TWI634115B - 普拉二烯內酯吡啶化合物及其使用方法 - Google Patents
普拉二烯內酯吡啶化合物及其使用方法 Download PDFInfo
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- TWI634115B TWI634115B TW104115293A TW104115293A TWI634115B TW I634115 B TWI634115 B TW I634115B TW 104115293 A TW104115293 A TW 104115293A TW 104115293 A TW104115293 A TW 104115293A TW I634115 B TWI634115 B TW I634115B
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- C—CHEMISTRY; METALLURGY
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Abstract
本發明提供新穎的普拉二烯內酯吡啶化合物、含有該等化合物之醫藥組合物及使用該等化合物作為治療劑之方法。該等化合物可用於治療癌症,特定而言已知靶向剪接體及其中之突變之藥劑有用之癌症。
Description
本發明提供新穎有機化合物及含有該等化合物之醫藥組合物。該等化合物可用於治療癌症、特定而言已知靶向剪接體及其中之突變之藥劑有用之癌症。
在真核生物體中,新近合成之信使RNA通常具有多個內含子,將內含子切除以提供成熟mRNA。剪接體係完成此任務之多亞單位複合物。剪接體係由5種小核RNA(snRNA;U1-6)與各種蛋白質之組合組成。已在各種類型之癌症中發現剪接體基因中之突變。
舉例而言,剪接體之剪接因子3B亞單位1(SF3B1)中之突變存在與多種癌症中並包含抗癌劑之標靶。該等癌症包括(但不限於)骨髓發育不良症候群(MDS)、白血病(例如慢性淋巴球性白血病(CLL)、慢性骨髓單核球白血病(CMML)及急性類骨髓性白血病(AML))及實體腫瘤(例如乳癌及葡萄膜黑色素瘤)。
自細菌普拉特鏈黴菌(Streptomyces platensis)分離之稱為普拉二烯內酯且在篩選血管內皮生長因子(VEGF)啟動子之抑制劑時發現之化合物(Sakai,Takashi;Sameshima,Tomohiro;Matsufuji,Motoko;Kawamura,Naoto;Dobashi,Kazuyuki;Mizui,Yoshiharu.Pladienolides,New Substances from Culture of Streptomyces platensis Mer-11107.I.Taxonomy,Fermentation,Isolation and Screening.The Journal of Antibiotics.2004,第57卷,第3期.)抑制由人類VEGF啟動子控制之報導基因之表現,已知該抑制係抗癌劑作用之有用機制。
該等化合物亦抑制U251人類神經膠質瘤細胞活體外之增殖。該等化合物中最強效者普拉二烯內酯B以1.8nM之IC50抑制VEGF促進之基因表現,並以3.5nM之IC50抑制神經膠質瘤細胞增殖。普拉二烯內酯B之結構係已知的(Sakai,Takashi;Sameshima,Tomohiro;Matsufuji,Motoko;Kawamura,Naoto;Dobashi,Kazuyuki;Mizui,Yoshiharu.Pladienolides,New Substances from Culture of Streptomyces platensis Mer-11107.II.Physico-chemical Properties and Structure Elucidation.The Journal of Antibiotics.第57卷,第3期.(2004))且已知普拉二烯內酯B靶向SF3b剪接體以抑制剪接並改變基因表現圖譜(Kotake等人,「Splicing factor SF3b as a target of the antitumor natural product pladienolide」,Nature Chemical Biology 2007,3,570-575)。
某些普拉二烯內酯B化合物以及其他普拉二烯內酯化合物同樣已知,如以下專利申請案中所揭示:WO 2002/060890;WO 2004/011459;WO 2004/011661;WO 2004/050890;WO 2005/052152;WO 2006/009276;及WO 2008/126918。舉例而言,普拉二烯內酯化合物(8E,12E,14E)-7-((4-環庚基六氫吡嗪-1-基)羰基)氧基-3,6,16,21-四羥基-6,10,12,16,20-五甲基-18,19-環氧基二十三烷-8,12,14-三烯-11-內酯(亦稱為E7107)係天然產物普拉二烯內酯D之半合成衍生物,且亦報道其I期研究之結果。
然而,需要可用於治療癌症、特定而言已知靶向剪接體及其中之突變之藥劑有用之癌症之其他藥劑。
本發明之目的係提供式1化合物(「化合物1」)、式2化合物(「化
合物2」)、式3化合物(「化合物3」)及式4化合物(「化合物4」):
及其醫藥上可接受之鹽。
本發明之又一目的係提供包含化合物1、化合物2、化合物3、化合物4或其醫藥上可接受之鹽之醫藥組合物。該等醫藥組合物可與一或多種醫藥上可接受之載劑調配在一起。該等組合物經調配用於藉助各種習用投與途徑使用,包括靜脈內、經口、皮下或肌內投與。
本發明亦可係關於治療患有癌症之個體之方法,其包含向個體投與可有效產生治療有益之反應之量之化合物1、化合物2、化合物3、化合物4或其醫藥上可接受之鹽。該癌症可為骨髓發育不良症候群、白血病(例如慢性淋巴球性白血病、急性淋巴母細胞性白血病、慢性骨髓單核球白血病或急性類骨髓性白血病)或實體腫瘤(例如結腸癌、胰臟癌、子宮內膜癌、卵巢癌、乳癌、葡萄膜黑色素瘤、胃癌、膽道癌、肺癌)或其任一亞集。該癌症可測試對於剪接體基因或蛋白質(例如表1中所列示之彼等)中之一或多種突變呈陽性。
本發明亦可係關於化合物1、化合物2、化合物3、化合物4或其
醫藥上可接受之鹽用於治療性治療(例如治療癌症)之方法之用途。該癌症可為骨髓發育不良症候群、白血病(例如慢性淋巴球性白血病、急性淋巴母細胞性白血病、慢性骨髓單核球白血病或急性類骨髓性白血病)或實體腫瘤(例如結腸癌、胰臟癌、子宮內膜癌、卵巢癌、乳癌、葡萄膜黑色素瘤、胃癌、膽道癌、肺癌)或其任一亞集。該癌症可測試對於剪接體基因或蛋白質(例如表1中所列示之彼等)中之一或多種突變呈陽性。
本發明亦可係關於化合物1、化合物2、化合物3、化合物4或其醫藥上可接受之鹽用於製備藥劑之用途。具體而言,該藥劑可用於治療癌症。該癌症可為骨髓發育不良症候群、白血病(例如慢性淋巴球性白血病、急性淋巴母細胞性白血病、慢性骨髓單核球白血病或急性類骨髓性白血病)或實體腫瘤(例如結腸癌、胰臟癌、子宮內膜癌、卵巢癌、乳癌、葡萄膜黑色素瘤、胃癌、膽道癌、肺癌)或其任一亞集。該癌症可測試對於剪接體基因或蛋白質(例如表1中所列示之彼等)中之一或多種突變呈陽性。
本發明進一步可係關於化合物1、化合物2、化合物3、化合物4或其醫藥上可接受之鹽靶向剪接體(例如SF3B剪接體之亞單位1)之用途。
圖1顯示在以5mg/kg靜脈內(IV)或10mg/kg經口投與(PO)之劑量投與化合物2之CD-1小鼠中之藥物動力學(PK)研究之結果。
圖2顯示化合物2在具有經改造SF3B1K700E突變之Nalm-6(人類前體B細胞系)小鼠異種移植物模型中之效能。每天一次(QD)向小鼠投與2.5mg/kg、5mg/kg或10mg/kg化合物2並持續14天,並經40天時期量測腫瘤體積。
圖3顯示化合物2在具有經改造SF3B1K700E突變之Nalm-6(人類前
體B細胞系)異種移植物模型中之藥物動力學及藥效學分析。向小鼠投與10mg/kg PO劑量之化合物2,並測定前體EIF4A1(EIF4A1轉錄物之前體mRNA)及SLC25A19(SLC25A19轉錄物之成熟mRNA)之腫瘤濃度(μg/g)及相對於媒劑之表現倍數變化。
圖4顯示利用化合物2在PANC0504癌細胞系(SF3B1MUT)(突變體PANC 05.04)中與野生型SF3B1胰臟癌細胞系BXPC3、HPAFII、PANC0403、PANC1005、CFPAC1及MIAPACA2相比之結果細胞活力分析。
圖5顯示基於Nanostring分析對E7107及化合物2(cmpd 2)之替代剪接之調節。在陰影解釋中「+」及「-」分別指示正值或負值,陰影解釋指示不同剪接連接點之不同表現量。
圖6顯示在以5mg/kg靜脈內(IV)或12mg/kg經口投與(PO)之劑量投與化合物1之CD-1小鼠中之PK研究之結果。
圖7顯示化合物1在具有經改造SF3B1K700E突變之Nalm-6小鼠異種移植物模型之效能。每天一次(QD)向小鼠投與7.5mg/kg或10mg/kg化合物1並持續14天,並經30天時期量測腫瘤體積。
圖8顯示化合物1在具有經改造SF3B1K700E突變之Nalm-6異種移植物模型中之藥物動力學及藥效學分析。向小鼠投與單一PO劑量之化合物1,並測定前體EIF4A1(EIF4A1轉錄物之前體mRNA)及SLC25A19(SLC25A19轉錄物之成熟mRNA)之腫瘤濃度(μg/g)及相對於媒劑之表現倍數變化。
圖9顯示在以5.964mg/kg靜脈內(IV)或13.307mg/kg經口投與(PO)之劑量投與化合物3之CD-1小鼠中之PK研究之結果。
圖10顯示在以5mg/kg靜脈內(IV)或10mg/kg經口投與(PO)之劑量投與化合物4之CD-1小鼠中之PK研究之結果。
如本文中所使用,以下定義應適用,除非另有說明。
「異構物」係指具有相同數量及種類之原子及由此相同之分子量但在原子之排列或構形方面不同之化合物。「立體異構物」係指具有相同原子連接但其原子之空間排列不同之化合物。「非鏡像異構物(Diastereoisomer或diastereomer)」係指不為鏡像異構物之立體異構物。「鏡像異構物」係指彼此係不可重疊鏡像之立體異構物。「幾何異構物」係指其基團相對於雙鍵或環或中心原子之位置不同之順式-反式異構物。
本文之所教示之鏡像異構物可包括在一或多個特定不對稱中心處包含實質上單一鏡像異構物(例如大於或等於90%、92%、95%、98%或99%或等於100%之單一鏡像異構物)之「鏡像異構物純之」異構物。「不對稱中心」或「手性中心」係指包含四個不同取代基之四面體碳原子。
本文所用之「立體異構物純」意指包含化合物之一種立體異構物並實質上不含彼化合物之其他立體異構物之化合物或其組合物。例如,具有一個手性中心之立體異構純組合物實質上將不含該化合物之相對鏡像異構物。具有兩個手性中心之化合物之立體異構物純組合物實質上將不含該化合物之非鏡像異構物,且實質上不含相對鏡像異構物。典型立體異構純化合物包含大於化合物之約80重量%之一種立體異構物及小於化合物之約20重量%之其他立體異構物,更佳地大於化合物之約90重量%之一種立體異構物及小於化合物之約10重量%之其他立體異構物,甚至更佳地大於化合物之約95重量%之一種立體異構物及小於化合物之約5重量%之其他立體異構物,且最佳地大於化合物之約97重量%之一種立體異構物及小於化合物之約3重量%之其他立體異構物。例如,參見美國專利第7,189,715號。
描述異構物之術語「R」及「S」係在經不對稱取代碳原子處之立體化學構形之描述語。藉由應用Cahn-Ingold-Prelog優先序規則將經不對稱取代碳原子指定為「R」或「S」,如熟習此項技術者所熟知並於International Union of Pure and Applied Chemistry(IUPAC)Rules for the Nomenclature of Organic Chemistry.第E節,Stereochemistry中所闡述。
「治療(Treatment、treat或treating)」癌症係指逆轉(例如,克服細胞之分化障礙)、緩和(例如,緩和一或多種症狀,例如來自貧血之疲勞、低血球計數值等)及/或延遲本文所述癌症之進展(例如,延遲病狀之進展,例如向AML之轉變)。
本文所用之「個體」意指動物個體,較佳地哺乳動物個體,且特定而言人類。
本文所用「醫藥上可接受之載劑」係指不破壞與其一起調配之化合物之藥理學活性之無毒載劑、佐劑或媒劑。可用於本發明組合物中之醫藥上可接受之載劑、佐劑或媒劑包含但不限於:離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋白(例如人類血清白蛋白)、緩衝物質(例如磷酸鹽)、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸的偏甘油脂混合物、水、鹽或電解質(例如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽、膠體二氧化矽、三矽酸鎂、聚乙烯吡咯烷酮、纖維素基物質、聚乙二醇、環糊精、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯-嵌段共聚物、聚乙二醇及羊毛脂。
「醫藥上可接受之鹽」係保留母體化合物之期望生物活性且不賦予不期望毒理學效應之鹽。該等鹽之實例為:(a)與無機酸形成之酸加成鹽,例如鹽酸、氫溴酸、硫酸、磷酸、硝酸及諸如此類;及與有機酸形成之鹽,例如乙酸、草酸、酒石酸、琥珀酸、順丁烯二酸、反丁烯二酸、葡萄糖酸、檸檬酸、蘋果酸、抗壞血酸、苯甲酸、單寧
酸、棕櫚酸、海藻酸、聚麩胺酸、萘磺酸、甲烷磺酸、對甲苯磺酸、萘二磺酸、聚半乳糖醛酸及諸如此類;及(b)自諸如氯、溴及碘等元素陰離子形成之鹽。例如參見Haynes等人,「Commentary:Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database,」J.Pharmaceutical Sciences,第94卷,第10期(2005)及Berge等人,「Pharmaceutical Salts」,J.Pharmaceutical Sciences,第66卷,第1期(1977),該等文獻以引用方式併入本文中。
除非另外陳述,否則本文中繪示之結構可包括本文中所繪示結構之混合物及該結構之任一鏡像異構物、非鏡像異構物及幾何異構物(或構象)形式;例如,每一不對稱中心之R及S構型,(Z)及(E)雙鍵異構物,及(Z)及(E)構象異構物。除非另外陳述,否則本文所繪示之與互變異構物形式共存之化合物屬本發明範圍內。另外,除非另外陳述,否則本文繪示之結構亦意欲包括僅在一或多個同位素富集原子存在時不同之化合物。舉例而言,具有本發明結構之化合物(氫由氘或氚置換、或碳由13C-或14C-富集碳置換者除外)均屬本發明範圍內。該等化合物可用作(例如)生物分析中之分析工具或探測物。
本文中根據一些實施例提供式1化合物(「化合物1」)、式2化合物(「化合物2」)、式3化合物(「化合物3」)及式4化合物(「化合物4」):
及其醫藥上可接受之鹽。
本發明化合物可與醫藥上可接受之載劑組合以提供其醫藥調配物。載劑及調配物之特定選擇將取決於組合物意欲之特定投與途徑。
本發明醫藥組合物可經適宜調配用於非經腸、經口、吸入噴霧、局部、直腸、經鼻、經頰、經陰道或植入型儲存器投與等。本文所用術語「非經腸」包括皮下、靜脈內、肌內、關節內、滑膜內、胸骨內、鞘內、肝內、病灶內及顱內注射或輸注技術。在特定實施例中,靜脈內、經口、經皮下或經由肌內投與來投與該等化合物。本發明組合物之無菌可注射形式可為水性或油性懸浮液。該等懸浮液可根據業內已知技術使用適宜分散劑或濕潤劑及懸浮劑進行調配。無菌可注射製劑亦可為存於無毒不經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如存於1,3-丁二醇中之溶液。可用之可接受媒劑及溶劑尤其係水、林格氏溶液(Ringer's solution)及等滲氯化鈉溶液。此外,通常採用無菌不揮發性油作為溶劑或懸浮介質。
出於此目的,可採用任一溫和不揮發性油,包括合成之單-或二-甘油酯。脂肪酸(例如油酸及其甘油酯衍生物)可用於製備可注射物,例如天然之醫藥上可接受之油類,例如橄欖油或蓖麻油,其尤其呈其聚氧乙基化形式。該等油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑,例如羧甲基纖維素或通常用於調配包括乳液及懸浮液在內之醫藥
上可接受之劑型的類似分散劑。亦可將其他常用表面活性劑(例如吐溫(Tween)、司盤(Span)及其他通常用於製造醫藥上可接受之固體、液體或其他劑型之乳化劑或生物利用度增強劑)用於調配目的。
對於經口投與而言,可以可接受之經口劑型提供化合物,包括但不限於膠囊、錠劑、水性懸浮液或溶液。在經口使用之錠劑之情形下,通常使用之載劑包括乳糖及玉米澱粉。亦可添加潤滑劑,例如硬脂酸鎂。對於以膠囊形式經口投與而言,有用稀釋劑包括乳糖及乾燥玉米澱粉。當需經口使用水性懸浮液時,可將該活性成份與乳化劑及/或懸浮劑組合。若需要,則亦可添加某些甜味劑、調味劑或著色劑。
本發明化合物可用於治療各種類型之癌症,包括響應靶向SF3B1之藥劑之彼等。如上所述,據報道普拉二烯內酯B之抗腫瘤活性與其靶向SF3b複合物、抑制剪接並改變基因表現圖譜有關(Kotake等人,「Splicing factor SF3b as a target of the antitumor natural product pladienolide,」Nature Chemical Biology 2007,3,570-575)。已知剪接體基因(例如剪接因子3B亞單位1(SF3B1)蛋白質)中之突變參與多種癌症(例如血液惡性腫瘤及實體腫瘤)。Scott等人,「Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors」JNCI 105,20,1540-1549。
血液惡性腫瘤可包括血液癌症(白血病)或淋巴結癌症(淋巴瘤)。白血病可包括急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、慢性骨髓單核球白血病(CMML)、急性單核白血病(AMoL)等。淋巴瘤可包括霍奇金氏淋巴瘤及(Hodgkin’s lymphoma)非霍奇金氏淋巴瘤。其他血液惡性腫瘤可包括骨髓發育不良症候群(MDS)。
實體腫瘤可包括癌瘤,例如腺癌、例如乳癌、胰臟癌、前列腺癌、結腸或結腸直腸癌、肺癌、胃癌、子宮頸癌、子宮內膜癌、卵巢癌、膽道癌、神經膠質瘤、黑色素瘤等。
本發明化合物亦可用於治療可響應靶向除SF3B1以外之剪接體基因或蛋白質之藥劑之癌症。以下實例係用於說明一些可響應靶向剪接體之藥劑之各種癌症,且並不意欲以任何方式限制本發明範圍。因此,可向個體投與本發明化合物以治療各種該等癌症或病狀,力量如罹患以下疾病之患者或個體:
a)骨髓發育不良症候群(MDS):例如參見「SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications」 Damm F.等人Leukemia, 2011, 1-4;「Frequent pathway mutations in splicing machinery in myelodysplasia,」 Yoshida K.等人,Nature, 2011, 478, 64-69;「Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms,」 Malcovati L.等人,Blood, 2011, 118, 24, 6239-6246;「Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis,」 Makishima等人,Blood, 2012, 119, 3203-3210;「Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts,」 Pappaemannuil, E.等人,New England J. Med. 2011, DOI 10.1056/NEJMoa1103283。
b)慢性淋巴球性白血病(CLL):例如參見「Defects in the spliceosomal machinery: a new pathway of leukaemogenesis,」 Maciejewski, J.P.、Padgett, R.A.、Br. J. Haematology, 2012, 1-9;「Mutations in the SF3B1 splicing factor in chronic lymphocytic leukemia: associations with progression and fludarabine-refractoriness,」 Rossi等人,Blood, 2011, 118, 6904-6908;「Exome
sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia,」 Quesada等人,Nature Genetics, 2011, 44, 47-52。
c)慢性骨髓單核球白血病(CMML):例如參見Yoshida等人,Nature 2011;「Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia,」 Kar S.A.等人,Haematologia, 2012, DOI: 10.3324/haematol.2012.064048;DeBoever等人,「Transcriptome sequencing reveals potential mechanism of cryptic 3’ splice site selection in SF3B1-mutated cancers,」 PLOS Computational Biology, 2013, DOI: 10.1371/journal.pcbi.1004105。
d)急性類骨髓性白血病(AML):例如參見Malcovati等人,Blood 2011;Yoshida等人,Nature 2011。
e)乳癌:例如參見「Whole genome analysis informs breast cancer response to aromatase inhibition,」 Ellis等人,Nature, 2012, 486, 353-360;DeBoever等人,「Transcriptome sequencing reveals potential mechanism of cryptic 3’ splice site selection in SF3B1-mutated cancers,」 PLOS Computational Biology, 2013, DOI: 10.1371/journal.pcbi.1004105;Maguire等人,「SF3B1 mutations constitute a novel therapeutic target in breast cancer,」 J Pathol 2015, 235, 571-580。
f)葡萄膜黑色素瘤:例如參見「SF3B1 mutations are associated with alternative splicing in uveal melanoma,」 Furney等人,Cancer Disc. 2013, 10, 1122-1129;DeBoever等人,「Transcriptome sequencing reveals potential mechanism of cryptic 3’ splice site selection in SF3B1-mutated cancers,」 PLOS Computational Biology, 2013, DOI:
10.1371/journal.pcbi.1004105。
g)子宮內膜癌:例如參見Tefferi等人,「Myelodysplastic syndromes.」 N Engl J Med. 2009; 361:1872-85。
h)胃癌:例如參見Int J Cancer. 2013 Jul;133(1):260-5, 「Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors.」 Je等人。
i)卵巢癌:例如參見Int J Cancer. 2013 Jul;133(1):260-5, 「Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors.」 Je等人。
j)膽道癌症,例如膽道癌及胰臟癌:例如參見Biankin等人,「Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes,」 Nature 2012, 491, 399-405。
k)肺癌:例如參見「Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia,」 Quesada等人,Nature Genetics 44, 47-52 (2012);Scott等人,「Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors,」 JNCI 105, 20, 1540-1549。
另外,癌症體細胞突變之目錄(Catalogue of somatic mutations in cancer,COSMIC)(Wellcome Trust Sanger Institute,Genome Research 有限公司,England)報道已在各種類型之癌症樣品中發現SF3B1突變。
可以治療有效或治療上有效量向個體投與本發明化合物。可與載劑材料組合已產生呈單一劑型之組合物之本發明化合物之量將視所治療之個體及特定投與途徑而變。較佳地,組合物應經調配,以使得可向接受該等組合物之個體投與介於0.01mg/kg體重/天至100mg/kg體重/天之間之劑量之活性劑。在某些實施例中,本發明組合物提供0.01mg至50mg之劑量。在其他實施例中,提供0.1mg至25mg或5
mg至40mg之劑量。
亦應瞭解,用於任一特定患者之具體劑量及治療方案可取決於多種因素,包括所採用具體化學化合物之活性、年齡、體重、一般健康、性別、飲食、投與時間、排泄速率、藥物組合、治療醫師之判斷及所治療特定疾病之嚴重性。組合物中之本發明活性劑之量亦將取決於組合物中之特定化合物/鹽。
在一些實施例中,測試癌症中剪接體基因或蛋白質中之一或多種突變及/或癌症對於該一或多種突變呈陽性,其中一或多種突變之存在(「陽性」)可只是個體之癌症響應包含投與靶向此蛋白質及/或剪接體之化合物之治療方法。該等剪接體基因之實例包括(但不限於)表1中所呈現之彼等。
MDS=骨髓發育不良症候群
AML=急性類骨髓性白血病
CMML=慢性骨髓單核球白血病
LUAD=肺腺癌
UCEC=子宮體子宮內膜癌
PMF=進行性大塊型纖維化
PRAD=前列腺腺癌
COAD=結腸腺癌
OV=卵巢漿液囊腫腺癌
SKCM=皮膚黑色素瘤
LUSC=肺鱗狀細胞癌
STAD=胃腺癌
GBM=多形性神經膠母細胞瘤
LGG=腦低級別神經膠質瘤
DLBCL=彌散性大B細胞淋巴瘤
至一些實施例中,個體之癌症可響應包含甚至在剪接體基因或蛋白質中不存在該等突變之情況下靶向此蛋白質及/或剪接體之化合物投與的治療方法。
可藉由任何已知方式(例如基因分型、表現型分析等)、藉助核酸擴增、電泳、微陣列、墨點法、功能分析、免疫分析等篩選或測試該等突變。篩選方法可包括(例如)自含有癌細胞/組織之該個體收集生物樣品。
為使得可更全面地瞭解本文所述本發明,闡述以下實例。應瞭解,該等實例僅出於闡釋目的且不應視為以任何方式限制本發明。
使用Biotage Emrys Liberator或Initiator微波爐進行微波爐加熱。使用Isco Rf200d實施管柱層析。使用Büchi旋轉蒸發器或Genevac離心蒸發器實施溶劑去除。使用Waters自動純化器及19×100mm XTerra 5微米MS C18管柱在酸性移動相條件下實施製備型LC/MS。使用Varian 400MHz光譜儀記錄NMR光譜。
當使用術語「惰性化」闡述反應器(例如,反應容器、燒瓶、玻璃反應器及諸如此類)時,其意味著已利用基本上不含水分或乾的惰性氣體(例如氮、氬及諸如此類)置換反應器中之空氣。
下文闡述用於製備本發明化合物之一般方法及實驗。
本文使用以下縮寫:
MeOH:甲醇
DMF:二甲基甲醯胺
KHMDS:雙(三甲基甲矽烷基)醯胺鉀
LCMS:液相層析-質譜
TBSCl:第三丁基二甲基矽烷基氯
THF:四氫呋喃
TLC:薄層層析
材料:以下化合物市面有售及/或可以多種熟習有機合成技術者熟知之方式製備。更特定而言,可使用本文所述反應及技術製備所揭示化合物。除非另有說明,否則在下文所述合成方法之說明中,應理解,所有所提出反應條件(包括溶劑選擇、反應氣氛、反應溫度、實驗持續時間及處理程序)可選擇為對於該反應而言標準之條件。熟習有機合成技術者應瞭解,分子之不同位置上存在之官能團應與所提出之試劑及反應相容。熟習此項技術者易見與反應條件不相容之取代基,且由此指示替代方法。用於該等實例之起始材料市面有售或係容易地藉由標準方法自已知材料製備。
移動相:A(存於H2O中之0.1%甲酸)及B(存於乙腈中之0.1%甲酸)。
梯度:在1.8分鐘B 5%→95%中。
管柱:Acquity BEH C18管柱(1.7um,2.1×50mm)。
題目均為:Total Synthesis of Pladienolide B and Pladienolide D之美國專利第7,884,128號及第7,816,401號闡述業內已知用於合成普拉二烯內酯B及D之方法。普拉二烯內酯B及D之合成亦可使用業內已知並在Kanada等人,「Total Synthesis of the Potent Antitumor Macrolides Pladienolide B and D,」Angew.Chem.Int.Ed.46:4350-4355(2007)中闡述之方法來實施。題目為:Novel Physiologically Active Substances之Kanada等人及PCT申請公開案WO 2003/099813闡述業內已知用於自普拉二烯內酯D(WO‘813之11107D)合成E7107(WO’813之化合物45)
之方法。相應美國專利為頒給Kotake等人之7,550,503。
步驟1:4-環庚基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-((R,2E,4E)-7-((2R,3R)-3-((2S,3S)-3-((第三丁基二甲基矽基)氧基)戊-2-基)-6-羥基-6-甲基庚-2,4-二烯-2-基)-7-羥基-3,7-二甲基-12-側氧基氧雜環十二-4-烯-6-基酯之合成。在0℃下在氮下用咪唑(2.5g,36.1mmol,7.0當量)處理E7107(A,3.7g,5.1mmol,1.0當量)存於DMF(100mL,0.05M)中之溶液並添加TBSCl(3.9g,25.7mmol,5.0當量)。使該反應物升溫之室溫,並攪拌20小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用乙酸乙酯
稀釋,並將有機層用鹽水洗滌,經硫酸鈉乾燥,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析液)純化所得油狀物,以提供期望產物(B,4.7g,5.0mmol,96%)。
步驟2:4-環庚基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-2-((6R,E)-7-((2R,3R)-3-((2S,3S)-3-((第三丁基二甲基矽基)氧基)戊-2-基)環氧乙烷-2-基)-4,5,6-三羥基-6-甲基庚-2-烯-2-基)-7-羥基-3,7-二甲基-12-側氧基氧雜環十二-4-烯-6-基酯之合成。在氮下在0℃下向烯烴B(4.7g,5.0mmol,1.0當量)存於THF:H2O(10:1,133mL:13mL,0.03M)中之溶液中添加四氧化鋨(12.4mL,1.0mmol,0.2當量,2.5%溶液),接著添加N-甲基嗎啉N-氧化物(1.16g,9.9mmol,2.0當量)。使該反應物升溫至室溫,並攪拌13小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用亞硫酸鈉驟冷,用乙酸乙酯稀釋,並將有機層用水洗滌,經乾燥硫酸鎂,過濾,並在真空下濃縮。藉由矽膠管柱層析(二氯甲烷/甲醇作為溶析劑)純化所得油狀物,以提供期望產物(C,4.8g,4.9mmol,99%)。
步驟3:4-環庚基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基-7-羥基-3,7-二甲基-12-側氧基-2-((E)-4-側氧基丁-2-烯-2-基)氧雜環十二-4-烯-6-基酯之合成。在氮下在室溫下向二醇C(4.4g,4.5mmol,1.0當量)存於苯(100mL,0.05M)中之溶液中添加四乙酸鉛(4.0g,9.0mmol,2.0當量)。將該反應物攪拌30分鐘,或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用亞硫酸鈉驟冷並用二氯甲烷稀釋。將有機層用水洗滌,經硫酸鈉乾燥,過濾,並在真空下濃縮。期望產物(D,1.5g,2.3mmol,52%)係以粗物質形式前進。
步驟4:4-環庚基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基-7-羥基-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-
(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯之合成。
注意:(S)-2-(1-((1-苯基-1H-四唑-5-基)磺醯基)丙-2-基)吡啶之合成係闡述與下文中並繪示於方案V中。
在氮下在-78℃下向存於乾THF(30.0mL,0.05M)中之(S)-2-(1-((1-苯基-1H-四唑-5-基)磺醯基)丙-2-基)吡啶(1.67g,5.08mmol,2.5當量)中逐滴添加KHMDS(8.53ml,4.265mmol,2.1當量)並將該反應物攪拌10分鐘。然後逐滴添加存於THF(10mL)中之醛D 4-環庚基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-7-羥基-3,7-二甲基-12-側氧基-2-((E)-4-側氧基丁-2-烯-2-基)氧雜環-十二-4-烯-6-基酯(1.318g,2.031mmol,1.0當量)。在-78℃下將該反應物攪拌1小時,且然後使其升溫至室溫過夜。將該反應物用水驟冷並用乙酸乙酯稀釋。將有機層用水及鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析劑)純化所得油狀物,以提供期望產物(E,1.20g,2.03mmol,79%)。
步驟5:4-環庚基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羥基-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯(化合物1)之合成。在氮下在室溫下用pTsOH(1.14g,5.98mmol,2.5當量)處理矽基醚E(1.80g,2.39mmol,1.0當量)存於MeOH(10.0mL,0.24M)中之溶液。將該反應物攪拌2小時,或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用乙酸乙酯稀釋,並用鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。藉由製備型TLC(二氯甲烷/甲醇作為溶析液)純化所得油狀物,以提供期望產物(化合物1,1.19g,1.83mmol,76%)。1H NMR(400MHz,氯仿-d)δ:0.88(d,J=6.65Hz,6 H)1.23(s,3 H)1.34-1.78(m,12 H)1.44(d,J=7.03Hz,3 H)1.73(s,3 H)2.28-2.39(m,1 H)2.45-2.66(m,8 H)3.48(br.s.,5 H)3.72(m,2 H)5.01(d,J=9.54Hz,1 H)5.14
(d,J=10.67Hz,1 H)5.55-5.72(m,2 H)6.00(dd,J=15.00,7.47Hz,1 H)6.11(d,J=11.29Hz,1 H)6.28-6.35(m,1 H)7.12(ddd,J=7.47,4.89,1.07Hz,1 H)7.16(d,J=7.78Hz,1 H)7.61(t,J=7.65Hz,1 H)8.55(d,J=4.91Hz,1 H)。MS(ES+)=638.4[M+H]+。
步驟1:乙酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-2-((R,2E,4E)-7-((2R,3R)-3-((2S,3S)-3-((第三丁基二甲基矽基)氧基)戊-2-基)環氧乙烷-2-基)-6-羥基-6-甲基庚-2,4-二烯-2-基)-7-羥基-3,7-二甲基-12-側氧基氧雜環十二-4-烯-6-基酯之合成。在氮下在0℃下用咪唑(4.6g,67.8mmol,7.0當量)及TBSCl(7.3g,48.4mmol,5.0當量)處理普拉二烯內酯D(F,5.3g,9.7mmol,1.0當量)存於DMF(80mL,0.1M)中之溶液。使該反應物升溫至室溫,並攪拌20小時或直至該反應藉由LCMS或TLC測定完成為止。用乙酸乙酯萃取該反應物,並將有機層用鹽水洗滌,經乾燥硫酸鈉,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析液)純化所得油狀物,以提供期望產物(G,7.5g,9.6mmol,99%)。
步驟2:乙酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-2-((6R,E)-7-((2R,3S)-3-((第三丁基二甲基矽基)氧基)戊-2-基)環氧乙烷-2-基)-4,5,6-三羥基-6-甲基庚-2-烯-2-基)-7-羥基-3,7-二甲基-12-側氧基氧雜環十二-4-烯-6-基酯之合成。在氮下在0℃下向烯烴G(7.6g,9.7mmol,1.0當量)存於經脫氣THF:H2O(210mL:21mL,0.01M)中之溶液中添加四氧化鋨(24.4mL,1.9mmol,0.2當量,存於第三丁醇中之2.5%溶液),接著添加N-甲基嗎啉N-氧化物(2.3g,19.5mmol,2.0當量)。使該反應物升溫至室溫,並攪拌13小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用亞硫酸鈉驟冷,用乙酸乙酯稀釋,並將有機層用水洗滌,經乾燥硫酸鎂,過濾,並在真空下濃縮。藉由矽膠管柱層析(二氯甲烷/甲醇作為溶析劑)純化所得油狀物,以提供期望產物(H,6.8g,8.3mmol,86%)。
步驟3:乙酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-7-羥基-3,7-二甲基-12-側氧基-2-((E)-4-側氧基丁-2-烯-2-基)氧雜環十二-4-烯-6-基酯之合成。在氮下在室溫下向二醇H(7.9g,9.7
mmol,1.0當量)存於苯(350mL,0.03M)中之溶液中添加四乙酸鉛(8.6g,19.4mmol,2.0當量)。將該反應物攪拌30分鐘或直至該反應藉由LCMS或TLC測定完成為止。將該反應物濃縮,並藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析劑)純化,以提供期望產物(I,2.5g,5.26mmol,54%)。
步驟4:乙酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-側氧基-2-((E)-4-側氧基丁-2-烯-2-基)氧雜環十二-4-烯-6-基酯之合成。在室溫下向醛I(1.4g,2.9mmol,1.0當量)存於THF(9.5mL,0.5M)中之溶液中添加乙氧基乙烯(11.1mL,40.0當量)及對甲苯磺酸吡啶鎓(0.07g,0.3mmol,0.1當量)。將該反應物攪拌24小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用碳酸氫鈉驟冷並用乙酸乙酯稀釋。將乙酸乙酯用水、鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析劑)純化所得油狀物,以提供期望產物(J,1.2g,2.2mmol,75%)。
步驟5:乙酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基)酯之合成。在氮下在-78℃下向(S)-2-(1-((1-苯基-1H-四唑-5-基)磺醯基)丙-2-基)吡啶(695.0mg,2.1mmol,1.5當量)存於THF(20mL,0.06M)中之溶液中逐滴添加KHMDS(4.2mL,2.1mmol,1.5當量),並將該反應物攪拌20分鐘。然後逐滴添加存於THF(1.0mL)中之醛J(780.0mg,1.4mmol,1.0當量)。在-78℃下將該反應物攪拌90分鐘,且然後使其升溫至-20℃並持續1小時。將該反應物用氯化銨驟冷,用乙酸乙酯稀釋,並升溫至室溫。將有機層用水、鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析劑)純化所得油
狀物,以提供期望茱莉亞產物(Julia product,K,490mg,0.7mmol,53%)。
步驟6:(4R,7R,8S,11S,E)-4-((第三丁基二甲基矽基)氧基)-7-(1-乙氧基乙氧基)-8-羥基-7,11-二甲基-12-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-9-烯-2-酮之合成。在室溫下向乙酸酯K(490mg,0.7mmol,1.0當量)存於甲醇(15mL,0.05M)中之溶液中添加碳酸鉀(155mg,0.4mmol,1.5當量)。使該反應運行24小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用水驟冷,用乙酸乙酯稀釋,用鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。所得多泡固體(L,459mg,0.7mmol,100%)未經其他純化即前進至下一步驟中。
步驟7:4-甲基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯之合成。在室溫下向醇L(459mg,0.7mmol,1.0當量)存於二氯甲烷(0.5mL,0.1M)中之溶液中添加N,N-二甲基胺基吡啶(27.3mg,0.2mmol,0.3當量)及三乙胺(1.0mL,7.4mmol,10.0當量),接著添加氯甲酸4-硝基苯基酯(451mg,2.2mmol,3.0當量)。將該反應物於室溫下攪拌3小時。接著,在室溫下添加N-甲基-六氫吡嗪(299mg,2.98mmol,4.0當量)。在攪拌1小時後,將該反應物用水驟冷並用二氯甲烷稀釋。用1N氫氧化鈉溶液洗滌有機層,並濃縮有機層。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析液)純化所得油狀物,以提供期望產物(M,553mg,0.75mmol,100%)。
步驟8:4-甲基六氫吡嗪-1-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羥基-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯(化合物2)之合成。在室溫下向矽基醚(M,553
mg,0.74mmol,1.0當量)存於甲醇(20mL,0.04M)中之溶液中添加對甲氧基甲苯磺酸(425mg,2.2mmol,3.0當量)。將該反應物攪拌3小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用碳酸氫鈉驟冷並用乙酸乙酯稀釋。將有機層用水、鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析劑)純化所得油狀物,以提供期望產物(化合物2,184mg,0.33mmol,44%)。1H NMR(400MHz,氯仿-d)δ:0.82-1.00(m,3H)1.22-1.48(m,8H)1.50-1.63(m,1H)1.66-1.83(m,4H)1.97(s,1H)2.07(s,1H)2.33(s,3H)2.40(br.s.,3H)2.45-2.68(m,3H)3.44-3.61(m,5H)3.74(dd,J=14.2,7.2Hz,2H)5.04(d,J=9.3Hz,1H)5.17(d,J=10.5Hz,1H)5.57-5.76(m,2H)6.02(dd,J=15.1,7.5Hz,1H)6.13(d,J=10.8Hz,1H)6.34(ddd,J=15.1,10.7,1.0Hz,1H)7.14(t,J=6.2Hz,1H)7.18(d,J=7.4Hz,1H)7.63(t,J=7.3Hz,1H)8.57(d,J=5.1Hz,1H)。MS(ES+)=556.4[M+H]。
步驟1至6係如上文於化合物2之合成中所提供,從而得到醇L。
步驟7:4-(氮雜環庚烷-1-基)六氫吡啶-1-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯之合成。在室溫下向醇L(300mg,0.49mmol,1.0當量)存於二氯甲烷(3.0mL,0.15M)中之溶液中添加N,N-二甲基胺基吡啶(71.4mg,0.58mmol,1.2當量)及三乙胺(0.27mL,1.95mmol,4.0當量),接著添加氯甲酸4-硝基苯基酯(196mg,0.97mmol,2.0當量)。將該反應物於室溫下攪拌3小時。接著,在室溫下添加1-(六氫吡啶-4-基)氮雜環庚烷(265mg,1.46mmol,3.0當量)。在攪拌1小時後,將該反應物用水驟冷並用二氯甲烷稀釋。用1N氫氧化鈉溶液洗滌有機層,並濃縮有機層。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析液)純化所得油狀物,以提供期望產物(N,400mg,0.48mmol,100%)。
步驟8:4-(氮雜環庚烷-1-基)六氫吡啶-1-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羥基-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯(化合物3)之合成。在室溫下向矽基醚(N,400mg,0.48mmol,1.0當量)存於甲醇(4.0mL,0.1M)中之溶液中添加對甲氧基甲苯磺酸(231mg,1.2mmol,2.5當量)。將該反應物攪拌3小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用碳酸氫鈉驟冷並用乙酸乙酯稀釋。將有機層用水、鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析劑)純化所得油狀物,以提供期望產物(化合物3,226mg,0.35mmol,73%)。1H NMR(400MHz,氯仿-d)δ:0.88(d,J=6.53Hz,3 H)1.20-1.28(m,4 H)1.35(s,3 H)1.45(d,J=7.03Hz,4 H)1.59(br.s.,10 H)1.74(d,J=0.75Hz,3 H)1.75-1.83(m,2 H)1.99(s,1 H)2.46-2.62(m,3 H)2.62-2.71(m,4
H)2.79(br.s.,2 H)3.51(d,J=9.79Hz,1 H)3.63-3.82(m,2 H)4.03-4.26(m,2 H)5.01(d,J=9.54Hz,1 H)5.16(d,J=10.79Hz,1 H)5.54-5.64(m,1 H)5.65-5.75(m,1 H)6.01(dd,J=15.06,7.53Hz,1 H)6.12(d,J=11.04Hz,1 H)6.25-6.39(m,1 H)7.12(ddd,J=7.47,4.83,1.25Hz,1 H)7.17(dt,J=8.03,1.00Hz,1 H)7.62(td,J=7.65,1.76Hz,1 H)8.56(ddd,J=4.96,1.82,1.00Hz,1 H)。MS(ES+)=638.6[M+H]。
步驟1至6係如上文與化合物2之合成中所提供,從而得到醇L。
步驟7:[1,4’-二六氫吡啶]-1’-甲酸(2S,3S,6S,7R,10R,E)-10-((第三丁基二甲基矽基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯之合成。在室溫下向醇L(20mg,0.032mmol,1.0當量)存於二氯甲烷(0.3mL,0.1M)中之溶液中添加N,N-二甲基胺基吡啶(4.8mg,0.04mmol,1.2當量)及三乙胺(0.02mL,0.13mmol,4.0當量),接著添加氯甲酸4-硝基苯基酯(13.1mg,0.065mmol,2.0當量)。將該反應物於室溫下攪拌3小時。接著,在室溫下添加1,4’-二六氫吡啶(16.4mg,
0.97mmol,3.0當量)。在攪拌1小時後,將該反應物用水驟冷並用二氯甲烷稀釋。用1N氫氧化鈉溶液洗滌有機層,並濃縮有機層。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析液)純化所得油狀物,以提供期望產物(N,18mg,0.22mmol,68.4%)。
步驟8:[1,4’-二六氫吡啶]-1’-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羥基-3,7-二甲基-12-側氧基-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧雜環十二-4-烯-6-基酯(化合物4)之合成。在室溫下向矽基醚(N,18mg,0.022mmol,1.0當量)存於甲醇(0.5mL,0.04M)中之溶液中添加對甲氧基甲苯磺酸(10.6mg,0.56mmol,2.5當量)。將該反應物攪拌3小時或直至該反應藉由LCMS或TLC測定完成為止。將該反應物用碳酸氫鈉驟冷並用乙酸乙酯稀釋。將有機層用水、鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。藉由矽膠管柱層析(己烷/乙酸乙酯作為溶析劑)純化所得油狀物,以提供期望產物(化合物4,4.0mg,0.006mmol,29%)。1H NMR(400MHz,氯仿-d)δ:0.90(d,J=6.8Hz,3H)1.17-1.42(m,5H)1.46(d,J=7.0Hz,6H)1.51-1.65(m,6H)1.65-1.78(m,5H)1.85(d,J=11.5Hz,2H)2.44(d,J=11.3Hz,2H)2.49-2.66(m,6H)2.80(br.s.,2H)3.42-3.62(m,1H)3.63-3.82(m,2H)4.18(br.s.,2H)5.02(d,J=9.5Hz,1H)5.17(d,J=10.8Hz,1H)5.57-5.75(m,2H)6.02(dd,J=15.2,7.4Hz,1H)6.14(d,J=11.0Hz,1H)6.34(ddd,J=15.1,10.8,1.0Hz,1H)7.14(t,J=6.1Hz,1H)7.18(d,J=7.5Hz,1H)7.29(s,2H)7.63(td,J=7.7,1.9Hz,1H)8.57(d,J=5.1Hz,1H)。MS(ES+)=624.6[M+H]。
步驟1:在0℃下向2-(吡啶-2-基)乙酸鹽酸鹽MMMMMM(50.0g,288.0mmol,1.0當量)存於甲醇(500mL,0.5M)中之溶液中逐滴添加亞硫醯氯(31.5mL,432.0mmol,1.5當量)。在0℃下將該反應物攪拌60分鐘或直至該反應藉由LCMS或TLC測定完成為止。小心地用碳酸鈉使該反應物驟冷,並用乙酸乙酯萃取水性層。將合併之有機層用水、鹽水洗滌,經硫酸鎂乾燥,過濾,並在真空下濃縮。所得產物(NNNNNN,41.5g,275.0mmol,95%)未經進一步純化即用於下一步驟中。
步驟2:在0℃下向酯NNNNNN(41.5g,275.0mmol,1.0當量)存於THF(1500mL,0.2M)中之溶液中添加2-甲基丙-2-醇鈉(28.6g,288.3mmol,1.05當量),並在0℃下將該反應混合物攪拌30分鐘,然後添加碘甲烷(34.3mL,549.1mmol,2.0當量)。在室溫下將該反應物攪拌1小時或直至該反應藉由LCMS或TLC測定完成為止。用氯化銨使該反應物驟冷,並在真空下去除過量溶劑。然後用乙酸乙酯萃取粗材料。將合併之有機層用鹽水洗滌,並經硫酸鈉乾燥。過濾後,在真空下濃縮該混合物。所得甲基酯(OOOOOO,41.3g,250mmol,91%)未經純化即前進。
步驟3:在0℃下向甲酯OOOOOO(43.0g,260.3mmol,1.0當
量)存於THF(1500mL,0.1M)中之溶液中逐滴添加氫化鋁鋰(312mL,312.4mmol,1.2當量,存於THF中之溶液)。使該反應物逐漸升溫至0℃並持續30分鐘,且然後升溫至室溫並持續1小時或直至該反應藉由LCMS或TLC測定完成為止。小心地用水、氧化鈉及水使該反應物驟冷氫。在將該混合物攪拌30分鐘後,降白色沈澱物過濾掉,並在真空下去除溶劑。然後用二乙醚萃取該反應物,並將合併之有機流分用水、鹽水洗滌,經乾燥硫酸鎂,過濾,並在真空下濃縮。所得醇(PPPPPP,30.0g,219.0mmol,84%)未經純化即前進。
步驟4:在0℃下向醇PPPPPP(30.0g,219.0mmol,1.0當量)存於二氯甲烷(700mL,0.3M)中之溶液中添加三乙胺(61.5mL,437.4mmol,2.0當量)及DMAP(2.7g,21.9mmol,0.1當量)。添加乙酸酐(24.8mL,262.4mmol,1.2當量),並將該反應混合物攪拌30分鐘或直至該反應藉由LCMS或TLC測定完成為止。用氯化銨使該反應物驟冷,將有機層用鹽水洗滌,經硫酸鎂乾燥,並過濾。然後蒸發所得溶液,並粗乙酸酯(QQQQQQ,37.0g,206.0mmol,94%)未經進一步純化即用於下一步驟中。
步驟5:將乙酸酯QQQQQQ(39.4g,219.8mmol,1.0當量)之溶液溶解於二乙醚(100mL)中,且然後添加118g之矽膠。在真空下去除過量醚,且然後將粗固體稀釋於pH 7水性緩衝液(1970mL,0.1M)(氫氧化鈉/磷酸二氫鈉/水)中。添加豬胰脂酶II型(3.3g,(15mg/mmol)),並在37℃下將該反應物攪拌4小時或直至藉由TLC或LCMS測定完成。(4小時後,根據ELSD轉化率達到40%,且藉由手性SFC測定鏡像異構物超越值,並顯示13:1 S:R之鏡像異構物比率)。(SFC條件:SFC Investigator(Waters/Thar),軟體:Chromscope v1.2,方法:等度15%共溶劑95:5庚烷:IPA+0.1% DEA,經10分鐘,管柱:Lux-Amylose-2,4.6×250mm,5μm,總流速:4ml/min(自CO2幫浦為3.80ml,自
改性劑幫浦為0.20ml),設定至35℃之烘箱溫度及設定至100巴(bar)之系統壓力,滯留時間:期望且主要之(S)-鏡像異構物為6.9min,次要(R)-鏡像異構物為8.4min)。將矽膠過濾掉,且用乙酸乙酯將水性層萃取3次。將合併之有機層用鹽水洗滌,經無水硫酸鎂乾燥,並濃縮。藉由矽膠管柱層析(己烷:乙酸乙酯作為溶析液)純化產物,以提供期望醇(RRRRRR,12.5g,91mmol,41%)。
步驟6:在室溫下向醇RRRRRR(12.5g,91.0mmol,1.00當量)存於二氯甲烷(570mL,0.16M)中之溶液中添加三乙胺(13.9mL,100.1mmol,1.1當量)。將該反應物冷卻至0℃,且然後添加甲烷磺醯基氯(7.44mL,95.5mmol,1.05當量)。在0℃下將該反應物攪拌30分鐘或直至藉由TLC或LCMS測定完成為止TLC或LCMS。用碳酸氫鈉使該反應物驟冷並分離各層。然後用二氯甲烷萃取水層。將合併之有機物用鹽水洗滌,經硫酸鎂乾燥,並在真空下濃縮。所得磺酸酯SSSSSS(19.2g,89mmol,98%)未經其他純化即前進。
步驟7:在室溫下向磺酸酯SSSSSS(19.2g,89mmol,1.0當量)存於DMF(120mL,0.1M)中之溶液中添加碳酸銫(40.7g,125.0mmol,1.4當量)及1-苯基-1H-四唑-5-硫醇(19.1g,107.1mmol,1.2當量)。在50℃下將所得混合物攪拌48小時,或直至藉由TLC或LCMS測定完成為止。在將該混合物冷卻至室溫後,添加鹽水並用二乙醚將水性層萃取3次。將合併之有機層用水、鹽水洗滌並經硫酸鎂乾燥。過濾後,在真空下去除溶劑,並使用矽膠管柱層析(己烷/乙酸乙酯)純化殘餘物,從而得到期望產物(TTTTTT,28.9g,88mmol,99%)。
步驟8:在-10℃下向硫化物TTTTTT(31.5g,105.9mmol,1.0當量)存於EtOH(700mL,0.1M)中之溶液中添加鉬酸銨四水合物(6.5g,5.3mmol,0.05當量)及過氧化氫(108mL,1060mmol,5.0當量,33%水溶液)。在-10℃下將該反應物攪拌4小時或直至藉由TLC或
LCMS測定完成為止。用水及偏二亞硫酸鈉溶液使該反應物驟冷。藉由過濾收集粗產物並藉由矽膠管柱層析(己烷:乙酸乙酯作為溶析液)進行純化,以提供期望產物(UUUUUU,23.2g,70.4mmol,66%)。1H NMR(400MHz,氯仿-d)δ:1.50(d,J=7.03Hz,3 H)1.66(br.s.,1 H)3.75(m,1 H)3.94(dd,J=14.81,5.02Hz,1 H)4.55(dd,J=14.68,7.91Hz,1 H)7.14-7.22(m,2 H)7.29(s,1 H)7.57-7.70(m,6 H)8.44-8.49(m,1 H)。
然後使用甲苯/庚烷(1/1)(每100mg之化合物1mL之甲苯及1mL之庚烷)使無色油狀物再結晶。溫和地加熱該混合物以混合該兩種溶劑。使該混合物冷卻至室溫並持續12h。(若未觀測到再結晶,則將一種晶體添加至該溶液中。該晶體將有助於經由引晶製程得到晶體)該等晶體隨時間而緩慢形成。其可經由過濾或經由吸量管去除液體層來分離。然後用庚烷且然後快速地用甲苯洗滌該等晶體。在再結晶之前及之後分析碸之er。(SFC條件:SFC Investigator(Waters/Thar),軟體:Chromscope v1.2,方法:等度10%共溶劑MeOH,經10分鐘,管柱:手性Pak IC,4.6×250mm,5um,總流速:4ml/min(自CO2幫浦為3.80ml,自改性劑幫浦為0.20ml),設定至35℃之烘箱溫度及設定至100巴之系統壓力,滯留時間:期望且主要之(S)-鏡像異構物為3.5min,次要(R)-鏡像異構物為3.8min)。
化合物係提供於96孔板中並一式三份進行測試。將4微升化合物存於DMSO中之10mM原液分配至3個孔中之每一者中。將該板儲存在-20℃下或低於-20℃,直至分析當天為止。使用甲醇(HPLC級)及0.1N HCl(EMD目錄HX0603A-6)用於稀釋。使用乙腈(HPLC級)、水(經過濾Milli-Q)、三氟乙酸(光譜級)及0.2M磷酸鹽緩衝液(Wako,目錄編號163-14471)製備用於兩種分析之移動相。
使用配備有UV檢測器(Waters TUV)及單一四級柱MS檢測器(Waters SQD)之Waters Acquity UPLC獲得穩定性數據。自冷凍器去除含有所關注化合物之96孔板,並使其升溫至室溫並持續1小時。對UPLC灌注,平衡,並藉由注射標準物驗證系統性能。1小時候,用266μL 0.1N HCl稀釋3個孔中之每一者以得到pH=1。覆蓋該板並將其置於振盪器(Eppindorf Thermomixer R)上並於600rpm下45分鐘。自振盪器去除該板,並藉助過濾板(Millipore目錄編號MSSLBPC50)藉由真空過濾每一孔之內容物並將其注射至UPLC中。大約24小時後,將該等孔之內容物再次注射至UPLC中。
藉由比較在24hr時間點注射中在甲醇中之分析物之峰面積%對分析物在相同滯留時間下在0.1N HCl緩衝液中之峰面積-%來量測在各種緩衝液中之穩定性。表2中所報導之穩定性分析顯示,經24小時時期相比於化合物E7107,化合物1至4在pH 1下具有較大穩定性。
以2000細胞/100μL/孔將細胞(自ATCC獲得之WiDr及Panc05.04)接種於96孔板中,並培育過夜。去除廢培養基,並添加含有9種不同濃度之化合物之新鮮培養基(100μL/孔),且將來自化合物原液之DMSO濃度調整至0.1%。一式二份或一式三份地以每一濃度進行每一化合物處理。
接種細胞之另一板係專用作時間0(Tz)板,向其中添加存於培養基中之0.1% DMSO(100μL/孔)、接著添加CellTiter-Glo®試劑(Promega Corporation,Madison,Wisconsin)(50μL/孔)用於ATP量測來替代細胞活力。使用來自此板之多個孔之量測之平均值作為Tz。
在37℃下將經化合物處理之板培育72hr。然後,添加CellTiter-Glo®試劑(50μL/孔)並量測ATP。使用來自一式二份或一式三份經化合物處理之孔之量測之平均值作為Ti,並使用其中培養基具有0.1% DMSO且無化合物之經接種板作為對照生長(C)。
生長抑制百分數/活力百分數係計算為:
[(Ti-Tz)/(C-Tz)]×100,對於Ti>/=Tz之濃度而言
[(Ti-Tz)/Tz]×100,對於Ti<Tz之濃度而言。
*時間0(Tz),對照生長(C),及在存在化合物情況下之測試生長
(Ti)
對生長抑制百分數/活力百分數相對於化合物濃度作圖,以測定Emax。
自[(Ti-Tz)/(C-Tz)]×100=50計算50%之生長抑制(GI50),其係導致在化合物處理期間對照生長(C)之ATP淨增加之50%降低之藥物濃度。
藉由活體外轉錄製備介入序列缺失之腺病毒2型構築體(Ad2)之經生物素標記之前體mRNA(Berg,M.G.等人2012 Mol.Cell Bio.,32(7):1271-83)。含有外顯子1(41個核苷酸)、內含子(231個核苷酸)及外顯子2(72個核苷酸)之Ad2構築體係藉由基因合成生成並藉由Genewiz®(South Plainfield,New Jersey)選殖至pGEM®-3Z載體(Promega)之EcoRI及XbaI位點中。然後藉由XbaI消化使該質體線性化並純化。遵循製造商說明書分別使用MEGAscript® T7轉錄套組(InvitrogenTM,Life TechnologiesTM,Grand Island,New York)及MEGAclearTM轉錄清潔處理套組(InvitrogenTM,Life TechnologiesTM,Grand Island,New York)實施經轉錄前體mRNA之活體外轉錄及純化。生物素-16-UTP(Roche Diagnostics公司,Indianapolis,Indiana)對冷UTP之比率為1:13以使得每個經剪接Ad2 mRNA納入大約兩個生物素分子。
在30℃下在含有95μg HeLa核提取物(Promega Corporation,Madison,Wisconsin)、47nM Ad2前體mRNA、25U RNasin RNA酶抑制劑(Promega Corporation,Madison,Wisconsin)、1X SP緩衝液(0.5mM ATP,20mM磷酸肌酸,1.6mM MgCl2)及存於DMSO中之化合物(具有1%最終濃度之DMSO)之25μL反應混合物中實施活體外剪接分析。在培育90min後,藉由添加18μL之5M NaCl來終止反應,且在室
溫下將該混合物與10μL經M-280鏈黴抗生物素蛋白塗覆之磁珠(InvitrogenTM,Life TechnologiesTM,Grand Island,New York)一起培育30min以捕獲Ad2前體及經剪接mRNA。用含有10mM Tris pH=7.5、1mM EDTA及2M NaCl之100uL緩衝液將珠粒洗滌兩次,且然後在70℃下於含有95%甲醯胺之RNA凝膠上樣緩衝液中培育10min以溶析RNA。藉由6% TBE-UREA凝膠將Ad2 RNA拆分,轉移至耐綸膜,UV交聯,並用經IRDye®標記之鏈黴抗生物素蛋白(LI-COR,Lincoln,Nebraska)探測。藉由量測條帶螢光強度使用LI-COR Image Studio軟體來量化經剪接RNA之量。
數據係報導與下文表3中。Emax係指在所測試劑量範圍內對化合物之最大可達成反應,其中負值指示細胞致死率。較大負Emax值指示特定化合物之較大細胞致死率。舉例而言,在Panc 05.04細胞(即突變體SF3B1細胞系)中,較大負Emax值指示相比於化合物2,化合物1具有較大細胞致死性。
WiDr-R細胞係具有化學誘導之R1074H突變之結腸癌細胞且已顯示在生長抑制方面對普拉二烯內酯B具有抗性(Yokoi,A.等人,2011 FEBS Journal,278:4870-4880)。在此活力分析中利用「抗性」WiDr-R細胞系反篩選化合物可指示該等化合物是否具有脫離標靶效應。在抗性WiDr-R細胞系中缺乏生長抑制(GI50)活性但在親本WiDr細胞系中維持活性之化合物表明符合機制的(on-mechanism)剪接調節負責在親本WiDr細胞系中觀測到之生長抑制。
上文所述之活體外剪接(IVS)分析係監測對將實例性前體mRNA剪接成mRNA之抑制之生物化學分析。此生物化學分析使研究者能夠評價在何種化合物濃度下此特定轉錄物之剪接在非細胞背景中受到抑制並用於證實機械剪接抑制活性。
Panc 05.04細胞:胰臟癌細胞,突變體SF3B1細胞系(SF3B1中之Q699H及K700E突變)
WiDr細胞:結腸癌細胞(野生型SF3B1)
WiDr-R細胞:結腸癌細胞(對E7107(R1074H突變)具有抗性之化學誘導之SF3B1突變體)
以5mg/kg IV(靜脈內)或10mg/kg PO(經口投與)向CD-1小鼠投藥化合物2。投與後,在預定時間點處自5只小鼠經由尾靜脈之連續出血收集血液樣品。在投與後0.083小時(僅0.167小時PO)、0.5小時、1小時、2小時、4小時、6小時、8小時及24小時處收集血液。在血液收
集30分鐘內以5000RPM使血液樣品離心5分鐘以收集血漿。提取後,使用LCMS分析樣品。使用WinNonlin v6.3中之非分室分析計算PK參數。
數據指示,在小鼠模型中化合物2顯示經口生物利用度及有利藥物動力學性質(圖1,表4)。
在小鼠異種移植物模型中測試化合物2之效能。將Nalm-6 SF3B1K700E同基因細胞(人類前體B細胞系,10×106個細胞)皮下移植至雌性CB17-SCID小鼠之側面中。用化合物2(10%乙醇,5%吐溫-80,85%鹽水)或媒劑對照治療小鼠。以圖2中所示之量每天經口投藥動物並持續14天(QD×14 PO),並監測該等動物直至其達到以下終點中之任一者為止:1)每週量測3次之過度腫瘤體積(藉由使用橢圓體公式:(長度×寬度2)/2)計算之腫瘤體積;或2)諸如麻痹或過度體重損失等任何健康問題之發展。根據實驗動物之照護及使用之H3生物醫
學指南(H3 Biomedicine Guide for the Care and Use of Laboratory Animals)實施所有動物研究。
結果指示,在異種移植物小鼠模型中化合物2在經由經口途徑投與時係有效的並降低腫瘤生長(圖2)。
亦在Nalm-6小鼠異種移植物模型中分析化合物2之藥物動力學(PK)/藥效學(PD)。將Nalm-6 SF3B1K700E同基因細胞(人類前體B細胞系,10×106個細胞)皮下移植至雌性CB17-SCID小鼠之側面中。向小鼠投與單一經口劑量之10 mg/kg化合物2(10%乙醇,5%吐溫-80,85%鹽水),並在投與後所示時間處收集腫瘤用於分析。
使用RiboPureTM RNA純化套組(Ambion®)分離RNA並用於qPCR分析。根據SuperScript® VILOTM cDNA合成套組(InvitrogenTM)之說明書逆轉錄RNA,並使用0.04μl之cDNA用於定量PCR(qPCR)。如先前所報道實施針對前體mRNA EIF4A1及成熟mRNA SLC24A19之qPCR及PK評估(Eskens,F.A.等人Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors.Clin Cancer Res.19,6296-6304,doi:10.1158/1078-0432.CCR-13-0485(2013))。根據實驗動物之照護及使用之H3生物醫學指南實施所有動物研究。.
圖3中所顯示之結果指示,化合物2在耐受劑量下經由經口投與途徑顯示PD反應。
為在存在化合物2之情況下評價Panc 05.04癌細胞(SF3B1MUT)(SF3B1中之Q699H及K700E突變)之活力,以750個細胞/孔將細胞接種於384孔板中並在37℃下以圖4中所指示濃度用化合物2處理72小時。使用CELLTITER-GLO®發光細胞活力分析(Promega)藉由發光量測活
細胞或凋亡細胞之相對數量。
結果指示突變體SF3B1胰臟癌細胞系優於野生型SF3B1胰臟癌細胞系之差別細胞致命性(圖4)。
使用nCounter®分析系統(NanoString Techologies公司,Seattle,Washington)測定E7107及化合物2之替代剪接之調節。用化合物2或E7107(自Eisai公司獲得)以10×GI50將Nalm-6同基因細胞處理6小時。使用RiboPureTM RNA純化套組(Ambion®)分離RNA並用於分析。根據SuperScript® VILOTM cDNA合成套組(InvitrogenTM)之說明書逆轉錄RNA並使用0.04μl之cDNA用於qPCR。
圖5中所顯示之結果指示化合物2之剪接調節特徵與E7107之特徵不同。
以5mg/kg IV或12mg/kg PO向CD-1小鼠投藥化合物1。投與後,在預定時間點處自5只小鼠經由尾靜脈之連續出血收集血液樣品。在投與後0.083小時(僅0.167小時PO)、0.5小時、1小時、2小時、4小時、6小時、8小時及24小時處收集血液。在血液收集30分鐘內以5000RPM使血液樣品離心5分鐘以收集血漿。提取後,使用LCMS分析樣品。使用WinNonlin v6.3中之非分室分析計算PK參數。
數據指示,在小鼠模型中化合物1顯示經口生物利用度及有利藥物動力學性質(圖6,表5)。
在小鼠異種移植物模型中測試化合物1之效能。將Nalm-6 SF3B1K700E同基因細胞(人類前體B細胞系,10×106個細胞)皮下移植至雌性CB17-SCID小鼠之側面中。用化合物2(10%乙醇,5%吐溫-80,85%鹽水)或媒劑對照治療小鼠。用7.5mg/kg或10mg/kg化合物1或媒劑每天經口投藥動物並持續14天(QD×14 PO),並監測該等動物直至其達到以下終點中之任一者為止:1)每週量測3次之過度腫瘤體積(藉由使用橢圓體公式:(長度×寬度2)/2)計算之腫瘤體積;或2)諸如麻痹或過度體重損失等任何健康問題之發展。根據實驗動物之照護及使用之H3生物醫學指南實施所有動物研究。.
結果指示,在異種移植物小鼠模型中化合物1在經由經口途徑投與時係有效的並降低腫瘤生長(圖7)。
亦在Nalm-6小鼠異種移植物模型中分析化合物1之藥物動力學
(PK)/藥效學(PD)將Nalm-6 SF3B1K700E同基因細胞(人類前體B細胞系,10×106個細胞)皮下移植至雌性CB17-SCID小鼠之側面中。向小鼠投與單一經口劑量之化合物1(10%乙醇,5%吐溫-80,85%鹽水),並在投與後所示時間處收集腫瘤用於分析。
使用RiboPureTM RNA純化套組(Ambion®)分離RNA並用於qPCR分析。根據SuperScript® VILOTM cDNA合成套組(InvitrogenTM)之說明書逆轉錄RNA,並使用0.04μl之cDNA用於定量PCR(qPCR)。如先前所報道實施針對前體mRNA EIF4A1及成熟mRNA SLC24A19之qPCR及PK評估(Eskens,F.A.等人Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors.Clin Cancer Res.19,6296-6304,doi:10.1158/1078-0432.CCR-13-0485(2013))。根據實驗動物之照護及使用之H3生物醫學指南實施所有動物研究。
圖8中所顯示之結果指示,化合物1在耐受劑量下經由經口投與途徑顯示PD反應。
以5.964mg/kg IV或13.307mg/kg PO向CD-1小鼠投藥化合物3。投與後,在預定時間點處自5只小鼠經由尾靜脈之連續出血收集血液樣品。在投與後0.083小時(僅0.167小時PO)、0.5小時、1小時、2小時、4小時、6小時、8小時及24小時處收集血液。在血液收集30分鐘內以5000RPM使血液樣品離心5分鐘以收集血漿。提取後,使用LCMS分析樣品。使用WinNonlin v6.3中之非分室分析計算PK參數。
數據指示,在小鼠模型中化合物3顯示經口生物利用度及有利藥物動力學性質(圖9,表6)。
以5mg/kg IV或10mg/kg PO向CD-1小鼠投藥化合物4。投與後,在預定時間點處自5只小鼠經由尾靜脈之連續出血收集血液樣品。在投與後0.083小時(僅0.167小時PO)、0.5小時、1小時、2小時、4小時、6小時、8小時及24小時處收集血液。在血液收集30分鐘內以5000RPM使血液樣品離心5分鐘以收集血漿。提取後,使用LCMS分析樣品。使用WinNonlin v6.3中之非分室分析計算PK參數。
數據指示,在小鼠模型中化合物4顯示經口生物利用度及有利藥物動力學性質(圖10,表7)。
上文所呈現結果證實,化合物1、2、3及4各自擁有經口生物利用度及有利藥物動力學性質。此係優於E7107之改良,其已因其不足經口生物利用度以靜脈內輸注形式向患者投與(Hong等人(2014),Invest New Drugs 32,436-444)。
Claims (54)
- 一種化合物,其選自式1化合物:式2化合物:式3化合物:式4化合物:及其醫藥上可接受之鹽。
- 一種化合物,其選自式1化合物:及其醫藥上可接受之鹽。
- 一種化合物,其選自式2化合物:及其醫藥上可接受之鹽。
- 一種化合物,其選自式3化合物:及其醫藥上可接受之鹽。
- 一種化合物,其選自式4化合物:及其醫藥上可接受之鹽。
- 如請求項1之化合物,其中該化合物係純的立體異構物。
- 如請求項1之化合物,其中該化合物包含大於約80重量%之該化合物的一種立體異構物。
- 如請求項1之化合物,其中該化合物包含大於約90重量%之該化合物的一種立體異構物。
- 如請求項1之化合物,其中該化合物包含大於約95重量%之該化合物的一種立體異構物。
- 如請求項1之化合物,其中該化合物包含大於約97重量%之該化合物的一種立體異構物。
- 一種醫藥組合物,其包含如請求項1至10中任一項之化合物及/或其醫藥上可接受之鹽。
- 如請求項11之醫藥組合物,其中該組合物係經調配用於靜脈內、經口、皮下或肌內投與。
- 如請求項12之醫藥組合物,其中該組合物係經調配用於經口投與。
- 一種如請求項1至10中任一項之化合物或其醫藥上可接受之鹽或如請求項11至13中任一項之醫藥組合物之用途,其係用於製備治療選自骨髓發育不良症候群、慢性淋巴球性白血病、急性淋巴母細胞性白血病、慢性骨髓單核球白血病、急性類骨髓性白血病、結腸癌、胰臟癌、子宮內膜癌、卵巢癌、乳癌、葡萄膜黑色素瘤、胃癌、膽道癌及肺癌之癌症的藥劑。
- 如請求項14之用途,其中該癌症係結腸癌。
- 如請求項14之用途,其中該癌症係胰臟癌。
- 如請求項14之用途,其中該癌症係選自骨髓發育不良症候群、慢性淋巴球性白血病、急性淋巴母細胞性白血病、慢性骨髓單核球白血病、急性類骨髓性白血病。
- 如請求項14之用途,其中該癌症係急性類骨髓性白血病。
- 如請求項14之用途,其中該癌症係骨髓發育不良症候群。
- 如請求項14之用途,其中該癌症係慢性淋巴球性白血病。
- 如請求項14之用途,其中該癌症係急性淋巴母細胞性白血病。
- 如請求項14之用途,其中該癌症係慢性骨髓單核球白血病。
- 如請求項14之用途,其中該癌症係子宮內膜癌。
- 如請求項14之用途,其中該癌症係卵巢癌。
- 如請求項14之用途,其中該癌症係乳癌。
- 如請求項14之用途,其中該癌症係葡萄膜黑色素瘤。
- 如請求項14之用途,其中該癌症係胃癌。
- 如請求項14之用途,其中該癌症係膽道癌。
- 如請求項14之用途,其中該癌症係肺癌。
- 如請求項14至29中任一項之用途,其中該癌症對於剪接體基因或蛋白質中之一或多種突變呈陽性。
- 如請求項30之用途,其中該剪接體基因或蛋白質係選自剪接因子3B亞單位1(SF3B1)、U2小核RNA輔助因子1(U2AF1)、富含絲胺酸/精胺酸之剪接因子2(SRSF2)、富含鋅指(CCCH類型)RNA結合基序及絲胺酸/精胺酸之2(ZRSR2)、前體mRNA加工剪接因子8(PRPF8)、U2小核RNA輔助因子2(U2AF2)、剪接因子1(SF1)、剪接因子3a亞單位1(SF3A1)、PRP40前體mRNA加工因子40同系物B(PRPF40B)、RNA結合模體蛋白10(RBM10)、聚(rC)結合蛋白1(PCBP1)、曲頸前體mRNA剪接因子1(CRNKL1)、DEAH(Asp-Glu-Ala-His)盒解旋酶9(DHX9)、肽基-脯胺醯基順式-反式異構酶樣2(PPIL2)、RNA結合基序蛋白22(RBM22)、小核核糖核蛋白Sm D3(SNRPD3)、可能ATP依賴性RNA解旋酶DDX5(DDX5)、前體mRNA-剪接因子ATP依賴性RNA解旋酶DHX15(DHX15)及聚腺苷酸結合蛋白1(PABPC1)。
- 如請求項31之用途,其中該剪接體基因或蛋白質係剪接因子3B亞單位1(SF3B1)。
- 一種醫藥組合物,其包含化合物,該化合物選自式2化合物:及其醫藥上可接受之鹽。
- 如請求項33之醫藥組合物,其中該組合物係經調配用於靜脈內、經口、皮下或肌內投與投與。
- 如請求項34之醫藥組合物,其中該組合物係經調配用於經口投與。
- 一種如請求項33至35中任一項之醫藥組合物之用途,其係用於製備治療選自骨髓發育不良症候群、慢性淋巴球性白血病、急性淋巴母細胞性白血病、慢性骨髓單核球白血病、急性類骨髓性白血病、結腸癌、胰臟癌、子宮內膜癌、卵巢癌、乳癌、葡萄膜黑色素瘤、胃癌、膽道癌及肺癌之癌症的藥劑。
- 如請求項36之用途,其中該癌症係結腸癌。
- 如請求項36之用途,其中該癌症係胰臟癌。
- 如請求項36之用途,其中該癌症係選自骨髓發育不良症候群、慢性淋巴球性白血病、急性淋巴母細胞性白血病、慢性骨髓單核球白血病、急性類骨髓性白血病。
- 如請求項36之用途,其中該癌症係急性類骨髓性白血病。
- 如請求項36之用途,其中該癌症係骨髓發育不良症候群。
- 如請求項36之用途,其中該癌症係慢性淋巴球性白血病。
- 如請求項36之用途,其中該癌症係急性淋巴母細胞性白血病。
- 如請求項36之用途,其中該癌症係慢性骨髓單核球白血病。
- 如請求項36之用途,其中該癌症係子宮內膜癌。
- 如請求項36之用途,其中該癌症係卵巢癌。
- 如請求項36之用途,其中該癌症係乳癌。
- 如請求項36之用途,其中該癌症係葡萄膜黑色素瘤。
- 如請求項36之用途,其中該癌症係胃癌。
- 如請求項36之用途,其中該癌症係膽道癌。
- 如請求項36之用途,其中該癌症係肺癌。
- 如請求項36至51中任一項之用途,其中該癌症對於剪接體基因或蛋白質中之一或多種突變呈陽性。
- 如請求項52之用途,其中該剪接體基因或蛋白質係選自剪接因子3B亞單位1(SF3B1)、U2小核RNA輔助因子1(U2AF1)、富含絲胺酸/精胺酸之剪接因子2(SRSF2)、富含鋅指(CCCH類型)RNA結合基序及絲胺酸/精胺酸之2(ZRSR2)、前體mRNA加工剪接因子8(PRPF8)、U2小核RNA輔助因子2(U2AF2)、剪接因子1(SF1)、剪接因子3a亞單位1(SF3A1)、PRP40前體mRNA加工因子40同系物B(PRPF40B)、RNA結合模體蛋白10(RBM10)、聚(rC)結合蛋白1(PCBP1)、曲頸前體mRNA剪接因子1(CRNKL1)、DEAH(Asp-Glu-Ala-His)盒解旋酶9(DHX9)、肽基-脯胺醯基順式-反式異構酶樣2(PPIL2)、RNA結合基序蛋白22(RBM22)、小核核糖核蛋白Sm D3(SNRPD3)、可能ATP依賴性RNA解旋酶DDX5(DDX5)、前體mRNA-剪接因子ATP依賴性RNA解旋酶DHX15(DHX15)及聚腺苷酸結合蛋白1(PABPC1)。
- 如請求項53之用途,其中該剪接體基因或蛋白質係剪接因子3B亞單位1(SF3B1)。
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WO2017040526A2 (en) | 2015-09-01 | 2017-03-09 | Eisai R&D Management Co., Ltd. | Splice variants associated with neomorphic sf3b1 mutants |
JP6312282B2 (ja) | 2015-11-18 | 2018-04-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 固体形態のプラジエノライドピリジン化合物及び使用の方法 |
CA3056389A1 (en) | 2017-03-15 | 2018-09-20 | Eisai R&D Management Co., Ltd. | Spliceosome mutations and uses thereof |
AU2018360559B2 (en) | 2017-10-31 | 2024-08-22 | Eisai R&D Management Co., Ltd. | Combination comprising at least one spliceosome modulator and at least one inhibitor chosen from BCL2 inhibitors, BCL2/BCLXL inhibitors, and BCLXL inhibitors and methods of use |
AU2019251096B2 (en) * | 2018-04-09 | 2023-04-20 | Eisai R&D Management Co., Ltd. | Pladienolide compounds and their use |
BR112020020956A2 (pt) * | 2018-04-12 | 2021-03-02 | Eisai R&D Management Co., Ltd. | derivados de pladienolida como spliceossoma que tem como alvo agentes para tratar câncer |
EP3801523B1 (en) * | 2018-06-01 | 2024-09-11 | Eisai R&D Management Co., Ltd. | Splicing modulators |
IL262658A (en) * | 2018-10-28 | 2020-04-30 | Memorial Sloan Kettering Cancer Center | Prevention of age related clonal hematopoiesis and diseases associated therewith |
BR112022024833A2 (pt) * | 2020-06-05 | 2023-02-14 | Eisai R&D Man Co Ltd | Conjugados anticorpo anti-bcma-fármaco e métodos de uso |
TW202233187A (zh) | 2020-11-04 | 2022-09-01 | 日商衛材R&D企管股份有限公司 | 骨髓發育不良症候群(mds)之生物標記物及其使用方法 |
WO2022263702A1 (es) * | 2021-06-18 | 2022-12-22 | Universidad de Córdoba | Compuesto para el tratamiento del glioblastoma |
CN113876771B (zh) * | 2021-11-12 | 2022-09-23 | 中国医学科学院基础医学研究所 | 一种靶向pabpc1的小分子药物及其在慢性髓系白血病中的应用 |
WO2023131866A1 (en) | 2022-01-05 | 2023-07-13 | Eisai R&D Management Co., Ltd. | Biomarkers for myelodysplastic syndrome (mds) and methods of using the same |
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JP4459051B2 (ja) | 2002-07-31 | 2010-04-28 | メルシャン株式会社 | 新規生理活性物質 |
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WO2004050890A1 (ja) | 2002-11-29 | 2004-06-17 | Mercian Corporation | マクロライド系化合物の製造方法 |
KR20060110865A (ko) | 2003-11-27 | 2006-10-25 | 에자이 가부시키가이샤 | 매크로라이드계 화합물의 수산화에 관여하는 dna |
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