TW201619145A - 作為癌症標靶藥物載體之磷脂乙醚同類物 - Google Patents
作為癌症標靶藥物載體之磷脂乙醚同類物 Download PDFInfo
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Abstract
本發明係關於可鎖定癌細胞及癌幹細胞之治療性化合物,本發明係進一步關於具有該等治療性化合物之組合物,以及治療癌症之方法,其中包括施用該等治療性化合物。
Description
本發明係關於藥物之載體,更詳而言之,係特指一種抗癌藥物之載體。
於2012年,全世界有1410萬人經診斷確定罹癌,並有820萬人死於癌症。在美國,約百分之40人們會在有生之年經診斷罹癌,儘管能接受最佳的治療手斷,當中仍有百分之44病患死於癌症。
癌症是細胞無限制分裂的結果,健康細胞可具有預防細胞無限制分裂之查驗機制,其中舉例而言可包括養分可用性、DNA損傷以及接觸抑制等(例如細胞與另一細胞產生接觸)。另外,大部份細胞僅能經過有限次數之複製,故其本質上於經過特定次數之細胞分裂後即會死亡。
癌症是細胞跨越此等內在查驗機制而於不受控之情況下不斷增殖之結果,此種不受控之增殖將導致腫瘤之形成。腫瘤可分為兩種,良性及惡性。良性腫瘤無法跨越不同組織種類間之自然邊界,相反地,惡性腫瘤則可侵入附近組織或進入血流中並轉移至不同部位。只有惡性腫瘤係被視為癌症,正是此種滲透且轉移之能力,使癌症成為如此致命疾病。
對抗癌症更複雜的地方在於,惡性腫瘤具有不同細胞種類,其中尤其麻煩之一者為癌幹細胞(CSC),癌幹細胞能夠自我修復並分化為不同種類之惡性腫瘤癌細胞,故,癌幹細胞細微腫瘤轉移能力的主要因子。癌幹細胞通常可於放射線於化學療法下存活,現今普遍假設,癌症於放射線及化學療法後會再度復發,係為放射線及化學療法無法殺死所有癌幹細胞,並加上癌幹細胞生成新腫瘤之能力所導致之結果。
其中一種尤其麻煩之癌症係為腦癌。腦癌,例如高度神經膠質瘤(high-grade gilomas)係常以手術以及術後放射線療法治療。腦瘤手術極為複雜,外科醫師必須在不傷及附近腦部組織之情況下移除腫瘤,否則將導致肢體或認知障礙。通常外科醫師無法移除腫瘤接觸健康組織之邊界。放射性療法常用於殺死此等殘留癌細胞,然而,放射線劑量係受到對健康腦部組織之可能損傷所限制,而不幸的是,腦癌通常都對化學療法具有抗性,此番抗性大多係由血腦屏障(BBB)所造成,血腦屏障係將腦部周圍液體與血球細胞與血流中其他成分相互分隔之身體屏障,大部份抗癌藥物皆無法穿透血腦屏障。
腦癌治療方法之一係為阻斷使腫瘤持續增大所不可或缺之新生血管成長,以商標名Avastin®(Avastin係為Genentech, Inc.之註冊商標) 所行銷之Bevacizumab係可用以阻止甚至逆轉腫瘤血管化作用。然而,Rich J.及同僚發現(Canc Res, 2006, 66, 7843,)當Avastin®用以考部腫瘤所衍生治療神經膠質瘤幹細胞時,會導致組織缺氧及pH值降低。Sathornsumetee S.針對惡性神經膠質瘤復發患者所進行bevacizumab及erlotinib之第二階段試驗中(Neuro-Oncol, 2010, Dec, 12(12), 1300-1310),組織缺氧及低pH值兩者係經得知可造成癌幹細胞增殖,並促進癌幹細胞所激發之腫瘤復發作用。
化學療法係為用以描述特性種類癌症治療方法之術語,其中包括利用細胞毒殺抗癌藥物。化學療法中所使用之細胞毒殺藥物可分為幾種主要類別,包括烷化劑類(alkylating agents)、抗代謝物類(antimetabolites)、抗腫瘤抗生素類、拓撲異構酶抑制劑類(topoisomerase inhibitors)以及核分裂抑制劑類(mitotic inhibitors)。細胞毒殺抗癌藥物類一般可造成細胞分裂停止,藉以影響健康的組織以及癌組織。烷化劑類可藉由破壞癌細胞之DNA以阻止癌細胞分裂,幾種用於治療癌症之常見烷化劑類包括氮芥類(nitrogen mustards)(例如環磷酸醯胺cyclophosphamide (Cytoxan®,Cytoxan係為Baxter International)之註冊商標)、亞硝基尿素類(nitrosoureas)、烷磺酸鹽類(alkyl sulfonates)、三𠯤類(triazeines)以及二亞甲亞胺類(ethylenimines)。鉑藥類(platinum drugs),例如順鉑(cisplatin)以及卡鉑(carboplatin)等,作用係類似於烷化劑類。抗代謝物類可藉由抑制DNA及RNA合成以阻止癌細胞分裂,幾種用於治療癌症之常見抗代謝物類包括6-硫醇嘌呤(6-mercaptopurine)、吉姆賽他賓(Gemcitabine(Gemzar®
, Gemzar係為Eli Lilly Company之註冊商標))、胺甲喋呤(methotrexate)以及培美曲塞(pemetrexed(Alimta®
,Alimta係為Eli Lilly Company之註冊商標))。拓撲異構酶抑制劑類可藉由抑制拓撲異構酶酵素分離複製作用之DNA以阻止癌細胞分裂,幾種拓撲異構酶抑制劑類包括托伯狄肯(topotecan)、愛萊諾迪肯(irinotecan)、伊妥普賽(etoposide)以及坦尼玻賽(teniposide)。核分裂抑制劑類可藉由抑制關鍵細胞分裂酵素以阻止癌細胞分裂,幾種核分裂抑制劑類包括紅豆杉烷類(taxanes)(例如紫杉醇paclitaxel (Taxol®,Taxol係為Bristol-Myers Squibb Company之註冊商標)以及多烯紫杉醇(docetaxel)(Taxotere®
,Taxotere係為Aventis Pharma SA之註冊商標),伊波西隆類(epothilones)以及長春花生物鹼類(vinca alkaloids)。
該等所有抗癌藥物之缺點在於會同時對健康組織造成傷害,因為該等藥物係透過抑制正常細胞作用來治療癌症,但同樣仰賴持續不斷之細胞分裂作用的健康組織,例如血球細胞、黏膜表皮以及皮膚等,同樣會受到嚴重損傷。此等傷害會導致嚴重病狀,並會限制可成功實施之化學療法數量。於化學療法中所產生之副作用包括如血球數量低落、落髮、肌肉及關節疼痛、噁心、嘔吐、腹瀉、嘴破、發燒及惡寒。為了克服此問題,係將藥物之開發以影響僅存在於癌細胞內部之蛋白質及細胞機能為方向。幾種此類特定癌症藥物包括伊馬替尼(imatinib)(基立克Gleevec®
,Gleevec係為Novartis AG之註冊商標)、吉菲替尼(gefitinib)(艾瑞莎Iressa®
,Iressa係為AstraZeneca UK Limited之註冊商標)、舒癌特(sunitinib)(Sutent®
,Sutent係為C.P. Pharmaceuticals, International C.V.之註冊商標)以及伯特佐米(bortezomib)(萬科Velcade®
,Velcade係為Millennium Pharmaceuticals, Inc.之註冊商標)。然而,該等藥物並未經確認可治療所有種類之癌症,而且與各種療法之抵抗性發展皆有關聯。故,相關技藝領域需要一種抗癌藥物輸送載體,其可將具有藥效、可發揮作用又廣泛之抗癌藥物輸送至包括癌幹細胞在內之癌細胞,並同時避免藥物受健康細胞所攝入。此外,該種抗癌藥物輸送載體應可穿越血腦屏障並將抗癌藥物輸送至腦部之癌細胞。
目前,有幾種化學化合物可優先鎖定癌細胞,其中一種化合物係為CLR1404。總括而言,CLR1404係為新的腫瘤選擇性診斷成像劑,用以監測數種腫瘤療法之治療反應。經放射性碘化之CLR1404係為一種第二代磷脂乙醚(PLE)同類物,其結構為,並於55/60異種移植(xenograft)、原位模式(orthotopic)及基因轉殖(transgenic)癌以及由癌幹細胞衍生之動物模組中表現出極佳之腫瘤選擇性,使該核心分子成為抗癌藥物輸送載體之理想平台。參照美國專利No. 8535641、美國專利公開案No. 2014/0030187以及Weichert, J.P.等人於Sci Transl Med( 2014, Jun 11, 6(240), 240ra75)之烷基磷膽鹼(Alkylphosphocholine)同類物用於廣泛為癌症成像及療法,該等文件係於此之引用文獻。
目前業界未知,受癌細胞及癌幹細胞所選擇性螫合之化合物是否能夠輸送抗癌藥物至同樣該等細胞中。再者,目前亦未知此種化合物是否能夠亦能輸送抗癌藥物穿越血腦屏障以治療腦癌。最後,亦未知此種或其類似化合物是否能導致癌細胞留滯足量之抗癌藥物長達足夠之期間,以消滅腫瘤病預防其進一步成長及轉移。本發明利用CLR1404核心分子作為一種抗癌藥物輸送載體,其可將抗癌藥物鎖定至包括腦癌細胞在內之癌細胞及癌幹細胞。另外,本發明所揭露之化合物可留滯於癌細胞中。
本發明係關於具有治療性化合物,其可鎖定包括腦腫瘤細胞在內之癌細胞及癌幹細胞。本發明亦係關於其他種類之治療性化合物,其可受包括腦癌腫瘤細胞在內之癌細胞及癌幹細胞所螫合並足量滯留至一足夠期間,以治療癌症病預防其轉移與復發。
於一實施例中,本發明係關於一種具有結構式A-B-D之治療性化合物,其中: A係為結構式(I)之至少一種化合物,(I), 結構式(II)之至少一種化合物,(II), 結構式(III)之至少一種化合物,(III), 或該等之結合, 其中W係選自由一芳香基(aryl)、一C1
-C6
烷基(C1
-C6
alkyl)、一烯基(alkenyl)、一選擇性取代之C3
-C6
環烷基(C3
-C6
cycloalkyl)以及一選擇性取代之C3
-C6
異環烷基(C3
-C6
heterocycloalkyl)所構成之群組,其中R係為氫(H)或一烷基,且其中m係為12至24間之一整數,B係為一鏈結化合物,較佳者係為一鍵結或為一具有結構式(IV),Y-(CH2
)n
-Z之化合物,其中: Y係鍵結於A; Z係鍵結於D; Y係選自由一鍵結、O、NH、 C=O、 NHSO2
O及OC(=O)O所構成之群組; Z係選自由O、NH、 C=O、 C(=O)O、 C(=O)NH、 SO2
、OC(=O)OCH2
及–S-S-所構成之群組;且 n係為0至6間之一整數;且 D係為一抗癌藥物, 其中A與D之比例係介於1:2至2:1之間。
於另一實施例中,本發明係關於一種治療性化合物,其具有之結構式A-B-D係選自由、、以及上述之結合所構成之群組,其中: W係選自由一芳香基(aryl)、一C1
-C6
烷基(C1
-C6
alkyl)、一烯基(alkenyl)、一選擇性取代之C3
-C6
環烷基(C3
-C6
cycloalkyl)以及一選擇性取代之C3
-C6
異環烷基(C3
-C6
heterocycloalkyl)所構成之群組; R係為H或一烷基; m係為12至24間之一整數; Y係選自由一鍵結、O、NH、 C=O、 NHSO2
O及OC(=O)O所構成之群組; Z係選自由O、NH、C=O、C(=O)O、C(=O)NH、SO2
、OC(=O)OCH2
及–S-S-所構成之群組; n係為0至6間之一整數;且 D係為一抗癌藥物, 其中B係選擇性為A與D間之一鍵結。
於一較佳實施例中,本發明係關於一種治療性化合物,其具有結構式A-B-D,其中: A係為具有結構式(I)之一化合物,其中W係選自由C1烷基(C1
alkyl)、、及所構成之群組,且其中m係為18; B係為一鏈結化合物,其係選自由一鍵結以及具有一結構式(IV),Y-(CH2
)n
-Z之化合物所構成之群組,其中:n係為介於0至6間之一整數,Y係鍵結於A,Z係鍵結於D,Y係選自由一鍵結以及C=O所構成之群組,且Z係選自由NH、 C=O、 C(=O)NH及C(=O)O所構成之群組;且 D係選自由紫杉醇(paclitaxel)、愛萊諾迪肯(irinotecan)、托伯狄肯(topotecan)、吉姆賽他賓(gemcitabine)、順鉑(cisplatin)、葛爾德黴素( geldanamycin)及美登素(mertansine)所構成之群組。
於另一更佳實施例中,本發明係關於一種治療性化合物,其具有結構式A-B-D,其中: A係為具有結構式(I)之一化合物,其中W係為,且m係為18; B係為具有結構式(IV)之一鏈結化合物,其中Y係為C=O,且Z係為C=O、 C(=O)NH或C(=O)O,且n係為3或4;且 D係為紫杉醇(paclitaxel), 其中A與D之比例係為1:1。
於另一更佳實施例中,本發明係關於一種治療性化合物,其具有結構式A-B-D,其中: A係為具有結構式(I)之一化合物,其中W係為,且m係為18; B係為一鍵結或具有結構式(IV)之一鏈結化合物,其中Y係為C=O,且Z係為NH,且n係為1或3;且 D係為葛爾德黴素( geldanamycin), 其中A與D之比例係為1:1。
於另一更佳實施例中,本發明係關於一種治療性化合物,其具有結構式A-B-D,其中: A係為具有結構式(I)之一化合物,其中W係為,且m係為18; B係為一鍵結;且 D係為美登素(mertansine), 其中A與D之比例係為1:1。
另一方面,本發明提供一種治療性組合物,其包含一種本發明之化合物結合於一種或多種藥用載體。
另一方面,本發明提供一種治療癌症之方法,其包含提供有效劑量之本發明治療性化合物予患有癌症之對象。
於一實施例中,本發明提供一種治療癌症之方法,其包含提供有效劑量之本發明治療性化合物予患有癌症之對象,其中該癌症係包含癌幹細胞。
於另一實施例中,本發明提供一種治療癌症之方法,其包含提供有效劑量之本發明治療性化合物予患有癌症之對象,其中該癌症係為復發癌症。
定義:於此,「治療」一詞包含預防性以及失調馳張治療,包括降低、壓抑及抑制癌症進程或復發。於此,「降低」、「壓抑」以及「抑制」等詞句有其一般性理解,亦即減輕或減少。於此,「進程」代表範圍或嚴重性之增加、演進、增長或更加嚴重。於此,「復發」一詞代表症狀消除後再次出現。
於此,「施以」一詞代表使患者、組織、器官或細胞接觸本發明之一抗癌化合物。於此,施以方式可藉由離體(例如於試管中)或體內(例如於活體生物如人類之細胞或組織中)。於特定實施例中,本發明包含將本發明之化合物有效地施於患者或個體。「患者」或「個體」二詞於此係可等同互用,亦指一哺乳類動物,較佳者係指人類,其:(1)具有一可利用磷脂乙醚(PLE)化合物施以抗癌藥物以補救或治療之失調症,或(2)可能受一失調症所影響,該失調症可藉由施以本發明抗癌化合物加以預防。
於此,「有效量」一詞係指足以影響一目標生物效果之含量,該效果可造成有益結果,該結果包括但不限於預防、降低、改善或消除一疾病或失調症之症狀。故,該藥用化合物或方法之各活性成分係足以顯示對個體有益之意義。一有效量係可用於施以一種或多種預防性藥物或治療性藥物實施。
於此,「治療性化合物」一詞係指任何可提供癌症治療效果之化學化合物。
於此,「癌症」一詞係指經未受控制之可轉移細胞之分裂所導致之任何疾病。
「化學療法藥物」、「抗癌藥物」及「抗腫瘤藥物」等詞於說明書中係可互換使用。
於此,「惡性腫瘤細胞」以及「癌細胞」係於可說明書中互換使用。「惡性腫瘤幹細胞」以及「癌幹細胞」係可於說明書中互換使用。
於此,「組合物」一詞係包含一產品,該產品具有特定含量之特定成分,亦指任何可直接或間接經組合特定含量之特定成分後所形成之產品。
於此,「A」一字係指一具有結構式、或之一磷脂乙醚(phospholipid ether)。
於此,「W」一字係指一芳香基(aryl)、一C1
-C6
烷基(C1
-C6
alkyl)、一烯基(alkenyl)、一選擇性取代之C3
-C6
環烷基(C3
-C6
cycloalkyl)以及一選擇性取代之C3
-C6
異環烷基(C3
-C6
heterocycloalkyl)。
於此,「芳香基」一詞係指一芳香環,其具有一苯基(phenyl group)。
於此,「烷基」一詞於未特別敘述時,皆係指一分支或直鏈烷基,其係由具有1至24個碳原子(C1
-C24
)之一飽和羥基(hydrocarbon group)所構成。該烷基係可為有環結構(cyclic)或無環(acyclic)結構。
於此,「烯基」一詞係指一雙碳雙鍵結構。
於此,「環烷基」一詞係指具有3至24個碳原子(C3
-C24
)之一環烷基。
於此,「異環烷基」一詞係指具有3至24個碳原子(C3
-C24
)之一環烷基,其係選自碳(carbon)、氮( nitrogen)、 硫(sulfur)、 磷(phosphate)及氧(oxygen),其中至少一原子係為碳。
總括而言,「經取代」一詞無論其前方是否存在「選擇性」一詞,皆係指目標官能基之至少一氫係由一合適之取代基加以取代。除額外特別敘述,否則一「選擇性取代」基可於其中各適當位置具有一合適之取代基,且當任何結構中至少一位置可由超過一特定基所取代時,該每一位置之取代基係可為彼此相同或相異。由本發明所衍生之取代基組合較佳者,係為由穩定或化學上可行之化合物所形成者。
於此,「R」一字係指一氫(H)或一烷基。
於此,「m」一字係指12至24間之一整數。
於此,「n」一字係指0至6間之一整數。
於此,「B」一字係指一鏈結化合物。於此,「鏈結化合物」一字係指可利用兩種以上其他不同化學化合物形成一化學鍵之任何化學化合物,藉此,所有化合物可形成一單一較大化合物。於一實施例中,該鏈結化合物係為一鍵結。複數鏈結化合物可用於形成該較大化合物。於特定實施例中,鏈結化合物一詞係為一鍵結或具有結構式Y-(CH2
)n
-Z之一化合物。
於此,「Y」一字係指一鍵結、O、NH、 C=O、 NHSO2
O或OC(=O)O。
於此,「Z」一字係指O、NH、C=O、C(=O)O、C(=O)NH、SO2
、OC(=O)OCH2
或–S-S-。
於此,「D」一字係指目前已知或已於開發中之任何抗癌藥物。
於此,「異構」一詞係括但不限於光學異構物及其同類物、結構異構物及其同類物、構形異構物及其同類物以及類似物。於一實施例中,本發明包含本發明不同光學異構物之用途。本領域精通技藝之人士可瞭解本發明所揭露有益之抗癌化合物可具有至少一立體異構源中心(steriogenic center)。於此,本發明方法中所使用之化合物可以光學活性(optically-active form)或外消旋型態(racemic form)存在,並可以該等型態分離。
應可理解地,本發明可含利用任何異消旋、光學活性、多形或立體異構化(stereroisomeric)型態或該等型態混合之用途,該等型態之屬性適用於此處所描述與主張之癌症相關症狀治療。於一實施例中,該等抗癌化合物可包含純粹(R)-異構物。於另一實施例中,該等抗腫瘤化合物可含純粹(S)-異構物。於另一實施例中,該等化合物可包含(R)及(S)異構物之混合。於另一實施例中,該等化合物可包含一異消旋混合物,其中具有(R)及(S)異構物兩者。該領域中已知如何製備光學活性型態物(例如藉由再結晶化技術將異消旋型態解析、藉由自光學活性起始物進行合成、藉由對掌性合成(chiral synthesis)或利用一對掌性固相進行層析分離)。
本發明包含胺基取代化合物之可藥用鹽類搭配有機及無機酸類之用途,舉例而言,檸檬酸(citric acid)與氫氯酸(hydrochloric acid)。本發明亦包含此處所述化合物之胺基取代基的N-氧化物類(N-oxides)。可藥用鹽類亦可藉由無機鹼(inorganic base)處理而自酚類化合物所製備,例如氫氧化鈉(sodium hydroxide)。再者,酚類化合物之酯類(esters)可利用脂族羧酸類及芳香族羧酸類(aliphatic and aromatic carboxylic acids)加以製備,例如乙酸酯及苯甲酸酯(acetic acid and benzoic acid ester)。於此,「可藥用鹽」一詞係指自一基底化合物所配置之化合物,其可實質上達成與該基底化合物相同之藥用效果。
本發明進一步包含該等抗癌化合物之衍生物。「衍生物」一詞包含但不限於乙醚類衍生物、酸類衍生物、胺基衍生物、酯類衍生物以及類似物.此外,本發明進一步包含利用該抗腫瘤化合物之水合物(hydrate)的方法。「水合物」一詞包括但不限於半水合物(hemihydrate)、單水合物(monohydrate)、二水合物(dihydrate)、三水合物(trihydrate)以及類似物。
本發明進一步包含該等抗癌化合物之代謝物。「代謝物」一詞代表自另一物質藉由新陳代謝或代謝作用所產生之物質。
可以本發明化合物所治療之癌症包括但不限於:乳癌,包含男性乳癌;消化道/胃腸癌,包含肛門癌、盲腸癌、肝外膽管癌、胃腸類癌腫瘤、結腸癌、食道癌、膽囊癌、胃癌、胃腸道基質腫瘤(gist)、胰島細胞腫瘤、成人原發性肝癌、幼兒肝癌、胰臟癌、直腸癌、小腸癌以及胃癌(gastric cancer);內分泌腺及神經內分泌腺癌,包含胰腺癌、腎上腺皮質癌(adrenocortical carcinoma)、胰臟神經內分泌腺腫瘤(pancreatic neuroendocrine tumor)、莫柯爾氏細胞癌(Merkel cell carcinoma)、非小細胞肺神經內分泌腺腫瘤(non-small cell lung neuroendocrine tumor)、小細胞肺神經內分泌腫瘤(small cell lung neuroendocrine tumor)、副甲狀腺癌(parathyroid cancer)、嗜鉻細胞瘤(pheochromocytoma)、腦下腫瘤(pituitary)及甲狀腺癌(thyroid cancer);眼癌類,包括眼球內黑色素瘤(intraocular melanoma)及視網膜母細胞瘤(retinoblastoma);生殖泌尿道癌,包含膀胱癌、腎臟(腎細胞)癌、陰莖癌(penile cancer)、前列腺癌(prostate cancer)、過渡性腎盂及輸尿管癌(transitional cell renal pelvis and ureter cancer)、睪丸癌、尿道癌(urethral cancer)及威爾姆斯瘤(Wilms tumor);生殖細胞癌類,包含幼童中樞神經系統癌(childhood central nervous system cancer)、幼童顱外生殖細胞腫瘤(childhood extracranial germ cell tumor)、生殖腺外生殖細胞腫瘤(extragonadal germ cell tumor)、卵巢生殖細胞腫瘤(ovarian germ cell tumor)及睪丸癌;婦科癌類,包含子宮頸癌(cervical cancer)、子宮內膜癌(endometrial cancer)、妊娠滋養細胞腫瘤(gestational trophoblastic tumor)、卵巢上皮癌(ovarian epithelial cancer)、卵巢生殖細胞腫瘤(ovarian germ cell tumor)、子宮肉瘤(uterine sarcoma)、陰道癌(vaginal cancer)及陰門癌(vulvar cancer);頭頸癌類,包含咽下癌(hypopharyngeal cancer)、喉頭癌(laryngeal cancer)、嘴唇及口腔癌、隱匿原發性轉移鱗狀頸部癌(metastatic squamous neck cancer with occult primary)、口癌、鼻咽癌(nasopharyngeal cancer)、口咽癌(oropharyngeal cancer)、富鼻竇及鼻腔癌(paranasal sinus and nasal cavity cancer)、副甲狀腺癌(parathyroid cancer)、咽癌(pharyngeal cancer)、唾液腺癌(salivary gland cancer)及喉癌(throat cancer);白血病,包括成人急性淋巴母細胞白血病(adult acute lymphoblastic leukemia)、幼兒急性淋巴母細胞白血病(childhood acute lymphoblastic leukemia)、成人急性骨髓性白血病(adult myeloid leukemia)、幼兒急性骨髓性白血病(childhood acute myeloid leukemia)、慢性淋巴球性白血病(chronic lymphocytic leukemia)、慢性骨髓性白血病(chronic myelogenous leukemia)及毛細胞白血病(hairy cell leukemia);淋巴瘤類,包括愛滋病引發淋巴瘤(AIDS-related lymphoma)、皮膚T細胞淋巴瘤(cutaneous t-cell lymphoma)、成人何杰金氏淋巴瘤(adult Hodgkin lymphoma)、幼兒何杰金氏淋巴瘤(childhood Hodgkin lymphoma)、懷孕期何杰金氏淋巴瘤(Hodgkin lymphoma during pregnancy)、原發性中樞神經系統淋巴瘤(primary central nervous system lymphoma)、塞澤里症候群(Sézary syndrome)及華氏巨球蛋白血症(Waldenström macroglobulinemia);肌肉骨骼癌類,包含埃文氏肉瘤(Ewing sarcoma)、骨肉瘤(osteosarcoma)以及惡性纖維組織細胞瘤(malignant fibrous histocytoma)、幼兒橫紋肌肉瘤(childhood rhabdomyosarcoma)以及軟組織肉瘤(soft-tissue sarcoma);神經系統瘤類,包括成人腦腫瘤、幼兒腦腫瘤、星細胞瘤(astrocytomas)、腦幹神經膠質瘤(brain stem 神經膠質瘤)、中樞神經系統非典型畸胎/類橫紋肌細胞瘤(central nervous system atypical teratoid/rhabdoid tumor)、中樞神經系統胚胎細胞瘤(central nervous system embryonal tumor)、顱咽管瘤(craniopharyngioma)、室管膜瘤(ependymoma)、神經母細胞瘤(神經母細胞瘤)、原發性中樞神經系統(CNS)淋巴瘤(primary central nervous system (CNS) lymphoma);呼吸道/胸癌類(respiratory/thoracic cancers),包括非小細胞肺癌(non-small cell lung cancer)、小細胞肺癌(small cell lung cancer)、惡性中皮瘤(malignant mesothelioma)、胸腺瘤及胸腺癌(thymoma and thymic carcinoma);以及皮膚癌類,包括卡波西氏肉瘤(Kaposi sarcoma)、黑色素瘤(melanoma)以及鱗狀上皮細胞瘤(squamous cell carcinoma)。
本發明具有結構式(I)之化合物顯示可受癌幹細胞所螫合,參照Weichert J.P., et al. (2014) 所著文獻之圖2之2(顯示一CLR1404之螢光同類物CLR-1501受人類神經膠母細胞瘤類幹細胞以及經血清培養之人類神經膠母細胞瘤細胞之攝入效果較一般人類星細胞及人胚神經幹細胞而言有所增進。癌幹細胞就算並未與所有癌症相關,也與各主要類型的癌症有所關聯。腫瘤缺氧會刺激癌幹細胞增殖,導致抵抗性以及轉移可能性增加。確切而言,癌幹細胞係與化學療法抗性、腫瘤再生以及化療與放射線療法後轉移作用有所關聯。故,本發明之化合物具有治療經證實對傳統療法會產生抗性之各種型態癌症的效果。本發明之化合物:
本發明可用之藥物輸送載體包括但不限於之化合物係具有結構式(I)(I)或結構式(II)(II)或結構式(III)(III)或該等之結合, 其中W係選自由一芳香基(aryl)、一C1
-C6
烷基(C1
-C6
alkyl)、一烯基(alkenyl)、一選擇性取代之C3
-C6
環烷基(C3
-C6
cycloalkyl)以及一選擇性取代之C3
-C6
異環烷基(C3
-C6
heterocycloalkyl)所構成之群組,其中R係為氫(H)或一烷基,且其中m係為12至24間之一整數。
本發明化合物選擇性鎖定腫瘤之基礎係在於癌細胞之細胞膜與大部分正常細胞之細胞膜之間存在差異,更精確而言,癌細胞膜富含「脂膜筏」。癌細胞所含之脂膜筏係為健康細胞之五至十倍之多,脂膜筏係為細胞膜磷脂雙層之特定區域,其含有高濃度之膽固醇與神經脂質(sphingolipid),係用以組織細胞表面與細胞間傳訊分子(例如生長因子及細胞激素受體,磷脂酸肌醇3-激酶(PI3K)/Akt生存通道)。資料顯示,脂膜筏可作為供磷脂乙醚(PLE)進入之門戶。此等化合物對於癌細胞與非癌細胞之間卓越的選擇性,係歸功於磷脂乙醚(PLE)對於膽固醇之高吸引力以及癌細胞中大量富含膽固醇的脂膜筏。脂膜筏所扮演之樞紐角色相當重要,因為脂膜筏構造之崩解會抑制磷脂乙醚(PLE)受癌細胞攝入之作用,其顯示於脂膜筏受阻礙無法形成時,磷脂乙醚(PLE)之攝入會降低百分之60(見範例2及圖1)。
在超過55例異種移植及自發性腫瘤模組中所取得之初步結果顯示,CLR1404經歷選擇性攝入並經延長留滯於腫瘤中.由於該劑係於某程度上於肝臟中代謝,因肝臟之背景放射性值較高之緣故,發明人避免於肝腫瘤模組中進行早期化合物評估。
CLR1404係為一磷脂乙醚,於各種腫瘤模組中所取得之結果顯示,CLE1404受到癌細胞及癌幹細胞螫合並選擇性滯留於其內。事實上,CLR1404經顯示可於癌細胞內滯留長達20日,參見圖3。CLR1404位於初期及轉移病灶兩者中,無關乎包括淋巴結中之解剖定位何在,參見圖3-8。CLR1404之腫瘤與背景活性比以及腫瘤選擇性較高,代表核心分子相當適合作為抗癌藥物輸送載體使用。
本發明可用之鏈結化合物包括可將本發明之藥物輸送載體鏈結於本發明之抗癌藥物之任何化學鏈結體。本發明可用之鏈結化合物包括可裂解與不可裂解者。於一實施例中,本發明可用之鏈結化合物包括但不限於胺基丁醯胺(aminobutyramide)、胺基酸類(amino acids)、穀氨酸類(glutaramic acids)、二羧酸類(dicarboxylic acids)、胺甲酸類(carbamic acids)、一羰基(carbonyl)、9,10-蔥二羧酸(9,10-anthracenedicarboxylic acid)、連苯-3,3′,5,5′-四羧酸(biphenyl-3,3′,5,5′-tetracarboxylic acid)、連苯-3,4′,5-三羧酸(biphenyl-3,4′,5-tricarboxylic acid)、5-溴基異苯二甲酸(5-bromoisophthalic acid)、5-氰基-1,3-苯二甲酸(5-cyano-1,3-benzenedicarboxylic acid)、2,2′-胺基-4,4′-二苯乙基羧酸(2,2′-diamino-4,4′-stilbenedicarboxylic acid)、2,5-二胺基對苯二甲酸(2,5-diaminoterephthalic acid)、2,5-二羥基對苯二甲酸(2,5-dihydroxyterephthalic acid)、5-乙炔基-1,3-苯二甲酸(5-ethynyl-1,3-benzenedicarboxylic acid)、2-羥基對苯二甲酸(2-hydroxyterephthalic acid)、咪唑(imidazole)、2-甲基咪唑(2-methylimidazole)、2,6-萘二羧酸(2,6-naphthalenedicarboxylic acid)、草酸脫水物(oxalic acid dehydrate)、對苯二甲酸(terephthalic acid)、[1,1′:4′,1″]三苯- 3,3″,5,5″-四羧酸(terphenyl- 3,3″,5,5″-tetracarboxylic acid)、3,3′,5,5′-四羧二苯甲烷(3,3′,5,5′-tetracarboxydiphenylmethane)、1,2,4,5-四(4-羧苯基)苯(1,2,4,5-tetrakis(4-carboxyphenyl)benzene)、4,4′,4″-s-三𠯤-2,4,6-三基-三苯甲酸(4,4′,4″-s-triazine-2,4,6-triyl-tribenzoic acid)、對苯三甲酸(trimesic acid)、1,3,5-三(4′-羧基[1,1′-聯苯]-4-基)甲苯(1,3,5-tris(4′-carboxy[1,1′-biphenyl]-4-yl)benzene)、1,3,5-三(4-羧苯基)苯(1,3,5-tris(4-carboxyphenyl)benzene)以及1,3,5-三羧苯基乙炔基苯(1,3,5-triscarboxyphenylethynylbenzene)。
於另一實施例中,本發明可用之鏈結化合物亦包含但不限於對溶小體蛋白質水解酵素敏感之鏈結體(lysosomal protease sensitive linker),其可具有或不具苯胺基自我斷裂斷片(self-immolative fragment)者。非用於限定之對溶小體蛋白質水解酵素敏感之鏈結體範例係為及,其具有纈氨酸-瓜氨酸雙胜肽(valine–citrulline dipeptide)鏈結體,用以表現細胞穩定性(plasma stability)及細胞間蛋白質水解酵素裂解間之光學均衡,參見於此所引Tranoy-Opalinski I.之參考文獻,用於腫瘤激發前驅藥療法之自我斷裂鏈結體之設計(Design of self-immolative linkers for tumour-activated prodrug therapy,Anticancer Agents Med Chem
, 2008 Aug, 8(6):618-637)。
於另一實施例中,本發明可用之鏈結化合物亦包含但不限於自我斷裂鏈結體,其係由β-葡萄醣醛酸酶(β-glucuronidase)所裂解.β-葡萄醣醛酸酶係於癌細胞周圍壞死區域中高濃度存在,參照於此所引Tranoy-Opalinski I. 之參考文獻,對β-葡萄醣醛酸酶產生反應之前驅藥用於選擇性癌症化學療法:更新版(β-glucuronidase- responsive prodrugs for selective cancer chemotherapy: An update,Eur J Med Chem
, 2014 Mar 3, 74, 302-313)。非用於限定之由β-葡萄醣醛酸酶所裂解之自我斷裂鏈結體範例係為及,其中X係為NH2
或NO2
,且其中Y係為O或NCH3
。
本發明可用之鏈結化合物較佳者係為一鍵結或具有結構式(IV),Y-(CH2
)n
-Z之一化合物,其中: Y係鍵結於A; Z係鍵結於D; Y係選自由一鍵結、O、NH、 C=O、 NHSO2
O及OC(=O)O所構成之群組; Z係選自由O、NH、 C=O、 C(=O)O、 C(=O)NH、 SO2
、OC(=O)OCH2
及–S-S-所構成之群組;且 n係為0至6間之一整數。
本發明可用之鏈結化合物更加者係為一鍵結或具有結構式(IV)之一化合物,其中n係為0至6間之一整數,Y係鍵結於A,Z係鍵結於D,Y係選自由一鍵結及 C=O所構成之群組,且Z係選自由NH、 C=O、 C(=O)NH及C(=O)O所構成之群組。
本發明可用之抗癌藥物可包括但不限於paclitaxel、 irinotecan、 topotecan、 gemcitabine、 cisplatin、 geldanamycin、 mertansine、 abiraterone、 afatinib、 aminolevulinic acid、 aprepitant、 axitinib、 azacitidine、 belinostat、 bendamustine、 bexarotene、 bleomycin、 bortezomib、 bosutinib、 busulfan、 cabazitaxel、 cabozantinib、 capecitabine、 carboplatin、 carfilzomib、 carmustine、 ceritinib、 cetuximab、 chlorambucil、 clofarabine、 crizotinib、 cyclophosphamide、 cytarabine、 dabrafenib、 dacarbazine、 dactinomycin、 dasatinib、 daunorubicin、 decitabine、 denosumab、 dexrazoxane、 docetaxel、 dolastatins (如 monomethyl auristatin E)、 doxorubicin、 enzalutamide、 epirubicin、 eribulin mesylate、 erlotinib、 etoposide、 everolimus、 floxuridine、 fludarabine phosphate、 fluorouracil、 ganetespib、 gefitinib、 gemtuzumab ozogamicin、 hexamethylmelamine、 hydroxyurea、 ibritumomab tiuxetan、 ibrutinib、 idelalisib、 ifosfamide、 imatinib、 ipilimumab、 ixabepilone、 lapatinib、 leucovorin calcium、 lomustine、 maytansinoids、 mechlorethamine、 melphalan、 mercaptopurine、 mesna、 methotrexate、 mitomycin C、 mitotane、 mitoxantrone、 nelarabine、 nelfinavir、 nilotinib、 obinutuzumab、 ofatumumab、 omacetaxine mepesuccinate、 oxaliplatin、 panitumumab、 pazopanib、 pegaspargase、 pembrolizumab、 pemetrexed、 pentostatin、 pertuzumab、 plicanycin、 pomalidomide、 ponatinib hydrochloride、 pralatrexate、 procarbazine、 radium 223 dichloride、 ramucirumab、 regorafenib、 retaspimycin、 ruxolitinib、 semustine、 siltuximab、 sorafenib、 streptozocin、 sunitinib malate、 tanespimycin、 temozolomide、 temsirolimus、 teniposide、 thalidomide、 thioguanine、 thiotepa、 toremifene、 trametinib、 trastuzumab、 vandetanib、 vemurafenib、 vinblastine、 vincristine、 vinorelbine、 vismodegib、 vorinostat、以及ziv-aflibercept。任何已知或可作為抗癌藥物之化合物皆可受本發明所使用。
本發明之磷脂乙醚藥物輸送載體可單獨或多數結合於任意數量之一抗癌藥物,其可透過鏈結化合物以達成穩定之結合效果或可直接結合。本發明成分:
另一方面,本發明提供一種藥用組合物,其包含本發明之一化合物結合一種以上可藥用載體。於較佳方面,該藥用組合物中不含Kolliphor® EL (Kolliphor係為BASF SE之註冊商標)。Kolliphor® EL先前係已知為Cremophor® EL(Cremophor係為BASF SE之註冊商標)。
本發明中藥用組合物之活性成分確切劑量可有所變動,藉以取得使一特定患者或組合物或施用方式可達到目標治療反應之有效活性化合物量。選定之劑量將依該特定化合物之活性、施用之途徑、欲治療症狀之嚴重性,以及受治療患者之症狀及病史而定。然而,本領域精通技藝者可使該化合物之初期劑量低於能達成目標藥效之必須劑量,並逐漸將劑量增加至達成目標效果為止。
本發明化合物之「藥效劑量」一詞係指該化合物於存在合理效益/風險比例之情況下使用於任何醫療方式並足以治療失調症之用量。然而應理解,本發明之化合物及組合物之每日總用量,需經諮詢具有可靠醫學判斷背景之醫師來決定。對於任何特定患者之特定藥效劑量需依照多種因素而定,包括該失調症為何及其嚴重性;所使用特定化合物之活性;所使用之特定組合物為何;患者年齡、體重、整體健康狀況、性別及飲食狀況;施用時間、途徑以及所使用特定化合物之排泄比率;治療期間長短;與所使用之特定化合物結合使用或同時使用之藥物;以及醫療領域其他已知相關因素。舉例而言,本領域精通技藝之人士已知,可使化合物初期劑量低於能發揮目標藥效之必須劑量,再逐漸增加劑量至達到目標效果。
本發明化合物施予人類或較低等動物之每日總用量範圍係介於約0.0001mg至約1000 mg/公斤/每日。用於口服時,較佳劑量範圍係介於約0.0001mg至約5mg/公斤/每日。若有需求時,每日有效劑量可依照施用方式分為數次使用;因此,可施予多次組合物以使其各單一劑量加總達到每日有效劑量。
本發明亦提供藥用組合物,其包含本發明化合物與一種以上可藥用載體共同調配。該藥用組合物可以口服為目的經特別調配為固態或液態,或非口服型態或直腸施用型態。
本發明藥用組合物可以口服、直腸、非口服、腦池內、陰道內、經皮(例如使用貼片)、經黏膜、舌下、肺部、腹膜內、外用(如粉末、軟膏或滴劑)、口腔、口腔噴霧或鼻腔噴霧等方式施予人類或其他哺乳類。於此,「非外用」一詞係指包含靜脈內、肌肉內、腹膜內、胸骨內、皮下或關節內注射或注入等施用方式。
另一方面,本發明提供一種藥用組合物,其包含本發明之一成分以及一生理可忍受之稀釋劑。本發明包含一種以上之化合物,與組合物以及一種以上此處所通稱為稀釋劑之生理可忍受或可接受之稀釋劑、載體、佐劑或輸送載體一同調配,用於非口服注射、鼻內施用、固態或液態口服、直腸或局部施用。
非口服注射之適用組合物可包含生理可接受精消毒或非水性溶液、分散液、懸浮液或乳液,以及用於還原為經消毒可注射溶液或分散液之經消毒粉末。可用之水性及非水性載體、分散液、溶劑或輸送載體包含例如水、乙醇(ethanol)、多元醇類(polyols)(丙二醇(propylene glycol)、聚乙二醇(polyethylene glycol)、甘油(glycerol)及類似物)、蔬菜油(例如橄欖油)、可注射有機酯類如油酸乙酯(ethyl oleate),以及上述該等可用之混合物。
該等組合物亦可含有佐劑例如防腐劑、濕潤劑、乳化劑及分散劑。微生物活性之預防可藉由各種抗菌及抗真菌劑加以確保,例如對羥基苯甲酸酯(paraben)、氯丁醇(chlorobutanol)、苯酚(phenol)、山梨酸(sorbic acid)及類似物。亦可具有等張劑(isotonic agent),例如糖、食鹽(sodium chloride)及類似物。可注射藥用型態之吸收延長效果可利用吸收延遲劑達成,例如鋁單硬脂酸酯(aluminum monostearate)與明膠(gelatin)。
懸浮液除活性化合物外亦可具有懸浮劑,例如乙氧基化異十八醇類(ethoxylated isostearyl alcohols)、聚氧乙烯山梨醇(polyoxyethylene sorbitol)、山梨醇酐酯類(sorbitan esters)、微晶性纖維素(microcrystalline cellulose)、偏氫氧化鋁(aluminum metahydroxide)、膨土(bentonite)、洋菜(agar-agar)以及黃蓍膠(tragacanth)或該等之類似物。
儲存型可注射型態之製備可藉由於生物可分解之聚合物如聚乳酸-聚乙交酯(polylactide-polyglycolide)中形成微膠囊體之方式達成。依據藥物與聚合物之比例,以及所使用特定聚合物之性質而定,藥物釋放比率可受到控制。其他生物可分解聚合物之包括例如聚(原酸酯)類(poly(orthoesters))以及聚(酐酸)類(poly(anhydrides))。儲存型可注射配方亦可藉由將藥物包覆於可存於身體組織之脂質體(liposome)或微乳液(microemulsion)中加以製備。
可注射配方可經消毒,例如,藉由可濾除細菌之過濾器加以過濾,或於使用前利用可溶於或可散於消毒水之固態消毒組合物型態之消毒劑或利用其他可注射消毒介質加以消毒。
口服之固體劑量型態包含膠囊、藥錠、藥片、藥粉與藥粒。於此等固體型態中,活性化合物可與至少一惰性可藥用賦形劑或載體混合,例如檸檬酸鈉(sodium citrate)或磷酸氫鈣(dicalcium phosphate)以及/或(a)充填劑或延伸劑如澱粉、乳糖、蔗糖、葡萄糖、甘露醇(mannitol)及矽酸(silicic acid);(b)黏結劑如羧甲基纖維素(carboxymethylcellulose)、海藻酸鹽類(alginates)、明膠、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、蔗糖及阿拉伯膠(acacia);(c)保濕劑(humectant)如甘油(glycerol);(d)崩散劑(disintegrating agent)如洋菜、碳酸鈣(calcium carbonate)、馬鈴薯或樹薯澱粉、海藻酸(alginic acid,)、矽酸鹽(silicate)及碳酸鈉(sodium carbonate);(e)溶液阻滯劑(solution retarding agents)如石蠟(paraffin);(f)吸收促進劑如四級銨化合物(quaternary ammonium compound);(g)濕潤劑如鯨蠟醇(cetyl alcohol)及甘油單硬脂酸酯(glycerol monostearate);(h)吸收劑類(absorbents)如高嶺土(kaolin)以及膨土(bentonite clay);以及(i)潤滑劑如滑石(talc)、鈣硬脂酸酯(calcium stearate)、鎂硬脂酸酯(magnesium stearate)、固態聚乙二醇類(solid polyethylene glycols)、月桂硫酸鈉(sodium lauryl sulfate)以及上述該等之混合。於膠囊、藥錠及藥片狀態時,該劑量型態亦可包含緩衝劑類。
近似種類之固態組合物亦可利用乳糖或高分子聚乙二醇類(high molecular weight polyethylene glycols)及相似物作為軟充填及硬充填明膠膠囊中之充填劑。
固態劑量型態之藥錠、糖衣錠、膠囊、藥片與藥粒等,可使用塗層與外殼方式製備,例如腸衣或其他藥用配方技藝中已知之塗層,其可選擇性具有失透劑類(opacifying agents),且亦可為僅釋放活性成分或較佳者僅於腸道中釋放成分,或選擇性延遲釋放成分之組合物。可用於包覆組合物之素材可例如聚合物質與蠟。
該等活性化合物亦可製為微膠囊型態,其中可搭配上述一種或多種賦形劑。
用於口服之液體劑量型態包括可藥用乳液、溶液、懸浮液、糖漿與馳劑(elixir)。於了該等活性化合物外,液體劑量型態亦具有此技術領域常用之惰性稀釋劑,例如水或其他溶劑類、助溶劑與乳化劑如乙醇(ethyl alcohol)、異丙醇(isopropyl alcohol)、碳酸乙酯(ethyl carbonate)、乙酸乙酯(ethyl acetate)、苯甲醇(benzyl alcohol)、苯甲酸苯甲酯(benzyl benzoate)、丙二醇(propylene glycol)、1,3-丁二醇(1,3-butylene glycol)、二甲基甲醯胺(dimethyl formamide)、油脂類(更詳而言之係為棉花籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油(caster oil)及芝麻油)、甘油、四氫糠醇(tetrahydrofurfuryl alcohol)、聚乙二醇類(polyethylene glycols)及脂肪酸酯山梨醇酐,以及上述該等之混合。
除了惰性稀釋劑外,口服組合物亦可具有佐劑,如濕潤劑、乳化及懸浮劑、甘味劑、風味與香味劑。
用於直腸或陰道施用之組合物較佳者係為栓劑,其可藉由混合本發明化合物以及是用之無刺激性賦形劑或載體加以製備,例如可可脂、聚乙二醇或栓劑蠟,該等成分於室溫下為固體,但於體溫環境則為液體狀,可於直腸或陰道腔中融化並釋放活性化合物。
本發明化合物亦可以脂質體型態施用。如技藝領域中已知,脂質體一般係衍生自磷脂或其他脂質物質。脂質體係藉由一水性介質所擴散之單層或多層狀脫水液晶形成。任何生理可接受或可代謝並可形成脂質體脂之脂質皆可使用。本發明之組合物於脂質體型態,除本發明化合物外,還可具有穩定劑、防腐劑、賦形劑及類似物。較佳之脂質係為天然脂質及合成磷脂類及膽鹼磷脂類(phosphatidyl cholines)(卵磷脂類),其可個別使用或共同使用。形成脂質體之方法係為業界所習知,舉例而言,可參見Prescott, Ed所著,細胞生物學方法(Methods in Cell Biology ,
Volume XIV, Academic Press, New York, N.Y. (1976), p. 33et seq. )
。此類組合物可影響物理狀態、溶解度、穩定度、體內釋放率以及體內清除率。
於本發明之一方法中,一藥用組合物可輸送於一受控制釋放系統中。舉例而言,該劑可利用靜脈內注射、可植入式滲透幫浦、皮膚貼片、脂質體之方式或其他方法施用。於一實施例中係可利用一幫浦(參見Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987)以及 Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989));於另一實施例中係可利用聚合物質;又於另一實施例中,可將一受控制釋放系統置於治療目標附近,例如肝臟,故全身僅需小部分劑量(參見Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984))。其他受控制釋放系統則經Langer於評閱中((Science 249:1527-1533 (1990))有所討論。
於另一實施例中,本發明係關於一種治療個體之疾病或症狀之方法,其包含對個體施以有效劑量之本發明化合物。
總括而言,本發明並非限於治療任何特定疾病或症狀,而係包含治療任何能受本發明化合物影響其機轉之疾病或症狀。
代表性實施例:Paclitaxel-CLR1404 之共軛物
於本發明一實施例中,治療性化合物係為藉由二羧酸(dicarboxylic acid)連結劑與CLR1404核心化合物連結之紫杉醇(paclitaxel),其中二羧酸連結劑係藉由一醯胺鍵與CLR1404核心化合物連結,並透過2’-OH官能基上之一酯鍵與紫杉醇連結。
於本發明一較佳實施例中,治療性化合物係為藉由穀氨酸(glutaramic acid)連結劑與CLR1404核心化合物連結之紫杉醇(paclitaxel),其中穀氨酸連結劑係藉由一醯胺鍵與CLR1404核心化合物連結,並透過2’-OH官能基上之一酯鍵與紫杉醇連結。CLR1601之共軛物。
於本發明另一實施例中,治療性化合物係為藉由二羧酸(dicarboxylic acid)連結劑與CLR1404核心化合物連結之紫杉醇(paclitaxel),其中二羧酸連結劑係藉由一醯胺鍵與CLR1404核心化合物連結,並透過7-OH官能基上之一酯鍵與紫杉醇連結。
於本發明另一實施例中,治療性化合物係為藉由胺甲酸(carbamic acid)連結劑與CLR1404核心化合物連結之紫杉醇(paclitaxel),其中胺甲酸連結劑係藉由一醯胺鍵與CLR1404核心化合物連結,並透過7-OH官能基上之一酯鍵與紫杉醇連結。
於本發明另一實施例中,治療性化合物係為藉由碳-羧酸(carbonic-carboxylic acid)連結劑與CLR1404核心化合物連結之紫杉醇(paclitaxel),其中碳-羧酸連結劑係藉由一醯胺鍵與CLR1404核心化合物連結,並透過7-OH官能基上之一酯鍵與紫杉醇連結。CLR1603之共軛物。
於本發明另一實施例中,治療性化合物係為藉由二羧酸(dicarboxylic acid)連結劑與二CLR1404核心化合物連結之紫杉醇(paclitaxel),其中碳-羧酸連結劑係藉由醯胺鍵與CLR1404核心化合物連結,並透過2’-OH group 及7-OH官能基兩者上之酯鍵與紫杉醇連結。
於本發明另一實施例中,治療性化合物係為藉由二羧酸(dicarboxylic acid)連結劑與CLR1404核心化合物連結之紫杉醇(paclitaxel),其中二羧酸連結劑係藉由一醯胺鍵與CLR1404核心化合物連結,並透過2’-OH官能基上之一碳酸鍵或一氨基甲酸鍵(carbamate bond)與紫杉醇連結。
於本發明另一實施例中,治療性化合物係為藉由二羧酸(dicarboxylic acid)連結劑與CLR1404核心化合物連結之紫杉醇(paclitaxel),其中二羧酸連結劑係藉由一醯胺鍵與CLR1404核心化合物連結,並透過7-OH官能基上之一碳酸鍵或一氨基甲酸鍵(carbamate bond)與紫杉醇連結。
於本發明另一實施例中,治療性化合物係為藉由二羧酸(dicarboxylic acid)連結劑與二CLR1404核心化合物連結之紫杉醇(paclitaxel),其中二羧酸連結劑係藉由醯胺鍵與二CLR1404核心分子連結,並透過2’-OH官能基及7-OH官能基兩者上之一碳酸鍵或一氨基甲酸鍵(carbamate bond)與紫杉醇連結。
於本發明一實施例中,治療性化合物係為藉由羧酸(carboxylic acid)連結劑與C18烷基磷膽鹼(alkyl phosphocholine)化合物連結之紫杉醇(paclitaxel),其中羧酸連結劑係藉由一醯胺鍵或碳酸鍵與C18烷基磷膽鹼化合物連結,並透過2’-OH官能基上之一碳酸鍵或一氨基甲酸鍵(carbamate bond)與紫杉醇連結。 愛萊諾迪肯( irinotecan )- CR1404 之共軛物
於本發明一實施例中,治療性化合物係為藉由二羧酸(dicarboxylic acid)連結劑與CLR1404核心化合物連結之愛萊諾迪肯(irinotecan),其中二羧酸連結劑係藉由一碳酸鍵或一氨基甲酸鍵(carbamate bond)與CLR1404核心化合物連結,並透過一酯鍵(ester bond)與愛萊諾迪肯連結。 愛萊諾迪肯( irinotecan )- C18 烷基磷膽鹼( alkyl phosphocholine )之共軛物
於本發明一實施例中,治療性化合物係為藉由一羰基(carbonyl)連結劑與C18烷基磷膽鹼(alkyl phosphocholine)化合物連結之愛萊諾迪肯(irinotecan),其中羰基連結劑係藉由一雙碳鍵與C18烷基磷膽鹼(alkyl phosphocholine)化合物連結,並透過一酯鍵(ester bond)與愛萊諾迪肯連結。 托伯狄肯( topotecan )- CLR1404 之共軛物
於本發明一實施例中,治療性化合物係為藉由一非可水解之二苯醚(non-hydrolyzable phenyl ether)與CLR1404核心化合物連結之托伯狄肯(topotecan)。
於本發明另一實施例中,治療性化合物係為藉由一二羧酸(dicarboxylic acid)連結劑與CLR1404核心化合物連結之托伯狄肯(topotecan),其中二羧酸連結劑係藉由一碳酸鍵或一氨基甲酸鍵(carbamate bond)與CLR1404核心化合物連結,並透過一酯鍵(ester bond)與托伯狄肯連結。 吉姆賽他賓( Gemcitabine )- C18 烷基磷膽鹼( alkyl phosphocholine )之共軛物
本發明一實施例中,治療性化合物係為藉由羰基(carbonyl)連結劑與二C18烷基磷膽鹼(alkyl phosphocholine)化合物連結之吉姆賽他賓(Gemcitabine),其中羰基連結劑係藉由雙碳鍵與C18烷基磷膽鹼化合物連結,並透過酯鍵(ester bond)與吉姆賽他賓連結。
本發明另一實施例中,治療性化合物係為藉由一羰基(carbonyl)連結劑與一C18烷基磷膽鹼(alkyl phosphocholine)化合物連結之吉姆賽他賓(Gemcitabine),其中羰基連結劑係藉由一雙碳鍵與C18烷基磷膽鹼化合物連結,並透過一酯鍵(ester bond)與吉姆賽他賓連結。 順鉑( cisplatin ) -CLR1404 核心之共軛物
本發明一實施例中,治療性化合物係為直接與CLR1404核心化合物連結之順鉑(cisplatin)。 葛爾德黴素( geldanamycin ) -CLR1404 核心之共軛物
本發明一實施例中,治療性化合物係為直接與CLR1404核心化合物連結之葛爾德黴素( geldanamycin)。
本發明另一實施例中,治療性化合物係為藉由一短氨基酸連結劑與CLR1404核心化合物連結之葛爾德黴素( geldanamycin),其中短氨基酸連結劑係藉由一碳酸鍵或一氨基甲酸鍵(carbamate bond)與CLR1404核心化合物連結,並透過一醯胺鍵(amide bond)與葛爾德黴素連結。
本發明一較佳實施例中,治療性化合物係為藉由一胺基丁醯胺(aminobutyramide)連結劑與CLR1404核心化合物連結之葛爾德黴素( geldanamycin),其中胺基丁醯胺連結劑係藉由一氨基甲酸鍵(carbamate bond)與CLR1404核心化合物連結,並透過一醯胺鍵(amide bond)與葛爾德黴素連結。,CLR1606之共軛物以及CLR1607之共軛物。美登素( mertansine )- CLR1404 之共軛物
本發明另一實施例中,治療性化合物係為藉由一順丁烯二醯亞胺(maleimide)連結劑與CLR1404核心化合物連結之美登素(mertansine),其中順丁烯二醯亞胺連結劑係藉由一醯胺鍵(amide bond)與CLR1404核心化合物連結,並透過一碳硫鍵(carbon-sulfur bond)與美登素連結。,CLR1608之共軛物。
就所有代表性實施例中,n係為介於2至6間之整數,且X係為O或NH。 範例: 範例1-共軛物之合成 I. CLR1601之合成 A. CLR1401疊氮(azide)之合成
將18-(p-碘基苯酚)十八基磷膽鹼(18-(p
-Iodophenyl)octadecyl phosphocholine)(4.01克,6.3 毫莫耳)、疊氮化鈉(sodium azide)(818毫克,12.6毫莫耳)以及抗壞血酸鈉(sodium ascorbate)(14. 毫克,0.71毫莫耳)溶於反應容器中之經脫氣乙醇(28毫升)及水(12毫升)混合物中。將銅(I)碘化物(iodide)(120毫克,0.63毫莫耳)以及N
,N’
-二甲基-乙二胺(N
,N’
-dimethyl-ethylenediamine)(0.1毫升,0.94毫莫耳)加入混合物中。反應容器係經緊密封閉,且將該混合物於80°C攪拌45分鐘。反應混合物經冷卻至室溫,並加入水(60毫升),將混合物與空氣接觸狀態下腳半30分鐘。將混合物轉移至分液漏斗,加入三氯甲烷(chloroform)(80毫升)以及甲醇(methanol)(52毫升),藉由搖晃形成萃取液。將三氯甲烷層取出,再重複萃取作業(2 x 80毫升之三氯甲烷)。將三氯甲烷萃取液結合後以0.01N之鹽酸(HCl)沖洗,並以硫酸鈉(Na2
SO4
,)脫水,再經過濾與蒸發乾燥。將殘留物融於三氯甲烷(4毫升),並緩慢加入丙酮(acetone)(170 毫升)且同時進行攪拌。混合物經攪拌30分鐘後進行過濾,再將產物於過濾器上以丙酮沖淨,並於高真空狀態下乾燥以取得3.31克(95%)之18-(p-疊氮苯酚)十八基磷膽鹼(18-(p
-azidophenyl)octadecyl phosphocholine)。 B. CLR1401胺之合成
將18-(p-疊氮苯酚)十八基磷膽鹼(18-(p
-azidophenyl)octadecyl phosphocholine)(3.116 克)置於帕爾壓力瓶(Parr pressure bottle)中,加入甲醇(30毫升)以及催化劑10% Pd/C(100毫克)。於氫壓(55 psi)下搖晃24小時進行氫化反應(hydrogenation)。將壓力瓶減壓,加入三氯甲烷及甲醇以溶解部分沉澱反應產物,再將混合物過濾以去除催化劑。濾出液經蒸發乾燥,再將殘留物溶於溫熱之三氯甲烷-甲醇(1:1)混合物(10毫升)。將熱丙酮(150毫升)緩慢地攪拌加入,將混合物經攪拌冷卻至環境溫度後進行過濾。將產物置於過濾器上以丙酮沖淨,再於高真空狀態下乾燥,製得18-(p
-對胺笨) 十八基磷膽鹼(18-(p
-aminophenyl)octadecyl phosphocholine):2.957克(87%)。 C. 紫杉醇- 2'-半戊二鹽酸(paclitaxel-2'-hemiglutarate)之合成
將紫杉醇(404毫克,0.437毫莫耳)以及戊二酸酐(67毫克,0.588毫莫耳)溶於三氯甲烷(8毫升),並加入比啶(pyridine)(0.5毫升)。反應混合物於室溫攪拌24小時,並經蒸發乾燥。將殘留物至於高真空狀態下1.5小時以去除殘留之比啶。將粗產物藉由矽膠層析法(silica gel chromatography)於三氯甲烷-甲醇(梯度介於98.2至95.5)中進行純化,以製得452毫克(99%)之紫杉醇- 2'-半戊二鹽酸。 D. CLR1601之合成
將紫杉醇- 2'-半戊二鹽酸(paclitaxel-2'-hemiglutarate)(947毫克,0.978毫莫耳)及18-(p
-對胺笨) 十八基磷膽鹼(18-(p
-aminophenyl)octadecyl phosphocholine)(492毫克,0.934毫莫耳)於三氯甲烷(40毫升)及異丙醇(isopropanol)(1.2毫升)之混合物中進行懸浮。為此懸浮作用,將三甲基胺(trimethylamine)(0.27毫升,1.957毫莫耳)及COMU(419毫克,0.978毫莫耳)加入。反應混合物於室溫攪拌20小時,使其呈現清澈且勻相。將反應混合物轉移至分液漏斗,並與三氯甲烷(40毫升)、甲醇(80毫升)及冷水(72毫升)混合。將三氯甲烷層取出,再重複萃取作用(2 x 80毫升三氯甲烷)。結合後之三氯甲烷萃取液以硫酸鈉脫水,經過濾並蒸發乾燥。剩餘殘留物於矽膠上以三氯甲烷-甲醇(梯度介於9:1至5:5)進行層析法純化,再以三氯甲烷-甲醇-水(65:25:4)進行最後洗提。將溶劑蒸發後,將產物於高真空狀態下乾燥,以取得1.167克(85%)之CLR1601。 II. CLR1602之合成 A. 18-[p
-(4-N
-BOC-胺基丁酰氨基)苯基] 十八基磷膽鹼(18-[p
-(4-N
-BOC-aminobutyramido)phenyl]octadecyl phosphocholine)之合成
將18-(p
-對胺笨) 十八基磷膽鹼(18-(p
-aminophenyl)octadecyl phosphocholine)(76毫克,0.144毫莫耳)及18-[p
-(4-N
-BOC-胺基丁酰氨基)苯基] 十八基磷膽鹼(18-[p
-(4-N
-BOC-aminobutyramido)phenyl]octadecyl phosphocholine)(38毫克,0.188毫莫耳)於三氯甲烷(5毫升)及異丙醇(isopropanol)中進行懸浮,加入三乙胺(triethylamine)(0.05毫升,0.38毫莫耳),再加入COMU(80毫克,0.188毫莫耳)。反應混合物於室溫攪拌24小時,並以2毫升保合水性碳酸氫鈉(NaHCO3
)溶液進行冷卻。冷卻後之反應混合物移至一分液漏斗,並與三氯甲烷(35毫升)、甲醇(40毫升)及冷水(36毫升)混合。將三氯甲烷層取出,再重複萃取作業(2 x 40毫升之三氯甲烷。)結合後之三氯甲烷萃取液以硫酸鈉(Na2
SO4
,)脫水,經過濾及蒸發乾燥。殘留物於矽膠上以三氯甲烷-甲醇(梯度介於9:1至5:5)進行層析法純化,再以三氯甲烷-甲醇-水(65:25:4)進行最後洗提。將溶劑蒸發後,將產物溶於溫暖之三氯甲烷-甲醇混合物(1.5毫升),並以丙酮進行沉降。經由過濾並於高真空狀態下乾燥,以取得一白色粉末之產物(100毫克,97%)。 B. 18-[p
-(4-胺基丁酰氨基)苯基] 十八基磷膽鹼(18-[p
-(4- aminobutyramido)phenyl]octadecyl phosphocholine)之合成
將18-[p
-(4-N
-BOC-胺基丁酰氨基)苯基] 十八基磷膽鹼(18-[p
-(4-N
-BOC-aminobutyramido)phenyl]octadecyl phosphocholine)(98毫克,0.138毫莫耳)溶於三氯甲烷(4毫升)、甲醇(2毫升)及濃縮鹽酸(0.2毫升)之混合物中。反應混合物於環境溫度下攪拌隔夜,並經由緩慢加入飽和水性碳酸氫鈉(NaHCO3
)溶液(3毫升)家以冷卻。經冷卻之反應混合物轉移至一分液漏斗中,並與三氯甲烷(40毫升)、甲醇(40毫升)與冷水(36毫升)混合。將三氯甲烷層取出,並再次進行萃取作業(2 x 40毫升之三氯甲烷)。結合後之三氯甲烷萃取液以硫酸鈉(Na2
SO4
,)脫水,經過濾及蒸發乾燥。殘留物於矽膠上以三氯甲烷-甲醇(100:65)進行層析法純化,再以三氯甲烷-甲醇-氫氧化銨(NH4
OH)(100:65:15)進行最後洗提。將溶劑蒸發後,將產物於高真空狀態下乾燥,以取得50毫克(60%)之18-[p
-(4-胺基丁酰氨基)苯基] 十八基磷膽鹼(18-[p
-(4- aminobutyramido)phenyl]octadecyl phosphocholine)。 C. 7-(p
-硝基苯基碳酸) 紫杉醇(7-(p
-nitrophenyl carbonate) paclitaxel)之合成
將紫杉醇(100毫克,0.117毫莫耳)溶於三氯甲烷(4.5毫升)之中,加入8滴比啶(pyridine),並將溶液冰浴冷卻。將固體之p
-硝基苯基碳酸氯甲酸酯(p
-nitrophenyl chloroformate)(200豪攝,1毫莫耳)之一部分加入。反應混合物經加溫至環境溫度並攪拌24小時,再以水(1毫升)冷卻後攪拌15分鐘。混合物以三氯甲烷萃取,萃取液以水洗淨,並以硫酸鈉(Na2
SO4
,)脫水,以及過濾病蒸發乾燥。將粗(雙-2',7-(p
-硝基苯基碳酸) 紫杉醇)溶於三氯甲烷並盛裝至矽膠管柱。粗產物至於管柱中72小時,以完成p
-硝基苯基碳酸(p
-nitrophenyl carbonate)於2’位置之水解。管柱以二氯甲烷-乙酸乙酯(dichloromethane-ethyl acetate)(梯度介於98:2至90:10)進行洗提。於溶液蒸發後,產物以己烷(hexane)進行沉降,並於高真空狀態下以己烷(hexane)進行沉降,並於高真空狀態下乾燥以取得63毫克(53%)之7-(p
-硝基苯基碳酸) 紫杉醇(7-(p
-nitrophenyl carbonate) paclitaxel),參見Arpicco S., et al.,Int J Pharm
, 2013, 454, 653-659。 D. CLR1602之合成
將7-(p
-硝基苯基碳酸) 紫杉醇(7-(p
-nitrophenyl carbonate) paclitaxel)(53毫克,0.052毫莫耳)及18-[p
-(4-胺基丁酰氨基)苯基] 十八基磷膽鹼(18-[p
-(4- aminobutyramido)phenyl]octadecyl phosphocholine)(47毫克,0.077毫莫耳)於三氯甲烷(2毫升)以及比啶(pyridine)(0.5毫升)中進行懸浮,並於40°C攪拌5小時。反應混合物經蒸發乾燥,其殘留物於矽膠上以三氯甲烷-甲醇(梯度介於9:1至5:5)進行層析法純化,再以三氯甲烷-甲醇-水(65:25:4)進行最後洗提。將溶劑蒸發後,將產物於高真空狀態下乾燥,以取得67豪攝(86%)之固體CLR1602。 III. CLR1603之合成 A. 18-[p
-(5-苯甲氧基-正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(5-benzyloxy-valeramido)phenyl]octadecyl phosphocholine)之合成
將18-(p
-對胺笨) 十八基磷膽鹼(18-(p
-aminophenyl)octadecyl phosphocholine)(760毫克,1.443毫莫耳)以及5-苯甲基氧基戊酸(5-benzyloxyvaleric acid)(361毫克,1.732毫莫耳;可依據Can J Chem
, 1992, 70, 1472-1445及Org Lett
, 2014, 16, 516-519進行合成)於三氯甲烷(25毫升)中進行懸浮,並加入三乙胺(triethylamine)(0.3毫升,2.164毫莫耳),之後再加入固體COMU(741毫克,1.732毫莫耳)。反應混合物於室溫攪拌24小時,完成後轉移至一分液漏斗,並與三氯甲烷(55毫升)、甲醇(80毫升)以及冷水(72毫升)混合。將三氯甲烷層取出,再重複萃取作用(2 x 80毫升三氯甲烷)。結合後之三氯甲烷萃取液以硫酸鈉(Na2
SO4
)脫水,經過濾並蒸發乾燥。剩餘殘留物於矽膠上以三氯甲烷-甲醇(梯度介於9:1至5:5)進行層析法純化,再以三氯甲烷-甲醇-水(65:25:3)進行最後洗提。將溶劑蒸發後,將產物於高真空狀態下乾燥,將產物溶於溫熱三氯甲烷-甲醇混合物(3毫升),並緩慢攪拌加入熱丙酮(75毫升)。混合物經攪拌冷卻至室溫並過濾,所得產物於高真空狀態下乾燥,以取得白色粉末之18-[p
-(5-苯甲氧基-正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(5-benzyloxy-valeramido)phenyl]octadecyl (887 毫克, 86%)。 B. 18-[p
-(羥基-正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(hydroxy-valeramido)phenyl]octadecyl phosphocholine)之合成
將18-[p
-(5-苯甲氧基-正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(5-benzyloxy-valeramido)phenyl]octadecyl phosphocholine)(868克)溶於甲醇(15毫升),並轉移至一帕爾壓力瓶(Parr pressure bottle),並加入10% Pd/C (75毫克)之催化劑。於氫壓(55 psi)下搖晃24小時進行氫化反應(hydrogenation)。將壓力瓶減壓,再將混合物過濾以去除催化劑。濾出液經蒸發乾燥,再將殘留物溶於溫熱之三氯甲烷-甲醇混合物( 3至4毫升)。將熱丙酮(75毫升)緩慢地攪拌加入,將混合物經攪拌冷卻至環境溫度後進行過濾。將產物於高真空狀態下乾燥,製得白色粉末之18-[p
-(羥基-正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(hydroxy-valeramido)phenyl]octadecyl phosphocholine)(718毫克,95%)。 C. 18-[p
-(5-(p
-硝基-苯氧羰氧基) 正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(5-(p
-nitro-phenoxycarbonyloxy)valeramido)phenyl]octadecyl phosphocholine)之合成
將18-[p
-(羥基-正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(hydroxy-valeramido)phenyl]octadecyl phosphocholine)(40毫克,0.064毫莫耳)以及p
-硝基苯基碳酸氯甲酸酯(p
-nitrophenyl chloroformate)(25毫克,0.124毫莫耳)於三氯甲烷(3毫升)中進行懸浮,並加入比啶(pyridine)(0.2毫升)。反應產物於室溫攪拌24小時,再額外加入p
-硝基苯基碳酸氯甲酸酯(15毫克),再繼續攪拌1.5小時。反應係經由薄層層析分析法(TLC analysis)完成。反應混合物利用1毫克之1N鹽酸冷卻,並與三氯甲烷(20毫升)、甲醇(20毫升)以及冷水(15毫升)一併轉移至分液漏斗。重複進行萃取作業(3 x 20毫升之三氯甲烷)。結合之三氯甲烷萃取液以硫酸鈉(Na2
SO4
,)脫水,經過濾及蒸發乾燥。殘留物於矽膠上以三氯甲烷-甲醇(梯度介於9:1至5:5)進行層析法純化,再以三氯甲烷-甲醇-水(65:25:4)進行最後洗提。將溶劑蒸發後,以丙酮進行沉降。將殘留物經由於高真空狀態下乾燥,以取得48毫克(95%)之固體材料。 D. CLR1603之合成
將紫杉醇(46毫克,0.054毫莫耳)以及18-[p
-(5-(p
-硝基-苯氧羰氧基) 正戊醯胺基) 苯基] 十八基磷膽鹼(18-[p
-(5-(p
-nitro-phenoxycarbonyloxy)valeramido)phenyl]octadecyl phosphocholine)(43毫克,0.054毫莫耳)在反應瓶中於三氯甲烷(2毫升)以及比啶(pyridine)(0.5毫升)中進行懸浮。加入DMAP(8毫克,0.065毫莫耳),反應瓶係經緊密封閉,且內容物於60°C攪拌48小時。加入額外之紫杉醇(20毫克),且於60°C繼續進行反應48小時。反應混合物經過濃縮,殘留物藉由矽膠層析法以三氯甲烷-甲醇(梯度介於9:1至5:5)進行純化,再以三氯甲烷-甲醇-水(65:25:2)以及(65:25:4)進行最後洗提。將溶劑蒸發後於高真空狀態下乾燥,以取得CLR1603(50毫克,62%)。 IV. CLR1607之合成
將葛爾德黴素( geldanamycin)(111毫克,0.198毫莫耳)以及18-[p
-(4-胺基丁酰氨基)苯基] 十八基磷膽鹼(18-[p
-(4- aminobutyramido)phenyl]octadecyl phosphocholine)(110毫克,0.18毫莫耳)溶於三氯甲烷(3.5毫升)及甲醇(1毫升)中。加入1滴三乙胺(triethylamine),將反應混合物於室溫攪拌24小時。薄層層析(TLC)顯示約80%之反應完成度。額外加入葛爾德黴素(10毫克),並繼續攪拌24小時。反應混合物經過濃縮,殘留物藉由矽膠層析法以三氯甲烷-甲醇(梯度介於9:1至5:5)進行純化,再以三氯甲烷-甲醇-水(65:25:2)、(65:25:3)及(65:25:4)進行最後洗提。將溶劑蒸發後,於高真空狀態下進行乾燥,並加入丙酮,再將混合物進行蒸散,取得一紫色固體之CLR1607(174毫克,85%)。
各經分離之產物係藉由1
H-nmr以及質譜分析(mass spectral analysis)進行辨別。
範例2至8顯示CLR1404以及相關分子受不同種類癌症組織所螫合與留滯以及自健康組織排除之能力。 V. CLR1608之合成A. CLR1401順丁烯醯胺酸(maleamic acid)之合成
將CLR1401胺(300毫克,0.57毫莫耳)於90°C溶於N
,N
-二甲基乙醯胺(N
,N
-dimethylacetamide)(12毫升),並加入一部分之順丁烯二酸酐(maleic anhydride)(61毫克,0.627毫莫耳)。反應混合物於90°C攪拌1小時,並冷卻至室溫後再攪拌24小時。將丙酮(25毫升)緩慢攪拌加入,再將混合物於室溫攪拌1小時。經沉降之產物經過濾並於過濾器上以丙酮沖淨,再於高真空狀態下乾燥,製得327毫克(92%)。 B. CLR1401順丁烯二醯亞胺(maleimide)之合成
將CLR1401順丁烯醯胺酸(maleamic acid)(100毫克,0.15毫莫耳)於無乙醇三氯甲烷(5毫升)中懸浮,再加入三乙胺(triethylamine)(0.05毫升,0.352毫莫耳)以及COMU(75毫克,0.176毫莫耳)。反應混合物經攪拌24小時,再與三氯甲烷(40毫升)、甲醇(40毫升)以及冷水(36毫升)一併轉移至分液漏斗。將三氯甲烷層取出,並重複進行萃取作業(2 x 40毫升之三氯甲烷)。結合之三氯甲烷萃取液以硫酸鈉(Na2
SO4
,)脫水,經過濾及蒸發乾燥。殘留物於矽膠上以三氯甲烷-甲醇(梯度介於9:1至5:5)進行層析法純化,再以三氯甲烷-甲醇-水(65:25:4)進行最後洗提。將溶劑蒸發後,將產物以丙酮進行沉降,再提取殘留物於高真空狀態下乾燥,以取得87毫克(90%)之CLR1401順丁烯二醯亞胺(maleimide)。 C. CLR1608之合成
將CLR1401順丁烯二醯亞胺(maleimide)(40毫克,0.066毫莫耳)以及美登素(mertansine)(53毫克,0.072毫莫耳)溶於三氯甲烷(1.7毫升)與甲醇(0.3毫升)之混合物中。將三乙胺(triethylamine)(0.08毫升)加入,並將混合物於37°C攪拌24小時。反應混合物經濃縮,殘留物於矽膠上以三氯甲烷-甲醇(梯度介於9:1至5:5)進行層析法純化,再以三氯甲烷-甲醇-水(65:25:3)進行最後洗提。將溶劑蒸發後,將產物於高真空狀態下乾燥,以取得62毫克(70%)之CLR1608。範例 2 - CLR1501 較佳者係藉由癌細胞之脂膜筏螫合
材料與方法:
PC-3細胞系以2 μg/毫升之 filipin III 或vehicle進行前處理15分鐘,再以2 μCi之125
I-CLR1404沖洗與培養1小時。將培養液排除,並將細胞以含有0.1%牛血清白蛋白(bovine serum albumin)之磷酸緩衝鹽溶液PBS(phosphate buffered saline)洗淨,再經trypsin作業,並分為兩份樣本,用以藉由DNA測定細胞數量(A280
比較一細胞系特定標準曲線),並利用伽瑪計數儀(Gamma Counter)(Perkin Elmer)計算每分鐘計數。 結果:
以可遮合膽固醇並干擾脂膜筏之介質filipin III對PC-3細胞進行前處理,造成125
I-CLR1404攝入程度與未經處理之控制組細胞減少將近40%(圖1)。此結果支持CLR1404利用脂膜筏作為進入癌細胞入口之假設。顯著地,高濃度之filipin III係具有細胞毒素,故無法顯現出完整之脂膜筏剝離(ablation)(可推測為CLR1404同類物攝入之抑制作用)。範例 3 -癌細胞優先於健康細胞攝入 CLR-1501
材料及方法:
自美國菌種中心(ATCC)購入人類癌細胞系,其中包括:Caki-2 (腎;亮細胞癌 clear cell carcinoma)、 HCT-116 (結腸直腸癌);MES-SA/Dx5 (子宮肉瘤) [皆保存於McCoy’s 5a培養液,輔以10% 胎牛血清(FBS)]、 Ovcar-3 (卵巢腺癌) [保存於RPMI培養液,輔以20%胎牛血清]、 U87-MG (神經膠質瘤) [保存於必須培養液,輔以 10%胎牛血清]、 Mia Paca-2 (胰臟癌) (保存於DMEM培養液(Dulbecco’s modified Eagle’s medium),輔以10%胎牛血清)、 PC-3 (前列腺癌) (保存於F-12K培養液,輔以10%胎牛血清)、 MDA-MB-231 (三陰性乳腺癌) (保存於Leibovitz培養液,輔以10胎牛血清)以及 A549 (非小細胞肺癌)(保存於F-12培養液,輔以10%胎牛血清)。正常人類皮膚纖維母細胞系購自ATCC並培養於Fibroblast Basal培養液PCS-201-030,輔以無血清培養套組(Fibroblast Growth Kit-Serum-Free PCS-201-040)。所有培養液(除用於MDA-MB- 231細胞系者外)亦含有青黴素(penicillin)(100 U/毫升)以及鏈黴素(100 μg/毫升),並保存於37°C環境,空氣中CO2
含量為5%。
所有細胞皆於37°C環境保存於適當培養液中,輔以10%之胎牛血清(FBS)及5%之CO2。於成像前將所有細胞以0.25% 之trypsin自容器取出,並使其於載玻片 VI (Ibidi)上成長隔夜。隔天,將細胞以磷酸緩衝鹽溶液(PBS)清洗並以5 或7.5 μM (依所示)之CLR1501培養於適當無血清培養液中培養24小時。CLR1501係為螢光標示之CLR1404同類物,CLR1501係以0.4% 之聚山梨醇酯二十(Polysorbate 20)、2%之乙醇以及鹽水調製。在以PBS徹底清洗後,將細胞利用Bio-Rad Radiance 2100 MP Rainbow雷射掃描/多光子共焦顯微鏡以1-s曝光時間進行成像。或者,將細胞利用Nikon A1R共焦顯微鏡(Keck Laboratory, University of Wisconsin-Madison)進行顯像。CLR1501之發射訊號係利用Alexa Fluor 488濾波器(ex/em 480/520 nm)偵測。 結果:
CLR1501係施用於五種不同癌細胞系(腎臟癌、卵巢癌、胰臟癌、黑色素瘤以及前列腺癌)以及一種體外之正常人類皮膚纖維母細胞系。經過24小時候,CLR1501於該等體外癌細胞系中展現出相較於正常纖維母細胞(圖2)高出五倍至九倍之攝入程度。留滯之CLR1501係與血漿及胞器膜相關連。範例 4 -大鼠神經膠質瘤膜組
材料及方法:所有動物體係依照威斯康辛大學研究動物資源中心(University of Wisconsin Research Animal Resources Center)之指示豢養照護。大鼠C6神經膠質瘤細胞係於DMEM培養液(Life Technologies, Gaithersburg, MD)中輔以10%之胎牛血清(BioWhittaker, Walkersville, MD)、100 U/毫升之青黴素G、100毫克/毫升之鏈黴素(streptomycin)以及0.01 M之HEPES(Life Technologies, Gaithersburg, MD)進行增殖。顱內腫瘤移植係如前所示方式進行。依照Cohen JD, et al.所揭露( Intracranial C6 神經膠質瘤 model in adult Wistar-Furth rats.J Neuro Onco
l 1990 8(1):95-6)之方法,簡言之,將1x106
之C6細胞於5毫升之1.2 % 甲基纖維素(methylcellulose)中進行再懸浮,並注射入經麻痺之威斯達大鼠(Wistar rat)(Harlan, Indianapolis, IN)額葉中。偽對照組之動物則於顱內注入等量之假基纖維素,但其中不含腫瘤細胞。
成像研究:移植十日後,以MRI確認產生顱內腫瘤。簡言之,麻痺大鼠(6)於腹膜內接受2毫升之Gadodiamide顯影劑(Gd, Omniscan 287 mg/ml, Nycomed, Princeton, NJ),並於10分鐘後利用1.5 Tesla醫療用MR系統 (GE Signa LX)以及GE相位陣列肢體線圈進行成像。進行涵蓋各大鼠全腦部之連續多斷層切面T1加權(TR=500 ms, TE=16.5 ms)成像,用以選定含有不同腫瘤大小之腫瘤大鼠以及偽對照組之大鼠,以進行NM404之注射。
如Weichert, et al.所揭露( Weichert, et al.Int J Appl Rad Isotopes
. 1986; 37:907-913),將NM404[18-(p-碘基苯酚)十八基磷膽鹼](18-(4-iodophenyl)octadecyl phosphocholine)(100毫克)於融解之三甲基乙酸(pivalic acid)中以125
I透過與Na125
I之同位素交換進行放射線碘化標記(radioiodinated)。NM404具有與CLR1404之相同化學結構,差異僅在於利用125
I進行放射線碘化標記,而非利用124
I或131
I。於HPLC純化後,NM404係溶於水性2%聚山梨醇酯二十(Polysorbate 20)溶液中,再以尾靜脈注射製四隻具腫瘤大鼠以及三隻偽操作組大鼠中(5-20μCi/每200克大鼠)。於NM404注射之1 (n=1)、2 (n=1)以及4 (n=2)日後,將該等動物進行安樂死(CO2
),將其腦部切下並於Bioscan AR2000 radio-TLC掃描器(增量1毫米於2 分鐘取像/道以及1毫米高解析度準值儀)進行成像。另外,正常腦部、血液、腎臟、肝臟、脾臟、甲狀腺及腫瘤細胞皆經秤重,並於伽瑪計數儀(Gamma Counter)進行放射性計數,其後並將放射性之組織分布與腦部組織對應關聯。
結果與探討:利用NM404之初期成像結果顯示所有直徑介於3至5毫米之神經膠質瘤皆有顯著之攝入增加及滯留延長效果。偽對照組動物正常腦部組織中之放射性最小(圖4A及4B),且NM404於神經膠質瘤中之濃度大幅上升(圖4A’至D’)。具C6神經膠質瘤之大鼠的腫瘤與腦部比例(%注射劑量/克)於24、48及96小時時分別為10.5、12.2以及 6.7。如先前之細胞培養及體內動物模組研究所觀測,NM404顯然可受正常細胞代謝及排出,但卻會滯留於腫瘤細胞膜內。先前於其他腫瘤模組所進行之自放射攝影術(autoradiography)實驗顯示,NM404僅能透過腫瘤細胞加以累積,而非正常組織或壞死組織,而即使是直徑僅數毫米之小腫瘤,仍可於施予後檢測到NM404。此初步發現顯示,CLR1404或許亦可用於使微小之侵入性腫瘤病灶顯像。 結論:
正如先前所檢視之所有腫瘤模組所示,NM404於此研究中展現出對於C6神經膠質瘤之選擇性以及留滯延長之作用。範例 5 - 124 I-CLR1404 於各種惡性腫瘤之攝入
材料及方法:
所有所述動物研究係根據經實驗動物照護及使用委員會(Institutional Animal Care and Use Committee)所認可之動物規範所進行。約4至5周大之雌性無胸腺裸鼠(Hsd:Athymic Nude-Foxn1nu or Crl:NU-Foxn1nu, Charles River Laboratories),介於16至18克重(n=6),用於人類腫瘤異種移殖研究。裸鼠以愛弗寧(isoflurane)進行麻醉,並將100 μl含有可用於移植之腫瘤細胞之Dulbecco’s PBS(或針對神經膠質瘤細胞時使用50毫升之PBS)以皮下注入右脅腹。接種體尺寸為1 × 106
(用於腎臟、卵巢、神經膠質瘤、胰臟、前列腺以及非小細胞肺癌模組)、2 × 106
(用於結腸直腸及子宮模組)或3 × 106
(乳癌)。 結果:
將經放射性碘化標記之124
I-CLR1404於60種不同之自發、轉基因、人類及嚙齒類惡性細胞係與腫瘤之皮下及原位異種移植進行測試。於靜脈內施用後,124
I-CLR1404出現於幾乎所有員發性及轉移性惡性腫瘤中,無論其解剖位置差異。代表性範例係為人類(圖5A至5I)以及嚙齒類(圖5J至M)腫瘤。 表1,124
I-CLR1404於廣範圍癌症種類之攝入 *腫瘤肌肉比率大於3者表示腫瘤攝入現象係為肯定 腫瘤肌肉比率小於2者係為否定範例 6 -評估非小細胞肺癌( NSCLC )患者之 CLR1404 臨床試驗
雖然CLR1404於55/60種異種移植及自發性嚙齒類模組中展現出選擇性及腫瘤內留滯延長現象,但有醫師贊助且由IND發起,對於之臨床評估非小細胞肺癌(NSCLC)第四期患者評估其是否對人類亦能產生相似之腫瘤攝入及滯留特性。迄今,有兩名患有非小細胞肺癌末期之患者,於注射<1 mCi 之 131I-CLR1404後進行成像作業,係於預定時間點取樣血液及尿液樣本,並於不同時間點施予後進行伽馬成像。對兩位患者而言,皆表現出原發性肺腫瘤攝入CLR1404作用顯著增加之現象,如圖6所示。與先前所見具高肝臟攝入值之其第一代產物,NM324相較之下,施予CLR1404之肝臟與腹部活性相當低,顯示此劑於其他腹部癌症包括胰臟、結腸與前列腺癌等之評估亦為可行。
材料與方法:將經iodine-13l標記之CLR1404(1 mCi/20 µg)以靜脈注射後,非小細胞肺癌末期之患者於第3、6、24、48及 96小時以及第7天及第11天時,分別利用GE Maxxus dual Head SPECT掃描器進行掃描,亦採集血液及尿液樣本進行藥物動力學分析(pharmacokinetic analysis)以及臨床血液學(hematologic)、腎臟及肝臟分析。
結果:初期性成像結果指出,注射24小時後之初期內,經iodine-13l標記之CLR1404清楚定位於兩側肺質內,並留滯於該等腫瘤內長達11日。再者,肝臟及下腹部包括膀胱、腎臟及腸子之背景放射性比使用先前產物NM324所觀測之放射性顯著較低,且患者皆未出現有害反應。
結論:此等初期發現顯示CLR1404於人類非小細胞匪癌中展現與先前嚙齒類模組相似之腫瘤攝入及留滯性質。雖然僅以兩位患者為基準,但此表示CLR1404能確實定位並經選擇性攝入與延長留滯於人類非小細胞肺癌之腫瘤。
患者1:55歲男性,兩側皆有3公分腫瘤,係為左肺葉及滲透性右肺葉之非小細胞肺癌,並有腦部轉移以及右側腎上腺小腫瘤。其曾參與眾多標準與實驗性療法。圖片如圖6A至C所示。
患者2:70歲男性,近期經診斷於上肺葉具有6公分非小細胞肺癌腫瘤以及5公分肝臟腫瘤,並有腸骨轉移及腦部極小部分轉移。其最近於CLR1404試驗前完成低劑量卡鉑(carboplatin)/taxol化學療法,以及對胸骨及腦部轉移進行保守性放射治療。圖片如圖6D至G所示。範例 7 -利用 124 I-CLR1404 檢測 3 位非小細胞肺癌患者原先未知之腦腫瘤。
材料及方法:
於注射約5 mCi之124
I-CLR1404後之多次時間點,於一64-斷層 PET/CT掃描器(Discovery VCT, General Electric)上利用90分鐘動態取樣順序(2D,每10分鐘9禎,VIP 表單模式)取得人類腦部正子放射造影(PET)並經重建[Advantage Workstation版 AW4.4, General Electric, 30公分 DFOV (顯示視野), 128 × 128, OSEM VUE Point, 10子集兩次循環,標準z軸,衰減修正及無感時間、散射及衰變校正]。 結果:
於無神經症狀之非小細胞肺癌患者體內利用124
I-CLR1404 PET/CT取得初步結果,成像顯示三種先前未知之腦部病灶,其高度疑似轉移病灶,而其後以釓增強磁振造影(gadolinium-enhanced MRI)獲得證實(圖7)。範例 8 -利用 124 I-CLR1404 檢測右前大腦鐮( falcine )之轉移腫瘤復發
患有惡性黑色素瘤之60歲女性腦部轉移復發,針對磁振(MR)(圖8A)、124
I-CLR1404 PET成像(圖8B)以及針對右前大腦鐮轉移腫瘤復發進行立體定位放射手術後八個月之成像(圖8C),皆透過CLR1404(箭頭所指)呈現出不正常活性病灶。當放射性壞死接觸可能復發處,使初期磁振造影上之對應病灶之增強受到干擾。後續磁振造影顯示非特定增強病變之尺寸增加,伴隨病灶周圍水腫,代表惡性腫瘤之復發。此等結果顯示,124
I-CLR1404受癌細胞所螫合,並對放射手術產生抵抗性,最後指出復發之腫瘤所在。
本發明化合物包含與CLR1404核心分子連結之抗癌藥物,此等化合物可用於鎖定癌細胞及癌幹細胞,包含腦癌細胞在內,藉此,抗癌藥物係受到癌細胞所螫合並留滯。此等化合物提供之癌症治療方法,係為首見可將多種抗癌藥物投至癌細胞以治療癌症同時預防轉移與復發之療法。範例 9 -紫杉醇-共軛物及 IC50 用於多種癌細胞細
包括MDA-MB-468 (乳癌)、 NCI-H1299(肺癌)、 NCI-H460 (肺癌)、 Capan-2(胰臟癌)、MiaPaCa-1(胰臟癌)、 HT29(結腸直腸癌)、HCT116(結腸直腸癌)以及PC-3(前列腺癌)在內之癌細胞系,係利用不同濃度之紫杉醇及CLR1404-紫杉醇共軛物(例如CLR1601、CLR1602集CLR1603)進行治療,該等細胞系並經測定細胞存活力並於各治療中表示為IC50。 結果
CLR1601及CLR1603系可減少MDA-MB-468 (乳癌)、 NCI-H1299(肺癌)、 NCI-H460 (肺癌)、 Capan-2(胰臟癌)、MiaPaCa-1(胰臟癌)、 HT29(結腸直腸癌)、HCT116(結腸直腸癌)以及PC-3(前列腺癌)之細胞存活力,分別參見圖9至16。各紫杉醇-1404共軛物(例如CLR1601及CLR1603)以及紫杉醇之IC50係表示於表2。CLR1602之IC50並未標出,然而CLR1602並無法顯著降低癌細胞系之存活力,因為CLR1602係為於不可水解。於體內,自由紫杉醇受癌腫瘤細胞之攝入率極低,其係因為紫杉醇攝入之非特定性質所導致。故,於體內,使癌細胞死亡所必須之磷脂乙醚(PLE)-紫杉醇共軛物之含量應等同或少於與紫杉醇之含量,且對於非癌細胞應可大幅降低其毒性。 表2,CLR1601、CLR1603及紫杉醇(Paclitaxel)之IC50 範例 10 -流式細胞計數分析法
方法
藉由流式細胞計數所色之Annexin V及PI (phosphatidylinositide)係用以測定存活、早期凋亡、晚期凋亡及壞死之細胞。簡言之,細胞系經由細胞毒性劑處理並以Annexin V/PI標記套組(Life Technologies)所染色。細胞接著於一LSRII流式細胞計數儀(BD Biosciences)上進行分析。如表3至9所示,細胞系分為:存活(Annexin V負、PI負)、早期凋亡(Annexin V正、PI負)、晚期凋亡(Annexin V正、PI正)以及壞死(Annexin V負、PI正)等。代表性散布圖係如圖17所示,MDA-MB-468細胞經5 µM之CLR1601處理72小時,Annexin V (附於AlexaFluor 488)係標於X軸,PI係標於Y軸。左下象限代表存活細胞,左上象限代表壞死細胞,右上象限代表晚期凋亡細胞,右下象限代表早期凋亡細胞,本分析中已排除殘骸。 結果
MDA-MB-468細胞係為一種三陰性乳癌細胞系,經CLR共軛物(CLR1601及CLR1603)處理72小時並以紫杉醇(PTX)處理24小時,參見表3。MDA-MB-468細胞亦經CLR共軛物(CLR1606及CLR1607)處理72小時並以葛爾德黴素( geldanamycin)(GEL)處理48小時,參見表4。就PTX共軛物而言,細胞存活力經1 µM之CLR1601、5 µM之CLR1601、1 µM之CLR1603、5 µM之CLR1603、 100 nM之PTX以及1 µM之PTX分別處理後,自61.1%(無藥物治療)分別降低至17.0%、17.8%、22.2%、19.7%、53.8%及48.9%,參見表3。就GEL共軛物而言,細胞存活力經1 µM之CLR1606、10µM之CLR1606、1 µM之CLR1607、10µM之CLR1607以及1 µM之GEL分別處理後,自61.1%分別降低至58.8%、42.7%、52.7%、56.9%及26.2%,參見表4。 表3, MDA-MB-468細胞以紫杉醇共軛物處理72小時
表4, MDA-MB-468 細胞以葛爾德黴素共軛物處理72小時
COLO829細胞係為一種黑色素瘤細胞系,經GEL共軛物(CLR1606及CLR1607)處理72小時並經GEL處理48小時,參見表5。細胞存活力經1 µM之CLR1606、10 µM之CLR1606、1 µM之CLR1607、10 µM之CLR1607、100 nM之GEL以及1 µM之GEL分別處理後,自80.8%(無藥物處理)分別降至70.4%、21.1%、67.9%、54.3%、32.4%以及18.6%,參見表5。 表5,COLO 829細胞經葛爾德黴素共軛物處理72小時
PANC-1細胞係為一種胰臟癌細胞系,經GEL共軛物(CLR1606及CLR1607)處理72小時並經GEL處理48小時,參見表6。細胞存活力經1 µM之CLR1606、10 µM之CLR1606、1 µM之CLR1607、10 µM之CLR1607、100 nM之GEL以及1 µM之GEL分別處理後,自44.2%(無藥物處理)分別降至42.0%、21.5%、44.0%、33.0%、23.3%以及18.9%,參見表6。 表 6, PANC-1細胞經葛爾德黴素共軛物處理72小時
22RV1細胞係為一種前列腺細胞系,經GEL共軛物(CLR1606及CLR1607)處理72小時並經GEL處理48小時,參見表7。細胞存活力經無藥處理、1 µM之CLR1606、10 µM之CLR1606、1 µM之CLR1607、10 µM之CLR1607、100 nM之GEL以及1 µM之GEL處理後分別為20.3%、21.3%、16.0%、21.9%、15.7%、19.4%以及28.1%,參見表7。此細胞系之基底細胞死亡數較高,細胞並未對於細胞採集之方法產生良好反應。 Table 7. 22RV1 Cells Treated with Geldanamycin for 72 Hours
CLR共軛物似乎需要較長之治療期間以誘發細胞死亡,MDA-MB-468細胞系以1 µM之CLR1601及1 µM之CLR1603分別處理48小時之治療後,造成細胞存活力自86.2%(無藥物治療)分別降至79.4%以及81.4%,參見表8。COLO 829細胞系以1 µM之CLR1606及1 µM之CLR1607分別處理48小時之治療後,造成細胞存活力自91.7%(無藥物治療)分別降至90.1%以及82.7%,參見表9。 表8,MDA-MB-468細胞以紫杉醇共軛物治療48小時
表9,COLO 829細胞以葛爾德黴素共軛物處理48小時
總括而言,磷脂乙醚(PLE)-紫杉醇與磷脂乙醚(PLE)-葛爾德黴素共軛物經顯示能降低癌細胞存活力,其中包含誘發多種腫瘤細胞之死亡。
圖1係為透過脂膜筏受螫合之磷脂乙醚(PLE)同類物。 圖2係顯示受癌細胞所攝入之CLR1501,並將(A)及(C)至(F)之癌細胞系(cancer cell line)與(B)之正常細胞相互比對;(A)腎臟癌細胞 (Caki-2); (B) 正常人類纖維母細胞;(C) 卵巢癌細胞 (OVcar-3); (D)胰臟癌細胞(Panc-1); (E) 黑色素瘤細胞 (A-375); (F)前列腺癌細胞(PC-3)。 圖3係顯示131
I-CLR1404受異種移植於嚴重合併性免疫缺失病(SCID)老鼠之人類RL-251腫瘤之留滯延長。 圖4係為利用125
I-NM404檢測大鼠腦中之C6-神經膠質瘤;(A)偽對照組大鼠腦部之Bioscan生物掃描;(B)圖(A)層疊於顯示正常腦部組織中125
I-NM404背景值之數位照片之大鼠腦部Bioscan生物掃描成像;(A’)具有C6-神經膠質瘤之大鼠腦部於注射125
I-NM404後四日之數位照片;(B’)圖(A’)之大鼠腦部Bioscan生物掃描成像;(C’)圖(A’)及(B’)層疊後之同比例對照圖,顯示腫瘤中NM404之確切位置;(D’) H&E染色樣本,以確認腫瘤存在。 圖5係顯示受多樣化惡性腫瘤所攝入之124
I-CLR1404;(A)至(I)係為受人類癌細胞異種移植之嚙齒目樣本;(J)至(M)係為嚙齒目癌症樣本;(A)原位U87神經膠質瘤(大鼠);(B)結腸癌HCT-116;(C)結腸癌HT-29,箭頭係指示腫瘤位置;(D)乳癌MDA-MB-231,箭頭係指示腫瘤位置;(E)前列腺癌PC-3;(F)轉移性PC-3;(G)異種移植脛骨癌;(H)胰臟癌BxPC3,較下方箭頭係指示腫瘤位置,較上方箭頭係指示肝轉移瘤;(I)伊文氏肉瘤(Ewing sarcoma),箭頭係指示腫瘤位置;(J)老鼠膀胱;(K)老鼠乳癌4T1;(L)老鼠胰臟癌c-myc;(M)大鼠腦部CNS-1。 圖6係為利用131
I-CLR1404對人類患者之非小細胞肺癌(NSCLC)進行檢測;(A)顯示患者1於注射131
I-CLR1404後第4日及第11日之伽馬(gamma)攝影成像,須留意CLR1404於NSCLC腫瘤中之強烈留滯延長;(B及C)顯示左肺(A)中之3公分病灶尺寸以及右肺(B)中之大範圍滲透性物質(箭頭所指);(D及E)顯示患者2於注射131
I-CLR14041日、2日及4日後之全身平面核醫成像;(F及G)顯示軸向(F)及頭顱(G)電腦斷層掃描所指出6公分大NSCLC腫瘤(剪頭指示)之位置。 圖7係為利用124
I-CLR1404檢測NSCLC患者體內3顆先前未知之腦部腫瘤轉移瘤,箭頭所指係為癌細胞攝入124
I-CLR1404後利用正子放射造影(PET)/電腦斷層掃描(CT)所成像之腫瘤位置。 圖8係為利用124
I-CLR1404對右前大腦鐮(falcine)所檢測之腫瘤復發,(A)大腦經放射手術後之磁振造影(MRI),箭頭指示病灶係解釋為放射性壞死;(B)利用124
I-CLR1404顯示受病灶所攝入之124
I-CLR1404的正子放射造影(PET);(C)經立體定位放射手術(stereotactic radiosurgery)8個月後之磁振造影,顯示病灶之尺寸增加代表復發之可能性。 圖9係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於MDA-MB-468;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。 圖10係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於NCI-H1299;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。 圖11係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於NCI-H460;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。 圖12係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於Capan-2;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。 圖13係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於MiaPaCa-1;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。 圖14係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於HT29;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。 圖15係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於HCT116;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。 圖16係為磷脂乙醚(PLE)-
紫杉醇(Paclitaxel)共軛IC50
於PC-3;(A)自由紫杉醇;(B)CLR1601;(C)CLR1603。
無。
Claims (12)
- 一種治療性化合物,其具有結構式A-B-D,其中: A係為具有結構式(I)之至少一種化合物,(I), 具有結構式(II)之至少一種化合物,(II), 具有結構式(III)之至少一種化合物,(III), 或上述之結合, 其中W係選自由一芳香基(aryl)、一C1 -C6 烷基(C1 -C6 alkyl)、一烯基(alkenyl)、一選擇性取代之C3 -C6 環烷基(C3 -C6 cycloalkyl)以及一選擇性取代之C3 -C6 異環烷基(C3 -C6 heterocycloalkyl)所構成之群組,其中R係為氫(H)或一烷基,且其中m係為12至24間之一整數; B係為一鏈結化合物;且 D係為一抗癌藥物, 其中A與D之比例係介於1:2至2:1。
- 如請求項1所述之治療性化合物,其中該鏈結化合物係為一鍵結或一具有結構式(IV)之化合物,其中結構式(IV)為 Y-(CH2 )n -Z,其中: Y係鍵結於A; Z係鍵結於D; Y係選自由一鍵結、O、NH、 C=O、 NHSO2 O及OC(=O)O所構成之群組; Z係選自由O、NH、 C=O、 C(=O)O、 C(=O)NH、 SO2 、OC(=O)OCH2 及–S-S-所構成之群組;且 n係為0至6間之一整數。
- 如請求項1所述之治療性化合物,其中: A係為具有結構式(I)之一化合物,其中W係選自由C1烷基(C1 alkyl)、、及所構成之群組,且其中m係為18; B係為一鏈結化合物,其係選自由一鍵結以及具有一結構式(III)之化合物所構成之群組,其中結構式(III)係為Y-(CH2 )n -Z,其中n係為介於0至6間之一整數,Y係鍵結於A,Z係鍵結於D,Y係選自由一鍵結以及C=O所構成之群組,且Z係選自由NH、 C=O、 C(=O)NH及C(=O)O所構成之群組;且 D係選自由紫杉醇(paclitaxel)、愛萊諾迪肯(irinotecan)、托伯狄肯(topotecan)、吉姆賽他賓(gemcitabine)、順鉑(cisplatin)、葛爾德黴素( geldanamycin)及美登素(mertansine)所構成之群組。
- 如請求項3所述之治療性化合物,其中: A係為具有結構式(I)之一化合物,其中W係為,且m係為18; B係為具有結構式(III)之一鏈結化合物,其中Y係為C=O,且Z係為C=O、 C(=O)NH或C(=O)O,且n係為3或4;且 D係為紫杉醇(paclitaxel), 其中A與D之比例係為1:1。
- 如請求項3所述之治療性化合物,其中: A係為具有結構式(I)之一化合物,其中W係為,且m係為18; B係為一鍵結或具有結構式(IV)之一鏈結化合物,其中Y係為C=O,且Z係為NH,且n係為1或3;且 D係為葛爾德黴素( geldanamycin), 其中A與D之比例係為1:1。
- 如請求項3所述之治療性化合物,其中: A係為具有結構式(I)之一化合物,其中W係為,且m係為18; B係為一鍵結;且 D係為美登素(mertansine), 其中A與D之比例係為1:1。
- 一種治療性化合物,其係選自由下列所構成之群組,包括:;;;;;;;;;;;;;;;;;;;;;以及所構成之群組, 其中n係為介於0至6間之一整數,且X係為O或NH。
- 一種具有結構式(V)之治療性化合物,其中結構式(V)係為(V)。
- 一種藥用組合物,其包含如請求項1、7或8任一項所述之一治療性化合物以及至少一種可藥用載體。
- 一種治療癌症之方法,其包含將有效劑量之如請求項1、7或8任一項所述之一治療性化合物施予一癌症個體。
- 如請求項10所述之治療癌症之方法,其中該癌症包含癌幹細胞。
- 如請求項10所述之治療癌症之方法,其中該癌症係為可復發癌症。
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