TW200934491A - 1,3,5-trisubstituted triazole derivative - Google Patents
1,3,5-trisubstituted triazole derivative Download PDFInfo
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- TW200934491A TW200934491A TW097139807A TW97139807A TW200934491A TW 200934491 A TW200934491 A TW 200934491A TW 097139807 A TW097139807 A TW 097139807A TW 97139807 A TW97139807 A TW 97139807A TW 200934491 A TW200934491 A TW 200934491A
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Description
200934491 六、發明說明: 【發明所屬之技術領域】 ’本發明係關於2-[3-(2,2_二氟-苯并[1,3]二噚茂-5-基胺 基)-5-(2,6-二甲基-吼啶-4-基χυ/]三唑-1-基]-N-乙基-乙 醯胺及其醫藥上可接受之鹽,該等之製備方法,含有該等 之醫藥纽成物,及該等在治療之用途。本發明係關於選擇 性’ α7菸鹼酸乙醯膽鹼受體之有效的正變構調節劑,其具 有增強終驗酸受體激動劑功效的性能。 10 15 20 【先前技術】 ΕΡ1044970揭示作為神經肽γ受體配位體之3_烷基胺 基-1,2,4-三唾0
由 Makara G.M.等人(有機報告書(2〇〇2) V〇1.4(10); 1751-1754)揭示3-烧基胺基4,2,4-三唑之固相合成且例示 N-(4-甲氧基苯基)-1-甲基_5(4-甲基苯基三唑_3_ 胺[CAS No: 433710-55-5]之不成功的合成,並對該化合物 之潛在治療性應用無關,尤其是關於其用作α7菸鹼酸的乙 醯膽鹼受體之正變構調節劑之用途無關。 men men 書U (麗)3购⑽:;=ΓΓ與醫藥化學 卿,2,似之合成,尤其 -5-(2,4-二氣苯基)-1Η-1,2,4-三唑_3_胺,、土 本基)_1_ 腺皮質釋放因子-l(CRFl)拮抗劑。 ,、作馬從 97511發明說明窖 4 200934491 發明背景 膽鹼能受體一般係結合内生性神經诚睹 乙 (ACh),從而觸發離子孔道開放。在哺乳類中樞神經系^中 ACh,受體根據各毒蕈鹼與菸鹼之激動齊j活性而可被二類 5 ❹ 10 15 ❹ 毒蕈驗(mAChR)與菸鹼酸(nAChR)亞型。菸鹼 ?分=為 ,,00 、赋駿的乙醯膽鹼 受體係包括五個次早元之配位體驅動式離丨、* 哪卞钆道。根據該 等胺基酸序列nAChR次單元基因族系之部份被分成兩種群 組;一種群組包括所謂β次單元,而第二個群組包括^ a 單元。三種α次單元,α7、(Χ8及α9。在單獨表現5已二$ 形成功能性受體’因此被推定可形成同系低聚物的五聚物 受體。 吾人已發展出nAChR變構轉換狀態模式,其涉及至少 一靜止狀態,一活性狀態與一”脫敏化”關閉的孔道狀態, 藉由一製程使受體變成對激動劑不敏感。不同的nACh^配 位體可使該配位體所優先結合之受體之構形狀態予以穩定 化。例如,各激動劑ACh與(-)-菸鹼可使活性化與脫敏化狀 態穩定化。 改變终驗酸受體之活性已涉及頗多疾病。有一些例如 重症肌無力與正染色體顯性夜間發作前葉癲癇(adnfle) 係與菸鹼酸的傳送之活性降低相關連,此係因為受體數目 之減低或脫敏作用之增加,兩者之原因之一。 菸鹼酸受體之減低亦被假設為中介可見諸於如阿茲海 默症與精神分裂症之疾病的認知不足。 來自煙草之於驗效果亦被於驗酸受體所中介,而由於 20 200934491 菸鹼之作用在於在脫敏化狀態中使受體穩定化,菸鹼酸受 體之活性增加可降低對抽煙之慾望。 結合nAChR之化合物已被建議用於治療某些範圍之 疾患,包含膽鹼能功能減低,諸如學習障礙、認知不足、 5 注意力不足或記憶喪失。調節α7菸鹼酸受體活性被期望在 至少包括阿茲海默症、路易體失智症、注意力不足過動障 礙症、焦慮症、精神分裂症、狂燥、躁狂抑鬱狀態、帕金 森氏病、杭丁頓氏舞蹈症、妥瑞氏症候群、腦外傷或其他 神經病學的,基因退化的或精神病學的疾患之頗多疾病為 10 有益的,在該等疾病中,有包括時差感,菸鹼癮,疼痛的 膽鹼能突觸之喪失。 無論如何,以在相同部位作用為ACh之於鹼酸受體激 動劑之治療是有問題的,這是因為ACh不僅活化、但亦經 由包括脫敏作用與非競爭性阻斷之方法來阻斷受體活性。 15 再者,延長的激活作用顯示可誘導常效的去激活。因此, ACh之激動劑可期望減低活性並予增強。 一般在菸鹼酸受體且尤其是在α7-菸鹼酸受體上,脫敏 作用限制所用到激動劑之作用期間。 2〇 【發明内容】 令人驚異的,本發明人首先發現2-[3-(2,2-二氟-苯并 [1,3]二口等茂-5-基胺基)-5-(2,6-二曱基比啶-4-基)-[1,2,4]三 唑-1-基]-N-乙基-乙醯胺在菸鹼酸的乙醯膽鹼受體可增強激 動劑之功效。具有此作用形式之化合物被稱為π正變構調節 200934491 劑"並可能用以治療與終驗酸傳送之減低為相關連之疾 病。在一種治療裝置’中該化合物可回復正常神經元間傳 達而不會影響激活作用之暫時的型態。此外,正' ' … 劑並不被期望可產生受體之長期非激活作用,如 調即 劑重覆或延長的使用之後所發生的情況。 5激動 本發明之正nAChR調節劑可用以治療或預防 ❹ 10 15 ❹ 疾患、智能障礙疾患或疾病,調節(X7菸鹼酸A 炎性疾病或症狀。 :、、、有皿之 本發明係關於2-[3-(2,2-二氟·苯并[U]二啐茂5某胺 基)-5-(2,6-二甲基-吡啶_4_基H1,2,4]三唑小基]·队乙^乙 醯胺’其具有正變構的調節劑性質,在„7菸鹼土, 強激,劑之功效。本發明㈣係關於製備方法與包含該^ =醫藥組成物。本發明亦係關於使用該衍生物用以製^供 f療或預防精神病疾患、智能障礙疾患或疾病、或調節α7 '驗酸雙體為有益之疾病或症狀之藥劑。 本發明之化合物及其鹽類與先前技術之化合物在構造 上=同’且藉由其作為α7菸鹼酸的乙醯膽鹼受體之正變構 調痛^丨^增強活性,並藉由其增強之水溶性,且藉由其增 進的°式管内心血管安全參數,尤其是對hERGf鉀孔道之親 和性降低而在藥理學上不同。 本發明係關於化合物(1) 20 200934491
或醫藥上可接受之鹽或其水合物、或其溶劑化物。 對於治療性用途,根據一船彳 等中抗衡離子為醫藥上可接受i式之鹽類係該 ^然而非醫藥上可接·
5 10 15 鹽類亦可發現其錢,勤,在製備或純化醫藥上可= 之化合物。所有鹽類,無論是否為醫藥上可接受者均包含 於本發明之領域。 如前述或後述之醫藥上可接受之加成鹽類意指至少包 括化合物(I)可形成之治療性地活性非毒性之酸加成鹽形 式。醫藥上可接受之酸加成鹽類可藉由進行鹼形式與該等 適當酸之處理而便利地獲得。適當的酸類至少包括例如諸 如氫鹵酸之無機酸,例如氫氣酸或氫溴酸、硫酸、硝酸、❹ 填酸之類之酸;或諸如例如乙酸、丙酸、羥乙酸、乳酸、 丙酮酸、草酸(例如乙二酸)、丙二酸、破珀酸(例如丁二酸)、 順丁烯二酸、反丁稀二酸、蘋果酸、酒石酸、檸檬酸、曱 續酸、乙橫酸、苯確酸、對甲苯確酸、環己炫氣基續酸、 水楊酸、對胺基水楊酸、雙羥萘酸之類酸的有機酸。相反 地該鹽形式可藉由進行適當鹼成為游離鹼形式之處理而被 轉換。 水合物與溶劑化物一詞係關於水合物與醇鹽’其根據 8 20 200934491 式(i)之化合物以及其鹽類可形成。 根據式(I)之化合物亦可以互變異構物形式存在,該等 形式雖然在上述一般式並無詳盡地說明但仍然包含於^ 明之範疇。 ' 本化合物之贺備 ❹ 根據本發明之化合物一般可由一系列步驟來製備,各 步驟對熟悉該項技藝人士為已知。尤其是,在本專利申請 案中之化合物可根據下列之製造方法來製備(圖解丨至5): 圖解1
Gl 1)NH4NGS (I)
2) H2N
(II) (III) 酿基硫脲(II)在2階段獲得。在第1階段,醯基氣(1) 與諸如例如硫氰酸銨之單價陽離子硫氰酸鹽反應,以產生 對應的酿基異硫氰酸鹽。此反應可使用作為溶劑之内綱 在溫度介於0。(:與70。(:之間來進行,較佳為在室溫進行。 在第二階段可有利的在相同反應媒質中進行:笨賤 在無隔離+間物之縣異硫氰酸鹽下,被添加以產生 之N-酿基硫脲。該反應通常係在溫度介於〇。〇與 進行,較佳為在室溫(圖解D。 間 9 20 200934491 圖解2
c, (II) Cl (IV) q f 在下一步驟中’ N-酿基硫腺(II)之S-曱基化提供N-酿 基石反亞胺硫代酸(carbomimidothioic acid),為一般式(iv)之 甲基酯衍生物。此種轉化需要鹼之存在,較佳為諸如NaH 或碳酸鉀之強無機鹼,且在諸如例如DMF、THF之類的無 質子溶劑進行,溫度係在_70。〇至室溫,較佳為〇艺(圖解2)。 圖解3
15 N-醯基碳亞胺硫代酸(carb〇mimid〇thi〇ic狀⑻,一般: =之甲_生物制2•肼乙酸乙基⑽,氯化氫鹽可被4 ^為式(V)之1,2,4_三嗤。此轉化典型為在諸如曱醇或丨 =醇之親質子溶劑實施,且需要溫度介於室溫與15代: 在一特定具體例中,高級醇為三級丁基醇且反應溫2 計晷12GC之間’最佳$ 1G(rc。較佳為添加驗之化d 1之量。該驗可為諸如乙酸鉀或碳酸_之無機驗,更4 …無論如何祕為三級胺,諸如二^基乙基胺或編 20 200934491 之物(圖解3)。 圖解4
©式(V)之[1,2,4]三唑-1-基]-乙酸乙基酯被轉換成對應的 [1,2,4]三唑-1-基]-N-乙基-乙醯胺(VI),藉由在親質子溶劑中 10 於溫度介於〇與80°C之間,較佳為在室溫下以過量乙基胺 處理(圖解4)。 15
圖解5
一般式(I)之最終二甲基取代吡啶并三唑,可在由75% 至85容積%THF與15%至25容積%NMP所組成之溶劑系 統中,在乙醯丙酮鐵(III)之催化劑量存在下,藉由使2-氯 吡啶基前體(VI)與過量(3至15當量)格利亞試劑MeMgBr 之處理來製備。該轉化可在溫度介於0°C與50°C之間進行, 最佳為介於〇°C與25°C之間(圖解5)。 20 200934491 藥理學 5 10 15 20 本發明之化合物經發現為α7菸鹼峻受 節劑。α7菸鹼酸受體(a7nAChR)係屬於 正變構調 (cys彻p)之超科,離子轉移配位體驅動式胺酸套圈 5-HT3 ’ GABAa與甘胺酸受體族系。其被乙 =素與α%·之主要特徵在於於激動劑之 寺存在下之快速脫敏作用。其在腦内為第二充 0 酸受體亞型且為多種神經遞#釋放之重要調節劑在 連於注意與認知過程之某些腦部構造具有離散的八備 如海馬迴與前額葉皮質區,且已涉及人類之多種ς神病學 的與神經病學的疾患。其亦涉及膽鹼能炎性路徑。 其與精神分裂症結合之遺傳學上證據已見諸於精神分 裂症標記(感覺閘道缺損)及在叫叫4之 基因之核心啟動基因區域中之多形現象之間有著強大連結 之形式。 ^病理學上證據指向在精神分裂症腦部之海馬迴、前額 f皮質區與扣帶皮質區十,在帕金森氏病與阿兹海默症與〇 至旁核’與孤獨症中之連合核(nudeus刚心㈣中,α<7免 疫反應性與a-Btx-結合之喪失。 藥理學上證據諸如與正常人比較之有標記的精神分裂 患者的抽煙癖好已被詮釋為病人之企圖自我藥物治療以補 償a7菸鹼能傳送之缺乏。當前腦膽鹼能活性低(例如第2 階#又.睡覺)時,於精神分裂患者之於驗投與與暫時恢復正 常感覺閘道之際,於動物模型與人兩者在感覺閘道(前脈衝 12 200934491 = 時性正常化’兩者均被_為 時的激活作用接著是脫敏化之結果。 抽^此魏好的理由假設餘a7nAChR騎乡CNS (精 神病予的與神_學的)疾患會有治療㈣有益效果。 ❹ ίο
15 Q 20 “如已敘述者’ a7nACh^持久的存在天然傳遞素乙醯 邊以及諸如祕之外目性驗體下迅速地賴化。在脫 敏化狀態巾受體保細有配㈣但是功能上為;f活性。此 ?諸如乙,膽鹼與膽素之天然傳遞素並非為問題所在,這 是因為該等為用以非常強力的分解(乙醯膽義酶)與清除 率(膽素傳遞者)機制之基冑。料傳遞素分解/清除率機制 在生理學上可用的範圍可能維持在可活性化與脫敏化 a7nAChR間之平衡。然而合成激動劑,其並非用以天然分 解及清除率機制之基質,而可理解具有對過度刺激,與亦 為推動a7nAChR種群平衡至一持久的脫敏化狀態兩者均具 有潛在傾向,而此在缺乏〇1711八(:1111表現或功能扮演重要角 色之疾患中並非所需。激動劑本來必須以ACh結合囊袋為 目標’竽囊袋遍及不同的菸鹼酸受體亞型為高度守恆導至 藉由其他於驗酸受體亞型之非特定激活作用之不良反應之 可能性。因此為避免此種潛在性的傾向,一種對a7催動作 用之可替代的治療性策略係以正變構調節劑(pAM)增強對 天然激動劑之受體反應性。PAM係定義為與激動劑結合部 位有區別之部位之藥劑,因此並不被期望具有激動劑或脫 敏作用之性質’但是會增強a7nAChR對天然傳遞素之反應 性。該策略之價值在於對一已知傳遞素之量,與於其不存 13 200934491 在時可能之傳料級相比較,cx7nAChR反應之強度在pAM 之存在下增加。因此對疾患在a7nAChR蛋白有缺乏之處, 在a7菸鹼能傳送之pAM誘導增加則為有益的。就如 仰賴於天然傳遞素之存在,對過度刺激之可能性則受限於 對天然傳遞素之分解/清除機制。 本發明之化合物係根據定性的動力性質,如全細胞電 屋箝制紀錄所定義’而可分類為Μ $。該分類係根據 α7ΡΑΜ化合物之效力,如前述之在被激動劑應用所引發之 信號。特別是該激動劑為濃度在lmM之膽素。在一較佳的Ο 實驗設定,如後述該a7 PAM化合物與膽素同時被應用於 細胞。如說明於後之脫敏作用係在應用激動劑於全細胞電 壓箝制電生理測量之期間,於激活作用之際關閉受體,可 由在被激動劑之初始激活作用之後向外電流之減少所示。 PAM第1-4型之定義係如下述: 第1型:化合物增強由lmM膽素所引發之電流之有效 大小’但疋在受體動力學之後為最小。尤其是,由激動劑 所引發之脫敏作用之速率與脫敏化之程度並不受影響。對❹ lmM膽素之化合物調節反應,因而在缺乏a7pAM化合物 下為lmM膽素反應之線性比例調整之結束。 第2型:化合物增強被lmM膽素所引發之電流有效大 小,而降低脫敏作用速率及/或程度。 第3型:化合物增強被lmM膽素所引發之電流有效大 小。當在更高濃度至高ΙΟμΜ測試時,其完全抑制脫敏化, 尤其是使用250毫秒之lmM膽素。 200934491 5 ❹ 10 15 ❹ 第4型··化合物允許於受體之初始脫敏作用,接著是 在激動劑使用期間之受體再開。在PAM化合物之低效 力濃度,激動劑誘導激活作用’接著是脫敏作用’仍然能 自化合物誘導再開被分離而作為初始向内電流之最大值。 在α7 ΡΑΜ化合物之較高的效力濃度,由於脫敏作用使得 再開發生得比關閉更快,以致於初始電流最大值消失。 因此本發明之一標的係提供一種治療方法’其包括投 與:正變構調節劑作為唯一的活性物質,因而可調節諸如 乙醯膽鹼或膽素的内生性菸鹼酸受體激動劑之活性;或者 將正變構調節劑與於驗酸受體激動劑一起投與,兩者之 一。在本發明態樣之一的特定形式中’治療方法至少包括: 如在此所述之以α7菸驗酸受體之正變構調節劑,及α7菸 驗酸受體激動劑或部伤激動劑之治療。具有α7終驗酸受體 激動劑活性之適當化合物之例子包含但非限於: -1,4-二氮雜雙環[3.2.2]壬烷-4-羧酸,4-溴苯基酯,單氯化 氫(SSR180711A); -(_)_螺[1_氮雜雙壤[2.2.2]辛烧-3,5'-'1寻1»坐。定]_2|__; _ 3-[(2,4·二甲氧基)亞苄基[假木賊因二氫氯化物 (GTS-21); 醯胺氫氯 [N-[(3R)-1 氮雜雙環[2.2.2]辛士基Μ-氣苯甲 化物;1PNU_282987)。 對/α療或預防精神病疾患、智能障;^ 疾病或疾患、或調節(Χ7菸鹼醴总驹芏w ^ 3月匕暉礙 士路日日的方法★ 體活性為有益的症狀為有 用。本發 之1職樣為治療學習障礙、認知不 15 200934491 足、注意力不足或記憶喪失之方法,調節α7於驗酸受體活 性在眾多疾病被期望為有益,這些疾病包含阿兹海默症、 路易邀失智症、注意力不足過動障礙症、焦慮症、精神分 裂症、狂燥、躁狂抑鬱狀態、帕金森氏病、杭丁頓氏舞蹈 症、妥瑞氏症候群、腦外傷或其他神經病學的、基因退化 的或精神病學的疾患’其中有包含時差感、於驗瘾、疼痛 之膽鹼能突觸喪失。 本化合物(一種或多種)可作為(一種或多種)抗炎性藥 物之治療性用途,此係因為菸鹼酸的乙醯膽鹼受體α7次單〇 元藉由膽鹼能炎性經路抑制細胞因子(cytokine)合成為主 要。可以本化合物(一種或多種)治療之適應症之例有内毒素 血症(endotoxemia)、内毒素休克、敗血症、類風濕性關節 炎、氣喘、多發性硬化症、炎性腸疾病、炎性膽疾病、克 隆氏疾病、胰臟炎、心臟衰竭、與異體移植物注射(all〇graft rejection)。 鑒於上述藥理學上性質,化合物與其醫藥上可接受之 加成鹽可做藥物使用。尤其是本發明之化合物可用以製造〇 用於精神病疾患、智能障礙疾患或疾病、或調節α7菸鹼酸 受體為有益的疾病之治療或預防的藥劑。 鑒·於本化合物之用途,茲提供一種治療包含人類之溫 血動物所患疾病之治療方法,或包含人類之溫血動物之預 防方法,其患有之疾病中以調節α7菸鹼酸受體為有益的疾 病,諸如精神分裂症、狂燥、與躁狂抑鬱狀態、焦慮症、 阿茲海默症、學習障礙、認知不足、注意力不足、記憶喪 200934491 ❹ 10 15 ❹ 20 易體失智症、注意力不足過動障礙症、帕金森氏病、 瘧月疚、虑分+、女^氏症候群、腩外傷、時差感、於驗 i r杵a。法至少包括投與例如系統性或局部性投 ,、,較仫為!口投與根據式 合 化學,的異構形式,㈣上w 3 /、之所有立體接 成鹽、溶劑化物、或 ”尺口物之有效I,於包含人類在内之溫血動物。 對熟悉該項技藝人士而言可確認本發明PAM之治療 =有效量射調節α7祕較體活性之 ==’在治療性配方中之化合物濃度,: 二右μ的左:同’一般而言’用以治療調節α7菸鹼酸受 體為有现的錢之料治療性_所欲投與之ΡΑΜ之量 ^由,之醫師因個人之情況來決定,該等疾病有諸如精 神为裂症、狂燥與躁狂抑態、焦慮症、阿兹海默症、 學習障礙、認知不足、注意力不足、記憶喪失、路易體失 智症、注意力不足過動障礙症、帕金森氏病、杭丁頓氏舞 蹈症、妥瑞氏症候群、腦外傷、時差感、菸鹼癮及疼痛。 一般而s,適當的劑量為一種在治療部位造成ρΑΜ濃 度於0.5ηΜ至200μΜ之範圍’且更普遍為5ηΜ至卿μ之 範圍。為獲得該等治療濃度,需要治療之病人似乎會以 0.005毫克/公斤至10毫克/公斤體重之量投與,尤其是〇1 毫克/公斤至0.50毫克/公斤體重。根據本發明之化合物量, 在此亦稱為活性成份,其被要求可獲致治療性地效果當然 端視個人情況而不同’並因特定化合物、投與經路、年齡 與接文者條件、與所治療之特定疾患或疾病而不同。治療 17 200934491 方法亦可包括服用方式(regimen)為介於每天一次服用與四 次服用之間投與活性成份。根據本發明化合物之該等治療 方法較佳為在投藥(admission)之前配製。如下述,適當的'醫 藥調配物係使用一般所熟知且可即時用到之成份,^以 知之程序製備。 ° 本發明亦提供一種用以預防或治療調節&7菸鹼酸受 體為有益的疾病之組成物,該等疾病有諸如精神分裂症、 狂燥與躁狂抑鬱狀態、焦慮症、阿茲海默症、學習障礙、 認知不足、注意力不足、記憶喪失、路易體失智症、注竞〇 力不足過動障礙症、帕金森氏病、杭丁頓氏舞蹈症、妥瑞 氏症候群、腦外傷、時差感、菸鹼瘾及疼痛。該組成物包 括根據本式(I)之治療上有效量之化合物、與醫藥上可接受 之載劑或稀釋劑。 & 雖然活性成份可單獨投與,但較佳為其呈一種醫藥組 成物。因此本發明進而提供一種醫藥組成物,其包含根據 本發明之化合物,以及醫藥上可接受之載劑或稀釋劑。就 與組成物之其他成份可相容且對接受者本身並非有害的之〇 意義而言,該載劑或稀釋劑必需為”可接受”。 本發明之醫藥組成物對熟悉藥學人士可以任何周知之 方法製備,例如使用諸如揭示於Gennaro等人,Remington's 製藥科學(第18版,Mack出版公司,1990,可參照尤其是 第8部:製藥配方與其製造)之方法。治療上有效量之以鹼 形式或加成鹽形式的特定化合物,作為活性成份係與醫藥 上可接受之載劑結合為密切的混合物,其可根據用以投與 200934491 Ο 10 15 ❹ 20 二!採用廣泛多樣的形式,該等醫藥組成物以 服所需,其適合較佳為系統性投與,諸如口 5 腸外投與;或局部投與,諸如經吸入、魯嘴 劑、凝勝、洗髮精或其他同樣之: 醫藥的介質:=Γ服劑型形式’可使用任意的-般 配方之情形有ϋ 糖衆、_及溶液之口服液體 在粉太,=例如水、乙二醇類、油類、醇類之類:或 類、糖類、囊與鍵劑之情形如固體載劑,諸如殿粉 由於該等容、湖滑劑類、黏合劑類、崩解劑之類。 量單糾tr’錠劑與膠嚢代表大部分有利的口服劑 田二 情形固體醫藥的載劑可明確的使用。斜 二分載劑通常至少包括滅菌水,至少為大 然而其他組成份例如有助於溶解 =例如可注射溶液中載劑至少包括鹽水;液:葡= :或生理食鹽水及葡萄糖溶液之混合物,亦可製=: 懸浮劑之類。在適於經皮虽的液體載劑、 至少包括穿透增強劑及二;成的物二載劑可任意地 喂m),以較小的比例任意與適當的任何種類 =(職able 而此添加劑並不會對皮膚造成任何重大 4、劑結合, 添加劑可促進對皮膚之投與及/或可有助、害的效果。該 物。該等組成物可以不同方式投與,例如於製備所需之組成 作為滴劑(sp〇t-on)或作為軟膏。 作為經皮膚膜片、 調配上述醫藥組成物呈劑量單 t式以使劑量容易投 200934491 性為特別有利。用於本說明書與申請專利範圍之 >里_㈣式係指適於料單一射之物理性離散單位, 母一 f位包括—財之活性成份之量加以計算以產生與所 ,醫藥上載劑結合之所要求的治療效果。該等劑量單位形 、之例有1¾:劑(包含力口截痕(sc〇red)或包膜的錠劑)、膠囊、 劑&末小包、糯米紙、可注射溶液或懸液、一茶匙容 量、一大砑哒容量之類,及其隔離的成組(multiples)。 田本發明之化合物可使用於系統投與,諸如口服、經皮 或月腸外投與;或局部投與,諸如經吸入、鼻喷劑、眼滴Ο 劑或經乳膏、凝膠、洗髮精或其他同樣之物。化合物較佳 為口服投藥。正確的劑量與投與之頻度則依照根據式(1)所 使用之特定化合物、所治療之特定疾病 、所治療疾病之嚴 重性、年齡、體重、性別、疾患之程度與特定病人之身體 情況以及個人所服用之其他藥物,而為如熟悉該項技藝人 士所周知者。再者,有證據顯示該有效的每日量依照所治 療標的之反應及/或依照醫師對本發明的化合物開處方之評 估可予以減低或增加。 〇 根據一般式(I)之化合物可與其他傳統之α7菸鹼酸受 體激動劑做組合,諸如例如丨,4_二氮雜雙環[3.2.2]壬烷-4-竣酸、4_溴苯基酯、單氯化氫(SSR18〇711A);螺[1-氣 雜雙環P·2.2]辛烷_3,5,-呤唑啶]_2,_酮;3-[(2,4_二曱氧基)亞 节基]-假木賊因二氫氣化物(GTS-21);或[N-[(3R)-1-氮雜雙 環[2.2.2]辛-3-基]-4-氣苯曱醯胺氫氯化物]PNU—282987)。 因此本發明亦係關於根據式⑴之化合物與α7菸鹼酸受體 200934491 激,劑之組合。該組合可作為藥劑使用。本至 ⑷根據式⑴之化合物,與⑻《7終驗^體激動劑, 有=時、分開或連續、 藥上可接==合不同的藥物可在單-製劑與醫 【實施方式】 ❹ 冑備本發明化合物之—些方法獅於T狀實施例。 除非另有說明,所有起始原料均獲自供應商且其之使用並 10 無進一步純化。 在此之後及在此之前之内容,”DMF"意指Ν,Ν·二甲基 甲酿胺,ΝΜΡ”意指1-甲基_2-»比„各烧酮;,,THF”意指四氫 呋喃’且"DIPE”意指二異丙基醚。 〜 對中間物之LCMS-特徵與本發明之化合物,係使用下 15 列方法。 ❹ 一般程庠 HPLC測量法之進行係使用Alliance HT 2790〇Vaters 公司)系統,以如下所述之各方法來進行,該系統至少包括 2〇 具有除氣裝置之四元幫浦、自動進樣器、高低溫管柱恆溫 器(對LCMS程序1設定在60°C,且對LCMS程序2設定 在40°C),二極體陣列檢測器(DAD)及管柱。來自管柱之液 流被分流至MS光譜儀。MS檢測器係以電喷灑離子化來源 構成。質譜係藉由使用0.1秒之停留時間在1秒内由1〇〇 21 200934491 掃瞄.至1000來獲得。毛細針電壓為3kv且來源溫度被維持 於140 C。鼠係用作喷霧器氣體。資料掏取係以 Waters-Micromass Mass Lynx-〇penlynx 數據系統來進行。 LCMS葙序1 除了 一般程序之外:逆相HPLC係在流動率丨.6毫升/分 之 XtermMS C18 管柱(3.5μΜ、4.6x l〇〇mm)上進行。三二 動相(移動相A: 95% 25mM乙酸銨+ 5%乙腈;移動相B 乙腈;移動相c:曱醇)被使用以執行梯度條件在65分鐘中❹ 自100%A至50%B與50%C,在0.5分鐘内至10〇%B,並 保持此條件1分鐘,且以100%A進行再平衡丨5分鐘。使 用了注射體積1〇μ1。對正離子化模式之錐電壓為1〇v且 負離子化模式為20V。 15 20 L_CMS裎庠2 Γ僅用於中閂物) 除了 一般程序之外:逆相HPLC以流速3毫升/分在 ChromoHth (4.6 X 25mm)進行。三移動相(移動相Α· %%❹ 25福乙_+5%乙腈;移動相Β:乙腈;移動相c:; 被使用以執行梯度條件自96%Α、2%Β與2%c,在〇 9八; 鐘内至49%B與49%C ’在〇 3分鐘内至1〇〇%B並保持 分鐘。使用了注射體積加。對正離子化模式之錐電壓為 ιόν,且對負離子化模式為2〇v。 馮 熔點 22 200934491 熔點(m.p.)係以 DSC823e(Mettler-Toledo)來決定。熔點 係以30°C/分鐘之溫度梯度來測量《最高溫度為4〇(rc。數 值之獲得存有一般與此種分析方法相關連之實驗的不確定 性。 4·中間物之事$ 描述1 ❹ 氟-苯并[1,3]二畤茂 15 ❹ 20 1-(2-氯-6-甲基-吡啶-4-羰基)-3-(2,2-. -5-基)-硫脲(D1)
硫氰酸、銨鹽(1:1)(9.35克;0.1230莫耳)在室溫於2_ 丙酮(300毫升)攪拌。其後添加2_氯_6_曱基_4^比啶羰基氯 (22.2克:0.1170莫耳)且反應混合物在室溫經攪拌2小時。 添加在一些2_丙烷中之2,2-二氟-1,3-苯并二噚唑_5_胺(19.2 克,0.1110莫耳)且反應混合物在室溫攪拌丨小時。反應混 合物其後被傾注於冰且殘留物被濾出並乾燥。產率.中間物 D1 38.1 克。 LCMS 保持時間:1 〇3 ; [M_H]-峰值:384 ; lCMs 程序 2 描述2 23 200934491 糾基硫院基
F
F
NaH、6〇% (2.2克;〇 〇55〇莫耳)於N2下在冰洛中於 ™F(170毫升)授拌。中間物Dl(19.3g ; 0.500莫耳)其後被❹ 添加並在0C攪拌1小時。其後添加CH3l(7 8g ; 〇 〇55〇莫 耳)且反應混合物被允許加溫至室溫竟夜。添加水且蒲在 ίο 真空巾蒸發。驗物被濾'出’以水清洗並乾狀。產率:中 間物D2 22.86克。 LCMS 保持時間:1.15 ; [M-Η]—峰值:398 ; LCMS 程序 2 描述3 〇 15 [5_(2_氣心甲基_„比啶_4_基)_3_(2,2_二氟-苯并二噚茂^ 基胺基)-[1,2,4]三唾-1-基]-乙酸乙基酯(D3)
20 中間物D2(13.6克;0.0340莫耳),2_肼乙酸乙基酯, 24 200934491 氯化虱(1:1)(10.5克;0.0680莫耳),N-乙基甲基乙 基)-2-丙胺(13.2克:0.1020莫耳)與t-BuOH(40〇毫升)進行回 流2小時。反應混合物其後予以蒸發。添加水且產物以 (¾¾萃取。有機層在MgS〇4中乾燥。在真空中過遽並蒸 5 發。殘留物在乙醇/HC1被加熱至6〇°C經1小時。反應混合 物進行部份蒸餾,沈澱物被濾出並乾燥之。產率:中間物D3 4.57’克。 ❺ LCMS保持時間:1.03;[Μ-ΗΓ峰值:450 ; LCMS程序2 10 描述4 2-[5-(2-氯-6-曱基-吼啶-4-基)_3_(2,2·二氟_苯并[L3]二畤茂 -5-基胺基)-[1,2,4]三唑-1-基]乙基-乙醯胺(D4)
G
Cl
F F 在CH3〇H(4〇毫升;2M)之中間物D3(l克;0.0022莫 耳)與乙胺在室溫攪拌竟夜。產物自反應混合物結晶化。結 晶被濾出並乾燥。產率:中間物D4 7〇〇毫克。 LCMS 保持時間:〇·95 ; [Μ-ΗΓ 峰值:449 ; LCMS 程序 2 25 200934491 g.最終化合物之y $ 2-[3-(2,2-二氟-苯并[ι,3]二呤茂 基胺基)_5-(2,6_二曱基_ 吼啶_4_基)-[1,2,4]三唑-1-基)-N-乙基·乙醯胺(E1) Η
中間物D4(0.70克;0.0016莫耳)、乙醯丙酮鐵(ιπ)(0 067 克;0.0002莫耳)、THF(20毫升)與ι_曱基·2·吡咯烷酮(5毫 10 升)在Ν2下於〇°C攪拌。在二乙基醚(2Μ)中添加過量 CH;jMgBr且混合物被置於室溫。反應混合物其後以ch3〇H 分解並在真空中蒸發。添加水與CH2C12且混合物經白色石夕 藻土載劑(dicalite)過濾。濾液被蒸發且添加水與DIPE。沈 澱物被濾出’並溶解於CH2C12,使用MgS04乾燥,過濾◎ 15 並在真空中蒸發。殘留物在水中攪拌,沈殿物被濾出且乾
燥。產率:化合物E1 400毫克 熔點:242.28°C LCMS 保持時間:5.12 ; [M+H]+ 峰值:431 ; LCMS 程序 1 ]HNMR (Bruker DPX 360MHz > DMSO-d6) 5ppm 20 9.62(s),8.37(t,J=5.4Hz),7.67(d,J= 2.1Hz),7.38(s),7.29(d, J=8.8Hz),7.22(dd,J=8.8,2·2Ηζ),4.84(s),3.13(qd,J=7.2, 26 200934491 5.5Hz),2.50(s),1.03(t,J=7.2Hz) C.藥理學實施例 實施例C.l b:Ca+2通詈成後(FDSS) 5 材料 a) 分析緩衝液
Hanks緩衝鹽水溶液(比利時HBSS ’ Invitrogen公 ❹司,),補充 10mM HEPES(比利時 Invitrogen 公司)、CaCl2 至最終濃度為5mM、0.1%牛血清白蛋白(比利時Sigma — ίο Aldrich NV 公司)。
b) 鈣敏感染料-Fluo-4 AM
Fluo-4AM(美國Molecular Probes公司)被溶解於包括 10%普盧蘭尼克酸(美國Molecular Probes公司)之DMSO以 產生備用溶液,該備用溶液係在補充以5mM彼洛喜錠 15 (probenicid)(比利時Sigma’ Aldrich NV公司)之分析緩衝液 中稀釋,以產生最終濃度2μΜ。 ® c) 384孔孤 黑色384孔皿黑/乾淨皿’ pdl預塗膜(美國康寧公司) d) 約通量測量 20 使用功能性藥物篩選系統(FDSS,Hamamatsu)以測量 細胞内游離妈通量訊號。 方法 在裝填螢光鈣指示器之前24小時將ha7-wtnAChR-表 現GH4C1細胞之單層在多孔皿中生長,該多孔皿尤其是以 27 200934491 聚D-離胺酸包膜的黑色邊之透明底部384孔皿,在一特定 之具體例中則是裝填fluo-4AM至$120分鐘。 在FDSS中藉由螢光經常性監測在細胞的約活動之期 間,PAM活性之即時被偵測係藉由應用欲被測試之化合物 於與α7於驗酸受體激動劑一起之經裝填之細胞。化合物產 生峰值螢光反應大於歸因於單獨激動劑之反應,被認為係 a7 nAChRPAM。在一特定之具體例中’ α7菸驗酸受體激動 劑為膽素,更特定之具體例中膽素在ΙΟΟμΜ之次極大濃度 使用。在本發明之進一步設定欲測試之化合物在α7终驗酸〇 受體激動劑之前使用,在一特定之具體例中,在激動劑之 前為至多10分鐘。 對膽素之控制反應在各並計鼻,係自接收膽素或單獨 分析缓衝液兩者之一之jnL中在螢光中峰值之差異來計算。 本發‘明之化合物係在濃度0.01 μΜ至30μΜ之範圍測試。當 在30μΜ(100μΜ膽素之效力係在無ΡΑΜ存在時,被定義為 100%)之濃度測試時,本化合物被認為當使膽素信號至少增 強250%時具有有趣的活性。 〇 藉由使用GraphPad Prism (美國加州聖地牙哥 GraphPad軟體公司)使S型(sigmoidal)方程式符合於數據而 可估計ECso值(效力)、最大效果(%功效)與Hins i〇pes之 值。當獲得具有頂部曲線平穩段之明確的S型曲線時, EC50(或pEC50)被定義為關於最大效果之一半的濃度。 當在GH4C1細胞中穩定的過度表現人類野生型α7受 體時,如後述以全細胞電壓箝制電生理記錄系統測量時, 28 200934491 本發明之化合物亦在對膽素之反應上具有增強效果。 實施例C.2 :全細胞雷懕箝制紀錄 '來自哺乳類細胞之全細胞電壓箝制紀錄已提供一有力 5 的手段以評價被認為係配位體驅動式離子孔道之次單元膜 蛋白之功能。藉由内生性或外因性配位體之該等蛋白質之 激活作用造成與受體相關連孔之開啟,離子經由孔流下至 該等電化學梯度。在ha7-wt nAChR-表現GH4C1重組細胞 ^ 系之情形下,對本受體之鈣的優先滲透性意指在受到 1〇 ACh、膽素與其他菸鹼配位體之激活作用時,鈣流入細胞 中,造成鈣電流。由於該受體在激動劑存在下迅速脫敏化, 重要的是吾人使用能夠非常迅速的轉換溶液(<100ms)之應 用系統以防止與激動劑應用之時間一致之受體反應之部分 或完全之脫敏作用。結果’第二種評估菸鹼酸的功效增強 15 作用之便利的技術係以來自與一迅速應用系統相結合之 ha7-wtnAChR-表現GH4C1細胞的全細胞電位箝制紀錄。 ❹ 材料 a) 分析緩衝液 外部記錄液係由152mM NaCl、5mM KC1、ImM 2〇 MgCl2、ImM 約、l〇mM HEPES ; pH 7.3 所組成。内部記 錄液係由 140mM CsCI,lOmM HEPES ’ lOmM EGTA ’ ImM MgCl2,pH 7.3 所組成。 b) 膜片箝制紀錄係使用膜片箝制放大器(MulticlamP 700A,美國加州Axon儀器公司)來進行。ha7-wt nAChR· 29 200934491 表現GH4C1細胞在充填内部記錄液時,在全細胞構型 (Hamill 等人 ’ 1981)以 L5_3MQf 尖電阻(tipresistance) 之硼矽酸鹽玻璃電極進行電壓箝制。紀錄係在具有臈電 阻>500ΜΩ且更佳為ΐ(}Ω與串聯電阻<ΐ5ΜΩ而具有至 5 少60%串聯電阻補償之細胞進行。膜電位在-70mV進行 搬位(clamp))。 c) 激動劑 ACh ’膽素’係購自比利時sigma-Aldrich NV公司。 d) 化合物應用 Ο 10 一台用以迅速轉換溶液(轉換分解時間<100ms)之16- 孔道Dynflow DF-16微流體系統(瑞典cellectriccm公司)被 用於使用控制,激動劑與PAM化合物於ha7-wtnAChR-表 現之GH4C1細胞。 方法 15 ha7-wt nAChR-表現之GH4C1細胞被置於Dynaflow灌 注腔室中外部記錄液之皿(plate)中,並允許雜質沈澱至$20 分鐘。個體細胞為全細胞膜片並溫和地以膜片吸量管離腔❹ 室底部提升,進入外部記錄液之連續流動灌注流(0.75μ1/ 分)。在經常監視細胞膜流動之期間,PAM活性藉由預先使 20 用欲測試之化合物至經裝填之細胞,接著是α7菸鹼酸受體 激動劑而在即時被偵測。產生電流反應大於導因於單獨激 動劑反應之化合物,被認為係a7 nAChR ΡΑΜ。在一特定 之具體例中,cx7菸鹼酸受體激動劑係以非選擇性菸鹼酸的 激動劑所激活,在一更為特定之具體例中,激動劑為膽素, 200934491 且在一最為特定之具體例中’膽素係使用lmM之次極大濃 度。在一進一步之本發明之設定中’欲測定之化合物在α7 於鹼酸受體激動劑之前被應用,在一更為特定之具體例中 為在激動劑之前至多30秒。控制反應之計算,係自各細胞 中所引發之電流之曲線下面積至經250ms次極大膽素之應 用來計算。在此曲線下之面積為經時間之淨電流之積分且 為總離子通量通過孔道之普通表述。正異構調節劑所引發 激動劑功效之增高係以激動劑反應',曲線下面積” (AUC)之 百分比增效作用來δ十算。本發明之化合物所造成大於對照 組AUC之增效作用係顯示預期具有有用的治療活性。 表3 :對化合物Ε1之效力(卩£0:5〇)與%功效 化合物 Nr. pECso %效力 ρ— ΡΑΜ_型式 El 6.51 1920 -— 2 第2型化合物減少脫敏作用之速率與程度 ❹ 31
Claims (1)
- 200934491 七、申請專利範圍: 1. 一種式(I)之化合物:或醫藥上可接受之鹽、其水合物或其溶劑化物。 10 2. —種使用化合物用以製造用於預防(prevention)、治療或 治療性預防(prophylaxis)精神病疾患、智能障礙疾患或疾 病、或調節α7於驗酸受體為有益的炎性疾病或症狀之藥 劑之用途,其中該化合物為如申請專利範圍第1項之化 合物。 15 3. —種醫藥組成物,其包含醫藥上可接受之載劑與作為活 性成分之治療上有效量之如申請專利範圍第1項之化合q 物。 4. 一種製備如申請專利範圍第3項之組成物的方法,其特 徵為,將一醫藥上可接受之載劑與治療上有效量之如申 20 請專利範圍第1項之化合物密切的混合。 5. ’ 一種產物,其包含: (a)如申請專利範圍第1項之化合物,及 32 200934491 (b) α7菸鹼酸受體激動劑,作為用於同時、分開或連續 使用以預防或治療α7菸鹼酸受體之調節為有益的疾 病之組合製劑。 Ο 6. —種製備如申請專利範圍第1項化合物之方法,其包含: 於溫度〇°C至50°C,在由75%至85容積%THF與15%至 25容積% NMP所組成之溶劑系統中,使一般式(VI)之中 間物與過量格利亞試劑MeMgBr在乙醯丙酮鐵(III)催化 劑量之存在下進行反應之步驟。 • 10 ❹33 200934491 四、指定代表圖: (一) 本案指定代表圖為:第(無)圖。 (二) 本代表圖之元件符號簡單說明: 無 五、本案若有化學式時,請揭示最能顯示發明特徵的化學式:
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EP1954696B1 (en) * | 2005-01-19 | 2011-02-23 | Bristol-Myers Squibb Company | 2-phenoxy-n-(1,3,4-thiadizol-2-yl)pyridin-3-amine derivatives and related compounds as p2y1 receptor inhibitors for the treatment of thromboembolic disorders |
AU2006290814B2 (en) * | 2005-09-13 | 2012-06-07 | Janssen Pharmaceutica N.V. | 2-aniline-4-aryl substituted thiazole derivatives |
JO3019B1 (ar) | 2006-04-19 | 2016-09-05 | Janssen Pharmaceutica Nv | ثلاثي مستبدل 4،2،1-ثلاثي زولات |
US8440701B2 (en) | 2007-10-18 | 2013-05-14 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4 triazoles |
KR101564303B1 (ko) | 2008-03-19 | 2015-11-06 | 얀센 파마슈티카 엔.브이. | 니코틴성 아세틸콜린 수용체 조절제로서의 삼치환된 1,2,4-트리아졸 |
US8377941B2 (en) | 2008-04-17 | 2013-02-19 | Proximagen Limited | Indoles as modulators of nicotinic acetylcholine receptor subtype alpha-7 |
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WO2011033018A1 (en) | 2009-09-17 | 2011-03-24 | Janssen Pharmaceutica Nv | Substituted n-phenyl-1-(4-pyridinyl)-1h-pyrazol-3-amines |
JO3078B1 (ar) | 2009-11-27 | 2017-03-15 | Janssen Pharmaceutica Nv | مورفولينوثيازولات بصفتها منظمات الوستيرية نوع الفا 7 موجبة |
UA109803C2 (xx) | 2011-02-25 | 2015-10-12 | (ПІРИДИН-4-ІЛ)БЕНЗИЛАМІДИ ЯК АЛОСТЕРИЧНІ МОДУЛЯТОРИ АЛЬФА-7 nAChR |
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2008
- 2008-09-15 JO JO2008412A patent/JO2784B1/en active
- 2008-10-15 ES ES08805280T patent/ES2371863T3/es active Active
- 2008-10-15 AU AU2008313775A patent/AU2008313775B2/en not_active Ceased
- 2008-10-15 WO PCT/EP2008/063844 patent/WO2009050185A1/en active Application Filing
- 2008-10-15 JP JP2010529360A patent/JP2011500624A/ja active Pending
- 2008-10-15 EP EP08805280A patent/EP2205594B1/en active Active
- 2008-10-15 AT AT08805280T patent/ATE522523T1/de not_active IP Right Cessation
- 2008-10-15 CN CN2008801119538A patent/CN101827839B/zh not_active Expired - Fee Related
- 2008-10-15 MX MX2010004176A patent/MX2010004176A/es active IP Right Grant
- 2008-10-15 CA CA2697982A patent/CA2697982C/en not_active Expired - Fee Related
- 2008-10-15 RU RU2010119458/04A patent/RU2476433C2/ru active
- 2008-10-15 US US12/738,725 patent/US8404851B2/en active Active
- 2008-10-16 CL CL2008003067A patent/CL2008003067A1/es unknown
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Also Published As
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RU2010119458A (ru) | 2011-11-27 |
MX2010004176A (es) | 2010-05-03 |
JO2784B1 (en) | 2014-03-15 |
CL2008003067A1 (es) | 2009-11-27 |
US8404851B2 (en) | 2013-03-26 |
JP2011500624A (ja) | 2011-01-06 |
AR068919A1 (es) | 2009-12-16 |
ES2371863T3 (es) | 2012-01-10 |
IL205102A0 (en) | 2010-11-30 |
CN101827839A (zh) | 2010-09-08 |
CN101827839B (zh) | 2012-10-24 |
EP2205594A1 (en) | 2010-07-14 |
PE20091080A1 (es) | 2009-08-03 |
IL205102A (en) | 2015-04-30 |
AU2008313775B2 (en) | 2012-12-13 |
ATE522523T1 (de) | 2011-09-15 |
AU2008313775A1 (en) | 2009-04-23 |
EP2205594B1 (en) | 2011-08-31 |
RU2476433C2 (ru) | 2013-02-27 |
PA8799901A1 (es) | 2009-05-15 |
CA2697982C (en) | 2015-09-22 |
US20100240707A1 (en) | 2010-09-23 |
CA2697982A1 (en) | 2009-04-23 |
WO2009050185A1 (en) | 2009-04-23 |
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