TWI762579B - 六氫吡啶經取代之MnK抑制劑及其相關方法 - Google Patents
六氫吡啶經取代之MnK抑制劑及其相關方法 Download PDFInfo
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Abstract
Description
本發明通常關於具有作為與MAP激酶相互作用激酶(Mnk)的抑制劑之活性的化合物,以及包含或利用該等化合物的相關組成物和方法。該等化合物發現在許多治療應用(包含治療癌症)之效用。
真核生物起始因子4E(eIF4E)是一般轉譯因子,但是其具有優先增強導致惡性相關蛋白產生之信使RNA(mRNAs)的轉譯之可能性。此選擇性可與對於eIF4E及其用於轉譯在彼等的5'-未轉譯區(5'-UTRs)中之含有廣泛二級結構的mRNA結合伴體之增加需求有關。這些mRNA包含彼等編碼某些控制細胞週期進行和腫瘤形成之蛋白質者。在正常細胞條件下,當活性eIF4E的可獲得性受限時,這些與惡性相關的mRNA之轉譯就會被抑制;然而,當eIF4E被過量表現或過度活化時,彼等的含量會增加。在包含結腸、乳房、膀胱、肺、前列腺、腸胃道、頭和頸、霍奇金氏(Hodgkin's)淋巴腫瘤和神經纖維瘤的癌症之許多類型的腫瘤和癌細胞株中已發現eIF4E的含量增加。
帽蓋依賴型(cap-dependent)轉譯作用的起始被認為是依賴eIF4F、包括eIF4E的起始因子複合物、支架蛋白eIF4G、和RNA解旋酶 eIF4A的組合。因為eIF4E為這些蛋白中唯一直接結合mRNA帽結構的蛋白,所以其為eIF4F組合於5'帽的關鍵因素。支架蛋白eIF4G也經由其與eIF3的相互作用將40S核醣體的次單元補充至mRNA且結合eIF4B(一種幫助eIF4A之RNA-解旋酶功能從而促進含有結構化5'-UTR之mRNA的轉譯之蛋白)。eIF4E作為eIF4F複合物之部分的可用性為控制轉譯之速率的限制因子,且因此eIF4E為mRNA轉譯的重要調節劑。
eIF4E活性之調節形成PI3K/Akt/mTOR和Ras/Raf/MAPK傳訊途徑的會合點。PI3K(肌醇磷脂3-激酶)/PTEN(第十對染色體缺失的磷酸酶和張力素(tensin)同源物)/Akt/mTOR(哺乳動物雷帕黴素(rapamycin)標靶)途徑經常涉及腫瘤形成和對於癌症療法的敏感性與抗藥性。透過PI3K/PTEN/Akt/mTOR途徑解除傳訊經常是由於此途徑之關鍵組分的基因改變及/或上游生長因子受體或傳訊組分之突變所造成的結果。PI3K當被例如細胞外生長因子、促分裂原、細胞介素及/或受體活化時會啟動一連串的事件,PDK1活化Akt,其依次磷酸化且使包含TSC1和2之腫瘤抑制複合物(結節性硬化複合物1/2)失活,導致mTORC1(雷帕黴素複合物1的標靶)被Rheb-GTP活化。以PI3K活化PDK1和Akt係被PTEN負調節。
PTEN是一種關鍵的腫瘤抑制基因且經常在人類癌症中突變或被壓制(silenced)。其之喪失導致Akt之活化且增加下游mTORC1傳訊。mTOR複合物1(mTORC1)參與腫瘤轉形似乎取決於其對於eIF4F複合物的調節角色;eIF4E的過表現可賦予對雷帕黴素的抗藥性。mTORC1調節eIF4F複合物組合,這對於與細胞生長相關的mRNA轉譯、預防細胞凋亡和轉形至關重要的。mTORC1藉由磷酸化和使4E-BP失活並接著使4E-BP從eIF4E離解來達成此目的。此接著使eIF4E能夠與支架蛋白eIF4G相互作用,允許eIF4F複合物的組合用於結構化mRNA的轉譯。mTORC1亦促進轉譯活 化子S6K的活化作用,其使核醣體蛋白S6和其他受質(包括eIF4B)磷酸化。mTORC1傳訊係被雷帕黴素及其類似物(rapalogs)抑制,雖然這些化合物異位地作用而不是直接抑制mTOR激酶活性。
考慮到在高比例的癌症中PI3K/Akt/mTOR途徑在調節編碼原致癌基因蛋白和經活化之mTORC1傳訊的基因之mRNA轉譯的重要性,這些激酶已在積極地進行作為腫瘤藥物標靶。已經確定許多藥理抑制劑,其中一些已經達到高階臨床階段。然而,最近已經清楚知道mTOR途徑參與會損害Akt活性的複雜回饋迴路(feedback Loop)。已顯示用mTOR抑制劑長時間治療癌細胞或病患造成PI3K活性升高,導致Akt和eIF4E之磷酸化,及促進癌細胞存活。作用於Akt和mTOR的下游之eIF4E概括在腫瘤形成和抗藥性的Akt作用,及經由eIF4E的Akt傳訊為體內腫瘤形成和抗藥性的重要機制。
除了PI3K/Akt/mTOR途徑以外,eIF4E亦為被生長因子活化之Ras/Raf/MAP傳訊級聯的標靶且用於應激活化的p38 MAP激酶途徑。Erk1/2和p38接著將MAP激酶相互作用激酶1(Mnk1)和MAP激酶相互作用激酶2(Mnk2)磷酸化。在許多癌症中Erk途徑也被活化,反應例如活化Ras中的突變(在約20%的腫瘤中發現)或Ras GTPase-活化子蛋白NF1的功能喪失。Mnk1和Mnk2為蘇胺酸/絲胺酸蛋白激酶且由於eIF4E和Mnks之間的相互作用,特異性磷酸化eIF4F複合物內之eIF4E的絲胺酸209(Ser209),其用於徵集Mnks以作用在eIF4E上。具有突變eIF4E的小鼠,其中eIF4E的Ser209被丙胺酸置換,顯示沒有eIF4E磷酸化和顯著衰減的腫瘤生長。顯著地,雖然Mnk活性為eIF4E-媒介之致癌轉形所必要的,但對於正常發育為非必要的。藥理上抑制Mnks因此提供誘人的癌症治療策略。
儘管對Mnk結構和功能的瞭解有所增加,但是關於藥理 Mnk抑制劑之發現的進展極微,且較少Mnk抑制劑被報導出來:CGP052088(Tschopp等人,Mol Cell Biol Res Commun.3(4):205-211,2000);CGP57380(Rowlett等人,Am J Physiol Gastrointest Liver Physiol.294(2):G452-459,2008);和尾孢醯胺(Cereosporamide)(Konicek等人,Cancer Res.71(5):1849-1857,2011)。然而,這些化合物已主要使用於Mnk標靶驗證之目的。最近,研究人員已提出其他用於治療受抑制Mnk1及/或Mnk2的激酶活性影響之疾病的化合物,包括例如在國際專利申請公開案WO 2014/044691和其中引用的各種專利文件中所揭示的化合物、Yu等人揭示於European Journal of Med.Chem.,95:116-126,2015之4-(二氫吡啶酮-3-基)胺基-5-甲基噻吩并[2,3,-d]嘧啶、及6'-((6-胺基嘧啶-4-基)胺基)-8'-甲基-2'H-螺[環己烷-1,3'-咪唑并[1,5-a]吡啶]-1',5'-二酮和國際專利申請公開案WO 2015/200481中所揭示的各種化合物。
因此,雖然在此領域已有進展,但對於具有改良溶解度同時保持特異性抑制Mnk和其他受體活性之效力的化合物仍然存在顯著需求。本發明滿足此需求並提供其他相關的優點。
本發明係關於抑制或調節Mnk活性的化合物以及該等化合物之立體異構物、互變異構物和醫藥可接受的鹽作為候選治療劑。本發明亦關於包含該等化合物之組成物以及治療將從Mnk抑制受益的病況(諸如癌症)之相關方法。
在一具體實例中,本發明係關於符合式I之化合物以及該等化合物之立體異構物、互變異構物或醫藥可接受的鹽:
其中:X1為CH2和X2為NR2或X1為NR2及X2為CH2;R1為H、(C1-C4)烷基、鹵素或氰基;R2為H、(C1-C8)烷基或(C1-C8)鹵烷基;R3為(C1-C8)烷基,或R2和相鄰的R3,或R3和相鄰的R3,與彼等所連接的環原子一起,形成稠合的五員或六員雜環或環烷基環;及n為0、1、2、3或4;其中烷基、雜環和環烷基視需要經OH、CN、NH2、NO2、鹵素、烷基和烷氧基取代。
在另一具體實例中,揭示包含結構(I)之化合物與醫藥上可接受載劑、稀釋劑或賦形劑組合的組成物。
在另一具體實例中,提供用於治療需要其之哺乳動物的Mnk依賴型病況之方法。該等方法包含將有效量的結構(I)之化合物或包含該化合物的組成物投予至該哺乳動物。該病況包括但不限於如更詳細討論於下的各種形式之癌症。
參考以下詳細說明,本發明的這些和其他態樣將變得顯而易見。為此目的,本文中闡述各種參考文獻,其更詳細的說明某些背景資訊、程序、化合物及/或組成物,且各自特此以其全文引用方式併入。
在下列說明中,闡述某些特定細節以提供本發明各種具體實例之徹底瞭解。然而,熟習該項技術者將理解本發明不需要這些細節便可實行。除非上下文另有要求,否則整個說明書和申請專利範圍,用語“包含(comprise)”及其變形諸如“包含(comprises)”和“包含(comprising)”應理解為開放性包容的意義(亦即“包括但不限於”)。
在本說明書整個中引用“一個(one)具體實例”或“一(an)具體實例”意指與關於該具體實例所述的特定特徵、結構或特性係包含在本發明的至少一個具體實例中。因此,在整個本說明書各處出現之“在一個具體實例中”或“在一具體實例中”詞組並不一定全部都指同一具體實例。而且,特定特徵、結構或特性可以任何適當的方式合併於一或多個具體實例中。
如本文所用,且除非有相反的說明,否則以下術語和詞組具有以下所指明的意義。
“胺基”係指-NH2取代基。
“羧基”係指-CO2H取代基。
“羰基”係指-C(O)-或-C(=O)-基團。兩個符號在本說明書中互換使用。
“氰基”係指-C≡N取代基。
“乙醯基”係指-C(O)CH3取代基。
“羥基(Hydroxy或hydroxyl)”係指-OH取代基。
“側氧基(Oxo)”係指-O-取代基的氧。
“MAP激酶相互作用激酶”詞組或術語“Mnk”係指MAP激酶相互作用激酶蛋白的所有同功型,包含Mnk-1和Mnk-2。
“烷基”係指飽和直鏈或支鏈烴鏈基團,其僅由碳和氫原子組 成,具有1到12個碳原子(C1-C12烷基),1到8個碳原子(C1-C8烷基)或1到6個碳原子(C1-C6烷基),且其藉由單鍵連接至分子的其餘部分。例示性烷基包括甲基、乙基、正丙基、1-甲基乙基(異丙基)、正丁基、正戊基、1,1-二甲基乙基(三級丁基)、3-甲基己基、2-甲基己基、等等。
“低碳烷基”具有與上述定義之烷基相同的意義,但具有一至四個碳原子(C1-C4烷基)。
“伸烷基”或”伸烷基鏈”係分別指將分子其餘部分連接到一個基團之直鏈或支鏈二價烴(烷基)鏈,其只由碳和氫組成。伸烷基可具有一至十二個碳原子,例如,亞甲基、伸乙基、伸丙基、伸正丁基、等等。該伸烷基鏈係經由單鍵或雙鍵連接至分子其餘部分。伸烷基鏈連接至分子其餘部分的連接點可透過該鏈中的一個碳或任何兩個碳原子。“視需要經取代之伸烷基”係指伸烷基或經取代之伸烷基。
“‘烷氧基”係指式-ORa的基團,其中Ra為如以上定義的具有指定數目之碳原子的烷基。烷氧基的實例包括但不限於-O-甲基(甲氧基)、-O-乙基(乙氧基)、-O-丙基(丙氧基)、-O-異丙基(異丙氧基)等等。
“醯基”係指式-C(O)Ra的基,其中Ra為具有指定數目之碳原子的烷基。
“芳基”係指包含氫、6至18個碳原子及至少一個芳環之烴環系統基。例示性芳基為包含氫和6至9個碳原子及至少一個芳環之烴環系統基;包含氫和9至12個碳原子及至少一個芳環之烴環系統基;包含氫和12至15個碳原子及至少一個芳環之烴環系統基;或包含氫和15至18個碳原子及至少一個芳環之烴環系統基。就本發明之目的而言,芳基可為單環、雙環、三環或四環系統,其可包括稠合或橋聯環系統。芳基包括(但不限於)衍生自乙烯合蒽(aceanthrylene)、乙烯合萘(acenaphthylene)、乙烯合 菲(acephenanthrylene)、蒽、薁、苯、筷(chrysene)、1,2-苯并苊(fluoranthene)、茀、as-苯并二茚、s-苯并二茚、二氫茚、茚、萘、萉、菲、七曜烯(pleiadene)、芘和聯伸三苯之芳基。“視需要經取代之芳基”係指芳基或經取代之芳基。
“環烷基”係指僅由含碳和氫原子組成之穩定非芳族單環或多環烴基,其可包括具有從三到十五個碳原子(較佳地具有三到十個碳原子、三到九個碳原子、三到八個碳原子、三到七個碳原子、三到六個碳原子、三到五個碳原子)之稠合或橋聯環系統、具有四個碳原子之環或具有三個碳原子之環。環烷基環可為飽和或不飽和且以單鍵連接至分子的其餘部分。單環基包括例如環丙基、環丁基、環戊基、環己基、環庚基和環辛基。多環基包括例如金剛烷基、降莰基、十氫萘基、7,7-二甲基-雙環[2.2.1]庚基、等等。
“稠合”係指本文所述的任何環結構,其稠合至本發明化合物中現存環結構。當稠合環為雜環基環或雜芳基環時,現存環結構上的任何碳原子(其變成稠合雜環基環或稠合雜芳基環之部份)可經氮原子取代。
“鹵基”或“鹵素”係指溴基(溴)、氯基(氯)、氟基(氟)或碘基(碘)。
“鹵烷基”係指如本文所定義之具有所指碳原子數的烷基,其中一或多個烷基之氫原子係經如上所定義之鹵素(鹵基)取代。鹵素原子可相同或不同。例示性鹵烷基為三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1,2-二氟乙基、3-溴-2-氟丙基、1,2-二溴乙基、等等。
“雜環基”、”雜環”或”雜環”係指由二至十二個碳原子和從一至六個雜原子(諸如一至五個雜原子、一至四個雜原子、一至三個雜原子、一至二個雜原子)選自由氮、氧和硫所組成群組之雜原子所組成的穩定3-至18-員飽和或不飽和基。例示性雜環包括但不限於穩定3-15員飽和或不飽和 基,穩定3-12員飽和或不飽和基,穩定3-9員飽和或不飽和基,穩定8-員飽和或不飽和基,穩定7-員飽和或不飽和基,穩定6-員飽和或不飽和基,或穩定5-員飽和或不飽和基。
除非在說明書中另有具體說明,否則雜環基可為單環、雙環、三環或四環,其可包括稠合環或橋聯環系統;且雜環基中的氮、碳或硫原子可視需要氧化;氮原子可視需要四級化;且該雜環基可部份或完全飽和。非芳族雜環基之實例包括(但不限於)吖呾基、二氧戊環基、噻吩基[1,3]二硫環己烷基、十氫異喹啉基,咪唑啉基,咪唑啶基、異噻唑啶基、異唑啶基、嗎啉基、八氫吲哚基、八氫異吲哚基、2-側氧六氫吡基、2-側氧六氫吡啶基、2-側氧吡咯啶基、唑啶基、六氫吡啶基、六氫吡基、4-六氫吡啶酮基、吡咯啶基、吡唑啶基、啶基、噻唑啶基、四氫呋喃基、噻呾基、三硫環己烷基(trithianyl)、四氫哌喃基、硫佅啉基、噻嗎啉基(thiamorpholinyl)、1-側氧-硫嗎啉基及1,1-二側氧-硫嗎啉基。雜環基包括如本文所定義之雜芳基,及芳族雜環基之實例係列於下述雜芳基之定義中。
“雜芳基”或”伸雜芳基”係指5-到14-員環系統基,其包含氫原子、一至十三個碳原子、從一至六個選自由氮、氧和硫所組成群組的雜原子,和至少一個芳環。為了本發明之目的,雜芳基可為穩定5-12員環、穩定5-10員環、穩定5-9員環、穩定5-8員環、穩定5-7員環、或穩定6員環,該環包含至少1個雜原子、至少2個雜原子、至少3個雜原子、至少4個雜原子、至少5個雜原子、或至少6個雜原子。雜芳基可為單環、雙環、三環、或四環的環系統,其可包含稠合或橋接環系統;且雜芳基中的氮、碳或硫原子可視需要經氧化;氮原子可視需要經四級化。雜原子可為芳族或非芳族環的成員,其限制條件為雜芳基中的至少一個環為芳族。實例包括但不限於氮呯基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚 基、苯并二氧雜環戊烷(benzodioxolyl)、苯并呋喃基、苯并唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧呯基(dioxepinyl)、1,4-苯并二烷基(benzodioxanyl)、苯并萘并呋喃基、苯并唑基、苯并二茂基(benzodioxolyl)、苯并二基(benzodioxinyl)、苯并哌喃基、苯并哌喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并硫苯基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、啉基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、異噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、異吲哚基、吲哚啉基、異吲哚啉基、異喹啉基、吲基、異唑基、萘啶基、二唑基、2-側氧氮呯基、唑基、環氧乙烷基、1-氧化吡啶基、1-氧化嘧啶基、1-氧化吡基、1-氧化嗒基、1-苯基-1H-吡咯基、啡基、啡噻基、啡基、呔基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡基、嘧啶基,嗒基、喹唑啉基、喹啉基、喹啉基、啶基、異喹啉基、四氫喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三基、和硫苯基(亦即噻吩基)。
本發明之化合物可以各種異構物形式存在,以及以一或多種互變形式,包括單一互變異構物和互變異構物的混合物二者存在。術語“異構物”意欲涵蓋本發明化合物的所有異構物形式,包括該化合物的互變異構物形式。
本文所述之一些化合物可具有不對稱中心且因此存在不同的鏡像異構物和非鏡像異構物形式。本發明之化合物可於光學異構物或非鏡像異構物之形式。因此,本發明涵蓋本發明之化合物及彼等如本文所述於彼等光學異構物、非鏡像異構物及其混合物形式(包括外消旋混合物)之用途。本發明化合物之光學異構物可藉由已知的技術諸如不對稱合成、掌性層析或透過利用光學活性解析劑之立體異構物的化學分離來獲得。
除非另有說明,否則“立體異構物”意指化合物的一種立體異構物,其實質上無含該化合物的其他立體異構物。因此,具有一個掌性中心之立體異構上純的化合物應實質上無此化合物之相反鏡像異構物。具有二掌性中心之立體異構上純的化合物,應實質上無化合物之其他非鏡像異構物。典型的立體異構上純的化合物包含大於約80%重量之該化合物的一種立體異構物和少於約20%重量之該化合物的其他立體異構物,例如大於約90%重量之該化合物的一種立體異構物和少於約10%重量之該化合物的其他立體異構物,或大於約95%重量之該化合物的一種立體異構物和少於約5%重量之該化合物的其他立體異構物,或大於約97%重量之該化合物的一種立體異構物和少於約3%重量之該化合物的其他立體異構物。
若所描繪的結構和給予此結構命名之間有差異,則以所描繪之結構為主。另外,若結構或結構之部份的立體化學並未以例如粗線或虛線指明,則此結構或結構之部分則解釋為涵蓋其之所有立體異構物。然而,在某些情況下,當有超過一個掌性中心存在時,結構和名稱可以單一鏡像異構物表示,以幫助描述相對的立體化學。熟習有機化學合成之技術者應知道化合物是否係由用於製備彼等之方法製備成單一鏡像異構物形式。
在本說明中,“醫藥上可接受的鹽”為本發明化合物之醫藥上可接受的有機或無機酸或鹼鹽。代表性的醫藥上可接受的鹽包括例如鹼金屬鹽、鹼土金屬鹽、銨鹽、水溶解度及水不溶性鹽,諸如乙酸鹽、胺芪磺酸鹽(amsonate)(4,4-二胺基芪-2,2-二磺酸鹽)、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、丁酸鹽、鈣、依地酸鈣、樟腦磺酸鹽、碳酸鹽、氯化物、檸檬酸鹽、克拉維酸鹽(clavulariate)、二鹽酸鹽、依地酸鹽、乙二磺酸鹽、依托酸鹽(estolate)、乙磺酸鹽、反丁烯二酸鹽(fiunarate)、葡庚糖酸鹽、葡糖酸鹽、麩胺酸鹽、乙醇醯基對胺基苯胂酸 鹽(glycollylarsanilate)、六氟磷酸鹽、己基苯間二酚酸鹽、海巴明(hydrabamine)、溴酸鹽、鹽酸鹽、羥基萘甲酸鹽、碘化物、異硫代硫酸鹽、乳酸鹽、乳糖醛酸鹽、月桂酸鹽、蘋果酸鹽、順丁烯二酸鹽、扁桃酸鹽、甲磺酸鹽、溴甲烷、甲基硝酸鹽、甲基硫酸鹽、黏酸鹽、萘磺酸鹽、硝酸鹽、N-甲基葡糖胺銨鹽、3-羥基-2-萘甲酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、巴莫酸鹽(1,1-亞甲基-雙-2-羥基-3-萘甲酸鹽、恩波酸鹽(einbonate))、泛酸鹽、磷酸鹽/二磷酸鹽、苦味酸鹽、多聚半乳糖酸酸鹽、丙酸鹽、對甲苯磺酸鹽、水楊酸鹽、硬脂酸鹽、鹼式乙酸鹽、丁二酸鹽、硫酸鹽、磺基水楊酸鹽(sulfosaliculate)、蘇拉酸鹽(suramate)、鞣酸鹽、酒石酸鹽、茶氯酸鹽、甲苯磺酸鹽、三乙基碘化物及戊酸鹽。醫藥上可接受的鹽在其結構中可具有超過一個帶電原子。在此情形中,醫藥上可接受的鹽可具有多個相對離子。因此,醫藥上可接受的鹽可具有一或多個帶電原子及/或一或多個相對離子。
術語“治療(treat)”,”治療(treating)”和”治療(treatment)”係指改善或根除疾病或與疾病相關的症狀。在某些具體實例中,該等術語係指因將一或多種預防性或治療性藥劑投予至患有該疾病的病患而將疾病的蔓延或惡化減至最小。
術語“有效量”係指本發明化合物或其他活性成分足以在治療或預防疾病中提供醫療或預防效益或足以將疾病相關的症狀延緩或最小化的量。另外,與本發明化合物相關的治療有效量意指治療劑的單獨、或與其他療法合併的量,其足以在治療或預防疾病中提供治療效益。與本發明化合物結合使用,該術語可涵蓋改善整個療法、降低或避免疾病的症狀或病因、或增強治療效力或與另一種治療劑的增效作用之量。
術語“調節(modulate)”、“調節(modulation)”等等係指化合物 增加或減少例如MAP激酶相互作用激酶(Mnk)之功能或活性的能力。“調節(modulation)”以其各種形式係意欲涵蓋與Mnk相關的活性之抑制、拮抗、部分拮抗、活化、增效、及/或部分增效。Mnk抑制劑為結合、部分或完全阻斷刺激作用、降低、防止、延緩活化、失活、去敏化或向下調節信號傳導的化合物。化合物調節Mnk活性之能力可以酵素性分析或以細胞為基礎的分析證明。
“病患”或“對象”包括動物,諸如人類、牛、馬、羊、羔羊、豬、雞、火雞、鵪鶉、貓、狗、小鼠、大鼠、兔或天竺鼠。動物可為哺乳動物諸如非靈長類和靈長類(例如猴子和人類)。在一具體實例中,病患為人類,諸如人類嬰兒、孩童、青少年或成人。
術語“前驅藥”係指藥物之前驅物,其為在投予病患後必須藉由代謝過程進行化學轉化之後變成活性藥劑的化合物。根據式(I)化合物的例示性前驅藥為酯、乙醯胺類和醯胺。
本發明通常係關於由式(I)之種類所所包含的化合物或其立體異構物、互變異構物或醫藥上可接受的鹽。
在一具體實例中X1為CH2及X2為NR2。在另一具體實例中X1為NR2及X2為CH2。
在一具體實例中R1為H。在另一具體實例中R1為甲基。在另一具體實例中R1為Cl。在又一具體實例中R1為氰基。
在一具體實例中R2為H。
在一具體實例中R2為甲基。在另一具體實例中R2為乙基。在另一具體實例中R2為異丙基。在另一具體實例中R2為三級丁基。
在一具體實例中R2為3,3,3-三氟丙基。在另一具體實例中 R2為2,2-二氟乙基。
在另一具體實例中R2為甲基環丙烷。
在一具體實例中R3為H或甲基。
在一具體實例中根據式(I)之化合物、或其立體異構物、互變異構物或醫藥上可接受的鹽係選自化合物3D、3K、3L、3X、3Y、rac-1F、1Fa、1Fb、rac-2F、2Fa和2Fb。
本發明根據式(I)之化合物可經具有一或多個原子被具有不同原子質量或質量數的原子置換之原子同位素標記。可併入根據式(I)之化合物的同位素之實例包括氫、碳、氮、氧、磷、氟、氯或碘之同位素。該等同位素之例證分別為2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I、和125I。這些同位素標記之化合物可用於測量生物分布、組織濃度及從生物組織(包括投予該標記化合物的對象)輸送和排泄之動力學。標記化合物亦可用於側定治療效用、作用之位置或模式,以及候選治療劑與藥理上重要目標之結合親和力。因此,某些放射性標記的根據式I之化合物可用於藥物及/或組織分布研究。放射性同位素氚(亦即3H),和碳-14(亦即14C)鑑於其易於併入和現成的檢測方法而特別可用於此種目的。
用較重的同位素諸如氘(亦即2H)之取代提供因較大的代謝穩定性而產生之利益,諸如含氘化合物的活體內半衰期增加。以氘取代氫可減少治療效果所需的劑量,且因此在發現或臨床環境可為較佳。
經正電子發射同位素(諸如11C、18F、15O和13N)之取代提供本發明化合物之標記類似物,其可用於正電子發射斷層攝影術(PET)研究,例如用於檢測基質受體佔有率。例如,同位素標記的根據式I之化合物一般可藉由熟習該項技術者已知的習用技術,或藉由類似於下述製備和實施例 部分中所描述的方法使用適當同位素標記試劑來製備。
本文所揭示的本發明具體實例也意欲涵蓋根據式(I)之化合物的體內代謝產物。該等產物主要由於投予本發明化合物時之酵素活性而可從例如氧化、還原、水解、醯胺化、酯化、及類似方法產生。因此,本發明係包括在本發明化合物投予至哺乳動物經一段足以產生代謝產物的時間後所產生的酵素或非酵素活性之副產物的化合物。代謝產物,特別是醫藥上活性代謝物典型地藉由將可偵測劑量的放射性標記之本發明化合物投予至對象(諸如大鼠、小鼠、天竺鼠、猴子或人類)歷經一段期間代謝發生的足夠時間,並從得自接受此放射性標記之化合物的對象之尿液、血液或其他生物樣品中分離來鑑定。
本發明亦提供式(I)化合物之醫藥上可接受的鹽形式。本發明範疇中所涵蓋者為酸和鹼加成鹽二者,其係藉由使醫藥上適合的酸或醫藥上適合的鹼與本發明之化合物接觸而形成。
為此目的,“醫藥上可接受的酸加成鹽”係指彼等保留游離鹼之生物效用及性質的鹽類,其並非生物上或其他所不欲的,且其係與無機酸(諸如但不限於氫氯酸、氫溴酸、硫酸、硝酸、磷酸等等)及有機酸(諸如但不限於乙酸、2,2-二氯乙酸、己二酸、藻酸、抗壞血酸、天冬胺酸、苯磺酸、苯甲酸、4-乙醯胺基苯甲酸、樟腦酸、樟腦-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、檸檬酸、環拉酸(cyclamic acid)、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羥基乙烷磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、葡庚糖酸、葡萄糖酸、葡萄糖醛酸、麩胺酸、戊二酸、2-側氧-戊二酸、甘油磷酸、乙醇酸、馬尿酸、異丁酸、乳酸、乳糖酸、月桂酸、順丁烯二酸、蘋果酸、丙二酸、苦杏仁酸、甲磺酸、黏液酸、萘-1,5-二磺酸、萘-2-磺酸、1-羥基-2-萘甲酸、菸鹼酸、油酸、乳清酸、草酸、棕櫚酸、撲 酸(pamoic acid)、丙酸、焦麩胺酸、丙酮酸、水楊酸、4-胺基水楊酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫代氰酸、對甲苯磺酸、三氟乙酸、十一烯酸、等等)所形成。
同樣地,”醫藥上可接受的鹼加成鹽”係指彼等保留游離酸之生物效用及性質的鹽,其並非生物上或其他所不欲的。此等鹽係藉由將無機鹼或有機鹼添加到游離酸中而製備。衍生自無機鹼的鹽包括(但不限於)鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽、鐵鹽、鋅鹽、銅鹽、錳鹽、鋁鹽、等等。較佳的無機鹽類為銨鹽、鈉鹽、鉀鹽、鈣鹽和鎂鹽。衍生自有機鹼之鹽包括(但不限於)一級、二及和三級胺之鹽、經取代胺,包括天然經取代之胺、環胺和鹼離子交換樹脂,諸如氨、異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲基乙醇胺(deanol)、2-二甲胺基乙醇、2-二乙胺基乙醇、二環己胺、離胺酸、精胺酸、組胺酸、咖啡因、普魯卡因、海巴胺、膽鹼、甜菜鹼、苄乙胺(benethamine)、苄星(benzathine)、乙二胺、葡糖胺、甲基還原葡糖胺、可可豆鹼、三乙醇胺、胺丁三醇(tromethamine)、嘌呤、六氫吡、六氫吡啶、N-乙基六氫吡啶、聚胺樹脂等。特佳的有機鹼為異丙胺、二乙胺、乙醇胺、三甲胺、二環己胺、膽鹼和咖啡因。
經常結晶產生本發明化合物之溶劑合物。如本文所用,術語”溶劑合物”係指包含一或多個本發明化合物之分子與一或多個溶劑分子的聚集體。溶劑可為水,在該情況下溶劑合物可為水合物。或者,溶劑可為有機溶劑。因此,本發明之化合物可以水合物(包括單水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等等)以及對應的溶劑化形式存在。本發明化合物可為真溶劑合物,而在其他情況下,本發明之化合物可僅保留外來的水或是為水加一些外來溶劑的混合物。
“立體異構物”係指由以相同的鍵鍵結但具有不同三維結構 之相同原子所構成的化合物,彼等不可互換。本發明考慮各種立體異構物及其混合物並包括“鏡像異構物”,其係指二種其分子彼此為不能重疊的鏡像之立體異構物。
本發明之化合物或其醫藥上可接受的鹽可含有一或多個不對稱中心且因此可產生鏡像異構物、非鏡像異構物和其他立體異構物形式,其可根據絕對立體化學定義為(R)-或(S)-,或用於胺基酸定義為(D)-或(L)-。本發明意欲包括所有該等可能的異構物,以及其消旋和光學上純的形式。光學活性(+)和(-),(R)-和(S)-,或(D)-和(L)-異構物可使用掌性合成子或掌性試劑製備,或使用習用技術(諸如層析和分結晶)解析來製備。用於製備/分離個別鏡像異構物之習用技術包括從適當光學純前驅物之掌性合成,或使用例如掌性高壓液相層析(HPLC)之消旋物(或鹽或衍生物之消旋物)的解析。當本文所述之化合物含有烯烴雙鍵或其他幾何不對稱中心時,且除非另有指明,否則意欲化合物係包括E和Z二種幾何異構物。同樣地,亦意欲包括所有的互變異構物形式。
術語“互變異構物”係指質子從分子之一原子位移至相同分子的另一原子。互變異構物的非限制性實例包括烯醇/酮、內醯胺/內醯亞胺、醯胺/醯亞胺和胺/亞胺形式。
就式(I)化合物而言存在相似的互變異構物。本發明之化合物係使用習知合成方法合成,且更具體地說使用以下所指明的一般方法合成。數種根據本發明之化合物的特定合成草案係說明於實施例中。
在一具體實例中,根據式(I)之化合物係調配成醫藥上可接受的組成物,其含有在該醫藥組成物投予一哺乳動物後有效治療所感興趣之特定疾病或病況的量之式I化合物。根據本發明之醫藥組成物可包含式(I) 化合物與醫藥上可接受載劑、稀釋劑或賦形劑組合。
關於此點,“醫藥上可接受的載劑、稀釋劑或賦形劑”包括不限於任何經美國食品藥物管理局核准可接受使用於人類或家庭動物的佐劑、載劑、賦形劑、助流劑、甜味劑、稀釋劑、防腐劑、染料/色料、增味劑、界面活性劑、濕潤劑、分散劑、懸浮劑、安定劑、等張劑、溶劑或乳化劑。
另外,“哺乳動物”包括人類和家畜諸如實驗動物和家庭寵物(例如,貓、狗、豬、牛、綿羊、山羊、馬、兔),及非家養動物例如野生動物等等。
本發明之醫藥組成物可藉由將本發明化合物與適當醫藥上可接受載劑、稀釋劑或賦形劑組合來製備,且可調配成固體、半固體、液體或氣體形式之製劑,諸如錠劑、膠囊、粉末、顆粒、軟膏、溶液、栓劑、注射劑、吸入劑、凝膠、微球和氣溶膠。投予該等醫藥組成物之典型路徑包括但不限於口服、局部、經皮、吸入、非經腸、舌下、頰內、直腸、陰道和鼻內。術語非經腸如本文所用包括皮下注射、靜脈內、肌肉內、胸骨內注射或輸注技術。本發明之醫藥組成物係經調配以使在將組成物投予病患後允許包含在其中之活性成分為生物可利用的。投予至對象或病患之組成物係採一或多劑量單元形式,其中,諸如錠劑可為單一劑量單元,及氣溶膠形式的本發明化合物之容器可包含多個劑量單元。製備該等劑型之實際方法為己知的,或熟習該項技術者顯然易見的;諸如,參見:The Science and Practice of Pharmacy,20th Edition(Philadelphia College of Pharmacy and Science,2000)。待投予的組成物在任何情況下含有治療有效量的本發明化合物,或其醫藥上可接受的鹽,用於根據本發明的技術治療所感興趣的疾病或病況。
本發明之醫藥組成物可於固體或液體的形式。在一態樣中, 該載劑為顆粒,使得該組成物為例如錠劑或粉末的形式。該載劑可為液體,且組成物為例如口服糖漿、可注射液體或氣溶膠,其可用於例如吸入性投予。當意欲用於口服投予時,該醫藥組成物較佳於固體或液體的形式,其中半固體、半液體、懸浮液和膠體的形式係包括在本文視為固體或液體的形式中。
作為口服投予之固體組成物,醫藥組成物可調配成粉末、顆粒、壓製錠劑、藥丸、膠囊、口嚼劑、薄片或類似形式。該類固體組成物典型地將含有一或多種惰性稀釋劑或可食用載劑。此外,下列之一或多者可存在:黏合劑諸如羧甲基纖維素、乙基纖維素、微晶纖維素、黃蓍膠或明膠;賦形劑諸如澱粉、乳醣或糊精,崩解劑諸如藻酸、藻酸鈉、Primogel、玉米澱粉等等;潤滑劑諸如硬脂酸鎂或Sterotex;助流劑諸如膠體二氧化矽;甜味劑諸如蔗糖或糖精;風味劑諸如薄荷、水楊酸甲酯或柳橙調味劑;及著色劑。
當藥物組成物於膠囊的形式(諸如明膠膠囊)時,除上述類型的物質以外,其可含有液體載劑諸如聚乙二醇或油。
醫藥組成物可於液體的形式,諸如:酏劑、糖漿、溶液、乳液或懸浮液。液體可用於口服投予或以注射遞送,作為二種實例。當意欲用在口服投予時,較佳組成物除了本發明之化合物之外,包含一或多種甜味劑、防腐劑、染料/著色劑和風味增進劑。在意欲以注射投予的組成物中,可包括一或多種界面活性劑、防腐劑、濕潤劑、分散劑、懸浮劑、緩衝液、穩定劑和等張劑。當意欲用於口服投予時,較佳組成物,除了本發明化合物之外,含有一或多種甜味劑、防腐劑、染料/色料和增味劑。在意欲以注射投予的組成物中,可包括一或多種界面活性劑、防腐劑、濕潤劑、分散劑、懸浮劑、緩衝劑、安定劑和等張劑。
本發明之液體醫藥組成物,無論其為溶液、懸浮液或其他類似形式,可包括下列佐劑中之一或多者:無菌稀釋劑諸如注射用水、食鹽水溶液(較佳地生理食鹽水)、林格氏液(Ringer’s solution)、等張氯化鈉、不揮發油諸如合成單或二甘油酯(其可充當溶劑或懸浮介質)、聚乙二醇、甘油、丙二醇或其他溶劑;抗細菌劑諸如苯甲醇或對羥基苯甲酸甲酯;抗氧化劑諸如抗壞血酸或亞硫酸氫鈉;螯合劑諸如乙二胺四乙酸;緩衝劑諸如乙酸鹽、檸檬酸鹽或磷酸鹽和用於調整滲壓性之試劑諸如氯化鈉或右旋糖。非經腸製劑可封裝在由玻璃或塑膠製成的安瓶、可丟棄注射器或多劑量小瓶中。生理食鹽水為較佳的佐劑。可注射的醫藥組成物較佳為無菌的。
意欲用於非經腸或口服投予之本發明液體醫藥組成物應含有致使獲得適當劑量之量的本發明化合物。
本發明之醫藥組成物可意欲用於局部投予,在該情況下載劑可適當地包括溶液、乳液、軟膏或凝膠基底。該基底例如可包含下列之一或多者:凡士林、羊毛脂、聚乙二醇、蜂蠟、礦物油,稀釋劑諸如水和醇,及乳化劑和安定劑。增稠劑可存在用於局部投予的醫藥組成物中。若意欲用於經皮投予,則該組成物可包括經皮貼片或離子電滲裝置。
本發明之醫藥組成物可意欲以例如栓劑之形式用於直腸投予,其將溶於直腸中並釋放藥物。用於直腸投予之組成物可含有油質的基底作為適當無刺激性賦形劑。該等基底包括但不限於羊毛脂、可可脂和聚乙二醇。
本發明之醫藥組成物可包括修飾固體或液體劑量單元之物理形式的各種物質。例如,組成物可包括在活性成分周圍形成塗層外殼之物質。形成塗層外殼之物質典型地為惰性的,且可選自例如糖、蟲膠和其他腸溶膜衣。或者,此活性成分可裝入明膠膠囊中。
呈固體或液體形式的本發明之醫藥組成物可包括與本發明化合物結合且因此幫助化合物遞送之試劑。可以此種能力作用的適當試劑包含單株或多株抗體、蛋白質或微脂體。
本發明之醫藥組成物可由以氣溶膠投予的劑量單元組成。術語氣溶膠係用於指示範圍從膠體性質者至由加壓包裝所組成之系統的各種系統。遞送可藉由液化或加壓氣體或藉由分配活性成分之適當幫浦系統。本發明化合物的氣溶膠可以單相、二相或三相系統遞送以便遞送活性成分。氣溶膠的遞送包含必需的容器、活化劑、閥、子容器、等等,彼等一起可形成一種套組。熟習該項技術者,無需過度的實驗即可測定較佳的氣溶膠。
本發明之醫藥組成物可藉由任何醫藥技術中所熟知的方法製備。例如,意欲以注射投予的醫藥組成物可藉由將本發明化合物與殺菌蒸餾水合併以形成溶液來製備。可添加界面活性劑以促進均勻溶液或懸浮物的形成。界面活性劑為與本發明化合物非共價相互作用以促進該化合物溶解或均勻懸浮在水性遞送系統中的化合物。
在某些具體實例中,包含式I化合物的醫藥組成物以投予時足以抑制Mnk活性且較佳對該動物具有可接受的毒性之量投予至哺乳動物。式(I)化合物的Mnk活性可由熟習該項技術者來測定,諸如以下實施例中所述。適當的濃度和劑量可藉由熟習該項技術者來測定。
本發明化合物或其醫藥上可接受的鹽係以治療有效量投予,該量將視包括所使用之特定化合物的活性;代謝穩定性及該化合物的作用時間長度;病患的年齡、體重、一般健康情形、性別和飲食;投予的模式和時間;排出的速率;藥物之組合;特殊病症或病況的嚴重性;以及進行治療的對象之各種因素而改變。
“有效量”或”治療有效量”係指本發明化合物當投予至哺乳動物(較佳為人類)時足以在哺乳動物(較佳為人類)中產生治療(如下所定義)Mnk相關的病況或疾病的量。組成“治療有效量”之本發明化合物的量將視化合物、病況及其嚴重性、投予方式、以及待治療之哺乳動物的年齡而改變,但由熟習該項技術者參考其本身知識及此揭示內容而可例行地測得。
本發明之化合物或其醫藥上可接受的鹽亦可在投予一或多種其他治療劑之同時、之前或之後投予。該組合治療包括投予包含本發明化合物和一或多種其他活性劑的單一醫藥劑量調配物,以及投予本身呈分開醫藥劑量調配物的本發明化合物和各活性劑。例如,本發明之化合物和其他活性劑可以單一口服劑量組成物(諸如錠劑或膠囊),或各藥劑以分開口服劑量調配物投予至病患。在使用分開劑量調配物時,本發明化合物和一或多種另外的活性劑基本上可同時(亦即在同一時間)投予或在分別錯開的時間(亦即連續)投予;組合療法係理解為包括所有這些方案。
在某些具體實例中,所揭示的化合物可用於抑制Mnk活性及/或可有用於分析模型系統中Mnk的傳訊活性及/或預防、治療或改善涉及Mnk之疾病、病症或病理情況有關的症狀,較佳為人類所患者。抑制Mnk活性的化合物將可用於預防、治療、改善或降低不受控制的細胞生長、增生及/或存活的疾病、不適當的細胞免疫反應、或不適當的細胞發炎反應之症狀或進展,或伴隨不受控制的細胞生長、增生及/或存活的疾病、不適當的細胞免疫反應、或不適當的細胞發炎反應的疾病,尤其是其中不受控制的細胞生長、增生及/或存活、不適當的細胞免疫反應、或不適當的細胞發炎反應係由Mnk所媒介者,諸如,例如,血液腫瘤、實體腫瘤及/或其轉移,包含白血病和骨髓增生不良症候群、惡性淋巴瘤,例如B細胞淋巴瘤、 T細胞淋巴瘤、毛細胞淋巴瘤、霍奇金氏(Hodgkins)淋巴瘤、非霍奇金氏淋巴瘤和巴氏(Burkitt)淋巴瘤、包括腦腫瘤和腦轉移癌之頭頸部腫瘤、包括非小細胞和小細胞肺腫瘤之胸部腫瘤、胃腸腫瘤、內分泌腫瘤、乳房和其他婦科腫瘤、包括腎、膀胱和前列腺腫瘤之泌尿腫瘤、皮膚腫瘤、皮膚腫瘤、和肉瘤,及/或其轉移。
此外,本發明之化合物及其醫藥組成物為用於預防及/或治療與細胞介素相關的疾病(諸如發炎疾病、過敏或其他與前發炎性細胞介素相關的病況之候選療法。例示性發炎疾病包括但不限於慢性或急性發炎,關節發炎諸如慢性發炎性關節炎、類風濕性關節炎、牛皮癬性關節炎、骨關節炎、幼年型類風濕性關節炎、Reiter氏症候群、類風濕性創傷性關節炎、風疹性關節炎、急性滑膜炎和痛風性關節炎;發炎性皮膚病諸如曬傷、乾癬、紅皮性乾癬、膿皰性乾癬、濕疹、皮膚炎、急性或慢性移植物(graft)形成、異位性皮膚炎、接觸性皮膚炎、蕁麻疹和硬皮病;胃腸道發炎諸如炎症性腸病、克隆氏症和相關症狀、潰瘍性結腸炎、結腸炎和憩室炎;腎炎、尿道炎、輸卵管炎、卵巢炎、子宮肌內膜炎、脊椎炎、全身性紅斑性狼瘡和相關病症、多發性硬化症、氣喘、腦膜炎、脊髓炎、腦脊髓炎、腦炎、靜脈炎、血栓性靜脈炎,呯吸道疾病諸如氣喘、支氣管炎、慢性阻塞性肺臟疾病(COPD)、炎性肺病和成人呯吸窘迫症侯群和過敏性鼻炎;心內膜炎、骨髓炎、風濕熱、風濕性心包炎、風濕性心內膜炎、風濕性心肌炎、風濕性二尖瓣疾病、風濕性主動脈瓣疾病、前列腺炎、前列腺膀胱炎、脊柱關節病(spondoarthropathies)僵直性脊椎炎、滑膜炎、腱鞘炎、肌炎、咽炎、風濕性多發性肌痛症、肩部腱炎或黏液嚢炎、痛風、假痛風、血管炎、選自由肉芽腫性甲狀腺炎、淋巴細胞性甲狀腺炎、侵襲性纖維性甲狀腺炎、急性甲狀腺炎所組成群組之甲狀腺的發炎疾病;橋本氏甲狀腺炎、川崎氏病、 雷諾氏現象(Raynaud's phenomenon)、休格倫氏症候群(Sjogren's syndrome)、神經發炎疾病、敗血症、結膜炎、角膜炎、虹膜睫狀體炎、視神經炎、耳炎、淋巴結炎(lymphoadenitis)、鼻咽炎(nasopaharingitis)、鼻竇炎、咽炎、扁桃體炎、喉炎、會厭炎、支氣管炎、肺炎、口腔炎、牙齦炎、食道炎、胃炎、腹膜炎、肝炎、膽結石、膽嚢炎、腎小球腎炎、古帕斯捷氏病(goodpasture's disease)、新月形腎絲球腎炎、胰腺炎、子宮肌內膜炎、子宮肌炎、子宮炎、子宮頸炎、子宮頸內膜炎、外宮頸炎、子宮旁炎、結核病、陰道炎、外陰炎、矽肺病、結節病、肺塵症、熱症(pyresis)、發炎性多發性關節病、乾癬性關節病、腸纖維化、支氣管擴張症和腸病性關節病。
雖然發炎是這些疾病的一致的致病過程,但是目前的療法僅治療疾病的症狀並未治療發炎之根本原因。本發明之組成物可用於治療及/或預防發炎性疾病及其相關的併發症和病症。
因此,某些具體實例係關於一種治療需要其之哺乳動物的MnK依賴型病況之方法,該方法包含將有效量的如上所述之醫藥組成物(亦即包含任一或多種式(I)化合物之醫藥組成物)投予至哺乳動物。
“治療(Treating)”或”治療(treatment)”如本文所用涵蓋哺乳動物(較佳為具有感興趣之疾病或病況的人類)中感興趣之疾病或病況,且包括:(i)預防疾病或病況在哺乳動物中發生,特別地,當該哺乳動物預先暴露於該病況但卻尚未被診斷出罹患該病況時;(ii)抑制疾病或病況,亦即遏止其發展;(iii)減輕疾病或病況,亦即造成疾病或病症的消退;或(iv)減輕疾病或病況所產生的症狀,亦即減輕痛苦但沒有解決根本的疾病或病症。如本文所用,術語“疾病”和“病況”可交換使用或可為不同, 因為特定的病或病況可能沒有已知的病因(所以尚未找出病因)且因此尚未辨認為疾病但僅為一不欲的病況或癥狀,其中或多或少特定癥狀已由臨床醫師鑑定出。
如上所述,蛋白質合成的失調是人類癌症中的常見事件。轉譯控制之關鍵調節劑為eIF4E,其活性為致腫瘤性之關鍵決定因素。因為eIF4E之活化涉及以MAP激酶相互作用激酶(Mnk)將關鍵絲胺酸(Ser209)特異性磷酸化,Mnk之抑制劑為治療細胞增生病症(諸如癌症)的適當候選治療劑。種類繁多的癌症(包括實體腫瘤、淋巴瘤和白血病)係可以本文所揭示的組成物和方法處理。可治療的癌症類型包括(但不限於)乳房、前列腺和大腸之腺癌;所有形式的肺支氣管上皮癌;骨髓;黑色素瘤;肝腫瘤;神經胚細胞瘤;乳頭狀瘤;胺前體攝取與脫羧細胞瘤(apudoma);迷芽瘤;鰓瘤;惡性類癌症候群;類癌性心臟病;及惡性腫瘤(諸如Walker癌、基底細胞癌、基底鱗狀細胞癌、布朗-皮西二氏上皮癌(Brown-Pearce)、導管癌、埃利希腫瘤(Ehrlich tumor)、Krebs 2、默克爾細胞癌、黏蛋白癌、非小細胞肺癌、燕麥細胞癌、乳頭狀癌、硬癌、支氣管癌、支氣管原癌、鱗狀細胞癌和移行細胞癌)。可治療的另外類型之癌症包括組織細胞病症;白血病;惡性組織細胞增生症;霍奇金氏(Hodgkin)症;免疫增生的小(immunoproliferative small);霍奇金氏淋巴瘤;瀰漫性大B細胞淋巴瘤;T細胞淋巴瘤、B細胞淋巴瘤、毛細胞淋巴瘤、巴氏(Burkitt)淋巴瘤、漿細胞瘤;網狀內皮細胞增生症;黑色素瘤;軟骨胚細胞瘤;軟骨瘤;軟骨肉瘤;纖維瘤;纖維肉瘤;巨細胞瘤;組織細胞瘤;脂瘤;脂肉瘤;間皮瘤;黏液瘤;黏液肉瘤;骨瘤;骨肉瘤;脊索瘤;顱咽管瘤;惡性胚胎瘤;缺陷瘤;間葉瘤;中腎瘤;肌肉瘤;成釉細胞瘤;齒堊質瘤;齒瘤;畸胎瘤;胸腺瘤;滋養層細胞瘤。
其他可使用本發明化合物治療的癌症包括但不限於腺瘤;膽 管瘤;膽硬脂瘤;圓柱瘤;囊腺癌;囊腺瘤;粒層細胞瘤;半陰陽胚細胞瘤;肝腫瘤;汗腺瘤;胰島細胞腫瘤;萊氏(Leydig)細胞瘤;乳頭狀瘤;支援細胞(sertoli cell)瘤;鞘細胞瘤;平滑肌瘤;平滑肌肉瘤;肌胚細胞瘤;肌瘤;肌肉瘤;橫紋肌瘤;橫紋肌肉瘤;室管膜瘤;神經節細胞瘤;神經膠質瘤;神經管胚細胞瘤;腦脊髓膜瘤;神經鞘瘤;神經胚細胞瘤;神經上皮細胞瘤;神經纖維瘤;神經瘤;副神經節瘤;非嗜鉻性副神經節瘤。
在一具體實例中,本發明化合物為治療癌症(諸如血管角化瘤;血管淋巴球增生伴嗜伊紅球增多症;血管瘤硬化;血管瘤病;球塊狀血管瘤;血管內皮瘤;肝臟血管瘤;血管外皮細胞瘤;血管肉瘤;淋巴管瘤;淋巴管肌瘤;淋巴管肉瘤;松果腺瘤;癌肉瘤;軟骨肉瘤;葉狀囊肉瘤;纖維肉瘤;血管肉瘤;平滑肌肉瘤;白血病性肉瘤;脂肪肉瘤;淋巴管肉瘤;肌肉瘤;黏液肉瘤;卵巢惡性腫瘤;橫紋肌肉瘤;肉瘤;贅瘤;神經纖維瘤;和子宮頸上皮分化不良)之候選治療劑。
在一特定具體實例中,本揭示提供治療實體腫瘤、結腸癌、直腸癌、大腸直腸癌、膀胱癌、胃癌、食道癌、頭頸部癌、骨髓增生不良症候群、腦癌、CNS癌、惡性神經膠質瘤、神經膠母細胞瘤、肝細胞癌、肝细胞惡性腫瘤、甲狀腺癌、肺癌、非小細胞肺癌、血液癌、白血病、B細胞淋巴瘤、T細胞淋巴瘤、毛細胞淋巴瘤、瀰漫性大B細胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、巴氏淋巴瘤、胰臟癌、黑色素瘤、骨髓瘤、多發性骨髓瘤、胰臟惡性腫瘤、腎細胞惡性腫瘤、腎癌、子宮頸癌、泌尿上皮癌、前列腺癌、去勢抵抗性前列腺癌、卵巢癌、乳癌或三重陰性乳癌之方法。根據該種方法,可將治療有效量的至少一種根據式(I)之化合物或其立體異構物、互變異構物或其醫藥上可接受的鹽投予至已診斷出具有細胞增生疾病(諸如癌症)的對象。或者,可將一種包含至少一種根據式(I) 之化合物或其立體異構物、互變異構物或其醫藥上可接受的鹽之醫藥組成物投予至已被診斷具有癌症的對象。
在某些具體實例中,根據本發明之化合物與其它習知癌症療法(如放射治療或外科手術)一起投予至罹癌的對象。放射療法在該項技術中為眾所周知的且包括X-射線療法,諸如加瑪輻射和放射藥物療法。
在某些具體實例中,本發明的Mnk抑制劑化合物與至少一種抗癌劑一起使用。抗癌劑包含化學治療藥。化學治療劑包括但不限於染色質功能的抑制劑、拓樸異構酶抑制劑、微管抑制藥、DNA破壞劑、抗代謝物(諸如葉酸鹽拮抗劑、嘧啶類似物、嘌呤類似物、和糖改性之類似物)、DNA合成抑制劑、DNA相互作用劑(如嵌入劑)及DNA修復抑制劑。
例示性化學治療劑包括但不限於下列群組:抗代謝劑/抗癌劑,諸如嘧啶類似物(5-氟尿嘧啶、氟尿苷(floxuridine)、卡培他濱(capecitabine)、吉西他濱(gemcitabine)和阿糖胞苷(cytarabine))及嘌呤類似物、葉酸鹽拮抗劑和相關抑制劑(巰嘌呤、硫鳥嘌呤、噴司他汀(pentostatin)和2-氯去氧腺苷(克拉屈濱(cladribine));抗增生/抗有絲分裂劑,包括天然產物諸如長春花生物鹼類(長春鹼(vinblastine)、長春新鹼(vincristine)和長春瑞濱(vinorelbine)),微管破壞劑諸如紫杉烷(taxane)(紫杉醇(paclitaxel)、多西他賽(docetaxel))、長春新鹼、長春花鹼、諾考達唑(nocodazole)、埃坡黴素(epothilones)和溫諾平(navelbine)、表鬼臼毒素(epidipodophyllotoxins)(依託泊苷(etoposide)、替尼泊苷(teniposide))、DNA損傷劑(放線菌素(actinomycin)、安吖啶(amsacrine)、蒽環類(anthracyclines)、博萊黴素(bleomycin)、白消安(busulfan)、喜樹鹼(camptothecin)、卡鉑(carboplatin)、氯芥苯丁酸(chlorambucil)、順鉑(cisplatin)、環磷醯胺(cyclophosphamide)、賽多新(Cytoxan)、更生黴素(dactinomycin)、道諾黴素(daunorubicin)、多柔比星 (doxorubicin)、表柔比星(epirubicin)、六甲三聚氰胺奧沙利鉑(hexamelamineoxaliplatin)、異環磷醯胺(iphosphamide)、黴法蘭(melphalan)、二氯甲基二乙胺(merchlorehtamine)、絲裂黴素(mitomycin)、米托蒽醌(mitoxantrone)、亞硝脲、普卡黴素(plicamycin)、丙卡巴肼(procarbazine)、泰素(taxol)、泰索帝(taxotere)、替莫唑胺(temozolamide)、替尼泊苷(teniposide)、三伸乙基硫代磷醯胺和依託泊苷(VP16));抗生素諸如更生黴素(放線菌素D)、道諾黴素(daunorubicin)、多柔比星(doxorubicin)(阿德力黴素(adriamycin))、伊達比星(idarubicin)、蒽環類、米托蒽醌(mitoxantrone)、博來黴素、普卡黴素(光輝黴素(mithramycin))和絲裂黴素;酵素(L-天冬醯胺酶,其係全身性代謝L-天冬醯胺並剝奪不具有合成自己的天冬醯胺酸之能力的細胞);抗血小板劑;抗增生/抗有絲分裂烷化劑諸如氮芥類(甲基二(氯乙基)胺、環磷醯胺及類似物、黴法蘭、氯芥苯丁酸)、乙烯亞胺和甲基三聚氰胺(六甲嘧胺和噻替派(thiotepa)、磺酸烷酯-白消安(busulfan)、亞硝基脲(卡莫司汀(carmustine)(BCNU)及類似物、鏈脲佐菌素(streptozocin)、特拉辛(trazenes)-達卡巴(dacarbazinine)(DTIC);抗增生/抗有絲分裂抗代謝物諸如葉酸類似物(胺甲喋呤(methotrexate));鉑配位錯合物(順鉑、卡鉑)、丙卡巴肼)、羥基脲、米托坦(mitotane)、胺魯米特(aminoglutethimide);激素、激素類似物(諸如雌激素、他莫昔芬(tamoxifen)、戈舍瑞林(goserelin)、比卡魯胺(bicalutamide)及尼魯米特(nilutamide))及芳香酶抑制劑(來曲唑(letrozole)、阿那曲唑(anastrozole);抗凝劑(肝素、合成肝素鹽和其他凝血酶抑制劑);纖維蛋白溶解劑(諸如組織纖維溶酶原活化劑、鏈球菌激酶和尿激酶)、阿斯匹靈(aspirin)、雙嘧達莫(dipyridamole)、噻氯匹啶(ticlopidine)、氯吡格雷(clopidogrel)、阿昔單抗(abciximab);antimigratory agents;抗分泌劑(antisecretory agents)(布雷非德菌素(breveldin));免疫抑制劑(環孢黴素(cyclosporine)、他克莫司 (tacrolimus)(FK-506)、西羅莫司(sirolimus)(雷帕黴素(rapamycin)、硫唑嘌呤(azathioprine)、黴酚酸酯(mycophenolate mofetil));抗血管生成化合物(TNP-470、金雀異黃酮(genistein)和生長因子抑制劑(血管內皮生長因子(VEGF)抑制劑、纖維母細胞生長因子(FGF)抑制劑);血管收縮素受體阻斷劑;一氧化氮供體;反義寡核苷酸;抗體(曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab));嵌合抗原受體;細胞週期抑制劑和分化誘導劑(維甲酸tretinoin));mTOR抑制劑、拓撲異構酶抑制劑(多柔比星(阿德力黴素)、安吖啶、喜樹鹼、道諾黴素、更生黴素、恩尼泊苷(eniposide)、表柔比星、依託泊苷、伊達比星(idarubicin)伊立替康(irinotecan)(CPT-11)和米托蒽醌、拓撲替康(topotecan)、伊立替康(irinotecan))、皮質類固醇(皮質酮、地塞米松(dexamethasone)、氫皮質酮、甲基培尼皮質醇(methylpednisolone)、普賴松(prednisone)及潑尼松龍(prenisolone));長因子訊息傳導激酶抑制劑;粒線體功能障礙誘發劑,毒素諸如霍亂毒素、蓖麻毒蛋白、假單胞菌外毒素、百日咳博德氏桿菌(Bordetella pertussis)腺苷酸環化酶毒素或白喉毒素(diphtheria toxin)、和凋亡蛋白酶(caspase)活化劑;及染色質破壞劑。
在某些具體實例中,根據本發明的Mnk抑制劑係以相同調配物或以分開的調配物同時使用,或與另外的藥劑連續使用作為組合治療方案的一部分。
根據式(I)之Mnk抑制劑,包括彼等的對應鹽和式(I)化合物之醫藥組成物,亦有效作為用於治療或預防病患(尤其是人類)之細胞介素媒介的病症(諸如發炎)之治療劑。在一具體實例中,根據本發明之化合物或組成物特別可用於治療或預防選自由下列所組成群組的疾病:慢性或急性發炎、慢性炎性關節炎、類風濕性關節炎、牛皮癬、COPD、炎症性腸病、敗血性休克、克隆氏症、潰瘍性大腸炎、多發性硬化症和氣喘。
在本發明之另一態樣中,本發明化合物或本發明化合物之醫藥上可接受的調配物係提供作為Mnk活性的抑制劑。該抑制係藉由使表現Mnk的細胞與化合物或一種醫藥上可接受的調配物接觸以降低或抑制Mnk活性來達成,對需要其的哺乳動物提供Mnk依賴型病況的治療效力。
根據式(I)之化合物或式(I)化合物之組成物的治療有效劑量一般範圍將從約1到2000mg/日,從約10到約1000mg/日,從約10到約500mg/日,從約10到約250mg/日,從約10到約100mg/日,或從約10到約50mg/日。該治療有效劑量可以單或多劑量投予。然而,應瞭解本發明之化合物用於任何特定病患的具體劑量將視各種因素諸如年齡、性別、體重、一般健康情形、飲食、待治療病患的個別反應、投予時間、待治療疾病的嚴重性、施用之特定化合物的活性、劑型、施用模式和伴隨用藥而定。某一情形之治療有效量將藉由例行實驗立即測定,且為在一般臨床醫師或醫生的技巧與判斷範圍內的。在任何情況下,該化合物或組成物將以允許治療有效量根據病患的獨特病況遞送之劑量和方式投予。
方法1:
中間物IV之形成,其中X=鹵素或其他脫離基,諸如-OTf、-OTs或-OMs,係藉由在酸性條件下將化合物II暴露於酮III或酮等價物諸如IIIa、IIIb或IIIc完成。更具體地說,將II(其中X為Cl或Br)暴露於在1,4-二烷和濃硫酸中的酮III並加熱產生中間物IV。
式I化合物係經由Buchwald-Hartwig偶合、Ullmann-型偶合、或親核芳族取代合成。因此,使中間物IV,其中X=鹵素或其他脫離基,諸如-OTf、-OTs或-OMs,與式V或Va之化合物在適合於偶合、或親核芳族取代之條件下接觸產生式I或Ia化合物。可將Ia去保護而產生I。
方法2:
在一替代方法中,中間物IV之脫離基X,其中X=鹵素或其他脫離基諸如-OTf、-OTs或-OMs,可在類似於上述合成I的條件下用適當的N親核劑置換以提供中間物V或經保護的中間物Va。可將Va去保護 而產生V。
式I或Ia化合物係藉由在Buchwald-Hartwig偶合、Ullmann-型偶合、或親核芳族取代的條件下使中間物V與嘧啶化合物VI或VIa接觸而容易地合成,其中X=鹵素或其他脫離基諸如-OTf、-OTs或-OMs。可將Ia去保護而產生I。
用於式I化合物之更具體的合成方法闡述於下。應理解的是若在合成中間物期間使用保護基團(“P”),或者若式I化合物含有一或多個保護基團,則藉由化學技術中已知的方法移除該等保護基。
也應理解的是可在合成的合適階段經由化學技術中已知的習用方法供給式I化合物的R1、R2或R3基團。
為了說明而非限制之目的提供下列實施例。
將N-(6-胺基-5-甲基嘧啶-4-基)環丙烷甲醯胺(1,0.82g,4.29mmol)、6-溴-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(2,1.40g,4.29mmol)、和碳酸銫(2.79g,8.58mmol)在1,4-二烷(20mL)中的懸浮液用氬氣沖洗15min。將9,9-二甲基-4,5-雙(二苯膦基)二苯并哌喃(0.12g,0.21mmol)、2-(二環己膦基)-2',4',6'-三異丙基聯苯(0.10g,0.21mmol)、參(亞苄丙酮)二鈀(0.20g,0.21mmol)和乙酸鈀(0.049g,0.21mmol)加至此混合物。將混合物沖洗另5min和將小瓶密封。將反應在100℃下攪拌16h。完成後,將反應塊用在二氯甲烷中之5%甲醇(150mL)稀釋並通過矽藻土床。將濾液濃縮並將粗製產物藉由使用3-5%甲醇在二氯甲烷中之combiflash管柱層析法純化以提供呈黃色固體之N-(6-((1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺基)-5-甲基嘧啶-4-基)環丙烷甲醯胺(3)。產率:0.96g,51%;MS(ESI)m/z 438.1[M+1]+。
將氫氧化鉀(1.22g,21.71mmol)加至N-(6-((1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺基)-5-甲基嘧啶-4-基)環丙烷甲醯胺(3,0.95g,2.17mmol)在四氫呋喃、乙醇和水(1:1:1,30mL)中之溶液。將反應物在60℃下攪拌18h。完成後,將反應混合物冷卻至室溫並用在二氯甲烷中之10%甲醇萃取(3×50mL)。將合併的有機層用水、鹽水洗滌,經無水硫酸鈉乾燥,過濾並在減壓下濃縮。藉由使用在二氯甲烷中之7-8%甲醇的combiflash管柱層析法純化粗製化合物以提供呈灰白色固體之6-((6-胺基-5-甲基嘧啶-4-基)胺基)-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(rac-1F)。產率:555mg,69%;MS(ESI)m/z 370.4[M+1]+。
消旋化合物6-((6-胺基-5-甲基嘧啶-4-基)胺基)-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(化合物編號1F)之掌性純化係藉由使用掌性pak-IA(250×21mm,5μm)管柱之SFC掌性HPLC使用15%甲醇/二氧化碳的等度混合物進行。Peak-1:Rt=17min,ee=98.16%;1H NMR(400MHz,DMSO-d6)δ 9.82(bs,1H),8.48(s,1H),8.12(s,1H),7.98(s,1H),6.50(s,2H),3.33-3.30(m,1H),3.02-2.93(m,1H),2.81-2.79(m,1H),2.46-2.45(m,1H),2.44(s,3H),2.21(s,3H),1.98(s,3H),1.93-1.91(m,2H),1.72-1.68(m,1H),1.49-1.47(m,1H)。Peak-2:Rt=19.8min,ee=96.58%;1H NMR(400MHz,DMSO-d6)δ 9.87(bs,1H),8.48(s,1H),8.11(s,1H),7.98(s,1H),6.48(s,2H),3.33-3.30(m,1H),2.99-2.93(m,1H),2.81-2.79(m, 1H),2.49-2.48(m,1H),2.44(s,3H),2.21(s,3H),1.98(s,3H),1.93-1.91(m,2H),1.71-1.68(m,1H),1.47(d,J=12Hz,1H)。
將5-溴-3-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺(1,10.0g,43.2 mmol)、3-側氧六氫吡啶-1-甲酸三級丁酯(2,10.31g,51.8mmol)和在1,4-二烷(100mL)中之4M氯化氫裝入密封管。將反應混合物在110℃下加熱16h。完成後,將反應混合物在減壓下蒸發並用乙醚洗滌固體殘餘物以提供呈淡黃色固體之6-溴-8-甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮鹽酸鹽(3)。產量:20.0g,93%;MS(ESI)m/z 312.27[M+1]+。
在室溫下將N,N-二異丙基乙胺(9.29g,72.04mmol)和碘甲烷(4.50g,31.7mmol)加至6-溴-8-甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮鹽酸鹽(3,10.0g,28.8mmol)在N,N-二甲基甲醯胺(75mL)中之溶液。將反應混合物在室溫下攪拌3h。然後將反應混合物用冰水淬滅並藉由過濾分離固體沈澱物。將固體用乙醚洗滌並在減壓下乾燥以提供呈淺棕色固體之6-溴-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(4)。產量:5.3g,57%;MS(ESI)m/z 326.2[M+1]+。
在氬氛圍下將胺甲酸三級丁酯(7.01g,59.0mmol)和碳酸銫(30.0g,92.0mmol)加至在密封管中的6-溴-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(4,15.0g,46.1mmol)在1,4-二烷(150mL)中之溶液。將反應混合物用氬氣沖洗15min接著添加9,9-二甲基-4,5-雙(二苯膦基)二苯并哌喃(2.66g,4.6mmol)和參(亞苄丙酮)二鈀(4.1g,4.60mmol)。用氬氣將混合物沖洗另5min並將反應混合物在100℃加熱16h。完成後,將反應塊在真空下濃縮以產生粗製化合物,其藉由矽膠管柱層析法(在二氯甲烷中之3-5%甲醇)純化以提供呈深棕色固體之(1',8-二甲基-1,5-二側氧 -1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺甲酸三級丁酯(5),其不需要進一步純化即可用於下一步驟。產率:9.0g,54%;MS(ESI)m/z 363.14[M+1]+。
消旋化合物(1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺甲酸三級丁酯(5,8.0g)藉由使用掌性pak-IG管柱(250×21mm,5μm)之掌性-SFC,使用等度梯度之在甲醇/二氧化碳(40:60)中的0.2%三乙胺純化。純化之後分離在Rt=8.0min的峰-1(2.4g,ee=99.82%)和分離在Rt=12.8min的peak-2(3.4g,ee=99.60%)。沒有指定峰1和峰-2的絕對立體化學。為了便於說明,Peak-1係隨機指定為(R)-(1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺甲酸三級丁酯(5A)和Peak-2係隨機指定為(S)-(1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺甲酸三級丁酯(5B)
將在1,4-二烷(20mL)中之4M氯化氫加至(R)-(1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺甲酸三級丁酯(5A,2.40g,6.6mmol)在二氯甲烷(20mL)中之溶液。將反應混合物在室溫下攪拌3h。完成後,將反應塊在真空下濃縮並將粗製化合物懸浮於碳酸氫鈉的飽和溶液中。用二氯甲烷萃取水層;將有機層經硫酸鈉乾燥,過濾和濃縮。將殘餘物用乙醚洗滌以產生呈淺棕色固體之所需化合物 (R)-6-胺基-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(6A)。產率:1.7g,98%;MS(ESI)m/z 263.3[M+1]+
將4-胺基-6-氯嘧啶-5-甲腈(7,1.0g,6.4mmol)和對甲苯磺酸(1.10g,6.4mmol)加至(R)-6-胺基-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(6A,1.70g,6.4mmol)在三級丁醇(25mL)中之溶液。將反應混合物在密封管中於120℃下加熱15h。然後濃縮反應混合物並將殘餘物溶解於20%異丙醇/氯仿(100mL)中。將有機層用飽和碳酸氫鈉溶液之溶液洗滌,經硫酸鈉乾燥,過濾和濃縮。將殘餘物以使用combiflash之矽膠管柱層析法(在二氯甲烷中之5-7%甲醇)純化以提供呈白色固體之(R)-4-胺基-6-((1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺基)嘧啶-5-甲腈(化合物編號2Fa)。產率:0.61g,25%。MS(ESI)m/z 381.13[M+1]+;ee=97.94%;Rt=19.96min,Chiralpak IC(4.6×250mm,5μm)使用等度梯度的甲醇/二氧化碳(40:60)。1H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),8.58(s,1H),8.49(s,1H),8.34(s,1H),7.79(bs,2H),3.31-3.28(m,1H),2.98-2.94(m,1H),2.82-2.81(m,1H),2.45(s,3H),2.23(s,3H),1.99-1.94(m,2H),1.72-1.70(m,1H),1.50(d,J=12.76Hz,1H)。
將在1,4-二烷(30mL)中之4M氯化氫加至(S)-(1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺甲酸三級丁酯(5B,3.40g,9.3mmol)在二氯甲烷(30mL)中之溶液。將反應混合物在室溫下攪拌3h。完成後,將反應塊在真空下濃縮並將粗製化合物懸 浮於碳酸氫鈉之飽和溶液中。用二氯甲烷萃取水層;將有機層經硫酸鈉乾燥和濃縮。將殘餘物用乙醚洗滌以產生呈淺棕色固體之所需化合物(S)-6-胺基-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(6B)。產率:2.1g,85%;MS(ESI)m/z 263.3[M+1]+。
將4-胺基-6-氯嘧啶-5-甲腈(7,1.17g,7.6mmol)和對甲苯磺酸(1.30g,7.6mmol)加至(S)-6-胺基-1',8-二甲基-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-1,5-二酮(6B,2.0g,7.6mmol)在三級丁醇(30mL)中之溶液。將反應混合物在密封管中於120℃下加熱15h。然後將反應混合物濃縮並將殘餘物溶解於20%異丙醇/氯仿(100mL)中。將有機層用飽和碳酸氫鈉溶液之溶液洗滌,經硫酸鈉乾燥,過濾和濃縮。將殘餘物以使用combiflash之矽膠管柱層析法(在二氯甲烷中之5-7%甲醇)純化以提供呈白色固體之(S)-4-胺基-6-((1',8-二甲基-1,5-二側氧-1,5-二氫-2H-螺[咪唑并[1,5-a]吡啶-3,3'-六氫吡啶]-6-基)胺基)嘧啶-5-甲腈(化合物編號2Fb)。產率:0.49g,18%。MS(ESI)m/z 381.17[M+1]+;ee=95.58%,Rt=8.89min,Chiralpak IC(4.6×250mm,5μm)使用等度梯度之甲醇/二氧化碳(40:60)。1H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),8.58(s,1H),8.49(s,1H),8.34(s,1H),7.79(bs,2H),3.29-3.28(m,1H),2.94-2.91(m,1H),2.81-2.80(m,1H),2.45(s,3H),2.22(s,3H),1.93-1.88(m,2H),1.72-1.70(m,1H),1.49(d,J=12.76Hz,1H)。
利用適當反應物,可根據一般方法1或2製造下列化合物。
化合物4a可根據美國專利第9,382,248號之實施例223中所述的程序來製備。
使用CisBio peIF4E HTRF®分析套組(CisBio,目錄編號64EF4PEG)分析磷酸化eIF4E。將於適當的生長培養基(90μL)中之細胞鋪在96-孔組織培養處理板上。用三倍連續稀釋的方式將化合物(10X)稀釋在細胞培養基中並加至細胞。將該等板在37℃下培養2小時。藉由抽吸上澄液或藉由輕敲該培養板把細胞上澄液小心移除。立即添加50μL補充細胞溶解緩衝液(1X)並在振動下於室溫培育至少30分鐘。藉由上下抽吸均質化後,將16μL細胞溶解物從96-孔的細胞培養板轉移至384-孔的小容量白色板中。製備並添加在檢測緩衝液中之4μL預先混合的抗體溶液(體積/體積)。將板用板密封器覆蓋並在室溫下培養過夜。用Wallac Victor2讀取兩個不同波長的螢光發射(665nm和620nm)。將發射比轉換成抑制百分比並輸入GraphPad Prism軟體中。使用20μM到0.1nM的濃度範圍(12-點曲線)計算抑制酵素活性達50%所需的化合物濃度(IC50)。使用GraphPad Prism 5中可獲得的非線性迴規模式測定IC50值。
這些分析的結果闡述於下表1中。為此目的,小於0.001 μM之IC50值標記為“+++”,從0.001至0.01μM標記為“++”,大於0.01μM標 記為“+”(NA意指“無法得到”)。
在T細胞受體(TCR)傳訊之活化時,T細胞增生,產生細胞介素(諸如,IL-2)和誘發免疫檢查點受體之表現。程序性死亡-1(PD-1)為在活化的T細胞表面以及髓樣細胞上表現的抑制性檢查點受體。PD-1之配體,程序性死亡配體1(PD-L1、B7-H1/CD274)不是由T細胞或正常上皮細胞表現,而是由抗原呈現細胞表現及在幾種癌症中過表現。PD-1與PD-L1的相互作用導致對T細胞之抗增生作用及最終T細胞衰竭的增加和細胞凋亡。為了研究MNK在活化T細胞和腫瘤細胞中的作用,檢查MNK抑制劑對免疫檢查點控制之分子的影響。
為了檢查MNK抑制劑對PD-1表現的影響,使用Jurkat細胞(Clone E6.1,ATCC,轉化T細胞),其當經由T細胞受體(TCR)傳訊活化時表現PD-1。簡而言之,將Jurkat細胞在含有1X Pen/Strep的1X RPMI和10% FBS中生長,然後在1μg/mL PHA(Sigma)和50ng/mL PMA(Sigma)的存在下活化約3 x 106個Jurkat細胞。將測試細胞以各種濃度的MNK抑制劑(0、0.01、0.1、1、3和10μM)同時處理。48小時後,收穫培養物上清液,並使用人類IL-2ELISA DuoSet(R&D Systems,Minneapolis,MN)經由夾心ELISA檢測IL-2的存在。Jurkat細胞上的PD-1含量藉由以人類FcR段(block)培養,然後在4℃下與別藻藍蛋白(APC)共軛的抗PD-1抗體(每100μl體積的測試為5μl,Biolegend,San Diego,CA)接觸25分鐘,而不洗滌細胞,添加可固定的死細胞染色劑(1:10,000;BD Biosciences,San Jose,CA),並在4℃下進一步培養10分鐘。將細胞用流動緩衝液洗滌兩次,及最後將細胞在4℃用固定緩衝液固定15分鐘。固定後,將細胞用流動緩衝液洗滌 兩次並再懸浮於流動緩衝液中,且使用BD Accuri C6流式細胞儀評估螢光。使用C6細胞計數器軟體(BD Biosciences,San Jose,CA)或Attune Nxt細胞計數器(Invitrogen,Carlsbad,CA)分析數據。
相較於未誘發的細胞(Unstim),用PHA和PMA活化Jurkat T細胞分別誘發在約25-30%之經刺激的Jurkat細胞的細胞表面上之PD-1的表現及誘發IL-2細胞介素產生之1000倍增加。用MNK抑制劑處理PHA/PMA活化的Jurkat T細胞導致免疫抑制性受體PD-1之表現的濃度依賴性減少,相較於對照組,在最高濃度下高達50%減少。此外,此PD-1的減少不是由於Jurkat T細胞活化本身中之段(block),因為如以IL-2含量測量,藉由MNK抑制劑之MNK抑制作用不改變細胞介素產生。最後,藉由各種不同的MNK抑制劑之MNK抑制作用對細胞活力沒有影響。事實上,在Jurkat T細胞分析中各種不同的MNK抑制劑顯示下調免疫檢查點抑制劑而不影響細胞活力的能力。這些分析的結果闡述於下表1中。為此目的,PD-1陽性細胞(10μM)的抑制百分比大於50%標記為“+++”,從10%至50%標記為“++”,和小於10%標記為“+”(NA意指“無法得到”)。
溶解度,溶質溶解在溶劑中以產生均勻系統的現像,為化合物在體循環中達到所要(預期的)藥理反應之濃度的重要參數之一。具有良好水溶解度的化合物是令人滿意的,因為彼等由於彼等在投予至對像後具有高溶解而具有良好的體內生體可用率。具有良好水溶解度的化合物也有助於調配物的展開、調配物的製造和調配物的穩定性。
在96孔板中,使用SPE-96板式乾燥器(上流速=50L/min,溫度=60℃,下流速=20L/min,溫度=80℃)在加熱氮氣流下乾燥各化 合物的10mM DMSO原液(50-100uL)。在DMSO完全除去後,將剩餘材料溶解在包括去離子水、禁食狀態模擬腸液(FaSSIF,pH 6.5)和禁食狀態模擬胃液(FaSSGF,pH 1.6)之測試溶劑中。在有及沒有添加1當量TFA的條件下進行評估製備成游離鹼之化合物。水溶液的理論最大濃度為10mM。將各孔加蓋並在室溫或37℃下培養18小時。在培養期間溶液的混合係藉由以750rpm搖動該板或加入StirStix(stainless steel capillaries)並使用旋轉磁性滾筒攪拌器攪拌混合物來進行。培養期後,過濾每孔的等分試樣。藉由HPLC-UV與已知濃度的標準品比較之後,定量所有樣品的溶解度。
水溶解度之結果係闡述於下表1中。
本發明人出乎意料地發現:Mnk抑制劑化合物的溶解速率可因下列而顯著改良超過比較化合物4a:(i)以3-或4-六氫吡啶取代化合物中的咪唑并吡啶;及(ii)用低碳烷基、鹵素或氰基取代化合物中的嘧啶。這些取代或結構特徵誘發分子中的掌性。
本發明化合物的水溶解度之改良在低pH環境中,例如在胃液或胃液中,尤其顯著。例如,如表1中所示,化合物3D、3K、3L、3X、3Y、rac-1F、1Fa、1Fb、rac-2F、2Fa和2Fb在具有1.6之pH值的禁食狀態模擬胃液(FaSSGF)呈現極佳的溶解度。
重要地,除了改良水溶解度之外,3-和4-經六氫吡啶取代之化合物也以彼等抑制pEIF4E傳訊的能力之形式保留彼等的抗癌效力。在一 些情況下,抗癌效力以這些3-和4-六氫吡啶經取代之化合物抑制PD-1的能力進一步表現,如於表1中可見。
上述各種具體實例可組合以提供其他具體實例。所有的美國專利、美國專利申請公開案、美國專利申請案、外國專利、外國專利申請案和與本說明書所引用及/或列於申請資料表中的非專利刊物係以全文引用的方式併入本文中。若需要可採用各種專利、申請案和公開案的觀念來修改具體實例的態樣,以再提供其他具體實例。
鑑於上述詳細說明,可對該具體實例進行此等和其他改變。一般而言,在下列申請專利範中,所使用的術語不應解釋為將申請專利範圍限制於本說明書和申請專利範圍中所揭示的特定具體實例,而應解釋為包括所有可能的具體實例以及該等申請專利範圍的等同物之全部範圍。因此,該等申請專利範圍並不受限於該揭示內容。
Claims (8)
- 根據申請專利範圍第1至4項中任一項之化合物或其立體異構物、互變異構物或醫藥上可接受的鹽,其中該化合物之醫藥上可接受的鹽為選自由下列所組成之群組的有機或無機酸鹽:乙酸鹽,甲 磺酸鹽,硫酸鹽,檸檬酸鹽,草酸鹽,鹽酸鹽,二鹽酸鹽,異硫代硫酸鹽,乳酸鹽和月桂酸鹽。
- 一種醫藥組成物,其包含(i)治療有效量之至少一種根據申請專利範圍第1至4項中任一項之化合物或其立體異構物、互變異構物或醫藥上可接受的鹽;(ii)與一種醫藥上可接受的載劑、稀釋劑或賦形劑組合。
- 一種申請專利範圍第1至4項中任一項之化合物或其立體異構物、互變異構物或醫藥上可接受的鹽用於製備治療需要其之哺乳動物的Mnk依賴型病況的藥物之用途,其中該Mnk依賴型病況為癌症或發炎。
- 一種申請專利範圍第1至4項中任一項之化合物或其立體異構物、互變異構物或醫藥上可接受的鹽用於製備藥物之用途,該藥物係用於治療需要其之哺乳動物的實體腫瘤、大腸直腸癌、膀胱癌、胃癌、食道癌、頭頸部癌、CNS癌、惡性神經膠質瘤、神經膠母細胞瘤、肝細胞癌、甲狀腺癌、肺癌、非小細胞肺癌、小細胞肺癌、黑色素瘤、骨髓瘤、胰腺癌、胰臟惡性腫瘤、腎細胞惡性腫瘤、子宮頸癌、泌尿上皮癌、前列腺癌、去勢抵抗性前列腺癌、卵巢癌、乳癌、三重陰性乳癌、白血病、霍奇金氏(Hodgkins)淋巴瘤、非霍奇金氏淋巴瘤、B細胞淋巴瘤、T細胞淋巴瘤、毛細胞淋巴瘤、瀰漫性大B細胞淋巴瘤、巴氏(Burkitt)淋巴瘤、多發性骨髓瘤、或骨髓增生不良症候群。
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AU2018220840A1 (en) | 2017-02-14 | 2019-09-19 | Effector Therapeutics, Inc. | Piperidine-substituted Mnk inhibitors and methods related thereto |
MX2021004763A (es) | 2018-10-24 | 2021-06-08 | Effector Therapeutics Inc | Formas cristalinas de inhibidores de quinasa de interaccion con map quinasa (mnk). |
CN111484494B (zh) * | 2019-01-29 | 2022-09-13 | 诺沃斯达药业(上海)有限公司 | 抑制mnk1和mnk2的多环化合物 |
CN114728966B (zh) | 2019-11-18 | 2023-08-18 | 成都嘉葆药银医药科技有限公司 | 作为mnk抑制剂的吡咯并三嗪类化合物 |
EP4200296A1 (en) * | 2020-08-20 | 2023-06-28 | Hepagene Therapeutics (HK) Limited | Mnk inhibitors |
AU2022271540A1 (en) * | 2021-05-08 | 2023-11-16 | Jumbo Drug Bank Co., Ltd. | Salt form of pyrrolotriazine compound, crystal form thereof, and preparation method therefor |
CN114853756B (zh) * | 2022-03-31 | 2023-03-28 | 武汉九州钰民医药科技有限公司 | 化合物Tomivosertib的制备工艺 |
CN114736205B (zh) * | 2022-03-31 | 2023-03-03 | 武汉九州钰民医药科技有限公司 | 化合物Tomivosertib的制备方法 |
WO2024017229A1 (zh) * | 2022-07-19 | 2024-01-25 | 成都嘉葆药银医药科技有限公司 | 一种吡咯并三嗪类化合物在制备抗肿瘤药物中的应用 |
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CA3053493A1 (en) | 2018-08-23 |
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