TWI582096B - 用於酒精依賴及濫用處理之４',５'－二氫螺［哌啶－４,７'－噻吩并[２，３－c]哌喃］化合物 - Google Patents
用於酒精依賴及濫用處理之４',５'－二氫螺［哌啶－４,７'－噻吩并[２，３－c]哌喃］化合物 Download PDFInfo
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- TWI582096B TWI582096B TW101143326A TW101143326A TWI582096B TW I582096 B TWI582096 B TW I582096B TW 101143326 A TW101143326 A TW 101143326A TW 101143326 A TW101143326 A TW 101143326A TW I582096 B TWI582096 B TW I582096B
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- alcohol
- methyl
- fluorine
- ylmethyl
- hydrogen
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Description
本發明係關於痛敏肽/孤啡肽FQ受體(NOC/OFQ)拮抗劑(特定而言為ORL-1受體拮抗劑)用於酒精使用病症處理之用途。
酒精使用病症(諸如酒精依賴及酒精濫用)呈現出重大的健康及社會問題。世界貿易組織(World Trade Organization，WTO)已將酒精使用病症確認為「世界上第三大導致過早死亡及傷殘之風險因素」。世界範圍內每年約有250萬人死於酒精相關之病因，其中約10%死亡發生於小於30歲之個體。如傷殘調整壽命年損失所量測，有害使用酒精佔全球疾病負擔之約4.5%，且為神經精神疾病及其他健康問題(諸如心血管疾病、肝硬化及口、喉、咽、食道、乳房及腸道癌症)之主要風險因素。目前所關注之標準物為那屈酮(naltrexone)及阿坎酸(acamprosate)，其藉由減輕酒癮且阻斷消耗酒精時其之有益方面而有助於患者保持戒酒。然而，目前可用之處理對於處理併發的情緒障礙的作用極小。實際上，那屈酮在某些個體中會產生快感缺乏。因此，需要改良之藥物療法來處理酒精使用病症。
痛敏肽/孤啡肽FQ受體(NOC/OFQ)(尤其ORL-1受體)為主要在中樞神經系統及周邊神經系統以及在胃腸道、平滑肌及免疫系統中表現之A類G蛋白偶合受體(Class A G-protein coupled receptor，GPCR)。儘管在結構上與類鴉片受體相關，但OFQ/痛敏肽系統對於經典之類鴉片受體(μ、δ及κ)並未展示顯著之交叉反應性。此外，痛敏肽在活體
內展示抗鴉片活性(例如，已報導ORL-1受體之天然配體ORQ/痛敏肽展示抗痛敏特性)。
痛敏肽/孤啡肽FQ受體(NOC/OFQ)拮抗劑(尤其ORL-1受體之拮抗劑)已在抑鬱症及攝食行為之若干動物模型中展示抗抑鬱樣活性及減食慾活性。因此，認為ORL-1拮抗劑適用於處理抑鬱症及/或處理超重、肥胖症及/或超重或肥胖症治療後之體重維持。其他研究表明拮抗劑可用於處理疼痛、癡呆及帕金森氏症(Parkinsonism)。另一方面，痛敏肽/孤啡肽FQ受體(NOC/OFQ)促效劑已牽涉於處理酒精使用病症、焦慮、疼痛、壓力誘發性厭食、咳嗽、神經性膀胱功能障礙、水腫及藥物依賴。(參見例如Murphy,Niall P.(2010),The Nociceptin/Orphanin FQ System as a Target for Treating Alcoholism.CNS & Neurological Disorders-Drug Tartgets 9：87-93.；及Chiou,L.C.,Liao,Y.Y.,Fan,P.C.,Kuo,P.H.,Wang,C.H.,Riemer,C.及Prinssen,E.P.(2007),Nociceptin/Orphanin FQ Peptide Receptors：Pharmacology and Clinical Implications.Current Drug Targets 8：117-135.)
WO 2011/060035及WO 2011/060217描述作為ORL-1拮抗劑用於處理抑鬱症、超重、肥胖症、體重維持及偏頭痛之某些螺哌啶化合物。
出乎意料地，吾人現已發現ORL-1拮抗劑化合物可用於處理酒精使用病症，如例如用於處理酒精濫用或處理酒精依賴。因此，本發明提供適用於處理酒精使用病症之對ORL-1受體具有高拮抗效能之一系列4',5'-二氫螺[哌啶-4,7'-噻吩并[2,3-c]哌喃]化合物。
本發明之一個態樣提供一種式I化合物：
或其醫藥學上可接受之鹽；其用於處理酒精使用病症；其中A為或；R1為氟或氯；R2a與R2b各自為氫或各自為氟；R3為氫、甲基、羥基甲基或(C1-C3)烷氧基甲基；R4係選自由以下組成之群：氟、氯、氰基、氰基甲基、(C1-C3)烷基、環丙基、羥基甲基、甲氧基、環丙基甲氧基、胺基羰基甲氧基、(C1-C3)烷氧基甲基、環丙氧基甲基、環丙基甲氧基甲基、1-羥基-1-甲基乙基、胺基羰氧基甲基、甲胺基羰氧基甲基、二甲胺基羰氧基甲基、胺基羰基、胺基羰基甲基、-CH2-NR5R6、羥基亞胺、甲氧基亞胺、嗎啉-4-基、嗎啉-4-基甲基、Ar1、-CH2Ar1、四氫呋喃-2-基、3-側氧基嗎啉-4-基甲基、2-側氧基吡咯啶-1-基甲基及2-側氧基哌啶-1-基甲基；
R4'係選自由以下組成之群：氟、氯、氰基、氰基甲基、(C1-C3)烷基、環丙基、羥基甲基、甲氧基、甲氧基甲基、胺基羰氧基甲基、甲胺基羰氧基甲基、二甲胺基羰氧基甲基、甲基羰基、胺基羰基、甲胺基羰基、二甲胺基羰基、-NR5'R6、-CH2-NR5'Rb、嗎啉-4-基、嗎啉-4-基甲基、Ar2、-CH2Ar2、3,3-二氟氮雜環丁烷-1-基甲基、吡咯啶-1-基甲基、1-胺基環丙基、1-甲胺基環丙基及1-二甲胺基環丙基；R5為氫、C1-C3烷基、氰基甲基、-C(O)CH3或胺基羰基甲基；R5'為氫、C1-C4烷基、環丙基、羥基乙基、甲氧基乙基、-C(O)CH3或-C(O)O(C1-C3)烷基；R6為氫或甲基；R7為氫、氟、氯、甲基、羥基甲基或甲氧基；Ar1為選自由以下組成之群之部分：咪唑-1-基、咪唑-2-基、2-甲基咪唑-1-基、吡唑-1-基、1,2,3-三唑-1-基；1,2,3-三唑-2-基；1,2,4-三唑-1-基、異噁唑-3-基、噁唑-5-基及3-甲基-1,2,4-噁二唑-5-基；且Ar2為選自由以下組成之群之部分：咪唑-1-基、咪唑-2-基、2-甲基咪唑-1-基、1-甲基咪唑-2-基及1,2,4-三唑-3-基。
在本發明此態樣之其他實施例中，酒精使用病症為酒精依賴或酒精濫用或兩者。在另一實施例中，該使用係與另一治療成分同時、獨立或相繼組合。
在本發明之另一態樣中，提供一種用於處理酒精使用病症之醫藥組合物，其包含式I化合物或其醫藥學上可接受之鹽及一或多種其醫藥學上可接受之賦形劑、載劑或稀釋劑。在本發明此態樣之另一實施例中，提供一種用於處理酒精依賴或酒精濫用或兩者之醫藥組合物，其包含式I化合物或其醫藥學上可接受之鹽及一或多種其醫藥學上可接受之賦形劑、載劑或稀釋劑。本發明此態樣之又一實施例提供一種醫藥組合物，其包含式I化合物或其醫藥學上可接受之鹽及至少
一種醫藥學上可接受之載劑、賦形劑或稀釋劑，且視情況包含其他治療成分。
本發明之另一態樣提供一種處理人類酒精使用病症之方法，其包含向需要此處理之人類投與有效量之式I化合物或其醫藥學上可接受之鹽。本發明此態樣之其他實施例提供一種處理酒精依賴或酒精濫用或兩者之方法，其包含向需要此處理之人類投與有效量之式I化合物或其醫藥學上可接受之鹽。
本發明之另一態樣提供式I化合物或其醫藥學上可接受之鹽在製造用以處理酒精使用病症之藥劑中的用途。在本發明此態樣之其他實施例中，酒精使用病症為酒精依賴或酒精濫用或兩者。
用於本發明之化合物為鹼，且因此與多種有機及無機酸反應以形成醫藥學上可接受之鹽。本發明各化合物之醫藥學上可接受之鹽涵蓋於本申請案之範疇內。如本文所用之術語「醫藥學上可接受之鹽」係指對活有機體實質上無毒之式I化合物之任何鹽。該等醫藥學上可接受之鹽及其常見製備方法在此項技術中係熟知的。參見例如P.Stahl等人，HANDBOOK OF PHARMACEUTICAL SALTS：PROPERTIES,SELECTION AND USE,(VCHA/Wiley-VCH,2008)。在一實施例中，此鹽為酒石酸鹽。在另一實施例中，此鹽為鹽酸鹽。
用於本發明之較佳化合物為以下化合物，其中：1)R1為氯；2)R2a與R2b各自為氟；3)R1為氯且R2a與R2b各自為氟；4)R1為氟且R2a與R2b各自為氫；5)R3為氫、甲基、羥基甲基或甲氧基甲基；6)R3為甲基；7)R3為羥基甲基；
8)R1為氯，R2a與R2b各自為氟，且R3為甲基；9)R1為氯，R2a與R2b各自為氟，且R3為羥基甲基；10)R4為氟、羥基甲基、甲氧基甲基或吡唑-1-基甲基；11)R4為氟；12)R4為羥基甲基；13)R4為甲氧基甲基；14)R4為吡唑-1-基甲基；15)較佳實施例1)至9)中之任一者，其中R4為氟；16)較佳實施例1)至9)中之任一者，其中R4為羥基甲基；17)較佳實施例1)至9)中之任一者，其中R4為甲氧基甲基；18)較佳實施例1)至9)中之任一者，其中R4為吡唑-1-基甲基；19)R7為氫、氟或氯；20)R7為氟；21)R1為氯，R2a與R2b各自為氟，且R7為氟；22)R1為氯，R2a與R2b各自為氟，R3為甲基，且R7為氟；23)R1為氯，R2a與R2b各自為氟，R3為羥基甲基，且R7為氟；24)R4'為氟、羥基甲基、甲氧基甲基、甲基羰基或2-甲基咪唑-1-基25)R4'為氟；26)R4'為羥基甲基；27)R4'為甲氧基甲基；28)R4'為甲基羰基；29)R4'為2-甲基咪唑-1-基；30)較佳實施例1)至9)或19)至23)中之任一者，其中R4'為氟；31)較佳實施例1)至9)或19)至23)中之任一者，其中R4'為羥基甲基；
32)較佳實施例1)至9)或19)至23)中之任一者，其中R4'為甲氧基甲基；33)較佳實施例1)至9)或19)至23)中之任一者，其中R4'為甲基羰基；34)較佳實施例1)至9)或19)至23)中之任一者，其中R4'為2-甲基咪唑-1-基。
用於本發明方法及用途中之某些較佳化合物為下表中之彼等及其醫藥學上可接受之鹽：
其中R2a與R2b各自為氟之化合物較佳，因為該等化合物具有更有利之藥物動力學概況，對氧化代謝更穩定。此具有改良化合物口服生物可用性之一般作用。
用於本發明之化合物及其製備方法在此項技術中已知且表徵為有效且具選擇性之ORL-1受體拮抗劑。其可藉由此項技術中熟知且瞭解之方法根據已知合成流程來製備。參見例如WO 2011/060035及WO 2011/060217。
非臨床動物研究中產生之資料支持ORL-1受體拮抗劑在處理酒精使用病症(諸如酒精濫用及酒精依賴)中之作用。特定而言，已發現某些ORL-1受體拮抗劑在酒精使用病症之齧齒動物模型中有效。為證明本發明化合物之該等特徵，可在以下活體內檢定中測試代表性化合物：
已經由選擇性育種技術產生滿足已證實酒精中毒動物模型準則
之若干品系之嗜酒大鼠。特定而言，其在不存在禁食或禁水之情況下自主消耗藥理學相關含量之乙醇，其飲用過度含量乙醇以達成其醉酒作用，而非味覺、嗅覺或熱量值，維持長時間醉酒、努力獲取乙醇且獲取時間延長，產生耐受性及依賴性。(參見例如Lester D及Freed EX(1973),Criteria for an animal model of alcoholism.Pharmacology Biochemistry & Behavior 1：103-107.)該等品系(包括嗜酒(P)及Marchigian撒丁島嗜酒(Marchigian Sardinian Alcohol-Preferring，msP)大鼠)被認為適用於評估用於酒精使用病症之潛在藥理學療法，因為其滿足以上準則且因為減少人類體內酒精消耗之藥劑(包括那屈酮及阿坎酸)減少該等品系體內之乙醇攝取。可使用操作性且自由選擇之自行投與程序來評估新穎痛敏肽/ORL1拮抗劑在P及msP大鼠體內之潛在治療性抗癮活性。
自私有群體(Taconic,Germantown,NY)獲得雌性P大鼠且成對圈養。為減少新穎性誘發之乙醇迴避，以含有15%乙醇於水中(v/v，於水中)之瓶子替代飼養籠上之水瓶兩天，然後進行操作訓練。在實驗之其餘時間內，大鼠隨意獲取水及標準實驗室飼料，且不另外獲取飼養籠內之乙醇。
在消音室內包含之標準大鼠操作室(MED Associates,Inc.,St.Albans,VT)內進行之每天30分鐘訓練期(sessions)中訓練大鼠按槓桿以補充乙醇。該等室係由兩個不鏽鋼及兩個透明普列克斯玻璃(Plexiglas)壁組成。操作室之地板格係由間隔約1.5 cm放置之0.5 cm直徑不鏽鋼條組成。每一操作室含有安置於格形地板上方約6 cm且間隔13 cm之兩個伸縮式操作槓桿。一凹槽位於槓桿之間的空間內，經由該凹槽舉起勺杯(dipper cup)(0.1 mL容量)來傳遞反應應變之乙醇(15%，v/v，於水中)。在增強反應時，刺激光照亮於該反應之槓桿上
於4秒勺杯獲取期間。藉由個人電腦控制及記錄刺激及行為反應之操作以供離線分析(MED Associates,Inc.,St.Albans,VT)。
在操作訓練期間，任一槓桿上之反應被認為是正確反應且用0.1 mL乙醇補充獎賞。一旦大鼠學會按槓桿來獲得乙醇獎賞，則改變反應應變性(response contingency)，使用固定比率(FR)-1增強時程來增強一個槓桿(有效槓桿)上之反應，而不增強另一(無效)槓桿上之反應。一旦於FR-1增強時程達到穩定基線反應，則將反應應變性增加至FR-2，隨後再增加至FR-3，使得每次補充需要按3次槓桿。一旦大鼠於FR-3時程達到穩定反應水準，則將反應應變性改變為漸進比率之增強時程，為此在每一實驗期間內緩慢增加反應需求以致大鼠必須逐漸地更努力來獲得每次乙醇獎賞。特定而言，如下增加反應需求：所有大鼠均以FR-1增強時程開始每一作業期；三次補充之後，將時程增加至FR-2；在彼水準下補充三次之後，將時程增加兩級至FR-4；補充三次後，將時程增加兩級至FR-6；等等(參見例如Oster SM、Toalston JE、Kuc KA、Pommer TJ、Murphy JM、Lumeng L、Bell RL、McBride WJ及Rodd ZA(2006),Effects of multiple alcohol deprivations on operant ethanol self-administration by high-alcohol-drinking replicate rat lines.Alcohol 38：155-164)。每一作業期持續總計30分鐘，此後關閉所有刺激且收回槓桿。作業期結束時，記錄有效與無效槓桿上之反應次數及斷點(其定義為在作業期內達到之最高FR值)。由有效槓桿按動次數計算乙醇消耗量，且轉化為g/kg EtOH消耗。在此作業期之前60分鐘，使用個體內交叉設計，大鼠接受3、10或30 mg/kg劑量範圍內之媒劑或測試化合物口服投藥(3 mL/kg劑量體積，溶解於由20% Captisol®於25 mM磷酸鹽緩衝液(pH=2)中組成之媒劑中)或接受非選擇性類鴉片受體拮抗劑那屈酮(10 mg/kg)作為陽性對照(後續各次給藥之間為3至4天清除期)。在另一情形下，在此作業期之
前30分鐘使用交叉設計，大鼠接受媒劑或30 mg/kg測試化合物之口服投藥(1 mL/kg劑量體積，溶解於由20% Captisol®於25 mM磷酸鹽緩衝液中組成之媒劑中)。
基本上如上所述分析代表性化合物且發現其在維持漸進比率增強時程之P大鼠中減少以乙醇為動機之回應，且因此減少乙醇消耗。基本上如上所述測試化合物1及2且發現其如表1中減少以乙醇為動機之回應。重要的是，無效槓桿上之反應不受ORL-1拮抗劑影響(p>0.05)，表明無非特異性運動副作用。
(ANOVA分析：化合物1：F(4,55)=5.2，p=0.001；化合物2：F(1,24)=16.8，p<0.001)。
壓力為人類及齧齒動物尋求藥物及酒精復發之重要觸發因子(Sinha R(2008)Chronic stress,drug use,and vulnerability to addiction.Ann N Y Acad Sci 1141：105-130)，且可使用壓力誘發復原程序在大鼠內建立模型。在此程序中，藉由投與α2腎上腺素受體拮抗劑育亨賓(yohimbine，一種已知的藥理學應激子)來引發酒精尋求之壓力誘發性復原(Le AD、Harding S、Juzytsch W、Funk D及Shaham Y(2005),Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats.Psychopharmacology (Berl)179：366-373)。
雄性msP大鼠係自卡梅里諾大學(University of Camerino)(Marche,Italy)獲得且個別圈養，可隨意獲取水及標準實驗室飼料。在位於消音、通風環境箱之標準操作室(MED Associates,Inc.,St.Albans,VT)中訓練大鼠按槓桿以獲取於水中之10%乙醇(v/v)。該等室由兩個不鏽鋼及兩個透明普列克斯玻璃壁組成。操作室之地板格由間隔約1.5 cm置放之0.5 cm直徑不鏽鋼條組成。每一操作室裝配有位於格形地板上方4 cm處之飲用水箱，在飲水容器之每一側面上具有間隔約3 cm安置之兩個伸縮式操作槓桿。流體傳遞、槓桿按動及視覺刺激呈現(白色室內光照射)由IBM相容性電腦控制以供離線分析。
首先訓練大鼠在FR1增強時程下在每天30分鐘之操作性作業期中自行投與乙醇溶液，其中有效槓桿上之每次反應引起0.1 ml乙醇傳遞。每次乙醇傳遞均與以白色室內光照射為信號之5秒暫停相結合。繼續酒精自行投與訓練直至達到穩定之基線回應。一旦達到穩定回應，即使動物經歷30分鐘消退作業期，在此期間槓桿上之反應啟動傳遞機制，但不引起傳遞乙醇。每一作業期之程序與乙醇自行投與作業期相同，但槓桿反應不再增強。以媒劑將動物預處理3天，之後初始投與ORL-1受體拮抗劑以使其熟悉經口投藥程序。隨後使msP大鼠經歷在相同消退條件下進行之復原測試。復原由經口投與媒劑或測試化合物(3或30 mg/kg，n=10/組，溶解於蒸餾水與1M H3PO4之1：1混合物中，使用在45-60℃水浴中緩和加溫)、繼而在30分鐘後腹膜內投與育亨賓(2.0 mg/kg)，30分鐘後進行操作性作業期組成。
基本上如上所述檢定代表性化合物且發現其以劑量依賴方式減少乙醇尋求之壓力誘發性復原。重要的是，無效槓桿回應不受處理影響，表明育亨賓誘發之復原的減少並非由於運動活動之非特異性變化。基本上如所述測試化合物1及2且發現其如表2中減少乙醇尋求之壓力誘發性復原。
ANOVA分析：化合物1主動桿：F(2,27)=18.2，p<0.0001；被動桿：F(2,27)=0.2，p>0.05；化合物2主動桿：F(2,27)=18.16，p<0.001；被動桿：F(2,27)=1.2，p>0.05。
在此程序中(修改自Rodd-Henricks ZA、McKinzie DL、Shaikh SR、Murphy JM、McBride WJ、Lumeng L及Li TK(2000),Alcohol deprivation effect is prolonged in the alcohol preferring(P)rat after repeated deprivations.Alcohol Clin Exp Res 24：8-16)，自私有群體(Taconic,Germantown,NY)獲得雌性P大鼠，個別地圈養，可隨意獲取食物、15%乙醇(v/v，於水中)及水，且維持12小時亮/暗循環(16：00時關燈)。各室裝配有連接至乙醇、水及食物容器之力轉導系統(TSE Systems,Bad Homburg,Germany)以使得可連續監測食物及液體消耗。大鼠自主消耗15%乙醇，平均每天攝取約5 g/kg歷時數月之後進行藥物測試。以3、10或30 mg/kg劑量範圍內之媒劑或測試化合物(3 mL/kg劑量體積，溶解於由20% Captisol®於25 mM磷酸鹽緩衝液(pH=2)中組成之媒劑中)或以那屈酮(10 mg/kg，1 mL/kg劑量體積，溶解於水中)經口處理大鼠，之後即刻使用個體內交叉設計(後續各次劑量之間為3至4天清除期)開始黑暗循環。在另一實驗中，大鼠接受媒劑之經口投與，繼而接受4天媒劑或30 mg/kg測試化合物之每天口服劑
量，之後即刻使用個體間設計開始黑暗循環。
在另一研究中，自私有群體卡梅里諾大學(Marche,Italy)獲得雄性msP大鼠，個別地圈養，可隨意獲取食物、10%乙醇(v/v，於水中)及水，且維持12小時亮/暗循環。使用刻度瓶量測乙醇及水以評估乙醇消耗體積(Economidou D、Fedeli A、Fardon RM、Weiss F、Massi M及Ciccocioppo R(2006)Effect of novel nociceptin/orphanin FQ-NOP receptor ligands on ethanol drinking in alcohol-preferring msP rats.Peptides 27：3299-3306.)。藉由對食物容器進行稱重來監測食物攝取。一旦大鼠達到每天5-6 g/kg之自主乙醇消耗穩定基線(約4至5個月大)，即用在由1：1蒸餾水：1 M H3PO4(1-5 mL/kg劑量體積)組成之調配物中的3或30 mg/kg劑量範圍內之測試化合物經口處理大鼠，一小時之後使用個體內交叉設計開始黑暗循環(後續各次劑量之間為3至4天清除期)。在黑暗循環開始時將乙醇、水及食物呈予動物，且以2、8及24小時間隔量測食物及流體之消耗。
基本上如上所述檢定代表性化合物且發現其在可自由選擇獲取乙醇之P大鼠及msP大鼠中均產生乙醇自行投與之選擇性劑量依賴性減少，而不顯著影響食物或水攝取。基本上如所述檢定化合物1、2及5且發現其如表3中所示顯著減少乙醇自行投與。在另一實驗中，如表4中所示，發現在每天一次給藥之4天內，化合物1在P大鼠中維持對乙醇攝取之抑制作用而無急速減敏作用。
ANOVA分析：化合物1：P大鼠，F(4,40)=6.03，p<0.001，msP大鼠，F(2,18)=27.78，p<0.001；化合物2：P大鼠，F(3,52)=6.6；p<0.001，msP大鼠，F(2,20)=18.05，p<0.001；化合物5：P大鼠，F(4,28)=3.48；p<0.02；對食物或水攝取無顯著影響，p>0.05。
ANOVA分析：F(2,19)=10.67，p<0.001。
已知乙醇及其他藥物濫用會使得大腦獎賞迴路(特定而言為伏隔核)內之細胞外多巴胺(DA)含量增加(Yoshimoto K、McBride WJ、Lumeng L及Li TK(1992)Alcohol stimulates the release of dopamine and serotonin in the nucleus accumbens.Alcohol 9：17-22；Di Chiara G及Imperato A(1988)Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.Proc Natl Acad Sci U S A 85：5274-5278)。伏隔核DA含量之大幅增加與愉悅及獎賞之主觀報導直接相關聯，且與濫用潛能相關。那屈酮(一種用於處理酒精依賴之市售藥物)阻止乙醇刺激伏隔核中之DA釋放(Gonzales RA及Weiss F(1998)Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens.J Neurosci 18：10663-10671)。
在實驗之前5至7天，由供應商在來自Taconic Farms(Germantown,NY)之體重為260至300 g之雄性史泊格多利大鼠(Sprague-Dawley rat)之伏隔核中植入引導套管(Bioanalytical Systems Inc,West Lafayette,IN)。伏隔核套管之立體定位座標為：A(前囪前部)，1.7 mm；L(正中矢狀縫側向，右側)，1.0 mm；及V(硬腦膜表面腹側)，-6.0 mm(Paxinos及Watson,1986)。用水沖洗來自Bioanalytical Systems Inc.(West Lafayette,IN)之同心型探針(BR-2)且在實驗前約16小時謹慎地插入穿過套管以使得2 mm之膜尖端延伸至引導套管末端下方。隨後將大鼠置於塑膠測試碗中以適應隔夜。基於修改自Melendez等人之方法(Melendez RI、Rodd-Henricks ZA、McBride WJ及Murphy JM(2003),Alcohol stimulates the release of dopamine in the ventral pallidum but not in the globus pallidus：a dual-probe
microdialysis study.Neuropsychopharmacology 28：939-946)，在實驗當日清晨將大鼠連接至餾分收集系統以使得動物可自由移動(Raturn,BioAnalytical Systems Inc,West Lafayette,IN)。將透析探針之輸入管連接至注射泵(BeeHive及BabyBee,Bioanalytical Systems Inc,West Lafayette,IN)，其以1.5 μL/min之最終收集速率將人工腦脊髓液(150 mM NaCl、3 mM KCl、1.7 mM CaCl2及0.9 mM MgCl2(pH 6.0))傳遞至探針。將來自大鼠之輸出管連接至冷凍餾分收集器(Bioanalytical Systems Inc,West Lafayette,IN)。以5.0 μL/min之初始灌注速率歷時約1小時之時間段之後，將流動速率降至2.0 μL/min以使探針平衡且建立穩定之基線含量歷時1小時，隨後開始收集20分鐘餾分。在注射任何藥物之前收集四種基線樣品。
經口投與測試化合物30 mg/kg(2 ml/kg劑量體積，溶解於由20% Captisol®於25 mM磷酸鹽緩衝液(pH=3)中組成之媒劑中)。該化合物係單獨投與(10分鐘投與至第4樣品中；0分鐘時間點)或與乙醇組合投與(10分鐘投與至第1樣品中；-60分鐘時間點)。乙醇係以1.1 g/kg於0.9%生理鹽水中之15%(v/v)溶液以每隻大鼠2.9 ml體積之劑量經腹膜內(ip)投與。10分鐘投與乙醇至第4樣品中(0分鐘時間點)。將透析物樣品轉移至具有樣品冷卻托盤設定5℃之Alcott 718自動取樣器/注射器(Alcott Inc.,Norcross,GA)中。HPLC分析方法同時偵測同一透析物中之去甲腎上腺素(NE)、多巴胺(DA)及血清素(5-HT)及其代謝物3,4-二羥基苯基乙酸(DOPAC)、高香草酸(HVA)、3-甲氧基-4-羥基-苯基二醇(MHPG)及血清素代謝物5-羥基吲哚乙酸(5-HIAA)。使用具有十向HPLC閥及20 μL樣品環路之BDS-Hypersil 3 μm C18分析管柱(2×150 mm，來自Thermo-Fisher)配置有小樣品淨化管柱(BDS-Hypersil 3 μm C18，2×10 mm)，其截獲透析物樣品中所含之一個後溶離峰。兩管柱之移動相相同且由75 mM磷酸二氫鈉、350 mg/L 1-辛烷磺酸鈉鹽、
0.5 mM EDTA、0.8%四氫呋喃(HPLC級，無抑制劑)及8%乙腈，pH 3(用磷酸調整)組成。兩管柱之流動速率為0.20 mL/min。以管柱加熱器使分析管柱維持在40℃，同時在室溫下將樣品淨化管柱安裝在十向閥上。使用具有兩個玻璃碳電極之電化學偵測器(EG & G PARC,Princeton,NJ)(E1=680 mV、E2=100 mV、兩電極上之範圍=0.5 nA)。在E1偵測代謝物，而在E2偵測NE及DA。由於細胞外DOPAC、HVA及5-HIAA含量遠高於DA及NE含量，因此在EG&G偵測器上使用10伏特(volt)輸出來分析DOPAC、HVA及5-HIAA峰，EG&G偵測器向電腦輸送一個獨立頻道，允許該等代謝物峰維持規模。使用EZChrom層析數據系統(Scientific Software,San Ramon,CA)收集所有三個頻道之數據，該系統計算峰高度及樣品濃度。對於NE、DA及5HT之敏感度為0.1 pmol/mL透析物或2 fmol/樣品(20 μL)。
媒劑+乙醇(1.1 g/kg，IP)使大鼠伏隔核內之細胞外DA含量增加至基線含量之約125-130%，此為與文獻中所報導類似且由所有濫用藥物不同程度地產生之作用。基本上如上所述檢定代表性化合物且發現其防止大鼠伏隔核內之細胞外DA濃度增加。重要的是，在不存在乙醇之情況下給藥時，該等化合物對伏隔核內之細胞外DA含量無影響。基本上如上所述檢定化合物1且發現其如表5中所示防止伏隔核內之細胞外DA濃度增加。
ANOVA分析：
化合物1+EtOH與媒劑+EtOH：F(3,28)=7.25，p=0.001。
化合物1+媒劑與媒劑+媒劑：p>0.05。
基於本文呈現之數據，預期本發明化合物展現處理酒精使用病症之功效。
雖然本發明方法中所用之化合物可能在無任何調配之情況下直接投與，但該等化合物通常以醫藥組合物之形式投與，該等醫藥組合物包含至少一種式I化合物或其醫藥學上可接受之鹽作為活性成分及至少一種醫藥學上可接受之載劑、稀釋劑及/或賦形劑。該等組合物可經各種途徑投與，包括經口、鼻內、經皮、皮下、靜脈內、肌肉內及經肺。該等醫藥組合物及其製備方法在此項技術中為熟知的。參見例如Remington：The Science and Practice of Pharmacy(University of the Sciences in Philadelphia編，第21版，Lippincott Williams & Wilkins Co.,2005)。
該等組合物較佳以單位劑型調配，每一劑量含有約0.1至約500 mg、更通常約1.0至約200 mg(例如約5至50 mg)活性成分。術語「單位劑型」係指適用作用於人類個體及其他哺乳動物之單一劑量的物理離散單元，每一單元含有經計算可產生所需治療作用之預定量活性物質，與至少一種適合之醫藥學上可接受之載劑、稀釋劑及/或賦形劑締合。
式I化合物通常在寬劑量範圍內有效。舉例而言，每日劑量通常在每公斤體重約0.01至約50 mg範圍內、更通常在每公斤體重約0.05至5.0 mg範圍內且例如在每公斤體重0.1與1.0 mg之間。在一些情形下，低於上述範圍下限之劑量含量可能已足夠，而在其它情形下，即使使用較大劑量可能亦不會引起任何有害副作用，且因此上述劑量範圍不欲以任何方式限制本發明之範疇。應瞭解，將由醫師根據相關情況確定實際投與化合物之量，該等相關情況包括欲處理之病狀、所選之投
藥路徑、實際投與之化合物、個體患者之年齡、體重及反應，及患者症狀之嚴重性。
Claims (14)
- 一種下式化合物用於製備用以處理人類酒精使用病症之藥劑的用途：
- 如請求項1之用途，其中R2a與R2b各為氟。
- 如請求項2之用途，其中R1為氯且R3為甲基或羥基甲基。
- 如請求項3之用途，其中R3為甲基。
- 如請求項1之用途，其中該化合物為[2-[4-[(2-氯-4,4-二氟-螺[5H-噻吩并[2,3-c]哌喃-7,4'-哌啶]-1'-基)甲基]-3-甲基-吡唑-1-基]-3-吡啶基]甲醇、 2-氯-4,4-二氟-1'-[[1-(3-氟-2-吡啶基)-3-甲基-吡唑-4-基]甲基]螺[5H-噻吩并[2,3-c]哌喃-7,4'-哌啶]或2-氯-1'-[[1-(2,6-二氟苯基)-3-甲基-吡唑-4-基]甲基]-4,4-二氟-螺[5H-噻吩并[2,3-c]哌喃-7,4'-哌啶]，或其醫藥學上可接受之鹽。
- 如請求項1之用途，其中該化合物為[2-[4-[(2-氯-4,4-二氟-螺[5H-噻吩并[2,3-c]哌喃-7,4'-哌啶]-1'-基)甲基]-3-甲基-吡唑-1-基]-3-吡啶基]甲醇，或其醫藥學上可接受之鹽。
- 如請求項1之用途，其中該酒精使用病症為酒精依賴。
- 如請求項2之用途，其中該酒精使用病症為酒精依賴。
- 如請求項5之用途，其中該酒精使用病症為酒精依賴。
- 如請求項6之用途，其中該酒精使用病症為酒精依賴。
- 如請求項1之用途，其中該酒精使用病症為酒精濫用。
- 如請求項2之用途，其中該酒精使用病症為酒精濫用。
- 如請求項5之用途，其中該酒精使用病症為酒精濫用。
- 如請求項6之用途，其中該酒精使用病症為酒精濫用。
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