TW201325589A - 調節某些酪氨酸激酶 - Google Patents
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Abstract
本發明提供了與治療與酪氨酸激酶活性相關的紊亂相關之治療形式和診斷形式。
Description
本申請案要求於2011年11月14日提交的第61/559,592號美國臨時申請案的權益和優先權,將其全部通過引用結合到本文中。
酪氨酸激酶調節大量的生物學事件和生物學活動。許多有力的且有效的治療劑均通過調節一種或多種酪氨酸激酶產生作用。然而,某些酪氨酸激酶(包括,例如,間變性淋巴瘤激酶(anaplastic lymphoma kinase)[ALK])已知對許多治療劑產生抗性。而且,不同的酪氨酸激酶可能具有不同的(儘管一些時候會重疊)活性;需要顯著的努力驗證具有活性及選擇性的酪氨酸激酶調節物(例如,抑制劑)、其適用於治療任意某些疾病、紊亂或病症。
本發明涵蓋某些針對酪氨酸激酶顯示所需的活性和/或特異性曲線(profile)的苯並咪唑(benzimidazole)化合物的發現。
例如,本發明證實某些此類化合物可有效地抑制抗ALK-相關疾病或紊亂。本發明還證實某些此類化合物抑制一種或多種原肌球蛋白受器激酶(tropomyosin receptor kinase)(TRK)以及原癌基因(proto-oncogene)(RET)家族的成員。
其中,本發明提供了包括將式I的化合物、或其藥學可接受的鹽給予患有與一種或多種特定酪氨酸激酶(例如,ALK抑制劑抗性酪氨酸激酶(ALK-inhibitor-resistant tyrosine kinase)、TRK家族成員,等)活性相關的病症的受試者的方法:
其中W、X、Y和Z如本文中所描述的。
在一些實施方式中,本發明提供了包括將式I的化合物給予患有ALK相關病症的受試者的方法,所述受試者顯示一個或多個抗性標記(indicia)。
在一些實施方式中,本發明提供了包括將式I的化合物與一種或多種另外的化療劑聯合給予患有ALK抑制劑抗性ALK-相關病症的受試者、或ALK抑制劑抗性ALK-相關病症易感的受試者的方法。
在一些實施方式中,本發明提供了方法,包括以下步驟:(i)檢測受試者中的一個或多個抗性標記(例如,抗性相關標記的存在或水準、疾病進展,等);以及(ii)基於檢測的一個或多個標記的存在,確定該受試者係為使用式I的化合物治療的候選者。
在一些實施方式中,本發明提供了方法,包括以下步驟:(i)檢測受試者中的一個或多個抗性標記(例如,抗性相關標記的存在或水準,疾病進展,等);(ii)基於檢測的一個或多個標記的存在,確定該受試者係為使用式I的化合物治療的候選者,以及(iii)將治療有效劑量的式I的化合物給予患者。
在一些實施方式中,本發明提供了治療ALK相關病症的方法,所述方法包括將式I的化合物給予需要其的受試者,其中ALK相關病症位於或存在於中樞神經系統。在一些此類實施方式中,ALK相關病症係為中樞神經系統的癌症。在一些實施方式中,中樞神經系統的癌症係為腦癌或腦瘤。在一些實施方式中,中樞神經系統的癌症係為脊髓癌或脊髓瘤。
在一些實施方式中,本發明提供了治療TRK-介導的病症的方法,所述方法包括將式I的化合物給予需要其的患者。在一些此類實施方式中,TRK介導的病症係為癌症。
在一些實施方式中,本發明提供了治療TRK介導的病症的方法,所述方法包括將式I的化合物給予需要其的患者,其中TRK介導的病症係為癌症疼痛。
在一些實施方式中,本發明提供了預防或抑制神經周侵襲(perineural invastion)發展的方法,所述方法包括將式I的化合物給予需要其的患者。在一些實施方式中,本發
明提供了預防或抑制癌症轉移的方法,所述方法包括將式I的化合物給予需要其的患者。
定義
ALK-相關病症(ALK-associated condition):如本文中使用的,術語“ALK-相關病症”指已知或疑似ALK或其突變體在其中起作用的任意疾病或其它有害病症。因此,本發明的另一實施方式涉及治療一種或多種已知或疑似ALK或其突變體在其中起作用的疾病。具體地,本發明涉及治療選自增生性失調或自身免疫性失調的疾病或病症的方法,其中所述方法包括將本發明的化合物或組成物給予需要其的患者。在一些實施方式中,ALK相關病症係為癌症。在一些此類實施方式中,ALK相關病症係為肺癌、成神經細胞瘤、間變性大細胞淋巴瘤、膠質母細胞瘤、乳腺癌、結腸癌或炎性肌纖維母細胞瘤(IMT)。
ALK-相關標記(ALK-associated marker):如本文中使用的,術語“ALK-相關標記”指任意相關標記,例如核酸(例如,基因或基因突變)、化學化合物(例如,礦物、金屬、或小分子)、肽、或特徵,其存在或水準與ALK相關病症相關。在一些實施方式中,ALK相關標記係為遺傳標記(例如基因或基因序列,包括基因或基因序列的多拷貝的存在)。在一些實施方式中,ALK相關標記係為融合基因。在一些實施方式中,ALK相關標記係為蛋白。在一些實施方式中,ALK相關標記係為融合蛋白。在一些實施方式中,
ALK相關標記係為生物活性的水準(例如,ALK激酶活性的水準)。
聯合治療:如本文中使用的,術語“聯合治療”涉及在一些情況下,兩種或更多種不同的藥劑以重疊的給藥方案(overlapping regimens)給藥,使得受試者同時暴露於兩種藥劑下。例如,本發明的化合物可與其它治療劑同時地或連續地、以分開的單位劑量形式或一起以單一的單位劑量形式給藥。為了清楚,如本文中使用的,術語“連續地”指本發明的化合物可在另外的治療劑給藥前、給藥中或給藥後給予。
給藥方案(Dosing regimen):如本文中使用的,術語“給藥方案”(或治療方案(therapeutic regimen))係為分別地將一組單位劑量(代表性地多於一個)給予受試者,通常以一段時間分開。在一些實施方式中,給定的治療劑具有建議的給藥方案,其涉及一個或多個劑量。在一些實施方式中,給藥方案包含多個劑量,其相互之間以一段等長的時間週期分開;在一些實施方式中,給藥方案包含多個劑量且以至少兩個不同的時間週期將各個劑量分開。在一些實施方式中,治療劑在一段預定的時間週期內持續給藥。在一些實施方式中,治療劑每天一次(QD)或每天兩次(BID)給予。
受試者(Subject):如本文中使用的,術語“受試者”或“患者(patient)”涉及本發明的實施方式可使用或給予的任意生物體,例如出於實驗、診斷、預防、和/或治療的目的。
典型的受試者包括動物(例如:哺乳動物諸如小鼠、大鼠、兔、非人靈長類、以及人類;昆蟲;蠕蟲;等)。
患有(Suffering from):某個體,其“患有”疾病、失調、或病症(如,癌症),已被診斷具有和/或顯示該疾病、失調或病症的一種或多種症狀。
治療方案(Therapeutic regimen):如本發明中所使用的,術語“治療方案”涉及任意方案,使用所述方案可部分地或完全地使某些疾病、失調、和/或病症的一個或多個症狀或特徵減輕、改善、解除、抑制、預防、延緩發作、降低嚴重性和/或減少發病率。在一些具體實施方式中,治療方案可包括一次治療或一系列治療,其給藥與相關群體的特定結果的實現相關。在一些實施方式中,治療方案涉及將一種或多種治療劑,或者同時地、連續地或者以不同次數的、針對相同或不同的時間次數給藥。可替代地、或進一步地,治療可包括暴露方案(exposure to protocols),如放射物、化療劑或外科手術。可替代地、或進一步地,“處治方案(treatment regimen)”可包括遺傳方法如基因療法、基因消融(gene ablation)或其它已知減少特定基因的表達或基因來源的mRNA的翻譯的方法。
治療劑(Therapeutic agent):如本文中使用的,短語“治療劑”涉及任意藥劑當給予生物體後可產生所需藥效的藥劑。在一些實施方式中,如果在適當群體範圍內顯示出統計學顯著有效性,則該藥劑被認為為治療劑。在一些實施方式中,適當群體可以為模式生物體(model organism),
在一些實施方式中,適當群體可通過不同標準定義,如某些年齡組、性別、遺傳背景、先前存在的臨床病症等。在一些實施方式中,適當群體可通過功能測定(functional assay)定義。在一些實施方式中,治療劑係為可用於使某些疾病、失調、和/或病症的一個或多個症狀或特徵減輕、改善、解除、抑制、預防、延緩發作、降低嚴重性和/或減少發病率的任意物質。
治療有效量:如本文中所使用的,術語“治療有效量”涉及治療劑的量,當在相關群體中觀察時,其給藥量與特定治療效果的達成相關或與合理預期特定治療效果的達成相關。所述治療效果可為客觀的(例如通過測試或標記檢測的)或主觀的(受試者給出效果指征或感受其效果)。治療有效量通常以可包含多單位劑量的給藥方案給藥。對於任意的特定治療劑,治療有效量(和/或有效給藥方案中的適當單位劑量)可以變化,例如,取決於給藥的途徑或與其它藥學試劑的組合。同樣,針對任意的特定受試者的具體治療有效量(和/或單位劑量)可能依賴於多種因素,包括待治療的疾病以及疾病的嚴重性;所使用的具體藥學試劑的活性;所使用的具體組成物(組成);患者的年齡、體重、一般健康情況、性別及飲食;給藥時間、給藥途徑,和/或所使用的具體藥劑的排泄率或新陳代謝率;治療的持續時間;以及在醫藥領域所熟知的其它因素。
治療(處治,Treatment):本文中使用的術語“治療(處治,Treatment)”(以及其它語法形式,如“處治(treating)”)
涉及一種治療方案,其使疾病、失調或病症的一個或多個症狀或方面減輕、延緩發作、降低嚴重性或發病率、和/或產生預防作用。在一些實施方式中,治療係為在各種症狀開始發作(onset)前、開始發作時、和/或開始發作後給予。在一些實施方式中,治療可以給予未顯示疾病、失調、和/或病症徵兆的受試者。在一些實施方式中,治療可以給予僅顯示疾病、失調、和/或病症的早期徵兆的受試者,例如用於降低與疾病、失調、和/或病症有關的病理發展的風險。
TRK-相關病症(TRK-associated condition):如本文使用的,術語“TRK-相關病症”指任何其中已知或疑似至少一種TRK受器或其突變體發揮作用的疾病或其它有害病症。在一些實施方式中,TRK受器選自TRKA、TRKB、TRKC、p75,或它們的組合。可替代地或進一步地,TRK-相關病症係為其出現、發病率和/或嚴重性與TRK的存在和/或TRK活性水準相關的任何疾病或其它有害病症。如本文中所討論的,已知或疑似TRK參與的多種生物學病症或生物學事件,包括例如,細胞增殖、癌症轉移及疼痛。這些生物學病症或生物學事件中的一些可能涉及其它激酶;一些可能唯一涉及TRK。在一些實施方式中,本發明涉及治療一種或多種已知或疑似TRK或其突變體在其中起作用的疾病。例如,在一些具體實施方式中,本發明涉及治療選自增生性疾病或疼痛的疾病或病症的方法,其中所述方法包括將根據本發明的化合物或組成物、特別是用於抑制TRK活性的化合物或組成物給予需要其的受試者。在一些實施方式
中,TRK-相關病症係為癌症。在一些實施方式中,TRK-相關病症係為疼痛。
酪氨酸激酶相關病症(Tyrosine kinase associated condition):如本文中使用的,術語“酪氨酸激酶相關病症”指任意已知或疑似酪氨酸激酶或其突變體在其中起作用的疾病或其它有害病症。可替代地或進一步地,酪氨酸激酶相關病症係為其出現、發病率和/或嚴重性與酪氨酸激酶的存在和/或活性水準相關的任何疾病或其它有害病症。
酪氨酸激酶
蛋白酪氨酸激酶係為一類將磷酸基團從ATP或GTP中催化轉移至位於蛋白質底物中的酪氨酸殘基上的酶。受器酪氨酸激酶通過磷酸化事件啟動次級信號效應物(secondary messaging effector)將信號由細胞外傳導至細胞內起作用。多種細胞過程由這些信號引發,包括增殖、碳水化合物利用、蛋白質合成、血管發生、細胞生長、及細胞生存。事實上,已在多種癌症的患者中證實了酪氨酸激酶結構域上的啟動突變,如非小細胞肺癌(Lin,N.U.;Winer,E.P.,Breast Cancer Res 6:204-210,2004)。
受器酪氨酸激酶係為針對許多多肽生長因數、細胞因數類和激素的高度親和細胞表面受器。在人類基因組中的90個獨特的酪氨酸激酶基因中,58個編碼受器酪氨酸激酶蛋白。已經顯示受器酪氨酸激酶不僅在正常細胞過程中係
為關鍵調節器,而且在許多類型的癌症的發展及進展過程中扮演重要角色。
間變性淋巴瘤激酶(Anaplastic Lymphoma Kinase)
間變性淋巴瘤激酶(ALK)係為一種受器酪氨酸激酶,其涉及數種疾病及失調,諸如非小細胞肺癌、成神經細胞瘤及間變性大細胞淋巴瘤(ALCL)。數種已知的ALK突變或ALK的易位導致產生一個或多個ALK融合基因,其促進了激酶活性並導致了致瘤事件。
伴隨著對間變性大細胞淋巴瘤(ALCL)中的核仁磷蛋白-ALK(nucleophosmin-ALK)(NPM-ALK)融合基因的描述,在二十世紀九十年代第一次將ALK描述為人類癌症中的癌基因(oncogene),其以首字母縮寫的方式命名為ALK。此後,在種類大量增加的腫瘤中描述了大量的ALK易位,在其中,綜合主題(uniting theme)係為二聚作用(dimerization),和正在討論的通過融合伴侶的ALK酪氨酸激酶活性的不適當的配體不依賴的啟動(inappropriate ligand-independent activation)。除了在血液性惡性腫瘤中的作用,ALK易位也在眾多實體腫瘤類型中被發現,包括NSCLC、鱗狀細胞癌、以及最近發現的甲狀腺癌。儘管最初被認為極為罕見,但是如前列腺癌中的TMPRSS2-ERG(跨膜蛋白酶,絲氨酸2-ETS-相關基因)等融合物的鑒定提示實體腫瘤中此類融合物的出現被低估。
ALK在腦發育過程中具有重要作用並且在神經系統中的特定神經元上發揮其影響。已知至少兩種不同類型的突
變致使ALK基因的致瘤性:與任意的幾個其它基因的融合、以及ALK基因序列的單點突變或位點突變(例如缺失、插入、倒位、易位)。最近幾年中鑒定了數個ALK融合物。典型地,這些融合物的特徵在於:(i)與ALK融合的伴侶基因在發生融合的細胞中被組成型轉錄(constitutively transcribed)和/或(ii)各種融合伴侶能夠介導嵌合蛋白(例如由基因融合所產生的蛋白)的二聚作用(或寡聚作用(oligomerization))。值得注意地,所有鑒定的ALK融合蛋白均顯示組成型ALK活性(constitutive ALK activity)。由於ALK酪氨酸激酶活性對於ALK融合蛋白致瘤性係為必須的,因此研究已被集中於鑒定ALK激酶抑制劑。特別興趣在於針對任意ALK融合蛋白顯示抑制活性的ALK激酶抑制劑均擁有(harboring)ALK活性位點。
某些ALK抑制劑,如克唑替尼可使大多數攜帶(harboring)ALK融合基因的患者腫瘤收縮或穩定。然而,儘管有這些顯著的初始反應,但是癌症最終對ALK抑制劑產生抗性,包括克唑替尼,由此限制了潛在的臨床益處。
NPM-ALK。t(2;5)(p23;q35)染色體易位產生由來自於5號染色體的核仁磷蛋白(NPM)的5'部分以及來自於2號染色體的間變性淋巴細胞瘤激酶(ALK)基因的3'部分構成的融合基因。NPM-ALK嵌合基因編碼組成型啟動的酪氨酸激酶,其顯示強致癌活性。NPM-ALK激酶,以二聚體形式,顯示磷酸轉移酶的活性並且在體外實驗(in vitro)中通過其與多種ALK-銜接蛋白(ALK-adapter protein)相互作
用引發細胞轉化及增加細胞增殖。因此,NPM-ALK融合基因的產物係為致癌性的(Pileri等,Am.J.Pathology,1997,150(4),1207-1211,將其全部通過引用結合到本文中)。
ELM4-ALK。涉及2號染色體短臂(2p21和2p23)的染色體重排產生了EML4(類棘皮動物微管相關蛋白-4(echinoderm microtubule-associated protein-like 4))與ALK之間的融合基因。EML4-ALK通過每個單體的EML4區域內的捲曲螺旋結構域(coiled-coil domain)之間的相互作用形成組成型二聚體(constitutive dimerization),從而啟動ALK並且產生致癌活性。在所有NSCLC的病例中的大約4%報導了EML4-ALK融合致癌基因(Choi等,New England J.Medicine,2010,363(18),1734-1739;Sasaki等,European J.Cancer,2010,46,1773-1780,將以上文獻其全部通過引用結合到本文中)。
其它ALK融合蛋白。已經鑒定了其它具有組成型活性的ALK融合蛋白。近期的研究證明,ALK可能還涉及變異體易位作用,即:t(1;2)(q25;p23)、t(2;3)(p23;q21)、t(2;17)(p23;q23)以及inv(2)(p23q35),其對應產生TPM3-ALK、TFG-ALK、CLTC-ALK以及ATIC-ALK融合基因。ATIC-ALK融合蛋白中保留的ALK部分與NPM-ALK中保留的部分以及ALK-融合蛋白TPM3-ALK及TFG-ALK中保留的部分相同。這些X-ALK變異體融合蛋白具有相同的ALK胞質內區域但缺失NMP核定位元結構域,其解釋TPM3-ALK、TFG-ALK、CLTC-ALK、ATIC-ALK和
ELM4-ALK融合蛋白的限制性細胞質分佈(De Paepe等,Blood,2003,102(7),2638-2641;Brunangelo等,Blood,1999,94(10),3509-3515,將以上文獻其全部通過引用結合到本文中)。
TPM3-ALK。TPM3-ALK蛋白由非肌肉的原肌球蛋白(nonmuscular tropomyosin)(TPM3)基因與ALK基因之間以t(1;2)(q25;p23)易位的融合而產生。
TFG-ALK。TFG-ALK融合蛋白由TRK-融合基因(TFG)與ALK基因以t(2;3)(p23;q21)易位的融合而產生。TFG-ALK融合蛋白在細胞內與NPM-ALK所用的用於信號轉導的信號肽中間體(signaling intermediate)相關,提示不同的ALK嵌合產物可能使用類似的轉化途徑(Hernandez等,Blood,1999,94(9),3265-3268;Hernandez等,American J.Pathology,2002,160(4),1487-1494,將以上文獻其全部通過引用結合到本文中)。
ATIC-ALK。ATIC基因(之前命名為Pur H)編碼一種雙功能酶(5-氨基咪唑-4-羧醯胺核苷酸轉甲醯酶和IMP環水解酶活性),其催化嘌呤核苷酸生物合成途徑的倒數第二步和最終步驟的酶活性。在小鼠成纖維細胞中表達全長ATIC-ALK cDNA提示該融合蛋白(a)具有組成型酪氨酸激酶活性;(b)與信號蛋白(signaling protein)Grb2及Shc形成穩定的複合體;(c)誘導Shc的酪氨酸磷酸化;以及(d)引起致癌性轉化。(Colleoni等,Am.J.Pathology,2000,156
(3),781-789;Trinei等,Cancer Res.,2000,60,793-798,將以上文獻其全部通過引用結合到本文中)。
KIF5B-ALK。KIF5B定位於人類10號染色體的短臂並且編碼蛋白的激酶家族成員5B。KIF5B係為與微管相關(締合,associate)的動力蛋白複合體(motor protein complex)的成分之一,並介導真核細胞內的細胞器運輸。其由氨基末端的動力結構域(motor domain)及緊接著的頸區域(neck region)及柄區域(stalk region)構成,後者直接介導KIF5B的同型二聚體作用(homodimerization)。可以預期KIF5B的外顯子1至外顯子24與ALK的外顯子20的融合將導致產生包含幾乎全部的由KIF5B序列連接至ALK細胞內區域的融合蛋白。因此,同樣可預期KIF5B-ALK將經歷由KIF5B的柄區域介導的同型二聚體作用,以及隨之發生的ALK的激酶功能的啟動,這與EML4-ALK的情況類似,在EML4-ALK中的同源低聚作用(同源寡聚作用,homo-oligomerization)及啟動由EML4的氨基末端的捲曲螺旋結構域介導。為確定KIF5B-ALK融合基因的同一性,使用一條靶向KIF5B的外顯子24的引物和另一條靶向ALK外顯子22的引物通過RT-PCR直接擴增KIF5B-ALK cDNA中的融合點(Takeuchi等,Clinical Cancer Research 2009,15(9),3143-3149,將其全部通過引用結合到本文中)。擴增獲得一個具有預期的546 bp尺寸的單一的PCR產物並且產物的核苷酸測序進一步在cDNA水準證實了KIF5B-ALK的融合點。
ALK-相關紊亂
間變性大細胞淋巴瘤(ALCL)。淋巴瘤係為最常見的血液癌症。淋巴瘤的兩種主要形式係為何傑金氏淋巴瘤(Hodgkin’s lymphoma)(HL)及非何傑金氏淋巴瘤(non-Hodgkin’s lymphoma)(NHL)。淋巴瘤發生於白細胞的一種的淋巴細胞異常生長時。體內有兩類主要的可發展成淋巴瘤的淋巴細胞:B-淋巴細胞(B-細胞)和T-淋巴細胞(T-細胞)。癌性淋巴細胞可傳播至體內眾多部位,包括淋巴結、脾臟、骨髓、血液或其它器官,並且可積累以形成腫瘤。
大細胞淋巴瘤約占所有兒童和年輕成人中患非何傑金氏淋巴瘤的四分之一。1985年,第一次將ALCL描述為之前未識別的淋巴腫瘤,其中通過單克隆抗體Ki-1標記腫瘤細胞(隨後顯示可識別CD30受器分子)。ALCL係為一類罕見的NHL,但卻是T細胞淋巴瘤的所有亞型中第二或第三最為常見的亞型。有三類ALCL並一起佔有了大約3%的成人NHL及大約10%至30%的兒童NHL。ALCL可存在於全身(淋巴結中或遍及全身的組織中)或存在於皮膚組織中。
當ALCL存在于皮膚組織時,其被稱為原發皮膚性ALCL並伴隨較低的侵略性過程。在幾乎所有的原發皮膚性ALCL病例中,該疾病被限制於皮膚中。儘管具有復發的趨勢,但復發通常也僅限於皮膚。由於被限制於皮膚中,其通常表現為慢性(indolent)(緩慢生長的)淋巴瘤。大約有10%的時間,原發皮膚性ALCL擴散超出皮膚至淋巴結或各
組織。當這種情況發生時,其通常被稱為類似於全身性ALCL形式。
偶爾,原發皮膚性ALCL與另一種罕見的稱為淋巴瘤樣丘疹病(LyP)的病症相伴。LyP係為一種具有與原發皮膚性ALCL類似特徵的皮膚病症。當將LyP分類為淋巴瘤時,其皮膚傷害可在約4至8周的時間內自愈,因此,其並未表現為類似惡性腫瘤。
原發皮膚性ALCL的特徵症狀包括出現單發的或多發的凸起的紅色皮膚損傷、結節或腫瘤,其不可消失,具有潰爛趨勢並且可能瘙癢。在身體的任意部位可見損傷,其生長通常非常緩慢並且在被診斷前可能已存在較長時間。
大約三分之一的ALCL腫瘤為NPM-ALK融合陽性。伴有NPM-ALK融合的淋巴瘤典型地涉及淋巴結、皮膚、肺、軟組織、骨骼及腸胃道,並且主要從啟動的T細胞發生。大多數伴有NPM-ALK融合的腫瘤被歸類為間變性大細胞非何傑金氏淋巴瘤(A.G.Stansfeld等,Lancet.1:292(1988))。NPM-ALK2:5染色體易位與大約60%的間變性大細胞淋巴瘤相關。NPM-ALK蛋白不但典型地積累於細胞質中,也積累於淋巴細胞的核質(nucleus)及核仁中。
根據ALK的表達可將全身性ALCL患者分為兩組。當兩類淋巴瘤均作為進展的淋巴瘤治療時,ALCL的愈後依賴于該患者是否係為ALK陽性(表達該蛋白)或係為ALK陰性(不表達該蛋白)。ALK陽性疾病對化療的響應很好,使大多數患者長期好轉(remission)或治癒。大多數具有ALK
陰性ALCL的人們對化療有回應,但是許多會在五年內復發。由於此原因,他們往往需要更為侵襲性的(aggressively)治療,通常涉及幹細胞移植。ALK陽性亞型通常影響兒童及年輕成人。ALK陰性亞型則在60歲以上受試者中較為常見。
在第一次描述為ALCL後的五年,發現攜帶(2;5)(p23;q35)染色體易位的、涉及罕見的細胞生成畸形並在最初被認為係為惡性組織細胞增多症的腫瘤係為CD30(Ki-1)-陽性大細胞淋巴瘤。1994年,研究人員展示位於染色體5q35上的核仁磷蛋白(NPM)基因的(2;5)易位融合區域易位至位於染色體2p23上的ALK受器酪氨酸激酶基因的一部分,導致一個獨特的嵌合蛋白NPM-ALK的表達。已報導ALK激酶的特異性抗體,正常淋巴樣細胞中缺乏該分子意味著針對ALK蛋白的陽性免疫細胞化學反應對(2;5)易位特別有效。主要的例外情況係為在罕見的大B-細胞淋巴瘤(其機理未知)中表達了全長ALK蛋白。
非小細胞肺癌。美國癌症協會(the American Cancer Society)2008年發佈的圖形報導了全世界範圍內新增的160萬肺癌病例。事實上,肺癌係為男性中癌症死亡的第一大原因及女性癌症死亡的第二大原因,2008年全世界範圍內估計死亡達到140萬人。臨床上,主要的肺癌分為小細胞肺癌(SCLC)和非小細胞肺癌(NSCLC),而患者依據此標準接受不同的治療。NSCLC係為眾多腫瘤類型的、總共占全部肺癌80%的肺癌的總括術語。這些包括鱗狀細胞肺癌、
大細胞肺癌及腺癌三種主要亞型。腺癌占全部NSCLC的大約40%並且在從不吸煙的人群中更普遍。多年以來,對晚期NSCLC或轉移的NSCLC的治療已經對患者醫療護理使用效果有限的化學療法。這些患者的五年存活率非常不樂觀。然而,針對這些患者中的一個小組,近年來已發生了根本的改變。在分子水準上理解NSCLC背後的基本病理已提供了新型分子靶向治療的主體思路,其係為本領域的癌症護理方面的重大變革。啟動NSCLC中的EGFR(表皮生長因數受器)突變體提供了在分子水準上定義的治療(如抑制劑吉非替尼(gefitinib)和厄洛替尼(erlotinib))產生的第一個機會。近來臨床試驗的結果係為攜帶涉及間變性淋巴瘤激酶(ALK)受器酪氨酸激酶的致癌易位的NSCLC患者提供了希望。正如抑制BCR-ABL(中斷點簇區域-c-ab1癌基因1,非受器酪氨酸激酶)複合物已改變了慢性髓樣白血病的診斷方向,致癌的ALK融合向前推進了對ALK-陽性NSCLC的診斷及治療。近來在醫藥方面的進展,特別係為那些靶向ALK的藥物開發已見帶來顯著改變針對該患者群體及他們的未來治療前景。
2007年,兩個獨立的、使用了完全不同方法的研究首次描述了NSCLC中的ALK融合致癌蛋白的外觀。經典的腫瘤DNA文庫轉化分析用來鑒定了棘皮動物類微管相關蛋白-4-ALK(EML4)-ALK。NSCLC細胞系的起始的全程磷酸酪氨酸蛋白組學分析進一步鑒定了眾多致癌損害,包括ML4-ALK和TRK-融合基因-ALK(TFG-ALK)。
在NSCLC中鑒定出ALK融合蛋白之前,限定攜帶ALK融合的患者群,如ALCL中攜帶NPM-ALK的患者。該數量根據考慮內容的不同而顯著變化,占所有NSCLC患者的約3%-13%。以ALK易位率5%計算並基於2008年美國癌症協會的圖表,NSCLC中遵從ALK指導的治療的病例預測達到全世界範圍內每年80,000新增癌症患者。
出現有ALK易位的NSCLC患者組與更常見的吸煙有關肺癌群體有一定程度的不同。現在已經認識到,群體數量增加的“非吸煙相關肺癌”NSCLC患者中諸如EML4-ALK以及啟動的EGFR突變體的失常發生了富集。此群體通常主要係為女性,而腫瘤通常係為腺癌。
EML4-ALK融合基因係為造成大約3-5%的非小細胞肺癌(NSCLC)的原因。這些病例絕大多數係為腺癌。平均地,ALK肺癌在人群中的發病年齡較其它肺癌的發病年齡低10-15歲,並且其同樣顯著地在非吸煙者及在輕度的以前吸煙者中稍高。至今為止,在肺癌中已鑒定出多種EML4-ALK突變體。儘管融合體包括多種EML4的截斷(truncation)(發生於外顯子2、6、13、14、15、18和20),在所有突變體中ALK融合均開始於由該激酶基因的外顯子20編碼的部分。至今為止,所有EML4-ALK融合體實驗在生物學上證明了功能獲得性特性。
EML4-ALK轉錄本在約15%的非腫瘤肺部組織中表達,其意味著EML4-ALK的重排係為非腫瘤特異的。此外,在非腫瘤肺部組織中表達EML4-ALK mRNA的患者在配對的腫瘤中不攜帶融合轉錄本,從而提出了EML4-ALK重排是否與NSCLC發
病機制直接相關的疑問。事實上,肺癌中對EML4-ALK及EGFR1突變體的情況(scenario)看來非常不同。在帶有EGFR突變的肺腺癌的43%患者的正常呼吸上皮細胞中發現EGFR1突變體,但在無EGFR突變的肺腫瘤患者中未見,提示局部化區域影響現象。
在攜帶EML4-ALK轉錄本的NSCLC患者中,如通過石蠟包埋切片的FISH分析所檢測的,只有約2%的腫瘤細胞攜帶有相應的融合基因。通過組織微陣列FISH,603份NSCLC樣品中的9份(1.5%)檢測到包含或不包含EML4的ALK基因重排。然而,攜帶重排的腫瘤細胞的百分比高於(50%至100%)現有研究。兩個研究中的病例數量及技術的不同可以至少部分地解釋以上差異。
小鼠中的肺上皮細胞中被動表達EML4-ALK導致數以百計的肺癌結節的快速發展,將EML4-ALK的PTK活性抑制劑經口給藥顯示所述腫瘤從肺部清除,證明EML4-ALK在針對該融合激酶陽性的NSCLC發病機制中的關鍵作用。這種後者的觀察同樣支援了臨床上使用ALK抑制劑以治療人類EML4-ALK-陽性肺癌。然而應該注意的是,已在NSCLC樣本中識別了多種主要由於在EML4內的中斷點融合點多樣性所產生的EML4-ALK亞型。因此EML4-ALK-陽性腫瘤的精確診斷需要檢測所有EML4及ALK cDNA之間在讀碼框內(in-frame)的融合體,如通過我們的基於多倍反轉錄(multiplex reverse transcription)及PCR的針對EML4-ALK的檢測系統。NSCLC腫瘤樣品中同樣涉及TFG-ALK和KIF5B-ALK融合物。
成神經細胞瘤(Neuroblastoma)。成神經細胞瘤係為最常見的兒童癌症。近期的研究顯示ALK突變與10-15%的成神經細胞瘤。該疾病具有強的家族關聯性,在過去三十年中預測此病有遺傳因素。在成神經細胞瘤患者中已鑒定到ALK突變體。ALK表現為成神經細胞瘤易感基因,且在成神經細胞瘤病例中偶見發生於肉體的點突變。這些突變提升了ALK的激酶活性並且可將細胞轉化並在體內顯示出致瘤活性。
ALK-相關成神經細胞瘤易感性發生於針對ALK突變體雜合的個體並且其特徵在於發展為成神經細胞瘤、神經節神經母細胞瘤(ganglioneuroblastoma)或神經節瘤(ganglioneuroma)的風險增加。腫瘤發展的風險在幼年期最高,並在兒童期晚期降低。與不具家族性的易患病體質的個體相比(年齡2-3歲),具有家族性成神經細胞瘤的個體趨向於在更低的年齡發展腫瘤(平均9個月)。
乳腺癌。多效蛋白(pleiotrophin)(PTN)表達於乳腺癌及從人類乳腺癌來源的細胞系中;由於在體內通過顯性的反義PTN靶向結構性PTN信號(constitutive PTN signaling)扭轉了人類乳腺癌細胞的惡性表型,提示結構性PTN信號對乳腺癌發展的發病機制有貢獻。最近,對於通過以確定乳腺癌中Ptn的不適當表達的作用的不同模型進行測試並發現,通過鼠乳腺腫瘤病毒(MMTV)啟動子將Ptn的不適當表達靶向乳腺上皮細胞,並未在MMTV-Ptn轉基因小鼠乳腺癌模型中導致乳腺癌;然而MMTV-啟動的PTN信號與癌蛋白多瘤中部
T-抗原(PyMT)協同作用促進MMTV-PyMT-Ptn雙轉基因小鼠中的乳腺癌進展。進一步發現僅通過啟動基質細胞及感應顯著的微環境重塑(marked remodeling of the microenvironment),僅PTN的分泌可顯著提升乳腺癌進展,因此,資料潛在支援PTN信號在促進更具侵襲性的乳腺癌表型中具有非常重要的作用。
研究者分析了來自於人類乳腺癌的組織中ALK的表達並證明ALK在所研究的每一種人類乳腺癌亞型中均高表達(Perez-Pinera等,Biochem Biophys Res Commun.2007 June 29;358(2):399-403.)。進一步,乳腺癌細胞中ALK表達的細胞定位及其模式與其在正常乳腺組織中的表達模式顯著不同,其與在不適當表達Ptn的乳腺細胞中ALK可能通過結構性(constitutively)啟動的PTN/RPTPβ/ζ信號通路活化的可能性一致。
其它ALK-相關病症。最近,ALK被認為涉及一種被認為是炎性纖維原細胞腫瘤的罕見的非淋巴性贅生物的發病。該腫瘤與多種易位作用相關,包括ALK與TPM3、TPM4、CLTC或CARS(編碼半胱氨醯-tRNA合成酶)基因的融合。ALK同樣涉及成膠質細胞瘤(glioblastoma)、食道鱗狀上皮細胞癌及數種類型的乳腺癌(Webb等,Expert Review of Anticancer Therapy,2009,9(3);331-356,將其全部內容通過引用結合到本文中。
中樞神經系統紊亂(Disorders of the Central Nervous System)。中樞神經系統(CNS)癌症認為是所有癌症中最
具破壞性的癌症。腦和脊髓係為控制CNS、周圍神經系統、及身體中許多的自覺的(voluntary)和非自覺系統(involuntary)的複雜器官。當癌症攻擊CNS時對於患者和家庭來說結果都為災難性的。已發現所有癌症中20%-40%轉移到腦部。伴隨令人生畏的患有高級別腫瘤(high-grade tumor)患者的統計,中位生存率少於12個月,CNS癌症的診斷往往不給患者留有希望。
2009年,估計有12,920例死亡係為由於原發CNS癌症。CNS腫瘤的發病率在發達的工業化國家中係為每年大約每100,000人群診斷有6-11例新增病例;所有類型的原發CNS腫瘤的致死率係為每100,000人群3-7例。具有最常見類型的多形性成膠質細胞瘤(glioblastoma multiforme),神經膠質瘤包括所有腦部腫瘤的70%,也係為最具致死性的。從2003年至2007年,確診腦癌的患者的平均年齡係為56歲。儘管轉移性腦腫瘤的精確發病率目前未知,估計其為原發腦腫瘤的2-10倍,並且至少20%-40%的癌症患者在他們病程的某點發生腦部轉移。
針對ALK-相關紊亂的ALK抑制劑療法
已投入大量努力用於鑒定和/或表徵可抑制ALK的化合物。例如美國專利申請案號US2011/0257155、US2011/0257155、US2011/0256546、US2011/0190264、US2011/0190259、US2011/0135668、US2010/0298295、US2008/0300273、US2008/0176881,描述了多種被證明具有ALK抑制劑活性的化合物。
最近,核准使用氨基吡啶化合物克唑替尼治療局部晚期的(locally advanced)或已經轉移的非小細胞肺癌。克唑替尼對含有異常活化的EML4-ALK的腫瘤產生特異性作用,而僅在約5.5%的NSCLC患者中發現異常活化的EML4-ALK。在此小患者群體中,克唑替尼已顯示了驚人的活性,在8周時顯現出57%的回應率和87%的疾病控制率。
抗性。儘管ALK抑制劑諸如克唑替尼取得了顯著的治療承諾(治理希望,therapeutic promise),但有證據顯示抗性通常在一年內即快速發展。例如,已知至少兩個EML4-ALK激酶結構域內的從頭開始突變體(de novo mutation)帶有對多種ALK抑制劑的抗性。證據提示對克唑替尼產生抗性係為複雜的範例(paradigm。事實上,抗性可表現為(i)已知與抗性相關的ALK基因中的新突變,或者(ii)ALK基因的另外拷貝,其可勝過ALK抑制劑的效果。
獲得性抗性可以以數種途徑出現。與ALK突變體共存的突變係為獲得性抗性的一種此類途徑。使用ALK抑制劑治療確實無法抑制來自第二種突變(諸如EGFR或KRAS)的生物學作用,其發展為競爭性及優勢活性(overriding activity)並且產生抗性。
相反,占主導地位的新的、分離的致癌突變的出現可能是由於存在不同亞型的癌症細胞。治療之前,癌症主要由原發ALK-陽性癌細胞構成,並帶有少量具有其它突變如KRAS的細胞。使用靶向療法如ALK抑制劑治療改變癌症
細胞的平衡,使得ALK陽性細胞死亡,而癌症繼續生長成為KRAS陽性占主導地位的癌症。
與抗性有關的標記物(標記,marker)。可使用例如在給藥治療過程中及之後監控疾病級數來檢測抗性的發展。任意標記物,其存在或水準與ALK-相關病症的出現、或優選為發展狀況相關,均可用於評價抗性的發展情況。可替代的或進一步的,可使用與ALK水準或活性相關的標記物。特別感興趣的係為與抗性發展(例如,可反映特定ALK突變體的出現或與之出現相關)特異性相關的標記物。
多種合適的標記物係為可獲得的。例如,與克唑替尼抗性相關的最常見的遺傳標記物係為激酶看家突變體(kinase gatekeeper mutation),如L1196M。在一些實施方式中,其它相關標記物包括R1275Q、F1174L、EML4-ALK及NPM-ALK。在一些具體實施中,ALK-相關標記物係為高於閾值水準的ALK活性升高。
克唑替尼的給藥係為250mg口服劑量、每天兩次(BID)。基於安全性及耐受性的考慮可能需要劑量中斷和/或劑量降低至200 mg PO BID。臨床有害事件的強度通過NCI不良事件(AE)的通用術語標準(NCI Common Terminology Criteria for Adverse Events(AE))分級。在這種情況下,劑量減至250 mg PO每天一次(QD)。除了淋巴球減少症(淋巴細胞減少,lymphopenia)之外的其它血液學毒性(除非與臨床事件相關,例如,機會致病菌感染(opportunistic infection))需要劑量調整:三級AE(不
給予(withhold)直至恢復至級別2,然後重新開始相同劑量明細表);四級AE(不給予直至恢復至級別2,然後以200 mg PO BID重新開始;在復發的病例中,不給予直至恢復至級別2,然後以250mg PO每天(qDAY)重新開始;在四級復發病例中永遠停止)。非血液學毒性需要劑量調整包括三級或四級丙氨酸氨基轉氨酶(ALT)或天冬氨酸氨基轉氨酶(AST)升高伴隨總膽紅素級別1(不給予直至恢復至級別1或基線,然後以200 mg PO BID重新開始(在復發的病例中,不給予直至恢復至級別1,然後以250mg PO qDay重新開始;在超過三級或四級復發病例中永遠停止));三級QTc延長(不給予直至恢復至級別1,然後以200mg PO BID重新開始)。導致二級、三級或四級ALT或AST升高併發二級、三級或四級總膽紅素升高(不存在膽汁淤積或溶血)、任意級別的肺炎(pneumonitis)或四級QTc延長的劑量方案均要求(mandate)永遠停用克唑替尼。
治療抗ALK-相關紊亂。
在一些實施方式中,本發明包括確定對治療ALK-相關紊亂特別有用的式I的化合物的發現。在一些實施方式中,本發明包括對對治療那些係為抗ALK抑制劑、或具有成為抗ALK抑制劑風險的ALK-相關紊亂特別有用的式I的化合物的識別。在一些實施方式中,本發明提供用於治療對抗ALK抑制劑易感的ALK-相關病症的方法,其包括將式I的化合物給予需要其的患者。因此,在一些實施方式中,本發明提供包括將式I的化合物給予患有抗-ALK-抑制劑
(ALK抑制劑抗性,ALK-inhibitor-resistant)ALK-相關病症的患者的方法。在一些實施方式中,本發明提供治療抗-ALK-抑制劑ALK-相關病症的方法,該方法包括將式I的化合物給予需要其的患者。
在一些實施方式中,對ALK抑制劑的抗性係為克唑替尼抗性。在一些此類實施方式中,式I的化合物在治療克唑替尼抗性或可能成為克唑替尼抗性的ALK-相關紊亂中有效。因此,在一些實施方式中,本發明提供了治療克唑替尼抗性ALK-相關病症的方法,其包括將式I的化合物給予需要其的患者。
在一些實施方式中,ALK-相關紊亂係為癌症。因此,在一些實施方式中,本發明提供了治療抗-ALK-抑制劑癌症的方法,該方法將式I的化合物給予需要其的患者。在一些實施方式中,ALK-相關病症選自NSCLC、成神經細胞瘤、ALCL、炎性肌纖維母細胞瘤(inflammatory myofibroblastic tumor)、炎性乳腺癌、食道癌、胃癌及成膠質細胞瘤。
在一些實施方式中,本發明提供了治療ALK-相關紊亂的方法,其中ALK-相關紊亂表現於大腦和/或中樞神經系統。在一些所述實施方式中,ALK-相關紊亂係為癌症。在一些實施方式中,所述癌症係為腦癌和脊髓癌。在一些實施方式中,腦癌係為成膠質細胞瘤。
在一些實施方式中,本發明提供了治療轉移性腦癌的方法,該方法包括將式I得化合物給予需要其的患者。
在一些實施方式中,本發明提供了治療ALK-相關紊亂的方法,該方法包括將式I的化合物給予需要其的患者,其中患者表現出一個或多個抗性標記(indicia of resistance)。
在一些實施方式中,本發明提供了一種方法,包括將式I的化合物給予患有ALK-相關病症、表現出一個或多個對ALK抑制劑的抗性標記的受試者。在一些實施方式中,ALK-相關病症係為抗克唑替尼。在一些實施方式中,抗性標記選自L1196M、R1275Q、F1174L、ELM4-ALK、NPM-ALK以及它們的組合。
在一些實施方式中,本發明提供了檢測受試者中ALK抑制劑抗性相關標記物的方法,以及確定該受試者係為適用式I的化合物治療的候選者的方法。在一些這類實施方式中,抗性標記物(resistance marker)係為L1196M。在一些實施方式中,在與對ALK抑制劑的抗性的升高概率相關的閾值水準之上檢測到抗性相關標記物。在一些這類實施方式中,ALK抑制劑係為克唑替尼。
在一些實施方式中,本發明提供包括步驟的方法:(i)檢測受試者中一個或多個抗性標記(例如,抗性相關標記物的存在或水準,疾病進展,等);以及(ii)基於檢測到的一個或多個標記的存在,確定受試者係為適用式I的化合物治療的候選者。
在一些實施方式中,本發明提供包括步驟的方法:(i)檢測受試者中的一個或多個抗性標記(例如,抗性相關標記物的存在或水準,疾病進展,等);
(ii)基於檢測到的一個或多個標記,確定受試者係為適用式I的化合物治療的候選者,以及(iii)向受試者給予治療有效劑量的式I化合物。
在一些實施方式中,所述一個或多個抗性標記係為ALK融合癌蛋白。在一些此類實施方式中,ALK融合癌蛋白選自NPM-ALK、ELM4-ALK、ATIC-ALK、TPM3-ALK、TFG-ALK、CLTC-ALK和KIF5B-ALK。在一些實施方式中,ALK融合癌蛋白係為NPM-ALK。在一些實施方式中,ALK融合致癌蛋白係為ELM4-ALK。在一些實施方式中,一個或多個抗性標記係為疾病的進展。
在一些實施方式中,式I的化合物選自化合物I-a和化合物I-b。
在一些實施方式中,本發明提供了包括將式I化合物與一種或更多種另外的化療劑聯合給予患有或易患抗性ALK-相關病症(resistant ALK-associated condition)的受試者的方法。
在一些實施方式中,本發明提供的方法包括將式I化合物及至少一種另外的化療劑給予需要其的患者。在一些此類實施方式中,將至少一種式I化合物及另外的化療劑以低於使用單獨藥劑的劑量給藥。在一些實施方式中,另外的化療劑選自由多烯紫杉醇(多西他賽,docetaxel)、培美曲塞、卡鉑、紫杉醇和順鉑構成的組。
原肌球蛋白受器激酶(Tropomyosin-Receptor Kinase)(TRK)
在式I化合物的發現過程中,令人驚奇地發現化合物I-a表現出相當的抗TRK(原肌球蛋白受器激酶)家族的活力。TRK係為調節神經元亞類(subset)、特別是感官及交感神經元的存活、發育及功能的一類酪氨酸激酶家族。TRK受器通過多條信號級聯(several signal cascade)影響神經元的存活及分化,其包括PI3K/Akt、Ras/MAPK STAT3、及PLCγ通路。TRK家族由TRKA、TRKB、TRKC及p75及針對每一種受器的特異性配體組成。神經生長因數(NGF)特異性結合TRKA,腦源性神經營養因數(brain-derived neurotrophic factor)(BDNF)和神經營養蛋白(Neurotrophin)(NT)-4/5結合TRKB,而NT3已知結合TRKC。由於需要更高濃度的神經營養蛋白以啟動其信號通路,因此p75受器通常被稱為低親和性TRK受器。在治療上,大量注意力已集中於NGF及BDNF在疼痛機理中的涉及(involvement),然而更多目光投向這些生長因數及它們的同源受器在神經性疾病、行為及癌症中的作用。
惡性細胞的關鍵性特徵係為它們通常通過三種常見的轉移擴散途徑(淋巴、神經及血管的通道)之一、從原發腫瘤中分離並在較遠部位建立轉移性積累(堆積,deposit)的能力。類似血管的及淋巴的轉移途徑,已發現神經侵襲(NI)(有時涉及神經周侵襲或PNI)係為許多癌症的關鍵病理特徵,包括胰腺癌、頭頸癌、鱗狀細胞癌、前列腺癌、結直腸癌、乳腺癌、膽道癌、胃癌及膽管上皮癌。通過PNI啟動的癌症轉移的分子機理有時同樣也作用於腫瘤的增
殖,列舉一小部分,如在胰腺癌、乳腺癌及頭頸癌中看到的。研究已證明PNI涉及腫瘤細胞與神經之間的互換信號交互(reciprocal signaling interaction),並且侵襲的腫瘤細胞具有潛在獲得性的回應腫瘤發生過程中神經內部促細胞侵襲信號(proinvasive signal)的能力。神經營養蛋白及它們的受器原肌球蛋白受器激酶(TRK)被暴露為PNI及一些腫瘤類型的增殖的關鍵調節者。
表1列舉了已報導過的神經周侵襲的腫瘤類型:
伴隨在甲狀腺乳突癌和甲狀腺髓樣癌(papillary and medullary thyroid carcinoma)中分別發現TRKA中的染色體重排或突變,首次發現了TRK和癌症的臨床關聯(clinical association。然而即使是在這類腫瘤中,TRK基因中的遺傳變異頻率仍較低,並且未在其它腫瘤中證實這類變異。數年來,大量研究詳細研究了不同腫瘤類型中的TRK表達,及相關的預後或腫瘤不同階段的表達。然而在這些文獻中沒有與伴隨預後的、與特定TRK亞型(isoform)相關的清楚的成形模式。在其中TRK沒有轉座或突變的病例中,越來越多的證據表明TRK在腫瘤細胞的生物學過程中起病理生理學作用。由於正常神經元中TRK的神經營養蛋白的啟動作用介導生存信號和刺激神經炎發生(神經炎形成,neuritogenesis)以及轉移,因此認為腫瘤細胞也採用相同的過程以避免細胞毒素存活(survive cytotoxic insults)或通過PNI的轉移。大量研究已顯示神經營養蛋白在腫瘤進展中至關重要,它們引發推動腫瘤生長的有絲分裂信號,避免細胞凋亡以及調節血管發生、細胞擴散及轉移。在關於失巢凋亡(anoikis)(失去細胞基質相互作用導致的細胞凋亡)的具有里程碑意義的文章中,進行了對轉移相關致癌基因的基因組範圍內的功能篩選,並確定TRKB係為允許系統迴圈及抗失巢凋亡過程中的細胞存活的關鍵調控者(mediator)。
不希望與任何特定理論相結合,可以認為對PNI易感的癌症在腫瘤發生過程中獲得以下特性,包括不僅可以通
過神經通道允許發生轉移擴散,而且可依賴這些機械論特性(mechanistic characteristic)以增殖、抵抗細胞毒性治療及局部環境應力,以及在推動物(促因,driver)致癌基因和腫瘤支援機理之間的介面上存在。
肺癌。 許多研究已證實了肺癌中NT和TRK受器的關係。儘管也有相反的結果,但是現在對於肺癌中NT和TRK作用的理解開始變得清晰。許多研究確認了肺部腫瘤中NT和TRK二者的表達,其中NSCLC中最常見的過表達的NT係為NGF和BDNF,以及TRKA和TRKB比TRKC起的作用更加重要。許多研究已顯示在來自NSCLC患者的經挑選的細胞系及肺癌細胞二者中,TRKA或TRKB信號的刺激增加了腫瘤侵襲及集群形成(colony formation)。相反,已顯示NGF在神經內分泌來源(neuroendocrine origin)的腫瘤(如SCLC)中係為抗增殖的。對TRK在肺癌中的研究範圍的通常觀點未顯示其比NSCLC中的TRKB和BDNF以及SCLC中的TRKA和NGF起更重要的作用,但是這並不是結論性的。同樣需要注意,儘管可在自分泌和旁分泌方式中均觀察到TRK信號的過表達及增強,但是仍沒有TRK或NT係為NSCLC形成的促因(推動物,driver)的結論性證據。然而,應當注意的是在腫瘤中未檢測到p75,可能是由於其在腫瘤發展的過程中丟失。TRKA和TRKB在NSCLC腫瘤發展和轉移過程中發揮作用,其中在腫瘤發生過程中過表達被選擇為有利表型。次級假設(secondary hypothesis)係為在NSCLC腫瘤細胞群內表達NT和TRK產生更具侵略
性的腫瘤表型。以前的研究顯示NSCLC中TRKB的陽性率在24%至86.7%之間變化。近期的研究顯示75.5%和82.4%的NSCLC樣品對應的TRKB和BDNF係為陽性,並且TRKB和BDNF在肺癌組織中高表達。對比具有其它組織學亞型的患者,TRKB和BDNF的陽性率和平均得分在LCNEC患者中最高。TRKB和BDNF的高表達水準可能涉及LCNEC的神經內分泌分化。該研究同樣顯示,單獨TRKB的表達與疾病解除(disease free)、存活率具有顯著的負相關性(inverse correlation),而且BDNF和TRKB二者的表達與比TRKB單獨表達更差的存活率相關,與自分泌信號的相關性一致。
頭頸癌。 許多研究已證實了頭頸癌中BDNF與TRKB受器的相互關係。剛開始闡述BDNF及TRKB在頭頸癌中的作用,但是所有資料提示頭頸癌的侵襲性(invasiveness)受BDNF和TRKB自分泌/旁分泌信號通路的影響。TRK以及通過頭頸癌癌細胞顯示的對失巢(anoikis)的抗性可能是由於TRKB信號通路。
乳腺癌。 對乳腺癌中神經營養蛋白及它們的受器的作用的研究始於1993年。總體上,關於神經營養蛋白、TRK和乳腺癌可總結為幾種觀點。第一,NGF在乳腺癌中過表達並通過TRKA和p75引發細胞存活和增殖。NGF及其前體由乳腺癌細胞分泌並且通過TRKA驅動侵襲。BDNF及其它TRK配體可以自分泌產生並通過p75及TRKB刺激腫瘤細胞存活及抵抗細胞凋亡。靶向神經營養蛋白及其受器已經顯示導致在體內抑制乳腺癌腫瘤生長和轉移。
胰腺癌。 NT和TRK在胰腺癌中的作用優先地受TRKA和NGF相關訊息控制。許多研究已證明胰腺癌中NT和TRK受器的相互關係。多個實驗室已確認在胰腺癌中NGF和TRKA的過表達。另外,在體外和體內使用TRK拮抗劑或抗-NT抗體已顯示癌症細胞系生長的限制。TRKA和NGF在神經周侵襲和癌症疼痛中也有重要作用。
前列腺癌。 神經系統之外,前列腺含有最豐富來源的NGF。由前列腺分泌的NGF和NGF-免疫反應蛋白能夠刺激前列腺上皮細胞的生長。針對正常前列腺的平滑肌細胞、非轉移細胞、及轉移癌細胞的免疫細胞化學和mRNA分析表明惡性前列腺癌涉及由神經營養蛋白活性控制的由旁分泌轉至自分泌的開關以及由此導致的增殖及轉移。
大量研究已證實前列腺癌中神經營養蛋白與TRK受器之間的關係。多數證據指向TRKA和TRKB涉及前列腺癌生長、侵襲和轉移,同時認為低親和性p75受器係為腫瘤抑制物(tumor suppressor)(並且通常在前列腺癌發展過程中丟失)。非臨床研究支持以下結果:通過NT抗體和具有TRK抑制活性的小分子多激酶抑制劑在體外和體內均抑制表達前列腺腫瘤生長的TRK。研究最清楚的化合物係為CEP-701(來他替尼,Lestaurtinib),臨床上當在癌症患者中評價減少的PSA時未產生所期望的結果。然而,來他替尼遭遇的差的藥物代謝動力學及非常高的蛋白結合特性,在患者中廣泛未能達到其指明的可耐受濃度的資料。
圓柱瘤(Cylindroma)。 具有在腫瘤抑制基因CYLD中的生殖細胞系突變的個體具有發展有損外貌的皮膚附屬腫瘤(disfiguring cutaneous appendageal tumor)的高風險。最近的研究中,作者通過陣列比較基因組雜交和基因表達微陣列分析了CYLD突變體腫瘤基因組。CYLD突變體腫瘤通過從LOH染色體16q(CYLD基因的基因組定位)分離異常的拷貝數的不存在來表徵。CYLD突變體腫瘤的基因表達譜(Gene expression profiling)顯示調節異常的(dysregulated)原肌球蛋白受器激酶(TRK)信號,當與病灶周圍的(perilesional)皮膚比較時,腫瘤中的TRKB及TRKC過表達。腫瘤微陣列的免疫組織化學分析顯示圓柱瘤中TRKB和TRKC的強膜染色,也顯示升高的ERK磷酸化水準及BCL2表達水準。在70%的皮膚中的零星發生的基底細胞癌中也觀察到膜狀TRKC的過量表達。RNA干擾介導的TRKB及TRKC的沉默,以及使用小分子TRK抑制劑來他替尼治療,在由CYLD突變體腫瘤產生的3D基礎細胞培養物中減少了群落形成和增殖。這些結果提示TRK抑制可作為治療功能缺失性CYLD腫瘤的策略,以及依次進一步研究基底細胞癌中TRK信號通路及TRKCi敏感性。
疼痛中的TRK。 半個世紀以來,已知神經發育中NGF的作用。NGF通過在發育的胚胎中促進一些神經脊來源的細胞、特別是感覺神經元和交感神經元的生長和存活在周圍神經系統的發育中起著關鍵作用。TRKA基因中的功能缺失性突變導致先天性無痛無汗症(congenital insensitivity to
pain with anhidrosis)(CIPA)。CIPA係為常染色體隱性遺傳病,特徵為對有害刺激不明感、無汗症(不能出汗)以及無汗症引發的高熱導致的智力低下。先天性無痛無汗症,一種患者通常具有正常的本體感受、對無害壓力的正常感覺但對熱刺激異常感覺的人類病症,由TRKA基因的突變引起,導致影響無髓鞘的末梢神經纖維的結構性神經病。確實,通過遺傳修飾缺失NGF或TRKA基因的動物生來沒有小直徑初級感覺神經元(small-caliber primary sensory neuron)並且對有害刺激完全無反應。為進一步支持其在疼痛中的作用,當向AD患者給予NGF時,最顯著的副作用係為嚴重的可逆性背痛。
隨著對NGF/TRK在神經性疾病中的作用的興趣的持續增加,對於NGF/TRKA信號通路的抑制的研究大多數集中於NGF/TRKA信號通路在損傷後及癌症相關的骨痛中對於傷害性感受器的致敏作用(nociceptor sensitization)所起的作用。對發育過程中NGF缺失(deprivation)及突變的免疫學和遺傳性研究顯示NGF具有三種分離的功能:其一涉及感覺和交感神經元的存活及發育,其二係為在出生後早期階段維持初級傳入神經元的肽能表型,其三係為作為大量由成人傷害性感受器表達的神經傳遞素、受器及離子通道的表達及致敏作用的主要上游調控者。然而,成人感覺神經元是否需要NGF以維持它們的表型,以及,如果需要,需要多少NGF以維持其表型有待確定。臨床前資料提示降低或抑制NGF的生成與一些類型的傷害相關,在動物
模型中,通過隔離(sequestering)NGF或對NGF-TRKA信號通路的抑制對降低超敏性及降低傷害性感受器的活性有效。重要地,這些研究提示這些方法不明顯危及正常傷害性感受器功能的安全或者引起分佈於皮膚或骨骼的交感神經或感官神經纖維的缺失。例如NGF阻斷並不影響組織中正常的炎性反應(紅斑、發熱或腫脹),並且抗NGF療法顯示沒有改變股骨(femur)的生物機械特性或骨骼康復及負荷承受(load bearing)的組織學形態指數(histomorphometric indices)。在骨癌模型中,新的NGF隔絕抗體顯示對正在發生的骨癌疼痛及運動引起的骨癌疼痛相關行為產生顯著的降低,其效果比以10或30 mg/kg的嗎啡精確給藥更快達到。該治療同樣在背根神經節(dorsal root ganglion)及脊椎中降低了數種與末梢的(周圍)及中樞的致敏作用相關的神經化學改變,儘管該治療未影響疾病進展或在皮膚或骨骼中的感覺或交感神經支配(sympathetic innervation)的標記物。
超過100次臨床試驗具體涉及NGF的增加或阻斷。
NGF/TRKA在慢性疼痛中起重要作用變得越來越清楚,並且由此發展了三種靶向NGF/TRKA信號通路的主要藥理學策略。其包括隔離NGF或抑制其結合至TRKA、拮抗TRKA以便阻斷NGF結合至TRKA、以及阻斷TRKA激酶活性。數種人源化的抗-NGF單克隆抗體已進入臨床試驗,而這些單克隆抗體包括RN624(他尼珠單抗(tanezumab),Pfizer)、AMG-403(fulranumab,Amgen)、
REGN475(Regeneron/Sanofi-Aventis)、Medi-578(Medimmune)、及ABT-110(Abbott)。輝瑞公司(Pfizer)的他尼珠單抗(Tanezumab)具有眾多關於人類功效及安全的訊息,以及4個完整的在骨關節炎相關疼痛方面的III級臨床試驗且治療了超過10,000名患者。他尼珠單抗(Tanezumab)在骨關節炎疼痛及慢性背痛中顯示了顯著的效果。在評價骨關節炎疼痛減輕的研究中,450名患者暴露于增加的他尼珠單抗(Tanezumab)劑量下。相對於使用安慰劑的44%,回應率係為74-93%,並且不良事件的比率係為68%及55%分別對應於他尼珠單抗(Tanezumab)和安慰劑。患者中最常見的不良事件係為頭痛(9%),上呼吸道感染(7%)及感覺異常(paresthesia)(7%)。
癌症疼痛。 已報導在癌症擴散期或晚期,75-90%的患者將體驗明顯的癌症引發的疼痛。已證實與晚期惡性腫瘤(advanced malignancies)相關的慢性疼痛與NGF信號通路相關。通常導致骨轉移的前列腺癌及乳腺癌的特徵即為嚴重的骨痛。大鼠腫瘤實驗模型中,由腫瘤細胞和/或腫瘤相關間質細胞產生的NGF涉及骨骼組織中大範圍的感覺神經纖維的萌發並因此產生痛覺過敏。通過給予TRK選擇性抑制劑減弱了惡性腫瘤導致的骨癌疼痛並顯著地阻斷了感覺神經纖維的異位(ectopic)萌發以及荷瘤骨骼中類神經瘤結構的形成。
治療TRK-相關病症
在一些實施方式中,本發明提供治療TRK-相關病症的方法,該方法包括將式I化合物給予需要其的患者。
在一些實施方式中,本發明提供抑制TRK的方法,該方法包括將細胞與式I化合物接觸。在一些實施方式中,本發明提供治療ALK相關疾病或紊亂的方法,其包括將治療有效量的式I化合物給予受試者,其中治療有效量的式I化合物足以治療TRK-相關病症。
在一些實施方式中,本發明提供同時治療ALK-相關病症及TRK-相關病症的方法,該方法包括將式I化合物給予需要其的患者。
在一些實施方式中,TRK-相關病症係為TRKA-相關病症。在一些實施方式中,TRK-相關病症係為TRKB-相關病症。在一些實施方式中,TRK-相關病症係為TRKC-相關病症。
在一些實施方式中,TRK-相關病症係為癌症。在一些此類實施方式中,癌症選自胰腺癌、肺癌、膽管上皮癌、頭頸癌、前列腺癌、膽道癌、胃癌、乳腺癌、結直腸癌、鱗狀細胞癌,基底細胞癌以及圓柱癌。
在一些實施方式中,本發明包括對在治療癌症疼痛中有用的式I化合物、特別是式I-a和I-b化合物的識別。因此,在一些實施方式中,TRK-相關病症係為疼痛。在一些此類實施方式中,疼痛係為癌症疼痛。在一些實施方式中,疼痛係為骨痛。
在一些實施方式中,本發明提供抑制TRK的方法,該方法包括將式I化合物給予需要其的患者。
在一些實施方式中,本發明提供治療神經周侵襲(perineural invasion)的方法,該方法包括將式I化合物給予需要其的需要其的患者。在一些實施方式中,本發明提供預防或抑制癌症轉移的方法,該方法包括將式I化合物給予需要其的受試者。在一些此類實施方式中,式I化合物選自化合物I-a及化合物I-b。
在一些實施方式中,本發明提供預防或抑制神經周侵襲介導的癌症轉移的方法,該方法包括將式I化合物給予需要其的患者。
在一些實施方式中,本發明提供預防或抑制通過神經通路的癌症轉移性擴散的方法,該方法包括將式I化合物給予需要其的患者。
在一些實施方式中,本發明提供治療癌症疼痛的方法,該方法包括將式I化合物給予需要其的患者。在一些實施方式中,本發明提供治療與晚期惡性腫瘤(advanced malignancies)相關的慢性疼痛的方法,該方法包括將式I化合物給予需要其的患者。在一些實施方式中,本發明提供治療與骨轉移相關的疼痛的方法,包括將式I化合物給予需要其的患者。在一些實施方式中,本發明提供抑制感覺神經纖維萌生的方法,包括將式I化合物給予需要其的患者。在一些實施方式中,式I化合物選自化合物I-a及化合
物I-b。在一些實施方式中,式I化合物係為化合物I-a。在一些實施方式中,式I化合物係為化合物I-b。
在一些實施方式中,患者中的TRK抑制水準係為指示ALK抑制顯著性的生物標記物。因此,在一些實施方式中,TRK抑制係為用於評價和監測ALK抑制的生物標記物。
在一些實施方式中,提供用於測定和/或定量患者中的TRK抑制水準的方法。
提供根據本發明的應用的化合物
本發明提供式I化合物的應用,例如用於治療酪氨酸激酶相關失調且特別用於與抗ALK-抑制劑ALK和/或TRK相關的紊亂。式I化合物結構如下:
或其藥學可接受的鹽形式,其中:X選自CH或N;Y選自C3-C12環烷基或3-10元雜環基,其包含1、2、或3個選自O、S、或N的雜環原子;其中C3-C12環烷基和3-10元雜環基可能係為單環的、雙環的、或三環的,並且進一步其中C3-C12環烷基和3-10元雜環基係為未取代的或用1、2、或3個獨立地選自以下的取代基可選取代:-R’、-Y’、-SO2-Y”、-C(=O)-Y”、-SO2NH-Y”、-C(=O)NH-Y”或-C(=O)NH-(C1-C4)亞烷基-Y”;其中Y環烷基或雜環基的環碳成員上的兩個取代可以連接形成
3-7元環烷基基團或3-7元雜環基基團,其包括1至3個選自N、O、或S的雜環原子;並且進一步,其中由兩個位於Y環烷基或雜環基的碳環成員上的兩個取代基形成的3-7元環烷基或3-7元雜環基基團的1或2個碳原子環成員可以以雙鍵連接至O原子;Y’係為C6-C10芳基,包含1、2、3或4個獨立地選自O、S、或N的雜原子的5-10元雜環芳基,或包含1、2或3個選自O、S或N的雜原子的3-7元雜環基,其中C6-C10芳基、5-10元雜環芳基、或3-7元雜環基Y’基團係為未取代的或用1、2或3個獨立地選自-R’的取代基可選取代;Y”選自C3-C10環烷基;包含1、2或3個選自N、O、和S的雜原子的3-10元雜環基;C6-C10芳基;或包含1、2、3、或4個獨立地選自N、O、或S的雜原子的5-10元雜環芳基;其中C3-C10環烷基及3-10元雜環基可以係為單環的或雙環的,且進一步其中C3-C10環烷基、3-10元雜環基、C6-C10芳基、或5-10元雜芳基Y”基團係為未取代的或用1、2或3個獨立地選自-R’的取代基可選取代的;R’係為-F、-Cl、-Br、-I、-C≡N、-NO2、-OH、-O-(C1-C6)烷基、-SH、-S-(C1-C6)烷基、-OCF3、-OCHF2、-CF3、-(C1-C6)烷基、-(C2-C6)烯基、-(C2-C6)炔基、-NH2、-NH((C1-C4)烷基)、-N((C1-C4)烷基)2、-NHSO2-(C1-C6)烷基、-NHC(=O)-(C1-C6)烷
基、-C(=O)NH2、-C(=O)NH((C1-C6)烷基)、-C(=O)NH-(C1-C4)亞烷基-CF3、-C(=O)NH-(C1-C4)亞烷基-F、-C(=O)NH-(C2-C4)烯基、-C(=O)N((C1-C6)烷基)2、-C(=O)NH-OH、-C(=O)NH-O-(C1-C6)烷基、-C(=O)-(C1-C4)亞烷基-CF3、-C(=O)N-(C1-C4)亞烷基、-C(=O)-(C2-C4)烯基、-C(=O)-(C1-C4)亞烷基-NH2、-C(=O)-(C1-C4)亞烷基-NH((C1-C4)烷基)、-C(=O)-(C1-C4)亞烷基((C1-C4)烷基)2、-C(=O)NH-(C1-C4)亞烷基-OH、-C(=O)NH-(C1-C4)亞烷基-O-(C1-C6)烷基、-C(=O)-(C1-C6)烷基、-CO2H、-C(=O)-O-(C1-C6)烷基、-C(=O)NH-(C1-C4)亞烷基-NH2、-C(=O)NH-(C1-C4)亞烷基-NH((C1-C6)烷基)、-C(=O)NH-(C1-C4)亞烷基-N((C1-C6)烷基)2、-SO2NH2、-SO2NH((C1-C6)烷基)、-SO2N((C1-C6)烷基)2、-SO2NH((C2-C4)烯基)、-SO2NH((C2-C4)炔基)、-SO2NH-(C1-C4)亞烷基-OH、-SO2NH-(C1-C4)亞烷基-O-(C1-C4)烷基、-SO2-(C1-C6)烷基、-SO-(C1-C6)烷基、-(C1-C4)亞烷基-NH-C(=O)-(C1-C6)烷基、-(C1-C4)亞烷基-NH2、-(C1-C4)亞烷基-NH-(C1-C6)烷基、-(C1-C4)亞烷基-N((C1-C6)烷基)2、-(C1-C4)亞烷基-NH-(C1-C4)亞烷基-CF3、-CH(CF3)(OH)、-SO3H、-(C1-C4)亞烷基-OH、-(C1-C4)亞烷基-O-(C1-C6)烷基、-(C1-C4)亞烷基-C(=O)-(C1-C6)烷基、-(C1-C4)亞烷
基-C(=O)-O-(C1-C6)烷基、或-(C1-C4)亞烷基-C(=O)-OH;W選自-H、-F、-Cl、-Br、-I、-(C1-C6)烷基、-(CRaRa’)q-OH、-(CRaRa’)q-O-(C1-C6)烷基、-(CRaRa’)q-O-W’、-O-(CRaRa’)q-W’、-O-(CRaRa’)q-OH、-O-(CRaRa’)q-O-(C1-C6)烷基、-(CRaRa’)q-O-(CRaRa’)q-OH、-(CRaRa’)q-O-(CRaRa’)q-O-(C1-C6)烷基、-(CRaRa’)q-SH、-(CRaRa’)q-S-(C1-C6)烷基、-(CRaRa’)q-S-W’、-S-(CRaRa’)q-W’、-(CRaRa’)q-S(O)2-(C1-C6)烷基、-(CRaRa’)q-S(O)2-W’、-S(O)2-(CRaRa’)q-W’、-(CRaRa’)q-NH2、-(CRaRa’)q-NH-(C1-C6)烷基、-(CRaRa’)q-N-((C1-C6)烷基)2、-(CRaRa’)q-N+-((C1-C6)烷基)3、-(CRaRa’)q-NH-W’、-(CRaRa’)q-NH-(CRaRa’)q-OH、-NH-(CRaRa’)q-W’、或-(CRaRa’)q-W’;W’選自C3-C10環烷基;包含1、2、或3個選自N、O、和S的雜原子的3-10元雜環基;C6-C10芳基;包含1、2、3、或4個獨立地選自N、O、或S的雜原子的5-10元雜環芳基;其中C3-C10環烷基和3-10元雜環基可以係為單環或雙環,並且進一步其中C3-C10環烷基、3-10元雜環基、C6-C10芳基、或5-10元雜芳基W’基團係為未取代的或用1、2、3或4個獨立地選自-R’或-C(=O)-W”的取代基可選取
代;且進一步其中當W’係為C3-C10環烷基或3-10元雜環基時,W’可包括0、1、或2個=O基團,並且進一步其中=O基團可連接至環碳原子或環S原子;W”選自C3-C10環烷基;包含1、2、或3個選自N、O、和S的雜原子的3-10元雜環基;C6-C10芳基;或包含1、2、3、或4個獨立地選自N、O、或S的雜原子的5-10元雜芳基;其中C3-C10環烷基和3-10元雜環基可以係為單環的或雙環的,並且進一步其中C3-C10環烷基、3-10元雜環基、C6-C10芳基、或5-10元雜芳基W”基團係為未取代的或用1、2、3或4個獨立地選自-R’的取代基可選取代;以及進一步其中當W”係為C3-C10環烷基或3-10元雜環基時,W”可包括0、1、或2個=O基團,以及進一步其中=O基團可連接至環碳原子或環S原子;q在每一個實例中,獨立地選自0、1、2、3、或4;Ra和Ra’在每一個實例中獨立地選自-H、-CH3、-CH2CH3、-F、-CF3、或-C≡N;或:Ra和Ra’可連接並同與它們相連接的碳原子一起形成環丙基環;Z選自C6-C10芳基;包含1、2、3或4個獨立地選自O、S、或N的雜原子的5-10元雜環芳基;包含1、2、
或3個選自O、S、或N的雜原子的4-7元雜環基,C3-C7環烷基;-N(H)-雜環基,其中-N(H)-雜環基的雜環基係為包含1、2、或3個選自O、S、或N的雜原子的4-7元的雜環基;-N(H)-(C3-C7)環烷基;或Z係為-O-(C1-C6)烷基;其中C6-C10芳基、5-10元雜環芳基、4-7元雜環基、C3-C7環烷基、-N(H)-雜環基,以及-N(H)-(C3-C7)環烷基係為未取代的或用1、2或3個獨立地選自-R’的取代基可選取代;如果X係為CH,則W不為-H、-F、-Cl、-Br、-I、或未取代的-(C1-C6)烷基;如果W係為-H、-F、-Cl、-Br、-I、或-(C1-C6)烷基,則Y不為未取代的環丙基、環丁基或環戊基;如果Y係為以下式的基團,,則W不為-CH2OH或-CH2O(C1-C4烷基);並且如果Z係為-O-(C1-C6)烷基,則W不為-SH、-OH、-S-(C1-C6)烷基)、或-S-(C1-C6)烷基);其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
在一些實施方式中,X係為N。
在一些實施方式中,X係為CH。
在一些實施方式中,Z選自-OMe或-NH-環己基;或未取代的或取代的苯基、吡啶基、苯並噻吩基
(benzothiophenyl)、噻唑基、噠嗪基、嘧啶基、吲哚基、環己基、嗎啉基、吡咯烷基、呱嗪基、呱啶基、異噻唑基、或硫嗎啉基(thiomorpholinyl)基團。在一些此類實施方式中,Z選自-OMe或-NH-環己基;或未取代的或取代的苯基、吡啶基、苯並噻吩基、噻唑基、噠嗪基、嘧啶基、吲哚基、環己基、嗎啉基、吡咯烷基、呱嗪基、或呱啶基基團。
在一些實施方式中,Z係為未取代的或取代的苯基、吡啶基、苯並噻吩基、噻唑基、噠嗪基、嘧啶基、吲哚基、環己基、嗎啉基、吡咯烷基、呱嗪基、呱啶基、異噻唑基或硫嗎啉基基團。在一些實施方式中,Z係為未取代的或取代的苯基、吡啶基、苯並噻吩基、噻唑基、噠嗪基、嘧啶基、吲哚基、環己基、嗎啉基、吡咯烷基、呱嗪基或呱啶基基團。在一些此類實施方式中,Z係為取代的苯基、吡啶基、苯並噻吩基、噻唑基、噠嗪基、嘧啶基、吲哚基、環己基、嗎啉基、吡咯烷基、呱嗪基或呱啶基基團。
在一些實施方式中,Z係為未取代的或取代的苯基或吡啶基。在一些此類實施方式中,Z係為取代的苯基或吡啶基。在另外的一些此類實施方式中,Z係為取代的苯基。
在一些實施方式中,Z選自:
,或,其中符號當與鍵交叉繪時,表示與該分子的其餘部分的連接點。在一些實施方式中,Z選自
其中符號當與鍵交叉繪製時,表示與該分子的其餘部分
的連接點。
在一些實施方式中,Y係為未取代的或取代的環庚基、環己基、環戊基、環丁基、呱啶基、吡咯烷基、氮雜環丁基(azetidinyl)、金剛烷基、雙環[2.2.2]辛基、雙環[3.2.1]辛基、雙環[4.1.1]辛基、雙環[2.2.1]庚基、雙環[3.1.1]庚基、或雙環[2.1.1]己基。在一些此類實施方式中,Y係為取代的環庚基、環己基、環戊基、環丁基、呱啶基、吡咯烷基、金剛烷基、雙環[2.2.2]辛基、雙環[3.2.1]辛基、雙環[4.1.1]辛基、雙環[2.2.1]庚基、雙環[3.1.1]庚基、或雙環[2.1.1]己基基團。在一些此類實施方式中,Y係為未取代的或取代的環己基。在一些此類實施方式中,Y係為取代的環己基。在另一些此類實施方式中,Y係為未取代的或取代的金剛烷基。在一些此類實施方式中,Y係為未取代的金剛烷基。在其它實施方式中,Y係為取代的金剛烷基。在其它此類實施方式中,Y係為未取代的或取代的環丁基。在一些此類實施方式中,Y係為取代的環丁基。在另外的其它實施方式中,Y係為未取代的或取代的環戊基或環庚基。在一些此類實施方式中,Y係為取代的環戊基或環庚基。在其它實施方式中,Y係為未取代的或取代的呱啶基。在一些此類實施方式中,Y係為取代的呱啶基。在Y被取代的實施方式中,Y被包含羰基(C=O)功能基團的基團取代。實例包括但不局限於酮、酯及醯胺。
在一些實施方式中,Y選自
其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
在一些實施方式中,Y選自
,或,其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
在一些實施方式中,Y選自
或,其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
在一些實施方式中,Y係為,其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
在一些實施方式中,W選自-CH2OH、-CH2OCH3、-CH2OCH2CH2OH、-CH2OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2OMe、-W’、-CH2W’、-OW’、-OCH2W’、-OCH2CH2W’、-OCH2CH2CH2W’、-NHW’、-NHCH2W’、-NHCH2CH2W’、-NHCH2CH2CH2W’、或-W’-C(=O)-W”;其中如果存在W’,則其選自包含1或2個選自N、O、和S的雜原子的3-10元雜環基;C6-C10芳基;或包含1、2、3、或4個獨立地選自N、O、或S的雜原子的5-10元雜芳基;其中3-10元雜環基W’基團可以係為單環或雙環的,並且進一步,其中3-10元雜環基、C6-C10芳基、或5-10元雜芳基W’基團係為未取代的或用1、2、3、或4個獨立地選自以下的取代基取代的:-F、-Cl、-Br、-(C1-C6)烷基、-CH(CF3)(OH)、-(C1-C4)亞烷基-NH2、-(C1-C4)亞烷基-NH-(C1-C4)亞烷基-CF3、-C(=O)NH2、-SO2-(C1-C6)烷基、-CF3、-CO2H、-(C1-C4)亞烷基
-C(=O)-(C1-C4)烷基、-(C1-C4)亞烷基-C(=O)-O-(C1-C4)烷基、-(C1-C4)亞烷基-C(=O)-OH、-(C1-C4)亞烷基-OH、-OH、-O-(C1-C6)烷基、或-SO3H;且進一步,當W’係為3-10元雜環基時,其中W’可包括0、1、或2個=O基團,且進一步其中=O基團可連接至環碳原子環或S原子;且進一步,如果存在W”,則其係為包括1、2、或3個選自N、O、及S的雜原子的3-10元雜環基,其中3-10元雜環基W”基團可以係為單環的或雙環的,且進一步,其中3-10元雜環基W”基團係為未取代的或用1、2、3、或4個獨立地選自以下的取代基可選取代的:-F、-Cl、-Br、-I、-C≡N、-NO2、-(C1-C6)烷基、-(C2-C6)鏈烯基、-(C2-C6)炔基、-OH、-NH2、-NH((C1-C4)烷基)、-N((C1-C4)烷基)2、-CF3、-CO2H、-C(=O)-O-(C1-C4)烷基、-SH、-S-(C1-C6)烷基、-OCF3、或-OCHF2,或它們的藥學可接受的鹽、它們的互變異構體、互變異構體藥學可接受的鹽、前述任意化合物的立體異構體,或它們的混合物。
在一些實施方式中,W選自-W’、-CH2W’、-OW’、-OCH2W’、-OCH2CH2W’、-OCH2CH2CH2W’、-NHW’、-NHCH2W’、-NHCH2CH2W’、-NHCH2CH2CH2W’、或-W’-C(=O)-W”;其中W’選自包含1或2個選自N、O、和S的雜原子的3-10元雜環基;C6-C10芳基;或包含1、2、3、或4個獨立地選自N、O、或S的雜原子的5-10元雜環芳基;其中3-10元雜環基W’基團可以係為單環的或雙環的,且進一步,其中3-10元雜環基、C6-C10芳基,或5-10元雜芳基W’基團係為未取代的或用1、2、3、或4個獨立地選自以下的取代基取代:-F、-Cl、-Br、-(C1-C6)烷基、-CH(CF3)(OH)、-(C1-C4)亞烷基-NH2、-(C1-C4)亞烷基-NH-(C1-C4)亞烷基-CF3、-C(=O)NH2、-SO2-(C1-C6)烷基、-CF3、-CO2H、-(C1-C4)亞烷基-C(=O)-(C1-C4)烷基、-(C1-C4)亞烷基
-C(=O)-O-(C1-C4)烷基、-(C1-C4)亞烷基-C(=O)-OH、-(C1-C4)亞烷基-OH、-OH、-O-(C1-C6)烷基、或-SO3H;且進一步當W’係為3-10元雜環基時,其中W’可以包括0、1、或2個=O基團,且進一步,其中=O基團可連接至環碳原子或環硫原子;並且進一步,其中如果存在W”,則其係為包含1、2、或3個選自N、O、和S的雜原子的3-10元雜環基,其中3-10元雜環基W”基團可以係為單環的或雙環的,且進一步,其中3-10元雜環基W”基團係為未取代的用或1、2、3、或4個獨立地選自以下的取代基可選取代:-F、-Cl、-Br、-I、-C≡N、-NO2、-(C1-C6)烷基、-(C2-C6)鏈烯基、-(C2-C6)炔基、-OH、-NH2、-NH((C1-C4)烷基、-N((C1-C4)烷基)2、-CF3、-CO2H、-C(=O)-O-(C1-C4)烷基、-SH、-S-(C1-C6)烷基、-OCF3、或-OCHF2。
在一些實施方式中,W選自-H、-F、-Cl、-OH、-OMe、-SO2Me、-CH2OH、-CH2OMe、-OCH2CH2OH、-OCH2CH2OMe,或選自以下基團:
,其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
在一些實施方式中,W不為-H、-F、-Cl、-OH、或-OMe。
在一些實施方式中,W選自-OH、-SO2Me、-CH2OH、-CH2OMe、-OCH2CH2OH、-OCH2CH2OMe,或選自以下基團
,或,其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
在一些實施方式中,W選自:
,其中符號當與鍵交叉繪製時,表示與該分子的其餘部分的連接點。
本發明的化合物可存在多種互變異構體。這些形式在下文中以“互變異構體A”和“互變異構體B”示出:
本發明以兩種異構體形式的任一種提供化合物(例如,基本不包含另一種形式),或者以組合形式提供化合物(無論為等量或不等量)。本領域技術人員會理解,在其中描述單一的互變異構體形式,在一些實施方式中,可哥以採用另一種形式的互變異構體或互變異構體的組合形式。本領域技術人員可進一步理解,在一些實施方式中,可以對所描述結構的不同的鹽和/或立體異構體形式應用相同的原則。
本發明披露的化合物包括但不限於式I的化合物及其所有的藥學可接受的形式。此處所描述的化合物藥學可接受的形式包括藥學可接受的鹽、溶劑化物、晶體形式(包括多晶形物及籠形包合物(clathrates))、螯合物、非共價複合物、前藥,以及它們的混合物。在某些實施方式中,本文所描述的化合物表現為藥學可接受的鹽形式。如本文中所使用的,術語“化合物”不僅涵蓋化合物本身,而且涵蓋其藥學可接受的鹽、其溶劑化物、其螯合物、其非共價複合物、其前藥,以及任意前述物質的混合物。在一些實施方式中,術語“化合物”涵蓋化合物本身、其藥學可接受的鹽、化合物的互變異構體、互變異構體的藥學可接受的鹽、以及前藥酯如(C1-C4)烷基酯。在其它實施方式中,術語“化合物”涵蓋化合物本身、其藥學可接受的鹽、化合物的互變異構體、互變異構體的藥學可接受的鹽。
在一些實施方式中,式I的化合物具有以下結構:
其中W、Z和R’如上文所定義和本文所描述的。
在一些實施方式中,式I的化合物具有以下結構:
其中W、Z和R’如上文所定義和本文所描述的。
在一些實施方式中,式I化合物具有以下結構:
其中W、Z、R’和q如上文所定義和本文所描述的。
在一些實施方式中,本發明涵蓋式I、特別是式I-a和I-b的化合物穿過血腦屏障(BBB)的發現。因此,本發明提供了用於治療位於或存在於中樞神經系統的疾病、紊亂或病症的方法,該方法包括將式I化合物給予需要其的患者。在一些此類實施方式中,式I化合物選自化合物I-a和I-b。在一
些實施方式中,位於或存在於中樞神經系統的疾病、紊亂或病症係為癌症。在一些實施方式中,位於或存在於中樞神經系統的疾病、紊亂或病症係為腦癌。在一些實施方式中,位於或存在於中樞神經系統的疾病、紊亂或病症係為脊髓癌(spinal cancer)。
在一些實施方式中,化合物選自
,或它們的藥學可接受的鹽、它們的互變異構體、互變異構體的藥學可接受的鹽、前述任意化合物的立體異構體,以及它們的混合物。
在一些實施方式中,式I化合物選自
在前文所描述的任意實施方式的一些實施方式中,以藥學可接受的鹽提供式I化合物。在一些實施方式中,式I化合物係為單一的立體異構體,然而在另一些實施方式中,式I化合物係為對映體的混合物或立體異構體的混合物,並且這樣的混合物可以包含等量或不等量的特定立體異構體。在一些實施方式中,式I化合物係為立體異構體的外消旋混合物。
在一些實施方式中,作為鹽提供式I化合物。這樣的鹽可以係為無水的或與水結合成為水合物。
在一些實施方式中,提供的化合物特徵在於它們顯示對於一種或多種酪氨酸激酶的抑制活性。在一些此類實施方式中,所提供的化合物在約0.05 μM至約5 μM的範圍內、或在約0.05 μM至約1 μM的範圍內、或在約0.05 μM至約0.1 μM的範圍內顯示對於ALK的抑制活性(即,IC50)。在一些實施方式中,所提供的化合物在小於1 μM的範圍內、或在約1 nM至大約100 nM的範圍內顯示對於TRKA、TRKB或TRKC的抑制活性(即,IC50)。在一些實施方式中,所提供的化合物在小於1 μM的範圍內顯示對於TRKA的抑制活性(即,IC50)。
在一些此類實施方式中,一種或多種酪氨酸激酶選自由以下構成的組:ALK、TRKA、TRKB、TRKC、p75和RET。
在一些實施方式中,所提供的化合物特徵在於它們對於某些酪氨酸激酶顯示相對的抑制活性,如TRKA>TRKB>TRKC。在一些實施方式中,所提供的化合物特徵在於它們對於某些酪氨酸激酶顯示了相對的抑制活性,例如ALK>TRKA>TRKB>TRKC。在一些實施方式中,所提供的化合物特徵在於它們對於某些酪氨酸激酶顯示相對的抑制活性,如ALK>TRKA>TRKB>TRKC>RET。
同樣,所提供的藥物配製品(製藥配方,pharmaceutical formulation),其包括至少一種藥學可接受的載體、賦形劑或稀釋劑,以及治療有效量的本文中任意實施方式所描述的化合物。在一些此類實施方式中,化合物以對治療癌症的有效量存在。
進一步提供的係為醫藥配製品,其包括至少一種藥學可接受的載體、以及治療有效量的本文中任意實施方式所描述的物質與至少一種另外的化合物,如細胞毒素劑或抑制其它激酶的化合物聯合的組成物。
在一些實施方式中,本發明提供醫藥配製品,其包括至少一種藥學可接受的載體、以及治療有效量的本文中任意實施方式所描述的物質與至少一種另外的化療劑聯合的組成物。
在一些實施方式中,一種或多種另外的化療劑係為抗代謝物(antimetabolite)抗腫瘤劑(antineoplastic agent),選自5-FU-纖維蛋白原、acanthifolic acid、氨基噻重氮(aminothiadiazole)、布喹那鈉(brequinar sodium)、卡莫氟、洛丁新片CGP-30694(Ciba-Geigy CGP-30694)、環戊基胞嘧啶、阿糖胞苷磷酸硬脂酸鹽(cytarabine phosphate stearate)、阿糖胞苷結合物(cytarabine conjugates)、Lilly DATHF、Merrel Dow DDFC、地紮呱寧(dezaguanine)、雙去氧胞苷(dideoxycytidine)、雙去氧鳥苷(dideoxyguanosine)、3,4-二羥基苯氧肟酸(didox)、Yoshitomi DMDC、去氧氟尿苷、Wellcome EHNA、Merck & Co.EX-015、法紮拉濱、氟尿苷(floxuridine)、磷酸氟達拉濱(fludarabine phosphate)、5-氟尿嘧啶、N-(2'-呋喃烷基)-5-氟尿嘧啶、Daiichi Seiyaku FO-152、異丙基吡咯嗪(isopropyl pyrrolizine)、Lilly LY-188011、Lilly LY-264618、methobenzaprim、甲氨蝶呤(methotrexate)、Wellcome MZPES、降亞精胺(去甲精胺,norspermidine)、NCI NSC-127716、NCI NSC-264880、NCI NSC-39661、NCI NSC-612567、Warner-Lambert PALA、噴司他丁(pentostatin)、吡曲克辛(piritrexim)、普卡黴素、Asahi Chemical PL-AC、Takeda TAC-788、硫鳥嘌呤(thioguanine)、噻唑呋
林(噻唑羥胺核苷,tiazofurin)、Erbamont TIF、三甲曲沙、酪氨酸激酶抑制劑、Taiho UFT及優你生(uricytin)。
在一些實施方式中,一種或多種另外的化療劑係為烷基化類型的抗腫瘤劑,選自Shionogi 254-S、醛-磷醯胺類似物(aldo-phosphamide analogues)、六甲蜜胺、阿那昔酮、Boehringer Mannheim BBR-2207、阿莫司汀(bestrabucil)、布度鈦(budotitane)、Wakunaga CA-102、卡鉑、卡莫司汀(亞硝脲氮芥,carmustine)、Chinoin-139、Chinoin-153、苯丁酸氮芥、順鉑、環磷醯胺、American Cyanamid CL-286558、Sanofi CY-233、cyplatate、Degussa D-19-384、Sumimoto DACHP(Myr)2、聯苯螺莫司汀(diphenylspiromustine)、diplatinum cytostatic、Erba偏端黴素衍生物(Erba distamycin derivatives)、Chugai DWA-2114R、ITI E09、依莫司汀、Erbamont FCE-24517、雌氮芥磷酸鈉、福莫司汀、Unimed G-6-M、Chinoin GYKI-17230、hepsulfam、異環磷醯胺、異丙鉑、環己亞硝脲、馬磷醯胺、二溴衛矛醇、Nippon Kayaku NK-121、NCI NSC-264395、NCI NSC-342215、奧沙利鉑、Upjohn PCNU、潑尼莫司汀(松龍苯芥,prednimustine)、Proter PTT-119、雷莫司汀、司莫司汀、SmithKIine SK&F-101772、Yakult Honsha SN-22、螺莫司汀、Tanabe Seiyaku TA-077、牛碘莫司汀、替莫唑胺、替羅昔隆、四鉑(四氯合鉑,tetraplatin)和三甲密醇(trimelamol)。
在一些實施方式中,一種或多種另外的化療劑係為抗生素類抗腫瘤劑選自Taiho 4181-A、阿柔比星、放線菌素D、遊放線酮(actinoplanone)、Erbamont ADR-456、aeroplysinin衍生物、Ajinomoto AN-201-II、Ajinomoto AN-3、Nippon Soda茴香黴素(Nippon Soda anisomycins)、蒽環類抗生素(anthracycline)、阿嗪黴素-A(azino-mycin-A)、bisucaberin、
Bristol-Myers BL-6859、Bristol-Myers BMY-25067、Bristol-Myers BMY-25551、Bristol-Myers BMY-26605、Bristol-Myers BMY-27557、Bristol-Myers BMY-28438、硫酸博來黴素、苔蘚抑素-1(bryostatin-1)、Taiho C-1027、卡奇黴素(calichemycin)、chromoximycin、更生黴素、道諾黴素、Kyowa Hakko DC-102、Kyowa Hakko DC-79、Kyowa Hakko DC-88A、Kyowa Hakko DC89-A1、Kyowa Hakko DC92-B、二丙八疊紅菌素B(ditrisarubicin B)、Shionogi DOB-41、多柔比星(doxorubicin)、多柔比星-纖維蛋白原(doxorubicin-fibrinogen)、愛薩黴素-A(elsamicin-A)、表柔比星、製錶菌素(erbstatin)、依索比星、埃斯波黴素-A1(esperamicin-A1)、埃斯波黴素-Alb、Erbamont FCE-21954、Fujisawa FK-973、福司曲星、Fujisawa FR-900482、滑桿菌素(glidobactin)、聚頭孢素-A(gregatin-A)、淺內紅黴素(grincamycin)、除莠黴素、伊達比星(去甲氧基柔紅黴素,idarubicin)、隱杯傘黴素(illudins)、上總黴素(kazusamycin)、kesarirhodins、Kyowa Hakko KM-5539、Kirin Brewery KRN-8602、Kyowa Hakko KT-5432、Kyowa Hakko KT-5594、Kyowa Hakko KT-6149、American Cyanamid LL-D49194、Meiji Seika ME 2303、美諾立爾、絲裂黴素、米托蒽醌、SmithKline M-TAG、新擬定黴素(neoenactin)、Nippon Kayaku NK-313、Nippon Kayaku NKT-01、SRI International NSC-357704、噁溶菌素(oxalysine)、oxaunomycin、培洛黴素、必杯菌素(pilatin)、吡柔比星、porothramycin、pyrindanycin A、Tobishi RA-I、納巴黴素(雷帕黴素,rapamycin)、根黴素(rhizoxin)、羅多比星、西班米星、思文黴素(siwenmycin)、Sumitomo SM-5887、Snow Brand SN-706、Snow Brand SN-07、堆囊菌素-A(sorangicin-A)、稀疏黴素、SS Pharmaceutical
SS-21020、SS Pharmaceutical SS-7313B、SS Pharmaceutical SS-9816B、司替黴素B(steffimycin B)、Taiho 4181-2、他利黴素、Takeda TAN-868A、類萜黴素(terpentecin)、thrazine、雄黃蘭醌A(tricrozarin A)、Upjohn U-73975、Kyowa Hakko UCN-10028A、Fujisawa WF-3405、Yoshitomi Y-25024、和佐柔比星。
在一些實施方式中,一種或多種另外的化療劑係為選自微管蛋白相互作用劑、、拓撲異構酶II抑制劑、拓撲異構酶I抑制劑及激素藥劑的抗腫瘤劑,選自但不限於由以下構成的組:α-胡蘿蔔素、α-二氟甲基-精氨酸、阿維A(acitretin)、Biotec AD-5、Kyorin AHC-52、雞骨常山堿、氨萘非特、amphethinile、胺苯吖啶、血管抑制素(Angiostat)、安諾黴素(ankinomycin)、抗瘤酮A10(anti-neoplaston A10)、抗瘤酮A2、抗瘤酮A3、抗瘤酮A5、抗瘤酮AS2-1、Henkel APD、阿非科林甘氨酸酯(aphidicolin glycinate)、天門冬醯胺酶、阿瓦醇、燕茜素(酒神菊素,baccharin)、達尼喹酮(batracylin)、苯氟倫(benfluron)、氯苯酶色氨酸(benzotript)、Ipsen-Beaufour BIM-23015、比生群、Bristol-Myers BMY-40481、Vestar boron-10、bromofosfamide、Wellcome BW-502、Wellcome BW-773、卡醋胺、carmethizole氫氯化物(carmethizole hydrochloride)、Ajinomoto CDAF、chlorsulfaquinoxalone、Chemes CHX-2053、Chemex CHX-100、Warner-Lambert CI-921、Warner-Lambert CI-937、Warner-Lambert CI-941、Warner-Lambert CI-958、克蘭氟脲、claviridenone、ICN化合物1259(ICN compound 1259)、ICN化合物4711(ICN compound 4711)、Contracan、Yakult Honsha CPT-11、克立那托、curaderm、細胞鬆弛素B、阿糖胞苷、cytocytin、MerzD-609、DABIS馬來酸鹽(DABIS maleate)、氮烯唑胺、datelliptinium、代代寧-B
(didemnin-B)、二血卟啉醚(dihaematoporphyrin ether)、dihydrolenperone、地那林、偏端黴素、Toyo Pharmar DM-341、Toyo Pharmar DM-75、Daiichi Seiyaku DN-9693、多西他賽elliprabin(docetaxel elliprabin)、依利醋銨(elliptinium acetate)、Tsumura EPMTC、埃博黴素(epothilone)、麥角胺、依託泊苷、依曲替酯(etretinate)、芬維A胺(fenretinide)、Fujisawa FR-57704、硝酸鎵、苯甲醯氧瑞香毒素(芫花烯,genkwadaphnin)、Chugai GLA-43、Glaxo GR-63178、灰樹花多糖NMF-5N(grifolan NMF-5N)、十六烷基磷酸膽鹼(hexadecylphosphocholine)、Green Cross HO-221、高三尖杉酯堿(homoharringtonine)、羥基脲、BTG ICRF-187、伊莫福新、異榖醯胺、異維甲酸(isotretinoin)、Otsuka JI-36、Ramot K-477、Otsuak K-76COONa、Kureha Chemical K-AM、MECT Corp KI-8110、American Cyanamid L-623、白細胞調節素(leukoregulin)、氯尼達明、Lundbeck LU-23-112、Lilly LY-186641、NCI(US)MAP、marycin、Merrel Dow MDL-27048、Medco MEDR-340、美巴龍(merbarone)、merocyanlne衍生物(merocyanlne derivatives)、methylanilinoacridine、Molecular Geneti cs MGI-136、茗萘酊(minactivin)、米托萘胺、米托喹酮、莫呱達醇、莫維A胺(motretinide)、Zenyaku Kogyo MST-16、N-(異維A醯基)氨基酸(N-(retinoyl)amino acids)、Nisshin Flour Milling N-021、N-乙醯化-脫氫丙氨酸、那法紮瓊、Taisho NCU-190、諾考達唑衍生物、精氨酸血紅素(Normosang)、NCI NSC-145813、NCI NSC-361456、NCI NSC-604782、NCI NSC-95580、奧曲肽(ocreotide)、Ono ONO-112、oquizanocine、Akzo Org-10172、紫杉醇、水鬼蕉堿(pancratistatin)、帕折普汀、Warner-Lambert PD-111707、Warner-Lambert PD-115934、
Warner-Lambert PD-131141、Pierre Fabre PE-1001、ICRT肽D、吡羅蒽醌、聚血卟啉(polyhaematoporphyrin)、聚烯瑞尼酸(polypreic acid)、月見草卟啉(Efamol porphyrin)、嗎丙嗪(probimane)、甲苄肼、丙榖胺、Invitron蛋白酶連結素I(Invitron protease nexin I)、Tobishi RA-700、雷佐生、Sapporo Breweries RBS、限制蛋白-P(restrictin-P)、瑞替普汀(retelliptine)、視黃酸、Rhone-Poulenc RP-49532、Rhone-Poulenc RP-56976、SmithKline SK&F-104864、Sumitomo SM-108、Kuraray SMANCS、SeaPharm SP-10094、褐舌藻醇(spatol)、螺環丙烷衍生物(spirocyclopropane derivatives)、鍺螺胺(spirogermanium)、Unimed、SS Pharmaceutical SS-554、strypoldinone、棕葉藻酮(Stypoldione)、Suntory SUN 0237、Suntory SUN 2071、過氧化物歧化酶(superoxide dismutase)、Toyama T-506、Toyama T-680、泰素(紫杉醇,taxol)、Teijin TEI-0303、替尼泊苷、唐松草堿(thaliblastine)、Eastman Kodak TJB-29、生育三烯酸(生育三烯酚,tocotrienol)、托泊替康(topotecan)、拓撲酶抑素(Topostin)、Teijin TT-82、Kyowa Hakko UCN-01、Kyowa Hakko UCN-1028、ukrain、Eastman Kodak USB-006、硫酸長春堿、長春新堿、長春地辛、vinestramide、長春瑞濱、長春曲醇、長春利定、睡茄交酯(withanolides)、和Yamanouchi YM-534。
在一些實施方式中,一種或多種化療劑選自:醋孟南(acemannan)、阿柔比星、阿地白介素、阿來組單抗(阿倫珠單抗,alemtuzumab)、阿利維A酸(alitretinoin)、六甲蜜胺、氨磷汀(安福定氨磷汀,amifostine)、氨基乙醯丙酸、氨柔比星、胺苯吖啶、阿那格雷、阿那曲唑(anastrozole)、ANCER、安西司亭、ARGLABIN、三氧化二砷、BAM 002(Novelos)、貝沙羅汀、比卡魯胺、溴尿苷(溴甙,broxuridine)、卡培他濱、西莫白
介素、西曲瑞克、克拉屈濱、克黴唑、阿糖胞苷十八烷基磷酸鹽(cytarabine ocfosfate)、DA 3030(Dong-A)、達克珠單抗、地尼白介素、地洛瑞林、右雷佐生、地拉齊普(地拉卓,dilazep)、多西他賽(多烯紫杉醇)、二十二烷醇(docosanol)、度骨化醇、去氧氟尿苷、多柔比星(doxorubicin)、溴麥角環肽、卡莫司汀、阿糖胞苷、氟尿嘧啶、HIT雙氯芬酸(HIT diclofenac)、α-干擾素、道諾黴素、多柔比星、維甲酸(維A酸,tretinoin)、依地福新、依決洛單抗(edrecolomab)、依氟鳥氨酸、乙嘧替氟、表柔比星、β依伯汀(epoetin beta)、磷酸依託泊苷、依西美坦、依昔舒林、法倔唑、非格司亭、非那雄胺、磷酸氟達拉濱、福美坦、福莫司汀、硝酸鎵、吉西他濱、吉妥珠單抗奧唑米星(gemtuzumab zogamicin)、吉美嘧啶/奧替拉西/替加氟組成物(gimeracil/oteracil/tegafur combination)、glycopine、戈舍瑞林、庚鉑(依鉑,heptaplatin)、人絨毛膜促性腺素(human chorionic gonadotropin)、人類胎兒甲胎蛋白(human fetal alpha fetoprotein)、伊班膦酸、伊達比星、咪喹莫特、干擾素α、天然干擾素α(interferon alfa,natural)、干擾素α-2、干擾素α-2a、干擾素α-2b、干擾素α-N1、干擾素α-n3、干擾素α-1(interferon alfacon-1,一種高度糖基化的干擾素)、天然干擾素α(interferon alpha,natural)、干擾素β、干擾素β-1a、干擾素β-1b、干擾素γ、天然干擾素γ-1a、干擾素γ-1b、白細胞介素-1β、碘苄胍(iobenguane)、伊立替康(irinotecan)、伊索格拉定、蘭樂肽、LC 9018(Yakult)、來氟米特、來格司亭、硫酸香菇多糖(lentinan sulfate)、來曲唑(letrozole)、白細胞α干擾素(leukocyte alpha interferon)、亮丙瑞林、左旋咪唑+氟尿嘧啶、利阿唑、洛鉑、氯尼達明、洛伐他汀、馬索羅酚、美拉胂醇、甲氧氯普胺、米非司酮、米替福新、米立司亭、錯配的雙鏈RNA、米托胍腙、二溴衛矛醇、米托蒽醌、莫拉司亭、
那法瑞林、納洛酮+噴他佐辛、那托司亭、奈達鉑、尼魯米特、諾斯卡品、新的紅細胞生成刺激蛋白(novel erythropoiesis stimulating protein)、NSC 631570奧曲肽、奧普瑞白介素、奧沙特隆、奧沙利鉑、紫杉醇、帕米膦酸(帕米磷酸,pamidronic acid)、培加帕酶(培門冬酶,pegaspargase)、培干擾素α-2b(聚乙二醇干擾素α-2b,peginterferon alfa-2b)、木聚硫鈉(戊聚糖多硫酸鈉,pentosan polysulfate sodium)、噴司他丁、溶血性鏈球菌製劑(溶鏈菌製劑,picibanil)、吡柔比星、兔抗胸腺細胞多克隆抗體(rabbit antithymocyte polyclonal antibody)、聚乙二醇幹擾素α-2a、卟吩姆鈉、雷洛昔芬、雷替曲塞、拉布立酶、依替膦酸錸Re 186(rhenium Re 186 etidronate)、異維A醯胺RII(維甲醯酚胺,RII retinamide)、利妥昔單抗、羅莫肽、來昔決南釤(153 Sm)(samarium(153 Sm)lexidronam)、沙莫司亭、西索菲蘭、索布佐生、索納明、氯化鍶-89、蘇拉明、他索納明、他佐羅汀、替加氟、替莫泊芬、替莫唑胺、替尼泊苷、四氯十氧化物(tetrachlorodecaoxide)、沙立度胺、胸腺法新、促甲狀腺素α、托泊替康、托瑞米芬、托西莫單抗-碘131、曲妥珠單抗、曲奧舒凡、維甲酸(tretinoin)、曲洛司坦、三甲曲沙、曲普瑞林、天然腫瘤壞死因數α(tumor necrosis factor alpha,natural)、烏苯美司、膀胱癌疫苗、丸山疫苗(Maruyama vaccine)、黑色素瘤溶解物疫苗(黑素瘤溶化菌苗,melanoma lysate vaccine)、戊柔比星、維替泊芬、長春瑞濱、維魯利秦、淨司他丁斯酯(zinostatin stimalamer)、或唑來膦酸;阿巴瑞克;AE 941(Aeterna)、氨莫司汀、反義寡核苷酸、bcl-2(Genta)、APC 8015(Dendreon)、西妥昔單抗、地西他濱、右旋氨魯米特(dexaminoglutethimide)、地吖醌、EL 532(Elan)、EM 800(Endorecherche)、恩尿嘧啶、依他硝唑、芬維A胺、非格司亭SD01(Amgen)、氟維司群、加洛他濱、促胃液素
17免疫原、HLA-B7基因治療(Vical)、粒細胞巨噬細胞集落刺激因數、二鹽酸組胺(組胺二鹽酸化物)、替伊莫單抗(ibritumomab tiuxetan)、伊洛馬司他、IM 862(Cytran)、白細胞介素-2、iproxifene、LDI 200(Milkhaus)、來立司亭、林妥珠單抗、CA 125單克隆抗體(CA 125 Mab)(Biomira)、癌症單克隆抗體(cancer MAb)(Japan Pharmaceutical Development)、HER-2和Fc單克隆抗體(Medarex)、個體基因型105AD7單克隆抗體(idiotypic 105AD7 MAb)(CRC Technology)、個體基因型CEA單克隆抗體(Trilex)、LYM-1-碘131單克隆抗體(Techniclone)、多形態上皮粘蛋白-釔90單克隆抗體(polymorphic epithelial mucin-yttrium 90 MAb)(Antisoma)、馬立馬司他(marimastat)、美諾立爾、米妥莫單抗、莫特沙芬釓(motexafin gadolinium)、MX6(Galderma)、奈拉濱、諾拉曲塞、P 30蛋白、培維索孟、培美曲塞、泊非黴素、普啉司他、RL 0903(Shire)、盧比替康、沙鉑(賽特鉑,satraplatin)、苯乙酸鈉(sodium phenylacetate)、膦門冬酸、SRL 172(SR Pharma)、SU 5416(SUGEN)、TA 077(Tanabe)、四硫鉬酸鹽(tetrathiomolybdate)、唐松草堿(thaliblastine)、促血小板生成素、錫乙基初紫紅素(tin ethyl etiopurpurin)、替拉紮明、癌症疫苗(Biomira)、黑瘤疫苗(New York University)、黑瘤疫苗(Sloan Kettering Institute)、黑素瘤溶解物疫苗(melanoma oncolysate vaccine)(New York Medical College)、病毒性黑素瘤細胞溶解物疫苗(Royal Newcastle Hospital)、或伐司朴達。
在一些實施方式中,一種或多種化療劑選自赫賽汀TM(HERCEPTINTM)(曲妥單抗)、RITUXANTM(利妥昔單抗)、澤娃靈TM(ZEVALINTM)(替伊莫單抗)、和LYMPHOCIDETM(依帕珠單抗)、格列衛TM(GLEEVECTM)(伊馬替尼)、BEXXARTM(托西莫單抗-碘131)、愛必妥TM(ERBITUXTM)
(IMC-C225)、阿瓦斯汀TM(AVASTINTM)(貝伐珠單抗)或VEGF-TRAPTM(阿柏西普(aflibercept))、ABX-EGF(帕尼單抗(panitumumab))、伊麗沙TM(IRESSATM)(吉非替尼)和塔西法TM(TARCEVATM)(厄洛替尼(arlotinib))。
所提供的化合物可通過使用以下方案1、方案2、和方案3所示的一般合成路線製備.
方案2
如方案1和方案2中所示,當X係為N時,Y-取代的4-氨基-2-氯-5-硝基吡啶提供了良好的取得(access to)式I化合物的途徑。如方案1和方案2中所示,當X係為N時,親核試劑,如2-(呱啶-1-基)乙醇或嗎啡可與Y-取代的4-氨基-2-氯-5-硝基吡啶化合物反應代替氯基團從而形成適當連接所選W基團的鍵。採用氫化條件將硝基基團還原係為胺後,與選定的異硫氰酸鹽/酯如4-氟苯甲醯異硫氰酸酯反應形成5元環並提供適當的Z基團以確保隨時可取得式I的化合物。
如方案3中所示,當X係為C時,(3-氟-4-硝基苯基)甲醇為製備多種式I化合物提供合適的起始物質。攜帶選定的Y基團的氨基親核試劑,如N-(順式-4-氨基環己基)異丁醯胺可與(3-氟-4-硝基苯基)甲醇反應形成Y取代的(3-氟-4-硝基苯基)甲醇化合物。將硝基基團還原以形成胺化合物後,與適當的異硫氰酸鹽/酯如4-苯甲醯異硫氰酸酯反應形成五元環並添加上所需的Z基團以提供有用的、可容易地被轉化為多種式I化合物的羥甲基化合物。例如,羥甲基化合物可通過與亞硫醯氯的反應而被轉化為具有反應性的氯甲基中間體。氯甲基中間體可接著與適當的親核試劑如2-(呱啶-4-基)丙-2-醇反應獲得式I的化合物。
對本領域技術人員來說,很清楚地,可利用上述方案的變更以合成多種本發明的化合物。
在一些實施方式中,式I的化合物每天給藥一次、兩次、三次或四次。在一些實施方式中,式I的化合物以從約1mg至約20mg、從約5mg至約20mg、從約10mg至約30mg、從約20mg至約50mg、從約50mg至約1200mg、從約300mg至約1200mg、從約600mg至約1200mg、從約800mg至約1200mg、從約1000mg至約1200mg、從約50mg至約500mg、從約100mg至約500mg、或從約300mg至約500mg的劑量給藥。在一些實施方式中,式I的化合物以約1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、825mg、850mg、875mg、900mg、925mg、950mg、975mg、1000mg、1025mg、1050mg、1075mg、1100mg、1125mg、1150mg、1175mg或1200mg的劑量給藥。
在某些實施方式中,式I的化合物、或其藥學可接受的組成物,與選自以下的一種或多種抗增殖劑或化療劑組合給藥:阿巴瑞克、阿地白介素、阿侖珠單抗、阿利維A酸、別嘌呤醇、六甲蜜胺、安磷汀(阿密磷定,amifostine)、阿那曲唑、三氧化二砷、天門冬醯胺酶、阿紮胞苷、BCG Live(卡介苗活菌)、貝伐單抗(bevacizumab)、氟尿嘧啶、貝沙羅汀、博來黴素、硼替佐米、白消安、卡魯睾酮、卡培他濱、喜樹堿、卡鉑、卡莫司汀(卡氮芥)、塞來昔布(塞來考昔)、西妥昔單抗、苯丁酸氮芥、克拉屈濱、氯法拉濱、環磷醯胺、阿糖胞苷、更生黴素、達依泊汀α(darbepoetin
alfa,)、道諾黴素、地尼白介素、右雷佐生(右丙亞胺,dexrazoxane)、多西他賽、多柔比星(天然)、鹽酸多柔比星、丙酸屈他雄酮、表柔比星、依伯汀α(epoetin alfa)、厄洛替尼、雌莫司汀(雌氮芥)、磷酸依託泊苷、依託泊苷、依西美坦、非格司亭、氟尿苷、氟達拉濱、氟維司群、吉非替尼、吉西他濱、吉妥珠單抗、醋酸戈舍瑞林、醋酸組氨瑞林、羥基脲、替伊莫單抗(ibritumomab)、伊達比星(去甲氧基柔紅黴素)、異環磷醯胺、甲磺酸伊馬替尼、干擾素α-2a、干擾素α-2b、依立替康、來那度胺(lenalidomide)、來曲唑、甲醯四氫葉酸(亞葉酸,leucovorin)、醋酸亮丙瑞林、左旋咪唑、洛莫司汀、醋酸甲地孕酮、美法侖(左旋苯丙氨酸氮芥)、巰嘌呤、6-MP、美司鈉(巰乙磺酸鈉)、甲氨蝶呤、甲氧沙林、絲裂黴素C、米托坦、米托蒽醌、諾龍、奈拉濱、諾非單抗、奧普瑞白介素、奧沙利鉑、紫杉醇、帕利夫明、帕瑪二磷酸(氨羥二磷酸二鈉,pamidronate)、培加酶、培門冬酶、培非司亭、培美曲塞二鈉、噴司他丁、呱泊溴烷、普卡黴素、卟酚姆鈉、丙卡巴肼、奎納克林(喹吖因,quinacrine)、拉布立酶、利妥昔單抗、沙格司汀(沙莫司亭)、索拉非尼、鏈佐星(鏈脲黴素)、舒尼替尼馬來酸鹽(馬來酸舒尼替尼)、滑石、他莫昔芬(三苯氧胺)、替莫唑胺、替尼泊苷、VM-26、睾內脂、硫鳥嘌呤、6-TG、塞替派、托泊替康、托瑞米芬、托西莫單抗、曲妥珠單抗、維甲酸(tretinoin)、全反式維甲酸(ATRA)、烏拉莫司丁(尿嘧啶氮芥)、戊柔比星、長春堿、長春新堿、長春瑞濱、唑來膦酸酯/鹽(唑來磷酸酯/鹽zoledronate)、或唑來膦酸(唑來磷酸)。
本發明的抑制劑還可以結合的其它藥劑的實例,包括但不限於:用於治療阿爾茨海默氏病(的藥劑)如鹽酸多奈呱齊(多奈呱齊鹽酸鹽)(安理申®(Aricept®))和利斯的明(rivastigmine)(艾斯能®(Exelon®));用於治
療帕金森氏病(的藥劑)如L-DOPA/卡比多巴(甲基多巴肼)、恩他卡朋、羅吡尼洛、普拉克索、溴麥角隱亭、培高利特、三己芬迪(苯海索,trihexyphenidyl)、和金剛烷胺;用於治療多發性硬化症(MS)的藥劑如β干擾素(例如Avonex®和利比®(Rebif®))、乙酸格拉默(Copaxone®)、及米托蒽醌;用於治療哮喘的藥劑如沙丁胺醇和孟魯司特(順爾寧®)(Singulair®));治療精神分裂症的藥劑如再普樂、維思通、思瑞康、和氟呱啶醇;抗炎藥劑如皮質甾類、TNF阻斷劑、IL-1RA、咪唑硫嘌呤(azathioprine)、環磷醯胺、及柳氮磺胺吡啶;免疫調節劑及免疫抑制劑如環孢菌素、他克莫司、雷帕黴素(納巴黴素)、黴酚酸酯(嗎替麥考酚酯)、干擾素、皮質甾類、環磷醯胺、咪唑硫嘌呤(硫唑嘌呤)、以及柳氮磺胺吡啶;神經營養因數如乙醯膽鹼酯酶抑制劑、MAO抑制劑、干擾素、抗驚厥劑、離子通道阻斷劑、利魯唑、和抗帕金森綜合征劑;用於治療心血管疾病的藥劑如β-阻斷劑、ACE抑制劑、利尿劑、硝酸鹽、鈣通道阻斷劑、以及他汀類藥物(statins);用於治療肝臟疾病的藥劑如皮質甾類、考來烯胺、干擾素、和抗病毒劑;用於治療血液病藥劑如皮質甾類、抗-白血病藥劑、和生長因數;以及用於治療免疫缺陷的藥劑如丙種球蛋白。
在某些實施方式中,式I化合物或其藥學可接受的組成物,與單克隆抗體組合或與siRNA治療劑組合給藥。
這些另外的藥劑可與包含式I化合物的組成物單獨給藥,作為多劑量給藥方案的一部分。可替代的,這些藥劑也可以係為單一劑量形式的一部分,與本發明的化合物在單一組成物中混合。如果作為多劑量方案的一部分給
藥,兩種活性藥劑可同時、依次、或在與另一種間隔一段時間內服用,通常與另一種的間隔在5小時以內。
根據所治療的主體及給藥的特定模式,式I化合物及另外的治療劑(在包含另外的治療劑的如上所描述的那些組成物中)二者的量(其可以與載體物質合併在一起以製成單一劑量形式)會改變。優選地,本發明的組成物應被配製,使得可被給予的式I化合物的劑量在0.01-100 mg/kg體重/日範圍內。
在包含另外的治療劑的那些組成物中,所述另外的治療劑和式I化合物可以協同起作用。因此,在此類組成物中另外的治療劑的量將少於單獨使用該治療劑的單一療法(monotherapy)中所需要的量。在此類組成物中,另外的治療劑可以以0.01-1,000 μg/kg體重/日的劑量給藥。
存在于本發明的組成物中的另外的治療劑的量將不多於正常情況下以包括作為單一活性藥劑的該治療劑的組成物給藥的含量。優選地,另外的治療劑在前述披露的組成物中的量將一般係為存在于包含作為單一治療活性藥劑的組成物中該藥劑的量的約50%至100%。
也可將式I化合物或其醫藥組成物併入用於包覆可植入醫療設備的組成物中,如假體、人造瓣膜、血管移植物、支架和導尿管。例如,已使用血管支架克服再狹窄(創傷後血管壁再變窄)。然而,使用支架或其它可植入設備的患者具有血塊形成或血小板活化的風險。可通過使用含有激酶抑制劑的藥學可接受的組成物預包覆的設備預防或減輕這些不利作用。以本發明的化合物包覆的可植入設備係為本發明的另一個實施方式。
具體實施方式
實施例1
使用遷移率位移試驗平臺(遷移位移試驗平臺,Mobility Shift Assay platform)測定了針對克唑替尼、化合物I-a和化合物I-b的IC50值。將每種試驗化合物溶解於二甲亞碸(DMSO)及試驗緩衝液中,並用二甲亞碸及試驗緩衝液連續稀釋,使試驗化合物的終濃度達到1.0、0.3、0.1、0.03、0.01、0.003、0.001、0.0003、0.0001和0.00003 μM。測試了克唑替尼、化合物I-a和I-b對抗19種由以下構成的組中激酶(的活性):ALK、ALK[F1174L]、ALK[L1196M]、ALK[R1275Q]、EML4-ALK、EGFR[T790M]、FAK、FLT1、FLT3、FLT4、KDR、RET、RET[G691S]、RET[M918T]、RET[S891A]、RET[Y791F]、TRKA、TRKB和TRKC。
晶片外遷移率試驗(Off-Chip Mobility Assay)使用試驗緩衝液(20 mM HEPES,0.01% Triton X-100,2 mM DTT,pH 7.5)製備了5 μL的x4化合物溶液、5 μL的x4底物/ATP/金屬溶液、及10 μL的x2激酶溶液,混合並在聚丙烯384孔微孔板的孔中室溫孵育1或5小時*(*;取決於激酶)。然後向孔中加入60 μL的終止緩衝液(QuickScout Screening Assist MSA;Carna Biosciences)。將反應混合物施加至LabChip3000系統(Caliper Life Science),使產物峰和底物峰分開並定量。通過由產物的峰高(P)和底物肽的峰高(S)計算產物比率(P/(P+S)),從而評價激酶反應。
試驗反應的條件在下列表2中給出。計算的IC50值列於表3中。
實施例2
酶活分析中的ALK抑制
在SF9細胞中作為N-端GST融合蛋白表達野生型人類ALK的胞質結構域(氨基酸1058-1620)。使用Lance®時間分辨螢光分析系統(Lance® TR-FRET assay)測定經純化蛋白的激酶活性。激酶反應在384-孔微滴定板(384-well microtiter plate)中進行,使用在20mM HEPES(pH 7.5)、0.05% BSA、2mM DTT、10mM MgCl2、1 μM肽底物(Biotin-Ahx-EQEDEPEGIYGVLF-OH)(SEQ ID NO:1)中的2nM酶,以及40μM ATP(表觀Km)。使反應在室溫下進行90分鐘,然後用在50mM Tris(pH 7.5)中的20 mM EDTA、100 mM NaCl、0.05% BSA和0.1%吐溫-20終止反應。使用Lance®檢測試劑鏈親和素-別藻藍蛋白(SA-APC)和來自Perkin Elmer Life Sciences(Waltham,MA)的Eu-W1024抗-磷酸酪氨酸抗體(PT66)檢測肽底物的磷酸化作用。使用RUBY star讀板儀(BMG LABTECH,Cary,NC)在激發波長320 nm處讀板,在615 nm和665 nm處監測發射,在665 nm處增加的發射表明肽磷酸化。由655nm發射通道中信號的大小計算化合物的IC50值,並以三次重複實驗的平均值表示。
表4列出使用上述流程獲得的、針對本文所描述的實施例化合物的ALKIC50值。
aIC50範圍:+ IC50>10 μM++ 5 μMIC50 10 μM+++ 1 μMIC50<5 μM++++ 0.1 μMIC50<1 μM+++++ 0.05 μMIC50<0.1 μM++++++ IC50<0.05 μM
b不可應用
本領域技術人員使用不超過常規實驗的方法即可辨認、或者可確定本文中所描述的本發明的具體實施方式的多種等價形式。本發明的範圍並不局限於上述描述,而為如權利要求所列出的。
Claims (29)
- 一種方法,包括以下步驟:將式I的化合物給予患有ALK-相關病症的受試者,其中所述受試者顯示一種或多種ALK-抑制劑抗性的標記。
- 如申請專利範圍第1項之方法,其中所述一種或多種ALK-抑制劑抗性的標記選自L1196M、R1275Q、F1174L、ELM4-ALK、NPM-ALK以及它們的組合。
- 如申請專利範圍第1項或第2項中任一項之方法,其中所述ALK-抑制劑係為克唑替尼(crizotinib)。
- 如申請專利範圍第3項之方法,其中所述式I的化合物按照選自從約50mg至約1200mg的劑量給藥。
- 如申請專利範圍第4項之方法,其中所述式I的化合物按照每天一次、兩次、三次或四次給藥。
- 一種方法,包括以下步驟:將式I的化合物與另外的化療劑聯合給予患有ALK-相關病症或對ALK-相關病症易感的受試者。
- 如申請專利範圍第6項之方法,其中所述另外的化療劑選自由多烯紫杉醇、培美曲塞、卡鉑、紫杉醇和順鉑構成的組。
- 如申請專利範圍第6項或第7項中任一項之方法,其中所述式I的化合物和所述另外的化療劑的至少一種以低於作為單一藥劑給藥時的劑量給藥。
- 如申請專利範圍第1項或第6項中任一項之方法,其 中所述受試者具有選自L1196M、R1275Q、F1174L、ELM4-ALK、NPM-ALK以及它們的組合的ALK-相關遺傳標記。
- 如申請專利範圍第9項之方法,其中通過螢光原位雜交檢測所述ALK-相關遺傳標記。
- 如申請專利範圍第6項之方法,其中所述受試者具有克唑替尼抗性相關標記。
- 如申請專利範圍第11項之方法,其中在高於與針對克唑替尼抗性的升高概率相關的閾值時所述檢測克唑替尼抗性相關標記。
- 如申請專利範圍第12項之方法,其中通過螢光原位雜交檢測所述克唑替尼抗性相關標記。
- 如申請專利範圍第11項、第12項或第13項中任一項之方法,其中所述克唑替尼抗性相關標記係為L1196M。
- 一種方法,包括以下步驟:檢測受試者中ALK-抑制劑抗性相關標記;以及確定所述受試者係為使用式I的化合物治療的候選者。
- 一種方法,包括以下步驟:檢測受試者中ALK-抑制劑抗性相關標記;確定所述受試者係為使用式I的化合物治療的候選者,以及以治療有效劑量的所述式I的化合物給予所述受 試者。
- 如申請專利範圍第15項或第16項中任一項之方法,其中所述ALK-抑制劑抗性相關標記係為克唑替尼抗性相關標記。
- 如申請專利範圍第17項之方法,其中所述克唑替尼抗性相關標記係為L1196M。
- 如申請專利範圍第15項至第18項中任一項之方法,其中所述受試者正在或已經接受過克唑替尼治療。
- 一種用於治療TRK-相關病症之方法,所述方法包括將式I的化合物給予需要其的患者。
- 如申請專利範圍第20項之方法,其中所述TRK-相關病症係為癌症。
- 如申請專利範圍第20項之方法,其中所述TRK-相關病症係為疼痛。
- 如申請專利範圍第22項之方法,其中所述TRK-相關病症係為癌症疼痛。
- 一種用於治療ALK-相關病症之方法,所述方法包括將式I的化合物給予需要其的受試者,其中所述ALK-相關病症位於或存在於中樞神經系統。
- 如申請專利範圍第24項之方法,其中所述ALK-相關病症位於或存在於大腦。
- 如申請專利範圍第25項之方法,其中所述ALK-相關病症係為腦癌。
- 如申請專利範圍第26項之方法,其中所述ALK-相關病症係為轉移的腦癌。
- 如申請專利範圍第24項之方法,其中所述ALK-相關病症位於或存在於脊髓。
- 如申請專利範圍第28項之方法,其中所述ALK-相關病症係為脊髓癌。
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-
2012
- 2012-11-13 KR KR1020147016248A patent/KR20140128946A/ko not_active Application Discontinuation
- 2012-11-13 JP JP2014541406A patent/JP2014533286A/ja active Pending
- 2012-11-13 WO PCT/US2012/064822 patent/WO2013074518A1/en active Application Filing
- 2012-11-13 SG SG11201402221XA patent/SG11201402221XA/en unknown
- 2012-11-13 AU AU2012339753A patent/AU2012339753A1/en not_active Abandoned
- 2012-11-13 EP EP12849035.6A patent/EP2779833A4/en not_active Withdrawn
- 2012-11-13 US US14/357,884 patent/US20150306086A1/en not_active Abandoned
- 2012-11-13 CA CA2854936A patent/CA2854936A1/en not_active Abandoned
- 2012-11-13 RU RU2014119150/15A patent/RU2014119150A/ru not_active Application Discontinuation
- 2012-11-13 CN CN201280066991.2A patent/CN104202982A/zh active Pending
- 2012-11-13 BR BR112014011465A patent/BR112014011465A2/pt not_active IP Right Cessation
- 2012-11-13 MX MX2014005632A patent/MX2014005632A/es unknown
- 2012-11-14 TW TW101142430A patent/TW201325589A/zh unknown
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2015
- 2015-03-24 HK HK15102989.2A patent/HK1202377A1/zh unknown
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EP2779833A4 (en) | 2015-03-18 |
RU2014119150A (ru) | 2015-12-27 |
AU2012339753A1 (en) | 2014-06-19 |
EP2779833A1 (en) | 2014-09-24 |
CA2854936A1 (en) | 2013-05-23 |
HK1202377A1 (zh) | 2015-10-02 |
JP2014533286A (ja) | 2014-12-11 |
CN104202982A (zh) | 2014-12-10 |
WO2013074518A1 (en) | 2013-05-23 |
US20150306086A1 (en) | 2015-10-29 |
BR112014011465A2 (pt) | 2017-05-09 |
SG11201402221XA (en) | 2014-06-27 |
KR20140128946A (ko) | 2014-11-06 |
MX2014005632A (es) | 2014-10-17 |
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