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TWI552751B - 投予４－（（１ｒ，３ｓ）－６－氯－３－苯基－二氫茚－１－基）－１，２，２－三甲基－哌及其鹽用於治療精神分裂症的方法 - Google Patents

投予４－（（１ｒ，３ｓ）－６－氯－３－苯基－二氫茚－１－基）－１，２，２－三甲基－哌及其鹽用於治療精神分裂症的方法 Download PDF

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TWI552751B
TWI552751B TW101121870A TW101121870A TWI552751B TW I552751 B TWI552751 B TW I552751B TW 101121870 A TW101121870 A TW 101121870A TW 101121870 A TW101121870 A TW 101121870A TW I552751 B TWI552751 B TW I552751B
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瑞妮 赫姆
隆尼 布恩
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Description

投予4-((1R,3S)-6-氯-3-苯基-二氫茚-1-基)-1,2,2-三甲基-哌 及其鹽用於治療精神分裂症的方法
本發明係關於對多巴胺D1及D2受體以及血清素5HT2受體具有活性之4-((1R,3S)-6-氯-3-苯基-二氫茚-1-基)-1,2,2-三甲基-哌及其鹽，其用於在每週一次給藥攝生法中治療中樞神經系統疾病。
4-((1R,3S)-6-氯-3-苯基-二氫茚-1-基)-1,2,2-三甲基-哌及其鹽、含有該等鹽之醫藥組成物及其醫學用途(包括治療精神分裂症或其他涉及精神病症狀之疾病)係揭示於WO2005/016900中。4-((1R,3S)-6-氯-3-苯基-二氫茚-1-基)-1,2,2-三甲基-哌在以下稱為化合物(I)
化合物(I)亦稱為齊洛那平(Zicronapine)。
EP 638 073涵蓋在哌環之2-及/或3-位置經取代的一類3-芳基-1-(1-哌基)二氫茚反式異構體。該化合物被描述為對於多巴胺D1及D2受體及5-HT2受體具有高親和力，且 表明其適用於治療包括精神分裂症之若干中樞神經系統疾病。
上述化合物(I)已以反丁烯二酸鹽的形式描述於Bøgesø等人，J.Med.Chem,1995,38，第4380-4392頁(參見表5，化合物(-)-38)。該公開案推斷化合物38之(-)-對映異構體為展示特定活體外D1選擇性的有效D1/D2拮抗劑。該化合物亦被描述為一種有效5-HT2拮抗劑。亦提及該化合物並不誘發大鼠的強直性昏厥。
精神分裂症之病原學是未知的，但1960年代初期構想的精神分裂症之多巴胺假設提供了一種用於理解該病症之基礎生物學機製的理論構架(Carlsson,Am.J.Psychiatry 1978,135,164-173)。該多巴胺假設以其最簡單的形式說明精神分裂症與高多巴胺能狀態有關，此概念受到當今市場上所有抗精神病藥均發揮特定多巴胺D2受體拮抗作用這一事實支持(Seeman Science and Medicine 1995,2,28-37)。然而，雖然一般公認在腦邊緣區域中多巴胺D2受體之拮抗作用在治療精神分裂症之正性症狀中起重要作用，但在腦紋狀體區域中D2受體之阻斷作用導致錐體外症狀(EPS)。如EP 638 073中所述，在使用某些所謂的「非典型性」抗精神病化合物，尤其使用氯氫平(clozapine)(8-氯-11-(4-甲基哌-1-基)-5H-二苯并[b,e][1,4]二氮呯)治療精神分裂症患者的情況下，已經觀察到混合多巴胺D1/D2受體抑制作用之特徵。
此外，選擇性D1拮抗劑已用於治療睡眠障礙及酒精濫 用(D.N.Eder,Current Opinion in Investigational Drugs,2002,3(2)：284-288)。
多巴胺亦在情緒異常症之病原學中起重要作用(P.Willner,Brain,Res.Rev. 1983,6,211-224,225-236及237-246；Bøgesø等人，J.Med.Chem,1985,28,1817-1828)。
EP 638 073中描述哪些對5-HT2受體具有親和力之化合物、尤其5-HT2A受體拮抗劑已被建議用於治療不同疾病，諸如精神分裂症(包括精神分裂症患者之負性症狀)、抑鬱症、焦慮症、睡眠紊亂、偏頭痛發作及精神抑制劑誘發之帕金森氏病。5-HT2A受體拮抗作用亦已表明可減少由經典精神抑制劑誘發的錐體外副作用的發生率(Balsara等人，Psychopharmacology 1979,62,67-69)。
精神病患者、尤其精神分裂症患者通常不願意或不能規律地服用藥物；若干研究已顯示低頻率給藥產生較高程度的順應性且因此最終較好地治療患者。因此，對於抗精神病藥之長效製劑的需求亟待滿足。詳言之，需要呈非侵襲性形式之抗精神病藥之長效製劑，其代表肌肉內積存調配物之替代形式以使給藥攝生法、藥物頻率或藥物類型的變化更為靈活。
本發明之發明者意外發現化合物(I)在人體內之消除半衰期為約150小時。長消除半衰期以及對於多巴胺D1及D2受體兩者的親和力使得化合物(I)成為一種假定的長效抗 精神病化合物，例如其可以諸如瞬間釋放調配物(IR-調配物)之非侵襲性形式每週、每兩週或每半週投予一次。
此外，本發明之發明者意外發現化合物(I)之主要代謝物，亦即反式-1(6-氯-3-苯基-二氫茚-1-基)-3,3-二甲基-哌(化合物(II))在人體中具有約300-400小時之消除半衰期，該化合物(II)亦對多巴胺D1及D2受體兩者具有親和力。
化合物(I)及其主要代謝物之長半衰期與對於多巴胺D1及D2受體兩者的親和力的此種意外組合，導致本發明之發明者推斷化合物(I)的投予時間間隔可比常規精神病治療要長。因此，預期化合物(I)在精神病之維持治療中以及精神病急性惡化之治療中可每週一次、每週兩次(每半週一次)或每隔一週一次(每兩週一次)投予。
本申請案之發明者意外發現每週一次給予約30毫克/週與約45毫克/週之間的劑量的化合物(I)將PANSS總分至少減小至與10毫克/日之日劑量相同的程度。其容許對人類投予較低劑量，亦即對整個身體(例如肝臟)較小的負荷，及較低頻率的給藥。
如已指示，化合物(I)為一種對多巴胺D1及D2受體兩者具有親和力的假定抗精神病化合物。使用條件性回避反應(CAR)模型之大鼠臨床前實驗(實驗程序先前描述於Hertel P,Olsen CK,Arnt J.,Eur.J.Pharmacol. 2002；439(1-3)：107-11)已指出，化合物(I)在極低的D2受體佔據程度下即可具有抗精神病活性。
在使用11C-SCH23390及11C-雷氯必利(raclopride)作為D1及D2受體示蹤物之健康個體之正電子發射斷層攝影術(PET)研究中，發現當每日給予之劑量自2毫克/天增加至10毫克/天並持續18天時，化合物(I)誘發被殼中之D2受體佔據率自11%增加至43%。該等D2受體佔據程度低於當前使用之抗精神病藥之D2受體佔據程度，當前使用之抗精神病藥通常需要D2受體佔據率約為或超過50%以便在治療上有效(Stone JM,Davis JM,Leucht S,Pilowsky LS.Schizophr Bull.2008年2月26日)。在相同的PET研究中，發現當每日給予之劑量自2毫克/天增加至10毫克/天並持續18天時，化合物(I)誘發被殼內之D1受體佔據率自32%增加至69%。該等高D1佔據程度並不通常見於當前使用之抗精神病藥(Farde L,Nordström AL,Wiesel FA,Pauli S,Halldin C,Sedvall G.Arch Gen Psychiatry. 1992；49(7)：538-44)。因此，化合物(I)展現一種獨特的D1比D2受體佔據率比率。
基於以上所述，預期化合物(I)在僅誘發低D2受體佔據 程度的劑量(4毫克/劑至60毫克/劑)下對精神分裂症患者具有臨床上顯著的治療效果。此可能為化合物(I)呈現的高D1受體佔據率及獨特的D1比D2受體佔據率比率的結果。治療有效劑量下之低D2受體佔據率將有益於減小誘發D2受體阻斷作用所介導之煩人副作用(包括錐體外副作用及高促乳素血症)的傾向。
以自由鹼計算的4-60毫克治療有效量之化合物(I)係經口投予，且可以任何適用於該投予之形式呈現，例如錠劑、膠囊、粉末、糖漿或溶液形式。
在一個具體實例中，化合物(I)之鹽以固體醫藥實體之形式，適當地以錠劑(諸如經口崩解錠劑)或膠囊之形式投予。
醫藥學上可接受之鹽
本發明亦包含化合物(I)之鹽，典型地為醫藥學上可接受之鹽。該等鹽包括醫藥學上可接受之酸加成鹽。酸加成鹽包括無機酸以及有機酸之鹽。
適當的無機酸之代表性實例包括鹽酸、氫溴酸、氫碘酸、磷酸、硫酸、胺基磺酸、硝酸及其類似酸。適當有機酸之代表性實例包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、苯甲酸、肉桂酸、檸檬酸、反丁烯二酸、乙醇酸、衣康酸、乳酸、甲烷磺酸、順丁烯二酸、蘋果酸、丙二酸、苦杏仁酸、草酸、苦味酸、丙酮酸、水楊酸、丁二酸、甲烷磺酸、乙烷磺酸、酒石酸、抗壞血酸、雙羥萘酸、雙亞甲基水楊酸、乙烷二磺酸、葡萄糖酸、甲基順丁烯二酸、 天冬胺酸、硬脂酸、棕櫚酸、EDTA、乙醇酸、對胺基苯甲酸、麩胺酸、苯磺酸、對甲苯磺酸、茶鹼乙酸以及8-鹵基茶鹼(例如8-溴茶鹼)及其類似酸。醫藥學上可接受之無機或有機酸加成鹽之其他實例包括Berge,S.M.等人，J.Pharm.Sci.1977,66,2中所列舉之醫藥學上可接受之鹽，該文獻之內容以引用的方式併入本文中。
此外，本發明之化合物(I)及其鹽可以非溶劑化形式以及與醫藥學上可接受之溶劑(諸如水、乙醇及其類似溶劑)之溶劑化形式存在。對於本發明之目的而言，通常認為溶劑化形式與非溶劑化形式相當。
在本發明之一特定具體實例中，化合物(I)呈丁二酸鹽或丙二酸鹽之形式。
醫藥組成物
本發明進一步提供一種醫藥組成物，包含治療有效量之本發明之化合物(I)及醫藥學上可接受之載劑或稀釋劑。
本發明之化合物(I)可以單劑或多劑單獨投予或與醫藥學上可接受之載劑、稀釋劑或賦形劑組合投予。本發明之醫藥組成物可根據諸如Remington：The Science and Practice of Pharmacy，第19版，Gennaro編，Mack Publishing Co.,Easton,PA,1995揭示之習知技術，使用醫藥學上可接受之載劑或稀釋劑以及任何其他已知佐劑及賦形劑進行調配。
在一特定具體實例中，如根據Remington’s Pharmaceutical Sciences，第18版(A.R.Genaro編)，1990， 第1640-1641頁描述之程序所量測，包含化合物(I)之醫藥組成物在5分鐘內，尤其在4分鐘內、3分鐘內、2分鐘內或1分鐘內崩解。
醫藥組成物可經特別調配以用於經諸如口、鼻、局部(包括頰內及舌下)及非經腸(包括皮下、肌肉內、鞘內、靜脈內及皮內)途徑的任何合適途徑投予。應瞭解此途徑將視欲治療之個體之綜合情況及年齡、欲治療之病狀之性質及活性成份而定。
本發明之化合物(I)通常以自由物質或其醫藥學上可接受之鹽的形式使用。合適的有機及無機酸之實例如上所述。
給藥攝生法
長效抗精神病化合物、長效製劑及抗精神病化合物之長效製劑係指維持外源投予之化合物之醫藥學活性程度超過一天(諸如一週)，以使得不必每日而是每半週、每週或甚至每兩週給予該化合物的化合物或化合物之製劑。
本發明係關於用於治療中樞神經系統疾病之化合物(I)，該中樞神經系統疾病包括精神病，尤其精神分裂症或其他涉及精神病症狀之疾病，諸如精神分裂症、類精神分裂症精神障礙、感情分裂性精神障礙、妄想症、短期性精神病、共享型精神病以及其他伴隨精神病症狀(例如雙極症)同時出現之精神病症或疾病，諸如雙極症中之躁狂症，其中化合物(I)每半週、每週或每兩週投予一次。
本發明亦關於一種化合物(I)之醫學使用方法，諸如治療中樞神經系統疾病，其包括精神病，尤其精神分裂症或 其他涉及精神病症狀之疾病，諸如精神分裂症、類精神分裂症精神障礙、感情分裂性精神障礙、妄想症、短期性精神病、共享型精神病以及其他伴隨精神病症狀(例如雙極症)同時出現之精神病症或疾病，諸如雙極症中之躁狂症，其中化合物(I)每半週、每週或每兩週投予一次。
以自由鹼計算的化合物(I)之每週一次(亦即間隔7天)或每半週一次(亦即每週兩次，間隔3至4天)或每兩週一次(亦即間隔14天)的劑適當地介於1.0毫克/劑與60毫克/劑之間，更適當地介於1毫克/劑與100毫克/劑之間，例如較佳介於5毫克/劑與55毫克/劑之間，諸如介於10毫克/劑與45毫克/劑之間，尤其介於30毫克/劑與45毫克/劑之間，諸如40毫克/劑或45毫克/劑。
化合物(I)之每週一次、每半週一次(亦即每週兩次，間隔3至4天)或每兩週一次(亦即間隔14天)投予可用於維持治療中樞神經系統疾病，尤其精神病，以及用於治療精神病之急性惡化。
一旦患者已由本發明之化合物(I)或者不同的抗精神病化合物穩定，則設計維持治療用於防止復發。
急性惡化為精神病狀態之突然加重。
本文所引用之所有參考文獻(包括公開案、專利申請案及專利)均以全文引用的方式併入本文中，且該引用的程度就如同各參考文獻已個別地且特定地以全文引用的方式併入一般(以達到法律所允許之最大程度)。
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本說明書中任何及所有實例或例示性語言(包括「例如」、「舉例而言」及「諸如」)之使用僅意欲更好地說明本發明，且除非另有指示，否則對本發明範疇並不造成限制。
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實驗
結合檢定
人類D2結合檢定之描述
該檢定可在含有120 mM NaCl、5 mM KCl、4 mM MgCl2、1.5 mM CaCl2、1 mM EDTA之50 mM Tris(pH 7.4)檢定緩衝液中以基於SPA之競爭結合形式進行。
將1.5 nM 3H-雷氯必利(Perkin Elmer,NET 975)與測試化合物混合，隨後添加總體積為90微升之20微克均質化之人類D2受體膜製劑及0.25毫克SPA珠粒(WGA RPNQ 0001,Amersham)。在室溫下在振盪下保溫檢定板60分鐘，隨後用閃爍計數器(TriLux,Wallac)計數。包含約15%之所添加放射性配位體的總結合使用檢定緩衝液來確定，而非特異性結合則在10微莫耳氟哌啶醇(haloperidol)存在下進行確定。非特異性結合構成總結合之約10%。
以3H-雷氯必利之特異性結合之百分比表示資料點，且藉使用S形可變斜率曲線擬合之非線性回歸分析測定IC50值(導致3H-雷氯必利特異性結合之50%抑制的濃度)。自Cheng Prusoff方程式(Ki=IC50/(1+(L/KD))計算解離常數 (Ki)，其中自由放射性配位體L之濃度接近檢定中添加的3H-雷氯必利的濃度。由兩個獨立飽和檢定測定3H-雷氯必利之KD為1.5 nM，該兩個檢定每個重複進行三次。
人類D1結合檢定之描述
該檢定在含有120 mM NaCl、5 mM KCl、4 mM MgCl2、1.5 mM CaCl2、1 mM EDTA之50 mM Tris(pH 7.4)檢定緩衝液中，以基於SPA之競爭-結合形式進行。將約1 nM 3H-SCH23390(Perkin Elmer,NET 930)與測試化合物混合，隨後添加總體積為60微升之2.5微克均質化之人類D1受體膜-製劑及0.25毫克SPA珠粒(WGA RPNQ 0001,Amersham)。
在室溫下在振盪下保溫檢定板60分鐘，隨後離心該等板，且隨後在閃爍計數器(TriLux,Wallac)中計數。包含約15%之所添加放射性配位體的總結合使用檢定緩衝液來確定，而非特異性結合則在10微莫耳氟哌啶醇存在下進行確定。
以特異性結合之百分比表示資料點，且使用S形可變斜率曲線擬合藉由非線性回歸分析測定IC50值(導致特異性結合之50%抑制的濃度)。自Cheng Prusoff方程式(Ki=IC50/(1+(L/KD))計算解離常數(Ki)，其中自由放射性配位體L之濃度接近檢定中添加的放射性配位體的濃度。
人類5-HT2A結合之描述
該實驗在Cerep Contract Laboratories進行(目錄參考# 471)。
在大鼠腦中與D2受體之活體內結合之描述
根據經過若干改進(Kapur S.等人，J Pharm Exp Ther,2003,305,625-631)之Andersen等人(Eur J Pharmacol,(1987)144：1-6)進行活體內結合。簡言之，使用20 mg/kg之測試化合物皮下治療6隻大鼠(雄性Wistar，180-200 g)持續30分鐘，隨後經由尾部靜脈使其靜脈內接受9.4微居里(micro Ci)之[3H]-雷氯必利。
注射放射性配位體15分鐘後，藉由頸椎脫位術處死動物，迅速移除腦，剝離紋狀體及小腦，且將其在5 mL(小腦在20 mL中)冰冷緩衝液(50 mM K2PO4，pH 7.4)中均質化。通過已浸泡0.1% PEI之Whatman GF/C過濾器過濾1.0 mL勻漿。此在斷頭後的60秒內完成。使用5 mL冰冷緩衝液洗滌過濾器兩次並在閃爍計數器中計數。使用經媒劑治療之動物之群組測定[3H]-雷氯必利在紋狀體中之全部結合及在小腦中之非特異性結合。藉由BCA蛋白質測定檢定量測勻漿之蛋白質含量(Smith P.K.等人(1985)Anal.Biochem.,150：6-85)。
實施例1：化合物(I)之結合親和力
先前執行的活體外結合研究已顯示化合物(I)以以下親和力結合至D1、D2及5-HT2A受體：人類D1結合：Ki=19 nM
人類5-HT2A結合：Ki=4.2 nM
腦中活體內結合至D2受體：ED50=4.1 mg/kg
實施例2：研究設計
用於評估每週給藥一次化合物(I)之可行性的研究設計在圖1中概述，該化合物(I)以丁二酸氫鹽之形式投予。該研究為在精神分裂症患者中每日給藥化合物(I)對比每週給藥化合物(I)之安全性、耐受性及PK的隨機化、雙盲、平行組、探索性研究。
開放標籤階段(OL_Period)為自開放標籤治療起始(基線)直至開放標籤治療終止(開放標籤階段退出或隨機接受雙盲治療時，無論哪個先發生)的階段。
安慰劑階段(PBO_Period)為雙盲治療的第一週，其中隨機接受每週給藥之患者接受安慰劑治療，而隨機接受每日給藥之患者持續用10毫克/日之化合物(I)治療。
雙盲階段(DB_Period)為自雙盲治療起始(隨機化)直至雙盲治療終止(雙盲階段退出或完成時，無論哪個先發生)的階段，亦即，包括安慰劑階段之整個雙盲階段。
IMP給藥階段(IMP_Period)為自開放標籤治療起始(基線)直至雙盲治療終止(退出或完成時，無論哪個先發生)的階段，亦即，開放標籤階段加上雙盲階段。
實施例3：自隨機化時算起之PANSS總分變化用如實施例2中所述之研究設計進行研究。
自隨機化時算起之PANSS總分變化的結果在表1中提供：
上述資料顯示在20毫克/週至45毫克/週、尤其30毫克/週至45毫克/週之範圍內的每週一劑在減小PANSS總分方面與10毫克/日之日劑量一樣有效。
圖1顯示針對化合物(I)每週給藥一次所應用之研究設計。

Claims (9)

  1. 一種化合物(I)之用途，其係用於製造用於治療中樞神經系統疾病之醫藥品，其特徵在於以用於經口投予之瞬間釋放調配物(IR-調配物)、延長、控制或延緩釋放調配物將化合物(I)以相當於約30毫克/週與約45毫克/週之間的劑量每週投予一次，該劑量係以自由鹼化合物(I)計算，其中化合物(I)具有以下結構：
  2. 如申請專利範圍第1項之用途，其中化合物(I)以約30毫克/劑之劑量每週投予一次，該劑量係以自由鹼化合物(I)計算。
  3. 如申請專利範圍第1項之用途，其中化合物(I)以約45毫克/劑之劑量每週投予一次，該劑量係以自由鹼化合物(I)計算。
  4. 如申請專利範圍第1項之用途，其中該疾病係選自由以下組成之群：精神病以及伴隨精神病症狀同時出現之精神病症和疾病。
  5. 如申請專利範圍第4項之用途，其中該疾病為精神分裂症、類精神分裂症精神障礙、感情分裂性精神障礙、妄想症、短期性精神病、共享型精神病或雙極症。
  6. 如申請專利範圍第4項之用途，其中該疾病為精神分裂症、類精神分裂症精神障礙或感情分裂性精神障礙。
  7. 如申請專利範圍第6項之用途，其中該疾病為精神分裂症。
  8. 如申請專利範圍第4項之用途，其中該疾病為雙極症中的躁狂症。
  9. 一種醫藥組成物之用途，其係用於製造用於治療精神分裂症之醫藥品，該醫藥組成物包含化合物(I)或化合物(I)之鹽及一或多種醫藥學上可接受之載劑、稀釋劑及賦形劑，其特徵在於以用於經口投予之瞬間釋放調配物(IR-調配物)、延長、控制或延緩釋放調配物將該醫藥組成物中的化合物(I)以相當於約30毫克/週與約45毫克/週之間的劑量每週投予一次，該劑量係以自由鹼化合物(I)計算，其中化合物(I)具有以下結構：
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