TWI663971B - 猝倒症之治療 - Google Patents
猝倒症之治療 Download PDFInfo
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- TWI663971B TWI663971B TW103108612A TW103108612A TWI663971B TW I663971 B TWI663971 B TW I663971B TW 103108612 A TW103108612 A TW 103108612A TW 103108612 A TW103108612 A TW 103108612A TW I663971 B TWI663971 B TW I663971B
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Abstract
本發明係關於對有需要之個體治療猝倒症的方法，包括給予個體治療有效劑量之某些胺甲酸酯化合物。
Description
本發明係關於對有需要之個體治療猝倒症的方法，包括給予個體治療有效劑量之某些胺甲酸酯(carbamate)化合物。
猝倒症為突然及短暫性發作之肌肉張力喪失，時常由情緒諸如笑、害怕、憤怒、挫折、煩惱、焦燥、難堪及悲傷所引起。猝倒症之突然肌肉張力喪失係與睡眠期間與快速動眼(REM)有關聯之肌肉鬆弛相似，但係發生在覺醒期間。猝倒發作為突然的發病且局部化於特定之肌群或身體部位。個體在發作期間神志清明；猝倒症發病時總是維持清醒。可能發生全面發作並造成伴隨姿勢性虛脫之完全肌肉麻痺且可能受到傷害。然而，因為跌倒是緩慢且漸進的所以有姿勢性虛脫之患者往往具有避免傷害之能力。較通常限定之猝倒發作在包含頭與臉部、頸部及上肢，及較少在稱為“跪倒”之下肢。發作可持續數秒鐘至十分鐘，且可能每星期發生數次。有些病人發生猝倒持續狀態，或周期性之重複肌肉張力喪失，且可持續幾小時或幾天。
猝倒症為罕見疾病(社會中之盛行率為少於10,000分之5)，但是卻侵襲大約70%之患猝睡症者。然而，在有些例子中，猝倒症之發生並未伴隨猝睡症發生。再者，多於30%之猝睡
症患者可能從未經歷猝倒。猝倒症之確實成因未知，但是症狀與遭受強烈情緒及神經傳導物質下視丘分泌素濃度之減少有強力關聯。一般認為猝倒症係由於特定之腦部損害造成下視丘分泌素神經傳導物質之耗盡而伴隨繼發。猝倒症亦可能為某些藥物，諸如選擇性血清素再吸收抑制劑(SSRI)抗憂鬱劑，停藥後之副作用。
無論是否與猝睡症或其他成因有關聯，猝倒症會造成傷殘並有潛在的危險。不管成因如何，猝倒症與種種交通及工傷事故有關聯並造成工作績效下降及相當的主觀性憂傷。可用以減少或排除猝倒症之治療藥劑不僅對個別患者而且對公共健康與安全具有重要意義。
本發明係針對有需要之個體治療猝倒症的方法，包括給予個體治療有效劑量之式(I)化合物或其醫藥上可接受之鹽或酯：
其中R為選自由1至8個碳原子之烷基、鹵素、含有1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及含有1至3個碳原子之硫代烷氧基所構成之群組之一基團；x為0至3之整數，當x為2或3時附帶條件係R可為相同或不同；R1及R2可為彼此相同或不同，且獨立選自由氫、1至8個碳原子之低碳數烷基、芳基、芳基烷基、3至7個碳原子之環烷基所構成之群組；或R1及R2可連結而形成視需要經選自由烷基及芳基所構成之群組之一基團取代
之5至7-員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不直接彼此連接或與氧原子連接。
本發明之具體例包含對有需要之個體治療猝倒症的方法，該方法包括給予個體治療有效劑量之實質上無其他鏡像異構物之式(I)之鏡像異構物，或其中一種式(I)之鏡像異構物佔多數之鏡像異構物混合物之步驟。
一些具體例中，式(I)化合物為式(Ia)化合物：
或其醫藥上可接受之鹽或酯。
一些具體例中，式(I)化合物為式(Ib)化合物：
或其醫藥上可接受之鹽或酯。此化合物命名為(R)-胺甲酸(β-胺基-苯丙基)酯或O-胺甲醯基-(D)-苯丙胺醇及或者稱為ADX-N05、SKL-N05、YKP10A及R228060。
本發明之具體例包含實質上無其他鏡像異構物之式I之鏡像異構物，或其中一種式(I)之鏡像異構物佔多數之鏡像異構物混合物作為製備治療猝倒症之藥物之用途。
以下將參考附帶之描述及實施例而說明本發明，其中顯示發明之具體例。然而，本發明可由許多不同形式體現且不應當解釋為限制於本文所列之具體例。更確切地說，提供這些具體例而使得本揭露更為徹底及完整，而且將全面傳達本發明之範疇於所屬技術領域具通常知識者。
除非另有說明，否則本文使用之技術術語或科學術語具有一般本發明所屬技術領域具通常知識者通常瞭解之意義。本發明之說明中使用之術語僅用於說明特定具體例之目的而非意指限制本發明。
除非上下文另有指明，否則要特別指明本文所說明之發明的各種不同特徵可以任何組合而使用。再者，本發明亦涵蓋，在一些發明之具體例中可排除或略去本文所提出之任何特徵或特徵之組合。舉例說明，如果說明書陳述組成物包括成分A、B及C，係意欲指任何A、B及C或其組合可單獨地或任意組合地略去或放棄。
如本文所使用，“一(a)”、“一(an)”或“該(the)”可意指一個或多於一個。例如，“一(a)”細胞意指單一細胞或多數細胞。
亦如本文所使用，“及/或”意指且包含一種或多種相關表列項目之任何及所有可能組合，以及當解釋為兩者擇一(“或”)時則無組合。
術語“約”，如本文所使用，當意指可測量值諸如劑量(如，化合物量)等，則意為包含所指定量之±20%、±10%、±
5%、±1%、±0.5%或甚至±0.1%之變化。
術語“包括(comprise)”、“包括(comprises)”及“包括(comprising)”，如本文所使用，明確說明所述之特徵、整數、步驟、操作、元件及/或成分之存在，但並不排除一種或多種其他特徵、整數、步驟、操作、元件、成分及/或其群組之存在或添加。
如本文所使用，連接詞“基本上由…組成”意指申請專利之範圍係包含專利申請中所述之指定物質或步驟“而彼等不會重大影響所要求保護之發明之基本及新穎特性”。請參照，In re Herz,537 F.2d 549,551-52,190 U.S.P.Q.461,463(CCPA 1976)(原文強調)；亦請參照MPEP § 2111.03。因此，使用於申請專利範圍或本發明之說明時，術語“基本上由…組成”並非意指相當於“包括”。
如本文所使用，術語“增加(increase)”、“增加(increases)”、“增加(increased)”、“增加(increasing)”及相似之術語表明至少約25%、50%、75%、100%、150%、200%、300%、400%、500%或更多之提高。
如本文所使用，術語“減少(reduce)”、“減少(reduces)”、“減少(reduced)”、“減少(reduction)”及相似之術語表明至少約5%、10%、15%、20%、25%、35%、50%、75%、80%、85%、90%、95%、97%或更多之降低。特別的具體例中，此減少造成無或實質上無(即，無意義的量，如，少於約10%或甚至5%)可檢測出之活性或量。
“有效量”如本文所使用，意指化合物、組成物及
/或本發明調配物之量，而該量足夠產生可為治療及/或有益效用之所需效用。有效量隨年齡、個體之一般狀況、預治療症狀之嚴重性、給予之特別藥劑、治療期限、任何同時治療之性質、使用之醫藥上可接受之載體及所屬技術領域具通常知識者之知識及專門技術範圍內之類似因素而變化。視情況，所屬技術領域熟練之人員可經由參考有關文本及文獻及/或使用一般實驗而測定任何個別實例中之“有效量”。
術語“治療(treat)”、“治療(treating)或“治療(treatment of)”(及其文法上之變化)的意思為個體症狀之嚴重性降低，至少部分改進或改善及/或達到至少一種臨床症狀之一些緩解、減輕或降低及/或得到疾病或障礙進展之延緩。關於猝倒症，該術語意指發作次數之減少、發作期間之減短，及/或發作嚴重性之降低。例如，治療可產生至少每星期約20%猝倒事件次數之降低，如，至少約降低30%、40%、50%、60%、70%、80%或更多。
如本文所使用之“治療有效”量為足夠治療(如本文所定義)個體之量。所屬技術領域具通常知識者應瞭解治療效用不需要是完全或治癒，只要可提供個體一些益處。
本發明之“個體”包含任何已經或懷疑患有猝倒症之動物。此種個體通常為哺乳類動物個體(如，供實驗用動物諸如大鼠、小鼠、天竺鼠、兔、靈長類等)、農場或商業動物(如，牛、馬、山羊、驢、綿羊等)或家畜(如，貓、狗、雪貂等)。特別的具體例中，個體為靈長類個體、非人類之靈長類個體(如，黑猩猩、狒狒、猴子、大猩猩等)或人類。某些具體例中，本發明之個體可為已知有或認為患有猝倒症之個體。發明之個體可為已知有或認
為有患猝倒症風險之個體。替代地，根據本發明之個體亦可包含事先不知或不懷疑患有猝倒症之個體。發明之具體例中個體具有或懷疑有猝睡症。個體包含任何年齡之雄性及/或雌性，包含新生、幼年、成熟及老年個體。
本發明方法之“有需要之個體”可為已知患有猝倒症之個體、懷疑患有猝倒症之個體或有增加患猝倒症風險之個體。一些具體例中，“有需要之個體”為有中度或重度猝倒症者，如，每星期有3次或較多次猝倒事件，如，每星期有4、5、6、7、8、9或10次或較多次猝倒事件之個體。
術語“醫藥上可接受之鹽類或酯類”意指本發明所採用化合物之非毒性鹽類或酯類，通常經由使游離酸與適當之有機或無機鹼反應或使游離鹼與適當之有機或無機酸反應而製備該鹽類或酯類。此種鹽類之實例包含，但不限制於，乙酸鹽、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、鈣、依地酸鈣、右旋樟腦磺酸鹽、碳酸鹽、氯化物、克拉維酸鹽(clavulanate)、檸檬酸鹽、二鹽酸鹽、依地酸鹽、乙二磺酸鹽、丙酸酯月桂基硫酸鹽、乙磺酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、麩胺酸鹽、乙醇醯基對胺基苯胂酸鹽(glycollylarsanilate)、己基間苯二酚酸鹽(hexylresorcinate)、海巴明(hydrabamine)、氫溴酸鹽、鹽酸鹽、羥萘甲酸鹽、碘化物、異硫羥酸鹽(isothionate)、乳酸鹽、乳醣酸鹽、月桂酸鹽、蘋果酸鹽、順丁烯二酸鹽、苯乙醇酸鹽、甲磺酸鹽、溴化甲烷、甲基硝酸、硫酸甲酯、粘酸鹽、萘磺酸鹽、硝酸鹽、油酸鹽、草酸鹽、雙羥萘酸鹽、棕櫚酸鹽、泛酸鹽、磷酸鹽/二磷酸鹽、聚半乳醣醛酸鹽、
鉀、水楊酸鹽、鈉、硬脂酸鹽、次乙酸鹽、琥珀酸鹽、單寧酸鹽、酒石酸鹽、8-氯茶鹼鹽、甲苯磺酸鹽、三乙基碘化物及戊酸鹽。
如本文所使用，術語化合物、治療劑或已知藥物與本發明化合物之“合併給藥”或“組合給藥”意思為在這樣的時間點給予已知藥物治療或藥物，並加上本發明之一種或多種化合物而使已知藥物及化合物皆具有治療效果。在一些實例中這種治療效果是相乘的。此種合併給藥可包含給藥本發明化合物之同時(即，在相同時間)、之前或之後給藥已知藥物。所屬技術領域具通常知識者，應不難決定給藥特別藥物及本發明化合物之適當時間點、順序及劑量。
此外，一些具體例中，本發明化合物或彼等之鹽類或酯類係經單獨或彼此相組合或與上述之一種或多種其他治療藥物組合，而使用於製造其目的為提供給有需要之患者或個體治療猝倒症之藥物。
本發明部分地係基於式(I)之苯基烷基胺基胺甲酸酯具有新穎及獨特藥理性質之發現。這些化合物顯示對DREM及猝倒症具有益效用。雖然尚未完全瞭解作用之確切機制，一般相信這些化合物並非經由與大部分其他已知興奮劑相同之機制而產生彼等效用。因而式(I)化合物特別適合使用於治療猝倒症。因此，不管疾病之確切病因為何，這些化合物可安全地使用於此目的而提供猝倒症之有效治療。
發明之一方面係關於對有需要之個體治療猝倒症的方法，包括給予個體治療有效量之式(I)化合物：
或其醫藥上可接受之鹽或酯；其中R為選自由1至8個碳原子之低碳數烷基、鹵素、含有1至3個碳原子之烷氧基、硝基、羥基、三氟甲基及含有1至3個碳原子之硫代烷氧基所構成之群組之一基團；x為0至3之整數，當x為2或3時附帶條件為R可為相同或不同；R1及R2係獨立選自由氫、1至8個碳原子之低碳數烷基、芳基、芳基烷基及3至7個碳原子之環烷基所構成之群組；或R1及R2可連結而形成視需要可經選自由烷基及芳基所構成之群組之一基團取代之5至7-員雜環，其中該雜環可包括1至2個氮原子及0至1個氧原子，其中該氮原子不直接彼此連接或與氧原子連接。
一般瞭解所屬技術領域具通常知識者可選擇本發明化合物之取代基及取代類型而提供化學性穩定及易於由所屬領域已知之技術以及本文所提供之技術而合成之化合物。
具體例中，式(I)化合物為式(Ia)化合物：
或其醫藥上可接受之鹽或酯。
具體例中，式(I)化合物為(D)鏡像異構物，其中R1及R2為氫及x為0(化合物(Ib))。
本發明包含單離之式(I)化合物之鏡像異構物(如，式(Ia)或(Ib)化合物)之用途。具體例中，使用包括單離之式(I)之S-鏡像異構物的醫藥組成物而提供對個體之治療。另一個具體例中，使用包括單離之式(I)之R-鏡像異構物的醫藥組成物而提供對個體之治療。
本發明亦包含式(I)之鏡像異構物混合物之用途。在本發明之一方面，一種鏡像異構物佔大多數。在混合物中佔大多數之鏡像異構物係以較任何存在於混合物中之其他鏡像異構物更多量存在於混合物中之鏡像異構物，如，以大於50%之量。在一方面，一種鏡像異構物佔多數達90%或達91%、92%、93%、94%、95%、96%、97%或98%或更多。具體例中，在包括式(I)化合物之組成物中佔多數之鏡像異構物為式(I)之S-鏡像異構物。
本發明提供使用式(I)表示之化合物之鏡像異構物及鏡像異構物混合物之方法。式(I)之胺甲酸酯鏡像異構物在苯甲基位置含有不對稱手性碳原子，其為鄰接苯環之第二個脂族碳。
經單離之鏡像異構物為實質上無對應之鏡像異構物者。因此，單離之鏡像異構物意指通過分離技術而分離或經由摒
除對應鏡像異構物而製備之化合物。
術語“實質上無”，如本文所使用，意指化合物由顯著較大部分之一種鏡像異構物所構成。較佳具體例中，化合物包含至少約90重量%之一種鏡像異構物。發明之其他具體例中，化合物包含至少約99重量%之一種鏡像異構物。
可經由熟練之技術人員所熟知之方法合成式(I)化合物。可經由用適當之無機酸或有機酸(HX)在適當之溶劑中處理化合物或經由所屬技術領域具通常知識者所熟知之其他方法而製造式(I)化合物之鹽類及酯類。
合成式(I)化合物之詳細反應圖示以及製造特定化合物之代表性實例已說明於U.S.Pat.No.5,705,640、U.S.Pat.No.5,756,817、U.S.Pat.No.5,955,499、U.S.Pat.No.6,140,532，通過引用將其全部內容併入本文中。
從式(I)明顯地有些本發明化合物具有至少一個且可能有多個不對稱碳原子。意指本發明在其範圍內包含化合物之立體化學性純淨之異構物形態以及彼等之消旋物。可應用所屬領域已知之原理而得到立體化學性純淨之異構物形態。可經由物理分離方法諸如分步結晶及層析技術而分離非鏡像異構物，及可經由與光學活性酸或鹼所成之非鏡像異構物鹽類之選擇性結晶或經由手性層析法而使鏡像異構物彼此分離。亦可從適當之立體化學性純淨之起始物質以合成方式，或使用立體選擇性反應而製造純立體異構物。
製備本發明化合物之任何製程期間，可能需要及/或最好保護任何分子相關之敏感或反應性基團。可經由常用之保
護基方式而達成，諸如Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973及T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,Third Edition,John Wiley & Sons,1999中所說明者。可使用所屬領域熟知之方法在合宜之隨後階段移除保護基。
可由任何常用之給藥途徑將化合物給予個體，包含但不限於，口服、口腔、局部、全身(如，經皮、鼻腔或用栓劑)，或非口服(如，肌肉內、皮下或靜脈注射)。直接將化合物給予神經系統之給藥可包含，例如，藉由顱內或椎管(intravertebral)針或者有或無幫浦裝置之導管之遞送而給藥至大腦內、腦室內、側腦室內、鞘內、腦池內、脊柱內或脊柱旁路徑之給藥。隨著給藥途徑，可將式(I)化合物組成任何劑型。例如，適合口服給藥的劑型包含固體劑型，諸如丸劑、囊形片、錠劑、膜衣錠、膠囊、顆粒劑及粉劑(各包含立即釋放、經時釋放及持續釋放配方)。適合口服給藥的劑型亦包含液體劑型，諸如溶液、糖漿、酏劑、乳狀液及懸浮液。此外，適用於非口服給藥之形式包含滅菌溶液、乳狀液及懸浮液。
某些具體例中，本發明之醫藥組成物包括一種或多種式(I)化合物或其鹽或酯而無任何醫藥用載體或賦形劑。其他具體例中，本發明之醫藥組成物包括根據常用醫藥複合技術緊密摻合醫藥用載體之一種或多種式(I)化合物或其鹽或酯。載體為惰性醫藥賦形劑，包含但不限於，黏合劑、懸浮劑、潤滑劑、調味劑、甜味劑、防腐劑、染料及塗層。製備口服劑型之組成物時，可採用任何通常之醫藥用載體。例如，用於液體口服製劑，適合之載
體及添加物包含水、乙二醇、油、酒精、調味劑、防腐劑、著色劑等；用於固體口服製劑，適合之載體及添加物包含澱粉、糖、稀釋劑、製粒劑、潤滑劑、黏合劑、崩解劑等。
組成物之劑型可為錠劑、丸劑、膠囊、半固體、粉劑、持續釋放配方、溶液、懸浮液、乳狀液、糖漿、酏劑、氣霧劑或任何其他適合之組成物；包括至少一種本發明之化合物，視需要與至少一種醫藥上可接受之賦形劑組合。所屬領域一般熟練之技術人員熟知適當之賦形劑，且彼等，可從如Alfonso AR：Remington's Pharmaceutical Sciences,17th ed.,Mack Publishing Company,Easton Pa.,1985，之此類標準參考書目找到調配組成物之方法，通過引用將其所揭露之全部內容併入本文中並用於所有目的。適當之液體載體，特別是用於可注射溶液，包含水、鹽水溶液、葡萄糖水溶液及乙二醇。
可以水性懸浮液形式提供胺甲酸酯化合物。本發明之水性懸浮液可含有胺甲酸酯化合物，且與適合於製造水性懸浮液之賦形劑摻合。此類賦形劑可包含，例如，懸浮劑，諸如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯烷酮、黃蓍膠及阿拉伯膠，及分散劑或潤濕劑諸如天然生成之磷脂(如，卵磷脂)、環氧烷與脂肪酸之縮合產物(如，聚氧伸乙基硬脂酸酯)、環氧乙烷與長鏈脂族醇之縮合產物(如，十七伸乙基氧基鯨臘醇)、環氧乙烷與從脂肪酸和己糖醇衍生之偏酯的縮合產物(如，聚氧伸乙基山梨糖醇單油酸酯)或環氧乙烷與從脂肪酸和己糖醇酐衍生之偏酯的縮合產物(如，聚氧伸乙基去水山梨糖醇單油酸酯)。
水性懸浮液亦可含有一種或多種防腐劑諸如對羥苯甲酸乙酯或對羥苯甲酸正丙酯，一種或多種著色劑，一種或多種調味劑，及一種或多種甜味劑諸如蔗糖、阿斯巴甜或糖精，可調節配方的滲透性。
可將胺甲酸酯化合物懸浮於植物油中諸如花生油、橄欖油、芝麻油或椰子油，或礦物油中諸如液態石蠟，或其等之混合物中，而調配使用於本方法之油性懸浮液。油性懸浮液可含有增稠劑，諸如蜂蠟、硬石蠟或鯨臘醇。可添加甜味劑諸如甘油、山梨醇或蔗糖而提供美味之口服製劑。可添加抗氧化劑諸如抗壞血酸而保存此等配方。可注射油性賦形劑之實例，請參照Minto,J.Pharmacol.Exp.Ther.281：93(1997)。本發明藥物配方亦可為水包油乳狀液之形態。如上述，油相可為植物油或礦物油，或其等之混合物。
適合之乳化劑包含天然生成的膠，諸如阿拉伯膠及黃蓍膠，天然生成之磷脂，諸如大豆卵磷脂，從脂肪酸和己糖醇酐衍生之酯類或偏酯類，諸如去水山梨糖醇單油酸酯，及這些偏酯與環氧乙烷之縮合產物，諸如聚氧伸乙基去水山梨糖醇單油酸酯。乳狀液亦可含有甜味劑及調味劑，如糖漿及酏劑之配方。此類配方亦可含有緩和劑、防腐劑或著色劑。
可將選擇之化合物，單獨或與其他適當之成分組合而製成噴霧劑配方(即，可“霧化”)而可經由吸入給藥。可將噴霧劑配方放入可接受加壓之推進劑中，諸如二氯二氟甲烷、丙烷、氮等。
本發明配方適合非口服給藥，諸如，例如，經由關
節內(在關節內)、靜脈、肌肉內、皮內、腹膜內及皮下途徑，可包含水性及非水性、等張滅菌注射溶液，其可含有抗氧化劑、緩衝劑、抑菌劑，及使得配方與預定接受者之血液等張之溶質，及可包含懸浮劑、助溶劑、增稠劑、安定劑及防腐劑之水性及非水性滅菌懸浮液。可接受之載體及溶劑中可採用的為水及林格氏溶液、等張氯化鈉。此外，習慣上可採用滅菌固定油類作為溶劑或懸浮介質。為此目的可採用任何溫和的固定油包含合成之單或雙甘油酯。此外，同樣亦可使用脂肪酸諸如油酸於製備注射劑。這些溶液為滅菌的且一般不含不想要的物質。
在化合物充分可溶的情況，彼等可直接溶於正常鹽水且可使用或不使用適當之有機溶劑，諸如丙二醇或聚乙二醇。可在水性澱粉或羧甲基纖維素鈉溶液中或在適當之油，諸如花生油中，形成細碎化合物之分散液。可經由常用、熟知之滅菌技術來滅菌這些配方。配方可含有醫藥上可接受作為要求使近似於生理條件之輔助物質諸如pH調節劑及緩衝劑，毒性調節劑，如，乙酸鈉、氯化鈉、氯化鉀、氯化鈣、乳酸鈉等。
這些配方中之胺甲酸酯化合物濃度可有很大的差異，主要可基於液量、黏稠度、體重等，根據所選擇之給藥特別模式及患者之需求而加以選擇。用於IV給藥，配方可為滅菌注射製劑，諸如滅菌注射水性或油性的懸浮液。可根據已知技術使用適當之分散或潤濕劑及懸浮劑而調配此懸浮液。滅菌注射製劑亦可為在無毒非口服可接受之稀釋劑或溶劑中，諸如1,3-丁二醇溶液，之滅菌注射溶液或懸浮液。推薦的配方可以單位劑量或多劑量之密封容器呈現，諸如安瓿及小玻璃瓶。可從上述種類之滅菌
粉劑、粒劑及錠劑而製備注射溶液。
適合使用於實踐本發明之胺甲酸酯化合物可口服給藥。取決於組成物之類型、單位劑量之大小、賦形劑之種類及其他所屬技術領域熟練之人員熟知之因素，本發明化合物之量可有很大的差異。一般，最終組成物可包括，例如，0.000001重量百分率(% w)至100% w之胺甲酸酯化合物，如，0.00001% w至50% w，而其餘為賦形劑或賦形劑等。
使用所屬領域熟知之醫藥上可接受之載體可調配適合於口服給藥之劑量的口服給藥用藥物配方。此類載體使藥物配方能調配成單位劑型之錠劑、丸劑、粉劑、糖衣錠、膠囊、液體、含片、凝膠、糖漿、漿劑、懸浮液等而適合患者攝食。其他具體例中，可不使用任何醫藥上可接受之載體而調配口服給藥之藥物配方。
適合口服給藥之配方可包含(a)液體溶液，諸如有效量之藥物配方懸浮於稀釋劑，諸如水、鹽水或PEG 400中；(b)膠囊、袋裝粉劑或錠劑，各含有預定量之活性成分，如液體、固體、顆粒或明膠；(c)適當液體中之懸浮液；及(d)適當之乳狀液。
可透過組合本發明化合物與固體賦形劑而得到口服用之藥物製劑，視需要研磨所得混合物，如需要，添加適當之附加化合物後，處理顆粒之混合，而得到錠劑或糖衣錠。適合之固體賦形劑為碳水化合物或蛋白質填料及包含，但不限於糖類，包含乳糖、蔗糖、甘露醇或山梨醇；玉米、小麥、稻米、馬鈴薯或其他植物之澱粉；纖維素諸如甲基纖維素、羥甲基纖維素、羥丙基甲基纖維素或羧甲基纖維素鈉；及膠類包含阿拉伯膠及黃蓍
膠；以及蛋白質諸如明膠及膠原蛋白。
如需要，可添加崩解劑或助溶劑，諸如交聯聚乙烯吡咯烷酮、洋菜、海藻酸或其鹽，諸如海藻酸鈉。錠劑劑型可包含一種或多種乳糖、蔗糖、甘露醇、山梨醇、磷酸鈣、玉米澱粉、馬鈴薯澱粉、微晶纖維素、明膠、膠態二氧化矽、滑石、硬脂酸鎂、硬脂酸，及其他賦形劑、著色劑、填料、黏合劑、稀釋劑、緩衝劑、潤濕劑、防腐劑、調味劑、染劑、崩解劑及醫藥上可相容之載體。含片劑型可包括含於加味劑，如，蔗糖，之活性成分，以及在惰性基質，諸如明膠及甘油中包括活性成分之軟糖錠，或除了活性成分外含有所屬領域習知之載體之蔗糖及阿拉伯膠乳狀液、凝膠等。
亦可以栓劑之形態給予本發明化合物而用於直腸給藥。可將藥物與適當之無刺激性賦形劑混合而製備該等配方，而該賦形劑在常溫為固體但在直腸溫度為液體因而溶解於直腸而釋放藥物。此類物質為可可脂及聚乙二醇。
本發明化合物亦可經鼻腔內、眼內、陰道及直腸內途徑給藥包含栓劑、吹入劑、粉劑及噴霧劑配方(類固醇吸入劑實例，請參照Rohatagi,J.Clin.Pharmacol.35：1187(1995)；Tjwa,Ann.Allergy Asthma Immunol.75：107(1995))。
本發明化合物亦可經皮遞送，經局部途徑，調配成敷藥棒、溶液、懸浮液、乳狀液、凝膠、乳膏、軟膏、糊劑、膠凍劑、塗抹劑、粉劑及噴霧劑。
本發明化合物亦可採用膠囊封裝物質且術語“組成物”可包含與膠囊封裝物質組合作為配方之活性成分，有或沒有
其他載體。例如，本發明化合物亦可作為微球粒遞送而於體內緩慢釋放。具體例中，可經由皮內注射含有藥物(如，黃體素拮抗劑)之微球粒而給藥微球粒，其緩慢地於皮下釋出(請參照Rao,J.Biomater.Sci.Polym.Ed.7：623(1995)；作為生物可降解及注射凝膠配方(請參照，如，Gao,Pharm.Res.12：857(1995))；或，作為用於口服給藥之微球粒(請參照，如，Eyles,J.Pharm.Pharmacol.49：669(1997))。經皮及皮內途徑皆提供數個星期或數個月之持續遞送。本發明化合物之遞送亦可使用扁囊劑(Cachet)。
另一個具體例中，本發明化合物亦可使用與細胞膜融合或經胞吞之脂質體而遞送，即，利用附著於脂質體之配體，而該脂質體連結於造成胞吞作用之細胞之表面膜蛋白受體。亦可以脂質體遞送系統之形態給予活性藥物，諸如單層小微脂粒、單層大微脂粒及多層微脂粒。可從多種磷脂諸如膽固醇、硬脂基胺或磷脂醯膽鹼而形成脂質體。
使用脂質體，特別是在脂質體表面攜帶特定於目標細胞之配體之情況，或是優先導至特定器官之情況，可聚焦於在生物體中胺甲酸酯化合物至目標細胞之遞送(請參照，如，Al-Muhammed,J.Microencapsul.13：293(1996)；Chonn,Curr.Opin.Biotechnol.6：698(1995)；Ostro,Am.J.Hosp.Pharm.46：1576(1989))。
亦可使用與化合物分子偶合之單株抗體作為個別的載體而遞送活性藥物。活性藥物亦可與作為靶向藥物載體之可溶性聚合物偶合。此類聚合物可包含聚乙烯吡咯烷酮、哌喃共聚物、聚羥基丙基甲基丙烯醯胺酚、聚羥基乙基天門冬醯胺酚或經棕櫚
醯基殘基取代之聚環氧乙烷聚離胺酸。再者，活性藥物可與適用於達成控制藥物釋放之一種生物可降解聚合物偶合，例如，聚乳酸、聚乙醇酸、聚乳酸與聚乙醇酸之共聚物、聚ε-己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫哌喃、聚氰基丙烯酸酯及水凝膠之交聯或兩性嵌段共聚物。
某些具體例中組成物呈單位劑型諸如錠劑、丸劑、膠囊、粉劑、顆粒劑、滅菌非口服溶液或懸浮液、定量噴霧劑或液體噴霧劑、滴劑、安瓿、自動注射裝置或栓劑，用於口服、非口服、鼻腔、舌下或直腸給藥，或用於經吸入或吹入給藥。
替代地，組成物亦可呈現為適合於每星期一次或每月一次給藥之劑型；例如，活性化合物之不溶解鹽，諸如癸酸鹽，可適合於提供肌肉內注射用之長效製劑。
本文中之醫藥組成物，每劑量單位，如，錠劑、膠囊、粉劑、注射劑、一茶匙量、栓劑等，係含有如上述必需遞送之有效劑量之活性成分量。例如，本文中之醫藥組成物，每劑量單位可含有約10至約1000mg活性成分，如，約25至約600mg活性成分，如，約75至約400mg活性成分，如，約25、50、75、100、125、150、175、200、225、250、275、300、325、350、375、400、425、450、475、500、525、550、575或600mg或更多或其中之任何範圍。
本發明一些具體例中，適合使用於實踐本發明之胺甲酸酯化合物係為單獨給藥或與至少一種或多種其他化合物或治療劑合併給藥，如，與其他治療猝倒症及/或與猝倒症或猝睡症有關聯之其他障礙或症狀(如，白天過度嗜睡、入睡前幻覺及睡眠癱
瘓)之藥劑合併。治療猝倒症之治療劑的實例包含，而不限於，抗鬱劑(如，三環類(諸如氯米帕明(clomipramine)、丙咪嗪(imipramine)及普羅替林(protriptyline))及選擇性血清素再吸收抑制劑(諸如氟西汀(fluoxetine)、帕羅西汀(paroxetine)、舍曲林(sertraline)、西酞普蘭(citalopram))及羥丁酸鈉(γ-羥基丁酸酯[GHB])。治療白天過度嗜睡及其他猝睡症症狀之治療劑包含，而不限於，安非他命類(諸如右旋安非他命、甲基安非他命及呱醋甲酯(methylphenidate))、莫達非尼(modafinil)、阿莫達非尼(armodafinil)、阿托莫西汀(atomoxetine)及司立吉林(selegiline)。已知唯一能改善猝倒症及白天過度嗜睡兩者之藥物為羥丁酸鈉。
該方法包含給予需要治療之患者有效量之本文所揭露之胺甲酸酯化合物中之一種的步驟，而該胺甲酸酯化合物係與一種或多種有效量的其他化合物或治療劑組合，而該化合物或治療劑具有提供有益之組合效果，諸如加強本發明化合物之效用的能力。
醫藥上可接受之鹽類或酯類意指醫藥上可接受且具有所需藥理性質之鹽類或酯類。此種鹽類包含存在於化合物中之酸性質子能與無機或有機鹼反應而可形成之鹽類。適合之無機鹽類包含與鹼性金屬，如，鈉與鉀、鎂、鈣及鋁所形成者。適合之有機鹽類包含與有機鹼諸如胺鹼類，如，乙醇胺、二乙醇胺、三乙醇胺、胺基丁三醇、N-甲基葡糖胺等所形成者。醫藥上可接受之鹽類亦可包含酸加成鹽，而該酸加成鹽係親體化合物中之胺部分與無機酸(如，鹽酸及氫溴酸)及有機酸(如，乙酸、檸檬酸、順丁烯二酸及烷烴-及芳烴-磺酸諸如甲磺酸及苯磺酸)反應而形成
者。醫藥上可接受之酯類包含從存在於化合物中之羧基、磺醯氧基及膦氧基(phosphonoxy)所形成之酯類。有兩個酸性基存在時，醫藥上可接受之鹽或酯可為單酸單鹽或單酯或雙鹽或雙酯；同樣地，有多於兩個之酸基存在時，此類基團之一些或全部可經鹽化或酯化。
本發明中命名之化合物可以未鹽化或未酯化之形式，或鹽化及/或酯化之形式呈現，且此類化合物之命名意指包含初始(未鹽化及未酯化)化合物及其醫藥上可接受之鹽類或酯類兩者。本發明包含式(I)之醫藥上可接受之鹽或酯之形式。可存在不只一種晶形之式(I)之鏡像異構物，且亦同樣地包含於本發明。
本發明之醫藥組成物除了胺甲酸酯化合物之外，可視需要含有至少一種其他適用於治療猝倒症之治療劑。例如可將式(I)之胺甲酸酯化合物與其他化合物物理性組合為固定劑量複方而簡化彼等之給藥。
許多出版物說明調配醫藥組成物之方法諸如Pharmaceutical Dosage Forms：Tablets.Second Edition.Revised and Expanded.卷1-3,Lieberman et al.編輯；Pharmaceutical Dosage Forms：Parenteral Medications.卷1-2,Avis et al.編輯；及Pharmaceutical Dosage Forms：Disperse Systems.卷1-2,Lieberman et al.編輯；Marcel Dekker,Inc出版，通過引用將其各揭露之全部內容併入本文中並用於所有目的。
一般將醫藥組成物配製成滅菌、實質上等張的，且係完全遵照所有美國食品及藥物管理局之優良製造作業(GMP)規範。
本發明提供使用胺甲酸酯化合物供給治療哺乳類動物之猝倒症的方法。提供治療猝倒症所需之胺甲酸酯化合物量定義為治療或藥物有效劑量。此用途之劑量表及有效量，即，給藥或劑量方案取決於多種因素，包含疾病之階段、患者身體狀態、年齡等。為患者計算劑量方案時，亦考量給藥模式。
所屬技術領域之人士對於本揭露，不需做過多實驗即能夠決定用於實踐本發明之特定取代之胺甲酸酯化合物之治療有效量(請參照，如，Lieberman,Pharmaceutical Dosage Forms(卷1-3,1992)；Lloyd,1999,The Art,Science and Technology of Pharmaceutical Compounding；及Pickar,1999,Dosage Calculations)。治療有效劑量亦為治療有益效用，在臨床術語上重要性超過任何毒性或有害副作用之劑量。進一步要注意的是對各特定之個體，必需根據個別需要及給藥或監督給藥化合物之人員的專業判斷而經時評估及調整具體劑量方案。
為了治療之目的，可通過一段延長時間之持續遞送，或以重複之給藥方案(如，以小時計、以天計或以星期計之重複給藥方案)而單次大劑量遞送本文所揭露之組成物或化合物予個體。本發明藥物配方可經，例如，每天一次或多次、每星期3次或每星期1次而給藥。本發明之具體例中，本發明藥物配方為每天經口服給藥1次或2次。
由此而論，生物活性劑之治療有效劑量可包含經延長之治療方案內之重複劑量，該重複劑量產生臨床顯著結果而提供猝倒症之治療。由此而論，決定有效量一般係以動物模型研究隨後經人體臨床試驗為基礎及經由決定顯著降低個體之標靶暴露病徵或症狀之發生或嚴重性之有效劑量及給藥方案引導。在這方面之適當模型包含，例如，鼠科動物、大鼠、豬、貓、非人類靈長類及所屬領域習知之其他接受之動物模型個體。替代地，可使用生體外模型(如，免疫及組織病理分析)決定有效劑量。
使用此種模型，一般只需要普通計算及調整即可決定給予生物活性劑治療有效量之適當濃度及劑量(如，口服有效、鼻腔有效、經皮有效、靜脈有效或肌肉內有效而達到所需反應之量)。然而有效量可取決於所使用之特別化合物、給藥之模式、製劑之強度、給藥之模式及疾病症狀之進展而改變。另外，亦有與受治療之特定患者有關聯之因素，包含患者年齡、體重、膳食及給藥時間，而造成調整劑量之需要。
本發明之示例具體例中，配製化合物之單位劑型而用於標準給藥方案。依此方式，可將組成物照醫師的指示輕易地細分成較小的劑量。例如，單位劑量可製成裝成小包之粉劑、小玻璃瓶或安瓿及較佳為膠囊或錠劑形式。
本發明胺甲酸酯化合物之有效給藥可為，例如，口服或非口服劑量約0.01mg/kg/劑至約150mg/kg/劑。例如，給藥可為約0.1mg/kg/劑至約25mg/kg/劑，如，約0.2至約18mg/kg/劑，如，約0.5至約10mg/kg/劑。因此，活性成分之治療有效量可為，用於具有平均體重，例如，70kg之個體，例如，約1mg/天至約7000mg/天，如，約10至約2000mg/天，如，約50至約600mg/天，如，約10、25、50、75、100、125、150、175、200、225、250、275、300、325、350、375、400、425、450、475、500、525、550、575或600mg/天或更多或為其中之任何範圍。具體例
中，式I化合物係以劑量約150mg至約300mg而無賦形劑之膠囊形式給藥。
本發明之方法亦提供使用於供給治療猝倒症之檢測試劑盒。當包括一種或多種本發明胺甲酸酯化合物之醫藥組成物，與可能添加之一種或多種有益於治療之其他化合物經調配於適當之載體中之後，可放置於適當之容器中並標記而用於提供治療猝倒症。此外，也可將包括至少一種其他治療劑之另一種藥物放置於容器中並標記而用於治療指明之疾病。此種標記可包含，例如，關於各藥物給藥之量、次數及方法之指示。
於以下非限定之實施例中說明根據本發明之具體例。
對治療有猝睡症之個體白天過度嗜睡之ADX-N05的安全性及效能進行研究。該研究包含ADX-N05對在此研究中亦具患有猝倒症之猝睡症個體亞群之潛在效能的探索性分析。評估ADX-N05在患有猝倒症之個體亞群之主要及次要效能變量上之性能。此外，亦評估ADX-N05在降低猝倒事件數之效益。
該研究為雙盲、彈性標靶劑量、安慰劑對照、多中心、隨機、平行組之研究。成功完成篩選階段及基線階段之後，將個體隨機分至兩種治療組之其一並於12星期之治療期間，如表1所示接受ADX-N05或安慰劑(治療組#1：第1至4星期：ADX-N05 150mg/天；第5至12星期：ADX-N05 300mg/天；治療組#2：第1至12星期：安慰劑)。
開始12星期之治療期前，個體完成達28天之篩選階段，在這段時間期間進行所有篩選評估並中斷任何現有之猝睡症治療以及基線階段，包含於試驗場所之留宿，在這段時間期間得到基線效能及安全評估。治療階段期間，個體回到試驗場所完成1、2、4、6、8及12星期末之效能及安全評估；第4星期及第12星期就診亦包含試驗場所之留宿。在第12星期就診評估前，個體於第12星期就診時服用彼等之研究藥物最終劑量。個體在第13星期末返回作追蹤評估，且除非有任何顯著安全問題需要追蹤，否則該就診後個體即從研究退出。
研究之探測性指標為：(1)於第4星期及最後評估，服用ADX-N05相對於安慰劑之患有猝倒症個體亞群每星期猝倒發作中位數之基線改變量；及(2)患有猝倒症個體亞群之主要及次要效能指標。患者保留猝倒日誌而追蹤發作之數目。計算各治療組中患有猝倒症個體亞群之基線改變量，其為於第4星期及最後有效評估，服用ADX-N05相對於安慰劑之患有猝倒症個體亞群每星期猝倒發作於中位數之基線改變量。使用Wilcoxon等級和檢定比較兩治療組。
群體中總共有32位個體診斷為患有猝倒症，且係包含於猝倒症群體。一位個體(2002在安慰劑組)未完成基線猝倒症日誌而未包含於猝倒症日誌分析。
ADX-N05對猝倒症群體中主要及次要效能變數之效用示於表2(清醒度維持試驗(MWT))、表3(嗜睡度量表(ESS))、表4(臨床整體印象(CGI-C))及表5(患者整體印象(PGI-C))。
患有猝倒症個體亞群在第4星期及第12星期/最後評估，顯示前4個MWT試驗之平均值以及5個個別MWT試驗與整體群體之入睡潛伏期基線改變量有相似結果。而且，大多數ADX-N05組之個體相對於安慰劑組在各研究星期之CGI-C及PGI-C均經歷改善。治療組間在第12星期/最後評估之CGI-C(ADX-N05個體之94.1%相對於安慰劑個體之53.3%；p=0.0133)及PGI-C(ADX-N05個體之94.1%相對於安慰劑個體之53.3%；p=0.0133)皆有統計上之顯著差異。一致地觀察到在各研究星期經ADX-N05治療之個體相對於安慰劑個體平均ESS總評分之較大降低。此差異在第1星期及第12星期/最後評估為統計上顯著(第1星期降低6.8對2.4點，p=0.0170；及第12星期/最後評估降低9.8對2.5點，p=0.0010)。
表6提供在下列研究期間隨同計算之與基線相差之改變量及相應p-值一起報告之每星期猝倒發作數目總結：基線、第1至4星期、只第4星期、第5至12星期及只第12星期/最後評估。表7提供個體亞群之此等數據的總結，而該個體亞群報告於基線期間經歷每星期多於3次之猝倒發作。
包含所有猝倒症個體(N=31)時，用ADX-N05治療
未造成每星期猝倒事件與基線相差之中位數改變與安慰劑有明顯差異(表6)。此研究未特別地招募猝倒症個體，然而，結果猝倒症群體顯著地略為有病(基線每星期4猝倒事件中位數)。進行包含只有於基線每星期多於3次猝倒事件之個體之事後歸因分析時，顯示減少猝倒事件之趨向而有利於ADX-N05治療組(於第12星期/最後評估之每星期猝倒事件中位數之減少，ADX-N05之7相對於安慰劑之1.5)(表7)。超過一半之經ADX-N05治療之個體(6/11；55%)與安慰劑組之0%(0/6)比較，具有大於50%之每星期猝倒發作減少。
上述為本發明之說明，不當解釋為用以限制。本發明由下列申請專利範圍限定，也包含申請專利範圍其中之等同物。
本文引證之所有出版物、專利申請、專利及其他參考文獻均通過引用將其全部內容併入本文中而用於有關呈現引用之句子及/或段落之教導。
Claims (19)
- 一種治療有效量之式(Ia)化合物或其醫藥上可接受之鹽在用於製備治療猝倒症的藥物的用途，
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)化合物為實質上無其他鏡像異構物之式(Ia)之鏡像異構物，或其中一種式(Ia)之鏡像異構物佔多數之鏡像異構物混合物。
- 如申請專利範圍第2項所述之用途，其中，該式(Ia)之鏡像異構物佔多數達約90%或更多。
- 如申請專利範圍第2項所述之用途，其中，該式(Ia)之鏡像異構物佔多數達約98%或更多。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)之鏡像異構物為(R)或(D)鏡像異構物。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)之鏡像異構物為(S)或(L)鏡像異構物。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)之鏡像異構物佔多數達約90%或更多。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)之鏡像異構物佔多數達約98%或更多。
- 如申請專利範圍第2項所述之用途，其中，該實質上無其他鏡像異構物之式(Ia)之鏡像異構物為式(Ib)化合物或為式(Ib)化合物佔多數之鏡像異構物混合物：或其醫藥上可接受之鹽。
- 如申請專利範圍第9項所述之用途，其中，該式(Ib)化合物佔多數達約90%或更多。
- 如申請專利範圍第9項所述之用途，其中，該式(Ib)化合物佔多數達約98%或更多。
- 如申請專利範圍第1項所述之用途，其中，該猝倒症係與猝睡症有關。
- 如申請專利範圍第1項所述之用途，其中，該猝倒症係伴隨使個體下視丘分泌素濃度減少之症狀而繼發。
- 如申請專利範圍第13項所述之用途，其中，該症狀係選自由腦瘤、星狀細胞瘤、神經膠質母細胞瘤、神經膠質瘤、室管膜下瘤、顱咽管瘤、動靜脈畸形、缺血性事件、多發性硬化症、頭部外傷、腦部手術、腫瘤伴生症候群、Neimann-Pick氏症C型及腦炎所構成之群組。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)化合物之治療有效量為約0.01mg/kg/劑至約150mg/kg/劑。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)化合物之治療有效量為約1mg/天至約7000mg/天。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)化合物係口服給藥。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)化合物係以膠囊或錠劑之形式給藥。
- 如申請專利範圍第1項所述之用途，其中，該式(Ia)化合物係以劑量約150mg至約300mg且無任何賦形劑之膠囊形式給藥。
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