TW201708204A - 乙炔基衍生物 - Google Patents
乙炔基衍生物 Download PDFInfo
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- TW201708204A TW201708204A TW105117451A TW105117451A TW201708204A TW 201708204 A TW201708204 A TW 201708204A TW 105117451 A TW105117451 A TW 105117451A TW 105117451 A TW105117451 A TW 105117451A TW 201708204 A TW201708204 A TW 201708204A
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- methyl
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- heptan
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Abstract
本發明係關於式I之乙炔基衍生物
□其中R1 係氫或F;n 為1或2或其醫藥上可接受之酸加成鹽。
現已驚訝地發現,通式I之化合物係代謝型麩胺酸鹽受體拮抗劑(負向異位調節劑),其用於治療焦慮症及疼痛、抑鬱症、脆性X染色體症候群、自閉症譜系障礙、帕金森氏病(Parkinson’s disease)及胃食道逆流疾病(GERD)。
Description
本發明係關於式I之乙炔基衍生物
其中R1 係氫或F;n 為1或2或其醫藥上可接受之酸加成鹽。
較佳化合物係其中(R1)n係氫、3-氟、4-氟或2,5-二氟之彼等。
現已驚訝地發現,通式I之化合物係代謝型麩胺酸鹽受體拮抗劑(NAM=負向異位調節劑)。具有類似主要核心之化合物一般描述為mGluR5受體之正向異位調節劑。令人驚訝的是,已發現,獲得高效mGluR5拮抗劑而非mGluR5正向異位調節劑,其若與正向異位調節劑相比具有完全相反之藥理學。
mGluR5正向異位調節劑(PAM)在固定濃度之麩胺酸鹽存在下導致增加之受體活性(Ca2+動員),而異位拮抗劑(負向異位調節劑,NAM)導致受體活化之降低。
式I化合物因具有有價值之治療性質而著名。其可用於治療焦慮症及疼痛、抑鬱症、脆性X染色體症候群、自閉症譜系障礙、帕金森氏病(Parkinson’s disease)及胃食道逆流疾病(GERD)。
在中樞神經系統(CNS)中,刺激之傳遞係藉由神經遞質(其係由神經元釋放)與神經受體之相互作用而發生。
麩胺酸鹽係大腦中之主要興奮性神經遞質且在各種中樞神經系統(CNS)功能中起獨特作用。麩胺酸鹽依賴性刺激受體分成兩個主要群組。第一主要群組(即,離子型受體)形成配體控制離子通道。代謝型麩胺酸鹽受體(mGluR)屬第二主要群組,且此外屬G-蛋白偶聯受體家族。
目前,已知該等mGluR中之八個不同成員且該等中的一些甚至具有亞型。該八種受體根據其序列同源性、信號傳導機制及激動劑選擇性可細分成三個亞群:mGluR1及mGluR5屬I群,mGluR2及mGluR3屬II群且mGluR4、mGluR6、mGluR7及mGluR8屬III群。
屬第一群組之代謝型麩胺酸鹽受體之負向異位調節劑可用於治療或預防急性及/或慢性神經病症,例如帕金森氏病、脆性X染色體症候群、自閉症、認知障礙及記憶衰退,以及慢性及急性疼痛及胃食道逆流疾病(GERD)。
在此方面,其他可治療之適應症係由旁路手術或移植造成之大腦功能受限、至大腦之血液供應差、脊髓損傷、頭部損傷、由妊娠造成之缺氧、心跳停止及低血糖。其他可治療之適應症係局部缺血、亨庭頓氏舞蹈症(Huntington's chorea)、肌萎縮性脊髓側索硬化症(ALS)、由AIDS造成之失智症、眼部損傷、視網膜病、特發性帕金森症(parkinsonism)或由藥劑造成之帕金森症以及導致麩胺酸鹽缺乏功能之病狀,例如,肌肉痙攣、驚厥、偏頭痛、尿失禁、尼古丁成癮
(nicotine addiction)、鴉片成癮(opiate addiction)、焦慮症、嘔吐、運動障礙及抑鬱症。
完全或部分由mGluR5介導之病症係例如神經系統之急性、創傷性及慢性退化過程,例如,阿茲海默氏病(Alzheimer’s disease)、老年性癡呆、帕金森氏病、亨庭頓氏舞蹈症、肌萎縮性脊髓側索硬化症及多發性硬化、精神疾病(例如,精神分裂症及焦慮症)、抑鬱症、疼痛及藥物依賴(Expert Opin.Ther.Patents(2002),12,(12))。
選擇性mGluR5拮抗劑尤其可用於治療其中期望降低mGluR5受體活化之病症,例如焦慮症及疼痛、抑鬱症、脆性X染色體症候群、自閉症譜系障礙、帕金森氏病及胃食道逆流疾病(GERD)。
本發明之目標係式I化合物及其醫藥上可接受之鹽、作為醫藥上活性物質之上文所提及之化合物及其產生。本發明之其他目標係基於本發明化合物之藥劑及其製造,以及該等化合物在控制或預防mGluR5受體(NAM)介導之病症(該等係焦慮症及疼痛、抑鬱症、脆性X染色體症候群、自閉症譜系障礙、帕金森氏病及胃食道逆流疾病(GERD))及各別地用於生產相應藥劑之用途。
本發明之化合物在參考文獻1(WO2011128279)中一般描述為mGluR5受體之正向異位調節劑。大多數類似例示化合物連接至5員或6員環。已令人驚訝地發現,具有較小環大小(4員環)且具有二環之絕對立體化學(1R,5S)之化合物係高效mGluR5拮抗劑,其具有與WO2011128279中所闡述之正向異位調節劑完全相反之藥理學。
本發明之一個實施例係式I化合物,例如下列:(1S,5R)-2-甲基-4-(5-(苯基乙炔基)吡啶-2-基)-2,4-二氮雜二環[3.2.0]庚-3-酮
(1R,5S)-2-(5-((4-氟苯基)乙炔基)吡啶-2-基)-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮
(1R,5S)-2-(5-((3-氟苯基)乙炔基)吡啶-2-基)-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮或
(1R,5S)-2-(5-((2,5-二氟苯基)乙炔基)吡啶-2-基)-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮。
正向與負向異位調節劑間之主要差異可參見圖1。在固定濃度之麩胺酸鹽存在下,mGluR5正向異位調節劑(PAM)導致增加之受體活性(Ca2+動員),而異位拮抗劑(負向異位調節劑,NAM)導致受體活化之降低。在圖1中,受體對於PAM之親和力係約10-7M,且對於NAM之親和力係介於10-7M與10-8M之間。該等值亦可使用結合分析以置換放射性配體(=MPEP)來量測,參見分析描述。
圖1:mGluR5正向異位調節劑(PAM)與mGluR5拮抗劑(負向異位調節劑=NAM)之比較
可藉由該等化合物解決之適應症並不相同。mGluR5-NAM對其中期望降低過度受體活性之適應症有益,例如焦慮症、疼痛、脆性X染色體、自閉症譜系障礙及胃食道逆流疾病。另一方面,mGluR5 PAM可用於其中期望正規化降低之受體活性之適應症中,例如精神病、癲癇、精神分裂症、阿茲海默氏病及相關之認知障礙,以及結節性硬化症中。
此差異實際上可在(例如)焦慮症動物模型中顯示出,例如大鼠沃格爾(Vogel)衝突飲水測試,其中實例1之化合物以0.1mg/Kg之最小有效劑量顯示抗焦慮活性,而mGluR-PAM預期在此動物模型中不顯示活性(參見圖2)。
圖2:化合物「實例2」在大鼠沃格爾衝突飲水測試中之活性。
產生經編碼人類mGlu5a受體之cDNA穩定轉染之單株HEK-293細
胞系;為利用mGlu5正向異位調節劑(PAM)進行研究,選擇具有低受體表現程度及低組成型受體活性之細胞系以容許區別激動活性與PAM活性。根據標準方案(Freshney,2000)在具有高葡萄糖之杜貝克氏改良鷹氏培養基(Dulbecco's Modified Eagle Medium)中培養細胞,該培養基補充有1mM麩醯胺酸、10%(vol/vol)熱滅活胎牛血清、盤尼西林(Penicillin)/鏈黴素、50μg/ml潮黴素及15μg/ml殺稻瘟素(所有細胞培養試劑及抗生素均來自Invitrogen,Basel,Switzerland)。
在實驗前大約24hr,將5×104個細胞/孔接種於聚-D-離胺酸塗佈之黑色/透明底的96孔板中。將細胞與裝載緩衝液(1×HBSS,20mM HEPES)中之2.5μM Fluo-4AM一起於37℃下裝載1hr,並用裝載緩衝液洗滌五次。將細胞轉移至功能藥物篩選系統(Functional Drug Screening System)7000(Hamamatsu,Paris,France)中,並於37℃下添加測試化合物之11個半對數連續稀釋液並將細胞培育10-30min,同時線上記錄螢光。此預培育步驟之後,將激動劑L-麩胺酸鹽以對應於EC20之濃度(通常約80μM)添加至細胞,同時線上記錄螢光;為計及細胞反應性之每日變化,在每一試驗即將開始之前藉由記錄麩胺酸鹽之全劑量反應曲線確定麩胺酸鹽之EC20。
將反應量測為螢光減去基線(即,不添加L-麩胺酸鹽之螢光)之峰值增加,將其正規化成利用飽和濃度之L-麩胺酸鹽獲得之最大刺激效應。使用XLfit繪製最大刺激%之曲線圖,XLfit係使用Levenburg Marquardt演算法以迭代方式對數據繪圖之曲線擬合程式。所用之單一位點競爭分析方程式係y=A+((B-A)/(1+((x/C)D))),其中y係最大刺激效應%,A係y最小值,B係y最大值,C係EC50,x係log10競爭化合物濃度且D係曲線斜率(希爾係數(Hill Coefficient))。自該等曲線計算EC50(達成半最大刺激之濃度)、希爾係數以及利用飽和濃度之L-麩胺酸鹽獲得的以最大刺激效應%表示之最大反應。
在與PAM測試化合物一起預培育期間(即,在施加EC20濃度之L-麩胺酸鹽之前)所獲得之正信號指示激動活性,缺少該等信號表明缺乏激動活性。添加EC20濃度之L-麩胺酸鹽之後所觀察到的信號衰減指示測試化合物之抑制活性。
在以下實例列表中顯示化合物之相應結果,所有該等化合物均具有小於或等於100nM之EC50值。
WO2011128279=參考文獻1
對於結合實驗,使用Schlaeger及Christensen[Cytotechnology 15:1-13(1998)]所闡述之程序將編碼人類mGlu 5a受體之cDNA瞬時轉染至EBNA細胞中。將細胞膜勻漿儲存在-80℃下直至進行分析之日為止,彼時將其解凍並於15mM Tris-HCl、120mM NaCl、100mM KCl、25mM CaCl2、25mM MgCl2結合緩衝液(pH 7.4)中重新懸浮並均質化至最終分析濃度為20μg蛋白質/孔。
藉由在4℃下將12個濃度(0.04-100nM)之[3H]MPEP添加至該等膜(總體積為200μl)持續1h來測定飽和等溫線。利用固定濃度(2nM)之[3H]MPEP實施競爭試驗且使用11個濃度(0.3-10,000nM)評估測試化合
物之IC50值。在4℃下實施培育1h。
在培育結束時,利用Filtermate 96收穫器(Packard BioScience)將膜過濾至unifilter(具有結合GF/C過濾器並在0.1% PEI之洗滌緩衝液中預培育1h之96孔白色微板,Packard BioScience,Meriden,CT)上,並用冷50mM Tris-HCl pH 7.4緩衝液洗滌3次。在10μM MPEP存在下量測非特異性結合。在Packard Top-count微板閃爍計數器上計數(3min)過濾器上之放射性,添加45μl之microscint 40(Canberra Packard S.A.,Zürich,Switzerland)並振盪20min後進行淬滅校正。
在以下實例之列表中顯示化合物之相應結果,所有該等化合物均具有小於或等於20nM之EC50值。
本發明之化合物與WO2011128279實例106及實例109中所述之最類似化合物之比較:如下表中可見,與結構上類似之先前技術化合物相比,本發明之化合物顯示明顯不同之型態,此在期望化合物顯示NAM活性時係優點。
可藉由下文給出之方法、藉由實例中給出之方法或藉由類似方法來製造式I化合物。個別反應步驟之適當反應條件已為熟習此項技術者所知。然而,反應順序並不限於方案中所展示者,端視起始材料及其各別反應性,可自由地改變反應步驟之順序。起始材料有市售或可藉由類似於下文所給出方法之方法、藉由說明或實例中引用之參考文獻中所述之方法或藉由業內已知之方法製備。
可藉由此項技術中已知之方法製備本發明式I化合物及其醫藥上可接受之鹽,例如,藉由下文所述之製程變化形式,該製程包含使式II化合物
其中X係選自溴或碘之鹵素原子與式III之適宜芳基-乙炔反應
以形成式I化合物
其中取代基R1闡述於上文,該化合物係呈具有如式I中所繪之絕對立體化學之鏡像異構純形式,或藉由使用呈外消旋形式之II、隨後手性分離I以獲得光學純鏡像異構物;及若期望,將所獲得之化合物轉化為醫藥上可接受之酸加成鹽。
式I化合物之製備進一步更詳細地闡述於方案1至方案3及實例1至實例4中。
式IIa化合物之合成闡述於方案1中。式IIa之鹵基-吡啶化合物可藉由適宜二鹵化吡啶(例如2-溴-5-碘-吡啶)與式5之適宜經取代環脲之鈀催化反應來獲得(方案1)。亦可使用鹼性條件(例如NaH/THF或碳酸銫/DMF)藉由芳香族親核取代反應使在5位處具有溴或碘之2-氯-或2-氟-吡啶與式5之二環脲的反應來形成式IIa化合物。式5化合物可自式1之經適當保護之2-胺基-1-甲酸起始獲得,該經適當保護之2-胺基-1-甲酸可使用類似於彼等由Gorrea等人,Tetrahedron asymmetry,21,339(2010)所闡述之程序獲得。1之酸官能團經由醯基疊氮化物中間體轉變為相應異氰酸酯2(庫爾提斯(Curtius)重排),然後使其環化以形成二環脲化合物3。可根據標準程序將3之自由NH基團甲基化以形成化合物4,然後使化合物4去保護以獲得環脲5。亦可自式1之光學純經保護酸起始或藉由在合成之任何階段使用熟習此項技術者已知之程序分離外消旋混合物來獲得光學純中間體2至5。
其中此方案中之R1意指經(R1)n取代之苯基。
可使式IIa化合物(X=Br、I)與式III之適宜芳基-乙炔(其中W係氫或原位可解離之保護基團,例如三烷基矽基-或芳基二烷基矽基-,較佳氫或三甲基矽基)在鈀催化偶合條件下反應(Sonogashira反應)以形成式Ia化合物,其中取代基R1闡述於上文。另一可能性係由以下組成:使IIa與三甲基矽基乙炔反應以獲得其中R1係三甲基矽基之式Ia化合物,且然後利用適宜芳基溴或芳基碘實施第二Sonogashira反應以獲得式I化合物(方案未示出)。
在其中胺基酸衍生物1呈外消旋形式之情形下,鏡像異構物可在式I化合物之合成期間之任何給定階段使用熟習此項技術者已知之程序進行分離。
亦可顛倒產生式I化合物之反應順序(方案3)。在此情形中,首先實施芳基乙炔衍生物III與二鹵基-吡啶之間之Sonogashira反應以獲得式6之芳基乙炔-吡啶化合物,其然後與二環脲1縮合以獲得式I化合物。
其中此方案中之R1意指經(R1)n取代之苯基。
可根據本身已知之方法並慮及欲轉化為鹽之化合物之性質容易地製造式I化合物之醫藥上可接受之鹽。諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸或檸檬酸、甲酸、富馬酸、馬來酸、乙酸、琥珀酸、酒石酸、甲烷磺酸、對甲苯磺酸及諸如此類之無機或有機酸適於形成式I之鹼性化合物之醫藥上可接受之鹽。含有諸如鈉、鉀、鈣、鎂或諸如此類之鹼金屬或鹼土金屬之化合物、鹼性胺或鹼性胺基酸適於形成酸性化合物之醫藥上可接受之鹽。
正如上文已提及,式I化合物及其醫藥上可接受之鹽係代謝型麩胺酸鹽受體拮抗劑且可用於治療或預防mGluR5受體介導之病症,例如急性及/或慢性神經病症、認知障礙及記憶衰退,以及急性及慢性疼痛。可治療之神經病症係(例如)癲癇;精神分裂症;焦慮症;神經系統之急性、創傷性或慢性退化過程,例如阿茲海默氏病、老年失智症、亨庭頓氏舞蹈症、ALS、多發性硬化;由AIDS造成之失智症;眼部損傷;視網膜病變;特發性帕金森症或由藥劑造成之帕金森症;以及導致麩胺酸鹽缺乏功能之病狀,例如肌肉痙攣、驚厥、偏頭痛、尿失禁、尼古丁成癮、精神病、鴉片成癮、焦慮症、嘔吐、運動障礙及抑鬱症。其他可治療之適應症係由旁路手術或移植造成之大腦功能受限、至大腦之血液供應差、脊髓損傷、頭部損傷、由妊娠造成之缺氧、心跳停止及低血糖。
式I化合物及其醫藥上可接受之鹽尤其可用作止痛藥。可治療之疼痛種類包括發炎性疼痛,例如關節炎及類風濕性疾病;血管炎;神經病性疼痛,例如三叉神經或皰疹性神經痛;糖尿病性神經病變疼痛;灼痛;痛覺過敏;嚴重慢性疼痛;手術後疼痛及與各種病狀(例如癌症、心絞痛、腎或膽絞痛、月經、偏頭痛及痛風)相關聯之疼痛。
使用以下方法測試化合物之藥理學活性:使用E.-J.Schlaeger及K.Christensen(Cytotechnology 1998,15,1-13)所闡述之程序將編碼大鼠mGlu 5a受體之cDNA瞬時轉染至EBNA細胞中。使經mGlu 5a轉染之EBNA細胞與Fluo 3-AM(可自FLUKA獲得,0.5μM最終濃度)一起在37℃下培育1小時、隨後用分析緩衝液(補充有漢克氏鹽(Hank’s salt)及20mM HEPES之DMEM)洗滌4次之後,在該等細胞上實施[Ca2+]i量測。使用螢光成像板讀數器(FLIPR,Molecular Devices Corporation,La Jolla,CA,USA)實施[Ca2+]i量測。當化合物作為拮抗劑進行評估時,其係針對作為激動劑之10μM麩胺酸鹽進行測試。
使用迭代非線性曲線擬合軟體Origin(Microcal Software Inc.,Northampton,MA,USA)將抑制(拮抗劑)曲線與四參數邏輯斯諦方程(logistic equation)擬合,以給出IC50及希爾係數。
給出所測試化合物之Ki值。Ki值由下式定義:
其中,IC50值係50%之化合物效應受到拮抗之所測試化合物之濃度(以μM表示)。[L]係濃度且EC50值係引起約50%刺激之化合物之濃度(以μM表示)。
本發明之化合物係mGluR 5a受體拮抗劑。在上述分析中所量測之式I化合物之活性係在Ki<100μM範圍內。
式I化合物及其醫藥上可接受之鹽可用作藥劑,例如,呈醫藥製劑之形式。醫藥製劑可經口投與,例如,呈錠劑、包衣錠劑、糖衣九、硬明膠及軟明膠膠囊、溶液、乳液或懸浮液形式。然而,該投與亦可經直腸(例如呈栓劑形式)或以非經腸方式(例如呈注射溶液形式)實現。
式I化合物及其醫藥上可接受之鹽可與醫藥上惰性之無機或有機載劑一起處理來生產醫藥製劑。乳糖、玉米澱粉或其衍生物、滑石粉、硬脂酸或其鹽及諸如此類均可用作(例如)錠劑、包衣錠劑、糖衣九、硬明膠膠囊之此等載劑。用於軟明膠膠囊之適宜載劑係(例如)植物油、蠟、脂肪、半固體及液體多元醇及諸如此類;然而,端視活性物質之性質而定,在軟明膠膠囊之情形下通常不需要載劑。用於製備溶液及糖漿之適宜載劑係(例如)水、多元醇、蔗糖、轉化糖、葡萄糖及諸如此類。諸如醇、多元醇、甘油、植物油及諸如此類等佐劑可用於式I化合物之水溶性鹽之水性注射溶液,但通常並非必需的。栓劑之適宜載劑係(例如)天然或硬化油、蠟、脂肪、半液體或液體多元醇及諸如此類。
另外,醫藥製劑可含有防腐劑、增溶劑、穩定劑、潤濕劑、乳化劑、甜味劑、著色劑、矯味劑、用於改變滲透壓之鹽、緩衝劑、掩蔽劑或抗氧化劑。其亦可含有其他有治療價值之物質。
如先前所提及,含有式I化合物或其醫藥上可接受之鹽及治療惰性賦形劑之藥劑亦係本發明之標的,同樣製造該等藥劑之方法亦係本發明之標的,該方法包含將一或多種式I化合物或其醫藥上可接受之鹽及若期望一或多種其他有治療價值之物質以及一或多種治療惰性載劑製成蓋倫劑型(galenical dosage)。
劑量可在寬範圍內變化且當然將適於每一特殊情形之個體需要。通常而言,用於經口或非經腸投與之有效劑量係介於0.01-10mg/kg/天之間,對於所述之所有適應症,0.1-5mg/kg/天之劑量較佳。因此,重70kg之成年人之日劑量係介於0.7-700mg/天之間,較佳介於7mg/天與350mg/天之間。
提供下列實例以進一步闡明本發明:
向(外消旋)-(順式)-(1RS,2SR)-環丁烷-1,2-二甲酸單甲基酯(CAS:31420-52-7)(10.8g,68.3mmol)及N-甲基嗎啉(7.6g,8.26ml,75.1mmol)於160ml 1,2-二氯乙烷中之充分攪拌溶液中逐滴添加二苯基磷醯基疊氮化物(20.7g,16.2ml,75.1mmol)。在室溫下攪拌10min後,將反應物升溫至60℃。添加2-萘基甲基醇(10.8g,68.3mmol)及氯化銅(I)(68mg,0.68mmol)並將反應物於60℃下再攪拌16h。將反應物在真空中濃縮,用15ml二氯甲烷稀釋淺棕色油性殘餘物(51g)並藉由矽膠上之急驟層析(SiO2(650g),乙酸乙酯/庚烷20:80)進行純化以獲得16.8g含有未反應之萘基甲醇之不純材料。將材料再純化(Aminophase,0%至35%乙酸乙酯於庚烷中之梯度)以獲得11.1g(52%)為白色結晶固體之標題化合物,MS:m/e=314.2(M+H+)。
向(外消旋)-(1SR,2RS)-2-(萘-2-基甲氧基羰基胺基)環丁烷甲酸甲基酯(實例1,步驟1)(4.2g,13.4mmol)於20ml二噁烷中之充分攪拌溶液中添加水(70ml)。將溶液冷卻至5℃並經5min之時期逐滴添加53.6ml(26.8mmol)之0.5M氫氧化鈉溶液。在5℃下攪拌1h之後,使反應物在劇烈攪拌下升溫至室溫。然後,將澄清溶液冷卻至5℃並藉由添加約13ml 2N鹽酸溶液將pH調整至2.5。將反應物用乙酸乙酯進行處
理。乾燥、過濾並在真空中濃縮後,獲得3.87g(97%)為結晶白色固體之標題化合物,MS:m/e=300.2(M+H+)。
在室溫下,將(外消旋)-(1SR,2RS)-2-(萘-2-基甲氧基羰基胺基)環丁烷-甲酸(實例1,步驟2)(2.34g,7.82mmol)及N-甲基嗎啉(0.79g,0.86ml,7.82mmol)於34ml二氯乙烷中之溶液攪拌10min。然後,在室溫下逐滴添加二苯基磷酸疊氮化物(2.15g,1.69ml,7.82mmol)並將該無色溶液在室溫下攪拌1h,在此期間溶液變成淺黃色。然後將溶液升溫至50℃,攪拌6h並使其冷卻。用二氯甲烷/水處理之後,將合併之有機相蒸發至乾燥以獲得黃色固體,將該黃色固體自乙酸乙酯/庚烷重結晶。獲得為白色結晶固體之標題化合物(1.86g,80%),MS:m/e=297.3(M+H+)。
向(外消旋)-(1RS,5SR)-3-側氧基-2,4-二氮雜-二環[3.2.0]庚烷-2-甲酸萘-2-基甲基酯(實例1,步驟3)(1.13g,3.81mmol)於11ml DMF中之溶液中添加氫化鈉於礦物油中之60%懸浮液(0.198g,4.96mmol)。在室溫下,將懸浮液攪拌35分鐘(氣體逸出),然後添加碘甲烷(0.81g,0.36ml,5.72mmol)並將混合物在室溫下攪拌過夜。藉由添加3ml飽和氯化銨溶液淬滅並在真空中濃縮之後,用乙酸乙酯/水處理殘餘物。將合併之有機相乾燥並在真空中濃縮。藉由矽膠(50g)上之急驟層析用20-100%乙酸乙酯於庚烷中之梯度溶析來純化殘餘物以獲得0.98g(82%)無色油狀物,MS:m/e=311.2(M+H+)。
將(外消旋)-(1RS,5SR)-4-甲基-3-側氧基-2,4-二氮雜-二環[3.2.0]庚
烷-2-甲酸萘-2-基甲基酯(實例1,步驟4)(0.97g,3.13mmol)於15ml甲醇中之溶液於10% Pd/C(0.333g,0.313mmol)上氫化48h。用氬吹掃溶液,將觸媒濾出並用乙酸乙酯洗滌。在真空中濃縮濾液。藉由矽膠(20g)上之急驟層析用50-100%乙酸乙酯於庚烷中之梯度溶析來純化殘餘物以獲得0.375g(95%)為結晶白色固體之標題化合物,該化合物未經進一步表徵即直接用於下一步驟中。
向(外消旋)-(1SR,5RS)-2-甲基-2,4-二氮雜-二環[3.2.0]庚-3-酮(實例1,步驟5)(375mg,2.97mmol)及2-氟-5-碘吡啶(683mg,3.06mmol)於DMF(10ml)中之溶液添加氫化鈉於礦物油中之60%懸浮液(155mg,3.86mmol)。將反應物於室溫下攪拌過夜。藉由添加3ml飽和氯化銨溶液淬滅並在真空中濃縮以去除DMF之後,用乙酸乙酯/水處理殘餘物。乾燥並在真空中濃縮之後,藉由急驟層析(SiO2,20g)使用0%至65%乙酸乙酯於庚烷中之梯度來純化殘餘物。獲得為結晶白色固體之標題化合物(549mg,56%),MS:m/e=330.1(M+H+)。
於5ml微波管中將110mg(0.33mmol)之(外消旋)-(1RS,5SR)-2-(5-碘-吡啶-2-基)-4-甲基-2,4-二氮雜-二環[3.2.0]庚-3-酮(實例1,步驟6)溶解於1.5ml DMF中。使氬鼓泡穿過溶液。添加乙炔基苯(73μl,68mg,0.67mmol)、雙(三苯基膦)氯化鈀(II)(14mg,20μmol)、碘化銅(I)(1.9mg,10.0μmol)、三苯基膦(1.8mg,7.7μmol)及107μl之三乙胺(101mg,140μl,1.0mmol)。在60℃下將該深棕色溶液攪拌3h。反應物用乙酸乙酯/水處理,乾燥並在真空中濃縮。藉由急驟層析(矽膠,20g,0%至50% EtOAc於庚烷中之梯度)來純化殘餘物,以獲得
95mg(94%)為淺棕色結晶固體之標題化合物,MS:m/e=304.2(M+H+)。
藉由手性HPLC:(Chiralpak AD®-5cm×50cm,20mM;40%異丙醇/庚烷,35ml/min,18巴(Bar))來分離(外消旋)-(+/-)-(1SR,5RS)-2-甲基-4-(5-(苯基乙炔基)吡啶-2-基)-2,4-二氮雜二環[3.2.0]庚-3-酮之外消旋混合物(實例1,步驟7)(95mg)。使用UV檢測器以及光學旋轉檢測器(ORD)實現峰檢測,其中一個峰具有負信號((-)-鏡像異構物),且另一峰具有正信號((+)-鏡像異構物)。(-)-鏡像異構物(-)-(1S,5R)-2-甲基-4-(5-(苯基乙炔基)吡啶-2-基)-2,4-二氮雜二環[3.2.0]庚-3-酮(39mg)係作為結晶淺黃色固體獲得,MS:m/e=304.1(M+H+)。(+)-鏡像異構物(-)-(1R,5S)-2-甲基-4-(5-(苯基乙炔基)吡啶-2-基)-2,4-二氮雜二環[3.2.0]庚-3-酮(40mg)係作為淺黃色固體獲得,MS:m/e=304.1(M+H+)。
標題化合物係根據實例1步驟7之一般方法自(外消旋)-(1RS,5SR)-2-(5-碘-吡啶-2-基)-4-甲基-2,4-二氮雜-二環[3.2.0]庚-3-酮(實例1,步驟6)(110mg)及1-乙炔基-3-氟苯開始來製備,以獲得107mg(96%)為
淺黃色結晶固體之外消旋材料(+/-)-(1R,5S)-2-[5-(3-氟-苯基乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮;MS:m/e=322.3(M+H+),然後藉由手性HPLC使用如實例1步驟8中所述之類似分離條件將其分離以獲得為淺黃色固體之鏡像異構純鏡像異構物(-)-(1R,5S)-2-[5-(3-氟-苯基乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮,MS:m/e=322.3(M+H+);及為淺黃色固體之其鏡像異構物(+)-(1S,5R)-2-[5-(3-氟-苯基乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮,MS:m/e=322.3(M+H+)。
標題化合物係根據實例1步驟7之一般方法自(外消旋)-(1RS,5SR)-2-(5-碘-吡啶-2-基)-4-甲基-2,4-二氮雜-二環[3.2.0]庚-3-酮(實例1,步驟6)(110mg)及1-乙炔基-4-氟苯開始來製備,以獲得104mg(97%)為淺黃色結晶固體之外消旋材料(+/-)-(外消旋)-(1SR,5RS)-2-[5-(4-氟-苯基乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮;MS:m/e=322.3(M+H+),然後藉由手性HPLC使用如實例1步驟8中所述之類似分離條件將其分離以獲得為淺黃色固體之鏡像異構純鏡像異構物(-)-(1R,5S)-2-[5-(4-氟-苯基乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮,MS:m/e=322.3(M+H+);及為淺黃色固體之其鏡像異構物(+)-(1S,5R)-2-[5-(4-氟-苯基乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮,MS:m/e=322.3(M+H+)。
標題化合物係根據實例1步驟7之一般方法自(外消旋)-(1RS,5SR)-2-(5-碘-吡啶-2-基)-4-甲基-2,4-二氮雜-二環[3.2.0]庚-3-酮(實例1,步驟6)(110mg)及2-乙炔基-1,4-二氟苯開始來製備,以獲得110mg(97%)為淺黃色結晶固體之外消旋材料(+/-)-(外消旋)-(1SR,5RS)-2-[5-(2,5-二氟-苯基乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮;MS:m/e=340.1(M+H+),然後藉由手性HPLC使用如實例1步驟8中所述之類似分離條件將其分離以獲得為淺黃色固體之鏡像異構純鏡像異構物(-)-(1R,5S)-2-[5-(2,5-二氟-苯基-乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮,MS:m/e=340.1(M+H+);及為淺黃色固體之其鏡像異構物(+)-(1S,5R)-2-[5-(2,5-二氟-苯基-乙炔基)-吡啶-2-基]-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮,MS:m/e=340.1(M+H+)。
以下組成之錠劑係以習用方式製備:
以下組成之錠劑係以習用方式製備:
製造具有以下組成之膠囊:
將具有適宜粒徑之活性成份、結晶乳糖及微晶纖維素彼此均勻地混合,篩分並之後混合滑石粉及硬脂酸鎂。將最終混合物填充於適宜大小之硬明膠膠囊中。
圖1:mGluR5正向異位調節劑(PAM)與mGluR5拮抗劑(負向異位調節劑=NAM)之比較。
圖2:化合物「實例2」在大鼠沃格爾衝突飲水測試中之活性。
Claims (7)
- 一種式I化合物,
- 如請求項1之式I化合物,該等化合物係(1S,5R)-2-甲基-4-(5-(苯基乙炔基)吡啶-2-基)-2,4-二氮雜二環[3.2.0]庚-3-酮(1R,5S)-2-(5-((4-氟苯基)乙炔基)吡啶-2-基)-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮(1R,5S)-2-(5-((3-氟苯基)乙炔基)吡啶-2-基)-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮或(1R,5S)-2-(5-((2,5-二氟苯基)乙炔基)吡啶-2-基)-4-甲基-2,4-二氮雜二環[3.2.0]庚-3-酮。
- 如請求項1或2中任一項之化合物,其用作治療活性物質。
- 一種製備如請求項1或2中任一項之式I化合物之方法,其包含以下變化形式使式II化合物
- 一種醫藥組合物,其包含如請求項1或2中任一項之化合物及治療活性載劑。
- 一種如請求項1或2中任一項之化合物之用途,其用於製造用於治療焦慮症及疼痛、抑鬱症、脆性X染色體症候群、自閉症譜系障礙、帕金森氏病(Parkinson’s disease)及胃食道逆流疾病(GERD)之藥劑。
- 如請求項1或2中任一項之化合物,其用於治療焦慮症及疼痛、抑鬱症、脆性X染色體症候群、自閉症譜系障礙、帕金森氏病及胃食道逆流疾病(GERD)。
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