TWI838350B - 抗癌劑 - Google Patents
抗癌劑 Download PDFInfo
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- TWI838350B TWI838350B TW107139170A TW107139170A TWI838350B TW I838350 B TWI838350 B TW I838350B TW 107139170 A TW107139170 A TW 107139170A TW 107139170 A TW107139170 A TW 107139170A TW I838350 B TWI838350 B TW I838350B
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Abstract
本文揭示一種醫療方法,其係投與調控C-C趨化介素受體第4型(CCR4)之化合物,供治療艾伯斯坦-巴爾病毒(Epstein Barr virus)(EBV)陽性癌症與惡性病。
Description
本文特別提供一種利用調控C-C趨化介素受體第4型(CCR4)之化合物或其醫藥上可接受之鹽用以治療或管控某些癌症與惡性病之方法。例如,本文提供之方法係由CCR4調控劑單獨投藥或與一或多種抗癌劑組合投藥,來治療癌症與惡性病。此外,本文提供用於此等方法之醫藥組成物。
癌症為全世界重大的健康問題;單美國一地,2005年就有約570,000個癌症相關死亡例。參見例如,Jemal等人,CA Cancer J.Clin.55(1):10-30(2005)。癌症發生率隨著一般人口年齡及新型態癌症發展而持續攀升中。
艾伯斯坦-巴爾病毒(Epstein-Barr virus)(EBV)為一種普遍存在的皰疹病毒,最早被發現是勃奇氏淋巴瘤(Burkitt’s lymphoma)的主因。後來發現EBV普及性極高,感染超過95%成人族群。感染時通常沒有症狀,但EBV可為傳染性單核白血球增多症的原因。EBV-陽性亦與各種不同癌症有關,包括各種不同淋巴瘤、鼻咽癌(NPC)、 與胃癌(Hjalgrim,H.,Friborg,J.and Melbye,M.2007.Human Herpesviruses)。
許多年來,研究者已試圖加強免疫反應來對抗癌症。雖然早期介入的成功效力有限,但近來使用抗體如抗-CTLA-4與抗-PD-1/PD-L1,亦已知為免疫檢查點抑制劑(CPI))已在多種類型癌症中達成顯著抗腫瘤免疫反應(Pardoll,2012;Sharma,2015;Shin,2015)。
腫瘤可以適應天然免疫壓制機轉並從其中受益,來規避免疫系統的檢測(Hanahan,2011;Dunn,2002)。癌症為此採行的一種途徑即為募集及暗中破壞壓制免疫之稱為調節性T細胞(Treg)的淋巴球。雖然此等壓制性細胞有助於保持針對外來抗原(如:病毒、共生細菌、與檢查及限制自體免疫疾病之外來體)之免疫反應,但Treg亦可干預免疫監控,讓腫瘤逃避被免疫系統根除(Chaudrhy,2013;Nishikawa,2014;Tanaka,2017)。
許多人類癌症研究已發現,Treg累積在腫瘤中及周圍,其可阻止或抑制細胞毒性(效應子)T細胞(Teff)殺死腫瘤細胞(Fridman,2017)。腫瘤中Treg數上升或Teff對Treg之比例下降,係與許多種癌症患者之預後不佳有關,包括黑色素瘤、肺癌與乳癌(Fridman,2011;Gobert,2009;Bates,2006;Curiel,2004)。此等數據已啟動研究探討遏制Treg細胞活性,試圖引發或擴增醫療性抗腫瘤免疫反應。一種靶向Treg細胞之療法藉由排除其對本來有效之抗腫瘤反應之壓制效應時,即可能有助於根除腫瘤。
壓制Treg細胞之策略包括調控細胞介素訊號傳導、利用抗體耗減、或使用細胞毒性劑治療。然而,此等策略經常影響其他需要強力免疫反應之細胞族群,因干擾健康組織中Treg細胞之正常角色而引發副作用(Kurose,2015)。另一種策略為壓制Treg募集至腫瘤微環境(TME)。
白血球之全身性循環為可以進行免疫監控之重要因子。趨化介素為小型分泌蛋白質,其形成梯度,依組織特異性方式從循環中吸引白血球次細胞族群(Solari,2015)。為了可以募集至各種不同組織,Treg表現許多種趨化介素受體,但以C-C趨化介素受體第4型(CCR4)為主(Lellem,2001;Hirahara,2006)。CCR4為G-蛋白質偶聯受體(GPCR),其選擇性結合趨化介素配體CCL17(TARC)與CCL22(MDC),此配體結合性在募集Treg及其在TME中之累積上扮演關鍵角色(Curiel,2004;Gobert,2009;Li,2013)。因此,CCR4可能為選擇性阻斷Treg細胞募集至TME中之理想標靶。CCR4拮抗作用可能可以使免疫系統引發更強力之抗腫瘤反應,特別當與其他免疫調控劑組合時。
EBV潛伏蛋白質LMP1可能造成CCL17與CCL22之表現(Nakayama等人,J Virol,2004;Takegawa等人,Cancer Sci 2008)。EBV-相關胃癌中之Treg相較於EBV-陰性胃癌中提高(Zhang等人,Sci.Reports,2015),並在EBV+胃癌中與CCL22產量升高呈相關性。鼻咽癌係與 EBV相關(Neparidze,N.與Lacy,J.2014.Malignancies associated with Epstein-Barr Virus:Pathobiology,Clinical Features,and Evolving Treatments.Clinical advances in hematology & oncology:H&O.12,6(2014),358-71),且在NPC中之Treg數量隨著階段演進而增加(Ren等人,Clinical Onc and Cancer Res,2011)。
一項態樣中,本文提供一種使用如式(I)、(II)、(III)、(IV)、或(V)化合物或其鹽、溶劑合物、或水合物治療或管控EBV-相關癌症之方法。
具體實施例中,本文所揭示方法所使用之化合物揭示於Beck等人於2017年7月28日申請之美國專利申請案15/662,861(例如,式I至VII化合物),其等全文已以引用之方式併入本文中用於所有目的。一項具體實施例中,該等化合物具有根據本文式I之化學結構。
具體實施例中,本文所揭示方法所使用之化合物揭示於Beck等人於2017年9月8日申請之美國專利申請案15/700,040(例如,式I至X化合物),其等全文已以引用之方式併入本文中用於所有目的。具體實施例中,該等化合物具有根據本文式II之化學結構。
具體實施例中,本文所揭示方法所使用之化合物揭示於Beck等人於2017年4月4日申請之美國專利申請案62/481,515(例如,式I至VI化合物),其等全文已以引用之方式併入本文中用於所有目的。具體實施例 中,該等化合物具有根據本文式III之化學結構。
具體實施例中,本文所揭示方法所使用之化合物揭示於Robles-Resendiz等人於2018年1月26日申請之美國專利申請案62/622,774(例如,式I至VII化合物),其等全文已以引用之方式併入本文中用於所有目的。具體實施例中,該等化合物具有根據本文式IV之化學結構。
具體實施例中,本文所揭示方法所使用之化合物揭示於Jackson等人於2018年1月26日申請之美國專利申請案62/622,771(例如,式I化合物),其等全文已以引用之方式併入本文中用於所有目的。具體實施例中,該等化合物具有根據本文式V之化學結構。
具體實施例中,CCR4調控劑為一種揭示於以下一種公開專利申請案中之化合物:Hobbs等人,US 2012/0015932;Cheshire等人,US 2010/0144759;Cheshire等人,US 2008/0293742;Cheshire US 2006/0189613;Mete等人,US 2006/0128723;Harrison等人,US 2006/0122195;Habashita等人,US 2006/0004010;Collins等人,US 2004/0039035;Collins等人,US 2003/0018022;Collins等人,US 2002/0173524;Dairaghi等人,US 2002/0132836;美國專利案5,300,498;美國專利案6,509,357;US 2003/149018;WO 01/005758;WO 03/051876;WO 97/042174;WO 2006/101456;WO 2007/065683;WO 2007/065924;WO 2007/115231;WO 2008/045529;WO 2008/094575;WO 2008/094602;WO 2010/118367;及WO 2013/082429,揭示CCR4調控化合物之文獻已以引用之方式併入本文中。
具體實施例中,CCR4調控劑為一種揭示於下列公開專利申請案中之一種抗體:Marasco等人之US 2017/0290911;Lin等人之US 2017/0088627;Marasco等人之US 2016/0185865;Ishii等人之US 2015/0147321;Shitara等人之US 2013/0295045;Wu等人之US 2007/0031896;Shitara等人之US 2007/0020263;與Iida等人之US 2005/0287138,揭示CCR4結合性抗體之文獻已以引用之方式併入本文中。
具體實施例中,EBV-相關癌症為實體腫瘤。一項具體實施例中,該EBV-相關癌症為復發性或難治性。另一項具體實施例中,本發明方法係治療EBV-相關癌症。一項具體實施例中,該EBV-相關癌症為鼻咽癌。一項具體實施例中,該EBV-相關癌症為胃癌。一項具體實施例中,EBV-相關癌症為淋巴增生疾病(例如,勃奇氏淋巴瘤(Burkitt’s lymphoma)、霍奇金氏淋巴瘤(Hodgkin lymphoma)、瀰漫性大B細胞淋巴瘤、NK/T細胞白血病或淋巴瘤等等)。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係經口或非經腸式投與。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係經口投與。 具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係連續一段時間投與有此需要之個體。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係週期性投與有此需要之個體(例如,投與一天或更多天後,接著休止期)。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係歷經多個用藥週期投與有此需要之個體。一項具體實施例中,該外加之抗癌劑係經口或非經腸式投與。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係與一或多種外加之抗癌劑經由相同途徑投與。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係與一或多種外加之抗癌劑經由不同途徑投與(例如,其中一種經口投與,另一種非經腸式投與)。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係依特定用藥週期投與。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物或其鹽、溶劑合物、或水合物與一或多種外加之抗癌劑(包括,但不限於,羅醚酯肽(romidepsin)、卡鉑(carboplatin)、太平洋紫杉醇(paclitaxel)、或Abraxane®)依特定用藥週期共同投與。特定具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係先投與有此需要之個體一天或更多天(例如,7天或更多天)後,再投與一或多種外加之抗癌劑給個體(例 如,從治療週期第8天或之後開始)。特定具體實施例中,當對個體投與一或多種外加之抗癌劑時,亦可對個體投與式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物。特定具體實施例中,當對個體投與一或多種外加之抗癌劑時,不會同時對個體投與式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係單獨呈單一製劑投與有此需要之個體。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係與一或多種外加之抗癌劑組合,包括,但不限於,羅醚酯肽、卡鉑、太平洋紫杉醇、或Abraxane®(結合太平洋紫杉醇蛋白質之粒子)等等。一項具體實施例中,該外加之抗癌劑為烷化劑、細胞毒性劑、抗血管新生劑、抗微管蛋白劑、抗代謝物、激酶抑制劑、生物製劑、或任何其他已知之抗癌劑(例如,本文其他內容提供之抗癌劑)。某些具體實施例中,除了式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物或一或多種外加之抗癌劑之外,亦投與止吐劑給有此需要之個體。一項特定具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係與卡鉑組合投藥。另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係與Abraxane®組合投藥。另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合 物、或其鹽、溶劑合物、或水合物係與羅醚酯肽組合投藥。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係與一或多種外加之免疫調控劑組合投藥,包括,但不限於,(1)靶向PD-1、PD-L1、CTLA-4、CD40、GITR、LAG3與/或CD137之抗體;(2)IDO、TDO、A2AR、A2BR、CD39、CD73、USP7、GCN2與/或HPK1之抑制劑;(3)先天免疫力之活化劑,包括TLR、STING、cGAS等等;(4)細胞免疫療法,包括後天性T細胞轉移、嵌合抗原受體(CAR)-T細胞轉移、NK細胞療法等等;(5)疫苗策略,包括細菌、病毒、或合成性疫苗接種;(6)溶瘤病毒療法;與/或(7)雙特異性/三特異性T細胞結合子。
一項態樣中,本文提供一種包含式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物之醫藥組成物,用於本文說明之任何方法。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物係調配成本文提供之口服劑型(例如,錠劑或膠囊)。
具體實施例中,本文提供包含式(I)、(II)、(III)、(IV)、或(V)化合物或其鹽、溶劑合物、或水合物之醫藥組成物,其中該組成物經口投藥時,實質上於胃中釋放活性醫藥成份(API)。一項具體實施例中,本文提供包含式(I)、(II)、(III)、(IV)、或(V)化合物或其鹽、溶劑合物、或水合物之醫藥組成物,其中該組成物經口投藥時,實質 上於胃與/或上腸道中釋放API。一項具體實施例中,本文提供包含式(I)、(II)、(III)、(IV)、或(V)化合物或其鹽、溶劑合物、或水合物之醫藥組成物,其中該組成物經口投藥時,實質上於胃、上腸道/與或下腸道中釋放API。亦提供製造該組成物之方法,及使用該組成物於治療或管控疾病與病變之方法,其包括EBV-相關癌症、與異常細胞增生相關之病變、實體腫瘤、與血液病變。
一項態樣中,本文提供一種包含式(I)、(II)、(III)、(IV)、或(V)化合物、或其鹽、溶劑合物、或水合物之套組,用於本文說明之任一種方法。
除非另有其他定義,否則本文所採用所有技術及科學術語均具有習此相關技藝者習知之相同意義。本文所提及所有公開文獻與專利案全文均已以引用之方式併入本文中。
定義
本說明書所定義術語「約」或「大約」意指由習此相關技藝者所測定特定數值之可接受誤差,其一部份取決於如何測量或測定該數值。某些具體實施例中,術語「約」或「大約」意指在1、2、3、或4個標準偏差內。某些具體實施例中,術語「約」或「大約」意指在指定數值或範圍之30%、25%、20%、15%、10%、9%、8%、 7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、或0.05%內。
本文採用之縮寫具有其在化學與生物技藝上之習知定義。本文所示化學結構與化學式係依據化學技藝已知化學價之標準規則構成。
若一般化學式中,以從左向右書寫之方式指明取代基時,其等同樣包括可能從右向左書寫之結構之相同化學取代基,例如,-CH2O-等同-OCH2-。
術語「烷基」本身或作為另一個取代基之一部份時,除非另有其他說明,否則意指直鏈(亦即不分支)或分支之碳鏈(或碳)、或其組合,其可能為完全飽和、單-或多不飽和,且可包括單價、二價與多價基團。烷基可包括指定碳數(例如,C1-C10意指1至10個碳)。烷基為無環鏈。飽和烴基實例包括,但不限於基團如甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基、甲基、例如正戊基、正己基、正庚基、正辛基等等之同系物與異構物。不飽和烷基為具有一或多個雙鍵或參鍵之基團。不飽和烷基實例包括,但不限於,乙烯基、2-丙烯基、巴豆基、2-異戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-與3-丙炔基、3-丁炔基,及較高碳同系物與異構物。烷氧基為經由氧連接基(-O-)附接其餘分子之烷基。烷基部份基團可能為烯基部份基團。烷基部份基團可能為炔基部份基團。烷基部份基團可能為完全飽和。除了一或多個雙鍵以外,烯基可能再包括超過一個雙 鍵與/或一或多個參鍵。除了一或多個參鍵以外,炔基可能再包括超過一個參鍵與/或一或多個雙鍵。
術語「伸烷基」本身或作為另一個取代基之一部份時,除非另有其他說明,否則意指由烷基衍生之二價基團,其不設限實例為-CH2CH2CH2CH2-。通常,烷基(或伸烷基)具有1至24個碳原子,以彼等具有10或更少個碳原子之基團為本發明較佳基團。「低碳數烷基」或「低碳數伸烷基」為較短鏈烷基或伸烷基,通常具有8個或更少個碳原子。術語「伸烯基」本身或作為另一個取代基之一部份時,除非另有其他說明,否則意指由烯衍生之二價基團。
術語「雜烷基」本身或與另一個術語組合時,除非另有其他說明,否則意指安定之直鏈或分支鏈、或其組合,其中包括至少一個碳原子與至少一個雜原子(例如,O、N、P、Si、與S),其中該氮原子與硫原子可視需要氧化,且氮雜原子可視需要四級化。雜原子(群)(例如,N、S、Si、或P)可能位在雜烷基之任何內部位置或位在烷基附接其餘分子之位置。雜烷基為無環鏈。實例包括,但不限於,-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3、與-CN。多至有兩個或三個連續雜原子,如例如,-CH2-NH-OCH3與-CH2-O-Si(CH3)3。雜烷 基部份基團可能包括一個雜原子(例如,O、N、S、Si、或P)。雜烷基部份基團可能包括兩個視需要之不同雜原子(例如,O、N、S、Si、或P)。雜烷基部份基團可能包括三個視需要之不同雜原子(例如,O、N、S、Si、或P)。雜烷基部份基團可能包括四個視需要之不同雜原子(例如,O、N、S、Si、或P)。雜烷基部份基團可能包括五個視需要之不同雜原子(例如,O、N、S、Si、或P)。雜烷基部份基團可能包括多至8個視需要之不同雜原子(例如,O、N、S、Si、或P)。
同樣地,術語「雜伸烷基」本身或作為另一個取代基之一部份時,除非另有其他說明,否則意指由雜烷基衍生之二價基團,其實例,但不限於為-CH2-CH2-S-CH2-CH2-與-CH2-S-CH2-CH2-NH-CH2-。雜伸烷基中,雜原子亦可佔據一個或兩個鏈末端(例如,伸烷基氧基、伸烷基二氧基、伸烷基胺基、伸烷基二胺基,與類似物)。此外,針對伸烷基與雜伸烷基連接基,連接基化學式之書寫方向並未暗示連接基之方向。例如,式-C(O)2R'-同時代表-C(O)2R'-與-R'C(O)2-。如上述,本文所採用雜烷基包括彼等利用雜原子附接其餘分子之基團,如-C(O)R'、-C(O)NR'、-NR'R"、-OR'、-SR'、與/或-SO2R'。當列舉「雜烷基」,接著列舉特定雜烷基,如-NR'R",或類似物時,咸了解術語雜烷基與-NR'R"並非冗餘或互斥。該等列舉之特定雜烷基反而更清楚。因此,術語「雜烷基」不應在本文中排除特定之雜烷基,如-NR'R"或類似物。
術語「環烷基」與「雜環烷基」本身或與其他術語組合時,除非另有其他說明,否則分別意指環狀之「烷基」與「雜烷基」。環烷基與雜環烷基不為芳香系。此外,雜環烷基之雜原子可佔據雜環附接其餘分子之位置。環烷基實例包括,但不限於,環丙基、環丁基、環戊基、環己基、1-環己烯基、3-環己烯基、環庚基、與類似物。雜環烷基實例包括,但不限於,1-(1,2,5,6-四氫吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-嗎啉基、3-嗎啉基、四氫呋喃-2-基、四氫呋喃-3-基、四氫噻吩-2-基、四氫噻吩-3-基、1-哌基、2-哌基、與類似物。「伸環烷基」與「伸雜環烷基」單獨或作為另一個取代基之一部份時,分別意指由環烷基與雜環烷基衍生之二價基團。「環烷基」亦指雙環與多環烴環,如例如,雙環[2.2.1]庚烷、雙環[2.2.2]辛烷等等。
術語「鹵」或「鹵素」本身或作為另一個取代基之一部份時,除非另有其他說明,否則意指氟、氯、溴、或碘原子。此外,如「鹵烷基」之術語意指包括單鹵烷基與多鹵烷基。例如,術語「鹵(C1-C4)烷基」包括,但不限於,氟甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基、與類似物。
術語「醯基」除非另有其他說明,否則意指-C(O)R,其中R為經取代或未經取代之烷基、經取代或未經取代之環烷基、經取代或未經取代之雜烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經 取代或未經取代之雜芳基。
術語「芳基」除非另有其他說明,否則意指多不飽和之芳香烴取代基,其可為單環或共同稠合(亦即稠合之環芳基)或共價連接之多環(較佳為1至3個環)。稠合之環芳基係指共同稠合之多環,其中至少一個稠合環為芳基環。術語「雜芳基」係指包含至少一個雜原子(如N、O、或S)之芳基(或環),其中該氮原子與硫原子可視需要氧化,且氮原子(群)可視需要四級化。因此,術語「雜芳基」包括稠合之環雜芳基(亦即多個環共同稠合,其中至少一個稠合環為雜芳香環)。5,6-稠合環伸雜芳基係指兩個環共同稠合,其中一個環具有5員且另一個環具有6員,其中至少一個環為雜芳基環。同樣地,6,6-稠合環伸雜芳基係指兩個環共同稠合,其中一個環具有6員且另一個環具有6員,其中至少一個環為雜芳基環。及6,5-稠合環伸雜芳基係指兩個環共同稠合,其中一個環具有6員且另一個環具有5員,其中至少一個環為雜芳基環。雜芳基可透過碳或雜原子附接其餘分子。芳基與雜芳基之不設限實例包括苯基、萘基、吡咯基、吡唑基、嗒基、三基、嘧啶基(pyrimidinyl)、咪唑基、吡基、嘌呤基、唑基、異唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基(pyrimidyl)、苯并噻唑基、苯并唑基、苯并咪唑基、苯并呋喃、異苯并呋喃基、吲哚基、異吲哚基、苯并噻吩基、異喹啉基、喹啉基、喹啉基、1-萘基、2-萘基、4-聯苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡基、2- 唑基、4-唑基、2-苯基-4-唑基、5-唑基、3-異唑基、4-異唑基、5-異唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-異喹啉基、5-異喹啉基、2-喹啉基、5-喹啉基、3-喹啉基、與6-喹啉基。上述各芳基與雜芳基環系之取代基係選自下文說明之可接受之取代基之群中。「伸芳基」與「伸雜芳基」單獨或作為另一個取代基之一部份時,意指分別由芳基與雜芳基衍生之二價基團。雜芳基取代基可為-O-鍵結環雜原子氮。
螺環為兩個或更多個環,其中相鄰環透過單一原子附接。螺環內之各環可相同或相異。螺環內之各環可經取代或未經取代,且一組螺環內之各環可彼此具有不同取代基。螺環內各環之可能取代基為該同一個環不作為螺環一部份時之可能取代基(例如,環烷基或雜環烷基環之取代基)。螺環可為經取代或未經取代之環烷基、經取代或未經取代之伸環烷基、經取代或未經取代之雜環烷基、或經取代或未經取代之伸雜環烷基,且螺環基內之各環可為前述任何環,包括一種型態之所有環(例如,所有環均為經取代之伸雜環烷基,其中各環可為相同或相異之經取代之伸雜環烷基)。當提及螺環系時,雜環狀螺環意指螺環中至少一個環為雜環,其中各環可為相異環。當提及螺環系時,經取代之螺環意指至少一個環經取代,且各取代基可視需要相異。
本文所定義術語「側氧基」意指利用雙鍵與碳原子鍵結之氧。
伸烷基芳基部份基團可於伸烷基部份基團或伸芳基連接基(例如,在碳2、3、4、或6)上經取代(例如,經一個取代基取代),其係經鹵素、側氧基、-N3、-CF3、-CCl3、-CBr3、-CI3、-CN、-CHO、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO2CH3-SO3H、-OSO3H、-SO2NH2、NHNH2、ONH2、NHC(O)NHNH2、經取代或未經取代之C1-C5烷基、或經取代或未經取代之2至5員雜烷基取代。具體實施例中,伸烷基芳基係未經取代。
上述各術語(例如,「烷基」、「雜烷基」、「環烷基」、「雜環烷基」、「芳基」、與「雜芳基」)同時包括上述基團之取代型與未取代型。各類型基團之較佳取代基說明如下。
烷基與雜烷基(包括彼等常稱為伸烷基、烯基、雜伸烷基、雜烯基、炔基、環烷基、雜環烷基、環烯基、與雜環烯基者)之取代基可為,但不限於選自下列之一 或多個各種不同基團:-OR'、=O、=NR'、=N-OR'、-NR'R"、-SR'、-鹵素、-SiR'R"R'''、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R'''、-NR"C(O)2R'、-NR-C(NR'R"R''')=NR''''、-NR-C(NR'R")=NR'''、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、-NRSO2R'、NR'NR"R'''、ONR'R"、NR'C(O)NR"NR'''R''''、-CN、-NO2、-NR'SO2R"、-NR'C(O)R"、-NR'C(O)-OR"、-NR'OR",其數為0至(2m’+1)之範圍,其中m’為此等基團之碳原子總數。R、R'、R"、R'''、與R''''較佳係分別獨立地指氫、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基(例如,經1至3個鹵素取代之芳基)、經取代或未經取代之雜芳基、經取代或未經取代之烷基、烷氧基、或硫烷氧基、或芳基烷基。當本文說明之化合物包括超過一個R基團時,例如,當出現超過一個R'、R"、R'''、與R''''基團時,各R基團係獨立地選自各R'、R"、R'''、與R''''基團。當R'與R"附接同一個氮原子時,其等可與氮原子組合形成4-、5-、6-、或7-員環。例如,-NR'R"包括,但不限於,1-吡咯啶基與4-嗎啉基。本領域技術人員從上述取代基之討論即可了解,術語「烷基」意指包括包含與氫基以外之基團結合之碳原子之基團,如鹵烷基(例如,-CF3與-CH2CF3)與醯基(例如,-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3、與類似物)。
類似烷基所說明之取代基,芳基與雜芳基 之取代基可以變化且係選自例如,-OR'、-NR'R"、-SR'、-鹵素、-SiR'R"R'''、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R'''、-NR"C(O)2R'、-NR-C(NR'R"R''')=NR''''、-NR-C(NR'R")=NR'''、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、-NRSO2R'、NR'NR"R'''、ONR'R"、NR'C(O)NR"NR'''R''''、-CN、-NO2、-R'、-N3、-CH(Ph)2、氟(C1-C4)烷氧基、與氟(C1-C4)烷基、-NR'SO2R"、-NR'C(O)R"、-NR'C(O)-OR"、-NR'OR",其數為從零至芳香環系上開放價數總數之範圍;且其中R'、R"、R'''、與R''''較佳係獨立地選自氫、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、與經取代或未經取代之雜芳基。當本文說明之化合物包括超過一個R基團時,例如,當出現超過一個R'、R"、R'''、與R''''基團,各R基團獨立地選自各R'、R"、R'''、與R''''基團。
環(例如,環烷基、雜環烷基、芳基、雜芳基、伸環烷基、伸雜環烷基、伸芳基、或伸雜芳基)之取代基可為環上之取代基,而非環上特定原子之取代基(通常稱為浮動取代基)。此時,取代基可附接任何環原子(遵循化學電價規則),且以稠合環或螺環為例,所示之取代基係與稠合環或螺環中一個組員結合(單一環之浮動取代基),可為任何稠合環或螺環之取代基(多環之浮動取代基)。當取代基附接一個環,而非特定原子(浮動取代基),且取代基 之下標為超過1之整數時,該等多重取代基可能在同一個原子、同一個環、不同原子、不同稠合環、不同螺環上,且各取代基可視需要相異。若環與其餘分子之附接點不限於單一原子(浮動取代基)時,該附接點可為環之任何原子,且以稠合環或螺環為例,可遵循化學價規則,為任何稠合環或螺環之任何原子。若環、稠合環、或螺環包含一個或多個環雜原子且該環、稠合環、或螺環係以一個或多個浮動取代基(包括,但不限於與其餘分子之附接點)表示時,浮動取代基可鍵結在雜原子。若具有浮動取代基之結構式或化學式中,所出示之環雜原子與一個或多個氫鍵結(例如,一個環氮的兩個鍵與環原子鍵結,第三個鍵與氫鍵結),當雜原子與浮動取代基鍵結時,咸了解該等取代基可置換氫,同時遵循化學價規則。
兩個或更多個取代基可視需要結合形成芳基、雜芳基、環烷基、或雜環烷基。此等所謂形成環之取代基雖然不一定,但通常係附接環狀基本結構。一項具體實施例中,該形成環之取代基係附接該基本結構之相鄰組員。例如,兩個形成環之取代基附接環狀基本結構之相鄰組員,形成稠合之環結構。另一項具體實施例中,該形成環之取代基附接該基本結構之單一組員。例如,兩個形成環之取代基附接環狀基本結構之單一組員,形成螺環結構。再另一項具體實施例中,該形成環之取代基附接該基本結構之非相鄰組員。
在芳基或雜芳基環之相鄰原子之兩個取代 基可視需要形成如式-T-C(O)-(CRR')q-U-之環,其中T與U獨立地為-NR-、-O-、-CRR'-、或單鍵,及q為整數0至3。或者,在芳基或雜芳基環之相鄰原子之兩個取代基可視需要被如式-A-(CH2)r-B-取代基置換,其中A與B獨立地為-CRR'-、-O-、-NR-、-S-、-S(O)-、-S(O)2-、-S(O)2NR'-、或單鍵,及r為整數1至4。所形成新環之其中一個單鍵可視需要被雙鍵置換。或者,芳基或雜芳基環之相鄰原子之兩個取代基可視需要被如式-(CRR')s-X'-(C"R"R''')d-取代基取代,其中s與d獨立地為整數0至3,及X'為-O-、-NR'-、-S-、-S(O)-、-S(O)2-、或-S(O)2NR'-。取代基R、R'、R"、與R'''較佳係獨立地選自氫、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、與經取代或未經取代之雜芳基。
本文所定義術語「雜原子」或「環雜原子」意指包括氧(O)、氮(N)、硫(S)、磷(P)、與矽(Si)。
本文所採用「取代基」意指選自下列部份基團之基團:(A)側氧基、鹵素、-CCl3、-CBr3、-CF3、-CI3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl3、-OCF3、-OCBr3、-OCI3、-OCHCl2、-OCHBr2、-OCHI2、-OCHF2、未經 取代之烷基(例如,C1-C8烷基、C1-C6烷基、或C1-C4烷基)、未經取代之雜烷基(例如,2至8員雜烷基、2至6員雜烷基、或2至4員雜烷基)、未經取代之環烷基(例如,C3-C8環烷基、C3-C6環烷基、或C5-C6環烷基)、未經取代之雜環烷基(例如,3至8員雜環烷基、3至6員雜環烷基、或5至6員雜環烷基)、未經取代之芳基(例如,C6-C10芳基、C10芳基、或苯基)、或未經取代之雜芳基(例如,5至10員雜芳基、5至9員雜芳基、或5至6員雜芳基),及(B)烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基,其係經選自下列之至少一個取代基取代:(i)側氧基、鹵素、-CCl3、-CBr3、-CF3、-CI3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl3、-OCF3、-OCBr3、-OCI3、-OCHCl2、-OCHBr2、-OCHI2、-OCHF2、未經取代之烷基(例如,C1-C8烷基、C1-C6烷基、或C1-C4烷基)、未經取代之雜烷基(例如,2至8員雜烷基、2至6員雜烷基、或2至4員雜烷基)、未經取代之環烷基(例如,C3-C8環烷基、C3-C6環烷基、或C5-C6環烷基)、未經取代之雜環烷基(例如,3至8員雜環烷基、3至6員雜環烷基、或5至6員雜環烷基)、未經取代之芳基(例如,C6-C10芳基、C10芳基、或苯基)、或未經取代之雜芳基(例如,5至10員雜芳基、5至9員雜芳基、或5至6員雜芳基),及 (ii)烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基,其係經選自下列之至少一個取代基取代:(a)側氧基、鹵素、-CCl3、-CBr3、-CF3、-CI3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl3、-OCF3、-OCBr3、-OCI3、-OCHCl2、-OCHBr2、-OCHI2、-OCHF2、未經取代之烷基(例如,C1-C8烷基、C1-C6烷基、或C1-C4烷基)、未經取代之雜烷基(例如,2至8員雜烷基、2至6員雜烷基、或2至4員雜烷基)、未經取代之環烷基(例如,C3-C8環烷基、C3-C6環烷基、或C5-C6環烷基)、未經取代之雜環烷基(例如,3至8員雜環烷基、3至6員雜環烷基、或5至6員雜環烷基)、未經取代之芳基(例如,C6-C10芳基、C10芳基、或苯基)、或未經取代之雜芳基(例如,5至10員雜芳基、5至9員雜芳基、或5至6員雜芳基),及(b)烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基,其係經選自下列之至少一個取代基取代:側氧基、鹵素、-CCl3、-CBr3、-CF3、-CI3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC(O)NHNH2、-NHC(O)NH2、-NHSO2H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl3、-OCF3、-OCBr3、-OCI3,-OCHCl2、-OCHBr2、-OCHI2、-OCHF2、未經取代之烷基(例如,C1-C8烷基、C1-C6烷基、 或C1-C4烷基)、未經取代之雜烷基(例如,2至8員雜烷基、2至6員雜烷基、或2至4員雜烷基)、未經取代之環烷基(例如,C3-C8環烷基、C3-C6環烷基、或C5-C6環烷基)、未經取代之雜環烷基(例如,3至8員雜環烷基、3至6員雜環烷基、或5至6員雜環烷基)、未經取代之芳基(例如,C6-C10芳基、C10芳基、或苯基)、或未經取代之雜芳基(例如,5至10員雜芳基、5至9員雜芳基、或5至6員雜芳基)。
本文所採用「限制大小之取代基」或「限制大小之取代基基團」意指選自上述「取代基基團」中所有取代基之基團,其中各經取代或未經取代之烷基為經取代或未經取代之C1-C20烷基,各經取代或未經取代之雜烷基為經取代或未經取代之2至20員雜烷基,各經取代或未經取代之環烷基為經取代或未經取代之C3-C8環烷基,各經取代或未經取代之雜環烷基為經取代或未經取代之3至8員雜環烷基,各經取代或未經取代之芳基為經取代或未經取代之C6-C10芳基,及各經取代或未經取代之雜芳基為經取代或未經取代之5至10員雜芳基。
本文所採用「低碳數取代基」或「低碳數取代基基團」意指選自上述「取代基基團」中之所有取代基之基團,其中各經取代或未經取代之烷基為經取代或未經取代之C1-C8烷基、各經取代或未經取代之雜烷基為經取代或未經取代之2至8員雜烷基、各經取代或未經取代之環烷基為經取代或未經取代之C3-C7環烷基、各經取代 或未經取代之雜環烷基為經取代或未經取代之3至7員雜環烷基、各經取代或未經取代之芳基為經取代或未經取代之C6-C10芳基、與各經取代或未經取代之雜芳基為經取代或未經取代之5至9員雜芳基。
有些具體實施例中,本發明化合物中說明之各取代基係經至少一個取代基取代。更明確言之,有些具體實施例中,本發明化合物中說明之各經取代之烷基、經取代之雜烷基、經取代之環烷基、經取代之雜環烷基、經取代之芳基、經取代之雜芳基、經取代之伸烷基、經取代之伸雜烷基、經取代之環伸烷基、經取代之伸雜環烷基、經取代之伸芳基、與/或經取代之伸雜芳基係經至少一個取代基取代。其他具體實施例中,至少一個或所有此等基團係經至少一個限制大小之取代基取代。其他具體實施例中,至少一個或所有此等基團係經至少一個低碳數取代基取代。
本發明化合物之其他具體實施例中,各經取代或未經取代之烷基可能為經取代或未經取代之C1-C20烷基、各經取代或未經取代之雜烷基為經取代或未經取代之2至20員雜烷基、各經取代或未經取代之環烷基為經取代或未經取代之C3-C8環烷基、各經取代或未經取代之雜環烷基為經取代或未經取代之3至8員雜環烷基、各經取代或未經取代之芳基為經取代或未經取代之C6-C10芳基、與/或各經取代或未經取代之雜芳基為經取代或未經取代之5至10員雜芳基。本發明化合物之有些具體實施例中, 各經取代或未經取代之伸烷基為經取代或未經取代之C1-C20伸烷基、各經取代或未經取代之伸雜烷基為經取代或未經取代之2至20員伸雜烷基、各經取代或未經取代之伸環烷基為經取代或未經取代之C3-C8伸環烷基、各經取代或未經取代之伸雜環烷基為經取代或未經取代之3至8員伸雜環烷基、各經取代或未經取代之伸芳基為經取代或未經取代之C6-C10伸芳基、與/或各經取代或未經取代之伸雜芳基為經取代或未經取代之5至10員伸雜芳基。
有些具體實施例中,各經取代或未經取代之烷基為經取代或未經取代之C1-C8烷基、各經取代或未經取代之雜烷基為經取代或未經取代之2至8員雜烷基、各經取代或未經取代之環烷基為經取代或未經取代之C3-C7環烷基、各經取代或未經取代之雜環烷基為經取代或未經取代之3至7員雜環烷基、各經取代或未經取代之芳基為經取代或未經取代之C6-C10芳基、與/或各經取代或未經取代之雜芳基為經取代或未經取代之5至9員雜芳基。有些具體實施例中,各經取代或未經取代之伸烷基為經取代或未經取代之C1-C8伸烷基、各經取代或未經取代之伸雜烷基為經取代或未經取代之2至8員伸雜烷基、各經取代或未經取代之伸環烷基為經取代或未經取代之C3-C7伸環烷基、各經取代或未經取代之伸雜環烷基為經取代或未經取代之3至7員伸雜環烷基、各經取代或未經取代之伸芳基為經取代或未經取代之C6-C10伸芳基、與/或各經取代或未經取代之伸雜芳基為經取代或未經取代之 5至9員伸雜芳基。有些具體實施例中,化合物為如下文中實例章節、圖式、或表格所示之化學物質。
某些本發明化合物具有不對稱碳原子(光學或對掌性中心)或雙鍵;可依絕對立體化學定義之對映異構物、消旋物、非對映異構物、互變異構物、幾何異構物、立體異構物等型式(如(R)-或(S)-、或胺基酸之(D)-或(L)-)與個別異構物均涵括在本發明範圍內本發明化合物。本發明化合物不包括本領域所習知之太不安定以致無法合成與/或單離之化合物。本發明意指包括呈消旋型或純光學型之化合物。光學活性(R)-與(S)-、或(D)-與(L)-異構物可採用對掌性合成單元或對掌性試劑製備,或採用習知技術解析。當本文說明之化合物包含烯烴鍵或其他幾何不對稱中心時,除非另有說明,否則意指同時包括E與Z幾何異構物之化合物。
本文所定義術語「異構物」係指具有相同原子數及相同種類原子,因此具有相同分子量,但原子之結構排列或組態不同之化合物。
本文所定義術語「互變異構物」係指兩種或更多種結構異構物其中之一,其呈平衡態且很容易由其中一種異構型轉換成另一種。
本領域技術人員咸了解,某些本發明化合物可能呈互變異構型,化合物之所有此等互變異構型均在本發明範圍內。
除非另有其他說明,否則本文出示之結構 亦包括該結構之所有立體化學型;亦即各不對稱中心之R與S組態。因此,本化合物之單一立體化學異構物及對映異構物與非對映異構物混合物均在本發明範圍內。
除非另有其他說明,否則本文出示之結構亦包括其差異僅在於一個或多個富集放射活性原子之化合物。例如,具有本結構但一個氫被氘或氚置換之化合物、或碳被富集13C或14C之碳置換之化合物均在本發明範圍內。
本發明化合物亦可在構成此等化合物之一個或多個原子中包含非天然比例之原子同位素。例如,化合物可經過放射性同位素標記放射性,如,例如,氚(3H)、碘-125(125I)、或碳-14(14C)。本發明化合物之所有同位素變化,不論是否具有放射活性,均涵括在本發明範圍內。
應注意,本申請書全文中,替代項係以馬庫西群組(Markush group)書寫,例如,包含超過一個可能胺基酸之各胺基酸位置。其明確包含該馬庫西群組中應視為分開之各成員,藉以構成另一項具體實施例,且該馬庫西群組不應解讀為單一單位。
「類似物(analog與analogue)」係依據化學與生物學之一般定義使用,係指結構上類似另一種化合物(亦即所謂「參考」化合物),但組成上不同之化學化合物,例如,其中一個原子被不同元素之原子置換、或出現特定官能基、或其中一個官能基被另一個官能基置換、或參考化合物之一個或多個對掌性中心之絕對立體化學。因此, 類似物為功能與外觀上類似或比擬參考化合物,但結構或來源不同於參考化合物之化合物。
本文所定義術語「一個(a或an)」意指一或多個。此外,本文所採用「經一個取代」意指該指定基團可能經任何一個或多個或所有指名之取代基取代。例如,若基團,如烷基或雜芳基「經未經取代之C1-C20烷基、或未經取代之2至20員雜烷基取代」時,該基團可包含一個或多個未經取代之C1-C20烷基、與/或一個或多個未經取代之2至20員雜烷基。
此外,若部份基團經R取代基取代時,該基團可稱為「R-取代」。若部份基團為R-取代時,該部份基團係經至少一個R取代基取代,且各R取代基可視需要相異。若化學物質之說明(如:式(I))中出現特定R基團時,可採用羅馬字母代號來區分每次出現之特定R基團。例如,若出現多個R13取代基時,各R13取代基可區分為R13A、R13B、R13C、R13D等等,其中各R13A、R13B、R13C、R13D等等係如R13之定義範圍內之定義,且可視需要相異。
本文所採用「可檢測之部份基團」係指可共價或非共價附接可以採用例如,本領域所習知之技術檢測之化合物或生物分子之部份基團。具體實施例中,該可檢測之部份基團係共價附接。該可檢測之部份基團可以讓所附接之化合物或生物分子顯影。該可檢測之部份基團可以指示兩種化合物之間之接觸。可檢測之部份基團實例為螢光團、抗體、反應性染料、標記放射性之部份基團、磁 造影劑、與量子點。螢光團實例包括螢光素、若丹明(rhodamine)、GFP、香豆素、FITC、Alexa fluor螢光染料、Cy3、Cy5、BODIPY、與花青素染料。放射性核種實例包括氟-18、鎵-68、與銅-64。磁造影劑實例包括釓、氧化鐵與氧化鉑、與錳。
本發明化合物之說明受到彼等本領域技術人員已知之化學鍵結原理之限制。因此,若基團可經一個或多個許多種取代基取代時,可選擇此等符合化學鍵結原理之取代法,並產生不會出現本性不安定性質及/或不會在本領域技術人員已知環境條件,如水性、中性、與數種已知生理條件下不安定之化合物。例如,雜環烷基或雜芳基係依符合彼等本領域技術人員已知之化學鍵結原理,利用環雜原子附接其餘分子,藉以避免產生本性不安定之化合物。
除非另有說明,否則本文所定義術語「治療(treat、treating、與treatment)意指根除或緩解疾病或病變、或與該疾病或病變相關之一或多種症狀。某些具體實施例中,該術語意指使患有該疾病或病變之個體接受投與一或多種預防性或醫藥性藥劑後,使該疾病或病變達到最低程度之散播或惡化。有些具體實施例中,該術語係指在特定疾病症狀開始發作之後投與本文所提供之化合物或劑型,可併用或不併用一或多種其他活性劑。有些具體實施例中,該術語係指預防疾病或病變或其一或多種症狀發作、復發或散播。某些具體實施例中,該術語係指在症狀 發作之前之治療,尤其針對處於本文所提供疾病或病變風險之個體。該術語涵括抑制或降低特定疾病之症狀。在某些具體實施例中,具有疾病家族病史之個體為預防療程之候選人。此外,具有復發病史之個體亦為該預防法之潛在候選人。此方面,術語「預防」可與術語「預防性治療」交換使用。
除非另有說明,否則本文所定義術語「處理(manage、managing、與management)」係指預防或減慢疾病或病變、或其一或多種症狀之進展、散播或惡化。個體因預防劑與/或醫療劑得到之有利效益經常不會造成疾病或病變痊癒。此時,術語「處理」涵括治療曾罹患特定疾病且試圖防止疾病復發或使其最小化之個體。
本文所採用,藉由投與特定醫藥組成物「緩解」特定病變之症狀時,意指可因投與該組成物所造成或相關之任何減輕,不論永久或暫時,持續性或過渡性。
除非另有說明,否則本文所定義術語,化合物之「醫療有效量」與「有效量」意指在治療或管控疾病或病變,或延遲或最小化與該疾病或病變相關之一或多種症狀時,足以提供醫療效益時之用量。化合物之「醫療有效量」與「有效量」意指醫療劑在單獨或組合一或多種其他製藥劑治療或管控疾病或病變時,提供醫療效益時之用量。該術語「醫療有效量」與「有效量」可以涵括改善整體療法、減輕或避免疾病或病變之症狀或肇因、或加強另一種醫療劑之醫療效力時之用量。
除非另有說明,否則本文所定義術語,化合物之「預防有效量」意指足以防止疾病或病變或防止其復發時之用量。化合物之預防有效量意指醫療劑在單獨或組合一或多種其他製藥劑預防疾病時,提供醫療效益時之用量。術語「預防有效量」可以涵括改善整體預防性或加強另一種預防性藥劑之預防效力時之用量。
除非另有說明,否則本文所定義術語「個體」之定義包括動物,如哺乳動物,包括,但不限於,靈長類(例如,人類)、乳牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠等等。特定具體實施例中,個體為人類。術語「個體」與「患者」在本文中可交換使用,例如,哺乳動物個體,如:人類。
除非另有說明,否則本文所定義術語「腫瘤」係指所有贅瘤細胞生長與增生(不論惡性或良性),及所有癌前性與癌性細胞與組織。本文所採用「贅瘤」係指任何失調或不受調節之細胞生長形式(不論惡性或良性),造成異常組織生長。因此「贅瘤細胞」包括失調或不受調節之細胞生長之惡性與良性細胞。
除非另有說明,否則本文所定義術語「癌症」與「癌性」係指或說明哺乳動物之生理條件,其典型特徵在於不受調節之細胞生長。癌症實例包括,但不限於,血液性(例如,淋巴瘤、白血病)與實體腫瘤。
除非另有說明,否則本文所定義術語「增生」病變或疾病係指多細胞生物體中一或多種子群細胞之 不期望之細胞生長,造成傷害該多細胞生物體(亦即不適或縮短壽命)。例如,本文所採用增生病變或疾病包括贅瘤病變與其他增生病變。
除非另有說明,否則本文所定義術語「復發性」係指個體在醫療後消退之癌症再度出現癌細胞之狀況。
除非另有說明,否則本文所定義術語「難治性」或「抗性」係指其中個體即使接受積極治療後,體內仍有殘留之癌細胞之狀況。
除非另有說明,否則本文所定義術語「抗藥性」係指當疾病對藥物或藥物群之治療沒有反應時之狀態。抗藥性可為內因性,此表示該疾病未曾對藥物或藥物群有反應,或其可為後天性,此表示該過去曾對藥物或藥物群有反應之疾病停止產生反應。某些具體實施例中,抗藥性為內因性。某些具體實施例中,抗藥性為後天性。
本文所定義術語「艾伯斯坦-巴爾病毒(Epstein-Barr virus)」與「EBV」在本文中可交換使用,且意指有時候亦稱為人類皰疹病毒4(HHV-4)之病毒。此病毒為皰疹家族中八種已知人類皰疹病毒之一,且為人類最常見之病毒之一。該病毒最常造成傳染性單核白血球增多症(淋巴腺熱)。其亦與特定癌症型式有關,如霍奇金氏淋巴瘤、勃奇氏淋巴瘤、胃癌、鼻咽癌、及與人類免疫缺乏症病毒(HIV)相關之症狀,如絨毛狀白斑病與中樞神經系統淋巴瘤。
除非另有說明,否則本文所定義術語「EBV-相關」、「EBV陽性」與「EBV+」,當用於說明癌症或惡性病時,係指與艾伯斯坦-巴爾病毒(EBV)相關之癌症或惡性病,亦即包含EBV基因組之癌症,或呈miRNA、mRNA或蛋白質之型式表現來自EBV基因組之一或多種基因。
除非另有說明,否則本文所定義術語「C-C趨化介素受體第4型」與「CCR4」係指C-C-型趨化介素(例如,CCL2(MCP-1)、CCL4(MIP-1)、CCL5(RANTES)、CCL17(TARC)、與CCL22(MDC))之高親和性受體之蛋白質(包括同系物、同工型、與其功能片段)。其在科學文獻中有許多不同名稱,包括「CC-CKR-4」、「C-C CKR-4」、「K5-5」、「CD194」、「CMKBR4」、「ChemR13」、「HGCN」、與「14099」。該術語包括維持CCR4活性(例如,相較於野生型CCR4,在至少30%、40%、50%、60%、70%、80%、90%、95%、或100%活性內)之其CCR4變體之任何重組體或天然型。該術語包括維持CCR4活性(例如,相較於野生型CCR4,在至少30%、40%、50%、60%、70%、80%、90%、95%、或100%活性內)之其CCR4變體之任何突變型(例如,框移突變)。具體實施例中,由CCR4基因編碼之CCR4蛋白質具有如Entrez 1233、UniProt P51679、或RefSeq(蛋白質)NP_005499.1所示或對應之胺基酸序列。具體實施例中,CCR4基因具有如RefSeq(mRNA)NM_005508所示之核酸序列。具體實施例中,該胺基酸序列或核酸序列係本申請案申請時間點已知之序列。具體實施例中,該序列對 應於GI:5031627。具體實施例中,該序列對應於NP_005499.1。具體實施例中,該序列對應於NM_005508.4。具體實施例中,該序列對應於GI:48762930。具體實施例中,CCR4為人類CCR4,如引發人類癌症之CCR4。雖然CCR4經常出現在樹突細胞、巨噬細胞、NK細胞、血小板、與嗜鹼性細胞,但主要與T細胞有關。其在多種發炎相關病變之進展中扮演某種角色,且如本文所說明,其亦涉及許多其他病症。CCR4之基因組序列出現在染色體3(NC_000003.12)上,且許多物種仍保留CCR4基因,包括黑猩猩、普通獼猴、狗、乳牛、小鼠、大鼠、雞、與斑馬魚。CCR4多肽包含360個胺基酸殘基(NP_005499.1),且如同其他趨化介素受體,CCR4為一種出現在白血球表面之G蛋白質-偶聯受體(參見Horuk(1994)Trends Pharm.Sci.15:159-165)。
除非另有說明,否則本文所定義術語「抗癌藥劑」、「抗癌劑」、「抗癌醫療劑」意指包括抗增生劑與化療劑,包括,但不限於,抗代謝物(例如,5-氟尿嘧啶、胺甲蝶呤(methotrexate)、氮雜西定(azacitidine)、地西他濱(decitabine)、福達樂(fludarabine)、阿糖胞苷(cytarabine)(亦稱為胞嘧啶阿拉伯糖苷或Ara-C),及高劑量阿糖胞苷)、抗微管蛋白劑(例如,長春花生物鹼類,如長春新鹼(vincristine)與長春花鹼(vinblastine);及紫杉烷類,如太平洋紫杉醇(paclitaxel)與歐洲紫杉醇(docetaxel))、烷化劑(例如,二氯甲基二乙胺(mechlorethamine)、苯丁酸氮芥 (chlorambucil)、環磷醯胺、馬法蘭(melphalan)、卡莫司汀(carmustine)、洛莫司汀(lomusitne)、異環磷醯胺(ifosfamide)、卡莫司汀(carmustine)、白消安(busulfan)、環磷醯胺、達卡巴仁(dacarbazine)、異環磷醯胺(ifosfamide)、及硝基脲類,如雙氯乙基硝基脲、與羥基脲)、鉑劑(例如,順鉑(cisplatin)、卡鉑(carboplatin)、奧沙利鉑(oxaliplatin)、沙鉑(satraplatin)(JM-216)、與CI-973)、蒽環類藥物(例如,多柔比星(doxorubicin)與唐黴素(daunorubicin))、抗腫瘤抗生素(例如,絲裂黴素(mitomycin)、博來黴素(bleomycin)、伊達比星(idarubicin)、阿黴素(adriamycin)、道諾黴素(daunomycin)(亦稱為唐黴素(daunorubicin)、柔紅黴素(rubidomycin)、或紅比黴素(cerubidine))、及拓樸異構酶抑制劑(例如,依託泊苷(etoposide)、米托蒽醌(mitoxantrone)與喜樹鹼)、嘌呤拮抗劑或嘧啶拮抗劑(例如,6-氫硫基嘌呤、5-氟尿嘧啶、阿糖胞苷(cytarabine)、克羅拉濱(clofarabine)、與吉西他濱(gemcitabine))、細胞成熟劑(例如,三氧化二砷與維甲酸(tretinoin))、DNA修復酵素抑制劑(例如,鬼臼毒素、依託泊苷(etoposide)、伊立替康(irinotecan)、托普替康(topotecan)、與替尼泊苷(teniposide))、防止細胞存活之酵素(例如,天冬醯胺酶與培門冬酶(pegaspargase))、組織蛋白去乙醯酶抑制劑(例如,凡力諾特(vorinostat)與羅醚酯肽(romidepsin))、任何其他細胞毒性劑(例如,磷酸雌莫司汀(estramustine phosphate)、地塞美松(dexamethasone)、潑尼莫司汀(prednimustine)、與丙卡巴肼(procarbazine))、激素(例如,地塞美松(dexamethasone)、潑尼松(prednisone)、甲基潑尼松龍(methylprednisolone)、它莫西芬(tamoxifen)、柳菩林(leuprolide)、氟他胺(flutamide)、與甲地孕酮(megestrol))、單株抗體(例如,吉妥珠單抗(gemtuzumab ozogamicin)、阿侖單抗(alemtuzumab)、利妥昔單抗(rituximab)、與釔-90-替伊莫單抗(yttrium-90-ibritumomab tiuxetan))、免疫調控劑(例如,沙利竇邁(thalidomide)與來那竇邁(lenalidomide))、Bcr-Abl激酶抑制劑(例如,AP23464、AZD0530、CGP76030、PD180970、SKI-606、伊馬替尼(imatinib)、BMS354825(達沙替尼(dasatinib))、AMN107(尼洛替尼(nilotinib))、與VX-680)、激素促效劑或拮抗劑、部份促效劑或部份拮抗劑、激酶抑制劑、外科手術、放射療法(例如,γ-放射線、中子束放療法、電子束放療法、質子療法、近距離療法、與全身放射活性同位素)、內分泌療法、生物反應修飾劑(例如,干擾素、間白素、與腫瘤壞死因子)、高熱與冷療、免疫系統調節劑、及減弱任何副作用之藥劑(例如,止吐劑)及其他核准之化療藥物,包括,但不限於,烷化劑(二氯甲基二乙胺(mechlorethamine)、苯丁酸氮芥(chlorambucil)、環磷醯胺、馬法蘭(melphalan)、與異環磷醯胺(ifosfamide))、抗代謝物(阿糖胞苷(cytarabine)、高劑量阿糖胞苷(cytarabine)、與胺甲蝶呤(methotrexate))、嘌呤拮抗劑與嘧啶拮抗劑(6-氫硫基嘌 呤、5-氟尿嘧啶、阿糖胞苷(cytarabine)、與吉西他濱(gemcitabine))、紡錘體毒素(長春花鹼(vinblastine)、長春新鹼(vincristine)、長春瑞濱(vinorelbine)、歐洲紫杉醇(docetaxel)、與太平洋紫杉醇(paclitaxel)、例如,Abraxane®)、鬼臼毒素(依託泊苷(etoposide)、伊立替康(irinotecan)、與托普替康(topotecan))、抗生素(唐黴素(daunorubicin)、多柔比星(doxorubicin)、博來黴素(bleomycin)、與絲裂黴素(mitomycin))、硝基脲類(卡莫司汀(carmustine)與洛莫司汀(lomusitne))、無機離子(順鉑(cisplatin)與卡鉑(carboplatin))、酵素(天冬醯胺酶)、與激素(它莫西芬(tamoxifen)、柳菩林(leuprolide)、氟他胺(flutamide)、與甲地孕酮(megestrol))、伊馬替尼(imatinib)、阿黴素(adriamycin)、地塞美松(dexamethasone)、與環磷醯胺。有關其他可採用之癌症療法,例如,http://www.nci.nih.gov/;有關FDA核准之腫瘤藥物,參見例如,http://www.fda.gov/,The Merck Manual,第18版,2006,與PDR:Physician Desk Reference 2010,第64版,2009;其等全文已分別以引用之方式併入本文中。
除非另有說明,否則本文所定義術語「共同投藥」及「與…組合」包括由兩種或更多種醫療劑同時投與或在沒有指定時間限制內(除非另有說明)連續投與。一項具體實施例中,該等藥劑可同時存在於細胞中或個體體內,或同時具有生物或醫療效力。一項具體實施例中,醫療劑係呈相同組成物或單位劑型。其他具體實施例中, 醫療劑係呈分開組成物或單位劑型。某些具體實施例中,可先投與第一種藥劑(例如,5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週、或12週之前),基本上同時或接續(例如,5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週、或12週之後)投與第二醫療劑。
本文所定義術語「組成物」、「調配物」、與「劑型」計畫包括包含指定成份(群)(若有指定時之指定量)之組成物,及可能因指定量之指定成份(群)組合直接或間接形成之任何產物(群)。「醫藥上」或「醫藥上可接受」意指組成物、調配物、或劑型中可與其中成份(群)相容且不會傷害其接受者之任何稀釋劑(群)、賦形劑(群)、或載劑(群)。除非另有說明,否則術語「組成物」、「調配物」、與「劑型」可在本文中交換使用。
除非另有說明,否則當本文中提及「組成物」、「調配物」、與「劑型」使用術語「立即釋放」時,意指該組成物、調配物、或劑型不包含用於在經口投與組成物、調配物、或劑型後,在空間上及/或時間上延緩某些或所有API釋放之組份(例如,包衣)。某些具體實施例中,立即釋放之組成物、調配物、或劑型係指在口服後實質上在胃中釋放API者。某些具體實施例中,立即釋放之組成 物、調配物、或劑型係指在口服後實質上在胃或上腸道中釋放API者。特定具體實施例中,立即釋放之組成物、調配物、或劑型係指不會延緩釋放者。特定具體實施例中,立即釋放之組成物、調配物、或劑型不包含腸溶性包衣。
除非另有說明,否則本文所定義術語「非包覆腸衣」係指該醫藥組成物、調配物、或劑型不包含計畫在胃部以下(例如,腸部)中釋放活性成份(群)之包衣。某些具體實施例中,非包覆腸衣組成物、調配物、或劑型之設計在於實質上在胃中釋放活性成份(群)。某些具體實施例中,非包覆腸衣組成物、調配物、或劑型之設計在於實質上在胃及上腸道中釋放活性成份(群)。
除非另有說明,否則當在本文所提供之組成物、調配物、或劑型中提及本文所定義術語「實質上在胃中釋放」時,意指在胃中釋放至少約99%、至少約95%、至少約90%、至少約85%、至少約80%、至少約75%、至少約70%、至少約65%、至少約60%、至少約55%、至少約50%、至少約45%、至少約40%、至少約35%、至少約30%、至少約25%、至少約20%、至少約15%、或至少約10%之CCR4調控劑。本文所採用「在胃中釋放」與相關術語係指CCR4調控劑可被胃中細胞層吸收或跨過胃中細胞層轉運,然後可被身體利用。
某些本發明化合物具有不對稱碳原子(光學或對掌性中心)或雙鍵;可依絕對立體化學定義之對映異構物、消旋物、非對映異構物、互變異構物、幾何異構物、 立體異構物等型式(如(R)-或(S)-,或胺基酸之(D)-或(L)-)與個別異構物均涵括在本發明範圍內。本發明化合物不包括本領域所習知之太不安定以致無法合成與/或單離之化合物。本發明化合物包括呈消旋型或純光學型之化合物。光學活性(R)-與(S)-、或(D)-與(L)-異構物可採用對掌性合成單元或對掌性試劑製備,或採用習知技術解析。當本文說明之化合物包含烯烴鍵或其他幾何不對稱中心時,除非另有說明,否則意指同時包括E與Z幾何異構物之化合物。
本領域技術人員咸了解,某些本發明化合物可能呈互變異構型,化合物之所有此等互變異構型均在本發明範圍內。
除非另有其他說明,否則本文出示之結構亦包括該結構之所有立體化學型;亦即各不對稱中心之R與S組態。因此,本化合物之單一立體化學異構物及對映異構物與非對映異構物混合物均在本發明範圍。
除非另有其他說明,否則本文出示之結構亦包括其差異僅在於一個或多個富集放射活性原子之化合物。例如,具有本結構但一個氫被氘或氚置換之化合物、或碳被富集13C或14C之碳置換之化合物均在本發明範圍內。
本發明化合物亦可在構成此等化合物之一個或多個原子中包含非天然比例之原子同位素。例如,化合物可經過放射性同位素標記放射性,如,例如,氚(3H)、碘-125(125I)、或碳-14(14C)。本發明化合物之所有同位素 變化,不論是否具有放射活性,均涵括在本發明範圍內。
除非另有說明,否則本文所定義術語「醫藥上可接受之載劑」、「醫藥上可接受之賦形劑」、「生理上可接受之載劑」、或「生理上可接受之賦形劑」係指醫藥上可接受之材料、組成物、或媒劑,如例如,液體或固體填料、稀釋劑、賦形劑、溶劑、或包埋材料。一項具體實施例中,各組份為「醫藥上可接受」係指可與醫藥調配物中其他成份相容,並適合與人類及動物之組織或器官接觸,不會有過度毒性、刺激性、過敏反應、免疫性、或其他問題或併發症,並符合合理之效益/風險比例。一項具體實施例中,「醫藥上」或「醫藥上可接受」意指組成物、調配物、或劑型中可與其他成份相容且不會傷害其接受者之任何稀釋劑(群)、賦形劑(群)或載劑(群)。參見例如,Remington,The Science and Practice of Pharmacy,第21版;Lippincott Williams & Wilkins:Philadelphia,Pa.,2005;Handbook of Pharmaceutical Excipients,第5版;Rowe等人編輯,The Pharmaceutical Press and the American Pharmaceutical Association:2005;及Handbook of Pharmaceutical Additives,第3版;Ash與Ash編輯,Gower Publishing Company:2007;Pharmaceutical Preformulation and Formulation,Gibson編輯,CRC Press LLC:Boca Raton,Fla.,2004。
除非另有說明,否則本文所定義術語「水合物」意指本文所提供化合物及其鹽進一步包括利用分子 內非共價力結合之化學計量或非化學計量水。
除非另有說明,否則本文所定義術語「溶劑合物」意指由一或多個溶劑分子與本文所提供化合物結合形成之溶劑合物。術語「溶劑合物」包括水合物(例如,單水合物、二水合物、三水合物、四水合物、與類似物)。
除非另有說明,否則本文所採用「本文所說明化合物」計畫涵括所有可能之立體異構物,除非有指明特定立體化學。若化合物之結構異構物可以經由低能障轉換時,該化合物可能出現互變異構物或互變異構物之混合物。其可在化合物中呈質子互變異構化形式;或所謂價數互變異構化,例如,包含芳香系部份基團。
除非另有說明,否則本文所定義術語「接觸」係依據其一般定義使用,且係指讓至少兩種不同物種(例如,化學化合物,包括生物分子或細胞)足以緊密接近而反應、交互作用或物理上接觸。然而應咸了解,所得反應產物可由外加之試劑之間反應直接產生或由一或多種外加試劑於反應混合物中生成之中間物產生。術語「接觸」可能包括讓兩種物種反應、交互作用或物理上接觸,其中該兩種物種可能為如本文說明之化合物及蛋白質或酵素。有些具體實施例中,「接觸」包括讓本文說明之化合物與涉及訊號轉導途徑之蛋白質或酵素交互作用。
除非另有說明,否則本文所定義術語「調控作用」、「調控」、或「調控劑」係依據其一般定義使用,且係指改變或變化一或多種性質之作用。「調控劑」係指提 高或降低標靶分子含量或標靶分子功能或標靶分子物理狀態之組成物。「調控」係指改變或變化一或多種性質之過程。例如,調控劑效力應用在生物標靶上時,調控意指藉由提高或降低生物標靶之性質或功能或生物標靶之量之變化。
除非另有說明,否則本文所定義術語「CCR4調控劑」係指增加或降低細胞或組織中CCR4含量、增加或降低CCR4功能或其物理狀態之化合物或組成物。
除非另有說明,否則當提及標靶-抑制劑交互作用時,術語「活化作用」、「活化」、「活化性」與類似術語意指標靶(例如,蛋白質)之活性或功能相對於標靶(例如,蛋白質)在沒有抑制劑下之活性或功能受到正向影響(例如,增加)。該等術語係指疾病中下降之訊號轉導或酵素活性或蛋白質含量之活化作用、或活化、敏化、或上調。
除非另有說明,否則本文所定義術語「促效劑」、「活化劑」、「上調劑」等等係指可以使特定基因或蛋白質表現或活性相對於對照組(例如,沒有促效劑)顯著增加之物質。促效劑可以使表現或活性比沒有促效劑之對照組增加10%、20%、30%、40%、50%、60%、70%、80%、90%或更高。某些例子中,可以使表現或活性比沒有促效劑時之表現或活性增加1.5倍、2倍、3倍、4倍、5倍、10倍或更高。具體實施例中,促效劑為會與標靶交互作用而導致或促進增加標靶活化作用之分子。具體實施例中,活化劑為會增加、活化、促進、加強、激活、敏化、或上 調例如,基因、蛋白質、配體、受體、或細胞之分子。
除非另有說明,否則本文在提及蛋白質-抑制劑交互作用時所定義術語「抑制作用(inhibition)」、「抑制(inhibit)」、「抑制性(inhibiting)」,與類似術語意指相對於沒有抑制劑時之標靶(例如,蛋白質)之活性或功能,反向影響(例如,降低)標靶(例如,蛋白質)活性或功能。在具體實施例中,抑制作用意指相對於沒有抑制劑之標靶(例如,蛋白質)濃度或含量,反向影響(例如,降低)標靶(例如,蛋白質)濃度或含量。在具體實施例中,抑制作用係指降低疾病或疾病症狀。具體實施例中,抑制作用係指降低特定蛋白質標靶之活性。因此,抑制作用包括至少部份、部份或完全阻斷刺激、降低、防止、或延緩活化、或滅活、失敏、或下調標靶(例如,蛋白質)之訊號轉導或酵素活性或含量。具體實施例中,抑制係指與標靶(例如,蛋白質)直接交互作用,造成標靶(例如,蛋白質)活性減低(例如,抑制劑結合標靶(例如,蛋白質))。具體實施例中,抑制係指與標靶(例如,蛋白質)間接交互作用,造成標靶(例如,蛋白質)活性減低(例如,抑制劑與激活標靶(例如,蛋白質)之蛋白質結合,藉以阻止標靶(例如,蛋白質)活化)。
除非另有說明,否則本文所定義術語「抑制劑」、「壓制劑」或「拮抗劑」或「下調劑」可交換使用,係指可以使特定基因或蛋白質表現或活性比對照組(例如,沒有抑制劑)顯著降低之物質。拮抗劑可以使表現或活性比沒有拮抗劑之對照組降低10%、20%、30%、40%、50%、 60%、70%、80%、90%或更多。某些例子中,可以使表現或活性比沒有拮抗劑時之表現或活性降低1.5倍、2倍、3倍、4倍、5倍、10倍或更低。拮抗劑阻止、降低、抑制、或中和促效劑之活性,且即使沒有已判別之促效劑,拮抗劑亦可阻止、抑制、或降低標靶(例如,標靶受體)之組成活性。具體實施例中,抑制劑為降低、阻斷、阻止、延緩活化、滅化、失敏、或下調例如,基因、蛋白質、配體、受體、或細胞之分子。抑制劑之定義亦可為降低、阻斷、或滅活組成活性之分子。「拮抗劑」為與促效劑具有相反作用之分子。
除非另有說明,否則本文所定義術語「表現」包括涉及製造多肽之任何步驟,包括,但不限於,轉錄、轉錄後修飾、轉譯、轉譯後修飾、與分泌。可採用常用於檢測蛋白質之技術來檢測表現(例如,ELISA、西方墨點、流式細胞計、免疫螢光、免疫組織化學等等)。
除非另有說明,否則本文所定義術語「疾病」或「病症」係指可接受本文所提供化合物或方法治療之患者或個體體之狀態或健康狀態。該疾病可為癌症。該疾病可為自體免疫疾病。該疾病可為發炎性疾病。該疾病可為感染性疾病。有些其他例子中,「癌症」係指人類癌症與癌瘤、肉瘤、腺癌瘤、淋巴瘤、白血病等等,包括實體與類淋巴癌、腎臟、乳房、肺、膀胱、結腸、卵巢、攝護腺、胰臟、胃、腦、頭與頸、皮膚、子宮、睪丸、膠質瘤、食道、與肝臟之癌症,包括肝細胞癌、淋巴瘤,包括B- 急性淋巴母細胞淋巴瘤、非霍奇金氏淋巴瘤(例如,勃奇氏、小細胞、與大細胞之淋巴瘤)、霍奇金氏淋巴瘤、白血病(包括MDS、AML、ALL、ATLL與CML)、或多發性淋巴瘤。
除非另有說明,否則本文所定義術語「發炎性疾病」係指特徵在於異常發炎之疾病或病症(例如,發炎程度比對照組(如未罹患疾病的健康人)增加)。發炎性疾病實例包括自體免疫疾病、關節炎、類風濕關節炎、乾癬性關節炎、幼年型特發性關節炎、多發性硬化、全身紅斑性狼瘡(SLE)、重肌無力症、幼年型糖尿病、1型糖尿病、格林-巴利症候群(Guillain-Barre syndrome)、橋本氏(Hashimoto’s)腦炎、橋本氏甲狀腺炎、僵直性脊椎炎、乾癬、薛格連氏症候群(Sjogren’s syndrome)、脈管炎、腎小球腎炎、自體免疫甲狀腺炎、白塞病(Behcet’s disease)、克隆氏症(Crohn’s disease)、潰瘍性結腸炎、大水皰性類天皰瘡、結節病、魚鱗癬、葛瑞夫茲氏眼病變(Graves ophthalmopathy)、發炎性腸部疾病、愛迪生氏症(Addison’s disease)、白斑症、氣喘、過敏性氣喘、痤瘡、乳糜瀉、慢性攝護腺炎、發炎性腸部疾病、骨盆發炎性疾病、再灌流傷害、絕血再灌流傷害、中風、結節病、移植排斥、間質性膀胱炎、動脈粥樣硬化、硬皮病、與異位性皮膚炎。此等病症經常無法擺脫與其他疾病、病變、及病症糾纏。例如,可為由發炎性細胞素引起之發炎性相關疾病、病變與病症之不設限列表包括關節炎、腎衰竭、狼瘡、氣喘、乾 癬、結腸炎、胰炎、過敏症、纖維化、手術併發症(例如,其中發炎性細胞素阻止癒合)、貧血、與纖維肌痛。與慢性發炎相關之其他疾病與病變包括阿茲海默症(Alzheimer’s disease)、充血性心臟衰竭、中風、主動脈瓣狹窄、動脈硬化、骨質疏鬆症、帕金森氏症(Parkinson’s Disease)、感染、發炎性腸部疾病(IBD)、過敏性接觸性皮膚炎與其他濕疹、全身性硬化、移植與多發性硬化。有些上述疾病、病變與病症中,本發明化合物(例如,CCR4抑制劑)特別有效者(因為例如,受限於目前療法者)將更詳細說明於下文中。發炎性疾病實例包括創傷性腦傷害、關節炎、類風濕關節炎、乾癬性關節炎、幼年型特發性關節炎、多發性硬化、全身紅斑性狼瘡(SLE)、重肌無力症、幼年型糖尿病、1型糖尿病、格林-巴利症候群(Guillain-Barre Syndrome)、橋本氏腦炎、橋本氏甲狀腺炎、僵直性脊椎炎、乾癬、薛格連氏症候群(Sjogren’s Syndrome)、脈管炎、腎小球腎炎、自體免疫甲狀腺炎、白塞病(Behcet’s disease)、克隆氏症(Crohn’s disease)、潰瘍性結腸炎、大水皰性類天皰瘡、結節病、魚鱗癬、葛瑞夫茲氏眼病變(Graves ophthalmopathy)、發炎性腸部疾病、愛迪生氏症(Addison’s disease)、白斑症、氣喘、氣喘、過敏性氣喘、痤瘡、乳糜瀉、慢性攝護腺炎、發炎性腸部疾病、骨盆發炎性疾病、再灌流傷害、結節病、移植排斥、間質性膀胱炎、動脈粥樣硬化、與異位性皮膚炎。
除非另有說明,否則本文所定義術語「癌 症」係出現在哺乳動物中的所有類型癌症、新生瘤或惡性腫瘤,包括白血病、癌瘤與肉瘤。可接受本文所提供化合物或方法治療之癌症實例包括腦癌、膠質瘤、膠母細胞瘤、神經母細胞瘤、攝護腺癌、結腸直腸癌、胰臟癌、子宮頸癌、胃癌、卵巢癌、肺癌、與頭部癌症。可採用本文所提供化合物或方法治療之癌症實例包括甲狀腺癌、內分泌系統癌、腦癌、乳癌、子宮頸癌、結腸癌、頭與頸癌、肝癌、腎癌、肺癌、非小細胞肺癌、黑色素瘤、間皮瘤、卵巢癌、肉瘤、胃癌、子宮癌、髓母細胞瘤、結腸直腸癌、胰臟癌。其他實例包括甲狀腺癌瘤、膽管癌、胰臟腺癌瘤、皮膚黑色素瘤、結腸腺癌瘤、直腸腺癌瘤、胃腺癌瘤、食道癌瘤、頭與頸鱗狀細胞癌瘤、乳房侵襲性癌瘤、肺腺癌瘤、肺鱗狀細胞癌瘤、霍奇金氏症、非霍奇金氏淋巴瘤、多發性淋巴瘤、神經母細胞瘤、膠質瘤、多形性膠質母細胞瘤、卵巢癌、橫紋肌肉瘤、原發性血小板增多症、原發性巨球蛋白血症、原發性腦腫瘤、癌症、惡性胰臟胰島素瘤、惡性類癌症、泌尿膀胱癌、惡性前皮膚損傷、睪丸癌、淋巴瘤、甲狀腺癌、神經母細胞瘤、食道癌、生殖泌尿道癌、惡性高血鈣症、子宮內膜癌、腎上腺皮質癌、內分泌或外分泌胰臟之新生贅瘤、髓質甲狀腺癌、髓質甲狀腺癌瘤、黑色素瘤、結腸直腸癌、乳突狀甲狀腺癌、肝細胞癌瘤、或攝護腺癌。
除非另有說明,否則本文所定義術語「白血病」廣義上指造血器官的進行性惡性疾病,並且一般特 徵在於血液和骨髓中白血球與其前體異常增生和發育。白血病通常在臨床上基於以下幾點進行分類:(1)急性或慢性疾病的持續時間和特性;(2)所涉及細胞之類型:骨髓細胞(骨髓產生)、淋巴細胞(淋巴產生)、或單核細胞;及(3)白血病或白血球缺乏症(亞白血病)血液中異常細胞數增加或不增加。可接受本文所提供化合物或方法治療之白血病實例包括例如,急性非淋巴球性白血病、慢性淋巴球性白血病、急性粒細胞性白血病、慢性粒細胞性白血病、急性前骨髓細胞性白血病、成人T-細胞白血病、白血球缺乏性白血病、白細胞不增多性白血病、嗜鹼性白血病、母細胞性白血病、牛白血病、慢性髓細胞性白血病、皮膚白血病、胚胎白血病、嗜伊紅性白血病、格羅斯白血病(Gross’ leukemia)、毛細胞白血病、血母細胞性白血病、血胚細胞性白血病、組織細胞性白血病、幹細胞白血病、急性單核細胞性白血病、白血球減少性白血病、淋巴性白血病、淋巴母細胞性白血病、淋巴細胞性白血病、淋巴系源性白血病、淋巴性白血病、淋巴肉瘤細胞白血病、肥大細胞白血病、巨核細胞白血病、小骨髓母細胞性白血病、單核細胞性白血病、髓母細胞性白血病、髓細胞性白血病、骨髓粒細胞性白血病、髓單核細胞性白血病、內格利(Naegeli)白血病、漿細胞白血病、多重骨髓瘤、漿細胞性白血病、前骨髓細胞性白血病、利達(Rieder)細胞白血病、席林氏(Schilling’s)白血病、幹細胞白血病、亞白血病性白血病、或未分化細胞白血病。
除非另有說明,否則本文所定義術語「淋巴瘤」係指一種會影響造血與淋巴組織之癌症。其起源於淋巴細胞(係主要出現在淋巴結、脾臟、胸腺、與骨髓之血液細胞)。兩種主要淋巴瘤型態為非霍奇金氏淋巴瘤與霍奇金氏疾病。霍奇金氏疾病佔所有確診淋巴瘤之約15%。其係一種與立德-史登堡氏(Reed-Sternberg)惡性B淋巴細胞有關之癌症。非霍奇金氏淋巴瘤(NHL)可依據癌症生長速度及所涉及細胞型態分類。分成侵襲性(高惡性度)與和緩性(低惡性度)NHL。依據所涉及之細胞型態,分成B-細胞與T-細胞NHL。可使用本文所提供化合物或方法治療之B-細胞淋巴瘤實例包括,但不限於,小淋巴細胞淋巴瘤、套細胞淋巴瘤、濾泡淋巴瘤、邊緣區型淋巴瘤、結節外(MALT)淋巴瘤、結節(單核細胞樣B-細胞)淋巴瘤、脾臟淋巴瘤、瀰漫性大細胞B-淋巴瘤、勃奇氏淋巴瘤、淋巴母細胞性淋巴瘤、免疫母細胞性大細胞淋巴瘤、或前體B-淋巴母細胞性淋巴瘤。可使用本文所提供化合物或方法治療之T-細胞淋巴瘤實例包括,但不限於,皮膚T-細胞淋巴瘤、外周T-細胞淋巴瘤、分化不良型大細胞淋巴瘤、蕈狀肉芽腫、與前體T-淋巴母細胞性淋巴瘤。
除非另有說明,否則本文所定義術語「肉瘤」一般係指由如胚胎結締組織之物質構成之腫瘤,通常由緊密堆疊之細胞包埋在纖絲狀或均質狀物質中組成。可接受本文所提供化合物或方法治療之肉瘤包括軟骨肉瘤、纖維瘤、淋巴瘤、黑色素瘤、黏液肉瘤、骨肉瘤、艾比氏 (Abemethy's)肉瘤、脂肪肉瘤(adipose sarcoma)、脂肪瘤(iiposarcoma)、肺泡狀軟組織肉瘤、釉質母細胞肉瘤、葡萄狀肉瘤、綠色瘤肉瘤、絨毛膜癌、胚胎性肉瘤、威姆爾氏腫瘤肉瘤(Wilms' tumor sarcoma)、子宮內膜肉瘤、基質肉瘤、尤因氏(Ewing's)肉瘤、筋膜肉瘤、纖維母細胞肉瘤、巨細胞肉瘤、粒細胞肉瘤、霍奇金氏(Hodgkin's)肉瘤、特發性多發性色素沉著出血性肉瘤、B細胞之免疫母細胞肉瘤、淋巴瘤、T細胞之免疫母細胞肉瘤、延森氏(Jensen's)肉瘤、卡波西氏(Kaposi's)肉瘤、枯氏(Kupffer)細胞肉瘤、血管肉瘤、白血病性肉瘤、惡性間葉肉瘤、骨膜外肉瘤、網狀細胞肉瘤、勞斯(Rous)肉瘤、漿液囊性肉瘤、滑膜肉瘤、或毛細管擴張性肉瘤。
除非另有說明,否則本文所定義術語「黑色素瘤」意指起源於皮膚與其他器官的黑色素細胞系統的腫瘤。可接受本文所提供化合物或方法治療之黑色素瘤包括,例如,肢端雀斑樣黑色素瘤、無黑色素黑色素瘤、良性幼年黑色素瘤、克勞德曼氏(Cloudman's)黑色素瘤、S91黑色素瘤、哈丁-帕希(Harding-Passey)黑色素瘤、幼年型黑色素瘤、惡性雀斑樣黑色素瘤、惡性黑色素瘤、結節性黑色素瘤、指甲下黑色素瘤(subungal melanoma)、或淺表擴張性黑色素瘤。
除非另有說明,否則本文所定義術語「癌瘤」係指由容易浸潤周圍組織並產生轉移的上皮細胞組成的惡性新生物(new growth)。可接受本文所提供化合物或 方法治療之癌瘤實例包括例如,甲狀腺癌瘤、膽管癌瘤、胰臟腺癌瘤、皮膚黑色素瘤、結腸腺癌瘤、直腸腺癌瘤、胃腺癌瘤、食道癌瘤、頭與頸鱗狀細胞癌瘤、乳房侵襲性癌瘤、肺腺癌瘤、肺鱗狀細胞癌瘤、甲狀腺髓質癌瘤、家族性甲狀腺髓質癌瘤、腺泡癌瘤(acinar carcinoma)、腺泡癌瘤(acinous carcinoma)、腺囊性癌瘤(adenocystic carcinoma)、腺樣囊性癌瘤(adenoid cystic carcinoma)、腺瘤性癌瘤、腎上腺皮質癌瘤、肺泡癌瘤、肺泡細胞癌瘤、基底細胞癌瘤(basal cell carcinoma)、基底細胞癌瘤(carcinoma basocellulare)、基底細胞樣癌瘤、基底鱗狀細胞癌瘤、細支氣管肺泡癌瘤、細支氣管癌瘤、支氣管原癌瘤、腦質樣癌瘤、膽管細胞癌瘤、絨毛膜癌瘤、膠體癌瘤、粉刺狀癌瘤、子宮體癌瘤、篩板狀癌瘤、鎧甲狀癌瘤、皮膚癌瘤、柱狀癌瘤、柱狀細胞癌瘤、管癌瘤(duct carcinoma)、導管癌瘤(ductal carcinoma)、硬癌瘤(carcinoma durum)、胚胎性癌瘤、腦狀癌瘤、表皮樣癌瘤、腺樣上皮細胞癌瘤、外生性癌瘤、潰瘍性癌瘤、纖維癌瘤(carcinoma fibrosum)、膠樣癌瘤(gelatiniforni carcinoma)、膠樣癌瘤(gelatinous carcinoma)、巨細胞癌瘤(gigant cell carcinoma)、巨細胞癌瘤(carcinoma gigantocellulare)、腺癌瘤、顆粒細胞癌瘤、毛基質癌瘤、血樣癌瘤、肝細胞癌瘤、許特爾細胞(Hurthle cell)癌瘤、玻璃樣變性癌瘤、腎上腺樣癌瘤(hypernephroid carcinoma)、幼年型胚胎性癌瘤、原位癌瘤、表皮內癌瘤、上皮內癌瘤、克羅佩柯氏 (Krompecher's)癌瘤、庫爾契茨基細胞癌瘤(Kulchitzky-cell carcinoma)、大細胞癌瘤、豆狀癌瘤(lenticular carcinoma)、豆狀癌瘤(carcinoma lenticulare)、脂瘤樣癌瘤、淋巴上皮癌瘤、髓樣癌瘤(carcinoma medullare)、髓樣癌瘤(medullary carcinoma)、黑色素癌瘤、軟癌瘤、黏液癌瘤(mucinous carcinoma)、黏液癌瘤(carcinoma muciparum)、黏液細胞癌瘤、黏液表皮樣癌瘤、黏液癌瘤(carcinoma mucosum)、黏液癌瘤(mucous carcinoma)、黏液變性樣癌瘤(carcinoma myxomatodes)、鼻咽癌瘤、燕麥細胞癌瘤、骨化性癌瘤(carcinoma ossificans)、骨化性癌瘤(osteoid carcinoma)、乳頭狀癌瘤、門脈周癌瘤、浸潤前癌瘤、棘細胞癌瘤、髓樣癌瘤、腎臟之腎細胞癌瘤、儲備細胞癌瘤、肉瘤樣癌瘤、施奈德氏(Schneiderian)癌瘤、硬癌瘤(scirrhous carcinoma)、陰囊癌瘤、印戒細胞癌瘤、單純癌瘤、小細胞癌瘤、硬癌瘤(solanoid carcinoma)、球形細胞癌瘤、梭形細胞癌瘤、髓樣癌瘤(carcinoma spongiosum)、鱗狀癌瘤、鱗狀細胞癌瘤、繩捆癌瘤、血管擴張性癌瘤(carcinoma telangiectaticum)、血管擴張性癌瘤(carcinoma telangiectodes)、移行細胞癌瘤、結節性皮癌瘤(carcinoma tuberosum)、結節性皮癌瘤(tuberous carcinoma)、疣狀癌瘤、或絨毛狀癌瘤。
除非另有說明,否則本文所定義術語「自體免疫疾病」係指個體之免疫系統對在健康人體中不引發免疫反應之物質具有異常免疫反應之疾病或病症。可接受 本文所說明化合物、醫藥組成物、或方法治療之自體免疫疾病實例包括急性瀰漫性腦脊髓炎(ADEM)、急性壞死出血性腦脊髓炎、愛迪生氏症(Addison’s disease)、無伽瑪球蛋白血症、斑禿、澱粉樣變性、僵直性脊椎炎、抗-GBM/抗-TBM腎炎、抗磷脂質症候群(APS)、自體免疫血管性水腫、自體免疫再生不良性貧血、自體免疫自主神經障礙、自體免疫肝炎、自體免疫高脂血症、自體免疫性免疫缺陷、自體免疫內耳疾病(AIED)、自體免疫心肌炎、自體免疫卵巢炎、自體免疫胰炎、自體免疫視網膜病變、自體免疫血小板減少性紫癜(ATP)、自體免疫甲狀腺疾病、自體免疫蕁麻疹、軸索型或神經元型神經病變、巴婁病(Balo disease)、白塞病(Behcet’s disease)、大水皰性類天皰瘡、心肌病、凱撒曼氏症(Castleman disease)、乳糜瀉、查加斯氏症(Chagas disease)、慢性疲勞症候群、慢性發炎性脫髓鞘多發性神經病變(CIDP)、慢性復發性多病灶性骨髓炎(CRMO)、查格-施特勞斯症候群(Churg-Strauss syndrome)、瘢痕性類天皰瘡/良性黏膜類天皰瘡、克隆氏症(Crohn’s disease)、柯根症候群(Cogans syndrome)、冷凝集素症、先天性心臟傳導阻滯、克沙奇病毒性心肌炎、CREST疾病、特發性混合型冷凝球蛋白血症、脫髓鞘性神經病、疱疹性皮膚炎、皮肌炎、戴維克氏症(Devic’s disease)(視神經脊髓炎)、圓盤狀狼瘡、卓斯勒症候群(Dressler’s Syndrome)、子宮內膜異位症、嗜伊紅性食道炎、嗜伊紅性肌膜炎、結節性紅斑、實驗性過敏性腦脊髓 炎、伊凡斯症候群(Evan’s Syndrome)、纖維肌痛、纖維化肺泡炎、巨細胞動脈炎(顳動脈炎)、巨細胞心肌炎、腎小球腎炎、古巴士德氏症候群(Goodpasture’s Syndrome)、肉芽腫併多發性血管炎(GPA)(過去稱為韋格納肉芽腫(Wegener’s Granulomatosis))、葛瑞夫茲氏症(Graves’disease)、格林-巴利症候群(Guillain-Barre Syndrome)、橋本氏腦炎、橋本氏甲狀腺炎、溶血性貧血、過敏性紫斑症(Henoch-Schonlein purpura)、妊娠皰疹、低珈瑪球蛋白血症、特發性血小板減少性紫癜(ITP)、IgA腎病變、IgG4-相關之硬化疾病、免疫調節性脂蛋白、包涵體肌炎、間質性膀胱炎、幼年型關節炎、幼年型糖尿病(1型糖尿病)、幼年型肌炎、川崎症候群(Kawasaki Syndrome)、藍伯-伊頓症候群(Lambert-Eaton Syndrome)、白血球細胞破裂性脈管炎、扁平苔蘚、硬化性苔癬、木樣結膜炎、線狀IgA疾病(LAD)、狼瘡(SLE)、萊姆病(Lyme disease)、慢性梅尼爾氏症(Meniere’s disease)、顯微性多血管炎、混合型結締組織疾病(MCTD)、莫倫氏潰瘍(Mooren’s ulcer)、慕奇-赫巴二氏症(Mucha-Habermann disease)、多發性硬化、重肌無力症、肌炎、猝睡症、視神經脊髓炎(戴維克氏症(Devic’s))、中性粒細胞減少症、眼科瘢痕性類天皰瘡、視神經炎、復發性風濕症、PANDAS(與鏈球菌有關的小兒自體免疫性神經精神病變)、腫瘤伴生性小腦變性、陣發性夜間血紅蛋白尿(PNH)、帕里-羅姆伯格症候群(Parry Romberg Syndrome)、帕森納特-特納症候群 (Parsonnage-Turner Syndrome)、平坦部炎(周圍性葡萄膜炎)、天皰瘡、外周神經病變、靜脈周圍腦脊髓炎、惡性貧血、POEMS症候群、結節性多動脈炎、I型,II型和III型自體免疫多腺體症候群、風濕性多發性肌痛、多發性肌炎、心肌梗塞後症候群、心包膜切開後症候群、孕激素皮炎、原發性膽汁性肝硬化、原發性硬化性膽管炎、乾癬、乾癬性關節炎、特發性肺纖維化、壞疽性皮炎、純紅細胞發育不良、雷諾現象(Raynauds phenomenon)、反應性關節炎、反射交感神經營養不良、萊特氏症候群(Reiter’s Syndrome)、復發性多軟骨炎、不寧腿症候群、腹膜後纖維化、風濕熱、類風濕關節炎、結節病、施密特症候群(Schmidt Syndrome)、鞏膜炎、硬皮病、薛格連氏症候群(Sjogren’s Syndrome)、精子與睪丸自體免疫、僵硬人症候群、亞急性細菌性心內膜炎(SBE)、蘇薩克症候群(Susac’s Syndrome)、交感性眼炎、高安氏動脈炎(Takayasu’s arteritis)、顳動脈炎/巨細胞動脈炎、血小板減少性紫癜(TTP)、特勒-亨特症候群(Tolosa-Hunt Syndrome)、橫貫性脊髓炎、1型糖尿病、潰瘍性結腸炎、未分化結締組織疾病(UCTD)、葡萄膜炎、脈管炎、囊泡性皮膚病、白斑症、或韋格納肉芽腫(Wegener’s Granulomatosis)(亦即肉芽腫併多發性血管炎(GPA))。
除非另有說明,否則本文所定義術語「處理」或「治療」係指在成功治療或緩解損傷、疾病、病變或病症時之任何指標,包括任何主觀或客觀參數,如:症 狀減少、減輕、消退或讓患者更能耐受傷害、病變或病症;減慢變性或退化速率;減輕變性終點時之耗弱性;改善患者之身心健康。症狀之治療或緩解可依據客觀或主觀之參數;包括身體檢查結果、神經精神性檢查、與/或心理評估。術語「治療」與其接合術語可包括預防傷害、病變、病症、或疾病。具體實施例中,該治療係預防。具體實施例中,該治療不包括預防。具體實施例中,該處理或治療不為預防性處理。
本文所採用「處理」或「治療」(且係相關技藝咸了解者)亦廣義包括任何可在個體之病症上達到有利或所需結果(包括臨床結果)之方法。有利或所需結果包括,但不限於一或多種症狀或病症減輕或緩解、疾病程度消退、疾病狀態穩定(亦即不惡化)、預防疾病傳播或擴散、疾病演進延緩或減慢、疾病狀態緩解或緩和、疾病復發減少及減輕,不論部份或完全及不論可檢測或不可檢測。換言之,本文所採用「治療」包括疾病之任何治癒、緩解、或預防。治療可以預防該疾病發生;抑制該疾病擴散;解除該疾病的症狀(例如,眼睛疼痛、在燈光周圍看到光暈、紅眼、眼內壓極高)、完全或部份排除該疾病的肇因、縮短罹病時間、或此等事件之組合。
本文所採用「處理」或「治療」包括預防性處理。處理方法包括對個體投與醫療有效量之本文說明之化合物。投藥步驟可包括單次投藥或可包括一系列投藥。治療期長度依各種不同因素而定,如病症嚴重性、患 者年齡、化合物濃度、用於治療之組成物之活性、或其組合。亦咸了解,用於治療或預防之藥劑之有效量可能隨特定治療或預防過程增加或降低。劑量有可能改變,而且係本領域所習知之標準診斷分析法咸了解者。有些例子中,可能需要長期投藥。例如,投與個體之組成物用量及持續時間應足以治療該患者。
除非另有說明,否則本文所定義術語「預防」係指減少患者之疾病症狀發生。如上述,預防法可能為完全(沒有可檢測之症狀)或部份預防,因此比沒有治療時觀察到較少症狀。具體實施例中,預防係指減慢該疾病、病變或病症演進,或抑制其演進成有害或不期望的狀態。
除非另有說明,否則本文所定義術語「患者」或「有此需要之個體」係指罹患或易感可因投與本文所提供醫藥組成物而治療之疾病或病症之活生物體。其不設限實例包括人類、其他哺乳動物、牛、大鼠、小鼠、狗、猴子、山羊、綿羊、乳牛、鹿、與其他非哺乳動物。有些具體實施例中,患者為人類。
除非另有說明,否則本文所定義術語「有效量」為相對於沒有使用化合物時,該化合物足以完成所陳述目的時之用量(例如,達到投藥效力、治療疾病、減低酵素活性、增加酵素活性、減低訊號轉導途徑、或減低疾病或病症之一或多種症狀)。「有效量」之實例為足以造成治療、預防、或減低疾病之一或多種症狀時之用量,其亦可稱為「醫療有效量」。一或多種症狀之「減低」(及文法 上同等用法之片語)意指降低症狀(群)之嚴重性或頻率、或消除症狀(群)。藥物之「預防有效量」為藥物在投與個體時將具有計畫之預防效果時之用量,例如,預防或延緩傷害、疾病、病變或病症之發作(或復發),或降低該傷害、疾病、病變或病症發作(或復發)之可能性。投與一劑不一定可以產生完全預防效力,且可能僅在投與一系列劑量後才會產生。因此,預防有效量可能投與一或多次。本文所採用「降低活性之用量」係指相對於沒有拮抗劑時,為了降低酵素活性時所需之拮抗劑用量。本文所採用「瓦解功能之用量」係指相對於沒有拮抗劑時,為了瓦解酵素或蛋白質功能時所需之拮抗劑用量。確實用量將隨治療目的而定,將由本領域技術人員採用已知技術確認(參見例如,Lieberman,Pharmaceutical Dosage Forms(vols.1-3,1992);Lloyd,The Art,Science and Technology of Pharmaceutical Compounding(1999);Pickar,Dosage Calculations(1999);及Remington:The Science and Practice of Pharmacy,第20版,2003,Gennaro編輯,Lippincott,Williams & Wilkins)。可藉由測定相關生理效應來確定醫療有效量,並可隨投藥療程及個體病症之診斷分析等等來調整。例如,在投藥後特定時間點測定血清中CCR4抑制劑(或例如,其代謝物)濃度,即可能指示是否已投與醫療有效量。
本文所說明之任何化合物中,可先由細胞培養分析法測定醫療有效量。目標濃度為彼等可以達成本 文所說明方法之活性化合物(群)濃度,其係採用本文說明之方法或本領域習知之方法測定。
如本領域所習知,亦可由動物模式決定用於人類之有效量。例如,用於人類之劑量可以調配至已在動物中發現有效之濃度。可藉由追蹤化合物有效性來調整人類之劑量,並如上述向上或向下調整劑量。依據上述方法及本領域技術人員能力範圍內之其他方法調整劑量,以在人體中達到最大效力。依據上述方法及本領域技術人員能力範圍內之其他方法調整劑量,以在人體中達到最大醫療窗口效力或毒性。
除非另有說明,否則本文所定義術語「醫療有效量」意指醫療劑足以如上述緩解病變時之用量。例如,醫療有效量將使特定參數增加或降低至少5%、10%、15%、20%、25%、40%、50%、60%、75%、80%、90%、或至少100%。醫藥有效量亦可呈增加或降低之「倍數」表示。例如,醫療有效量可比對照組具有至少1.2倍、1.5倍、2倍、5倍、或更高之效應。
劑量可以隨患者之需求及所使用之化合物改變。本發明內容中,投與患者之劑量應足以在患者中隨時間產生有利之醫療效應。亦可由任何不良副作用之存在、性質、與程度來決定劑量大小。本領域技術人員有能力針對特定情況決定適當劑量。通常,先以低於化合物最佳劑量之較小劑量開始治療。然後,以小量遞增劑量,直到達到環境下最佳效應時為止。可以個別調整投藥劑量與 間隔,以針對所治療特定臨床病症投與該化合物之有效量。此舉將可配合個人之疾病狀態之嚴重性提供療程。
除非另有說明,否則本文所定義術語「投藥」意指經口投與、呈栓劑投與、外用局部接觸、經靜脈內、非經腸道、經腹膜內、經肌內、病灶內、鞘內、顱內、鼻內或皮下投與,或將緩釋裝置,例如,迷你滲透幫浦,植入個體內。可採用任何途徑投藥,包括非經腸道與穿黏膜(例如,頰內、舌下、上顎、齒齦、鼻、陰道、直腸、或穿皮式)。非經腸道投藥法包括例如,靜脈內、肌內、細動脈內、皮內、皮下、腹膜內、心室內、與顱內。其他傳遞模式包括,但不限於使用微脂體內調配物、靜脈內輸注、穿皮式貼布等等。「共同投藥」意指本文所說明組成物係同時間投與、或在即將投與一或多種其他療法(例如,抗癌劑、化療或治療神經退化性疾病)之前或之後投與。具體實施例中,投藥法不包括投與所述活性劑以外之任何其他活性劑。本發明化合物可以單獨投與或可共同投與患者。共同投藥法包括同時或依序個別投與該化合物或組合投藥(超過一種化合物或藥劑)。因此,若需要時,製劑亦可與其他活性物質組合(例如,減少代謝降解)。本發明組成物之傳遞法可採用穿皮式、外用局部途徑、調配成施藥用膏條、溶液、懸浮液、乳液、凝膠、乳霜、油膏、糊劑、凍膠、塗料、粉劑、與氣霧劑。口服劑包括適合患者服用之錠劑、丸劑、粉劑、糖衣錠、膠囊、液體、喉糖、膜衣錠、凝膠、糖漿、漿液、懸浮液等等。固體型製劑包括粉劑、 錠劑、丸劑、膠囊、膜衣錠、栓劑、與勻散性粒劑。液體型製劑包括溶液、懸浮液、與乳液,例如,水或水/丙二醇溶液。本發明組成物可另外包括產生持續釋放與/或舒適感之組份。此等組份包括高分子量、陰離子性擬黏膜聚合物、膠凝多醣與細碎分散之藥物載劑基質。此等組份更詳細討論於美國專利案案號4,911,920;5,403,841;5,212,162;及4,861,760。此等專利案之完整內容已針對所有目的,以引用方式完全併入本文中。本發明組成物亦可呈微球傳遞,於體內慢慢釋放。例如,微球之投藥法可經由皮內注射含藥物之微球,在皮下慢慢釋放(參見Rao,J.Biomater Sci.Polym.Ed.7:623-645,1995);呈生物可降解且可注射之凝膠調配物(參見例如,Gao Pharm.Res.12:857-863,1995);或呈口服用之微小球(參見例如,Eyles,J.Pharm.Pharmacol.49:669-674,1997)。另一項具體實施例中,本發明組成物之調配物可使用與細胞膜融合或被細胞吞噬之脂質體傳遞,亦即利用附接脂質體之受體配體傳遞,其會與細胞之表面膜蛋白質受體結合,造成細胞吞噬。藉由使用脂質體,特別當脂質體表面帶有針對標靶細胞或優先針對特定器官之受體配體時,即可著重於活體內傳遞本發明組成物至標靶細胞內(參見例如,Al-Muhammed,J.Microencapsul.13:293-306,1996;Chonn,Curr.Opin.Biotechnol.6:698-708,1995;Ostro,Am.J.Hosp.Pharm.46:1576-1587,1989)。本發明組成物亦可呈奈米粒子傳遞。具體實施例中,該投藥法不包括投與所述活性劑以外 之任何其他活性劑。
除非另有說明,否則本文所定義術語「共同投藥」意指本文所說明組成物係同時間投與、或在即將投與一或多種其他療法之前或之後投與。本發明化合物可以單獨投與或可共同投與患者。共同投藥法意指包括同時或依序個別投與該化合物或組合投與(超過一種化合物)。本發明組成物之傳遞法可採用穿皮式、外用局部途徑、調配成施藥用膏條、溶液、懸浮液、乳液、凝膠、乳霜、油膏、糊劑、凍膠、塗料、粉劑、與氣霧劑。
本文所說明之任何化合物中,可先由細胞培養分析法測定醫療有效量。目標濃度為彼等可以達成本文所說明方法之活性化合物(群)濃度,其係採用本文說明之方法或本領域習知之方法測定。
如本領域所習知,亦可由動物模式決定用於人類之醫療有效量。例如,用於人類之劑量可以調配至已在動物中發現有效之濃度。可藉由追蹤化合物有效性來調整人類之劑量,並如上述向上或向下調整劑量。依據上述方法及本領域技術人員能力範圍內之其他方法調整劑量,以在人體中達到最大效力。
劑量可以隨患者之需求及所使用之化合物改變。本發明內容中,投與患者之劑量應足以在患者中隨時間產生有利之醫療效應。亦可由任何不良副作用之存在、性質、與程度來決定劑量大小。本領域技術人員有能力針對特定情況決定適當劑量。通常,先以低於化合物最 佳劑量之較小劑量開始治療。然後,以小量遞增劑量,直到達到環境下最佳效應時為止。
可以個別調整投藥劑量與間隔,以針對所治療特定臨床病症投與該化合物之有效量。此舉將可配合個別之疾病狀態之嚴重性提供療程。
利用本文提供之教示,可以計畫不會造成實質毒性且仍可有效治療特定患者所出現之臨床症狀之有效預防或治療療程。此計畫應涉及考量如:化合物效力、相對生體可用率、患者體重、不良副作用之存在與嚴重度、較佳投藥模式、及所選用藥劑之毒性型態等因素,小心選擇活性化合物。
本文所說明化合物可以彼此組合,與其他已知適用於治療癌症(例如,結腸癌)、心血管疾病、代謝疾病、免疫或發炎性疾病或病變之活性劑組合使用。
有些具體實施例中,共同投藥法包括其中一種活性劑之投藥時間係在第二種活性劑之0.5、1、2、4、6、8、10、12、16、20、24小時、2天、4天、1週或1個月內。共同投藥法包括兩種活性劑係同時投藥、約同時投藥(例如,彼此在約1、5、10、15、20、或30分鐘內)、或依任何次序連續投藥。有些具體實施例中,共同投藥法採用共同調配法來達成,亦即製成同時包括兩種活性劑之單一醫藥組成物。其他具體實施例中,活性劑可以分開調配。另一項具體實施例中,活性劑與/或佐劑可以彼此連接或接合。有些具體實施例中,本文所說明化合物可與癌症 (例如,結腸癌)、心血管疾病、代謝疾病、免疫或發炎性疾病或病變之治療法組合。
除非另有說明,否則本文所定義術語「心血管藥劑」係依據其一般定義使用,且係指以任何方式用於治療心臟或循環系統或血管系統病症之組成物(例如,化合物、藥物、拮抗劑、抑制劑、調控劑)。有些具體實施例中,心血管藥劑為本文中已判別可用於治療心血管疾病或病變之方法之藥劑。有些具體實施例中,心血管藥劑為FDA或美國以外的國家之類似管理機關所核准用於治療心血管疾病或病變之藥劑。
除非另有說明,否則本文所定義術語「消炎劑」係依據其一般定義使用,且係指以任何方式使發炎或腫大比對照組(例如,沒有該藥劑)減低之組成物(例如,化合物、藥物、拮抗劑、抑制劑、調控劑)。有些具體實施例中,消炎劑為本文中已判別可用於治療發炎性疾病或病變之藥劑。有些具體實施例中,消炎劑為FDA或美國以外的國家之類似管理機關所核准用於降低腫大及發炎之藥劑。
可投與本文所說明化合物來治療免疫或發炎性疾病或病變、心血管或代謝疾病或病變與/或癌症。此時,本文所揭示化合物可以單獨投與來治療此等疾病或病變,或可與另一種醫療劑共同投藥來治療此等疾病或病變。
本文所揭示化合物可與細胞素或細胞素功能之促效劑或拮抗劑共同投藥(包括作用在細胞素訊號轉 導途徑之藥劑,如SOCS系統之調控劑),包括α-、β-、與γ-干擾素;類胰島素生長因子I型(IGF-1);間白素(IL),包括IL1至17、與間白素拮抗劑或抑制劑,如安納希拉(analcinra);腫瘤壞死因子α(TNF-.α.)抑制劑,如抗-TNF單株抗體(例如,抑菲單抗(infliximab);艾利單抗(adalimumab)、與CDP-870)與TNF受體拮抗劑,包括免疫球蛋白分子(如恩博(etanercept))與低分子量劑,如:配妥西菲林(pentoxyfylline)。
本文所揭示化合物可以共同投與消炎劑,如沙利竇邁(thalidomide)或其衍生物、類視黃素、蒽三酚(dithranol)或鈣泊三醇(calcipotriol)、非類固醇消炎劑(下文稱為NSAID),包括非選擇性環氧合酶COX-1/COX-2抑制劑,不論係局部或全身投藥(如:吡羅昔康(piroxicam)、雙氯芬酸(diclofenac),丙酸類藥物,如萘普生(naproxen)、夫比普洛芬(flurbiprofen)、芬諾普芬(fenoprofen)、酮洛芬(ketoprofen)與布洛芬(ibuprofen),芬那酸類藥物(fenamates),如甲芬那酸(mefenamic acid)、吲哚美辛(indomethacin)、蘇林達克(sulindac)、阿扎丙酮(azapropazone),吡唑酮類藥物,如苯丁吡唑酮(phenylbutazone),水楊酸鹽類藥物,如:阿斯匹靈(aspirin));選擇性COX-2抑制劑(如美洛昔康(meloxicam)、塞來昔布(celecoxib)、羅非昔布(rofecoxib)、伐地考昔(valdecoxib)、魯米昔布(lumarocoxib)、帕瑞考昔(parecoxib)與依托考昔(etoricoxib));環氧合酶抑制性氧化 氮供體(CINOD);糖皮質類固醇(不論係局部、經口、肌內、靜脈內、或關節內途徑投藥);胺甲蝶呤(methotrexate);來氟米特(leflunomide);羥氯喹(hydroxychloroquine);D-青黴胺(d-penicillamine);金蘭諾芬(auranofin)或其他非經腸式或口服黃金製劑;止痛藥;雙醋瑞因(diacerein);關節內療法,如玻尿酸衍生物;及營養補充劑,如葡糖胺。
本文所揭示化合物可以共同投與鈣通道阻斷劑、β-腎上腺素受體阻斷劑、血管收縮素轉換酶(ACE)抑制劑、血管收縮素-2受體拮抗劑;降脂質劑,如抑制素(statin)或纖維酸酯類(fibrate);血細胞形態調控劑,如配妥西菲林(pentoxyfylline);溶血栓劑、或抗凝血劑,如血小板凝集抑制劑。
除非另有說明,否則本文所定義「抗癌劑」與「抗癌藥劑」係依據其一般常見方式使用,且係指具有抗新生瘤性質或有能力抑制細胞生長或增生之組成物(例如,化合物、藥物、拮抗劑、抑制劑、調控劑)。有些具體實施例中,抗癌劑為化療劑。有些具體實施例中,抗癌劑為本文已判定可用在治療癌症之方法中之藥劑。有些具體實施例中,抗癌劑為FDA或美國以外的國家之類似管理機關所核准用於治療癌症之藥劑。抗癌劑實例包括,但不限於,MEK(例如,MEK1、MEK2、或MEK1與MEK2)抑制劑(例如,XL518、CI-1040、PD035901、斯利替尼(selumetinib)/AZD6244、GSK1120212/曲美替尼(trametinib)、GDC-0973、ARRY-162、ARRY-300、 AZD8330、PD0325901、U0126、PD98059、TAK-733、PD318088、AS703026、BAY 869766)、烷化劑(例如,環磷醯胺、異環磷醯胺(ifosfamide)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、馬法蘭(melphalan)、二氯甲基二乙胺(mechlorethamine)、尿嘧啶氮芥(uramustine)、噻替哌(thiotepa)、亞硝基脲、氮芥類(例如,雙(2-氯乙基)甲胺(mechloroethamine)、環磷醯胺、苯丁酸氮芥、美法蘭(meiphalan))、乙烯亞胺與甲基三聚氰胺(例如,六甲基三聚氰胺、噻替哌)、磺酸烷基酯類(例如,白消安(busulfan))、亞硝基脲(例如,卡莫司汀(carmustine)、洛莫司汀(lomusitne)、希莫司汀(semustine)、鏈脲佐菌素(streptozocin))、三氮烯類(triazenes)(達卡巴仁(decarbazine)))、抗代謝物(例如,硫唑嘌呤(5-azathioprine)、若克瘤(leucovorin)、卡培他濱(capecitabine)、氟達拉濱(fludarabine)、吉西他濱(gemcitabine)、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、葉酸類似物(例如,胺甲蝶呤(methotrexate)、或嘧啶類似物(例如,氟尿嘧啶、氟脫氧尿苷(floxouridine)、阿糖胞苷(cytarabine))、嘌呤類似物(例如,氫硫基嘌呤、硫鳥嘌呤(thioguanine)、噴司他汀(pentostatin))等等)、植物生物鹼(例如,長春新鹼(vincristine)、長春花鹼(vinblastine)、長春瑞濱(vinorelbine)、長春地辛(vindesine)、鬼臼毒素、太平洋紫杉醇(paclitaxel)、歐洲紫杉醇(docetaxel)等等)、拓樸異構 酶抑制劑(例如,伊立替康(irinotecan)、托普替康(topotecan)、安吖啶(amsacrine)、依託泊苷(etoposide)(VP16)、依託泊苷磷酸鹽、替尼泊苷(teniposide)等等)、抗腫瘤抗生素(例如,多柔比星(doxorubicin)、阿黴素(adriamycin)、唐黴素(daunorubicin)、泛艾黴素(epirubicin)、放線菌素(actinomycin)、博來黴素(bleomycin)、絲裂黴素(mitomycin)、米托蒽醌(mitoxantrone)、普卡黴素(plicamycin)等等)、基於鉑之化合物(例如,順鉑(cisplatin)、奧沙利鉑(oxaloplatin)、卡鉑(carboplatin))、蒽醌(anthracenedione)(例如,米托蒽醌(mitoxantrone))、經取代之脲(例如,羥基脲)、甲基肼衍生物(例如,丙卡巴肼(procarbazine))、腎上腺皮質抑制劑(例如,米托坦(mitotane)、氨苯哌酮(aminoglutethimide))、表鬼臼毒素(例如,依託泊苷(etoposide))、抗生素(例如,唐黴素(daunorubicin)、多柔比星(doxorubicin)、博來黴素(bleomycin))、酵素(例如,L-天冬胺酸酶)、受促分裂原活化之蛋白質激酶訊號轉導之抑制劑(例如,U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青黴素(wortmannin)、或LY294002、Syk抑制劑、mTOR抑制劑、抗體(例如,利妥昔單抗(rituxan))、棉酚(gossyphol)、淨尼辛(genasense)、多酚E、氯福辛(Chlorofusin)、全反式視黃酸(ATRA)、苔藓抑素(bryostatin)、與腫瘤壞死因子相關之誘發細胞凋亡之配體(TRAIL)、5-氮雜-2'-去氧胞苷、全反 式視黃酸、多柔比星(doxorubicin)、長春新鹼(vincristine)、依託泊苷(etoposide)、吉西他濱(gemcitabine)、伊馬替尼(imatinib)(Gleevec.RTM.)、格爾德黴素(geldanamycin)、17-N-烯丙基胺基-17-去甲氧基格爾德黴素(geldanamycin)(17-AAG)、夫拉平度(flavopiridol)、LY294002、硼替佐米(bortezomib)、曲妥珠單抗(trastuzumab)、BAY 11-7082、PKC412、PD184352、20-表-1,25二羥基維生素D3;5-乙炔基尿嘧啶;阿比特龍(abiraterone);阿柔比星(aclarubicin);阿希夫吩(acylfulvene);腺環戊醇(adecypenol);阿多來新(adozelesin);阿地白介素(aldesleukin);ALL-TK拮抗劑;六甲蜜胺(altretamine);胺莫司汀(ambamustine);2,4二氯苯氧乙酸(amidox);阿米福汀(amifostine);胺基酮戊酸(aminolevulinic acid);胺柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);安耐柔(anastrozole);穿心蓮內酯(andrographolide);血管新生抑制劑;拮抗劑D;拮抗劑G;安塔利斯(antarelix);抗背部形態形成蛋白質-1;抗雄激素,攝護腺癌;抗雌激素;抗腫瘤物質(antineoplaston);反義寡核苷酸;艾菲地可寧甘胺酸鹽(aphidicolin glycinate);細胞凋亡基因調控劑;細胞凋亡調節劑;無嘌呤酸(apurinic acid);ara-CDP-DL-PTBA;精胺酸脫胺酶;苯胺吖啶(asulacrine);阿他美坦(atamestane);阿莫司汀(atrimustine);洋蟲膠抑制素1(axinastatin 1);洋蟲膠抑制素2(axinastatin 2);洋蟲膠抑制素3(axinastatin3);阿紮司 瓊(azasetron);阿紮毒素(azatoxin);氮雜酪胺酸;漿果赤黴素III(baccatin III)衍生物;博拉諾(balanol);巴馬司他(batimastat);BCR/ABL拮抗劑;苯并二氫氯吩(benzochlorins);苯甲醯星狀孢子鹼(benzoylstaurosporine);β-內醯胺衍生物;β-艾利辛(β-alethine);β-克拉黴素B(betaclamycin B);樺木酸;bFGF抑制劑;比卡魯胺(bicalutamide);比生群(bisantrene);雙乙烯亞胺基精胺(bisaziridinylspermine);雙奈法德(bisnafide);雙崔特A(bistratene A);比折來新(bizelesin);布來福林(breflate);溴匹立明(bropirimine);布度鈦(budotitane);丁硫胺酸硫酸亞胺(buthionine sulfoximine);鈣泊三醇(calcipotriol);鈣磷酸蛋白C(calphostin C);喜樹鹼衍生物;金絲雀痘IL-2(canarypox IL-2);卡培他濱(capecitabine);羧醯胺-胺基-三唑;羧醯胺基三唑;CaRest M3;CARN700;軟骨衍生之抑制劑;卡折來新(carzelesin);酪蛋白激酶抑制劑(ICOS);粟精胺(castanospermine);天蠶抗菌肽B(cecropin B);西曲瑞克(cetrorelix);二氫卟酚(chlorins);磺胺氯喹啉(chloroquinoxaline sulfonamide);西卡前列素(cicaprost);順卟啉(cis-porphyrin);克拉屈濱(cladribine);氯米芬類似物(clomifene analogues);克黴唑(clotrimazole);克裡斯黴素A(collismycin A);克裡斯黴素B(collismycin B);考布他汀A4(combretastatin A4);考布他汀類似物;康奈精(conagenin);甘藍海綿(crambescidin)816;克立那托 (crisnatol);念珠藻環肽8(cryptophycin8);念珠藻環肽A(cryptophycin A)衍生物;鞘絲藻素A(curacin A);環戊烯蒽醌(cyclopentanthraquinones);環鉑(cycloplatam);環青黴素(cypemycin)、阿糖胞苷十八烷基磷酸鹽(Cytarabine ocfosfate);溶胞因子;磷酸己烷雌酚(cytostatin);達昔單抗(dacliximab);地西他濱(decitabine);脫氫膜海鞘素B(dehydrodidemnin B);地洛瑞林(deslorelin);地塞美松(dexamethasone);右異環磷醯胺(dexifosfamide);右雷佐生(dexrazoxane);右維拉帕米(dexverapamil);地吖醌(diaziquone);膜海鞘素B(didemnin B);第達(didox);二乙基去甲精胺(diethylnorspermine);二氫-5-氮雜胞苷;9-二氧黃溶黴素(9-dioxamycin);二苯基螺莫司汀(diphenylspiromustine);二十二烷醇(docosanol);朵拉司瓊(dolasetron);去氧氟尿苷(doxifluridine);屈洛昔芬(droloxifene);四氫大麻酚(dronabinol);倍癌黴素(duocannycin SA);依布硒(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依決洛單抗(edrecolomab);依氟鳥胺酸(eflornithine);欖香烯(elemene);乙嘧替氟(emitefur);泛艾黴素(epirubicin);愛普列特(epristeride);雌氮芥類似物(estramustine analogue);雌激素促效劑;雌激素拮抗劑;依他硝唑(etanidazole);磷酸依託泊苷(etoposide phosphate);依西美坦(exemestane);法倔唑(fadrozole);法紮拉濱(fazarabine);芬維A胺(fenretinide);非格司亭 (filgrastim);非那甾胺(finasteride);夫拉平度(flavopiridol);氟卓斯汀(flezelastine);氟海星酮(fluasterone);氟達拉濱(fludarabine);鹽酸氟代柔紅黴素(fluorodaunorunicin hydrochloride);福酚美克(forfenimex);福美坦(formestane);福司曲星(fostriecin);福莫司汀(fotemustine);莫特沙芬釓(gadolinium texaphyrin);硝酸鎵(gallium nitrate);加洛他濱(galocitabine);加尼瑞克(ganirelix);明膠酶抑制劑;吉西他濱(gemcitabine);穀胱甘肽抑制劑;赫素磺醯胺(hepsulfam);赫林蛋白(heregulin);六亞甲基雙乙醯胺;金絲桃素(hypericin);伊班膦酸(ibandronic acid);伊達比星(idarubicin);艾多昔芬(idoxifene);伊決孟酮(idramantone);伊莫福新(ilmofosine);伊洛馬司他(ilomastat);咪唑吖啶酮(imidazoacridones);咪喹莫特(imiquimod);免疫刺激肽;類胰島素生長因子-1受體抑制劑;干擾素促效劑;干擾素;間白素;碘節胍(iobenguane);碘多柔比星(iododoxorubicin);4-甘薯苦醇(ipomeanol,4-);伊羅普拉(iroplact);伊索拉定(irsogladine);異苯唑(isobengazole);同功軟海棉素(isohomohalicondrin)B;伊他司瓊(itasetron);促微絲聚合劑(jasplakinolide);環縮肽F(kahalalide F);三乙酸片螺素(lamellarin-N triacetate);蘭瑞肽(lanreotide);雷拉黴素(leinamycin);來格司亭(lenograstim);硫酸蘑菇多糖(lentinan sulfate);來泊司汀(leptolstatin);來曲唑 (letrozole);白血病抑制因子;白細胞α干擾素;柳菩林(leuprolide)+雌激素+黃體酮;亮丙瑞林(leuprorelin);左旋咪唑(levamisole);利阿唑(liarozole);線性聚胺類似物;親脂性雙醣肽;親脂性鉑化合物;利絲醯胺7(lissoclinamide 7);洛鉑(lobaplatin);胍乙基磷酸絲胺酸(lombricine);洛美曲索(lometrexol);氯尼達明(lonidamine);洛索蒽醌(losoxantrone);洛伐他汀(lovastatin);洛索立賓(loxoribine);勒托替康(lurtotecan);藍花贗靛素鎦(lutetium texaphyrin);利索茶鹼(lysofylline);溶解肽(lytic peptides);美坦新(maitansine);抑甘露糖苷酶素(mannostatin A);馬立馬司他(marimastat);馬索羅酚(masoprocol);乳腺絲胺酸蛋白酶抑制劑(maspin);基質溶解因子(matrilysin)抑制劑;基質金屬蛋白酶抑制劑;美諾立爾(menogaril);美巴龍(merbarone);美替瑞林(meterelin);甲硫胺酸酶;甲氧氯普胺(metoclopramide);MIF抑制劑;米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);錯配雙股RNA;米托胍腙(mitoguazone);二溴衛矛醇(mitolactol);絲裂黴素(mitomycin)類似物;米托萘胺(mitonafide);絲裂毒素(mitotoxin)纖維母細胞生長因子-皂草素;米托蒽醌(mitoxantrone);莫法羅汀(mofarotene);莫拉司亭(molgramostim);單株抗體,人類絨毛膜促性腺激素;單磷醯基脂質A+分枝桿菌(myobacterium)細胞壁sk;莫比達醇(mopidamol);多種抗 藥性基因抑制劑;基於多重腫瘤抑制基因-1之療法;氮芥抗癌劑;印度洋海綿B(mycaperoxide B);分枝桿菌細胞壁抽出物(mycobacterial cell wall extract);苔蘚蟲海綿(myriaporone);N-乙醯基地那林(N-acetyldinaline);N-經取代之苯甲醯胺;那法瑞林(nafarelin);那哥斯普(nagrestip);納洛酮(naloxone)+噴他佐辛(pentazocine);納帕維(napavin);萘萜二醇(naphterpin);那托司亭(nartograstim);奈達鉑(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);中性肽內切肽酶;尼魯米特(nilutamide);尼薩黴素(nisamycin);一氧化氮調控劑;硝基氧抗氧化劑;尼楚林(nitrullyn);O6-苯甲基鳥嘌呤;奧曲肽(octreotide);奧克三諾(okicenone);寡核苷酸;奧那司酮(onapristone);昂丹司瓊(ondansetron);昂丹司瓊(ondansetron);奧瑞森(oracin);口服細胞素誘導劑;奧馬鉑(ormaplatin);奧沙特隆(osaterone);奧沙利鉑(oxaliplatin);奧諾黴素(oxaunomycin);鈀銨(palauamine);棕櫚醯根黴素(palmitoylrhizoxin);帕米磷酸(pamidronic acid);人參三醇(panaxytriol);帕諾米芬(panomifene);副菌鐵素(parabactin);帕折普汀(pazelliptine);培門冬酶(pegaspargase);培得星(peldesine);戊聚糖聚硫酸鈉(pentosan polysulfate sodium);噴司他汀(pentostatin);噴曲唑(pentrozole);全氟溴烷(perflubron);培磷醯胺(perfosfamide);紫蘇子醇(perillyl alcohol);吩嗪黴素(phenazinomycin);乙酸苯酯;磷酸酶抑制劑;必醫你舒 (picibanil);毛果蕓香鹼鹽酸鹽(pilocarpine hydrochloride);比柔比星(pirarubicin);比曲克辛(piritrexim);普拉汀A(placetin A);普拉汀B(placetin B);纖溶酶原活化因子抑制劑;鉑複合物;鉑化合物;鉑-三胺複合物;葉吩姆鈉(porfimer sodium);泊非黴素(porfiromycin);潑尼松(prednisone);丙基雙吖啶酮(propyl bis-acridone);前列腺素J2;蛋白酶體抑制劑;基於蛋白質A之免疫調控劑;蛋白質激酶C抑制劑;蛋白質激酶C抑制劑,微海藻類(microalgal);蛋白質酪胺酸磷酸酶抑制劑;嘌呤核苷磷酸化酶抑制劑;紅紫素(purpurins);吡唑并吖啶(pyrazoloacridine);吡哆醇酸化血紅蛋白聚氧乙烯接合物;raf拮抗劑;雷替曲塞(raltitrexed);雷莫司瓊(ramosetron);ras法尼基(ras farnesyl)蛋白質轉移酶抑制劑;ras抑制劑;ras-GAP抑制劑;脫甲基瑞替普汀(retelliptine demethylated);錸Re186依替膦酸鹽(rhenium Re 186 etidronate);根黴素(rhizoxin);核酶;RII維甲醯酚胺(retinamide);羅穀亞胺(rogletimide);羅稀吐鹼(rohitukine);羅莫肽(romurtide);羅喹美克(roquinimex);如彼給諾(rubiginone)B1;如波斯(ruboxyl);沙芬戈(safingol);沙托品(saintopin);SarCNU;肌肉葉綠醇A(sarcophytol A);沙格司亭(sargramostim);Sdi 1擬似物;希莫司汀(semustine);衰老細胞衍生的抑制劑1;正義寡核苷酸;訊號轉導抑制劑;訊號轉導調控劑;單鏈抗原結合性蛋白質;西佐非蘭(sizofuran);索布佐生 (sobuzoxane);硼卡鈉(sodium borocaptate);苯乙酸鈉;索菲醇(solverol);生長調節素結合性蛋白質;索納明(sonermin);磷乙醯天冬胺酸(sparfosic acid);穗黴素D(spicamycin D);螺莫司汀(spiromustine);脾五肽(splenopentin);海綿他汀素1(spongistatin 1);角鯊胺(squalamine);幹細胞抑制劑;幹細胞分化抑制劑;密擠青黴醯胺(stipiamide);基質降解酶(stromelysin)抑制劑;硫福辛(sulfinosine);強效血管活性腸肽拮抗劑;磺酸偏端黴素(suradista);舒拉明(suramin);苦馬豆素(swainsonine);合成性葡糖胺基聚醣;他莫司汀(tallimustine);它莫西芬甲碘化物(tamoxifen methiodide);牛磺莫司汀(tauromustine);他紮羅汀(tazarotene);替可加蘭鈉(tecogalan sodium);替加氟(tegafur);締哌喃鐵(tellurapyrylium);端粒酶抑制劑;替莫泊芬(temoporfin);替莫唑胺(temozolomide);替尼泊苷(teniposide);四氯十氧化物(tetrachlorodecaoxide);四氫唑環(tetrazomine);白蓬草硝酸鈉(thaliblastine);噻可拉林(thiocoraline);血小板生成素;血小板生成素擬似物;胸腺法新(thymalfasin);胸腺生成素受體促效劑;胸腺曲南(thymotrinan);甲狀腺刺激激素;本紫紅素乙酯錫(tin ethyl etiopurpuron);替拉紮明(tirapazamine);二氯環戊二烯鈦(titanocene bichloride);淺水海綿素(topsentin);托瑞米芬(toremifene);全能幹細胞因子;轉譯抑制劑;維甲酸(tretinoin);三乙醯尿苷(triacetyluridine);曲西立濱 (triciribine);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司瓊(tropisetron);妥羅雄脲(turosteride);酪胺酸激酶抑制劑;酪胺酸激酶阻斷劑(tyrphostins);UBC抑制劑;烏苯美司(ubenimex);泌尿生殖竇衍生之生長抑制因子;尿激酶受體拮抗劑;伐普肽(vapreotide);瓦裡奧林B(variolin B);載體系統,紅細胞基因療法;維拉雷瑣(velaresol);藜蘆明(veramine);維爾定(verdins);維替泊芬(verteporfin);長春瑞濱(vinorelbine);維夏汀(vinxaltine);維它新(vitaxin);伏氯唑(vorozole);紮諾特隆(zanoterone);折尼鉑(zeniplatin);亞苄維C(zilascorb);淨司他丁斯酯(zinostatin stimalamer),阿黴素(Adriamycin)、放線菌素D(Dactinomycin)、博來黴素(Bleomycin)、長春花鹼(Vinblastine)、順鉑(Cisplatin)、阿西維辛(acivicin);阿柔比星(aclarubicin);鹽酸諾考達唑(acodazole hydrochloride);山油柑鹼(acronine);阿多來新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);安波黴素(ambomycin);乙酸阿美蒽醌(ametantrone acetate);氨苯呱酮(aminoglutethimide);安吖啶(amsacrine);安耐柔(anastrozole);胺茴黴素(anthramycin);天冬胺酸酶;曲林菌素(asperlin);氮雜西定(azacitidine);阿紮替派(azetepa);阿佐黴素(azotomycin);巴馬司他(batimastat);苯佐替派(benzodepa);比卡魯胺(bicalutamide);鹽酸比生群 (bisantrene hydrochloride);二甲磺酸雙奈法德(bisnafide dimesylate);比折來新(bizelesin);硫酸博來黴素(bleomycin sulfate);布喹那鈉(brequinar sodium);溴匹立明(bropirimine);白消安(busulfan);放線菌素C(cactinomycin);二甲睾酮(calusterone);卡醋胺(caracemide);卡貝替姆(carbetimer);卡鉑(carboplatin);卡莫司汀(carmustine);鹽酸洋紅黴素(carubicin hydrochloride);卡折來新(carzelesin);西地芬戈(cedefingol);苯丁酸氮芥(chlorambucil);西洛黴素(cirolemycin);克拉屈濱(cladribine);甲磺酸克立那托(crisnatol mesylate);環磷醯胺;阿糖胞苷(cytarabine);達卡巴仁(dacarbazine);鹽酸唐諾黴素(daunorubicin hydrochloride);地西他濱(decitabine);右奧馬鉑(dexormaplatin);地紮胍寧(dezaguanine);甲磺酸地紮胍寧(dezaguanine mesylate);地吖醌(diaziquone);多柔比星(doxorubicin);鹽酸多柔比星(doxorubicin hydrochloride);屈洛昔芬(droloxifene);檸檬酸屈洛昔芬(droloxifene citrate);丙酸屈他雄酮(dromostanolone propionate);重氮黴素(duazomycin);依達曲沙(edatrexate);鹽酸依氟鳥胺酸(eflornithine hydrochloride);依沙蘆星(elsamitrucin);恩洛鉑(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);鹽酸泛艾黴素(epirubicin hydrochloride);厄布洛唑(erbulozole);鹽酸依索比星(esorubicin hydrochloride);雌氮芥(estramustine);雌氮芥磷酸鈉鹽;依他硝唑(etanidazole);依託泊苷(etoposide);磷酸依託泊苷;氯苯乙嘧胺(etoprine);鹽酸法羅唑啉(fadrozole hydrochloride);法紮拉濱(fazarabine);芬維A胺(fenretinide);氟尿嘧啶脫氧核苷(floxuridine);磷酸氟達拉濱(fludarabine phosphate);氟尿嘧啶;氟西他濱(fluorocitabine);氟喹酮(fosquidone);福司曲星鈉(fostriecin sodium);吉西他濱(gemcitabine);鹽酸吉西他濱;羥基脲;鹽酸伊達比星(idarubicin hydrochloride);異環磷醯胺(ifosfamide);伊莫福新(iimofosine);間白素11(包括重組間白素II、或rlL.sub.2)、干擾素α-2a;干擾素α-2b;干擾素α-n1;干擾素α-n3;干擾素β-1a;干擾素γ-1b;異丙鉑(iproplatin);鹽酸伊立替康(irinotecan hydrochloride);乙酸蘭瑞肽(lanreotide acetate);來曲唑(letrozole);乙酸柳菩林(leuprolide acetate);鹽酸利阿唑(liarozole hydrochloride);洛美曲索鈉(lometrexol sodium);洛莫司汀(lomustine);鹽酸洛索蒽醌(losoxantrone hydrochloride);馬索羅酚(masoprocol);美坦辛(maytansine);二氯甲基二乙胺鹽酸鹽(mechlorethamine hydrochloride);乙酸甲地孕酮(megestrol acetate);乙酸美侖孕酮(melengestrol acetate);馬法蘭(melphalan);美諾立爾(menogaril);氫硫基嘌呤;胺甲蝶呤(methotrexate);胺甲蝶呤鈉(methotrexate sodium);氯苯胺啶(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡星 (mitocarcin);絲裂紅素(mitocromin);米托潔林(mitogillin);米托馬星(mitomalcin);絲裂黴素(mitomycin);米托司培(mitosper);米托坦(mitotane);鹽酸米托蒽醌(mitoxantrone hydrochloride);黴酚酸(mycophenolic acid);諾考達唑(nocodazole);諾拉黴素(nogalamycin);奧馬鉑(ormaplatin);奧昔舒侖(oxisuran);培門冬酶(pegaspargase);培利黴素(peliomycin);戊氮芥(pentamustine);硫酸培洛黴素(peplomycin sulfate);培磷醯胺(perfosfamide);雙溴丙基哌嗪(pipobroman);哌泊舒凡(piposulfan);鹽酸吡羅蒽醌(piroxantrone hydrochloride);普卡黴素(plicamycin);普洛美坦(plomestane);蔔吩姆鈉(porfimer sodium);泊非黴素(porfiromycin);潑尼莫司汀(prednimustine);鹽酸丙卡巴肼(procarbazine hydrochloride);嘌呤黴素(puromycin);鹽酸嘌呤黴素(puromycin hydrochloride);吡唑呋喃菌素(pyrazofurin);利波腺苷(riboprine);羅穀亞胺(rogletimide);沙芬戈(safingol);鹽酸沙芬戈;希莫司汀(semustine);辛曲(simtrazene);磷乙醯天冬胺酸鈉(sparfosate sodium);稀疏黴素(sparsomycin);鹽酸鍺螺胺(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺鉑(spiroplatin);鏈黑黴素(streptonigrin);鏈脲佐菌素(streptozocin);磺氯苯脲(sulofenur);他利黴素(talisomycin);替可加蘭鈉(tecogalan sodium);替加氟(tegafur);鹽酸替洛蒽醌(teloxantrone hydrochloride);替 莫泊芬(temoporfin);替尼泊苷(teniposide);替羅昔隆(teroxirone);睾內酯(testolactone);硫咪嘌呤(thiamiprine);硫鳥嘌呤(thioguanine);噻替哌(thiotepa);噻唑羧胺核苷(tiazofurin);替拉紮明(tirapazamine);檸檬酸托瑞米芬(toremifene citrate);乙酸曲托龍(trestolone acetate);磷酸曲西立濱(triciribine phosphate);三甲曲沙(trimetrexate);葡糖醛酸三甲曲沙(trimetrexate glucoronate);曲普瑞林(triptorelin);鹽酸妥布氯唑(tubulozole hydrochloride);尿嘧啶氮芥(uracil mustard);烏瑞替派(uredepa);伐普肽(vapreotide);維替泊芬(verteporfin);硫酸長春花鹼(vinblastine sulfate);硫酸長春新鹼(vincristine sulfate);長春地辛(vindesine);硫酸長春地辛(vindesine sulfate);硫酸長春匹定(vinepidine sulfate);硫酸長春甘酯(vinglycinate sulfate);硫酸長春羅辛(vinleurosine sulfate);酒石酸長春瑞濱(vinorelbine tartrate);硫酸長春羅定(vinrosidine sulfate);硫酸長春利定(vinzolidine sulfate);伏氯唑(vorozole);折尼鉑(zeniplatin);淨司他丁(zinostatin);鹽酸佐柔比星(zorubicin hydrochloride),在G2-M期遏止細胞及/或調控微管蛋白形成或穩定性之藥劑(例如,Taxol.TM(亦即太平洋紫杉醇(paclitaxel))、Taxotere.TM,包含紫杉烷架構之化合物,厄布洛唑(Erbulozole)(亦即R-55104)、海兔毒素10(Dolastatin 10)(亦即DLS-10與NSC-376128)、米弗林羥乙磺酸鹽(Mivobulin isethionate)(亦即CI-980)、長春新鹼 (Vincristine)、NSC-639829、圓皮海綿內酯(Discodermolide)(亦即如NVP-XX-A-296)、ABT-751(Abbott,亦即E-7010)、奧圖來爾亭類(Altorhyrtins)(例如,奧圖來爾亭A與奧圖來爾亭C)、海綿他汀素類(Spongistatin)(例如,海綿他汀素1(spongistatin 1)、海綿他汀素2、海綿他汀素3、海綿他汀素4、海綿他汀素5、海綿他汀素6、海綿他汀素7、海綿他汀素8、與海綿他汀素9)、鹽酸西馬多亭(Cemadotin hydrochloride)(亦即LU-103793與NSC-D-669356)、埃坡黴素類(Epothilones)(例如,埃坡黴素A、埃坡黴素B、埃坡黴素C(亦即去氧埃坡黴素(desoxyepothilone)A或dEpoA)、埃坡黴素D(亦即KOS-862、dEpoB、與去氧埃坡黴素B)、埃坡黴素E、埃坡黴素F、埃坡黴素B N-氧化物、埃坡黴素A N-氧化物、16-氮雜-埃坡黴素B、21-胺基埃坡黴素B(亦即BMS-310705)、21-羥基埃坡黴素D(亦即去氧埃坡黴素F與dEpoF)、26-氟埃坡黴素、奧立司達汀(Auristatin)PE(亦即NSC-654663)、索利多汀(Soblidotin)(亦即TZT-1027)、LS-4559-P(Pharmacia,亦即LS-4577)、LS-4578(Pharmacia,亦即LS-477-P)、LS-4477(Pharmacia)、LS-4559(Pharmacia)、RPR-112378(Aventis)、硫酸長春新鹼(Vincristine sulfate)、DZ-3358(Daiichi)、FR-182877(Fujisawa,亦即WS-9885B)、GS-164(Takeda)、GS-198(Takeda)、KAR-2(Hungarian Academy of Sciences)、BSF-223651(BASF,亦即ILX-651與LU-223651)、SAH-49960(Lilly/Novartis)、SDZ-268970 (Lilly/Novartis)、AM-97(Armad/Kyowa Hakko)、AM-132(Armad)、AM-138(Armad/Kyowa Hakko)、IDN-5005(Indena)、念珠藻環肽(Cryptophycin)52(亦即LY-355703)、AC-7739(Ajinomoto,亦即AVE-8063A與CS-39.HCl)、AC-7700(Ajinomoto,亦即AVE-8062、AVE-8062A、CS-39-L-Ser.HCl、與RPR-258062A)、海鞘二環肽(Vitilevuamide)、微管溶素(Tubulysin)A、迦納單索(Canadensol)、矢車菊黃素(Centaureidin)(亦即NSC-106969)、T-138067(Tularik,亦即T-67、TL-138067與TI-138067)、COBRA-1(Parker Hughes Institute,亦即DDE-261與WHI-261)、H10(Kansas State University)、H16(Kansas State University)、殺腫瘤素(Oncocidin)A1(亦即BTO-956與DIME)、DDE-313(Parker Hughes Institute)、富士內酯(Fijianolide)B、勞利醯胺(Laulimalide)、SPA-2(Parker Hughes Institute)、SPA-1(Parker Hughes Institute,亦即SPIKET-P)、3-IAABU(Cytoskeleton/Mt.Sinai School of Medicine,亦即MF-569)、那可辛(Narcosine)(亦稱為NSC-5366)、納司卡濱(Nascapine)、D-24851(Asta Medica)、A-105972(Abbott)、哈米特林(Hemiasterlin)、3-BAABU(Cytoskeleton/Mt.Sinai School of Medicine,亦即MF-191)、TMPN(Arizona State University)、凡納多新乙醯基丙酮酸鹽(Vanadocene acetylacetonate)、T-138026(Tularik)、孟沙醇(Monsatrol)、引納諾新(Inanocine)(亦即NSC-698666)、3-IAABE(Cytoskeleton/Mt.Sinai School of Medicine)、A-204197(Abbott)、T-607(Tuiarik,亦即T-900607)、RPR-115781(Aventis)、艾榴素類(Eleutherobin)(如:去甲基艾榴素(Desmethyleleutherobin)、去乙醯基艾榴素(Desaetyleleutherobin)、異艾榴素-A(Isoeleutherobin A)和Z-艾榴素)、卡利貝苷(Caribaeoside)、卡利貝林(Caribaeolin)、海利軟骨膠(Halichondrin)B、D-64131(Asta Medica)、D-68144(Asta Medica)、重氮醯胺(Diazonamide)A、A-293620(Abbott)、NPI-2350(Nereus)、他卡諾內酯(Taccalonolide)A、TUB-245(Aventis)、A-259754(Abbott)、二唑司汀(Diozostatin)、(-)-苯基阿西司汀(phenylahistin)(亦即NSCL-96F037)、D-68838(Asta Medica)、D-68836(Asta Medica)、肌基質蛋白(Myoseverin)B、D-43411(Zentaris,亦即D-81862)、A-289099(Abbott)、A-318315(Abbott)、HTI-286(亦即SPA-110,三氟乙酸鹽)(Wyeth)、D-82317(Zentaris)、D-82318(Zentaris)、SC-12983(NCI)、利弗司汀(Resverastatin)磷酸鈉、BPR-OY-007(National Health Research Institutes)、與SSR-250411(Sanofi))、類固醇(例如,地塞美松(dexamethasone))、非那甾胺(finasteride)、芳構酶抑制劑、促性腺激素釋放激素促效劑(GnRH),如:戈舍瑞林(goserelin)或柳菩林(leuprolide)、腎上腺皮質類固醇(例如,潑尼松(prednisone))、助孕素類(progestin)(例如,羥基黃體酮己酸酯、乙酸甲地孕酮(megestrol acetate)、乙酸甲羥黃體酮(medroxyprogesterone acetate))、雌激素類(例如,乙烯雌酚(diethlystilbestrol)、 乙炔雌二醇(ethinyl estradiol))、抗雌激素類(例如,它莫西芬(tamoxifen))、雄激素類(例如,丙酸睪固酮、氟羥甲睪酮(fluoxymesterone))、抗雄激素類(例如,氟他胺(flutamide))、免疫刺激劑(例如,卡介苗(Bacillus Calmette-Guérin)(BCG)、左旋咪唑(levamisole)、間白素-2、α-干擾素等等)、單株抗體(例如,抗CD20、抗HER2、抗CD52、抗HLA-DR、與抗VEGF單株抗體)、免疫毒素(例如,抗CD33單株抗體-卡奇黴素(calicheamicin)接合物、抗CD22單株抗體-假單胞菌外毒素接合物等等)、放射免疫療法(例如,接合111In、90Y、或131I等等之抗CD20單株抗體)、雷公藤內酯(triptolide)、高三尖杉酯鹼(homoharringtonine)、放線菌素D(dactinomycin)、多柔比星(doxorubicin)、泛艾黴素(epirubicin)、托普替康(topotecan)、伊曲康唑(itraconazole)、長春地辛(vindesine)、西立伐他汀(cerivastatin)、長春新鹼(vincristine)、去氧腺苷、舍曲林(sertraline)、匹伐他汀(pitavastatin)、伊立替康(irinotecan))、氯苯吩嗪(clofazimine)、5-壬基氧色胺、維莫非尼(vemurafenib)、達布非尼(dabrafenib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、EGFR抑制劑、靶向表皮生長因子受體(EGFR)之療法或醫療劑(例如,吉非替尼(gefitinib)(Iressa TM)、厄洛替尼(erlotinib)(Tarceva TM)、西妥昔單抗(cetuximab)(ErbituxTM)、拉帕替尼(lapatinib)(TykerbTM)、帕尼單抗(panitumumab)(VectibixTM)、凡德他尼(vandetanib) (CaprelsaTM)、阿法替尼(afatinib)/BIBW2992、CI-1033/卡奈替尼(canertinib)、來那替尼(neratinib)/HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、達克替尼(dacomitinib)/PF299804、OSI-420/去甲基厄洛替尼(desmethyl erlotinib)、AZD8931、AEE788、培利替尼(pelitinib)/EKB-569、CUDC-101、WZ8040、WZ4002、WZ3146、AG-490、XL647、PD153035、BMS-599626)、索拉非尼(sorafenib)、伊馬替尼(imatinib)、舒尼替尼(sunitinib)、達沙替尼(dasatinib),或類似物。
「化療」或「化療劑」係依據其一般定義使用,且係指具有抗新生贅瘤性質或有能力抑制細胞生長或增生之化學組成物或化合物。
此外,本文所說明化合物可以共同投與常用之免疫醫療劑,包括,但不限於,免疫刺激劑(例如,卡介苗(Bacillus Calmette-Guérin)(BCG)、左旋咪唑(levamisole)、間白素-2、α-干擾素等等)、單株抗體(例如,抗-CD20、抗-HER2、抗-CD52、抗-HLA-DR、與抗-VEGF單株抗體)、免疫毒素(例如,抗-CD33單株抗體-卡奇黴素(calicheamicin)接合物、抗-CD22單株抗體-假單胞菌外毒素(pseudomonas exotoxin)接合物等等)、及放射免疫療法(例如,接合111In、90Y、或131I之抗-CD20單株抗體等等)。
本文所揭示化合物可以共同投與用於腫瘤內科之抗增生/抗新生贅瘤藥物或其組合,如烷化劑(例 如,順鉑(cis-platin)、卡鉑(carboplatin))、環磷醯胺、氮芥、馬法蘭(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulphan)或硝基脲);抗代謝物(例如,抗葉酸鹽,如氟嘧啶類,如5-氟尿嘧啶或替加氟(tegafur)、雷替曲塞(raltitrexed)、胺甲蝶呤(methotrexate)、阿糖胞苷、羥基脲、吉西他濱(gemcitabine)、或太平洋紫杉醇(paclitaxel));抗腫瘤抗生素(例如,蒽環類,如阿黴素(adriamycin)、博來黴素(bleomycin)、多柔比星(doxorubicin)、道諾黴素(daunomycin)、泛艾黴素(epirubicin)、伊達比星(idarubicin)、絲裂黴素(mitomycin)-C、放線菌素D(Dactinomycin)或光輝黴素(mithramycin));抗有絲分裂劑(例如,長春花植物鹼,如長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)或長春瑞濱(vinorelbine),或類紫杉醇,如紫杉醇或歐洲紫杉醇(taxotere));或拓樸異構酶抑制劑(例如,表鬼臼毒素,如依託泊苷(etoposide)、替尼泊苷(teniposide)、安吖啶(amsacrine)、托普替康(topotecan)或喜樹鹼);(ii)細胞生長抑制劑,如抗雌激素(例如,它莫西芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)或碘昔芬(iodoxyfene)),雌激素受體下調劑(例如,氟維司群(fulvestrant)),抗雄激素(例如,比卡魯胺(bicalutamide)、氟他胺(flutamide)、尼魯米特(nilutamide)或乙酸環丙孕酮),LHRH拮抗劑或LHRH促效劑(例如,戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)或布舍瑞林 (buserelin)),助孕素(例如,乙酸甲地孕酮(megestrol acetate)),芳構酶抑制劑(例如,安耐柔(anastrozole)、來曲唑(letrozole)、伏拉唑(vorazole)或依西美坦(exemestane))或5α-還原酶之抑制劑,如非那甾胺(finasteride);(iii)抑制癌細胞入侵之藥劑(例如,金屬蛋白酶抑制劑,如馬立馬司他(marimastat)或尿激酶胞漿素原活化劑受體功能之抑制劑);(iv)生長因子功能之抑制劑,例如,生長因子抗體(例如,抗-erbb2抗體曲妥珠單抗(trastuzumab)、或抗-erbb1抗體西妥昔單抗(cetuximab)[C225])、法呢基(farnesyl)轉移酶抑制劑、酪胺酸激酶抑制劑或絲胺酸/蘇胺酸激酶抑制劑、表皮生長因子家族之抑制劑(例如,EGFR家族酪胺酸激酶抑制劑,如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-N-嗎啉基丙氧基)喹唑啉-4-胺(吉非替尼(gefitinib)、AZD 1839)、N-(3-乙炔基苯基)-6,7-雙(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼(erlotinib)、OSI-774)或6-丙烯醯胺基-N-(3-氯-4-氟苯基)-7-(3-N-嗎啉基丙氧基)喹唑啉-4-胺(CI 1033))、血小板衍生之生長因子家族之抑制劑、或肝細胞生長因子家族之抑制劑;(v)抗血管新生劑,如抑制血管內皮生長因子效應之製劑(例如,抗血管內皮生長因子抗體貝伐單抗(bevacizumab),揭示於WO 97/22596、WO 97/30035、WO 97/32856或WO 98/13354之化合物)、或依另一種機轉運作之化合物(例如,三羧胺基喹啉(linomide),一種整合素.α.v.β.3功能之抑制劑或血管生長抑素);(vi)血管傷害 劑,如:考布他汀A4(combretastatin A4)、或揭示於WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434或WO 02/08213之化合物;(vii)用於反義療法之藥劑,例如,直接針對上列一種標靶之藥劑,如ISIS 2503、抗-ras反義;(viii)用於基因療法之藥劑,例如,置換異常基因之方法,如異常p53或異常BRCA1或BRCA2,GDEPT(基因導向之酵素前藥療法)方法,如彼等使用胞嘧啶脫胺酶、胸苷激酶或細菌硝基還原酶酵素,及提高患者對化療或放療耐受性之方法,如多重藥物抗性基因療法;或(ix)用於免疫療法之藥劑,例如提高患者腫瘤細胞免疫原性之離體與活體內方法,如使用細胞素(如間白素2、間白素4或粒細胞-巨噬細胞群落刺激因子)轉染,降低T-細胞變應性缺失之方法,使用以已轉染之免疫細胞(如經細胞素轉染之樹突胞)之方法,使用經細胞素轉染之腫瘤細胞株之方法,及使用抗-個體遺傳型抗體之方法。
CCR4調控劑
任何已知CCR4調控劑均可用於進行本文揭示之治療方法。某些具體實施例中,CCR4調控劑為適合經口投藥者。其他具體實施例中,CCR4調控劑為適合非經腸式投藥者。其他具體實施例中,CCR4調控劑為CCR4-結合性抗體。
經口投藥之CCR4調控劑
本文提供一種適用於治療EPV+惡性病之化合物。有一類CCR4調控劑為揭示於Beck等人於2017年 7月28日申請之美國專利申請案15/662,861之化合物(例如,例如,式I至VII化合物),其全文已針對所有目的以引用之方式併入本文中。具體實施例中,一種式I化合物:
或其醫藥上可接受之鹽,其中:X1為CR8或N;X2為CR9或N;X3為CR10或N;n1、n2、n3、n4、n5、n6、n7、n8、n9與n10獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m7、m8、m9、m10、v1、v2、v3、v4、v5、v6、v7、v8、v9與v10獨立地為1或2;z1為整數0至5;z2為整數0至2;z3為整數0至11;z4為整數0至2;L7為鍵結、-O-、-S-、-NR7.2B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經 取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-N3、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-N3、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-N3、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、 -OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-N3、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-N3、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基; R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-N3、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R7為氫、鹵素、-CX7.1 3、-CHX7.1 2、-CH2X7.1、-CN、-N3、-SOn7R7A、-SOv7NR7BR7C、-NHNR7BR7C、-ONR7BR7C、-NHC(O)NHNR7BR7C、-NHC(O)NR7BR7C、-N(O)m7、-NR7BR7C、-C(O)R7D、-C(O)OR7D、-C(O)NR7BR7C、-OR7A、-NR7BSO2R7A、-NR7BC(O)R7D、-NR7BC(O)OR7D、-NR7BOR7D、-OCX7.1 3、-OCHX7.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-N3、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、- NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-N3、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-N3、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、 R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R7A、R7B、R7C、R7D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C與R10D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B、R1C、R2B、R2C、R3B、R3C、R4B、R4C、R5B、R5C、R6B、R6C、R7B、R7C、R8B、R8C、R9B、R9C、R10B與R10C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X7.1、X8.1、X9.1與X10.1獨立地為-Cl、-Br、-I或-F,其中X1、X2與X3中至少一者為N。
具體實施例中,式(I)化合物為CCR4活性之調控劑。具體實施例中,式(I)化合物為CCR4拮抗劑。
具體實施例中,使用Beck等人於2017年7月28日申請之美國專利申請案15/662,861中所揭示化合物(例如,式I至VII化合物)之醫藥上可接受之鹽作為CCR4調控劑。具體實施例中,CCR4調控劑為選自下列各物所組成群中之化合物:
,或任何上述化合物之醫藥上可接受之鹽。
另一類CCR4調控劑為Beck等人於2017年9月8日申請之美國專利申請案15/700,040所揭示之化 合物(例如,例如,式I至X化合物),其全文已針對所有目的以引用之方式併入本文中。具體實施例中,式II化合物:
或其醫藥上可接受之鹽,其中:A為經取代或未經取代之雜環烷基;X1為CR8或N;X2為CR9或N;X3為CR10或N;X4為C、CR11或N;z1為整數0至5;z2為整數0至13;z3為整數0至12;z4為整數0至3;為單鍵或雙鍵,其中若為單鍵時,則X4為CR11或N,及若為雙鍵時,則X4為C;L7為鍵結、-O-、-S-、-NR7B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸 芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、- NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、 -ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取 代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R11為氫、鹵素、-CX11.1 3、-CHX11.1 2、-CH2X11.1、-CN、-SOn11R11A、-SOv11NR11BR11C、-NHNR11BR11C、-ONR11BR11C、-NHC(O)NHNR11BR11C、-NHC(O)NR11BR11C、-N(O)m11、-NR11BR11C、-C(O)R11D、-C(O)OR11D、-C(O)NR11BR11C、-OR11A、-NR11BSO2R11A、-NR11BC(O)R11D、-NR11BC(O)OR11D、-NR11BOR11D、-OCX11.1 3、-OCHX11.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、 R9D、R10A、R10B、R10C、R10D、R11A、R11B、R11C與R11D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B與R1C、R2B與R2C、R3B與R3C、R4B與R4C、R5B與R5C、R6B與R6C、R8B與R8C、R9B與R9C、R10B與R10C、R11B與R11C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;n1、n2、n3、n4、n5、n6、n8、n9、n10與n11獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m8、m9、m10、m11、v1、v2、v3、v4、v5、v6、v8、v9、v10、與v11獨立地為1或2;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X8.1、X9.1、X10.1、與X11.1獨立地為-Cl、-Br、-I或-F,其中X1、X2、與X3中至少一者為N。
具體實施例中,式(II)化合物為CCR4活性之調控劑。具體實施例中,式(II)化合物為CCR4拮抗劑。
具體實施例中,使用Beck等人於2017年9月8日申請之美國專利案申請案15/700,040所揭示化合物(例如,例如式I至X之化合物)之醫藥上可接受之鹽作為CCR4調控劑。具體實施例中,CCR4調控劑為選自下列各 物所組成群中之化合物:
及,或上述任一化合物之醫藥上可接受之鹽。
另一類CCR4調控劑為Beck等人於2017年4月4日申請之美國專利申請案62/481,515中所揭示化合物(例如,式I至VI化合物),其全文已針對所有目的以引用之方式併入本文中。具體實施例中,化合物具有式III:
或其醫藥上可接受之鹽,其中: A為經取代或未經取代之環烷基或經取代或未經取代之雜環烷基;X1為CR8或N;X2為CR9或N;X3為CR10或N;X4為C、CR11或N;X7為NR17或N,其中當L7共價結合X7時,則X7為N;n1、n2、n3、n4、n5、n6、n8、n9、n10、n11、與n17獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m8、m9、m10、m11、m17、v1、v2、v3、v4、v5、v6、v8、v9、v10、v11、與v17獨立地為1或2;z1為整數0至5;z2為整數0至8;z3為整數0至12;為單鍵或雙鍵,其中若為單鍵時,則X4為CR11或N,及若為雙鍵時,則X4為C;L7為鍵結、-O-、-S-、-NR7B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、 -SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR3A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之 環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、 -OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、- CN、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R11為氫、鹵素、-CX11.1 3、-CHX11.1 2、-CH2X11.1、-CN、-SOn11R11A、-SOv11NR11BR11C、-NHNR11BR11C、-ONR11BR11C、-NHC(O)NHNR11BR11C、-NHC(O)NR11BR11C、-N(O)m11、-NR11BR11C、-C(O)R11D、-C(O)OR11D、-C(O)NR11BR11C、-OR11A、-NR11BSO2R11A、-NR11BC(O)R11D、-NR11BC(O)OR11D、-NR11BOR11D、-OCX11.1 3、-OCHX11.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R17為氫、鹵素、-CX17.1 3、-CHX17.1 2、-CH2X17.1、-CN、-SOn17R17A、-SOv17NR17BR17C、-NHNR17BR17C、-ONR17BR17C、-NHC(O)NHNR17BR17C、-NHC(O)NR17BR17C、-N(O)m17、-NR17BR17C、-C(O)R17D、-C(O)OR17D、-C(O)NR17BR17C、-OR17A、-NR17BSO2R17A、 -NR17BC(O)R17D、-NR17BC(O)OR17D、-NR17BOR17D、-OCX17.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C、R10D、R11A、R11B、R11C、R11DR17A、R17B、R17C與R17D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B與R1C、R2B與R2C、R3B與R3C、R4B與R4C、R5B與R5C、R6B與R6C、R8B與R8C、R9B與R9C、R10B與R10C、R11B與R11C、及R17B與R17C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X8.1、X9.1、X10.1、X11.1與X17.1獨立地為-Cl、-Br、-I或-F,其中X1、X2與X3中至少一者為N。
具體實施例中,式(III)化合物為CCR4活性之調控劑。具體實施例中,式(III)化合物為CCR4拮抗劑。
具體實施例中,使用Beck等人於2017年4月4日申請之美國專利申請案62/481,515中所揭示化合物(例如,式I至VI化合物)之醫藥上可接受之鹽作為CCR4調控劑。具體實施例中,CCR4調控劑為選自下列各物所組成群中之化合物:
及,或上述任一化合物之醫藥上可接受之鹽。
另一類CCR4調控劑為Robles-Resendiz等人於2018年1月26日申請之美國專利申請案62/622,774所揭示之化合物(例如,式I至VII化合物),其全文已針對所有目的以引用之方式併入本文中。具體實施例中,化合物具有式IV:
或其醫藥上可接受之鹽,其中:X1為CR8或N;X2為CR9或N;X3為CR10或N;n1、n2、n3、n4、n5、n6、n7、n8、n9、n10、與n44 獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m7、m8、m9、m10、v1、v2、v3、v4、v5、v6、v7、v8、v9、v10、與v44獨立地為1或2;z1為整數0至5;z2為整數0至4;z3為整數0至11;z4為整數0至2;L7為鍵結、-O-、-S-、-NR7.2B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-N3、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、-OCH2X1.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-N3、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、 -NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、-OCH2X2.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-N3、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、-OCH2X3.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-N3、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、-OCH2X4.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取 代或未經取代之芳基、或經取代或未經取代之雜芳基,或當X2為CR9時,則R4與R9可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-N3、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、-OCH2X5.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-N3、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、-OCH2X6.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基; R7為氫、鹵素、-CX7.1 3、-CHX7.1 2、-CH2X7.1、-CN、-N3、-SOn7R7A、-SOv7NR7BR7C、-NHNR7BR7C、-ONR7BR7C、-NHC(O)NHNR7BR7C、-NHC(O)NR7BR7C、-N(O)m7、-NR7BR7C、-C(O)R7D、-C(O)OR7D、-C(O)NR7BR7C、-OR7A、-NR7BSO2R7A、-NR7BC(O)R7D、-NR7BC(O)OR7D、-NR7BOR7D、-OCX7.1 3、-OCHX7.1 2、-OCH2X7.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-N3、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、-OCH2X8.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-N3、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、-OCH2X9.1、經取代或 未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基,或當X2為CR9時,則R4與R9可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;或當X2為CR9及X3為CR10時,則R9與R10可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-N3、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、-OCH2X10.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;或當X2為CR9及X3為CR10時,則R9與R10可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、或未經取代之芳基、或經取代或未經取代之雜芳基;R44為氫、-CX44.1 3、-CHX44.1 2、-CH2X44.1、-SOn44R44A、-SOv44NR44BR44C、-C(O)R44D、-C(O)OR44D、- C(O)NR44BR44C、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R7A、R7B、R7C、R7D、R7.2B、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C、R10D、R44A、R44B、R44C、與R44D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B、R1C、R2B、R2C、R3B、R3C、R4B、R4C、R5B、R5C、R6B、R6C、R7B、R7C、R8B、R8C、R9B、R9C、R10B、R10C、R44B、與R44C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X7.1、X8.1、X9.1、X10.1、與X44.1獨立地為-Cl、-Br、-I或-F;其中X1、X2與X3中至少一者為N。
一項具體實施例中,式(IV)化合物為CCR4活性之調控劑。具體實施例中,式(IV)化合物為CCR4拮抗劑。
具體實施例中,使用Robles-Resendiz等人 於2018年1月26日申請之美國專利申請案62/622,774所揭示之化合物(例如,式I至VII化合物)之醫藥上可接受鹽作為CCR4調控劑。具體實施例中,CCR4調控劑為選自下列各物所組成群中之化合物:
、與,或上述任一化合物之醫藥上可接受之鹽。
另一類CCR4調控劑為Jackson等人於2018年1月26日申請之美國專利申請案62/622,771所揭示之化合物,其全文已針對所有目的以引用之方式併入本文中。一項具體實施例中,化合物具有式V:
或其醫藥上可接受之鹽。
具體實施例中,式(V)化合物為CCR4活性之調控劑。具體實施例中,式(V)化合物為CCR4拮抗劑。
其他經口投藥之CCR4調控劑包括下列已公開之專利申請案所揭示之化合物:US 2012/0015932(Hobbs等人);US 2010/0144759(Cheshire等人);US 2008/0293742(Cheshire等人);US 2006/0189613(Cheshire);US 2006/0128723(Mete等人);US 2006/0122195(Harrison等人);US 2006/0004010(Habashita等人);US 2004/0039035(Collins等人);US 2003/0018022(Collins等人);US 2002/0173524(Collins等人);US 2002/0132836(Dairaghi等人);美國專利案5,300,498;美國專利案6,509,357;US 2003/149018;WO 01/005758;WO 03/051876;WO 97/042174;WO 2006/101456;WO 2007/065683;WO 2007/065924;WO 2007/115231;WO 2008/045529;WO 2008/094575;WO 2008/094602;WO 2010/118367;與WO 2013/082429,其等全文已以引用之方式併入本文中。
非經腸式投與之CCR4調控劑
本文所揭示醫療方法所使用之CCR4調控劑亦可為CCR4-結合性抗體。此等抗體已揭示於下列已公開之專利申請案中;US 2017/0290911(Marasco等人);US 2017/0088627(Lin等人);US 2016/0185865(Marasco等人);US 2015/0147321(Ishii等人);US 2013/0295045(Shitara等人);US 2007/0031896(Wu等人);US 2007/0020263(Shitara等人);與US 2005/0287138(Lida等人),其等全文已以引用之方式併入本文中。
某些本文具體實施例提供本文所提供CCR4調控劑之鹽類、共晶體、溶劑合物(例如,水合物)、複合物、前藥、前體、代謝物、與/或其他衍生物。例如,特定具體實施例提供CCR4調控劑之鹽類、共晶體、溶劑合物(例如,水合物)、複合物、前體、代謝物、與/或其他衍生物。某些具體實施例提供之CCR4調控劑不為本文所提供CCR4調控劑之鹽類、共晶體、溶劑合物(例如,水合物)、或複合物。例如,特定具體實施例提供一種非離子化、非溶劑合化(例如,無水)、非複合化型之CCR4調控劑。
應注意,若所出示之結構式與提供之化學名稱之間有差異時,以所出示之結構式為主。此外,若未採用例如,粗字體或短折線代表結構或一部份結構之立體化學時,該結構或一部份結構應解讀為涵括所有立體異構物。若本文所提供化合物包含烯基或伸烯基時,該化合物可能出現一種幾何(亦即順/反式或E/Z)異構物或幾何(亦即順/反式或E/Z)異構物之混合物。除非另有說明,否則本 文所提供化合物計畫包括所有幾何異構物。
若結構異構物為分子內可轉化時,化合物可能出現單一互變異構物或互變異構物混合物。此可在包含例如,亞胺基、酮基、或肟基之化合物中出現質子互變異構性;或在包含例如,芳香系部份基團之化合物中出現所謂之價數互變異構性。因此單一化合物可能出現超過一種異構性。咸了解,除非另有說明,否則本文所提供化合物計畫涵括所有可能互變異構物。同樣地,除非另有說明,否則本文所提供化合物計畫涵括所有可能之立體異構物。
本文所提供化合物可為純對應異構性,如單一對應異構物或單一非對應異構物,或為立體異構性混合物,如對應異構物混合物,例如,兩種對應異構物之消旋性混合物;或兩種或更多種非對應異構物之混合物。常用於製備/單離個別對應異構物之技術包括從合適純光學前體合成、從非對掌性起始物進行不對稱性合成、或解析對應異構性混合物,例如,藉由對掌性層析法、再結晶法、解析法、形成非對應異構性鹽、或衍化成非對應異構性加合物後再分離。有些例子中,習此相關技藝者咸了解,於活體內進行差向異構化之化合物呈其(R)型投藥時係等同呈其(S)型投藥,反之亦然。
當本文所提供化合物包含酸性或鹼性部份基團時,亦可呈醫藥上可接受之鹽提供(參見Berge等人之J.Pharm.Sci.1977,66,1-19;與「Handbook of Pharmaceutical Salts,Properties,and Use」,Stahl與 Wermuth編輯;Wiley-VCH and VHCA,Zurich,20022)。
適用於製備醫藥上可接受之鹽類之酸類包括,但不限於,乙酸、2,2-二氯乙酸、醯基化胺基酸、己二酸、藻酸、抗壞血酸、L-天冬胺酸、苯磺酸、苯甲酸、4-乙醯胺基苯甲酸、硼酸、(+)-樟腦酸、樟腦磺酸、(+)-(1S)-樟腦-10-磺酸、癸酸、己酸、辛酸、肉桂酸、檸檬酸、環己胺磺酸、環己烷胺基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羥基-乙磺酸、甲酸、富馬酸、半乳糖二酸、龍膽酸、葡庚酸、D-葡糖酸、D-葡糖醛酸、L-麩胺酸、α-酮基戊二酸、乙醇酸、馬尿酸、氫溴酸、鹽酸、氫碘酸、(+)-L-乳酸、(+-)-DL-乳酸、乳糖酸、月桂酸、馬來酸、(-)-L-蘋果酸、丙二酸、(+-)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羥基-2-萘甲酸、菸鹼酸、硝酸、油酸、乳清酸、草酸、棕櫚酸、雙羥萘酸、過氯酸、磷酸、L-焦麩胺酸、葡萄糖二酸、水楊酸、4-胺基-水楊酸、癸二酸、硬脂酸、琥珀酸、硫酸、單寧酸、(+)-L-酒石酸、硫氰酸、對甲苯磺酸、十一碳烯酸、與戊酸。
適用於製備醫藥上可接受鹽類之鹼類包括,但不限於,無機鹼類,如氫氧化鎂、氫氧化鈣、氫氧化鉀、氫氧化鋅、或氫氧化鈉;及有機鹼類,如一級、二級、三級、與四級脂系及芳香系胺類,包括L-精胺酸、苯甲基苯乙胺、苄乙二胺(benzathine)、膽鹼、二甲基乙醇胺(deanol)、二乙醇胺、二乙基胺、二甲基胺、二丙基胺、二異丙基胺、2-(二乙基胺基)-乙醇、乙醇胺、乙基胺、乙二 胺、異丙基胺、N-甲基-葡糖胺、哈巴胺(hydrabamine)、1H-咪唑、L-離胺酸、嗎啉、4-(2-羥基乙基)-嗎啉、甲基胺、哌啶、哌、丙基胺、吡咯啶、1-(2-羥基乙基)-吡咯啶、吡啶、奎寧環、喹啉、異喹啉、二級胺、三乙醇胺、三甲基胺、三乙基胺、N-甲基-D-葡糖胺、2-胺基-2-(羥基甲基)-1,3-丙二醇、與三羥甲基胺基甲烷。
本文所提供化合物亦可呈前藥提供,其係本文所提供化合物之功能性衍生物,且很容易於活體內轉化成母化合物。因為前藥在有些情況下比母化合物更容易投藥,因此經常較適用。例如,其等經口投藥時可被生體利用,但母化合物則無法利用。在醫藥組成物中之前藥之溶解性亦可能比母化合物加強。前藥可藉由各種不同機轉轉化成母藥,包括酶解過程與代謝性水解。參見Harper之Progress in Drug Research 1962,4,221-294;Morozowich 等人之「Design of Biopharmaceutical Properties through Prodrugs and Analogs」,Roche編輯,APHA Acad.Pharm.Sci.1977;「Bioreversible Carriers in Drug in Drug Design,Theory and Application」,Roche編輯,APHA Acad.Pharm.Sci.1987;「Design of Prodrugs」,Bundgaard,Elsevier,1985;Wang等人,Curr.Pharm.Design 1999,5,265-287;Pauletti等人,Adv.Drug.Delivery Rev.1997,27,235-256;Mizen等人,Pharm.Biotech.1998,11,345-365;Gaignault等人,Pract.Med.Chem.1996,671-696;Asgharnejad之「Transport Processes in Pharmaceutical Systems」,Amidon等人編輯,Marcell Dekker,185-218,2000;Balant等人,Eur.J.Drug Metab.Pharmacokinet.1990,15,143-53;Balimane與Sinko,Adv.Drug Delivery Rev.1999,39,183-209;Browne之Clin.Neuropharmacol.1997,20,1-12;Bundgaard,Arch.Pharm.Chem.1979,86,1-39;Bundgaard,Controlled Drug Delivery 1987,17,179-96;Bundgaard,Adv.Drug Delivery Rev.1992,8,1-38;Fleisher等人,Adv.Drug Delivery Rev.1996,19,115-130;Fleisher等人,Methods Enzymol.1985,112,360-381;Farquhar等人,J.Pharm.Sci.1983,72,324-325;Freeman等人,J.Chem.Soc.,Chem.Commun.1991,875-877;Friis與Bundgaard,Eur.J.Pharm.Sci.1996,4,49-59;Gangwar等人,Des.Biopharm.Prop.Prodrugs Analogs,1977,409-421;Nathwani與Wood,Drugs 1993,45,866-94;Sinhababu與Thakker,Adv.Drug Delivery Rev.1996,19,241-273;Stella等人,Drugs 1985,29,455-73;Tan等人,Adv.Drug Delivery Rev.1999,39,117-151;Taylor,Adv.Drug Delivery Rev.1996,19,131-148;Valentino與Borchardt,Drug Discovery Today 1997,2,148-155;Wiebe與Knaus,Adv.Drug Delivery Rev.1999,39,63-80;及Waller等人,Br.J.Clin.Pharmac.1989,28,497-507。
醫藥組成物
一項態樣提供一種治療EBV+惡性病之組 成物。本揭露化合物(式(I)、(II)、(III)、(IV)、或(V)化合物)可呈適合投與個體之組成物型式。通常,此等組成物為包含化合物(例如,式(I)、(II)、(III)、(IV)、或(V)化合物)與一或多種醫藥上可接受或生理上可接受之稀釋劑、載劑或賦形劑之「醫藥組成物」。某些具體實施例中,化合物(例如,式(I)、(II)、(III)、(IV)、或(V)化合物)係呈醫療上可接受之量。醫藥組成物可用於本揭露中;因此例如,醫藥組成物可於離體或活體內投與個體,以操作本文所說明醫療性與預防性方法。
本揭露醫藥組成物可配合計畫之投藥方法或投藥途徑調配;投藥途徑實例係如本文所示。
包含活性成份(例如,式(I)、(II)、(III)、(IV)、或(V)化合物)之醫藥組成物可呈適合口服用之型式,例如,錠劑、膠囊、口含錠、喉糖、水性或油性懸浮液、可勻散粉劑或粒劑、乳液、硬式或軟式膠囊、或糖漿、溶液、微小珠或酏劑。計畫用於口服之醫藥組成物可依據本領域所習知製造醫藥組成物之任何方法製備,此等組成物可包含一或多種製劑,如例如,甜味劑、調味劑、著色劑、與防腐劑,以產生醫藥上美觀且適口之製劑。錠劑、膠囊與類似物包含活性成份與適合其製法之醫藥上可接受之無毒賦形劑混合。此等賦形劑可為例如,稀釋劑,如碳酸鈣、碳酸鈉、乳糖、磷酸鈣、或磷酸鈉;造粒劑與崩解劑,例如,玉米澱粉、或藻酸;結合劑,例如,澱粉、明膠、或金合歡膠;與潤滑劑,例如,硬脂酸鎂、硬脂酸或 滑石。
適合口服之錠劑、膠囊與類似物可以沒有包衣或採用已知技術包覆包衣,以延緩在胃腸道中崩解及吸收,藉以提供持續作用。可使用例如,緩釋材料,如單硬脂酸甘油酯或二硬脂酸甘油酯。其等亦可採用本領域所習知技術包覆,以形成滲透性醫療錠劑,供控制釋放。其他製劑包括生物可降解性或生物相容性粒子或聚合性物質,如聚酯、聚胺酸類、水合膠、聚乙烯基吡咯烷酮、聚酸酐、聚乙醇酸、乙烯-乙酸乙烯酯、甲基纖維素、羧甲基纖維素、硫酸精蛋白、或丙交酯/乙交酯共聚物、聚丙交酯/乙交酯共聚物、或乙烯乙酸乙烯基酯共聚物,以控制所投與組成物之傳遞。例如,該口服劑可包埋在採用凝聚技術或界面聚合法,分別使用羥甲基纖維素或明膠-微膠囊或聚(甲基丙烯酸甲酯)微膠囊製備之微膠囊中,或含於膠體藥物傳遞系統中。膠體勻散系統包括大分子複合物、奈米膠囊、微球粒、微珠粒、與基於脂質之系統,包括水包油乳液、膠束、混合膠束、與脂質體。製備上述調配物之方法係本領域技術人員所習知者。
口服用調配物亦可呈硬式明膠囊,其中由活性成份與惰性固體稀釋劑混合,例如,碳酸鈣、磷酸鈣、高嶺土或微晶纖維素,或呈軟明膠囊,其中活性成份係與水或油狀基質混合,例如,花生油、液態石蠟、或橄欖油。
水性懸浮液包含活性材料與適合其製造之賦形劑混合。此等賦形劑可為懸浮劑,例如,羧甲基纖維 素鈉、甲基纖維素、羥基-丙基甲基纖維素、藻酸鈉、聚乙烯基-吡咯烷酮、黃耆膠與金合歡膠;勻散劑或濕化劑,例如,天然磷脂(例如,卵磷脂)、或伸烷基氧化物與脂肪酸之縮合產物(例如,聚氧基-硬脂酸伸乙基酯)、或環氧乙烷與長鏈脂醇之縮合產物(例如,十七烷伸乙基氧基十六烷醇(heptadecaethyleneoxycetanol))、或環氧乙烷與衍生自脂肪酸與己糖醇之部份酯之縮合產物(例如,聚氧伸乙基山梨糖醇單油酸酯)、或環氧乙烷與衍生自脂肪酸與己糖醇酐之部份酯之縮合產物(例如,聚伸乙基山梨糖醇酐單油酸酯)。水性懸浮液亦可包含一或多種防腐劑。
油性懸浮液之調配法可由活性成份懸浮於植物油中,例如,花生油、橄欖油、芝麻油或椰子油,或礦物油,如液態石蠟。油狀懸浮液可包含增稠劑,例如,蜂蠟、硬石蠟或鯨蠟醇。可添加甜味劑,如彼等如上述,與調味劑,產生適口之口服劑。
適合製備水性懸浮液之勻散性粉劑與粒劑可以加水,形成活性成份與勻散劑或濕化劑,及視需要選用一或多種懸浮劑與/或防腐劑之混合物。本文將例舉合適之勻散劑或濕化劑與懸浮劑。
本發明醫藥組成物亦可呈水包油型乳液。油相可為植物油,例如,橄欖油或花生油、或礦物油,例如,液態石蠟,或此等之混合物。合適乳化劑可為天然膠質,例如,金合歡膠或黃耆膠;天然磷脂,例如,大豆、卵磷脂,及衍生自脂肪酸之酯或部份酯;己糖醇酸酐,例 如,山梨糖醇酐單油酸酯;及部份酯與環氧乙烷之縮合產物(例如,聚氧伸乙基山梨糖醇酐單油酸酯)。
醫藥組成物通常包含醫療有效量之本發明範圍內之CCR4抑制劑與一或多種醫藥上與生理上可接受之調配劑。合適之醫藥上可接受或生理上可接受之稀釋劑、載劑或賦形劑包括,但不限於,抗氧化劑(例如,抗壞血酸與硫酸氫鈉)、防腐劑(例如,苯甲基醇、對羥基苯甲酸甲酯、對羥基苯甲酸乙酯或正丙酯)、乳化劑、懸浮劑、勻散劑、溶劑、填料、增積劑、清潔劑、緩衝劑、媒劑、稀釋劑、與/或佐劑。例如,合適媒劑可為生理食鹽水溶液或檸檬酸鹽緩衝之生理食鹽水,可能補充常用於非經腸式投藥之醫藥組成物中之其他材料。其他媒劑實例為中性緩衝生理食鹽水或與血清白蛋白混合之生理食鹽水。彼等習此相關技藝者咸了解有許多種不同緩衝劑可以用於本文所涵括之醫藥組成物與劑型中。典型緩衝劑包括,但不限於醫藥上可接受之弱酸、弱鹼、或其混合物。例如,緩衝劑組份可為水溶性材料,如磷酸、酒石酸、乳酸、琥珀酸、檸檬酸、乙酸、抗壞血酸、天冬胺酸、麩胺酸、與其鹽。可接受之緩衝劑包括例如,Tris緩衝劑;N-(2-羥基乙基)哌-N'-(2-乙磺酸)(HEPES);2-(N-嗎啉基)乙磺酸(MES);2-(N-嗎啉基)乙磺酸鈉鹽(MES);3-(N-嗎啉基)丙磺酸(MOPS);及N-參[羥基甲基]甲基-3-胺基丙磺酸(TAPS)。
醫藥組成物調配後,可呈溶液、懸浮液、凝膠、乳液、固體或脫水或凍乾粉末存放在無菌小瓶中。 此等調配物可呈現成可用之型式、臨用前需要再組成之凍乾型式、臨用前需要稀釋之型式、或其他可接受之型式。有些具體實施例中,醫藥組成物係呈單次使用之容器提供(例如,單次使用之小瓶、安瓿、針筒、或自動注射器(類似例如,EpiPen®)),而其他具體實施例則提供多重使用之容器(例如,多重使用之小瓶)。
調配物亦可包括載劑,以保護組成物免於快速崩解或被身體消除,如控制釋放調配物,包括脂質體、水合膠、前藥、與微包埋傳遞系統。例如,可使用緩釋材料,如單硬脂酸甘油酯或硬脂酸甘油酯單獨或與蠟組合使用。任何藥物傳遞裝置均可用於傳遞CCR4調控劑,包括植入物(例如,可植入之幫浦)與導管系統、緩慢注射幫浦與裝置,其均係本領域技術人員習知者。
亦可利用通常經皮下或肌內投藥之儲積式注射劑,在一段長時間期內釋放本文所揭示之化合物(例如,CCR4調控劑)。儲積式注射劑通常基於固體或油,通常包含至少一種本文說明之調配組份。本領域技術人員即熟悉儲積式注射劑之可能調配物與用法。
醫藥組成物可呈無菌注射用之水性或油性懸浮液。此懸浮液可依據已知技藝,使用本文所述之彼等合適勻散劑或濕化劑與懸浮劑調配。無菌之注射劑亦可為含於非經腸式可接受之無毒稀釋劑或溶劑中之無菌注射液或懸浮液(例如,含於1,3-丁二醇中之溶液)。可使用之可接受之稀釋劑、溶劑與勻散介質包括水、林格氏溶液 (Ringer's solution)、等滲性氯化鈉溶液、Cremophor® EL(BASF,Parsippany,NJ)或磷酸鹽緩衝生理食鹽水(PBS)、乙醇、多元醇(例如,甘油、丙二醇、與液態聚乙二醇)、及其合適混合物。此外,常使用無菌之不揮發性油作為溶劑或懸浮介質;為了此目的,任何溫和之不揮發性油均可使用,包括合成之單酸-或二酸甘油酯。此外,脂肪酸,如油酸可用於製備注射劑。可藉由包括延緩吸收之製劑(例如,單硬脂酸鋁或明膠)來延長特定注射調配物之吸收。
本發明包括以栓劑型式經直腸投與該化合物(例如,CCR4調控劑)。栓劑製法為混合藥物與合適之無刺激性賦形劑,其在常溫下為固體,但在直腸溫度下為液態,因此可在直腸中融化釋放藥物。此等材料包括,但不限於可可脂與聚乙二醇。
本發明涵括之化合物(例如,CCR4調控劑)可呈目前已知或未來將開發之任何其他合適醫藥組成物型式(例如,鼻用或吸入用鼻噴液)。
外加醫療劑
有些具體實施例中,本文提供一種醫藥組成物,其包含一、二、三種、或更多種其他醫藥活性物質(本文亦稱為「外加醫療劑」、「第二活性劑」,或類似物)(例如,CCR4調控劑以外者)。有些具體實施例中,本文所提供式(I)、(II)、(III)、(IV)、或(V)化合物之調配物進一步包含一、二、三種、或更多種其他醫療活性物質(本文亦稱為「外加醫療劑」、「第二活性劑」,或類似物)。其他具體實施例 中,本文所提供式(I)、(II)、(III)、(IV)、或(V)化合物之調配物係與一、二、三種、或更多種其他醫藥活性物質共同投與。特定具體實施例中,本文所提供口服調配物包含醫療有效量之外加醫療劑(群)。特定具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物之調配物與外加醫療劑(群)係由式(I)、(II)、(III)、(IV)、或(V)化合物之調配物與外加醫療劑(群)採用共同調配活性醫藥成份調配成為同一劑型之方法,包括本文所提供之方法及本領域所習知之方法,一起調配。其他具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物與外加醫療劑(群)之調配物係呈分開劑型共同投與。咸信,某些組合在治療特定疾病或病變(包括例如,EBV-相關型癌症及某些與不期望之血管新生或異常細胞增生有關之疾病與病症,例如,實體腫瘤)具有協同性作用性。本文所提供式(I)、(II)、(III)、(IV)、或(V)化合物之調配物亦可緩解與某些第二活性劑相關之副作用,且可使用有些第二活性劑來緩解與本文所提供CCR4調控劑劑型相關之副作用。某些具體實施例中,本文所提供CCR4調控劑之調配物係與一或多種醫療劑共同投與,以便為有此需要之個體提供再敏化效應。外加醫療劑可為例如,大分子(例如,蛋白質)或小分子(例如,合成性無機分子、有機金屬分子、或有機分子)。
適用於本文所揭露組成物與方法之特定外加醫療劑實例包括,但不限於,例如,細胞毒性劑、抗代謝物、抗葉酸鹽、HDAC抑制劑(例如,恩替諾特 (entinostat),亦稱為SNDX-275或MS-275;或凡力諾特(vorinostat)(亦稱為辛二醯苯胺異羥肟酸(SAHA)或N-羥基-N-苯基-辛二醯胺)、DNA嵌入劑、DNA交聯劑、DNA烷化劑、DNA裂解劑、拓樸異構酶抑制劑、HDAC抑制劑(如MGCD0103(a.k.a.N-(2-胺基苯基)-4-((4-(吡啶-3-基)嘧啶-2-基胺基)甲基)苯甲醯胺)、CDK抑制劑、JAK抑制劑、抗血管新生劑、Bcr-Abl抑制劑、HER2抑制劑、EGFR抑制劑、VEGFR抑制劑、PDGFR抑制劑、HGFR抑制劑、IGFR抑制劑、c-Kit抑制劑、Ras途徑抑制劑、PI3K抑制劑、多重靶向激酶抑制劑、mTOR抑制劑、抗雌激素、抗雄激素、芳構酶抑制劑、體抑素類似物、ER調控劑、抗微管蛋白劑、長春花生物鹼類、紫杉烷、HSP抑制劑、Smo蛋白(Smoothened)拮抗劑、端粒酶抑制劑、COX-2抑制劑、抗轉移劑、免疫壓制劑、生物製劑(如抗體)、與激素療法。特定具體實施例中,該共同投藥之醫療劑為免疫調控劑。特定具體實施例中,該免疫調控化合物為沙利竇邁(thalidomide)、來那竇邁(lenalidomide)、或泊馬竇邁(pomalidomide)。特定具體實施例中,該共同投藥之醫療劑為卡鉑(carboplatin)。特定具體實施例中,該共同投藥之醫療劑為太平洋紫杉醇(paclitaxel)(例如,Abraxane®)。參見例如,美國專利案7,758,891、7,771,751、7,820,788、7,923,536、8,034,375;美國專利公開案案號2007/0082838與2010/0048499;美國專利案5,916,596;6,506,405;6,749,868、與6,537,579;PCT公告案案號WO08/057562、 WO09/126938、WO09/126401、與WO09/126175;其等之全文均已以引用之方式併入本文中。
具體實施例中,共同投與之藥劑可以經口投藥。另一項具體實施例中,共同投與之藥劑可以注射投藥。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物之投藥途徑與第二療法/共同投與之療法之投藥途徑分別獨立。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係經口投藥。另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物經靜脈內或皮下投藥。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係經口投藥,而第二療法之投藥法係經口、非經腸式、腹膜內、靜脈內、動脈內、穿皮、舌下、肌內、直腸、頰內、鼻內、脂質體、吸入、陰道內、眼內、經由導管或人工支架局部傳遞、皮下、脂肪內、關節內、鞘內,或呈緩釋劑型。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物與第二醫療劑係採用相同投藥模式投藥,例如,經口、靜脈內、或皮下。另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係採用一種模式投藥,例如,經口,而第二種藥劑(例如,抗癌劑)係採用另一種模式投藥,例如,靜脈內或皮下。再另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係採用一種模式投藥,例如,靜脈內或皮下,而第二藥劑(例如,抗癌劑)係採用另一種模式例如,經口投藥。
外加醫療劑之其他實例包括,但不限於, 造血生長因子、細胞介素、粒細胞群落刺激因子(G-CSF)、粒細胞-巨噬細胞群落刺激因子(GM-CSF)、紅血球生成素(EPO)、間白素(IL)、干擾素(IFN)、奥利默森(oblimersen)、馬法蘭(melphalan)、托普替康(topotecan)、己酮可可鹼(pentoxifylline)、歐洲紫杉醇(taxotere)、伊立替康(irinotecan)、環丙沙星(ciprofloxacin)、多柔比星(doxorubicin)、長春新鹼(vincristine)、達卡巴仁(dacarbazine)、Ara-C、長春瑞濱(vinorelbine)、潑尼松(prednisone)、環磷醯胺、硼替佐米(bortezomib)、三氧化二砷。特別適用於本文所揭示方法與組成物之此等外加醫療劑包括,但不限於,彼等與治療勃奇氏淋巴瘤、霍奇金氏淋巴瘤、瀰漫性大B細胞淋巴瘤、NK/T-細胞淋巴瘤、皮膚T-細胞淋巴瘤、鼻咽癌及胃癌有關者。
其他外加醫療劑實例包括,但不限於,抗體(例如,利妥昔單抗(rituximab)、抗-CD33)、造血生長因子、細胞介素、抗生素、cox-2抑制劑、免疫調控劑、免疫壓制劑、皮質類固醇、或其醫藥活性突變株或衍生物。參見例如,S.Nand等人之Leukemia and Lymphoma,2008,49(11):2141-47(說明涉及以羥基脲、氮雜西定(azacitidine)與低劑量吉妥珠單抗(gemtuzumab ozogamicin)之組合投與患有AML與高風險MDS之老年患者之第II期試驗,其結論為該組合似乎在此組患者中為治療AML與高風險MDS之安全且有效之療法)。此等特別適用於本文所揭示方法與組成物之外加醫療劑包括,但不限於,彼等與治療本文所 揭示疾病與病變有關者。
大分子活性劑實例包括,但不限於,造血生長因子、細胞素、及單株與多株抗體。典型大分子活性劑為生物性分子,如天然發生或人造蛋白質。特別適用之蛋白質包括於活體外或活體內刺激造血前體細胞與免疫活性造血細胞之存活與/或增生之蛋白質。其他則於活體外或活體內刺激定向紅血球祖細胞之細胞分裂與分化。特定蛋白質包括,但不限於間白素,如IL-2(包括重組IL-II(「rIL2」)與金絲雀痘(canarypox)IL-2)、IL-10、IL-12、與IL-18;干擾素,如干擾素α-2a、干擾素α-2b、干擾素α-n1、干擾素α-n3、干擾素β-I a、與干擾素γ-I b;GM-CF與GM-CSF;與EPO。
可用於本文所提供方法與組成物之特定蛋白質包括,但不限於,非格司亭(filgrastim),其已在美國以商標名稱Neupogen®出售(Amgen,Thousand Oaks,Calif.);沙格司亭(sargramostim),其已在美國以商標名稱Leukine®出售(Immunex,Seattle,Wash.);與重組EPO,其已在美國以商標名稱Epogen®出售(Amgen,Thousand Oaks,Calif.)。
GM-CSF之重組體與突變型可依美國專利案5,391,485;5,393,870;與5,229,496之說明製備;其等全文均已以引用之方式併入本文中。G-CSF之重組體與突變型可依美國專利案4,810,643;4,999,291;5,528,823;與5,580,755之說明製備;其等全文均已以引用之方式併 入本文中。
本文具體實施例涵括原始、天然、與重組蛋白質。特定具體實施例涵括天然蛋白質之突變體與衍生物(例如,修飾型),其在活體內具有其基礎蛋白質之至少有些醫藥活性。突變體實例包括,但不限於,具有一個或多個胺基酸殘基不同於天然型蛋白質中對應胺基酸殘基之蛋白質。術語「突變體」亦涵括缺少原本應正常存在於天然型中之碳水合物部份基團之蛋白質(例如,非糖基化型)。衍生物實例包括,但不限於,聚乙二醇基化衍生物與融合蛋白質,如由IgG1或IgG3與蛋白質或所需蛋白質之活性部份融合之蛋白質。參見例如,Penichet,M.L.與Morrison,S.L.,J.Immunol.Methods 248:91-101(2001)。
可與式(I)、(II)、(III)、(IV)、或(V)化合物共同投藥之抗體包括單株抗體與多株抗體。抗體實例包括,但不限於,曲妥珠單抗(trastuzumab)(Herceptin®)、利妥昔單抗(rituximab)(Rituxan®)、貝伐單抗(bevacizumab)(AvastinTM)、帕妥珠單抗(pertuzumab)(OmnitargTM)、托西莫單抗(tositumomab)(Bexxar®)、依決洛單抗(edrecolomab)(Panorex®)、尼弗樂單抗(nivolumab)(OpdivoTM)、皮布利單抗(pembrolizumab)(KeytrudaTM)、艾弗單抗(avelumab)(BavencioTM)、艾齊利單抗(atezolizumab)(TecentriqTM)、度伐魯單抗(durvalumab)(ImfinziTM)與易普利單抗(ipilimumab)(YervoyTM)與G250。本文所揭示口服調配物亦可包含、組合、或併用抗-TNF-α抗體。
大分子活性劑可呈抗癌疫苗型式投藥。例如,分泌或導致分泌細胞介素(如IL-2、G-CSF、與GM-CSF)之疫苗均可用於本文所提供方法、醫藥組成物、與套組中。參見例如,Emens,L.A.等人之Curr.Opinion Mol.Ther.3(1):77-84(2001)。
具體實施例中,可外加會減少、消除、或預防因投與(例如,口服投與)本文所說明式(I)、(II)、(III)、(IV)、或(V)化合物有關之副作用之外加醫療劑(例如,大分子化合物或小分子)。依所治療疾病或病變而定,式(I)、(II)、(III)、(IV)、或(V)化合物之副作用包括,但不限於,貧血、嗜中性白血球減少症、嗜中性白血球減少症發燒、血小板減少症、肝毒性(例如,包括,但不限於,已出現肝損傷之患者中之肝毒性)、血清肌酸酐上升、腎衰竭、腎小管性酸中毒、低血鉀、肝昏迷、噁心、嘔吐、消化不良、腹部疼痛、發熱、白血球減少症、腹瀉、便秘、瘀斑、瘀點、寒顫、虛弱、肺炎、焦慮、失眠、昏睡、及體重下降等等本領域所習知與投與CCR4調控劑相關者。
如同有些大分子,咸信許多小分子化合物當與本文所揭示式(I)、(II)、(III)、(IV)、或(V)化合物投藥(例如,之前、之後或同時)時,可以提供協同性效應。小分子第二活性劑實例包括,但不限於,抗癌劑、抗生素、免疫壓制劑、免疫調控劑與類固醇。
抗癌劑實例包括,但不限於,阿西維辛(acivicin);阿柔比星(aclarubicin);鹽酸諾考達唑 (acodazole hydrochloride);山油柑鹼(acronine);阿多來新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);安波黴素(ambomycin);乙酸阿美蒽醌(ametantrone acetate);安吖啶(amsacrine);安耐柔(anastrozole);胺茴黴素(anthramycin);天冬胺酸酶;曲林菌素(asperlin);氮雜西定(azacitidine);阿紮替派(azetepa);阿佐黴素(azotomycin);巴馬司他(batimastat);苯佐替派(benzodepa);比卡魯胺(bicalutamide);鹽酸比生群(bisantrene hydrochloride);二甲磺酸雙奈法德(bisnafide dimesylate);比折來新(bizelesin);硫酸博來黴素(bleomycin sulfate);布喹那鈉(brequinar sodium);溴匹立明(bropirimine);白消安(busulfan);放線菌素C(cactinomycin);二甲睾酮(calusterone);卡醋胺(caracemide);卡貝替姆(carbetimer);卡鉑(carboplatin);卡莫司汀(carmustine);鹽酸洋紅黴素(carubicin hydrochloride);卡折來新(carzelesin);西地芬戈(cedefingol);塞來昔布(celecoxib)(COX-2抑制劑);苯丁酸氮芥(chlorambucil);西洛黴素(cirolemycin);順鉑(cisplatin);克拉屈濱(cladribine);甲磺酸克立那托(crisnatol mesylate);環磷醯胺;阿糖胞苷(cytarabine);達卡巴仁(dacarbazine);放線菌素D(Dactinomycin);鹽酸唐諾黴素(daunorubicin hydrochloride);地西他濱(decitabine);右奧馬鉑(dexormaplatin);地紮胍寧(dezaguanine);甲磺酸地紮胍寧(dezaguanine mesylate); 地吖醌(diaziquone);歐洲紫杉醇(docetaxel);多柔比星(doxorubicin);鹽酸多柔比星(doxorubicin hydrochloride);屈洛昔芬(droloxifene);檸檬酸屈洛昔芬(droloxifene citrate);丙酸屈他雄酮(dromostanolone propionate);重氮黴素(duazomycin);依達曲沙(edatrexate);鹽酸依氟鳥胺酸(eflornithine hydrochloride);依沙蘆星(elsamitrucin);恩洛鉑(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);鹽酸泛艾黴素(epirubicin hydrochloride);厄布洛唑(erbulozole);鹽酸依索比星(esorubicin hydrochloride);雌氮芥(estramustine);雌氮芥磷酸鈉;依他硝唑(etanidazole);依託泊苷(etoposide);磷酸依託泊苷;氯苯乙嘧胺(etoprine);鹽酸法羅唑啉(fadrozole hydrochloride);法紮拉濱(fazarabine);芬維A胺(fenretinide);氟尿嘧啶脫氧核苷(floxuridine);磷酸氟達拉濱(fludarabine phosphate);氟尿嘧啶;氟西他濱(fluorocitabine);氟喹酮(fosquidone);福司曲星鈉(fostriecin sodium);吉西他濱(gemcitabine);鹽酸吉西他濱;羥基脲;鹽酸伊達比星(idarubicin hydrochloride);異環磷醯胺(ifosfamide);伊莫福新(ilmofosine);異丙鉑(iproplatin);伊立替康(irinotecan);鹽酸伊立替康;乙酸蘭瑞肽(lanreotide acetate);來曲唑(letrozole);乙酸柳菩林(leuprolide acetate);鹽酸利阿唑(liarozole hydrochloride);洛美曲索鈉(lometrexol sodium);洛莫司 汀(lomustine);鹽酸洛索蒽醌(losoxantrone hydrochloride);馬索羅酚(masoprocol);美坦辛(maytansine);二氯甲基二乙胺鹽酸鹽(mechlorethamine hydrochloride);乙酸甲地孕酮(megestrol acetate);乙酸美侖孕酮(melengestrol acetate);馬法蘭(melphalan);美諾立爾(menogaril);氫硫基嘌呤;胺甲蝶呤(methotrexate);胺甲蝶呤鈉(methotrexate sodium);氯苯胺啶(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡星(mitocarcin);絲裂紅素(mitocromin);米托潔林(mitogillin);米托馬星(mitomalcin);絲裂黴素(mitomycin);米托司培(mitosper);米托坦(mitotane);鹽酸米托蒽醌(mitoxantrone hydrochloride);黴酚酸(mycophenolic acid);諾考達唑(nocodazole);諾拉黴素(nogalamycin);奧馬鉑(ormaplatin);奧昔舒侖(oxisuran);太平洋紫杉醇(paclitaxel);培門冬酶(pegaspargase);培利黴素(peliomycin);戊氮芥(pentamustine);硫酸培洛黴素(peplomycin sulfate);培磷醯胺(perfosfamide);雙溴丙基哌嗪(pipobroman);哌泊舒凡(piposulfan);鹽酸吡羅蒽醌(piroxantrone hydrochloride);普卡黴素(plicamycin);普洛美坦(plomestane);蔔吩姆鈉(porfimer sodium);泊非黴素(porfiromycin);潑尼莫司汀(prednimustine);鹽酸丙卡巴肼(procarbazine hydrochloride);嘌呤黴素(puromycin);鹽酸嘌呤黴素(puromycin hydrochloride);吡唑呋喃菌素(pyrazofurin);利波腺苷(riboprine);沙芬戈(safingol);鹽 酸沙芬戈;希莫司汀(semustine);辛曲(simtrazene);磷乙醯天冬胺酸鈉(sparfosate sodium);稀疏黴素(sparsomycin);鹽酸鍺螺胺(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺鉑(spiroplatin);鏈黑黴素(streptonigrin);鏈脲佐菌素(streptozocin);磺氯苯脲(sulofenur);他利黴素(talisomycin);替可加蘭鈉(tecogalan sodium);歐洲紫杉醇(taxotere);替加氟(tegafur);鹽酸替洛蒽醌(teloxantrone hydrochloride);替莫泊芬(temoporfin);替尼泊苷(teniposide);替羅昔隆(teroxirone);睾內酯(testolactone);硫咪嘌呤(thiamiprine);硫鳥嘌呤(thioguanine);噻替哌(thiotepa);噻唑羧胺核苷(tiazofurin);替拉紮明(tirapazamine);檸檬酸托瑞米芬(toremifene citrate);乙酸曲托龍(trestolone acetate);磷酸曲西立濱(triciribine phosphate);三甲曲沙(trimetrexate);葡糖醛酸三甲曲沙(trimetrexate glucoronate);曲普瑞林(triptorelin);鹽酸妥布氯唑(tubulozole hydrochloride);尿嘧啶氮芥(uracil mustard);烏瑞替派(uredepa);伐普肽(vapreotide);維替泊芬(verteporfin);硫酸長春花鹼(vinblastine sulfate);硫酸長春新鹼(vincristine sulfate);長春地辛(vindesine);硫酸長春地辛(vindesine sulfate);硫酸長春匹定(vinepidine sulfate);硫酸長春甘酯(vinglycinate sulfate);硫酸長春羅辛(vinleurosine sulfate);酒石酸長春瑞濱(vinorelbine tartrate);硫酸長春羅定(vinrosidine sulfate);硫酸長春利 定(vinzolidine sulfate);伏氯唑(vorozole);折尼鉑(zeniplatin);淨司他丁(zinostatin);及鹽酸佐柔比星(zorubicin hydrochloride)。
其他抗癌藥包括,但不限於,20-表(epi)-1,25二羥基維生素D3;5-乙炔基尿嘧啶;阿比特龍(abiraterone);阿柔比星(aclarubicin);阿希夫吩(acylfulvene);腺環戊醇(adecypenol);阿多來新(adozelesin);阿地白介素(aldesleukin);ALL-TK拮抗劑;六甲蜜胺(altretamine);胺莫司汀(ambamustine);2,4二氯苯氧乙酸(amidox);阿米福汀(amifostine);胺基酮戊酸(aminolevulinic acid);胺柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);安耐柔(anastrozole);穿心蓮內酯(andrographolide);血管新生抑制劑;拮抗劑D;拮抗劑G;安塔利斯(antarelix);抗背部形態形成蛋白質-1;抗雄激素,攝護腺癌;抗雌激素;抗腫瘤物質(antineoplaston);反義寡核苷酸;艾菲地可寧甘胺酸鹽(aphidicolin glycinate);細胞凋亡基因調控劑;細胞凋亡調節劑;脫嘌呤酸(apurinic acid);ara-CDP-DL-PTBA;精胺酸脫胺酶;苯胺吖啶(asulacrine);阿他美坦(atamestane);阿莫司汀(atrimustine);洋蟲膠抑制素1(axinastatin 1);洋蟲膠抑制素2(axinastatin 2);洋蟲膠抑制素3(axinastatin3);阿紮司瓊(azasetron);阿紮毒素(azatoxin);氮雜酪胺酸;漿果赤黴素III(baccatin III)衍生物;博拉諾(balanol);巴馬司他(batimastat);BCR/ABL拮 抗劑;苯并二氫氯吩(benzochlorins);苯甲醯星狀孢子鹼(benzoylstaurosporine);β-內醯胺衍生物;β-艾利辛(β-alethine);β-克拉黴素B(betaclamycin B);樺木酸;bFGF抑制劑;比卡魯胺(bicalutamide);比生群(bisantrene);雙乙烯亞胺基精胺(bisaziridinylspermine);雙奈法德(bisnafide);雙崔特A(bistratene A);比折來新(bizelesin);布來福林(breflate);溴匹立明(bropirimine);布度鈦(budotitane);丁硫胺酸硫酸亞胺(buthionine sulfoximine);鈣泊三醇(calcipotriol);鈣磷酸蛋白C(calphostin C);喜樹鹼衍生物;卡培他濱(capecitabine);羧醯胺-胺基-三唑;羧醯胺基三唑;CaRest M3;CARN700;軟骨衍生之抑制劑;卡折來新(carzelesin);酪蛋白激酶抑制劑(ICOS);粟精胺(castanospermine);天蠶抗菌肽B(cecropin B);西曲瑞克(cetrorelix);二氫卟酚(chlorins);磺胺氯喹啉(chloroquinoxaline sulfonamide);西卡前列素(cicaprost);順卟啉(cis-porphyrin);克拉屈濱(cladribine);氯米芬類似物(clomifene analogues);克黴唑(clotrimazole);克裡斯黴素A(collismycin A);克裡斯黴素B(collismycin B);考布他汀A4(combretastatin A4);考布他汀類似物;康奈精(conagenin);甘藍海綿(crambescidin)816;克立那托(crisnatol);念珠藻環肽8(cryptophycin8);念珠藻環肽A(cryptophycin A)衍生物;鞘絲藻素A(curacin A);環戊烯蒽醌(cyclopentanthraquinones);環鉑(cycloplatam);環青黴素(cypemycin)、阿糖胞苷十八烷基 磷酸鹽(cytarabine ocfosfate);溶胞因子;磷酸己烷雌酚(cytostatin);達昔單抗(dacliximab);地西他濱(decitabine);脫氫膜海鞘素B(dehydrodidemnin B);地洛瑞林(deslorelin);地塞美松(dexamethasone);右異環磷醯胺(dexifosfamide);右雷佐生(dexrazoxane);右維拉帕米(dexverapamil);地吖醌(diaziquone);膜海鞘素B(didemnin B);第達(didox);二乙基去甲精胺(diethylnorspermine);二氫-a CCR4調控劑;9-二氫紫杉醇(dihydrotaxol);二氧黃溶黴素(dioxamycin);二苯基螺莫司汀(diphenylspiromustine);歐洲紫杉醇(docetaxel);二十二烷醇(docosanol);朵拉司瓊(dolasetron);去氧氟尿苷(doxifluridine);多柔比星(doxorubicin);屈洛昔芬(droloxifene);四氫大麻酚(dronabinol);倍癌黴素(duocannycin SA);依布硒(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依決洛單抗(edrecolomab);依氟鳥氨酸(eflornithine);欖香烯(elemene);乙嘧替氟(emitefur);泛艾黴素(epirubicin);愛普列特(epristeride);雌氮芥類似物(estramustine analogue);雌激素促效劑;雌激素拮抗劑;依他硝唑(etanidazole);磷酸依託泊苷(etoposide phosphate);依西美坦(exemestane);法倔唑(fadrozole);法紮拉濱(fazarabine);芬維A胺(fenretinide);非格司亭(filgrastim);非那甾胺(finasteride);夫拉平度(flavopiridol);氟卓斯汀(flezelastine);氟海星酮 (fluasterone);佛達拉濱(fludarabine);鹽酸氟代柔紅黴素(fluorodaunorunicin hydrochloride);福酚美克(forfenimex);福美坦(formestane);福司曲星(fostriecin);福莫司汀(fotemustine);莫特沙芬釓(gadolinium texaphyrin);硝酸鎵(gallium nitrate);加洛他濱(galocitabine);加尼瑞克(ganirelix);明膠酶抑制劑;吉西他濱(gemcitabine);穀胱甘肽抑制劑;赫素磺醯胺(hepsulfam);赫林蛋白(heregulin);六亞甲基雙乙醯胺;金絲桃素(hypericin);伊班膦酸(ibandronic acid);伊達比星(idarubicin);艾多昔芬(idoxifene);伊決孟酮(idramantone);伊莫福新(ilmofosine);伊洛馬司他(ilomastat);伊馬替尼(imatinib)(例如,Gleevec®);咪喹莫特(imiquimod);免疫刺激肽;胰島素樣生長因子-1受體抑制劑;干擾素促效劑;干擾素;間白素;碘節胍(iobenguane);碘多柔比星(iododoxorubicin);4-甘薯苦醇(ipomeanol,4-);伊羅普拉(iroplact);伊索拉定(irsogladine);異苯唑(isobengazole);同功軟海棉素(isohomohalicondrin)B;伊他司瓊(itasetron);促微絲聚合劑(jasplakinolide);環縮肽F(kahalalide F);三乙酸片螺素(lamellarin-N triacetate);蘭瑞肽(lanreotide);雷拉黴素(leinamycin);來格司亭(lenograstim);硫酸蘑菇多糖(lentinan sulfate);來泊司汀(leptolstatin);來曲唑(letrozole);白血病抑制因子;白細胞α干擾素;柳菩林(leuprolide)+雌激素+黃體酮;亮丙瑞林(leuprorelin);左旋 咪唑(levamisole);利阿唑(liarozole);線性聚胺類似物;親脂性雙醣肽;親脂性鉑化合物;利絲醯胺7(lissoclinamide 7);洛鉑(lobaplatin);胍乙基磷酸絲胺酸(lombricine);洛美曲索(lometrexol);氯尼達明(lonidamine);洛索蒽醌(losoxantrone);洛索立賓(loxoribine);勒托替康(lurtotecan);藍花贗靛素鎦(lutetium texaphyrin);利索茶鹼(lysofylline);溶解肽(lytic peptides);美坦新(maitansine);抑甘露糖苷酶素(mannostatin A);馬立馬司他(marimastat);馬索羅酚(masoprocol);乳腺絲胺酸蛋白酶抑制劑(maspin);基質溶解因子(matrilysin)抑制劑;基質金屬蛋白酶抑制劑;美諾立爾(menogaril);美巴龍(merbarone);美替瑞林(meterelin);甲硫胺酸酶;甲氧氯普胺(metoclopramide);MIF抑制劑;米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);米托胍腙(mitoguazone);二溴衛矛醇(mitolactol);絲裂黴素(mitomycin)類似物;米托萘胺(mitonafide);絲裂毒素(mitotoxin)纖維母細胞生長因子-皂草素;米托蒽醌(mitoxantrone);莫法羅汀(mofarotene);莫拉司亭(molgramostim);Erbitux,人類絨毛膜促性腺激素;單磷醯基脂質A+分枝桿菌(myobacterium)細胞壁sk;莫比達醇(mopidamol);氮芥抗癌劑;印度洋海綿B(mycaperoxide B);分枝桿菌細胞壁抽出物(mycobacterial cell wall extract);苔蘚蟲海綿(myriaporone);N-乙醯基地那林 (N-acetyldinaline);N-經取代之苯甲醯胺;那法瑞林(nafarelin);那哥斯普(nagrestip);納洛酮(naloxone)+噴他佐辛(pentazocine);納帕維(napavin);萘萜二醇(naphterpin);那托司亭(nartograstim);奈達鉑(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);尼魯米特(nilutamide);尼薩黴素(nisamycin);一氧化氮調控劑;硝基氧抗氧化劑;尼楚林(nitrullyn);奥利默森(oblimersen)(Genasense®.);O6-苯甲基鳥嘌呤;奧曲肽(octreotide);奧克三諾(okicenone);寡核苷酸;奧那司酮(onapristone);昂丹司瓊(ondansetron);昂丹司瓊(ondansetron);奧瑞森(oracin);口服細胞素誘導劑;奧馬鉑(ormaplatin);奧沙特隆(osaterone);奧沙利鉑(oxaliplatin);奧諾黴素(oxaunomycin);太平洋紫杉醇(paclitaxel);太平洋紫杉醇類似物;太平洋紫杉醇衍生物;鈀銨(palauamine);棕櫚醯根黴素(palmitoylrhizoxin);帕米磷酸(pamidronic acid);人參三醇(panaxytriol);帕諾米芬(panomifene);副菌鐵素(parabactin);帕折普汀(pazelliptine);培門冬酶(pegaspargase);培得星(peldesine);戊聚糖聚硫酸鈉(pentosan polysulfate sodium);噴司他汀(pentostatin);噴曲唑(pentrozole);全氟溴烷(perflubron);培磷醯胺(perfosfamide);紫蘇子醇(perillyl alcohol);吩嗪黴素(phenazinomycin);乙酸苯酯;磷酸酶抑制劑;必醫你舒(picibanil);毛果蕓香鹼鹽酸鹽(pilocarpine hydrochloride);比柔比星(pirarubicin);比曲克辛(piritrexim);普拉汀A(placetin A);普拉汀B(placetin B);纖溶酶原活化因子抑制劑;鉑複合物;鉑化合物;鉑-三胺複合物;葉吩姆鈉(porfimer sodium);泊非黴素(porfiromycin);潑尼松(prednisone);丙基雙吖啶酮(propyl bis-acridone);前列腺素J2;蛋白酶體抑制劑;基於蛋白質A之免疫調控劑;蛋白質激酶C抑制劑;蛋白質激酶C抑制劑,微海藻類(microalgal);蛋白質酪胺酸磷酸酶抑制劑;嘌呤核苷磷酸化酶抑制劑;紅紫素(purpurins);吡唑并吖啶(pyrazoloacridine);吡哆醇酸化血紅蛋白聚氧乙烯接合物;raf拮抗劑;雷替曲塞(raltitrexed);雷莫司瓊(ramosetron);ras法尼基(ras farnesyl)蛋白質轉移酶抑制劑;ras抑制劑;ras-GAP抑制劑;脫甲基瑞替普汀(retelliptine demethylated);錸Re186依替膦酸鹽(rhenium Re 186 etidronate);根黴素(rhizoxin);核酶;RII維甲醯酚胺(retinamide);羅稀吐鹼(rohitukine);羅莫肽(romurtide);羅喹美克(roquinimex);如彼給諾(rubiginone)B1;如波斯(ruboxyl);沙芬戈(safingol);沙托品(saintopin);SarCNU;肌肉葉綠醇A(sarcophytol A);沙格司亭(sargramostim);Sdi 1擬似物;希莫司汀(semustine);衰老細胞衍生的抑制劑1;正義寡核苷酸;訊號轉導抑制劑;西佐非蘭(sizofuran);索布佐生(sobuzoxane);硼卡鈉(sodium borocaptate);苯乙酸鈉;索菲醇(solverol);生長調節素結合性蛋白質;索納明(sonermin);磷乙醯天冬胺 酸(sparfosic acid);穗黴素D(spicamycin D);螺莫司汀(spiromustine);脾五肽(splenopentin);海綿他汀素1(spongistatin 1);角鯊胺(squalamine);密擠青黴醯胺(stipiamide);基質降解酶(stromelysin)抑制劑;硫福辛(sulfinosine);強效血管活性腸肽拮抗劑;磺酸偏端黴素(suradista);舒拉明(suramin);苦馬豆素(swainsonine);他莫司汀(tallimustine);它莫西芬甲碘化物(tamoxifen methiodide);牛磺莫司汀(tauromustine);他紮羅汀(tazarotene);替可加蘭鈉(tecogalan sodium);替加氟(tegafur);締哌喃鐵(tellurapyrylium);端粒酶抑制劑;替莫泊芬(temoporfin);替尼泊苷(teniposide);四氯十氧化物(tetrachlorodecaoxide);四氫唑環(tetrazomine);白蓬草硝酸鈉(thaliblastine);噻可拉林(thiocoraline);血小板生成素;血小板生成素擬似物;胸腺法新(thymalfasin);胸腺生成素受體促效劑;胸腺曲南(thymotrinan);甲狀腺刺激激素;本紫紅素乙酯錫(tin ethyl etiopurpuron);替拉紮明(tirapazamine);二氯環戊二烯鈦(titanocene bichloride);淺水海綿素(topsentin);托瑞米芬(toremifene);轉譯抑制劑;維甲酸(tretinoin);三乙醯尿苷(triacetyluridine);曲西立濱(triciribine);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司瓊(tropisetron);妥羅雄脲(turosteride);酪胺酸激酶抑制劑;酪胺酸激酶阻斷劑(tyrphostins);UBC抑制劑;烏苯美司(ubenimex);泌尿生殖竇衍生之生長抑制因子;尿激酶受 體拮抗劑;伐普肽(vapreotide);瓦裡奧林B(variolin B);維拉雷瑣(velaresol);藜蘆明(veramine);維爾定(verdins);維替泊芬(verteporfin);長春瑞濱(vinorelbine);維夏汀(vinxaltine);維它新(vitaxin);伏氯唑(vorozole);紮諾特隆(zanoterone);折尼鉑(zeniplatin);亞苄維C(zilascorb);與淨司他丁斯酯(zinostatin stimalamer)。
特定之外加醫療劑包括,但不限於,奥利默森(oblimersen)(Genasense®)、瑞米卡(remicade)、歐洲紫杉醇(docetaxel)、塞來昔布(celecoxib)、馬法蘭(melphalan)、地塞美松(dexamethasone)(Decadron®)、類固醇、吉西他濱(gemcitabine)、順鉑(cisplatinum)、替莫唑胺(temozolomide)、依託泊苷(etoposide)、環磷醯胺、替莫唑胺(temodar)、卡鉑(carboplatin)、丙卡巴肼(procarbazine)、格立得(gliadel)、它莫西芬(tamoxifen)、托普替康(topotecan)、胺甲蝶呤(methotrexate)、Arisa®、紫杉醇、歐洲紫杉醇(taxotere)、氟尿嘧啶、若克瘤(leucovorin)、伊立替康(irinotecan)、截瘤達(xeloda)、CPT-11、干擾素α、聚乙醇基化之干擾素α(例如,PEG INTRON-A)、卡培他濱(capecitabine)、順鉑(cisplatin)、噻替哌(thiotepa)、福達樂(fludarabine)、卡鉑(carboplatin)、脂質體唐黴素(daunorubicin)、阿糖胞苷(cytarabine)、歐洲紫杉醇(doxetaxol)、太平洋紫杉醇(pacilitaxel)、長春花鹼(vinblastine)、IL-2、GM-CSF、達卡巴仁(dacarbazine)、長春瑞濱(vinorelbine)、唑來膦酸(zoledronic acid)、裴米卓 耐特(palmitronate)、甲紅黴素(biaxin)、白消安(busulphan)、潑尼松(prednisone)、雙膦酸鹽、三氧化二砷、長春新鹼(vincristine)、多柔比星(doxorubicin)(Doxil)、太平洋紫杉醇(paclitaxel)、更昔洛韋(ganciclovir)、阿黴素(adriamycin)、雌莫司汀磷酸鈉(estramustine sodium phosphate)(Emcyt®)、蘇林達克(sulindac)、與依託泊苷(etoposide)。
使用方法
於態樣中,本文提供一種藉由對患有癌症之個體投與式(I)、(II)、(III)、(IV)、或(V)化合物、或其醫藥上可接受之鹽,治療或管控EBV-相關癌症之方法。一項具體實施例中,該方法包括使用式(I)、(II)、(III)、(IV)、或(V)化合物、或其醫藥上可接受之鹽治療EBV-相關癌症。一項具體實施例中,該方法包括使用式(I)、(II)、(III)、(IV)、或(V)化合物、或其醫藥上可接受之鹽管控EBV-相關癌症。某些具體實施例中,該方法包括共同投與一或多種外加活性劑(例如,如本文揭示之抗癌劑)。某些具體實施例中,個體為哺乳動物。某些具體實施例中,個體為人類。特定具體實施例中,EBV-相關癌症為實體腫瘤(例如,復發性或難治性實體腫瘤)。
具體實施例中,本文提供一種以式(I)、(II)、(III)、(IV)、或(V)化合物、或其醫藥上可接受之鹽於製造醫藥供治療與/或管控EBV-相關癌症(例如,復發性或難治性實體腫瘤)之用途。
具體實施例中,本文提供式(I)、(II)、(III)、(IV)、或(V)化合物、或其醫藥上可接受之鹽,用於治療與/或管控EBV-相關癌症(例如,復發性或難治性實體腫瘤)。
具體實施例中,本文提供治療或管控某些類型EBV-相關癌症之方法,包括,但不限於,EBV-相關實體腫瘤;難治性EBV-相關癌症或復發性EBV-相關癌症;或難治性EBV-相關實體腫瘤或復發性EBV-相關實體腫瘤。一項具體實施例中,本文提供治療或管控某些類型EBV-相關癌症之方法,其包括,但不限於,勃奇氏淋巴瘤、霍奇金氏淋巴瘤、瀰漫性大B細胞淋巴瘤,、NK/T-細胞淋巴瘤、皮膚T-細胞淋巴瘤、鼻咽癌、胃癌、外陰鱗狀細胞癌、唾液腺癌、眼脈絡膜黑色素瘤、與胰膽管系腺癌瘤。
具體實施例中,本文提供治療或管控EBV-相關癌症之方法,包括勃奇氏淋巴瘤、霍奇金氏淋巴瘤、瀰漫性大B細胞淋巴瘤、NK/T-細胞淋巴瘤、皮膚T-細胞淋巴瘤、鼻咽癌、胃癌、外陰鱗狀細胞癌、唾液腺癌、眼脈絡膜黑色素瘤、與胰膽管系腺癌瘤。
具體實施例中,本文提供一種治療或管控胰膽管系腺癌瘤之方法。
具體實施例中,本文提供一種治療或管控淋巴瘤之方法。具體實施例中,本文提供治療或管控勃奇氏淋巴瘤之方法。
具體實施例中,本文提供一種治療或管控鼻咽癌之方法。一項具體實施例中,鼻咽癌為角化麟狀細 胞癌瘤(舊稱WHO第I型)。一項具體實施例中,鼻咽癌為非角化癌瘤。一項具體實施例中,鼻咽癌為類基底麟狀細胞癌瘤。一項具體實施例中,非角化癌瘤為分化之非角化癌瘤(舊稱WHO第II型)。一項具體實施例中,非角化癌瘤為未分化之非角化癌瘤(舊稱WHO第III型)。
具體實施例中,該方法包括治療或管控某些階段之EBV-相關癌症,例如,第0期、第I期、第II期、第III期、與第IV期,其係對罹患此等癌症之個體投與式(I)、(II)、(III)、(IV)、或(V)化合物、或其醫藥上可接受之鹽。癌症之分期可依據本領域所習知之方法定義,例如,依據美國癌症協會(American Joint Committee on Cancer)(AJCC)提供之準則。一項具體實施例中,罹患EBV-相關癌症之個體之癌症分期係依據TNM分級法指定及分級,亦即依據初級腫瘤之狀態(例如,TX、T0、Tis、T1、T2、T3、T4)、區域淋巴結(例如,NX、N0、N1、N2、N3)、與/或遠距離轉移(例如,MX、M0、M1)分級。
特定具體實施例提供採用本文所提供本文所提供一或多種方法,併用外科手術,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用本文所提供一或多種方法,併用化學療法,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用本文所提供一或多種方法,併用免疫療法,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用本文所提供一或多種方法,併用標靶療法,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用 本文所提供一或多種方法,併用放射療法,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用本文所提供一或多種方法,併用細胞療法,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用本文所提供一或多種方法,併用疫苗接種療法,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用本文所提供一或多種方法,併用基因療法,治療罹患EBV-相關癌症之個體之方法。特定具體實施例提供採用本文所提供一或多種方法,併用選自外科手術、化學療法、免疫療法、標靶療法、放射療法、細胞療法、疫苗接種療法或基因療法中兩種或更多種治療法,治療罹患EBV-相關癌症之個體。特定具體實施例提供採用本文所提供一或多種方法,併用選自外科手術、化學療法、免疫療法、與放射療法中兩種或更多種治療法,治療罹患EBV-相關癌症之個體之方法。
具體實施例中,接受本文所提供一或多種方法治療之個體在接受投與式(I)、(II)、(III)、(IV)、或(V)化合物之前未曾接受抗癌療法治療。某些具體實施例中,接受本文所提供一或多種方法治療之個體在接受投與式(I)、(II)、(III)、(IV)、或(V)化合物之前,曾經接受一或多種抗癌療法治療。某些具體實施例中,接受本文所提供一或多種方法治療之個體曾經接受本文所說明癌症治療劑治療。某些具體實施例中,接受本文所提供一或多種方法治療之個體已對抗癌療法發展出抗藥性。某些具體實施例中,接受本文所提供方法治療之個體患有復發性EBV-相關 癌症。某些具體實施例中,接受本文所提供方法治療之個體患有難治性EBV-相關癌症。某些具體實施例中,接受本文所提供方法治療之個體患有轉移性EBV-相關癌症。某些具體實施例中,接受本文所提供方法治療之個體患有EBV-相關淋巴瘤。某些具體實施例中,接受本文所提供方法治療之個體患有勃奇氏淋巴瘤。
具體實施例中,本文提供之方法包括不分患者年齡來治療個體,雖然有些疾病或病變較好發於某些年齡層。本文進一步提供一種為曾接受外科手術試圖治療所關注之疾病或病症之個體治療之方法。本文進一步提供一種為未曾接受外科手術試圖治療所關注之疾病或病症之個體治療之方法。由於罹患EBV-相關癌症之個體具有不同臨床徵狀及各種不同臨床結果,因此特定個體所接受之治療可能有變化,端賴其預後而定。習此相關技藝者不需要繁複實驗即很容易決定可用於有效治療罹患EBV-相關癌症之個別個體特定之第二藥劑、外科手術型態、及不基於藥物之標準療法型態。
本文所提供具體實施例中,該方法可進一步包括一或多個診斷步驟,以決定例如,EBV-相關癌症型態、特定細胞型態之存在、個體之遺傳型態、及/或個體之疾病分期。
本文所提供具體實施例中,該方法進一步包括在對個體投與式(I)、(II)、(III)、(IV)、或(V)化合物之後評估疾病之步驟,以決定例如,本文其他內容所說明 一或多種分子標記物之變化、腫瘤大小與位置之變化、及/或彼等相關技藝者所採用之其他基準物之變化,以決定EBV-相關癌症在個體中之預後。
本文具體實施例提供一種式(I)、(II)、(III)、(IV)、或(V)化合物之投藥法,例如,經靜脈內(IV)、皮下(SC)或口服途徑投藥。本文某些方法提供採用口服途徑投藥法投與式(I)、(II)、(III)、(IV)、或(V)化合物。本文某些具體實施例提供由式(I)、(II)、(III)、(IV)、或(V)化合物與一或多種外加活性劑共同投藥,為有此需要之個體提供協同性醫療效力。共同投與之藥劑(群)可以為本文說明之癌症治療劑。某些具體實施例中,共同投與之劑(群)可以例如,經口或注射(例如,IV或SC)投藥。
本文具體實施例提供一種治療異常細胞增生病變之方法,其包括採用例如,IV、SC與/或口服投藥法投與式(I)、(II)、(III)、(IV)、或(V)化合物。本文某些具體實施例提供一種治療異常細胞增生病變之方法,其包括採用口服投藥方法投與式(I)、(II)、(III)、(IV)、或(V)化合物。某些具體實施例中,治療週期包括歷經多天(例如,1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28天、或超過28天),可視需要接著停藥期(例如,1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28天、或超過28天)對有此需要之個體投與多重劑量。本文所提供方 法之合適劑量包括例如,醫療有效量與預防有效量。特定具體實施例中,治療週期包括一天一次或一天超過一次,對有此需要之個體投與多重劑量,連續3天、5天、7天、14天、21天、或28天。特定具體實施例中,治療週期包括停藥期1天、2天、3天、4天、5天、7天、14天、21天、或28天。特定具體實施例中,個體接受多重治療週期治療,例如,多重7天、14天、21天、28天、35天、或42天治療週期,總治療期為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、或24個月、或超過24個月。特定具體實施例中,個體係接受多重治療週期治療,治療週期可以相同或相異(例如,7天治療週期接著14天、21天、或28天治療週期)。
具體實施例中,本文所提供方法中之式(I)、(II)、(III)、(IV)、或(V)化合物投藥量範圍可為例如,約1mg/天至約2,000mg/天之間、約1mg/天至約1,000mg/天之間、約50mg/天至約500mg/天之間、或約100mg/天至約400mg/天之間。某些具體實施例中,特定劑量為例如,約50mg/天、約75mg/天、約100mg/天、約120mg/天、約140mg/天、約160mg/天、約180mg/天、約200mg/天、約220mg/天、約240mg/天、約240mg/天、約260mg/天、約280mg/天、約300mg/天、約320mg/天、約340mg/天、約360mg/天、約380mg/天、約400mg/天、約420mg/天、約440mg/天、約460mg/天、約480mg/天、或約500mg/天。某些具體實施例中,特定劑量為例如,高至約50mg/ 天、高至約75mg/天、高至約100mg/天、高至約125mg/天、高至約150mg/天、高至約175mg/天、高至約200mg/天、高至約225mg/天、高至約250mg/天、高至約275mg/天、高至約300mg/天、高至約325mg/天、高至約350mg/天、高至約325mg/天、高至約350mg/天、高至約375mg/天、高至約400mg/天、高至約425mg/天、高至約450mg/天、高至約475mg/天、高至約500mg/天、高至約750mg/天、或高至約1000mg/天。
具體實施例中,依所治療之疾病與個體條件而定,式(I)、(II)、(III)、(IV)、或(V)化合物可經口、非經腸式(例如,肌內、腹膜內、靜脈內、CIV、腦池內注射或輸注、皮下注射、或植入)、吸入、經鼻、陰道、直腸、舌下、或局部表面(例如,穿皮或局部)途徑投藥。有些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物可以單獨調配或與一或多種活性劑(群)共同調配,使用醫藥上可接受之賦形劑、載劑、佐劑與媒劑,形成適合各投藥途徑之劑量單位。一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係經口投藥。另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係非經腸式投藥。再另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係經靜脈內投藥。再另一項具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係經皮下投藥。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係呈單一劑量投藥,如例如,單一推注、或口 服錠劑或丸劑;或長時間投藥,如例如,長時間連續輸注或隨時間分開推注。具體實施例中,若必要時,式(I)、(II)、(III)、(IV)、或(V)化合物係重覆投藥,例如,直到患者出現穩定疾病或進展,或直到患者出現疾病進展或無法接受之毒性。例如,實體腫瘤之穩定疾病通常意指可量測之病灶處之垂直直徑比前一次測量值未增加25%或以上。參見例如,Response Evaluation Criteria in Solid Tumors(RECIST)Guidelines,Journal of the National Cancer Institute 92(3):205-216(2000)。穩定疾病或缺乏穩定之疾病係採用本領域所習知之方法測定,如評估患者症狀、身體檢查、利用X-射線、CAT、PET、或MRI掃描顯影及其他通常可接受之評估法來檢視腫瘤。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次(QD)、或由日劑量分成多次投藥,如每天兩次(BID)、每天三次(TID)、及每天四次(QID)。具體實施例中,係連續投藥(亦即連續幾天每天或每一天)、或間斷式,例如,週期式(亦即包括停止投藥幾天、幾週、或幾個月)。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥,例如,一天一次或超過一次連續一段時間。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥,不中斷地連續至少7天,有些具體實施例中,長達52週。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係間斷性投藥,亦即在規律性或不規律性間隔下停止與開始投藥。具體實施例中,式(I)、(II)、 (III)、(IV)、或(V)化合物係每週投藥1至6天。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係按週期投藥(例如,每天投藥連續約1、2、3、4、5、6、7、或8週,然後為不投藥之停藥期連續一、二、三、或四週)。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每隔一天投藥。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係按週期投藥(例如,每天或連續投藥一段時間,穿插一段停藥期)。
具體實施例中,投藥頻率在約每天投藥至每個月投藥之範圍內。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物之投藥係一天一次、一天兩次、一天三次、一天四次、每隔一天一次、一週兩次、每隔一週一次、每週一次、每兩週一次、每三週一次、或每四週一次。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係一天投藥一次。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係一天投藥兩次。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係一天投藥三次。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係一天投藥四次。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次連續一天至六個月、一週至三個月、一週至四週、一週至三週、或一週至兩週。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次連續一週、兩週、三週、或四週。具體實施例 中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次連續一週。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次連續兩週。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次連續三週。具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次連續四週。
具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係每天投藥一次連續約1週、約2週、約3週、約4週、約6週、約9週、約12週、約15週、約18週、約21週、或約26週。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係間斷性投藥。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係間斷性投藥,用量為約50mg/天與約1,000mg/天之間。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係間斷性投藥,用量為約100mg/天與約500mg/天之間。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係連續投藥。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係連續投藥,用量為約50mg/天與約1,000mg/天之間。某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係連續投藥,用量為約100mg/天與約500mg/天之間。
某些具體實施例中,式(I)、(II)、(III)、(IV)、或(V)化合物係依週期性投與患者。週期性療法涉及投與活性劑一段時間後,接著一段停藥期,並重覆此連續投藥法。週期性療法可減少抗性發展、避免或降低副作用、及/或改 善治療效力。
套組
另一態樣中,本文提供一種包括本文所說明式(I)、(II)、(III)、(IV)、或(V)化合物或其醫藥組成物之套組。該套組通常呈物理結構盛裝如下說明之各種不同組份,並可用於例如,操作本文所說明方法。
具體實施例中,套組包括一或多種本文揭示之式(I)、(II)、(III)、(IV)、或(V)化合物(例如,含在無菌容器中提供),其可能呈適合投與個體之醫藥組成物型式。本文所說明化合物可呈即用型式提供(例如,口服調配物,如錠劑或膠囊,或呈注射型式,如呈無菌溶液)或呈需要例如,在投藥前先復水或稀釋之型式(例如,粉劑)。具體實施例中,當式(I)、(II)、(III)、(IV)、或(V)化合物呈需要使用者復水或稀釋之型式時,該套組亦包括稀釋劑(例如,無菌水)、緩衝劑、醫藥上可接受賦形劑,與類似物,可與化合物共同或分開包裝。具體實施例中,套組中各組份可包封在個別容器中,所有各種不同組份可容納在同一個包裝內。具體實施例中,本發明套組可設計用於需要適當維持其中所容納組份之條件下(例如,冷藏或冷凍)。
具體實施例中,套組可包含標籤或包裝仿單,包括指明其中組份之資訊,及其使用說明書(例如,劑量參數、活性成份(群)之臨床藥理學,包括作用機轉、藥物動力學與藥效學、副作用、禁忌等等)。標籤或仿單可包括製造商的資料,如批號與使用效期。具體實施例中,標 籤或包裝仿單可例如,整合在容納組份之物理結構中、分開含在該物理結構內、或固定在套組之組份上(例如,安瓿、管子或小瓶)。
具體實施例中,標籤或仿單可以另外包括或納入電腦可讀取媒體,如磁碟片(例如,硬碟、卡、記憶卡)、光碟,如:CD-或DVD-ROM/RAM、DVD、MP3、磁帶、或電子儲存媒體,如RAM與ROM或此等之混合體,如磁碟/光碟儲存媒體、快閃(FLASH)媒體或記憶卡。有些具體實施例中,套組中沒有真正之說明書,但會提供從例如,網路之遠端來源上取得說明書之方式。
具體實施例P
具體實施例P1. 一種治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括對有此需要之個體投與醫療有效量之式(I)化合物:
或其醫藥上可接受之鹽,其中:X1為CR8或N;X2為CR9或N;X3為CR10或N;n1、n2、n3、n4、n5、n6、n7、n8、n9與n10獨立地為整數0至4; m1、m2、m3、m4、m5、m6、m7、m8、m9、m10、v1、v2、v3、v4、v5、v6、v7、v8、v9與v10獨立地為1或2;z1為整數0至5;z2為整數0至2;z3為整數0至11;z4為整數0至2;L7為鍵結、-O-、-S-、-NR7.2B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-N3、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-N3、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、- NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-N3、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-N3、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基; R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-N3、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-N3、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R7為氫、鹵素、-CX7.1 3、-CHX7.1 2、-CH2X7.1、-CN、-N3、-SOn7R7A、-SOv7NR7BR7C、-NHNR7BR7C、-ONR7BR7C、-NHC(O)NHNR7BR7C、-NHC(O)NR7BR7C、-N(O)m7、-NR7BR7C、-C(O)R7D、-C(O)OR7D、-C(O)NR7BR7C、-OR7A、 -NR7BSO2R7A、-NR7BC(O)R7D、-NR7BC(O)OR7D、-NR7BOR7D、-OCX7.1 3、-OCHX7.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-N3、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-N3、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、- CN、-N3、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R7A、R7B、R7C、R7D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C與R10D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B、R1C、R2B、R2C、R3B、R3C、R4B、R4C、R5B、R5C、R6B、R6C、R7B、R7C、R8B、R8C、R9B、R9C、R10B與R10C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X7.1、X8.1、X9.1與X10.1獨立地為-Cl、-Br、-I或-F,其中X1、X2與X3 中至少一者為N。
具體實施例P3. 一種治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括對有此需要之個體投與醫療有效量之式(II)化合物:
或其醫藥上可接受之鹽,其中:A為經取代或未經取代之雜環烷基;X1為CR8或N;X2為CR9或N;X3為CR10或N;X4為C、CR11或N;z1為整數0至5;z2為整數0至13;z3為整數0至12;z4為整數0至3;為單鍵或雙鍵,其中若為單鍵時,則X4為CR11或N,及若為雙鍵時,則X4為C;L7為鍵結、-O-、-S-、-NR7B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、 -NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取 代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、 -NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、 -ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R11為氫、鹵素、-CX11.1 3、-CHX11.1 2、-CH2X11.1、-CN、-SOn11R11A、-SOv11NR11BR11C、-NHNR11BR11C、-ONR11BR11C、-NHC(O)NHNR11BR11C、-NHC(O)NR11BR11C、-N(O)m11、-NR11BR11C、-C(O)R11D、-C(O)OR11D、-C(O)NR11BR11C、-OR11A、-NR11BSO2R11A、-NR11BC(O)R11D、-NR11BC(O)OR11D、-NR11BOR11D、-OCX11.1 3、-OCHX11.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C、R10D、R11A、R11B、R11C與R11D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代 之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B與R1C、R2B與R2C、R3B與R3C、R4B與R4C、R5B與R5C、R6B與R6C、R8B與R8C、R9B與R9C、R10B與R10C、R11B與R11C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;n1、n2、n3、n4、n5、n6、n8、n9、n10與n11獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m8、m9、m10、m11、v1、v2、v3、v4、v5、v6、v8、v9、v10、與v11獨立地為1或2;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X8.1、X9.1、X10.1、與X11.1獨立地為-Cl、-Br、-I或-F,其中X1、X2、與X3中至少一者為N。
具體實施例P5. 一種為有此需要之個體治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括投與醫療有效量之式(III)化合物:
或其醫藥上可接受之鹽,其中:A為經取代或未經取代之環烷基或經取代或未經取代之雜環烷基;X1為CR8或N;X2為CR9或N;X3為CR10或N;X4為C、CR11或N;X7為NR17或N,其中當L7共價結合X7時,則X7為N;n1、n2、n3、n4、n5、n6、n8、n9、n10、n11、與n17獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m8、m9、m10、m11、m17、v1、v2、v3、v4、v5、v6、v8、v9、v10、v11、與v17獨立地為1或2;z1為整數0至5;z2為整數0至8;z3為整數0至12;為單鍵或雙鍵,其中若為單鍵時,則X4為CR11或N,及若為雙鍵時,則X4為C;L7為鍵結、-O-、-S-、-NR7B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸 芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、- NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、 -ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取 代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R11為氫、鹵素、-CX11.1 3、-CHX11.1 2、-CH2X11.1、-CN、-SOn11R11A、-SOv11NR11BR11C、-NHNR11BR11C、-ONR11BR11C、-NHC(O)NHNR11BR11C、-NHC(O)NR11BR11C、-N(O)m11、-NR11BR11C、-C(O)R11D、-C(O)OR11D、-C(O)NR11BR11C、-OR11A、-NR11BSO2R11A、-NR11BC(O)R11D、-NR11BC(O)OR11D、-NR11BOR11D、-OCX11.1 3、-OCHX11.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R17為氫、鹵素、-CX17.1 3、-CHX17.1 2、-CH2X17.1、-CN、-SOn17R17A、-SOv17NR17BR17C、-NHNR17BR17C、-ONR17BR17C、-NHC(O)NHNR17BR17C、 -NHC(O)NR17BR17C、-N(O)m17、-NR17BR17C、-C(O)R17D、-C(O)OR17D、-C(O)NR17BR17C、-OR17A、-NR17BSO2R17A、-NR17BC(O)R17D、-NR17BC(O)OR17D、-NR17BOR17D、-OCX17.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C、R10D、R11A、R11B、R11C、R11D、R17A、R17B、R17C與R17D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B與R1C、R2B與R2C、R3B與R3C、R4B與R4C、R5B與R5C、R6B與R6C、R8B與R8C、R9B與R9C、R10B與R10C、R11B與R11C、及R17B與R17C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X8.1、X9.1、X10.1、X11.1與X17.1獨立地為-Cl、-Br、-I或-F,其中X1、X2與X3中至少一者為N。
具體實施例P7. 如具體實施例P1至P6中任一項之方法,其中該EBV陽性惡惡性病為勃奇氏淋巴瘤、霍奇金氏淋巴瘤、瀰漫性大B細胞淋巴瘤、NK/T-細胞淋巴瘤、皮膚T-細胞淋巴瘤、鼻咽癌、胃癌、外陰鱗狀細胞癌、唾液腺癌、眼脈絡膜黑色素瘤、或胰膽管系腺癌瘤。
具體實施例P8. 如具體實施例P7之方法,其進一步包括對有此需要之個體共同投與化療劑或抗癌劑。
具體實施例P9. 如具體實施例P8之方法,其中該化療劑或抗癌劑為抗增生/抗新生贅瘤藥物、抗代謝物、抗腫瘤抗生素、抗有絲分裂劑、拓樸異構酶抑制劑、細胞生長抑制劑、雌激素受體下調劑、抗雄激素、LHRH拮抗劑或LHRH促效劑、助孕素、芳構酶抑制劑、5-α-還原酶之抑制劑、抑制癌細胞入侵之藥劑、生長因子功能之 抑制劑、法呢基(farnesyl)轉移酶抑制劑、酪胺酸激酶抑制劑、絲胺酸/蘇胺酸激酶抑制劑、表皮生長因子家族之抑制劑、血小板衍生之生長因子家族之抑制劑、肝細胞生長因子家族之抑制劑;抗血管新生劑、血管傷害劑、用於反義療法之藥劑、抗-ras反義物藥劑、基因療法藥劑、免疫醫療劑、或抗體。
具體實施例P10. 如具體實施例P9之方法,其中該化療劑或抗癌劑為抗增生劑、化療劑、抗代謝物、抗微管蛋白劑、烷化劑、鉑劑、蒽環類藥物、抗腫瘤抗生素、拓樸異構酶抑制劑、嘌呤拮抗劑、嘧啶拮抗劑、細胞成熟劑、DNA修復酵素抑制劑、阻止細胞存活之酵素、組織蛋白去乙醯酶抑制劑、細胞毒性劑、激素、抗體、免疫調控劑、Bcr-Abl激酶抑制劑、激素促效劑或拮抗劑、部份促效劑或部份拮抗劑、激酶抑制劑、外科手術、放療法、內分泌療法、生物反應修飾劑、高熱劑、低溫治療劑、免疫調控劑、減弱任何副作用之藥劑、紡錘體毒素、鬼臼毒素、抗生素、或亞硝基脲。
具體實施例P11. 如具體實施例P10之方法,其中該抗代謝物為5-氟尿嘧啶、胺甲蝶呤(methotrexate)、氮雜西定(azacitidine)、地西他濱(decitabine)、氟達拉濱(fludarabine)或阿糖胞苷(cytarabine)。
具體實施例P12. 如具體實施例P10之方法,其中該抗微管蛋白劑為長春花生物鹼或紫杉烷。
具體實施例P13. 如具體實施例P10之方法,其中該烷化劑為二氯甲基二乙胺(mechlorethamine)、苯丁酸氮芥(chlorambucil)、環磷醯胺、馬法蘭(melphalan)、卡莫司汀(carmustine)、洛莫司汀(lomusitne)、異環磷醯胺(ifosfamide)、卡莫司汀(carmustine)、白消安(busulfan)、環磷醯胺、達卡巴仁(dacarbazine)、異環磷醯胺(ifosfamide)、雙氯乙基硝基脲或羥基脲。
具體實施例P14. 如具體實施例P10之方法,其中該鉑劑為順鉑(cisplatin)、卡鉑(carboplatin)、奧沙利鉑(oxaliplatin)、沙鉑(satraplatin)(JM-216)或CI-973。
具體實施例P15. 如具體實施例P9之方法,其中該化療劑或抗癌劑為抗體。
具體實施例P16. 如具體實施例P9之方法,其中該化療劑或抗癌劑為免疫調控劑。
具體實施例P17. 一種以具體實施例P1至P6中任一項之化合物於治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之用途。
具體實施例P18. 一種以具體實施例P1至P6中任一項之化合物於製造供治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之醫藥之用途。
其他具體實施例
具體實施例1. 一種治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括對有此需要之 個體投與醫療有效量之式(I)化合物:
或其醫藥上可接受之鹽,其中:X1為CR8或N;X2為CR9或N;X3為CR10或N;n1、n2、n3、n4、n5、n6、n7、n8、n9與n10獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m7、m8、m9、m10、v1、v2、v3、v4、v5、v6、v7、v8、v9與v10獨立地為1或2;z1為整數0至5;z2為整數0至2;z3為整數0至11;z4為整數0至2;L7為鍵結、-O-、-S-、-NR7.2B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、 -N3、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-N3、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-N3、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之 環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-N3、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-N3、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-N3、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、 -NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R7為氫、鹵素、-CX7.1 3、-CHX7.1 2、-CH2X7.1、-CN、-N3、-SOn7R7A、-SOv7NR7BR7C、-NHNR7BR7C、-ONR7BR7C、-NHC(O)NHNR7BR7C、-NHC(O)NR7BR7C、-N(O)m7、-NR7BR7C、-C(O)R7D、-C(O)OR7D、-C(O)NR7BR7C、-OR7A、-NR7BSO2R7A、-NR7BC(O)R7D、-NR7BC(O)OR7D、-NR7BOR7D、-OCX7.1 3、-OCHX7.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-N3、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取 代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-N3、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-N3、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R7A、R7B、R7C、R7D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C與R10D 獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B、R1C、R2B、R2C、R3B、R3C、R4B、R4C、R5B、R5C、R6B、R6C、R7B、R7C、R8B、R8C、R9B、R9C、R10B與R10C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X7.1、X8.1、X9.1與X10.1獨立地為-Cl、-Br、-I或-F,其中X1、X2與X3中至少一者為N。
具體實施例3. 一種治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括對有此需要之個體投與醫療有效量之式(II)化合物:
或其醫藥上可接受之鹽,其中:A為經取代或未經取代之雜環烷基;X1為CR8或N;X2為CR9或N;X3為CR10或N;X4為C、CR11或N; z1為整數0至5;z2為整數0至13;z3為整數0至12;z4為整數0至3;為單鍵或雙鍵,其中若為單鍵時,則X4為CR11或N,及若為雙鍵時,則X4為C;L7為鍵結、-O-、-S-、-NR7B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、 -NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、 -CH2X5.1、-CN、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之 環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R11為氫、鹵素、-CX11.1 3、-CHX11.1 2、-CH2X11.1、-CN、-SOn11R11A、-SOv11NR11BR11C、-NHNR11BR11C、-ONR11BR11C、-NHC(O)NHNR11BR11C、-NHC(O)NR11B R11C、-N(O)m11、-NR11BR11C、-C(O)R11D、-C(O)OR11D、-C(O)NR11BR11C、-OR11A、-NR11BSO2R11A、-NR11BC(O)R11D、-NR11BC(O)OR11D、-NR11BOR11D、-OCX11.1 3、-OCHX11.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C、R10D、R11A、R11B、R11C與R11D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B與R1C、R2B與R2C、R3B與R3C、R4B與R4C、R5B與R5C、R6B與R6C、R8B與R8C、R9B與R9C、R10B與R10C、R11B與R11C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;n1、n2、n3、n4、n5、n6、n8、n9、n10與n11獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m8、m9、m10、m11、v1、v2、v3、v4、v5、v6、v8、v9、v10、與v11獨立地為 1或2;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X8.1、X9.1、X10.1、與X11.1獨立地為-Cl、-Br、-I或-F,其中X1、X2、與X3中至少一者為N。
具體實施例5. 一種治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括對有此需要之個體投與醫療有效量之式(III)化合物:
或其醫藥上可接受之鹽,其中:A為經取代或未經取代之環烷基或經取代或未經取代 之雜環烷基;X1為CR8或N;X2為CR9或N;X3為CR10或N;X4為C、CR11或N;X7為NR17或N,其中當L7共價結合X7時,則X7為N;n1、n2、n3、n4、n5、n6、n8、n9、n10、n11、與n17獨立地為整數0至4;m1、m2、m3、m4、m5、m6、m8、m9、m10、m11、m17、v1、v2、v3、v4、v5、v6、v8、v9、v10、v11、與v17獨立地為1或2;z1為整數0至5;z2為整數0至8;z3為整數0至12;為單鍵或雙鍵,其中若為單鍵時,則X4為CR11或N,及若為雙鍵時,則X4為C;L7為鍵結、-O-、-S-、-NR7B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、 -NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、-NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為氫、鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取 代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為氫、鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為氫、鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、- NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、 -ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R11為氫、鹵素、-CX11.1 3、-CHX11.1 2、-CH2X11.1、-CN、-SOn11R11A、-SOv11NR11BR11C、-NHNR11BR11C、-ONR11BR11C、-NHC(O)NHNR11BR11C、-NHC(O)NR11BR11C、-N(O)m11、-NR11BR11C、-C(O)R11D、-C(O)OR11D、-C(O)NR11BR11C、-OR11A、-NR11BSO2R11A、-NR11BC(O)R11D、-NR11BC(O)OR11D、-NR11BOR11D、-OCX11.1 3、-OCHX11.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R17為氫、鹵素、-CX17.1 3、-CHX17.1 2、-CH2X17.1、-CN、-SOn17R17A、-SOv17NR17BR17C、-NHNR17BR17C、-ONR17BR17C、-NHC(O)NHNR17BR17C、-NHC(O)NR17BR17C、-N(O)m17、-NR17BR17C、-C(O)R17D、-C(O)OR17D、-C(O)NR17BR17C、-OR17A、-NR17BSO2R17A、-NR17BC(O)R17D、-NR17BC(O)OR17D、-NR17BOR17D、- OCX17.1 3、-OCHX1.1 2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C、R10D、R11A、R11B、R11C、R11DR17A、R17B、R17C與R17D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B與R1C、R2B與R2C、R3B與R3C、R4B與R4C、R5B與R5C、R6B與R6C、R8B與R8C、R9B與R9C、R10B與R10C、R11B與R11C、及R17B與R17C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X8.1、X9.1、X10.1、X11.1與X17.1獨立地為-Cl、-Br、-I或-F,其中X1、X2與X3中至少一者為N。
具體實施例7. 一種治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括對有此需要之個體投與醫療有效量之式(IV)化合物:
或其醫藥上可接受之鹽,其中:X1為CR8或N;X2為CR9或N;X3為CR10或N;n1、n2、n3、n4、n5、n6、n7、n8、n9、n10、與n44獨立地為整數0至4; m1、m2、m3、m4、m5、m6、m7、m8、m9、m10、v1、v2、v3、v4、v5、v6、v7、v8、v9、v10、與v44獨立地為1或2;z1為整數0至5;z2為整數0至4;z3為整數0至11;z4為整數0至2;L7為鍵結、-O-、-S-、-NR7.2B-、-C(O)-、-C(O)O-、-S(O)-、-S(O)2-、經取代或未經取代之伸烷基、經取代或未經取代之伸雜烷基、經取代或未經取代之伸環烷基、經取代或未經取代之伸雜環烷基、經取代或未經取代之伸芳基、或經取代或未經取代之伸雜芳基;R1為氫、鹵素、-CX1.1 3、-CHX1.1 2、-CH2X1.1、-CN、-N3、-SOn1R1A、-SOv1NR1BR1C、-NHNR1BR1C、-ONR1BR1C、-NHC(O)NHNR1BR1C、-NHC(O)NR1BR1C、-N(O)m1、-NR1BR1C、-C(O)R1D、-C(O)OR1D、-C(O)NR1BR1C、-OR1A、-NR1BSO2R1A、-NR1BC(O)R1D、-NR1BC(O)OR1D、-NR1BOR1D、-OCX1.1 3、-OCHX1.1 2、-OCH2X1.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R2為氫、鹵素、-CX2.1 3、-CHX2.1 2、-CH2X2.1、-CN、-N3、-SOn2R2A、-SOv2NR2BR2C、-NHNR2BR2C、-ONR2BR2C、-NHC(O)NHNR2BR2C、-NHC(O)NR2BR2C、-N(O)m2、- NR2BR2C、-C(O)R2D、-C(O)OR2D、-C(O)NR2BR2C、-OR2A、-NR2BSO2R2A、-NR2BC(O)R2D、-NR2BC(O)OR2D、-NR2BOR2D、-OCX2.1 3、-OCHX2.1 2、-OCH2X2.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R3獨立地為鹵素、-CX3.1 3、-CHX3.1 2、-CH2X3.1、-CN、-N3、-SOn3R3A、-SOv3NR3BR3C、-NHNR3BR3C、-ONR3BR3C、-NHC(O)NHNR3BR3C、-NHC(O)NR3BR3C、-N(O)m3、-NR3BR3C、-C(O)R3D、-C(O)OR3D、-C(O)NR3BR3C、-OR3A、-NR3BSO2R3A、-NR3BC(O)R3D、-NR3BC(O)OR3D、-NR3BOR3D、-OCX3.1 3、-OCHX3.1 2、-OCH2X3.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R4為氫、鹵素、-CX4.1 3、-CHX4.1 2、-CH2X4.1、-CN、-N3、-SOn4R4A、-SOv4NR4BR4C、-NHNR4BR4C、-ONR4BR4C、-NHC(O)NHNR4BR4C、-NHC(O)NR4BR4C、-N(O)m4、-NR4BR4C、-C(O)R4D、-C(O)OR4D、-C(O)NR4BR4C、-OR4A、-NR4BSO2R4A、-NR4BC(O)R4D、-NR4BC(O)OR4D、-NR4BOR4D、-OCX4.1 3、-OCHX4.1 2、-OCH2X4.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基,或 當X2為CR9時,則R4與R9可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R5獨立地為鹵素、側氧基、-CX5.1 3、-CHX5.1 2、-CH2X5.1、-CN、-N3、-SOn5R5A、-SOv5NR5BR5C、-NHNR5BR5C、-ONR5BR5C、-NHC(O)NHNR5BR5C、-NHC(O)NR5BR5C、-N(O)m5、-NR5BR5C、-C(O)R5D、-C(O)OR5D、-C(O)NR5BR5C、-OR5A、-NR5BSO2R5A、-NR5BC(O)R5D、-NR5BC(O)OR5D、-NR5BOR5D、-OCX5.1 3、-OCHX5.1 2、-OCH2X5.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R6獨立地為鹵素、側氧基、-CX6.1 3、-CHX6.1 2、-CH2X6.1、-CN、-N3、-SOn6R6A、-SOv6NR6BR6C、-NHNR6BR6C、-ONR6BR6C、-NHC(O)NHNR6BR6C、-NHC(O)NR6BR6C、-N(O)m6、-NR6BR6C、-C(O)R6D、-C(O)OR6D、-C(O)NR6BR6C、-OR6A、-NR6BSO2R6A、-NR6BC(O)R6D、-NR6BC(O)OR6D、-NR6BOR6D、-OCX6.1 3、-OCHX6.1 2、-OCH2X6.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R7為氫、鹵素、-CX7.1 3、-CHX7.1 2、-CH2X7.1、-CN、 -N3、-SOn7R7A、-SOv7NR7BR7C、-NHNR7BR7C、-ONR7BR7C、-NHC(O)NHNR7BR7C、-NHC(O)NR7BR7C、-N(O)m7、-NR7BR7C、-C(O)R7D、-C(O)OR7D、-C(O)NR7BR7C、-OR7A、-NR7BSO2R7A、-NR7BC(O)R7D、-NR7BC(O)OR7D、-NR7BOR7D、-OCX7.1 3、-OCHX7.1 2、-OCH2X7.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R8為氫、鹵素、-CX8.1 3、-CHX8.1 2、-CH2X8.1、-CN、-N3、-SOn8R8A、-SOv8NR8BR8C、-NHNR8BR8C、-ONR8BR8C、-NHC(O)NHNR8BR8C、-NHC(O)NR8BR8C、-N(O)m8、-NR8BR8C、-C(O)R8D、-C(O)OR8D、-C(O)NR8BR8C、-OR8A、-NR8BSO2R8A、-NR8BC(O)R8D、-NR8BC(O)OR8D、-NR8BOR8D、-OCX8.1 3、-OCHX8.1 2、-OCH2X8.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R9為氫、鹵素、-CX9.1 3、-CHX9.1 2、-CH2X9.1、-CN、-N3、-SOn9R9A、-SOv9NR9BR9C、-NHNR9BR9C、-ONR9BR9C、-NHC(O)NHNR9BR9C、-NHC(O)NR9BR9C、-N(O)m9、-NR9BR9C、-C(O)R9D、-C(O)OR9D、-C(O)NR9BR9C、-OR9A、-NR9BSO2R9A、-NR9BC(O)R9D、-NR9BC(O)OR9D、-NR9BOR9D、-OCX9.1 3、-OCHX9.1 2、-OCH2X9.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或 未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基,或當X2為CR9時,則R4與R9可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;或當X2為CR9及X3為CR10時,則R9與R10可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、或未經取代之芳基、或經取代或未經取代之雜芳基;R10為氫、鹵素、-CX10.1 3、-CHX10.1 2、-CH2X10.1、-CN、-N3、-SOn10R10A、-SOv10NR10BR10C、-NHNR10BR10C、-ONR10BR10C、-NHC(O)NHNR10BR10C、-NHC(O)NR10BR10C、-N(O)m10、-NR10BR10C、-C(O)R10D、-C(O)OR10D、-C(O)NR10BR10C、-OR10A、-NR10BSO2R10A、-NR10BC(O)R10D、-NR10BC(O)OR10D、-NR10BOR10D、-OCX10.1 3、-OCHX10.1 2、-OCH2X10.1、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;或當X2為CR9及X3為CR10時,則R9與R10可視需要連結形成經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、或未經取代之芳基、或經取代或未經取代之雜芳基;R44為氫、-CX44.1 3、-CHX44.1 2、-CH2X44.1、-SOn44R44A、-SOv44NR44BR44C、-C(O)R44D、-C(O)OR44D、-C(O)NR44BR44C、經取代或未經取代之烷基、經取代或未經 取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;R1A、R1B、R1C、R1D、R2A、R2B、R2C、R2D、R3A、R3B、R3C、R3D、R4A、R4B、R4C、R4D、R5A、R5B、R5C、R5D、R6A、R6B、R6C、R6D、R7A、R7B、R7C、R7D、R7.2B、R8A、R8B、R8C、R8D、R9A、R9B、R9C、R9D、R10A、R10B、R10C、R10D、R44A、R44B、R44C、與R44D獨立地為氫、鹵素、-CF3、-CCl3、-CBr3、-CI3、-COOH、-CONH2、經取代或未經取代之烷基、經取代或未經取代之雜烷基、經取代或未經取代之環烷基、經取代或未經取代之雜環烷基、經取代或未經取代之芳基、或經取代或未經取代之雜芳基;鍵結在同一個氮原子之R1B、R1C、R2B、R2C、R3B、R3C、R4B、R4C、R5B、R5C、R6B、R6C、R7B、R7C、R8B、R8C、R9B、R9C、R10B、R10C、R44B、與R44C取代基可視需要連結形成經取代或未經取代之雜環烷基或經取代或未經取代之雜芳基;及X1.1、X2.1、X3.1、X4.1、X5.1、X6.1、X7.1、X8.1、X9.1、X10.1、與X44.1獨立地為-Cl、-Br、-I或-F;其中X1、X2與X3中至少一者為N。
具體實施例10. 如具體實施例1至9中任一項之方法,其中該EBV陽性惡性病為勃奇氏淋巴瘤、霍奇金氏淋巴瘤、瀰漫性大B細胞淋巴瘤、NK/T-細胞淋巴瘤、皮膚T-細胞淋巴瘤、鼻咽癌、胃癌、外陰鱗狀細胞癌、唾液腺癌、眼脈絡膜黑色素瘤、或胰膽管系腺癌瘤。
具體實施例11. 如具體實施例10之方法,其進一步包括對有此需要之個體共同投與化療劑或抗癌劑。
具體實施例12. 如具體實施例11之方法,其中該化療劑或抗癌劑為抗增生/抗新生贅瘤藥物、抗代謝物、抗腫瘤抗生素、抗有絲分裂劑、拓樸異構酶抑制 劑、細胞生長抑制劑、雌激素受體下調劑、抗雄激素、LHRH拮抗劑或LHRH促效劑、助孕素、芳構酶抑制劑、5-α-還原酶之抑制劑、抑制癌細胞入侵之藥劑、生長因子功能之抑制劑、法呢基(farnesyl)轉移酶抑制劑、酪胺酸激酶抑制劑、絲胺酸/蘇胺酸激酶抑制劑、表皮生長因子家族之抑制劑、血小板衍生之生長因子家族之抑制劑、肝細胞生長因子家族之抑制劑;抗血管新生劑、血管傷害劑、反義療法藥劑、抗-ras反義物藥劑、基因療法藥劑、免疫醫療劑、或抗體。
具體實施例13. 如具體實施例12之方法,其中該化療劑或抗癌劑為抗增生劑、化療劑、抗代謝物、抗微管蛋白劑、烷化劑、鉑劑、蒽環類藥物、抗腫瘤抗生素、拓樸異構酶抑制劑、嘌呤拮抗劑、嘧啶拮抗劑、細胞成熟劑、DNA修復酵素抑制劑、阻止細胞存活之酵素、組織蛋白去乙醯酶抑制劑、細胞毒性劑、激素、抗體、免疫調控劑、Bcr-Abl激酶抑制劑、激素促效劑或拮抗劑、部份促效劑或部份拮抗劑、激酶抑制劑、外科手術、放療法、內分泌療法、生物反應修飾劑、高熱劑、低溫治療劑、免疫調控劑、減弱任何副作用之藥劑、紡錘體毒素、鬼臼毒素、抗生素、或亞硝基脲。
具體實施例14. 如具體實施例13之方法,其中該抗代謝物為5-氟尿嘧啶、胺甲蝶呤(methotrexate)、氮雜西定(azacitidine)、地西他濱(decitabine)、佛達拉濱(fludarabine)或阿糖胞苷 (cytarabine)。
具體實施例15. 如具體實施例13之方法,其中該抗微管蛋白劑為長春花生物鹼或紫杉烷。
具體實施例16. 如具體實施例13之方法,其中該烷化劑為二氯甲基二乙胺(mechlorethamine)、苯丁酸氮芥(chlorambucil)、環磷醯胺、馬法蘭(melphalan)、卡莫司汀(carmustine)、洛莫司汀(lomusitne)、異環磷醯胺(ifosfamide)、卡莫司汀(carmustine)、白消安(busulfan)、環磷醯胺、達卡巴仁(dacarbazine)、異環磷醯胺(ifosfamide)、雙氯乙基硝基脲或羥基脲。
具體實施例17. 如具體實施例13之方法,其中該鉑劑為順鉑(cisplatin)、卡鉑(carboplatin)、奧沙利鉑(oxaliplatin)、沙鉑(satraplatin)(JM-216)或CI-973。
具體實施例18. 如具體實施例12之方法,其中該化療劑或抗癌劑為抗體。
具體實施例19. 如具體實施例12之方法,其中該化療劑或抗癌劑為免疫調控劑。
具體實施例20. 一種如具體實施例1至9中任一項之化合物之用途,其係用於治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病。
具體實施例21. 一種如具體實施例1至9中任一項之化合物之用途,其係用於製造供治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之醫藥。
具體實施例22. 一種治療艾伯斯坦-巴爾病毒(EBV)陽性惡性病之方法,該方法包括對有此需要之個體投與醫療有效量之C-C趨化介素受體第4型(CCR4)調控劑。
具體實施例23. 如具體實施例22之方法,其中該CCR4調控劑為下列文獻所揭示之化合物:Hobbs等人,US 2012/0015932;Cheshire等人,US 2010/0144759;Cheshire等人,US 2008/0293742;Cheshire US 2006/0189613;Mete等人,US 2006/0128723;Harrison等人,US 2006/0122195;Habashita等人,US 2006/0004010;Collins等人,US 2004/0039035;Collins等人,US 2003/0018022;Collins等人,US 2002/0173524;Dairaghi等人,US 2002/0132836;美國專利案5,300,498;美國專利案6,509,357;US 2003/149018;WO 01/005758;WO 03/051876;WO 97/042174;WO 2006/101456;WO 2007/065683;WO 2007/065924;WO 2007/115231;WO 2008/045529;WO 2008/094575;WO 2008/094602;WO 2010/118367;與WO 2013/082429。
具體實施例24. 如具體實施例22之方法,其中該CCR4調控劑為抗體。
具體實施例25. 如具體實施例24之方法,其中該CCR4調控抗體為下列文獻所揭示者之一:Marasco等人之US 2017/0290911;Lin等人之US 2017/0088627;Marasco等人之US 2016/0185865;Ishii等人之US 2015/0147321;Shitara等人之US 2013/0295045;Wu等人之US 2007/0031896;Shitara等人之US 2007/0020263;與Iida等人之US 2005/0287138。
本說明書全文參考之所有揭示內容(例如,專利案、公開案、與網頁)之全文均已以引用之方式併入本文中。
本揭露已說明於某些具體實施例與實例中;然而,除非另有說明,否則所揭示之此等特定具體實施例與實例不應限制申請專利範圍。
Claims (15)
- 如申請專利範圍第1項所述之用途,其中該EBV陽性惡性病為勃奇氏淋巴瘤、霍奇金氏淋巴瘤、瀰漫性大B細胞淋巴瘤、NK/T-細胞淋巴瘤、皮膚T-細胞淋巴瘤、鼻咽癌、胃癌、外陰鱗狀細胞癌、唾液腺癌、眼脈絡膜黑色素瘤、或胰膽管系腺癌瘤。
- 如申請專利範圍第3項所述之用途,其進一步包括對有此需要之個體共同投與抗癌劑。
- 如申請專利範圍第4項所述之用途,其中該抗癌劑為化療劑。
- 如申請專利範圍第4項所述之用途,其中該抗癌劑為抗增生藥物、抗代謝物、抗腫瘤抗生素、抗有絲分裂劑、拓樸異構酶抑制劑、細胞生長抑制劑、雌激素受體下調劑、激素促效劑或拮抗劑、激素部份促效劑或部份拮抗劑、激素、芳構酶抑制劑、5-α-還原酶之抑制劑、抑制癌細胞入侵之藥劑、生長因子功能之抑制劑、法呢基轉移酶抑制劑、激酶抑制劑、高熱劑、低溫治療劑、免疫調控劑、減弱任何副作用之藥劑、表皮生長因子家族之抑制劑、血小板衍生之生長因子家族之抑制劑、肝細胞生長因子家族之抑制劑;抗血管新生劑、血管傷害劑、 反義療法藥劑、抗-ras反義物藥劑、基因療法藥劑、免疫醫療劑、或抗體。
- 如申請專利範圍第6項所述之用途,其中該抗癌劑為抗微管蛋白劑、烷化劑、鉑劑、蒽環類藥物、嘌呤拮抗劑、嘧啶拮抗劑、細胞成熟劑、DNA修復酵素抑制劑、阻止細胞存活之酵素、組織蛋白去乙醯酶抑制劑、細胞毒性劑、助孕素、免疫調控劑、Bcr-Abl激酶抑制劑、酪胺酸激酶抑制劑、絲胺酸/蘇胺酸抑制劑、LHRH拮抗劑或LHRH促效劑、生物反應修飾劑、紡錘體毒素、鬼臼毒素、抗生素、或亞硝基脲。
- 如申請專利範圍第6項所述之用途,其中該抗代謝物為5-氟尿嘧啶、胺甲蝶呤、氮雜西定、地西他濱、氟達拉濱或阿糖胞苷。
- 如申請專利範圍第7項所述之用途,其中該抗微管蛋白劑為長春花生物鹼或紫杉烷。
- 如申請專利範圍第7項所述之用途,其中該烷化劑為二氯甲基二乙胺、苯丁酸氮芥、環磷醯胺、馬法蘭、卡莫司汀、洛莫司汀、異環磷醯胺、白消安、達卡巴仁、雙氯乙基硝基脲或羥基脲。
- 如申請專利範圍第7項所述之用途,其中該鉑劑為順鉑、卡鉑、奧沙利鉑、沙鉑(JM-216)或CI-973。
- 如申請專利範圍第6項所述之用途,其中該抗癌劑為抗體。
- 如申請專利範圍第12項所述之用途,其中該抗體為皮布利單抗。
- 如申請專利範圍第4項所述之用途,其中該抗癌劑為免疫調控劑。
- 如申請專利範圍第1項所述之用途,其中R4為-CF3、-CN或甲基。
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WO2023196432A1 (en) * | 2022-04-06 | 2023-10-12 | Rapt Therapeutics, Inc. | Chemokine receptor modulators and uses thereof |
WO2023232130A1 (zh) * | 2022-06-02 | 2023-12-07 | 西藏海思科制药有限公司 | 一种杂环化合物ccr4抑制剂及其用途 |
CN118084873A (zh) * | 2022-11-28 | 2024-05-28 | 上海美悦生物科技发展有限公司 | 螺杂环取代的嘧啶类化合物及其制备方法和用途 |
CN118084893A (zh) * | 2022-11-28 | 2024-05-28 | 上海美悦生物科技发展有限公司 | 杂环取代的嘧啶类化合物及其制备方法和用途 |
CN118344343A (zh) * | 2023-01-16 | 2024-07-16 | 上海美悦生物科技发展有限公司 | 一种杂环取代的吡嗪类化合物及其制备方法和用途 |
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WO2019090272A1 (en) | 2019-05-09 |
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EP3706750A1 (en) | 2020-09-16 |
TW201922251A (zh) | 2019-06-16 |
AU2018360766A1 (en) | 2020-05-21 |
IL274444A (en) | 2020-06-30 |
BR112020009055A2 (pt) | 2020-11-03 |
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JP2021502345A (ja) | 2021-01-28 |
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