TW553934B - (+)-norcisapride - Google Patents
(+)-norcisapride Download PDFInfo
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- TW553934B TW553934B TW087111013A TW87111013A TW553934B TW 553934 B TW553934 B TW 553934B TW 087111013 A TW087111013 A TW 087111013A TW 87111013 A TW87111013 A TW 87111013A TW 553934 B TW553934 B TW 553934B
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Description
553934 Α7 Β7 五、發明説明(1 ) 、 本發明相關於( + )-σ若希沙普立得(norcisapride),及其 藥學上可接受的酸加成鹽類、其製法、及其用來製備供治 療胃腸疾病但不受中樞神經系統影響的醫藥品之用途。 喏希沙普立得係已廣被使用於調整胃動力學上之商品, 其商品名為"Prepulsid TM",目前其主要用途為供治療胃 -食道之反流疾病,此疾病的特點係胃中的内容物會回流 至食道。其他發病因子則係因延遲的胃排空、食道蠕動不 全而無法淨空,也由於回流物質使食道粘膜受傷所致。 由於其活性而被做為前動力學的(prokinetic)試劑,希 沙普立得(cisapride)也有用於供治療消化不良、胃輕癱、 便秘、手術後腸隔、及假性腸阻塞。 希沙普立得的代謝主要係經由酵素P 451) 3A4細胞色 素,經口服的希沙普立得於全面代謝後,尿液及糞便中回 收得的未經改變的希沙普立得,其回收率少於10%,而在 胞聚、糞便與尿液中發現的主要代謝物,依Meuldermans I 專 k發表於 Drug Metab. Dispos· 16(3):410-419, 7夕似中之報告,稱之為”喏希沙普立得π,係其兩種鏡相物 之消旋混合物。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 1983年4,月13日發表的ΕΡ-Α-0, 076, 530中揭示過消旋 性喏希沙普立得,其經編為化合物211,據稱其對胃腸有 刺激特性。 ( + )-喏希沙普立得係其中一種光學立體異構物,其化學 全名為( + )-4-胺基-5-氯-Ν-(3 -曱氧基-4-六氫5比口定基)-2-曱氧基苯醯胺,後面將總稱之為π( + )-喏希沙普立得’’。 ~3_ 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公釐) 553934 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(2 ) ^ ”( + )-喏希沙普立得π—詞,特別是”光學上純態( + )-喏希 沙普立得”,意指實質上不含其(-)-立體異構物之( + )-立 體異構物。 / W0 96/40133中教示,可使用(-)-°若希沙普立得以治療 消化道疾病,特別是用於治療胃-食道的反流疾病,一方 面能實質減少因施用消旋性希沙普立得伴隨之反效果。 此文件尚提及,光學純態的(-)-喏希沙普立得將是種有效 的止吐劑,在癌症治療上,可有效減輕因化學療法或放射 線療法所引起之噁心及嘔吐。 _ 已發現,( + )-喏希沙普立得,特別是”光學純態( + )-喏 希沙普立得'亦即實質不含其(-)-立體異構物者,同時 具有5-ΗΤ3拮抗性與UT4催動性,且進一步實質上全不 受中樞神經系統之影響。 本發明相關於( + )-喏希沙普立得,特別是不帶有其-立體異構物之(0-喏希沙普立得,其藥學上可接受的酸加 成鹽,及其用於治療5-ΗΤ3及/或5-ΗΤ4媒介之疾病, 但能避過受中槐神經糸統影響之用途,。 ( + )-喏希沙普立得的化學結構式可以下式代表:
(+)-cis 上述( + )-喏希沙普立得的結構式中,連結NH-CO與OCH基 至六氫眈啶環之鍵係以粗線表示,代表此兩基圑係呈順式 -4- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) (請先閲讀背面之注意事項再填寫本頁)
、1T 553934 A7 B7 五 經濟部中央標準局員工消費合作社印製 、發明説明(3) - 結構。 (·+)-喏希沙普立得,特別是所稱"光學純態(+ )—喏希沙 普立得’’,係包括實質不含其立體異構物之(+ )立體異 構物。而”實質不含其卜)—立體異構物"一詞係指此喏希 沙普立得的立體異構物混合物中含有至少9〇%重量計的(+ ) -喏希沙普立得與10%或更少之( —)-喏希·沙普立得。更佳的 貫體而言,此"實質不含( —)—立體異構物”意指此喏希沙 普立得的立體異構物混合物含有至少98%重量計的) 一喏 希沙普立得,與2%或更少之(—)—喏希沙普立得。最佳的實 體而言,”實質不含(-)-立體異構物”意指組成物中含有 超過99%重量計的⑴-。若希沙普立得。這些百分比係以總 立體混合物之量為計算依據。 , 能將平面偏光挺轉的化合物,稱之為具光學活性。於描 述具光學活性的化合物時,字頭D與L,或R與3係用以 表示其分子相對於不對稱中心的絕對結構,字頭"與/, 或(+ )與(-)係用以代表此化合物對平面偏光的旋轉性, ()及/代表此化合物係左旋性的,(+)與V則是代表其為 右旋性的。就所給化學結構,這些化合物,稱之為立體異 構物,除了互為鏡相對稱外,彼此完全相同。對特定的立 體異構物尚可歸之為對映體,這類對映體之混合物常被稱 之為消旋異構物混合物。 士就所給對映體,其旋光度α並非一個常數,要視樣品被 I載的官長、溫度、溶劑及溶液濃度與光的波長而定。故 ,比旋光度U]被定義成:a/lc之參數,其中的^為觀
(請先閱讀背面之注意事項再填寫本頁)
、1T • 1 - j = ml 553934
經濟部中央標準局員工消費合作社印裝 Α7 五、發明説明(4 ) . 測得的旋光度,1為管長(單位為公寸),c為濃度(單位為克/ 耄斤)。比旋光度通常與溫度及波長一起記錄成[a go, 其中的20代表攝氏溫度,D代表利用鈉光照射(波長為5⑽ nm)測得之旋光度。 ( + )-喏希沙普立得的L-酒石酸鹽,即(+)—(3s,4R)-順 式-4-胺基-5-氯-2-曱氧基-[(3一甲氧基一4一六氫〇比啶基) 苯醯胺[R-(R*,R*)]—2,3-二羥基丁烷二羧酸鹽單水合物, 利用X-射線分析結果顯示,其絕對結構為(3S,4R)之(+)一 °右希沙普立得。故,(+)喏希沙普立得具有如下的絕對立 體化學結構式: 〇〇i3 ci (3S,4R)-順式-4-胺基-5-氯-2-曱氧基—ν一(3-甲氧基一4- 六氫此啶基)苯醯胺· 上述的藥學上可接受的酸加成鹽類係指包括(+ )—喏希沙 、曰'立彳于鹽基悲物能形成的,具治療活性的無毒酸加成鹽類 。使用適當的酸可將( + )-嘆希沙普立得鹽基態物轉變成其 藥學上可接受的酸加成鹽類,適當的酸有,例如有機酸類 例如氫鹵酸類,例如鹽酸或氫溴酸;硫酸;端酸;鱗酸等 酸類;或有機酸類,例如,醋酸、丙酸、羥基乙酸、乳酸 、丙酮酸、草酸、丙二酸、琥珀酸(即丁二酸)、馬來酸、 富馬酸、蘋果酸、酒石酸、檸檬酸、甲磺酸、乙績酸、苯 -6- 本紙張^度適用中國國家標準((:奶)八4規格(210'乂297公釐) ---- (請先閱讀背面之注意事項再填寫本頁)
553934 A7 B7 五、發明説明(5 ) ^ 磺酸、對曱苯磺酸、環己烷胺磺酸、水揚酸、對胺基水揚 酸、棕櫚酸等酸類。 反之,所述的酸加成鹽類可經適當的鹼處理轉變成游離 態( + )-喏希沙普立得鹽基態物。 此處所指酸加成鹽類也包括(+)-嗜希沙普立得及其鹽類 所能形成的溶劑化物。這類溶劑化物有如水合物、醇化物 此後,凡提到( + )-喏希沙普立得,意指也包括其藥學上 可接受的酸加成鹽類及其溶劑化物。 鹽基態( + )-喏希沙普立得之製法如下面圖表1所示: 圖表1 (請先閲讀背面之注意事項再填寫本頁)
經濟部中央標準局員工消費合作社印製 -~~> (+)-喏希沙普立得 (I) 順式-(II)之中間物,與順式-(IV).之反應產品,其六 氫咏匕啶環上的胺基與曱氧基取代基具有順式-構型,即, 其甲氧基與胺基係位於由六氫吡啶環為主平面之同一邊, 且為含二種對映體之消旋異構物。為顯示此種結構,圖表 1中係以粗線示出此鍵結。依圖表1,係將順式-(II)的中 間物,其PG係適當的保護基,例如曱氧羰基、乙氧羰基、 -7- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 553934 A7 —_B7 __ 五、發明説明(6 ) ^ 第三丁氧羰基、苯甲基等,與式(III)的羧酸或其具反應 性的官能基衍生物反應,成醯胺化後,製得具順式-(IV) 化學式的中間物。順式-(II)與(III)的中間物在脫水劑( 例如二環己基碳化二亞胺)存在下反應,或順式-(II)的中 間物與具反應性的羧酸(III)衍生物(例如其酸氯化物或混 合的酸酐類)反應。此反應可在惰性溶劑(例如二氣甲烷或 氯仿)中,且選擇地含適當的驗,例如碳酸納、碳酸鉀或 四乙基胺存在下進行。予以攪拌可加速反應速率,可方便 地於介於室溫及反應混合物的回流溫度下反應,接著,分 出順式-(IV)的中間物之對映體,並將單離出的各順式一( IV)中間物,經除去保護基PG而轉變成其相關的喏希沙普 立得對映體,視PG的性質而進行酸性或鹼性溶劑溶解化反 應,或經由催化氳化反應,例如,使用氫氧化鉀的無機鹼, 於水溶液中進行。或是,將順式一(IV)中間物的保護基叩 移除,形成消旋性喏希沙普立得·的混合物,接著再進行分 出其對映體之步驟。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 圖表1中製得的順式-(IV)中間物係對映體之混合物,其 可依文獻已知的解析法將之彼此分開。順式_(IV)中間物 的對映體混合物可藉與適當的不對稱酸作用而將之轉變成 其相關的非對映立體異構物鹽,&著分開此非對映立=異 構物鹽,例如進行選擇性或㈣結晶法分出,料用2類 將對映體釋出。另種分開順式一⑽對映體的方法為 用適當的不對稱固定相,進行液相層析,適當的不對稱固 疋相為,例如,多_,特別是纖維素或直鏈殿粉衍生物 _8 - 石嫌尺家標準(見格(2l〇x—釐3-- 553934 A7 B7 五、發明説明(7 ) ^ 。市售屬於多醣類的不對稱固定相有ChiralCelTM CA, OA,OB,OC,OD,OF, OG,0J 與 0K,以及 ChiralpakTM AD,AS,0P( + )與0T(+)6配合此多醣類不對稱固定相使 用的適當的流洗劑或移動相為己烷等,可加入醇類,例如 乙醇,異丙醇等修飾之。 順式-(IV)中間物的純態對映體亦可由相當的純態起始 材料衍生之,只要其間的反應具專性反應,如想特製某種 立體異構物,此化合物將依立體專性的方法合成。這些方 法宜使用純態起始材料進行。 · 本發明也提供具式(V)的新穎中間物。式(V)的中間物係 順式-(IV)之中間物,其六氫此啶環具絕對的(3S,4R)構型 且PG係一種適當的保護基,例如甲氧羰基'、乙氧羰基、第 三丁氧羰基、苯甲基等等。 (請先閱讀背面之注意事項再填寫本頁)
經濟部中央標準局員工消費合作社印製 起始化合物及部分的中間物係已知化合物,通常可自市 面購得或可藉文獻已知的反應方法製得,例如:順式-(II) 之中間物(即,順式_乙基4-胺基-3-曱氧基-1-六氳此。定 羧酸鹽,在EP-0,076,530被編為中間物54者),及順式 -(IV)之中間物(即,順式-乙基4-(4-胺基-5-氯-2-曱氧 基苯醯基胺基)-3-曱氧基-l-六氫。比啶羧酸鹽,在£?-0, 076, 530被編為化合物168者)。此外,中間物(111)(即 -9- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 553934 A7 B7 五、發明説明(8 ) ^ ,4-胺基-5-氯-2-曱氧基苯甲酸),均可購得。 由於(+ )喏希沙普立得具有5-HT3-拮抗活性,故在治療 因過度刺激5-HT3-受體活性之疾病上相當有用,受5-HT3-媒介的疾病為,例如嘔吐,例如細胞毒藥物及輻射引起之 嘔吐(Drugs 42(4),51-568(1991)),敏感性腸徵候,尤 其是痢疾性腸炎與相關症狀^因此,本發明提供一種治療 溫血動物因過度刺激5-HT3-受體活性所引發或通常係由5-HT3-媒介之疾病(例如°區吐)的方法,例如細胞毒藥物及輻 射引起之0區吐、敏感性腸徵候,特別是痢疾性腸炎與相關 症狀。此方法包括對溫血動物投用具療效量的( + )-喏希沙 普立得,或其藥學上可接受的酸加成鹽。 或者,將(+)-喏希沙普立得,及其藥學1可接受的酸加 成鹽類,製作成醫藥品,用於治療因過度刺激5-HT3-受體 活性所引發或通常係由5-HT3-媒介之疾病或症狀,例如嘔 吐,例如細胞毒藥物及輻射引起之呕吐、敏感性腸徵候, 特別是痢疾性腸炎與相關症狀。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 明確地說,( + )-喏希沙普立得係一種有效的止吐劑,有 用於辅佐治療在癌症治療上因使用化學療法或照射所引起 之噁心及嘔吐現象。 ( + )-喏希沙普立得也具有5-HT4-興奮劑的特性,因此, 本發明也提供一種方法用於治療溫血動物,包括人類,因 5-HT4-受體活性不足刺激所起之疾病,更通常的說法為, 提供一種治療5-HT4-媒介的疾病或狀態之方法,這種狀態 的例子為,有如胃排空發生紊亂或不全,或更常見的例子 本紙張尺度適用中國國家標準(CNS ) A4規格(公釐) 553934 A7 __^---!Z_^——^^. 五、發明説明(9 ) ^ 為胃腸迢的移轉發生紊亂或不全。因此,提供了此種方法 用於緩和溫血動物的這類病況,例如胃-食道的反流(包括 食道炎的治療及維持性療法)、消化不良、及胃輕瘫。此 方法包括對溫血動物投用有療效量的(+ )_喵希沙普立得, 或其藥學上可接受的酸加成鹽。 經濟部中央標準局員工消費合作社印製 胃輕癱的發生可能因胃之不正常或因某呰疾病所導致的 併發症,例如糖尿病、進行性全身硬化症、神經性厭食症 、迷走神經或部分胃切除術之後、及肌強直性的營養不良 。消化不良係消化功能不全所致,可因胃腸功能不彰所起 ,特別是因肌肉緊張度或因其他疾病(例如蘭尾炎,膀胱 炎,或營養不良)所造成者,因此(+)-喏希沙普立得可被 用於治療實際發病之原因或缓和其所引起之徵狀。消化不 良的病徵也可能係因攝入化學物質所起,例如選擇性血清 素再利用抑制劑(SSRI’s),例如富克辛(fluoxetine)、巴 洛克心(paroxetine)、富沃胺(fluvoxamine)、色特林( sertraline)等。其他可被治療的症狀包括術後腸隔(其係 因手術後腸道的肌肉緊張度被打斷而造成阻礙或自動力不 足所致)、上消化道的X-射線或内視鏡檢查後的病徵、嬰 兒方面疾病、慢性及過度的反胃或17區吐、因自動性官能障 礙而使胃腸螺動性不全及内容物停滯之假性腸jj且塞、因腸 的緊張度不足或腸痙攣產生之便秘,特別是於長期治療慢 性秘結後結腸自動能力的復元。 因此,提供的用途包括使用(+ )-喏希沙普立得做為一種 醫藥品,用於治療因5-HT4-受體活性的刺激不足所起的疾 一11 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 553934 • - s - · A7
(請先閱讀背面之注意事項再填寫本頁)
553934 五 ‘發明説明(11 ^合❹,包括手術前後,對患有錢及其他肛門盘直 知疾病者,均能維持軟便狀態。 =劑量的渗透性試劑常在欲做胃腸道,腎臟,或其他 心版膜内結構的照射檢視以及選擇性腸外科手術之前 、二故在销應用之前,(+)_㈣沙普立得與輕濱劑的 作匕合使用法頗為有用。. 經濟部中央標準局員工消費合作社印製 另外,心合⑴-嗓希沙普立得與輕萬劑的用法,也可應 =在供治療藥物的過量使用與中毒上,利用其將腸道内的 、二掉。廷樣的混合物尚可與某些驅蟲藥混合使用。 輕瀉劑係—種^助通便的藥物。許多輕瀉劑的正確作 用機制仍未明,乃因有複雜的因素影響結腸的功能,在此 地帶,實驗的種類與製劑,衫種研究的秘結性間,水與 電解貝的移動為主要變因。輕瀉劑作用的三種一般機制可 予描述成··⑴藉其親水特性或渗透特性,輕瀉劑可讓液 體停留在結腸内容物内,因而增加體積與軟度及使移動容 易⑵輕渴劑可直接或間接作用於結腸钻膜以減少水與 氯化納的淨吸收。⑶輕填劑可增加腸子之自動性,造成 鹽與水^減少吸收以減少移轉時間。大致上,輕填劑可被 ^分成三大類,即,υ食用纖維與形成大體積之物質的輕 瀉劑,2)鹽水及滲透性輕瀉劑類,與3)刺激物類輕瀉劑。 (參考 Goodman and Gilman,第七版,994_1〇〇3頁)。 本發明中使用的主要輕瀉劑係鹽水與滲透性輕瀉劑。鹽 水與參透性輕渴劑包括各種鎮鹽;納與鉀<硫酸鹽,鱗酸 鹽與酒石酸鹽類;乳果糖;甘油;與山梨糖醇。它們被
本紙張尺度適财國^^準(CNS ) A4規格(21^ 297公釐) 553934 經濟、那中央標準局員工消費合作杜印製 A7 B7 五、發明説明(12 ) ^ 量缓慢地吸收,藉其滲透特性在内腔流體中作用。屬於這 類滲透性試劑,可購自市面供清理腸道的兩例為·· KleanPrep® 與 GoLytely⑧。KieanPrep@ 溶液含有聚乙 二醇3350(59克/升)、硫酸納(5· 克/升)、碳酸氫鈉 (1.685克/升)、氯化鈉(1465克/升)、氯化鉀(〇7425克/ 升),阿斯巴甜(〇· 0494克/升)與香草精(〇· 3291克/升)。 另外,( + )-喏希沙普立得及其藥學上可接受的鹽類實質 上不受中枢神經系統之影響,特別是中杈的多巴胺拮抗劑 與中樞的血清素拮抗劑活性。 已發現,( + )-喏希沙普立得的代謝路徑與希沙普立得的 代謝路徑不同。後者顯然主要係經由細胞色素p45〇系統。 某些用於抑制希沙普立得的主要代謝途徑的治療試劑可能 會使血液中的希沙普立得值升至過高而引起副作用。因此 不可將這類治療劑與希沙普立得混合製藥,但喏希沙 普立得則無此情況。 本發明也相關於含有( + )-喏希沙普立得的(L)-酒石酸鹽 或(D)-酒石酸鹽的口服劑量型藥劑,此鹽類型態整體而言 ,宜為其溶散性較不受pH影響,但藥物之吸收及生化可利 用性則受pH影響而有不同溶解度者,當經由口服時,會受 存在於胃腸道(GI),特別是胃中食物之影響。藥物在胃中 的殘留時間顯然會因有食物存在而呆得更久,即,食物的 存在會延長藥物在相對為酸性狀態的胃中時間。如果藥物 的生物可利用性會因存在於胃腸道的食物達某一量時受影 音,此樂物被認為具食物效果’’或具衆物—食物交互作用 —14 一 本紙張尺度適用中國國家標準(CNS ) A4規格(2ΐ〇χ297公酱) (請先閲讀背面之注意事項再填寫本頁}
經濟部中央標準局員工消費合作社印製 553934 A7 _____ B7 五、發明説明(13) ^ -- 影響,為使藥物達足夠的生物可利用性,常需於特定的狀 態下服食(例如飯前),服用希沙普立得即為一例。含前述 酒石酸鹽類的口服製劑,其( + )-喏希沙普立得的生物可利 用性有不受食物影響之好處。這類藥劑因此極具吸引力 乃因患者無需嚴袼要求服藥的最適當時刻,以免有不同的 結果,有時則效果不足,特別是小兒科用藥之情況,這樣 的劑量型可有隨時(指視病況)投藥的額外好處。此外因 其不受pH影響,這類藥劑可與會改變胃之酸鹼度(例如增 加胃的pH)的藥劑一同服用。這類可並用的藥劑包括,.例 如抗酸劑類,例如含鋁的抗酸劑類,如Al(〇H)3;含詞的 抗酸劑類,如CaC〇3;或含鎂的抗酸劑類,如 Η2-括抗劑類,如曱腈咪胺(cimetidine)、,雷尼丁(rani一 tidine)、費莫提丁(fam〇tidine)、尼查丁(nizatidine)、 螺塞丁( roxat i d i ne)等;質子誘出抑制劑類,例如歐莫比 ^(omeprazole)、蘭索普唾(lansoprazole)、蝶比普口坐 (rabeprazole)、貝多普嗤(pantoprazole)等。因此提供 的劑量型,宜為供口服用的固態劑型,含有(+ ) - Π若希沙普 立得酒石酸鹽與任何這類制酸劑者,可被做成供同時使用 的混合製劑、分別使用或接續使用之劑型。 因此,另方面而言,本發明相關於一種醫藥製劑,特別 是固態型式,宜為供口服用,適於迅速溶出,含(+)一。若希 沙普立得之L-或D-酒石酸鹽為活性成分與適當的載劑者。 π適於迅速溶出π—詞,意指此活性成分在pH為1-7的範圍 間,一小時内自藥劑型式可溶出超過60%之劑量。溶出作 -15- 本紙張尺度適用中國國家標準(CNS ) A4規格( 210X297公釐) ' " ~ (請先閲讀背面之注意事項再填寫本頁)
553934 A7 B7 五、發明説明(14 ) ^ 用可依歐洲藥典所述方法或USP-2溶出裝置中之USP試驗法 <711〉(美國藥典XXII,pp 1578-1579中所載)測定。為達 到迅速溶出,應選用能讓錠劑足夠迅速分散之賦形劑,這 類賦形劑宜能在少於約30分鐘、甚或少於20分鐘、15分 鐘,更佳地在少於約3或1.5分鐘下即能崩散。另一方面, 本發明相關於一種不必考慮到藥物-食物間之交互作用而 治療患胃腸道疾病者之方法,包括對已服用他種會增加胃 的酸鹼度的藥劑者,施用含( + )-喏希沙普立得(D)-或(L)-酒石酸鹽;或使用其製備不受藥物-食品交互作用影響的 醫藥品供治療這類胃腸病之用途。 本發明的配製劑可能選擇地含有防胃腸脹氣劑,例如喜 美斯康(simethicone), α-D-半乳糖戒等 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 為製備本發明的醫藥品組成物,將有效量的此種化合物 ,呈鹽基態或酸加成鹽態者,做為活性成分,與藥學上可 接受的載劑充分混合,後者可視欲投藥的劑型而選用多種 適當的載劑,這些藥學上製劑宜被做成單一的劑量型,供 口服、經直腸或非經胃腸注射施用,例如,製備口服用製 劑時,可使用任何習用的藥學上介質,例如可採用水、甘 醇類、油質類、醇類等,配製懸濁劑、濃漿劑、酏劑與溶 液類之口服製劑;使用澱粉類、糖類、高嶺土、潤滑劑、 粘結劑、崩散劑等配製粉劑、丸劑、膠囊劑與錠劑等。以 使用方便性而言,錠劑與膠囊劑為最適當的口服劑型,顯 然,即可配合使用固態藥學上的載劑配製。欲製備非供胃 腸使用的組成物時,可使用的載劑為滅菌水(至少佔大部 -16- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 553934 A7 B7 五、發明説明(15 ) ^ 分),也可包括其他成分,例如助溶劑。配製可注射溶液 可以使用的載劑為,例如鹽液、葡萄糖溶液或鹽與葡萄糖 之混合溶液。可注射的懸濁劑可使用適當的液體載劑、懸 浮劑等配製。製備適於經皮下注射施用之組成物時,可選 擇地在載劑中包括使用助穿透試劑及/或適當的潤濕劑, 也可選擇地配合少量適當的,不會對皮膚造成傷害的任何 天然添加劑。這類添加劑可幫助對皮膚施用及/或幫助所-要組成物的配製。這類組成物的施用途徑有各種方式,例 如經皮貼片、塗抹上去、做成油膏。由於式(I)化合物的 酸加成鹽類較其相對之鹽基態物更能溶解在水中,因此顯 然於配製含水的組成物時較適合。 尤其適宜的方式係將上述醫藥組成物做成易於供施用及 均勻劑量的藥劑單位型式。說明書及申請專利範圍中所稱 之藥劑單位型式意指適於單獨服用的分立態單位,各單位 中含有預計能達療效的活性成分量及所要的藥學上載劑。 這種劑量型式為錠劑(包括藥心或經包衣過者)、膠囊劑、 丸劑、粉劑包、扁片、可注射的溶液或懸浮劑、茶匙量、 湯匙量等,以及其分隔的多重包裝。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 供口服投藥時,此醫藥品組成物可被做成固態劑量型式 ,例如錠劑(僅供吞服及可咀嚼的劑型)、膠囊劑、利用傳 統方法配合藥學上可接受的賦形劑(例如粘結劑、填料戒 稀釋劑、潤滑劑、崩散劑、可濕劑(如十二烧基硫酸鈉)) 及其他賦形劑(例如著色劑與色料)配製之。這些錠劑可依 文獻所載方法將之包層。 — 17— 本纸張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 553934 A7
五、發明説明(16 ) 經濟部中央標準局員工消費合作社印製 枯結劑可能為阿㈣勝、藻酸、”基纖維 維素(微晶纖維素)、糊精、乙基纖維素、動物膠、葡萄= (液態)、古阿膠、經丙基纖維素、經丙基甲基纖维辛、甲 基纖維素、聚氧化乙浠、聚乙稀 澱粉(預糊化過者)、羥丙基甲其縫他主』 ^ 卷甲基絲素類,特別是低钻性 的羥丙基甲基纖維素類。 填料或稀釋劑的例子為經噴霧乾燥的或無水的乳糖、斧 糖、葡萄糖、甘露糖、山梨糖醇、殺粉、纖維素(例如微 晶纖維素;AvicelTM)、經水合的或無水的磷酸二朗、 及其他文獻已知者,或它們的混合物,例如可使用乳糖與 微晶纖維素的混合物,乳糖可被當作純稀釋劑使用,而微 晶纖維素係-種填料,.可令疑劑產生適當的硬度,且因纖 維素與水接觸後會膨脹而具有崩散劑的特性。較佳的乳糖 係乳糖單水合物DC,特別是經噴霧乾燥的乳糖單水合物( Phannatose DCL 11TM)。填料及稀釋劑的量可介於約训 %至約95%,或介於約65%至約90%,或介於約66%至約860/〇, 以含約75%(w/w)重量計者最佳(以整顆藥錠或藥心量為計 算標準)。此75%的混合物可購得,商品名為MICROCELAC® ,其用量宜佔約80%(w/w)至95%(w/w),相對藥心(經塗裝 薄膜之樂键)或整顆藥旋而計。 潤滑劑的例子為硬脂酸鎂、滑石粉、二氧化矽、硬脂酸 、富馬酸硬脂醯鈉、十二烷基硫酸鎂、氫化植物油及其 他文獻所知者。潤滑劑的量通常約佔錠劑總重量或錠劑心 (以薄膜塗裝之錠片而言)之〇. 2%(w/w)至7. 0%(w/w)。較佳 -18- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) —-------— (請先閱讀背面之注意事項再填寫本頁) 訂 553934 A7 B7 五、發明説明(17) ‘ 的潤滑劑量為使用約〇.5%(w/w)至約3.0%(w/w),更佳的 用量為使用約〇· 9%(w/w)矣約l 25%(w/w)之潤滑劑。 崩散劑包括殿粉,例如玉米殿粉、預糊化殺粉、殿粉糖 酸鈉(Explotab®)、交聯的聚乙烯此咯啶酮、交聯的羧甲 基纖維素鈉、粘土、微晶纖維素(Avice1®)、藻酸鹽、膠 質物、羥曱基纖維素鈉、以及其他文獻中已知者。崩散劑 的存在量為約2%(w/w)至約15%(w/w),或為約3%(w/w)至 約 10%(w/w)。 在這兒,百分比係依重量對重量表示,戎表相對於整個 錠劑(或僅是包衣的錠劑心)的總重量之成分或賦形劑之百 分比。 通常,在製成錠片之前,鍵劑混合物係呈乾態團粒或潤 濕態團粒,某些命)子下,特別是當使用(D)-或(L)-酒石酸 鹽類時,或可直接進行壓製,可製得具更好溶解性之物。 經濟部中央標準局員工消費合作社印製 |_------Φ ! (請先閲讀背面之注意事項再填寫本頁) 供口服的製劑可予做成,例如,溶液,濃漿液或懸浮劑 ,或可被做成乾態產品,於服用前再加水或其他適當載劑 使用。這類液態製劑可用習用方法製備,選擇地配合使用 藥學上可接受的添加劑,例如懸浮劑(例如山梨糖醇濃漿 液、曱基纖維素、經基-丙基曱基纖維素或經氳化的食用 油脂);乳化劑(例如卵填脂或阿拉伯膠);非含水的載劑 (例如杏仁油,油質酯類或乙酸乙酯);以及防腐劑類(例 如曱基或丙基對羥基苯甲酸類或山梨酸)。 藥學上可接受的甜味劑包括,宜含有至少一種強甜味劑 ,例如糖精、糖精鈉或鈣、阿斯巴甜、艾西斯費钾(ace一 -19 一 本纸張尺度通用肀國國家榡準(CNS ) A4規格(210X297公釐) 553934 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(18) . sulfame potassium)、環己胺石黃酸鈉、阿力甜(aHtaffle) 、^氫抑素甜味劑、莫内林(monelHn)、司特維塞糖( stevioside)或蔡可洛糖($ucrai〇se)(4, 1’,6,—三氯—4 1, ,6’—三去氧半乳糖蔗糖),其中又以糖精、糖精鈉或鈣較 佳,選擇地配合使用大體積之甜味劑,例如山梨糖醇、甘 露糖醇、果糖、蔗糖、麥芽糖、異麥芽糖、葡萄糖、經氫 化的葡萄糖濃漿、木糖、焦糖或蜂蜜。 - 具強甜味之甜味劑通常以低濃度使用。例如使用糖精鈉 時,其用量可能介於0 04%至0.1%(w/v),·相對最後配製 劑之總體積而計。在低劑量的配方中使用約〇 〇6%,高劑 $的配方中使用約〇 〇8%(w/v),更佳。體積量較大的甜 味劑其使用量介於約,10%至約35%,宜為介淤約1〇%至15% (w/v) 。 · 選擇地,組成物中亦可添加入矯味用香料,例如,用於 矯飾苦味而使用者。低劑量的配方中可用來矯飾苦味成分 者,且使用水果香味,例如櫻桃、覆盆子、黑醋栗或草莓 曰味。使用兩種香味混合物也可產生極好的結果。高劑量 的配方中或需使用較強烈的矯味劑,例如牛奶巧克力香味 、薄荷、迷迭香等藥學上可接受的強烈香味。各種香味劑 在最後組成物中的濃度可介於0.05%至1%(W/V)。混合使用 這犬員強烈香味劑也甚有利。使用的香味劑宜在配方的酸性 狀態下也不會發生任何改變或減少味道及色澤者。 本發明的化合物也可被配製成貯存的配製劑。這類長時 間作用的配方可經植入法施'用(例如經皮或經肌肉)或經由 -20—
(請先閱讀背面之注意事項再填寫本頁) -fr填寫太 訂 I# 553934 經濟部中央標準局員工消費合作社印製 對患者施用活性成分 Α7 Β7 五、發明説明(19 ) - 肌肉注射。故,例如,使用適當的聚合性或疏水性材料( 例如在可接受的油質中之乳劑)或離子交換樹脂配製本化 合物,或予做成難溶的衍生物,例如製成難溶的可溶性鹽 〇 本發明的化合物可予配成供非經胃腸施用的配製劑,經 由注射、經靜脈、經肌肉或經皮下注射而施用,例如經大 丸藥注射或連續式經靜脈灌注。供注射用配方可呈單位劍 量型,例如,製成安瓿劑或置於多重容器内,配合添加防 腐劑。組成物的型式可為懸濁劑、溶液或分配於油質或含 水載劑中之乳化液、且另可含有配方試劑,例如調節渗透 壓的、懸濁用的、安定用的及/或分散用的試劑。或者
此活性成分可被做成粉狀,使用前再配合適當載劑,例如 滅過菌無熱質的水P 本發明的化合物也可予以配成供直腸使用的組成物,例 如坐藥或灌腸劑,例如含傳統坐藥基質(例如可可脂或其 他甘油脂)之製品。 ’ 經鼻使用的本發明化合物配方可以是液態噴劑,粉劑或 滴劑。 ""一 通常,為達到治療效果,相對每公斤體重,建議使用約 0.001至約2毫克,更佳為自約0 02至約〇5 υ冤兄的量。適 ▲的固態口服製劑,其單位劑量相當於包含約〇· i至古 克的活性成分,特別是約丨至約5〇毫克或至約2 毛 笔見者。 治療的方法也可能包括在一天當中,分多次,例如 必丄由+ 乙〜4次, —21 — 本紙張尺度適用中國國家梯準(CNS ) A4規格(21 Οχ297公釐 ------------- (請先閲讀背面之注意事項再填寫本頁} 、訂 553934 A7 _ _ _B7 五、發明説明(2〇 ) ^ 下述實例係用於對本發明再做詳細說明,非指本發明僅 限於此。 實‘部分 後面提到的nACN"意指乙腈,"CH3OHn意指甲醇,而 "DIPE"係指二異丙基醚。 本發明的部分化合物,若未予進行測定其絕對立體結構 時,係將先行分離得的立體異構物標示成"BM,再次分離_ 得者標示成"A",不代表其真正的立體構型。 其旋光度(OR),或其比旋光度[α]2ρ〇,係使用Perkin Elmer 241型的觀測儀測定得者。在20 °C,鈉光線(波長 為589nm)下,裝在長度為100毫米之觀測管中測其[α ]。 化合物係溶解於甲醇裡,濃度為1% w/v。,Chiralpak AD( 直鏈澱粉3, 5-二甲基苯基胺基甲酸酯)係一種不對稱固定 相柱層材料,購自日本的Daicel Chemical Industries, LTd 〇 ki+ )°笔產沙普立得的合成 實例Α·丄 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 利用不對稱柱層層析法,使用ChiralpakAD(2公斤;柱 層内徑(ID)為no毫米,流洗液為正己烷/乙醇70/30;注 入量:5克/升,流速·· 400毫升/分,檢測:254nm波長), 將順式〜乙基4-(4-胺基-5-氯-2-曱氧基苯醯基胺基)-3-甲 氧基—卜六氫吡啶羧酸酯(0. 12莫耳,46克)(EP-0, 076, 303 編號為168之化合物)分離成其鏡相異構物。收集所要的兩 組劃分,蒸發除去其溶劑。將首次流出的鏡相物溶解在甲 -11 - 本紙張尺度適财( CNS ) A4祕(2似297公«1 '~~ 經濟部中央標準局員工消費合作社印製 553934 A7 五、發明説明(21 ) 醇中,經dicalite過濾,將溶劑基發。殘 料一
( — )_順式—乙基4♦胺基Ά2-甲氧基笨 酉服基胺基)—3_甲氧基—卜六氫此錢酸醋(鏡相物U
Tmi^: 164〇C); [α]2.〇 = -55·8δ〇 (c=i%w/v, -)(中間物1)。此中間物的光學純度超過99%。 將其-欠流洗出的鏡相物之殘存物溶於甲醇’經dicalHe 過;慮後’蒸發除去溶劑。將殘存物分散至_内,再冷卻 至〇 c,濾下所得沈澱’乾燥i(4(rc,真空 克的( + ),式-乙基4-(4-胺基_5_氣_2_甲氧基苯醯基胺 基)-3_甲氧基-1-六氫此啶羧酸酯(鏡相物2; 〇R(+);熔 li: 164°C); [α]20-= +55.10 ° (c=l% w/v, fS|t)(t 間物2),此中間物的光學純度超過98%。
實例AJ 將中間物(2)(0.042莫耳,16克)與氫氧化鉀(23克)的混 合物共置於2-丙醇(230毫升)中,攪拌並予迴流6小時。將 反應混合物冷卻後,蒸發除去溶劑。加水。溶劑蒸發除去 後將殘存物懸浮於水中,過濾,將固體溶解於二氯甲烷。 有機層經水洗,乾燥,過濾,濃縮。自ACN令殘存物結晶 。將沈澱過濾出,經真空乾燥後,得到劃分1(57%;熔點 :188 C )。此劃分再置入ACN行再結晶,濾出沈澱並予乾 燥,得到劃分2(5.3克)。收集全部結晶後濾液,蒸發除 去溶劑。殘存物與劃分2,經矽膠柱層純化(流洗液為: CH2C12ACH30H/NH3) 90/10)。收集純態劃分,除去 —23- 本紙張尺度適用中國國家榡準(CNS ) A4規格(2!OX297公釐) ---Γ·--------- (請先閱讀背面之注意事項再填寫本頁} -訂 經濟部中央標準局員工消費合作社印製 553934
_將固:態殘存物乾燥,得5·6克的⑴_順式+胺基一 5_ 氣·2曱氧基Ν (3-甲氧基一 4〜六氫此咬基)苯酿胺(此即為 ⑴-口若希沙普立得);[0:]2}+5 6〇。(c=1%w/v,甲醇 中)(化合物1)。 實例A. 3 將中間物⑴(0.044莫耳,17克)與氫氧化鉀⑵克)的混 合物共置於2-丙醇(250毫升)中,祕並予迴流6小時。將 反應混合物冷卻後,蒸發除去溶劑。加水。將溶劑蒸發除 去後,殘存物攪拌入水中,過濾,將固體查於ACN中結晶。 濾出沈澱後,使溶解於DCM内。將有機溶液經水洗,乾燥, 過濾,》辰縮除去溶劑。自ACN中行結晶。濾下沈澱並予乾 燥後,收得7克(54%)的(-)-順式—4-胺基'—5—氯—2-甲氧基 -N-(3-曱氧基-4-六氫献*啶基)苯醯胺(此即為(―戶喏希沙 普立得);[a]2p〇=_6.09。(c=50.90毫克/5毫升曱醇)( 化合物2)。 實例A. 4 對攪拌中,溶解於於水及甲醇中的(+ )一順式—4-胺基-5-氣-2-曱氧基-N-(3-曱氧基-4-六氫此啶基)苯醯胺(化合 物1),加入溶解於水及乙醇的[r(r*,r*)]—2, 3-二羥基丁 二酸(L-酒石酸)溶液,然後令其產生結晶。濾下結晶,乾 燥後可得(+)-(3S,4R)-順式-4-胺基-5-氣-2-曱氧基-N-( 3-曱氧基-4-六氫此啶基)苯醯胺[R(R*,R*)]-2, 3-二羥基 丁二酸鹽單水合物。X-射線繞射測定係使用Siemens P4 four-circle繞射機進行。 _______-_-24- ______ 本紙張尺度適用中國國家標準(CNS ) A4k^ U10X297公釐) ' (請先閲讀背面之注意事項再填寫本頁)
經濟部中央標準局員工消費合作社印製 553934 A7 B7 五、發明説明(23 ) | B.藥學上實例 實例&丄硫酸鎂引起的腸灌洗法 以一種小獵犬(Beagle dogs)進行試驗,性別不拘,各 種體重均有,先經16小時禁食,預先使其服用(+ )喏希沙 普立得或溶劑,一小時後令其於服用硫酸鎂(MgS〇4. 7H2〇, 64克/升,0.26M; 200毫升),評估因硫酸鎂而發作的腸灌 洗四小時,以蒸餾水處理的對照組在四小時期間幾乎無液 態糞便發生(2· 5%偽正值;n=200),被當做能反映受硫酸 鎮引起的腸灌洗之有意義加速作用,每種試驗的活性物質 劑量各施用於五隻動物,於分隔的實驗階段進行,包括以 溶劑處理的對照組動物。依Finney的重覆試驗法(Finney, 1962),全夯―或—全無之標準,為大量經溶劑處理的動物 所得結果之分佈,,用來計算^^㈤—值(有效劑量)及95%確 認限度。 如表B.1中之說明,劑量只要由〇 〇32毫克/公斤略增加 至0· 15宅克/公斤,即足以在經硫酸鎂挑起腸灌洗後一小 時達到瀉肚子之作用。 表-給狗口服硫酸鎂一小時後,(〇喏希沙 普立得可促進其腸灌洗效果之EDsg值(95%確認 限度,毫克/公斤,經口),以硫酸鎂進行腸灌洗, 欲在卜4小時内得到液態糞便之ED50,S值 本紙張尺度通用宁關家檩準(CNS) A4規格(21GX297公羡 (請先閲讀背面之注意事項再填寫本頁) 、τ 553934 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(24 ) 效果 ED50值(毫克/公斤,經口) 發作於四小時 0.032 發作於三小時 0.049 發作於二小時 0.064 發作於一小時 0. 15 實例B. 2:以:t星進行"阿朴嗎啡,色胺k正腎上腺素(ATN)試驗" 本發明化合物不在意中樞的多巴胺拮抗劑及血清素拮抗 劑活性可藉對老鼠進行混合的阿朴嗎啡(APO)、色胺(TRY) 與原腎上腺素(NOR)試驗數據證明,此種混合的阿朴嗎啡、 色胺與原腎上腺素試政法被述於Arch. Int/Pharmacodyn., 227,238-253(19^7),能提供一種經驗評估,解釋那種藥 物特別會影響中樞的與周圍的神經介質系統,此試驗裡, 可觀察到老鼠係受周圍的或中樞的活性影響或反應,中樞 的多巴胺拮抗作用藉受試老鼠經皮下注入不同劑量的受試 化合物及阿朴嗎啡(其為一種多巴胺興奮劑)進行評估。其 次,血清素的拮抗作用藉同樣受試老鼠經皮下注入不同劑 量的受試化合物及色胺(其為一種血清素5HT2-受體興奮劑 )進行評估。中樞的與周圍的血清素拮抗作用均可在此試 驗中評估。中樞的血清素拮抗作用係具潛力的抗精神病藥 物,特別是同時顯現多巴胺拮抗作用於本試驗的第一部分 - 26- 本紙張尺度適用中國國家橾準(CNS ) Α4規格(210 X 297公釐) ---^-------- (請先閱讀背面之注意事項再填寫本頁)
、1T
時。最後,本發明化合物的a_腎上 553934 性係藉相同老鼠,,經皮下注」、激導性的拮抗活 腎上腺素(其為上腺量的受試化合物及原 _ . ., .. ., _ 素激ir性的興奮劑)進行評估。 體記於表δ.2,示出㈣值,*克/公斤 物質喚起的有==物保護_的受試動物免於受上述 與塑 外反應之劑量。ΑΡΟ—攔列出阿朴嗎啡之 表中樞的多巴胺拮抗活性。TRY痙攣與TRY充‘ 、色胺之衫響,&別代表中樞的與周 圍的血清素拮抗 〇R攔列出原腎上腺素之影響,代表α 一腎上腺素激 興奮劑活性。⑴-料沙普立得的受歡迎的藥學上 特&係其顯不不受中樞的多巴胺(ΑΡ0欄)與中樞的血清素( TRY痙擎攔)拮抗作用活性影響。 · —--------衣-- (請先閲讀背面之注意事項再填寫本頁) ’訂· 表B· 經濟部中央標準局員工消費合作衽印製 -^--- 化合物 —以老鼠飾見合織ED50值(毫公斤) AP0 TRY 痙攣 TRY 充血 NOR (+)-喏希沙普立得 >40 >40 4.7 >40 27- 本紙G度適用中CNS 規格「210>〇97公餐) 553934 A7 ___________B7 五、發明説明(26) . 實魁一B,·.3:以立呈行的5-羥基犬尿胺拮抗作用” 已知5-HT3受體在嘔吐上扮演一相當重要的角色。由於 5 OH K(5 ·基犬尿胺,5-hydroxykynuramine)對 5-HT3 受體有專性興奮性,乃用其評估5_Ητ3拮抗效果的潛力。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 選用體重為450克左右,公母不拘的天竺鼠,以斬首方 式宰殺,取其非末端(除去10公分),完整的迴腸段,清洗 後,4·5公分長,預先加料〇·75克一起垂直懸吊置於1〇〇毫 升浴液裡供專滲記錄:[(DiSpiacemen*t; Transducer Control Unit; Jassen Scientific Instrument Division ),HP7DGDT- 1000(Hewlett-Packard CY)]·此器官浴係 以Tyrode溶液(37.5。〇充填,混有由95%氧氣與5%二氧化 碳所成混合氣體,經20分鐘的穩定期間後;加曱基膽汁鹼 (3· 16-6M,接觸30秒)至浴液中以評估潛在的最大收縮, 其後更新浴液,接著,加入血清素興奮素5-0H-K(接觸30 秒)(最後濃度為3· 10-6 m),間隔十分鐘,每次加入後經 30秒即將浴液更新,待達到具再現性的收縮效果時,於加 入5-0H-K之後五分鐘,加入一劑量的受試化合物,待建立 了受試化合物之對數濃度反應曲線後,利用線性回歸分析 ,計算還原50%受5-OH-K誘發之影響的IC5〇值. 化合物1 [即:( + )-喏希沙普立得]具有的IC5〇為93 nM; 化合物2 [即:喏希沙普立得]具有的IC5〇為450nM。 實例Β·4: π天竺鼠迴腸的同軸刺激作用π 取體重介於600-900克,公母不拘的Dunk in-Hartley天 竺鼠,以斬首方式宰殺,取出其迴腸,以溫熱並加有氧氣 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇χΐϋ釐)~一 553934 經濟部中央標準局負工消費合作社印製 A7 B7 五、發明説明(27 ) ^ 的Krebs-Henseleit溶液清洗·將迴腸部分(15公分)披在 玻璃吸管上·以經Krebs溶液潤濕的棉線將腸肌叢的縱向 肌肉層除去,·將長8公分的長條片摺疊並將這些長條片( 4公分)架在兩白金電極間(8公分長,分開0.5公分),此長 條片與預先加料1· 5克共懸吊於1〇〇毫升Krebs-Henseleit 液中(37· 5 °C),打入由95%氧氣與5%二氧化碳所成氣體, 使用單長方形刺激物激發此處理物[lms; O lUz;次高反, 應(電流指向最高反應之80%),自可預定程序之刺激器發 出(Jassen Scientific Instrument Division)。測量其 寺長收細(Stathain UC2,Jassen Scientific Instruments amplifer,Kipp BD-9 pen-recoder),於 30 分鐘穩定期間 ,此長條片被反覆拉伸以得到1· 5克的穩定狀態張力。於 開始進行電刺激作用之前,給予乙醯基膽素的累加的濃度 反應曲線(3.10-9,10-8,3.10-8與10-71〇,以1^以3溶液 將浴液更新並讓其再經30分鐘的穩定化·接著以〇· 1Ηζ頻 率將長條片做電刺激lms·測試電壓係逐步調升2V(最高 為15V)至觀察到發展至最大力量,抽搐反應漸減(藉減弱 電壓)至約以最大電壓操作下的80%。小心調整電麼有可能 得到至少兩小時期間不會改變的次抽搐反應,當抽搐反應 安定至少15分鐘時,將受試化合物加至浴液經3〇分鐘,如 果受試化合物引起少於50%的抑制作用時,加入3· 1〇—7 μ的 希沙普立得至浴液裡,看看受試化合物是否能拮抗希沙普 立得的刺激效果,如果受試化合物引起多於5〇%的抑制作 用Ν*,則加入10 7 Μ的那諾松(nai〇xone),看看是否 (請先閱讀背面之注意事項再填寫本頁)
—29-
553934 經濟部中央標準局員工消費合作社印裝 Α7 Β7 五、發明説明(28) , 作用係藉由鴉片劑受體媒介。於加入希沙普立得或那諾松 後,會再得到超大的刺激作用,其後,中斷電流刺激,再 給予乙醯基膽素做累加的濃度反應曲線,此兩種乙醯基膽 素的累加的濃度反應曲線係為了用來區分效果係來自減少 乙醯基膽素之釋出(直接的抗膽素激發的影響),或係來自 提高的乙醯基膽素釋出影響(經由蕈毒素受體的敏感化作 用所致)。化合物的EC50 (即,其刺激得的反應能達電刺 激50%之濃度)係以當受試化合物能引起刺激作用時利用線 性回歸分析計算得者。 化合物1 [即:( + )-喏希沙普立得]具有的EC5〇為0.6//M •,化合物2 [即:(-)-喏希沙普立得]具有的EC5〇為5//M。 實例B.5: ”天竺鼠結腸的同軸刺激作用"· 取體重在450克左右,公母不拘的天竺鼠,以斬首方式 宰殺,取出其上升結腸,予以淋洗,其後準備約3公分長 之段落,將這些條片懸吊於100毫升器官浴中,連結至預 先加料2克的等滲功率轉換器;[Displacement Transducer Control Unit((Jassen Scientific Instrument Division); HP 7 DGDT lOOO(Hewlett-Packard)]。此器官浴使用 DeJalon 溶液 (37· 5 °C)浸泡,打入由95%氧氣與5%二氧化碳所成氣體, 經20分鐘的穩定期間後,加入甲基膽汁驗(3·ΐ〇-6 μ)至 浴液中以評估潛在的最大影響(接觸30秒);其後,更新 浴液,每間隔十分鐘重覆做一次,待達到具再現性的效 果,其後,加入受試化合物經十分鐘。其後,不再更新浴 液下,加入3·1〇-7Μ的希沙普立得以評估5ΗΤ4的影響。 _— ---------~3 0 ~______ 本紙張尺度適财國國㉟準(CNS ) Α4規格(210X297公釐) " ~ ' JU---Γ·--------- (請先閲讀背面之注意事項再填寫本頁)
、1T 553934 A7 B7 五、發明説明(29) 、 當希沙普立得的影響達到穩定的最高值後,加入曱基膽汁 鹼(3. 1(TS M)至達到最高的收縮值,用於評估潛在的抗膽 素激導性的影響。化合物的EC5G (即,其刺激得的反應能 達最高強度50%之濃度)係利用線性回歸分析計算得到。 化合物1 [即:( + )-喏希沙普立得]具有的EC5〇為1.9 "M;化合物2 [即:(-)-:1 若希沙普立得]具有的EC50為 11 。 C.藥學上組成物實例 C. 1加薄膜塗層的婉劑 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 在流動床(fluid-bed)製法中,將活性成分,乳糖,及 未經修飾過的澱粉予以充分混合,使用溶解在水中的HPMC 溶液喷灑所得粉劑,叙成被均勻潤濕的團教,將其乾燥, 與微晶纖維素、交聯的聚乙烯吡咯啶酮、膠體無水二氧化 矽及硬脂酸鎂一同過篩。將篩過的粉末混合後,予以壓製 成錠劑。塗層用的懸浮液係先將HPMC與丙二醇一起溶解於 水中,再將其加入至含水、滑石粉、二氧化鈦及染料的經 均質化混合物中。在加熱的塗層裝備中,將塗層液喷灑至 錠劑上。 錠劑的錠心(tablet core)成分為: 成分 量 %(w/w) 相對藥心計量 (+)-喏希沙普立得-(L)-酒石酸鹽 13. 23毫克 7. 35%(w/w) 乳糖單水合物200篩目(*1) 107. 73毫克 59.85%(w/w) 未修飾過玉米澱粉 36. 00毫克 20. 00%(w/w) -31 — 本紙張尺度適用中國國家標準(CNS ) A4規格(21 OX297公釐) 553934 A7 B7 五、發明説明(30 ) HPMC 2910 15 mPa.s(*2) 3.60毫克 2.00%(w/w) 微晶纖維素 12. 60毫克 7.00%(w/w) 交聯的羥甲基纖維素鈉 5.43毫克 3.00%(w/w) 膠體無水二氧化矽 0.54毫克 0.30%(w/w) 硬脂酸鎮 0.90毫克 0.50%(w/w) 藥心總重量: 180.00毫克 錠劑塗層組成: 成 分 量 %(w/w) 相對塗層物計量 HPMC 2910 15 mPa. s 4.00毫克 55.95%(w/w) 丙二醇 , 1.00毫克 '13.99%(w/w) 二氧化鈦(E171) · 1.20毫克 16.78%(w/w) 滑石粉 0.80毫克 11.19%(w/w) 黃色氧化鐵(E172/C177492) 0. 15毫克 2.10%(w/w) 總塗層物量: 7. 15毫克 (*1) 200篩目,指所用乳糖單水合物的類型。 (*2) HPMC係羥基丙基甲基纖維素,數字"2910",指所用羥 丙基曱基纖維素的類型,前兩個數字π29",代表曱氧基所佔 的大約比例,第三及第四個數字,"10”,代表羥丙基所佔的 大約比例。也示出其钻度(15 mPa. s),係2%的水溶液於20 °C 下測定得者。為所用HPMC的分子量之表示法。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 -32- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 553934 A7 B7 五、發明説明) C. 2 不力口塗層的鍵劑 經濟部中央標準局員工消費合作社印製 將各成分置於齒輪帶動混合機中混合,並在製錠裝置中 予以壓製成錠劑。 成 分 量 %(w/w) 錠劑C. 2. 1 ( + )-喏希沙普立得 10.387毫克 5.8 %(w/w) 乳糖單水合物200篩目 110.393 毫克 61.3 %(w/w) 未修飾過玉米澱粉 36. 毫克 20.0 %(w/w) 微晶纖維素 18. 毫克 10.0 %(w/w) polyvidone K90 3.6 毫克 2·0 %(w/w) 硬脂酸鎂 0.9 毫克 0.5 %(w/w) 膠體無水二氧化矽 ' 0.54毫克 # 0·3 %(w/w) 聚山梨糖醇酯2(Τ 0.18毫克 0.1 %(w/w) 藥錠總重量: 180.00毫克 錠劑C. 2. 2 (+)-喏希沙普立得-(L)-酒石酸鹽13. 23毫克 7.35%(w/w) MICROCELAC 157.23毫克 87.35%(w/w) 羥曱基纖維素鈉 7.2毫克 4. 00%(w/w) 膠體無水二氧化矽 0.54毫克 0.3 %(w/w) 硬脂酸鎂 1.8毫克 1.00%(w/w) (請先閱讀背面之注意事項再填寫本頁) -33- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)
Claims (1)
1¾
利範圍 專利申請案第87111013號 ROC Patent Appln. No. 87111013 修正之申請專利範圍中文本—附件二 Amended Claims in Chinese- Enel. IT (92年1月A曰送呈) (Submitted on January 'Ψ,2003) 種製備具下式的(+)喏希沙普立得鹼的製法 10
經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 特點為 15 a)藉液相層析法,經由不對稱固定相,將順式-乙基4_ …胺基-5-氣-2_甲氧基_苯醯基胺基)^甲氧基+六 氫比咬魏酸S旨之鏡相對映體分開且 ^離出溶解在甲醇中具比旋光度㈣。為右旋性的 S1】分,且 相係-種纖維素或直鏈㈣之多_、。的不對稱固定 3·根據申請專利範圍第2項的製法复 用己燒與乙醇或異丙醇之混合液。…、的流洗液係使 25《根射請專利範圍第!項的製法, 包括在鹼性含水介質中進行水解作用。、冷刎化作用 5· 一種根據申請專利範圍第〗 a第4項的任1製法製 87224-claim(接) 計 線 # 553934 A8 B8 C8 D8 六、申請專利範圍 備得的化合物。 6.根據申請專利範圍第5項的化合物,其係含有至少 90%重量計的(+)-喏希沙普立得與10%重量計或更少 量的(-)-立體四構物。 5 7.根據申請專利範圍第5項的化合物,其係含有多於 99%重量計的(+)-喏希沙普立得。 8. 根據申請專利範圍第5項的化合物,實質上其中不帶 有其(-)-立體異構物。 9. 一種溶解在曱醇中而具比旋光度[a if為右旋性的(+)-10 嘆希沙普立得。 10. —種具比旋光度[α]2。声+5.60。± 0.2 (c = 1% w/v,甲 醇中)之(+)-σ若希沙普立得。 11· 一種化學式如下之具(3S,4R)絕對結構的(+)-喏希沙普立 得
經濟部智慧財產局員工消費合作社印製 (3 S,4R)_順式-4-胺基-5-氣-2-甲氧基-N-(3_甲氧基-4·六 20 氫比啶基)苯醯胺。 12. 根據申請專利範圍第5至第11項中任一項之化合物其 藥學上可接受的酸加成鹽。 13. —種具有5-HT3-拮抗活性之醫藥組成物,其係包括藥 學上可接受的載劑,以及具療效量之根據申請專利範 -35 - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 553934 六、申請專利範圍 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印製 圍第5至第11項中任—項之化合物作為活性成份。 14:1 用=療甘敏感性腸疾或泌瀉為主的敏感性腸疾之 ^樂組成物,其係包含如申請專利範圍第5至第^項 中任一項之化合物作為活性成份。 15. -種㈣治療細胞輕物或輻射⑽之包之醫藥组 成物,其係包含如_料利朗第5至第u項中任一 〜項之化合物作為活性成份。 16. -種用於治療飲食額之醫藥组成物,其係包含 2利範圍第5至第u項中任—項之化合物作為活性 1U 成份。 17. 根據申請專利範圍第16項之醫藥組成物,其中的飲食 疾病係神經性厭食症。 18. -種用於加速進行輕填劑清除腸道之醫藥組成物直 係包含如中請專利範圍第5至第u項中任—項之化^ 物作為活性成份。 19·根據申請專利範圍第18項之醫藥組成物,其中的輕渴 劑係一種滲透劑。 2〇·根據申請專利範圍第18項之醫藥組成物,其中的輕渴 萬1係種^^乙一醇(PEG)-電解質溶液。 2〇 21· -種用於治療胃腸道穿過滞礙或不足之醫藥組成物, 其係包含如中請專利範圍第5至第n項中任_項之化 合物作為活性成份。 、 22·-種用於治療胃_食道反流之f藥組餘,其係、包含如 申明專利範圍苐5至第11項中任一項之化合物作為活 5 15 本紙張尺度0目 計 線 36 553934 S C8 _D8_' 六、申請專利範圍 性成份。 23.—種用於治療消化不良或胃輕癱之醫藥組成物,其係 包含如申請專利範圍第5至第11項中任一項之化合物 作為活性成份。 5 24. —種具式(V)之化合物,其中的吡啶環具有絕對的 (3S,4R)結構且PG為曱氧羰基、乙氧羰基、第三丁氧 羰基或苯曱基
經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
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US6147093A (en) | 1996-07-19 | 2000-11-14 | Sepracor Inc. | Methods for treating gastroesophageal reflux disease |
JP2003522103A (ja) * | 1998-06-15 | 2003-07-22 | セプラコア インコーポレーテッド | 無呼吸、過食症およびその他の障害を治療するための光学的に純粋な(−)−ノルシスアプリドの使用 |
EP1089733B1 (en) | 1998-06-15 | 2005-03-23 | Sepracor Inc. | Use of optically pure (+)-norcisapride for treating irritable bowel syndrome |
EP1464333A3 (en) * | 1998-06-15 | 2004-12-15 | Sepracor Inc. | Use of optically pure (-) norcisapride in the treatment of apnea, bulimia, and other disorders |
EP1468685A3 (en) * | 1998-06-15 | 2004-12-15 | Sepracor Inc. | Use of optically pure (+)-norcisapride for treating apnea, bulimia and other disorders |
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US6362202B1 (en) * | 1999-03-02 | 2002-03-26 | Sepracor Inc. | Methods and compositions using (−) norcisapride in combination with proton pump inhibitors or H2 receptor antagonists |
EP1200090B1 (en) * | 1999-08-03 | 2013-09-11 | ICOS Corporation | Pharmaceutical formulation comprising a beta-carboline and its use for treating sexual dysfunction |
AU2001275326C1 (en) * | 2000-06-07 | 2006-09-21 | Aryx Therapeutics | Treatment of gastroesophageal reflux disease using piperidine derivatives |
WO2002041918A2 (en) * | 2000-11-24 | 2002-05-30 | Janssen Pharmaceutica N.V. | Use of a triple combination comprising a 5ht3 antagonist, a 5ht4 agonist and a laxative for promoting intestinal lavage |
AU2002356418A1 (en) * | 2001-10-08 | 2003-04-22 | Sun Pharmaceutical Industries Limited | An antispasmodic agent spaced drug delivery system |
JP2003342186A (ja) * | 2002-05-24 | 2003-12-03 | Taisho Pharmaceut Co Ltd | 鼻炎用内服液剤組成物 |
US8524736B2 (en) | 2004-01-07 | 2013-09-03 | Armetheon, Inc. | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
US8138204B2 (en) | 2004-01-07 | 2012-03-20 | Aryx Therapeutics, Inc. | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
WO2005068461A1 (en) | 2004-01-07 | 2005-07-28 | Aryx Therapeutics | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
US20060247180A1 (en) * | 2005-04-29 | 2006-11-02 | Bergey James L | Purgative composition and uses thereof |
CA2620379C (en) | 2005-08-31 | 2015-02-24 | Aryx Therapeutics, Inc. | Synthetic methods and intermediates for stereoisomeric compounds useful for the treatment of gastrointestinal and central nervous system disorders |
KR20100026641A (ko) * | 2008-09-01 | 2010-03-10 | 동아제약주식회사 | 신규한 벤즈아미드 유도체 화합물 및 그의 제조방법 |
JP7203083B2 (ja) * | 2017-07-19 | 2023-01-12 | イグナイタ インコーポレイテッド | エントレクチニブを含む薬学的組成物 |
EP3820468A4 (en) * | 2018-07-11 | 2022-03-23 | Duke University | USE OF 5-HYDROXYTRYPTOPHANE EXTENDED RELEASE IN THE TREATMENT OF GASTROINTESTINAL DISORDERS |
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- 1998-07-07 AU AU88575/98A patent/AU757077B2/en not_active Ceased
- 1998-07-07 IL IL13322598A patent/IL133225A/xx not_active IP Right Cessation
- 1998-07-07 SK SK1829-99A patent/SK284941B6/sk unknown
- 1998-07-07 DK DK98940159T patent/DK1000029T3/da active
- 1998-07-07 BR BR9811676-2A patent/BR9811676A/pt not_active Application Discontinuation
- 1998-07-07 AT AT98940159T patent/ATE251139T1/de not_active IP Right Cessation
- 1998-07-07 EP EP98940159A patent/EP1000029B1/en not_active Expired - Lifetime
- 1998-07-07 DE DE69818678T patent/DE69818678T2/de not_active Expired - Fee Related
- 1998-07-07 CZ CZ0461799A patent/CZ296212B6/cs not_active IP Right Cessation
- 1998-07-07 EA EA200000057A patent/EA002362B1/ru not_active IP Right Cessation
- 1998-07-07 PL PL98337648A patent/PL190296B1/pl unknown
- 1998-07-07 CA CA002292480A patent/CA2292480A1/en not_active Abandoned
- 1998-07-07 NZ NZ502207A patent/NZ502207A/en unknown
- 1998-07-07 ES ES98940159T patent/ES2209190T3/es not_active Expired - Lifetime
- 1998-07-08 MY MYPI98003108A patent/MY129130A/en unknown
- 1998-07-08 TW TW087111013A patent/TW553934B/zh not_active IP Right Cessation
- 1998-07-09 CO CO98038980A patent/CO4940432A1/es unknown
-
1999
- 1999-11-30 BG BG103934A patent/BG64824B1/bg unknown
-
2000
- 2000-01-05 HR HR20000004A patent/HRP20000004A2/xx not_active Application Discontinuation
- 2000-01-07 NO NO20000093A patent/NO315183B1/no unknown
- 2000-07-08 HK HK00104200A patent/HK1025092A1/xx not_active IP Right Cessation
-
2002
- 2002-09-16 US US10/244,365 patent/US20030060485A1/en not_active Abandoned
-
2004
- 2004-03-23 US US10/807,035 patent/US20040176414A1/en not_active Abandoned
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