TWI301129B - Substituted 1,2,3,4-tetrahydroisoquinoline derivatives - Google Patents
Substituted 1,2,3,4-tetrahydroisoquinoline derivatives Download PDFInfo
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- TWI301129B TWI301129B TW094106070A TW94106070A TWI301129B TW I301129 B TWI301129 B TW I301129B TW 094106070 A TW094106070 A TW 094106070A TW 94106070 A TW94106070 A TW 94106070A TW I301129 B TWI301129 B TW I301129B
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- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 title claims description 22
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Classifications
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1301129 九、發明說明: 【發明所屬之技術領域】 本卷明係關於通式⑴之新穎經取代丨,2,3,乒四氫異喹啉 行生物及其作為藥品之用途。本發明亦涉及包括該等化合 物之衣備方法之相關癌樣、含有一或多種通式⑴化合物之 商藥組合物’且尤其涉及其作為食慾素受體拮抗劑之用 途。 【先前技術】 艮慾素(食慾素A或OX-A及食慾素〇χ_Β)係由兩個研 九組在1998年發現之新穎神經肽,食慾素a為33胺基酸肽 且R慾素B為28胺基酸肽(Sakurai T.等人,Cell,1998,92 573 585) $慾素在下丘腦側區之離散神經元中生成且與 G-蛋白質·偶合受體(〇&及οχ:受體)結合。食慾素_丨受體 (OXi)具有〇Χ-Α選擇性,且食慾素_2受體(〇Xj可結合〇χ_ Α及ΟΧ-Β。已發現食慾素可刺激大鼠食物消耗,表明該等 狀在调節進食行為之中樞反饋機制中作為介體之生理作用 (8&1〇11^11:.等人,〇611,1998,92,第 573-5 85 頁)。另一方 面’亦觀察到食慾素調節睡眠及失眠狀態,其潛在地提供 猝睡症及失眠與其它睡眠障礙之新穎治療方法(Cheinelli R.M.等人,Cell,1999,98,第 437-451 頁)。 食慾素受體係發現於哺乳動物腦中且可具有多種病理學 薇涵,諸如下列疾病··抑鬱;焦慮;成癮、強迫症;情感 性神經症;抑鬱性神經症,·焦慮性神經症;輕型憂鬱症; 情緒障礙;性功能障礙;心理性功能障礙;性別障礙;精 99857.doc 1301129 广刀j症鬱症;譫妄;癡呆;重度智能不足及運動障 礙:諸如:廷頓氏病及妥瑞症候群;飲食障礙;睡眠障 : 血s病,糖尿病;食慾/味覺障礙;嘔吐/噁心;哮
壓 塞 敏 * 金林氏病,庫欣氏症候群/疾病丨嗜鹼細胞腺瘤; 促乳素瘤;高泌乳素土症;腦m力能減退;腦下垂體 二腺瘤;下丘腦疾病;發炎性腸道疾病;胃運動障礙; 胃潰癌;佛洛利希症候群;腦下垂體疾病,下丘腦性腺功 能減退症;卡門氏症候群(嗅覺喪失,嗅覺減退);功能性 或精神性閉經;腦下垂體功能減退;下丘腦性甲狀腺功能 減退症;下丘腦-腎上腺功能障礙;特發性高泌乳素血 症生長放素缺乏之下丘腦病症;特發性生長缺陷;侏儒 症;巨人症;肢端肥大症;生物及晝夜節律紊亂;與睡眠 障礙相關之疾病,諸如神經病症、神經病變性疼痛及過動 腳症候群;心及肺疾病,急性及充血性心臟衰竭丨低血 一高血壓;尿液滯留;骨質疏鬆症;心絞痛;心肌梗 缺血性或出血性中風;蜘蛛網膜下腔出血;潰瘍;過 良性前列腺肥大;慢性腎衰竭;腎病;葡萄糖耐受性 異常;偏頭痛;痛覺過敏;疼痛;增強或誇大對疼痛之敏 感性,諸如痛覺過敏、灼痛及觸摸痛;急性疼痛;燒傷疼 痛;非典型顏面痛;神經病變性疼痛;背部疼痛;複雜性 區域疼痛症候群I及II ;關節炎疼痛;運動損傷疼痛;與感 染(例如HIV)相關之疼痛;化學治療後疼痛;中風後疼 痛;手術後疼痛;神經痛;與内臟疼痛相關之症狀,諸如 大腸急躁症;偏頭痛及心絞痛;膀胱失禁,例如急迫性尿 99857.doc 1301129 失禁;麻醉藥品耐受性或戒斷麻醉藥品;睡眠呼吸暫停; 猝睡症;失眠;類睡症;及包括疾病分類學實體之神經退 化性病症,諸如去抑制-癡呆·帕金森氏病-肌萎縮症複合、 蒼白·腦橋-黑質退化癲癇症、發作病症及與全身性食慾素 系統功能障礙相關之其它疾病。
本發明提供經取代之1,2,3,4-四氫異噎琳衍生物,其為 人類食慾素受體之非肽拮抗劑。詳言之,該等化合物在 (例如)飲食障礙或睡眠障礙之治療中具有潛在用途。 迄今為止,已知一些低分子量化合物具有特定地拮抗 ox14〇x2或同時拮抗兩種受體之潛力。在一些專利申請 案中,例如SmithKline Beecham報導了作為OXi選擇性拮 抗劑之苯基脲、苯基硫脲及肉桂醯胺衍生物(W099/09024、 WOOO/47576及WO00/47580)。最近,在其專利申請案中, SmithKline Beecham提出將2-胺基-甲基旅唆衍生物 (W001/96302)、3-胺基甲基-嗎啉衍生物(WO02/44172)及N-芳醯基環胺類(W002/090355、W003/002559及 W003/002561) 作為食慾素受體拮抗劑。在WO01/85693中,Banyu Pharmaceuticals主張N-醯基四氫異喧淋衍生物。 W002/05 183 8揭示了其它食慾素受體拮抗劑,諸如新穎苯 幷氮呼衍生物。
Actelion Pharmaceuticals Ltd.主張 1,2,3,4 -四氫異啥琳衍 生物及其在醫藥組合物製備中作為活性成份之用途 (W001/68609)。另外,溶液相化學在作為潛在食慾素受體 拮抗劑之1,2,3,4-四氫異喹啉衍生物的先導物優化上之用 99857.doc 1301129 支鏈烧基。直鏈與支鏈Ci-C6烧基之實例為曱基、乙基、 丙基、異丙基、丁基、第二丁基、異丁基、第三丁基、戊 基、己基、異構戊基、異構己基,較佳為甲基、乙基、丙 基、異丙基、丁基、第二丁基、異丁基或第三丁基。
術語π烷氧基"單獨或與其它基團結合意謂反_〇-基團,其 中R為如上所定義之烷基,諸如曱氧基、乙氧基、正丙氧 基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基及第三 丁氧基,較佳為甲氧基及乙氧基。 陳述"醫藥學上可接受之鹽”涵蓋無機酸或有機酸(如氫氯 酸、氫溴酸、氫碘酸、硫酸、磷酸、硝酸、檸檬酸、甲 酸、乙酸、順丁烯二酸、酒石酸、反丁烯二酸、苯甲酸、 雙羥酸、硬脂酸、甲磺酸、對甲苯磺酸、水揚酸、丁二 酸、二氟乙酸及對活有機體無毒之其類似物)之鹽,或在 式⑴化合物㈣性之情況下與諸如驗金屬錢土金屬驗之 無機鹼(例如氫氧化鈉、氫氧化鉀、氫氧化鈣及其類似物) 形成之鹽。對其它醫藥學上可接受之鹽而言,可參考” selection f0r basic drugs",lnt· j· Pharm (1986),%,第 201-217頁。 成鹽基團為具有鹼性或酸性特性之基團化⑺叩)或美 ㈣㈣。舉例而言,具有至少—驗性基團如卿)或至^ -驗性基(mi)(例如胺基、不形成肽鍵之第:胺基或吼 咬基)之化合物可與無機酸形成酸加成鹽。當存在數個驗 性基團時,可形成單-或聚-酸加成鹽。 具有諸如絲或㈣基线絲團之化合物可形成金屬 99857.doc -10- 1301129 二銨鹽’諸如鹼金屬或鹼土金屬鹽(例如納1、鎮或舞 ^或與氨或諸如三級—元胺(例如三乙胺或三I經乙 之混合物 =雜環_如或N,N’_二m秦)之適當 有機胺形成之銨鹽。可能為鹽 /、有S文性及驗性基團之化合物可形成内鹽
、:了達成分離或純化…,且在化合物係作為中間體 進—步使用之情況下,亦有可能使用醫藥學上不可接受之 二:例如苦味酸鹽。然而,$了達成治療目的,僅可使用 西藥學上可接受之無毒鹽且彼等鹽因此為較佳。 本發明之第一態樣係由以下通式⑴之新穎經取代 i,2,3,4_四氫異喹啉衍生物組成:
(I) 其中: R1與R2獨立代表氫或<^<4烷氧基; R3代表CVC6-烧基; X代表-CH-或氮原子。 本發明亦涵蓋式I之化合物及其光學純對映異構體、對 99857.doc -11- 1301129 映異構體之混合物 巧呎吳構體、非對 映異構體之混合物、非對映異構消旋體、非對映異構消旋 體之混合物、内消旋形式及醫藥學上可接受之鹽、溶劑複 合物及形態學形式。 應瞭解對通式⑴化合物之任何參考亦係心態異構體、 對映異構體之混合物(諸如消旋體)、非對映異構體、非對
映異構體之混合物、非對映異構消旋體及非對映異構消旋 體之混合物及鹽,醫藥學上可接受之鹽、溶劑複合物 態學形式尤其適當及適合。 如以上所提及,本發明亦涵蓋通式⑴化合物之溶合複人 物。該溶合作用可在製造過程中實現或可(例如)因通式⑴ 之取初無水化合物之吸水特性而個別發生。本發明進一牛 涵蓋不同形態學形式,例如通式⑴化合物及其鹽及溶合i 合物之結晶形態。特定多晶體可顯示不同溶解特性、 概况及其相似純’且所有特性均包括在本發明範嘴内。 較佳之經取获丨9 1 /1 卜 戈,2,3,4_四氫異喹啉衍生物為其中r1^ 均代表㈣燒氧基(詳言之,氧基)之彼等衍生物。,、 在根據本發明之較佳實施例中,χ代表视。在另 佳實施例中,X代表氮原子。 又 在根據本發明之g I _ 車父仏貫施例中,R3代表甲基。 n本發明之尤其較佳實施例中,^㈣代表子氧 基1代表-cm3代表貌基。 :物之Λ例係係選自由以下各物組成之群: 2-{6,7-二甲裊其 1 暴三氟甲基-苯基)-乙基]-3,4-二 99857.doc -12- 1301129 氯]Η-異喧琳_2_基}_N-甲基I苯基_乙醯胺; 2-{6,7-二甲氧基-^[2^6•三氟 34 -气…^ 1甲基+定-3_基)_乙基]_ ,、乳異嗤啉-2-基}士_甲基4苯基{醯胺。 根據通式⑴之化合物適用於製備用於預防或治 |藥品,該等疾病係選自由以 喲 隹 卜谷疾病組成之群··抑鬱;
“、…〜、,成癮,強迫症;情感性神經症;抑鬱性神經症;焦 慮性神經症;輕型憂鬱症;情緒障礙;性功能障礙;心理、 性功能障礙;精神分裂症;碌營症;擔妄;瘍呆;重度知 能不足及運動障礙,諸如亨廷頓氏病及妥瑞症候群;= 病,食慾/味覺障礙;唱吐/喔心;哮喘;帕金森氏病;庫 欣氏症候群/疾病;嗜鹼細胞腺瘤;促乳素瘤;高泌乳素 血症,腦下垂體功能減退;腦下垂體瘤/腺瘤;下丘腦疾 病,發炎性腸道疾病;胃運動障礙;胃潰瘍;佛洛利= 症;腦下垂體疾病,下丘腦性腺功能減退症;卡門氏症候 群(嗅覺喪失、嗅覺減退);功能性或精神性閉經;下丘腦 性甲狀腺功能減退症;下丘腦-腎上腺功能障礙;特發性 咼泌乳素血症;生長激素缺乏之下丘腦病症;特發性生長 缺陷,侏儒症;巨人症;肢端肥大症;生物及晝夜節律紊 亂;與睡眠障礙相關之病症,諸如神經病症、神經病變性 疼痛及過動腳症候群;心及肺疾病,急性及充血性心臟衰 竭;低血壓;高也壓;尿液滯留;骨質疏鬆症;心絞痛; 心肌梗塞;缺血性或出血性中風;蜘蛛網膜下腔出血;潰 瘍;過敏;良性前列腺肥大;慢性腎衰竭;腎病;葡萄糖 而才受性異4,偏頭痛;疼痛;增強或誇大對疼痛之敏咸 99B57.doc -13- 1301129
性’諸如錢職、灼痛及_痛;急性疼痛;燒傷疼 痛;非典型顏面痛;神經病變性疼痛;背部疼痛;複雜性 區域疼痛症候群1及11;關節炎疼痛;運動損傷疼痛;與感 染(例如HIV)相關之疼痛;化學治療後疼痛;中風後疼 痛;手術後疼痛;神經痛;與内臟疼痛相關之症狀,諸如 大腸急躁症;偏頭痛及心絞痛;膀耽失禁,例如急迫性尿 2禁;麻醉藥品耐受性或戒斷麻醉藥品;睡眠障礙;飲食 P早礙’〜血官病症;神經退化性病症;睡眠呼吸暫停;摔 睡症,失眠,類睡症;及包括疾病分類學實體之神經退化 性病症’諸如去抑制.癡呆_帕金森氏病.肌萎縮症複合、蒼 白-滕橋黑質退化癲癇症、發作病症及與全身性食您素系 統功能障礙相關之其它疾病。 、 通式(I)化合物尤其適用於治療選自由飲食障礙或睡眠障 祕組成之群之疾病或病症。 飲食障礙可定義為包含代謝功能障礙、不正常食慾控 制、強迫肥胖症、催吐貪食症或神經性厭食症。該病變之 食物攝取可由食慾奮亂(對食物吸引或厭惡)、能量平衡改 W攝取㈣耗)、食物品f之感覺紊亂(高腊肪或碳水化合 物,高可口性)、食物可用性蒼亂(無限制飲食或剥奪)或水 分平衡紊亂引起。 睡眠卩早礙包括·失眠、猝睡症及過度嗜睡之其它症狀、 與睡眠相關之肌張力障礙;過動腳症候群;睡眠啤吸暫 分’時差症候群,·輪班作業症候群;延時或提前睡眠狀態 症候群。失眠係定義為包含下列病症··與老化相關之睡眠 99857.doc -14- 1301129 Ί.慢性失眠之間歇治療,·情境式暫時失眠(新環境、 '、)或歸因於壓力、悲傷、疼痛或疾病之短期失眠。 殺^明之另-目的係含有至少一根據通式⑴之化合物及 面藥學上可接受之载劑材料之醫藥組合物。 本發明之另一目的係-種用於治療或預防與食慾素受體 二關的疾病(諸如飲食障礙或睡眠障礙)之方法,其包含將 。療有效里之根據通式⑴之^心四氫異㈣衍生物投 與至患者。 在本發明之較佳實施例中,該量係包含每天!邮與膽邮 之間,較佳為每天2叫至5〇〇 mg,更佳為每天5呵至細 mg 〇 、二發明亦涉及一種藉由本身已知之方式使一或多種根據 ^⑴之活性成份與载劑材料混合以製備包含根據通式⑴ 之1,2,3,4-四氫異喹啉衍生物之醫藥組合物之方法。 通式(I)之化合物及其醫藥學上可接受之鹽可用作醫藥品 以商藥衣劑形式)。該等醫藥製劑可經腸投藥,諸 例如,以錠劑、包衣㈣、糖衣藥丸、硬及軟明 勝膝囊、溶液、乳液或懸浮液形式)、經鼻(例如,以鼻用 :劑形式)或經直腸(例如’以栓劑形式)投藥。然而,該投 :亦可以非經腸方式來實現,諸如經肌肉内或經靜脈内 列如以注射溶液形式)或局部投藥,例如以軟膏、乳 油之形式投藥。 通式⑴之化合物及其醫藥學上可接受之鹽可由醫藥學上 月性、無機或有機佐劑進行來加卫以產生錠劑、包衣鏡 "857.doc -15- 1301129 劑、糖衣藥丸及硬明膠膠囊。舉例而言,可使用乳糖、玉 米炎粉或其衍生物、滑石粉、硬脂酸或其鹽等來作為旋 劑、糖衣藥丸及硬明膠膠囊之該等佐劑。例如,適用於軟 明膠膠囊之佐劑為植物油、蠟、脂肪、半固體物質及液體 多元醇等。 例如’適用於產生溶液及糖漿之佐劑為水、醇、多元 醇、蔗糖、轉化糖、葡萄糖等。例如,適用於注射溶液之 ^ #劑為水、醇、多元醇、甘油、植物油等。例如,適用於 才王背丨之佐劑為天然或硬化油、蠟、脂肪、半固體或液體多 ' 元醇等。 $經口給藥或可注射之組合物而言,上述組份僅為代表 陘只例。Remington,s pharmaceutical Sci_es,如化版 2〇〇1,Marck Publishing Company,Easton,PennSylvania陳 述了其它材料及其加工技術及相似物,其係以引用的方式 併入本文中。
本發明之化合物亦可藉由使用已知持續釋放藥物傳遞秀 統以持續釋放形式給藥。 本發明之另一目的係一種用於製備根據通式(I)之 1,2,3,4·四氫異㈣衍生物之方法。根據通式⑴之本發明 化合物係根據以下流程所概述之—般反應順序來製備,其 中X、R1、R2及R3係如通式⑴所定義般。所得化合物亦可 、本身已知方式轉化為其醫藥學上可接受之鹽。 體^以下流程1所述,在通式⑴化合物合成中,關鍵中間 '、、、-取代3’4_一風異喹啉衍生物。該等化合物係由尽 99857.doc -16- 1301129 笨乙基-丙薩胺與POCI3之環化作 F用或由1·甲其一34 -气思 喹啉與烷基溴之烷基化作用所 p -一風一 τ表侍。以硼氫化鈉將所得 3,4-二氳異喹啉還原為1,2,3,4-四赛s ^ ,四虱異喹啉以生成外消旋混 合物形式之產物。在掌性RU(II)__ ^ 錯合物(掌性觸媒)存在
下,藉由個別3,4-二氫異喹啉之轉移氫化可獲得高度富含 對映異構體之1,2,3,4-四氫異喹啉,其最初係由R N〇y〇H 等人描述(J. Am. Chem. Soc. 1996,118 ’ 第 4916-4917 頁及
WO 97/20789)。所用之掌性觸媒(Ru(II)錯合物)係如下所 不:
99857.doc -17-
1301129
如以下流程2及流程3所說明,根據本發明之1 2 3 4_四氫 異啥淋中間體可根據三個不同合成路徑a)、b)或〇中之一 轉化成通式(I)之化合物。在路轳 隹峪仫a)中,由經取代之2-溴-乙 酸甲酯使1,2,3,4-四盞里邊必p # n 風異圭啉烷基化。將所得之酯水解為 相應的酸且敢終在偶合試 蜊廿隹卜糟由與所要之胺發生醯 胺-偶合反,而轉化成該酿胺。在路叫中,由個別 四乱異喹啉與2_溴-乙醯胺衍生物之直接烷基化作 用來引入側鏈。 99857.doc 18- 1301129
流程2 根據路徑c),通式(I)之1,2,3,4-四氫異喹啉衍生物亦可由對 映異構純甲基扁桃酸酯開始以立體選擇方式來製備 (對照下文之流程3)。用醇胺溶液來處理該酯,藉此獲得可 由對甲苯確m氯而甲笨磺酸化之相應醯胺。在最後步驟 中’使该甲笨崎酸鹽與1,2,3,4-四氫異啥琳衍生物偶合以 生成通式⑴之個別化合物。 99857.doc -19- 1301129
Ph C02Me
TsCl
R3
本發明所例示之1,2,3,4 -四氫異嗤琳衍生物可使用以下通 用方法及程序由易於獲得之起始材料來製備。應瞭解在給
出典型或較佳之實驗條件(意即,反應溫度、時間、試: 之莫耳數“!丨等)之處,除非另有規定,否則 條件亦可使用。最適宜之$ _政μ 、匕貝驗 或溶劑而變化,然而該箸 應物 規優化程序來測定。 者使用常 【實施方式】 實驗部分: aq。 含水 atm 大氣壓 99857.doc '20- 1301129 BSA 牛血清白蛋白 CHO 中國倉鼠卵巢 d 天 DCM 二氯甲烷 DIPEA 二異丙基乙胺 DMAP N,N-二甲基-4-胺基吡啶 DMF 二甲基甲醯胺 DMSO 二甲亞砜 EA 乙酸乙酯 EDC 1-(3-二甲基胺基丙基)-3-乙基碳化二酸亞胺 ES 電子喷霧 FCS 胎牛血清 FLIPR 螢光成像板讀取器 h 小時 HBSS 漢克氏平衡鹽溶液 HEPES 4-(2-羥乙基)-哌嗪-1-乙磺酸 HOBt 羥基苯幷三唑 HPLC 南效能液相層析 Hex 己院 HV 高真空條件 LC 液相層析 LDA 二異丙基醯胺鋰 MeOH 甲醇 min 分鐘 99857.doc -21 - 1301129 MS 質譜 ρ.ο. 經口 prep. 製備 PyBOP 本幷二唾-1 -基-氧基-蒼-11比略σ定-鱗-六氣填酸西旨 Rf 滯留前 RT 室溫 rt 滯留時間 sat. 飽和 tic 薄層層析 THF 四氫呋喃 化學
以下實例舉例說明本發明之藥理學活性化合物之製備, 然而並非侷限於其範疇内。 所有溫度均規定為°c。 使用基於RP_C18之管柱對非對掌相進行所有分析及製備 HPLC研究。在兩種不同器具上分別以約2.5分鐘及約3.5分 鐘之循環時間來進行分析性HPLC研究。關於對掌相之 HPLC 分離,可使用講自 Daicel Chemical Industries 之 Chiralcel OD管柱。由1H-NMR(300 MHz)或 13C-NMR(75 MHz)(Varian Oxford ;相對於所用溶劑之化學位移係以 ppm給出;多樣性:s=單峰、d=雙峰、三重♦'qs四 重峰、m =多重峰、b =寬峰,偶合常數係以Hz給出)、LC-MS(rt係以min給出)、TLC(購自Merck之TLC板,矽膠60 F254)或熔點來表徵化合物。 99S57.doc -22- !3〇1129 A•合成丙酸衍生物 • ϋ成3-(6-二氣甲基-β比咬-3_基)-丙酸: U合成3_(6_三氟甲基-吡啶-3-基)_丙烯酸曱酯:
將6-三氟甲基-吡啶_3_甲醛(570 mg)之DCM(1.0 mL)溶液 添加至(三苯基-λ5_亞磷基)-乙酸甲酯(990 mg)之DCM(2.5 ml)溶液中。在氮氣下,將該混合物於回流下攪拌20小時 且在真空中濃縮。由急驟層析法(EA/庚烷,3/7)來純化該 殘餘物以生成呈白色固體狀之所要不飽和酯。 1H-NMR(300MHz,CDC13) ·· δ=3·85 (s,3H),6.59 (d,J = 16·2 Hz,1H),7.70 (d,J = 16·2 Hz,1H),7.71 (d,J = 8·1 Hz, 1H),7.98 (dd,J = 8·1 Hz,J = 2·1 Hz,1H),8.84 (bs,1H)。 12合成3-(6-三氟甲基-吡啶-3-基)-丙酸甲酯:
將3-(6-三敗甲基-。比唆-3-基)-丙烯酸甲酉旨(720 mg)之甲醇 (5.0 mL)溶液用Pd/C(10%,240 mg)處理且在氮氣氛(約1 巴)下於室溫下授拌2 0小時。該懸浮液係經石夕藻土過濾、且 在真空中濃縮以生成呈無色油狀之丙酸@旨。 iH-NMRQOOMHz,CDC13) : δ= 2.69 (t,J = 7.4 Hz,2H), 3.05 (t,J = 7.4 Hz,2H),3.68 (s,3H),7.60 (d,J = 7·8 Hz, 1H),7·71 (bd,J = 8·1 Hz,1H),8.58 (bs,1H) 〇 1.3合成3_(6_二亂甲基-。比淀-]-基)-丙酸: 99857.doc 1301129
將氫氧化鋰單水合物(330 mg)—次性添加至3_(6-三氟甲 “ 基-吡啶-3-基)-丙酸甲酯(610 111§)在11117(15 mL)與水(5 mL) 之此合物中的溶液中。將該混合物在室溫下攪拌小時且 添加DCM及HC1水溶液(1.〇 M),分離該等層且用DCM將含 水層萃取兩次。將經組合之有機萃取物經MgS04乾燥且在 W 真空中濃縮以生成呈米色固體狀之所要丙酸。 - lH-NMR(300MHz,CDC13) : δ= 2.75 (t,J = 7·4 Hz,2H), 3.06 (t,J = 7.4 Hz,2H),7.62 (d,J = 8.1 Hz,1H),7.73 (bd, .· J = 8·1 Hz,1H),8.62 (bs,1H)。 Β·合成2_溴-乙醯胺衍生物: 1·合成2_溴-小甲基_2_苯基-乙醯胺: 1.1合成N-羥基_Ν·甲基_2_苯基-乙醯胺:
ΟΗ 在0 C下將苯基乙醯氯(11.2 mL)逐滴添加至ΛΓ-甲基_羥基 胺鹽酸鹽(7.07 g)及三乙胺(59 ml)之DCM(300 mL)溶液 中。在攪拌90分鐘之後加入飽和NaHC〇3水溶液,分離該 等層且用DCM(2x200 mL)將該含水層萃取兩次。在真空中 移除该等溶劑且由急驟層析法(EA/庚烷,ιη)來純化該殘 餘物以生成呈無色液體狀之所要Ν_羥基·乙醯胺。 LC’MS : rt = 0.63分鐘,166(M+1,ES+)。 99857.doc -24- 1301129 1.2.合成2-溴-ΛΓ-曱基-2-苯基-乙醯胺: 0
N/ Η
在0°C下,將三乙胺(5_49 mL)添加至尽羥基-AT-甲基-2-苯 基-乙醯胺(6.5 g)之DCM(200 mL)溶液中。將該混合物用甲 磺醯氯(3.21 mL)之DCM(60 ml)溶液逐滴處理。2小時之後 加入水(150 mL),分離該等層且用EA(2xl00 mL)將含水層 萃取兩次。將該等有機萃取物組合且在真空中濃縮以生成 呈淺黃色油狀之粗甲磺酸酯。 將該甲磺酸酯溶解在乙腈(200 mL)中。加入溴化鋰(15.3 g)且將該反應混合物用超音處理5分鐘。在添加二異丙基-乙胺(6.78 mL)之後,將該混合物用超音再次處理5分鐘且 在室溫下另外攪拌60分鐘。添加水(150 mL)及乙酸乙醋 (200 mL),分離該等層且用乙酸乙酯(2x200 mL)將含水層 萃取兩次。將經組合之有機萃取物在真空中濃縮且由急驟 層析法(乙酸乙酯/庚烷,2 ·· 3)純化以生成呈白色固體狀之 所要溴化物。 LC-MS ·· rt= 0.75 分鐘,228(M+1,ES+)。 C·合成甲苯_4_磺酸(8)-甲基胺甲醯基-苯基-甲酯: 1。合成(S)-2-羥基-N-甲基-2-苯基-乙醯胺:
99857.doc -25 - 1301129 將甲基(S)_(+)·•扁桃酸酯(π g)溶解在甲胺之甲醇溶液(23〇 mL, 2·0 Μ)中且在室溫下保持1天。添加另一部分在甲醇中之 甲胺(10 mL,2_0 Μ)。一天以後,添加第三部分在甲醇中 之甲胺(10 mL,2.0 M)。在另外24小時之後,在真空中移 除溶劑以生成呈淺黃色晶體狀之所要扁桃醯胺,其無需進 一步純化即可使用。 LC-MS : rt = 0.52分鐘,166(M+1,ES + )。
2·合成甲苯-4-磺酸(S)-甲基胺甲醯基_苯基_甲酯:
在室溫下,將DIPEA(2.74 mL)及DMAP(145 mg)添加至 (S)-2-羥基_尽甲基_2_苯基-乙醯胺(2.4 g)之DCM(5〇 mL)溶 液中。將該混合物用對甲苯磺醯氯(2·75 g)逐份處理且在 室溫下保持2小時。在真空中移除溶劑且將殘餘物溶解在 乙酸乙酯中。將該溶液用飽和NaHC〇3溶液洗滌兩次且用 塩水洗滌一次,在真空中移除溶劑且使殘餘物自乙酸乙酯 /第三丁基甲基醚中再結晶以生成呈白色晶體狀之甲苯磺 酸鹽。 LC-MS : rt = 0.93分鐘,320(M+1,ES+)。 D·合成N_((lR,2R)-2-胺基_1,2_二苯基_乙基)_2,4,6_三甲 基-苯-績醯胺(觸媒前驅物): 99857.doc -26- 1301129
在0°C下,將2,4,6-三甲苯磺醯氯(3·09 g)之THF(150 ml) 溶液逐滴添加至(111,2尺)-1,2-二苯基-乙烧-1,2-二胺(3.00 g)、二異丙基乙胺(3.87 mL)及碳酸鉀(3.12 g)在THF(120 mL)與DMF(30 mL)之混合物中之懸浮液中。3小時之後, 添加水(300 mL)及乙酸乙酯(300 mL),分離該等層且用乙 酸乙酯(3x300 mL)將含水層萃取三次。在真空中移除溶劑 且由製備HPLC層析法來純化該殘餘物。為移除曱酸,將 所得產物用飽和NaHC03溶液/乙酸乙S旨萃取以生成呈白色 固體狀之單磺醯胺。 LC-MS · rt = 0.82分鐘,395(M+1,ES+) 〇 Ε·合成苯基乙基醯胺(通用程序)·· 將個別苯乙胺(110 mmol)之甲苯(350 mL)溶液用個別丙 酸衍生物(110 mmol)處理,在丁史塔克(Dean-Stark)疏水器 存在下回流90小時且緩慢冷卻至室溫。過濾該沉殿物且在 真空中乾燥以生成所要醯胺。 1·合成N-[2-(3,4-二甲氧基-苯基)-乙基]-3-(4-三氣甲基-苯
該化合物係由3,4-二甲氧基苯基乙胺與4-(三氟甲基)-氫 99857.doc -27- 1301129 化肉桂酸之反應來製備。 LC-MS : rt = 0.97分鐘,382(M+1,ES+) 〇 2·合成N-[2-(3,4_二曱氧基·苯基)_乙基]_3_(6_三氟甲基-吼 啶-3-基)-丙醯胺:
該化合物藉由3,4-二甲氧基苯基乙胺與3_(6•三氟曱基_,比 啶-3-基)-丙酸反應來製備。 LC-MS : rt = 0.88分鐘,383(M+1,ES+)。 F·經由醯胺-環化作用來合成3,4-二氫異喹啉衍生物(通用 程序):
將磷驢氯(123 mmol)添加至個別醯胺(55·3 mm〇1)之乙腈 (300 mL)懸浮液中。將該混合物回流9〇分鐘且在真空中移 除溶劑。添加曱醇(100 mL)且使其再次蒸發。將所得產物 自二噁烧或二噁烷/乙醇中再結晶。在過濾之後,藉由添 加飽和NaHC〇3水溶液且用二氯甲烷萃取而將所得鹽酸鹽 轉化為游離鹼。在真空中移除溶劑以生成個別二氕異疮 琳。 1·合成6,7-二甲氧基-:142-(4-三氟甲基_苯基)_乙基]_3,4_ 二氫異喹啉: 99857.doc -28· 1301129
呑亥化合物係由[2_(3,4--田每# 一甲虱基-苯基)-乙基]-3-(4•三氟 甲基-本基)-丙酿胺之環化作用來製備
LC-MS : rt = 0.81 分鐘,364(M+1,Es+)。 2·合成6,7 - —·甲氧基二翁田盆l > q装、,甘ί L —既甲基-°比。定-3-基)-乙基]- 3,4-二氫異喹啉:
該化合物係由7V-[2-(3,4-二甲氧基_苯基)_乙基]_3_(6_三氟 甲基-吼咬-3-基)-丙醯胺之環化作用來製備。 LC-MS ·· rt = 0.73分鐘,365(M+1,ES+)。 G·合成1,2,3,4·四氫異喹啉: 1·由Bisehler-Napieralski反應來合成ι,2,3,4_四氫異嗓琳 (通用程序): 向個別醯胺(44.8 mmol)之乙腈(500 mL)懸浮液中添加石舞 醯氣(224 mmol)。將該混合物加熱回流2小時且在真空中 移除溶劑。在甲苯或曱醇(MeOH)(20 mL)中萃取所得油, 99857.doc -29- 1301129 將其療發至乾燥,溶解在甲醇Me〇H(200 mL)中且冷卻至 〇。(:。以小份來添加NaBH4(135 mm〇1)且將該反應混合物攪 拌2小時。在真空中移除溶劑,添加ea(4〇〇 mL)及水(400 niL) ’分離該等層且用EA(3x2〇〇 ^乙)將含水層萃取三次。 將經組合之有機萃取物在真空中濃縮以生成呈外消旋混合 物之以下1,2,3,4-四氫異喹啉,其係藉由使鹽酸鹽自異丙 酵中再結晶而純化。
1.1.合成外消旋-6,7-二甲氧基^·!^气4-三氟甲基_苯基乙 基]-1,2,3,4 -四氫異喹琳:
該化合物係由#-[2-(3,4-二甲氧基-苯基)_乙基]-3-(4-三氟 甲基-苯基)-丙醯胺之反應來製備。 LC-MS : rt = 0.85分鐘,366(M+1,ES+)。 1.2.合成6,7 - 一甲氧基-1-[2-(6_三氟曱基定-3 -基)-乙 基]-1,2,3,4-四氫異啥琳: 99857.doc -30- 1301129
F 、F 該化合物係由#-[2-(3,4-二甲氧基-苯基)·乙基]-3-(6-三氟 甲基-吡啶-3-基)-丙醯胺之反應來製備。
LC-MS : rt = 0.73分鐘,367(M+1,ES+) 〇 2.經由轉移氫化作用來合成1,2,3,4-四氫異喹啉(通用程 序)·· 將二氯-(對·曱-異丙苯)釕(II)二聚物(0.20 mmol)添加至 7V-((lR,2R)-2-胺基-1,2-二苯基-乙基)-2,4,6-三甲基苯-磺醯 胺(0.40 mmol)與三乙胺(0.80 mmol)在乙腈(3.0 mL)中之溶 液中。將該混合物在80°C下攪拌1小時且添加至個別二氫 異喹淋(28.0 mmol)之二氯甲烧(30 mL)溶液中。添加甲酸 與三乙胺之共沸混合物(5 : 2,14 mL)(氣體析出)。在90分 鐘之後,將飽和NaHC03水溶液(200 mL)添加至該暗紅色 溶液中。分離該等層,用DCM(2x200 mL)將含水層萃取兩 次且使經組合之有機萃取物在真空中濃縮。將殘餘物溶解 在異丙醇(1600 mL)中且用HC1之異丙醇溶液(5-6 Μ,10 mL) 處理。使所得鹽酸鹽再結晶以生成如掌性HPLC所測定具 有高對映異構體過量之個別1,2,3,4-四氫異喹啉。該鹽酸 鹽係藉由用飽和NaHC03溶液/二氯甲烷萃取而轉化為游離 鹼。個別產物之絕對組態分配係類似於該文獻(N. 99857.doc -31 - 1301129
Uematsu,A. Fujii,S· Hashiguchi,Τ· Ikariya,R. Noyori,J· Am· Chem. Soc· 1996, 118, 4916-4917)。 2·1合成(lS)-6,7-二曱氧基-l-[2-(4-三氟甲基-苯基)-乙基]-1,2,3,4-四氫異喹啉:
該化合物係由6,7_二曱氧基-l-[2-(4-三氟甲基·笨基)_乙 基]-3,4-二氫異喹啉之轉移氫化作用來製備。 LC-MS : rt = 〇.8〇分鐘,366(M+1,ES+)。 掌性HPLC : rt = 12.0分鐘(己烷/乙醇,9/1 ;對映異構 物:rt = 17.1 分鐘)。 2.2合成(lS)-6,7-二甲氧基-1-[2·(6-三氟甲基-吼啶-3_基)、
該化合物係由6,7-二甲氧基-1-[2-(6-三氟甲基-吡咬 基)-乙基;1-3,4-二氫異喹啉之轉移氫化作用來製備。 LC-MS : rt = 〇·73分鐘,367(M+1,ES+) 〇 99857.doc -32- 1301129 掌性HPLC ·· rt = 1〇·9分鐘(己烷/乙醇,4/1 ;對映異構 物:rt = 24·4分鐘)。 3·經由1-甲基_3,4_二氫異喹啉之烷基化作用來合成 1,2,3,4·四氫異喹啉(通用程序)··
在〇C下將正丁基裡之己烧溶液(ι·6 μ’ 0.63 mmo 1)逐 滴添加至6,7-二甲氧基-1-甲基_3,4_二氫異喹啉(〇·5〇 mm〇i) 與一異丙胺(0·63 mmol)在THF(1.0 mL)中之混合物中。將 該反應混合物在室溫下攪拌1小時且在〇它下添加至個別苄 基溴(0·50 mmol)之THF (1.0 mL)溶液中。將該溶液攪拌! 小時,溫至室溫且用DCM(3.0 mL)稀釋。 在第二燒瓶中,將二氯(對-甲-異丙苯)釕(Π)二聚物(0.15 mmol)添加至 iV-((1R,2R)_2-胺基 二苯基-乙基)-2,4,6三 甲基-本-石頁酿胺(0.30 mmol)與三乙胺(〇·60 mmol)之乙猜 (3.3 mL)溶液中。將該混合物在8〇°C下攪拌1小時。將該溶 液之一部分(0· 10 mL)添加至個別二氫異哇琳(以上所述)之 溶液中。添加曱酸與三乙胺之共沸混合物(5 : 2,0.3 mL)(氣體析出)。2天之後將該混合物在真空中濃縮且由製 備HPLC來純化以生成個別1,2,3,4-四氫異喹啉。 該對映異構體過量係由掌性HPLC來測定。 個別產物之絕對組態分配係類似於該文獻(N. Uematsu, A· Fujii,S. Hashiguchi,Τ· Ikariya,R. Noyori,J. Ame Chem。 Soc· 1996, 118, 4916-4917)。 3·1·合成(lS)-6,7-二曱氧基-1-[2-(4·三氟甲基-苯基)_乙 基]_1,2,3,4_四氫異喹啉: 99857.doc 33· 1301129
該化合物係由6,7-二甲氧基-1-甲基_3,4_二氫異喹啉與卜 溴甲基-4-三氟甲基_苯之烧基化作用來製備。
LC_MS ·· rt = 0.80分鐘,366(M+1,ES+) 〇 掌性HPLC ·· rt = 12·0分鐘(己烷/乙醇,9/1 ;對映異構 物· rt = 17· 1 分鐘)。 H·合成(3,4-二氫-1H-異喹啉-2·基)-苯基·乙酸甲酯衍生物 (通用程序): 將 DIPEA(43.0 mmol)與 α-溴-苯基-乙酸甲酯(21·5 mm〇1) 依次添加至個別1,2,3,4·四氫異喹琳(21.5 mmol)在THF/二 噁烷或甲苯(150 mL)中之溶液中。將該混合物回流20小時 且讓其達到室溫。添加水(250 mL)與EA(200 mL),分離該 等層且用ΕΑ(2χ 100 mL)將含水層萃取兩次。使經組合之有 機萃取物在真空中濃縮且由急驟層析法來純化或無需進一 步純化即可使用。獲得下文所述之下列酯衍生物。 I合成{6,7-二甲氧基-l-[2-(4-三氟甲基-苯基)-乙基]-3,4-二氫-1H-異喹啉-2-基卜苯基-乙酸甲酯: 99857.doc -34- 1301129
該化合物係由6,7-二曱氧三氟甲基-苯基)-乙 基]-1,2,3,4-四氫異喹啉與〇!_溴_苯基_乙酸甲 酯之反應來槊 備。 9 LC_MS : rt = 〇·93分鐘,514(M+1,ES+)。 - 2·合成{6,7_二甲氧基-1-[2-(6·三氟甲基-吡啶-3-基)-乙 ' 基]-3,4-二氫-iH_異喹啉_2_基卜苯基-乙酸甲酯:
4化合物係由6,7_二甲氧基_丨_[2_(6-三氟甲基-吡啶-3_ 基)-乙基]-1,2,3,4_四氫異喹啉與溴-苯基-乙酸甲酯之反 應來製備。 LC-MS · rt。168分鐘,515(M+1,ES+)。 3·合成{(1S)_6,7-二甲氧基-1-[2-(4_三氟甲基-苯基)-乙基l· 3,4-一虱-iH_異喹啉_2•基卜苯基_乙酸甲酯: 99857.doc -35- 1301129
"亥化合物係由(lS)-6,7-二甲氧基-l-[2-(4_三氟甲基-苯 基乙基]-1,2,3,4·四氫異喹啉與α·溴-苯基-乙酸甲酯之反 應來製備。
LC-MS · rt = 〇·93分鐘,514(M+1,ES+)。 I·合成(3,4_二氩-1Η-異喹啉基)_苯基-乙酸衍生物(通用 程序): 將氫氧化鈉之水溶液(2·〇 Μ,50 mL)添加至個別酯(21.5 mmol)之甲醇(400 mL)溶液中。將該混合物加熱至60°C且 攪拌20小時。將大部分甲醇在真空中移除且在氫氧化鈉溶 液(2·0 Μ,20 mL)、水(1〇〇 mL)及 DCM(100 mL)中萃取殘 餘物。分離該等層且用DCM(3xlOO mL)將含水層萃取三 次。使經組合之有機萃取物在真空中濃縮以生成個別羧 酸,其無需進一步純化即可使用: 1·合成{6,7-二甲氧基三氟甲基_苯基)_乙基卜3,4-二氫-1H-異喹啉-2_基卜苯基-乙酸··
99857.doc -36- 1301129 該化合物係由{6,7-二甲氧基-1-[2-(4·三氟曱基_苯基)_乙 基]-3,4-二氫· 1Η-異喹啉-2-基卜苯基-乙酸甲酯之皂化作用 來製備。 LC-MS : rt :=0·88分鐘,500(M+1,Es+)。
2·合成{6,7-二甲氧基-1-[2-(6•三氟甲基-吼啶-3-基)-乙 基]·3,4_二氫_1Η-異喹啉-2-基卜苯基·乙酸:
該化合物係由{6,7-二甲氧基-1-[2-(6-三氟甲基-吡啶-3-基)-乙基]_3,4-二氫-1Η-異喹啉-2-基卜苯基-乙酸曱酯之皂 化作用來製備。 LC-MS : rt==118分鐘,499(m_:1,ES·),501(M+;l,ES+)。 3·合成{(lS)-6,7-二甲氧基-1_[2-(4-三氟甲基-苯基)-乙基]_ 3,4_二氫異喹啉-2_基}-苯基-乙酸:
该化合物係由{(lS)-6,7-二甲氧基·1-[2-(4-三氟甲基-苯 基)_乙基]·3,4_二氫-1Η•異喹啉_2_基}•苯基-乙酸甲酯之皂 化作用來製備。 99857.doc -37- 1301129 LC-MS : rt =0.88分鐘,500(M+1,ES+)。 實例1 :合成2-{6,7-二甲氧基_l-[2-(4-三氟曱基-苯基)-乙 基】-3,4-二氮-1H-異喧琳-2-基}_1^-甲基-2-苯基·乙酿胺
在〇°C下,將甲胺鹽酸鹽(15.0 mmol)與NaHC03(20.0 mmol)添加至{6,7-二甲氧基-1_[2·(4-三氟甲基-苯基)-乙 基]-3,4-二鼠-1Η-異喧琳-2-基}-苯基-乙酸(10·0 mmol)之 DMF(200 mL)溶液中。15分鐘之後添加HOBt(12.0 mmol) 及EDC鹽酸鹽(22·0 mmol)。將該混合物攪拌10分鐘且在不 攪拌之狀態下另外在〇°C下保持14+時。添加水(100 mL)、 EA(300 mL)及環己烷(100 mL),分離該等層且用3: 1之 EA/環己烧(2 X 15 0 mL)將含水層萃取兩次。使經組合之有 機萃取物用飽和NaHC03水溶液(100 mL)及塩水(100 mL)洗 條且經Na2S〇4乾燥。在真空中移除溶劑且由急驟層析法 (梯度:EA/庚烷(1/2)至EA/乙醇/庚烷(2/1/2))來純化殘餘物 以生成所要醯胺,其為所有四種可能立體異構體之混合 物。 LC-MS ·· rt = 0.89分鐘,513(M+1,ES+)。 實例2 :合成(2R)_2-{(lS)-6,7_二甲氧基_1-[2-(4-三襄甲 基-苯基)-乙基】-3,4 -二氮-1H-異唾琳-2-基}- N-甲基-2苯基_ 99857.doc -38- 1301129 乙醯胺
cf3 /° 、〇 a) 程序I(經由醯胺-偶合):
在〇°C下,將甲胺鹽酸鹽(23.7 mmol)及NaHCO3(2.01 g, 23·9 mmol)添加至{(lS)-6,7-二甲氧基-l_[2-(4-三氟甲基-苯 基)-乙基]-3,4-二氫-1H-異喹啉-2-基卜苯基-乙酸(21.5 mmol)之DMF(300 mL)溶液中。在5分鐘之後,添力口 HOBt(23.8 mmol)及 EDC鹽酸鹽(47.6 mmol)。將該混合物 攪拌2小時且在不攪拌狀態下另外在0°C下保持14小時。添 加水(300 mL)及EA(300 mL),分離該等層且用EA(3xl50 mL)將含水層萃取三次。用水(3x100 mL)及塩水(100 mL) 洗滌經組合之有機萃取物。在真空中移除溶劑且由急驟層 析法(EA/庚烷,3/2)來純化殘餘物以生成呈獨立非對映異 構體之所要醯胺。 b) 程序11(經由溴化物衍生物之烷基化作用): 將DIPEA(119 mmol)添加至2-溴-7V-甲基-2-苯基-乙醯胺 (59.6 mmol)之 THF(150 mL)溶液中。添加(lS)-6,7-二甲氧 基-1-[2-(4·三氟甲基-苯基)-乙基]-1,2,3,4-四氫異啥琳(62.7 mmol)之THF(200 mL)溶液且在60°C下將該反應混合物攪拌 7天。添加乙酸乙酯(200 mL)及飽和NaHC03水溶液(200 99857.doc -39- 1301129 mL),分離該等層且將含水層用乙酸乙酯(2χΐ〇〇 mL)萃取 兩次。使經組合之有機萃取物用水(3x5〇 mL)洗滌,經
MgSCU乾煉且在真空中濃縮。由急驟層析法(乙酸乙酯/庚 烷,3/2)來純化殘餘物以生成呈獨立非對映異構體之所要 醯胺。 c)粒序111(經由甲苯石黃酸鹽衍生物之烧基化作用): 將(1S)_6,7-二甲氧基三氟曱基_苯基乙基]· 1,2,3,4-四氫異喹啉(100 mg)、甲苯_4_磺酸(s)_甲基胺甲醯 基-苯基-甲基酯(1〇〇 mg)&DIPEA(0 065 mL)之丁酮(5 〇 mL)’合液加熱回流3天且冷卻至室溫。添加乙酸乙酯且將該 混合物用飽和NaHC〇3水溶液及塩水洗滌。使有機層經
NaJO4乾燥且在真空中移除溶劑。將〇 mL)及在異 丙醇中之HC1溶液(5-6 Μ,〇·ΐ〇 mL)添加至粗產物中且在 真空中移除溶劑。使所得固體自THF(2 〇 mL)中再結晶以 生成呈白色晶體狀之所要酸胺。 給出更多活性非對映異構體之游離鹼之資料(IC^, FLIPR) 〇
Rf = 〇·21(ΕΑ/庚烷,2/1); LC-MS : rt = 0.90分鐘,513(M+1,ES+); 軍HHPLC · rt = 18.9分鐘(己烧/乙醇,95/5 ;非對映異 構體4 = 22.3分鐘;y,2,3,4_w氫異料環系統中具有 相對組態之其它兩個可能立體異構體係類似於上述合成來 製備,其使用iV-((iS,2s)_2_胺基],2_二苯基_乙基)_2,4,6_ 三甲基-苯-磺醯胺(步驟α2)來進行轉移氫化〔該等異構體 99857.doc -40- 1301129
具有下列滯留時間:rt = 26·2分鐘,33.8分鐘); iH-NMRpOOMHz,CDC13) : δ= 1·74_1·87 (m,1Η),2·04· 2·19 (m,1H),2.40-2.52 (m,1H),2.59-2.72 (m,1H),2·86 (d,J = 4·8 Hz,3H),2.86-3.01 (m,1H),3·03-3·18 (m,2H), 3.30-3.41 (m,2H),3.69 (s,3H),3.84 (s,3H),4.25 (s,1H), 6.03(s,lH),6.57(s,lH),6.87(q,J = 4.8Hz,lH),7.10-7.16 (m,2H),7·19·7·28 (m,5H),7.50 (d,J = 8·1 Hz,2H); 13C-NMR(75MHz,CDC13) : δ= 21.9, 26.1,33.4, 37.8, 40.7, 55.8, 55.9,57.0,70.1,110.0,111.4,124.2 (q,JC,F = 271 Hz),124.9,125.1 (q,JC,F = 4 Hz),128.0 (q,JC,F = 32 Hz), 128.1,128.4,128.5,129.0,137.0,146.2,147.1,147.6, 172.2。 實例3 :合成2_{6,7_二甲氧基-l_[2-(6-三氟甲基·吡啶-3_ 基)-乙基】-3,4-二氫_1H-異喹啉-2_基}-1\·甲基-2_苯基-乙醯 胺
將{6,7-二甲氧基- l-[2-(6-三氟甲基-吡啶-3-基)-乙基l· 3,4-二氫-1H-異喹啉-2_基}_笨基-乙酸(〇·2〇 mm〇1)、甲胺鹽 酸鹽(0.20 mmol)、PyBOP(〇.2〇 mm〇i)及 〇ΙΡΕΑ(0·46 mmol) 在DMF(1.0 mL)中之混合物在室溫下攪拌2〇小時。添加水 及E A ’分離該等層且將含水層用e a萃取。使經組合之有 99857.doc -41- 1301129 機萃取物經MgS04乾燥且在真空中濃縮。由急驟層析法 (EA)來純化殘餘物以生成呈黏性油狀之所要產物。 LC_MS : rt = 1.17分鐘,514(M+1,ES+) 〇 實例4 :合成(2R)_2_{(1S)_6,7·二甲氧基_1_[2_(6_三氟甲基· °比啶-3·基)-乙基卜3,4-二氫-1H-異喹啉_2_基}-]^-曱基-2-苯 基-乙醯胺
將 DIPEA(20.8 mmol)添加至(lS)-6,7-二甲氧基小[2-(6- 二氟甲基-°比啶-3-基)-乙基]-1,2,3,4-四氫異喹琳(1〇.〇 mmol)之THF(40 mL)溶液中。添加2_溴_,甲基_2_苯基乙 醯胺(10·4 mmol)且將該混合物在60〇c下攪拌5天。添加水 (100 mL)及乙酸乙酯(2〇〇 mL),分離該等層且用乙酸乙酯 (2x100 mL)將含水層萃取兩次。使經組合之有機萃取物在 真空中濃縮且由急驟層析法(乙酸乙酯/庚烷,3/丨)來純化 殘餘物以生成呈獨立非對映異構體之所要醯胺。 給出更多活性非對映異構體之資料(IC5〇,FLIPR)。
Rf =0·15(ΕΑ/庚烷,3/1); LC-MS : rt = 0.81 分鐘,514(M+1,ES+); H-NMR(300MHz,CDC13) : δ= 1_73-1·86 (m,1Η),2 〇2 2.16 (m,1H),2.41-2.52 (m,1H),2·59-2·71 (m,IH),2·87 (d,J = 5.1 Hz,3H),2.88-3.03 (m,1H),3.04-3.17 (m,2H) 99857.doc -42- 1301129 6 (m,2H),3.69 (s5 3H),3.83 (s,3H),4.23 (s,1H), 6.04 (s, 1H),6.55 (s,1H),6.74 (q,J = 5el Hz,1H),7 1〇_ 7.16 (m5 2H)5 7.19-7.27 (m? 3H)? 7.51-7.61 2Η^ 8.52 (s,1H)。 生物檢定 活體外檢定
、弋()化&物之食怒素受體结抗劑活性係根據以下實驗 方法來測定。 、 實驗方法: •細胞内鈣量測: - 使分別表現人類食慾素-1受體及人類食慾素_2受體之中 國倉鼠印巢(CHO)細胞在含有300 pg/mL G418、1〇〇 u/ml 月破素1 〇〇 Mg/mL鍵彳致素及1 〇%去活化胎牛血清(peg)之 培養基(具有L-麩胺醯胺之Ham f-12)中生長。將該等細胞 以80,〇〇〇個細胞/孔接種至已預塗覆1 %明膠於漢克斯平衡 % 鹽溶液(HBSS)中之96孔黑色透明底部無菌盤(c〇star)中。 所有試劑均係購自Gibco BRL。將接種盤在37它下5%c〇2 中隔夜培養。 作為激動劑之人類食慾素係被配成1 mM溶於甲醇:水 (1 ·丨)之儲備溶液,將其在含有0.1%牛血清白蛋白(BSA) , 及2 mM HEPES之HBSS中稀釋以10 nM最終濃度用於檢 定。 拮抗劑係被配成1 〇 mM溶於DMSO儲備溶液,接著將其 稀釋於96孔盤上,首先在DMSO中,接著在含有0.1%牛血 99857.doc -43 - 1301129 清白蛋白(BSA)及2mMHEPES之HBSS中。 在檢定當天,將1〇〇 μΐ負載培養基(含有1% FCS、2 mM HEPES、5 mM 丙石黃舒(probenecid)(Sigma)及 3 μΜ 螢光 I弓指 示劑fluo-3 AM(具有10%泊洛尼克酸之1 mM溶於DMSO之 儲備溶液)(分子探針)之HBSS)添加至各孔中。
將該等96孔盤在37°C下於5% C02中培養60分鐘。接著抽 出負載溶液且將細胞用200 μΐ含有2.5 mM丙磺舒、0.1% BSA、2 mM HEPES之HBSS洗滌三次。將100 μΐ該相同緩 衝液留在各孔中。 在螢光成像板讀取器(FLIPR,分子元件)中,將50 μΐ體 積之拮抗劑添加至該盤上’培養20分鐘且最終添加100 μΐ 激動劑。以1秒時間間隔來量測各孔之螢光,且將各螢光 峰之高度與用緩衝劑代替拮抗劑由1 〇 ηΜ食慾素-Α誘發之 螢光峰的高度相比。對各拮抗劑而言,測定IC5〇值(抑制 50%激動劑回應所需之化合物濃度)。化合物之拮抗劑活性 係在毫微莫耳範圍内。 •量測對抗不同CYP之抑制效能: 使用人類肝微粒體(共1〇個個體)、文獻已建立之CYP重 整異構體選擇性基質及由LC-MS/MS(用於CYP3A4及 CYP2C9)或習知HPLC用螢光探測(適用於CYP2D6)所進行 之量化來進行CYP抑制作用研究。該等特定探針為用於 CYP3A4之口米達嗤命(midazolam)l’-經基化作用、用於 CYP2D6之右甲嗎喃3-羥基化作用及用於CYP2C9之雙氣芬 酸4’-羥基化作用。在96孔盤中以約為個別Km值之基質濃 99857.doc -44- 1301129 度(表1顯示該等實驗條件之概述)及7個高達50 μΜ之抑制 劑濃度重複進行兩次實驗。在各盤中對對照組(用於 CYP2C9之磺胺苯吡唑、用於CYP2D6之氟西汀及用於
CYP3A4之尼卡地平)進行平行實驗。 CYP重整異 基質與 微粒體濃度 培養時間 構體 濃度(μΜ) (mg/ml) (min) CYP3A4 咪達吐舍(5) 0.25 5 CYP2C9 雙氯芬酸(5) 0.10 6 CYP2D6 右甲嗎喃(8) 0.20 30 表1 如下表2所說明,在實例1至4中所述之化合物顯示出對 抗CYP3A4之極低親合力。 實例 CYP3A4 IC5〇 [μΜ] 實例1 CF3 32 實例2 CF3 46 99857doc -45- 1301129
由無線電遙測術來量測實驗室大鼠之自發性籠内活性及體溫: 本測試之目的係記錄在經口施以根據本發明通式⑴之化 合物之後大鼠之晝夜行為活性。
據認為藉由遙測雄性威斯塔(wistar)大鼠所量測之減少 的籠内活性指示受限數目之高度優化l52,3,4_四氫異喹啉 衍生物的睡眠誘發潛力。 口人已热知諸如抗抑鬱劑、精神抑制劑、睡眠誘發劑或 精神刺激劑之精神藥物在實驗室動物經口投藥之後會減少 ^支曰強龍内活性及體溫。體溫調節為複雜過程,其藉由配 ^代謝、能量平衡及行為來促成體内恆^。體溫隨著晝夜 仃為活ίΐ而變化且隨著運動增加而增加。該等兩個東數係 ::遙剛有意識自由活動之威斯塔大鼠來量測。在無菌條 内。在::體温’活性遙測元件植入經麻痹動物之腹膜腔 遙測糸統植入兩週以上之後,於96小時内以5分 99857.doc 46 1301129 ”間間隔來收集資料。計算各大鼠之每小時平均值。將 :一個48小時用作内部控制跡線且將藥物效應與媒劑安慰 =比。藉由量測由諸如唾吼坦(zolpidem)之gabaa受體 °1切所誘發的活動減退與體溫過低之振幅及時間過程來 在藥理學上證實該方法。
+下表3所說明,諸如在實例1至4中所述之彼等投藥,
99857.doc -47-
Claims (1)
- I I 々ί年/>月7曰修(更)正本 i70號專利申請案 呀專利範圍替換本(96年12 '申請專利範圍:氫異喧琳衍生物 .R3 -種通式⑴之1,2,3,4, 其中: Rl與R2獨立代表氫或Ci_C4^氧基; 反代表Ci-C6-烧基; X代表-CH-或氮原子; 及其光學純對映異構體、對映異構體之混合物、消旋 體、光學純非對映異構體、非對映異構體之混合物、非 對映異構消旋體、非對映異構消旋體之混合物或内消旋 形式及醫藥學上可接受之鹽、溶劑複合物及形態學形 式。 如μ求項1之1,2,3,4·四氫異喹啉衍生物,其中R1與化2兩 者均代表(VC4烷氧基。 如叫求項2之l,2,3,4-四氳異喹啉衍生物,其中111與112兩 者均代表甲氧基。 ^ 4·如凊求項1至3中任一項之心四氫異喧琳衍生物,豆 中Χ代表氮原子。 5·如睛求項丨至3中任一項之四氫異喹啉衍生物,其 99857-961207.doc 1301129 中X代表-CH-。 6·如請求項1至3中任一項之1,25354_四氫異喹啉衍生物,其 中R3代表甲基。 如明求項1至3中任一項之ΐ,2,3,4·四氫異喧琳衍生物,其 中R1與R2代表曱氧基,Χ代表_CH_且r3代表Ci_C6_烷基。 8.如請求項1至3中任一項之i,2,3,4_四氫異喹啉衍生物,其 係選自由以下各物組成之群·· φ 2_{6,7-二甲氧基-1·[2-(4-三氟甲基_苯基)_乙基]_3,4_二 氫-17/_異喹啉_2_基}善甲基-2·苯基-乙醯胺; • 2-{6,7-二甲氧基-1-[2-(6-三氟甲基_吡啶-3-基)_乙基]_3,4_ ' 二氫異喹啉_2·基卜…甲基·2·苯基乙醯胺。 • 9·如請求項1至3中任一項之1,2,3,4-四氫異喹啉衍生物,其 係用作醫藥品。 ' 10· 一種預防或治療選自由飲食障礙及睡眠障礙組成之群之 疾病之醫藥組合物,其含有至少一種如請求項丨至8中任 Φ 一項之化合物及醫藥學上可接受之載劑材料。 u· —種如請求項1至8中任一項之1,2,3,4-四氳異喹啉衍生物 供製備預防或治療疾病之醫藥品之用途,其中該等疾病 係選自由飲食障礙或睡眠障礙組成之群。 12.如請求項11之用途,其中該等飲食障礙包含代謝功能障 礙、不正常食慾控制、強迫肥胖症、催吐貪食症或神經 性厭食症。 U·如請求項π之用途,其中該等睡眠障礙包含失眠、猝睡 症及其它過度嗜睡病症、與睡眠相關之肌張力障礙、過 99857.961207.doc 1301129 動腳症候群、睡眠呼吸暫停、時差症候群、輪班作業症 候群、延時或提前睡眠狀態症候群。99857-961207.doc
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Families Citing this family (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1751111B1 (en) * | 2004-03-01 | 2014-12-31 | Actelion Pharmaceuticals Ltd. | Substituted 1,2,3,4-tetrahydroisoquinoline derivatives |
MX2008011647A (es) * | 2006-03-15 | 2008-09-22 | Actelion Pharmaceuticals Ltd | Derivados de tetrahidroisoquinolina para mejorar la funcion de la memoria. |
JP2009533419A (ja) | 2006-04-11 | 2009-09-17 | アクテリオン ファーマシューティカルズ リミテッド | 新規スルホンアミド化合物 |
EP2013209B1 (en) * | 2006-04-26 | 2011-01-19 | Actelion Pharmaceuticals Ltd. | Pyrazolo-tetrahydropyridine derivatives as orexin receptor antagonists |
JP2009543785A (ja) | 2006-07-14 | 2009-12-10 | メルク エンド カムパニー インコーポレーテッド | 架橋ジアゼパンオレキシン受容体アンタゴニスト |
PE20081229A1 (es) | 2006-12-01 | 2008-08-28 | Merck & Co Inc | Antagonistas de receptor de orexina de diazepam sustituido |
US8188082B2 (en) * | 2006-12-22 | 2012-05-29 | Actelion Pharmaceuticals Ltd. | 5,6,7,8-tetrahydro-imidazo[1,5-α]pyrazine derivatives |
CL2007003827A1 (es) * | 2006-12-28 | 2008-09-26 | Actelion Pharmaceuticals Ltd | Compuestos derivados de n-(2-aza-biciclo(3.1.0)hex-3-ilmetil)amida; y su uso para prevenir o tratar la depresion, neurosis, esquizofrenia, ansiedad, adicciones, epilepsia, dolor, enfermedades cardiacas, entre otras. |
CN101646668A (zh) * | 2007-04-04 | 2010-02-10 | 弗·哈夫曼-拉罗切有限公司 | 作为食欲肽拮抗剂的杂环类 |
JP2010527924A (ja) | 2007-05-18 | 2010-08-19 | メルク・シャープ・エンド・ドーム・コーポレイション | オキソ架橋ジアゼパンオレキシン受容体アンタゴニスト |
US8030495B2 (en) | 2007-05-23 | 2011-10-04 | Coleman Paul J | Cyclopropyl pyrrolidine orexin receptor antagonists |
MY148544A (en) | 2007-05-23 | 2013-04-30 | Merck Sharp & Dohme | Pyridyl piperidine orexin receptor antagonists |
CZ302135B6 (cs) * | 2007-07-09 | 2010-11-10 | Zentiva, A. S. | Zpusob výroby 5-[2-cyklopropyl-1-(2-fluorfenyl)-2-oxoethyl]-4, 5, 6, 7-tetrahydrothieno[3,2-c]pyridin-2-yl acetátu (prasugrelu) |
PE20091010A1 (es) | 2007-10-10 | 2009-08-08 | Actelion Pharmaceuticals Ltd | Derivados de tetrahidroquinolina |
JP5100298B2 (ja) * | 2007-10-11 | 2012-12-19 | 株式会社トクヤマ | 光学活性α−スルホニルオキシカルボン酸アミド誘導体及びその製造方法 |
US8084464B2 (en) * | 2007-12-18 | 2011-12-27 | Concert Pharmaceuticals, Inc. | Tetrahydroisoquinoline derivatives |
US8314238B2 (en) * | 2007-12-28 | 2012-11-20 | Actelion Pharmaceuticals Ltd. | Process for the preparation of an enantiomeric trisubstituted 3,4-dihydro-isoquinoline derivative |
CA2709694C (en) | 2007-12-28 | 2016-04-05 | Actelion Pharmaceuticals Ltd | Trisubstituted 3,4-dihydro-1h-isoquinolin compound, process for its preparation, and its use |
JP2011524398A (ja) * | 2008-06-16 | 2011-09-01 | エフ.ホフマン−ラ ロシュ アーゲー | オレキシニン受容体アンタゴニストとしてのヘテロ芳香族モノアミド |
JP2011525910A (ja) * | 2008-06-25 | 2011-09-29 | アクテリオン ファーマシューティカルズ リミテッド | 5,6,7,8−テトラヒドロ−イミダゾ[1,5−a]ピラジン化合物 |
CN101402643B (zh) * | 2008-11-11 | 2012-11-28 | 上海现代制药股份有限公司 | 一种适于工业生产的普拉格雷的制备方法 |
JP2012510493A (ja) | 2008-12-02 | 2012-05-10 | グラクソ グループ リミテッド | N−{[(ir、4s、6r)−3−(2−ピリジニルカルボニル)−3−アザビシクロ[4.1.0]ヘプタ−4−イル]メチル}−2−ヘテロアリールアミン誘導体およびその使用 |
WO2010064212A1 (en) | 2008-12-05 | 2010-06-10 | Actelion Pharmaceuticals Ltd | Method for obtaining an optically pure 1,2,3,4 tetrahydro-isoquinoline derivative |
GB0823467D0 (en) | 2008-12-23 | 2009-01-28 | Glaxo Group Ltd | Novel Compounds |
WO2010095106A1 (en) | 2009-02-20 | 2010-08-26 | Actelion Pharmaceuticals Ltd | Solid forms of ( 2r) -2- { ( is ) -6, 7 -dimethoxy- 1- [2- (4-triflu0r0methyl-phenyl) -ethyl] -3, 4-dihydr0-1h -isoquinolin-2-yl} -n-methyl-2-phenyl-acetamide hydrochloride |
AU2010240871A1 (en) | 2009-04-24 | 2011-10-27 | Glaxo Group Limited | 3 -azabicyclo [4.1.0] heptanes used as orexin antagonists |
WO2011001373A1 (en) | 2009-06-30 | 2011-01-06 | Actelion Pharmaceuticals Ltd | Process for the preparation of an enantiomerically pure trisubstituted 1,2,3,4-tetrahydroisoquinoline derivative |
WO2011005636A1 (en) * | 2009-07-09 | 2011-01-13 | Merck Sharp & Dohme Corp. | Tetrahydronapthyridine orexin receptor antagonists |
JP2013502448A (ja) | 2009-08-24 | 2013-01-24 | グラクソ グループ リミテッド | オレキシンアンタゴニストとして用いられるピペリジン誘導体 |
US20120149723A1 (en) | 2009-08-24 | 2012-06-14 | Romano Di Fabio | 5-methyl-piperidine derivatives as orexin receptor antagonists for the treatment of sleep disorder |
CZ2009686A3 (cs) | 2009-10-19 | 2011-04-27 | Zentiva, K. S | Zpusob prípravy (1S)-6,7-dimethoxy-1-[2-(4-trifluormethylfenyl)ethyl]-1,2,3,4-tetrahydroisochinolinu |
EP2491038B1 (en) | 2009-10-23 | 2016-04-06 | Janssen Pharmaceutica N.V. | Disubstituted octahy - dropyrrolo [3,4-c]pyrroles as orexin receptor modulators |
CZ2009791A3 (cs) | 2009-11-25 | 2011-06-01 | Zentiva, K. S. | Krystalická a amorfní forma hydrochloridu (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-fenyl)-ethyl]-3,4-dihydro-1H-isochinolin-2-yl}-N-methyl-2-fenyl-acetamidu (almorexantu) a zpusob jejich prípravy |
CZ20106A3 (cs) * | 2010-01-05 | 2011-08-10 | Zentiva, K. S | Zpusob prípravy 6,7-dimethoxy-1-[2-(4-trifluormethylfenyl)ethyl]-3,4-dihydroisochinolinu |
EP2402322A1 (en) | 2010-07-02 | 2012-01-04 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-tetrahydroisoquinoline derivative and its use as orexin receptor antagonist |
JP5744203B2 (ja) | 2010-08-24 | 2015-07-08 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | オレキシン受容体拮抗薬としてのプロリンスルフォンアミド誘導体 |
BR112013006594B1 (pt) | 2010-09-22 | 2021-08-17 | Eisai R&D Management Co., Ltd | Composto ciclopropano antagonista de receptor da orexina e composição farmacêutica |
US9242970B2 (en) | 2010-11-10 | 2016-01-26 | Actelion Pharmaceuticals Ltd. | Lactam derivatives useful as orexin receptor antagonists |
WO2012085857A1 (en) | 2010-12-22 | 2012-06-28 | Actelion Pharmaceuticals Ltd | 3,8-diaza-bicyclo[4.2.0]oct-3-yl amides |
WO2012089606A1 (en) | 2010-12-28 | 2012-07-05 | Glaxo Group Limited | Azabicyclo [4.1.0] hept - 4 - yl derivatives as human orexin receptor antagonists |
WO2012089607A1 (en) | 2010-12-28 | 2012-07-05 | Glaxo Group Limited | Novel compounds with a 3a-azabicyclo [4.1.0] heptane core acting on orexin receptors |
JP5987005B2 (ja) | 2011-02-18 | 2016-09-06 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | オレキシン拮抗薬として有用な新規なピラゾール及びイミダゾール誘導体 |
WO2012114252A1 (en) | 2011-02-21 | 2012-08-30 | Actelion Pharmaceuticals Ltd | Novel indole and pyrrolopyridine amides |
WO2012135465A2 (en) * | 2011-04-01 | 2012-10-04 | Indiana University Research And Technology Corporation | Treatment of glaucoma |
WO2013050938A1 (en) | 2011-10-04 | 2013-04-11 | Actelion Pharmaceuticals Ltd | 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives |
AR088352A1 (es) | 2011-10-19 | 2014-05-28 | Merck Sharp & Dohme | Antagonistas del receptor de 2-piridiloxi-4-nitrilo orexina |
SG11201401665WA (en) | 2011-11-08 | 2014-09-26 | Actelion Pharmaceuticals Ltd | 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives as orexin receptor antagonists |
EP2811997B1 (en) | 2012-02-07 | 2018-04-11 | Eolas Therapeutics Inc. | Substituted prolines/piperidines as orexin receptor antagonists |
US9440982B2 (en) | 2012-02-07 | 2016-09-13 | Eolas Therapeutics, Inc. | Substituted prolines/piperidines as orexin receptor antagonists |
EP2647377A1 (en) | 2012-04-06 | 2013-10-09 | Sanofi | Use of an h3 receptor antagonist for the treatment of alzheimer's disease |
DK2855453T3 (en) | 2012-06-04 | 2017-02-06 | Actelion Pharmaceuticals Ltd | Benzimidazol-proline derivatives |
SG11201502493XA (en) | 2012-10-10 | 2015-04-29 | Actelion Pharmaceuticals Ltd | Orexin receptor antagonists which are [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone derivatives |
JP2016510810A (ja) | 2013-03-12 | 2016-04-11 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | オレキシン受容体アンタゴニストとしてのアゼチジンアミド誘導体 |
UA119151C2 (uk) | 2013-12-03 | 2019-05-10 | Ідорсія Фармасьютікалз Лтд | КРИСТАЛІЧНА СОЛЬОВА ФОРМА (S)-(2-(6-ХЛОР-7-МЕТИЛ-1H-БЕНЗО[d]ІМІДАЗОЛ-2-ІЛ)-2-МЕТИЛПІРОЛІДИН-1-ІЛ)(5-МЕТОКСИ-2-(2H-1,2,3-ТРИАЗОЛ-2-ІЛ)ФЕНІЛ)МЕТАНОНУ ЯК АНТАГОНІСТ ОРЕКСИНОВОГО РЕЦЕПТОРА |
EA030137B1 (ru) | 2013-12-03 | 2018-06-29 | Идорсиа Фармасьютиклз Лтд | Кристаллическая форма (s)-(2-(6-хлор-7-метил-1н-бензо[d]имидазол-2-ил)-2-метилпирролидин-1-ил)(5-метокси-2-(2h-1,2,3-триазол-2-ил)фенил)метанона и ее применение в качестве антагонистов орексинового рецептора |
MX366642B (es) | 2013-12-04 | 2019-07-17 | Idorsia Pharmaceuticals Ltd | Uso de derivados de bencimidazol-prolina. |
EP3180332B1 (en) | 2014-08-13 | 2021-10-27 | Eolas Therapeutics Inc. | Difluoropyrrolidines as orexin receptor modulators |
WO2016063995A1 (en) | 2014-10-23 | 2016-04-28 | Eisai R&D Management Co., Ltd. | Compositions and methods for treating insomnia |
US10377763B2 (en) | 2015-10-29 | 2019-08-13 | University Of Tsukuba | Morphinan derivative and medical usage thereof |
KR20180107232A (ko) | 2016-02-12 | 2018-10-01 | 아스트라제네카 아베 | 오렉신 수용체 조정제로서의 할로-치환된 피페리딘 |
MY197558A (en) | 2016-03-10 | 2023-06-23 | Janssen Pharmaceutica Nv | Methods of treating depression using orexin-2 receptor antagonists |
KR101671008B1 (ko) * | 2016-04-13 | 2016-12-01 | 한국과학기술원 | TNP(N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 식욕억제용 약학적 조성물 |
WO2017194548A1 (en) | 2016-05-10 | 2017-11-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of autoimmune inflammatory diseases |
CN110117271A (zh) * | 2018-02-06 | 2019-08-13 | 中国科学院上海药物研究所 | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
WO2020007964A1 (en) | 2018-07-05 | 2020-01-09 | Idorsia Pharmaceuticals Ltd | 2-(2-azabicyclo[3.1.0]hexan-1-yl)-1h-benzimidazole derivatives |
WO2020007977A1 (en) | 2018-07-06 | 2020-01-09 | Idorsia Pharmaceuticals Ltd | 7-trifluoromethyl-[1,4]diazepan derivatives |
WO2020099511A1 (en) | 2018-11-14 | 2020-05-22 | Idorsia Pharmaceuticals Ltd | Benzimidazole-2-methyl-morpholine derivatives |
WO2023218023A1 (en) | 2022-05-13 | 2023-11-16 | Idorsia Pharmaceuticals Ltd | Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives |
CN117126134A (zh) * | 2022-05-20 | 2023-11-28 | 中国科学院上海药物研究所 | 新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 |
Family Cites Families (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3480714A (en) | 1966-02-07 | 1969-11-25 | Ciba Geigy Corp | N-substituted isoquinolines as antiprotozoal agents |
DD204917A1 (de) | 1981-12-31 | 1983-12-14 | Gerhard Kempter | Verfahren zur herstellung phenylsubstituierter und benzkondensierter cycloalkylaminoacetanilide |
DE3419642A1 (de) | 1984-05-25 | 1985-11-28 | Boehringer Mannheim Gmbh, 6800 Mannheim | Verfahren und reagenz zur vollenzymatischen bestimmung von harnstoff |
JPS6153268A (ja) | 1984-08-24 | 1986-03-17 | Hokuriku Seiyaku Co Ltd | アントラニルアミド誘導体 |
DD261158A1 (de) | 1987-01-08 | 1988-10-19 | Univ Halle Wittenberg | Verfahren zur herstellung von 2-aminoalkyl-3,4-dihydro-4-oxo-7h-pyrrolo 2.3-d pyrimidinen |
DD258817A1 (de) | 1987-01-19 | 1988-08-03 | Univ Halle Wittenberg | Verfahren zur herstellung von 2-(aminoalkyl) -pyrimido-4,5'-5,4 pyrrolo 3,2-f 1,4 thiazepinderivaten |
WO1992012132A1 (en) | 1991-01-11 | 1992-07-23 | Laboratoires Glaxo S.A. | Acridine derivatives |
JPH07267961A (ja) | 1994-03-30 | 1995-10-17 | Taisho Pharmaceut Co Ltd | ベンゾフロ[3,2−dピリミジン−4−オン誘導体 |
EP1300381B1 (en) | 1995-12-06 | 2006-03-08 | Japan Science and Technology Agency | Process for preparing optically active alcohols |
US6635479B1 (en) | 1996-08-02 | 2003-10-21 | The Scripps Research Institute | Hypothalamus-specific polypeptides |
JPH1095766A (ja) | 1996-09-19 | 1998-04-14 | Sanwa Kagaku Kenkyusho Co Ltd | アセトアミド誘導体、及びその用途 |
WO1998023593A1 (en) | 1996-11-27 | 1998-06-04 | Pfizer Inc. | Apo b-secretion/mtp inhibitory amides |
AR016817A1 (es) | 1997-08-14 | 2001-08-01 | Smithkline Beecham Plc | Derivados de fenilurea o feniltiourea, procedimiento para su preparacion, coleccion de compuestos, compuestos intermediarios, composicion farmaceutica,metodo de tratamiento y uso de dichos compuestos para la manufactura de un medicamento |
DE69906960T2 (de) | 1998-05-08 | 2004-01-29 | Smithkline Beecham Plc | Phenylurea und phenylthio urea derivate |
WO2000029399A1 (en) | 1998-11-12 | 2000-05-25 | Boehringer Ingelheim (Canada) Ltd. | Antiherpes compounds |
GB9827467D0 (en) | 1998-12-15 | 1999-02-10 | Zeneca Ltd | Chemical compounds |
GB9914015D0 (en) | 1999-06-17 | 1999-08-18 | Zeneca Ltd | Chemical compounds |
ATE241345T1 (de) | 1999-02-12 | 2003-06-15 | Smithkline Beecham Plc | Neue verwendung von orexinrezeptorantagonisten |
WO2000047576A1 (en) | 1999-02-12 | 2000-08-17 | Smithkline Beecham Plc | Cinnamide derivatives as orexin-1 receptors antagonists |
ATE274512T1 (de) | 1999-02-12 | 2004-09-15 | Smithkline Beecham Plc | Phenylharnstoffe und phenylthioharnstoffe als orexinrezeptorantagonisten |
ATE282614T1 (de) | 1999-02-12 | 2004-12-15 | Smithkline Beecham Plc | Phenylharnstoff und phenylthioharnstoffderivate |
GB9914025D0 (en) | 1999-06-17 | 1999-08-18 | Zeneca Ltd | Chemical compounds |
WO2001002368A1 (en) | 1999-07-06 | 2001-01-11 | Vertex Pharmaceuticals Incorporated | N-heterocyclic derivatives with neuronal activity |
EP1252329A4 (en) | 1999-07-30 | 2004-12-22 | Univ Leland Stanford Junior | HYPOCRETINE AND HYPOCRETINE RECEPTORS FOR THE REGULATION OF SLEEP AND SLEEP DISORDERS |
US6319710B1 (en) | 1999-08-23 | 2001-11-20 | Decode Genetics Ehf. | Human narcolepsy gene |
US6410712B1 (en) | 1999-10-25 | 2002-06-25 | Decode Genetics Ehf. | Human narcolepsy gene |
WO2001040304A1 (en) | 1999-12-01 | 2001-06-07 | Smithkline Beecham Corporation | Monkey orexin 2 receptor |
WO2001040259A2 (en) | 1999-12-02 | 2001-06-07 | Smithkline Beecham Corporation | Monkey orexin 1 receptor |
US20020064814A1 (en) | 1999-12-07 | 2002-05-30 | Ellis Catherine E. | Dog orexin 1 receptor |
CN100393703C (zh) | 2000-03-14 | 2008-06-11 | 埃科特莱茵药品有限公司 | 1,2,3,4-四氢异喹啉的衍生物 |
AU2001251306A1 (en) | 2000-04-04 | 2001-10-15 | Siegel, Jerome M. | Treatment of sleep disorders with hypocretin-1 |
CA2408343A1 (en) | 2000-05-11 | 2002-11-07 | Banyu Pharmaceutical Co., Ltd. | N-acyltetrahydroisoquinoline derivatives |
EP1289955B1 (en) | 2000-06-16 | 2005-04-13 | Smithkline Beecham Plc | Piperidines for use as orexin receptor antagonists |
EP1353918B1 (en) | 2000-11-28 | 2005-01-12 | Smithkline Beecham Plc | Morpholine derivatives as antagonists of orexin receptors |
US20020166135A1 (en) | 2000-12-20 | 2002-11-07 | Waleh Nahid S. | Modulators of the hypocretin system and methods of screening therefor |
WO2002051232A2 (en) | 2000-12-27 | 2002-07-04 | Actelion Pharmaceuticals Ltd. | Novel benzazepines and related heterocyclic derivatives |
EP1435955A2 (en) | 2001-05-05 | 2004-07-14 | SmithKline Beecham P.L.C. | N-aroyl cyclic amine derivatives as orexin receptor antagonists |
ES2299567T3 (es) | 2001-05-05 | 2008-06-01 | Smithkline Beecham Plc | N-aroilaminas ciclicas. |
GB0115862D0 (en) | 2001-06-28 | 2001-08-22 | Smithkline Beecham Plc | Compounds |
HUP0400326A2 (hu) | 2001-06-28 | 2004-09-28 | Smithkline Beecham P.L.C. | Orexin receptor antagonistákként alkalmazható ciklikus N-(aril-karbonil)-amin-származékok és ezeket tartalmazó gyógyszerkészítmények |
GB0124463D0 (en) | 2001-10-11 | 2001-12-05 | Smithkline Beecham Plc | Compounds |
GB0126292D0 (en) | 2001-11-01 | 2002-01-02 | Smithkline Beecham Plc | Compounds |
GB0127145D0 (en) | 2001-11-10 | 2002-01-02 | Smithkline Beecham | Compounds |
GB0130341D0 (en) | 2001-12-19 | 2002-02-06 | Smithkline Beecham Plc | Compounds |
GB0130335D0 (en) | 2001-12-19 | 2002-02-06 | Smithkline Beecham Plc | Compounds |
GB0130393D0 (en) | 2001-12-19 | 2002-02-06 | Smithkline Beecham Plc | Compounds |
GB0130388D0 (en) | 2001-12-19 | 2002-02-06 | Smithkline Beecham Plc | Compounds |
NZ535885A (en) | 2002-04-26 | 2007-05-31 | Hoffmann La Roche | Isoquinoline derivatives and their use as monoamine oxidase B inhibitors |
AU2003262963A1 (en) | 2002-08-29 | 2004-03-19 | The Regents Of The University Of California | Hypocretin administration as a treatment for obesity |
US20060040937A1 (en) | 2002-09-18 | 2006-02-23 | Glaxo Group Limited | N-aroyl cyclic amines as orexin receptor antagonists |
GB0225944D0 (en) | 2002-11-06 | 2002-12-11 | Glaxo Group Ltd | Novel compounds |
GB0225884D0 (en) | 2002-11-06 | 2002-12-11 | Glaxo Group Ltd | Novel compounds |
GB0225938D0 (en) | 2002-11-06 | 2002-12-11 | Glaxo Group Ltd | Novel compounds |
AU2003299648A1 (en) | 2002-12-12 | 2004-06-30 | Janssen Pharmaceutica, N.V. | Substituted 4-phenyl-(1,3)-dioxanes |
US7618786B2 (en) | 2002-12-13 | 2009-11-17 | Janssen Pharmaceutica N.V. | Method for identifying modulators of human orexin-2 receptor |
US20060178515A1 (en) * | 2003-03-26 | 2006-08-10 | Hamed Aissaoui | Tetrahydroisoquinolyl acetamide derivatives for use as orexin receptor antagonists |
EP1751111B1 (en) * | 2004-03-01 | 2014-12-31 | Actelion Pharmaceuticals Ltd. | Substituted 1,2,3,4-tetrahydroisoquinoline derivatives |
MX2008011647A (es) | 2006-03-15 | 2008-09-22 | Actelion Pharmaceuticals Ltd | Derivados de tetrahidroisoquinolina para mejorar la funcion de la memoria. |
EP2013209B1 (en) | 2006-04-26 | 2011-01-19 | Actelion Pharmaceuticals Ltd. | Pyrazolo-tetrahydropyridine derivatives as orexin receptor antagonists |
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2005
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