TWI535436B - 腫瘤治療用醫藥組合製劑 - Google Patents
腫瘤治療用醫藥組合製劑 Download PDFInfo
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- TWI535436B TWI535436B TW099131408A TW99131408A TWI535436B TW I535436 B TWI535436 B TW I535436B TW 099131408 A TW099131408 A TW 099131408A TW 99131408 A TW99131408 A TW 99131408A TW I535436 B TWI535436 B TW I535436B
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- group
- hydroxy
- alkyl
- hydrogen
- substituted
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Description
本發明係關於抗腫瘤劑與脂肪酸衍生物之醫藥組合製劑，係用於哺乳類個體的腫瘤治療。本發明亦關於哺乳類個體的腫瘤治療方法。本發明復關於治療損傷，尤其是包括抗腫瘤劑所引發的黏膜炎(如口炎)之胃腸損傷的組成物及方法。
贅瘤疾病是全世界公認之嚴重且通常具生命威脅性的病症。這些贅瘤疾病已經並且持續的成為全世界研究的標的，研究係致力於找出對治療此等病症之患者有效的醫療劑。
有多種抗腫瘤劑被用於治療贅瘤疾病。例如，5－氟尿嘧啶(後文中稱為「5-FU」)，其具有嘧啶類似物之結構的抗代謝物，係用以作為治療贅瘤疾病的藥物。其主要應用於胃腸癌如胃癌、結腸癌、直腸癌及胰臟癌。其他的應用為例如肝癌、乳癌、子宮癌及卵巢癌。化療劑5-FU係主要作為胸苷酸合成酶抑制劑。胸苷酸合成酶抑制劑包括5-FU、截瘤達(capecitabine)、替吉奧(tegafur)、卡莫氟(carmofur)、氮尿苷(floxuridine)等。已知在活體內活化替吉奧後能釋放5-FU。5-FU已經被發現會產生嚴重的問題，在活體內持續存在有5-FU會造成消化器官如口腔及腸的損傷。接受5-FU的單獨連續靜脈輸注的患者，通常會歷經該等損傷。
順鉑(cisplatin、cisplatinum或cis-diamminedichloroplatinum(II)(CDDP))是含鉑的化療藥物，係用於治療多種癌症，包括睪丸瘤、膀胱癌、前列腺癌、卵巢癌、非小細胞肺炎、食道惡性腫瘤、子宮頸癌、胃癌、骨肉瘤、淋巴瘤及生殖細胞瘤。其為抗癌類藥物類別的第一個成員，現亦包含卡鉑定(carboplatin)、奈達鉑(nedaplatin)及草酸鉑(oxaliplatin)。這些鉑複合物作用於活體內，係結合至DNA並造成其交聯，如此便最終引起細胞凋亡(計畫性的細胞死亡)。
一般來說，該等抗腫瘤劑的劇烈副作用會對劑量累增(dose escalation)造成限制，並使得無法達到較高的醫療效果。
為了改善醫療效果，已發表了一些含有多種具有不同機轉與不同副作用之藥物的組合製劑。然而，仍強烈地需要更有力的藥物及醫療方法，以使癌症病患的存活時間能更加延長並改善癌症病患之QOL。
前列腺素(prostaglandin，後文中稱為PG)係脂肪酸衍生物，為有機羧酸類別的成員，其內含於人類或其他哺乳類的組織或器官中，且顯現出廣範圍的生理活性。自然界中發現的PG(初級PG)一般具有如式(A)所示的前列腺酸(prostanoic acid)骨架：
另一方面，某些合成的初級PG類似物具有經修飾的骨架。初級PG基於五員環部分的結構而區分成PGA、PGB、PGC、PGD、PGE、PGF、PGG、PGH、PGI及PGJ，且依據碳鏈部分之不飽和鍵的數目及位置而進一步區分成下列三種類型：
下標1：13,14-不飽和-15-OH
下標2：5,6-及13,14-二不飽和-15-OH
下標3：5,6-、13,14-及17,18-三不飽和-15-OH。
再者，PGF根據在9-位置的羥基之組態而區分成α型(其中，該羥基為α-組態)以及β型(其中，該羥基為β-組態)。
已知PG具有多種藥理及生理活性，例如，血管擴張、發炎的引發、血小板凝集、刺激子宮肌肉、刺激腸肌肉、抗潰瘍效果等。
已知某些15-酮基(在15-位置具有側氧基以代替羥基)-PG及13,14-二氫(在13及14-位置之間具有單鍵)-15-酮基-PG係脂肪酸衍生物，為初級PG代謝期間由酵素的作用而自然產生之物質。
Ueno等人之美國專利申請公開案第2006/0281818號描述了特定前列腺素化合物在TJ之構形改變上具有顯著的效果，其導致胃腸黏膜屏障功能的恢復。
本發明之目的係提供方法及藥劑以藉由降低抗腫瘤劑引發之毒性副作用而達到較高的抗腫瘤醫療效果。
本發明之另一目的係提供方法及藥劑以治療抗腫瘤劑引發之疾病或病症。
本發明之又一目的係提供方法及藥劑以治療黏膜炎。
本發明係關於醫藥組合製劑，其包括：
(a)醫藥有效量的抗腫瘤劑，其係選自由烷化劑、抗代謝物、抗生素、植物鹼、分子標靶藥物、荷爾蒙、鉑複合物、反義股(antisense)、抗體及RNAi所組成的群組，以及(b)醫藥有效量的式(I)所示之脂肪酸衍生物：
式中，L、M及N為氫、羥基、鹵素、低碳數烷基、羥基(低碳數)烷基、低碳數烷醯氧基或側氧基，其中，L及M之至少一者係不為氫之基團，並且該五員環可具有至少一個雙鍵；A為-CH3、或-CH2OH、-COCH2OH、-COOH或其官能性衍生物；B為單鍵、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-；Z為或單鍵其中，R4及R5為氫、羥基、鹵素、低碳數烷基、低碳數烷氧基或羥基(低碳數)烷基，其中R4及R5不同時為羥基及低碳數烷氧基；R1為飽和或不飽和二價低碳數或中等碳數脂肪族烴殘基，其係未經取代或經鹵素、烷基、羥基、側氧基、芳基或雜環基取代，且該脂肪族烴中之至少一個碳原子係視需要地經氧、氮或硫取代；以及Ra為飽和或不飽和低碳數或中等碳數脂肪族烴殘基，其係未經取代或經鹵素、側氧基、羥基、低碳數烷基、低碳數烷氧基、低碳數烷醯氧基、環(低碳數)烷基、環(低碳數)烷氧基、芳基、芳基氧基、雜環基或雜環-氧基(heterocyclic-oxy group)取代；低碳數烷氧基；低碳數烷醯氧基；環(低碳數)烷基；環(低碳數)烷氧基；芳基；芳基氧基；雜環基；雜環-氧基。
藉由組合抗腫瘤劑及式(I)之脂肪酸衍生物，擴大了抗腫瘤劑的效果及/或使抗腫瘤劑的不利副作用受到相當的壓制。
本發明的另一個態樣提供了醫藥組成物，其包括：
(a)醫藥有效量的抗腫瘤劑，其係選自由烷化劑、抗代謝物、抗生素、植物鹼、分子標靶藥物、荷爾蒙、鉑複合物、反義股、抗體及RNAi所組成的群組，以及
(b)醫藥有效量的式(I)所示之脂肪酸衍生物，結合醫藥上適當之賦形劑。
根據本發明，包含兩種組份的組成物，可調配成含有組分(a)及(b)兩者之單一劑量單位，或調配成單獨含有組份(a)及單獨含有組分(b)的各別計量單位。
再者，本發明提供治療腫瘤的方法，其包括對有需要的個體投予下列組合製劑：
(a)醫藥有效量的抗腫瘤劑，其係選自由烷化劑、抗代謝物、抗生素、植物鹼、分子標靶藥物、荷爾蒙、鉑複合物、反義股、抗體及RNAi所組成的群組，以及
(b)醫藥有效量的式(I)所示之脂肪酸衍生物。
根據本發明，組分(a)及(b)可同時、分開或接續地投予。
此外，本發明提供治療哺乳類個體之毒性副作用例如胃腸損傷(包括抗腫瘤劑引發之黏膜炎)的組成物，其包括醫藥有效量的式(I)所示之脂肪酸衍生物，其中，接受治療的個體係正接受選自由烷化劑、抗代謝物、抗生素、植物鹼、分子標靶藥物、荷爾蒙、鉑複合物、反義股、抗體及RNAi所組成的群組之抗腫瘤劑。
另外，本發明亦提供治療哺乳類個體之黏膜炎例如口炎的組成物，其包括醫藥有效量的式(I)所示之脂肪酸衍生物。
本發明所指之抗腫瘤劑係選自由烷化劑、抗代謝物、抗生素、植物鹼、分子標靶藥物、荷爾蒙、鉑複合物、反義股、抗體及RNAi所組成的群組。
抗腫瘤劑的實例為烷化劑，例如環磷醯胺及白消安(buslfan)；抗代謝物，例如胺甲葉酸、6-巰嘌呤(6-MP)、硫唑嘌呤、氟尿嘧啶(5-FU)、替吉奧及阿拉伯糖基胞嘧啶(ara-C)；抗生素，例如博來黴素、絲裂黴素C、道諾黴素、阿黴素及放線菌黴素D；植物鹼，例如長春新鹼、長春花鹼、長春地辛(vindesine)、紫杉醇、多烯紫杉醇(docetaxel)、依妥普賽(etoposide)及愛萊諾迪肯(irinotecan)；分子標靶藥物，例如伊瑪提尼(imatinib)、吉非替尼(gefinitib)、埃羅替尼(erlotinib)、蕾莎瓦(sorafenib)、舒尼替尼(sunitinib)、曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab)、吉妥單抗(gemtuzumab-ozogamicin)、吉妥單抗及西妥昔單抗(cetuximab)；荷爾蒙，例如去氫皮質醇、二乙基人造春情素(diethylstilbestrol)及它莫西芬(tamoxifen)；鉑複合物，例如順鉑、卡鉑定及奧沙利鉑(oxaliplatin)；反義股，例如：bcl-2反義股諸如G3139、hsp27反義股諸如OGX427、XIAP反義股諸如AEG35156、PKC-alpha反義股諸如LY900003、缺氧誘發因子反義股諸如EZN-2968；抗體，例如：CD20抗體諸如利妥昔單抗、Her2抗體諸如曲妥珠單抗、VEGF抗體諸如貝伐珠單抗(bevacizumab)、EGFR抗體諸如西妥昔單抗；RNAi，例如RNAi標靶之核糖核苷酸還原酶諸如CALAA-01。抗腫瘤劑的較佳實例包括5-FU、替吉奧及順鉑。
本文使用之脂肪酸衍生物的命名係依據上述式(A)所示之前列腺酸的編號系統。
式(A)顯示C-20碳原子的基本骨架，但本發明不限於彼等具有相同碳原子數者。式(A)中，構成PG化合物基本骨架的碳原子編號始於羧酸(編號1)，α-鏈中的碳原子以朝五員環方向編號為2至7，環中的碳原子編號為8至12，而ω-鏈中的碳原子則編號為13至20。當α-鏈中之碳原子數減少時，則從位置2開始依序刪減編號；而當α-鏈中之碳原子數增加時，化合物係以取代化合物命名，該取代化合物於位置2具有個別取代基以替代羧基(C-1)。同理，當ω-鏈中之碳原子數減少時，則從位置20開始依序刪減編號；而當ω-鏈中之碳原子數增加時，位置20之後的碳原子則以取代基命名之。除非另行指明，否則化合物之立體化學與上式(A)之立體化學相同。
一般而言，術語PGD、PGE及PGF各表示在位置9及/或11具有羥基之PG化合物，但本說明書中，此等術語亦包括彼等於位置9及/或11具有羥基以外之其他取代基者。此等化合物稱為9-去羥基-9-經取代-PG化合物或11-去羥基-11-經取代-PG化合物。具有氫以替代羥基之PG化合物則簡單地命名為9-或11-去氧-PG化合物。
如上述，PG化合物之命名係依據前列腺酸骨架。然而，在化合物具有與前列腺素相似的部分結構之情況下，亦可使用縮寫「PG」。因此，α-鏈延長兩個碳原子(亦即α-鏈中具有9個碳原子)之PG化合物係命名為2-去羧基-2-(2-羧基乙基)-PG化合物。同理，α-鏈中具有11個碳原子之PG化合物則命名為2-去羧基-2-(4-羧基丁基)-PG化合物。此外，ω-鏈延長兩個碳原子(亦即ω-鏈中具有10個碳原子)之PG化合物係命名為20-乙基-PG化合物。然而，此等化合物亦可根據IUPAC命名法予以命名。
類似物(包括經取代之衍生物)或衍生物的實例包括：於α鏈末端之羧基經酯化之PG化合物；α鏈延長之化合物；其生理上可接受之鹽；在2-3位置具有雙鍵或在位置5-6具有參鍵之化合物，在位置3、5、6、16、17、18、19及/或20具有取代基的化合物；以及，在位置9及/或11具有低碳數烷基或羥基(低碳數)烷基以替代羥基之化合物。
根據本發明，位置3、17、18及/或19之較佳取代基包括具有1-4個碳原子的烷基，尤其是甲基及乙基。位置16之較佳取代基包括低碳數烷基，例如甲基及乙基、羥基、鹵素原子諸如氯及氟以及芳基氧基諸如三氟甲基苯氧基。位置17之較佳取代基包括低碳數烷基，例如甲基及乙基、羥基、鹵素原子諸如氯及氟以及芳基氧基諸如三氟甲基苯氧基。位置20之較佳取代基包括飽和或不飽和之低碳數烷基例如C1-4烷基、低碳數烷氧基例如C1-4烷氧基以及低碳數烷氧基烷基例如C1-4烷氧基C1-4烷基。位置5之較佳取代基包括鹵素原子諸如氯及氟。位置6之較佳取代基包括形成羰基之側氧基。在位置9及/或11具有羥基、低碳數烷基或羥基(低碳數)烷基之取代基的PG之立體化學可為α、β或其混合。
此外，前述之類似物或衍生物可為在ω鏈末端具有烷氧基、環烷基、環烷氧基、苯氧基或苯基之化合物，該ω鏈係短於初級PG者。
本發明使用之脂肪酸衍生物係如式(I)所示：
式中，L、M及N為氫、羥基、鹵素、低碳數烷基、羥基(低碳數)烷基、低碳數烷醯氧基或側氧基，其中，L及M之至少一者係不為氫之基團，並且該五員環可具有至少一個雙鍵；A為-CH3、或-CH2OH、-COCH2OH、-COOH或其官能性衍生物；B為單鍵、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-；Z為或單鍵其中，R4及R5為氫、羥基、鹵素、低碳數烷基、低碳數烷氧基或羥基(低碳數)烷基，其中R4及R5不同時為羥基及低碳數烷氧基；R1為飽和或不飽和二價低碳數或中等碳數脂肪族烴殘基，其係未經取代或經鹵素、烷基、羥基、側氧基、芳基或雜環基取代，且該脂肪族烴中之至少一個碳原子係視需要地經氧、氮或硫取代；以及Ra為飽和或不飽和低碳數或中等碳數脂肪族烴殘基，其係未經取代或經鹵素、側氧基、羥基、低碳數烷基、低碳數烷氧基、低碳數烷醯氧基、環(低碳數)烷基、環(低碳數)烷氧基、芳基、芳基氧基、雜環基或雜環-氧基取代；低碳數烷氧基；低碳數烷醯氧基；環(低碳數)烷基；環(低碳數)烷氧基；芳基；芳基氧基；雜環基；雜環-氧基。
本發明使用之較佳化合物係如式(II)所示：
式中，L及M為氫原子、羥基、鹵素、低碳數烷基、羥基(低碳數)烷基、低碳數烷醯氧基或側氧基，其中，L及M之至少一者係不為氫之基團，並且該五員環可具有一或多個雙鍵；A為-CH3、或-CH2OH、-COCH2OH、-COOH或其官能性衍生物；B為單鍵、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-；Z為或單鍵其中，R4及R5為氫、羥基、鹵素、低碳數烷基、低碳數烷氧基或羥基(低碳數)烷基，其中R4及R5不同時為羥基及低碳數烷氧基；X1及X2為氫、低碳數烷基或鹵素；R1為飽和或不飽和二價低碳數或中等碳數脂肪族烴殘基，其係未經取代或經鹵素、烷基、羥基、側氧基、芳基或雜環基取代，且該脂肪族烴中之至少一個碳原子係視需要地經氧、氮或硫取代；R2為單鍵或低碳數伸烷基；以及R3為低碳數烷基、低碳數烷氧基、低碳數烷醯氧基、環(低碳數)烷基、環(低碳數)烷氧基、芳基、芳基氧基、雜環基或雜環-氧基。
上式中，R1及Ra定義中的術語「不飽和」意欲包括至少一個或多個雙鍵及/或參鍵，其單獨地(isolatedly)、分開地(seperately)或連續地存在於主鏈及/或側鏈的碳原子之間。根據常用的命名法，於兩個連續位置間之不飽和鍵係以該兩個位置中編號較低者表示，而於兩個遠端位置間之不飽和鍵係以該兩個位置表示。
術語「低碳數或中等碳數脂肪族烴」係指直鏈或分支鏈烴基，其具有1至14個碳原子(對側鏈而言，以1至3個碳原子為佳)，較佳為1至10個碳原子，尤佳為1至8個碳原子。
術語「鹵素原子」係涵蓋氟、氯、溴及碘。
除非另行指明，否則通篇說明書中的術語「低碳數」意欲包括具有1至6個碳原子之基團。
術語「低碳數烷基」係指含有1至6個碳原子之直鏈或分支鏈飽和烴基，包括例如：甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、戊基及己基。
術語「低碳數伸烷基」係指含有1至6個碳原子之直鏈或分支鏈二價飽和烴基，包括例如：伸甲基、伸乙基、亞丙基、伸異丙基、伸丁基、伸異丁基、伸第三丁基、伸戊基及伸己基。
術語「低碳數烷氧基」係指低碳數烷基-O-基團，其中，低碳數烷基係如前文所定義。
術語「羥基(低碳數)烷基」係指經至少一個羥基取代之如前文定義的低碳數烷基，例如羥基甲基、1-羥基乙基、2-羥基乙基及1-甲基-1-羥基乙基。
術語「低碳數烷醯基氧基」係指由式RCO-O-表示之基團，其中，RCO-為如前文定義之低碳數烷基經由氧化所形成的醯基，例如乙醯基。
術語「環(低碳數)烷基」係指如前文定義之低碳數烷基(但含有三個或更多個碳原子)經由環化所形成的環狀基團，包括例如：環丙基、環丁基、環戊基及環己基。
術語「環(低碳數)烷氧基」係指環(低碳數)烷基-O-基團，其中，環(低碳數)烷基係如前文所定義。
術語「芳基」可包括未經取代或經取代之芳香族烴環(較佳為單環基團)，例如：苯基、甲苯基、二甲苯基。取代基之實例為鹵素原子及鹵(低碳數)烷基，其中，鹵素原子及低碳數烷基係如前文所定義。
術語「芳基氧基」係指由式ArO-表示之基團，其中，Ar為芳基其係如前文所定義。
術語「雜環基」可包括單環至三環雜環基，較佳為單環雜環基其係5至14員環，較佳為5至10員環，且具有視需要經取代之碳原子與1至4個，較佳為1至3個選自氮原子、氧原子及硫原子的一或二種雜原子。雜環基之實例包括呋喃基、噻吩基、吡咯基、唑基、異唑基、噻唑基、異噻唑基、咪唑基、吡唑基、呋呫基、哌喃基、吡啶基、嗒基、嘧啶基、吡基、2-吡咯啉基、吡咯啶基、2-咪唑啉基、咪唑啶基、2-吡唑啉基、吡唑啶基、N-哌啶基、哌基、N-嗎啉基、吲哚基、苯并噻吩基、喹啉基、異喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、啡啶基、苯并咪唑基、苯并咪唑啉基、苯并噻唑基及啡噻基。此種情況下，取代基之實例包括鹵素、以及經鹵素取代之低碳數烷基，其中，鹵素原子及低碳數烷基係如前文所定義。
術語「雜環-氧基」意指由式HcO-表示之基團，其中，Hc為雜環基其係如前文所定義。
術語「官能性衍生物」包括鹽類(較佳為醫藥上可接受之鹽類)、醚類、酯類及醯胺類。
適當的「醫藥上可接受之鹽類」包括習用之無毒性鹽類，例如與無機鹼所成之鹽，如鹼金屬鹽(諸如鈉鹽及鉀鹽)、鹼土金屬鹽(諸如鈣鹽及鎂鹽)、銨鹽；或與有機鹼所成之鹽，如胺鹽(諸如甲胺鹽、二甲胺鹽、環己胺鹽、苯甲胺鹽、哌啶鹽、乙二胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、參(羥基甲基胺基)乙烷鹽、單甲基-單乙醇胺鹽、普羅卡因(procaine)鹽及咖啡因鹽)、鹼性胺基酸鹽(諸如精胺酸鹽及離胺酸鹽)、四烷基銨鹽等等。此等鹽類可藉由習知方法製備，例如由對應的酸與鹼製備或藉由鹽交換法製備。
醚類之實例包括：烷基醚類，例如，低碳數烷基醚類，如甲醚、乙醚、丙醚、異丙醚、丁醚、異丁醚、第三丁醚、戊醚及1-環丙基乙基醚；以及，中等碳數或較高碳數烷基醚類，如辛醚、二乙基己基醚、月桂醚及鯨蠟醚；不飽和醚類，如油醚(oleyl ether)及次亞麻油醚(linolenyl ether)；低碳數烯基醚類，如乙烯醚、烯丙醚；低碳數炔基醚類，如乙炔醚及丙炔醚；羥基(低碳數)烷基醚類，如羥基乙基醚及羥基異丙基醚；低碳數烷氧基(低碳數)烷基醚類，如甲氧基甲基醚及1-甲氧基乙基醚；視需要經取代之芳基醚類，如苯基醚、甲苯磺醯基醚(tosyl ether)、第三丁基苯基醚、水楊酸基醚、3,4-二-甲氧基苯基醚及苯甲醯胺基苯基醚；以及，芳基(低碳數)烷基醚類，如苯甲醚、三苯甲醚及二苯甲醚。
酯類之實例包括脂肪族酯類，例如，低碳數烷基酯類，如甲酯、乙酯、丙酯、異丙酯、丁酯、異丁酯、第三丁酯、戊酯及1-環丙基乙基酯；低碳數烯基酯類，如乙烯酯及烯丙酯；低碳數炔基酯類，如乙炔酯及丙炔酯；羥基(低碳數)烷基酯類，如羥基乙基酯；低碳數烷氧基(低碳數)烷基酯類，如甲氧基甲基酯及1-甲氧基乙基酯；以及視需要經取代之芳基酯類，例如，苯酯、甲苯酯、第三丁基苯基酯、水楊酸酯、3,4-二-甲氧基苯基酯及苯甲醯胺基苯基酯；以及，芳基(低碳數)烷基酯，如苯甲酯、三苯甲酯及二苯甲酯。
A之醯胺意指由式-CONR’R"表示之基團，其中，R’及R"各為氫、低碳數烷基、芳基、烷基-或芳基-磺醯基、低碳數烯基及低碳數炔基，且包括例如：低碳數烷基醯胺類，如甲醯胺、乙醯胺、二甲醯胺及二乙醯胺；芳基醯胺類，如苯胺化物(anilide)及甲苯胺化物(toluidide)；以及，烷基-或芳基-磺醯胺類，如甲基磺醯胺、乙基磺醯胺及甲苯基磺醯胺。
L及M之較佳實例包括氫、羥基及側氧基，尤其是M為羥基或氫而L為側氧基。
A之較佳實例為-COOH、其醫藥可接受之鹽、其酯或醯胺。
X1及X2之較佳實例皆為鹵素原子，且更佳為氟原子，即所謂16,16-二氟類型。
較佳的R1為含有1至10個碳原子，最佳含有6至10個碳原子之烴殘基。再者，該脂肪族烴中之至少一個碳原子係視需要經氧、氮或硫取代。
R1之實例包括，例如，下列基團：-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-O-CH2-、-CH2-CH=CH-CH2-O-CH2-、-CH2-C≡C-CH2-O-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-、-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-以及-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
較佳的Ra為含有1至10個碳原子，更佳1至8個碳原子之烴。Ra可具有1或2個各具有一個碳原子之側鏈。
較佳的化合物包括式(I)中Ra係經鹵素取代及/或Z為C=O，或者，式(II)中X1及X2之一者為經鹵素取代及/或Z為C=O。
較佳具體實施例的實例為(-)-7-[(2R,4aR,5R,7aR)-2-(1,1-二氟戊基)-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基(-6-oxoocta hydro cyclo penta[b]pyran-5-yl)]庚酸、(-)-7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-二氟-3-甲基戊基]-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基}庚酸及(-)-7-[(1R,2R)-2-(4,4-二氟-3-氧辛基)-5-側氧基環戊基]庚酸或其功能性衍生物。
上式(I)及(II)中該環與α-及/或ω鏈的組態係與初級PG之組態相同或不同。然而，本發明亦包括具有初級類型組態之化合物及具有非初級類型組態之化合物的混合物。
於本發明中，二氫係於13及14之間，且酮基(=O)在15位置的脂肪酸衍生物可藉由在位置11的羥基及位置15的酮基之間形成半縮醛而處於酮基-半縮醛平衡。
舉例來說，已顯示當X1及X2兩者為鹵素原子，尤其是氟原子時，化合物含有為雙環化合物之互變異構物。
若存在前述之此等互變異構物時，兩互變異構物之比例係隨其餘分子之結構而改變，或隨存在之取代基種類而改變。有時，相較於另一種異構物，某種異構物可能以顯著多量存在。然而，咸了解兩互變異構物皆為本發明所涵蓋。
再者，本發明所使用之脂肪酸衍生物包括雙環化合物及其類似物或衍生物。
雙環化合物係由式(III)表示：
式中，A為-CH3、或-CH2OH、-COCH2OH、-COOH或其官能性衍生物；X1’及X2’為氫、低碳數烷基或鹵素；Y為 或 式中，R4’及R5’為氫、羥基、鹵素、低碳數烷基、低碳數烷氧基或羥基(低碳數)烷基，其中，R4’及R5’不同時為羥基及低碳數烷氧基。
R1為飽和或不飽和二價低碳數或中等碳數脂肪族烴殘基，其係未經取代或經鹵素、烷基、羥基、側氧基、芳基或雜環基取代，且該脂肪族烴中之至少一個碳原子係視需要經氧、氮或硫取代；以及R2’為飽和或不飽和低碳數或中等碳數脂肪族烴殘基，其係未經取代或經鹵素、側氧基、羥基、低碳數烷基、低碳數烷氧基、低碳數烷醯氧基、環(低碳數)烷基、環(低碳數)烷氧基、芳基、芳基氧基、雜環基或雜環-氧基取代；低碳數烷氧基；低碳數烷醯氧基；環(低碳數)烷基；環(低碳數)烷氧基；芳基；芳基氧基；雜環基；雜環-氧基。
R3’為氫、低碳數烷基、環(低碳數)烷基、芳基或雜環基。
另外，雖然本發明所使用之化合物不論是否存在異構物均可由以酮基型為基準之化學式或名稱表示，但應注意此等結構或名稱並未意圖排除半縮醛型之化合物。
本發明中，任何異構物，例如個別之互變異構物、其混合物、或光學異構物、其混合物、消旋混合物及其他立體異構物均可用於相同目的。
本發明所使用之某些化合物可藉由美國專利第5,073,569、5,166,174、5,221,763、5,212,324、5,739,161及6,242,485號所揭示之方法製備(此等參考文獻之內容係以參考資料之方式併入本文中)。
根據本發明，組合製劑之各組分可一起或獨立地調配為任何形式以獲得醫藥組成物。醫藥上合適之賦形劑可因此依據組成物之所需形式而選擇。根據本發明，「醫藥上合適之賦形劑」意指合適於該形式之惰性物質，其係與本發明之活性成分組合。
舉例而言，本發明之口服投藥的固形組成物可包括錠劑、膠囊、丸劑、粉劑、顆粒劑等。於此固形組成物中，一或多種活性物質可與至少一種失活稀釋劑混合，例如乳糖、甘露醇、葡萄糖、羥丙基纖維素、微晶纖維素、澱粉、聚乙烯吡咯烷酮、間矽酸鎂鋁等。根據通常之做法，組成物可含有除了失活稀釋劑以外之添加劑，例如潤滑劑如硬脂酸鎂；崩散劑如纖維性葡萄酸鈣；安定劑諸如環糊精(如α,β-或γ-環糊精；醚化之環糊精如二甲基-α-環糊精、二甲基-β-環糊精、三甲基-β-環糊精或羥丙基-β-環糊精；分支狀的環糊精如葡萄糖基-環糊精、麥芽糖基-環糊精；甲醯化環糊精；含硫環糊精)；磷脂質等。當使用上述環糊精時，有時可使用環糊精形成包容化合物(inclusion compound)以增進安定性。或者有時可使用磷脂質來形成微脂體，造成加強之安定性。
錠劑或丸劑可依需要加覆一層可溶於胃或腸中的膜，例如糖、明膠、羥丙基纖維素或羥丙基甲基纖維素鄰苯二甲酸酯等。再者，其亦可與可吸收之物質如明膠形成膠囊。組成物較佳係調製成軟明膠膠囊，其具有脂肪酸衍生物及中等鏈長脂肪酸三酸甘油脂之液體內容物。本發明使用之中等鏈長脂肪酸三酸甘油脂之實例包含飽和或不飽和脂肪酸之三酸甘油脂，其具有6至14個碳原子，並可具有分支鏈。較佳之脂肪酸為直鏈之飽和脂肪酸，例如羊油酸(C6)、羊脂酸(caprylic acid;C8)、葵酸(capric acid;C10)、月桂酸(C12)、以及肉豆蔻酸(C14)。此外，組合製劑中可使用二種或更多種中等鏈長之脂肪酸三酸甘油脂。其他合適之賦形劑係揭示於WO 01/27099。
口服投予之液態組成物可為醫藥上可接受之乳劑、溶液劑、懸浮劑、糖漿劑或酏劑，以及，常用之失活稀釋劑。除了失活稀釋劑外，此組成物可另含有佐劑如潤滑劑及懸浮劑、甜味劑、調味劑、防腐劑、安定劑、抗氧化劑等。更詳細的添加物可選自一般藥劑學領域教科書之記述。此液態組成物可直接封在軟膠囊中。根據本發明，非口服投予所使用之溶液(如栓劑、灌腸劑等)包含無菌、水性或非水性之溶液、懸浮液、乳液、消毒劑等。水溶液及懸浮劑包含如蒸餾水、生理食鹽水及林格氏溶液(Ringer’s solution)。
非水性溶液及懸浮劑包含，如丙二醇、聚乙二醇、脂肪酸三酸甘油脂以及蔬菜油如橄欖油、醇類如乙醇、聚山梨醇酯等。此組成物中可含佐劑如防腐劑、濕潤劑、乳化劑、分散劑及抗氧化劑等。
非口服投予之本發明注射用組成物的實例包含無菌水性或非水性溶液、懸浮液及乳液。水性溶液或懸浮液的稀釋劑可包含，例如，注射用之蒸餾水、生理食鹽水及林格氏溶液。
溶液及懸浮液之非水性稀釋劑可包含，例如，丙二醇、聚乙二醇、蔬菜油如橄欖油、醇類如乙醇及聚山梨醇酯。此組成物可進一步包括添加劑如防腐劑、濕潤劑、乳化劑、分散劑等。其可藉由下列方式而予以滅菌：經由，例如通過細菌保留過濾器予以過濾；與滅菌劑混製，或藉由氣體或放射性同位素輻射滅菌的方式。注射用組成物亦可以無菌粉末組成物來提供，於使用前，係將其溶解於無菌溶劑以進行注射。
本發明之組成物可為噴霧組成物之形式，其可依據習知方法予以製備。
本發明組成物可為鼻內製劑之形式。鼻內製劑之實例可為包括一種或多種活性成分的水性或油性溶液、懸浮液或乳液。對於經由吸入而投予活性成分而言，本發明組成物可以是懸浮物、溶液或乳液之形式，其可提供噴霧，或是適用於亁粉吸入之粉劑形式。作為吸入投予之組成物可復包括習用的推進劑。
外用劑的實例包括所有皮膚科及耳鼻喉科領域使用之外用製劑，其包括軟膏劑、乳膏劑、液體劑、洗劑、貼片及噴霧劑。
本發明組成物之另一種劑型為栓劑或塞劑(pessary)，其可藉由將活性成分混合入習知基劑(例如，可可脂，其可於體溫軟化)而製備，且可使用具有適當軟化溫度之非離子性界面活性劑來改良吸收能力。
根據本發明之方法，本發明之組成物可以藉由口服或非口服之方式(包括栓劑、灌腸劑等)而全身性投予或局部投予。為達所需劑量，可以單一組成物或多組成物來進行投予。
本文中所使用之表述「投予組合製劑」或「被投予組合製劑」係指兩組分以單一實體(entity)或單一劑量的形式同時投予個體，或兩組分係為各別實體以同時或依序投予個體而無特定的時序限制，其中此等投予能在體內提供醫藥有效濃度的兩組分，較佳為同時地。
根據本發明，藉由投予本發明之組合製劑，可利用本發明來治療哺乳類個體之腫瘤。哺乳類個體可為包括人類患者之任何個體。可全身性或局部施用此組成物。通常，化合物係藉由口服投予、鼻內投予、吸入投予、靜脈注射(包括輸注)、皮下注射、直腸內投予、陰道內投予、經皮投予而進行投予，且其可為外用劑，包括液體劑、軟膏劑、糊劑或貼片等。
各組分之劑量可依據動物種系、年齡、體重、欲治療的症狀、期望療效、投予途徑、治療期長短等而改變。每日全身性投予1至4次或連續投予組合製劑可獲得滿意的效果。組合製劑之組分(a)的含量可為，例如，以替吉奧而言，約0.1至約100毫克/公斤/日(mg/kg/day)，較佳為約0.5至約30 mg/kg/day；以5-FU而言，0.1至約100 mg/kg/day，較佳為約10至約40 mg/kg/day；以順鉑而言，0.1至100 mg/kg/day，較佳為5至30 mg/kg/day。組分(b)或式(I)之脂肪酸衍生物的含量可為約每日0.00001至500 mg/kg，更佳為每日0.001至1000微克/公斤(μg/kg)，尤其為每日0.01至100 μg/kg。以組成物的總量為基準計，式(I)之脂肪酸衍生物的局部調配物可為0.000001至10.0重量%，更佳為0.00001至5.0重量%。
本發明之組合製劑可每日投予單一劑量，或每日投予2至4個分開的劑量。當以可注射溶液的形式用於如靜脈內注射時，組成物(必要時可以生理食鹽水或可注射之葡萄糖溶液稀釋)可以超過5分鐘或更久的時間而逐步地對成人進行投予。當使用栓劑的形式時，則以插入直腸的方式對成人個體投予組成物，每日1或2次，間隔為6至12小時。
再者，抗腫瘤劑於哺乳類個體引起的損傷可藉由投予含有式(I)之脂肪酸衍生物之組成物來治療。於此具體實施例中，可藉由與前述相同之方式來製備及投予含有式(I)之脂肪酸衍生物之組成物。
本文中所使用之術語「治療」("treatment"或"treating")係包括控制之手段，如預防、照護、舒緩病症，減輕病症及遏止病程。
本發明組合製劑所治療的腫瘤類型並無限制，其可為例如：頭頸癌、胃腸癌如食道癌、胃癌、結腸癌、直腸癌(大腸的癌症)及胰臟癌、肝癌、膽囊/膽道(biliary)癌、肺癌、乳癌、膀胱癌(vesical cancer)、前列腺癌、子宮癌、咽癌、腎癌、卵巢癌等等。尤其，可預期對胃腸癌有顯著效果。
根據本發明，以抗腫瘤劑為活性成分之抗腫瘤效果可顯著地加強而不會特別增加其毒性。
此外，根據本發明，脂肪酸衍生物係適用於降低或預防毒性副作用，尤其是抗腫瘤劑引發的胃腸損傷。抗腫瘤劑引發的胃腸損傷可為黏膜炎如口炎、腸炎、胃腸潰瘍、胰臟炎、肝異常及膽異常。
本發明之醫藥組成物可進一步含有其他醫藥成分，只要其不牴觸本發明之目的。
以下將參考試驗實施例而更詳細地說明本發明，惟該等實施例並不意圖對本發明之範疇構成侷限。
於一星期的馴化期後，開始實驗(第0日)。自第0日至第4日共5日，每日一次，投予化合物A((-)-7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-二氟-3-甲基戊基]-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基}庚酸)(3、10、30微克/公斤(μg/kg))或載劑(時程(Schedule)1)。
於其他的投劑時程組，自第4日至第6日，每日口服投予一次化合物A(30微克/公斤)(時程2)。
自第1日至第4日共4日，每日進行一次5-FU(50毫克/公斤)的腹膜內投予。於第1、2、3及4日時，在投予化合物A或載劑後，立即投予5-FU。於實驗期間(第0至7日)，每日測量動物體重。於第7日，以異氟烷(isofluran)麻醉動物。截取迴腸並於10%甲醛液中固定。製備埋蠟切片(paraffin-embedded section)並以H&E染色以進行組織損傷之組織病理學評估。依據下列基準將組織損傷分級：
0.無改變，
1：少量，
2：輕度，
3：中度，
4：重度。
以組織損傷之總分評估各化合物的效果。
各處理組之總分如下表所示。不論投劑時程為何，10或30微克/公斤化合物A都使其總分降低。這意味著化合物A在抗毒性，尤其是胃腸毒性如5-FU引發之黏膜炎方面，是有效力的。
採用雄性倉鼠(5週大)。於一星期的馴化期後，對倉鼠進行60毫克/公斤之5-氟尿嘧啶(5-FU)的腹膜內投予(第1日)。於第2日，重覆一次5-FU的投予。於第4日，在麻醉下，以具有18-規(gauge)之針的吸管進行淺刮(superficial scratch)而對倉鼠之口腔頰黏膜(cheek pouch mucosa)進行機械性刺激，以產生暫時性紅斑。於第8及10日，進行相同的刮傷程序並完成投予5-FU。自第1至第14日，將劑量為24微克/部位(μg/site)的化合物A或載劑局部投予至口腔頰。處理期間，對口腔頰黏膜做巨觀之觀察，根據如下基準將口腔損傷分級(口腔炎分數)：
0：正常黏膜
1：觀察到紅斑
2：觀察到重度紅斑
3：觀察到一或多個地方之重度紅斑及潰瘍形成。潰瘍之累加尺寸涵蓋約25%的口腔頰。有明顯的偽膜(pseudomembrane)形成。
4：觀察到重度紅斑及潰瘍形成。潰瘍之累加尺寸涵蓋約25%的口腔頰。喪失黏膜可撓性。
5：擴散性、大規模的潰爛。喪失黏膜可撓性。僅能從口中作部份口腔萃取。
使用每個處理組之分數的平均數來評估口炎的嚴重度。
與載劑對照組相較，化合物A可改善因5-FU處理而加劇的口炎。
*p<0.05，與載劑對照組相比(學生之t-檢定(Student’s t-test)
Claims (27)
- 一種式(I)所示之脂肪酸衍生物之用途，其係用於製造治療哺乳類個體之黏膜炎之醫藥組成物：
- 如申請專利範圍第1項所述之用途，其中，Ra係經單或二鹵素取代。
- 如申請專利範圍第1項所述之用途，其中，Z為C=O。
- 如申請專利範圍第1項所述之用途，其中，B為-CH2-CH2-，Ra係經單或二鹵素取代。
- 如申請專利範圍第1項所述之用途，其中，B為-CH2-CH2-且Z為C=O。
- 如申請專利範圍第1項所述之用途，其中，B為-CH2-CH2-，Z為C=O且Ra係經單或二鹵素取代。
- 如申請專利範圍第1項所述之用途，其中，B為-CH2-CH2-且Ra係經單或二氟取代。
- 如申請專利範圍第1項所述之用途，其中，Z為C=O且Ra係經單或二氟取代。
- 如申請專利範圍第1項所述之用途，其中，B為-CH2-CH2-，Z為C=O且Ra係經單或二氟取代。
- 如申請專利範圍第1項所述之用途，其中，L為側氧基，M為氫或羥基，N為氫，B為-CH2-CH2-且Ra係經單或二鹵素取代。
- 如申請專利範圍第1項所述之用途，其中，L為側氧基，M為氫或羥基，N為氫，Z為C=O且Ra係經單或二鹵素取代。
- 如申請專利範圍第1項所述之用途，其中，L為側氧基，M為氫或羥基，N為氫，B為-CH2-CH2-，Z為C=O且Ra係經單或二鹵素取代。
- 如申請專利範圍第1項所述之用途，其中，L為側氧基，M為氫或羥基，N為氫，B為-CH2-CH2-，R1為飽和或不飽和二價低碳數或中等碳數脂肪族烴，且Ra係經單或二氟取代。
- 如申請專利範圍第1項所述之用途，其中，L為側氧基，M為氫或羥基，N為氫，B為-CH2-CH2-，Z為C=O，R1為飽和或不飽和二價低碳數或中等碳數脂肪族烴，且Ra係經單或二氟取代。
- 如申請專利範圍第1項所述之用途，其中，該脂肪酸衍生物為(-)-7-[(2R,4aR,5R,7aR)-2-(1,1-二氟戊基)-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基(-6-oxooctahydrocyclopenta[b]pyran-5-yl)]庚酸、(-)-7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-二氟-3-甲基戊基]-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基}庚酸或(-)-7-[(1R,2R)-2-(4,4-二氟-3-側氧基辛基)-5-側氧 基環戊基]庚酸，或其功能性衍生物。
- 如申請專利範圍第1項所述之用途，其中，該脂肪酸衍生物為(-)-7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-二氟-3-甲基戊基]-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基}庚酸。
- 如申請專利範圍第1項所述之用途，其中，該黏膜炎為口腔黏膜炎。
- 一種醫藥組合製劑，包括：(a)醫藥有效量的抗腫瘤劑，該抗腫瘤劑係選自由烷化劑、抗代謝物、抗生素、植物鹼、分子標靶藥物、荷爾蒙、鉑複合物、反義股、抗體及RNAi所組成的群組，以及(b)醫藥有效量的脂肪酸衍生物，該脂肪酸衍生物為(-)-7-[(2R,4aR,5R,7aR)-2-(1,1-二氟戊基)-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基]庚酸、(-)-7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-二氟-3-甲基戊基]-2-羥基-6-側氧基八氫環戊烯並[b]哌喃-5-基}庚酸或(-)-7-[(11R,2R)-2-(4,4-二氟-3-側氧基辛基)-5-側氧基環戊基]庚酸，或其功能性衍生物。
- 如申請專利範圍第18項所述之醫藥組合製劑，其中，該抗腫瘤劑為5-FU或替吉奧(tegafur)。
- 如申請專利範圍第18項所述之醫藥組合製劑，其中，該抗腫瘤劑為順鉑(cisplatin)。
- 如申請專利範圍第18至20項中任一項所述之醫藥組合 製劑，其中，該組合製劑之組分係同時、分別或接續地投予。
- 如申請專利範圍第18至20項中任一項所述之醫藥組合製劑，其係用於腫瘤治療。
- 一種商業套組，包括如申請專利範圍第18至22項中任一項所述之醫藥組合製劑和指示同時、分開或接續地使用該醫藥組合製劑之說明書，以治療腫瘤。
- 一種式(I)所示之脂肪酸衍生物之用途，其係用於製造治療哺乳類個體中由抗腫瘤劑引發之黏膜炎的醫藥組成物：
- 如申請專利範圍第24項所述之用途，其中該黏膜炎為口炎。
- 如申請專利範圍第24項所述之用途，其中該黏膜炎為口腔黏膜炎。
- 一種抗腫瘤劑和脂肪酸衍生物之用途，其係用於製造如 申請專利範圍第18至22項中任一項所述之用於腫瘤治療之醫藥組合製劑。
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| CN101180096B (zh) * | 2005-03-21 | 2015-04-22 | 苏坎波公司 | 用于治疗粘膜疾病的方法和组合物 |
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| CN107050458A (zh) | 2017-08-18 |
| NZ598618A (en) | 2014-10-31 |
| KR101760963B1 (ko) | 2017-07-24 |
| IL218392A0 (en) | 2012-04-30 |
| CA2772314A1 (en) | 2011-03-24 |
| WO2011034210A1 (en) | 2011-03-24 |
| ZA201201894B (en) | 2012-11-28 |
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| US20150272961A1 (en) | 2015-10-01 |
| RU2016103415A (ru) | 2018-11-22 |
| TW201116277A (en) | 2011-05-16 |
| BR112012005896A2 (pt) | 2016-03-15 |
| US20170079986A1 (en) | 2017-03-23 |
| RU2012114771A (ru) | 2013-10-27 |
| EP2477632A4 (en) | 2013-06-12 |
| RU2577700C2 (ru) | 2016-03-20 |
| IL218392A (en) | 2016-05-31 |
| SG179153A1 (en) | 2012-04-27 |
| JP2013504520A (ja) | 2013-02-07 |
| MX2012003188A (es) | 2012-04-30 |
| CN102481302A (zh) | 2012-05-30 |
| US20110064748A1 (en) | 2011-03-17 |
| KR20120081139A (ko) | 2012-07-18 |
| AR078182A1 (es) | 2011-10-19 |
| US9084815B2 (en) | 2015-07-21 |
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| EP2477632A1 (en) | 2012-07-25 |
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| SG10201405467PA (en) | 2014-10-30 |
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