TW201340971A - Ｄｎａ損傷劑 - Google Patents
Ｄｎａ損傷劑 Download PDFInfo
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- TW201340971A TW201340971A TW102108245A TW102108245A TW201340971A TW 201340971 A TW201340971 A TW 201340971A TW 102108245 A TW102108245 A TW 102108245A TW 102108245 A TW102108245 A TW 102108245A TW 201340971 A TW201340971 A TW 201340971A
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Abstract
本發明欲解決之課題為提供治療劑、醫藥組成物給肇因於DNA損傷之疾病，特別是固態癌。本發明提供之DNA損傷劑是1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽為有效成分。
Description
本申請案依據業於2012年3月9日提出申請之日本專利申請案第2012-053517號說明書(藉由參照其整體揭示內容而援用於本說明書中)主張優先權。
本發明關於一種1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽為有效成分之DNA損傷劑、及肇因於DNA損傷之疾病之治療劑，特別是關於一種固態癌之治療劑及醫藥組成物。
根據記載，1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶在抑制白血病細胞L1210增殖之效果上具有和5-氟基-2’-去氧尿苷(以下稱為FdUrd)同等或是更好的效果，而暗示了其用作抗腫瘤劑之有用性(非專利文獻1)。另外，專利文獻1及2記載，包含本發明化合物之化合物群用作抗病毒劑及抗腫瘤劑甚是有用。
白血病細胞L1210的增殖抑制作用係自從前即用於篩選抗腫瘤劑。然而實際上具有白血病細胞L1210之增殖抑制作用的化合物能否顯示出抗腫瘤作用則屬未知，特別是與針對固態癌之抗腫瘤效果不具相關性。例如，阿糖
胞苷(cytarabine；Ara-C)係一在臨床上主要用作白血病等血液性癌症之治療劑的藥劑，其雖係對白血病細胞L1210具有抑制增殖效果之核酸衍生物，然而如非特許文獻2所示，其對於固態癌幾乎不顯示抗腫瘤效果。
如同上述，1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶係一可造成DNA損傷之化合物一事目前完全未為人所知，並且其對於固態癌是否顯示出治療效果一事亦未獲暗示。
【專利文獻1】國際公開WO91/04033號公報
【專利文獻2】國際供該WO91/01326號公報
【非專利文獻1】Nucleosides & Nucleotides., 12(2), 139-147(1993)
【非專利文獻2】Nucleosides & Nucleotides., 18(4&5), 877-878(1999)
本發明之目的在於提供一種用作DNA損傷劑甚是有用之1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽，更進一步則是提供一種針對肇因於DNA損傷之疾病(特別是固態癌)的治療劑及醫藥組成物，其係以1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽作為
有效成分。
本案發明人為了解決上述課題而精心探討，結果發現，以下述通式(1)表示之1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽係一會被攝入DNA引起損傷，結果可長時間持續顯示出抗腫瘤效果之化合物，且更進一步發現，以本發明化合物作為有效成分之醫藥組成物在用作針對固態癌之治療劑上尤為有用。
亦即，本發明提供一種用作DNA損傷劑甚是有用之1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽，且更進一步提供一種針對肇因於DNA損傷之疾病(特別是固態癌)的治療劑及醫藥組成物，其係以1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽作為有效成分。
依據本發明，可有效治療肇因於DNA損傷之疾病，特別是固態癌。
由於以酵素抑制劑為首之既存抗腫瘤劑係利用腫瘤增殖(DNA合成)之快速性來對腫瘤發揮抗腫瘤效果，對於與腫瘤同樣快速增殖之骨髓、消化管等正常組織也會
產生毒性。
另一方面，本發明化合物(1)則是利用腫瘤係肇因於伴有基因異常之DNA損傷的疾病一事，藉由使暨已伴有基因異常之腫瘤的DNA攝入本發明化合物(1)來引導進一步之基因異常而導致不可修復之重度DNA損害，進而發揮抗腫瘤效果。此時，雖然本發明化合物(1)也會被攝入包含骨髓及消化管等在內之正常組織的DNA，但在保有正常基因之正常組織中，即使攝入本發明化合物(1)而導致基因異常，在此情況下，其亦不過是輕度且可修復之基因異常，與對於腫瘤造成的DNA損傷作用完全不同。
亦即，本發明化合物(1)係一於攝入腫瘤內之DNA後發揮DNA損傷作用之藥劑，且基於這項作用機制，而具有選擇性地對腫瘤發揮其抗腫瘤效果之特徵。
【圖1】人類培養細胞中之細胞增殖抑制效果及去除藥劑後對細胞增殖帶來之影響。
本發明之1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽為習知化合物，舉例來說，可利用國際公開WO91/04033號公報記載之方法製造。
本發明所稱之「治療」意指疾病的預防和治療，以及用以減輕或防止症狀再度發作之維持療法。
於本說明書中，「DNA損傷」意指1-[2’-去氧-4’-
硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶攝入腫瘤細胞之DNA而導致之基因異常，其結果則為不可修復之重度DNA損傷，例如導致DNA一級結構中之鹼基變化、DNA股斷裂、交聯形成或是影響DNA修復的耐受性。DNA一級結構中之鹼基變化則意指：構成DNA之鹼基的氧化、甲基化、水解、去胺化、核苷酸的插入或是缺損等。
此外，「DNA損傷劑」意指藉由引起上述DNA損傷而可治療「肇因於DNA損傷之疾病」之藥劑。具有DNA損傷作用一事可藉由實驗例2的Comet Assay(Method in Molecular Biology vol.113 DNA repair Protocols,HUMANA PRESS,Edited by Daryl S.Henderson,p203-212)來確認。
可藉本發明化合物或醫藥組成物來治療之「肇因於DNA損傷之疾病」可列舉如固態癌。
本說明書中，「固態癌」可例示如頭頸部癌、食道癌、胃癌、大腸癌(結腸癌、直腸癌)、肝癌、膽囊/膽管癌、胰臟癌、肺癌、乳癌、卵巢癌、子宮癌(子宮頸癌、子宮體癌)、腎癌、膀胱癌、前列腺癌、睪丸瘤、骨/軟組織肉瘤、皮膚癌或腦瘤。且宜為胃癌、乳癌、子宮癌、胰臟癌和大腸癌。
本發明之1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽，可藉由藥學上可接受之載體並以習知製劑方法而製成各種投藥型態。此投藥型態並無特別限制，可例示如：錠劑、膜衣錠劑、丸劑、粉劑、顆粒劑、膠囊劑、液劑、懸浮劑及乳劑等經口劑；或是，注射劑及
栓劑等之非經口劑。
形成為錠劑形態時，載體可為例如乳糖、白糖、氯化鈉、葡萄糖、尿素、澱粉、碳酸鈣、高嶺土、結晶纖維素、矽酸等賦形劑；水、乙醇、丙醇、玉米澱粉、單糖漿、葡萄糖液、澱粉液、明膠溶液、羧甲基纖維素、蟲膠、甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素、磷酸鉀、聚乙烯吡咯啶酮等結合劑；乾燥澱粉、海藻酸鈉、洋菜粉、昆布糖粉、碳酸氫鈉、碳酸鈣、聚氧乙烯山梨醇脂肪酸酯系化合物、月桂基硫酸鈉、硬脂酸單甘油脂、乳糖等崩解劑；白糖、硬脂酸、可可脂、氫化油等崩解抑制劑；四級銨鹽、月桂基硫酸鈉等吸收促進劑；甘油、澱粉等保濕劑；澱粉、乳糖、高嶺土、皂土、膠狀矽酸等吸附劑；精製滑石、硬脂酸鹽、硼酸粉、聚乙二醇等潤滑劑。更進一步來說，錠劑可依需要而製成施加有一般膜衣之錠劑，例如糖衣錠、明膠包封錠、腸溶衣錠、膜衣包覆錠、雙重錠和多層錠等形式。
成形為丸劑形態時，載體可使用例如葡萄糖、乳糖、澱粉、可可脂、硬化植物油、高嶺土、滑石等賦形劑；阿拉伯膠粉、黃蓍膠粉、明膠、乙醇等結合劑；昆布糖、洋菜等崩解劑。膠囊劑則遵照一般製法，與上述例示之各種載體混合再填充至硬質明膠膠囊、軟質膠囊等予以調製。
製成口服液態劑時，可使用矯味/矯臭劑、緩衝劑、安定劑等，並可以一般製法製成內服液劑、糖漿劑、酏劑等。在此情況下，矯味/矯臭劑可列舉如白糖、橙皮、
檸檬酸、酒石酸等，緩衝劑可列舉如檸檬酸鈉等，安定劑可列舉如黃蓍膠、阿拉伯膠、明膠等。
成形為栓劑形態時，載體可使用聚乙二醇、可可脂、高級醇、高級醇之酯系化合物、明膠、半合成甘油脂等。
製成注射劑時，液劑、乳劑及懸浮劑宜經滅菌且與血液等張，且製成此等型態時，稀釋劑可使用例如水、乳酸水溶液、乙醇、丙二醇、聚乙二醇(macrogol)、乙氧化異硬脂醇、聚氧乙烯化異硬脂醇、聚氧乙烯去水山梨醇脂肪酸酯系之化合物等。
此外，在此情況下，可令醫藥製劑中含有足以調製等張性溶液之量的食鹽、葡萄糖或甘油等，也可添加一般之溶解佐劑、緩衝劑、無痛化劑等。上述各製劑亦可依需要而進一步添加著色劑、防腐劑、香料、調味料、甘味劑及/或其他醫藥品。
本發明之DNA損傷劑之投藥方式並未特別受限，可依據各種投藥形態、患者年齡、性別、其他條件或患者症狀之程度等而予以適當決定。例如，錠劑、丸劑、粉劑、顆粒劑、膠囊劑、液劑、懸浮劑及乳劑為經口投藥。注射劑可以單獨或混合葡萄糖、胺基酸等一般之輸液投藥至靜脈，更可依需要而單獨投藥至動脈內、肌肉內、皮內、皮下或是腹腔內。栓劑則是投藥至直腸內。
雖然應調配至上述各種投藥單位型態之本發明化合物或其鹽的量會依所應適用之患者症狀或其劑型而非
一定，但一般而言，以每一投藥單位形態來論，以口服劑計宜為約0.005~1,000mg，以注射劑計宜為約0.001~500mg，以栓劑計宜為約0.01~1,000mg。又，具有上述投藥型態之藥劑的每日投藥量雖然依患者之症狀、體重、年齡、性別而異，無法一概而定，但通常成人一日約0.005~5,000mg(宜0.01~1,000mg)即可，且宜將其一天投藥1次或分成2~4次投藥為佳。
可投藥本發明化合物之哺乳動物，可列舉如人類、猴子、小鼠、大鼠、兔子、狗、貓、牛、馬、豬、綿羊等。
以下列舉實施例及試驗例俾更詳盡說明本發明，但本發明並不受其等所侷限。
以專利文獻1為基準，按照下述方法合成。
將專利文獻1記載之1-O-乙醯基-2-去氧-4-硫代-3,5-二-O-對甲醯基-α,β-D-核呋喃糖(203mg)溶解於無水二氯甲烷(4.0ml)，依序加入5-氟尿嘧啶(61.5mg)、六甲基二矽氮烷(75.9mg)、三甲基氯矽烷(51.0mg)懸浮攪拌20分鐘，之後冷卻至-78℃並加入三甲基矽基三氟甲烷磺酸酯(125.3mg)，更進一步再進行1.5小時之冷卻攪拌。昇溫至室溫後加入氯仿(5.0ml)稀釋，依序利用飽和碳酸氫鈉和水洗淨有機層。餾除溶劑後，殘渣以二氧化矽凝膠管柱層析法
(30%乙酸乙酯/己烷)純化後，獲得1-(2’-去氧-4’-硫代-3’,5’-二-O-甲醯基-1-β-D-核呋喃糖基)-5-氟尿嘧啶(85.4g)。將得到之純化物溶解於甲氧基鈉的甲醇溶液(0.25M,2.0ml)中，並在室溫下攪拌3個小時。利用Dowex 50-X8(H+)離子交換樹脂中和溶液，並在濾過懸浮物後以甲醇洗淨樹脂。在濃縮濾液及餾除溶劑後，以矽膠管柱層析法(15%甲醇/氯仿)純化殘渣，獲得化合物(1)(33mg,75%)的白色固體。
1H-NMR(DMSO-d6)δ 11.8(1H,brs),8.33(1H,d J=7.3Hz),6.23(1H,dd,J=7.3&7.3Hz),5.24-5.19(2H,m),4.35(1H,m),3.65-3.55(2H,m),3.31-3.28(1H,m),2.25-2.15(2H,m)；ESI-MS m/z 261(M-H)-。
在播種人類子宮癌株HeLa和人類胃癌株NUGC-3之翌日，分別添加本發明化合物(1)和FdUrd。就藥劑濃度與接觸時間，以HeLa細胞株而言，係添加10μM的本發明化合物(1)及1μM之FdUrd並使其等接觸8小時，以NUGC-3細胞株而言，則添加10μM的本發明化合物(1)及0.1μM之FdUrd並使其等接觸24小時。上述本發明化合物(1)及FdUrd的藥劑濃度即相當於：各細胞接觸藥劑達72小時之時，顯示出抑制50%之細胞增殖作用的濃度(IC50)。又，就本發明化合物(1)而言，添加了適量之非標示體，就FdUrd而言，則添加了已混合有適量之非標示體和氚標示體者。
從接觸藥劑後之細胞抽出DNA，並測定DNA溶
液濃度。
本發明化合物(1)的DNA攝入量係利用DNaseI、磷酸二酯酶I和鹼性磷酸酶，於分解成核苷後使用HPLC分析DNA溶液而算出每單位DNA的攝入量。另一方面，FdUrd的DNA攝入量則是將DNA溶液溶入液態閃爍劑並測定其放射活性來算出每單位DNA之攝入量。茲將實驗結果顯示於表1。
從表1的結果得知，本發明化合物(1)之DNA攝入量，不論在何種細胞株，和FdUrd之攝入量相較，均為約100倍或是100倍以上。
在播種人類子宮癌株HeLa及人類胃癌株NUGC-3之翌日，分別添加本發明化合物(1)及FdUrd並培養48小時。就藥劑濃度，以HeLa細胞株而言，係添加10μM之本發明化合物(1)及1μM之FdUrd，以NUGC-3細胞株而言，則添加10μM之本發明化合物(1)及0.1μM之FdUrd。另，本發明化合物(1)
及FdUrd分別的藥劑濃度即相當於各細胞接觸藥劑達72小時之時的IC50。
接觸藥劑後的細胞以胰蛋白酶處理後回收。已調製成適當濃度之細胞懸浮液係使用市售之套組(Comet AssayTM,Trevigen)來進行標本之製作。製成之標本使用SYBR(註冊商標)Gold nucleic acid gel stain(invitrogen)染色後，在顯微鏡下拍攝細胞之影像，茲將實驗結果顯示在表2。
如表2之結果所示，不論是對HeLa細胞株及NUGC-3細胞株中之任一者，FdUrd均未顯示出DNA損傷指標之DNA曳尾影像，相對來說，本發明化合物(1)則顯示出了顯著之DNA曳尾影像。即，相對於FdUrd幾乎沒有顯示出DNA損傷，本發明化合物(1)係一引發DNA損傷之化合物。
播種人類胃癌株NUGC-3(Day0)，於翌日分別添加本發明化合物(1)及FdUrd(Day1)。
藥劑接觸時間係以兩種時程進行試驗。即，接觸72小時之群，及接觸24小時後更換培養基以除去藥劑之群。藥劑濃度則是使其接觸10μM之本發明化合物(1)或0.1μM之FdUrd。任一藥劑濃度均相當於NUGC-3細胞株接觸藥劑72小時之時的IC50。
為了比較此2種時程中細胞增殖的經時變化，將Day2至Day4期間內之細胞數每日計數一次，並將數出之試驗結果顯示在圖1。
如圖1所明示，相對於除去FdUrd藥劑後可見到細胞開始快速增殖，本發明化合物(1)即使在藥劑除去2天後的Day4，仍然發揮其抑制細胞增殖之效果。此結果明確顯示，由於本發明化合物(1)係藉由攝入DNA中引起DNA損傷來發揮抗腫瘤效果，而與只在接觸藥劑時發揮暫時性效力之醛素抑制劑不同。
將已在BALB/cA Jcl-nu小鼠(日本CLEA株式會社)作皮下繼代之人類胃癌株SC-2、人類肺癌株LC-6、人類乳癌株MC-2、人類胰臟癌株PAN-4及人類大腸癌株Col-1作成邊長2mm之正方形片段，移植至6~8周大之BALB/cA Jcl-nu小鼠背部皮下。於分群後之平均腫瘤體積超過100mm3後，測量
腫瘤之長徑及短徑，利用下述公式算出腫瘤體積後，以使各群之腫瘤體積不發生偏差之方式進行分群(每群約5~7隻)。
(式1)Vt=1/2(V1)x(Vs)2[式中，Vt表示腫瘤體積，V1表示腫瘤長，Vs表示腫瘤寬]。
將本發明化合物(1)溶解至0.5%的羥丙基甲基纖維素水溶液裡，自分群後之翌日起，以1天1次的方式連續經口投藥14天。令投藥量為50mg/kg/day。
於分組後15天，測量各群小鼠之皮下移植腫瘤之長徑及短徑，從下式算出腫瘤體積比(relative tumor volume,RTV)及腫瘤增殖抑制率(inhibition rate,IR)，進行抗腫瘤效果之判定，茲將實驗結果顯示於表3。
(式2)RTV=Vt1/Vt2[式中，RTV表示腫瘤體積比，Vt1表示判定日之腫瘤體積，Vt2表示分群日之腫瘤體積]。
(式3)IR(%)=[1-(RTVtest)/(RTVcont)]x100[式中，IR表示腫瘤增殖抑制率，RTVtest表示藥劑投予群之平均RTV，RTVcont表示無處理群之平均RTV值]。
從表3可清楚得知，本發明化合物(1)的腫瘤增殖抑制率不論在任一腫瘤株中皆為50%以上的高數值，對人類之各種固態癌皆具有優異之抗腫瘤效果。
Claims (10)
- 一種DNA損傷劑，含有1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽作為有效成分。
- 一種醫藥組成物，含有用以治療肇因於DNA損傷之疾病的1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽以及藥學上容許之載體。
- 如申請專利範圍第2項之醫藥組成物，其中該肇因於DNA損傷之疾病為人類固態癌。
- 一種醫藥組成物，包含1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽以及藥學上容許之載體。
- 如申請專利範圍第4項之醫藥組成物，其係針對人類固態癌之治療劑。
- 如申請專利範圍第5項之醫藥組成物，其中該人類固態癌係選自於由胃癌、乳癌、肺癌、子宮癌、胰臓癌及大腸癌所構成群組中之至少一種。
- 如申請專利範圍第4至6項中任一項之醫藥組成物，其係藉由活體內(in vivo)投藥而對人類固態癌有效。
- 一種治療肇因於DNA損傷之疾病的治療方法，包含對哺乳動物投予有效量之1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽。
- 一種1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽之用途，係使用於製造一種治療肇因於DNA損傷之疾病的治療劑。
- 一種1-[2’-去氧-4’-硫代-1-β-D-核呋喃糖基]-5-氟尿嘧啶或其鹽，其係使用於治療肇因於DNA損傷之疾病。
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