載可將該醫藥組成物使用或應使用於糖尿病之治療及/或預防之有關該醫藥組成物之記載物。
所謂「製藥上所容許的鹽」係只要在該技術領域為已知之不伴隨過度毒性的鹽,亦可為任何的鹽。具體而言,係可舉例如與無機酸之鹽、與有機酸之鹽、與無機鹼之鹽、及與有機鹼之鹽等。各種形態之製藥上所容許的鹽在該領域為周知,例如記載於以下之參考文獻:(a)Berge等人,J.Pharm.Sci.,66,p1至19(1977)、(b)Stahl等人,「Handbook of Pharmaceutical Sait:Properties,Selection,and Use」(Wiley-VCH,Weinheim,Germany,2002)、(c)Paulekuhn等人,J.Med.Chem.,50,p6665-6672(2007)。
依據本身公知之方法,藉由使式[I]之化合物與無機酸、有機酸、無機鹼或有機鹼反應,可分別獲得其製藥上所容許的鹽。
與無機酸之鹽係例示與氫氟酸、氫氯酸、氫溴酸、氫碘酸、硝酸、磷酸或硫酸之鹽。較佳係可舉例如與氫氯酸、硝酸、硫酸、磷酸或溴化氫酸之鹽。
與有機酸之鹽係可例示與乙酸、己二酸、褐藻酸、4-胺基水楊酸、去水亞甲基檸檬酸、安息香酸、苯磺酸、乙二胺四乙酸鈣、樟腦酸、樟腦-10-磺酸、碳酸、檸檬酸、乙二胺四乙酸、乙烷-1,2-二磺酸、十二烷基硫酸、乙烷磺酸、富馬酸、葡萄庚酸、葡萄糖酸、葡萄糖醛酸、葡萄庚酸、羥乙醯基對胺苯胂酸、己基二羥苯甲酸、羥基-萘甲酸、2-羥基-1-乙烷磺酸、乳酸、乳糖醛酸、蘋果酸、馬來酸、苦杏仁酸、甲烷磺酸、甲基硫酸、甲基硝酸、亞甲基雙(水楊酸)、半乳糖二酸、萘-2-磺酸、2-萘甲酸、1,5-萘二磺酸、油酸、草酸、撲酸、泛酸、果膠酸、苦味酸、丙酸、聚半乳糖醛酸、水楊酸、硬脂酸、琥珀酸、單寧酸、酒石酸、茶氯酸、硫氰酸、三氟乙酸、對甲苯磺酸、十一碳酸、天冬醯胺酸或麩胺酸之鹽。較佳係可舉例如與草酸、馬來酸、檸檬酸、富馬酸、乳酸、蘋果酸、琥珀酸、酒石酸、乙酸、三氟乙酸、安息香酸、葡萄糖醛酸、油酸、撲酸、甲烷磺酸、苯磺酸、對甲苯磺酸或2-羥基-1-乙烷磺酸之鹽。
與無機鹼之鹽係例示與鋰、鈉、鉀、鎂、鈣、鋇、鋁、鋅、鉍或銨之鹽。較佳係可舉例如與鈉、鉀、鈣、鎂或鋅之鹽。
與有機鹼之鹽可例示與檳榔鹼、甜菜鹼、膽鹼、氯下咪唑(clemizole)、乙二胺、N-甲基還原葡糖胺、N-苯甲基苯乙基胺、參(羥基甲基)甲基胺、精胺酸或離胺酸之鹽。較佳係可舉例如與參(羥基甲基)甲基胺、N-甲基還原葡糖胺或離胺酸之鹽。
式[I]之化合物或其製藥上所容許的鹽係有時存在為溶劑合物。所謂「溶劑合物」係在式[I]之化合物或其製藥上所容許的鹽配位溶劑 分子者,亦包含水合物。溶劑合物係以製藥上所容許的溶劑合物為較佳,可舉例如式[I]之化合物或其製藥上所容許的鹽之水合物、乙醇合物、及二甲基亞碸合物等。具體而言,可舉例如式[I]之化合物之半水合物、1水合物、2水合物或1乙醇合物、或式[I]之化合物的鈉鹽之1水合物或2鹽酸鹽之2/3乙醇合物等。此等溶劑合物係可依據公知之方法獲得。
式[I]之化合物係可以同位素元素(2H、3H、14C、35S等)標識。
式[I]之化合物或其製藥上所容許的鹽較佳係實質上被純化之式[I]之化合物或其製藥上所容許的鹽。更佳係被純化至80%以上之純度的式[I]之化合物或其製藥上所容許的鹽。
式[I]之化合物或其製藥上所容許的鹽係因具有SGLT1抑制活性,故對藉由SGLT1活性之調節而可期待改善之各種疾病或狀態、例如糖尿病(例如1型糖尿病及2型糖尿病)、肥胖症、糖尿病性併發症(例如已知為細小血管症之網膜症、腎症及神經障礙、以及已知為大血管症之腦血管障礙、缺血性心疾病及下肢閉塞性動脈硬化症)、肥大型心肌症、缺血性心疾病、癌及便秘之治療及/或預防上有用。
所謂「抑制SGLT1」係意指抑制SGLT1之機能而使其活性消失或減弱,例如意指依據後述之試驗例1的條件,抑制SGLT1之機能。所謂「抑制SGLT1」較佳係「抑制人類SGLT1」。機能之抑制或活性的消失或減弱較佳係以人類之臨床適應進行。
所謂「SGLT1抑制劑」係只要為抑制SGLT1之物質即可,可為低分子化合物、核酸、多肽、蛋白質、抗體、疫苗等。所謂「SGLT1抑制」較佳係「人類SGLT1抑制劑」。
式[I]之化合物或其製藥上所容許的鹽對由於血糖值變高所引起之各種疾病或狀態之治療及/或預防上亦有用。
「由於血糖值變高所引起之各種疾病或狀態」可舉例如糖尿病(例如1型糖尿病及2型糖尿病)、肥胖症、及糖尿病性併發症(例如已知為細小血管症之網膜症、腎症及神經障礙、以及已知為大血管症之腦血管障礙、缺血性心疾病及下肢閉塞性動脈硬化症)。
在本說明書中所謂「治療」係包含症狀之改善、重症化之防止、緩解之維持、復發之防止、及再發之防止。
在本說明書中,所謂「預防」係包含抑制症狀之發病。例如所謂「糖尿病之預防」係包含對耐糖能異常之2型糖尿病的併發症之抑制。
本說明書中之醫藥組成物可在醫藥製劑之技術領域依據公知之方法,藉由使治療上有效量之式[I]之化合物或其製藥上所容許的鹽與至少1種以上之製藥上所容許的載體等適當混合等而製造。該醫藥組成物中之式[I]之化合物或其製藥上所容許的鹽之含量係依劑形、投與量等而異,但例如為組成物整體之0.1至100重量%。
式[I]之化合物或其製藥上所容許的鹽之劑形係可舉例如錠劑、膠囊劑、顆粒劑、散劑、口含劑、糖漿劑、乳劑、懸浮劑等經口劑、及外用劑、坐劑、注射劑、點眼劑、經鼻劑、經肺劑等非經口劑。
「製藥上所容許的載體」係可舉例如慣用之各種有機或無機載體物質作為製劑材料,固形製劑中之賦形劑、崩壞劑、結合劑、流動化劑、滑澤劑等;及液狀製劑中之溶劑、溶解補助劑、懸浮化劑、等張化劑、緩衝劑、止痛劑等及半固形製劑中之基劑、乳化劑、濕潤劑、安定劑、安定化劑、分散劑、可塑劑、pH調節劑、吸收促進劑、凝膠化劑、防腐劑、填充劑、溶解劑、溶解補助劑、懸浮化劑等。再者依需要亦可追加保存劑、抗氧化劑、著色劑、甘味劑等添加物。
「賦形劑」係可舉例如乳糖、白糖、D-甘露醇、D-山梨醇、玉米澱粉、糊精、微結晶纖維素、結晶纖維素、羧甲基纖維素、羧甲基纖維素鈣、羧基甲基澱粉鈉、低取代度羥基丙基纖維素及阿拉伯橡膠等。
「崩壞劑」係可舉例如羧甲基纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、羧基甲基澱粉鈉、交聯羧甲基纖維素鈉、交聯聚乙烯吡咯啶酮(crospovidone)、低取代度羥基丙基纖維素、羥基丙基甲基纖維素、及結晶纖維素等。
「結合劑」係可舉例如羥基丙基纖維素、羥基丙基甲基纖維素、聚乙烯吡咯啶酮、結晶纖維素、白糖、糊精、澱粉、明膠、羧甲基纖維素鈉、及阿拉伯橡膠等。
「流動化劑」係可舉例如輕質無水矽酸、及硬脂酸鎂等。
「滑澤劑」可舉例如硬脂酸鎂、硬脂酸鈣、及滑石等。
「溶劑」可舉例如純化水、乙醇、丙二醇、聚乙二醇、芝麻油、玉米油、及橄欖油等。
「溶解補助劑」可舉例如丙二醇、D-甘露醇、安息香酸苯甲基、乙醇、三乙醇胺、碳酸鈉、及檸檬酸鈉等。
「懸浮化劑」可舉例如氯化苄烷銨、羥甲基纖維素、羥丙基纖維素、丙二醇、聚乙烯吡咯啶酮、甲基纖維素、及單硬脂酸甘油等。
「等張化劑」可舉例如葡萄糖、D-山梨醇、氯化鈉、及D-甘露醇等。
「緩衝劑」可舉例如磷酸氫鈉、乙酸鈉、碳酸鈉、及檸檬酸鈉等。
「止痛劑」可舉例如苯甲基醇等。
「基劑」可舉例如水、動植物油(橄欖油、玉米油、落花生油、芝麻油、蓖麻油等)、低級醇類(乙醇、丙醇、丙二醇、1,3-丁二醇、酚等)、高級脂肪酸及其酯、臘類、高級醇、多價醇、烴類(白色凡士林、流動石蠟、石蠟等)、 親水凡士林、純化羊毛脂、吸水軟膏、加水羊毛脂、親水軟膏、澱粉、聚三葡萄糖、阿拉伯膠、黃耆膠、明膠、糊精、纖維素衍生物(甲基纖維素、羧基甲基纖維素、羥基乙基纖維素、羥基丙基纖維素等)、合成高分子(羧基乙烯聚合物、聚丙烯酸鈉、聚乙烯醇、聚乙烯吡咯啶酮等)、丙二醇、聚乙二醇(聚乙二醇200至600等)、及其等之2種以上之組合。
「保存劑」可舉例如對羥基安息香酸乙酯、氯丁醇、苯甲基醇、去氫乙酸鈉、及山梨酸等。
「抗氧化劑」可舉例如亞硫酸鈉、及抗壞血酸等。
「著色劑」可舉例如食用色素(食用紅色2號或3號、食用黄色4號或5號等)、及β-胡蘿蔔素等。
「甘味劑」可舉例如糖精鈉、甘草酸二鉀、及阿斯巴甜等。
本說明書中之醫藥組成物係可對人類以外之哺乳動物(鼠、小鼠、倉鼠、天竺鼠、兔子、貓、狗、豬、牛、馬、羊、猴等)及人類經口或非經口(局部、直腸、靜脈投與、肌肉內、皮下等)投與。投與量係依投與對象、疾病、症狀、劑形、投與路徑等而異,但例如對成人患者進行經口投與時之投與量,作為有效成分之式[I]的化合物係每1日通常約0.01mg至約1g之範圍。可將此等之量分成1次至數次而進行投與。
包含:含有式[I]之化合物或其製藥上所容許的鹽作為有效成分或活性劑之醫藥組成物、及記載可將該醫藥組成物使用或應使用於治療及/或預防之有關該醫藥組成物的記載物之套件(投與、治療及/或預防套件等)、包裝體(包裝物等)及藥劑組(及/或容器)亦為有用。如此之套件、包裝體及藥劑組係亦可具備填充有上述醫藥組成物或用以使用於上述醫藥組成物之1種以上的有效成分及其他之藥劑或藥物(或成分)的1種以上之容器。如此之套件、包裝體及藥劑組之例係可舉例如適合於對象疾病之治療 及/或預防之商業用套件、商業用包裝體及商業用藥劑套件。在如此之套件、包裝體及藥劑組所含之記載物,可舉例如醫藥或生物學性製品之製造、依據規定使用或販賣之政府機關所指示之形態的注意書或附件文書,有關投與於人類之製品的製造、顯示有關使用或販賣之該政府機關認可的注意書或附件文書。上述套件、包裝體及藥劑組係亦包含被包裝之製品,又,亦可包含適當的投與步驟(STEP)用所構成之構造物,或亦可包含:包含對象疾病之治療及/或預防等之可達成更佳之醫學上治療及/或預防之方式所構成的構造物。
將式[I]之化合物或其製藥上所容許的鹽之製造方法說明於以下。然而,式[I]之化合物或其製藥上所容許的鹽之製造方法並不限定於此等之製造方法。
在各步驟所得之化合物係可依需要而以蒸餾、再結晶、管柱色層分析術等公知之方法進行單離及/或純化,但視情況,可不單離及/或純化而進行後續步驟。
在本說明書中,所謂室溫係指不控制溫度之狀態的溫度,一個態樣係可舉例如1℃至40℃。
[製造方法A]
式[I]之化合物係可藉由以下流程圖所示之製造方法A1或A2來製造。
製造方法A1
(步驟A1-1)
式[I]之化合物係可藉由使式[1]之化合物或其鹽與式[2]之化合物或其鹽在溶劑中、縮合劑及添加劑存在下進行反應而製造。
縮合劑係可例示如二環己基碳二亞胺(DCC)、1-乙基-3-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽(WSC/HCl)、二異丙基碳二亞胺、1,1’-羰基二咪唑(CDI)、O-(7-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸鹽(HATU)、{{[(1-氰-2-乙氧基-2-側氧基亞乙基)胺基]氧基}-4-嗎啉基亞甲基}二甲基銨六氟磷酸鹽(COMU)、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基嗎啉鎓‧n水合物(DMT-MM)、六氟磷酸(苯并三唑-1-基氧基)三吡咯啶基鏻(PyBOP)、二苯基磷醯基疊氮、及丙基膦酸酐。
添加劑可例示如1-羥基苯并三唑(HOBt)、1-羥基-7-氮雜苯并三唑(HOAt)、N-羥基琥珀酸醯亞胺(HOSu)、4-二甲基胺基吡啶、及1-甲基咪唑。
溶劑係例示如氯仿等鹵化烴系溶劑;四氫呋喃等醚系溶劑;吡啶、乙腈、N,N-二甲基甲醯胺等極性溶劑;及此等之混合溶劑。
反應溫度係例如0℃至100℃。
使用式[1]之化合物的鹽時,只要在鹼存在下實施本反應即可。鹼係可例示如三乙胺等有機鹼、及碳酸鈉等鹼金屬鹽。
式[I]之化合物係可在溶劑中使用鹵化劑將式[2]之化合物轉換成羧酸鹵化物之後,在鹼存在下,藉由與式[1]之化合物反應的方法而製造。
使用於反應之鹵化劑可例示如草醯氯、及亞硫醯氯。較佳之鹵化劑為草醯氯。
使用於反應之鹼係例示如吡啶、三乙胺、N,N-二異丙基乙基胺等有機鹼;及碳酸氫鈉、碳酸鈉等鹼金屬鹽。較佳之鹼為吡啶。
溶劑係可例示如氯仿等鹵化烴系溶劑;環戊基甲基醚、四氫呋喃等醚系溶劑;甲苯等烴系溶劑;及此等與水之混合溶劑。較佳之溶劑為氯仿。
反應溫度係例如0℃至80℃,較佳係0℃至60℃。
在羧酸鹵化物之製造中,亦可添加N,N-二甲基甲醯胺作為添加劑。
製造方法A2
[式中,PN1為胺基之保護基。較佳之PN1為2,4-二甲氧基苯甲基。]
(步驟A2-1)
式[4]之化合物係可依照製造方法A1步驟A1-1,而從式[1]之化合物或其鹽及式[3]之化合物或其鹽製造。
(步驟A2-2)
式[I]之化合物或其鹽係可藉由將式[4]之化合物之PN1以去保護反應進行除去來製造。去保護反應係只要依照PN1之種類而以適合的條件實施即可。
例如,PN1為2,4-二甲氧基苯甲基時,式[I]之化合物或其鹽係可藉由在溶劑中添加劑存在下與酸反應來製造。
酸係可例示如甲烷磺酸、對甲苯磺酸及三氟乙酸。較佳之酸為三氟乙酸。
添加劑可例示如茴香醚及三乙基矽烷。較佳之添加劑為茴香醚。
溶劑可例示如二氯甲烷等鹵化烴系溶劑、甲苯等烴系溶劑、水、及此等之混合溶劑。亦可使用三氟乙酸等有機酸作為溶劑。
反應溫度係例如0℃至130℃,較佳係25℃至80℃。
在本步驟中,使用酸時,可獲得式[5]之化合物或其鹽。
式[I]之化合物或其鹽係可藉由公知之方法將式[5]之化合物或其鹽之羥基轉換成第三丁氧基來製造。
例如,式[I]之化合物或其鹽係可藉由在過氯酸鎂之存在下使式[5]之化合物或其鹽與二碳酸二第三丁酯反應來製造。
溶劑係可例示如氯仿等鹵化烴系溶劑、及四氫呋喃等醚系溶劑。較佳之溶劑為氯仿。
反應溫度係例如0℃至100℃,較佳係室溫至70℃。
[製造方法B]
式[1]之化合物係可藉由以下流程圖所示之製造方法B1來製造。
製造方法B1
[式中,L1為脫離基。較佳之L1為氯、溴或碘。PN2分別獨立地為胺之保護基。較佳係2個PN2為與其等鍵結之氮一起形成2,5-二甲基吡咯。]
(步驟B1-1)
式[7]之化合物係可藉由公知之方法而在式[6]之化合物或其鹽之胺基導入PN2來製造。保護基之導入係只要依照PN2之種類而以適當的條件實施即可。例如,2個PN2為與其等鍵結之氮一起形成2,5-二甲基吡咯時,式[7]之化合物係可使式[6]之化合物在溶劑中酸性條件下與2,5-己二酮反應而製造。
使用於反應之酸可例示如濃鹽酸、濃硫酸、醯胺硫酸、對甲苯磺酸、及乙酸。較佳之酸為乙酸。
溶劑可例示乙醇等醇系溶劑、四氫呋喃等醚系溶劑、甲苯等烴系溶劑、N,N-二甲基甲醯胺等極性溶劑、二氯乙烷等鹵化烴系溶劑、及此等之混合溶劑。亦可使用乙酸等有機酸作為溶劑。
反應溫度係例如室溫至150℃,較佳係80℃至140℃。
(步驟B1-2)
式[8]之化合物可藉由包含如下之方法來製造:例如在溶劑中鹼及觸媒之存在下使式[7]之化合物與二溴二氟甲烷進行反應之步驟(a);及在溶劑中、氟化四甲基銨或四氟硼酸銀(I)存在下進行氟化之步驟(b)。
在步驟(a)所使用之鹼係可例示如氫化鈉、及第三丁氧基鉀。較佳之鹼為氫化鈉。
在步驟(a)所使用之觸媒可例示如溴化四丁基銨、及鋅。較佳之觸媒為溴化四丁基銨。
在步驟(a)所使用之溶劑可例示如四氫呋喃等醚系溶劑、及N,N-二甲基甲醯胺等極性溶劑。較佳之溶劑為N,N-二甲基甲醯胺。
在步驟(a)之反應溫度係例如0℃至40℃,較佳係0℃至室溫。
步驟(b)之反應溫度,在使用氟化四甲基銨時,為例如80℃至180℃,較佳係100℃至140℃。使用四氟硼酸銀(I)時,為例如-78℃至50℃,較佳係-78℃至室溫。
(步驟B1-3)
式[9]之化合物係可藉由在溶劑中鹼存在下對式[8]之化合物導入L1來製造。例如L1為碘時,式[9]之化合物可藉由在溶劑中鹼存在下使式[8]之化合物進行碘化來製造。
使用於反應之鹼係例示如正丁基鋰、二異丙基胺化鋰、六甲基二矽氮化鋰、及四甲基哌啶鋰。較佳之鹼為正丁基鋰。
碘化劑可例示如碘、一氯化碘、N-碘琥珀醯亞胺、及1-氯-2-碘乙烷。較佳之碘化劑為碘。
溶劑可例示如四氫呋喃等醚系溶劑、甲苯等烴系溶劑、及此等之混合溶劑。較佳之溶劑為四氫呋喃。
反應溫度係例如-100℃至40℃,較佳係-78℃至20℃。
(步驟B1-4)
式[10]之化合物或其鹽係可藉由將式[9]之化合物之PN2以去保護反應進行除去來製造。去保護反應係只要依照PN2之種類而以適當的條件實施即可。例如,2個PN2為與其等鍵結之氮一起形成2,5-二甲基吡咯時,式[10]之化合物或其鹽係可藉由使式[9]之化合物在溶劑中與羥基胺反應而製造。
溶劑係可例示如乙醇等醇系溶劑、水、及此等之混合溶劑。較佳之溶劑為醇系溶劑與水之混合溶劑。
反應溫度係例如40℃至150℃,較佳係80℃至130℃。
亦可使用羥基胺鹽酸鹽取代羥基胺,其時,只要在鹼存在下實施本反應即可。鹼係可例示如三乙基胺等有機鹼、及碳酸鈉等鹼金屬鹽。較佳之鹼為三乙基胺。
(步驟B1-5)
式[1]之化合物或其鹽係可將式[10]之化合物或其鹽與式[11]之化合物經由鈴木偶合(coupling)反應而製造。例如,式[1]之化合物或其鹽係可藉由使式[10]之化合物或其鹽與式[11]之化合物在溶劑中、鹼及鈀觸媒之存在下反應而製造。
使用於反應之鈀觸媒係可例示如肆(三苯基膦)鈀、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)-二氯甲烷加成物、[1,1’-雙(二-第三丁基膦基)二茂鐵]二氯鈀(II)、及乙酸鈀(II)與三環己基膦、2-二環己基膦基-2’,6’-二甲氧基聯苯或2-二環己基膦基-2’,4’,6’-三異丙基聯苯之混合物。較佳之鈀觸媒係[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)-二氯甲烷加成物。
使用於反應之鹼可例示如磷酸三鉀、碳酸銫、碳酸鈉、碳酸氫鈉、碳酸鉀、及三乙胺。較佳之鹼為磷酸三鉀、碳酸銫或碳酸鈉。
溶劑可例示如1,4-二烷、四氫呋喃、二乙基醚、及1,2-二甲氧基乙烷等醚系溶劑;甲醇、乙醇、1-丙醇、及2-丙醇等醇系溶劑;甲苯、正-己烷、及二甲苯等烴系溶劑;N,N-二甲基甲醯胺、二甲基亞碸、及乙腈等極性溶劑;及此等與水之混合溶劑。較佳之溶劑為1,2-二甲氧基乙烷、甲苯、二甲基亞碸、或此等與水之混合溶劑。
反應溫度為例如20℃至150℃,較佳係80℃至130℃。
式[11]之化合物可依據公知之方法而製造。亦可使用對應之硼酸酯取代式[11]之化合物而進行步驟B1-5之反應。例如,硼酸酯係可藉由如下流程圖所示的製造方法B2來製造。
製造方法B2
[式中,R1為氟或羥基。L2為脫離基。較佳之L2為氯、溴、碘、對-甲苯磺醯氧、甲烷磺醯氧、或三氟甲烷磺醯氧。B(OR2)2為硼酸酯。R2例如分別獨立地為甲基、乙基、丙基、異丙基、正丁基、第二丁基或第三丁基、或OR2為可與其等鍵結之硼一起形成環狀硼酸酯。較佳之B(OR2)2為硼酸2,3-二甲-2,3-丁二醇酯。]
(步驟B2-1)
式[13]之化合物係可藉由將式[12]之化合物之R1轉換成第三丁氧基而製造。本反應係只要依據公知之方法而實施即可。
R1為氟時,式[13]之化合物係可藉由例如在溶劑中使式[12]之化合物與第三丁氧基鈉或第三丁氧基鉀反應而製造。溶劑係例示如四氫呋喃等醚 系溶劑;及N,N-二甲基甲醯胺、二甲基亞碸等極性溶劑。較佳之溶劑為N,N-二甲基甲醯胺。反應溫度係例如0℃至100℃,較佳係室溫至85℃。
R1為羥基時,式[13]之化合物係可藉由例如依據製造方法A2步驟A2-2記載之從式[5]之化合物或其鹽製造式[I]之化合物或其鹽的方法而製造。
(步驟B2-2)
式[14]之化合物係可藉由使式[13]之化合物與硼化合物在溶劑中鈀觸媒、有機磷化合物及鹼之存在下反應而製造。
鈀觸媒係例示如乙酸鈀(II)、氯化鈀(II)、及參(二亞苯甲基丙酮)二鈀(0)。
有機磷化合物例示如三苯基膦、三環己基膦、1,1’-雙(二苯基膦基)二茂鐵、2-二環己基膦基-2’,6’-二甲氧基聯苯、2-二環己基膦基-2’,4’,6’-三異丙基聯苯、及2-二環己基膦基-2’-(N,N-二甲基胺基)聯苯。
亦可使用肆(三苯基膦)鈀、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)-二氯甲烷加成物、或[1,1’-雙(二-第三丁基膦基)二茂鐵]二氯鈀(II)取代鈀觸媒及有機磷化合物。
鹼係例示如乙酸鉀、碳酸鈉、碳酸銫、及碳酸鉀。較佳之鹼為乙酸鉀。
硼化合物例示如雙(2,3-二甲-2,3-丁二醇合)二硼。
反應溫度係例如室溫至150℃,較佳係70℃至110℃。
[製造方法C]
式[2]之化合物或其鹽及式[3]之化合物或其鹽係可藉由如以下流程圖所示的製造方法C1而製造。
製造方法C1
[式中,PC1及PC2係分別獨立地為羧基之保護基。較佳之PC1及PC2係分別獨立地為甲基、乙基、第三丁基或苯甲基。R3分別獨立地為甲氧基或乙氧基。L3為脫離基。較佳之L3為溴或氯。其他各記號為與前述同意義。]
(步驟C1-1)
式[17]之化合物係可藉由在溶劑中鹼存在下使式[15]之化合物與式[16]之化合物反應而製造。
使用於反應之鹼係例示如第三丁氧基鉀、甲氧基鈉、乙氧基鈉、二異丙基胺化鋰、六甲基二矽氮化鉀、碳酸鉀、碳酸銫、及氫化鈉。較佳之鹼為第三丁氧基鉀。
溶劑係例示如四氫呋喃等醚系溶劑;甲醇、乙醇等醇系溶劑;及N,N-二甲基甲醯胺、二甲基亞碸等極性溶劑。較佳之溶劑為四氫呋喃。
反應溫度係例如-78℃至100℃,較佳係0℃至70℃。
(步驟C1-2)
式[18]之化合物係可藉由在溶劑中鹼存在下使式[17]之化合物與甲醛(較佳係甲醛水溶液)反應而製造。
使用於反應之鹼係例示如第三丁氧基鉀、甲氧基鈉、乙氧基鈉、二異丙基胺化鋰、六甲基二矽氮化鉀、碳酸鉀、碳酸銫及氫化鈉。較佳之鹼為碳酸鉀。
溶劑例示如四氫呋喃等醚系溶劑;甲醇、乙醇等醇系溶劑;及N,N-二甲基甲醯胺、二甲基亞碸等極性溶劑。較佳之溶劑為四氫呋喃。
反應溫度係例如-78℃至100℃,較佳係0℃至70℃。
(步驟C1-3)
式[20]之化合物係可藉由在溶劑中使化合物[18]與化合物[19]反應而製造。
溶劑係例示如甲苯等烴系溶劑;甲醇、乙醇等醇系溶劑;及此等之混合溶劑。較佳之溶劑為甲苯。
反應溫度係例如20℃至150℃,較佳係80℃至130℃。
(步驟C1-4)
化合物[21]或其鹽係可藉由將化合物[20]之PC1以去保護反應進行除去而製造。去保護反應係只要依照PC1之種類而以適合於各別之條件實施即可。例如,PC1為乙基時,化合物[21]或其鹽係可藉由在溶劑中鹼存在下使化合物[20]進行水解而製造。
使用於反應之鹼係例示如氫氧化鋰、氫氧化鈉、氫氧化鉀、及乙氧基鈉。較佳之鹼為乙氧基鈉。
溶劑係例示如乙醇等醇系溶劑、四氫呋喃等醚系溶劑、水、及此等之混合溶劑。較佳之溶劑係乙醇與水之混合溶劑。
反應溫度係例如0℃至100℃,較佳係0℃至40℃。
(步驟C1-5)
式[3]之化合物或其鹽係可藉由從式[21]之化合物或其鹽進行分離而得。式[3]之化合物或其鹽之分離係只要藉由該領域為人所熟知之方法以適合於其分離之條件實施即可。例如,式[3]之化合物或其鹽係可藉由作成與鹼性光學解析劑所成之非鏡像異構物鹽並分離後,將該鹽以酸進行分解而得。
鹼性光學解析劑係例示如(1R,2R)-(-)-2-胺基-1-(4-硝基苯基)-1,3-丙二醇。
使用於衍生為非鏡像異構物鹽的溶劑係例示如2-丙醇等醇系溶劑、1,2-二甲氧基乙烷等醚系溶劑、乙腈等極性溶劑、及此等與水之混合溶劑。較佳之溶劑為乙腈、1,2-二甲氧基乙烷或此等與水之混合溶劑。
該非鏡像異構物鹽係可藉由再結晶提高其光學純度。使用於再結晶之溶劑例示如1,2-二甲氧基乙烷等醚系溶劑、乙腈等極性溶劑、及此等與水之混合溶劑。較佳之溶劑為乙腈與水之混合溶劑。
使用於非鏡像異構物鹽之分解的酸係例示如鹽酸、硫酸、及硫酸氫鉀。較佳之酸為鹽酸。
使用於非鏡像異構物鹽之分解的溶劑係例示如乙酸乙酯等酯系溶劑、四氫呋喃等醚系溶劑、水、及此等之混合溶劑。較佳之溶劑為乙酸乙酯與水之混合溶劑。
(步驟C1-6)
式[2]之化合物或其鹽係可藉由將式[3]之化合物或其鹽之PN1以去保護反應進行除去而製造。去保護反應係只要依照PN1之種類而以適宜的條 件實施即可。例如,PN1為2,4-二甲氧基苯甲基時,式[2]之化合物或其鹽係可依據製造方法A2步驟A2-2而製造。
以下,舉出製造例、實施例、參考例、試驗例及製劑例而更詳細說明本發明,但本發明並非受此等限定。
在此,將在本說明書所使用之簡稱的意義表示於下。
DMF:N,N-二甲基甲醯胺
DMSO:二甲基亞碸
THF:四氫呋喃
CPME:環戊基甲基醚
1H-NMR光譜係在CDCl3或DMSO-d6中以四甲基矽烷作為內部標準而測定,將全δ值以ppm表示。又,只要無特別記載,係以400MHz之NMR裝置測定。實施例中之記號如以下之意義。
s:單峰(singlet)
d:雙峰(doublet)
t:三峰(triplet)
q:四峰(quartet)
dd:雙雙峰(double doublet)
ddd:雙雙雙峰(double double doublet)
brs:寬單峰(broad singlet)
m:複峰(multiplet)
J:偶合常數(coupling constant)
[製造例1]2-(3-(第三丁氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷之製造
(步驟1)1-溴-3-(第三丁氧基)-5-氟苯之製造
在氬氣氣流下在室溫於3-溴-5-氟酚(500mg)中依序加入二碳酸二-第三丁酯(1.14g)、過氯酸鎂(58mg)。將該反應混合物在50℃攪拌1小時20分鐘。在該反應混合液中於50℃加入二碳酸二-第三丁酯。將該反應混合液在50℃攪拌1小時,再於65℃攪拌1小時,冷卻至室溫。在該反應混合液中室溫下加入二碳酸二-第三丁酯。將該反應混合液在65℃攪拌3小時。將該反應混合液冷卻至室溫,加入正己烷/乙酸乙酯(1/1)混合液。將該反應混合液以3N鹽酸、飽和碳酸氫鈉水溶液、飽和食鹽水依序洗淨,以硫酸鈉乾燥,濃縮。藉由將該殘渣以矽膠管柱色層分析(展開溶劑:正己烷/乙酸乙酯=1/0至20/1)進行純化,獲得標題化合物(437mg)收率68%。
1H-NMR(CDCl3)δ:1.35(s,9H),6.62-6.66(m,1H),6.92-6.98(m,2H).
(步驟2)2-(3-(第三丁氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷之製造
在步驟1所得之1-溴-3-(第三丁氧基)-5-氟苯(437mg)的DMSO(5mL)溶液中,於氬氣環境下在室溫依序加入乙酸鉀(434mg)、雙(2,3-二甲-2,3-丁二醇合)二硼(898mg)、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)/二氯甲烷加成物(144mg)。將該反應混合液在90℃攪拌2.5小時。將該反應混合液冷卻至室溫。在該反應混合液中依序加入正己烷/乙酸乙酯(1/1)混合液、水。將該反應混合液在室溫攪拌50分鐘,靜置整夜。在該反應混合液中依序加入正己烷/乙酸乙酯(1/1)混合液、水、矽膠及矽鈣石(Celite)。攪拌該反應混合液後,濾去不溶物,將該不溶物以正己烷/乙酸乙酯(1/1)混合液洗淨。將該濾液以正己烷/乙酸乙酯(1/1)混合液萃取。將該有機層依序以水洗淨2次,以飽和食鹽水洗淨,以硫酸鈉乾燥,濃縮。藉由將該殘渣以矽膠薄層色層分析(展開溶劑:正己烷/乙酸乙酯=10/1)純化,獲得標題化合物(443mg)收率85%。
1H-NMR(CDCl3)δ:1.33(s,12H),1.36(s,9H),6.77-6.82(m,1H),7.18-7.23(m,2H).
[製造例2](3R,4R)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸之製造
(步驟1)2-甲基-3-亞甲基琥珀酸 二乙基酯之製造
在氮氣流下於第三丁氧基鉀(180g)中在室溫加入THF(2.55L)。在該混合液中冰冷下以13分鐘滴入膦乙酸三乙酯(314g)。將所使用之滴下漏斗以THF(511mL)洗淨,將洗淨液加入反應混合液中。將該反應混合液在冰冷下攪拌2小時9分鐘。在該反應混合液中在冰冷下以20分鐘滴下2-溴丙酸乙酯(247g)。將所使用之滴下漏斗以THF(79mL)洗淨,將洗淨液加入反應混合液中。將該反應混合液在室溫下攪拌22小時45分鐘。在該反應混合液中冰冷下以1分鐘加入碳酸鉀(188g)。在該反應混合液中冰冷下以10分鐘滴下37重量%甲醛水溶液(152mL)。將該反應混合液在室溫攪拌19小時44分鐘。在該反應混合液中在室溫以1分鐘加入水(1.57L)。將該反應混合液在室溫攪拌1小時48分鐘。使該反應混合液分層。將該水層以THF(200mL)萃取2次。合併所得之有機層並濃縮。在該殘渣中加入甲苯(471mL)與飽和食鹽水(471mL)。攪拌該反應混合液,經分層。將該有機層以硫酸鈉(63g)乾燥。濾去該硫酸鈉。另外,將使用膦乙酸三乙酯(300g)同樣地進行反應而得之濾液,與上述所得之濾液合併,藉此,獲得標題化合物(相當於2.66mol)之甲苯溶液(約921mL)。以所得之標題化合物的甲苯溶液為收率100%使用於如下步驟。標題化合物之生成係經HPLC分析確認。
將HPLC之測定機器及條件表示於下。
測定機器:HPLC系統 島津製作所 高速液體色層分析Prominence
測定條件:
管柱:Kinetex C18:2.6μm,50mm×2.1mm(Phenomenex)
管柱溫度:40℃
流速:0.4mL/min.
分析時間:10min.
檢測波長:UV(220nm)
移動相:(A液)水、(B液)乙腈
移動相之送液:A液及B液之混合比(A液/B液(體積%))係注入後從0分鐘至0.01分鐘保持80/20,0.01分鐘至7分鐘期間從80/20直線性變化至10/90為止,7分鐘至8分鐘係保持10/90,8分鐘至9分鐘期間從10/90直線性變化至80/20,9分鐘至10分鐘係保持80/20。
上述HPLC測定條件之標題化合物的保持時間約為3.7分鐘。
(步驟2)(順式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸乙酯及(反式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸乙酯之混合物的製造
在步驟1所得之2-甲基-3-亞甲基琥珀酸二乙酯(相當於2.66mol)之甲苯溶液(約921mL)中氮氣流下在室溫以2分鐘滴入2,4-二甲氧基苯甲基胺(468g)。將該反應混合液在120℃攪拌5小時45分鐘。將該反應混合液在 室溫靜置一週末。將該反應混合液冰冷,使內溫為約15℃。在該反應混合液中滴入2N鹽酸(1.33L),攪拌。將該反應混合液分層。將該水層以甲苯(150mL)萃取。合併所得之有機層,以飽和食鹽水與水之混合液(600mL、飽和食鹽水/水=1/1)洗淨,以硫酸鈉(120g)乾燥,濃縮,在室溫下減壓乾燥整夜,獲得標題化合物之粗生成物(790g;順式/反式=約1/1,包含5.5重量%之甲苯)。標題化合物之生成可藉由HPLC分析確認。
HPLC之測定機器及條件表示於以下。
測定機器:HPLC系統 島津製作所 高速液體色層分析Prominence
測定條件:
管柱:Atlantis T3:5μm,150mm×4.6mm(Waters)
管柱溫度:40℃
流速:1.15mL/min.
分析時間:18min.
檢測波長:UV(220nm)
移動相:(A液)10mM 磷酸(鈉)緩衝液(pH=2.6)、(B液)乙腈
移動相之送液:A液及B液之混合比(A液/B液(體積%))係注入後從0分鐘至0.5分鐘保持60/40,從0.5分鐘至8分鐘從60/40直線性變化至10/90,8分鐘至12.5分鐘保持10/90,從12.5分鐘至13.5分鐘從10/90直線性變化至60/40,從13.5分鐘至18分鐘保持60/40。
上述HPLC測定條件中之(順式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸乙酯的保持時間約為6.6分鐘,(反式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸乙酯之保持時間約為6.9分鐘。
(步驟3)(反式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸之製造
在步驟2所得之(順式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸乙酯及(反式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸乙酯之混合物的粗生成物(790g,包含5.5重量%之甲苯)中氮氣流下在室溫下加入乙醇(1.15L)。在該反應混合液中室溫下以31分鐘滴入乙氧基鈉(20重量%乙醇溶液,1.15L)。將該反應混合液在室溫下攪拌2小時57分鐘。冰冷該反應混合液,將水(1.84L)以33分鐘滴下。在該反應混合液中在室溫下加入CPME(1.8L)及甲苯(1.8L),進行分層(有機層1)。在該水層中加入CPME(1.8L),經分層(有機層2)。從該水層將溶劑餾去1.8L。在該水層於冰冷下滴入6N鹽酸(110mL),加入乙酸乙酯(1.8L)。在該混合液中冰冷下滴入6N鹽酸(300mL),攪拌約10分鐘。在該混合液於冰冷下依序加入水(2.2L)、6N鹽酸(50mL)、水(1.0L)、10重量%硫酸氫鈉水溶液(300mL)、乙醇(300mL)。將該混合液在室溫攪拌整夜。於該混合液中加入乙酸乙酯(600mL),經分層。將該水層以乙酸乙酯(600mL)萃取2次。合併所得之有機層(但,排除有機層1及有機層2),以飽和食鹽水與水之混合液(1L、飽和食鹽水/水=1/1)洗淨。在該有機層中加入硫酸鈉(120g)與活性碳(30g),在室溫攪拌1小時。將該混合液通過矽鈣石而過濾,濾去不溶物。將該不溶物以乙酸乙酯(3L)洗淨。合併所得之濾液並濃縮,在室溫下減壓乾燥3小時,獲得標題化合物之粗生成物(561g)。
另外,合併上述有機層1與有機層2並濃縮。在該殘渣中加入甲苯(450mL)與水(450mL),經分層。將該水層以甲苯(450mL)洗淨2次。在該水層中加入乙酸乙酯(450mL)。在該混合液中冰冷下滴入6N鹽酸(70mL)。在該混合液中加入乙酸乙酯(300mL),經分層。將該水層以乙酸乙酯(150mL)萃取。合併所得之乙酸乙酯之有機層,以飽和食鹽水與水之混合液(225mL、飽和食鹽水/水=1/1)洗淨。在該有機層中加入硫酸鈉(30g)與活性碳(7.5g),在室溫下攪拌1小時。過濾該混合液,濾去不溶物。將該不溶物以乙酸乙酯(750mL)洗淨。合併所得之濾液並濃縮,在室溫下減壓乾燥3小時,獲得標題化合物之粗生成物(87.3g)。
於該粗生成物與上述所得之標題化合物的粗生成物合併之混合物中,在氮氣流下加入CPME(3L)。將該混合液在120℃攪拌。將該混合液攪拌17小時34分鐘,徐緩冷卻至室溫。冰冷該混合液而在內溫約1℃攪拌3小時。濾取該析出物,以經冷卻之CPME(900mL)洗淨。將該析出物在50℃減壓乾燥整夜,以3步驟收率75%獲得標題化合物(585g)。標題化合物之生成係經HPLC分析及NMR確認。
HPLC之測定機器及條件係與步驟2相同。在本HPLC測定條件之標題化合物的保持時間約為3.1分鐘。
1H-NMR(CDCl3)δ:1.33(d,3H,J=6.5Hz),2.68-2.85(m,2H),3.33-3.48(m,2H),3.80(s,6H),4.43(s,2H),6.42-6.46(m,2H),7.11-7.15(m,1H).
(步驟4)(3R,4R)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸與(1R,2R)-(-)-2-胺基-1-(4-硝基苯基)-1,3-丙烷二醇之非鏡像異構物鹽的製造
在步驟3所得之(反式)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸(585g)中在氮氣流、室溫下加入乙腈(2.9L)。將該混合液在85℃下攪拌。於該混合液中在85℃下以14分鐘加入(1R,2R)-(-)-2-胺基-1-(4-硝基苯基)-1,3-丙二醇(254g)。將該反應混合液在90℃攪拌2小時48分鐘。將該反應混合液攪拌整夜,冷卻至室溫。濾取該析出物,以乙腈(2.4L)洗淨。將該析出物在室溫、常壓乾燥8.5小時,獲得標題化合物之粗結晶(516g)。於該粗結晶中在氮氣流、室溫下加入乙腈(2.5L)與水(0.5L)。將該混合液在100℃攪拌1小時14分鐘。在該混合液中在100℃以1小時7分鐘滴下乙腈(1.5L)。將該混合液在100℃攪拌10分鐘。將該混合液攪拌21小時10分鐘,冷卻至室溫。將該混合液在冰冷下攪拌3小時54分鐘。濾取該析出物,以乙腈(1.5L)洗淨。將該析出物在室溫、常壓乾燥4小時,獲得標題化合物(448g、99.8%de)收率45%。標題化合物之生成係經HPLC分析確認。
HPLC之測定機器及條件表示於以下。
測定機器:HPLC系統 島津製作所 高速液體色層分析Prominence
測定條件:
管柱:CHIRAL PAK AD-3R:3μm,150mm×4.6mm(Daicel)
管柱溫度:40℃
流速:0.50mL/min.
分析時間:10min.
檢測波長:UV(220nm)
移動相:(A液)10mM 磷酸(鈉)緩衝液(pH=2.6)、(B液)乙腈
移動相之送液:A液及B液之混合比(A液/B液(體積%))係保持60/40。
上述HPLC測定條件中之(3R,4R)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸的保持時間約為5.6分鐘,(3S,4S)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸之保持時間約為6.5分鐘。
標題化合物之立體構造係依據從甲基異丁基酮進行再結晶所得之單結晶的X線結晶構造解析而決定。
非鏡像異構物過剩率係依據本測定結果之HPLC面積百分率而決定((3R,4R)體/(3S,4S)體=99.886%/0.114%)。
(步驟5)(3R,4R)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸之製造
在步驟4所得之(3R,4R)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸與(1R,2R)-(-)-2-胺基-1-(4-硝基苯基)-1,3-丙二醇之非鏡像異構物鹽(448g)中在室溫下加入乙酸乙酯(1.8L)與水(1.34L)。在該混合液中室溫下以16分鐘滴下6N鹽酸(168mL)。使該混合液分層。將該水層以乙酸乙酯(450mL)萃取3次。合併所得之有機層,以2N鹽酸(224mL)、飽和食鹽水(224mL)依序洗淨,以硫酸鈉(90g)乾燥,濃縮。在該殘渣中加入甲苯(220mL),經濃縮。將該殘渣在室溫下減壓乾燥,獲得標題化合物(254g)收率98%。
1H-NMR(DMSO-D6)δ:1.15(d,3H,J=7.2Hz),2.50-2.58(m,1H),2.73-2.83(m,1H),3.18-3.25(m,1H),3.30-3.38(m,1H),3.75(s,3H),3.77(s,3H),4.19-4.35(m,2H),6.48(dd,1H,J=8.4,2.3Hz),6.56(d,1H,J=2.3Hz),7.00(d,1H,J=8.4Hz),12.61(br s,1H).
[實施例1](3R,4R)-N-(5-(3-(第三丁氧基)-5-氟苯基)-1-(三氟甲基)-1H-吡唑-3-基)-4-甲基-5-側氧基吡咯啶-3-甲醯胺之合成
(步驟1)3-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑之製造
在1H-吡唑-3-胺(100g)中室溫下加入乙酸(1L),攪拌5分鐘。在該混合液中室溫下加入2,5-己二酮(148mL),攪拌5分鐘。將該反應混合液在120℃攪拌2.5小時,冷卻至室溫。該反應混合液中室溫下加入水(1L)。將該反應混合液在室溫下攪拌50分鐘。濾取經析出之固體,以水(1L)洗淨。將所得之濕固體在室溫、常壓下乾燥整夜後,在65℃減壓乾燥3日與8.5小時,獲得標題化合物(172.47g)收率89%。
1H-NMR(CDCl3)δ:2.11(s,6H),5.90(s,2H),6.25(d,1H,J=2.4Hz),7.51(d,1H,J=2.4Hz).
(步驟2)1-(溴二氟甲基)-3-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑及1-(溴二氟甲基)-5-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑之混合物的製造
氬氣氣流下、冰冷下將DMF(100mL)加入氫化鈉(14.9g)中。在該混合液中將步驟1所得之3-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑(40g)的DMF(150mL)懸浮液在冰冷下以20分鐘滴下。以DMF(50mL)洗淨所使用之滴下漏斗,將洗淨液加至反應混合液。將該反應混合液在水冷下攪拌1.5小時。在該反應混合液中冰冷下加入溴化四丁基銨(0.80g)。將該反應混合液在冰冷下攪拌15分鐘。在該反應混合液中將二溴二氟甲烷(45mL)之DMF(50mL)溶液在冰冷下以15分鐘滴下。將該反應混合液在水冷下攪拌2小時10分鐘。在該反應混合液中氬氣環境下將二溴二氟甲烷(20mL)在水冷下滴下。將該反應混合液在水冷下攪拌40分鐘後,靜置整夜。在該反應混合液中在冰冷下加入飽和氯化銨水溶液(200mL)。在該反應混合液中加入乙酸乙酯及水。將該反應混合液通過矽鈣石而過濾,經分層。將該水層以乙酸乙酯萃取。合併所得之有機層,再於其中加入飽和食鹽水。將該混合液通過矽鈣石並過濾,經分層。將該水層以乙酸乙酯萃取。合併所得之有機層並以硫酸鈉乾燥,經濃縮。在該殘渣中加入甲苯(250mL),經濃縮。再度進行該作業。在該殘渣中加入乙酸乙酯(約150mL),濾去不溶物。將該不溶物以乙酸乙酯洗淨。合併所得之濾液並濃縮。一邊攪拌該殘渣一邊在室溫下減壓乾燥10分鐘。藉由將該殘渣以矽膠管柱色層分析(展開溶劑:正己烷/乙酸乙酯=30/1至20/1)純化,獲得標題化合物(40.6g、包含3.7重 量%的己烷之1-(溴二氟甲基)-3-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑:1-(溴二氟甲基)-5-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑=約3:1)收率54%。
1H-NMR(CDCl3)δ:2.03(s,1.5H),2.18(s,4.5H),5.89(s,1.5H),5.91(s,0.5H),6.39-6.41(m,1H),7.86-7.88(m,1H).
(步驟3)3-(2,5-二甲基-1H-吡咯-1-基)-1-(三氟甲基)-1H-吡唑及5-(2,5-二甲基-1H-吡咯-1-基)-1-(三氟甲基)-1H-吡唑之混合物的製造
在步驟2所得之1-(溴二氟甲基)-3-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑及1-(溴二氟甲基)-5-(2,5-二甲基-1H-吡咯-1-基)-1H-吡唑之混合物(40.6g、包含3.7重量%之己烷)的環丁碸(400mL)溶液中在氬氣氣流下室溫下加入氟化四甲基銨(13.0g)。將該反應混合液在100℃攪拌1小時。在該反應混合液中在100℃下追加氟化四甲基銨(9.4g)。將該反應混合液在100℃下攪拌1小時15分鐘。在該反應混合液中在100℃追加氟化四甲基銨(10g)。將該反應混合液在100℃攪拌40分鐘。再者,於該反應混合液中在100℃追加氟化四甲基銨(5g)。將該反應混合液在100℃攪拌2小時5分鐘,冷卻至室溫。在該反應混合液中冰冷下依序徐緩加入水(400mL)及飽和碳酸氫鈉水溶液(200mL)。在該反應混合液中加入正己烷/乙酸乙酯(2/3)混合液(400mL)。使該反應混合液通過矽鈣石並過濾,經分層。將該有機層以飽和食鹽水洗淨。合併所得之水層,以正己烷/乙酸乙酯(2/3)混合液(300mL)萃取。將該有機層以飽和食鹽水洗淨。合併所得之有機層,以硫酸鈉乾燥、濃縮。將該殘渣以矽膠管柱色層分析(展開溶劑:正己烷/乙酸乙酯=30/1至25/1)純化,藉此,獲得標題化合物(21.85g,包含24.4重量%之 正己烷之3-(2,5-二甲基-1H-吡咯-1-基)-1-(三氟甲基)-1H-吡唑:5-(2,5-二甲基-1H-吡咯-1-基)-1-(三氟甲基)-1H-吡唑=約6:1)收率51%。
1H-NMR(CDCl3)δ:2.00(s,0.86H),2.16(s,5.1H),5.89(s,1.7H),5.91(s,0.29H),6.40(d,0.86H,J=2.8Hz),6.42(d,0.14H,J=1.6Hz),7.83(d,0.14H,J=1.6Hz),7.87(d,0.86H,J=2.8Hz).
(步驟4)3-(2,5-二甲基-1H-吡咯-1-基)-5-碘-1-(三氟甲基)-1H-吡唑之製造
在步驟3所得之3-(2,5-二甲基-1H-吡咯-1-基)-1-(三氟甲基)-1H-吡唑及5-(2,5-二甲基-1H-吡咯-1-基)-1-(三氟甲基)-1H-吡唑之混合物(21.85g,包含24.4重量%之正己烷)之THF(180mL)溶液中,氬氣環境下在-70℃以5分鐘滴下正丁基鋰之正己烷溶液(1.55M、51.1mL)。將該反應混合液在-70℃攪拌25分鐘。在該反應混合液中於-70℃下以5分鐘滴下碘(18.3g)之THF(50mL)溶液。以THF(10mL)洗淨所使用之滴下漏斗,將洗淨液加入於反應混合液中。將該反應混合液在-70℃攪拌30分鐘。在該反應混合液中於-70℃下追加碘(0.90g)。將該反應混合液在-70℃攪拌0.5小時。在該反應混合液中在-70℃依序加入水(250mL)、乙酸乙酯(250mL)。將該反應混合液在室溫攪拌,經分層。將該有機層以10重量%之亞硫酸氫鈉水溶液(250mL)、飽和食鹽水(150mL)依序洗淨,以硫酸鈉乾燥,經濃縮。將該殘渣以矽膠管柱色層分析(展開溶劑:正己烷/乙酸乙酯=50/1至30/1)純化。收集含有標題化合物之區份,並經濃縮。在該殘渣中加入正己烷。濃縮至 殘渣之重量成為27.5g。在該殘渣中加入正己烷(20mL)。將該懸浮液在室溫攪拌10分鐘。濾取該析出物,以正己烷(30mL)洗淨,進行減壓乾燥,獲得標題化合物(17.14g)收率67%。再者,濃縮該濾液。使該殘渣從正己烷結晶化,獲得標題化合物(1.63g)收率6.4%。
1H-NMR(CDCl3)δ:2.15(s,6H),5.88(s,2H),6.60(s,1H).
(步驟5)5-碘-1-(三氟甲基)-1H-吡唑-3-胺之製造
在步驟4所得之3-(2,5-二甲基-1H-吡咯-1-基)-5-碘-1-(三氟甲基)-1H-吡唑(18.77g)中在室溫依序加入乙醇與水之混合液(乙醇/水=2/1、480mL)、羥基胺‧鹽酸鹽(73.5g)、三乙基胺(14.7mL)。將該反應混合液在100℃攪拌38小時20分鐘。將該反應混合液冷卻至室溫,餾去乙醇。在該反應混合液中冰冷下徐緩加入氫氧化鈉(42.3g)之水(130mL)溶液,繼而加入乙酸乙酯(200mL)。攪拌該反應混合液之後,經分層。將該水層以乙酸乙酯(200mL)萃取。合併所得之有機層,以飽和食鹽水洗淨,以硫酸鈉乾燥,經濃縮。在該殘渣中加入乙酸乙酯(30mL)及正己烷(30mL),濾去不溶物。濃縮該濾液。將該殘渣以矽膠管柱色層分析(展開溶劑:正己烷/乙酸乙酯=4/1至3/1)純化,藉此,獲得標題化合物(16.27g,包含14重量%之乙酸乙酯)收率96%。
1H-NMR(CDCl3)δ:3.93(br s,2H),6.09(s,1H).
(步驟6)5-(3-(第三丁氧基)-5-氟苯基)-1-(三氟甲基)-1H-吡唑-3-胺之製造
在步驟5所得之5-碘-1-(三氟甲基)-1H-吡唑-3-胺(80mg,包含14重量%之乙酸乙酯)之甲苯(3mL)溶液中氬氣環境、室溫下依序加入[製造例1]之(步驟2)所得的2-(3-(第三丁氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(127mg)、乙酸鈀(II)(6.5mg)、2-二環己基膦基-2’,6’-二甲氧基聯苯(20mg)。將該反應混合液在室溫下攪拌4分鐘。在該反應混合液中室溫下加入2M磷酸三鉀水溶液(1.5mL)。將該反應混合液在90℃攪拌47分鐘。將該反應混合液冷卻至室溫。在該反應混合液中加入乙酸乙酯及飽和碳酸氫鈉水溶液。使該反應混合液通過綿栓並過濾,以乙酸乙酯萃取。將該有機層依序以飽和碳酸氫鈉水溶液、飽和食鹽水洗淨,以硫酸鈉乾燥,並濃縮。將該殘渣、及另外使用步驟5所得之5-碘-1-(三氟甲基)-1H-吡唑-3-胺(70mg,包含14重量%之乙酸乙酯)進行與本步驟同樣操作所得之標題化合物的一部分(15mg)合併,將該等以矽膠薄層色層分析(展開溶劑:正己烷/乙酸乙酯=3/1)純化,藉此,獲得標題化合物(108mg)。
1H-NMR(CDCl3)δ:1.36(s,9H),3.93(br s,2H),5.83(s,1H),6.75-6.85(m,3H).
(步驟7)(3R,4R)-N-(5-(3-(第三丁氧基)-5-氟苯基)-1-(三氟甲基)-1H-吡唑-3-基)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-甲醯胺之製造
氬氣環境下、在與[製造例2]之(步驟5)同樣方式所得之(3R,4R)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-羧酸(55mg)的氯仿(0.55mL)溶液中,冰冷下依序加入DMF(1μL)與草醯氯(33μL)。將該反應混合液在冰冷下攪拌50分鐘。濃縮該反應混合液,並減壓乾燥。在該殘渣中氬氣環境下、冰冷下依序加入氯仿(0.4mL)、步驟6所得之5-(3-(第三丁氧基)-5-氟苯基)-1-(三氟甲基)-1H-吡唑-3-胺(40mg)。在該反應混合液中冰冷下加入吡啶(50μL)。將該反應混合液在冰冷下攪拌5分鐘,在室溫攪拌35分鐘。在該反應混合液中室溫下加入飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將該有機層以飽和食鹽水洗淨,以硫酸鈉乾燥,並濃縮。將該殘渣以矽膠薄層色層分析(展開溶劑:正己烷/乙酸乙酯=1/1)純化,藉此,獲得標題化合物(60mg)收率80%。標題化合物之生成係經薄層色層分析確認(展開溶劑:正己烷/乙酸乙酯=2/1,Rf值:0.19)。
(步驟8)(3R,4R)-N-(5-(3-氟-5-羥基苯基)-1-(三氟甲基)-1H-吡唑-3-基)-4-甲基-5-側氧基吡咯啶-3-甲醯胺之製造
在步驟7所得之(3R,4R)-N-(5-(3-(第三丁氧基)-5-氟苯基)-1-(三氟甲基)-1H-吡唑-3-基)-1-(2,4-二甲氧基苯甲基)-4-甲基-5-側氧基吡咯啶-3-甲醯胺(60mg)中,室溫下加入苯甲醚(58μL)及三氟乙酸(2mL)。將該反應混合液在80℃攪拌1小時20分鐘。濃縮該反應混合液。在該殘渣中加入飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將該有機層以飽和食鹽水洗淨,以硫酸鈉乾燥,並濃縮。將該殘渣以矽膠薄層色層分析(展開溶劑:氯仿/乙酸乙酯=1/1)純化,藉此,獲得標題化合物(29.9mg)收率76%。
1H-NMR(DMSO-d6)δ:1.06(d,3H,J=7.2Hz),2.50-2.53(m,1H),2.96-3.04(m,1H),3.17-3.23(m,1H),3.40-3.46(m,1H),6.67-6.81(m,3H),6.96(s,1H),7.67(s,1H),10.34(s,1H),11.26(s,1H).
(步驟9)(3R,4R)-N-(5-(3-(第三丁氧基)-5-氟苯基)-1-(三氟甲基)-1H-吡唑-3-基)-4-甲基-5-側氧基吡咯啶-3-甲醯胺之製造
在步驟8所得之(3R,4R)-N-(5-(3-氟-5-羥基苯基)-1-(三氟甲基)-1H-吡唑-3-基)-4-甲基-5-側氧基吡咯啶-3-甲醯胺(30mg)中,在室溫下依序加入二碳酸二-第三丁酯、氯仿(1mL)、過氯酸鎂。將該反應混合物在55℃攪拌0.5小時。在該反應混合液中55℃下加入過氯酸鎂。將該反應混合液在55℃攪拌1小時10分鐘。在該反應混合液中55℃下進一步加入過氯酸鎂。將該反應混合液在55℃攪拌20分鐘。將該反應混合液在室溫下冷却,加入乙酸乙酯。將該反應混合液依序以1N鹽酸、飽和食鹽水洗淨,以硫酸鈉 乾燥,並濃縮。將該殘渣以矽膠薄層色層分析(展開溶劑:氯仿/甲醇=15/1)純化,藉此,獲得標題化合物(19.2mg)收率56%。
1H-NMR(DMSO-d6)δ:1.08(d,3H,J=7.2Hz),1.34(s,9H),2.51-2.55(m,1H),2.98-3.06(m,1H),3.19-3.25(m,1H),3.42-3.48(m,1H),6.95(s,1H),7.00-7.07(m,2H),7.11-7.17(m,1H),7.68(s,1H),11.28(s,1H).
MS(M+H)443,MS(M-H)441
(步驟10)(3R,4R)-N-(5-(3-(第三丁氧基)-5-氟苯基)-1-(三氟甲基)-1H-吡唑-3-基)-4-甲基-5-側氧基吡咯啶-3-甲醯胺之結晶的製造
將標題化合物(100mg)於乙醇(0.4mL)中65℃下攪拌8分鐘以使其溶解。在該混合溶液中在65℃下以2分鐘滴下水(0.4mL)。將該混合液在65℃攪拌10分鐘。將該混合液以2小時攪拌至25℃。進一步,將該混合液在室溫攪拌2小時。從該混合液濾取所析出之固體。將所得之固體以乙醇/水(=1/1)洗淨,在60℃進行減壓乾燥,以88%之收率獲得標題化合物之結晶(87.8mg)。
[參考例]
依據國際公開第2013/031922號公報之記載獲得下述表所示之化合物A、化合物B及化合物C。
分別依據本實施例1及國際公開第2013/031922號公報之記載所得之下述表所示之代謝物1(化合物1之代謝物)及代謝物C(化合物C之代謝物)。
[試驗例1]
被驗化合物之SGLT1抑制活性(IC50值)係基於藉由SGLT1所輸送之α-甲基-D-葡哌喃糖苷的標識體(14C-AMG)之細胞內攝入量而算出。
1)人類SGLT1表現質體之構築
以pCMV6-hSGLT1(OriGene公司)作為模板,在源自載體之Kozac consensus序列之前附加NheI辨識切斷序列,在人類SGLT1之蛋白質轉譯區域之後即附加終止密碼子TAG與SalI辨識切斷序列,且使含有人類SGLT1之DNA斷片藉由PCR(Polymerase Chain Reaction)增大。經純化之DNA斷片以限制酵素NheI與SalI消化之後,與以NheI與XhoI消化後之pcDNA3.1(+)鍵結而建構人類SGLT1表現質體pcDNA-hSGLT1。插入於載體之人類SGLT1的鹼基序列係與GenBank註冊之人類SGLT1序列(Accession number NM_000343)的蛋白質轉譯區域完全一致,又,與載體之連接部分的序列亦如想定。
2)人類SGLT1安定表現細胞株之樹立
分別使用Lipofectamine2000(invitrogen公司)以人類SGLT表現質體pcDNA-hSGLT1轉染CHO-K1細胞,在G418(Nacalai Tesque)存在下選出藥劑耐性細胞株。從所得之藥劑耐性細胞株選出每個細胞之14C-AMG攝入量、與添加作為SGLT抑制劑之phlorizin時的14C-AMG攝入量的比(S/B比)為最高的細胞株作為人類SGLT1安定表現細胞株。
3)SGLT1抑制活性之評價
在BioCoatTM Poly-D-Lysine 96 well plate with Lid(Becton,Dickinson and Company公司)以5×104cells/well接種人類SGLT1安定表現細胞株,在37℃、5% CO2培養一整晚。將培養基交換成100μL/well之Na(-)緩衝液(140mM氯化膽鹼、2mM KCl、1mM MgCl2、1mM CaCl2、 10mM HEPES、5mM Tris、pH7.4),在37℃,5%CO2靜置20分鐘。除去Na(-)緩衝液後,以40μL/well添加使用含有BSA之Na(+)緩衝液(140mM NaCl、2mM KCl、1mM MgCl2、1mM CaCl2、10mM HEPES、5mM Tris、pH7.4)調製而成的被驗物質溶液。再者,加入含有8kBq之14C-AMG及2mM AMG的Na(+)緩衝液40μL/well並混合。空白組(blank)係添加含有BSA之Na(-)緩衝液40μL/well,再者,加入含有8kBq之14C-AMG及2mM AMG的Na(-)緩衝液40μL/well並混合。在37℃、5%CO2靜置1小時後,以100μL/well之冰冷的沖洗緩衝液(100mM AMG、140mM choline chloride、2mM KCl、1mM MgCl2、1mM CaCl2、10mM HEPES、5mM Tris、pH7.4)洗淨細胞2次而停止反應。添加50μL/well之0.2N NaOH水溶液而調製細胞溶解產物(lysate)。14C-AMG之攝入能評估係以100μL/well分注MicroScint-40(Perkin-Elmer公司)之OptiPlate96(Perkin-Elmer公司)全量移轉細胞溶解產物,以TOPCOUNT NXT(Perkin-Elmer公司)測定14C之CPM。
從經各處置之井(well)的CPM之平均值減去空白組井的CPM之平均值而得之值作為數據。被驗物質之各濃度的抑制率係從以下之式算出:[(A-B)/A]×100
(式中,A表示溶劑對照之數據,B係表示被驗物質處置之數據)
被驗物質之IC50值(50%抑制濃度)係從包夾抑制率50%之2點的濃度與其抑制率算出。在本試驗中,確認化合物1具有SGLT1抑制活性。
[試驗例2]
OGTT(經口葡萄糖負荷試驗)
對絕食約4小時之雄性、SD小鼠(8週大、日本Charles River股份有限公司)(各群6例)以5mL/kg經口投與介質(0.5%甲基纖維素液)、或懸浮 於0.5%甲基纖維素液之化合物1(1、3或10mg/kg)。其16小時後,藉由將0.4g/mL之葡萄糖溶液以5mL/kg進行經口投與,形成葡萄糖負荷。於即將葡萄糖負荷之前、負荷後30分鐘、負荷後60分鐘及負荷後120分鐘從尾靜脈進行採血,使用生化學自動分析裝置(HITACHI、型式7180)測定血糖值。
將結果表示於第1圖。數據係表示相對於介質群,化合物投與群的葡萄糖負荷後120分為止之血糖值的曲線下面積(△AUC)之比率(% of Vehicle)之平均值±標準偏差。統計解析係進行Steel之多重檢測。顯著程度係設為兩側5%。其結果,與介質比較化合物1係使葡萄糖負荷後之血糖值明顯地降低。
[試驗例3]
OGTT(經口葡萄糖負荷試驗)
絕食約4小時之雄性、SD小鼠(8週大、日本Charles River股份有限公司)(各群5例)以5mL/kg經口投與介質(0.5%甲基纖維素液)、或懸浮於0.5%甲基纖維素液之化合物1、化合物A或化合物B(各3mg/kg)。其16小時後,藉由將0.4g/mL之葡萄糖溶液以5mL/kg進行經口投與,形成葡萄糖負荷。於即將葡萄糖負荷之前、負荷後30分鐘、負荷後60分鐘及負荷後120分鐘從尾靜脈進行採血,使用生化學自動分析裝置(HITACHI、型式7180)測定血糖值。
將結果表示於第2圖。數據係表示相對於介質群,化合物投與群的葡萄糖負荷後120分為止之血糖值的曲線下面積(△AUC)之比率(% of Vehicle)之平均值±標準偏差。統計解析係進行Steel之多重檢測。顯著程度係設為兩側5%。其結果,與介質比較,僅化合物1使葡萄糖負荷後之血糖值明顯地降低。
[試驗例4]
Ames試驗(回復突變試驗)
將代謝物1及代謝物C如以下般試驗。本試驗之目的係評估對於各代謝物,於Salmonella Typhimurium菌(TA98、TA1537、TA100及TA1535)及大腸菌(WP2uvrA)之標準菌株之小鼠肝代謝活性化系(S9 mix)之存在下或非存在下,回復突變引發能之有無。
在本試驗中係使用二甲基亞碸(DMSO,100μL/板盤)作為溶劑。
在S9 mix之存在下或非存在下使用預保溫法而進行試驗。在S9 mix非存在下之試驗中,係加入磷酸鈉緩衝液(pH7.4)。
將S9 mix 0.5mL或0.1mol/L磷酸鈉緩衝液(pH7.4)0.5mL及菌培養液0.1mL加入含有陰性對照物質(僅DMSO)0.1mL、代謝物或陽性對照物質之試驗管中。將該混合物在37℃一邊振盪20分鐘一邊預保溫。預保溫後,加入上層瓊脂2mL,將混合物以Vortex Mixer混合,接種在板盤上。各處理係使用2個板盤。將各板盤在37±1℃保溫48小時以上,計數回復突變菌落。然後,算出各處理板盤之回復突變菌落的平均數。以肉眼或實體顯微鏡觀察有無因被驗物質之抗菌作用所致之生育抑制及被驗物質之析出。顯示平均回復突變菌落數為1以上之用量超過陰性對照之2倍的用量依存的增加時,將結果評估為陽性。不使用統計性比較,而依據平均值進行評估。
將本試驗之結果表示於以下之表(表1至4及表5至7)。結果顯示,對試驗菌株之任一者,代謝物1均未顯示回復突變誘發能,相對於此,代謝物C係在S9 mix存在下對TA98及在S9 mix存在下對TA100之試驗菌株顯示回復突變誘發能。
+:S9 mix存在下
*:生育抑制
†:析出
DMSO:二甲基亞碸
B[a]P:苯并[a]吡喃
回復突變菌落數係表示各板盤之平均數
+:S9 mix存在下
*:生育抑制
†:析出
--:未試驗
DMSO:二甲基亞碸
2AA:2-胺基蒽
B[a]P:苯并[a]吡喃
回復突變菌落數係表示各板盤之平均數
+:S9 mix存在下
*:生育抑制
DMSO:二甲基亞碸
2AA:2-胺基蒽
回復突變菌落數係表示各板盤之平均數
--:未試驗
*:生育抑制
†:析出
DMSO:二甲基亞碸
AF-2:2-(2-呋喃基)-3-(5-硝基-2-呋喃基)丙烯醯胺
SA:疊氮化鈉
ICR-191:2-甲氧基-6-氯-9-[3-(2-氯乙基)-胺基丙基胺基]吖啶二鹽酸鹽
回復突變菌落數係表示各板盤之平均數
#:顯示平均回復突變菌落數為超過陰性對照之2倍的用量依存性的增加時,結果判斷為陽性
*:生育抑制
DMSO:二甲基亞碸
B[a]P:苯并[a]吡喃
回復突變菌落數係表示各板盤之平均數
--:未試驗
*:生育抑制
†:析出
DMSO:二甲基亞碸
2AA:2-胺基蒽
B[a]P:苯并[a]吡喃
回復突變菌落數係表示各板盤之平均數
--:未試驗
*:生育抑制
†:析出
DMSO:二甲基亞碸
AF-2:2-(2-呋喃基)-3-(5-硝基-2-呋喃基)丙烯醯胺
SA:疊氮化鈉
ICR-191:2-甲氧基-6-氯-9-[3-(2-氯乙基)-胺基丙基胺基]吖啶二鹽酸鹽
回復突變菌落數係表示各板盤之平均數。
[製劑例]
本發明化合物之製劑例係可舉例如下述之製劑配方。然而,本發明係不受此等製劑例限定。
製劑例1(膠囊之製造)
混合成分(1)、(2)、(3)及(4),填充於明膠膠囊。
製劑例2(錠劑之製造)
將成分(1)、(2)、(3)之全量及30g之成分(4)以水混練,真空乾燥後,進行整粒。在該整粒末中混合14g之成分(4)及1g之成分(5),藉由打錠機進行打錠。如此方式,獲得每1錠含有10mg化合物1之錠劑1000錠。
式[I]之化合物或其製藥上所容許的鹽係因具有SGLT1抑制活性,對期待藉由SGLT1活性之調節可改善之各種疾病或狀態的治療及/或預防上為有用。式[I]之化合物或其製藥上所容許的鹽亦對由於血糖值變高所引起之各種疾病或狀態的治療及/或預防上有用。
Claims (8)
- 一種醫藥組成物,係包含申請專利範圍第1項所述之化合物或其製藥上所容許的鹽、及製藥上所容許之載體。
- 一種Na+-葡萄糖共輸送載體1(SGLT1)抑制劑,係包含申請專利範圍第1項所述之化合物或其製藥上所容許的鹽。
- 一種糖尿病之治療劑或預防劑,係包含申請專利範圍第1項所述之化合物或其製藥上所容許的鹽。
- 如申請專利範圍第4項所述之治療劑或預防劑,其中,糖尿病為2型糖尿病。
- 一種申請專利範圍第1項所述之化合物或其製藥上所容許的鹽的使用,係用以製造Na+-葡萄糖共輸送載體1(SGLT1)抑制劑。
- 一種申請專利範圍第1項所述之化合物或其製藥上所容許的鹽的使用,係用以製造糖尿病之治療劑或預防劑。
- 如申請專利範圍第7項所述之使用,其中,糖尿病為2型糖尿病。
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JP7130588B2 (ja) | 2018-04-04 | 2022-09-05 | 日本たばこ産業株式会社 | ヘテロアリールで置換されたピラゾール化合物及びその医薬用途 |
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2019
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2021
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TWI549949B (zh) * | 2011-08-31 | 2016-09-21 | 日本煙草產業股份有限公司 | 吡唑化合物及其醫藥用途 |
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RU2020131756A (ru) | 2022-03-28 |
MA52427A (fr) | 2021-01-06 |
US20190352284A1 (en) | 2019-11-21 |
CA3087859A1 (en) | 2019-09-06 |
EP3760624A4 (en) | 2021-11-03 |
JP2023026566A (ja) | 2023-02-24 |
ZA202004600B (en) | 2022-03-30 |
IL276311A (en) | 2020-09-30 |
MX2020009070A (es) | 2020-10-08 |
SG11202007120UA (en) | 2020-08-28 |
AU2019227770A1 (en) | 2020-07-09 |
BR112020016788A2 (pt) | 2021-01-12 |
WO2019168096A1 (ja) | 2019-09-06 |
CN111757877A (zh) | 2020-10-09 |
KR20200128033A (ko) | 2020-11-11 |
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