TW201412313A - 1’,3’-二取代-4-苯基-3,4,5,6-四氫-2h,1’h-〔1,4’〕聯吡啶基-2’-酮化物 - Google Patents
1’,3’-二取代-4-苯基-3,4,5,6-四氫-2h,1’h-〔1,4’〕聯吡啶基-2’-酮化物 Download PDFInfo
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Abstract
本發明係關於一種新穎化合物,尤其新穎的式(I)之吡啶酮衍生物:□其中所有基團係如本申請案及申請專利範圍中所定義。本發明化合物為代謝型受體-亞型2(“mGluR2”)之正向異位調節劑,其適用於治療或預防與麩胺酸鹽功能障礙有關之神經及精神病症及涉及代謝型受體之mGluR2亞型之疾病。詳言之,該等疾病為選自焦慮、精神分裂症、偏頭痛、抑鬱及癲癇症之群的中樞神經系統病症。本發明亦係關於醫藥組合物及製備該等化合物及組合物之方法,以及該等化合物用於預防及治療該等涉及mGluR2之疾病的用途。
Description
本發明係關於新穎吡啶酮衍生物,其為代謝型麩胺酸鹽受體亞型2("mGluR2")之正向異位調節劑且其適用於治療或預防與麩胺酸鹽功能障礙有關之神經病症及精神病症及涉及代謝型受體mGluR2亞型之疾病。本發明亦係關於包含該等化合物之醫藥組合物,製備該等化合物及組合物之方法,及該等化合物用於預防或治療神經病症及精神病症及涉及mGluR2之疾病的用途。
麩胺酸鹽為哺乳動物中樞神經系統中之主要胺基酸神經傳遞質。麩胺酸鹽在眾多生理功能中起主要作用,諸如學習及記憶,以及感觀感覺,突觸可塑性之產生、運動控制、呼吸及心血管功能之調節。此外,麩胺酸鹽處於若干不同神經及精神疾病之中心,其中麩胺酸神經傳遞中存在不平衡。
麩胺酸鹽藉由離子移變麩胺酸鹽受體通道(iGluR)之活化及造成快速興奮性傳遞之NMDA、AMPA及紅藻胺酸(kainate)受體介導突觸神經傳遞。
此外,麩胺酸鹽活化代謝型麩胺酸鹽受體(mGluR),其具有造成突觸功效微調之更多調節性作用。
麩胺酸鹽藉由與在本文中稱為鄰位(orthosteric)結合位點之受體
的大胞外胺基末端結構域的結合來活化mGluR。此結合誘發受體中之構形改變,從而導致G蛋白及胞內信號轉導路徑之活化。
mGluR2亞型經由Gαi蛋白之活化與腺苷酸環化酶負性偶合,且其活化導致抑制突觸中之麩胺酸鹽釋放。在中樞神經系統(CNS)中,mGluR2受體主要富含於整個皮質、丘腦區、副嗅球、海馬組織、扁桃體、尾殼核及伏隔核中。
臨床試驗中展示活化mGluR2有效治療焦慮症。此外,展示在各種動物模型中活化mGluR2為有效的,因此表示治療精神分裂症、癲癇症、成癮/藥物依賴、帕金森氏症(Parkinson's disease)、疼痛、睡眠失調及亨廷頓氏症(Huntington's disease)之潛在新穎治療方法。
迄今為止,多數可獲得之靶向mGluR之藥理學工具為活化若干家族成員之鄰位配位體,因為其為麩胺酸鹽之結構類似物。
研發作用於mGluR之選擇性化合物的新途徑為識別經由別位機制起作用之化合物,其藉由與不同於高度保守之鄰位結合位點之位點結合來調節受體。
最近已出現mGluR之正向異位調節劑,其為提供此誘人替代之新穎藥理學實體。已描述作為mGluR2正向異位調節劑之各種實例。WO 2004/092135(NPS及Astra Zeneca)、WO 2004/018386、WO 2006/014918及WO 2006/015158(Merck)、WO 2001/56990(Eli Lilly)及WO 2006/030032(Addex及Janssen Pharmaceutica)分別描述作為mGluR2正向異位調節劑之苯基磺醯胺、苯乙酮、茚酮、吡啶基甲基、磺醯胺及吡啶酮衍生物。其中特定揭示之化合物均不與本發明化合物結構上相關。
證明該等化合物自身不使受體活化。然而,其使受體能對麩胺酸鹽濃度產生最大反應,而自身誘發最小反應。突變分析已明確證明mGluR2正向異位調節劑之結合不在鄰位位點發生,而在位於受體之7
個跨膜區內之別位位點發生。
動物資料表明mGluR2之正向異位調節劑在焦慮症及精神病模型中起類似於彼等以鄰位激動劑獲得之作用。據展示mGluR2之別位調節劑在恐懼強化型驚跳及在焦慮之應激性體溫升高模型中具有活性。此外,該等化合物經展示在氯胺酮或安非他命(amphetamine)誘發之移動加快的逆轉中有活性,及在精神分裂症之聽覺驚跳(acoustic startle)效應模型中安非他命誘發之前脈衝抑制之中斷的逆轉中有活性。(J.Pharmacol.Exp.Ther.2006,318,173-185;Psychopharmacology 2005,179,271-283)。
最近,動物研究進一步揭示代謝型麩胺酸鹽受體亞型2之選擇性正向異位調節劑聯苯-茚酮(BINA)阻斷精神病之迷幻藥物模型,其支持靶向mGluR2受體用於治療精神分裂症中麩胺酸鹽功能障礙的策略。(Mol.Pharmacol.2007,72,477-484)。
正向異位調節劑能夠增強麩胺酸鹽反應,但其亦展示增強對鄰位mGluR2激動劑(諸如,LY379268或DCG-IV)之反應。此等資料提供治療上述涉及mGluR2之神經及精神疾病之另一新穎治療方法的證據,其將使用mGluR2之正向異位調節劑與mGluR2之鄰位激動劑的組合。
本發明係關於具有代謝型麩胺酸鹽受體2調節劑活性之化合物,該等化合物具有式(I):
及其立體化學異構形式,其中R1為C1-6烷基、或經C3-7環烷基取代之C1-3烷基、苯基或經鹵基取代之苯基、三氟甲基或三氟甲氧基;R2為鹵基、三氟甲基、C1-3烷基或環丙基;R3為氫、氟基、羥基、羥基C1-3烷基、羥基C1-3烷氧基、氟C1-3烷基、氟C1-3烷氧基或氰基;且Ar為未經取代之苯基、或經n個基團R4取代之苯基,其中n為1、2或3;R4係選自由氫、鹵基、C1-3烷基、羥基C1-3烷基、多鹵基C1-3烷基、氰基、羥基、胺基、羧基、C1-3烷氧基C1-3烷基、C1-3烷氧基、多鹵基C1-3烷氧基、C1-3烷基羰基、單及二(C1-3烷基)胺基及嗎啉基組成之群;或兩個鄰近R4基團一起形成下式之二價基團:-N=CH-NH-(a),-CH=CH-NH-(b),或-O-CH2-CH2-NH-(c);或鄰位之R3及R4基團一起形成下式之二價基團:-CH2-O-(d),或-O-CH2-(e);及其醫藥學上可接受之鹽及溶劑合物。
在一實施例中,本發明係關於式(I)之化合物或其立體化學異構形式,其中R1為C1-6烷基、或經C3-7環烷基取代之C1-3烷基、苯基或經鹵基取代之苯基、三氟甲基或三氟甲氧基;R2為鹵基、三氟甲基、C1-3烷基或環丙基;R3為氫、氟基、羥基、羥基C1-3烷基、羥基C1-3烷氧基、氟C1-3烷基、氟C1-3烷氧基或氰基;且Ar為未經取代之苯基,或經n個基團R4取代之苯基,其中n為1、2或3;
R4係選自由氫、鹵基、C1-3烷基、羥基C1-3烷基、多鹵基C1-3烷基、氰基、羥基、胺基、羧基、C1-3烷氧基C1-3烷基、C1-3烷氧基、多鹵基C1-3烷氧基、C1-3烷基羰基、單及二(C1-3烷基)胺基及嗎啉基組成之群;或兩個鄰近R4基團一起形成下式之二價基團:-N=CH-NH-(a),-CH=CH-NH-(b),或-O-CH2-CH2-NH-(c);及其醫藥學上可接受之鹽及溶劑合物。
在一實施例中,本發明係關於式(I)之化合物或其立體化學異構形式,其中R1為1-丁基、2-甲基-1-丙基、3-甲基-1-丁基、(環丙基)甲基或2-(環丙基)-1-乙基;R2為氯、溴、環丙基或三氟甲基;R3為氫、氟或氰基;且Ar為未經取代之苯基、或經鹵基取代之苯基、三氟甲基、嗎啉基或羥基C1-3烷基;或其醫藥學上可接受之鹽或溶劑合物。
在一實施例中,本發明係關於式(I)之化合物或其立體化學異構形式,其中R1為1-丁基、3-甲基-1-丁基、(環丙基)甲基或2-(環丙基)-1-乙基;R2為氯;R3為氫或氟;且Ar為未經取代之苯基、或經羥基C1-3烷基取代之苯基;或其醫藥學上可接受之鹽或溶劑合物。
在一實施例中,本發明係關於以下化合物:3'-氯-1'-環丙基甲基-4-苯基-3,4,5,6-四氫-2H,1'H-[1,4']聯吡啶基-2'-酮化物(E1)或
1'-丁基-3'-氯-4-苯基-3,4,5,6-四氫-2H,1'H-[1,4']聯吡啶基-2'-酮化物(E2)。
作為基團或基團之一部分的標記法C1-3烷基定義具有1至3個碳原子之飽和直鏈或支鏈烴基,諸如甲基、乙基、1-丙基及1-甲基乙基,例如,羥基C1-3烷基(例如)定義羥基甲基、2-羥基乙基、3-羥基丙基及1-羥基-1-甲基乙基。
作為基團或基團之一部分的標記法C1-6烷基定義具有1至6個碳原子之飽和直鏈或支鏈烴基,諸如甲基、乙基、1-丙基、1-甲基乙基、1-丁基、2-甲基-1-丙基、3-甲基-1-丁基、1-戊基、1-己基及其類似物。
標記法C3-7環烷基定義具有3至7個碳原子之飽和環狀烴基,諸如環丙基、環丁基、環戊基、環己基及環庚基。
作為基團或基團之一部分的標記法鹵基或鹵素為氟、氯、溴、碘之總稱。
對於治療用途而言,式(I)化合物之鹽為彼等其中平衡離子為醫藥學上可接受者。然而,非醫藥學上可接受之酸及鹼之鹽亦可(例如)用於製備或純化醫藥學上可接受之化合物。不管是否為醫藥學上可接受的,所有鹽均包括於本發明之範圍內。
醫藥學上可接受之鹽經定義為包含式(I)化合物能夠形成之治療活性無毒酸加成鹽形式。該等鹽可藉由以適當酸(例如,無機酸,例如尤其鹽酸、氫溴酸之氫鹵酸;硫酸;硝酸及磷酸;有機酸,例如乙酸、羥基乙酸、丙酸、乳酸、丙酮酸、草酸、丙二酸、丁二酸、順丁烯二酸、反丁烯二酸、蘋果酸、酒石酸、檸檬酸、甲烷磺酸、乙烷磺酸、苯磺酸、對甲苯磺酸、環拉酸、水楊酸、對胺基水楊酸及雙羥酸)處理式(I)化合物之鹼形式來獲得。
相反地,該等鹽形式可藉由以適當鹼處理而轉化為游離鹼形式。
含有酸性部分之式(I)化合物亦可藉由以適當有機鹼及無機鹼處
理而轉化為其治療活性無毒鹼鹽形式。適當鹼鹽形式包含(例如)銨鹽、鹼金屬及鹼土金屬鹽,尤其鋰、鈉、鉀、鎂及鈣鹽;有機鹼之鹽,例如苄星青黴素(benzathine)、N-甲基-D-還原葡糖胺、羥胺鹽及胺基酸之鹽,例如精胺酸及離胺酸之鹽。
相反地,該等鹽形式可藉由以適當酸處理而轉化為游離酸形式。
術語溶劑合物包含式(I)化合物能夠形成之溶劑加成形式以及其鹽形式。該溶劑加成形式之實例為(例如)水合物、醇化物及其類似物。
上文所用之術語"立體化學異構形式"定義式(I)化合物可具有之所有可能異構形式。除非另外提及或說明,化合物之化學命名表示所有可能的立體化學異構形式之混合物,該等混合物含有基本分子結構之所有非對映異構體及對映異構體。本發明亦涵蓋式(I)化合物及其鹽及溶劑合物之個別異構形式之每一者,其大體上游離,亦即與其他異構體之結合低於10%,較佳低於5%,尤其低於2%且最佳低於1%。因此,當式(I)化合物指定為(例如)(R),此意謂化合物大體上不含(S)異構體。立體中心可具有R-或S-構型;二價環狀(部分)飽和基團上之取代可具有順式或反式構型。
根據CAS命名慣例,當化合物中存在兩個已知絕對構型之立體中心時,向最低編號之對掌中心、參照中心指定R或S描述符(基於Cahn-Ingold-Prelog順序規則)。第二立體中心之構型使用相對描述符[R*,R*]或[R*,S*]表示,其中R*總是指定為參照中心且[R*,R*]表示具有相同對掌性之中心,且[R*,S*]表示不同對掌性之中心。舉例而言,若化合物中最低編號之對掌中心具有S構型,且第二中心為R,則立體描述符將指定為S-[R*,S*]。若使用"α"及"β",則具有最低環編號之環系統中不對稱碳原子上最優先取代基之位置總是任意地在環系統所決定之平面的"α"位置。環系統中其他不對稱碳原子上之最優先取代基的位置(式(I)化合物中之氫原子)相對於參照原子上最優先取代基之位置,
若在由環系統決定之平面同側則命名為"α",或若在由環系統決定之平面的另一側則命名為"β"。
在本申請案之構架中,尤其當相對於式(I)化合物提及之元素包含此元素之所有同位素及同位素混合物,該等同位素或同位素混合物為天然存在的或合成製造的,為天然富含的或為同位素富集形式。放射性標記之式(I)化合物可包含選自3H、11C、18F、122I、123I、125I、131I、75Br、76Br、77Br及82Br之群的放射性同位素。較佳地,放射性同位素係選自3H、11C及18F之群。
本發明化合物一般可藉由各自為熟習此項技術者已知之一連串步驟製備。詳言之,化合物可根據以下合成方法製備。
式(I)化合物可以對映異構體之外消旋混合物形式合成,其可根據此項技術中已知之拆分程序彼此分離。式(I)之外消旋化合物可藉由與合適對掌性酸反應轉化為相應非對映異構鹽形式。該等非對映異構鹽形式隨後藉由(例如)選擇性或分步結晶來分離且對映異構體藉由鹼自其釋放。分離式(I)化合物之對映異構形式的替代方式涉及使用對掌性固定相之液相層析法。該純立體化學異構形式亦可由適當起始材料之相應純立體化學異構形式產生,其限制條件為反應立體特異性發生。
在R2為鹵素之狀況下,式(I)化合物可藉由根據反應流程(1)使式(II)中間物與N-鹵基丁二醯亞胺試劑(諸如N-氯丁二醯亞胺、N-溴丁二醯亞胺或N-碘丁二醯亞胺)反應來製備。此反應係在合適反應惰性及非質子性溶劑(諸如,二氯甲烷或1,2-二氯乙烷)中進行,將反應混合物在合適溫度(通常室溫)下攪拌歷時所要時間(一般1小時)以完成反應。在反應流程(1)中,R2為鹵素且所有其他變數如式(I)中所定義。
或者,式(I)化合物可藉由使式(III)中間物與式(IV)中間物(其可為市售的或可藉由任何熟習此項技術者熟知的程序合成)根據反應流程(2)反應來製備。此反應係在合適反應惰性溶劑(諸如,甲苯)中,在合適鹼(諸如,第三丁醇鈉)、基於金屬之催化劑(特定言之,鈀催化劑,諸如乙酸鈀(II))及合適配位體(諸如,[1,1'-聯萘]-2,2'-二基雙[二苯膦](BINAP)存在下,在密封試管中加熱歷時使反應完成之合適時間(例如,在100℃下歷時16小時)進行。在反應流程(2)中,Za為適於與胺進行Pd介導之偶合的基團,例如鹵素或三氟甲磺酸鹽。所有其他變數如式(I)中所定義。
該等式(II)及式(III)之中間物可根據反應流程(3)至(11)(見下文)製備。最終化合物中存在之不同官能基向式(I)之其他官能基之轉換可藉由熟習此項技術者熟知的合成方法進行。
此外,式(I)化合物可由熟練技術人員使用此項技術已知之程序藉
由進一步修飾式(I)化合物來製備:
- 在加熱條件下,使用合適鹼(諸如氫化鈉),在合適反應惰性溶劑(諸如,1,2-二甲氧基乙烷或或二甲基甲醯胺)中以合適烷基化劑(諸如甲苯磺酸2-氟乙酯)使式(I)化合物烷基化,該等化合物在其結構中含有一或多個羥基取代基。
- 以合適氟化劑(諸如(二乙基胺基)三氟化硫)使式(I)化合物氟化,該等化合物在其結構中含有一或多個羥基取代基。此反應可在合適反應惰性溶劑(諸如,二氯甲烷)中,在適度低溫(諸如,在-78℃至30℃範圍內之溫度)下進行(例如)0.5至12小時之時間。
- 使式(I)化合物(在其結構中含有一或多個羥基取代基)與醇衍生物藉由使用合適偶合系統(諸如,偶氮二甲酸二第三丁酯/三苯膦)在加熱條件下反應。
式(II)中間物可藉由使式(V)中間物與式(IV)中間物根據反應流程(3)反應來製備。此反應係在合適反應惰性溶劑(諸如,甲苯)中,在合適鹼(諸如,第三丁醇鈉)、基於金屬之催化劑(特定言之,鈀催化劑,諸如乙酸鈀(II))及合適配位體(諸如,[1,1'-聯萘]-2,2'-二基雙[二苯膦](BINAP)存在下,在密封試管中加熱歷時使反應完成之合適時間(例如,在100℃下歷時16小時)進行。在反應流程(3)中,所有變數如式(I)中所定義。
反應流程3
式(III-a)與(III-b)中間物可藉由使式(VI)中間物(其中Y為H或R2(如式I中所定義))與合適鹵化劑(諸如,氧溴化磷)反應來製備。此反應可在合適反應惰性溶劑(諸如,DMF)中,在適度高溫(諸如,110℃)下歷時可完成反應之合適時期(例如,1小時)進行。在反應流程(4)中,變數R1如式(I)中所定義。
式(III-c)之中間物可藉由使式(VI-a)中間物與三氟甲磺酸酐(亦稱為,三氟甲烷磺酸酐)反應來製備。反應可在合適反應惰性溶劑(諸如,二氯甲烷)中,在鹼(諸如,吡啶)存在下,在低溫(諸如,-78℃)下進行。在反應流程(5)中,所有變數如式(I)中所定義。
式(VI)中間物可藉由使式(VII-a、VII-b或VII-c)中間物在合適反應
惰性溶劑(諸如,乙醇)中在催化劑(諸如,活性炭上10%鈀)存在下氫解歷時確保完成反應之時期(通常在室溫及1個氫氣大氣壓下歷時2小時)來製備。在反應流程(6)中,變數R1如式(I)中所定義。
或者,式(VI)中間物(其中Y=鹵素)可藉由使式(VII-d)中間物在乙酸與氫溴酸之混合物中反應,且將混合物在一定溫度下加熱歷時使反應完成所需之時間(通常在微波照射下在130℃下歷時30分鐘)來製備。在反應流程(7)中,變數R1如式(I)中所定義。
式(VII-a)中間物可藉由此項技術已知程序,藉由使用鹼(諸如,K2CO3)及視情況之碘鹽(諸如,KI)在惰性溶劑(諸如,乙腈或DMF)中在適度高溫(諸如,80-120℃)下使市售4-苯甲氧基-1H-吡啶-2-酮化物與市售之式(VIII)烷基化劑(其中Zb為合適離去基)反應歷時允許完成反應之時期(例如,16小時)來製備。在反應流程(8)中,變數R1如式(I)中定
義且Zb為合適離去基(諸如,鹵素)。
式(VII-b)中間物可藉由使式(VII-e)中間物(其中Y為碘)與市售2,2-二氟-2-(氟磺醯基)乙酸甲酯在合適反應惰性溶劑(諸如,DMF)中在合適銅鹽(諸如,碘化亞銅(I))存在下加熱歷時使反應完成之合適時期(例如,在100℃下歷時5小時)進行反應來製備。在反應流程(9)中,變數R1如式(I)中所定義。
式(VII-d)中間物可藉由使式(VII-a)中間物與市售N-鹵基丁二醯亞胺(諸如,N-氯-(NCS)、N-溴-(NBS)或N-碘丁二醯亞胺(NIS))在合適反應惰性溶劑(諸如,DMF、二氯甲烷或乙酸)中通常在室溫下反應1至24小時來製備。在反應流程(10)中,變數R1如式(I)中所定義。
反應流程10
式(VII-c)中間物可藉由使式(VII-d)中間物與C1-3烷基-或環丙基-酸衍生物(諸如,環丙基-酸或甲基-酸)在合適反應惰性溶劑(諸如,1,4-二噁烷)中,在合適鈀催化劑-錯合物(諸如,[1,1'-雙(二苯膦基)-二茂鐵]-二氯鈀(II)-DCM錯合物存在下且在合適鹼(諸如,碳酸氫鈉)存在下在微波照射下加熱歷時使反應完成之合適時期(例如在175℃下歷時20分鐘)進行反應來製備。在反應流程(11)中,變數R1如式(I)中所定義。
式(IV)中間物可藉由應用此項技術中已知之程序,根據反應流程(12)將式(IX)中間物(其中,L為吡啶衍生物之氮原子的合適保護基,諸如,第三丁氧羰基、乙氧羰基、苯甲氧羰基、苯甲基及甲基)中之吡啶氮去保護來製備。在反應流程(12)中,所有變數如式(I)中所定義。
式(IV-a)中間物可藉由應用此項技術中已知程序,根據反應流程(13)使式(X)中間物氫化反應來製備。在反應流程(13)中,Ar如式(I)中所定義。
式(IX-a)中間物可藉由應用此項技術中已知之程序,根據反應流程(14)使式(XI)中間物(其中,L為四氫吡啶衍生物之氮原子的合適保護基,諸如,第三丁氧羰基、乙氧羰基、苯甲氧羰基、苯甲基及甲基)氫化反應來製備。在反應流程(14)中,Ar如式(I)中所定義。
式(X)中間物可藉由應用此項技術中已知之程序,根據反應流程(15)將式(XI)中間物(其中,L為四氫吡啶衍生物之氮原子的合適保護基,諸如,第三丁氧羰基、乙氧羰基、苯甲氧羰基、苯甲基及甲基)中之四氫吡啶氮去保護來製備。在反應流程(15)中,Ar如式(I)中所定義。
反應流程(15)
式(XI)中間物可藉由使式(XII)中間物與式(XIII)中間物根據反應流程(16)反應來製備。反應可在合適反應惰性溶劑(諸如,1,4-二噁烷)或惰性溶劑混合物(諸如,1,4-二噁烷/DMF)中,在合適鹼(諸如,NaHCO3或Na2CO3水溶液)、合適催化劑(諸如,Pd-錯合物催化劑,諸如,Pd(PPh3)4)存在下在加熱條件(諸如,在微波照射下在150℃下加熱反應混合物)下進行(例如)10分鐘。在反應流程(16)中,所有變數如式(I)中所定義;Zc為適於與酸或酸酯之Pd介導之偶合的基團,諸如鹵基或三氟甲磺酸酯基;L為四氫吡啶衍生物之氮原子的合適保護基,諸如第三丁氧羰基、乙氧羰基、苯甲氧羰基、苯甲基及甲基,且R4及R5為氫或C1-4烷基,或可一起形成(例如)式-CH2CH2-、-CH2CH2CH2-或-C(CH3)2C(CH3)2-之二價基團。
式(IV)中間物(其中,R3表示氟或經氟取代之C1-3烷基,該R3由-L1-F表示,其中L1表示C1-3烷基或共價鍵,且該等中間物係由式(IV-b)表示)可藉由此項技術之已知程序,根據反應流程(17)步驟(a)藉由使式(IX-b)中間物(其中,L為哌啶部分之氮原子的合適保護基,諸如第三丁氧羰基、乙氧羰基、苯甲氧羰基、苯甲基及甲基)與合適氟化劑(諸如,(二
乙基胺基)三氟化硫)反應,產生式(IX-c)中間物來製備。反應可在合適反應惰性溶劑(諸如,二氯甲烷)中進行。反應可在適度低溫(諸如,在-78℃至30℃範圍內之溫度)下進行(例如)0.5至12小時。式(IX-c)之所得中間物可隨後根據反應流程(17)步驟(b),藉由應用此項技術之已知程序(諸如,上文實驗程序15中所述之彼等)將哌啶氮去保護來轉換為式(IV-b)中間物。在反應流程(17)中,Ar如式(I)中所定義。
式(IV)中間物(其中R3表示經氟取代之C1-3烷氧基,該C1-3烷氧基由Q表示,該R3由-Q-F表示,且該等中間物由式(IV-d)表示)可藉由此項技術之已知程序,根據反應流程(18)步驟(a)藉由使經羥基取代之式(IX-d)中間物(其中L為哌啶部分之氮原子的合適保護基,諸如第三丁氧羰基、乙氧羰基、苯甲氧羰基、苯甲基及甲基)與合適氟化劑(諸如,(二乙基胺基)三氟化硫)反應,產生式(IX-e)中間物來製備。反應可在合適反應惰性溶劑(諸如,二氯甲烷)中在適度低溫(諸如,在-78℃至30℃範圍內之溫度)下進行(例如)0.5至12小時之時間。式(IX-e)之中間物可隨後根據反應流程(18)步驟(b),藉由應用此項技術之已知程序(諸如,上文實驗程序17中所述之彼等)將哌啶氮去保護來轉換為式(IV-d)中間物。在反應流程(18)中,Ar如式(I)中所定義。
反應流程(18)
式(IX-b)中間物(其中L1表示CH2該等中間物由式(IX-f)表示)可藉由使式(XIV)中間物(其中L為哌啶部分之氮原子的合適保護基,諸如第三丁氧羰基、乙氧羰基、苯甲氧羰基、苯甲基及甲基)與合適還原劑(諸如,氫化鋰鋁)根據反應流程(19)反應來製備。反應可在合適溶劑(諸如,四氫呋喃)中在適度低溫(諸如,自-20℃)下進行。在反應流程(19)中,Ar如式(I)中所定義。
式(VIII)、(IX-b)、(IX-d)、(XII)、(XIII)及XIV之起始材料為市售的或可根據彼等熟習此項技術者一般已知的習知反應程序來製備。
本發明所提供之化合物為代謝型麩胺酸鹽受體之正向異位調節劑,詳言之,其為mGluR2之正向異位調節劑。本發明化合物看似不與麩胺酸鹽識別位點、鄰位配位體位點結合,而與受體之7個跨膜區內的別位位點結合。在麩胺酸鹽或mGluR2激動劑存在下,本發明化合物增加mGluR2反應。預期本發明所提供之化合物藉助於其增加該等受體對麩胺酸鹽或mGluR2激動劑之反應及增強受體反應之能力而對mGluR2
具有效應。因此,本發明係關於用作藥品之本發明化合物,以及本發明化合物或本發明醫藥組合物之用途,其係用於製造用以治療或預防,尤其治療哺乳動物(包括人類)之病況的藥物,其治療或預防受到mGluR2之別位調節劑,尤其其正向異位調節劑之神經調節作用的影響或促進。本發明亦係關於本發明化合物或本發明醫藥組合物,其係用於製造用以治療或預防,尤其治療哺乳動物(包括人類)之病況的藥物,其治療或預防受到mGluR2之別位調節劑,尤其其正向異位調節劑之神經調節作用的影響或促進。本發明亦係關於本發明化合物或本發明醫藥組合物,其係用於治療或預防,尤其治療哺乳動物(包括人類)之病況,其治療或預防受到mGluR2之別位調節劑,尤其其正向異位調節劑之神經調節作用的影響或促進。
本發明亦係關於本發明化合物或本發明醫藥組合物之用途,其係用於製造用以治療、預防、改善、控制或減輕哺乳動物(包括人類)之與麩胺酸鹽功能障礙有關的各種神經及精神病症風險的藥物,其治療或預防受到mGluR2正向異位調節劑之神經調節作用的影響或促進。
當據稱本發明係關於本發明化合物或組合物用於製造用以(例如)治療哺乳動物之藥物的用途時,應理解該用途在某些權限內欲解釋為(例如)治療哺乳動物之方法,包含向需要(例如)該治療之哺乳動物投與有效量之本發明化合物或組合物。
詳言之,與麩胺酸鹽功能障礙有關之神經及精神病症包括以下病況或疾病中之一或多者:急性神經及精神病症,諸如心臟旁路手術及移植後之大腦缺陷、中風、大腦缺血、脊髓損傷、頭部外傷、圍產期缺氧、心跳驟停、低血糖神經元損傷、癡呆(包括AIDS誘發之癡呆)、阿茲海默氏症(Alzheimer's disease)、亨廷頓氏舞蹈病(Huntington's Chorea)、肌肉萎縮性側索硬化、眼部損傷、視網膜病、認知障礙、特發性及藥物誘發之帕金森氏症(Parkinson's disease)、肌肉痙攣及與肌
肉強直有關之病症(包括震顫、癲癇症、抽搐)、偏頭痛(包括,偏頭痛性頭痛)、尿失禁、物質耐受、物質戒斷(包括諸如鴉片劑、菸鹼、煙草產品、酒精、苯并二氮呯、古柯鹼、鎮靜劑、安眠藥等之物質)、精神病、精神分裂症、焦慮(包括一般焦慮症、恐慌症及強迫症)、情緒障礙(包括抑鬱、躁症、雙極症)、三叉神經痛、聽力損失、耳鳴、眼睛黃斑變性、嘔吐、腦水腫、疼痛(包括急性及慢性狀態、劇痛、難治癒性疼痛、神經痛及外傷後疼痛)、遲發性運動障礙、睡眠失調(包括睡眠發作)、注意力缺陷/過動症及行為障礙。
詳言之,該病況或疾病為選自焦慮症、精神病症、人格障礙、物質關聯性病症、飲食障礙、情緒障礙、偏頭痛、癲癇症或抽搐症、兒童期病症、認知障礙、神經退化、神經毒性及局部缺血之群的中樞神經系統病症。
較佳地,中樞神經系統病症為選自空曠恐懼症、泛焦慮症(GAD)、強迫症(OCD)、恐慌症、創傷後症候群(PTSD)、社交恐懼症及其他恐懼症之群的焦慮症。
較佳地,中樞神經系統病症為選自精神分裂症、妄想症、分裂情感性精神障礙、類精神分裂症精神障礙及物質誘發之精神病症之群的精神病症。
較佳地,中樞神經系統病症為選自強迫性人格障礙及精神分裂症、分裂型障礙之群的人格障礙。
較佳地,中樞神經系統病症為選自酒精濫用、酒精依賴、酒精戒斷、酒精戒斷性譫妄、酒精誘發之精神病症、安非他命依賴、安非他命戒斷、古柯鹼依賴、古柯鹼戒斷、菸鹼依賴、菸鹼戒斷、類鴉片依賴及類鴉片戒斷之群的物質關聯性病症。
較佳地,中樞神經系統病症為選自神經性厭食症及神經性貪食症之群的飲食障礙。
較佳地,中樞神經系統病症為選自雙極症(I及II)、循環情感性精神障礙、抑鬱、低落性情感疾患重性抑鬱症及物質誘發之情緒障礙之群的情緒障礙。
較佳地,中樞神經系統病症為偏頭痛。
較佳地,中樞神經系統病症為選自全身性非驚厥性癲癇、全身性驚厥性癲癇、失神性癲癇持續狀態、大癲癇持續狀態、伴隨或不伴隨意識缺損之部分性癲癇、嬰兒痙攣症、部分性癲癇持續狀態及其他形式之癲癇之群的癲癇症或抽搐症。
較佳地,中樞神經系統病症為注意力缺陷/過動症。
較佳地,中樞神經系統病症為選自譫妄、物質誘發之持續譫妄、癡呆、HIV疾病引起之癡呆、亨廷頓氏症引發之癡呆、帕金森氏症引發之癡呆、阿茲海默氏型癡呆、物質誘發之持續性癡呆及輕度認知缺損之群的認知障礙。
在上文提及之病症中,焦慮、精神分裂症、偏頭痛、抑鬱及癲癇症之治療尤其重要。
目前,Diagnostic & Statistical Manual of Mental Disorders(DSM-IV)of the American Psychiatric Association之第4版提供用於識別本文所述之病症的診斷工具。熟習此項技術者將認識存在本文所述之神經及精神病症的替代命名、疾病分類及分類系統,且此等系統隨著醫學及科學之進程而進展。
因為該等mGluR2之正向異位調節劑(包括式(I)化合物)增強mGluR2對麩胺酸鹽之反應,所以本發明方法利用內源性麩胺酸鹽為有利的。
因為mGluR2之正向異位調節劑(包括式(I)化合物)增強mGluR2對激動劑之反應,所以應瞭解本發明擴展至治療與麩胺酸鹽功能障礙有關之神經及精神病症,其係藉由投與有效量之mGluR2的正向異位調節
劑(包括式(I)化合物)以及mGluR2激動劑進行。
本發明化合物可與一或多種其他藥物組合用於治療、預防、控制、改善或減輕式(I)化合物或其他藥物可具有效用之疾病或病況的風險,其中藥物在一起之組合比任何單獨藥物安全或有效。
本發明亦係關於醫藥組合物,其包含醫藥學上可接受之載劑或稀釋劑及作為活性成份的治療有效量之本發明化合物,尤其式(I)化合物,其醫藥學上可接受之鹽、其溶劑合物或其立體化學異構形式。
本發明化合物(尤其式(I)化合物)、其醫藥學上可接受之鹽、其溶劑合物及立體化學異構形式,或其任何子群或組合可經調配為各種用於投與目的之醫藥形式。可引用一般用於全身投與藥物之所有組合物作為適當組合物。
為製備本發明之醫藥組合物,作為活性成份的視情況為鹽形式之有效量之特定化合物與醫藥學上可接受載劑或稀釋劑密切摻雜組合,該載劑或稀釋劑可視投與所需之製劑形式採取多種形式。適於(尤其)口服、經直腸、經皮、非經腸注射或藉由吸入投與之單一劑型的此等醫藥組合物為合需要的。舉例而言,在製備口服劑型之組合物時,可採用任何之一般醫藥媒劑,例如就口服液體製劑(諸如,懸浮液、糖漿、酏劑、乳劑及溶液)而言,可採用諸如水、乙二醇、油類、醇類及其類似物;或就散劑、丸劑、膠囊及錠劑而言,可採用固體載劑,諸如澱粉、糖、高嶺土、稀釋劑、潤滑劑、黏合劑、崩解劑及其類似物。因為易於投與,所以口服投與為較佳的,且錠劑及膠囊呈現最有利之口服單位劑型,在此狀況下明顯採用固體醫藥載劑。對於非經腸道的組合物而言,儘管為幫助溶解可包括其他成份,但載劑一般將包含至少大部分的無菌水。舉例而言,可製備可注射溶液,其中載劑包含生理食鹽水溶液,葡萄糖溶液或生理食鹽水與葡萄糖溶液的混合物。亦可
製備可注射懸浮液,在該狀況下可採用適當液體載劑、懸浮劑及其類似物。亦包括固體形式製劑,意欲將其在即將使用前轉化為液體形式製劑。在適於經皮投與之組合物中,載劑視情況包含滲透增強劑及/或合適的濕潤劑,其視情況與微量比例的任何種類之合適添加劑組合,該等添加劑不對皮膚誘發顯著不利影響。該等添加劑可有助於對皮膚之投藥且/或可幫助製備所要組合物。此等組合物可以多種方式投與,例如作為經皮貼片、點劑(spot-on)、軟膏。
將前述醫藥組合物調配為單位劑型以便於投與及劑量均一性尤其有利。如本文所用之單位劑型係指適用作單一劑量之實體上分離之單位,各單位含有與所要醫藥載劑締合之經計算以產生所要治療作用的預定量之活性成份。該等單位劑型之實例為錠劑(包括截痕錠劑或包衣錠劑)、膠囊、丸劑、散劑封包、糯米紙囊劑、栓劑、可注射溶液或懸浮液及其類似物,及其隔離多倍型。
如彼等熟習此項技術者所熟知,投與之確切劑量及頻率視所用特定式(I)化合物、所治療之特定病況、所治療病況之嚴重性、特定患者之年齡、體重、性別、病症程度及一般身體狀況以及個體可服用之其他藥物而定。此外,該有效每日量顯然可視所治療個體之反應及/或視開出本發明化合物之醫師的評估而減少或增加。
視投藥模式而定,醫藥組合物將包含0.05至99重量%,較佳0.1至70重量%,更佳0.1至50重量%活性成份,及1至99.95重量%,較佳30至99.9重量%,更佳50至99.9重量%醫藥學上可接受之載劑,所有百分比係以組合物之總重量計。
如已提及,本發明亦係關於包含本發明之化合物及一或多種其他藥物的醫藥組合物,其係用於治療、預防、控制、改善或減輕式(I)化合物或其他藥物可具有效用之疾病或病況的風險,且係關於該組合物用於製造藥物的用途。本發明亦係關於本發明化合物與mGluR2鄰位激
動劑之組合。本發明亦係關於用作藥品之該組合。本發明亦係關於包含(a)本發明之化合物,其醫藥學上可接受之鹽或其溶劑合物,及(b)mGluR2鄰位激動劑之產品,其係以組合製劑形式同時、單獨或相繼用於治療或預防哺乳動物(包括人類)之病況,其治療或預防受到mGluR2別位調節劑,尤其正向mGluR2別位調節劑之神經調節作用的影響或促進。該組合或產品之不同藥物可在單一製劑中與醫藥學上可接受之載劑或稀釋劑組合,或其各自可與醫藥學上可接受之載劑或稀釋劑一起以分開製劑形式存在。
以下實例意欲說明(但不限制)本發明之範疇。
以下實例中說明用於製備本發明化合物之若干方法。除非另外註明,否則所有起始材料係購自供應商且無需進一步純化即使用。
下文中,"THF"意謂四氫呋喃;"DMF"意謂N,N-二甲基甲醯胺;"EtOAc"意謂乙酸乙酯;"DCM"意謂二氯甲烷;"DME"意謂1,2-二甲氧基乙烷;"DCE"意謂1,2-二氯乙烷;"DIPE"意謂二異丙醚;"DMSO"意謂二甲亞碸;"BINAP"意謂[1,1'-聯萘]-2,2'-二基雙[二苯膦];"DBU"意謂1,8-二氮-7-雙環[5.4.0]十一烯;Xantphos意謂(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙[二苯膦];MeOH意謂甲醇;"q.s."意謂足量;"M.P."意謂熔點。
在單模式反應器:InitiatorTM Sixty EXP微波反應器(Biotage AB),或多模式反應器:MicroSYNTH Labstation(Milestone,Inc.)中進行微波輔助反應。
向4-苯甲氧基-1H-吡啶-2-酮化物(5.0g,24.84mmol)於乙腈(200ml)中之溶液中添加溴甲基-環丙烷(3.68g,27.33mmol)及碳酸鉀(10.3g,74.52mmol),且將混合物在回流下加熱16小時。將反應混合物經矽藻土過濾且真空濃縮。接著將粗殘餘物以乙醚濕磨得到呈白色固體之純D1(6.32g,98%)。
在氫氣氣氛下將中間物D1(2.0g,7.83mmol)與催化量之10%鈀/活性炭在乙醇(300ml)中之混合物攪拌2小時。將混合物經由矽藻土過濾且將溶劑真空蒸發以產生中間物D2(1.3g,100%),其未經進一步純化即使用。
向中間物D2(1.42g,8.6mmol)於DMF(140ml)中之溶液中添加氧溴化磷(5.4g,18.9mmol)且將混合物在110℃下加熱1小時。在冰浴中冷卻後,使溶液在水與EtOAc之間分溶。以EtOAc萃取3次後,將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;DCM作為溶離劑)純化。收集所要溶離份且真空蒸發產生中間物D3(1.82g,93%)。
根據針對D3之合成所實施之相同程序使用4-羥基-1-(3-甲基丁基)-1H-吡啶-2-酮化物作為起始材料製備中間物D7,4-羥基-1-(3-甲基丁基)-1H-吡啶-2-酮化物係藉由針對中間物D2之合成所用之相同方法藉由使4-苯甲氧基-1H-吡啶-2-酮化物與1-溴-3-甲基丁烷反應來製備。
向4-苯甲氧基-1H-吡啶-2-酮化物(5.0g,24.84mmol)於乙腈(200ml)中之溶液中添加1-溴丁烷(3.75g,27.33mmol)及碳酸鉀(10.3g,74.52mmol),且將混合物在回流下加熱16小時。將反應混合物經矽藻土過濾且真空濃縮。接著將粗殘餘物用乙醚濕磨以產生呈白色固體之
純D4(6.26g,98%)。
在氫氣氣氛下將中間物D4(2.01g,7.83mmol)與催化量之10%鈀/活性炭在乙醇(300ml)中之混合物攪拌2小時。將混合物經矽藻土過濾且將溶劑真空蒸發以產生中間物D5(1.3g,100%),其未經進一步純化即使用。
向中間物D5(1.44g,8.6mmol)於DMF(140ml)中之溶液中添加氧溴化磷(5.4g,18.9mmol)且將混合物在110℃下加熱1小時。在冰浴中冷卻後,使溶液在水與EtOAc之間分溶。以EtOAc萃取3次後,將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生中間物D6(1.82g,93%)。
向中間物D5(2.0g,11.96mmol)於DMF(30ml)中之溶液中添加N-氯丁二醯亞胺(1.6g,11.96mmol)。將反應物在室溫下攪拌隔夜且接著將其真空濃縮。將粗產物藉由管柱層析法(矽膠;0-5%甲醇/DCM作為溶離劑)純化以產生中間物D8(2.0g,83%)。
向中間物D8(2.0g,9.92mmol)於DCM(80ml)中之冷(-78℃)溶液中添加吡啶(1.60ml,19.8mmol)。將所得溶液攪拌10分鐘,隨後添加三氟甲烷磺酸酐(1.90ml,10.9mmol),且將所得溶液在-78℃下攪拌3小時。接著將混合物溫至室溫且藉由添加飽和氯化銨水溶液中止反應。將混合物以水稀釋,以DCM萃取,乾燥(Na2SO4)且真空蒸發溶劑,產生作為粗產物之中間物D9(3.31g,100%),其未經進一步純化即使用。
向中間物D1(3.0g,11.74mmol)於乙酸(40ml)中之溶液中添加N-碘丁二醯亞胺(2.64g,11.74mmol)。將反應混合物在室溫下攪拌1小時,隨後將其真空濃縮,藉由急驟層析法(矽膠;0-3%甲醇/DCM作為溶離劑)純化且最終自乙醚再結晶以產生呈固體之中間物D10(4.12g,92%)。
將2,2-二氟-2-(氟磺醯基)乙酸甲酯(0.67ml,5.24mmol)及中間物D10(1.0g,2.63mmol)添加至碘化亞銅(I)(0.99g,5.24mmol)於DMF(30ml)中之溶液中。接著將混合物在100℃下加熱5小時,隨後將其經矽藻土過濾且將濾液真空濃縮。將殘餘物藉由管柱層析法(矽膠;DCM作為溶離劑)純化以產生中間物D11(0.76g,89%)。
在氫氣氣氛下將中間物D11(2.0g,6.19mmol)、催化量之10%鈀/活性炭及乙醇(60ml)之混合物攪拌2小時。將混合物經由矽藻土過濾且將溶劑真空蒸發以產生粗中間物D12(1.45g,100%),其未經進一步純化即使用。
向中間物D12(2.60g,11.1mmol)於DMF(50ml)中之溶液中添加氧溴化磷(7.03g,24.5mmol)且將混合物在110℃下加熱1小時。在冰浴中冷卻後,使溶液在水與EtOAc之間分溶。以EtOAc萃取3次後,將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生中間物D13(1.38g,42%)。
將1-溴甲基-4-三氟甲氧基苯(3.32g,13.04mmol)及碳酸鉀(3.51g,25.46mmol)添加至4-苯甲氧基-1H-吡啶-2-酮化物(2.5g,12.42mmol)於乙腈(10ml)中之混合物中。將反應混合物在回流溫度下加熱24小時。冷卻至室溫後,將其經由矽藻土過濾,將固體殘餘物以甲醇洗滌且將經合併之有機萃取物真空蒸發。將因此獲得之粗殘餘物用DIPE沈澱以產生呈白色固體之中間物D14(4.5g,96%)。
將N-氯丁二醯亞胺(1.68g,12.61mmol)添加至中間物D14(4.31g,11.47mmol)於DMF(30ml)中之溶液中且將混合物在室溫下攪拌24小時。將溶劑蒸發且將固體殘餘物以水洗滌(4×25ml)。將粗固體以DIPE洗滌以產生呈白色固體之中間物D15(4.5g,95%)。
將氫溴酸(0.1ml)添加至中間物D15(4.5g,10.98mmol)於乙酸(20ml)中之混合物中。在130℃下在微波照射下將溶液加熱30分鐘。冷卻至室溫後,將溶劑真空蒸發且將殘餘物以NaHCO3飽和水溶液處理直至溶液達到約8之pH值。將所沈澱之白色固體藉由過濾收集且以冷DIPE洗滌以產生中間物D16(1.1g,31%)。
向中間物D16(1.0g,3.13mmol)於DMF(5ml)中之溶液中添加氧溴
化磷(1.05g,3.75mmol)且將混合物在115℃下加熱4小時。將溶劑真空蒸發且將粗殘餘物以NaHCO3飽和水溶液處理。將混合物以DCM(3×5ml)萃取,將有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;乙醚作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈黃色油狀之中間物D17(0.21g,18%)。
將4-苯基哌啶(0.45g,2.78mmol)、乙酸鈀(II)(0.016g,0.069mmol)、第三丁醇鈉(0.34g,3.5mmol)及BINAP(0.065g,0.104mmol)添加至中間物D3(0.32g,1.39mmol)於甲苯(5ml)中之溶液中。在密封試管中在100℃下將反應混合物加熱16小時,隨後將其冷卻至室溫,以水(5ml)稀釋且接著以EtOAc(3×5ml)萃取。將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;0-4%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生中間物D18(0.33g,78%)。
將4-苯基哌啶(0.45g,2.78mmol)、乙酸鈀(II)(0.016g,0.069mmol)、第三丁醇鈉(0.34g,3.5mmol)及BINAP(0.065g,0.104mmol)添加至中間物D6(0.32g,1.39mmol)於甲苯(5ml)中之溶液中。在密封試管中在100℃下將反應混合物加熱16小時,隨後將其冷卻至室溫,且接著以水(5ml)稀釋且以EtOAc(3×5ml)萃取。將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;0-4%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生中間物D19(0.38g,89%)。
將4-氰基-4-苯基哌啶鹽酸鹽(0.314g,1.41mmol)、乙酸鈀(II)(0.013g,0.059mmol)、第三丁醇鈉(0.347g,3.54mmol)及BINAP(0.051g,0.08mmol)添加至中間物D3(0.27g,1.18mmol)於甲苯(5ml)中之經攪拌溶液中。在密封試管中在100℃下將反應混合物加熱16小時。冷卻至室溫後,將混合物以水稀釋且以EtOAc萃取。將經合併之有機相乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層
析法(矽膠;10%甲醇中之氨(7M)/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈淺黃色油狀之D20(0.35g,87%)。
將2-溴苯甲酸甲酯(1.816ml,12.936mmol)[CAS 610-94-6]添加至1,2,3,6-四氫-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-吡啶(4g,12.936mmol)[CAS 375853-82-0](如WO 2004072025 A2 20040826中所述合成)於1,4-二噁烷(28ml)及NaHCO3飽和水溶液(24ml)中之溶液中。將所得溶液使用氮氣流脫氣且向此溶液中添加Pd(PPh3)4(0.747g,0.647mmol)。接著在密封試管中在140℃下將反應物微波處理5分鐘。接著,將所得冷反應混合物以EtOAc稀釋且經矽藻土墊過濾。將濾液收集,經Na2SO4乾燥且真空濃縮。接著將粗反應混合物藉由管柱層析法(矽膠;DCM至DCM/至多6%EtOAc作為溶離劑)純化。收集所要溶離份且真空蒸發以產生D21(4.04g,98%)。
將4-溴-3-氟苯甲酸甲酯(2.261g,9.702mmol)[CAS 849758-12-9]添加至1,2,3,6-四氫-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-吡啶(3g,9.702mmol)[CAS 375853-82-0](如WO 2004072025 A2 20040826中所述合成)於1,4-二噁烷(21ml)及NaHCO3飽和水溶液(18ml)中之溶液中。將所得溶液使用氮氣流脫氣且向此溶液中添加Pd(PPh3)4(0.561g,0.485mmol)。接著在密封試管中在150℃下將反應物微波處理5分鐘。接著,將所得冷卻反應混合物以EtOAc稀釋且經矽藻土墊過濾。將濾液收集,經Na2SO4乾燥且真空濃縮。接著將粗反應混合物藉由管柱層析法(矽膠;DCM至DCM/至多6%EtOAc作為溶離劑)純化。收集所要溶離份且真空蒸發以產生D22(2.107g,65%)。
將中間物D22(2.81g,8.379mmol)於甲醇(120ml)中之溶液在室溫下在鈀10%/活性炭(0.588g)存在下氫化直至反應完成。將固體濾除且將濾液真空蒸發以產生D23(2.73g,97%)。
在氮氣氣氛下,將甲基溴化鎂於甲苯/THF(17.339ml,24.274mmol)中之1.4M溶液逐滴添加至中間物D23(2.73g,8.091mmol)於乙醚(150ml)中之冷卻(0℃)溶液中。接著將所得反應混合物在50℃下攪拌2小時。在冰浴中冷卻後,將混合物以氯化銨飽和水溶液小心地驟冷,且接著以EtOAc萃取。將經合併之有機相乾燥(Na2SO4)且將溶劑真空蒸發以產生D24(3.16g,100%)。
在密封試管中在180℃下,將中間物D24(3.067g,7.852mmol)及KOH(2.54g,45.268mmol)於異丙醇(13.5ml)及水(27ml)中之混合物微波處理60分鐘。接著將所得冷卻反應混合物以水及鹽水稀釋且以二氯甲烷萃取。將經合併之有機萃取物乾燥(Na2SO4)且將溶劑真空蒸發。將殘餘物用二氯甲烷處理以產生固體,將其濾除產生1.03g中間物D25。將濾液真空蒸發且接著將因此獲得之殘餘物藉由管柱層析法(矽膠;DCM/(NH3於MeOH中之7N溶液),梯度至多10%作為溶離劑)純化。將所要溶離份收集且真空蒸發以產生第二批0.5g D25(總量=1.53g,82%)。M.P.151℃。
將中間物D21(4.04g,12.729mmol)於甲醇(120ml)中之溶液在室溫下在鈀10%/活性炭(0.846g)存在下氫化直至反應完成。將固體濾除且將濾液真空蒸發以產生呈白色固體之D26(3.67g,90%)。
在氮氣氣氛下,將甲基溴化鎂於甲苯/THF(17.443ml,24.421mmol)中之1.4M溶液逐滴添加至中間物D26(2.6g,8.14mmol)於乙醚(150ml)中之冷卻(0℃)溶液中。接著將所得反應混合物在45℃下攪拌2小時。在冰浴中冷卻後,將混合物以氯化銨飽和水溶液小心地驟冷,且接著以EtOAc萃取。將經合併之有機相乾燥(Na2SO4)且將溶劑真空蒸發以產生D27(2.77g,69%)。
在密封試管中在180℃下,將中間物D27(2.77g,5.636mmol)及KOH(2.43g,43.357mmol)於異丙醇(13.5ml)及水(27ml)中之混合物微波處理60分鐘。接著將所得冷卻反應混合物以水及鹽水稀釋且以二氯甲烷萃取。將殘餘物以二氯甲烷處理產生固體,將固體濾除。產量:中間物D28,0.737g。將濾液真空蒸發且接著將殘餘物藉由管柱層析法(矽膠;DCM/(NH3於MeOH中之7N溶液),梯度至多10%作為溶離劑)純化。將所要溶離份收集且真空蒸發以產生第二批0.306g中間物D28(總量=1.04g,84%)。M.P.219.5℃。
將二碳酸二第三丁酯(2.95g,13.53mmol)添加至4-羥基-4-苯基哌啶(2g,11.28mmol)於DCM(50ml)中之溶液中。將反應物在室溫下攪拌5小時。將溶劑真空移除,產生作為粗產物之所要中間物D29(3.12g,100%),其未經進一步純化即使用。
在N2氣氛下,將(二乙基胺基)三氟化硫(0.74ml,5.67mmol)於無水DCM(q.s.)中之溶液添加至D29(1.5g,5.4mmol)於無水DCM(30ml)中之冷卻(-78℃)溶液中。添加完成後,將反應混合物在-78℃下攪拌1小時,且接著使其達到室溫,且再攪拌30分鐘。添加NaHCO3飽和水溶液(90ml)且將混合物攪拌15分鐘,接著分離有機層。此後,添加3-氯過氧基苯甲酸(0.2g,1.18mmol)且將反應物在室溫下攪拌30分鐘。將反應混合物以NaHCO3飽和水溶液、H2O及鹽水洗滌,經Na2SO4乾燥,過濾且真空濃縮以產生作為粗產物之所要中間物D30(1.48g,98%),其未經進一步純化即使用。
將D30(1.48g,5.29mmol)溶解於二噁烷中之4N HCl中。將反應物在室溫下攪拌2小時。將溶劑移除。將粗產物以乙醚濕磨且真空乾燥以產生作為氯水合物之所要中間物D31(1.10g,97%),其未經進一步純化即使用。
將D31(0.2g,0.94mmol)、乙酸鈀(II)(0.009g,0.04mmol)、第三丁醇鈉(0.25g,2.58mmol)及BINAP(0.037g,0.06mmol)添加至中間物D6(0.20g,0.86mmol)於甲苯(5ml)中之經攪拌溶液中。在密封試管中在100℃下將反應混合物加熱16小時。冷卻至室溫後,將混合物以水稀釋且以EtOAc萃取。將經合併之有機相乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;10%甲醇中之氨(7N)/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈淺黃色油狀之D32(0.21g,87%)。
將中間物D1(3.0g,11.7mmol)及N-溴丁二醯亞胺(2.09g,11.7mmol)於DCM(100ml)中之溶液在室溫下攪拌1小時。將溶劑真空蒸發且將粗殘餘物藉由管柱層析法(矽膠;DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生D33(3.56g,91%)。
將NaHCO3(1.0g,過量)、環丙基酸(0.74g,8.93mmol)、碳酸鉀(1.23g,8.93mmol)及[1,1'-雙(二苯膦)二茂鐵]二氯鈀(II)-DCM錯合物(0.36g,0.45mmol)添加至中間物D10(1.0g,2.98mmol)於1,4-二噁烷(10ml)中之溶液中。將所得混合物在175℃下在微波照射下加熱20分鐘,隨後將其經矽藻土過濾且將溶劑真空蒸發。將粗殘餘物藉由管柱層析法(矽膠;0-3%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生D34(0.6g,69%)。
在氫氣氣氛下將中間物D34(1.0g,3.38mmol)與催化量之10%鈀/活性炭在乙醇(150ml)中之混合物攪拌2小時。將混合物經矽藻土過濾且將溶劑真空蒸發以產生中間物D35(0.69g,100%),其未經進一步純化即使用。
向中間物D35(0.85g,4.14mmol)於DMF(60ml)中之溶液中添加氧
溴化磷(2.4g,8.28mmol)且將混合物在110℃下加熱1小時。在冰浴中冷卻後,使溶液在水與EtOAc之間分溶。將混合物以EtOAc(3×200ml)萃取,將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生中間物D36(0.99g,89%)。
將4-哌啶-4-基苯甲酸甲酯(0.40g,1.81mmol)、乙酸鈀(II)(0.015g,0.069mmol)、第三丁醇鈉(0.34g,3.44mmol)及BINAP(0.06g,0.096mmol)添加至中間物D3(0.31g,1.37mmol)於甲苯(10ml)中之經攪拌溶液中。在密封試管中在100℃下將反應混合物加熱16小時。冷卻至室溫後,將混合物以EtOAc稀釋且接著經矽藻土過濾,隨後將溶劑真空蒸發。將粗殘餘物以DCM/甲醇之混合物處理且接著濾除。將濾液在真空中蒸發至乾燥以產生粗D37(0.48g,100%),其未經進一步純化即使用。
在160℃下在微波照射下將中間物D37(0.43g,1.23mmol)、DBU(0.18g,1.23mmol)、碳酸二甲酯(4.5ml,過量,93mmol)與乙腈(5ml)之混合物加熱20分鐘。將冷卻粗混合物以水稀釋且添加EtOAc,隨後將有機層以10%檸檬酸水溶液洗滌,乾燥(Na2SO4)且真空蒸發溶劑。將粗殘餘物藉由管柱層析法(矽膠;0-3%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生D38(0.19g,38%)。
在氮氣氣氛下,將甲基溴化鎂於甲苯/THF(1.12ml,1.57mmol)中之1.4M溶液逐滴添加至中間物D38(0.19g,0.52mmol)於THF(20ml)中之冷卻(0℃)溶液中。將所得反應混合物在45℃下攪拌2小時。在冰浴中冷卻後,將混合物以氯化銨飽和水溶液小心地驟冷,且接著以EtOAc萃取。將經合併之有機相乾燥(Na2SO4)且將溶劑真空蒸發。將殘餘物藉由管柱層析法(矽膠;0-5%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈油狀之D39(0.077g,40%)。
將中間物D18(0.2g,0.65mmol)及N-氯丁二醯亞胺(0.09g,0.65mmol)於DCM(10ml)中之溶液在室溫下攪拌1小時。將溶劑真空蒸發且將粗產物藉由管柱層析法(矽膠;0-3%甲醇/DCM作為溶離劑)純化。將所要溶離份收集且真空蒸發,且將所得固體自乙醚再結晶以產生呈白色固體之化合物E1(0.10g,47%)。
熔點:170.8℃。
1H NMR(400MHz,CDCl3)δ ppm 0.35-0.42(m,2 H),0.57-0.64(m,2 H),1.19-1.33(m,1 H),1.85-2.00(m,4 H),2.64-2.76(m,1 H),2.85-2.99(m,2 H),3.76-3.87(m,4 H),6.05(d,J=7.6Hz,1 H),7.19-7.29(m,4 H),7.29-7.38(m,2 H)。
將中間物D19(0.43g,1.40mmol)及N-氯丁二醯亞胺(0.19g,1.40mmol)於DCM(10ml)中之溶液在室溫下攪拌1小時。將溶劑真空蒸發且將粗產物藉由管柱層析法(矽膠;0-3%甲醇/DCM作為溶離劑)純化。將所要溶離份收集且真空蒸發,且將所得固體自乙醚再結晶以產生呈白色固體之化合物E2(0.39g,82%)。
熔點:149.4℃。
1H NMR(400MHz,CDCl3)δ ppm 0.95(t,J=7.3Hz,3 H),1.31-1.42(m,2 H),1.68-1.78(m,2 H),1.85-1.98(m,4 H),2.64-2.73(m,1 H),2.87-2.96(m,2 H),3.82(br d,J=12.1Hz,2 H),3.93(t,J=7,3Hz,2 H),6.03(d,J=7.6Hz,1 H),7.10(d,J=7.6Hz,1 H),7.19-7.28(m,3 H),7.29-7.37(m,2 H)。
向中間物D18(0.25g,0.82mmol)於DCM(10ml)中之溶液中添加N-溴丁二醯亞胺(0.145g,0.82mmol)。將反應混合物在室溫下攪拌1小時。隨後,將溶劑真空蒸發且將粗殘餘物藉由管柱層析法(矽膠;0-3%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈白色固體之化合物E3(0.20g,64%)。
熔點:150℃。
1H NMR(500MHz,DMSO-d 6)δ ppm 0.34-0.40(m,2 H),0.44-
0.50(m,2 H),1.16-1.26(m,1 H),1.77(qd,J=12.38,3.61Hz,2 H),1.88(br d,J=12.1Hz,2 H),2.68-2.78(m,1 H),2.91(br t,J=11.9Hz,2 H)3.69(br d,J=12.1Hz,2 H),3.74(d,J=7.2Hz,2 H),6.21(d,J=7.5Hz,1 H),7.19-7.25(m,1 H),7.27-7.36(m,4 H),7.69(d,J=7.5Hz,1 H)。
將4-苯基哌啶(0.33g,2.02mmol)、乙酸鈀(II)(0.012g,0.05mmol)、第三丁醇鈉(0.24g,2.52mmol)及BINAP(0.05g,0.08mmol)添加至中間物D13(0.3g,1.01mmol)於甲苯(7ml)中之溶液中。在密封試管中在100℃下將反應混合物加熱16小時,隨後將其冷卻至室溫,且接著以水(5ml)稀釋且以EtOAc(3×5ml)萃取。將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;0-4%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈白色固體之化合物E4(0.11g,31%)。
熔點:177.2℃。
1H NMR(500MHz,DMSO-d 6)δ ppm 0.33-0.38(m,2 H),0.45-0.50(m,2 H),1.13-1.22(m,1 H),1.64-1.75(m,2 H),1.84(br d,J=11.0Hz,2 H),2.72-2.80(m,1 H),3.14(br t,J=12.1Hz,2 H),3.59(br d,J=13.0Hz,2 H),3.65(d,J=7.2Hz,2 H),6.21(d,J=7.8Hz,1 H),
7.19-7.23m,1 H),7.24-7.29(m,2 H),7.29-7.34(m,2 H),7.73(d,J=7.8Hz,1 H)。
將中間物D17(0.2g,0.52mmol)、4-苯基哌啶(0.1g,0.62mmol)、2-(2'-二-第三丁基膦)聯苯乙酸鈀(II)(0.01g,0.026mmol)及磷酸鉀(0.23g,1.1mmol)於1,4-二噁烷(3ml)中之混合物在90℃下攪拌35小時。將混合物經矽藻土過濾,且以更多1,4-二噁烷洗滌後將濾液蒸發至乾燥。將粗產物藉由管柱層析法(矽膠;庚烷/乙醚1:1作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈白色固體之化合物E5(0.075g,31%)。
熔點:168.6℃。
1H NMR(400MHz,CDCl3)δ ppm 1.83-1.98(m,4 H),2.65-2.75(m,1 H),2.89-2.98(m,2 H),3.84(br d,J=12.2Hz,2 H),5.12(s,2 H),6.06(d,J=7.6Hz,1 H),7.14(d,J=7.6Hz,2 H),7.15-7.28(m,5 H),7.29-7.40(m,4 H)。
將中間物D20(0.35g,1.03mmol)及N-氯丁二醯亞胺(0.14g,1.03mmol)於DCM(25ml)中之溶液在室溫下攪拌1小時。添加更多DCM後,將溶液以鹽水洗滌,乾燥(Na2SO4)且真空蒸發溶劑。將粗產物藉由管柱層析法(矽膠;甲醇中10%氨(7N)/DCM作為溶離劑)純化且藉由製備型HPLC進一步純化。收集所要溶離份且真空蒸發以產生呈白色固體之化合物E6(0.17g,47%)。
熔點:173.7℃。
1H NMR(400MHz,DMSO-d 6)δ ppm 0.17-0.23(m,2 H),0.26-0.33(m,2 H),0.97-1.09(m,1 H),1.91-2.02(m,2 H),2.11(br d,J=12.9Hz,2 H)2.98(br t,J=12.4Hz,2 H),3.54-3.63(m,4 H),6.14(d,J=7.4Hz,1 H),7.20-7.26(m,1 H),7.27-7.35(m,2 H),7.40-7.44(m,2 H),7.52(d,J=7.4Hz,1 H)。
將中間物D32(0.21g,0.66mmol)及N-氯丁二醯亞胺(0.08g,0.66mmol)於DCM(30ml)中之溶液在室溫下攪拌10分鐘。添加更多DCM後,將溶液以鹽水洗滌,乾燥(Na2SO4)且真空蒸發溶劑。將粗產物藉
由管柱層析法(矽膠;甲醇中10%氨(7M)/DCM作為溶離劑)純化且藉由製備型HPLC進一步純化。收集所要溶離份且真空蒸發以產生呈白色固體之化合物E7(0.065g,27%)。
熔點:136.7℃。
1H NMR(400MHz,DMSO-d 6)δ ppm 0.89(t,J=7.4Hz,3 H),1.21-1.32(m,2 H),1.54-1.64(m,2 H),2.03(t,J=11.8Hz,2 H),2.16(td,J=13.9,4.6Hz,1 H),2.26(td,J=13.6,4.6Hz,1 H),3.17(dd,J=12.3,11.1Hz,2 H),3.54-3.64(m,2 H),3.87(t,J=7.2Hz,2 H),6.26(d,J=7.6Hz,1 H),7.32-7.38(m,1 H),7.42(t,J=7.4Hz,2 H),7.45-7.51(m,2 H),7.62(d,J=7.4Hz,1 H)。
將4-苯基哌啶(0.22g,1.34mmol)、乙酸鈀(II)(0.008g,0.034mmol)、第三丁醇鈉(0.16g,1.68mmol)及BINAP(0.032g,0.05mmol)添加至中間物D36(0.18g,0.67mmol)於甲苯(5ml)中之溶液中。在密封試管中在100℃下將反應混合物加熱16小時,隨後將其冷卻至室溫,且接著以水(5ml)稀釋且以EtOAc(3×5ml)萃取。將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗產物藉由管柱層析法(矽膠;0-4%甲醇/DCM作為溶離劑)純化。收集所要溶離份且真空蒸發以產生呈白色固體之化合物E8(0.18g,77%)。
熔點:201.9℃。
1H NMR(500MHz,DMSO-d 6)δ ppm 0.30-0.35(m,2 H)0.41-0.47(m,2 H)0.74-0.80(m,2 H),0.86-0.92(m,2 H),1.11-1.21(m,1 H),1.60-1.67(m,1 H),1.73-1.89(m,4 H),2.63-2.72(m,1 H),2.87(br t,J=11.1Hz,2 H),3.57-3.65(m,4 H),6.07(d,J=7.5Hz,1 H),7.19-7.24(m,1 H),7.26-7.37(m,4 H),7.46(d,J=7.5Hz,1 H)。
將中間物D39(0.077g,0.21mmol)及N-氯丁二醯亞胺(0.03g,0.21mmol)於DCM(8ml)中之溶液在室溫下攪拌5分鐘。將粗混合物以NaHCO3飽和溶液洗滌,接著將其以DCM萃取,將經合併之有機溶離份乾燥(Na2SO4)且將溶劑真空蒸發。將粗殘餘物藉由管柱層析法(矽膠;0-5%甲醇/DCM作為溶離劑)純化。進行第二層析法(矽膠;DCM/EtOAc 1:1,且最終100% EtOAc作為溶離劑)。將所要溶離份收集且真空蒸發,且將所得固體自乙醚結晶以產生呈白色固體之化合物E9(0.06g,71%)。
1H NMR(400MHz,CDCl3)δ ppm 0.35-0.41(m,2 H),0.56-0.64(m,2 H),1.19-1.30(m,1 H),1.59(s,6 H),1.73(s,1 H),1.85-1.99(m,4 H),2.65-2.76(m,1 H),2.87-2.97(m,2 H),3.78-3.87(m,4 H),6.05
(d,J=7.6Hz,1 H),7.21-7.26(m,3 H),7.45(d,J=8.3Hz,2 H)。
在0℃下,將化合物E31(0.164g,0.46mmol)於1,2-二甲氧基乙烷(3ml)中之溶液逐滴添加至氫化鈉(0.023g,0.58mmol)於1,2-二甲氧基乙烷(0.5ml)中之混合物中。將反應混合物在室溫下攪拌15分鐘,且隨後添加甲苯磺酸2-氟乙酯[CAS:383-50-6](0.222g,1mmol)於1,2-二甲氧基乙烷(1ml)中之溶液。在密封試管中在180℃下將反應混合物微波處理20分鐘。將混合物冷卻至室溫且添加額外量之氫化鈉(0.023g,0.58mmol)。在180℃下在微波照射下將混合物加熱20分鐘。冷卻至室溫後,添加氯化銨飽和水溶液且將混合物以EtOAc萃取。將有機層分離,乾燥(Na2SO4)且將溶劑蒸發。將粗產物首先藉由管柱層析法(矽膠;溶離劑:DCM/EtOAc,100/0至90/10)純化。收集所要溶離份且真空蒸發以產生化合物E20(0.041g,18%)。
1H NMR(400MHz,CDCl3)δ ppm 0.36-0.40(m,2 H),0.58-0.62(m,2 H),1.22-1.28(m,1 H),2.12-2.21(m,4 H),3.27-3.36(m,4 H),3.57(br d,J=12.1Hz,2 H),3.80(d,J=7.2Hz,2 H),4.51(dm,J=47.7Hz,2 H),6.08(d,J=7.5Hz,1 H),7.23(d,J=7.5Hz,1 H),7.29-7.32(m,1 H),7.37-7.41(m,2 H),7.44-7.46(m,2 H)。
將(二乙基胺基)三氟化硫(0.046ml,0.35mmol)添加至化合物E30(0.119g,0.32mmol)於DCM(1ml)中之冷卻(-78℃)溶液中。將反應混合物在-78℃下攪拌3小時,且接著在0℃下再攪拌2小時。隨後,添加額外(二乙基胺基)三氟化硫(0.046ml,0.35mmol)且將混合物在室溫下進一步攪拌1小時。添加Na2CO3(飽和水溶液)且將混合物以DCM稀釋。將有機層分離,乾燥(Na2SO4)且蒸發至乾燥。將粗產物藉由管柱層析法(矽膠;溶離劑:DCM/EtOAc,100/0至80/20)純化。收集所要溶離份,真空蒸發且最終冷凍乾燥以產生呈白色發泡體之化合物E21(0.019g,16%)。
1H NMR(400MHz,CDCl3)δ ppm 0.33-0.40(m,2 H),0.52-0.65(m,2 H),1.17-1.29(m,1 H),1.74-1.96(m,4 H),2.96(d,J=22.7Hz,2 H),3.06(dt,J=11.6,3.7Hz,2 H),3.45-3.52(m,2 H),3.79(d,J=7.2Hz,2 H),6.01(d,J=7.6Hz,1 H),7.20-7.36(m,6 H)。
將4-羥基甲基-4-苯基哌啶(0.172g,0.9mmol)、乙酸鈀(II)(0.007g,0.03mmol)、碳酸銫(0.391g,1.2mmol)及Xantphos(0.035g,0.06mmol)添加至中間物D9(0.2g,0.6mmol)於三氟甲基苯(2ml)中之溶液中。在100℃下在密封試管中將反應混合物加熱24小時,隨後將其冷卻至室溫。隨後,將其以DCM、H2O(5ml)稀釋且以EtOAc(3×5ml)萃取。將混合物經矽藻土過濾,且將濾液蒸發至乾燥。將粗產物首先藉由管柱層析法(矽膠;溶離劑:DCM/EtOAc,90/10至0/100)純化,且接著藉由逆相HPLC純化。收集所要溶離份,真空蒸發且最終冷凍乾燥以產生呈白色發泡體之化合物E22(0.041g,18%)。
1H NMR(400MHz,CDCl3)δ ppm 0.93(t,J=7.3Hz,3 H),1.13(br t,J=6.7Hz,1 H),1.28-1.40(m,2 H),1.64-1.75(m,2 H),1.98-2.08(m,2 H),2.31-2.40(m,2 H),2.98-3.10(m,2 H),3.41-3.51(m,2 H),3.63(d,J=6.5Hz,2 H),3.90(t,J=7.3Hz,2 H),5.92(d,J=7.5Hz,1 H),7.04(d,J=7.5Hz,1 H),7.27-7.33(m,1 H),7.36-7.46(m,4 H)。
在180℃下,在微波照射下將中間物D9(0.254g,0.76mmol)、中間物D28(0.2g,0.912mmol)及二異丙基乙胺(0.199ml,1.114mmol)於乙腈(11ml)中之混合物加熱5分鐘。將冷卻粗混合物真空蒸發。將粗殘餘物藉由管柱層析法(矽膠;DCM/EtOAc/MeOH作為溶離劑)純化。將所要溶離份收集且真空蒸發。將所獲得之固體殘餘物以二異丙醚處理。將固體過濾以產生化合物E28(0.183g,61%)。
M.P.182℃。
1H NMR(400MHz,CDCl3)δ ppm 0.95(t,J=7.3Hz,3 H),1.32-1.42(m,2 H),1.70(s,6 H),1.71-1.77(m,2 H),1.79(s,1 H),1.82-1.90(m,2 H),1.91-2.05(m,2 H),2.88-2.98(m,2 H),3.76-3.87(m,3 H),3.93(t,J=7.3Hz,2 H),6.03(d,J=7.5Hz,1 H),7.11(d,J=7.5Hz,1 H),7.16(td,J=7.8,1.4Hz,1 H),7.28(td,J=7.4,1.4Hz,1 H),7.41(dd,J=7.7,1.6Hz,1 H),7.42(dd,J=7.6,1.7Hz,1 H)。
在180℃下,在微波照射下將中間物D9(0.261g,0.781mmol)、中間物D25(0.223g,0.938mmol)及二異丙基乙胺(0.204ml,1.172mmol)於乙腈(11ml)中之混合物加熱5分鐘。將冷卻粗混合物真空蒸發。將粗殘餘物藉由管柱層析法(矽膠;DCM/EtOAc/MeOH/NH3作為溶離劑)純化。將所要溶離份收集且真空蒸發。將所獲得之固體殘餘物以二異丙醚處理。將固體過濾以產生化合物E29(0.239g,73%)。M.P.150.5℃。
1H NMR(400MHz,CDCl3)δ ppm 0.95(t,J=7.3Hz,3 H),1.31-1.43(m,2 H),1.57(s,6 H),1.68-1.76(m,2 H),1.77(s,1 H),1.87-1.96(m,4 H),2.86-2.98(m,2 H),2.98-3.09(m,1 H),3.81(br d,J=12.0Hz,2 H),3.93(t,J=7.3Hz,2 H),6.03(d,J=7.5Hz,1 H),7.11(d,J=7.5Hz,1 H),7.16-7.25(m,3 H)。
在180℃下,在微波照射下將中間物D9(0.15g,0.45mmol)、3H-螺[2-苯并呋喃-1,4'-哌啶](0.102g,0.54mmol)及二異丙基乙胺(0.097ml,0.056mmol)於乙腈(4ml)中之混合物加熱5分鐘。將冷卻粗混合物真空蒸發。將粗殘餘物藉由管柱層析法(矽膠;DCM/EtOAc/MeOH/NH3作為溶離劑)純化。將所要溶離份收集且真空蒸發。將所獲得之固體殘餘物以二異丙醚處理。將固體過濾以產生化合物E32(0.14g,84%)。
1H NMR(400MHz,CDCl3)δ ppm 0.95(t,J=7.3Hz,3 H),1.30-1.43(m,2 H),1.67-1.79(m,2 H),1.85(dd,J=13.8,2.20Hz,2 H),2.12(dt,J=13.0,4.7Hz,2 H),3.25(dt,J=12.4,2.31Hz,2 H),3.57-3.68(m,2 H),3.94(t,J=7.3Hz,2 H),6.06(d,J=7.4Hz,1 H),7.12(d,J=7.4Hz,1 H),7.16-7.34(m,7 H)。
在180℃下,在微波照射下將中間物D9(0.15g,0.45mmol)、螺[1-苯并呋喃-3,4'-哌啶](0.102g,0.54mmol)及二異丙基乙胺(0.097ml,0.056mmol)於乙腈(4ml)中之混合物加熱5分鐘。將冷卻粗混合物真空蒸發。將粗殘餘物藉由管柱層析法(矽膠;DCM/EtOAc/MeOH/NH3作為溶離劑)純化。將所要溶離份收集且真空蒸發。將所獲得之固體殘餘物以二異丙醚處理。將固體過濾以產生化合物E33(0.116g,84%)。
1H NMR(500MHz,CDCl3)δ ppm 0.95(t,J=7.4Hz,3 H),1.30-1.43(m,2 H),1.66-1.79(m,2 H),1.86(d,J=13.3Hz,2 H),2.05-2.19(m,2 H),2.84-2.97(m,2 H),3.68(d,J=12.7Hz,2 H),3.94(t,J=7.4Hz,2 H),4.44(s,2 H),6.01(d,J=7.5Hz,1 H),6.83(d,J=7.8Hz,1 H),6.92(t,J=7.4Hz,1 H),7.07-7.24(m,3 H)。
根據實例1中所述之反應程序製備化合物E10、E11、E12、E13、
E14、E15、E16、E17、E18、E19、E23、E24、E25及E26。
根據實例9中所述之反應程序製備化合物E27。
根據實例22中所述之反應程序製備化合物E30及E31。
如下文各別方法中所規定,使用來自Agilent Technologies之HP 1100進行HPLC量測,其包含具有脫氣器之泵(四元或二元)、自動取樣器、柱式烘箱、二極體陣列偵測器(DAD)及管柱。將來自柱之液流分流至MS質譜儀中。將MS偵測器以電噴霧離子化源經組態。將氮氣用作噴霧器氣體。將源溫度維持在140℃下。以MassLynx-Openlynx軟體進行資料採集。
除了一般程序之外:在60℃下在來自Agilent之XDB-C18濾筒(1.8μm,2.1×30mm)上進行逆相HPLC,流動速率為1ml/min。所用梯度條件為:在6.5分鐘內,90% A(0.5g/l乙酸銨溶液)、5% B(乙腈)、5% C(甲醇)至50% B及50% C,在7分鐘時至100% B,且在7.5分鐘時平衡至初始條件直至9.0分鐘。注射體積2μl。僅在陽離子化模式中藉由使用0.1秒之停留時間以0.5秒自100至750掃描獲得高解析度質譜(Time of Flight,TOF)。毛細管針壓為2.5kV且錐壓為20V。白胺酸-內啡肽為用於鎖定質量校正之標準物質。
除了一般程序之外:在40℃下在來自Advanced Chromatography Technologies之ACE-C18管柱(3.0μm,4.6×30mm)上進行逆相HPLC,流動速率為1.5ml/min。所用梯度條件為:在6.5分鐘內,80% A(0.5g/l乙酸銨溶液)、10% B(乙腈)、10% C(甲醇)至50% B及50% C,在7分鐘
時至100% B,且在7.5分鐘時平衡至初始條件直至9.0分鐘。注射體積5μl。僅在陽離子化模式中藉由使用0.1秒之停留時間以0.5秒自100至750掃描獲得高解析度質譜(Time of Flight,TOF)。對於陽離子化模式而言,毛細管針壓為2.5kV且錐壓為20V。白胺酸-內啡肽為用於鎖定質量校正之標準物質。
除了一般程序之外:在60℃下在來自Agilent之XDB-C18濾筒(1.8μm,2.1×30mm)上進行逆相HPLC,流動速率為0.8ml/min。所用梯度條件為:在6.0分鐘內,90% A(0.5g/l乙酸銨溶液)、10% B(乙腈/甲醇混合物,1/1)至100% B,保持直至6.5分鐘,在7.0分鐘時平衡至初始條件直至9.0分鐘。注射體積2μl。僅在陽離子化模式中藉由使用0.08秒之通道間(inter-channel)延遲以0.1秒自100至1000掃描獲得低解析度質譜(SQD偵測器;四極聚焦器)。毛細管針壓為3kV且錐壓為20V。
除了一般程序之外:在60℃下在來自Waters之Sunfire-C18管柱(2.5μm,2.1×30mm)上進行逆相HPLC,流動速率為1.0ml/min。所用梯度條件為:在6.5分鐘內,95% A(0.5g/l乙酸銨溶液+5%乙腈)、2.5% B(乙腈)、2.5% C(甲醇)至50% B及50% C,保持直至7分鐘且在7.3分鐘時平衡至初始條件直至9.0分鐘。注射體積2μl。藉由使用0.3秒之停留時間以0.5秒自100至750掃描獲得高解析度質譜(Time of Flight,TOF)。對於陽離子化模式而言,毛細管針壓為2.5kV且對於負離子化模式而言為2.9kV。對於正離子化模式及負離子化模式而言,錐壓為20V。白胺酸-內啡肽為用於鎖定質量校正之標準物質。
除了一般程序之外:在60℃下,在不分流至MS偵測器之情況下,在來自Waters之BEH-C18管柱(1.7μm,2.1×50mm)上進行逆相HPLC,
流動速率為0.8ml/min。所用梯度條件為:在4.9分鐘內,95% A(0.5g/l乙酸銨溶液+5%乙腈)、5% B(乙腈/甲醇混合物,1/1)至20% A,80% B,在5.3分鐘內至100% B,保持直至5.8分鐘且在6.0分鐘時平衡至初始條件直至7.0分鐘。注射體積0.5μl。藉由使用0.08秒之通道間延遲以0.1秒自100至1000掃描獲得低解析度質譜(SQD偵測器;四極聚焦器)。毛細管針壓為3kV。對於陽離子化模式而言,錐壓為20V且對於負離子化模式而言為30V。
除了一般程序之外:在60℃下在來自Agilent之XDB-C18濾筒(1.8μm,2.1×30mm)上進行逆相HPLC,流動速率為1ml/min。所用梯度條件為:90% A(0.5g/l乙酸銨溶液)、5% B(乙腈)、5% C(甲醇),保持2分鐘,在3.5分鐘內,至50% B、50% C,保持直至3.65分鐘且在3.8分鐘時平衡至初始條件直至5.0分鐘。注射體積2μl。藉由使用0.3秒之停留時間以0.5秒自100至750掃描獲得高解析度質譜(Time of Flight,TOF)。對於陽離子化模式而言,毛細管針壓為2.5kV且對於負離子化模式而言為2.9kV。對於正離子化模式及負離子化模式而言,錐壓為20V。白胺酸-內啡肽為用於鎖定質量校正之標準物質。
對於多種化合物而言,在Mettler FP62設備上在開放毛細管中測定熔點。以每分鐘3或10℃之溫度梯度量測熔點。最大溫度為300℃。自數位顯示器讀取熔點且其係以通常與此分析方法有關之實驗不確定性獲得。
在分別於400及500MHz下操作之Bruker DPX400或Bruker AV-500質譜儀上記錄1H NMR譜。所有報導之化學位移(δ)相對於四甲基矽烷以ppm表示。
表1列出根據上述實例中之一者製備的式(I)化合物。
表2:
本發明所提供之化合物為mGluR2之正向異位調節劑。此等化合物看似藉由與別位位點而非麩胺酸鹽結合位點結合來加強麩胺酸鹽反應。當存在式(I)化合物時,mGluR2對麩胺酸鹽濃度之反應增加。預期式(I)化合物藉助於其增強受體功能之能力對mGluR2具有實質上作用。正向異位調節劑之行為在mGluR2處使用下文所述之[35S]GTPγS結合檢定法測試,且其適於識別該等化合物,且更特定言之如表3所示之式(I)化合物。
[35S]GTPγS結合檢定為用於研究G-蛋白偶聯受體(GPCR)功能之基於膜之功能性檢定,藉此量測不可水解形式之GTP,[35S]GTPγS(以γ發射35S標記之鳥苷5'-三磷酸)的併入。G蛋白α子單位催化鳥苷5'-二磷酸(GDP)交換轉換為鳥苷三磷酸(GTP),且在激動劑活化GPCR時,[35S]GTPγS併入且不能裂解以繼續交換循環(Harper(1998)Current Protocols in Pharmacology 2.6.1-10,John Wiley & Sons,Inc.)。放射活
性[35S]GTPγS併入之量為G蛋白活性之直接量度且因此可測定激動劑之活性。MGluR2受體經展示較佳與GαI蛋白偶聯(此方法之較佳偶聯),且其因此廣泛用於研究mGluR2受體在重組細胞系及組織中之受體活化(Schaffhauser等人2003,Pinkerton等人,2004,Mutel等人(1998)Journal of Neurochemistry.71:2558-64;Schaffhauser等人(1998)Molecular Pharmacology 53:228-33)。本文描述使用來自以人類mGluR2受體轉染且根據Schaffhauser等人((2003)Molecular Pharmacology 4:798-810)修改之細胞之膜的[35S]GTPγS結合檢定之用途,其係用於偵測本發明化合物之正向別位調節(PAM)特性。
將CHO細胞培養至預融合且以5mM丁酸鹽刺激24小時,隨後在PBS中洗滌,且接著藉由在均質緩衝液(50mM Tris-HCl緩衝液,pH 7.4,4℃)中刮擦來收集。使用ultra-turrax均質器將細胞溶胞物簡單均質化(15秒)。將均質物在23 500 x g下離心10分鐘且將上清液丟棄。將離心塊再懸浮於5mM Tris-HCl,pH 7.4中且再次離心(30 000 x g,20min,4℃)。將最終之離心塊再懸浮於50mM HEPES,pH 7.4中且在使用前以適當等分試樣儲存於-80℃下。以牛血清白蛋白作為標準,藉由Bradford法(Bio-Rad,USA)測定蛋白質濃度。
含有人類mGluR2之膜中測試化合物的mGluR2正向異位調節活性之量測係使用冷凍膜進行,將該等膜在96孔微孔培養盤中(每檢定孔15μg,30分鐘,30℃)在檢定緩衝液(50mM HEPES pH 7.4,100mM NaCl,3mM MgCl2,50μM GDP,10μg/ml皂素)中預培育之前解凍且簡單均質化,其中正向異位調節劑之濃度增加(0.3nM至50μM)且麩胺酸鹽為預定最小濃度(PAM檢定)或不添加麩胺酸鹽。對於PAM檢定而言,將膜以EC25濃度下之麩胺酸鹽根據公開資料(Pin等人,(1999)Eur.J.
Pharmacol.375:277-294)預培育,亦即產生25%最大反應麩胺酸鹽之濃度。添加[35S]GTPγS(0.1nM,f.c.)實現200μl之總反應體積後,將微孔培養盤簡單振盪且進一步培育使活化時發生[35S]GTPγS併入(30分鐘,30℃)。藉由使用96孔培養盤細胞採集器(Filtermate,Perkin-Elmer,USA)經玻璃纖維過濾盤(Unifilter 96-孔GF/B過濾盤,Perkin-Elmer,Downers Grove,USA)微孔培養盤迅速真空過濾,且接著以300μl冰冷洗滌緩衝液(Na2PO4.2H2O 10mM,NaH2PO4.H2O 10mM,pH=7.4)洗滌3次使反應停止。接著將過濾器風乾,且向各孔中添加40μl液體閃爍混合液(Microscint-O),且在96孔閃爍培養盤讀取器(Top-Count,Perkin-Elmer,USA)中量測膜結合之[35S]GTPγS。在10μM冷GTP存在下測定非特異性[35S]GTPγS結合。每資料點使用雙重樣本且在11個濃度下將各曲線至少進行一次。
在所添加mGluR2激動劑麩胺酸鹽之EC25存在下測定正向別位調節(PAM)之代表性本發明化合物之濃度反應曲線係使用Prism GraphPad軟體(Graph Pad Inc,San Diego,USA)產生。將曲線與允許測定EC50值之四參數邏輯斯蒂等式(four-parameter logistic equation)(Y=底部+(頂部-底部)/(1+10^((LogEC50-X)×坡度)擬合。EC50為引起麩胺酸鹽反應之最大增強之一半的化合物濃度。此係藉由自不存在正向異位調節劑之狀況下的麩胺酸鹽反應減去存在完全飽和濃度之正向異位調節劑狀況下的最大麩胺酸鹽反應來計算。接著計算產生最大作用之一半的濃度作為EC50。
表3:本發明化合物之藥理學資料。所有化合物係在mGluR2激動劑存在下,在預定EC25濃度之麩胺酸鹽下測試,以測定正向別位調節(GTPγS-PAM)。所展示之值為至少一個實驗的11個濃度反應曲線之雙重複值的平均值。所有測試化合物展
示大於5.0,6.05至7.20的pEC50(-logEC50)值。估算單個實驗之pEC50值的測定誤差為約0.3對數單位。
nd=未測定
全部此等實例中所使用之"活性成份"係關於式(I)之最終化合物,其醫藥學上可接受之鹽,其溶劑合物及立體化學異構形式。
本發明調配物之處方的典型實例如下:
在此實例中,活性成份可置換為相同量之本發明化合物中之任一者,尤其相同量之例示化合物中之任一者。
製備用於口服投與之水性懸浮液,使得每1mL含有1至5mg活性化合物中之一者,50mg羧甲基纖維素鈉,1mg苯甲酸鈉,500mg山梨糖醇及水(添加至1ml)。
藉由在水中之10體積%丙二醇中攪拌1.5重量%本發明之活性成份來製備非經腸組合物。
在此實例中,活性成份可置換為相同量之本發明化合物之任一者,尤其相同量之例示化合物中之任一者。
不認為合理變化悖離本發明之範疇。顯然,因此所描述之本發明可由彼等熟習此項技術者以許多方式變化。
Claims (17)
- 一種下式化合物:
- 一種醫藥組合物,其包含治療有效量之如請求項1之化合物及醫藥學上可接受之載劑或賦形劑。
- 如請求項1之化合物,其係用作藥物。
- 一種如請求項1之化合物或如請求項2之醫藥組合物的用途,其係用於製造用以治療或預防包括人類之哺乳動物之病況的藥物,該治療或預防受到mGluR2正向異位調節劑之神經調節作用的影響或促進。
- 一種如請求項1之化合物或如請求項2之醫藥組合物的用途,其係用於製造用以治療或預防中樞神經系統病症之藥物,該病症係選自焦慮症、精神病症、人格障礙、物質關聯性病症、飲食障礙、情緒障礙、偏頭痛、癲癇症或抽搐症、兒童期病症、認知障礙、神經退化、神經毒性及局部缺血之群。
- 如請求項5之用途,其中該中樞神經系統病症為選自空曠恐懼症、泛焦慮症(GAD)、強迫症(OCD)、恐慌症、創傷後症候群(PTSD)、社交恐懼症及其他恐懼症之群的焦慮症。
- 如請求項5之用途,其中該中樞神經系統病症為選自精神分裂症、妄想症、分裂情感性精神障礙、類精神分裂症精神障礙及物質誘發之精神病症之群的精神病症。
- 如請求項5之用途,其中該中樞神經系統病症為選自強迫性人格 障礙及精神分裂症、分裂型障礙之群的人格障礙。
- 如請求項5之用途,其中該中樞神經系統病症為選自酒精濫用、酒精依賴、酒精戒斷、酒精戒斷性譫妄、酒精誘發之精神病症、安非他命依賴、安非他命戒斷、古柯鹼依賴、古柯鹼戒斷、菸鹼依賴、菸鹼戒斷、類鴉片依賴及類鴉片戒斷之群的物質關聯性病症。
- 如請求項5之用途,其中該中樞神經系統病症為選自神經性厭食症及神經性貪食症之群的飲食障礙。
- 如請求項5之用途,其中該中樞神經系統病症為選自雙極症(I及II)、循環情感性精神障礙、抑鬱、低落性情感障礙、重性抑鬱症及物質誘發之情緒障礙之群的情緒障礙。
- 如請求項5之用途,其中該中樞神經系統病症為偏頭痛。
- 如請求項5之用途,其中該中樞神經系統病症為選自全身性非驚厥性癲癇、全身性驚厥性癲癇、失神性癲癇持續狀態、大癲癇持續狀態、伴隨或不伴隨意識缺損之部分性癲癇、嬰兒痙攣症、部分性癲癇持續狀態及其他形式之癲癇之群的癲癇症或抽搐症。
- 如請求項5之用途,其中該兒童期病症為注意力缺陷/過動症。
- 如請求項5之用途,其中該中樞神經系統病症為選自譫妄、物質誘發之持續譫妄、癡呆、HIV疾病引起之癡呆、亨廷頓氏症引發之癡呆、帕金森氏症引發之癡呆、阿茲海默氏型癡呆、物質誘發之持續性癡呆及輕度認知缺損之群的認知障礙。
- 如請求項5之用途,其中該中樞神經系統病症係選自焦慮、精神分裂症、偏頭痛、抑鬱及癲癇症之群。
- 一種如請求項1之化合物的用途,其與mGluR2之鄰位激動劑組合用於製造用以治療或預防如請求4至16中任一項所述之病況的藥物。
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Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0420722D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
AR059898A1 (es) | 2006-03-15 | 2008-05-07 | Janssen Pharmaceutica Nv | Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2 |
TW200900065A (en) | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
CN101801930B (zh) | 2007-09-14 | 2013-01-30 | 奥梅-杨森制药有限公司 | 1,3-二取代的-4-苯基-1h-吡啶-2-酮 |
BRPI0816767B8 (pt) | 2007-09-14 | 2021-05-25 | Addex Pharmaceuticals Sa | composto 4-fenil-3,4,5,6-tetra-hidro-2h,1'h-[1,4']bipiridi¬nil-2'-onas 1',3'-dissubstituídas, composição farmacêutica e uso dos mesmos |
AU2008297876B2 (en) | 2007-09-14 | 2011-07-07 | Addex Pharma S.A. | 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones |
ES2637794T3 (es) | 2007-11-14 | 2017-10-17 | Janssen Pharmaceuticals, Inc. | Derivados de imidazo[1,2-A]piridina y su uso como moduladores alostéricos positivos de receptores MGLUR2 |
AU2009289784B2 (en) | 2008-09-02 | 2012-03-22 | Addex Pharma S.A. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
WO2010043396A1 (en) | 2008-10-16 | 2010-04-22 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc. | Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors |
WO2010060589A1 (en) | 2008-11-28 | 2010-06-03 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc. | Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors |
US8946205B2 (en) | 2009-05-12 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
MY161325A (en) | 2009-05-12 | 2017-04-14 | Janssen Pharmaceuticals Inc | 1, 2, 4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders |
MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
WO2011149822A1 (en) | 2010-05-26 | 2011-12-01 | Boehringer Ingelheim International Gmbh | 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives |
CN103261195B (zh) | 2010-11-08 | 2015-09-02 | 杨森制药公司 | 1,2,4-三唑并[4,3-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途 |
AU2011328203B2 (en) | 2010-11-08 | 2015-03-19 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
PL2649069T3 (pl) | 2010-11-08 | 2016-01-29 | Janssen Pharmaceuticals Inc | Pochodne 1,2,4-triazolo[4,3-a]pirydyny i ich zastosowanie jako dodatnich allosterycznych modulatorów receptorów mGluR2 |
JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
JO3367B1 (ar) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2 |
UA121965C2 (uk) | 2014-01-21 | 2020-08-25 | Янссен Фармацевтика Нв | Комбінації, які містять позитивні алостеричні модулятори або ортостеричні агоністи метаботропного глутаматергічного рецептора 2 підтипу, та їх застосування |
KR102461134B1 (ko) * | 2014-01-21 | 2022-10-28 | 얀센 파마슈티카 엔.브이. | 대사 조절형 글루탐산 작동성 수용체 제2아형의 양성 알로스테릭 조절제 또는 오르토스테릭 작동제를 포함하는 조합 및 그 용도 |
TW201600522A (zh) * | 2014-02-20 | 2016-01-01 | 赫孚孟拉羅股份公司 | 螺-唑酮 |
RU2695651C2 (ru) * | 2014-12-11 | 2019-07-25 | Янссен Фармацевтика Нв | 1,2,4-ТРИАЗОЛО[4,3-a]ПИРИДИНОВЫЕ СОЕДИНЕНИЯ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ПОЛОЖИТЕЛЬНЫХ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ РЕЦЕПТОРОВ MGLUR2 |
Family Cites Families (464)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2976146A (en) | 1958-11-28 | 1961-03-21 | Eastman Kodak Co | Novel cyan-forming couplers |
BE790440A (zh) | 1971-10-23 | 1973-04-24 | Bayer Ag | |
JPS538707B2 (zh) | 1974-02-05 | 1978-03-31 | ||
JPS50106981U (zh) | 1974-02-08 | 1975-09-02 | ||
US3906953A (en) | 1974-05-23 | 1975-09-23 | American Optical Corp | Endoscopic surgical laser system |
SU509578A1 (ru) | 1974-09-19 | 1976-04-05 | Стерлитамакский Химический Завод | Способ получени пропилендиаминов |
IE43079B1 (en) * | 1975-03-20 | 1980-12-17 | Ici Ltd | Quinolone derivatives |
GB1502312A (en) | 1975-03-20 | 1978-03-01 | Ici Ltd | Quinolone derivatives |
FR2311776A1 (fr) * | 1975-05-23 | 1976-12-17 | Sogeras | Diamino-2,4 bromo-5 chloro-6 pyrimidines et procede pour leur preparation |
GB1570494A (en) * | 1975-11-28 | 1980-07-02 | Ici Ltd | Thienopyrimidine derivatives and their use as pesticides |
JPS5382783U (zh) | 1976-12-13 | 1978-07-08 | ||
JPS5382783A (en) | 1976-12-29 | 1978-07-21 | Yamanouchi Pharmaceut Co Ltd | Novel pyridone derivs and process for their preparation |
JPS5752334Y2 (zh) | 1977-03-16 | 1982-11-13 | ||
ZA782648B (en) * | 1977-05-23 | 1979-06-27 | Ici Australia Ltd | The prevention,control or eradication of infestations of ixodid ticks |
DE2750288A1 (de) * | 1977-11-10 | 1979-05-17 | Thomae Gmbh Dr K | Neue 9-(omega-heteroarylamino- alkylamino)-erythromycine, ihre salze, verfahren zu ihrer herstellung und diese enthaltende arzneimittel |
JPS6057300B2 (ja) | 1980-09-11 | 1985-12-14 | 株式会社東芝 | 超電導コイル間のエネルギ転送装置 |
US4432979A (en) | 1981-10-26 | 1984-02-21 | William H. Rorer, Inc. | Pyridone compounds |
EP0082023A3 (en) | 1981-12-16 | 1983-07-20 | Sankyo Company Limited | Thienopyrimidine derivatives, their preparation and their medical use |
US4358453A (en) * | 1982-01-08 | 1982-11-09 | Schering Corporation | 1,2,4-Triazolo[4,3-a]pyridines |
US4520025A (en) | 1982-07-21 | 1985-05-28 | William H. Rorer, Inc. | Bicyclic nitrogen heterocyclic ethers and thioethers, and their pharmaceutical uses |
DE3406329A1 (de) | 1984-02-22 | 1985-08-22 | Merck Patent Gmbh, 6100 Darmstadt | Pyridone |
US4550166A (en) * | 1984-05-21 | 1985-10-29 | American Cyanamid Company | (Pyridinyl)-1,2,4-triazolo[4,3-a]pyridines |
DE3717561A1 (de) | 1987-05-25 | 1988-12-08 | Thomae Gmbh Dr K | Indol-, isochinolin- und benzazepinderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
US5175157A (en) * | 1985-11-27 | 1992-12-29 | Boehringer Ingelheim Gmbh | Cyclic amine derivatives, pharmaceutical compositions containing these compounds and methods for preparing them |
US4866074A (en) * | 1987-05-08 | 1989-09-12 | Rorer Pharmaceutical Corporation | Naphtheridinone- and pyridooxazinone-pyridone compounds, cardiotonic compositions including same, and their uses |
EP0308020A3 (en) | 1987-09-18 | 1990-12-05 | Merck & Co. Inc. | 5-(aryl and heteroaryl)-6-(aryl and heteroaryl)-1,2-dihydro-2-oxo 3-pyridinecarboxylic acids and derivatives thereof |
US5260293A (en) * | 1988-01-30 | 1993-11-09 | Merck Sharp & Dohme Limited | Pyrazines, pyrimidines and pyridazines useful in the treatment of senile dementia |
GB8804448D0 (en) | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
JP2614081B2 (ja) * | 1988-05-27 | 1997-05-28 | 大塚化学株式会社 | 光学活性β−ラクタム誘導体の製造法 |
JPH02124871A (ja) | 1988-07-27 | 1990-05-14 | Dainippon Pharmaceut Co Ltd | 1位が置換された複素環式カルボン酸アミド誘導体 |
DE68923527D1 (de) | 1988-10-20 | 1995-08-24 | Sandoz Ag | Faserreaktive Azofarbstoffe. |
US5032602A (en) * | 1988-12-14 | 1991-07-16 | Bayer Aktiengesellschaft | Inhibiting HMG-CoA reductase with novel substituted 2-pyridones and pyrid-2-thiones |
HU206337B (en) | 1988-12-29 | 1992-10-28 | Mitsui Petrochemical Ind | Process for producing pyrimidine derivatives and pharmaceutical compositions |
JPH02277044A (ja) | 1989-04-19 | 1990-11-13 | Fuji Photo Film Co Ltd | ハロゲン化銀写真感光材料 |
US5236917A (en) * | 1989-05-04 | 1993-08-17 | Sterling Winthrop Inc. | Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
US5280026A (en) * | 1989-05-30 | 1994-01-18 | Smithkline Beecham Intercredit B.V. | Thienopyrimidines |
AU622330B2 (en) * | 1989-06-23 | 1992-04-02 | Takeda Chemical Industries Ltd. | Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides |
US4978663A (en) * | 1989-08-16 | 1990-12-18 | Hoechst-Roussel Pharmaceuticals Inc. | 5-(1-aminocyclohexyl)-2(1H)-pyridinone compounds which have pharmaceutical utility |
GB8926560D0 (en) | 1989-11-24 | 1990-01-17 | Zambeletti Spa L | Pharmaceuticals |
IL96432A0 (en) | 1989-11-30 | 1991-08-16 | Schering Ag | Pesticidal compositions containing pyridine derivatives and novel pyridine derivatives |
DE3940480A1 (de) * | 1989-12-07 | 1991-06-13 | Bayer Ag | Chromogene enaminverbindungen, ihre herstellung und verwendung als farbbildner |
AU6979091A (en) | 1989-12-22 | 1991-07-24 | Upjohn Company, The | Pyridinones useful as antiatherosclerotic agents |
FR2657610A1 (fr) | 1990-01-29 | 1991-08-02 | Rhone Poulenc Agrochimie | Triazolopyridines herbicides. |
GB9104238D0 (en) | 1990-03-16 | 1991-04-17 | Ici Pharma | 3-tetrazolylthiomethyl cephalosporin antibiotics |
DE4008726A1 (de) | 1990-03-19 | 1991-09-26 | Basf Ag | Thieno(2,3-d)pyrimidinderivate |
EP0452002A3 (en) | 1990-03-30 | 1992-02-26 | Dowelanco | Thienopyrimidine derivatives |
RU1796625C (ru) | 1990-06-27 | 1993-02-23 | Киевский Государственный Университет Им.Т.Г.Шевченко | 3-Амино-7-нитро-4(2,3,4-триметоксифенил)-2-фенил-1(2Н)изохинолон, обладающий аналептическим действием |
EP0478195B1 (en) | 1990-09-21 | 1999-05-26 | Rohm And Haas Company | Dihydropyridazinones and pyridazinones as fungicides |
KR920008026A (ko) | 1990-10-24 | 1992-05-27 | 오노 화아마슈티칼 캄파니 리미팃드 | 이소퀴놀리논 유도체 또는 이의 무독성 산부가염 또는 이의 수화물, 이의 제조방법 및 이를 포함하는 약제 조성물 |
AU1532492A (en) | 1991-04-18 | 1992-11-17 | Dr. Lo Zambeletti S.P.A. | Use of heterocyclic compounds for the treatment of inflammatory pain |
DE4122240A1 (de) | 1991-07-05 | 1993-01-07 | Boehringer Mannheim Gmbh | Dibenz(b,e)azepinderivate und diese enthaltende arzneimittel |
US5332750A (en) * | 1991-09-04 | 1994-07-26 | Merck Patent Gesellschaft Mit Beschrankter Haftung | 1,2-dihydro-2-oxopyridines |
DE4129340A1 (de) | 1991-09-04 | 1993-03-11 | Merck Patent Gmbh | 1,2-dihydro-2-oxopyridine |
DE4131924A1 (de) * | 1991-09-25 | 1993-07-08 | Hoechst Ag | Substituierte 4-alkoxypyrimidine, verfahren zu ihrer herstellung und ihre verwendung als schaedlingsbekaempfungsmittel |
US5204198A (en) * | 1991-10-28 | 1993-04-20 | Eastman Kodak Company | Photoelectrographic elements utilizing nonionic sulfonic acid photogenerators |
US5416099A (en) | 1991-10-29 | 1995-05-16 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
DE4221583A1 (de) | 1991-11-12 | 1993-05-13 | Bayer Ag | Substituierte biphenylpyridone |
JP2878531B2 (ja) * | 1991-12-16 | 1999-04-05 | 富士写真フイルム株式会社 | ハロゲン化銀写真感光材料 |
US5378720A (en) | 1991-12-19 | 1995-01-03 | Sterling Winthrop Inc. | Saccharin derivative proteolytic enzyme inhibitors |
AU668694B2 (en) | 1991-12-19 | 1996-05-16 | Sanofi-Synthelabo | Saccharin derivative proteolytic enzyme inhibitors |
TW219935B (zh) | 1991-12-25 | 1994-02-01 | Mitsubishi Chemicals Co Ltd | |
GB9200293D0 (en) | 1992-01-08 | 1992-02-26 | Wyeth John & Brother Ltd | Piperazine derivatives |
GB9201694D0 (en) | 1992-01-27 | 1992-03-11 | Smithkline Beecham Intercredit | Compounds |
JPH05204071A (ja) | 1992-01-29 | 1993-08-13 | Konica Corp | ハロゲン化銀写真感光材料 |
JP3042156B2 (ja) | 1992-02-20 | 2000-05-15 | 田辺製薬株式会社 | ナフタレン誘導体、その製法及びその合成中間体 |
DE4206045A1 (de) * | 1992-02-27 | 1993-09-02 | Bayer Ag | Sulfonylbenzyl substituierte pyridone |
US5922773A (en) * | 1992-12-04 | 1999-07-13 | The Children's Medical Center Corp. | Glaucoma treatment |
AU660132B2 (en) * | 1992-12-21 | 1995-06-08 | Bayer Aktiengesellschaft | Substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxypyridine |
JPH06211798A (ja) | 1993-01-19 | 1994-08-02 | Tosoh Corp | テトラヒドロイソキノリノン誘導体及びその製造方法 |
JPH06211797A (ja) | 1993-01-19 | 1994-08-02 | Tosoh Corp | テトラヒドロイソキノリン誘導体、その製法及び抗真菌剤 |
SE9300657D0 (sv) | 1993-02-26 | 1993-02-26 | Astra Ab | New compounds |
US5814645A (en) * | 1993-03-24 | 1998-09-29 | Bayer Aktiengesellschaft | Arylor hetaryl substituted nitrogen heterocycles and their use as pesticides |
DE4316077A1 (de) * | 1993-05-13 | 1994-11-17 | Bayer Ag | Substituierte Mono- und Bihydridylmethylpyridone |
WO1994029273A1 (en) | 1993-06-09 | 1994-12-22 | Smithkline Beecham Corporation | Bicyclic fibrinogen antagonists |
DE4326758A1 (de) | 1993-08-10 | 1995-02-16 | Basf Ag | [1,3,4]Triazolo[1,5-a]pyridine |
JPH07101861A (ja) | 1993-08-10 | 1995-04-18 | Tanabe Seiyaku Co Ltd | 抗喘息薬 |
PL181385B1 (pl) | 1993-08-19 | 2001-07-31 | Janssen Pharmaceutica Nv | Nowe pochodne dihydrobenzopiranu o wlasciwosciach naczyniozwezajacych, kompozycja farmaceutyczna i sposób wytwarzania pochodnych dihydrobenzopiranu PL PL PL PL PL PL |
KR100345046B1 (ko) | 1993-08-19 | 2002-12-05 | 얀센 파마슈티카 엔.브이. | 혈관수축성치환된아릴옥시알킬디아민 |
AU7467294A (en) | 1993-08-20 | 1995-03-21 | Banyu Pharmaceutical Co., Ltd. | Tyrosine kinase inhibitor |
JP3701984B2 (ja) | 1993-08-31 | 2005-10-05 | サントリー株式会社 | ラベル化シクロプロパン誘導体およびその製造方法 |
US5424435A (en) | 1993-10-18 | 1995-06-13 | Olin Corporation | 1-hydroxy-6-substituted-2-pyridones |
US5500420A (en) * | 1993-12-20 | 1996-03-19 | Cornell Research Foundation, Inc. | Metabotropic glutamate receptor agonists in the treatment of cerebral ischemia |
US5679683A (en) * | 1994-01-25 | 1997-10-21 | Warner-Lambert Company | Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
CA2185104A1 (en) | 1994-03-10 | 1995-09-14 | Kiyoshi Taniguchi | Naphthalene derivatives as prostaglandin 12 agonists |
ES2079323B1 (es) | 1994-06-21 | 1996-10-16 | Vita Invest Sa | Derivados de indol utiles para el tratamiento de la migraña, composicion y uso correspondientes. |
GB9416554D0 (en) | 1994-08-19 | 1994-10-12 | Ciba Geigy Ag | Glutamate receptor |
JPH10504569A (ja) | 1994-08-24 | 1998-05-06 | イーライ・リリー・アンド・カンパニー | 向代謝性グルタメート受容体拮抗剤としてのピロリジニルジカルボン酸誘導体 |
US5473077A (en) * | 1994-11-14 | 1995-12-05 | Eli Lilly And Company | Pyrrolidinyl di-carboxylic acid derivatives as metabotropic glutamate receptor agonists |
US6017697A (en) | 1994-11-14 | 2000-01-25 | Eli Lilly And Company | Excitatory amino acid receptor protein and related nucleic acid compounds |
US5512576A (en) * | 1994-12-02 | 1996-04-30 | Sterling Winthrop Inc. | 2-substituted 1,2,5,-thiadiazolidin-3-one 1,1-dioxides and compositions and method of use thereof |
US5789426A (en) | 1995-01-20 | 1998-08-04 | Cornell Research Foundation, Inc. | Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation |
US5869486A (en) | 1995-02-24 | 1999-02-09 | Ono Pharmaceutical Co., Ltd. | Fused pyrimidines and pyriazines as pharmaceutical compounds |
DE19507522C2 (de) | 1995-03-03 | 2003-05-28 | Basf Ag | Verfahren zur Herstellung von 3,4-Dihydroisochinolinverbindungen und 3,4-Dihydroisochinolinium-Salzen |
US5869428A (en) * | 1995-03-13 | 1999-02-09 | Ishihara Sangyo Kaisha Ltd. | Pyridonesulfonylurea compounds, process for their production and herbicides containing them |
DE19510965A1 (de) * | 1995-03-24 | 1996-09-26 | Asta Medica Ag | Neue Pyrido/3,2-e/pyrazinone mit antiasthmatischer Wirksamkeit und Verfahren zu deren Herstellung |
CN1131210C (zh) | 1995-04-27 | 2003-12-17 | 三菱制药株式会社 | 杂环类酰胺化合物及其医药用途 |
JPH08325248A (ja) | 1995-05-26 | 1996-12-10 | Chugoku Kayaku Kk | テトラゾール類の新規な合成試薬及びそれを用いたテトラゾール類の製造方法 |
US5849587A (en) | 1995-06-09 | 1998-12-15 | Cornell Research Foundation, Inc. | Method of inhibiting viral replication in eukaryotic cells and of inducing apoptosis of virally-infected cells |
US5659033A (en) | 1995-09-13 | 1997-08-19 | Neurogen Corporation | N-aminoalkylfluorenecarboxamides; a new class of dopamine receptor subtype specific ligands |
JP3335362B2 (ja) | 1995-09-15 | 2002-10-15 | サノフィ―サンテラボ | キノレイン−2(1h)−オン誘導体セロトニンアンタゴニスト |
JPH1045750A (ja) | 1995-09-20 | 1998-02-17 | Takeda Chem Ind Ltd | アゾール化合物、その製造方法及び用途 |
US6130217A (en) | 1995-09-20 | 2000-10-10 | Pfizer Inc | Compounds enhancing antitumor activity of other cytotoxic agents |
AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
DE69620445T2 (de) | 1995-12-08 | 2002-12-12 | Janssen Pharmaceutica N.V., Beerse | (imidazol-5-yl)methyl-2-chinolinoderivate als farnesyl protein transferase inhibitoren |
AU1608397A (en) | 1996-02-02 | 1997-08-22 | Zeneca Limited | Heterocyclic compounds useful as pharmaceutical agents |
GB9602166D0 (en) | 1996-02-02 | 1996-04-03 | Zeneca Ltd | Aminoheterocyclic derivatives |
GB9602294D0 (en) * | 1996-02-05 | 1996-04-03 | Zeneca Ltd | Heterocyclic compounds |
US6084084A (en) | 1996-02-21 | 2000-07-04 | Nps Pharmaceuticals, Inc. | Human metabotropic glutamate receptor |
US5710274A (en) * | 1996-02-28 | 1998-01-20 | Neurogen Corporation | N-aminoalkyldibenzofurancarboxamides; new dopamine receptor subtype specific ligands |
US5756518A (en) | 1996-04-02 | 1998-05-26 | Kowa Co., Ltd. | Phenylene derivatives |
JPH1029979A (ja) | 1996-04-12 | 1998-02-03 | Ajinomoto Co Inc | 新規ピリジン誘導体 |
WO1997046532A1 (en) | 1996-06-03 | 1997-12-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | 2-benzyl-4-sulfonyl-4h-isoquinolin-1,3-diones and their use as anti-inflammatory agents |
EP0915682B1 (de) | 1996-07-04 | 2003-10-01 | Erbe Elektromedizin GmbH | Gasunterstützte, axial verschiebbare chirurgische elektrode |
AU3783497A (en) | 1996-08-09 | 1998-03-06 | Yamanouchi Pharmaceutical Co., Ltd. | Metabotropic glutamate receptor agonists |
DE19632423A1 (de) * | 1996-08-12 | 1998-02-19 | Merck Patent Gmbh | Thienopyrimidine |
TR199900303T2 (xx) * | 1996-08-14 | 1999-06-21 | Zeneca Limited | �kame edilmi� pirimidin t�revleri ve bunlar�n farmas�tik kullan�m�. |
WO1998011075A1 (en) | 1996-09-16 | 1998-03-19 | Du Pont Pharmaceuticals Company | Pyrazinones and triazinones and their derivatives thereof |
DE19638484A1 (de) | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
DE19638486A1 (de) | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
DE19644228A1 (de) | 1996-10-24 | 1998-04-30 | Merck Patent Gmbh | Thienopyrimidine |
US6284794B1 (en) | 1996-11-05 | 2001-09-04 | Head Explorer Aps | Method for treating tension-type headache with inhibitors of nitric oxide and nitric oxide synthase |
JP2002514196A (ja) | 1996-12-05 | 2002-05-14 | アムジエン・インコーポレーテツド | 置換ピリミジノンおよびピリドン化合物ならびに使用方法 |
AU720451B2 (en) | 1997-01-24 | 2000-06-01 | Conpharma As | Gemcitabine derivatives |
US5855654A (en) * | 1997-01-30 | 1999-01-05 | Rohm And Haas Company | Pyridazinones as marine antifouling agents |
FR2759366B1 (fr) | 1997-02-11 | 1999-04-16 | Centre Nat Rech Scient | Composes constituant notamment des effecteurs de recepteurs du systeme nerveux central sensibles aux amino acides neuroexcitateurs, leur preparation et leurs applications biologiques |
US6262068B1 (en) | 1997-02-21 | 2001-07-17 | Bristol-Myers Squibb Company | Lactam derivatives as antiarrhythmic agents |
WO1998038168A1 (en) | 1997-02-27 | 1998-09-03 | Tanabe Seiyaku Co., Ltd. | Isoquinolinone derivatives, process for preparing the same, and their use as phosphodiesterase inhibitors |
ES2131463B1 (es) | 1997-04-08 | 2000-03-01 | Lilly Sa | Derivados de ciclopropilglicina con propiedades farmaceuticas. |
GB9708945D0 (en) | 1997-05-01 | 1997-06-25 | Merck Sharp & Dohme | Therapeutic agents |
DE19728996A1 (de) | 1997-07-07 | 1999-01-14 | Basf Ag | Triazolverbindungen und deren Verwendung |
US6204292B1 (en) | 1997-07-18 | 2001-03-20 | Georgetown University | Bicyclic metabotropic glutamate receptor ligands |
ATE214704T1 (de) * | 1997-07-18 | 2002-04-15 | Hoffmann La Roche | 5h-thiazolo(3,2-a)pyrimidinderivate |
EP1035848B1 (en) | 1997-07-31 | 2003-04-23 | Celgene Corporation | Substituted alkanohydroxamic acids and method of reducing tnf-alpha levels |
BR9811933A (pt) * | 1997-08-14 | 2000-09-05 | Hoffmann La Roche | Vinil éteres heterocìclicos contra distúrbios neurológicos |
US6358975B1 (en) | 1997-08-15 | 2002-03-19 | Johns Hopkins University | Method of using selective parp inhibitors to prevent or treat neurotoxicity |
US6121278A (en) | 1997-09-03 | 2000-09-19 | Guilford Pharmaceuticals, Inc. | Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity |
WO1999011622A1 (en) | 1997-09-03 | 1999-03-11 | Guilford Pharmaceuticals Inc. | Amino-substituted compounds, methods, and compositions for inhibiting parp activity |
US20020022636A1 (en) | 1997-09-03 | 2002-02-21 | Jia-He Li | Oxo-substituted compounds, process of making, and compositions and methods for inhibiting parp activity |
US6635642B1 (en) | 1997-09-03 | 2003-10-21 | Guilford Pharmaceuticals Inc. | PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same |
US20020028813A1 (en) | 1997-09-03 | 2002-03-07 | Paul F. Jackson | Thioalkyl compounds, methods, and compositions for inhibiting parp activity |
US6197785B1 (en) | 1997-09-03 | 2001-03-06 | Guilford Pharmaceuticals Inc. | Alkoxy-substituted compounds, methods, and compositions for inhibiting PARP activity |
AU9740998A (en) | 1997-09-08 | 1999-03-29 | F. Hoffmann-La Roche Ag | Piperidine derivatives against malaria |
DE69815008T2 (de) | 1997-09-19 | 2004-04-01 | Ssp Co., Ltd. | Alfa-substituierte Phenylpropionsäurederivate und diese enthaltende Arzneimittel |
US6465484B1 (en) | 1997-09-26 | 2002-10-15 | Merck & Co., Inc. | Angiogenesis inhibitors |
US6162804A (en) | 1997-09-26 | 2000-12-19 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
JP2001518470A (ja) | 1997-09-26 | 2001-10-16 | メルク エンド カムパニー インコーポレーテッド | 新規な血管形成阻害剤 |
WO2000012089A1 (en) | 1998-08-31 | 2000-03-09 | Merck & Co., Inc. | Novel angiogenesis inhibitors |
WO1999018096A1 (en) | 1997-10-02 | 1999-04-15 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
NZ504465A (en) | 1997-10-14 | 2001-11-30 | Welfide Corp | 1-Phenylacylamino substituted piperazine derivatives which are 4-substituted by a heteroaryl group |
WO1999021992A2 (en) | 1997-10-23 | 1999-05-06 | Ganimed Pharmaceuticals Gmbh | Nucleic acid molecules encoding a glutamate receptor |
AU1504599A (en) | 1997-12-17 | 1999-07-05 | Shionogi & Co., Ltd. | Novel pyridine compounds |
WO1999031066A1 (en) | 1997-12-18 | 1999-06-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pyridones as src family sh2 domain inhibitors |
US6013672A (en) * | 1997-12-18 | 2000-01-11 | Uab Research Foundation | Agonists of metabotropic glutamate receptors and uses thereof |
ATE389636T1 (de) | 1997-12-19 | 2008-04-15 | Amgen Inc | Substituierte pyridin- und pyridazinderivate und ihre pharmazeutische verwendung |
FR2772763B1 (fr) | 1997-12-24 | 2004-01-23 | Sod Conseils Rech Applic | Nouveaux analogues tetracycliques de camptothecines, leurs procedes de preparation, leur application comme medicaments et les compositions pharmaceutiques les contenant |
IT1298155B1 (it) | 1998-01-19 | 1999-12-20 | Moreno Paolini | Composti pirimidin 3-ossido per il trattamento delle patologie muscolo-scheletriche, in particolare per il trattamento della |
US6664250B2 (en) | 1998-01-20 | 2003-12-16 | Bristol-Myers Squibb Co. | Lactam derivatives as antiarrhythmic agents |
ES2191412T3 (es) | 1998-01-28 | 2003-09-01 | Taisho Pharmaceutical Co Ltd | Derivados de aminoacidos que contienen fluor. |
IL137922A0 (en) | 1998-02-17 | 2001-10-31 | Tularik Inc | Anti-viral pyrimidine derivatives |
NZ506227A (en) | 1998-03-17 | 2003-06-30 | Pfizer Prod Inc | Bicyclo[2.2.1]heptanes and their use in treating neurological and psychiatric disorders |
JP2002511461A (ja) | 1998-04-08 | 2002-04-16 | ノバルティス アクチエンゲゼルシャフト | N−ピリドニル除草剤 |
AU3170099A (en) | 1998-04-16 | 1999-11-08 | Yamanouchi Pharmaceutical Co., Ltd. | Remedies for obesity |
EP0955301A3 (en) | 1998-04-27 | 2001-04-18 | Pfizer Products Inc. | 7-aza-bicyclo[2.2.1]-heptane derivatives, their preparation and use according to their affinity for neuronal nicotinic acetylcholine receptors |
DE19822198C2 (de) | 1998-05-16 | 2003-02-13 | Wella Ag | Oxonolfarbstoffe enthaltende Mittel und Verfahren zur Erzeugung von semipermanenten Färbungen auf Haaren |
JP2002517396A (ja) | 1998-06-04 | 2002-06-18 | アボット・ラボラトリーズ | 細胞接着阻害抗炎症性化合物 |
DE19826671A1 (de) | 1998-06-16 | 1999-12-23 | Hoechst Schering Agrevo Gmbh | 1,3-Oxazolin- und 1,3-Thiazolin-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Schädlingsbekämpfungsmittel |
FR2781218B1 (fr) | 1998-07-15 | 2001-09-07 | Lafon Labor | Compositions pharmaceutiques comprenant des 2-quinolones |
JP2000072751A (ja) | 1998-08-26 | 2000-03-07 | Tanabe Seiyaku Co Ltd | イソキノリノン誘導体 |
CN1247527C (zh) | 1998-08-31 | 2006-03-29 | 大正制药株式会社 | 6-氟双环[3.1.0]己烷衍生物 |
JP2000072731A (ja) | 1998-08-31 | 2000-03-07 | Taisho Pharmaceut Co Ltd | 4−置換−2−アミノビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸誘導体及び製薬用組成物 |
CH694053A5 (de) | 1998-09-03 | 2004-06-30 | Hoffmann La Roche | Verfahren zur Herstellung von 2-Amino-bicyclo[3.1.0]hexan-2,6-dicarbonsäure-Derivaten. |
US6284759B1 (en) | 1998-09-30 | 2001-09-04 | Neurogen Corporation | 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands |
SE9803518D0 (sv) | 1998-10-15 | 1998-10-15 | Astra Pharma Prod | Novel compounds |
PE20001236A1 (es) | 1998-11-13 | 2000-11-10 | Lilly Co Eli | Moduladores del receptor de aminoacidos excitadores |
US6133271A (en) * | 1998-11-19 | 2000-10-17 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives |
US5948911A (en) * | 1998-11-20 | 1999-09-07 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells and related conditions by exposure to thienopyrimidine derivatives |
EP1006112A1 (en) | 1998-12-01 | 2000-06-07 | Cerebrus Pharmaceuticals Limited | 3-Hydroxy-2(1H)-pyridinone or 3-hydroxy-4(1H)-pyridinone derivatives useful as reactive oxygen species (ROS) scavengers |
AU755202B2 (en) | 1998-12-04 | 2002-12-05 | Bristol-Myers Squibb Company | 3-substituted-4-arylquinolin-2-one derivatives as potassium channel modulators |
US6575913B1 (en) | 1999-02-01 | 2003-06-10 | A.C. Cossor & Son (Surgical) Limited | Relating to sphygmometers |
LU90358B1 (fr) | 1999-03-01 | 2000-09-05 | Iee Sarl | Dispositif pour arr-ter le d-loiement d'un airbag dans un v-hicule |
US6245759B1 (en) | 1999-03-11 | 2001-06-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
TW564247B (en) | 1999-04-08 | 2003-12-01 | Akzo Nobel Nv | Bicyclic heteraromatic compound |
GB9908175D0 (en) | 1999-04-09 | 1999-06-02 | Lilly Co Eli | Method of treating neurological disorders |
US6723711B2 (en) | 1999-05-07 | 2004-04-20 | Texas Biotechnology Corporation | Propanoic acid derivatives that inhibit the binding of integrins to their receptors |
US6972296B2 (en) | 1999-05-07 | 2005-12-06 | Encysive Pharmaceuticals Inc. | Carboxylic acid derivatives that inhibit the binding of integrins to their receptors |
AU4797400A (en) | 1999-05-17 | 2000-12-05 | Eli Lilly And Company | Metabotropic glutamate receptor antagonists |
NO313534B1 (no) | 1999-06-01 | 2002-10-21 | Hanne Storm | Apparat og fremgangsmåte for overvåkning og fremgangsmåte for styring av et varselsignal |
CH1196397H1 (de) | 1999-06-02 | 2007-05-31 | Nps Pharma Inc | Metabotrope Glutamatrezeptorantagonisten zur Behandlung von Krankheiten des zentralen Nervensystems. |
US6498180B1 (en) | 1999-06-03 | 2002-12-24 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
CA2390948A1 (en) | 1999-06-03 | 2000-12-14 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
JP4783967B2 (ja) | 1999-07-21 | 2011-09-28 | 大正製薬株式会社 | 含フッ素アミノ酸誘導体を有効成分とする医薬 |
AU6420700A (en) | 1999-08-05 | 2001-03-05 | Prescient Neuropharma Inc. | Novel 1,4-benzodiazepine compounds and derivatives thereof |
US6660753B2 (en) | 1999-08-19 | 2003-12-09 | Nps Pharmaceuticals, Inc. | Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists |
US7040838B2 (en) | 1999-08-27 | 2006-05-09 | Kristar Enterprises, Inc. | High capacity catch basin filtration system with adjustable deflector ring |
CN2390948Y (zh) | 1999-09-17 | 2000-08-09 | 徐平武 | 混凝土屋顶、楼面施工金属组合专用模具 |
CN1195522C (zh) | 1999-10-15 | 2005-04-06 | 弗·哈夫曼-拉罗切有限公司 | 苯并二氮杂䓬衍生物 |
KR100481386B1 (ko) | 1999-10-15 | 2005-04-08 | 에프. 호프만-라 로슈 아게 | 벤조디아제핀 유도체 |
MXPA02003887A (es) | 1999-10-19 | 2002-09-30 | Merck & Co Inc | Inhibidores de tirosina cinasa. |
EP1230225A2 (en) | 1999-11-01 | 2002-08-14 | Eli Lilly And Company | Pharmaceutically active 4-substituted pyrimidine derivatives |
GB2355982A (en) | 1999-11-03 | 2001-05-09 | Lilly Co Eli | Heterocyclic amino acids |
WO2001046190A1 (fr) | 1999-12-22 | 2001-06-28 | Kyorin Pharmaceutical Co., Ltd. | Composes tricycliques et sels d'addition de ceux-ci |
CN1395575A (zh) | 2000-01-20 | 2003-02-05 | 卫材株式会社 | 新的哌啶化合物及其药物 |
GB0002100D0 (en) | 2000-01-28 | 2000-03-22 | Novartis Ag | Organic compounds |
US6800651B2 (en) | 2000-02-03 | 2004-10-05 | Eli Lilly And Company | Potentiators of glutamate receptors |
RU2277911C2 (ru) | 2000-02-25 | 2006-06-20 | Ф.Хоффманн-Ля Рош Аг | Модуляторы аденозиновых рецепторов |
DE10012373A1 (de) | 2000-03-14 | 2001-09-20 | Dresden Arzneimittel | Verwendung von Pyrido[3,2-e]-pyrazinonen als Inhibitoren der Phosphodiesterase 5 zur Therapie von erektiler Dysfunktion |
GB0007108D0 (en) | 2000-03-23 | 2000-05-17 | Novartis Ag | Organic compounds |
EP1268432A1 (en) | 2000-03-24 | 2003-01-02 | Millenium Pharmaceuticals, Inc. | ISOQUINOLONE INHIBITORS OF FACTOR Xa |
GB0007193D0 (en) | 2000-03-25 | 2000-05-17 | Univ Manchester | Treatment of movrmrnt disorders |
US6403588B1 (en) | 2000-04-27 | 2002-06-11 | Yamanouchi Pharmaceutical Co., Ltd. | Imidazopyridine derivatives |
AU2001252609A1 (en) | 2000-04-27 | 2001-11-12 | Imperial Cancer Research Technology Ltd. | Imidazopyridine derivatives |
AU4882101A (en) | 2000-04-28 | 2001-11-12 | Shionogi & Co., Ltd. | Mmp-12 inhibitors |
CN1209336C (zh) | 2000-04-28 | 2005-07-06 | 日本农药株式会社 | 生产2-卤代苯甲酸的方法 |
US20020009713A1 (en) | 2000-05-11 | 2002-01-24 | Miller Freda D. | Methods for identifying modulators of neuronal growth |
NZ522674A (en) | 2000-05-11 | 2004-10-29 | Kenneth Curry | Novel spiro[2.4]heptane amino carboxy compounds and derivatives thereof |
WO2001085716A1 (en) | 2000-05-11 | 2001-11-15 | Kyowa Hakko Kogyo Co., Ltd | 2-piperidone compounds for the treatment of cancer |
US7081481B2 (en) | 2000-05-31 | 2006-07-25 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
KR100850728B1 (ko) * | 2000-06-12 | 2008-08-06 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 1,2-디하이드로피리딘 화합물, 그의 제조 방법 및 그의 용도 |
JP2002003401A (ja) | 2000-06-27 | 2002-01-09 | Japan Science & Technology Corp | 脳由来神経栄養因子誘導剤 |
CA2413747A1 (en) | 2000-06-27 | 2002-01-03 | Centre National De La Recherche Scientifique | Mammal 2p domain mechano-sensitive k+ channel, cloning and applications thereof |
JP2002012533A (ja) * | 2000-06-27 | 2002-01-15 | Kao Corp | 染毛剤組成物 |
KR20030017562A (ko) | 2000-06-28 | 2003-03-03 | 다이쇼 세이야꾸 가부시끼가이샤 | 신규 디카르복실산 유도체 |
DE10031390A1 (de) | 2000-07-03 | 2002-01-17 | Knoll Ag | Pyrimidinderivate und ihre Verwendung zur Prophylaxe und Therapie der zerebralen Ischämie |
US20020041880A1 (en) * | 2000-07-05 | 2002-04-11 | Defeo-Jones Deborah | Method of treating cancer |
JP2002069057A (ja) | 2000-07-07 | 2002-03-08 | Kyowa Hakko Kogyo Co Ltd | ピペリジン誘導体 |
JP2002040252A (ja) | 2000-07-27 | 2002-02-06 | Shiseido Co Ltd | コレステリック液晶層を含む光学シート、それを用いた情報記録体、情報記録方法並びに情報判別方法 |
DE10038019A1 (de) | 2000-08-04 | 2002-02-14 | Bayer Ag | Substituierte Triazolopyrid(az)ine |
HUP0700086A2 (en) | 2000-08-11 | 2007-05-29 | Eisai Co Ltd | 2-aminopyridine compounds, use thereof as drugs and pharmaceutical compositions containing them |
EP1317442B1 (en) | 2000-09-11 | 2005-11-16 | Chiron Corporation | Quinolinone derivatives as tyrosine kinase inhibitors |
WO2002022622A2 (en) | 2000-09-13 | 2002-03-21 | Georgetown University | Synthesis of 2-hydroxymethylglutamic acid and congeners thereof |
JP2002105085A (ja) | 2000-09-28 | 2002-04-10 | Yamanouchi Pharmaceut Co Ltd | 新規イミダゾチアゾール誘導体 |
AU2001293847B2 (en) | 2000-10-02 | 2007-05-24 | Janssen Pharmaceutica N.V. | Metabotropic glutamate receptor antagonists |
FI20002525A (fi) | 2000-11-17 | 2002-05-18 | Orion Yhtymae Oyj | Tulehduksenvastaisia aineita |
DE10058663A1 (de) | 2000-11-25 | 2002-05-29 | Merck Patent Gmbh | Verwendung von Thienopyrimidinen |
JPWO2002051849A1 (ja) | 2000-12-26 | 2004-04-22 | 第一製薬株式会社 | Cdk4活性阻害剤 |
DK1357111T3 (da) | 2000-12-28 | 2009-11-02 | Shionogi & Co | 2-pyridonderivater med affinitet for cannabinoid type 2-receptor |
JP2002308882A (ja) | 2001-02-08 | 2002-10-23 | Yamanouchi Pharmaceut Co Ltd | チエノピリミジン誘導体 |
US20030130264A1 (en) | 2001-02-16 | 2003-07-10 | Tularik Inc. | Methods of using pyrimidine-based antiviral agents |
ATE497603T1 (de) | 2001-03-02 | 2011-02-15 | Gpc Biotech Ag | Drei-hybrid-assaysystem |
DE10291003D2 (de) | 2001-03-08 | 2004-04-15 | Ilfa Industrieelektronik Und L | Mehrschichtige Leiterplatte |
US6596731B2 (en) | 2001-03-27 | 2003-07-22 | Hoffmann-La Roche Inc. | Substituted imidazo[1,2-A] pyridine derivatives |
CA2443144A1 (en) | 2001-04-02 | 2002-10-10 | Merck & Co., Inc. | In vivo methods of determining activity of receptor-type kinase inhibitors |
DK1379511T3 (da) | 2001-04-12 | 2005-11-07 | Hoffmann La Roche | Dihydro-benzo[b][1,4]diazepin-2-on-derivater som mGLuR2-antagonister II |
DE60202761T2 (de) | 2001-04-12 | 2006-01-12 | F. Hoffmann-La Roche Ag | Dihydro-benzo(b)(1,4)diazepin-2-on-derivate als mglur2 antagonisten |
SE0101579D0 (sv) | 2001-05-04 | 2001-05-04 | Astrazeneca Ab | New compounds |
RU2003135424A (ru) * | 2001-05-14 | 2005-05-20 | Бристол-Маерс Сквибб Фарма Компани (Us) | Замещенные пиразиноны, пиридины и пиримидины в качестве лигандов кортикотропин высвобождающего фактора |
US7144903B2 (en) | 2001-05-23 | 2006-12-05 | Amgen Inc. | CCR4 antagonists |
WO2002096363A2 (en) | 2001-05-30 | 2002-12-05 | Alteon, Inc. | Method for treating fibrotic diseases or other indications |
CA2448317A1 (en) | 2001-05-30 | 2002-12-05 | Alteon Inc. | Method for treating glaucoma v |
JP4424983B2 (ja) | 2001-06-05 | 2010-03-03 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | 1,4−ジ置換ベンゾ−縮合シクロアルキルウレア化合物 |
JPWO2002102807A1 (ja) | 2001-06-14 | 2004-09-30 | 萬有製薬株式会社 | 新規イソキサゾロピリドン誘導体及びその用途 |
HUP0402352A2 (hu) | 2001-06-19 | 2005-02-28 | Bristol-Myers Squibb Co. | Foszfodiészteráz (PDE) 7 inhibitorként alkalmazható pirimidinszármazékok és ezeket tartalmazó gyógyszerkészítmények |
JP2003012653A (ja) | 2001-06-28 | 2003-01-15 | Yamanouchi Pharmaceut Co Ltd | キナゾリン誘導体 |
AU2002321878A1 (en) | 2001-08-02 | 2003-02-17 | Neurocrine Biosciences, Inc. | Pyridinone and pyridazinone derivatives as gonadotropin-releasing hormone receptor antagonists |
EP1425284A2 (en) | 2001-09-11 | 2004-06-09 | Smithkline Beecham Corporation | Furo- and thienopyrimidine derivatives as angiogenesis inhibitors |
WO2003029209A2 (en) | 2001-10-02 | 2003-04-10 | Smithkline Beecham Corporation | Chemical compounds |
TWI330183B (zh) | 2001-10-22 | 2010-09-11 | Eisai R&D Man Co Ltd | |
TW200406466A (en) | 2001-11-13 | 2004-05-01 | Ciba Sc Holding Ag | Compositions comprising at least one oxonol dye and at least one metal complex |
US6921762B2 (en) | 2001-11-16 | 2005-07-26 | Amgen Inc. | Substituted indolizine-like compounds and methods of use |
GB0129260D0 (en) | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
US7067517B2 (en) | 2001-12-14 | 2006-06-27 | Nero Nordisk A/S | Use of compounds for decreasing activity of hormone-sensitive lipase |
WO2003059884A1 (en) | 2001-12-21 | 2003-07-24 | X-Ceptor Therapeutics, Inc. | Modulators of lxr |
EP1459765B1 (en) | 2001-12-27 | 2008-08-20 | Taisho Pharmaceutical Co., Ltd | 6-fluorobicyclo 3.1.0 hexane derivatives |
DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
JP2005170790A (ja) | 2002-01-09 | 2005-06-30 | Ajinomoto Co Inc | N−アルキルスルフォニル置換アミド誘導体 |
US7282512B2 (en) | 2002-01-17 | 2007-10-16 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors |
WO2003062392A2 (en) | 2002-01-18 | 2003-07-31 | Ceretek Llc | Methods of treating conditions associated with an edg receptor |
US20050113283A1 (en) * | 2002-01-18 | 2005-05-26 | David Solow-Cordero | Methods of treating conditions associated with an EDG-4 receptor |
WO2003064428A1 (en) | 2002-01-29 | 2003-08-07 | H. Lundbeck A/S | Furano- and thienopyrimidines as neurokinase inhibitors |
US6949542B2 (en) | 2002-02-06 | 2005-09-27 | Hoffman-La Roche Inc. | Dihydro-benzo[b][1,4]diazepin-2-one derivatives |
US20030220280A1 (en) | 2002-02-07 | 2003-11-27 | Bunge Mary Bartlett | Schwann cell bridge implants and phosphodiesterase inhibitors to stimulate CNS nerve regeneration |
US20040116489A1 (en) | 2002-02-12 | 2004-06-17 | Massey Steven Marc | Synthetic excitatory amino acids |
AU2003211931A1 (en) | 2002-02-13 | 2003-09-04 | Takeda Chemical Industries, Ltd. | Jnk inhibitor |
EP1490064B1 (en) | 2002-02-14 | 2009-11-18 | Pharmacia Corporation | Substituted pyridinones as modulators of p38 map kinase |
WO2003070712A1 (en) | 2002-02-19 | 2003-08-28 | H. Lundbeck A/S | Thioibotenic acid and derivatives thereof |
US6833380B2 (en) | 2002-03-07 | 2004-12-21 | Warner-Lambert Company, Llc | Compounds that modulate PPAR activity and methods of preparation |
IL163957A0 (en) | 2002-03-14 | 2005-12-18 | Bayer Healthcare Ag | Monocyclic aroylpyridinones as antiinflammatory agents |
WO2003082191A2 (en) | 2002-03-28 | 2003-10-09 | Merck & Co., Inc. | Substituted 2,3-diphenyl pyridines |
KR101061561B1 (ko) * | 2002-03-29 | 2011-09-02 | 얀센 파마슈티카 엔.브이. | 대사자극성 글루타메이트 수용체 리간드로서 방사능표지된 퀴놀린 및 퀴놀리논 유도체 및 그의 용도 |
EP1492595A1 (en) | 2002-04-03 | 2005-01-05 | Eli Lilly And Company | Therapy for psychoses combining an atypical antipsychotic and an mglu2/3 receptor agonist |
US6864261B2 (en) | 2002-05-02 | 2005-03-08 | Euro-Celtique S.A. | Therapeutic agents useful for treating pain |
EP1503757B1 (en) | 2002-05-02 | 2007-12-19 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
MXPA04011470A (es) | 2002-05-21 | 2005-02-14 | Amgen Inc | Compuestos heterociclicos sustituidos y metodos de uso. |
CA2390348A1 (en) | 2002-06-10 | 2003-12-10 | Ibm Canada Limited-Ibm Canada Limitee | Systems, methods and computer programs for implementing and accessing webservices |
EP1517915B1 (en) | 2002-06-11 | 2009-01-21 | Eli Lilly And Company | Prodrugs of excitatory amino acids |
KR101052433B1 (ko) | 2002-06-13 | 2011-07-29 | 버텍스 파마슈티칼스 인코포레이티드 | 자이라제 및/또는 토포이소머라제 ⅳ 억제제로서의 2-우레이도-6-헤테로아릴-3h-벤조이미다졸-4-카복실산 유도체 및 이를 포함하는 세균 감염 치료용 약제학적 조성물 |
MY141867A (en) | 2002-06-20 | 2010-07-16 | Vertex Pharma | Substituted pyrimidines useful as protein kinase inhibitors |
GB0214268D0 (en) | 2002-06-20 | 2002-07-31 | Celltech R&D Ltd | Chemical compounds |
US20060063782A1 (en) | 2002-07-03 | 2006-03-23 | Murray Christopher W | 3-Hetero arylmethoxy ! pyridines and their analogues as p38 map kinase inhibitors |
US7262194B2 (en) | 2002-07-26 | 2007-08-28 | Euro-Celtique S.A. | Therapeutic agents useful for treating pain |
US20040138238A1 (en) | 2002-08-08 | 2004-07-15 | Dhanoa Dale S. | Substituted aminopyrimidine compounds as neurokinin antagonists |
GB0218630D0 (en) | 2002-08-10 | 2002-09-18 | Tanabe Seiyaku Co | Novel compounds |
GB0218800D0 (en) | 2002-08-13 | 2002-09-18 | Celltech R&D Ltd | Chemical compounds |
AU2003255845A1 (en) | 2002-08-22 | 2004-03-11 | Piramed Limited | Phosphadidylinositol 3,5-biphosphate inhibitors as anti-viral agents |
US20050288346A1 (en) | 2002-08-26 | 2005-12-29 | Cube Rowena V | Acetophenone potentiators of metabotropic glutamate receptors |
US20060110358A1 (en) | 2002-08-28 | 2006-05-25 | Hsu Henry H | Combination therapy for treatment of fibrotic disorders |
MY139563A (en) | 2002-09-04 | 2009-10-30 | Bristol Myers Squibb Co | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
EP1539149B1 (en) | 2002-09-10 | 2012-01-04 | Novartis AG | Combinations of metabotropic glutamate receptor antagonists and their use in treating addictive disorders |
EP1546201A4 (en) | 2002-09-11 | 2006-08-16 | Merck & Co Inc | NUCLEIC ACID SEQUENCES CODING TO MGLUR2 AND MGLUR3 FOR NEW POINT MUTATIONS |
ATE331716T1 (de) | 2002-09-19 | 2006-07-15 | Boehringer Ingelheim Ca Ltd | Nicht-nukleosidische inhibitoren der reverse transkriptase |
EP1543006A1 (en) | 2002-09-19 | 2005-06-22 | Boehringer Ingelheim (Canada) Ltd. | Non-nucleoside reverse transcriptase inhibitors |
AR044743A1 (es) | 2002-09-26 | 2005-10-05 | Nihon Nohyaku Co Ltd | Herbicida, metodo de emplearlo, derivados de tienopirimidina sustituida,compuestos intermediarios, y procedimientos que se utilizan para producirlos, |
US7067658B2 (en) | 2002-09-30 | 2006-06-27 | Bristol-Myers Squibb Company | Pyridino and pyrimidino pyrazinones |
US7998163B2 (en) | 2002-10-03 | 2011-08-16 | Boston Scientific Scimed, Inc. | Expandable retrieval device |
AU2003275612A1 (en) | 2002-10-23 | 2004-05-13 | Daiichi Pure Chemicals Co., Ltd. | Defructosylation method |
US20040138204A1 (en) | 2002-10-30 | 2004-07-15 | Harrington James Frederick | Compositions and methods for pain reduction |
US7902203B2 (en) | 2002-11-01 | 2011-03-08 | Abbott Laboratories, Inc. | Anti-infective agents |
AU2003291670A1 (en) | 2002-11-01 | 2004-06-07 | Abbott Laboratories | Anti-infective agents |
US6930117B2 (en) | 2002-11-09 | 2005-08-16 | The Procter & Gamble Company | N-alkyl-4-methyleneamino-3-hydroxy-2-pyridones |
ES2375111T3 (es) | 2002-11-21 | 2012-02-24 | Novartis Ag | Pirimidinas 2,4,6-trisustituidas como inhibidores de fosfotidilinositol (pi) 3-quinasa y su uso en el tratamiento de c�?ncer. |
AU2003289386A1 (en) | 2002-12-18 | 2004-07-09 | Takeda Pharmaceutical Company Limited | Jnk inhibitors |
ATE449081T1 (de) | 2002-12-30 | 2009-12-15 | Celgene Corp | Fluoralkoxy-substituierte 1, 3-dihydro-isoindolyl-verbindungen und ihre pharmazeutischen verwendungen |
NZ540612A (en) | 2003-01-14 | 2008-02-29 | Arena Pharm Inc | 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
ITMI20030151A1 (it) | 2003-01-30 | 2004-07-31 | Recordati Ind Chimica E Farma Ceutica S P A | Uso di antagonisti selettivi del recettore mglu5 per il trattamento di disfunzioni neuromuscolari del tratto urinario inferiore. |
WO2004069826A1 (en) | 2003-02-04 | 2004-08-19 | F. Hoffmann-La Roche Ag | Malonamide derivatives as gamma-secretase inhibitors |
DE10306250A1 (de) | 2003-02-14 | 2004-09-09 | Aventis Pharma Deutschland Gmbh | Substituierte N-Arylheterozyklen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
PL378295A1 (pl) | 2003-02-24 | 2006-03-20 | Arena Pharmaceuticals, Inc. | Podstawione pochodne arylowe i heteroarylowe jako modulatory metabolizmu glukozy oraz profilaktyka i leczenie zaburzeń tego metabolizmu |
CN100395237C (zh) | 2003-03-03 | 2008-06-18 | 弗·哈夫曼-拉罗切有限公司 | 用作5-ht6调节剂的2,5-取代的四氢异喹啉 |
ITFI20030058A1 (it) | 2003-03-06 | 2004-09-07 | Univ Firenze | Formulazioni farmaceutiche contenenti tiazolidinedioni |
DE10311065A1 (de) | 2003-03-13 | 2004-09-23 | Abbott Gmbh & Co. Kg | Pyrimidin-2-on-Verbindungen und ihre therapeutische Verwendung |
EP1602627B1 (en) | 2003-03-13 | 2015-07-08 | T.RAD Co., Ltd. | Steam reformer |
WO2004092123A2 (en) | 2003-04-10 | 2004-10-28 | Microbia, Inc. | Inhibitors of fungal invasion |
CA2527170A1 (en) | 2003-04-15 | 2004-10-28 | Astrazeneca Ab | Therapeutic compounds |
JP2004339080A (ja) | 2003-05-13 | 2004-12-02 | Tokyo Institute Of Technology | ピラゾ−ル誘導体を含有する高血圧治療剤 |
BRPI0410348A (pt) | 2003-05-14 | 2006-05-30 | Torreypines Therapeutics Inc | compostos e usos dos mesmos na modulação de amilóide-beta |
JP2007504283A (ja) | 2003-05-20 | 2007-03-01 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | β−アミロイド斑に作用物質を結合させる方法 |
GB0315950D0 (en) | 2003-06-11 | 2003-08-13 | Xention Discovery Ltd | Compounds |
WO2005002585A1 (en) | 2003-07-02 | 2005-01-13 | Warner-Lambert Company Llc | Combination of an allosteric inhibitor of matrix metalloproteinase-13 and a ligand to an alpha-2-delta receptor |
AU2004257748B2 (en) | 2003-07-14 | 2008-10-30 | Decode Genetics Ehf. | Method of diagnosis and treatment for asthma based on haplotype association |
GB0320300D0 (en) | 2003-08-29 | 2003-10-01 | Cancer Rec Tech Ltd | Pyrimidothiophene compounds |
AU2004268820B2 (en) | 2003-08-29 | 2011-07-21 | Cancer Research Technology Ltd | Pyrimidothiophene compounds |
GB0322016D0 (en) | 2003-09-19 | 2003-10-22 | Merck Sharp & Dohme | New compounds |
KR20070027504A (ko) | 2004-02-18 | 2007-03-09 | 아스트라제네카 아베 | 테트라졸 화합물 및 대사성 글루타메이트 수용체길항제로서 이들의 용도 |
DE102004009039A1 (de) | 2004-02-23 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel |
US7306631B2 (en) | 2004-03-30 | 2007-12-11 | The Procter & Gamble Company | Keratin dyeing compounds, keratin dyeing compositions containing them, and use thereof |
MXPA06011799A (es) | 2004-04-12 | 2006-12-15 | Sankyo Co | Derivados de tienopiridina. |
US7459562B2 (en) * | 2004-04-23 | 2008-12-02 | Bristol-Myers Squibb Company | Monocyclic heterocycles as kinase inhibitors |
GB0413605D0 (en) | 2004-06-17 | 2004-07-21 | Addex Pharmaceuticals Sa | Novel compounds |
US8063004B2 (en) | 2004-07-22 | 2011-11-22 | Malcera, L.L.C. | Chemical composition of matter for the liquefaction and dissolution of asphaltene and paraffin sludges into petroleum crude oils and refined products at ambient temperatures and method of use |
JP2008508306A (ja) | 2004-07-30 | 2008-03-21 | メルク エンド カムパニー インコーポレーテッド | メタボトロピックグルタミン酸受容体のインダノン増強剤 |
JP2008508288A (ja) | 2004-07-30 | 2008-03-21 | メルク エンド カムパニー インコーポレーテッド | 代謝調節型グルタミン酸受容体のヘテロ環式アセトフェノン増強剤 |
BRPI0514015A (pt) | 2004-08-02 | 2008-05-27 | Sanol Arznei Schwarz Gmbh | carboxamidas da indolizina e seus derivados aza e diaza |
EP1778093B1 (en) | 2004-08-11 | 2013-04-03 | Koninklijke Philips Electronics N.V. | Ultrasonic diagnosis of ischemic cardiodisease |
TW200613272A (en) | 2004-08-13 | 2006-05-01 | Astrazeneca Ab | Isoindolone compounds and their use as metabotropic glutamate receptor potentiators |
MX2007001612A (es) | 2004-08-18 | 2007-04-10 | Upjohn Co | Compuestos novedosos de triazolopiridina para el tratamiento de la inflamacion. |
DE102004044884A1 (de) | 2004-09-14 | 2006-05-24 | Grünenthal GmbH | Substituierte bizyklische Imidazo-3-yl-amin-Verbindungen |
GB0420722D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
GB0420719D0 (en) * | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
EP1807073A2 (en) | 2004-10-25 | 2007-07-18 | Merck & Co., Inc. | Heterocyclic indanone potentiators of metabotropic glutamate receptors |
ES2333979T3 (es) | 2004-11-22 | 2010-03-03 | Eli Lilly And Company | Potenciadores de los receptores del glutamato. |
US7434262B2 (en) * | 2004-12-08 | 2008-10-07 | At&T Intellectual Property I, L.P. | Methods and systems that selectively resurrect blocked communications between devices |
DE102004061288A1 (de) | 2004-12-14 | 2006-06-29 | Schering Ag | 3-Amino-Pyrazolo[3,4b]pyridine als Inhibitoren von Proteintyrosinkinasen, deren Herstellung und Verwendung als Arzneimittel |
EP1833800A1 (en) | 2004-12-27 | 2007-09-19 | AstraZeneca AB | Pyrazolone compounds as metabotropic glutamate receptor agonists for the treatment of neurological and psychiatric disorders |
US7456289B2 (en) * | 2004-12-31 | 2008-11-25 | National Health Research Institutes | Anti-tumor compounds |
WO2006091496A2 (en) | 2005-02-24 | 2006-08-31 | Merck & Co., Inc. | Benzazole potentiators of metabotropic glutamate receptors |
KR100973609B1 (ko) | 2005-03-23 | 2010-08-03 | 에프. 호프만-라 로슈 아게 | mGluR2 길항제로서 아세틸렌일-피라졸로-피리미딘유도체 |
US20090030017A1 (en) | 2005-04-08 | 2009-01-29 | Eisai R & D Management Co., Ltd | Therapeutic agent for dyskinesia |
US7579360B2 (en) * | 2005-06-09 | 2009-08-25 | Bristol-Myers Squibb Company | Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors |
US7572807B2 (en) * | 2005-06-09 | 2009-08-11 | Bristol-Myers Squibb Company | Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors |
WO2006137350A1 (ja) | 2005-06-22 | 2006-12-28 | Kissei Pharmaceutical Co., Ltd. | 新規なフロピリジン誘導体、それを含有する医薬組成物およびそれらの用途 |
WO2007018998A2 (en) * | 2005-08-05 | 2007-02-15 | Astrazeneca Ab | Tricyclic benzimidazoles and their use as metabotropic glutamate receptor modulators |
CN101277934A (zh) | 2005-08-12 | 2008-10-01 | 阿斯利康(瑞典)有限公司 | 使代谢型谷氨酸-受体-增效的异吲哚酮 |
WO2007027669A1 (en) | 2005-08-29 | 2007-03-08 | Cps Biofuels, Inc. | Improved biodiesel fuel, additives, and lubbricants |
CA2622082A1 (en) | 2005-09-17 | 2007-03-22 | Speedel Experimenta Ag | 5-amino-4-hydroxy-7- (imidazo [1,2-a] pyridin-6- ylmethyl)-8-methyl-nonamide derivatives and related compounds as renin inhibitors for the treatment of hypertension |
EP1764099A3 (en) * | 2005-09-17 | 2007-05-09 | Speedel Experimenta AG | Diaminoalcohol derivatives for the treatment of Alzheimer, malaria, HIV |
WO2008051197A2 (en) | 2005-09-20 | 2008-05-02 | Mayo Foundation For Medical Education And Research | Small-molecule botulinum toxin inhibitors |
DE602006013493D1 (de) | 2005-09-27 | 2010-05-20 | Hoffmann La Roche | Oxadiazolylpyrazolopyrimidine als mglur2-antagonisten |
US8648087B2 (en) | 2005-11-15 | 2014-02-11 | Array Biopharma, Inc. | N4-phenyl-quinazoline-4-amine derivatives and related compounds as ErbB type I receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases |
AR057218A1 (es) | 2005-12-15 | 2007-11-21 | Astra Ab | Compuestos de oxazolidinona y su uso como pontenciadores del receptor metabotropico de glutamato |
TW200804281A (en) | 2006-02-16 | 2008-01-16 | Astrazeneca Ab | New metabotropic glutamate receptor-potentiating isoindolones |
EP1993539A4 (en) | 2006-03-02 | 2010-05-19 | Glaxosmithkline Llc | THIAZOLONE AS A PI3 KINASE INHIBITOR |
AR059898A1 (es) * | 2006-03-15 | 2008-05-07 | Janssen Pharmaceutica Nv | Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2 |
GB0606774D0 (en) | 2006-04-03 | 2006-05-10 | Novartis Ag | Organic compounds |
GB0608263D0 (en) | 2006-04-26 | 2006-06-07 | Glaxo Group Ltd | Compounds |
WO2007135527A2 (en) | 2006-05-23 | 2007-11-29 | Pfizer Products Inc. | Benzimidazolyl compounds |
WO2007135529A2 (en) | 2006-05-23 | 2007-11-29 | Pfizer Products Inc. | Azabenzimidazolyl compounds as mglur2 potentiators |
KR101423347B1 (ko) | 2006-06-19 | 2014-07-24 | 도레이 카부시키가이샤 | 다발성 경화증의 치료 또는 예방제 |
US20100035756A1 (en) | 2006-07-12 | 2010-02-11 | Syngenta Limited | Triazolophyridine derivatives as herbicides |
PE20121506A1 (es) | 2006-07-14 | 2012-11-26 | Amgen Inc | Compuestos triazolopiridinas como inhibidores de c-met |
US8198448B2 (en) * | 2006-07-14 | 2012-06-12 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
US8217177B2 (en) | 2006-07-14 | 2012-07-10 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
WO2008012623A1 (en) | 2006-07-25 | 2008-01-31 | Pfizer Products Inc. | Benzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor |
WO2008012622A2 (en) | 2006-07-25 | 2008-01-31 | Pfizer Products Inc. | Azabenzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor |
EP2061775A2 (en) | 2006-09-13 | 2009-05-27 | Astra Zeneca AB | Spiro-oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators |
EP2086973B1 (en) | 2006-10-11 | 2012-01-25 | Amgen Inc., | Imidazo- and triazolo-pyridine compounds and methods of use therof |
WO2008057855A2 (en) | 2006-11-01 | 2008-05-15 | Bristol-Myers Squibb Company | Heterocyclic compounds as modulators of glucocorticoid receptor, ap-i, and/or np-kappa-b activity |
TW200831085A (en) | 2006-12-13 | 2008-08-01 | Merck & Co Inc | Non-nucleoside reverse transcriptase inhibitors |
US8895745B2 (en) | 2006-12-22 | 2014-11-25 | Astex Therapeutics Limited | Bicyclic heterocyclic compounds as FGFR inhibitors |
CN101679409B (zh) | 2006-12-22 | 2014-11-26 | Astex治疗学有限公司 | 双环杂环衍生化合物、其医药组合物和其用途 |
JP2010518104A (ja) | 2007-02-09 | 2010-05-27 | アストラゼネカ・アクチエボラーグ | アザ−イソインドロンおよび代謝型グルタミン酸レセプター増強剤−613としてのそれらの使用 |
ES2320955B1 (es) | 2007-03-02 | 2010-03-16 | Laboratorios Almirall S.A. | Nuevos derivados de 3-((1,2,4)triazolo(4,3-a)piridin-7-il)benzamida. |
EP1968272A1 (en) | 2007-03-05 | 2008-09-10 | Matsushita Electric Industrial Co., Ltd. | Loop detection for mobile IP home agents |
TW200900391A (en) * | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-phenyl-piperidin-1-yl)-pyridin-2-one derivatives |
US7846953B2 (en) | 2007-03-07 | 2010-12-07 | Janssen Pharmaceutica, Nv | Substituted phenoxy thiazolidinediones as estrogen related receptor-α modulators |
TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
TW200900065A (en) * | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
GB0704407D0 (en) | 2007-03-07 | 2007-04-18 | Glaxo Group Ltd | Compounds |
KR20090128454A (ko) | 2007-03-07 | 2009-12-15 | 얀센 파마슈티카 엔.브이. | 에스트로겐 관련 수용체-알파 조절제로서 치환된 페녹시 아미노티아졸론 |
KR20090118103A (ko) | 2007-03-07 | 2009-11-17 | 얀센 파마슈티카 엔.브이. | 에스트로겐 관련 수용체-알파 조절제로서 치환된 페녹시 n-알킬화 티아졸리딘디온 |
NZ579431A (en) | 2007-03-09 | 2012-04-27 | Sanofi Aventis | Substituted dihydro and tetrahydro oxazolopyrimidinones, preparation and use thereof |
WO2008124085A2 (en) | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
WO2008130853A1 (en) | 2007-04-17 | 2008-10-30 | Astrazeneca Ab | Hydrazides and their use as metabotropic glutamate receptor potentiators - 681 |
TWI443090B (zh) | 2007-05-25 | 2014-07-01 | Abbvie Deutschland | 作為代謝性麩胺酸受體2(mglu2 受體)之正向調節劑之雜環化合物 |
TWI417100B (zh) * | 2007-06-07 | 2013-12-01 | Astrazeneca Ab | 二唑衍生物及其作為代謝型麩胺酸受體增效劑-842之用途 |
TW200911255A (en) | 2007-06-07 | 2009-03-16 | Astrazeneca Ab | Metabotropic glutamate receptor oxadiazole ligands and their use as potentiators-841 |
WO2009004430A1 (en) | 2007-06-29 | 2009-01-08 | Pfizer Inc. | N-benzyl oxazolidinones and related heterocycleic compounds as potentiators of glutamate receptors |
CN101801930B (zh) | 2007-09-14 | 2013-01-30 | 奥梅-杨森制药有限公司 | 1,3-二取代的-4-苯基-1h-吡啶-2-酮 |
AU2008297876B2 (en) * | 2007-09-14 | 2011-07-07 | Addex Pharma S.A. | 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones |
BRPI0816767B8 (pt) | 2007-09-14 | 2021-05-25 | Addex Pharmaceuticals Sa | composto 4-fenil-3,4,5,6-tetra-hidro-2h,1'h-[1,4']bipiridi¬nil-2'-onas 1',3'-dissubstituídas, composição farmacêutica e uso dos mesmos |
WO2009041567A1 (ja) | 2007-09-27 | 2009-04-02 | Banyu Pharmaceutical Co., Ltd. | メラニン凝集ホルモン受容体拮抗作用を有するジアリールケチミン誘導体 |
US8119658B2 (en) | 2007-10-01 | 2012-02-21 | Bristol-Myers Squibb Company | Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors |
US8425426B2 (en) * | 2007-11-09 | 2013-04-23 | Western Clinical Engineering, Ltd | Tourniquet apparatus for measuring limb occlusion pressure |
ES2637794T3 (es) * | 2007-11-14 | 2017-10-17 | Janssen Pharmaceuticals, Inc. | Derivados de imidazo[1,2-A]piridina y su uso como moduladores alostéricos positivos de receptores MGLUR2 |
WO2009094265A1 (en) | 2008-01-24 | 2009-07-30 | Merck & Co., Inc. | 3,5-substituted-1,3-oxazolidin-2-one derivatives |
EP2268645B1 (en) | 2008-03-06 | 2014-11-12 | Sanofi | Substituted dihydro, trihydro and tetrahydro cycloalkyloxazolopyrimidinones, preparation and use thereof as allosteric modulators of mglur |
US10919672B2 (en) | 2008-03-31 | 2021-02-16 | Angelcare Feeding Usa, Llc | Seal indication mechanism for containers |
DE102008001056A1 (de) | 2008-04-08 | 2009-10-15 | Robert Bosch Gmbh | Umlenkeinrichtung für einen Strahl einer elektromagnetischen Welle |
US20110065669A1 (en) | 2008-05-15 | 2011-03-17 | Merck Sharp & Dohme Corp. | Oxazolobenzimidazole derivatives |
US20110124661A1 (en) | 2008-05-15 | 2011-05-26 | Merck Sharp & Dohme Corp. | Oxazolobenzimidazole derivatives |
US7790760B2 (en) | 2008-06-06 | 2010-09-07 | Astrazeneca Ab | Metabotropic glutamate receptor isoxazole ligands and their use as potentiators 286 |
TW201006801A (en) | 2008-07-18 | 2010-02-16 | Lilly Co Eli | Imidazole carboxamides |
WO2010019739A1 (en) * | 2008-08-14 | 2010-02-18 | Susan Connett | Method and apparatus for sandal with hidden strap adjustment |
UY32049A (es) | 2008-08-14 | 2010-03-26 | Takeda Pharmaceutical | Inhibidores de cmet |
TWI496779B (zh) | 2008-08-19 | 2015-08-21 | Array Biopharma Inc | 作為pim激酶抑制劑之三唑吡啶化合物 |
US8557809B2 (en) | 2008-08-19 | 2013-10-15 | Array Biopharma Inc. | Triazolopyridine compounds as PIM kinase inhibitors |
AU2009289784B2 (en) * | 2008-09-02 | 2012-03-22 | Addex Pharma S.A. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
WO2010043396A1 (en) | 2008-10-16 | 2010-04-22 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc. | Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors |
WO2010060589A1 (en) | 2008-11-28 | 2010-06-03 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc. | Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors |
AT507619B1 (de) | 2008-12-05 | 2011-11-15 | Oesterreichisches Forschungs Und Pruefzentrum Arsenal Ges M B H | Verfahren zur approximation des zeitlichen verlaufs von verkehrsdaten |
JP5344222B2 (ja) * | 2008-12-26 | 2013-11-20 | 日本ガスケット株式会社 | シリンダヘッドガスケットにおけるオイル落し穴のシール構造 |
EP2393807B1 (en) | 2009-02-04 | 2013-08-14 | Boehringer Ingelheim International GmbH | Cyclic inhibitors of 11 -hydroxysteroid dehydrogenase 1 |
WO2010114726A1 (en) | 2009-03-31 | 2010-10-07 | Merck Sharp & Dohme Corp. | Aminobenzotriazole derivatives |
US8685967B2 (en) | 2009-04-07 | 2014-04-01 | Merck Sharp & Dohme Corp. | Substituted triazolopyridines and analogs thereof |
WO2010123424A1 (en) | 2009-04-23 | 2010-10-28 | Saab Ab | Closable counter-measure compartments for a dispenser unit |
MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
MY161325A (en) * | 2009-05-12 | 2017-04-14 | Janssen Pharmaceuticals Inc | 1, 2, 4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders |
US8946205B2 (en) * | 2009-05-12 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
WO2010141360A1 (en) | 2009-06-05 | 2010-12-09 | Merck Sharp & Dohme Corp. | Biaryl benzotriazole derivatives |
WO2011022312A1 (en) | 2009-08-20 | 2011-02-24 | Merck Sharp & Dohme Corp. | Ether benzotriazole derivatives |
CN102002040A (zh) | 2009-09-01 | 2011-04-06 | 上海药明康德新药开发有限公司 | 一种三唑并吡啶环化合物的合成方法 |
AR078171A1 (es) | 2009-09-15 | 2011-10-19 | Sanofi Aventis | Dihidrobenzocicloalquiloximetil-oxazolopirimidinonas sustituidas, preparacion y uso de las mismas |
WO2011034741A1 (en) | 2009-09-15 | 2011-03-24 | Merck Sharp & Dohme Corp. | Imidazopyridin-2-one derivatives |
AR078173A1 (es) | 2009-09-15 | 2011-10-19 | Sanofi Aventis | Bifeniloximetil dihidro oxazolopirimidinonas sustituidas, su preparacion y su uso |
AR078172A1 (es) | 2009-09-15 | 2011-10-19 | Sanofi Aventis | Fenoximetil dihidro oxazolopirimidinonas sustituidas y uso de las mismas como moduladores de receptores metabotropicos de mglur |
JP5204071B2 (ja) | 2009-09-25 | 2013-06-05 | パナソニック株式会社 | 電気かみそり |
US8507521B2 (en) | 2009-11-02 | 2013-08-13 | Merck Sharp + Dohme B.V. | Heterocyclic derivatives |
AU2011223898A1 (en) | 2010-03-04 | 2012-09-13 | Merck Sharp & Dohme Corp. | Positive allosteric modulators of mGluR2 |
WO2011116356A2 (en) | 2010-03-19 | 2011-09-22 | Sanford-Burnham Medical Research Institute | Positive allosteric modulators of group ii mglurs |
US8314120B2 (en) * | 2010-03-30 | 2012-11-20 | Abbott Gmbh & Co. Kg | Small molecule potentiators of metabotropic glutamate receptors |
US8664214B2 (en) | 2010-03-30 | 2014-03-04 | AbbVie Deutschland GmbH & Co. KG | Small molecule potentiators of metabotropic glutamate receptors I |
US8784289B2 (en) | 2010-04-29 | 2014-07-22 | Illinois Tool Works Inc. | Process of forming a wide mouth gusseted bag with edge seals |
EP2563143A4 (en) | 2010-04-29 | 2013-09-25 | Merck Sharp & Dohme | SUBSTITUTED 1,3-BENZOTHIAZOL-2 (3H) -ONE AND [1,3-] THIAZOLO- [5,4-B] PYRIDINE-2 (-1H) -ONE AS POSITIVE ALLOSTERE MODULATORS OF MGLUR2 |
BR112012027628A2 (pt) | 2010-04-30 | 2016-08-09 | Astrazeneca Ab | polimorfos de um modulador alostérico positivo de receptor de glutamato metabotrópico |
US8765784B2 (en) | 2010-06-09 | 2014-07-01 | Merck Sharp & Dohme Corp. | Positive allosteric modulators of MGLUR2 |
CN101893589B (zh) * | 2010-06-29 | 2012-10-17 | 中国人民解放军第三0二医院 | 一种无菌检查方法及其使用的全封闭集菌安瓿培养器 |
US8993779B2 (en) | 2010-08-12 | 2015-03-31 | Merck Sharp & Dohme Corp. | Positive allosteric modulators of MGLUR2 |
US8785481B2 (en) * | 2010-09-29 | 2014-07-22 | Merck Sharp & Dohme Corp. | Ether benzotriazole derivatives |
PL2649069T3 (pl) | 2010-11-08 | 2016-01-29 | Janssen Pharmaceuticals Inc | Pochodne 1,2,4-triazolo[4,3-a]pirydyny i ich zastosowanie jako dodatnich allosterycznych modulatorów receptorów mGluR2 |
CN103261195B (zh) | 2010-11-08 | 2015-09-02 | 杨森制药公司 | 1,2,4-三唑并[4,3-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途 |
EP2638040A1 (en) | 2010-11-08 | 2013-09-18 | Janssen Pharmaceuticals, Inc. | RADIOLABELLED mGLuR2 PET LIGANDS |
AU2011328203B2 (en) | 2010-11-08 | 2015-03-19 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
WO2012151140A1 (en) | 2011-05-03 | 2012-11-08 | Merck Sharp & Dohme Corp. | Hydroxymethyl biaryl benzotriazole derivatives |
EP2704573A4 (en) | 2011-05-03 | 2014-10-15 | Merck Sharp & Dohme | AMINOMETHYL biaryl BENZOTRIAZOL DERIVATIVES |
WO2012151139A1 (en) | 2011-05-03 | 2012-11-08 | Merck Sharp & Dohme Corp. | Alkyne benzotriazole derivatives |
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