TW201722935A - Cgrp受體拮抗劑 - Google Patents
Cgrp受體拮抗劑 Download PDFInfo
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- TW201722935A TW201722935A TW105135022A TW105135022A TW201722935A TW 201722935 A TW201722935 A TW 201722935A TW 105135022 A TW105135022 A TW 105135022A TW 105135022 A TW105135022 A TW 105135022A TW 201722935 A TW201722935 A TW 201722935A
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- Prior art keywords
- piperidin
- pyridin
- propan
- migraine
- amino
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Abstract
本文之揭示內容係關於下式之新穎化合物□其中R1、R2、R3與R4係如本文中所定義的、與其等於治療、預防、改善、控制或減輕與CGRP受體功能聯結的腦血管或血管疾患的用途。
Description
本申請案主張2015年10月30日提申的大不列顛專利申請案編號1519196.8之利益,該申請案之完整內容係以引用方式併入本文中。
本申請案係關於新穎化合物與其等作為CGRP受體拮抗劑的用途。於本文中描述的化合物可用於治療或預防諸如偏頭痛的腦血管或血管疾患。本申請案亦係針對包含此等化合物的醫藥組成物與此等化合物與組成物之製造與於預防或治療如此腦血管或血管疾患的用途。
偏頭痛係高度失能性神經血管疾患,其特徵在於往往與噁心、嘔吐、畏光症、與懼音症聯結的中度至嚴重頭痛之發作。發作可持續4至72h,且平均發作頻率為每個月1或2次。約20-30%的偏頭痛患者會經歷稱為先兆的暫時性病灶神經症狀,其等通常係視覺的且可在頭痛之前或伴隨著頭痛。偏頭痛於全世界折磨著約11%的成人且在生活品質與喪失生產力兩方面皆造成顯著的社會經濟負荷。
儘管尚不清楚偏頭痛之病機為何,主要的假設之一係基於三叉神經血管系統(TS)之活化。數個神經胜肽參與此活化,而抑鈣素基因關連性胜肽(CGRP)於其等中扮演了關鍵性的角色。CGRP透過周圍與中
樞神經系統(CNS)發揮各種各樣的生物功效。功能性CGRP-受體(CGRP-R)複合物之特徵已被充分界定,且新穎的治療方法瞄準CGRP本身與其受體。本發明係關於CGRP受體拮抗劑(CGRP-RA)之開發。
CGRP(一種衍生自編碼抑鈣素的基因的37個胺基酸的神經胜肽)係由位於染色體11上的抑鈣素/CGRP基因之選擇式剪接形成。於人類中,CGRP有兩種同功型:α-與β-CGRP。β-同功型與α-同功型不同處在於位於位置3、22與25的胺基酸。CGRP之化學結構包含在殘基2與7間的二硫橋與經醯胺化C端。環狀的半胱胺酸2-半胱胺酸7模體於受體活化具有基礎作用。於人類三叉神經神經節(TRIG),CGRP免疫反應性神經元占所有神經元之至多50%。已透過原位雜交技術展示了所有神經細胞體之40%含有CGRP mRNA與CGRP。雙重免疫染色已顯示於人類TRIG中,CGRP係與一氧化氮合成酶、P物質(SP)、腦下垂體腺苷酸環化酶活化性胜肽(PACAP)及nociceptin位於相同位置,其可能於偏頭痛之病機中扮演一個角色。
功能性CGRP-R係由三個蛋白質所組成:i)類抑鈣素受體受體(稱為CRLR、CALCRL或CLR)係一個七個跨膜跨越性蛋白質,其與以下者形成配體結合位置;ii)RAMP1,決定受體之專一性;與iii)CGRP-R組份蛋白質(RCP),其將受體與細胞內訊號轉導途徑以及與腺苷酸環化酶拴在一起。
咸認為CGRP之C端區域最初與受體之大型N端細胞外功能域(ECD)結合,可能與CLR和RAMP1兩者皆交互作用。此最初的結合事件於CLR之近膜部分之附近大大地增加了CGRP之N端區域之局部濃
度,允許其等之相對上弱的交互作用發生並造成受體活化。由於突變誘發實驗表明大部分的小型分子拮抗劑與CLR/RAMP1之ECD交互作用,咸假設其等與受體之此區域結合並預防CGRP與受體的最初結合。此胜肽結合與小型分子受體拮抗作用之模型的一個顯著的例外係羥基吡啶類拮抗劑,其於CLR中顯然與跨膜功能域7(TM7)交互作用而不與細胞外功能域交互作用(Bell IM,J.Med.Chem.,2014,57(19),7838-58)。
第一個於臨床上測試的CGRP-RA(olcegepant)係基於二胜肽主鏈、具有高分子量、且於口服上並非生物可利用的。但是,當靜脈內地給藥時,olcegepant被證明為有效的抗偏頭痛劑,且此概念驗證研究大大地增加了於所屬技術領域的興趣。在olcegepant之成功後,一些口服上有活性的CGRP-RA被推進到臨床試驗。Telcagepant與化合物BI 44370、MK-3207、及BMS-927711皆已以口服劑的形式被用於偏頭痛之急性治療。來自此等臨床研究的結果結合在一起展示了CGRP-RA可展示與良好的標準triptan藥物類似的抗偏頭痛效力但有顯著比典型於triptan觀察到者低的不良事件之發生率。值得注意的是可得的數據表明此等CGRP封阻劑不會造成血管收縮且建議其等可能具有比triptan優秀的心血管安全性輪廓。一個已於一些CGRP-RA被報導的潛在的擔心係於一些患者中觀察到肝臟轉胺酶之水平升高,且據報導此導致MK-3207之中止。雖然肝臟酵素升高亦在長期給藥telcagepant後於少數受藥者中發現,不清楚此等發現是否係在某些方面上是基於機制的或是此二種化合物特有的。於急性偏頭痛治療之臨床試驗中,CGRP-RA顯示有利的功效,但頻繁地投予其等與肝臟毒性(肝臟轉胺酶升高)聯結,其限制了其等之臨床用途。因此,有需要去開發不會誘發
肝臟損害的新穎CGRP-RA。
一個解決肝臟損害之風險的可能性係去瞄準用於小型分子的非口服遞送途徑,其會造成較低的透過首渡暴露的對肝臟的負荷。本發明之化合物可用於皮下的、靜脈內的及/或鼻內的投予之途徑。意欲用於如此投予之途徑的CGRP-RA之分子輪廓與口服分子所需的輪廓不同:需要極高的親和力與功能潛力加上極高的可溶性。於本文中揭示者係新穎化合物、與該化合物作為CGRP受體拮抗劑的第一醫藥用途。
本發明之化合物包含式(I)之化合物或其鹽,
其中R1係選自H或Q-(C1-C6)烷基;其中Q係一鍵、C(O)或C(O)O且其中該(C1-C6)烷基可視需要地經N(C1-C3烷基)2或CO2H取代;R2係H或與R3形成螺環性雜環;R3與R2形成螺環性雜環,或若R2係H則R3係雜環;且R4係可為單環或與其他環稠合的視需要經取代的芳基基團。
本發明係關於新穎化合物。本發明亦係關於新穎化合物作為CGRP受體拮抗劑的用途。本發明進一步係關於化合物於製造供作為CGRP受體拮抗劑之用的醫藥品的用途。本發明進一步係關於用於治療以下者的化合物、組成物與醫藥品:腦血管或血管疾患,諸如偏頭痛(包含諸如以下者的亞型:無先兆的偏頭痛、慢性偏頭痛、純粹月經偏頭痛、與月經相關的偏頭痛、有先兆的偏頭痛、家族性偏癱偏頭痛、散發性偏癱偏頭痛、基底型偏頭痛、周期性嘔吐、腹部型偏頭痛、童年之良性陣發性眩暈、視網膜型偏頭痛)、偏頭痛持續狀態(status migrainosus)、頭痛群、透析頭痛、陣發性半側顱痛(paroxysmal hemicrania)、骨關節炎、與更年期或導因於外科手術或藥物治療的醫藥誘發性更年期聯結的潮熱、連續性半側顱痛(hemicrania continua)、週期性嘔吐症候群、過敏性鼻炎、或痤瘡。本發明進一步係關於用於治療包含以下者的更廣大的疼痛狀態與疾病的化合物、組成物與醫藥品:神經發炎,包含牙痛、耳痛、中耳發炎、曬傷、與骨關節炎及類風濕性關節炎聯結的關節疼痛、癌症疼痛、纖維肌痛、糖尿病神經病變、與發炎性腸病-克羅恩氏病聯結的疼痛、痛風、複雜性局部疼痛症候群、Behçet氏病、子宮內膜異位疼痛、背痛或咳嗽。
於本文中例示的化合物係基於以下結構:
其中R1係選自H或Q-(C1-C6)烷基;其中Q係一鍵、C(O)或C(O)O且其中該(C1-C6)烷基可視需要地經N(C1-C3烷基)2或CO2H取代;R2係H或與R3形成螺環性雜環;R3與R2形成螺環性雜環,或若R2係H則R3係雜環;且R4可為單環或與其他環稠合的視需要經取代的芳基基團。
用於R4的視需要的取代基可選自鹵基、羥基或甲基。更特別地,用於R4的取代基係經取代的苯基基團,其中該取代基係選自鹵基或羥基。於一個特殊的具體態樣中,R4係根據式II的部分
其中X係鹵基。
於一個更特殊的具體態樣中,X係Br。
於一個特殊的具體態樣中,用於R4的取代基係
於一個特殊的具體態樣中,用於R2的取代基係H且R3係選自:
於一個特殊的具體態樣中,R2與R3形成螺環性雜環以形成:
於一個特殊的具體態樣中,用於R1的取代基係H、CO2 tBu、CH2CH3、CH2CH2CH3、COCH2CH2CH2CH3、CH2CH2N(CH3)2或COCH2CO2H。於一個更特殊的具體態樣中,用於R1的取代基係H。
本發明之化合物包含該等為式(I)者
其中R1係選自H或Q-(C1-C6)烷基;其中Q係一鍵、C(O)或C(O)O且其中該
(C1-C6)烷基可視需要地經N(C1-C3烷基)2或CO2H取代;R2係H或與R3形成螺環性雜環以形成:
且其中當R2係H時,R3係選自:、或;且R4係選自
於一個更特殊的具體態樣中,用於R1的取代基係H。
本發明之進一步具體態樣包含治療方法,其包含投予式(I)之化合物作為CGRP受體拮抗劑。使用式(I)之化合物的治療可於治療以下者:腦血管或血管疾患,諸如偏頭痛(包含諸如以下者的亞型:無先兆的偏頭痛、慢性偏頭痛、純粹月經偏頭痛、與月經相關的偏頭痛、有先兆的偏頭痛、家族性偏癱偏頭痛、散發性偏癱偏頭痛、基底型偏頭痛、周期性嘔吐、腹部型偏頭痛、童年之良性陣發性眩暈、視網膜型偏頭痛)、偏頭痛持續狀態、頭痛群、透析頭痛、陣發性半側顱痛、骨關節炎、與更年期或導因於外科手術或藥物治療的醫藥誘發性更年期聯結的潮熱、連續性半側顱痛、週期性嘔吐症候群、過敏性鼻炎、或痤瘡。本發明進一步係關於用
於治療包含以下者的更廣大的疼痛狀態與疾病的化合物、組成物與醫藥品:神經發炎,包含牙痛、耳痛、中耳發炎、曬傷、與骨關節炎及類風濕性關節炎聯結的關節疼痛、癌症疼痛、纖維肌痛、糖尿病神經病變、與發炎性腸病-克羅恩氏病聯結的疼痛、痛風、複雜性局部疼痛症候群、Behçet氏病、子宮內膜異位疼痛、背痛或咳嗽。
某些本發明之新穎化合物顯示特別高的作為CGRP受體拮抗劑的活性。
例示性化合物包含:
此等化合物之NMR與LCMS特性以及生物活性係於表2及3中給出。
倘若所描述的化合物之任一者具有手性中心,本發明延伸至如此化合物之所有光學異構物,無論是呈外消旋物或經解析鏡相異構物的形式。於本文中描述的發明係關於所揭示的化合物之任一者之所有晶型、溶劑合物與水合物,無論是如何製備地。倘若於本文中揭示的化合物與中間物之任一者具有酸或鹼中心(諸如羧酸或胺基基團),則該化合物之所有鹽形式被包含於本文中。在醫藥用途之情況下,該鹽應被視為醫藥上可接受的鹽。
可提及的醫藥上可接受的鹽包含酸加成鹽與鹼加成鹽。如此鹽可藉由習用方式形成,例如藉由使化合物之自由酸或自由鹼形式與適當的酸或鹼之一或多個同等物反應(視需要地於溶劑中或於在其中該鹽不可溶的介質中),接著使用標準技術(例如在真空內、藉由冷凍乾燥或藉由過濾)移除該溶劑或該介質。鹽亦可藉由使呈鹽的形式的化合物之相對離子與另一個相對離子交換(例如使用適合的離子交換樹脂)來製備。
醫藥上可接受的鹽之實例包含衍生自礦物酸與有機酸的酸
加成鹽、與衍生自諸如鈉、鎂、或較佳為鉀與鈣的金屬的鹽。
酸加成鹽之實例包含與以下者形成的酸加成鹽:醋酸、2,2-二氯醋酸、己二酸、藻酸、芳基磺酸(例如苯磺酸、萘-2-磺酸、萘-1,5-二磺酸與對甲苯磺酸)、抗壞血酸(例如L-抗壞血酸)、L-天門冬胺酸、苯甲酸、4-乙醯胺基苯甲酸、丁酸、(+)-樟腦酸、樟腦-磺酸、(+)-(1S)-樟腦-10-磺酸、癸酸、己酸、辛酸、肉桂酸、檸檬酸、環己基胺基磺酸、十二烷基硫酸、乙-1,2-二磺酸、乙磺酸、2-羥基乙磺酸、甲酸、延胡索酸、半乳糖二酸、龍膽酸、葡萄庚酸、葡萄糖酸(例如D-葡萄糖酸)、葡萄糖醛酸(例如D-葡萄糖醛酸)、麩胺酸(例如L-麩胺酸)、α-酮己二酸、羥乙酸、馬尿酸、氫溴酸、氫氯酸、氫碘酸、羥乙磺酸、乳酸(例如(+)-L-乳酸與(±)-DL-乳酸)、乳糖酸、馬來酸、蘋果酸(例如(-)-L-蘋果酸)、丙二酸、(±)-DL-苦杏仁酸、偏磷酸、甲磺酸、1-羥基-2-萘甲酸、菸鹼酸、硝酸、油酸、乳清酸、草酸、棕櫚酸、撲酸、磷酸、丙酸、L-焦麩胺酸、水楊酸、4-胺基-水楊酸、癸二酸、硬脂酸、琥珀酸、硫酸、單寧酸、酒石酸(例如(+)-L-酒石酸)、硫氰酸、十一烯酸與戊酸。
鹽之特殊實例係衍生自諸如氫氯酸、氫溴酸、磷酸、偏磷酸、硝酸與硫酸的礦物酸的鹽;衍生自諸如酒石酸、醋酸、檸檬酸、蘋果酸、乳酸、延胡索酸、苯甲酸、羥乙酸、葡萄糖酸、琥珀酸、芳基磺酸、撲酸的有機酸的鹽;與衍生自諸如鈉、鎂、或較佳為鉀與鈣的金屬的鹽。
亦涵蓋者為化合物與其等之鹽之任何溶劑合物。較佳的溶劑合物係藉由將非毒性醫藥上可接受的溶劑(以下稱為溶劑合溶劑)之分子併入至本發明之化合物之固態結構(例如結晶結構)中來形成的溶劑合物。
如此溶劑之實例包含水、醇(諸如乙醇、異丙醇與丁醇)與二甲基亞碸。溶劑合物可藉由以含有溶劑合溶劑的溶劑或溶劑之混合物再結晶化本發明之化合物來製備。一溶劑合物是否已於任何給定實例中形成可藉由使用廣為人知的與標準的技術(諸如熱重量分析(TGE)、示差掃描熱析法(DSC)與X射線結晶學)分析化合物之結晶來測定。
該溶劑合物可為化學計量或非化學計量溶劑合物。特殊的溶劑合物可為水合物,且水合物之實例包含半水合物、單水合物與二水合物。
對於溶劑合物及用於製造其等與定其等之特徵的方法之更詳細的討論,參見Bryn等人,Solid-State Chemistry of Drugs,第二版,由SSCI,Inc出版,West Lafayette,IN,USA,1999,ISBN 0-967-06710-3。
如於本文中定義的,化合物之「醫藥功能性衍生物」包含酯衍生物及/或具有與任何相關的本發明之化合物相同的生物功能及/或活性或為如此功能及/或活性作準備的衍生物。因此,為了本發明之目的,該術語亦包含如於本文中定義的化合物之前藥。
術語相關的化合物之「前藥」包含任何在口服或非經腸投予後於預先決定的時間內(例如在介於6與24個小時之間的給藥間隔內(即每日一至四次))被活體內代謝以形成實驗上可偵測的量的該化合物的化合物。
化合物之前藥可藉由修飾出現在該化合物上的功能性基團來製備,其方式為當如此前藥被投予至哺乳動物受藥者時該修飾被活體內切下。該修飾典型係藉由以前藥取代基合成親本化合物來達成。前藥包含其中化合物中的羥基、胺基、氫硫基、羧基或羰基基團係與任何可被活體
內切下以分別重建自由羥基、胺基、氫硫基、羧基或羰基基團的基團鍵結的化合物。
前藥之實例包含(但不限於)羥基功能性基團之酯與胺甲酸酯、羧基功能性基團之酯基團、N-醯基衍生物與N-曼尼希鹼。前藥之一般資訊可於例如Bundegaard,H.“Design of Prodrugs”p.1-92,Elsevier,New York-Oxford(1985)中找到。
C
1
-C
6
烷基
烷基意謂脂肪族烴基團。烷基基團可為直鏈的或支鏈的。「支鏈的」意謂至少一個碳分支點存在於該基團中,例如異丙基或三級丁基。C1-C3烷基基團包含甲基、乙基、n-丙基、i-丙基。烷基基團可視需要地經取代。
雜環
雜環意謂其中至少一個環成員不為碳的可為芳香族的環狀基團。例如,至少一個環成員(例如一個、二個或三個環成員)可選自氮、氧與硫。雜芳基基團之接附點可經由環系統之任何原子。例示性雜芳基基團包含吡啶基、吲唑基、1,4-二氫-2H-吡啶并[2,3-d][1,3]-2-酮、1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮、3,4-二氫喹唑啉-2(1H)-酮、喹啉-2(1H)-酮、哌啶基、哌基、與類似者。
視需要地經取代的
如用於任何基團,「視需要地經取代的」意謂該基團若所欲可以一或多個可為相同或不同的取代基取代。
於本發明之前後文中,術語「醫藥組成物」意謂包含活性劑且另外包含一或多種醫藥上可接受的載劑的組成物。取決於投予模式與劑型之性質,該組成物可進一步含有選自例如以下者的成分:稀釋劑、佐劑、賦形劑、媒劑、保存劑、填充劑、崩散劑、潤溼劑、乳化劑、懸浮劑、甜味劑、調味劑、芳香劑、抗細菌劑、抗真菌劑、潤滑劑與分散劑。該組成物可採取例如以下者之形式:錠劑、糖衣錠、粉末、酏劑、糖漿、液體製劑,包含懸浮液、噴霧、吸入物、錠劑、菱形錠、乳液、溶液、藥包、顆粒、膠囊與栓劑、以及用於注射的液體製劑,包含脂質體製劑。
劑量可根據患者之需要、欲治療的病況之嚴重性、與所利用的化合物而變化。特定情況之適當劑量之測定係於所屬技術領域中的技術內。一般地,治療係以比化合物之最理想的劑量少的較小的劑量開始。之後,劑量係以小型增加量增加直到達到在該情況下的最理想的功效。為了方便起見,若所欲,總每日劑量可在該日期間被分成數個部分並逐部分投予。
當然,化合物之有效劑量之量會隨欲治療的病況之嚴重性之性質並隨特殊的化合物及其投予之途徑而變化。適當的劑量之挑選係落入所屬技術領域中具有通常知識者之能力內而無須過度負荷。一般而言,每日劑量範圍可為約10μg至約30mg每公斤體重的人類與非人類動物,較佳為約50μg至約30mg每公斤體重的人類與非人類動物,例如約50μg至約10mg每公斤體重的人類與非人類動物,例如約100μg至約30mg每公斤體重的人類與非人類動物,例如約100μg至約10mg每公斤體重的人類與非人類動物且最較佳為約100μg至約1mg每公斤體重的人類與非人
類動物。
本發明之化合物可藉由包含該等於流程圖1中者的程序製備。諸如該等於以下途徑中者以及可被用於執行相同轉變的其他者的許多標準轉變之細節可於諸如“Organic Synthesis”,M.B.Smith,McGraw-Hill(1994)或“Advanced Organic Chemistry”,第4版,J.March,John Wiley & Sons(1992)的標準參考教科書中找到。
胺基酸中間物(例如胺基酸之甲基酯)與胺中間物間的尿素形成可在使用諸如DSC或CDI的偶合劑的條件下在諸如三乙基胺或DIPEA的鹼的存在下於諸如DMF及/或DCM的溶劑中形成。隨後形成的尿素衍生物之甲基酯部分可使用諸如氫氧化鋰或氫氧化鈉的水性鹼於諸如THF、
MeOH、1,4-二、EtOAc或其混合物的適合的溶劑中皂化。所形成的酸中間物可在標準條件下(例如使用諸如HATU或HBTU的偶合劑,在諸如DIPEA的鹼的存在下在諸如DMF的適合的溶劑中)被轉變成醯胺實施例。供選擇地,醯氯可在諸如Et3N的鹼的存在下於諸如DCM的適合的溶劑中與胺偶合以產生醯胺。如此醯胺偶合之胺伙伴可使用標準轉變之適當組合製備(例如使用胺、醛或酮、以及諸如三乙醯氧基硼氫化鈉的還原劑於諸如DCM的溶劑中在醋酸的存在下的還原性胺化;或在諸如該等以上詳細描述者的條件下的醯胺形成)與在可於參考教科書(例如“Procting Groups”,第三版,P.J.Kocieski,Georg Thieme Verlag(2005))中找到的條件下移除標準保護性基團。一個如此轉變係在諸如HCl的酸性條件下於諸如1,4-二、MeOH、EtOH、DCM或其組合的溶劑中自胺移除tert-丁氧基羰基基團(通常稱為Boc基團)。咸可領會到具有另外的鹼性中心的本發明之胺中間物之Boc去保護可造成不同化學計量之氫氯化物鹽。例如,具有一個另外的鹼性中心的中間物之Boc去保護會造成為例如單氫氯化物或二氫氯化物鹽的新的胺中間物之形成,其往往會不經中和氫氯化物鹽就使用以製造該中間物之自由鹼,因為咸領會到在隨後的醯胺形成中過量的諸如DIPEA或三乙基胺的鹼典型係用於中和氫氯化物鹽。不經中和成自由鹼就使用的藉由Boc去保護形成的本發明之胺中間物於本文中被稱為氫氯化物(x HCl),且本發明延伸至該中間物之所有鹽形式。另一個如此保護性基團移除係使用諸如在碳上藉由鈀的催化的還原條件於諸如EtOH的溶劑中在氣體H2的存在下或藉由使用組合連續流化學與原位氫產生的商業上可購得的氫化反應器(例如H-Cube氫化反應器,ThalesNano Nanotechnology Inc.,布達佩斯,匈
牙利)的經苯甲氧羰基(通常稱為Cbz或Z基團)保護的胺之去保護。用於移除經Cbz保護的基團的供選擇的條件包含轉換氫化,例如使用在碳上的鈀催化劑在甲酸銨或環己-1,4-二烯或甲酸銨與環己-1,4-二烯兩者的存在下於諸如EtOH或水性EtOH的溶劑中於諸如70℃的提高的溫度下。
當未包含製備途徑時,相關的中間物係商業上可購得的。商業上可購得的試劑係不進一步純化就利用。室溫(rt)係關於大約20-27℃。1H NMR光譜係於400MHz在Bruker、Varian或JEOL儀器上記錄。化學位移值係以百萬分之一(ppm)(即(δ)值)表現。以下縮寫係用於NMR訊號之多重性:s=單重、br=寬、d=二重、t=三重、q=四重、quin=五重、h=七重、dd=二重之二重、dt=三重之二重、m=多重。偶合常數係列成J值,以Hz測量。NMR與質譜術結果係針對背景波峰作校正。色層分離法係關於使用矽石執行且在正壓(快速色層分離法)條件下實施的管柱色層分離法。LCMS實驗係使用電噴霧條件在以下條件下進行。LCMS數據係以以下格式給出:質量離子(Mass ion)、電噴霧模式(正或負)、滯留時間(實驗文字與表1);質量離子、電噴霧模式(正或負)、滯留時間、大約的純度(表2)。
方法A。儀器:有G1315A DAD的Hewlett Packard 1100,Micromass ZQ;管柱:Waters X-Bridge C-18,2.5微米,2.1 x 20mm或Phenomenex Gemini-NX C-18,3微米,2.0 x 30mm;梯度[時間(min)/於溶劑C中的溶劑D(%)]:0.00/2、0.10/2、8.40/95、10.00/95;溶劑:溶劑C=2.5L H2O+2.5mL 28%氨,於水溶液中;溶劑D=2.5L MeCN+135mL H2O+2.5mL 28%氨,於水溶液中;注射體積1L;UV偵測230至400nM;管
柱溫度45℃;流率1.5mL/min。
方法B。儀器:有Chemstation軟體的Agilent Technologies 1260 Infinity LC,二極體陣列偵測器,有API-ES來源的Agilent 6120B單一四極MS;管柱:Phenomenex Gemini-NX C-18,3微米,2.0 x 30mm;梯度[時間(min)/於溶劑C中的溶劑D(%)]:0.00/5、2.00/95、2.50/95、2.60/5、3.00/5;溶劑C與D係如以上於方法A中描述的;注射體積0.5μL;UV偵測190至400nM;管柱溫度40℃;流率1.5mL/min。
方法C。細節如於方法A中,除了梯度[時間(min)/於溶劑C中的溶劑D(%)]:0.00/2、0.10/2、2.50/95、3.50/95。
方法D。儀器:結合SQD質譜儀的Acquity UPLC;管柱:Acquity UPLC BEH C18,1.7微米,2.1 x 50mm;梯度[時間(min)/於溶劑A中的溶劑B(%)]:0.00/3、1.50/100、1.90/100、2.00/3;溶劑:溶劑A=10mM NH4HCO3之水溶液(以氨調整至pH 10);溶劑B=MeCN;注射體積1μL;UV偵測210至350nM;管柱溫度40℃;流率0.9mL/min。
CDI=1,1′-羰基二咪唑
DCM=二氯基甲烷
DIPEA=N,N-二異丙基乙基胺
DMAC=N,N-二甲基乙醯胺
DMF=二甲基甲醯胺
DSC=N,N’-二琥珀醯亞胺基碳酸酯
DMSO=二甲基亞碸
ES=電噴霧
EtOAc=乙酸乙酯
h=小時
HATU=1-[雙(二甲基胺基)次甲基]-1H-1,2,3-三唑并[4,5-b]吡啶陽離子3-氧陰離子六氟磷酸酯
HBTU=N,N,N′,N′-四甲基-O-(1H-苯并三唑-1-基)脲陽離子六氟磷酸酯
L=公升
LC=液相色層分離法
LCMS=液相色層分離法質譜法
MeCN=乙腈
min=分鐘
MS=質譜法
NMR=核磁共振
rcf=相對離心力
rpm=每分鐘轉數
rt=室溫
s=秒
TFA=三氟醋酸
THF=四氫呋喃
前綴n-、s-、i-、t-與tert-具有其等之通常意義:正、二級、異、與三級。
用於經由尿素形成與隨後皂化來製備羧酸中間物的典型程序,如由中間物7,(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]
]-1-基)羰基]胺基}丙酸之製備例示的。
步驟1)將Et3N(2.26mL,16.3mmol)加至(R)-甲基2-胺基-3-(7-甲基-1H-吲唑-5-基)丙酸酯二氫氯化物(中間物5,995mg,3.3mmol)與DSC(917mg,3.6mmol)於DMF(20mL)中的溶液並於rt下攪拌混合物共30min。接著逐部分地添加螺[哌啶-4,4'-[4H]吡啶并[2,3-d][1,3]]-2'(1'H)-酮(中間物4,785mg,3.6mmol)並於rt下攪拌反應混合物共18h,然後在真空內濃縮。在H2O與MeOH/DCM(1:9)間分配殘餘物,分離各相並以H2O洗滌水層。將來自分離步驟的殘餘的固體溶解在MeOH中並在真空內濃縮組合的有機層與藉由快速色層分離法純化,以EtOAc(於MeOH中)(20:1)洗提,以產生呈白色固體的甲基(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-基)羰基]胺基}丙酸酯(1.06g,2.22mmol)。
LCMS(方法A):m/z 479.3(ES+),於2.61min,100%。
1 H NMR:(400MHz,DMSO-d6)δ:1.59-1.75(m,2H),1.78-1.90(m,2H),2.45(s,3H),2.90-3.08(m,4H),3.59(s,3H),3.86-3.96(m,2H),4.28-4.38(m,1H),6.94-7.06(m,3H),7.32(dd,J=7.4,1.2,1H),7.39(s,1H),7.95(s,1H),8.18(dd,J=5.1,1.6,1H),10.79(s,1H),13.04(s,1H)。
步驟2)將甲基(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-基)羰基]胺基}丙酸酯(1.06g,2.22mmol)溶解於THF(15mL)與MeOH(3mL)中並逐滴添加LiOH之水溶液(1M,4.4mL,4.4mmol)。在於rt下攪拌共3.5h後,逐滴添加另外的水性LiOH(1M,2.2mL,2.2mmol)並於rt下攪拌混合物共1h,然後在氮氣流下濃縮。將殘餘物溶解於最小量的H2O中並冷卻至0℃。逐滴添加水性1M HCl以將pH調整至3並藉由過濾分離所得的沈澱物、以冷H2O與Et2O洗滌以產生呈淺黃色固體的標題化合物(877mg,1.89mmol)。
數據於表1。
中間物8,(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}胺基)丙酸
標題化合物(1.50g,3.2mmol)係以二步驟自(R)-甲基2-胺基-3-(7-甲基-1H-吲唑-5-基)丙酸酯(中間物5,1.00g,4.3mmol)與1-(哌啶-4-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮(中間物1,1.02g,4.7mmol)使
用中間物7之方法製備。
數據於表1。
中間物14,3,5-二溴基-N-[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]
]-1-基)羰基]-D-酪胺酸
標題化合物(561mg,1.0mmol)係以二步驟自3,5-二溴基-D-酪胺酸甲基酯(中間物6,530mg,1.5mmol)與螺[哌啶-4,4'-[4H]吡啶并[2,3-d][1,3]]-2'(1'H)-酮(中間物4,362mg,1.7mmol)使用中間物7之方法製備。
數據於表1。
中間物11,3,5-二溴基-N-{[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}-D-酪胺酸
標題化合物(214mg,0.37mmol)係以二步驟自3,5-二溴基-D-酪胺酸甲基酯(中間物6,357mg,1.01mmol)與1-(哌啶-4-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮(中間物1,362mg,1.42mmol)使用中間物7
之方法製備。
數據於表1。
中間物12,3,5-二溴基-N-{[4-(2-側氧基-1,4-二氫喹唑啉-3(2H)-基)哌啶-1-基]羰基}-D-酪胺酸
標題化合物(224mg,0.38mmol)係以二步驟自3,5-二溴基-D-酪胺酸甲基酯(中間物6,353mg,1.00mmol)與3-(哌啶-4-基)-3,4-二氫喹唑啉-2(1H)-酮(中間物3,254mg,1.10mmol)使用中間物7之方法製備。
數據於表1。
中間物13,(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-1,4-二氫喹唑啉-3(2H)-基)哌啶-1-基]羰基}胺基)丙酸
標題化合物(561mg,1.18mmol)係以二步驟自(R)-甲基2-胺基-3-(7-甲基-1H-吲唑-5-基)丙酸酯(中間物5,917mg,3.93mmol)與3-(哌啶-4-基)-3,4-二氫喹唑啉-2(1H)-酮(中間物3,1.00g,4.32mmol)使用中間物7之方法製備。
數據於表1。
中間物10,3,5-二溴基-N-{[4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-基]羰基}-D-酪胺酸
標題化合物(77mg,0.13mmol)係以二步驟自3,5-二溴基-D-酪胺酸甲基酯(中間物6,103mg,0.29mmol)與3-(哌啶-4-基)喹啉-2(1H)-酮(中間物2,73mg,0.32mmol)使用中間物7之方法製備。
數據於表1。
中間物9,(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-基]羰基}胺基)丙酸
步驟1)在N2下於大約-20℃下將CDI(8.40g,51.8mmol)加至(R)-甲基2-胺基-3-(7-甲基-1H-吲唑-5-基)丙酸酯(中間物5,6.05g,25.9mmol)於DMF(60mL)中的溶液並攪拌混合物共15min同時將溫度維持在低於-10℃。添加H2O(2.34mL)於一些mL的DMF中的溶液並持續攪拌共15min,同時將溫度維持在低於-10℃。接著以3-(哌啶-4-基)喹啉-2(1H)-酮(中間物2,6.99g,30.6mmol)、DIPEA(4.93mL,28.2mmol)與DCM
(20mL)的順序添加其等並在N2下將混合物加熱至40℃共12h。於冷卻至rt後,添加2M HCl(aq)(38.7mL)並以DCM萃取混合物兩次。以H2O洗滌組合的有機萃取物三次、乾燥(Na2SO4)並在真空內濃縮。藉由快速色層分離法純化,以MeOH/DCM(5:95)洗提,產生呈淺棕黃固體的甲基(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-基]羰基}胺基)丙酸酯(10.4g,21.3mmol)。
1 H NMR:(400MHz,CDCl3)δ:1.40-1.60(m,2H),1.95-1.97(m,2H),2.46(s,3H),2.90-3.00(m,2H),3.11-3.26(m,3H),3.76(s,3H),4.07-4.12(m,2H),4.86-4.91(m,1H),5.18(d,J=7.6,1H),6.93(s,1H),7.17-7.21(m,1H),7.24(s,1H),7.32(s,1H),7.43-7.54(m,3H),7.95(s,1H),10.70(s,2H)。
步驟2)將LiOH.H2O(1.26g,30.0mmol)於H2O(150mL)中的溶液加至甲基(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-基]羰基}胺基)丙酸酯(9.79g,20.1mmol)於1,4-二(150mL)中的溶液並於rt下攪拌混合物共2h。在真空內將反應混合物濃縮至接近乾燥並將其再溶解於H2O中,然後以水性2M HCl(大約15mL)酸化同時快速攪拌。藉由過濾分離所得的黏稠白色沈澱物並以H2O洗滌直到被洗滌物之pH接近中性。在真空內乾燥產生呈灰白色固體的標題化合物(8.11g,17.1mmol)。
數據於表1。
胺中間物之製備
中間物17,tert-丁基4-{(2S)-2-胺基-3-側氧基-3-[4-(吡啶-4-基)哌
-1-基]丙基}哌啶-1-甲酸酯
步驟1)將LiOH.H2O(856mg,20.4mmol)於H2O(50mL)中的溶液至tert-丁基4-[(2S)-2-{[(苯甲氧基)羰基]胺基}-3-甲氧基-3-側氧基丙基]哌啶-1-甲酸酯(中間物16,4.29g,10.2mmol)於1,4-二(50mL)中的溶液並攪拌混合物共5h。在真空內將反應混合物濃縮至接近乾燥並再溶解於H2O中,之後以0.5M NaHSO4(aq)酸化。將所得的黏稠白色沈澱物萃取至EtOAc中並以鹵水洗滌組合的有機層,乾燥(MgSO4)並在真空內濃縮以產生呈白色泡沫的N-[(苯甲氧基)羰基]-3-[1-(tert-丁氧基羰基)哌啶-4-基]-L-丙胺酸(4.01g,9.87mmol)。
1 H NMR:(400MHz,DMSO-d6)δ:0.85-1.07(m,2H),1.39(s,9H),1.45-1.68(m,5H),2.55-2.71(m,2H),3.86-3.94(m,1H),4.85-4.98(m,2H),5.04(s,2H),7.28-7.39(m,5H),7.53(d,J=8.3,1H),12.5(br s,1H)。
步驟2)將HBTU(4.10g,10.81mmol)添加至N-[(苯甲氧基)羰基]-3-[1-(tert-丁氧基羰基)哌啶-4-基]-L-丙胺酸(4.00g,9.84mmol)於DMF(80mL)中的溶液接著添加DIPEA(3.74mL,21.47mmol)與1-(4-吡啶基)哌(中間物15,1.69g,10.35mmol)並於rt下攪拌混合物共3h。在真空內將反應混合物濃縮至接近乾燥並將殘餘物溶解於EtOAc中,以H2O洗滌兩次,以NaHCO3(aq)與鹵水洗滌兩次、乾燥(Na2SO4)並在真空內
濃縮。藉由快速色層分離法純化,以MeOH/DCM(5:95)洗提,產生呈灰白色泡沫的tert-丁基4-{(2S)-2-{[(苯甲氧基)羰基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(4.51g,8.18mmol)。
1 H NMR:(400MHz,CDCl3)δ:1.07-1.16(br m,2H),1.44(s,9H),1.54-1.60(br m,2H),1.88-1.91(m,1H),2.62-2.65(br m,2H),3.47-3.65(br m,6H),3.81-3.86(br m,2H),4.05(br m,2H),4.26(br m,2H),4.70-4.74(m,1H),5.04-5.12(m,2H),5.70(d,J=8.8,1H),6.82(d,J=6.0,2H),7.26-7.34(m,5H),8.10(br s,2H)。
步驟3)透過Pd/C筒匣於50℃下使用連續流氫化反應器(H-Cube,ThalesNano Nanotechnology Inc.,布達佩斯,匈牙利)在H2的存在下(完全H2模式)洗提tert-丁基4-{(2S)-2-{[(苯甲氧基)羰基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(557mg,1.01mmol)於EtOH(20mL)中的溶液五次,藉由LCMS監視變成所欲的產物之轉換。於>95%轉換後,在真空內將反應混合物濃縮至產生呈黃色玻璃狀固體的標題化合物(455mg,1.09mmol)。
數據於表1。
中間物18,甲基N-[(苯甲氧基)羰基]-3-(1-丙基哌啶-4-基)-L-丙胺酸酯
步驟1)將於1,4-二中的HCl(4M,10mL,40mmol)添加至tert-丁基4-[(2S)-2-{[(苯甲氧基)羰基]胺基}-3-甲氧基-3-側氧丙基]哌啶-1-甲酸酯(中間物16,1.00g,2.38mmol)於MeOH(10mL)中的溶液。在於rt下攪拌共2h後,在真空內將反應混合物濃縮以產生甲基N-[(苯甲氧基)羰基]-3-哌啶-4-基-L-丙胺酸酯氫氯化物(850mg),其不經純化就被用於隨後的步驟中。
LCMS(方法C):m/z 321.2(ES+),於1.66min。
步驟2)於rt下攪拌甲基N-[(苯甲氧基)羰基]-3-哌啶-4-基-L-丙胺酸酯氫氯化物(500mg,1.40mmol)、丙醛(120μL,1.68mmol)與冰醋酸(96μL,1.68mmol)於DCM(10mL)中的混合物共1h,之後添加三乙醯氧基硼氫化鈉(356mg,1.68mmol)。在於rt下攪拌過夜後,在真空內濃縮混合物並藉由快速管柱色層分離法純化,以於DCM中的0-10% MeOH洗提以產生呈無色油的標題化合物(400mg,1.10mmol)。
數據於表1。
中間物19,(2S)-2-胺基-3-(1-丙基哌啶-4-基)-1-[4-(吡啶-4-基)哌
-1-基]丙-1-
酮
步驟1)將水性氫氧化鈉(1M,5mL,5.0mmol)添加至甲基N-[(苯甲氧基)羰基]-3-(1-丙基哌啶-4-基)-L-丙胺酸酯(中間物18,400mg,1.10mmol)於MeOH(5mL)中的溶液。在於rt下攪拌過夜後,在真空內部分濃縮反應混合物以移除MeOH並以1M水性HCl酸化至pH2。在真空內濃縮產生粗N-[(苯甲氧基)羰基]-3-(1-丙基哌啶-4-基)-L-丙胺酸(385mg),其不經純化就被用於隨後的步驟中。
LCMS(方法B):m/z 349.0(ES+),於0.79min。
步驟2)於rt下攪拌粗N-[(苯甲氧基)羰基]-3-(1-丙基哌啶-4-基)-L-丙胺酸(385mg)、1-(4-吡啶基)哌(中間物15,215mg,1.32mmol)、HATU(505mg,1.33mmol)與DIPEA(383μL,2.20mmol)於DMF(5mL)中的混合物共3h。在真空內濃縮產生呈黏滯的淺橙色油的苯甲基{(2S)-1-側氧基-3-(1-丙基哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯(542mg),其不經純化就被用於隨後的步驟中。
LCMS(方法B):m/z 493.9(ES+),於1.45min。
步驟3)將甲酸銨(643mg,11.0mmol)添加至苯甲基{(2S)-1-
側氧基-3-(1-丙基哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯(粗,542mg)於EtOH(40mL)與H2O(10mL)中的溶液。添加在碳上的鈀(10%,10mg)並於70℃下在N2下加熱混合物過夜。在冷卻至rt後,通過矽藻土過濾混合物並在真空內濃縮濾出物以產生呈黏滯的黃色油的標題化合物(115mg),其不經純化就被用於實施例4之形成中。
數據於表1。
中間物20,1-(4-{(2S)-2-胺基-3-側氧基-3-[4-(吡啶-4-基)哌
-1-基]丙基}哌啶-1-基)戊-1-酮
步驟1)將於1,4-二中的HCl(4M,2.30mL,9.20mmol)添加至tert-丁基4-{(2S)-2-{[(苯甲氧基)羰基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(中間物17,步驟2產物)(1.30g,2.30mmol)於EtOAc(23mL)中的溶液並於rt下攪拌混合物過夜。在真空內濃縮後,藉由快速管柱色層分離法純化以於MeOH中的DCM/MeOH/7N NH3(90:5:5)洗提產生苯甲基{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯(740mg,1.64mmol)。
LCMS(方法B):m/z 452.2(ES+),於1.30min。
步驟2)於rt下攪拌戊酸(137mg,0.36mmol)、苯甲基{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯(146mg,0.32mmol)、三乙基胺(209μL,1.50mmol)與HATU(137mg,0.36mmol)於DMF(3mL)中的混合物過夜。添加1M水性碳酸鈉溶液(20mL),在真空內濃縮混合物並藉由梯度快速管柱色層分離法純化,以於DCM中的0-10%(1:1 MeOH/7N NH3,於MeOH中)洗提,以產生苯甲基{(2S)-1-側氧基-3-(1-戊醯基哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯。
LCMS(方法B):m/z 536.2(ES+),於1.38min。
步驟3)透過Pd/C筒匣於50℃下使用連續流氫化反應器(H-Cube,ThalesNano Nanotechnology Inc.,布達佩斯,匈牙利)在H2的存在下(完全H2模式)洗提苯甲基{(2S)-1-側氧基-3-(1-戊醯基哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯於EtOH中的溶液,藉由LCMS監視變成所欲的產物之轉換。於>95%轉換後,在真空內將反應混合物濃縮以產生標題化合物,其全體(假定為0.32mmol)不經純化就被用於實施例6之形成中。
數據於表1。
中間物21,(2S)-2-胺基-3-(1-乙基哌啶-4-基)-1-[4-(吡啶-4-基)哌
-1-基]丙-1-酮
標題化合物(286mg,0.83mmol)係以四步驟自甲基N-[(苯甲氧基)羰基]-3-哌啶-4-基-L-丙胺酸酯氫氯化物(中間物18,步驟1產物)(320mg,0.90mmol)與乙醛(62μL,1.10mmol)使用中間物18與19之方法製備。
數據於表1。
中間物22,(2S)-2-胺基-3-{1-[2-(二甲基胺基)乙基]哌啶-4-基}-1-[4-(吡啶-4-基)哌
-1-基]丙-1-酮
標題化合物(306mg,於實施例12之形成中以不經純化的粗產物使用)係以四步驟自甲基N-[(苯甲氧基)羰基]-3-哌啶-4-基-L-丙胺酸酯氫氯化物(中間物18,步驟1產物)(1.0g,2.81mmol)與2-(二甲基胺基)乙醛亞硫酸酯(568mg,3.36mmol)使用中間物18與19之方法製備。
數據於表1。
中間物23,乙基3-(4-{(2S)-2-胺基-3-側氧基-3-[4-(吡啶-4-基)哌
-1-基]丙基}哌啶-1-基)-3-側氧基丙酸酯
步驟1)將於1,4-二中的HCl(4M,10.0mL,40.0mmol)添加至tert-丁基4-{(2S)-2-{[(苯甲氧基)羰基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(中間物17,步驟2產物)(600mg,1.09mmol)於MeOH(10mL)中的溶液並於rt下攪拌混合物過夜。在真空內濃縮產生呈黏性白色固體的苯甲基{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯二氫氯化物(570mg,1.09mmol)。
LCMS(方法B):m/z 452.2(ES+),於1.72min。
步驟2)將乙基3-氯基-3-側氧基丙酸酯(151μL,1.20mmol)添加至Et3N(608μL,4.36mmol)與苯甲基{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺甲酸酯二氫氯化物(570mg,1.09mmol)於DCM(20mL)中的溶液並將混合物於rt下攪拌過夜。於在真空內濃縮後,藉由梯度快速管柱色層分離法純化,以於DCM中的0-10% MeOH洗提產生了所欲的材料(乙基3-(4-{(2S)-2-{[(苯甲氧基)羰基]胺基}-3-側氧基
-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-基)-3-側氧基丙酸酯,黏性淺黃色固體,510mg),其呈與雙醯基化副產物(乙基3-(4-{(2S)-2-{[(苯甲氧基)羰基](3-乙氧基-3-側氧基丙醯基)胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-基)-3-側氧基丙酸酯)的大約2:1的混合物。該混合物係不經進一步純化就用於以下的步驟。
LCMS(方法B):m/z 566.2(ES+),於1.18min(所欲的材料);m/z 680.2(ES+),於0.79min(雙醯基化副產物)。
步驟3)以N2沖洗粗乙基3-(4-{(2S)-2-{[(苯甲氧基)羰基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-基)-3-側氧基丙酸酯(510mg)與環己-1,4-二烯(0.85mL,9.00mmol)於EtOH(20mL)中的混合物,然後添加10% Pd/C(10mg)。在於70℃下加熱共1h後,將反應混合物冷卻至rt並添加甲酸銨(568mg,9.00mmol)。於70℃下在N2下加熱混合物過夜,之後冷卻至rt與過濾。在真空內濃縮濾出物以產生粗標題化合物(194mg),其不經純化就被用於實施例13之形成中。
數據於表1。
如由以下實施例之製備例示的用於經由醯胺偶合(與在適當時去保護)來製備實施例的典型程序。
程序1:
實施例11,N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(哌
啶-4-基)-1-[4-(吡啶-4-基)哌
-1-基]丙-2-基}胺基)丙-2-基]-2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]
]-1-甲醯胺。
步驟1:將HATU(4.57g,12.0mmol)添加至(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3] ]-1-基)羰基]胺基}丙酸(中間物7,4.65g,10.0mmol)於DMF(150mL)中的溶液,接著於15min後添加tert-丁基4-{(2S)-2-胺基-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(中間物17,4.60g,11.0mmol)與DIPEA(6.86mL,40.1mmol)。於rt下攪拌混合物共17h,之後添加H2O(600mL)。藉由過濾分離所得的沈澱物,以H2O洗滌,並溶解於小量的MeOH中。以甲苯共蒸發兩次產生了粗tert-丁基4-{(2S)-2-{[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-基)羰基]胺基}丙醯基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(7.82g),其不經進一步純化就被用於下一個步驟。使用此方法製備一第二批次的材料(3.53g)。
LCMS(方法D):m/z 864.7(ES+),於0.88min。
步驟2:將TFA(31mL)添加至tert-丁基4-{(2S)-2-{[(2R)-3-(7-
甲基-1H-吲唑-5-基)-2-{[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-基)羰基]胺基}丙醯基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(步驟1,批次1,7.82g)於DCM(150mL)中的溶液並於rt下攪拌溶液共1h。添加甲苯(50mL)並在真空內濃縮混合物。添加DCM(200mL)與H2O(50mL)並以2M(aq)NaOH溶液將pH調整至大約12。分離各相並以DCM/異丙醇(1:1,5 x 200mL)萃取水層。在真空內濃縮組合的有機相。藉由梯度快速管柱色層分離法純化,以於DCM中的0-100%(DCM/MeOH/7N NH3,於MeOH中(4:1:0.4))洗提產生了標題化合物。使用此方法從步驟1,批次2材料製備一第二批次的標題化合物。將來自兩個批次的經純化的標題化合物組合在一起,溶解於DCM、MeOH與二異丙基醚之混合物中,音波振動處理並在真空內濃縮以產生標題化合物(5.30g,6.94mmol)。
數據於表2中。
實施例14,3,5-二溴基-N α-[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]
]-1-基)羰基]-N-{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌
-1-基]丙-2-基}-D-酪胺醯胺。
步驟1)於rt下將HATU(7.84g,20.6mmol)與3,5-二溴基
-N-[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-基)羰基]-D-酪胺酸(中間物14,10.0g,17.2mmol)於DMF(75mL)中的溶液攪拌共30min,之後添加tert-丁基4-{(2S)-2-胺基-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(中間物17,7.72g,18.5mmol)與DIPEA(11.8mL,68.8mmol)。於rt下攪拌反應混合物過夜,之後添加冷H2O(500mL)、飽和水性NaHCO3與DCM(200mL)。分離各相並以DCM(3 x 200mL)萃取水相。以鹵水(200mL)洗滌組合的有機相,在真空內濃縮,並以甲苯共蒸發。藉由梯度快速管柱色層分離法純化,以於DCM中的0-100%溶劑B洗提(其中溶劑B=DCM/MeOH/7N NH3,於MeOH中(90:9:1.5)產生了呈白色固體的3,5-二溴基-N α-{(2S)-3-[1-(tert-丁氧基羰基)哌啶-4-基]-1-側氧基-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}-N-[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-基)羰基]-D-酪胺醯胺(9.7g,9.86mmol)。
LCMS(方法D):m/z 984.5(ES+),於0.78min。
步驟2:將3,5-二溴基-N α-{(2S)-3-[1-(tert-丁氧基羰基)哌啶-4-基]-1-側氧基-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}-N α-[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-基)羰基]-D-酪胺醯胺(9.7g,9.86mmol)溶解於DCM中(70mL),冷卻至0℃,並逐滴添加TFA(15mL)。於rt下攪拌混合物共10min,之後添加甲苯(50mL)並在真空內濃縮。添加DCM(200mL)與H2O(100mL),以2N NaOH水溶液將pH調整至大約10。藉由過濾分離所得的沈澱物,溶解於DCM/MeOH(1:1,300mL)中,在真空內濃縮,並以MeOH與甲苯共蒸發數次。自MeOH/甲基tert-丁基醚研製產生了標題化合物(5.30g,6.00mmol)。
數據於表2中。
程序2:
實施例1,N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌
-1-基]丙-2-基}胺基)丙-2-基]-4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲醯胺。
步驟1:將DIPEA(0.12mL,0.66mmol)添加至HATU(99mg,0.22mmol)、(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}胺基)丙酸(中間物8,100mg,0.22mmol)與tert-丁基4-{(2S)-2-胺基-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(中間物17,92mg,0.22mmol)於DMF(2mL)中的溶液並於rt下攪拌反應混合物共10d,之後在真空內濃縮以產生粗tert-丁基4-{(2S)-2-{[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}胺基)丙醯基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(190mg,黏滯的棕色油),其不經純化就被用於隨後的步驟中。
LCMS(方法C):m/z 863.5(ES+),於1.89min。
步驟2:將粗tert-丁基4-{(2S)-2-{[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}胺基)丙醯基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯(190mg)溶解於MeOH(5mL)中並添加在二中的HCl(4M,5.0mL,20.0mmol)。於rt下攪拌反應混合物共2h,之後在真空內濃縮。藉由製備性逆相HPLC純化(Phenomenex Gemini-NX 5μm C18管柱,100 x 30mm,以15至90% MeCN/溶劑B於26min的期間以30mL/min洗提[其中溶劑B係0.2%的(28% NH3/H2O),於H2O中]與藉由於205nm下監視來收集流份)產生了呈米色固體的實施例1(25mg,0.03mmol)。
數據於表2中。
程序3:
實施例13,3-(4-{(2S)-2-{[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}胺基)丙醯基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌
-1-基]丙基}哌啶-1-基)-3-側氧基丙酸,銨鹽。
步驟1:於rt下攪拌DIPEA(0.27mL,1.52mmol)、HATU(172mg,0.45mmol)、(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-2,3-二
氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}胺基)丙酸(中間物8,176mg,0.38mmol)與乙基3-(4-{(2S)-2-胺基-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-基)-3-側氧基丙酸酯(中間物23,194mg,0.45mmol)於DMF(10mL)中的混合物過夜,之後在真空內濃縮。通過SiO2之短栓過濾粗材料,以MeOH洗提,之後藉由製備性HPLC進一步純化(Phenomenex Gemini-NX 5μm C18管柱,100 x 30mm,以15至35% MeCN/溶劑B在12.5min的期間以30mL/min洗提[其中溶劑B係0.2%的(28% NH3/H2O),於H2O中],藉由於205nm下監視來收集流份)。在純化期間,觀察乙基酯之切下。將含羧酸流份組合在一起並添加至10mL的濃縮氨水,並使混合物維持在rt下過夜,之後在真空內濃縮以產生呈無色固體的標題化合物(10mg,0.01mmol)。
數據於表2中。
藉由以上程序製備的進一步實施例係於表2中詳細說明。
選殖、桿狀病毒生產、Sf21細胞之大規模感染與膜製備。將人類類抑鈣素受體受體(CRLR)與人類RAMP1選殖至Invitrogen(ThermoFisher Scientific,UK)之pFastBac雙重表現載體中。CRLR/RAMP1 DNA之轉位係使用Invitrogen之Bac至Bac桿狀病毒表現系統執行。藉由以桿粒(bacmid)DNA使用Cellfectin® II轉染試劑(ThermoFisher Scientific,UK,目錄編號10362-100)轉染SF9細胞來生產P0桿狀病毒。於P0生產後,接著生產P1病毒以準備好用於大規模感染與膜製備。將Sf21細胞生長在以10%經熱失活的FBS與1% Pen/Strep補充的表現培養基ESF921(Expression Systems,USA,目錄編號96-001-01)中並於2.5x106個細胞/mL的細胞密度以及2的MOI下感染。在48h的期間於設在27℃下的震盪培養箱中進行表
現。於4℃下於2,500rcf下離心細胞培養物共10min。將沈澱小丸再懸浮於以Roche之完全無EDTA蛋白酶抑制劑混合錠(Roche Applied Sciences,目錄編號05056489001)、1mM PMSF與1mM EDTA補充的冷PBS中。接著於4℃下於3,273rcf下離心經再懸浮的細胞糊漿共12min。丟棄上清液並將沈澱小丸冷凍於-80℃下。將來自4L培養物的細胞沈澱小丸再懸浮於含有50mM Hepes pH 7.5、150mM NaCl、8個Roche無EDTA蛋白酶抑制劑混合錠與1mM PMSF的緩衝液中。將懸浮液放置於rt下攪拌共1h並接著使用VDI 25(VWR,USA)均質機於9,500rpm下均質化共90s。接著使用氣動式微流化處理器M-110L(Microfluidics,USA)溶胞細胞。於溶胞後,於9,500rpm下均質化混合物共90s並接著於335rcf下離心共10min。接著進一步於42,000rpm下超高速離心上清液共90min。於超高速離心後,丟棄上清液並將沈澱小丸再懸浮於50mL(對各2L培養物各25mL)含有50mM Hepes pH 7.5、150mM NaCl、3個Roche無EDTA蛋白酶抑制劑混合錠與1mM PMSF的緩衝液中。接著於9,500rpm下均質化懸浮液共90s。接著將所得的膜儲存於-80℃下。
放射性配體結合分析。將於昆蟲Sf21細胞膜均質物中表現的人類CGRP受體(由CRLR與RAMP1組成)再懸浮於結合緩衝液(10mM HEPES,pH 7.4、5mM MgCl2、0.2% BSA)中至每槽孔0.6μg蛋白質的最終分析濃度。藉由於rt下添加各種各樣的濃度的3H-telcagepant(Ho等人,The Lancet,2008,372,2115)(於250μL的總反應體積)共60min來測定飽和等溫線。於培養最後,以Tomtec細胞收集器將膜過濾至unifilter(其為有結合在其上的以0.5% PEI預先培養的GF/B濾紙的96槽孔白色微量盤)上並以
蒸餾水洗滌5次。在10nM MK-3207氫氯化物(CAS編號957116-20-0)的存在下測量非專一性結合(NSB)。在添加50μL的閃爍液後,在microbeta計數器上計數濾紙上的放射活性(1min)。對於抑制實驗,以0.5nM 3H-telcagepant與10種濃度的抑制性化合物(0.001-10μM)培養膜。自抑制曲線衍生IC50值並使用Cheng-Prussoff等式(Cheng等人,Biochem.Pharmacol.1973,22,3099-3108)計算親和力常數(Ki)值。一些本發明之化合物之pKi值(其中pKi=-log10 Ki)係於以下列表顯示。
cAMP功能性分析。使用均相時間分辨螢光(Homogeneous Time-Resolved Fluorescence,HTRF)cAMP dynamic-2分析(Cisbio,法國)測定於受體活化後的cAMP生產。以12,500個細胞/槽孔的密度將內生性表現人類CGRP受體的人類神經胚細胞瘤細胞系SK-N-MC種於實心壁96槽孔半面積盤(Costar,目錄編號3688,Corning Life Sciences,德國)中。在於37℃下培養16h後,移除培養基並於37℃下將細胞培養於含有500μM IBMX(Tocris,Abingdon,UK,目錄編號2845)與漸增濃度的測試拮抗劑的無血清培養基共30min。於此後,於37℃下以EC80濃度的人類CGRP(0.3nM)攻擊細胞另外30min並接著按製造商之指引測定cAMP生產,之後在PheraStar螢光讀盤機(BMG LabTech,德國)上讀盤。自抑制曲線衍生IC50值。使用經修改的Cheng-Prussoff等式(其中K d=促效劑EC50且L hot=促效劑攻擊濃度)將pIC50值(其中pIC50=-log10 IC50)轉變成功能性pK b值。一些本發明之化合物之pK b值係於表3中詳細說明。
受體動力學剖析。咸領會到了小型分子於相關生物標的的動力學輪廓可於活體內對該分子之藥效學功效有影響(Copeland,Expert Opin.Drug Discov.,2010,5,305)。例如,olcegepant於CGRP受體有緩慢的動力學(Schindler,Doods,Eur.J.Pharmacol.,2002,442,187),而此為一個可能對其在人類中的偏頭痛治療之延長的效力有貢獻的因子(於靜脈內輸液2.5mg劑後24h 47%無頭痛頻率;Olesen等人,N.Eng.J.Med.,2004,350,1104)。於類似的方式,MK-3207亦已被顯示會展示對於CGRP受體的相對上緩慢的解離(Salvatore等人,J.Pharmacol.Exp.Ther.,2010,333,152)。本發明之化合物與參考CGRP受體拮抗劑之CGRP受體動力學已使用以下表面電漿子共振技術剖析並於表4中詳細說明。
動力學分析係於Biacore T200儀器(GE Healthcare Bio-Sciences AB,Uppsala,Sweden)上於25℃下使用0.05mM EDTA、PBS
(10mM磷酸鹽緩衝液、2.7mM KCl、137mM NaCl)pH 7.4、0.005% v/v表面活性劑P20、5% DMSO作為運作緩衝液運行。藉由捕捉-偶合技術(Rich等人,Anal.Biochem.,2011,409,267-272)將含有六His標籤的經純化的CGRP受體胞外功能域複合物(Moore等人,Structure,2010,18,1083-1093)固定在感應晶片NTA(GE Healthcare Bio-Sciences AB)上。以Ni2+裝載晶片並藉由EDC/NHS活化聚右旋糖基之羧基基團。接著注入受體胞外功能域複合物(100nM,於運作緩衝液中)並經由His標籤與胺基基團固定。注入各個化合物之二倍稀釋系列(五種濃度,範圍為25-40nM)。將減去空白的數據擬合至1:1交互作用模型以獲得動力學參數,其等於表4中被表現成解離半生期(t1/2=(ln 2/解離速率(kd))/60)。
所呈現的數據表明實施例2、4、6、7、8、9、11、12與14之各者具有在解離速率上可與olcegepant或MK-3207相比或比其緩慢的緩慢的受體解離之特性。
藥動學剖析。實施例與參考化合物之藥動學輪廓已於雄性Sprague Dawley®大鼠中經由靜脈內的(iv)、皮下的(sc)與鼻內的(IN)遞送途徑評估,且已於雄性食蟹獼猴中經由iv與sc遞送途徑評估。本發明之實施例與參考化合物(olcegepant)之藥動學數據係於表5與6中詳細說明。
方法:對於大鼠研究,三隻雄性Sprague Dawley®大鼠之群組(重量典型於180與300g間的範圍)係經由以下途徑之一給予單劑的實施例或參考化合物:iv、sc或IN,使用表5中具體指明的劑量、劑量體積與媒劑。於IN給藥之前,大鼠係以一肌肉內劑的25-30mg/kg氯胺酮混合物(氯胺酮、xylazine
氫氯化物與乙醯丙嗪(acepromazine)順丁烯二酸鹽,於食鹽水中)麻醉且該劑係在20-30s的期間經由插入至大鼠之鼻腔中大約5mm的聚乙烯PE-10管來引入。
對於食蟹獼猴研究,三隻雄性猴子的群組(重量典型於3.0與4.5kg間的範圍)係經由以下途徑之一給予單劑的實施例或參考化合物:iv或sc,使用表5中具體指明的劑量、劑量體積與媒劑。在藉由以上途徑給藥後,於數個時間點(典型為給藥前、0.083、0.25、0.5 1、2、4、8與24h)經由連續尾靜脈抽血(大鼠)或頭靜脈或隱靜脈(猴子)自動物取血液樣本並離心以分離血漿以用於藉由LC/MS/MS分析來分析。使用WinNonlin v6.2統計軟體(Pharsight Corporation,加利福尼亞州,USA)以使用非隔間模型產生藥動學參數。
熱力學溶解度剖析。製備50mM測試化合物之DMSO儲備溶液,且由此藉由以DMSO稀釋來製備1mM之工作溶液。從220nm至1000nm掃描工作溶液之UV吸收以鑑認測試化合物之波長最大值。接著於DMSO中將1mM工作溶液連續稀釋至不同的濃度以測定線性/校準曲線。為確認測試化合物之熱力學水溶解度,將樣本添加至一體積的PBS緩衝液(pH 7.4)或磷酸鈉緩衝液(pH 6.0),其適用於在所有的測試化合物皆溶解時產生1
mg/mL的最終濃度。接著於rt下將所得的溶液放在RotoSpin搖動器上於50rpm下共24h,之後使用0.45微米PVDF注射過濾器過濾溶液以移除不可溶的化合物之流份。隨後,取150uL的濾出物以用於使用UV分光光度計定量,獲得於相同波長最大值下的標準溶液與測試化合物之光學密度。從測試化合物之光學密度,使用線性/校準曲線計算熱力學溶解度並以微莫耳濃度(μM)表現。一些本發明之化合物之溶解度輪廓係於表7中詳細說明。
Claims (20)
- 一種式(I)之化合物,
- 根據申請專利範圍第1項的化合物,其中R4係經取代的苯基基團,其中該取代基係選自鹵基或羥基。
- 根據申請專利範圍第1項或第2項的化合物,其中R4係根據式(II)的部分,
- 根據申請專利範圍第3項的化合物,其中X係Br。
- 根據申請專利範圍第1項的化合物,其中R4係
- 根據申請專利範圍第5項的化合物,其中R4係
- 根據前述申請專利範圍中任一項的化合物,其中R2係H且R3係:
- 根據申請專利範圍第1至6項中任一項的化合物,其中R2與R3形成螺環性雜環以形成:
- 根據申請專利範圍第1項的化合物,其中R2係H或與R3形成螺環性雜環以形成:
- 根據前述申請專利範圍中任一項的化合物,其中R1係H、CO2 tBu、CH2CH3、CH2CH2CH3、COCH2CH2CH2CH3、CH2CH2N(CH3)2、COCH2CO2H。
- 根據申請專利範圍第10項的化合物,其中R1係H。
- 根據前述申請專利範圍中任一項的化合物,其中該化合物係選自由以下者所組成的群組:N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)丙-2-基]-4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲醯胺;tert-丁基4-{(2S)-2-{[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-基]羰基}胺基)丙醯基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-甲酸酯;N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)丙-2-基]-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺;N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(1-丙基哌啶-4- 基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)丙-2-基]-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺;3,5-二溴基-N α-{[4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-基]羰基}-N-{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}-D-酪胺醯胺;N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(1-戊醯基哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)丙-2-基]-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺;N-[(2R)-1-({(2S)-3-(1-乙基哌啶-4-基)-1-側氧基-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基丙-2-基]-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺;3,5-二溴基-N α-{[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}-N-{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}-D-酪胺醯胺;3,5-二溴基-N α-{[4-(2-側氧基-1,4-二氫喹唑啉-3(2H)-基)哌啶-1-基]羰基}-N-{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}-D-酪胺醯胺;N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)丙-2-基]-4-(2-側氧基-1,4-二氫喹唑啉-3(2H)-基)哌啶-1-甲醯胺;N-[(2R)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基-1-({(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)丙-2-基]-2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]]-1-甲醯胺; N-[(2R)-1-({(2S)-3-{1-[2-(二甲基胺基)乙基]哌啶-4-基}-1-側氧基-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}胺基)-3-(7-甲基-1H-吲唑-5-基)-1-側氧基丙-2-基]-4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲醯胺;3-(4-{(2S)-2-{[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}胺基)丙醯基]胺基}-3-側氧基-3-[4-(吡啶-4-基)哌-1-基]丙基}哌啶-1-基)-3-側氧基丙酸,銨鹽;與3,5-二溴基-N α-[(2'-側氧基-1',2'-二氫-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3] ]-1-基)羰基]-N-{(2S)-1-側氧基-3-(哌啶-4-基)-1-[4-(吡啶-4-基)哌-1-基]丙-2-基}-D-酪胺醯胺。
- 根據申請專利範圍第12項的化合物,其中該化合物係:
- 一種經由非口服投予之途徑的根據申請專利範圍第1至13項中任一項的化合物的用途。
- 根據申請專利範圍第14項的用途,其中該非口服投予之途徑係鼻內的途徑、皮下的途徑或靜脈內的途徑。
- 一種根據申請專利範圍第1至13項中任一項的化合物的用途,其係用於治療腦血管或血管疾患,包含無先兆的偏頭痛、慢性偏頭痛、純粹月 經偏頭痛、與月經相關的偏頭痛、有先兆的偏頭痛、家族性偏癱偏頭痛、散發性偏癱偏頭痛、基底型偏頭痛、周期性嘔吐、腹部型偏頭痛、童年之良性陣發性眩暈、視網膜型偏頭痛、偏頭痛持續狀態(status migrainosus)、頭痛群、透析頭痛、陣發性半側顱痛(paroxysmal hemicrania)、骨關節炎、與更年期或導因於外科手術或藥物治療的醫藥誘發性更年期聯結的潮熱、連續性半側顱痛(hemicrania continua)、週期性嘔吐症候群、過敏性鼻炎、痤瘡、牙痛、耳痛、中耳發炎、曬傷、與骨關節炎及類風濕性關節炎聯結的關節疼痛、癌症疼痛、纖維肌痛、糖尿病神經病變、與發炎性腸病-克羅恩氏病聯結的疼痛、痛風、複雜性局部疼痛症候群、Behçet氏病、子宮內膜異位疼痛、背痛或咳嗽。
- 一種用於治療以下者的方法,其使用根據申請專利範圍第1至13項中任一項的化合物:腦血管或血管疾患,包含無先兆的偏頭痛、慢性偏頭痛、純粹月經偏頭痛、與月經相關的偏頭痛、有先兆的偏頭痛、家族性偏癱偏頭痛、散發性偏癱偏頭痛、基底型偏頭痛、周期性嘔吐、腹部型偏頭痛、童年之良性陣發性眩暈、視網膜型偏頭痛、偏頭痛持續狀態、頭痛群、透析頭痛、陣發性半側顱痛、骨關節炎、與更年期或導因於外科手術或藥物治療的醫藥誘發性更年期聯結的潮熱、連續性半側顱痛、週期性嘔吐症候群、過敏性鼻炎、痤瘡、牙痛、耳痛、中耳發炎、曬傷、與骨關節炎及類風濕性關節炎聯結的關節疼痛、癌症疼痛、纖維肌痛、糖尿病神經病變、與發炎性腸病-克羅恩氏病聯結的疼痛、痛風、複雜性局部疼痛症候群、Behçet氏病、子宮內膜異位疼痛、背痛或咳嗽。
- 根據申請專利範圍第17項的方法,其中該化合物係經由非口服途徑 投予。
- 根據申請專利範圍第18項的方法,其中該非口服投予之途徑係鼻內的途徑、皮下的途徑或靜脈內的途徑。
- 一種合成根據申請專利範圍第1至13項中任一項的化合物的方法。
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WO2018178938A1 (en) * | 2017-03-31 | 2018-10-04 | Heptares Therapeutics Limited | Cgrp receptor antagonists |
SG11202009199YA (en) | 2018-03-25 | 2020-10-29 | Biohaven Pharm Holding Co Ltd | Rimegepant for cgrp related disorders |
AU2019371400A1 (en) | 2018-11-02 | 2021-04-08 | Dana-Farber Cancer Institute, Inc. | Acetylation writer inhibitor development and uses thereof |
WO2021141662A1 (en) | 2020-01-10 | 2021-07-15 | Massachusetts Institute Of Technology | Proteolysis targeting chimeric molecules (protacs) with functional handles and uses thereof |
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US10300056B2 (en) | 2019-05-28 |
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