TWI305147B - Cathartic composition - Google Patents
Cathartic composition Download PDFInfo
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- TWI305147B TWI305147B TW090121835A TW90121835A TWI305147B TW I305147 B TWI305147 B TW I305147B TW 090121835 A TW090121835 A TW 090121835A TW 90121835 A TW90121835 A TW 90121835A TW I305147 B TWI305147 B TW I305147B
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- composition
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- triglyceride
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- 239000000203 mixture Substances 0.000 title claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 48
- -1 bicyclic compound Chemical class 0.000 claims description 43
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Classifications
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- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
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- A61P1/12—Antidiarrhoeals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pyrane Compounds (AREA)
Description
1305147 A7 B7 五、發明說明Ο ) [技術領域] 本發明係有關一新的瀉藥組成物其有助 力初於减輕或防止 人類便秘患者之便秘症狀*且亦可用以清除腸道 [發明背景】 前列腺素(Prostaglandins後文稱為PGs)係—群具有 各種不同生理活性且存在於人類與動物的組織和器官令的 磨妨酸之名稱。基本上PGs具有如下式之前列腺烧酸主 私 · W *
且一些合成的產物可能含有上述經修飾的主幹 五圓環的結構和取代基分類為數種形式9例如 PGs可由 • ill — — — — — — i — — — — — — ^-11111-- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1 312980 Ί 1305147 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(2 ) 0
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Ο
HO A系列之前列腺素(PGAs); B系列之前列腺素(PGBs); C系列之前列腺素(PGCs); / I D系列之前列腺素(PGDs); ο Ε系列之前列腺素(PGEs);
HO H〇
HO F系列之前列腺素(PGFs); 等。再者PGs可分類為在13 J4-含有一雙鍵的PGp ;在 5,6-及13,14-含有一雙鍵的?023;以及在5,6-、13,14-及 17,18-含有一雙鍵的1*035。 (請先閱讀背面之注意事項再填寫本頁)
本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 2 312980 1305147 A7 ________B7________ 五、發明說明(3 ) PGs係如下所述。PCs中,其構成一 α-鏈、一 ω-鏈以 及一五圓環的碳係根據基本主幹編號如下: 9 人 Jc〇OH (α-鏈)
13 15 t? 19 (G>-键) 經濟部智慧財產局員工消費合作社印製 亦即,在基本主幹中其構成碳原子之編號係以羰基的 碳原子為C-1,且α-鏈含有C-2至07,號碼朝環的方向 增加,五圓環含有C-8至C-12,以及ω-鏈含有CM3至C20。 當a-鏈的碳數較少時,應適當地改變接在C-2之後的碳原 子編號,且當α-鏈的碳數大於7時,在C-2位置上的碳具 有取代羰基(於C-1位置)之取代基,該化合物便依此命名。 當ω-鏈含有較少碳原子時其編號應相對地小於20,且當 ω-鏈的碳數大於8時,在第21位置以及之後的碳原子應視 為一取代基。如同PGs結構,其係根據前述必要的主幹考 慮,而不是其他敘述。 例如,POD、PGE以及PGF意指該化合物在C-9及/ 或C-11位置含有羥基。在本發明中,PGs也包含在C-9及 /或C-11位置含有除了羥基之外的取代基,其稱為9_去觀 基-9取代基或Π -去幾基_π取代基化合物。 另外,PGs可能含有異構物,例如雙環的互變異構物, 光學異構物;幾何異構物,或其相似者。 已知PGs具有多種藥理學上及生理上的活性,例如, 血管舒張、引起發炎、血小板聚集、刺激子宮肌肉、刺激 ---^------ (請先閱讀背面之注意事項再填寫本頁) 訂-------- ·. 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 3 312980 1305147 A7 B7 五、發明說明(1 ) 腸道肌肉、防止潰瘍作用等。經由腸道的剌激發現PGEs 或PGFs具有較強的腸道收縮能力,同時腸道淤積作用也 較弱。由於PGEs或PGFs的副作用如胃痛是由腸道的收縮 作用造成’於是可將PGEs或PGFs作為瀉藥。 另一方面,PGs含有13,14-單鍵與C-15構成之羰基, 並發現此種含有13,14-雙鍵且C-1 5構成之羰基的PGs存 在於人類或動物的代謝物令。這些13.14 -二氫-15 -鲷-前列 腺素以及15-酮-前列腺素(後文稱為15-酮PGs)係已知為生 物體内相關的PGS經由酵素代謝自然產生的代謝物。已有 報導和出彼等15-_-PGs很難展現PGs所具有之多種生埋 活性且其為藥理學及生理學上不具活性之代謝物[參見,
Acta Physioi〇gica Scandinavica, 66, p.509- (1966)]。 在Ueno等人之美國專利第5,317032案號中說明前列 腺素渴藥5包含雙環互變異構物的存在。然而,其已宣稱 的活性’作為抗-便秘之治療與雙環互變異構物之預防劑的 顯著活性迄今為止皆不了解a [發明概述] 經濟部智慧財產局員工消費合作杜印制衣 然而在測量15-闺-PGs類似物的藥理學活性之同時, 本發明者發現相對應的雙環化合物,例如5雙環互變異構 物,在少劑量服用以減輕便秘時可使羯一個或更多個鹵素 原子取代。於少劑量服用以減輕便秘時,在c_16位置可使 用氟原子。雖然本發明最初的目的係恢復腸道正常蠕動次 數(母星期3至7次)而當需要服用高劑量造成強烈導瀉的 作用時,亦可使用。 312980 (請先閱讀背面之注意事項再填寫本買) 1 1305147 A7 " 一 - . Β7 五、發明說明(5 ) 〜-- 本發明之目的係提供一渴藥組成物’其係用以治療便 秘亦即清除腸道而無大量的副作用例如胃痛。 因此,本發明提供一瀉藥组成物,其含有 ^ 人供 Μ /馬之,效 含量的雙環化合物,如式(1)所示:
其中 ' 及v2為碳或氧; 當Vi為碳時%如下,且當V2為碳時如下
與R4為氫或者其争之一為〇H ; X!與X2為氫、低碳燒基或鹵素,以及其中至少有— 個為鹵素;. z為碳、氧、硫或氮; R2為氫或烧基; Y為飽和或未飽和之Cm烴鏈’該烴鏈係未經取代或 經由氧、i素、貌基、羰基、芳基,或雜環基所取代者; A為-CH2OH、-COCH2〇H、-COOH或其機能性衍生物; 及 R!係由低碳烴所形成之直鏈或支鏠的飩和或未飽和 烴鏈,該烴鏈係未經取代或經由_素、氧、經基、低礙統 i 卜----- (請先閱讀背面之注意事項再填寫本頁)
ϋ n I n 1 NN M 1 ϋ n i awl f I '13 經濟部智慧財產局員工消費合作杜印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 5 312980 1305147 A7
五、發明說明(6) 經濟部智慧財產局員工消費合作社印製 氧基、低碳烷醯氧基、低碳環烷基、低碳環烷 芳氧基'雜環基或雜環氧基所取代 A方土 基^%貌氧基、芳基、芳氧基、雜環基或雜環氧基; C-13與C_14位置間的鍵結為—雙鍵或單鍵以及 c~15含有立體異構物R's,或其混合物。 本發明亦提供用式⑴化合物所製造的渴藥組成物。 本發明亦提供一方法給需要導瀉作用之病人其方法 包含給予式(I)化合物。 當式(I)之雙環鹵化化合物提供一極佳的導瀉作用的 同時,該化合物不會引起大量因腸道收縮而產生的副作用 例如胃痛。因此’本發明的組成物不僅可用以治療長期性 或間歇性為便秘所苦的病人也可用以治療或預防患有例 如’脫腸或心血管疾病的病人之便秘(當需要時如同作用在 鬆垮的腸道),使他們在解大便時不用太用力,或罹患直腸 性的疾病。此外’如果發生藥物或食物中毒時該組成物可 用以引其正常的腸道蠕動把腸令的有害物質洗掉β因此, 發明之雙環_化化合物可作為腸道先前的預防措施之準備 工作’診斷或外科手術程序之腸清除劑。 [發明之詳細說明] 本發明係提供一含有引瀉的有效含量之雙環化合物式 (Ϊ)的瀉藥組成物。 導瀉的作用係由下列4個機制中的1個或多個組合而 成’從而增加排泄物的水分含量並促進腸内容物的轉移: (i)由於藥物的親水性或滲透壓之故,水分與電解質會 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 χ四7公釐)
3129SO !——Μ丨F (請先閱讀背面之注意事項再填寫本頁) 丨訂-------- f 1305147 A7 B7 五、發明說明(7 ) 被保留於腸内,因此腸内内容物的體積增加其間接造成彼 等較抉速的遷移<= (ii) 該藥物能作羯於腸黏膜使之減少電解質和水分總 量之正常吸收作甩,因此水分含量增加,間接造成賜内内 容物較快速的遷移。 (iii) 該藥物能作用於腸黏膜使之增加電解質和水分總 莖之正常分泌作用s因此水分含量增加,直接及/或間接造 成腸内内容物較铗速的遷移。 (iv) 該藥物首先作用於腸道蠕動以加速遷移,間接造 成水分和電解質之淨吸收作用減少,係由於其吸收時間減 少之故。 本發明使用腸道游積試驗主要係用以研究作用(ϋ)及/ 或(111) ’其係測量腸内内容物之體積以評估該藥物對腸内 水分的作用。本發明之雙環豳化化合物可表現出極佳的腸 道淤積作用。然而該雙環齒化化合物幾乎不或稍微地造成 腸收縮’其係作為(iv)評估指標之一。於是,本發明之雙 環鹵化化合物式(I)係視為主要作用於腸黏膜,直接或間接 地影響電解質與水分自腸壁遷移到血管及/或從血管遷移 到腸中’經由踢壁造成減少水分之吸收作用及/或增加水分 之分泌作羯’增加腸内水分且促進腸内内容物之遷移以減 輕便秘。 在式⑴的定義_,該名詞,,不飽和,,係指包含至少一個 或更夕個雙鍵及/或二鍵,亦即分離的5個別的5或連續的 出現於主要的碳原子鏈及/或支鏈中。一位於兩連續位置中 本紙張尺度適用中國國家標準(CNS)A4規格X 297公髮) ---:- (請先閱讀背面之注意事項再填寫本頁) 訂-— 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 312980 1305147 A7 經濟部智慧財產局員工消費合作社印製 B7 "" I丨丨— 1 1丨丨丨丨1— ""― " 1 丨_丨_ 五、發明說明(8) 之不飽和鍵係以兩位置中編號較低者表示,且一位於兩末 端位置中之不飽和鍵係以兩位置皆可表示。較佳的不飽和 鍵係一位於第2位置的雙鍵以及一位於第5位置的雙鍵或 三鍵。 該名詞”低碳”除另有特別說明,係指包含一含有1到 8的碳原子群。 該名詞,,鹵素”包含氟、氣、溴或碘原子。尤其以氟原 子較佳。 該名詞”牴碳烷氧基”係指一群低碳的烷基-〇-,其中低 碳烷基係一含有Ϊ至6個碳原子以及包含的直鏈或支鏈飽 和烴群5例如,甲基、乙基、丙基、異丙基、丁基、異丁 基、第三丁基、戊基及己基。 該名詞”經(低碳)烧基”係指一如上述定義之低碳貌 基,其至少被一羥基所取代,例如羥甲基,1 -羥乙基,2 -羥乙基以及1-甲基-1-羥乙基。 該名詞”低碳烷醯氧基”係指一群以式RC0-0-表示, 其中RCO-係如上述定義之低碳烷基氧化而來的醯基,例 如乙醯基。 該名詞”低碳環燒基”係指由如上述定義低碳烧基環化 而成但是包含3個或更多個碳原子以及包括之環狀群5例 如’環丙基、環丁基、環戊基'環己基。 該名詞’’低碳環烷氧基,,係指低碳_環烷基群,其中 低碳環燒基如上述定義。 該名同芳基”係包含未經取代或經取代之芳族碳環群 1本紙張尺度適用中關家標準(CNS)A4規格.⑵0x297公爱) § 3Ϊ1980 -- f請先閱讀背面之注专?事項再填寫本頁>
Μ n I n n — 一.aJ_ 1· n I— n n n 1305147 A7 B7 五、發明說明(9 ) (較佳為單環群),例如苯基,萘基,甲苯基以及二甲苯基。 取代基之例子如_素原子及鹵(低碳)烷基,其中_素原子 及低碳烧基如上述所定義。 該名詞’’芳氧基,,係指一群以式Ar-Ο表示,其中Ar係 如前述定義之芳基。 該名詞’’雜環群,,係包含5至14,較佳為5至1〇個原 子組成視情況取代碳原子以及1至4,較佳為1至3個雜_ 原子’由氧原子、氮原子’以及硫原子所構成之群中選出 1至2種雜-原子之單環群,且一扼要的雜環群最多由3個 環狀部分最少1個即上述定義之單環群構成。雜環群之例 子包括咲喃基、噻吩基、u比洛基、嗜峻基、異嗜峻基、噻 唑基、異噻唑基、咪唑基、吡唑基、呋咭基、吡喃基、吡 啶基、吡嗒畊基、嘧啶基、吡畊基、2_吡咯啉基、吡咯烷 基、2-咪唑啉基、咪唑烷基、2_吡唑啉基、吡唑烷基、六 氫吡基、六氫吡哄基、嗎啉基、吲哚基、苯并噻吩基、喹 啉基、異喹啉基、嘌啉基、喹唑啉基、咔唑基、吖啶基、 菲啶基、苯并咪唑基、苯并咪嗤酮基、苯并噻唑基、吩噻 畊基。本發明_取代基之例子包括自素及_素取代基低碳 烧基’其中鹵素原子及低碳烧基如上述所定義。 該名詞’’雜環·氧基,,係指一群以式Hc〇_表示其中取 係如前述之雜環基。 本發明中所使用之雙-環-16-#化化合物為其鹽或其 酯化羧基或醚化基。雙-環-16-齒化化合物鹽類包含藥理可 接受的鹽類,例如,驗金族金屬如鈉、鉀;鹼土族金屬如 (請先閱讀背面之注意事項再填寫本頁}
^reJ 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製
經濟部智慧財產局員工消費合作社印製 1305147 A7 ____B7 五、發明說明(10 , 鈣、鎂;生理上可接受的鋁鹽類,例如,氨、甲胺、二甲 胺、環戌胺、環已胺、苯胺、六氫毗啶、乙二胺、單乙醇 胺、二乙醇胺、三乙醇胺、單甲基單乙醇胺、氨基丁酸胺、 離胺酸、普羅卡因、咖啡因、精胺酸及四烷基鋁鹽等。這 些鹽類可以傳統方法製備,例如,由相對的酸以及鹼或鹽 類互換而成。 此等醋以及醚包括,例如,直鏈或支鏈烷基酯和醚, 其可含有一個或多個不飽和鍵如甲基、乙基、丙基、丁基、 異丙基、異丁基、第三丁基、戊基、2_乙基己基;可含有 腊環基如環丙基5環戊基或環己基;可含有芳基如苯甲基 或苯基(其中芳基可含有一個或多個取代基);可含有一低 礙块基如乙炔以及丙炔,羥烷基炔或烷氧烷基炔如羥乙 基、羥異丙基、聚羥乙基、聚羥異丙基、甲氧乙基、乙氧 乙基或甲氧異丙基龜或鍵;視情況而經取代的芳基如苯 基、甲苯基、第三丁基苯基、水揚酸基、3,4-二-甲氧基苯 基以及苯甲龜胺苯基;烧基石夕烧基如三甲基石夕烧基或三乙 基♦烧基;或一四氫Π比喃龜或鍵。 較佳的酯類以及韃類包括’例如,直鏈或支鏈的低碳 烷基如甲基、乙基、丙基、正丁基、異丙基或第三丁基; 苯甲基;或羥烷基如羥乙基或羥異丙基。 較佳的A係-COOH或其藥理可接受的鹽或酿。 較佳的X!以及)^係皆為鹵素原子,且更佳者為氣原 〇 較佳的Wi係=〇。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 312980 -III — — — — «111 (請先閱讀背面之注意事項再填寫本頁) 1305147 A7 五、發明說明() 較隹的W2係當R3以及R4皆為氮原子 較佳的Z係一氧原子 德和的未經取代或不飽和0 g個 較佳的Y係 碳原子之烴鏈。 較佳的I係一飽和的未經取代或不 個碳原子之烴鏈。 較隹的R2係一氫原子。 _ #異 本發明之組成物可包括上述化合物之異 a密 ,C位 I 構物的例子包括在C-1 5位置含有一酮基以及# ^ .邀柄·異構物 含有鹵素之單-環互變異構物;光學異構物;幾’、 等。 飽和含 有 4 % X〜χ2
互變異構物I 經濟部智慧財產局員工消費合作社印製
HCi ΧΟΟΗ X,X2 互變異構物II 上圖顯示,在C-11位置的氧原子與在C-15位置的酮 基間之互變作用’在該化合物含有一 13,14-單鍵以及於 C-16位置含有二個氟原子之情況下係十分顯著。 已發現當化合物中在换之水分子時,如式(I)以雙_環化
312980 - I I I I I I I — — — —111 — . (請先閲讀背面之江意事項#填寫本頁)
1305147
五、發明說明(η 物开/存在者較佔優勢。於水溶液介質中相信於其令 a成氯鍵俗,在阻礙雙環結構的闺所在位置c七。 另外》相信在鹵素原+ ,^ 系原千所在位置C-16可促進雙-圓環之形 成單% ’雙·環結構比例,例如,在D2〇中呈現丨:6的 比例,在CD3〇D-D2G中呈現! : ! G的比例以及在cdc!3 t呈現4 . 96的比例。因此,本發明中較佳的具體實施例 係為化合物中以雙-環形態呈現之比例為雙_環/單_環為至 )1 . 1且較佳為20 : 1,或甚至更大的比例到所有皆為雙 _罐化合物;本發明的範疇也包含100%雙-環化合物。 上述式(ί)的雙·環-16-齒素化合物可經由一般如下述 的程序製備: ZdHU1^6S,7R)-3-庚基-3-轉基-螫-辕『4.3 〇1 壬-8-酮-7-基] 康_:_1二稀醇異丙酯以及7-[(lS,3R.6S-7R)-3-庚基-3-羥篡-雙-環.[土· ? .〇1壬_8_酮“7-某1庚-5-烯醇異丙醋之製備 1-(2)-7-[(1^_,2&,3&,58)-2-(3,3-乙'歸二氧癸基)-5-幾基-3-(對-甲苯磺醯基)環戊基]庚_5-烯醇異丙酯(2)之製備 靖 先 閱 背 面 之 項 再 填 % 本 頁
I I I i I 訂 I I 經濟部智慧財產局員工消費合作社印製
TsCl,py. 64.1% -♦·
將吡啶(0.77克)及溶於二氯甲烷之(Z)-7-[(111,2反,3]^53)-3 55-二羥基-2-(3,3-乙烯二氧癸基)環戊基] 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 312嫩 1305147 A7 B7 五、發明說明(U) 庚-5-稀醇異丙酯(1)(4.05克)混合’於0。(:加入含有甲苯橫 醯氯(1.86克)之二氣甲烷溶劑,且在相同溫度下攪拌2天。 於反應中,個別將甲苯磺醯氣(5.58克)與吡啶(2.31克)分 成三部份加入。當一般檢查反應完成之後所得的未如工產 物經由矽膠管柱經層析得到(Z)-7-[(iR,2R,3Rs5S)-2-(;353_ 乙稀二氧癸基)-5-羥基-3-(對-甲苯續醮基)環戊基]庚_5-晞 醇異丙酯(2)。產量3.45克,64.1%。 2. (Z)-7-[(lR,2S)-2-(3,3-乙烯二氧癸基)-5-氧環戊-3-烯基] 庚_5-烯醇異丙酯(3)之製備
TsO
1. 瓊氏氧化反應, 2. 矽膠管柱~: 64.6% (請先閱讀背面之注意事項再填寫本頁)
裝
在-4〇r 至-2CTC 中將(Z)-7-[(iR,2R,3R,5S)-2-(3,3-c 烯二氧癸基)-5-羥基-3-(對-甲苯磺醯基)環戊基】庚-5_稀醇 異丙酯(2)與瓊氏(Jones)試劑於丙酮中氧化4小時。當反應 完成後,將未加工產物通過由正己烷/乙酸乙酯(3.5Π)所填 充之矽膠管柱。在將產物經由矽膠層析(正己烷/乙釀乙酿 =4/1)經層析得到(Z)-7-[(lR,2S)-2-(3,3-乙烯二氧癸基 氧-環戊-3-婦基]庚-5-稀醇異丙醋。產量0.81克,64.6%。 3. 7-[(lR,2S,3R)-2-(3,3·乙烯二氧癸基)_3_羥甲基-5-氣環 戊]庚-5-缔醇異丙酯(4)之製備
V 經 濟 部 智 慧 財 產 局 消 費 合 作 社 印 製 本紙張尺度適用中關家標準(QNS)A4規格(21G X 297 13 m 1305147 A7 _B7 五、發明說明(Μ )
(請先閱讀背面之注意事項再填寫本頁) 將(2)-7-[(1尺,28)-2-(3,3-乙烯二氧癸基)-5-氧-環戊-3-烯基】庚-5-烯醇異丙酯(3)(0.81克)以及二笨基酮溶解於甲 醇中。在充滿氬氣的環境下將該溶液以300-瓦高壓水銀燈 照射4小時40分。之後將該溶液蒸餾’所得的未加工產物 經由矽膠管枉(正己烷/乙酸乙酯=3/2)經層析得到7-[(lR,2S,3R)-2-(3,3 -乙烯二氧癸基)-3-羥甲基-5-氧環戊]庚-5-烯醇異丙酯(4)。產量0.41克,47%。 4. 7-[(lR,2S,3R)-2-(3,3-乙烯二氧癸基)-5-氧基-3-(對·甲苯 磺羥甲基)環戊]庚-5-烯醇異丙酯(5)之製備
經濟部智慧財產局員工消費合作社印制衣 取(lR,2S,3R)-2-(3,3-乙烯二氧癸基)-3-輕甲基-5-氧環 戊基]庚-5-烯醇異丙酯(4)(0·21克)以及吡啶(〇.〇7克)溶於 二氯甲烷。於〇°C加入甲苯磺醯氯(〇.17克且攪拌72小 本紙張尺度適用中國國家標準(CNS〕A4規格(210x297公釐) 14 312980 1305147 A7 B7 五、發明說明(15 ) !——:_#裝 (請先閲讀背面之注意事項再填寫本頁) 時。當反應完成之後所得的未加工產物經由矽膠管柱經層 析得到7-[(111,2 8,311)-2-(3,3-乙烯二氧癸基)_5_氧基_3_(對-甲苯磺羥甲基)環戊基]庚烯醇異丙酯(5)。產量0.25克, 89%。 5. 7-[(lR,2R,3R)-2-(3,3 -乙烯二氧癸基)_3-碘甲基-5-氧環 戊基]庚-5-烯醇異丙酯(6)之製備
經濟部智慧財產局員工消費合作社印製 將7-[(111,23,311)-2-(3,3-乙烯二氧癸基)-5-氧基-3-(對-甲苯磺羥甲基)環戊基]庚-5-烯醇異丙酯(5)(0.25克)溶於丙 酿I中,且加入破化納(0.12克)。將該混合物回流3小時。 加入碘化鈉(0.097克)後再回流80分鐘。當反應完成之後 所得的未加工產物經由矽膠管柱(正己烷/乙酸乙酯=5/i ) 經層析得到7-[(1匕2尺,3汉)-2-(3,3-乙烯二氧癸基)_3_碘甲 基-5-氧環戊]庚_5·烯醇異丙酯(6)。產量〇. 16克5 68%。 6.7-[(111,2尺,311)-3-碘甲基-5-氧-2-(3-氧癸基)環戊基]庚-5- 烯醇異丙酯(7)之製備 本紙張聽· +a¥ii?7^rs_)A4規格⑵ο χ ϋΐτ 15 312980 305147 A7 B7 五、發明說明(
將7-【(1尺,211,3幻-2-(3,3-乙烯二氧癸基)-3-碘甲基-5-氧環戍]庚-5-烯醇異丙酯(6) (0.16克)溶於乙酸/水/四氫呋 喃(3/1/1)混合液中。該混合构於室温下攪拌20小時再於 50°C下攪拌2.5小時。將該溶液蒸餾之後5所得的殘餘物 經由矽膠管柱(正己烷/乙酸乙酯=)經層析得到7_ [(lR,2R,3R)-3-碘甲基_5-氧-2-(3-癸氧基)環戊基]庚-5-烯 醇異丙酯(7)。產量0.13克,86%。 7. 7-[(lS,3S,6S,7R)-3-庚基-3-羥基-雙環[4.3.0]壬-8-酮7-基]庚-5-烯醇異丙酯(8a)以及7-[(lS53R,6S,7R)-3-庚基-3-羥基-雙環[4.3.0】壬-8-嗣-7-基]庚-5-烯醇異丙酯(8b)之製 備 (請先閱讀背面之注意事項再填寫本頁) # 裝 訂--------
經濟部智慧財產局員工消費合作社印製 〆 °(7)
(8b)較不具極性 HO* 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 16 312980 1305147 A7 _ B7__ 五、發明說明(l7 ) 取7-[(lR,2R,3R)-3-碘甲基-2-(3-氧癸基)-5-氧環戊]庚 -5-烤醇異丙酯(7)(0,0574克)以及二氯鉛壬烯溶於四氫呋 喃中。將該混合物在氬氣流動下以聲波震盪清除其中的空 氣。以滴入法加入含有碘化釤之四氫咲喃(0 · 1M, 2.1毫 升於室溫下攪拌30分鐘,之後加入鹽酸(0.1 Μ, 1毫升)。 當反應完成之後所得的未加工產物經由矽膠管柱(正己烷/ 乙酸乙醋=5/1)經層析。發現兩種雙環產檢,較具極性(8 a) 及其差向異購物,較不具極性(8b)以及起始物(7)如下: 7-[(18,3 8,68,711)-3-庚基-3-羥基-雙環[4.3.0】壬-8-嗣-7-基]庚-5-烯醇異丙酯(8a)以及7-[(lS,3R,6S,7R)-3-庚基-3-羥基-雙環[4>3.0]壬-8-_-7-基]庚-5-烯醇異丙酯(8bV8(a) 產量5.1毫克,8(b)產量7.2毫克,回收之起始物(7) 26.7 毫克。 一化合物表示如式(I)其t Z為硫原子以及Wi為-Ο Η 基之理論性合成如下: (請先閱讀背面之注意事項再填寫本頁)
裝 訂---- 經濟部智慧財產局員工消費合作社印制衣
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 17 312980 1305147 A7 B7 五、發明說明(β ) ,於 McOHf
(β) π Ttuo-POf
^===^^-^0000¾
:四丁基銨氟化物 1,8-二氮雙環[5.4.0]十一-7-烯 二異丁基鋁氫化軔 4-二甲基胺毗啶 硼氫化鈉 一化合物表示如式(I)其中Z為硫原子以及w 1為酮基 之理論性合成如下: n-BU4N-F DBU : DIBAL-H DMAP : NaBH4 :
氧化反巍 AcOlvH^O 氣體 (請先閱讀背面之注意事項再填寫本頁)
裝 訂— 經濟部智慧財產局員工消費合作社印製 一化合构表示如式⑴其中z為疏原子’ w〗為酮基以 及父1與x2為氟原子之理論性合成如下: 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 18 312980 1305147 A7 B7
五、發明說明(19 ) HQ ^^C〇OCH3狐 氡化反應1 Ac0h-H20 -\==^v^c〇〇CH3 H2S 氣-Ο -^>^cooch3
化合勒表示如式(I)其中ζ為氮原子之理論性合成如 (請先閱讀背面之注意事項再填寫本頁)
裝 -n n In n- n n 下:
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) 19 312980 1305147 A7 B7 五、發明說明(2〇 )
,於 MeOH 申
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PhiPjCH^COOWr i5 K08u< 0
Cf^COCSH ---------訂·------- #_ 經濟部智慧財產局員工消費合作社印製
NH 0 1221
另一化合物表示如式(I)其中Z為氮原子之理論性合成 如下: 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 20 312980 1305147 A7 B7 五、發明說明(21
COOCH, fxm. Ncooet
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經濟部智慧財產局員工消費合作社印製
本發明中之製備方法並不能推斷為只限制於所提到 的’因此適當的方法用以保護、氧化及還原等皆可使雨 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 312980 (請先閱讀背面之注意事項再填寫本頁)
1305147
五、發明說明(a :發”所使爾的雙_環,_齒素化合物,當〜 子兩丨固鹵素原子取代尤i β 明顯的辨強… 腸游積作用之活性 他取圓環的結構以及取代基或是雙鍵或其 取代基的存在無關。尤其較佳的雙 的雙衣·16·鹵素化合物係 , "置含有一_基的單-環化合物以及在五圓严 中位置含有—择其你衣 組群传一包人一 5二基所形成之互變異構物。另-較佳的 、5,6·單鍵雙鍵或含有20至22個碳 其I包含4到6 .时原子較隹為线之雙 化合物。 圏素 一包含一個5,6-魏之單-環/雙環-161素化合物之 實例如下: <
HCT^^Ct 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 杜 印 制 本發明另一具體實施例包括本發明之组成物以及—中 等長度之脂肪酸甘油三酸_ a該甘油三酸_可為含有6至 14個碳原子也可含有支鏈的飽和或不飽和脂肪酸。較隹的 脂肪酸係一直鏈之飽和磨肪酸,例如,己酸、辛酸、癸酸、 月桂酸以及肖SUM以上中等長度之腊肪酸甘油三 酸酯可作為一混合物。 本發明之组成物可由中等長度之脂肪酸甘油三酸酯分 解或摻合式(I)之雙-環化合物製備而成。中等長度之脂肪酸 甘油二酸龜的用量沒名限制。然而,通常是以雙_環結構的 | 裝 ii — !—訂 ----! ί (請先閱讀背面之注音?事項再填寫本頁) _
本紙張尺度適用中國國家標準(CNS)A4規格(2】〇χ297公爱丁 22 1305147
獨(未溶解於溶劑中)置於如上述之容器内’且貯存於 以作為對照實驗。 在缺乏溶劑的情況下,藉由如下之HPlC法測定化入 物1以及化合物2之成分。 貯存的化合物1及2以及標準的化合物1及2各別精 確地秤取約0.025g ’以及精確量取内標準溶液之等份試量 5mL加入個別所秤好之化合物中。藉由加入乙腈(液相層析 等級)使精確的總量各為lOmL以得到試驗以及標準製劑。 由試驗以及標準製劑t各取ΙΟμί載入液相層析儀並以單 點校正曲線之内標準法測定化合物之成分。 含量_ X Ws X —
Us Wt ws :標準製劑(mg)中化合物之含量 WT:試驗製劑令化合物1以及化合物2之含量。
Qs:在標準製劑比内標準的化合物之峰面積比之比 例0
Qt :在試驗製劑比内標準的化合物之峰面積比之比 例。 測量條件: 偵測器:紫外線吸收分光光度計(波長294nm)
管柱:具有内直徑約5mm以及長度約25cm之不銹銅 管,以5μιη液相層析之十八砍烧石夕膠填充 管柱溫度:恆定於約35°C 移動相:乙腈(液相層析等級)/醋酸鈉水溶液(0.01莫耳 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公t ) 312980(修正本) ί靖先閱讀背面之注意事項再填寫本頁) --------tT·丨 經濟部智慧財產局員工消費合作社印製 24 1305147 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明(25 ) /L)/冰醋酸(800 : 200 : 1)之混合溶液 (2)在溶劑存在的情況下,藉由 合物之成分。 了之HPU:法測定化 基於上述第24頁第12行至本頁第"于等說明所干之 數值,溶液的量相當於所精確地秤得的36帅之化合物! 以及化合物2。精確地量取之内標準溶液加口入缺 後加入乙酸乙醋(液相層析等級)使總量各為i〇mL。由各ς 液中取O.lmL經過真空濃縮乾燥以得到試驗製劑。4 精確地秤得的18mg之各個標準化合物且與乙酸乙酯 (液相層析等級)混合,使總量準確地各為5〇mi^由溶液以 及内標準溶液中分別精確地測量取得i 〇mL以及ι〇Μ1並 與乙酸乙酯(液相層析等級)混合,使總量各為i〇〇mL。從 各溶液中各取〇. imL經過真空濃縮乾燥以得到標準製劑。 於試驗以及標準製劑中個別加入01mL的螢光標記試 劑以及0.85mL的螢光標記催化劑,然後於室溫下攪拌該 混合物30分鐘以上。分別將〇〇5mL含有2%的乙腈水溶 液(液相層析等級)加入該反應混合物中,擾拌,然後使其 靜置30分鐘以上以作為試驗以及標準溶液。 由試驗以及標準製劑中各取10μί載入液相層析儀並 以單點校正曲線之内標準法測定化合物之成分。 含量<%)
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Q X. s ---:----------------訂- (請先閱讀背面之注意事項再填寫本頁)
X
X 100 18 ws :標準製劑(mg)中化合物之含量 Qs:在標準製劑比内標準的化合物之峰面積比之比 卜紙張尺度適用t關家標準(CNS)A4規格(210 X 297公釐) 25 312980(修正本) 1305147 A7 ____B7___ 1 ........................... ........." ·___| ... —五、發明說明(% ) 例。 QT :在試驗製劑比内標準的化合物之峰面積比之比 例。 測量條件: 債測器:螢光分光光度計(激發波長259nm ;螢光波長 394nm) 管柱:具有内直徑約5mm以及長度約25cm之不錄鋼 管’以5μπι液相層析之十八矽烷矽膠填充 管柱溫度:恆定於約35°C 移動相:乙腈(液相層析等級)/甲醇(液相層析等級)/醋 酸銨水溶液(0.05莫耳/L) (4 : 11 : 5)之混合溶液 起始 6天 7天 14天 28天 38天 90天1 化合物1 結晶 100 97.2 94.1 87.4 MCT1 100. 101.4 102 1 100 9 ------ 化合物2 結晶 100 84.5 75.0 53.4 MCT2 100 99.6 98.9 ~99j~ ——-! 化合物1/溶劑:〇.36mg/g 化合物2/溶劑:〇.i2mg/g f靖先閱讀背面之注意事項再填寫本頁) 訂---- 經濟部智慧財產局員工消費合作社印制衣 該非-水溶液溶劑以及懸浮液包括,例如,丙二醇、聚 乙二醇、脂肪酸甘油三酸酯,植物油如撖欖油,酒精如乙 醇及聚山梨酸酯等。此組成物可含有佐劑如防腐劑、潤濕 劑、乳化劑、分散劑及抗-氧化劑等。 本發明將以下列實施例說明。本發明係僅以實施例之 方式說明但非限定本發明之範圍。 環/雙-環結構與生物活性之關聯 適用中國國家標準(CNS) A4規格⑵〇 x 297公楚广---- 26 312980(修正本) 13 05147
五、發明說明(27 ) ---- 以本發明之组成物中於C l6 /J. m «Ε ,. Λ 位置具有鹵原子的經鹵 化-雙-環化合物為例,製備 測試下列實施例。 貫施例1 — ΙΓ------- (請先閱讀背面之注音?事項再填寫本頁) 當一般式I之Z係氣肩早 虱原子U及於C-9位置存在一酮邊 之時由於單-環/雙-環結構之吐 馎之比例’使本發明组成物所具肩 的生物活性可由下列實施例理解。於c]6位置上之氣原巧 數以及單-環/雙-環結構之比例顯示於表丨中。
實施腸道游積試驗以及腹瀉試驗。其結果列於表 提高腸内容物含量達50%之給藥劑量稱為ed50。 表1 實施例A 實施例B 比較實施例A 於C-16位置上之 F原子數 2 1 0 單-環/雙-環結構 之比例* 4 : 96 1:1 未偵測到由雙-環 結構得到之訊息 森淤積活性,EDw 0.6|Lig/kg 2pg/kg 320pg/kg 於老鼠測得之腹 瀉作用 + :於 Smg/kgiPO1) + :於 0.3mg/kg(SC2) 土:於 0.3mg/kg(SC) 於 10mg/kg(P〇) -:於 lmg/kg(SC) *於CDC13溶劑中以NMR測量法測定 1 P 0係經口(口服給藥) 經濟部智慧財產局員工消費合作社印製 2 SC係經皮下給藥 實施例2 本纸張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 27 312980(修正本) 1305147 A7 B7 五、發明說明(28 ) 當一般式I之Z係氧原子於C-9位置存在一酮基,以 及於5,6-碳間有一雙鍵時由於單-環/雙-環結構之比例, 使本發明組成具有生物活性如下所示。
實施腸道淤積試驗以及腹瀉試驗。其結果列於表2。 提高腸内容物含量達50%之給藥劑量稱為ED50。 表2 (請先閱讀背面之注音?事項再填寫本頁) 實施例C 實施例D 比較實施例C 於C-16位置上之F 原子數 2 1 0 單-環/雙-環結構之 比例* 4 : 96 1:1 未偵測到由雙 -環結構得到 之訊息 腸淤積活性,ed50 0.3pg/kg 3pg/kg 220pg/kg 於老鼠測得之腹瀉 作用 + :於 lmg/kgCPO)1 -:於 lmg/kg(PO) + :於 5mg/kg(PO) -:於 10mg/kg(PO) 訂--- 經濟部智慧財產局員工消費合作社印製 28 *於CDC13溶劑中以NMR測量法測定。 1 PO係經口(口服給藥) 在單一口服給藥之後溶解於中等長度脂肪酸甘油三酸酯之 本發明對健康的男性自願受試者的腸蠕動作用之影響 3到9位健康的男性自願受試者服下含有下列單-環/雙-環 結構(於CDC13中)之比例為4 : 96之組成物。 本紙張尺度適用中國國家標準(CNS)A4規格(210x 297公釐) 312980(修正本) 1305147 A7 B7 五、發明說明(29
該測試物質(心以及I為F原子)係溶解於潘納賽特 (Panacet) 800 (中等長度脂肪酸甘油三酸醋由曰本油類& 脂肪股份有限公司製造,Amagasaki,曰本)且填充於膠囊 中(各膠囊含有200 L之混合物)。各受試者配以l〇〇mL 的水服下一個膠囊。 表3顯示出現解大便或腹瀉症狀之受試者數目 表3 劑量 受試者數目~~ ~~ 正常 解 ~" 5μΕ 1/3 1〇μ8 5/7 2/7 20μg 1/3 2/3 ~~~~~ 3〇μ8 2/9 7/9 ;——l·------- <請先閲讀背面之注意事項再填寫本.頁) 經濟部智慧財產局員工消費合作社印製 个I明t殂成物造成非常有效之腸道淤積作用,抑制 腸内水分之吸收。再者,本化合物不具有像PGEs或是PGFs 具有的腸收縮作用,若有也是大大地減輕。因此,以本發 明之組成治療便秘不會產生因腸收縮而造成的腹部不舒 服,如腹痛。另外,本化合物使便秘消失達到腸道狀態正 常。此外,如果是藉由具有良好的促進腸内輸送作用之本 化合物所造成的腹瀉症狀則需要一點時間恢復正常。因 此,本化合物可以說是非常有效的瀉藥。 本發明的組成物可作為動物與人類之治療以及預防便 秘的藥物’通常’以口服給藥、或栓劑、灌腸劑等作為全 本紙張尺^適用中國國家標準(CNS)A4規格(2〗0x297公——---- 29 312980(修正本)
n n ϋ I J'J· ϋ .1 n n n n I I 幻 1305147 A7
經濟部智慧財產局員工消費合作社印製 五、發明說明(% 身性的或局部性之施用。 華物的為丨旦 ’ %候,也施以靜脈或皮下注射。 樂物的劑量依照動物、 m ^ 年齡、體重、症狀、療效、 用樂方法、治療時間等 ,ΠΠΛ /t 令所不同。劑量係0.001至 looopg/kg為佳,且較加 為 0 01 至 i〇〇Pg/kg。 本么明的組成物也可用 斷忐主 作為腸的先前預防製劑,診 斷或手街程序如内視鏡檢杳、& 射線雙重-攝影與靜脈内之腎二鏡檢查、類灌腸法之-如去除藥物或食物毒素之目術,以及作為急救程序 本發明在CT服給藥 方面之固體組成物包括錠劑、配, 劑及粒狀等。此固體組成 枯⑹配1 ,丨、 或夕種具有活性之原料盥至 〆一種無活性之稀試劑 ,、至 s ^ , 例如,乳糖、甘露醇醇、_ 萄糖、經丙基纖維素、微晶纖維素、㈣、聚乙稀: 烷酮及異矽鋁酸鎂鹽類等。 比咯 冬古私卜 厶由—般的檢驗,該組成物可 含有除…、活性稀釋劑之外的添加物, 指.山加+丨 1〗如濁滑劑如硬脂酴 鎂,朋解劑如纖維狀之葡糖酸酸 敗巧,文定劑如環糊精,例如, α、^或r-環糊精;醚化之環糊精如二甲基巧_、二甲 ϋ甲基或羥丙基I環糊精;分支的環糊: 糖:及麥芽糖基-環糊精;甲酿化的環糊精、含硫之』糊: 及磷脂等。當使用上述環糊精時,環糊 月 時可形成加強安定力之作用。有時可擇二選擇二b::有 成微脂粒,導致加強安定力之作用。 Θ脂形 如需要的話可在錠劑或藥丸之外層塗覆一層、 腸尹可溶解之薄膜如糖、明膠、羥丙義 3於胃或小 , 办纖维常及炉1¾甘 ,酸鹽纖維素。再者,可以易吸^^ “ 土甲 ‘紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱)"----一乃膠製 '---^------— (請先閱讀背面之注意事項再填寫本頁) --訂·---
I n I 312980(修正太、 30 1305147
五、發明說明(31 囊。
在口服給藥方面之液體組成物可包括藥理上可接受之 乳狀液、溶液、懸浮液、糖漿、_如—般所使用之無活 性稀釋劑。此组成物可含有除了無活性稀釋劑外之佐劑如 懸浮劑、甜味劑、矯味劑、防腐劑、溶解劑及抗_氧化劑等。 添加物之細節可由選自任何一本一般製藥上的教科書之說 明而得知。此等液體组成物可直接封入軟膠囊中然而, 除了上述提及的稀釋劑外,由於雙·環/單_環化合物要溶解 於或混合於稀釋劑中,所以選擇稀釋劑時需仔細地選擇那 些不會影響雙-環/單-環化合物之比例的稀釋劑Q 根據本發明在非口服給藥方面之溶劑,(例如栓劑及 灌腸劑等)包括無菌的水溶液或非_水溶液溶劑、懸浮液及 乳液等。該水溶液溶劑以及懸浮液包括,例如,蒸餾水、 生理鹽水以及林嘉氏溶液β … 然而本發明已詳細敘述且以其具體實施例為參考,對 於熟知本技藝之人士來說可顯見各種改變及條飾仍不背離 本發明精神及其範圍。 (請先閲讀背面之注意事項再填寫本頁)
1· 1 ^1 ϋ I J:'J· n n n fei n n I 上5 經濟部智慧財產局員工消費合作社印製 312980(修正本) 31
Claims (1)
1305147 D8 匕請專利範圍 (96年10月 年丨。 種填藥組成物,包括引瀉的^ 其如式(I)所示: "3里
(I) 其中Vi及v2為碳 如下且w2如下
Ra R4
0 -裝·-- (請先閱讀背面之注意事項再填寫本頁) 訂- 經濟部智慧財產局員工消費合作社印製 R3及R4為氳或其中之—為OH; 1及X2為氫、C!_6烷基或鹵素,以及其中至少有 一為_素; Z為碳、氧、硫或氮; R2為氫或烷基; y為飽和或未飽和之c21〇煙 代或經由氧基取代者; A為-COOH或直睡麵、 、-頰 8日類、醚類及醯類; Ri為形成為直鍵或±赫r 吨兄文鏈Cm烴鏈,該烴鏈係未矣 取代或經由C3_6環烷基或芳其斛 乂方基所取代者;R!亦可為C 環烷基或芳基; C -1 3與C -1 4位置間的絲女士迄 I Π的鍵結為一雙鍵或單鍵;及 本紙張尺度適用+ ϋ 0家標準(CNS)A4規格(210 X 297公互) 該烴鏈係未經苹 32 312980(修正本)
1305147 經濟部智慧財產局員工消費合作社印製 --- ^ 10 月 16 :、申請專利範圍 C-15含有立體異構物R、S,或其混合物; ^瀉藥組成物復包括-化合物,該化合物係為 之早%互變異構物’其中雙環對單環結構的比例為至少 1 · 1 ° 2·如中1專利^[第丨項之組成物’其中該雙環對單環結 構的比例為至少2〇 : 1。 3. 如申請專利範圍第!項之組成物,其中八為__、 W!為鲷、Z為氧原子、尺2為氫原子,以及\與&為II 原子。 .'、、 4. 如申請專利範圍第丨項之組成物,其中z為硫原子或氮 原子。 5. 如申請專利範圍第1項之組成物’其中A為COOH ; Y 為(CH2)6 ; Wl為=〇 ; R3與r4為氫原子;%與%為碳 原子;Z為氧原子;Xl與&為氟原子;以及R〗為 (CH2)3CH3 0 6. 如申請專利範圍第1項之組成物,復包括可具有支鏈之 含6.至14個碳原子的飽和或不飽和脂肪酸之甘油三酸 西旨。 7. 如申請專利範圍第6項之組成物,其中該甘油三酸酯基 於一重量份式(I)的雙環化合物以約1至1〇〇〇 〇〇〇重量 份的量存在。 8. 如申請專利範圍第7項之組成物,其中該甘油三酸酯基 於一重量份式(I)的雙環化合物以約為5至500,000重量 份的量存在。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 33 312980(修正本) (靖先閱讀背面之注意事項再填寫本頁) Μ '^
1305147 第90121835號專利申請案 (96年10月16日) 六、申請專利範圍 9.如申請專利範圍第8項之組成物,其中該甘油三酸酯基 於—重量份式(I)的雙環化合物以約為10至200,000重 量份的量存在。 1 〇 ’如申請專利範圍第6項之組成物,其中該甘油三酸酯係 為辛酸甘油三酸酯以及/或癸酸甘油三酸酯。 11.如申請專利範圍第丨至丨〇項中任一項之組成物,其係 減輕或防止人類便秘患者之便秘症狀。 12·如申請專利範圍第1至10項中任一項之組成物,其係 用以清除腸道。 13.如申請專利範圍第1項之組成物,其中,該雙環化合物 為 (請先閱讀背面之注意事項再填寫本頁> 裝 訂
OH F F ' W 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) 34 i 12980(^
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