TWI579272B - 普多比啶（ｐｒｉｄｏｐｉｄｉｎｅ）之氫溴酸鹽 - Google Patents
普多比啶（ｐｒｉｄｏｐｉｄｉｎｅ）之氫溴酸鹽 Download PDFInfo
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- TWI579272B TWI579272B TW101146235A TW101146235A TWI579272B TW I579272 B TWI579272 B TW I579272B TW 101146235 A TW101146235 A TW 101146235A TW 101146235 A TW101146235 A TW 101146235A TW I579272 B TWI579272 B TW I579272B
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- disorders
- hydrobromide salt
- pridopidine
- salt
- propyl
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
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- Animal Behavior & Ethology (AREA)
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Description
本發明係關於普多比啶(Pridopidine)之新穎鹽，其係當前研發之用於治療亨汀頓氏舞蹈症(Huntington's disease)之藥物物質。更特定而言，本發明提供醫藥上可接受之氫溴酸鹽、包含此鹽之醫藥組合物及此鹽作為藥物物質之用途。
本申請案主張2011年12月9日申請之美國臨時申請案第61/569,157號及2011年12月8日申請之丹麥專利申請案第PA 2011 70684號之優先權，其全部內容係以引用方式併入本文中。
本申請案通篇提及各種公開案，且全文引用之該等公開案之揭示內容係以引用方式併入本申請案中，以更全面地闡述截至本文所闡述之本發明日期為止之最佳技術。
醫藥鹽之晶格係由離子化藥物分子及具有相反電荷之抗衡離子組成，其形成獨特晶體結構。由於藥物之物理化學特性取決於晶體結構，故藥物之不同鹽形式呈現不同物理化學特性，例如熔點、結晶度及吸濕性，該等因素最終可影響藥物之可加工性、生物利用度及穩定性。因此，製備並表徵各種鹽形式係有價值的。有不同形式可供選擇提供了改良醫藥產物之性能之新機會。
普多比啶(即4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶)係當前臨床研發之用於治療亨汀頓氏舞蹈症之藥物物質。4-(3-
甲磺醯基-苯基)-1-丙基-六氫吡啶之鹽酸鹽及其合成方法闡述於WO 01/46145中。在WO 2006/040155中，闡述合成4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶之替代方法。在WO 2008/127188中，報導某些多巴胺受體穩定劑/調節劑之N-氧化物及/或二-N-氧化物衍生物，包括4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶-1-氧化物。
本發明提供普多比啶之醫藥上可接受之氫溴酸鹽。
參考附圖來進一步圖解說明本發明。
普多比啶係呈三級胺形式之弱鹼，其所計算pKa值為8.9。
4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶；普多吡啶
在本發明第一態樣中，本發明提供4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶之新穎結晶形式(氫溴酸鹽)或其溶劑化物。
在較佳實施例中，結晶氫溴酸鹽係以無水形式來提供。
在另一較佳實施例中，結晶氫溴酸鹽係以無水形式及非溶劑化形式來提供。
本發明之結晶氫溴酸鹽之特徵在於粉末X-射線繞射圖具有展示於下表1中之d-間距或繞射圖實質上如圖1中所繪示。
因此，在第三較佳實施例中，本發明之結晶4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶氫溴酸鹽之特徵在於X-射線粉末繞射圖之反射對應於d-間距值6.0及3.8。
在更佳實施例中，本發明之結晶氫溴酸鹽之特徵在於X-射線粉末繞射圖之反射對應於d-間距值3.6及4.0。
在另一更佳實施例中，本發明之結晶氫溴酸鹽之特徵可在於X-射線粉末繞射圖之反射對應於d-間距值7.6、6.9、6.0、5.4、4.3、4.2、4.0、3.8、3.6、3.1。
在第四較佳實施例中，本發明之結晶氫溴酸鹽之特徵可在於具有實質上如圖2中所展示之DSC熱譜圖。
在第五較佳實施例中，本發明之結晶氫溴酸鹽之特徵可在於具有如用DSC獲得之開始於約196℃之吸熱曲線。
在第六較佳實施例中，本發明之結晶氫溴酸鹽之特徵可在於IR光譜實質上如圖3中所繪示。
在第七較佳實施例中，本發明之結晶氫溴酸鹽之特徵可在於TGA熱譜圖實質上如圖4中所繪示。
氫溴酸鹽以斜方晶空間群P212121結晶，且晶格參數如下：a=7.3170(10)Å、b=10.7189(15)Å、c=21.880(3)Å、α=90℃、β=90℃、γ=90℃，且晶胞體積為1716.05Å3。
動態蒸氣吸附(DVS)曲線展示，氫溴酸鹽不吸濕且不易
潮解，此乃因該鹽在95%相對濕度(RH)水準下增加小於1%之重量，參見圖5。因此，在第八較佳實施例中，本發明之結晶氫溴酸鹽之特徵可在於DVS曲線實質上如圖5中所繪示。
TGA展示氫溴酸鹽為非溶劑化形式(參見圖4)，且卡爾費雪分析(Karl Fisher analysis)證實該鹽之無水性質。
藥物研發過程中許多步驟中之一者係鑑別藥物之可用作有效藥物產物之固體形式。調配物必須將活性分子有效遞送至所靶向生物系統。Newman及Stahly，「Form Selection of Pharmaceutical Compounds」，Handbook of Pharmaceutical Analysis,18,18(2002)。生物活性有機分子與酸或鹼之反應產生鹽，該等鹽具有與基礎化合物不同之物理特性。藥物物質之一個重要特性係其吸濕性。Newman及Stahly,「Form Selection of Pharmaceutical Compounds」，Handbook of Pharmaceutical Analysis,18,19(2002)。
化合物之氫溴酸鹽之物理特性(例如吸濕性)不可預測。
文獻中有氫溴酸鹽之若干個實例，然而，該鹽有時吸濕且有時不吸濕。舉例而言，美國專利公開案第2012/0053195號及美國專利第6,110,940號中之氫溴酸鹽不吸濕。與之相比，Parenty等人，「General one-pot,three-step methodology leading to an extended class of N-heterocyclic cations：spontaneous nucleophilic addition,cyclization,and hydride loss.」J.Org.Chem.69(18)：5934-5946(2004)中之氫溴酸鹽吸濕。
WO 01/46145中所揭示之普多比啶之鹽酸鹽在低於86%之相對濕度下不吸濕，但在超過86%之相對濕度下易潮解。此意味著該鹽能夠自環境吸收如此多的水分而使該鹽溶解。所主張之發明保持與先前所揭示鹽酸鹽相同之治療特性，但在高達至少95%之相對濕度下不吸濕。
檢驗按照GMP(優良製造規範)製得之三個批次之普多比啶鹽酸(HCl)鹽。對兩個批次之普多比啶HCl鹽(批次A及B之普多比啶HCl鹽)實施DVS分析。獲得第三批次之普多比啶HCl鹽(批次C之普多比啶鹽酸鹽)之兩個完整週期之吸附及解吸附曲線。第一吸附週期中之水分吸附動力學相當快速。在90%相對濕度階段時及之後，吸附及解吸附動力學顯著較慢(參見圖7)。在90%相對濕度下，吸附大量水分且觀察到大約80%之重量增加。隨後之解吸附及吸附週期展示幾乎相同之特徵，但與第一吸附週期顯著不同。此指示材料固相之變化(參見圖7及圖8)。
在80%至90%(mid-eighties)相對濕度範圍內實施另一運行以更詳細地確定轉變點。(參見圖9)。為此，使用批次B之普多比啶鹽酸鹽，然而批次B之普多比啶鹽酸鹽之單一週期DVS運行展示與批次A之普多比啶鹽酸鹽相同之水分吸附特性。在週期結束時，觀察到樣本已完全溶解。此展示，普多比啶之鹽酸鹽在超過86%之相對濕度下易潮解。
本發明之4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶氫溴酸鹽可藉由習用鹽形成及結晶方法來製備，如(例如)工作實例中所闡述。
對HBr鹽實施DVS分析，且結果展示於圖5及圖6中。在介於0與95%之RH下，該鹽逐漸增加大約0.15%重量，此重量在解吸附期間流失。吸附及解吸附動力學較快速，此乃因兩個完整週期係在225分鐘內實施。在90%解吸附階段中，觀察到解吸附及吸附合併在一起(圖6)。
此觀察結果之起因有待研究。曲線在週期之間大致可重複，然而觀察到輕微滯後。因此，結果表明，NS30016-HBr鹽不吸濕。
WO 01/46145、WO 01/46146、WO 2005/121087、WO 2007/042295、WO 2008/127188及WO 2008/155357皆闡述經取代之4-苯基-N-烷基-六氫吡嗪及4-苯基-N-烷基-六氫吡啶，其據報導係多巴胺神經傳遞之調節劑且可用於治療各種中樞神經系統病症之症狀。人們認為本發明之4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶氫溴酸鹽可用於與該等公開案中所闡述相同之醫學適應症，且該等公開案因此係以引用方式併入。
該等公開案所涵蓋之神經學適應症包括治療亨汀頓氏舞蹈症及其他運動病症以及由藥物誘發之運動病症。因此，
在較佳實施例中，本發明係關於本發明4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶氫溴酸鹽之用途，其用作治療亨汀頓氏舞蹈症之藥劑。
該等公開案所涵蓋之其他適應症為：治療神經及精神病症(例如帕金森氏病(Parkinson's disease)及精神分裂症)；與衰老有關之病症，其用於預防動作遲緩及抑鬱症且用於改善心理功能。所主張化合物亦可用於在神經變性及發育性病症中以及在腦損傷後改善認知功能及相關情緒障礙。
本發明化合物可用於改善精神病之症狀，包括精神分裂症及精神分裂症樣病症以及藥物誘發之精神病。本發明化合物亦可用於通常在嬰兒期、兒童期或青年期首次診斷之行為異常，以及用於衝動控制病症中。另外，可改善言語障礙，例如口吃。亦可改善其他其特徵不在於精神分裂症、情感性分裂症候群以及由其他藥物誘發之精神病症狀、妄想及幻覺之精神病。亦可改善破壞性行為病症，例如注意力缺陷過動症(ADHD)、行為品行病症及對立性反抗病症。該等化合物亦可用於抽動病症中，例如杜萊德氏症候群(Gilles de Ia Tourette's syndrome)及其他抽動病症。另外，可改善言語障礙，例如口吃。該等化合物亦可用於治療藥物濫用病症以及特徵為食物濫用之病症。
亦可採用本發明化合物來治療情感及焦慮病症、人格異常及轉換性癔病。
神經學適應症包括治療亨汀頓氏舞蹈症及其他運動病症，及由藥物誘發之運動病症。亦可用本發明所包括之化
合物來治療不寧腿症及相關病症、及猝睡症。該等化合物亦可在帕金森氏症及相關帕金森氏症候群中改善心理及運動功能。其亦可用於改善不同起源之顫抖症。其可用於治療頭痛且可用於在血管損傷或創傷性腦損傷之後改善大腦功能。此外，其可用於在特徵為肌肉緊張度增加之病況中緩解疼痛。
已發現，本發明化合物可特異性地作用於大腦中之多巴胺能系統。其對選擇性多巴胺拮抗劑之特徵性特徵在大腦中之生化指標有效應，例如使多巴胺代謝物之濃度增加。
本發明化合物尤其適於治療中樞神經系統中之病症，且尤其用於治療多巴胺介導之病症。例如，其可用於改善情感病症之症狀，在肥胖症中用作厭食劑及用於其他飲食障礙中，用於改善認知功能及相關情緒障礙，用於改善與發育性病症有關之認知性及運動性功能異常，用於改善精神分裂症及精神分裂症樣病症以及其他精神病之症狀，用於改善持續性症狀以及用於預防新穎精神病發作之出現，用於調節因攝入食物、咖啡、茶、菸草、酒精、成癮藥物等引起之病理病症。
因此，本發明化合物可用於治療例如以下中之症狀：-神經學適應症，其包括治療亨汀頓氏舞蹈症；運動病症，例如運動困難，包括其他舞蹈症以及原發性、繼發性及陣發性張力障礙；遲發性運動病症，例如遲發性運動困難及遲發性張力障礙；以及其他藥物誘發之運動病症。不寧腿症、週期性腿動症及猝睡症亦可用本發明所包括之化
合物來治療。該等化合物亦可改善帕金森氏症及相關帕金森氏症候群(例如多系統萎縮症、進行性上眼神經核麻痺症、擴散性路易氏體症(diffuse Lewy body disorder)及血管性帕金森氏症)中之心理及運動功能。其亦可用於改善不同起源之顫抖症。本發明中之化合物亦可作為急性治療及預防性治療二者用於治療血管性頭痛，例如偏頭痛及叢集性頭痛。其可在血管性或創傷性腦損傷之後改善複健。此外，其亦可用於在特徵為肌肉緊張度增加之病況中緩解疼痛。
-精神分裂症及其他精神病，例如緊張型、錯亂型、妄想型、殘餘型或分化型精神分裂症；精神分裂症樣病症；情感型精神分裂症；妄想症；短期性精神病；共有型精神病；由一般醫學病況引起之具有妄想及/或幻覺之精神病；-情感病症，例如抑鬱症，例如，神經官能性憂鬱障礙或重鬱症；雙極性障礙，例如，I型雙極性障礙、II型雙極性障礙及循環性情感病症；由一般醫學病況引起之具有憂鬱及/或狂躁特徵之情感病症；及藥物誘發之情感病症；-焦慮症，例如急性壓力病症、無恐慌症史之懼空曠症、由一般醫學病況引起之焦慮症、廣泛性焦慮症、強迫症、具有懼空曠症之恐慌症、無懼空曠症之恐慌症、創傷後壓力病症、特定對象恐懼症、社交恐懼症及藥物誘發之焦慮症；-飲食障礙，例如神經性厭食症、心因性暴食症及肥胖
症；-睡眠障礙，例如睡眠異常，例如，呼吸相關之睡眠障礙、晝夜節律性睡眠障礙、睡眠過度、失眠症、猝睡症、「時差」及性功能障礙；-未在別處分類之衝動控制病症，例如陣發性暴怒病症、盜竊症、病態性賭博、縱火癖及拔毛癖；-人格異常，例如妄想型、精神分裂樣或精神分裂型病症；反社會型、邊緣型、戲劇型及自戀型病症；以及回避型、依賴型、強迫型病症；-藥物誘發之運動病症，例如抗精神病藥誘發之帕金森氏症、抗精神病藥惡性症候群、抗精神病藥誘發之急性及遲發性張力障礙、抗精神病藥誘發之靜坐不能、抗精神病藥誘發之遲發性運動困難、藥物誘發之顫抖症以及藥物誘發之運動困難；-藥物相關病症，例如因使用或濫用酒精、安非他命(amphetamine)(或類安非他命物質)、咖啡因、大麻、古柯鹼、迷幻劑、吸入劑、尼古丁(nicotine)、類鴉片藥、苯環己哌啶(或類苯環己哌啶物質)、鎮靜性物質、催眠性物質及/或抗焦慮物質而引起之濫用、依賴性、焦慮症、中毒、中毒譫妄、精神病、具有妄想之精神病、情感病症、持久性遺忘病症、持久性失智症、持久性知覺病症、性功能異常、睡眠障礙、戒斷及戒斷譫妄；-通常在嬰兒期、兒童期或青年期首次診斷之病症，例如心理遲滯；學習障礙；運動技能障礙，例如發育性協調障
礙；溝通障礙，例如語言表達障礙、音韻異常、語言接收與表達障礙及口吃；廣泛性發育障礙，例如亞斯伯格症(Asperger's disorder)、自閉症、兒童期崩解症及雷特氏症(Rett's disorder)；注意力缺陷症及破壞性行為病症，例如注意力缺陷/過動症、行為品行病症、及對立性反抗症；嬰兒期或兒童早期之餵食障礙及飲食障礙，例如嬰兒期或兒童早期之餵食障礙、異食症、反芻症；抽動症，例如慢性運動性或發聲性抽動症及杜瑞氏症(Tourette's disorder)；其他嬰兒期、兒童期或青年期病症，例如選擇性緘默症及製式行為病症；-譫妄、失智症、遺忘及其他認知病症，例如阿茲海默氏症(Alzheimer's disease)、庫賈氏症(Creutzfeldt-Jakob disease)、死亡創傷、亨汀頓氏舞蹈症、HIV疾病、匹克症(Pick's disease)及擴散性路易氏體失智症(diffuse Lewy body dementia)；-轉換性癔病；-與正常老化相關之病況，例如運動功能及心理功能中之障礙；-帕金森氏症及相關病症，例如多系統萎縮症，例如紋狀體黑質變性、橄欖體小腦腦橋萎縮症及雪德氏症候群(shydrager syndrome)；進行性上眼神經核麻痺症；大腦皮質基底核退化症；及血管性帕金森氏症；-顫抖症，例如原發性、直立性、靜止性、小腦性及繼發性顫抖症
-頭痛，例如偏頭痛、叢集性頭痛、緊張型頭痛及陣發性頭痛；-運動病症，例如運動困難(例如在一般醫學病況中，在創傷或血管性損傷後)、偏側抽搐、手指徐動病、辛登南氏舞蹈症(Sydenham's chorea)及陣發性張力障礙；爾氏症候群(Ekbom's syndrome，不寧腿症)；威爾森氏病(Wilson's disease)；哈-斯二氏病(Hallerworden-Spatz disease)；-複健醫學，例如用於改善血管性或創傷性腦損傷之後之複健；-由藥物誘發之運動病症-帕金森氏症早期，引入L-多巴或直接作用之多巴胺受體激動劑之前，或與低劑量之該等L-多巴或直接作用之多巴胺受體激動劑一起使用。不寧腿症，同樣用於單一療法或組合療法。與高齡、中風及腦炎後相關之精神衰弱。自閉症相關障礙。意識喪失，例如猝睡症及小癲癇、暈厥。睡眠障礙，例如由(例如)多巴胺受體激動劑誘發之睡眠過度、睡眠呼吸暫停、突然睡著。由多巴胺激動劑、其他藥物、動暈症及其他原因誘發之嘔吐及噁心。由抗精神病藥物誘發之多巴胺功能減退症，例如錐體束外症狀、抑鬱症、創始力喪失、認知缺陷(組合治療)。
-特徵為肌肉緊張度增加之病況(例如纖維肌痛、肌筋膜症候群、張力障礙及帕金森氏症)中之疼痛；以及-屬於較大類別但不滿足彼等類別內任一具體病症之準則
之與上述相關之病況。
根據另一態樣，本發明提供呈結晶形式之用作藥劑之4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶氫溴酸鹽或其溶劑化物。因此，在另一態樣中，本發明提供包含治療有效量之本發明化合物之新穎醫藥組合物。
儘管用於療法中之本發明化合物可以原始化學化合物之形式投與，但較佳在醫藥組合物中引入視情況呈生理上可接受之鹽之形式之活性成份以及一或多種佐劑、賦形劑、載劑、緩衝劑、稀釋劑及/或其他常用醫藥輔助物。
本發明醫藥組合物具體而言可如WO 01/46145中所闡述來調配。
關於調配及投與技術之其他細節可參見最新版之Remington's Pharmaceutical Sciences(Maack出版公司，Easton，PA)。
當然，所投與之劑量必須根據以下小心調節：所治療個體之年齡、體重及病況，以及投與途徑、劑型及方案，以及期望結果，且確切劑量當然應由從業醫師來確定。
實際劑量取決於所治療疾病之性質及嚴重程度，且由醫師決定，且可根據本發明之具體環境藉由劑量調整而變化以產生期望治療效應。然而目前預計，每一個別劑量含有約1mg至約500mg活性成份、較佳約10mg至約150mg、最佳約25mg至約50mg之醫藥組合物適於治療性治療。日劑量較佳將以每日1至4次個別劑量來投與。在另一較佳實
施例中，活性成份之劑量將為45mg且以每日兩次來投與。在另一較佳實施例中，活性成份之劑量將為67.5mg且以每日兩次來投與。
製備可用於本發明中之劑型之一般技術及組合物闡述於以下參考文獻中：7 Modern Pharmaceutics，第9章及第10章(Banker及Rhodes編輯，1979)；Pharmaceutical Dosage Forms：Tablets(Lieberman等人，1981)；Ansel,Introduction to Pharmaceutical Dosage Forms第2版(1976)；Remington's Pharmaceutical Sciences，第17版(Mack出版公司，Easton，Pa.，1985)；Advances in Pharmaceutical Sciences(David Ganderton、Trevor Jones編輯，1992)；Advances in Pharmaceutical Sciences第7卷(David Ganderton、Trevor Jones、James McGinity編輯，1995)；Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms(Drugs and the Pharmaceutical Sciences，第36輯(James McGinity編輯，1989)；Pharmaceutical Particulate Carriers：Therapeutic Applications：Drugs and the Pharmaceutical Sciences，第61卷(Alain Rolland編輯，1993)；Drug Delivery to the Gastrointestinal Tract(Ellis Horwood Books in the Biological Sciences.Series in Pharmaceutical Technology；J.G.Hardy、S.S.Davis、Clive G.Wilson編輯)；Modern Pharmaceutics Drugs and the Pharmaceutical Sciences，第40卷(Gilbert S.Banker、Christopher T.Rhodes編輯)。該等參考文獻係全文以引用方式併入本申請案中。
錠劑可含有適宜黏合劑、潤滑劑、崩解劑、著色劑、矯味劑、流動誘導劑及熔化劑。舉例而言，對於以劑量單位形式經口投與錠劑或膠囊而言，活性藥物組份可與諸如以下等醫藥上可接受之口服無毒惰性載劑組合：乳糖、明膠、瓊脂、澱粉、蔗糖、葡萄糖、甲基纖維素、磷酸二鈣、硫酸鈣、甘露醇、山梨醇、微晶纖維素及諸如此類。
適宜黏合劑包括澱粉、明膠、天然糖(例如葡萄糖或β-乳糖)、玉米澱粉、天然及合成膠(例如阿拉伯膠、黃蓍膠或海藻酸鈉)、聚維酮(povidone)、羧甲基纖維素、聚乙二醇、蠟及諸如此類。用於該等劑型中之潤滑劑包括油酸鈉、硬脂酸鈉、苯甲酸鈉、乙酸鈉、氯化鈉、硬脂酸、硬脂基富馬酸鈉、滑石粉及諸如此類。崩解劑包括(但不限於)澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠、交聯羧甲基纖維素鈉、羥乙酸澱粉鈉及諸如此類。
所主張之普多比啶氫溴酸鹽可含有以下無毒輔助物質中之任一者：
多種組態可含有進一步促進組織健康之其他有益生物活性劑。所主張之普多比啶氫溴酸鹽亦可含有於使用中無害之抗菌劑，例如乙汞硫柳酸鈉(thimerosal)、殺藻胺(benzalkonium chloride)、對羥苯甲酸甲酯及對羥苯甲酸丙酯、苯度溴銨(benzododecinium bromide)、苄醇或苯乙醇。
本文所揭示之所主張之普多比啶氫溴酸鹽亦可包含賦形劑，例如溶解度改變劑(例如，乙醇、丙二醇及蔗糖)及聚
合物(例如，聚己內酯及PLGA's)以及醫藥活性化合物。
所主張之普多比啶氫溴酸鹽亦可含有緩衝成份，例如乙酸鈉、葡萄糖酸鹽緩衝劑、磷酸鹽、碳酸氫鹽、檸檬酸鹽、硼酸鹽、ACES、BES、BICINE、BIS-Tris、BIS-Tris丙烷、HEPES、HEPPS、咪唑、MES、MOPS、PIPES、TAPS、TES及三(羥甲基)甲基甘胺酸(Tricine)。
所主張之普多比啶氫溴酸鹽亦可含有無毒醫藥有機載劑或具有無毒醫藥無機載劑。典型醫藥上可接受之載劑係(例如)水、水與水可混溶性溶劑(例如低碳數烷醇或芳烷醇)之混合物、植物油、花生油、聚伸烷基二醇、基於石油之凝膠、乙基纖維素、油酸乙酯、羧甲基纖維素、聚乙烯基吡咯啶酮、肉豆蔻酸異丙基酯及其他可接受之習用載劑。
所主張之普多比啶氫溴酸鹽亦可含有無毒的乳化劑；防腐劑；潤濕劑；質感化劑，例如，聚乙二醇200、300、400及600，卡波蠟(carbowax)1,000、1,500、4,000、6,000及10,000；抗菌組份，例如四級銨化合物、已知具有冷滅菌特性且在使用中無害之苯汞鹽、乙汞硫柳酸鈉、對羥苯甲酸甲酯及對羥苯甲酸丙酯、苄醇、苯乙醇；緩衝成份，例如硼酸鈉、乙酸鈉、葡萄糖酸鹽緩衝劑；以及其他習用成份，例如山梨醇酐單月桂酸酯、三乙醇胺、油酸酯、聚氧乙烯山梨醇酐單棕櫚酸酯、磺琥珀酸鈉二辛酯、硫代甘油、硫代山梨醇、乙二胺四乙酸。
所主張之普多比啶氫溴酸鹽亦可含有可採用之表面活性
劑，包括聚山梨醇酯表面活性劑、聚氧乙烯表面活性劑、膦酸鹽、皂素及聚乙氧基化蓖麻油，但較佳為聚乙氧基化蓖麻油。該等表面活性劑市面有售。聚乙氧基化蓖麻油係由(例如)BASF以商標Cremaphor來出售。
所主張之普多比啶氫溴酸鹽亦可含有通常用於眼用溶液中之潤濕劑，例如羧甲基纖維素、羥丙基甲基纖維素、甘油、甘露醇、聚乙烯醇或羥乙基纖維素，且稀釋劑可係水、蒸餾水、無菌水或人工淚液，其中潤濕劑係以約0.001%至約10%之量存在。
可改變本發明之調配物以包括用於調節pH之酸及鹼；滲性賦予劑，例如山梨醇、甘油及右旋糖；其他黏度賦予劑，例如羧甲基纖維素鈉、微晶纖維素、聚乙烯基吡咯啶酮、聚乙烯醇及其他膠；適宜吸收增進劑，例如表面活性劑、膽汁酸；穩定劑，例如抗氧化劑，如亞硫酸氫鹽及抗壞血酸鹽；金屬螯合劑，例如乙二胺四乙酸鈉；及藥物溶解度增強劑，例如聚乙二醇。該等其他成份有助於使商業溶液具有足夠穩定性，從而使其不必一經要求即進行複合。
其他材料以及處理技術及諸如此類闡述於Remington's Pharmaceutical Sciences，第17版，1985，Mack出版公司，Easton，Pa.之第8冊及International Programme on Chemical Safety(IPCS)中，該參考文獻係以引用方式併入本文中。
在另一態樣中，本發明提供治療、預防或緩解活動物體(包括人類)之多巴胺介導之病症之方法，該方法包含向此等有此需要之活動物體投與治療有效量之本發明4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶氫溴酸鹽之步驟。
在較佳實施例中，多巴胺介導之病症係亨汀頓氏舞蹈症。
為製備33g普多比啶HBr，在室溫下將28.5g游離鹼溶解於150ml 99%乙醇中。添加1.5當量之48%氫溴酸。沈澱自發進行，並將懸浮液在水箱中放置2.5小時。然後濾出晶體，隨後用99%乙醇及醚洗滌。在真空及40℃下將晶體乾燥過夜：熔點為196℃。CHN分析之結果呈現於下表2中。
NMR 1H NMR(DMSO-d6)：0.93(3H,t),1.68-1.80(2H,m),1.99-2.10(4H,m)2.97-3.14(5H,m),3.24(3H,s),3.57-3.65(2H,d),7.60-7.68(2H,m),7.78-7.86(2H,m)及9.41ppm(1H,bs)。
使用如以下所列示經組態之Bruker D8 Advance繞射計來實施X-射線粉末繞射(XRPD)實驗：
將試樣置於零背景矽單晶試樣架上之凡士林(vaseline)薄膜中。使用Bruker「XRD Commander」2.6.1版獲得繞射圖且使用「Bruker Evaluation」11,0,0,3版來評價。
在此程序之後，獲得展示於表1中之d-間距及展示於圖1中之繞射圖。
使用Mettler-Toledo StarE 9.2版軟體包在Mettler Toledo DSC 821e差示掃描量熱計上實施差示掃描量熱(DSC)實驗。在針孔式鋁盤中以10℃/min將試樣(大約3mg)自30℃
加熱至300℃。用乾燥氮連續吹掃DSC試樣，並用銦及鋅以常規方式進行校正。
在此程序之後，獲得展示於圖2中之DSC熱譜圖。
在Mettler Toledo TGA/SDTA 851e上實施熱重分析(TGA)實驗。在開口Al坩堝中以10℃/min將試樣(大約10mg)自30℃加熱至300℃。用乾燥氮連續吹掃TGA試樣，並用銦及鋁以常規方式進行校正。使用Mettler-Toledo StarE 9.2版軟體包評價數據。
在此程序之後，獲得展示於圖4中之TGA熱譜圖。
在配備有Specac供應之衰減全反射(ATR)單元Goldengate之Perkin-Elmer Spectrum One FTIR儀器上實施傅立葉轉換紅外光譜(FTIR)實驗。使用Spectrum 5.0.1版軟體來控制該系統。將試樣(大約1-2mg)直接放置於ATR單元之金剛石表面上，且將砧牢固按壓在試樣上。在4000-600cm-1波數區域中分析試樣。對照內部聚苯乙烯濾波器以常規方式校正儀器。
在此程序之後，獲得展示於圖3中之結晶普多比啶氫溴酸鹽之FT-IR光譜。
使用卡爾費雪(KF)滴定之水測定係使用配備有無隔膜發電機電極之Metrohm KF 756 KF電量計來實施。滴定器配備有Metrohm 832 KF Thermoprep烘箱。在小HPLC玻璃小
瓶中對試樣稱重，將其密封並引入烘箱中(130℃)。此處，用針刺穿HPLC小瓶之橡膠隔片，並使用乾燥載氣(N2)來將所釋放水經由已加熱管路攜載至滴定室。
在試樣滴定之前，滴定一系列空白來測定空白含量。根據空白值來自動校正結果。儀器係藉由使用具有經檢驗水含量之固體標準品以常規方式來控制。
動態蒸氣吸附(DVS)量測係使用來自TA儀器之Q5000 SA來實施。
在兩個介於0% RH與95% RH之間之吸附/解吸附週期中實施實驗。在第一吸附週期之前，使試樣在20% RH下平衡並記錄初始重量。在鋁盤中分析試樣。使濕度降至0% RH，並乾燥試樣直至重量穩定在給定限值內為止。使溫度在25℃下保持恆定。最大階段時間為720min。氣流量為200cm3/min。
在此程序之後，獲得展示於圖5中之DSC曲線。
CHN量測係在Mikroanalytisk Laboratorium,Kemisk Institut,University of Copenhagen使用Flash EA 1112分析器來實施。
將大約2毫克化合物稱重至小錫燒杯中並插入燃燒室中。在管柱上收集所得氣體並經由氣相層析加以分析。一式兩份地實施分析。
圖1展示結晶普多比啶氫溴酸鹽之特徵性X-射線粉末繞射圖；圖2展示結晶普多比啶氫溴酸鹽之特徵性DSC熱譜圖；圖3展示結晶普多比啶氫溴酸鹽之特徵性FT-IR光譜；圖4展示結晶普多比啶氫溴酸鹽之特徵性TGA熱譜圖；圖5展示結晶普多比啶氫溴酸鹽在0-95%相對濕度範圍內之特徵性動態蒸氣吸附(DVS)曲線。大小：8.6650mg，方法：吸附，0-95%，2個週期，25℃。儀器：TGA Q5000 V3.10 Build 258。
圖6展示結晶普多比啶氫溴酸鹽在0-95%相對濕度範圍內之特徵性動態蒸氣吸附(DVS)水分吸附及解吸附動力學曲線。大小：11.4530mg，方法：吸附，0-95%，2個週期，25℃。儀器：TGA Q5000 V3.5 Build 252。
圖7展示結晶普多比啶鹽酸鹽在0-95%相對濕度範圍內之特徵性動態蒸氣吸附(DVS)水分吸附及解吸附動力學曲線。大小：9.9530mg，方法：吸附，0-95%，2個週期，25℃。儀器：TGA Q5000 V3.5 Build 252。
圖8展示結晶普多比啶鹽酸鹽在0-95%相對濕度範圍內之特徵性動態蒸氣吸附(DVS)曲線。11.4530mg，方法：吸附，0-95%，2個週期，25℃。儀器：TGA Q5000 V3.5 Build 252。
圖9展示結晶普多比啶鹽酸鹽在0-95%相對濕度範圍內之特徵性動態蒸氣吸附(DVS)等溫線，其在80%至90%相對濕度範圍內具有較小步距。5.7650mg，方法：吸附，80-90-80%。儀器：TGA Q5000 V3.5 Build 252。
Claims (11)
- 一種4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶(普多比啶(Pridopidine))之氫溴酸鹽，其係以具有X-射線粉末繞射圖之反射對應於d-間距值7.6、6.9、6.0、5.4、4.3、4.2、4.0、3.8、3.6、3.1之呈實質上結晶形式來提供。
- 如請求項1之氫溴酸鹽，其係以無水形式來提供。
- 如請求項1之氫溴酸鹽，其係以無水形式及非溶劑化形式來提供。
- 如請求項1之氫溴酸鹽，其X-射線粉末繞射圖之反射對應於d-間距值10.8、7.6、6.9、6.0、5.7、5.4、5.3、4.7、4.6、4.3、4.2、4.0、3.8、3.7、3.6、3.5、3.4、3.3、3.2、3.1。
- 如請求項1之氫溴酸鹽，其特徵在於IR光譜於約2950cm-1、2700-2500cm-1、1550cm-1、1450cm-1、1300cm-1、1150cm-1、1100cm-1、950cm-1、900cm-1、850cm-1、750cm-1及650cm-1具有吸收值。
- 一種醫藥組合物，其包含治療有效量之如請求項1至5中任一項之氫溴酸鹽以及一或多種佐劑、賦形劑、載劑及/或稀釋劑。
- 如請求項6之醫藥組合物，其中4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶(普多比啶)之治療有效量為1mg至500mg。
- 如請求項6之醫藥組合物，其中4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶(普多比啶)之治療有效量為10mg至150 mg。
- 如請求項6之醫藥組合物，其中4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶(普多比啶)之治療有效量為45mg。
- 如請求項6之醫藥組合物，其中4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶(普多比啶)之治療有效量為67.5mg。
- 一種如請求項1至5中任一項之氫溴酸鹽之用途，其係用於製造治療患有中樞神經系統病症或亨汀頓氏舞蹈症之個體的醫藥組合物/藥劑。
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- 2012-12-07 MX MX2014006664A patent/MX347209B/es active IP Right Grant
- 2012-12-07 TW TW101146235A patent/TWI579272B/zh not_active IP Right Cessation
- 2012-12-07 US US13/708,816 patent/US9012476B2/en active Active
- 2012-12-07 EP EP12855452.4A patent/EP2787997A4/en active Pending
- 2012-12-07 UY UY34503A patent/UY34503A/es not_active Application Discontinuation
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2014
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| Publication number | Publication date |
|---|---|
| EP2787997A4 (en) | 2015-05-27 |
| MX347209B (es) | 2017-04-19 |
| CA2856749A1 (en) | 2013-06-13 |
| TW201331180A (zh) | 2013-08-01 |
| US9012476B2 (en) | 2015-04-21 |
| EP2787997A1 (en) | 2014-10-15 |
| MX2014006664A (es) | 2014-09-04 |
| US20130150406A1 (en) | 2013-06-13 |
| WO2013086425A1 (en) | 2013-06-13 |
| US9814706B2 (en) | 2017-11-14 |
| US20150209344A1 (en) | 2015-07-30 |
| IL232599A0 (en) | 2014-06-30 |
| UY34503A (es) | 2013-07-31 |
| IL232599A (en) | 2017-03-30 |
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