TW201408655A - 芳基乙炔基衍生物 - Google Patents
芳基乙炔基衍生物 Download PDFInfo
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- TW201408655A TW201408655A TW102125419A TW102125419A TW201408655A TW 201408655 A TW201408655 A TW 201408655A TW 102125419 A TW102125419 A TW 102125419A TW 102125419 A TW102125419 A TW 102125419A TW 201408655 A TW201408655 A TW 201408655A
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- ethynyl
- pharmaceutically acceptable
- derivative
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Abstract
本發明係關於呈純對映異構體形式之式I之乙炔基衍生物□或其醫藥上可接受的酸加成鹽,其中R1為苯基,其視情況經1-2個鹵素原子取代;鹵素原子係選自由氟或氯。咸已發現,通式I化合物為代謝型麩胺酸受體亞型5(mGluR5)之變構調節劑。
Description
本發明係關於具有如式I中所示絕對組態而呈純對映異構體形式之式I之乙炔基衍生物
或係關於其醫藥上可接受的酸加成鹽,其中R1為苯基,其視情況經1-2個鹵素原子取代;鹵素原子係選自由氟或氯。
現已出乎意料地發現,通式I化合物為代謝型麩胺酸受體亞型5(mGluR5)之變構調節劑,其與先前技術之化合物相比,顯示具有利的生物化學-、生理化學-及藥效動力學性質。
在中樞神經系統(CNS)中,刺激之傳遞係藉由神經元所釋放出之神經遞質與神經受體之相互作用而發生。
麩胺酸為腦中主要的興奮性神經遞質,且在各種中樞神經系統(CNS)功能中扮演獨特的作用。麩胺酸依賴型刺激受體係分為兩大類,第一大類(亦即離子移變受體)會形成配體控制離子通道。代謝型麩胺酸受體(mGluR)則屬於第二大類,且此外係屬於G-蛋白偶合受體家族。
目前,已知此等mGluR有8種不同成員,且此等成員中有些甚至存在亞類。根據其等序列的同源性、訊號傳導機制及激動劑選擇性,
此等8種受體可再細分為三個子群:mGluR1及mGluR5屬於組別I,mGluR2及mGluR3屬於組別II,而mGluR4、mGluR6、mGluR7及mGluR8屬於組別III。
屬於第一組別之代謝型麩胺酸受體的配體可用於治療或預防急性及/或慢性神經疾病,諸如精神病、癲癇症、精神分裂症、阿茲海默氏症(Alzheimer’s disease)、精神分裂症及記憶缺失,以及慢性與急性疼痛。
就此而言,其他可治療的適應症為繞道手術或移植所引起之腦功能受限、腦供血不足、脊髓損傷、頭部損傷、妊娠所引起之缺氧、心跳驟停及低血糖。另外可治療的適應症為局部缺血、亨丁頓氏舞蹈症(Huntington's chorea)、肌萎縮性側索硬化症(ALS)、結節性硬化症(TSC)、AIDS所引起之癡呆、眼損傷、視網膜病變、特發性帕金森氏症或藥劑所引起之帕金森氏症,以及會導致麩胺酸缺乏功能之病狀,諸如例如肌肉痙攣、驚厥、偏頭痛、尿失禁、尼古丁成癮、鴉片成癮、焦慮、嘔吐、運動困難及抑鬱。
完全或部分由mGluR5介導之病症為(例如)神經系統之急性、創傷性及慢性退化過程(諸如阿茲海默氏症、老年癡呆、帕金森氏症(Parkinson’s disease)、亨丁頓氏舞蹈症、肌萎縮性側索硬化症及多發性硬化)、精神疾病(諸如精神分裂症及焦慮、抑鬱、疼痛及藥物依賴性)(Expert Opin.Ther.Patents(2002),12,(12))。
一種開發選擇性調節劑之新型途徑係確定經由異位機制起作用之化合物,藉由將受體結合至不同於高度保守的正構(orthosteric)結合位點而調節該受體。最近,mGluR5之變構調節劑已成為提供此種具吸引力的替代物之新穎醫藥實體。變構調節劑已描述於(例如)WO2008/151184、WO2006/048771、WO2006/129199、WO2005/044797中,及尤其描述於WO2011/128279,以及Molecular Pharmacology,40, 333-336,1991;The Journal of Pharmacology and Experimental Therapeutics,Vol 313,No.1,199-206,2005;Nature,480(7375),63-68,2012中。
先前技術中所描述的是正向變構調節劑。該等正向變構調節劑並非依靠自身直接使受體活化,而是顯著增強受激動劑刺激之反應、提升效力及最大化效能之化合物。結合此等化合物可增加麩胺酸位點激動劑在其胞外N-端結合位點之親和力。因此,變構調節作用係一種可適當改善生理受體活化之具吸引力的機制。針對mGluR5受體之選擇性變構調節劑是缺乏的。習知mGluR5受體調節劑通常缺乏藥物安全性,此會導致藥物具有較多的副作用。
因此,仍需要能克服此等缺陷並有效提供針對mGluR5受體之選擇性變構調節劑之化合物。本發明可解決此問題,如下所示:比較本發明化合物對先前技術之類似化合物:先前技術之結構上類似的化合物業已揭示於WO2011128279(=參考1,Hoffmann-La Roche)中,且顯示該專利案在結構上最為類似的化合物(實例13、40及59)以供比較。
比較本發明化合物對參考化合物實例13、40及59:與參考化合物相比,本發明化合物均具有類似效力。此外,與參考化合物之較高值(高於80%)相比,其等均顯示遠低於60%之效能,此係關於mGluR5正向變構調節劑之耐受性問題之標準。在以彼等觀察到接近所需治療效果之劑量(低治療窗口)口服(癲癇發作)高效能值高於60%之化合物後,顯示會有嚴重的CNS相關副作用。效能低於60%之化合物在高於治療劑量30至1000倍之劑量下耐受性良好,同時維持其所需治療效果。因此,一般而言,與先前技術之結構上類似的化合物相比,就藥物安全性而言,本發明化合物因其效能值低於60%(其與不出現嚴重的CNS副作用傾向相關聯)而具有明顯優勢。
實例列表:
式I化合物之特徵在於具有可貴的治療性質。其等可用於治療或預防與mGluR5受體之變構調節劑有關之病症。
針對屬於變構調節劑之化合物的最佳適應症為精神分裂症及認知行為病症。
本發明係關於式I化合物及其醫藥上可接受的鹽、此等作為醫藥活性物質之化合物、其等生產方法及於治療或預防與mGluR5受體之變構調節劑有關之病症(諸如精神分裂症及認知行為病症)之用途及含該式I化合物之醫藥組合物。
不論所論及之術語係單獨或以組合方式出現,本說明中所用一般術語均適用以下定義。
如本文所用,術語「鹵素」表示氯或氟。
術語「醫藥上可接受的鹽」或「醫藥上可接受的酸加成鹽」包括與無機酸及有機酸(諸如鹽酸、硝酸、硫酸、磷酸、檸檬酸、甲酸、富馬酸、馬來酸、乙酸、琥珀酸、酒石酸、甲磺酸、對甲苯磺酸等)之鹽。
本發明之一實施例為具有如式I中所示絕對組態而呈純對映異構體形式之式I-A化合物
或係關於其醫藥上可接受的酸加成鹽,其中R1為苯基,其視情況經1-2個氟原子取代。
式I-A化合物係以下化合物:(3aR,6aR)-1-(5-(苯基乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮
(3aR,6aR)-1-(5-((3-氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮
(3aR,6aR)-1-(5-((4-氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮,或(3aR,6aR)-1-(5-((2,5-二氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮。
本發明式I化合物可依連續途徑或匯集合成途徑製備。以下流程1至2中顯示本發明化合物之合成。熟習此項技術者已知進行該反應及純化所得產物所需之技能。下文製法說明時所用之取代基及代號具有前文所指定之定義。
藉由下文所給定之方法、藉由實例中所給定之方法或藉由類似方法製造式I化合物。熟習此項技術者已知個別反應步驟之適宜反應條件。反應次序並不限於流程中所顯示之次序,然而,依據起始材料及其各別反應性,可自由變更反應步驟之次序。起始材料係可為市售購得或可藉由類似於下文所給定方法之方法、藉由說明或實例中所引用之參考文獻中所述之方法或藉由此項技術中已知之方法進行製備。
本發明式I化合物及其醫藥上可接受的鹽可藉由此項技術中已知之方法進行製備,例如藉由下文所述之方法變體,該方法包括:a)使式II化合物
(其中X為選自由溴或碘之鹵素原子,且其中該式II化合物為外消
旋混合物或呈純對映異構體形式)與適宜的式III之芳基-乙炔進行反應
以形成式I化合物
其中該等取代基係如上所述,或若需要,可將該等所得化合物轉化為醫藥上可接受的酸加成鹽,或者b)使下式化合物
與下式化合物反應
以得到下式化合物
其中該等取代基係描述在請求項1中,或若需要,可將該等所得化合物轉化為醫藥上可接受的酸加成鹽。
流程1及2中及實例1-4中更為詳細地進一步描述式I化合物之製備。
流程1
藉由適宜二-鹵化吡啶(諸如2-氟-5-碘-吡啶)及適宜式4雙環脲之鹼催化反應得到式II鹵代吡啶化合物(流程1)。式4化合物可如下製得,自式1外消旋酮酸開始,藉由與純對映異構體的(R)-苯基丙胺醇進行反應形成光學上純淨的三環中間體2,其中所有構中心均係在完全立體控制下使用M.Jida & al.,Green Chem.12,961(2010)之程序形成。使用與Dubuffet & Lecouve於EP1354875中針對6-員碳環類似物所述之類似程序將該三環中間體2轉化為4。在還原條件下,以三氟化硼合乙醚處理化合物2,以形成化合物3(4之N-苄基-保護之衍生物),其後經由氯化消除作用進行去保護,隨後使所形成的烯胺進行水解,以得到純對映異構體的二環醯胺4。亦已公開可得到外消旋或純對映異構體的4之其他合成程序(J.Boivin & al.,Tetrahedron,51(23),6517(1995);S.Knapp;A.Levorse,J.Org.Chem.53(17)4006(1988);Ishibashi,& al.Tet.Asym.7(9),2531(1996))。然後使內醯胺4與二鹵代吡啶(諸如2-氟-5-碘吡啶)在鹼催化條件(NaH/DMF;或Cs2CO3/甲苯)下進行縮合,以形成式II化合物,其中X為碘。使用鈀催化反應條件(Buchwald),使內醯胺4與二鹵代吡啶(諸如2-碘-5-溴吡啶)進行反應亦可形成式II化合物,其中X為溴。然後使化合物II與經適當取代之芳基乙炔衍生物5
(其中Q為氫或可原位切除之保護基,諸如三烷基甲矽烷基-或芳基二烷基甲矽烷基-基團,較佳為氫或三甲基甲矽烷基)在鈀催化偶聯條件下進行反應(索諾格席拉(Sonogashira)反應),以形成式I化合物。在使用外消旋4之情況中,可在合成式I化合物期間之任何給定階段,使用熟習此項技術者所知之程序分離出對映異構物。
亦可顛倒可得到式I化合物之反應的次序(流程2)。在該情況中,首先在芳基乙炔衍生物5與二鹵代吡啶之間進行索諾格席拉反應,以得到式6之芳基乙炔-吡啶化合物,然後使其與雙環內醯胺4縮合,以得到式I化合物。
如本文所述之式I化合物及其醫藥上可接受的鹽係用於治療或預防精神病、癲癇症、精神分裂症、阿茲海默氏症、認知病症及記憶缺失、慢性及急性疼痛、繞道手術或移植所引起之腦功能受限、腦供血不足、脊髓損傷、頭部損傷、妊娠所引起之缺氧、心跳驟停及低血糖、局部缺血、亨丁頓氏舞蹈症、肌萎縮性側索硬化症(ALS)、AIDS所引起之癡呆、眼損傷、視網膜病變、特發性帕金森氏症或藥劑所引起之帕金森氏症、肌肉痙攣、驚厥、偏頭痛、尿失禁、胃腸道逆流病、無論係藥物或疾病所誘發之肝損傷或肝衰竭、X染色體易碎症候群(Fragile-X syndrome)、唐氏(Down)症候群、自閉症、尼古丁成癮、鴉片成癮、焦慮、嘔吐、運動困難、進食障礙(尤其貪食症或神經性厭食症)及抑鬱,特別係用於治療及預防急性及/或慢性神經疾病、焦慮,治療慢性及急性疼痛、尿失禁及肥胖。
較佳適應症為精神分裂症及認知病症。
另外,本發明係關於以如本文所述之式I化合物及其醫藥上可接受的鹽於製造較佳用於治療及預防上述病症之藥劑之用途。
生物分析及數據:細胞內Ca
2+
流動分析
產生經編碼人類mGlu5a受體之cDNA穩定轉染之單株HEK-293細胞系;為了讓mGlu5正向變構調節劑(PAM)發揮作用,選拔受體表現程度低且組成性受體活性低之細胞系,以便讓激動活性與PAM活性呈現差異化。根據標準程序(Freshney,2000),將細胞培養於含有高葡萄糖之杜貝卡氏改良依格培養基(Dulbecco’s Modified Eagle Medium)中,該培養基補充有1mM穀胺醯胺、10%(vol/vol)熱滅活小牛血清、盤尼西林/鏈黴素、50μg/ml潮黴素(hygromycin)及15μg/ml殺稻瘟菌素(blasticidin)(所有細胞培養試劑及抗生素均來自Invitrogen,Basel,Switzerland)。
在實驗前約24小時,將5x104個細胞/孔接種於經聚-D-離胺酸塗覆之96-孔黑底/透明底板中。在37℃下,在該等細胞中添加含於加樣緩衝液(1xHBSS,20mM HEPES)中之2.5μM Fluo-4AM處理1小時,並以加樣緩衝液清洗五次。將該等細胞轉移至功能性藥物篩選系統(Functional Drug Screening System)7000(Hamamatsu,Paris,France)中,並在37℃下添加11份測試化合物之半對數連續稀釋液,並培育該等細胞歷時10-30分鐘,同時連線記錄螢光。在此預培育步驟後,以相當於EC20之濃度(通常約為80μM)的激動劑L-麩胺酸添加至該等細胞中,同時連線記錄螢光;為說明細胞日與日之間的反應性變化,在各次實驗前藉由記錄麩胺酸之全劑量-反應曲線測定麩胺酸之EC20。
將反應測定為以螢光減去基底(亦即在未添加L-麩胺酸下之螢光)計之峰增加,將其標準化為以L-麩胺酸之飽和濃度所獲得之最大刺激
效應。依據%最大刺激,使用XLfit繪製圖表,XLfit為一種使用萊文貝格馬奎特(Levenburg Marquardt)算法迭代地繪製數據之曲線擬合程式。所用之單點競爭分析方程式為y=A+((B-A)/(1+((x/C)D))),其中y為%最大刺激效應,A為最小y值,B為最大y值,C為EC50,x為競爭化合物之濃度之log10,而D為曲線斜率(希爾(Hill)係數)。由此等曲線計算出EC50(達到半數最大刺激時之濃度)、希爾係數及以L-麩胺酸之飽和濃度所獲得以最大刺激效應%計之最大反應。
在與PAM測試化合物預培育期間(亦即在運用L-麩胺酸之EC20濃度前)所獲得之正訊號係表示激動劑活性,缺乏此等訊號顯示是缺乏激動劑活性。添加L-麩胺酸之EC20濃度後觀察到訊號之減弱是表示該測試化合物具有抑制活性。
在以下實例之列表中,顯示EC50值均小於或等於10nM之化合物之相應結果。
式(I)化合物及其醫藥上可接受的鹽可用作(例如)呈醫藥製劑形式之藥劑。該等醫藥製劑可經口投與,例如呈錠劑、包衣錠劑、糖錠、硬及軟明膠膠囊、溶液、乳液或懸浮液之形式。然而,亦可以直腸給藥方式(例如呈栓劑之形式)進行投與,或以非經腸給藥方式(例如呈注射液之形式)進行投與。
式(I)化合物及其醫藥上可接受的鹽可與醫藥上之惰性無機或有機載劑一起進行加工,以製造醫藥製劑。可使用乳糖、玉米澱粉或其
衍生物、滑石粉、硬脂酸或其鹽等本身作為(例如)錠劑、包衣錠劑、糖錠及硬明膠膠囊之載劑。適用於軟明膠膠囊之載劑為(例如)植物油、蠟、脂肪、半固體及液體多元醇等;然而,依據活性物質之性質,在軟明膠膠囊之情況中,通常無需載劑。適合製造溶液及糖漿之載劑為(例如)水、多元醇、蔗糖、轉化糖、葡萄糖等。就式(I)化合物之水溶性鹽之注射水溶液而言,可使用佐劑(諸如醇類、多元醇、甘油、植物油等),但一般而言並非必要。適用於栓劑之載劑為(例如)天然油或硬化油、蠟、脂肪、半液體或液體多元醇等。
此外,醫藥製劑可包含保存劑、增溶劑、安定劑、潤濕劑、乳化劑、甜味劑、著色劑、矯味劑、用於使滲透壓變化之鹽、緩衝劑、掩蓋劑或抗氧化劑。其等亦可包含其他具治療價值之物質。
如之前所述,包含式(I)化合物或其醫藥上可接受的鹽及治療惰性賦形劑之藥劑亦為本發明之目標,製造此等藥劑之方法亦然,該方法包括將一或多種式I化合物或其醫藥上可接受的鹽及(若需要)一或多種其他有治療價值之物質連同一或多種治療惰性載劑變為蓋倫劑型。
另外,如之前所述,式(I)化合物於製備可用於預防及/或治療上述疾病之藥劑之用途亦為本發明之目標。
劑量可在寬廣範圍內變化,且理當符合各特定情況之個別要求。一般而言,經口或非經腸投與之有效劑量係介於0.01-20mg/kg/天之間,且就所有所述適應症而言,劑量較佳為0.1-10mg/kg/天。體重70kg之成人的每日劑量相應地處在0.7-1400mg/天之間,較佳在7與700mg/天之間。
製備包含本發明化合物之醫藥組合物:以習知方式製造以下組合物之錠劑:mg/錠
活性成分 100
實例1
(3aR,6aR)-1-(5-(苯基乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮
步驟1:(1S,5aR)-(R)-3-苯基-六氫-1-氧雜-3a-氮雜-環戊烷并[c]環戊二烯-4-酮:
在20ml封閉管中,於130℃下,加熱(rac)-2-(2-側氧基環戊基)乙酸(1030mg,7.25mmol)及(R)-2-胺基-2-苯基乙醇(994mg,7.25mmol)之混合物3小時,而後將其冷卻至室溫。將殘餘物溶解於50ml二氯甲烷中。以10ml 1N HCl溶液清洗有機相一次,再以10ml飽和NaHCO3溶液清洗一次。於硫酸鎂上乾燥後,並在真空中濃縮,得到1.6g(91%)呈淺棕色油之幾近純淨的標題化合物,直接將其用於下一步驟中。MS:m/e=244.0(M+H+)。
步驟2:(R)-1-((R)-羥基-1-(R)-苯乙基)-六氫-環戊烷并[b]吡咯-2-酮:
向(1S,5aR)-(R)-3-苯基-六氫-1-氧雜-3a-氮雜-環戊烷并[c]環戊二烯-4-酮(1.6g,6.58mmol)含於二氯甲烷(10ml)之溶液中添加三氟化硼合乙醚(5.6g,5.00ml,39.5mmol,6.0當量)及三乙基矽烷(1.53g,2.1ml,13.2mmol,2.0當量)。在50℃下攪拌20小時後,讓該反應溫至室溫,並藉由添加5% NaHCO3溶液將pH調整為7。在以二氯甲烷、水萃取後,於真空中濃縮,得到呈淺棕色油之幾近純淨的標題化合物(1.6g,99%),直接將其用於下一步驟中。MS:m/e=246.2(M+H+)。
步驟3:(R)-1-((R)-氯-1-(R)-苯乙基)-六氫-環戊烷并[b]吡咯-2-酮:
向(3aR,6aR)-1-((R)-2-羥基-1-苯乙基)六氫環戊烷并[b]吡咯-2(1H)-酮(1.6g,6.52mmol)含於二氯甲烷(10ml)之溶液中添加吡啶(929mg,950μl,11.7mmol)。然後將該溶液冷卻至0℃,並在5分鐘內逐份添加對甲苯磺醯氯(1.49g,7.83mmol,1.2當量)。在5℃下攪拌30分鐘後,讓該反應溫至室溫,並另外攪拌20分鐘。以二氯甲烷/水進行萃取後,進行標準處理,並在真空中濃縮,得到1.59g粗料,然後將其溶於50ml二氯甲烷中,向其中添加約15g矽膠。攪拌5分鐘後,蒸發掉溶劑。將殘餘物懸浮於二氯甲烷中。濾出固體,並以20ml二氯甲烷及乙酸乙酯之1:1混合物清洗三次。在真空中濃縮濾液,以得到1.45g(84%)呈淺棕色油之幾近純淨的標題化合物,直接將其用於下一步驟中。MS:m/e=264.1,266.2(M+H+)。
步驟4:(3aR,6aR)-1-(1-苯乙烯基)六氫環戊烷并[b]吡咯-2(1H)-酮:
使用DBU(1.01g,1.00ml,6.63mmol,1.25當量)處理(R)-1-((R)-氯-1-(R)-苯乙基)-六氫-環戊烷并[b]吡咯-2-酮(1.4g,5.31mmol)含於20ml甲苯之溶液。該反應回流2小時,於真空中濃縮,以乙酸乙酯/水進行萃取,經乾燥並於真空中濃縮,以得到1.19g(99%)呈淺棕色油之標題化合物,MS:m/e=228.3(M+H+),直接將其用於下一步驟中。
步驟5:(-)-(R)-六氫-環戊烷并[b]吡咯-2-酮:
向(3aR,6aR)-1-(1-苯乙烯基)六氫環戊烷并[b]吡咯-2(1H)-酮(1.2g,5.28mmol)含於5ml甲醇之溶液中添加4M HCl溶液(7.92ml,31.7mmol,6.0當量),並將該反應在室溫下攪拌1小時。藉由添加4M NaOH溶液(約8ml)將反應之pH調整為7,添加醚(20ml),並以氯化鈉使水相飽和,並以乙酸乙酯萃取兩次。於硫酸鎂上乾燥及於真空中濃縮後,得到1.0g含有產物及苯乙酮之淺黃色油。在使用乙酸乙酯含於庚烷之20%至100%梯度於矽膠(20g)上藉由急驟層析純化後,隨後以2% MeOH含於乙酸乙酯進行溶離,得到0.66g(53%)呈淺黃色固體之標題化合物,其NMR數據完全符合文獻中所報導之數據。直接將該材料用於下一步驟中。
步驟6:(3aR,6aR)-1-(5-碘吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮:
向(3aR,6aR)-六氫環戊烷并[b]吡咯-2(1H)-酮(210mg,1.68mmol)及2-氟-5-碘吡啶(412mg,1.85mmol,1.1當量)含於甲苯(1.1ml)之溶液
中添加Cs2CO3(656mg,2.01mmol,1.2當量)。在105℃下攪拌反應16小時。然後將殘餘物溶解於乙酸乙酯中,濾出固體並以乙酸乙酯加以清洗。在真空中濃縮濾液,並使用乙酸乙酯含於庚烷之0%至60%梯度藉由急驟層析(SiO2,20g)純化殘餘物。得到呈無色油之標題化合物(300mg 55%),MS:m/e=329.4(M+H+)。
步驟7:(-)-(3aR,6aR)-1-(5-(苯基乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮
在10ml派熱司(Pyrex)管中,將(3aR,6aR)-1-(5-碘吡啶-2-基)六氫-環戊烷并[b]吡咯-2(1H)-酮(107mg,326μmol)溶於2ml THF中。將氬氣鼓吹通過該溶液。添加乙炔苯(59.9mg,64.5μl,587μmol,1.8當量)、三乙胺(99.0mg,136μl,978μmol,3.0當量)、雙(三苯基膦)氯化鈀(II)(13.7mg,19.6μmol,0.06當量)、三苯基膦(1.71mg,6.52μmol,0.02當量)及碘化亞銅(I)(1.86mg,9.78μmol,0.03當量)。在50℃下攪拌深棕色溶液2小時。將殘餘物溶解於乙酸乙酯中,濾出固體並以乙酸乙酯加以清洗。在真空中濃縮濾液,並使用乙酸乙酯含於庚烷之0%至60%梯度藉由急驟層析(SiO2,20g)純化殘餘物。得到95mg(96%)呈黃色粘稠油之標題化合物,MS:m/e=303.2(M+H+)。
實例2
(3aR,6aR)-1-(5-((3-氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮
按照實例1之一般方法製備標題化合物,步驟7使用(3aR,6aR)-1-(5-碘吡啶-2-基)六氫-環戊烷并[b]吡咯-2(1H)-酮(107mg,0.326
mmol)(實例1,步驟6)及1-乙炔基-3-氟代苯,得到100mg(96%)呈黃色粘稠油之標題化合物;MS:m/e=321.2(M+H+)。
實例3
(3aR,6aR)-1-(5-((4-氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮
按照實例1之一般方法製備標題化合物,步驟7使用(3aR,6aR)-1-(5-碘吡啶-2-基)六氫-環戊烷并[b]吡咯-2(1H)-酮(100mg,0.305mmol)(實例1,步驟6)及1-乙炔基-4-氟代苯,得到75mg(77%)呈黃色粘稠油之標題化合物;MS:m/e=321.2(M+H+)。
實例4
(3aR,6aR)-1-(5-((2,5-二氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮
按照實例1之一般方法製備標題化合物,步驟7使用(3aR,6aR)-1-(5-碘吡啶-2-基)六氫-環戊烷并[b]吡咯-2(1H)-酮(140mg,0.427mmol)(實例1,步驟6)及1-乙炔基-2,5-二氟代苯,得到142mg(98%)呈淺棕色粘稠油之標題化合物;MS:m/e=339.5(M+H+)。
Claims (10)
- 一種呈純對映異構體形式之式I乙炔基衍生物
- 如請求項1之呈純對映異構體形式之乙炔基衍生物,其具有式I-A,或其醫藥上可接受的酸加成鹽
- 如請求項1或2之式I或I-A乙炔基衍生物,其中該等化合物為(3aR,6aR)-1-(5-(苯基乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮(3aR,6aR)-1-(5-((3-氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮(3aR,6aR)-1-(5-((4-氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮,或(3aR,6aR)-1-(5-((2,5-二氟苯基)乙炔基)吡啶-2-基)六氫環戊烷并[b]吡咯-2(1H)-酮。
- 一種製備如請求項1之式I乙炔基衍生物之方法,其包括a)使式II化合物
- 如請求項1或2之式I乙炔基衍生物,其係用作治療活性物質。
- 一種醫藥組合物,其包含如請求項1至3中任一項之式I乙炔基衍生物及其醫藥上可接受的鹽中之至少一者。
- 如請求項1或2之式I乙炔基衍生物(當可呈對映異構物、非對映異構物之混合物或呈純對映異構體形式施用時);及其醫藥上可接受的鹽,其係用作藥劑。
- 一種如請求項1至3中任一項之式I乙炔基衍生物及其醫藥上可接受的鹽之用途,其係用於製造治療或預防與mGluR5受體之變構調節劑有關之疾病之藥劑。
- 如請求項8之用途,其中該疾病為精神分裂症、認知疾病、X染色體易碎症候群或自閉症。
- 如請求項1或2之式I乙炔基衍生物,其係用於治療或預防精神分裂症、認知疾病、X染色體易碎症候群或自閉症。
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