TW202302535A - 化合物 - Google Patents
化合物 Download PDFInfo
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- TW202302535A TW202302535A TW111107022A TW111107022A TW202302535A TW 202302535 A TW202302535 A TW 202302535A TW 111107022 A TW111107022 A TW 111107022A TW 111107022 A TW111107022 A TW 111107022A TW 202302535 A TW202302535 A TW 202302535A
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- pharmaceutically acceptable
- compound
- prodrug
- acceptable salt
- cancer
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Abstract
本發明係關於作為DNA甲基轉移酶1 (DNMT1)活性之抑制劑的經取代之吡啶衍生物。本發明亦係關於包含此類化合物之醫藥組合物及使用此類化合物於治療癌症、癌前症候群、β血紅素病變病症及與不當DNMT1活性相關之其他疾病的方法。
Description
本發明係關於作為DNA甲基轉移酶1 (DNMT1)活性之抑制劑的經取代之吡啶衍生物。本發明亦係關於包含此類化合物之醫藥組合物及在治療癌症、癌前症候群、β血紅素病變(haemoglobinopathy)病症及與不當DNMT1活性相關之其他疾病中使用此類化合物的方法。
表觀遺傳學為與基礎DNA序列無關之開啟及關閉基因的方式。發生在基因啟動子中之DNA甲基化為抑制表觀遺傳標記的實例,其引起染色質壓緊(chromatin compaction)及基因緘默。DNA甲基化係由包含五個家族成員的DNA甲基轉移酶(DNMT)家族介導。其中三個家族成員DNMT1、DNMT3A及DNMT3B含有DNA甲基轉移酶活性。此等三個成員負責建立重新DNA甲基化模式,同時DNMT1亦負責維持在DNA複製之後子股中之甲基化模式。
在癌症中,DNA甲基化模式變得異常,造成整體低甲基化及啟動子區內之局部高甲基化。此可引起腫瘤抑制基因之下游緘默(Ting等人Genes Dev. 2006;20:3215-3231)。另外,DNMT1之緘默引起DNA去甲基化及引起腫瘤生長抑制之腫瘤抑制基因的再表現(Zhou等人Oncol. Lett. 2014;5: 2130-2134)。
DNA甲基化抑制劑(稱為DNA低甲基化劑)為經臨床證實之用於治療MDS、AML及CMML的抗癌療法。儘管此等藥劑為可供使用的,但仍存在關於改良毒性、實體腫瘤中之效用及口服生物可用性的許多可能性。因此,對於癌症及/或由DNA甲基化介導之任何疾病或病狀的治療,新穎DNMT抑制劑將為值得關注的。本發明尤其受關注的係特異性靶向DNMT1,以防止異常甲基化模式(諸如在癌症中出現之異常甲基化模式)在複製期間傳播至子股。
血紅素病症,諸如鐮狀細胞貧血及β-地中海貧血代表全球最常見的遺傳性血液疾病。鐮狀細胞貧血及β-地中海貧血之特徵為血紅素異常,血紅素為紅血球中之攜氧蛋白複合物。在結構上,血紅素通常由兩對蛋白加四個血基質分子構成。成人及年齡大於約四個月之兒童表現稱為成體血紅素之血紅素形式,其主要由與兩個β-血球蛋白配對之兩個α-血球蛋白加四個血基質分子組成。然而,胎兒及嬰兒通常大部分表現胚胎血紅素,其由與兩個γ-血球蛋白配對之兩個α-血球蛋白加四個血基質分子構成。應注意,存在兩種形式之γ-血球蛋白,稱為G-γ及A-γ,其由兩種不同基因(
HBG1及
HBG2)編碼但功能在很大程度上相同;胚胎血紅素係指一對G-γ及/或A-γ加一對α-血球蛋白加四個血基質分子的任何組合。
在鐮狀細胞貧血中,編碼β-血球蛋白之基因含有產生異常血紅素結構且使得紅血球在某些條件下採取特徵性鐮狀形狀的突變。此鐮狀形狀導致紅血球可塑性減小、毛細管轉移時間較長及血管閉塞過程頻繁發生,其可損傷組織且引起患者罹病。相比之下,β-地中海貧血之特徵為β-血球蛋白產量不足與正常產生之α-血球蛋白組合。所得之α血球蛋白積聚對紅血球前驅體有毒性,且產生低效的紅血球生成及廣泛的紅血球溶血現象。
當前尚無批准用於治癒鐮狀細胞貧血或β-地中海貧血的藥理學治療。然而,已證實,增加產生胚胎血紅素之紅血球的數目並且整體增加每個紅血球之胚胎血紅素含量,藉由減少急性血管閉塞危象之頻率,在鐮狀細胞貧血及鐮狀細胞疾病患者中提供臨床益處。另外,儘管未臨床證實,但β-地中海貧血之疾病生物學表明將胚胎血紅素產量提高至較高水準同樣可為此疾病之療法的可行策略。
此治療方法,亦即經緘默
HBG1及
HBG2基因之去抑制的目標可經由干預紅血球生成中之表觀遺傳過程來靶向。DNA甲基化之變化為造血過程中的關鍵確定性事件,其標記認定各種細胞譜系的分化里程碑(differentiation milestone)。在紅血球生成期間,整體DNA甲基化之快速減少區分(demark)針對紅血球系特異性調節子GATA1及KLF1之表現,及造血祖細胞調節子GATA2及PU.1之抑制的認定點(1,2)。對於成人骨髓中之紅血球系祖細胞,β-血球蛋白
HBB基因之啟動子區中的DNA變得未甲基化,對應於β-血球蛋白之高表現量。相比之下,
HBG1及
HBG2基因座之啟動子為高度甲基化的,使得γ-血球蛋白之表現大大減弱(3)。儘管DNA甲基轉移酶DNMT1、DNMT3A及DNMT3B各自表現於紅血球系祖細胞中,但DNMT1尤其在紅血球系分化之最終階段之表現相對較高,表明其在血球蛋白基因調節中起主要作用(2)。5-氮雜胞苷及5-氮雜-2'-去氧胞苷(地西他濱(decitabine))為係紅血球系祖細胞中胚胎血紅素之已知誘導劑的泛DNMT抑制劑。在紅血球系細胞培養物中及胚胎血紅素誘導之活體內模型中(4,5),用此等試劑處理引起
HBG啟動子中CpG位點的甲基化減少,伴隨γ血球蛋白表現相應增加。此外,在一組有限的臨床研究中,兩種試劑均引起患有鐮狀細胞貧血、鐮狀細胞疾病及β-地中海貧血之患者中胚胎血紅素的增加(6-9)。雖然誘導胚胎血紅素有效,但由於擔憂長期安全性、劑量限制性毒性及不適合的給藥途徑,此等試劑尚未廣泛用於治療鐮狀細胞貧血、鐮狀細胞疾病或β-地中海貧血。
參考文獻
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(4) Chin J, Singh M, Banzon V, Vaitkus K, Ibanez V, Kouznetsova T等人,Transcriptional activation of the +¦-globin gene in baboons treated with decitabine and in cultured erythroid progenitor cells involves different mechanisms. 2009;37:1131-42。
(5) Akpan I, Banzon V, Ibanez V, Vaitkus K, DeSimone J, Lavelle D. Decitabine increases fetal hemoglobin in Papio anubis by increasing +¦-globin gene transcription. 2010;38:989-93。
(6) Dover GJ, Charache SH, Boyer SH, Talbot J, Smith KD. 5-Azacytidine increases fetal hemoglobin production in a patient with sickle cell disease. 1983;134:475-88。
(7) Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L等人,Effects of 5-aza-2GǦ-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. 2003;102:3865-70。
(8) Ley TJ, DeSimone J, Noguchi CT, Turner PH, Schechter AN, Heller P等人,5-Azacytidine increases +¦-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. 1983;62:370-80。
(9) Lowrey CH, Nienhuis AW. Brief report: Treatment with azacitidine of patients with end-stage +¦- thalassemia. 1993;329:845-8。
本發明之目標為提供一種作為DNMT1抑制劑的新穎化合物。
本發明係針對新穎化合物。
本發明進一步係針對醫藥組合物,其包含式(I)化合物或其前藥或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑。
本發明進一步係針對治療與不當DNMT1活性相關之疾病的方法,其包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
本發明進一步係針對用於醫學療法之式(I)化合物或其前藥或其醫藥學上可接受之鹽。
本發明進一步係針對式(I)化合物或其前藥或其醫藥學上可接受之鹽,其用於治療與不當DNMT1活性相關之疾病。
本發明進一步係針對式(I)化合物或其前藥或其醫藥學上可接受之鹽的用途,其用於製造供治療與不當DNMT1活性相關之疾病用的藥劑。
本發明仍進一步係針對一種組合,其包含式(I)化合物或其前藥或其醫藥學上可接受之鹽及一或多種其他治療劑。
本發明之化合物含有至少一個不對稱中心(亦稱為對掌性中心)且因此可以個別對映異構體、非對映異構體或其他立體異構形式或以其混合物形式存在。對掌性中心,諸如對掌性碳原子亦可存在於諸如烷基之取代基中。當未指定存在於本發明之化合物中或本文所說明之任何化學結構中的對掌性中心的立體化學時,該結構意欲涵蓋任何立體異構體及其所有混合物。因此,本發明之化合物可用作外消旋混合物、對映異構性增濃混合物或作為對映異構性純的個別立體異構體。
本發明之化合物的個別立體異構體可藉由熟習此項技術者已知的方法解析。例如,此類解析可藉由以下進行:(1)藉由形成非對映異構鹽、複合物或其他衍生物;(2)藉由與立體異構體特異性試劑選擇性反應,例如藉由酶氧化或還原;或(3)在對掌性環境中,例如在對掌性載體,諸如具有結合之對掌性配位體之二氧化矽上,或在對掌性溶劑存在下,藉由氣-液或液相層析。熟習此項技術者應瞭解,當藉由上述分離程序中之一者將所要立體異構體轉化為另一化學實體時,需要又一步驟來釋放所要形式。替代地,特定立體異構體可藉由使用光活性試劑、受質、催化劑或溶劑不對稱合成或藉由不對稱轉變將一種對映異構體轉化為其他對映異構體來合成。
本發明之化合物亦可含有幾何不對稱中心。當未指定存在於本發明之化合物中或本文中所說明之任何化學結構中的幾何不對稱中心的立體化學時,該結構意欲涵蓋反式幾何異構體、順式幾何異構體及其所有混合物。同樣,亦包括所有互變異構形式,無論此類互變異構體在平衡中存在或主要呈一種形式。
本發明之化合物可以前藥形式投與。如本文所使用,式(I)化合物之「前藥」為化合物之功能性衍生物,其在向患者投與後最終在活體內釋放式(I)化合物。以前藥投與式(I)化合物可使得熟習此項技術者能夠進行以下中之一或多者:(a)修改活體內化合物之溶解度,(b)修改活體內化合物活性之起始;(c)修改活體內化合物之作用的持續時間;(d)修改活體內化合物之運輸或分佈;及(e)克服化合物所出現之副作用或其他困難。用於製備前藥之典型的功能性衍生物包括活體內化學或酶可裂解之化合物的修飾。此類修飾,包括磷酸酯、醯胺、酯、硫酯、碳酸酯及胺基甲酸酯之製備,為熟習此項技術者所熟知。在一個實施例中,前藥部分為-P(O)(OH)
2。
應理解,本文中對式(I)化合物及其前藥以及其鹽之提及涵蓋作為游離酸或游離鹼或作為其鹽,例如作為其醫藥學上可接受之鹽的式(I)化合物及其前藥。因此,在一個實施例中,本發明係針對作為游離酸或游離鹼之式(I)化合物或其前藥。在另一實施例中,本發明係針對式(I)化合物或其前藥或其鹽。在又一實施例中,本發明係針對式(I)化合物或其前藥或其醫藥學上可接受之鹽。
熟習此項技術者應瞭解,可製備根據式(I)之化合物或其前藥的醫藥學上可接受之鹽。實際上,在本發明之某些實施例中,根據式(I)之化合物或其前藥的醫藥學上可接受之鹽可比各別游離鹼或游離酸更佳,因為此類鹽可向分子賦予更大穩定性或溶解度,由此促進調配成劑型。
如本文所使用,術語「醫藥學上可接受之鹽」係指保留本發明化合物之所要生物活性且展現極小非所要毒理學作用的鹽。此等醫藥學上可接受之鹽可在化合物之最終分離及純化期間原位製備,或藉由分開地使呈其游離酸或游離鹼形式之經純化的化合物或非醫藥學上可接受之鹽分別與適合的鹼或酸反應來製備。
具有非醫藥學上可接受之相對離子或相結合溶劑的鹽及溶劑合物在本發明之範疇內,例如在製備式(I)化合物或其前藥及其醫藥學上可接受之鹽中用作中間物。因此,本發明之一個實施例涵蓋式(I)化合物及其前藥及其鹽。
醫藥學上可接受之鹽尤其包括描述於Berge, J. Pharm. Sci., 1977, 66, 1-19中之彼等鹽或列於P H Stahl及C G Wermuth編,
Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second EditionStahl/Wermuth: Wiley- VCH/VHCA, 2011中之彼等鹽(參見http://www.wiley.com/WileyCDA/WileyTitle/productCd-3906390519.html)。
在某些實施例中,根據式(I)之化合物或其前藥可含有酸性官能基。適合的醫藥學上可接受之鹽包括此類酸性官能基之鹽。代表性鹽包括但不限於鋁、2-胺基-2-(羥基甲基)-1,3-丙二醇(TRIS,緩血酸胺)、精胺酸、苯明(benethamine) (
N-苯甲基苯乙基胺)、苄星青黴素(benzathine) (
N,N ' -二苯甲基乙二胺)、雙-(2-羥乙基)胺、鉍、鈣、氯普魯卡因(chloroprocaine)、膽鹼、吡咯咪唑(clemizole) (1-對氯苯甲基-2-吡咯啶-1'-基甲基苯并咪唑)、環己胺、二苯甲基乙二胺、二乙胺、二乙基三胺、二甲胺、二甲基乙醇胺、多巴胺、乙醇胺、乙二胺、L-組胺酸、鐵、異喹啉、勒皮啶(lepidine)、鋰、L-離胺酸、鎂、葡甲胺(
N-甲基還原葡糖胺)、哌𠯤、哌啶、鉀、普魯卡因、奎寧(quinine)、喹啉、鈉、鍶、三級丁胺、甜菜鹼(betaine) (三-甲基甘胺酸)、L-脯胺酸、L-苯丙胺酸、L-丙胺酸、L-酪胺酸、L-白胺酸、咪唑、甘胺酸、L-纈胺酸、L-絲胺酸、嗎啉、三-膽鹼、二伸乙基三胺、1-(2-羥乙基)-2-吡咯啶及鋅。
此類鹼加成鹽可藉由使式(I)化合物或其前藥(其例如含有羧酸或其他酸性官能基)與適當鹼視情況於諸如有機溶劑之適合溶劑中反應,以得到可藉由包括結晶及過濾之多種方法分離的鹽而形成。
應理解,若式(I)化合物或其前藥含有兩個或更多個鹼性部分,則鹽形成之化學計量可包括1、2或更多當量之酸。此類鹽將含有1個、2個或更多個酸相對離子,例如二鹽酸鹽。
式(I)化合物或其前藥之醫藥學上可接受之鹽的化學計量及非化學計量形式包括於本發明之範疇內,包括次化學計量的鹽,例如其中相對離子含有超過一個酸性質子。
在某些實施例中,根據式(I)之化合物或其前藥可含有鹼性官能基且因此能夠藉由用適合酸處理形成醫藥學上可接受之酸加成鹽。適合之酸包括醫藥學上可接受之無機酸及醫藥學上可接受之有機酸。代表性醫藥學上可接受之酸加成鹽包括但不限於4-乙醯胺基苯甲酸鹽、乙酸鹽、己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽(benzenesulfonate/besylate)、苯甲酸鹽、硫酸氫鹽、酒石酸氫鹽、丁酸鹽、乙二胺四乙酸鈣、樟腦酸鹽、樟腦磺酸鹽(camphorsulfonate/camsylate)、癸酸鹽(caprate/decanoate)、己酸鹽(caproate/hexanoate)、辛酸鹽(caprylate/octanoate)、肉桂酸鹽、檸檬酸鹽、賽克拉美(cyclamate)、二葡糖酸鹽、2,5-二羥基苯甲酸鹽、二丁二酸鹽、十二烷基硫酸鹽(依託酸鹽(estolate))、乙二胺四乙酸鹽(edetate/ethylenediaminetetraacetate)、依託酸鹽(月桂基硫酸鹽)、乙烷-1,2-二磺酸鹽(乙二磺酸鹽)、乙磺酸鹽(ethanesulfonate/esylate)、甲酸鹽、反丁烯二酸鹽、半乳糖二酸鹽(galactarate/mucate)、龍膽酸鹽(2,5-二羥苯甲酸鹽)、葡庚糖酸鹽(glucoheptonate/gluceptate)、葡糖酸鹽、葡萄糖醛酸鹽、麩胺酸鹽、戊二酸鹽、甘油亞磷酸鹽(glycerophosphorate)、羥乙酸鹽、己基間苯二酚酸鹽(hexylresorcinate)、馬尿酸鹽、海卓胺(hydrabamine) (
N,
N'-二(去氫松香基)-乙二胺)、氫溴酸鹽、鹽酸鹽、氫碘酸鹽、羥基萘甲酸鹽(hydroxynaphthoate)、異丁酸鹽、乳酸鹽、乳糖酸鹽、月桂酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽(methanesulfonate/mesylate)、甲硫酸鹽、半乳糖二酸鹽(mucate)、萘-1,5-二磺酸鹽(萘二磺酸鹽)、萘-2-磺酸鹽(萘磺酸鹽)、菸鹼酸鹽、硝酸鹽、油酸鹽、棕櫚酸鹽、對
-胺基苯磺酸鹽、對-胺基水楊酸鹽、雙羥萘酸鹽(pamoate/embonate)、泛酸鹽、果膠酸鹽、過硫酸鹽、苯基乙酸鹽、苯乙基巴比妥酸鹽(phenylethylbarbiturate)、磷酸鹽、聚半乳糖醛酸鹽(polygalacturonate)、丙酸鹽、對-甲苯磺酸鹽(
p-toluenesulfonate) (甲苯磺酸鹽(tosylate))、焦麩胺酸鹽、丙酮酸鹽、水楊酸鹽、癸二酸鹽、硬脂酸鹽、次乙酸鹽、丁二酸鹽、胺基磺酸鹽、硫酸鹽、丹寧酸鹽、酒石酸鹽、茶氯酸鹽(teoclate) (8-氯茶酸鹽(8-chlorotheophyllinate))、硫氰酸鹽、三乙碘化鹽(triethiodide)、十一烷酸鹽、十一碳烯酸鹽及戊酸鹽。
此類酸加成鹽可藉由使式(I)化合物或其前藥(其例如含有鹼性胺或其他鹼性官能基)與適當酸視情況於諸如有機溶劑之適合溶劑中反應,以得到可藉由包括結晶及過濾之多種方法分離的鹽而形成。
鹽可在式(I)化合物或其前藥之最終分離及純化期間原位製備。若式(I)之鹼性化合物或其前藥經分離為鹽,則相應的游離鹼形式之彼化合物可藉由此項技術中已知之任何適合方法,包括用無機或有機鹼處理鹽來製備。類似地,若含有羧酸或其他酸性官能基之式(I)化合物或其前藥經分離為鹽,則相應的游離酸形式之彼化合物可藉由此項技術中已知之任何適合方法,包括用無機或有機酸處理鹽來製備。
式(I)化合物及其前藥的所有光學異構體、立體異構體、多晶型物及經放射性標記之衍生物以及其鹽包括於「本發明之化合物」之範疇內。
本發明之化合物可以固體或液體形式存在。呈固體狀態時,本發明之化合物可以結晶或非結晶形式或以其混合物形式存在。對於呈結晶形式之本發明化合物,熟習此項技術者應瞭解,可形成醫藥學上可接受之溶劑合物,其中在結晶期間溶劑分子併入結晶晶格中。本發明之化合物可以溶劑化及非溶劑化形式存在。溶劑合物可涉及非水性溶劑,諸如乙醇、異丙醇、DMSO、乙酸、乙醇胺及EtOAc,或其可涉及水,作為併入結晶晶格中之溶劑。其中水為併入結晶晶格中之溶劑的溶劑合物通常被稱作「水合物」。水合物包括化學計量之水合物以及含有可變量之水的組合物。
熟習此項技術者將進一步瞭解,以結晶形式存在之某些本發明化合物(包括其多種溶劑合物)可展現多形現象(亦即,以不同結晶結構出現的能力)。此等不同結晶形式通常被稱為「多晶型物」。本發明包括所有此類多晶型物。多晶型物具有相同化學組成,但在裝填、幾何配置及結晶固體狀態之其他描述性性質方面不同。因此,多晶型物可具有不同物理性質,諸如形狀、密度、硬度、變形性、穩定性及溶解性質。多晶型物通常展現不同熔點、IR光譜及X射線粉末繞射圖案,其可用於鑑別。熟習此項技術者應瞭解,不同多晶型物可例如藉由改變或調整製造化合物所用之反應條件或試劑產生。例如,溫度、壓力或溶劑之變化可產生多晶型物。另外,一種多晶型物可在某些條件下自發轉化成另一多晶型物。
本發明亦包括經同位素標記之化合物,其與本發明之化合物相同,除了一或多個原子經原子質量或質量數不同於自然界中最常發現之原子質量或質量數的原子置換。可併入至本發明之化合物中之同位素的實例包括氫、碳、氮、氧及氟之同位素,諸如
2H、
3H、
11C、
14C及
18F。
「對映異構性增濃」係指產物之對映異構體過量大於零。例如,對映異構性增濃係指產物之對映異構體過量大於50% ee、大於75% ee及大於90% ee。
「對映異構體過量」或
「 ee 」為一種對映異構體相對於另一種對映異構體的過量,以百分比表示。因此,由於兩種對映異構體以等量存在於外消旋混合物中,則對映異構體過量為零(0% ee)。然而,若一種對映異構體增濃使得其構成95%產物,則對映異構體過量將為90% ee (經增濃對映異構體之量95%,減去另一對映異構體之量5%)。在一些實施例中,關於R或S對映異構體,本發明之化合物可具有至少50% ee、至少60% ee、至少65% ee、至少70% ee、至少75% ee、至少80% ee、至少85% ee、至少90% ee、至少95% ee、至少96% ee、至少97% ee、至少98% ee或至少99% ee。
「對映異構性純」係指產物之對映異構體過量為99% ee或更大。
「醫藥學上可接受」係指在合理醫學判斷範疇內之彼等化合物、鹽、材料、組合物及劑型,其適用於與人類及動物組織接觸而無過度毒性、刺激或其他問題或併發症,滿足合理益處/風險比。
本發明之化合物可用作有需要之哺乳動物,尤其人類中的選擇性DNMT1抑制劑。作為DNMT1抑制劑之化合物可用於治療其中潛在病理學(至少部分)可歸因於不當DNMT1活性的疾病,諸如癌症。「不當DNMT1活性」係指偏離特定患者中預期之正常DNMT1活性的任何DNMT1活性。不當DNMT1可呈例如活性的異常增加或DNMT1活性之時序及/或控制的畸變的形式。因此,在另一態樣中,本發明係針對治療此類疾病之方法。
在本發明之一些態樣中,式(I)化合物及其前藥以及其鹽為DNMT1之強力抑制劑且相對於DNMT3A及DNMT3B對DNMT1具有選擇性。
此類疾病包括癌症、癌前症候群(有時被稱作癌前病狀)或β血紅素病變病症。癌前病狀為涉及異常細胞之病狀或病變,該等細胞與發展為癌症之風險增加相關。臨床上,癌前病狀涵蓋具有發展為癌症之增加風險的多種病狀或病變。
可治療之癌症包括:腺癌、基底細胞癌、鱗狀細胞癌、腺鱗癌、癌肉瘤、黑色素瘤、腎上腺癌、腎上腺皮質癌、嗜鉻細胞瘤、乳癌、乳腺管原位癌(ductal carcinoma in situ)、小葉癌、發炎性乳癌、侵襲性乳腺管癌、佩吉特氏乳頭病(Paget disease of the nipple)、乳頭狀乳癌、髓性癌、乳房癌(mammary carcinoma)、肛門癌、泄殖腔原癌(cloacogenic carcinoma)、肛門直腸黑色素瘤、闌尾癌、闌尾神經內分泌腫瘤、闌尾黏液囊腺癌(appendiceal mucinous cystadenocarcinomas)、結腸型腺癌、戒環狀細胞腺癌(signet-ring cell adenocarcinoma)、杯狀細胞癌瘤(goblet cell carcinoma)/腺神經內分泌癌(adenoneuroendocrine carcinoma)、膽管癌、肝內膽管癌瘤(intrahepatic cholangiocarcinoma)、肝外(extrahepatic)膽管癌瘤、門周(perihilar)膽管癌瘤、末端肝外膽管癌瘤(distal extrahepatic cholangiocarcinoma)、大腸直腸癌(CRC)、黏液腺癌、腸胃類癌腫瘤、腸胃基質腫瘤、原發性大腸直腸淋巴瘤、平滑肌肉瘤、食道癌、小細胞癌瘤、平滑肌瘤、膽囊癌、非乳頭狀腺癌、乳頭狀腺癌、胃癌、胃腺癌、肝癌、肝細胞癌、纖維層狀癌瘤(fibrolamellar carcinoma)、血管肉瘤(angiosarcoma)、淋巴管肉瘤(lymphangiosarcoma)、血管周圍細胞瘤(hemangiosarcoma)、肝母細胞瘤(hepatoblastoma)、胰臟癌、腺管腺癌、腺泡腺癌、腺泡細胞癌、膠質癌瘤、巨大細胞腫瘤、肝樣癌瘤(hepatoid carcinoma)、黏液囊性贅瘤、胰母細胞瘤(pancreatoblastoma)、漿液性囊腺瘤(serous cystadenoma)、管內乳頭狀黏液性贅瘤(intraductal papillary mucinous neoplasm)、胰臟神經內分泌腫瘤、胃泌素瘤、胰島素瘤、升糖素瘤、VIP瘤、體抑素瘤(somatostatinoma)、胰多肽瘤(PPoma)、小腸癌、眼癌、眼內黑色素瘤、眼內淋巴瘤、眼內視網膜母細胞瘤、結膜黑色素瘤、眼瞼癌瘤、皮脂癌瘤、淚腺腫瘤(lacrimal gland tumour)、惡性混合上皮腫瘤、腺樣囊性瘤(adenoid cystic carcinoma)、膀胱癌、尿道上皮癌、腎癌、腎細胞癌瘤(RCC)、透明細胞RCC、乳頭狀RCC、難染性RCC、集合管(collecting duct) RCC、多葉狀囊性RCC、腎黏液性管狀及梭狀細胞癌瘤、管狀囊性RCC、甲狀腺樣濾泡RCC、後天性囊性腎臟疾病相關之RCC、具有t(6;11)轉位(TFEB)之RCC、混合式嗜酸性腺瘤/難染性RCC、威爾姆氏腫瘤(Wilms tumor)、陰莖癌、前列腺癌、去勢抵抗性前列腺癌、移行細胞癌瘤、睪丸癌、精原細胞瘤、典型精原細胞瘤、精母細胞型精原細胞瘤、非精原細胞瘤、胚胎癌瘤、卵黃囊癌瘤、絨毛膜癌、畸胎瘤、萊迪希氏細胞(Leydig cell)腫瘤、塞特利氏細胞(Sertoli cell)腫瘤、睪丸網癌瘤(carcinoma of the rete testis)、尿道癌、顱外生殖細胞腫瘤、胚細胞瘤、性腺母細胞瘤、混合生殖細胞腫瘤、性腺外生殖細胞腫瘤、內胚竇瘤、宮頸癌、子宮內膜癌、卵巢癌、輸卵管癌、上皮癌、無性細胞瘤、生殖索基質腫瘤、妊娠期滋養細胞瘤(gestational trophoblastic tumour)、原發性腹膜癌、子宮肉瘤、子宮乳頭狀漿液性癌、陰道癌、透明細胞腺癌、外陰癌、疣狀癌、頭頸癌、頭頸部鱗狀細胞癌、咽癌、下咽癌、鼻咽癌、口咽癌、非角質化(non-keratinising)鱗狀細胞癌、未分化性癌瘤、喉癌、口腔癌(oral cavity cancer)、口癌(mouth cancer)、黏液表皮樣(mucoepidermoid)癌瘤、副鼻竇(paranasal sinus)及鼻腔癌、敏感性神經母細胞瘤、唾液腺癌、上皮性肌上皮癌、副甲狀腺癌、甲狀腺癌、乳頭狀甲狀腺癌、濾泡性甲狀腺癌、何氏細胞(Hurthle cell)癌瘤、甲狀腺髓樣癌、未分化甲狀腺癌、副神經節瘤、頸動脈副神經節瘤、頸鼓室(jugulotympanic)副神經節瘤、迷走神經副神經節瘤、白血病、急性淋巴母細胞白血病、T淋巴母細胞白血病、前驅體B細胞淋巴母細胞白血病、急性骨髓白血病(AML)、急性骨髓白血病、急性前髓細胞性白血病、急性骨髓單核球性白血病、急性單核球性白血病、急性巨核母細胞白血病、紅白血病、慢性淋巴球性白血病、B細胞慢性淋巴球性白血病、B細胞前淋巴球性白血病、T細胞前淋巴球性白血病、大顆粒淋巴球性白血病、T細胞大顆粒淋巴球性白血病、NK細胞顆粒淋巴球性白血病、毛細胞白血病、慢性骨髓白血病、慢性骨髓單核球性白血病、慢性嗜中性球白血病、慢性嗜酸性球白血病、漿細胞白血病、淋巴瘤、霍奇金氏淋巴瘤、典型霍奇金氏淋巴瘤、結節狀硬化性典型霍奇金氏淋巴瘤、混合細胞性典型霍奇金氏淋巴瘤、富淋巴球性典型霍奇金氏淋巴瘤、淋巴球耗乏性典型霍奇金氏淋巴瘤、結節狀淋巴球為主型霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤(NHL)、瀰漫性大B細胞淋巴瘤、原發性縱隔B細胞淋巴瘤、原發性積液淋巴瘤、富T細胞/組織細胞大B細胞淋巴瘤、淋巴漿細胞淋巴瘤、淋巴母細胞淋巴瘤、小淋巴球性淋巴瘤、雙重打擊/三重打擊淋巴瘤(double hit/triple hit lymphoma)、伯基特氏淋巴瘤(Burkitt lymphoma)、伯基特氏樣淋巴瘤、小非裂細胞淋巴瘤、濾泡性淋巴瘤、濾泡性大細胞淋巴瘤、免疫母細胞淋巴瘤、血管內大細胞淋巴瘤、原發性脾臟淋巴瘤、未分化大細胞淋巴瘤、套細胞淋巴瘤、緣帶淋巴瘤(MZL)、結外MZL、節點MZL、脾臟MZL、具有絨毛狀淋巴球之脾臟MZL、周邊T細胞淋巴瘤、血管免疫母細胞T細胞淋巴瘤、成人T細胞淋巴瘤/白血病、結外NK/T細胞淋巴瘤、腸病相關T細胞淋巴瘤、肝脾T細胞淋巴瘤、皮下脂層炎樣(subcutaneous panniculitis-like) T細胞淋巴瘤、非特指型T細胞非霍奇金氏淋巴瘤、γ/δ T細胞淋巴瘤、黏膜相關淋巴組織淋巴瘤、移植後淋巴增生病症、HIV相關淋巴瘤、蘭格漢氏細胞組織細胞增多症(Langerhans cell histiocytosis)、多發性骨髓瘤、和緩性多發性骨髓瘤、活性多發性骨髓瘤、漿細胞瘤、孤立性骨漿細胞瘤(solitary plasmacytoma of bone)、髓外漿細胞瘤、原發性澱粉樣變性、骨髓發育不良症候群(MDS)、難治癒貧血(refractory anaemia)、具有環形含鐵胚血球之難治癒貧血、具有過量母細胞之難治癒貧血、具有過量轉化中母細胞之難治癒貧血、骨髓增生性贅瘤、真性多紅血球症、本態性血小板增多症、骨髓纖維化、全身性肥大細胞增多症、骨癌、尤文氏肉瘤(Ewing sarcoma)、骨肉瘤、髓內骨肉瘤、皮質旁骨肉瘤(juxtacortical osteosarcoma)、骨外骨肉瘤、惡性骨纖維組織細胞瘤、脊索瘤、典型脊索瘤、軟骨狀脊索瘤、去分化(dedifferentiated)脊索瘤、軟骨肉瘤、傳統軟骨肉瘤、透明細胞軟骨肉瘤、黏液軟骨肉瘤、間葉軟骨肉瘤、去分化軟骨肉瘤、橫紋肌肉瘤、胚胎性橫紋肌肉瘤、齒槽橫紋肌肉瘤、葡萄樣橫紋肌肉瘤、多形態橫紋肌肉瘤、軟組織肉瘤、骨外肉瘤(extraosseus sarcoma)、隆突性皮纖維肉瘤(dermatofibrosarcoma protuberans)、上皮樣肉瘤、卡波西氏肉瘤(Kaposi's sarcoma)、脂肪肉瘤、惡性周邊神經鞘腫瘤、纖維肉瘤、黏液肉瘤、滑膜瘤、腦癌、未分化星形細胞瘤、神經膠母細胞瘤、多形性神經膠母細胞瘤、脊膜瘤、垂體癌、神經鞘瘤、寡樹突神經膠瘤、室管膜瘤、神經管母細胞瘤、星形細胞瘤、腦幹神經膠質瘤、非典型畸胎樣/橫紋樣腫瘤(atypical teratoid/rhabdoid tumour)、松果體瘤、神經母細胞瘤、原發性CNS淋巴瘤、原始神經外胚層腫瘤(primitive neuroectodermal tumour)、瀰漫性內因性腦橋神經膠質瘤、肺癌、非小細胞肺癌(NSCLC)、未分化NSCLC、小細胞肺癌、胸膜肺母細胞瘤、支氣管癌、惡性間皮瘤、惡性胸膜間皮瘤、惡性腹膜間皮瘤、胸腺瘤、胸腺癌、皮膚癌、角化棘皮瘤、皮脂腺癌瘤、汗腺腺癌、頂泌癌瘤(apocrine carcinoma)、外分泌癌瘤(eccrine carcinoma)、透明細胞外分泌癌瘤、梅克爾細胞癌(Merkel cell carcinoma)、皮膚T細胞淋巴瘤、蕈狀肉芽腫(mycosis fungoides)、塞紮里症候群(Sézary syndrome)、軟骨狀汗管瘤(chondroid syringoma)、HPV相關癌症、含有經轉化細胞之腫瘤、含有呈癌前狀態之細胞的腫瘤、癌前增生、癌前化生、癌前發育不良、原位癌瘤、混合腫瘤、惡性混合腫瘤及複合癌瘤。
可治療之癌症亦包括具有高腫瘤突變負荷(TMB)、缺陷性DNA錯配修復系統(dMMR)、高微衛星不穩定性狀態(MSI-H)、低微衛星不穩定性狀態(MSI-L)、所選擇四核苷酸重複序列處之升高微衛星變異(elevated microsatellite alterations at selected tetranucleotide repeats,EMAST)之癌症、微衛星穩定(MSS)癌症、包含聚合酶δ (POLD)突變之癌症、包含聚合酶ε (POLE)突變之癌症或具有同源重組修復缺陷之癌症。
可治療之癌症進一步包括由表現概況定義之乳癌(三陰性乳癌、HER2陽性乳癌、魯米那A型(luminal A)乳癌、魯米那B型乳癌、正常樣乳癌)或具有BRCA1或BRCA2突變之乳癌。
在本發明之一個實施例中,所治療之癌症係骨髓發育不良症候群(MDS)、急性骨髓白血病(AML)、大腸直腸癌(CRC)、非霍奇金氏淋巴瘤(NHL)、黑色素瘤或乳癌。在本發明之另一實施例中,癌症為急性骨髓白血病(AML)。在本發明之又一實施例中,癌症為大腸直腸癌(CRC)。
本發明之治療方法包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。本發明之個別實施例包括治療上述病症中之任一者的方法,其藉由向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
如本文所使用,關於病症之「治療」意謂:(1)改善或預防病症或病症之生理表現中之一或多者,(2)干擾(a)引起或負責病症之生理級聯中一或多個點,或(b)病症之生理表現中之一或多者,(3)緩解與病症相關之症狀或作用中之一或多者,或(4)減緩病症或病症之生理表現中之一或多者之進展。
如本文所使用,關於式(I)化合物或其前藥或其醫藥學上可接受之鹽或其他醫藥活性劑的「安全且有效量」意謂在合理醫學判斷之範疇內足以治療患者之病狀但又低至足以避免嚴重副作用(處於合理益處/風險比)的化合物之量。化合物之安全且有效量將隨以下變化:所選擇之特定化合物(例如,考慮化合物之效能、功效及半衰期);所選擇之投與途徑;所治療之病症;所治療之病症的嚴重程度;所治療之患者的年齡、體型、體重及身體狀況;待治療之患者的病史;治療之持續時間;並行療法之本質;所要治療效果;及類似因素,但無論如何可由熟習此項技術者常規地確定。
如本文所使用,「患者」係指人類(包括成人及兒童)或其他動物。在一個實施例中,「患者」係指人類。
因此,本發明係針對治療與不當DNMT1活性相關之疾病的方法,其包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
在一個實施例中,本發明提供一種治療癌症、癌前症候群或β血紅素病變病症之方法,其包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
在另一實施例中,本發明提供一種治療癌症、癌前症候群或β血紅素病變病症之方法,其包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
在另一實施例中,本發明提供一種治療骨髓發育不良症候群(MDS)、急性骨髓白血病(AML)、大腸直腸癌(CRC)、非霍奇金氏淋巴瘤(NHL)、黑色素瘤或乳癌的方法,其包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
在另一實施例中,本發明提供一種治療急性骨髓白血病(AML)的方法,其包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
在另一實施例中,本發明提供一種治療大腸直腸癌(CRC)的方法,其包含向有需要的患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。
在又一實施例中,本發明提供一種治療鐮狀細胞疾病、鐮狀細胞貧血或β地中海貧血的方法,其包含向有需要之患者投與安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。鐮狀細胞貧血為單一特異性疾病,其特徵為兩種β血球蛋白基因對偶基因中之同種接合E6V突變。相比之下,鐮狀細胞疾病為若干相關疾病之集合,所有疾病皆具有不同嚴重程度之類似症狀。鐮狀細胞疾病患者具有一個具有E6V突變之β血球蛋白基因對偶基因(如鐮狀細胞貧血),而第二β血球蛋白基因對偶基因攜帶任何數目的突變,但尤其引起β地中海貧血之突變。最常見鐮狀細胞疾病表現稱為『鐮狀β零』及『鐮狀β加』,但同樣存在其他表現。應注意鐮狀細胞疾病患者中之第二β血球蛋白對偶基因並非不含突變(一個E6V β血球蛋白對偶基因加一個正常β血球蛋白對偶基因稱為鐮狀細胞特點,其並非完全良性但一般不治療),僅第二對偶基因中之突變不為E6V突變。應注意鐮狀細胞特點不視為鐮狀細胞疾病。
本發明進一步係針對用於醫學療法之式(I)化合物或其前藥或其醫藥學上可接受之鹽。
本發明進一步係針對式(I)化合物或其前藥或其醫藥學上可接受之鹽,其用於治療與不當DNMT1活性相關之疾病。
本發明仍進一步係針對式(I)化合物或其前藥或其醫藥學上可接受之鹽的用途,其用於製造供治療與不當DNMT1活性相關之疾病用的藥劑。
式(I)化合物及其前藥以及其醫藥學上可接受之鹽通常但未必在向患者投與之前調配成醫藥組合物。
因此,在一個態樣中,本發明係針對醫藥組合物,其包含式(I)化合物或其前藥或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑。
在另一態樣中,本發明係針對醫藥組合物,其包含0.5至3500 mg式(I)化合物或其前藥或其醫藥學上可接受之鹽及0.1至2 g一或多種醫藥學上可接受之賦形劑。
在另一態樣中,本發明係針對包含式(I)化合物或其前藥或其醫藥學上可接受之鹽的醫藥組合物,其用於治療由不當DNMT1活性介導的疾病。
式(I)化合物或其前藥或其醫藥學上可接受之鹽可藉由任何適合投與途徑投與,包括全身投與及局部投與兩者。全身投與包括經口投與、非經腸投與、經皮投與及直腸投與。非經腸投與係指除經腸或經皮之外的投與途徑,且通常係藉由注射或輸注。非經腸投與包括靜脈內、肌肉內及皮下注射或輸注。局部投與包括施用至皮膚以及眼內、耳、陰道內、吸入及鼻內投與。吸入係指經由口或經由鼻道吸入向患者之肺中投與。在一個實施例中,式(I)化合物或其前藥或其醫藥學上可接受之鹽可經口投與。
在一些實施例中,式(I)化合物之某些前藥可尤其適用於經口投與,因為改良之溶解度使口服生物可用性提高。
式(I)化合物或其前藥或其醫藥學上可接受之鹽可投與一次或根據給藥方案投與,其中多次劑量以不同時間間隔持續給定時段投與。例如,可每天一次、兩次、三次、四次、五次或六次投與劑量。可投與劑量直至達成所要治療作用為止或無限期投與以維持所要治療作用。式(I)化合物或其前藥或其醫藥學上可接受之鹽的適合給藥方案取決於彼化合物之藥物動力學性質,諸如吸收、分佈及半衰期,其可由熟習此項技術者確定。另外,式(I)化合物或其前藥或其醫藥學上可接受之鹽的適合給藥方案(包括投與此類方案之持續時間)取決於所治療之病症、所治療之疾病的嚴重程度、所治療之患者的年齡及身體狀況、待治療之患者的病史、並行療法之本質、所要治療作用及熟習此項技術者之知識及專門知識內的類似因素。此類熟習此項技術者應進一步瞭解,考慮到個別患者對給藥方案之反應或隨時間推移個別患者之需求變化,適合的給藥方案可需要調節。
本發明之醫藥學上活性化合物在如上文所描述之醫藥劑量單位中的劑量將為較佳選自0.001至500 mg/kg、較佳0.01至100 mg/kg範圍之有效無毒數量的活性化合物。當治療需要DNMT1抑制劑之人類患者時,所選劑量較佳以每日1至6次經口或非經腸投與。較佳的非經腸投與形式包括局部、經直腸、經皮、藉由注射及連續藉由輸注形式。用於人類投與之口服劑量單位較佳含有0.5至3500 mg活性化合物。適當地,用於人類投與之口服劑量單位較佳含有0.5至1,000 mg活性化合物。使用較低劑量之經口投與係較佳的。然而,在對於患者而言安全且方便時,亦可使用高劑量下之非經腸投與。
式(I)化合物及其醫藥學上可接受之鹽通常但未必在向患者投與之前調配成醫藥組合物。
因此,在一個態樣中,本發明係針對醫藥組合物,其包含式(I)化合物或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑。
在另一態樣中,本發明係針對醫藥組合物,其包含0.05至1000 mg式(I)化合物或其醫藥學上可接受之鹽及0.1至2 g一或多種醫藥學上可接受之賦形劑。
在另一態樣中,本發明係針對包含式(I)化合物或其醫藥學上可接受之鹽的醫藥組合物,其用於治療或防治由不當DNMT1活性介導的病症。
本發明之醫藥組合物可以散裝形式製備及封裝,其中可提取安全且有效量的式(I)化合物或其醫藥學上可接受之鹽,且隨後諸如以散劑或糖漿向患者給出。替代地,本發明之醫藥組合物可以單位劑型製備及封裝,其中各物理離散單位含有式(I)化合物或其醫藥學上可接受之鹽。當以單位劑型製備時,本發明之醫藥組合物通常可含有例如0.5至1,000 mg,或1 mg至700 mg,或5 mg至100 mg式(I)化合物或其前藥或其醫藥學上可接受之鹽。
本發明之醫藥組合物通常含有一種式(I)化合物或其前藥或其醫藥學上可接受之鹽。
如本文所使用,「醫藥學上可接受之賦形劑」意謂涉及給與醫藥組合物形式或稠度之醫藥學上可接受的材料、組合物或媒劑。當共混時,各賦形劑必須與醫藥組合物之其他成分相容,使得避免當向患者投與時將實質上減少式(I)化合物或其前藥或其醫藥學上可接受之鹽的功效的相互作用,及將產生醫藥學上不可接受之醫藥組合物的相互作用。另外,各賦形劑當然必須為醫藥學上可接受的,例如具有足夠高的純度。
式(I)化合物或其前藥或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑將通常調配成適於藉由所要投藥途徑向患者投與的劑型。例如,劑型包括適用於以下之彼等劑型:(1)經口投與,諸如錠劑、膠囊、囊片(caplet)、丸劑、糖衣錠(troche)、散劑、糖漿、酏劑、懸浮液、溶液、乳液、囊袋(sachet)及扁囊劑;(2)非經腸投與,諸如無菌溶液、懸浮液及復原用散劑;(3)經皮投與,諸如經皮貼片;(4)經直腸投與,諸如栓劑;(5)吸入,諸如霧劑(aerosol)、溶液及無水散劑;及(6)局部投與,諸如乳膏、軟膏、乳劑、溶液、糊劑、噴霧劑(spray)、泡沫劑及凝膠。
適合的醫藥學上可接受之賦形劑將視所選之特定劑型而變化。另外,可針對可用於組合物中之特定功能選擇適合的醫藥學上可接受之賦形劑。例如,可針對促進產生均勻劑型之能力選擇某些醫藥學上可接受之賦形劑。可針對促進產生穩定劑型之能力選擇某些醫藥學上可接受之賦形劑。可針對促進在向患者投與後將式(I)化合物或其前藥或其醫藥學上可接受之鹽自一個器官或身體之部分攜帶或傳輸至另一器官或身體之部分的能力來選擇某些醫藥學上可接受之賦形劑。可針對增強患者順應性之能力選擇某些醫藥學上可接受之賦形劑。
適合的醫藥學上可接受之賦形劑包括以下類型之賦形劑:稀釋劑、填充劑、黏合劑、崩解劑、潤滑劑、助滑劑、成粒劑、塗佈劑、濕潤劑(wetting agent)、溶劑、共溶劑、懸浮劑、乳化劑、甜味劑、調味劑、風味掩蔽劑、著色劑、防結塊劑、潤濕劑(hemectant)、螯合劑、塑化劑、增黏劑、抗氧化劑、防腐劑、穩定劑、界面活性劑及緩衝劑。熟習此項技術者應瞭解,視調配物中存在多少賦形劑及調配物中存在何種其他賦形劑而定,某些醫藥學上可接受之賦形劑可提供超過一種功能且可提供替代功能。
熟習此項技術者具有此項技術中之知識及技能以使其能夠選擇適用於本發明之量的適合的醫藥學上可接受之賦形劑。另外,熟習此項技術者可獲得描述醫藥學上可接受之賦形劑且可用於選擇適合的醫藥學上可接受之賦形劑的許多來源。實例包括
Remington's Pharmaceutical Sciences(Mack Publishing公司)、
The Handbook of Pharmaceutical Additives(Gower Publishing有限公司)及
The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association及the Pharmaceutical Press)。
本發明之醫藥組合物係使用熟習此項技術者已知的技術及方法製備。此項技術中常用之方法中的一些描述於
Remington's Pharmaceutical Sciences(Mack Publishing公司)中。
因此,在另一態樣中,本發明係針對用於製備醫藥組合物之製程,該醫藥組合物包含式(I)化合物或其前藥或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑,該方法包含混合成分。包含式(I)化合物或其前藥或其醫藥學上可接受之鹽的醫藥組合物可藉由例如在環境溫度及大氣壓下摻合製備。
在一個實施例中,式(I)化合物或其前藥或其醫藥學上可接受之鹽將調配用於經口投與。在另一實施例中,式(I)化合物或其前藥或其醫藥學上可接受之鹽將調配用於非經腸投與。
在一個態樣中,本發明係針對諸如錠劑或膠囊之固體口服劑型,其包含安全且有效量的式(I)化合物或其前藥或其醫藥學上可接受之鹽及稀釋劑或填充劑。適合的稀釋劑及填充劑包括乳糖、蔗糖、右旋糖、甘露糖醇、山梨糖醇、澱粉(例如,玉米澱粉、馬鈴薯澱粉及預膠凝化澱粉)、纖維素及其衍生物(例如,微晶纖維素)、硫酸鈣及磷酸氫二鈣。口服固體劑型可進一步包含黏合劑。適合的黏合劑包括澱粉(例如,玉米澱粉、馬鈴薯澱粉及預膠凝化澱粉)、明膠、阿拉伯膠、海藻酸鈉、褐藻酸、黃蓍(tragacanth)、瓜爾豆膠、普維酮(povidone)及纖維素及其衍生物(例如,微晶纖維素)。口服固體劑型可進一步包含崩解劑。適合的崩解劑包括交聯普維酮(crospovidone)、羥基乙酸澱粉鈉、交聯羧甲纖維素(croscarmelose)、褐藻酸及羧甲基纖維素鈉。口服固體劑型可進一步包含潤滑劑。適合的潤滑劑包括硬脂酸、硬脂酸鎂、硬脂酸鈣及滑石。
適當時,用於經口投與之劑量單位調配物可經微囊封。亦可製備組合物以延長或維持釋放,如例如藉由將微粒材料包覆或嵌入於聚合物、蠟或其類似物中。
式(I)化合物或其前藥或其醫藥學上可接受之鹽亦可與作為可靶向藥物載劑之可溶性聚合物偶合。此類聚合物可包括聚乙烯吡咯啶酮、哌喃共聚物、聚羥丙基甲基丙烯醯胺-酚、聚羥乙基天冬醯胺酚或經軟脂醯基殘基取代之聚氧化乙烯聚離胺酸。此外,式(I)化合物或其前藥或其醫藥學上可接受之鹽可偶合至可用於實現藥物控制釋放之一類生物可降解聚合物,例如聚乳酸、聚ε己內酯(polepsilon caprolactone)、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫哌喃、聚氰基丙烯酸酯及水凝膠之交聯或兩性嵌段共聚物。
在另一態樣中,本發明係針對液體口服劑型。諸如溶液、糖漿及酏劑之口服液體可以單位劑型製備以使得給定數量含有預定量的式(I)化合物或其前藥或其醫藥學上可接受之鹽。糖漿可藉由將式(I)化合物或其前藥或其醫藥學上可接受之鹽溶解於適當調味的水性溶液中來製備,而酏劑經由使用無毒醇性媒劑來製備。懸浮液可藉由使式(I)化合物或其前藥或其醫藥學上可接受之鹽分散於無毒媒劑中調配。亦可添加增溶劑及乳化劑(諸如乙氧基化異硬脂醇及聚氧乙烯山梨糖醇醚)、防腐劑、風味添加劑(諸如薄荷油)或天然甜味劑或糖精或其他人工甜味劑及其類似物。
適於非經腸投與之醫藥組合物包括:水性及非水性無菌注射溶液,其可含有抗氧化劑、緩衝劑、抑菌劑及使調配物與預期接受者血液等張之溶質;及水性及非水性無菌懸浮液,其可包括懸浮劑及增稠劑。組合物可呈現於單位劑量或多劑量容器(例如,密封安瓿及小瓶)中,且可在冷凍乾燥(凍乾)條件下儲存,僅需要在即將使用之前添加無菌液體載劑,例如注射用水。可自無菌散劑、顆粒及錠劑製備即用型注射溶液及懸浮液。
式(I)化合物或其前藥或其醫藥學上可接受之鹽可與一或多種其他活性劑共同投與。因此,在一個實施例中,本發明提供一種組合,其包含式(I)化合物或其前藥或其醫藥學上可接受之鹽及一或多種其他活性劑。在另一實施例中,已知其他活性劑可用於治療癌症或癌前症候群。
如本文所使用,術語「共同投與」意謂同時投與或以任何方式各別依序投與如本文所描述之DMNT1活性抑制劑及已知可用於治療癌症(包括化學療法及輻射治療)的一或多種其他活性劑。如本文所使用,術語其他「活性成分(active ingredient/active ingredients)」或「活性劑(active agent/active agents)」包括當向患者投與時已知表現或表現有利性質的任何化合物或治療劑。較佳地,若不同時投與,則化合物以彼此緊密接近之時間投與。此外,化合物是否以相同劑型投與並不重要,例如一種化合物可藉由注射投與且另一種化合物可經口投與。
通常,在本發明之癌症治療中,可共同投與對所治療之易感腫瘤具有活性的任何抗贅生劑。此類藥劑之實例可見於Cancer Principles and Practice of Oncology, V.T. Devita, T.S. Lawrence及S.A. Rosenberg (編者),第10版(2014年12月5日), Lippincott Williams & Wilkins Publishers中。一般熟習此項技術者能夠基於所涉及之藥物及癌症之特定特徵辨別哪些藥劑組合將為有用的。可用於本發明之典型的抗贅生劑包括但不限於抗微管或抗有絲分裂劑;鉑配位錯合物;烷基化劑;抗生素劑;拓樸異構酶I抑制劑;拓樸異構酶II抑制劑;抗代謝物;激素及激素類似物;信號轉導路徑抑制劑;非受體酪胺酸激酶血管生成抑制劑;免疫治療劑;促凋亡劑;細胞週期信號傳導抑制劑;蛋白酶體抑制劑;熱休克蛋白抑制劑;癌症代謝抑制劑;及癌症基因治療劑。
與式(I)化合物或其前藥或其醫藥學上可接受之鹽組合使用或共同投與的一或多種其他活性成分的實例為抗贅生劑。抗贅生劑之實例包括但不限於化學治療劑;免疫調節藥劑;免疫調節劑;及免疫刺激佐劑。
抗微管或抗有絲分裂劑為在細胞週期之M或有絲分裂階段期間對腫瘤細胞微管具有活性的階段特異性藥劑。抗微管劑之實例包括但不限於雙萜及長春花屬生物鹼。
鉑配位錯合物為非階段特異性抗癌劑,其與DNA相互作用。鉑錯合物進入腫瘤細胞,經歷水合作用,且與DNA形成股內及股間交聯,對腫瘤產生不利生物作用。鉑配位錯合物之實例包括但不限於順鉑及卡鉑。
烷基化劑為非階段抗癌特異性藥劑及強親電子劑。通常,烷基化劑藉由烷基化,經由DNA分子之親核部分(諸如磷酸根、胺基、巰基、羥基、羧基及咪唑基團)形成與DNA之共價鍵。此類烷基化破壞核酸功能,使得細胞死亡。烷基化劑之實例包括但不限於氮芥,諸如環磷醯胺、黴法蘭(melphalan)及苯丁酸氮芥(chlorambucil);磺酸烷基酯,諸如硫酸布他卡因(busulfan);亞硝基脲(nitrosourea),諸如雙氯乙基亞硝脲(carmustine);及三氮烯(triazenes),諸如達卡巴嗪(dacarbazine)。
抗生素抗贅生劑為非階段特異性藥劑,其與DNA結合或插入。此動作會破壞核酸之一般功能,使得細胞死亡。抗生素抗贅生劑之實例包括但不限於放線菌素(actinomycin),諸如更生黴素(dactinomycin);蒽環黴素(anthrocyclin),諸如道諾黴素(daunorubicin)及阿黴素(doxorubicin);及博來黴素(bleomycin)。
拓樸異構酶I抑制劑包括但不限於喜樹鹼。咸信喜樹鹼之細胞毒性活性與其拓樸異構酶I抑制活性有關。
拓樸異構酶II抑制劑包括但不限於表鬼臼毒素。表鬼臼毒素為來源於鬼臼植株(mandrake plant)的階段特異性抗贅生劑。表鬼臼毒素通常藉由與拓樸異構酶II及DNA形成三元複合物,引起DNA股斷裂,而影響細胞週期之S及G
2階段中的細胞。股斷裂積聚且細胞死亡隨之而來。表鬼臼毒素之實例包括但不限於依託泊苷(etoposide)及替尼泊苷(teniposide)。
抗代謝物贅生劑為藉由抑制DNA合成或藉由抑制嘌呤或嘧啶鹼基合成,且從而限制DNA合成在細胞週期之S階段(DNA合成)起作用的階段特異性抗贅生劑。因此,S階段不繼續進行且細胞死亡隨之而來。抗代謝物抗贅生劑之實例包括但不限於氟尿嘧啶、甲胺喋呤、阿糖胞苷(cytarabine)、巰基嘌呤、硫鳥嘌呤及吉西他濱(gemcitabine)。
激素及激素類似物為治療癌症之有用化合物,其中激素與癌症之生長及/或生長缺乏之間存在關係。可用於癌症治療之激素及激素類似物的實例包括但不限於腎上腺皮質類固醇,諸如普賴松(prednisone)及普賴蘇穠(prednisolone);胺麩精(aminoglutethimide)及其他芳香酶抑制劑,諸如阿那曲唑(anastrozole)、來曲唑(letrazole)、維拉唑(vorazole)及依西美坦(exemestane);黃體素(progestrin),諸如乙酸甲地孕酮(megestrol acetate);雌激素、雄激素及抗雄激素,諸如氟他胺(flutamide)、尼魯胺(nilutamide)、比卡魯胺(nilutamide)、乙酸環丙孕酮(cyproterone acetate)及5α-還原酶(諸如非那雄安(finasteride)及度他雄胺(dutasteride));抗雌激素,諸如他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷諾昔酚(raloxifene)、曲洛昔芬(droloxifene)、艾多昔芬(iodoxyfene)以及選擇性雌激素受體調節劑(SERMS);及性腺釋素(GnRH)及其類似物,其刺激黃體生成激素(LH)及/或促濾泡激素(FSH)釋放,LHRH促效劑及拮抗劑(諸如乙酸戈舍瑞林(goserelin acetate)及亮丙立德(leuprolide))。
信號轉導路徑抑制劑為阻斷或抑制引發細胞內變化之化學過程的彼等抑制劑。如本文所使用,此變化為細胞增殖或分化。可用於本發明之信號轉導抑制劑包括但不限於受體酪胺酸激酶、非受體酪胺酸激酶、SH2/SH3域阻斷劑、絲胺酸/蘇胺酸激酶、磷脂醯基肌醇-3激酶、肌-肌醇信號傳導及Ras致癌基因的抑制劑。
若干蛋白酪胺酸激酶催化各種蛋白中涉及細胞生長調節之特定酪胺醯基殘基的磷酸化。此類蛋白酪胺酸激酶可廣泛地分類為受體或非受體激酶。
受體酪胺酸激酶為具有細胞外配位體結合域、跨膜域以及酪胺酸激酶域的跨膜蛋白。受體酪胺酸激酶涉及細胞生長調節且一般稱為生長因子受體。已展示許多此等激酶之不當或不受控活化,亦即異常激酶生長因子受體活性,例如藉由過度表現或突變,會引起不受控的細胞生長。因此,此類激酶之異常活性與惡性組織生長有關。因此,此類激酶之抑制劑可提供癌症治療方法。生長因子受體包括例如表皮生長因子受體(EGFr)、血小板衍生生長因子受體(PDGFr)、erbB2、erbB4、血管內皮生長因子受體(VEGFR)、具有免疫球蛋白樣及表皮生長因子同源域之酪胺酸激酶(TIE-2)、胰島素生長因子-I (IGFI)受體、巨噬細胞群落刺激因子(cfms)、BTK、ckit、cmet、纖維母細胞生長因子(FGF)受體、Trk受體(TrkA、TrkB及TrkC)、艾普瑞林(ephrin,eph)受體及RET原致癌基因。若干生長受體抑制劑處於研發中且包括配位體拮抗劑、抗體、酪胺酸激酶抑制劑及反義寡核苷酸。生長因子受體及抑制生長因子受體功能之藥劑描述於例如Kath J.C., Exp. Opin. Ther. Patents, 10(6):803-818 (2000);Shawver L.K.,等人, Drug Discov. Today, 2(2): 50-63 (1997);及Lofts, F. J.及Gullick W.J.,「Growth factor receptors as targets.」, New Molecular Targets for Cancer Chemotherapy, Kerr D.J.及Workman P. (編者),(1994年6月27日), CRC Press中。生長因子受體抑制劑之非限制性實例包括帕唑帕尼(pazopanib)及索拉非尼(sorafenib)。
非生長因子受體激酶之酪胺酸激酶稱為非受體酪胺酸激酶。可用於本發明之非受體酪胺酸激酶(其為抗癌藥物之目標或潛在目標)包括cSrc、Lck、Fyn、Yes、Jak、cAbl、局部黏著斑激酶(FAK,Focal adhesion kinase)、布魯東氏酪胺酸激酶(Brutons tyrosine kinase)及Bcr-Abl。此類非受體激酶及抑制非受體酪胺酸激酶功能之藥劑描述於Sinha S.及Corey S.J., J. Hematother. Stem Cell Res., 8(5): 465-480 (2004)及Bolen, J.B., Brugge, J.S., Annu. Rev. Immunol., 15: 371-404 (1997)中。
SH2/SH3域阻斷劑為破壞各種酶或轉接蛋白(adaptor protein)中之SH2或SH3域結合的藥劑,該等酶或轉接蛋白包括PI3-K p85子單位、Src家族激酶、轉接分子(Shc、Crk、Nck、Grb2)及Ras-GAP。作為抗癌藥物之目標的SH2/SH3域論述於Smithgall T.E., J. Pharmacol. Toxicol. Methods, 34(3): 125-32 (1995)中。
絲胺酸/蘇胺酸激酶之抑制劑包括但不限於MAP激酶級聯阻斷劑,其包括Raf激酶(rafk)、促分裂原或細胞外調節激酶(MEK)及細胞外調節激酶(ERK)的阻斷劑;蛋白激酶C家族成員阻斷劑,包括以下的阻斷劑:PKC (α、β、γ、ε、μ、λ、ι、ζ);IkB激酶(IKKa、IKKb);PKB家族激酶;AKT激酶家族成員;TGF β受體激酶;及雷帕黴素之哺乳動物目標(mammaliam target of rapamycin,mTOR)抑制劑,包括但不限於雷帕黴素(FK506)及雷帕黴素類似物(rapalog)、RAD001或依維莫司(everolimus,AFINITOR®)、CCI-779或坦羅莫司(temsirolimus)、AP23573、AZD8055、WYE-354、WYE-600、WYE-687及Pp121。絲胺酸/蘇胺酸激酶之抑制劑的實例包括但不限於曲美替尼(trametinib)、達拉非尼(dabrafenib)及Akt抑制劑阿弗替布(afuresertib)及N-{(1S)-2-胺基-1-[(3,4-二氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-呋喃甲醯胺。
包括PI3-激酶、ATM、DNA-PK及Ku之阻斷劑的磷脂醯基肌醇3-激酶家族成員的抑制劑亦可用於本發明。此類激酶論述於Abraham R.T., Curr. Opin. Immunol., 8(3): 412-418 (1996);Canman C.E.,及Lim D.S., Oncogene, 17(25): 3301-3308 (1998);Jackson S.P., Int. J. Biochem. Cell Biol., 29(7): 935-938 (1997);及Zhong H.,等人, Cancer Res., 60(6): 1541-1545 (2000)中。
諸如磷脂酶C阻斷劑及肌-肌醇類似物的肌-肌醇信號傳導抑制劑亦可用於本發明。此類信號抑制劑描述於Powis G.及Kozikowski A.,「Inhibitors of Myo-Inositol Signaling.」, New Molecular Targets for Cancer Chemotherapy, Kerr D.J.及Workman P. (編者), (1994年6月27日), CRC Press中。
另一組信號轉導路徑抑制劑為Ras致癌基因之抑制劑。此類抑制劑包括以下的抑制劑:法呢基轉移酶(farnesyltransferase)、香葉基-香葉基轉移酶(geranyl-geranyl transferase)及CAAX蛋白酶,以及反義寡核苷酸、核酶及其他免疫療法。已展示此類抑制劑阻斷含有野生型突變ras之細胞中的ras活化,從而充當抗增生劑。Ras致癌基因抑制論述於Scharovsky O.G.,等人, J. Biomed. Sci., 7(4): 292-298 (2000);Ashby M.N., Curr. Opin. Lipidol., 9(2): 99-102 (1998);及Bennett C.F.及Cowsert L.M., Biochim. Biophys. Acta., 1489(1): 19-30 (1999)中。
對於受體激酶配位體結合之拮抗劑亦可充當信號轉導抑制劑。此組信號轉導路徑抑制劑包括對於受體酪胺酸激酶之細胞外配位體結合域使用人類化抗體或其他拮抗劑。對於受體激酶配位體結合之抗體或其他拮抗劑的實例包括但不限於西妥昔單抗(cetuximab,ERBITUX®)、曲妥珠單抗(trastuzumab,HERCEPTIN®);曲妥珠單抗恩他新(trastuzumab emtansine,KADCYLA®);帕妥珠單抗(pertuzumab,PERJETA®);包括拉帕替尼(lapatinib)、埃羅替尼(erlotinib)及吉非替尼(gefitinib)之ErbB抑制劑;及2C3 VEGFR2特異性抗體(參見Brekken R.A.,等人, Cancer Res., 60(18): 5117-5124 (2000))。
非受體激酶血管生成抑制劑亦可用於本發明中。血管生成相關之VEGFR及TIE2的抑制劑在上文關於信號轉導抑制劑加以論述(兩種受體均為受體酪胺酸激酶)。血管生成一般與erbB2/EGFR信號傳導有關,因為已展示erbB2及EGFR之抑制劑抑制血管生成,主要抑制VEGF表現。因此,非受體酪胺酸激酶抑制劑可與本發明之EGFR/erbB2抑制劑組合使用。例如,不識別VEGFR (受體酪胺酸激酶)但結合至配位體的抗VEGF抗體;將抑制血管生成之整合素(α
vβ
3)的小分子抑制劑;內皮生長抑素及血管生長抑素(非RTK)亦可證明可用於與所揭示之化合物組合。(參見Bruns C.J.等人, Cancer Res., 60(11): 2926-2935 (2000);Schreiber A.B.等人, Science, 232(4755): 1250-1253 (1986);Yen L.等人, Oncogene, 19(31): 3460-3469 (2000))。
免疫治療方案中所使用之藥劑亦可與本發明組合使用。存在多種免疫策略來產生針對erbB2或EGFR之免疫反應。此等策略一般在腫瘤疫苗接種之範圍中。免疫方法之功效可經由使用小分子抑制劑之erbB2/EGFR信號傳導路徑的組合抑制而大大增強。針對erbB2/EGFR之免疫/腫瘤疫苗方法之論述見於Reilly R.T.等人, Cancer Res., 60(13): 3569-3576 (2000);及Chen Y.等人, Cancer Res., 58(9): 1965-1971 (1998)中。
促凋亡方案中所使用之藥劑(例如,Bcl-2反義寡核苷酸)亦可用於本發明之組合中。蛋白之Bcl-2家族的成員阻斷細胞凋亡。因此,Bcl-2之上調與化學抗性有關。研究已展示,表皮生長因子(EGF)刺激Bcl-2家族之抗凋亡成員(亦即Mcl-1)。因此,經設計以下調腫瘤中Bcl-2之表現的策略已展現臨床益處。使用Bcl-2之反義寡核苷酸策略的此類促凋亡策略論述於Waters J.S.,等人, J. Clin. Oncol., 18(9): 1812-1823 (2000);及Kitada S.,等人, Antisense Res. Dev., 4(2): 71-79 (1994)中。
細胞週期信號傳導抑制劑抑制涉及細胞週期控制之分子。稱為週期素依賴性激酶(CDK)之蛋白激酶家族及其與稱為週期素之蛋白家族的相互作用控制真核細胞週期進展。不同週期素/CDK複合物之配位活化及不活化為細胞週期正常進展所必需。正在研發細胞週期信號傳導之若干抑制劑。例如,包括CDK2、CDK4及CDK6的週期素依賴性激酶的實例及其抑制劑描述於例如Rosania G.R.及Chang Y.T., Exp. Opin. Ther. Patents, 10(2): 215-230 (2000)中的。此外,p21WAF1/CIP1已描述為週期素依賴性激酶(Cdk)之強力且通用的抑制劑(Ball K.L., Prog. Cell Cycle Res., 3: 125-134 (1997))。已知誘導p21WAF1/CIP1之表現的化合物牽涉到遏止細胞增殖且具有腫瘤遏制活性(Richon V.M.,等人, Proc. Natl. Acad. Sci. USA, 97(18): 10014-10019 (2000)),且包括為細胞週期信號傳導抑制劑。組蛋白脫乙醯基酶(HDAC)抑制劑牽涉到p21WAF1/CIP1之轉錄活化(Vigushin D.M.及Coombes R.C., Anticancer Drugs, 13(1): 1-13 (2002)),且為用於本文組合之適合的細胞週期信號傳導抑制劑。此類HDAC抑制劑之實例包括但不限於伏立諾他(vorinostat)、羅米地辛(romidepsin)、帕比諾他(panobinostat)、丙戊酸及莫塞諾他(mocetinostat)。
蛋白酶體抑制劑為阻斷蛋白酶體作用之藥物,蛋白酶體為分解蛋白,如p53蛋白之細胞複合物。若干蛋白酶體抑制劑經出售或經研究用於治療癌症。適用於本文中之組合的蛋白酶體抑制劑包括但不限於硼替佐米(bortezomib)、二硫龍(disulfiram)、表沒食子兒茶素沒食子酸酯(epigallocatechin gallate)、鹽孢菌醯胺A (salinosporamide A)及卡非佐米(carfilzomib)。
70千道爾頓熱休克蛋白(Hsp70)及90千道爾頓熱休克蛋白(Hsp90)為普遍表現之熱休克蛋白家族。Hsp70及Hsp90某些癌症類型過度表現。在癌症治療中研究若干Hsp70及Hsp90抑制劑。用於本文中之組合之Hsp70及Hsp90抑制劑的實例包括但不限於坦螺旋黴素(tanespimycin)及根赤殼菌素(radicicol)。
許多腫瘤細胞展示與正常組織之代謝明顯不同的代謝。例如,糖酵解,即將葡糖轉化成丙酮酸酯之代謝過程的速率增加,且所產生之丙酮酸酯還原成乳酸酯,而非經由三羧酸(TCA)循環在粒線體中進一步氧化。此作用甚至在好氧條件下亦常可見,且已知為瓦爾堡作用(Warburg Effect)。
乳酸去氫酶A (LDH-A),即肌肉細胞中表現之乳酸去氫酶之同功異型物藉由進行將丙酮酸酯還原成乳酸酯在腫瘤細胞代謝中起關鍵作用,該乳酸酯隨後可自細胞輸出。已展示該酶在許多腫瘤類型中上調。瓦爾堡作用中所描述之葡糖代謝的改變對於癌細胞之生長及增殖係至關重要的,且使用RNA-i減弱LDH-A基因表現已展示使得異種移植模型中細胞增殖及腫瘤生長減少(Tennant D.A.,等人, Nat. Rev. Cancer, 10(4): 267-277 (2010);Fantin V.R.,等人, Cancer Cell, 9(6): 425-434 (2006))。
已在癌症前驅病變中發現高含量之脂肪酸合成酶(FAS)。FAS之藥理學抑制影響涉及癌症發展及維持兩者之關鍵致癌基因的表現。Alli P.M.等人, Oncogene, 24(1): 39-46 (2005)。
癌症代謝之抑制劑,包括LDH-A抑制劑及脂肪酸生物合成抑制劑(或FAS抑制劑)適用於本文中之組合。
癌症基因療法涉及使用病毒或非病毒基因遞送載體選擇性轉移重組DNA/RNA,以改變需要治療的癌症。癌症基因療法之實例包括但不限於自殺及溶瘤基因療法以及授受性T細胞療法。
如本文所使用,「免疫調節劑」係指包括影響免疫系統之單株抗體的任何物質。本發明之式(I)化合物或其前藥或其醫藥學上可接受之鹽可視為免疫調節劑。免疫調節劑可用作用於治療癌症之抗贅生劑。例如,免疫調節劑包括但不限於針對CTLA-4之抗體或其他拮抗劑,諸如伊派利單抗(ipilimumab,YERVOY®)及曲美單抗(tremelimumab);PD-1,諸如多斯利單抗(dostarlimab)、納武單抗(nivolumab,OPDIVO®)、帕博利珠單抗(pembrolizumab,KEYTRUDA®)及測米匹單抗(cemiplimab,LIBTAYO®);及TIM-3,諸如考波力單抗(cobolimab)。其他免疫調節劑包括但不限於針對PD-L1、OX-40、LAG3、TIM-3、41BB及GITR之抗體或其他拮抗劑。
如本文所使用,「PD-1拮抗劑」意謂任何化合物或生物分子,其阻斷癌細胞上表現之PD-L1與免疫細胞(T細胞、B細胞或NKT細胞)上表現之PD-1的結合且較佳亦阻斷癌細胞上表現之PD-L2與免疫細胞表現之PD-1的結合。PD-1及其配位體之替代名稱或同義詞包括:PD-1:PDCD1、PD1、CD279及SLEB2;PD-L1:PDCD1L1、PDL1、B7H1、B7-4、CD274及B7-H;及PD-L2:PDCD1L2、PDL2、B7-DC、Btdc及CD273。人類PD-1胺基酸序列可見於NCBI基因座第NP_005009號中。人類PD-L1及PD-L2胺基酸序列可分別見於NCBI基因座第NP_054862號及第NP_079515號中。
可用於本發明之態樣中之任一者的PD-1拮抗劑包括單株抗體(mAb)或其抗原結合片段,其特異性結合於PD-1或PD-L1,且較佳特異性結合於人類PD-1或人類PD-L1。mAb可為人類抗體、人類化抗體或嵌合抗體,且可包括人類恆定區。在一些實施例中,人類恆定區係選自由IgG1、IgG2、IgG3及IgG4恆定區組成之群,且在較佳實施例中,人類恆定區為IgG1或IgG4恆定區。在一些實施例中,抗原結合片段係選自由以下組成之群:Fab、Fab'-SH、F(ab')2、scFv及Fv片段。
結合於人類PD-1且可用於本發明之各種態樣及實施例之mAb的實例描述於美國專利第8,552,154號;美國專利第8,354,509號;美國專利第8,168,757號;美國專利第8,008,449號;美國專利第7,521,051號;美國專利第7,488,802號;WO2004072286;WO2004056875;及WO2004004771。
可用於本發明之態樣及實施例中之任一者的其他PD-1拮抗劑包括特異性結合於PD-1且較佳特異性結合於人類PD-1的免疫黏附素,例如含有融合至恆定區(諸如免疫球蛋白分子之Fc區)之PD-L1或PD-L2的細胞外或PD-1結合部分的融合蛋白。特異性結合於PD-1之免疫黏附素分子的實例描述於WO2010027827及WO2011066342中。可用作本發明之治療方法、藥劑及用途中之PD-1拮抗劑的特異性融合蛋白包括AMP-224 (亦稱為B7-DCIg),其為PD-L2-FC融合蛋白且結合於人類PD-1。
納武單抗為人類化單株抗PD-1抗體,其以OPDIVO®市售。納武單抗經指示用於治療一些不可切除性或轉移性黑色素瘤。納武單抗藉由其配位體PD-L1及PD-L2結合於PD-1 (Ig超家族跨膜蛋白)且阻斷PD-1之活化,產生T細胞活化及針對腫瘤細胞或病原體之細胞介導的免疫反應。經活化PD-1經由P13k/Akt路徑活化之遏制來負調節T細胞活化及效應功能。納武單抗之其他名稱包括:BMS-936558、MDX-1106及ONO-4538。納武單抗之胺基酸序列及使用及製造方法揭示於美國專利第US 8,008,449號中。
帕博利珠單抗為人類化單株抗PD-1抗體,其以KEYTRUDA®市售。帕博利珠單抗經指示用於治療一些不可切除性或轉移性黑色素瘤。帕博利珠單抗之胺基酸序列及使用方法揭示於美國專利第8,168,757號中。
抗PD-L1抗體及其製造方法為此項技術中已知的。針對PD-L1之此類抗體可為多株或單株及/或重組及/或人類化的。PD-L1抗體作為用於治療癌症之免疫調節藥劑在研發中。
例示性PD-L1抗體揭示於美國專利第9,212,224號;美國專利第8,779,108號;美國專利第8,552,154號;美國專利第8,383,796號;美國專利第8,217,149號;美國專利公開案第20110280877號;WO2013079174;及WO2013019906中。針對PD-L1 (亦稱為CD274或B7-H1)之額外例示性抗體及使用方法揭示於美國專利第8,168,179號;美國專利第7,943,743號;美國專利第7,595,048號;WO2014055897;WO2013019906;及WO2010077634中。可用作本發明之治療方法、藥劑及用途中之PD-1拮抗劑的特定抗人類PD-L1單株抗體包括MPDL3280A、BMS-936559、MEDI4736、MSB0010718C。
阿特珠單抗(Atezolizumab)為以TECENTRIQ®市售之完全人類化單株抗PD-L1抗體。阿特珠單抗經指示用於治療一些局部晚期或轉移性尿道上皮癌。阿特珠單抗阻斷PD-L1與PD-1及CD80之相互作用。其他例示性PD-L1抗體包括阿維魯單抗(avelumab,BAVENCIO®)及德瓦魯單抗(durvalumab,IMFINZI®)。
靶向PD-1或PD-L1以及另一目標之雙功能融合蛋白亦可用於本發明。Bintrafusp α,一種經設計以同時阻斷PD-L1及TGF-β路徑之雙功能融合蛋白揭示於美國專利第9,676,863號中。
CD134 (亦稱為OX40)為受體之TNFR-超家族的成員,不同於CD28,CD134並不組成性地表現於休止初始(naïve) T細胞上。OX40為二級協同刺激分子,在活化之後24至72小時之後表現;其配位體OX40L亦不表現於休止抗原呈現細胞上,但在其活化之後表現。OX40之表現視T細胞之完全活化而定;無CD28之情況下,OX40之表現延遲且低四倍之量。OX-40抗體、OX-40融合蛋白及其使用方法揭示於美國專利第US 7,504,101號;第US 7,758,852號;第US 7,858,765號;第US 7,550,140號;第US 7,960,515號;WO2012027328;WO2013028231中。
與所揭示之化合物組合使用或共同投與的一或多種其他活性成分(抗贅生劑)的額外實例為針對CD20、類視黃素之抗體或其他拮抗劑或其他激酶抑制劑。此類抗體或拮抗劑的實例包括但不限於利妥昔單抗(rituximab,RITUXAN®及MABTHERA®)、奧伐木單抗(ofatumumab,ARZERRA®)及貝沙羅汀(bexarotene,TARGRETIN®)。
與所揭示之化合物組合使用或共同投與的一或多種其他活性成分(抗贅生劑)的額外實例為鐸樣受體4 (Toll-like Receptor 4,TLR4)拮抗劑,其包括但不限於胺基烷基葡萄胺糖磷酸酯(aminoalkyl glucosaminide phosphates,AGP)。
已知AGP可用作用於刺激細胞介素產生、活化巨噬細胞、促進先天性免疫反應及加強免疫化動物中之抗體產生的疫苗佐劑及免疫刺激藥劑。AGP為TLR4之合成配位體。AGP及其經由TLR4之免疫調節作用揭示於專利公開案(諸如WO 2006016997、WO 2001090129及/或美國專利第6,113,918號)中且已報導於文獻中。額外AGP衍生物揭示於美國專利第7,129,219號、美國專利第6,911,434號及美國專利第6,525,028號中。某些AGP充當TLR4之促效劑,而其他AGP被識別為TLR4拮抗劑。
與所揭示之化合物組合使用或共同投與的一或多種其他活性成分(抗贅生劑)的額外非限制性實例為針對ICOS之抗體。
具有促效活性之人類ICOS鼠類抗體的CDR展示於PCT/EP2012/055735 (WO 2012131004)中。針對ICOS之抗體亦揭示於WO 2008137915、WO 2010056804、EP 1374902、EP1374901及EP1125585中。
與所揭示之化合物組合使用或共同投與的一或多種其他活性成分(抗贅生劑)的額外實例為聚ADP核糖聚合酶(PARP)抑制劑。此類抑制劑之非限制性實例包括尼拉帕尼(niraparib)、奧拉帕尼(olaparib)、盧卡帕尼(rucaparib)及拉唑帕尼(talazoparib)。
B細胞成熟抗原(BCMA)之正常功能係藉由轉導來自兩種已知配位體(來自TNF家族之B細胞活化因子(BAFF/BLyS)及增殖誘導配位體(APRIL)的信號來促進細胞存活。BCMA表現限於在分化後期階段之B細胞,其中在扁桃體、血漿母細胞及長期存活漿細胞中之生發中心B細胞上表現。BCMA在不同B細胞惡性病中表現,該等B細胞惡性病包括不同頻率的多發性骨髓瘤(MM)、瀰漫性大B細胞淋巴瘤(DLBCL)、大B細胞淋巴瘤(LBCL)、慢性淋巴球性白血病(CLL)及瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's Macroglobulinemia,WM)。BCMA之受限正常組織表現概況以及其MM及其他癌症中之上調及存活功能使其成為具有直接細胞殺滅活性之治療性抗體的引人注目的目標。BCMA抑制劑及其他靶向劑,諸如抗體藥物結合物可與本發明一起使用。貝蘭單抗馬佛多坦(Belantamab mafodotin),即抗BCMA抗體藥物結合物揭示於美國專利第9,273,141號中。
與所揭示之化合物組合使用或共同投與的一或多種其他活性成分(抗贅生劑)的額外非限制性實例為STING調節化合物、CD39抑制劑及A2a腺苷拮抗劑。
可與式(I)化合物或其前藥或其醫藥學上可接受之鹽組合使用的選擇性抗贅生劑包括但不限於:阿巴瑞克(abarelix)、阿貝力布(abemaciclib)、阿比特龍(abiraterone)、阿法替尼(afatinib)、阿柏西普(aflibercept)、阿多比欣(aldoxorubicin)、阿來替尼(alectinib)、阿侖單抗(alemtuzumab)、三氧化二砷、天冬醯胺酶、阿西替尼(axitinib)、AZD-9291、貝利司他(belinostat)、苯達莫司汀(bendamustine)、貝伐單抗(bevacizumab)、博納吐單抗(blinatumomab)、伯舒替尼(bosutinib)、本妥昔單抗維多汀(brentuximab vedotin)、卡巴他賽(cabazitaxel)、卡博替尼(cabozantinib)、卡培他濱(capecitabine)、塞利替尼(ceritinib)、氯法拉濱(clofarabine)、考比替尼(cobimetinib)、克卓替尼(crizotinib)、達雷木單抗(daratumumab)、達沙替尼(dasatinib)、地加瑞克(degarelix)、德諾單抗(denosumab)、迪奴圖單抗(dinutuximab)、多西他賽(docetaxel)、埃羅妥珠單抗(elotuzumab)、恩替諾特(entinostat)、恩雜魯胺(enzalutamide)、表阿黴素(epirubicin)、艾日布林(eribulin)、非格司亭(filgrastim)、氟西替尼(flumatinib)、氟維司群(fulvestrant)、呋喹替尼(fruquintinib)、吉妥單抗奧佐米星(gemtuzumab ozogamicin)、布突默單抗(ibritumomab)、依魯替尼(ibrutinib)、艾代拉里斯(idelalisib)、伊馬替尼(imatinib)、伊立替康(irinotecan)、伊沙匹隆(ixabepilone)、依薩佐米(ixazomib)、來那度胺(lenalidomide)、樂伐替尼(lenvatinib)、甲醯四氫葉酸(leucovorin)、甲基二(氯乙基)胺(mechlorethamine)、萊西單抗(necitumumab)、奈拉濱(nelarabine)、奈妥吡坦(netupitant)、尼羅替尼(nilotinib)、阿托珠單抗(obinutuzumab)、奧拉帕尼(olaparib)、奧馬他辛(omacetaxine)、奧希替尼(osimertinib)、奧沙利鉑(oxaliplatin)、太平洋紫杉醇(paclitaxel)、帕柏西利(palbociclib)、帕洛諾司瓊(palonosetron)、帕尼單抗(panitumumab)、派非格司亭(pegfilgrastim)、聚乙二醇化干擾素α-2b (peginterferon alfa-2b)、培美曲塞(pemetrexed)、普樂沙福(plerixafor)、泊利度胺(pomalidomide)、普納替尼(ponatinib)、普拉曲沙(pralatrexate)、奎紮替尼(quizartinib)、鐳-223、雷莫蘆單抗(ramucirumab)、瑞戈非尼(regorafenib)、羅拉吡坦(rolapitant)、盧卡帕尼(rucaparib)、西普亮塞-T (sipuleucel-T)、索尼得吉(sonidegib)、舒尼替尼(sunitinib)、塔里穆尼拉赫帕雷普韋克(talimogene laherparepvec)、替吡嘧啶(tipiracil)、拓朴替康(topotecan)、曲貝替定(trabectedin)、曲氟尿苷(trifluridine)、曲普瑞林(triptorelin)、尿苷、凡德他尼(vandetanib)、維拉帕尼(velaparib)、維羅非尼(vemurafenib)、維納妥拉(venetoclax)、長春新鹼(vincristine)、維莫德吉(vismodegib)及唑來膦酸(zoledronic acid)。較佳的抗贅生劑包括維納妥拉。
較佳的藥劑包括BCL2靶向劑,諸如維納妥拉;酪胺酸激酶抑制劑,諸如靶向FLT3突變之彼等抑制劑(吉列替尼(gilteritinib)及米哚妥林(midostaurin));音蝟(sonic hedgehog)抑制劑格拉德吉(glasdegib);IDH1或IHD2突變靶向劑,諸如艾伏尼布(ivosidenib)或艾那尼布(enasidenib);NEDD8靶向劑,諸如派伏司他(pevonedistat);HDAC抑制劑,諸如伏立諾他(vorinostat)或帕比諾他(panobinostat);靶向PRC2複合物之藥劑,諸如他澤司他(EZH2i)或MAK683 (EEDi);基於鉑之抗贅生劑,諸如順鉑;IO靶向劑,諸如抗CD47 (馬羅單抗(magrolimab))、TIM-3 (薩巴托利單抗(sabatolimab))、CTLA-4 (伊派利單抗(ipilimumab))及抗PD-1/PD-L1 (派姆單抗(pembrolizmab));以及P53靶向藥物。
在一個實施例中,所主張之本發明的癌症治療方法包括共同投與式(I)化合物及/或其前藥及/或其醫藥學上可接受之鹽及至少一種抗贅生劑,諸如選自由以下組成之群的一者:抗微管劑、鉑配位錯合物、烷基化劑、抗生素劑、拓樸異構酶II抑制劑、抗代謝物、拓樸異構酶I抑制劑、激素及激素類似物、信號轉導路徑抑制劑、非受體酪胺酸激酶血管生成抑制劑、免疫治療劑、促凋亡劑、細胞週期信號傳導抑制劑;蛋白酶體抑制劑;及癌症代謝抑制劑。
式(I)化合物或其前藥及其醫藥學上可接受之鹽可與已知可用於治療β血紅素病,諸如鐮狀細胞疾病、鐮狀細胞貧血及β地中海貧血的至少一種其他活性劑共同投與。
與本發明之組合組合使用或共同投與的一或多種其他活性成分的實例為羥基脲。
本發明之化合物使用習知的有機合成方法來製備。適合的合成途徑在下文描繪於以下通用反應流程中。所有起始材料均為市售可得的或容易由熟習此項技術者由市售可得的起始材料製備。
如本文所使用,此等製程、流程及實例中所用之符號及定則與當代科學文獻,例如美國化學協會期刊(
Journal of the American Chemical Society)或生物化學期刊(
Journal of Biological Chemistry)中所用之符號及定則一致。除非另外指出,否則標準單字母或三字母縮寫一般用於表示假定呈L-組態之胺基酸殘基。除非另外指出,否則所有起始材料均獲自商業供應商且不經進一步純化即使用。尤其,在實例中及整個說明書中可使用以下縮寫:
Ac (乙醯基);
Ac
2O (乙酸酐);
CH
3CN (乙腈);
Boc (三級丁氧基羰基);
Boc
2O (二碳酸二三級丁酯);
Cbz (苯甲氧基羰基);
DCE (1,2-二氯乙烷);
DCM (二氯甲烷);
ATP (三磷酸腺苷);
雙-頻哪醇基二硼(4,4,4',4',5,5,5',5'-八甲基-2,2'-二-1,3,2-二氧硼㖦);
BSA (牛血清白蛋白);
C18 (係指在HPLC固定相中矽上之18-碳烷基)
Cy (環己基);
DCM (二氯甲烷);
DIEA (二異丙基乙胺);
DIPEA (休尼格氏鹼(Hünig's base),
N-乙基-
N-(1-甲基乙基)-2-丙胺);
二㗁烷(1,4-二㗁烷);
DMAP (4-二甲胺基吡啶);
DME (1,2-二甲氧基乙烷);
DMEDA (
N,
N '-二甲基伸乙基二胺);
DMF (
N,
N-二甲基甲醯胺);
DMSO (二甲亞碸);
DPPA (二苯基磷醯基疊氮化物);
EDC (
N-(3-二甲基胺基丙基)-
N'乙基碳化二亞胺)鹽酸鹽;
EDTA (乙二胺四乙酸);
EtOAc (乙酸乙酯);
EtOH (乙醇);
Et
2O (乙醚);
HEPES (4-(2-羥乙基)-1-哌𠯤基乙烷磺酸);
HATU (六氟磷酸O-(7-氮雜苯并三唑-1-基)-
N,N,N',N'-四甲);
HOAt (1-羥基-7-氮雜苯并三唑);
HOBt (1-羥基苯并三唑);
HOAc (乙酸);
HPLC (高壓液相層析);
HMDS (六甲基二矽烷胺化物);
休尼格氏鹼(Hunig's Base) (
N,N-二異丙基乙胺);
IPA (異丙醇);
吲哚啉(2,3-二氫-1
H-吲哚);
KHMDS (六甲基二矽烷胺化鉀(potassium hexamethyldisilazide));
LAH (氫化鋰鋁);
LDA (二異丙胺基鋰);
LHMDS (六甲基二矽烷胺化鋰);
MeOH (甲醇);
MTBE (甲基三級丁基醚);
mcM (微莫耳);
mCPBA (間氯過苯甲酸);
NaHMDS (六甲基二矽烷胺化鈉);
NCS (N-氯丁二醯亞胺);
NBS (
N-溴丁二醯亞胺);
PE (石油醚);
Pd
2(dba)
3(參(二亞苯甲基丙酮)二鈀(0));
Pd(dppf)Cl
2.DCM錯合物([1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II).二氯甲烷錯合物);
PyBOP (六氟磷酸苯并三唑-1-基-氧基三吡咯啶鏻);
PyBrOP (六氟磷酸溴三吡咯啶鏻);
RPHPLC (逆相高壓液相層析);
RT (室溫);
Sat. (飽和);
SFC (超臨界流體層析);
SGC (矽膠層析);
SM (起始材料);
TLC (薄層層析);
TEA (三乙胺);
TEMPO (2,2,6,6-四甲基哌啶基1-氧基,游離基);
TFA (三氟乙酸);
THF (四氫呋喃);及
Ts-Cl (對甲苯磺醯氯)。
所有提及的醚係指乙醚且鹽水係指NaCl之飽和水性溶液。
合成流程熟習此項技術者應瞭解,若本文所描述之取代基與本文所描述之合成方法不相容,則該取代基可由對反應條件穩定之適合的保護基保護。保護基可在反應順序中之適合點移除,以得到所要中間物或目標化合物。適合保護基及使用此類適合保護基來對不同取代基進行保護及去保護的方法為熟習此項技術者所熟知;其實例可發現於T. Greene及P. Wuts,
Protecting Groups in Organic Synthesis(第4版), John Wiley & Sons, NY (2006)中。在一些情況下,取代基可特定選擇為在所用反應條件下具有反應性。在此等情形下,反應條件將所選擇之取代基轉化為可用作中間化合物或目標化合物中之所要取代基的另一取代基。
流程1中式
16的前藥視是否進行對掌性解析而定可為單一對映異構體或外消旋體。二氰基吡啶核心中間物
6可容易地由2-氰基乙醯胺
1製備。含有中間物之前藥可藉由以經取代之杏仁酸(諸如市售的4-羥基杏仁酸
7)作為起始材料來製備。可想像多種保護基情境以及脫離基將允許
7轉化成S
N2親電搭配物
13。
特定的本發明之化合物在實例部分中製備。
實例 實例 1 方法 A (
R)-(2-((3,5-
二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸 步驟 1 : 5-(4- 羥苯基 )-2,2- 二甲基 -1,3- 二氧戊環 -4- 酮 將2-羥基-2-(4-羥苯基)乙酸(1000 g,5.947莫耳)以及二氯甲烷(DCM) (5000 mL)饋入16 L JLR (容器A)且開始攪拌。隨後,向反應混合物中添加2,2-二甲氧基丙烷(2925 mL,23.8莫耳)。使反應混合物冷卻至0℃。當反應溫度達到0至5℃時,經由吸液管經2分鐘添加BF
3•OEt
2複合物(45.2 mL,0.357莫耳)。DCM用於完成添加。隨後,在0℃下攪拌反應混合物4小時。
向各別的反應容器(容器B)中添加5 L飽和NaHCO
3水性溶液且將容器之內部溫度設定為0℃。經由真空轉移將來自容器A之反應混合物添加至容器B中之飽和碳酸氫鈉溶液中。一旦添加完成,則攪拌懸浮液10分鐘,隨後升溫至20℃。將有機層分離至20 L 大容量排水瓶(carboy)。水層用額外的DCM (1.2 L)萃取且此有機層與在20 L 大容量排水瓶中之有機層合併。將經合併之有機層傳回至JLR且用鹽水(3 L)洗滌。再次分離有機層。次日,將DCM蒸餾至最小攪拌體積。剩餘反應混合物在旋轉式蒸發器上濃縮至乾燥。隨後,在真空下乾燥剩餘的灰白色固體以得到呈灰白色固體狀的5-(4-羥苯基)-2,2-二甲基-1,3-二氧戊環-4-酮(720 g,58.1%產率)。
1HNMR (400 MHz, CDCl
3) δ ppm 7.28 - 7.24 (m, 2H), 6.83 - 6.78 (m, 2H), 5.37 (s, 1H), 1.75 (s, 3H), 1.70 - 1.67 (m, 3H)。
步驟 2 : 甲磺酸 4-(2,2- 二甲基 -5- 側氧基 -1,3- 二氧戊環 -4- 基 ) 苯酯 將溶解於二氯甲烷(DCM) (4390 mL)中之5-(4-羥苯基)-2,2-二甲基-1,3-二氧戊環-4-酮(720.0 g,3458毫莫耳)的溶液饋入16 L JLR (容器A)且將反應混合物冷卻至0℃。隨後,經過約5分鐘經由加料漏斗將甲磺醯氯(323 mL,4150毫莫耳)添加至反應混合物;藉由用100 mL DCM沖洗加料漏斗至反應器中來完成轉移。使用加料漏斗經約43分鐘緩慢添加三乙胺(723 mL,5187毫莫耳);藉由用100 mL DCM沖洗加料漏斗至反應器中來完成轉移。在0℃下攪拌反應混合物2小時。
向各別的反應容器(容器B)中添加4390 mL飽和NaHCO
3水性溶液且將容器之內部溫度設定為0℃。將容器B置於減壓下以促進來自容器A之反應混合物緩慢真空轉移至容器B中。用300 mL DCM沖洗容器A且亦將此洗滌溶液轉移至容器B中。停止攪拌,且經由噴球(sprayball)將500 mL DI水添加至容器B中以徹底洗滌反應器壁。重新開始攪動且將內部溫度設定為20℃。在30分鐘之後暫停攪拌且使二相混合物在20℃下靜置隔夜。將內部溫度設定為10℃且將容器置於真空下。30分鐘後,將內部溫度升高至25℃。在隨後1.5小時中,體積減小至1.5與2 L之間,且釋放真空。將容器B中之有機層瀝乾且用DCM沖洗反應器以完成轉移。剩餘的有機層在旋轉式蒸發器上濃縮至乾燥且在高真空下進一步乾燥,以得到呈灰白色固體狀的甲磺酸4-(2,2-二甲基-5-側氧基-1,3-二氧戊環-4-基)苯酯(689.67 g,69.7%產率)。LCMS m/z = 304.2 [M+H
2O]
+。
1HNMR (400 MHz, CDCl
3) δ ppm 7.61 - 7.56 (m, 2H), 7.39 - 7.35 (m, 2H), 5.44 (s, 1H), 3.18 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H)。
步驟 3 : 甲磺酸 4-(2- 胺基 -1- 羥基 -2- 側氧基乙基 ) 苯酯 將甲磺酸4-(2,2-二甲基-5-側氧基-1,3-二氧戊環-4-基)苯酯(689.67 g,2409毫莫耳)以及甲醇(2400 mL)饋入16 L JLR且攪拌溶液。將夾套溫度設定為0℃。歷經47分鐘向反應混合物中添加氨於MeOH (7M)中的溶液(1377 mL,9636毫莫耳)。在相同溫度下攪拌反應混合物7.5小時之後,隨後使夾套溫度升溫至10℃。添加額外250 mL (1750毫莫耳)含7 M氨之甲醇且在相同溫度下攪拌反應混合物16.5小時。隨後,經由盤形過濾器過濾反應混合物。所收集之固體用額外甲醇洗滌且乾燥,以得到呈白色固體狀的甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯(544.86 g,92%產率)。LCMS m/z = 268.1 [M+Na]
+。
1HNMR (400 MHz, DMSO-d
6) δ ppm 7.64 - 7.54 (m, 3H), 7.40 - 7.32 (m, 3H), 6.29 (d,
J= 4.4 Hz, 1H), 5.03 (d,
J= 4.4 Hz, 1H), 3.38 (s, 3H)。
步驟 4 : 甲磺酸 4-(2- 胺基 -1-(( 甲磺醯基 ) 氧基 )-2- 側氧基乙基 ) 苯酯 將甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯(545 g,2222毫莫耳)及二氯甲烷(DCM) (4331 mL)饋入16 L JLR (容器A)。開始攪拌,且將夾套溫度設定為0℃。25分鐘後,向反應混合物中添加甲磺醯氯(216 mL,2778毫莫耳)。隨後,經35分鐘經由加料漏斗緩慢添加三乙胺(465 mL,3333毫莫耳)。在添加完成之後,使夾套溫度經40分鐘升高至20℃。使反應混合物在相同溫度下攪拌19小時,但仍殘留起始材料。將夾套溫度重設至0℃。將額外甲磺醯氯(30 mL,385.8毫莫耳)與70 mL DCM一起添加至反應混合物以完成添加。隨後,添加額外量之三乙胺(70 mL,501.7毫莫耳)。添加完成時,將夾套溫度設定為22℃且攪拌反應混合物1小時。
將飽和碳酸氫鈉水性溶液(2166 mL)饋入各別的反應容器(容器B)且夾套溫度設定為0℃。以控制放熱及氣體散展的速率將來自容器A之反應混合物真空轉移至容器B。在轉移完成後,經30分鐘使夾套溫度升高至20℃,且在此溫度下再攪拌反應混合物30分鐘。隨後,經由盤形過濾器過濾反應混合物。所收集之固體材料用水(550 mL)洗滌且在真空下在盤形過濾器中乾燥隔夜。隨後,固體在真空烘箱中在45℃下進一步乾燥隔夜,以得到呈白色固體狀的甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(530.36 g,73.8%產率)。LCMS m/z = 346.1 [M+Na]
+。
1HNMR (400 MHz, DMSO-d
6) δ ppm 7.88 (s, 1H), 7.63 - 7.58 (m, 2H), 7.45 - 7.41 (m, 2H), 5.92 (s, 1H), 3.42 (s, 3H), 3.27 (s, 3H)。
步驟 5 : 甲磺酸 4-(2-(( 雙 ( 苯甲氧基 ) 磷醯基 ) 胺基 )-1-(( 甲磺醯基 ) 氧基 )-2- 側氧基乙基 ) 苯酯 在內部溫度設定為-5℃之情況下,將8 L四氫呋喃(THF)饋入16 L JLR (容器A)且開始攪拌。隨後,經由粉末加料漏斗向反應容器中饋入氫化鈉(60重量%) (203.45 g,5.087莫耳)。用1 L THF沖洗容器及漏斗至反應器中以完成轉移。經由粉末加料漏斗向反應混合物中添加焦磷酸四苯甲酯(1471 g,2.732莫耳)。用0.5 L THF沖洗容器及漏斗至反應器中以完成轉移。將反應溫度設定為-3℃且將額外2.5 L THF添加至反應混合物中。經30分鐘分7份向反應混合物中添加甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(736 g,2276莫耳),同時在添加之間使反應混合物洩氣(venting)。藉由用使反應器中之總THF變為15 L之額外的THF (3 L)沖洗二甲磺酸酯容器來完成添加。將攪拌提高至300 rpm且經30分鐘使反應夾套升溫至25℃。隨後,在相同溫度下攪拌反應混合物2小時。
反應物分2份淬滅。在內部溫度設定為0℃之情況下,向各別的反應容器(容器B)中添加6 L飽和檸檬酸溶液。經30分鐘向容器B中之此溶液中添加來自容器A之8.5 L反應混合物。在添加期間,將容器B之夾套溫度調節至-15℃。添加完成時,使容器B之夾套溫度升高至10℃。在10℃下攪拌1小時之後,經由盤形過濾器過濾混合物(使用兩種鯊魚皮過濾紙)。在容器B完全瀝乾之後,第二次向其中饋入6 L飽和檸檬酸溶液且將溫度調節至-15℃。藉由經35分鐘將來自容器A之剩餘反應混合物添加至容器B來重複淬滅程序。將容器B溫度再次調節至10℃。用500 mL THF沖洗容器A且將此沖洗液添加至容器B中。將容器B之夾套溫度調節至25℃且使混合物保持在相同溫度下25分鐘。反應混合物經由先前所用之相同盤形過濾器過濾。將三級丁基甲基醚(TBME)添加至盤形過濾器中以輔助過濾,但所提供改良很小,甚至沒有。在50分鐘之後,經由真空轉移將盤形過濾器中之材料轉移回至反應器容器中。將TBME (8 L)添加至反應器中且混合物再次經由盤形過濾器過濾。隨著過濾進行,固體混合物變成糊狀物且需要刮下以促進該過程。1.5小時後,已將來自容器之所有內含物添加至盤形過濾器,且用額外1.5 L TBME沖洗反應器容器。將此沖洗液添加至盤形過濾器中且使過濾靜置隔夜。在真空過濾隔夜之後,將經分離之固體轉移至玻璃乾燥托盤。將托盤置於25℃下之真空烘箱中隔夜。
在真空烘箱中乾燥隔夜之後,將固體材料轉移至12 L 3頸燒瓶且懸浮於8 L水中。使用頂置式機械攪拌器劇烈混合混合物1小時,且隨後經由配備有3層鯊魚皮濾紙之不鏽鋼盤形過濾器過濾。使用額外2 L水完成轉移。用2 L水,隨後用4 L TBME洗滌濾餅兩次。隨後,固體在真空下在盤形過濾器中乾燥隔夜。將固體自盤形過濾器轉移至兩個烤盤(baking dish)且在氮氣滲出而不加熱之情況下,在真空烘箱中進一步乾燥約48小時。合併固體,以得到呈白色固體狀的甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(1060 g,80%)。LCMS m/z = 584.3 [M+H]
+。
1HNMR (400 MHz, DMSO-d
6) δ ppm 10.51 (d,
J= 9.4 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.48 - 7.43 (m, 2H), 7.41 - 7.31 (m, 8H), 7.28 - 7.23 (m, 2H), 6.11 (s, 1H), 5.10 - 4.85 (m, 4H), 3.41 (s, 3H), 3.29 (s, 3H)。
步驟 6 : 3,5- 二氰基 -4- 乙基 -6- 羥基吡啶 -2- 醇銨 向冷卻至0℃的2-氰基乙醯胺(300 g,3.571莫耳)及氨(25重量%於水中,618 mL,7.142莫耳)於水(750 mL)中的經攪拌溶液中逐滴添加丙醛(128 mL,1.785莫耳)。在室溫下攪拌反應混合物3小時。藉由過濾收集經沈澱固體,用冰冷水(2 x 500 mL),接著用冷甲醇(300 mL)洗滌且乾燥,以得到呈灰白色固體狀的3,5-二氰基-4-乙基-6-羥基吡啶-2-醇銨(150 g,39%)。LCMS m/z = 188.0 [M-H]
-。
1H NMR (400 MHz, DMSO-d
6) δ ppm 10.35 (s, 1H), 7.1 (br s, 4H), 2.48 (q,
J= 7.6 Hz, 2H), 1.17 (t,
J= 7.6 Hz, 3H)。
步驟 7 : 2,6- 二氯 -4- 乙基吡啶 -3,5- 二甲腈 向冷卻至0℃之於POCl
3(750 mL,8046毫莫耳)中之3,5-二氰基-4-乙基-6-羥基吡啶-2-醇銨(150 g,697毫莫耳)的經攪拌懸浮液中逐滴添加N,N-二甲基苯胺(150 mL,1601毫莫耳)。在120℃下加熱反應混合物6小時。藉由TLC (TLC系統10% EtOAc於己烷中,Rf:0.6,偵測:UV)監測反應進程。在減壓下濃縮反應混合物,獲得粗材料。用冰冷的水稀釋粗材料且攪拌10分鐘。藉由過濾收集所沈澱之固體且乾燥。將固體溶解於二氯甲烷(2 L)中,用飽和碳酸氫鈉溶液(1 L)、水(1.5 L)及鹽水溶液(1 L)洗滌。有機層經無水Na
2SO
4乾燥,過濾且在減壓下濃縮,以得到黃色固體。固體材料用乙醚(500 mL)濕磨,過濾且乾燥,以得到呈黃色固體狀的2,6-二氯-4-乙基吡啶-3,5-二甲腈(130 g,571毫莫耳,82%產率)。LCMS m/z = 224.1 [M-H]
-。
1H NMR (400 MHz, CDCl
3) δ ppm 3.13 (q,
J= 7.6 Hz, 2H), 1.42 (t,
J= 7.6 Hz, 3H)。
步驟 8 : 2-( 二甲胺基 )-4- 乙基 -6- 巰基吡啶 -3,5- 二甲腈 將2,6-二氯-4-乙基吡啶-3,5-二甲腈(130.0 g,575毫莫耳)及DMF (1300 mL)饋入具有頂置式攪拌及溫度探針之3 L三頸燒瓶,且將其攪拌以形成淡紅色溶液。將反應燒瓶置於冰浴中且攪拌溶液直至內部溫度達到約3℃。經由加料漏斗以使得內部溫度保持< 5℃之速率添加二甲胺於THF中之溶液(288 mL,575毫莫耳)。逐滴添加三乙胺(80 mL,575毫莫耳),維持內部溫度< 7℃。在三乙胺添加快結束時,混合物變為深紫色。添加硫代乙酸鉀(164 g,1438毫莫耳)且移除冷卻浴。在室溫下攪拌混合物2小時且倒入冷的1 N HCl溶液(1150 mL,1150毫莫耳)及水(2600 mL)的混合物中。將混合物攪拌約30分鐘且藉由過濾收集經沈澱之固體。濾餅用若干份水(總計1 L)洗滌且在布赫納漏斗(Buchner funnel)上乾燥隔夜。將橙色固體轉移至具有頂置式攪拌的3 L 3頸燒瓶中。饋入乙酸乙酯(1200 mL)且攪拌漿液約30分鐘。藉由過濾收集固體。將餅用200 mL EtOAc漿化且在布赫納漏斗上抽乾燥。再重複漿化/乾燥兩次,得到呈亮黃色固體狀的2-(二甲胺基)-4-乙基-6-巰基吡啶-3,5-二甲腈(115.57 g,87%產率)。LCMS m/z = 233.0 [M+H]
+。
1HNMR: (400 MHz, DMSO-d
6) δ ppm 14.05 - 9.86 (m, 1H), 3.29 (s, 6H), 2.68 (q,
J= 7.3 Hz, 2H), 1.21 (t,
J= 7.6 Hz, 3H)。
步驟 9 : 甲磺酸 4-(2-(( 雙 ( 苯甲氧基 ) 磷醯基 ) 胺基 )-1-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2- 側氧基乙基 ) 苯酯 向16 L JLR中添加二氯甲烷(8 L)、甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(966 g,1.655莫耳)、2-(二甲胺基)-4-乙基-6-巰基吡啶-3,5-二甲腈(381 g,1.640莫耳)及二氯甲烷(8 L)。使反應混合物冷卻至5℃。經由加料漏斗歷經21分鐘向反應混合物中添加三乙胺(174 g,1.722莫耳),同時維持反應溫度在3.3與4.9℃之間。使反應混合物保持在5℃下5分鐘,隨後升溫至室溫。在室溫下30分鐘之後,反應完成。將水(6 L)歷經6分鐘添加至反應混合物中。隨後,添加額外1 L水且攪拌反應混合物13分鐘。讓各層分離且使用內聯(inline)過濾器將有機層轉移至20 L 大容量排水瓶(carboy)。用500 mL二氯甲烷洗滌水層,且分離各層。此有機層與20 L 大容量排水瓶中之原始有機層合併。將經合併之有機層在減壓下在20 L圓底燒瓶中使用旋轉蒸發器(rotovap)濃縮。所得之泡沫狀/膠狀半固體用6 L甲醇處理且在旋轉蒸發槽中,在50℃下無真空下旋轉20分鐘。在旋轉蒸發器上旋轉燒瓶的期間,開始出現淡黃色固體。將燒瓶自旋轉蒸發器移除且使混合物冷卻至室溫隔夜。次日早晨,使用配備有3層鯊魚皮濾紙之不鏽鋼盤形過濾器來過濾混合物。使用甲醇(1 L)促進轉移。用甲醇(2 L)沖洗濾餅兩次。固體在真空下在盤形過濾器中藉由在固體上方抽動空氣,隨後利用氮氣隔夜來乾燥。次晨,固體用3 L之2:1乙醚/乙酸乙酯溶劑混合物洗滌且乾燥,以得到呈棕色固體狀的甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(963 g,82%)。LCMS m/z = 720.3 [M+H]
+。
1HNMR: (400 MHz, DMSO-d
6) δ ppm 10.62 - 10.52 (m, 1H), 7.63 - 7.57 (m, 2H), 7.43 - 7.38 (m, 2H), 7.36 - 7.27 (m, 8H), 7.26 - 7.20 (m, 2H), 5.82 (s, 1H), 5.11 - 4.84 (m, 4H), 3.40 (s, 3H), 3.27 (s, 6H), 2.77 (q,
J= 7.6 Hz, 2H), 1.22 (t,
J= 7.6 Hz, 3H)。
步驟 10 : (R)- 甲磺酸 4-(2-(( 雙 ( 苯甲氧基 ) 磷醯基 ) 胺基 )-1-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2- 側氧基乙基 ) 苯酯 將甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(1 kg)溶解於乙腈:甲醇之90:10混合物中(120 g份溶解於2 L 90:10乙腈:甲醇中)。經由玻璃纖維紙過濾材料且在Varian Prep HPLC,Chiralpak AS 20 u 77x250mm管柱上使用等度95:5-CH
3CN:CH
3OH (50 mM NH
4OAc)方法純化(解析),以獲得所要E2 (
R)-對映異構體。標準注射為於150 mL移動相中9 g甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯。使用此方法加工1000 g外消旋體之後,獲得呈淺棕色固體狀的所要E2 (
R)-對映異構體,其具有99.73%化學純度(0.17% E1對映異構體;0.1%雜質)。在20 L Buchii燒瓶中將材料分離為具有殘餘溶劑之含有深褐色/黑色條紋的固體。將乙醚(1.5 L)添加至此材料且用大刮勺(spatula)將固體自燒瓶壁刮下。將燒瓶旋動以產生懸浮於黑色醚層中之灰白色固體。藉由過濾使用不鏽鋼盤形過濾器收集固體。將Buchii燒瓶用濾液沖洗3次,以便儘可能多地轉移來自燒瓶之所要的對映異構體。將所得濾液濃縮至乾燥且使剩餘殘餘物懸浮於乙醚(500 mL)中,以產生第二批所要的對映異構體。藉由在已含有第一批之相同盤形過濾器中過濾收集此固體。經合併之固體用額外乙醚(1 L)洗滌,隨後使其在真空下乾燥隔夜,以得到呈淺灰色固體狀的(
R)-甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(296.4 g,67.6%產率)。LCMS m/z = 720.3 [M+H]
+。
1HNMR (400 MHz, DMSO-d
6) δ ppm 10.57 (d,
J= 10.8 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.43 - 7.38 (m, 2H), 7.34 - 7.27 (m, 8H), 7.25 - 7.20 (m, 2H), 5.82 (s, 1H), 5.10 - 4.84 (m, 4H), 3.39 (s, 3H), 3.26 (s, 6H), 2.76 (q,
J= 7.6 Hz, 2H), 1.21 (t,
J= 7.6 Hz, 3H)。對掌性HPLC:99.6% (
R)-對映異構體。
步驟 11 : (
R)-(2-((3,5-
二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸 將(
R)-甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(200.0 g,278毫莫耳)及二氯甲烷(2000 mL)饋入配備有機械頂置式攪拌器的12 L 3頸圓底燒瓶,以得到均勻的橙色溶液。在室溫下,經50分鐘經由加料漏斗向此溶液中逐滴添加碘基三甲基矽烷(122 g,611毫莫耳)於二氯甲烷(200 mL)中之溶液。在添加碘基三甲基矽烷後攪拌25分鐘之後,等分試樣淬滅至MeOH/MeCN中的LCMS分析指示所要產物加4%單苯甲基磷酸酯。添加額外的碘基三甲基矽烷(1.660 mL,12.19毫莫耳),且將淡橙色懸浮液攪拌20分鐘。總共攪拌2小時後,經28分鐘經由加料漏斗逐滴添加甲醇(200 mL,4946毫莫耳)。添加額外200 mL二氯甲烷,且繼續攪拌。需要用200 mL二氯甲烷進一步稀釋以輔助攪拌。繼續攪拌15分鐘,隨後添加額外200 mL二氯甲烷(總二氯甲烷為2800 mL)。在甲醇添加完成之後,將混合物機械攪拌2小時及45分鐘。將懸浮液分開且經由裝配有聚乙烯燒結碟(fritted disc)之6個一次性聚丙烯過濾漏斗過濾。用二氯甲烷反覆地沖洗固體,直至在濾液中不存在紅色/粉色。所收集之白色固體在真空下在漏斗中乾燥,轉移至單一研缽(mortar),且緩慢研磨成精細自由流動之白色粉末。將固體置於真空烘箱中14小時,不加熱,以得到呈白色固體狀的(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸(123.4 g, 82%)。LCMS m/z = 540.0 [M+H]
+。
1H NMR (500 MHz, DMSO-d
6) δ ppm 11.55 (br s, 2H), 9.74 (br d,
J= 9.3 Hz, 1H), 7.61 (d,
J= 8.7 Hz, 2H), 7.39 (d,
J= 8.7 Hz, 2H), 5.79 (br s, 1H), 3.41 (s, 3H), 3.36 (s, 6H), 2.75 (q,
J= 7.6 Hz, 2H), 1.20 (t,
J= 7.6 Hz, 3H)。對掌性HPLC:98.9% (
R)-對映異構體。
實例1之游離酸母體的X射線粉末繞射(XRPD)圖案示於圖7,且在下表III中給出繞射角及晶格面距的概述。
表III 實例1游離酸母體之XRPD繞射角及晶格面距概述
峰 # | 繞射角 [°2θ] | 晶格面距 [Å] |
1 | 3.35 | 26.3903 |
2 | 6.64 | 13.3063 |
3 | 9.93 | 8.9008 |
4 | 10.28 | 8.5977 |
5 | 11.77 | 7.5142 |
6 | 13.22 | 6.6910 |
7 | 13.91 | 6.3629 |
8 | 16.56 | 5.3477 |
9 | 18.39 | 4.8217 |
10 | 19.19 | 4.6219 |
11 | 19.47 | 4.5551 |
12 | 19.74 | 4.4940 |
13 | 20.61 | 4.3065 |
14 | 20.78 | 4.2722 |
15 | 21.76 | 4.0808 |
16 | 22.18 | 4.0049 |
17 | 22.71 | 3.9118 |
18 | 23.03 | 3.8586 |
19 | 23.20 | 3.8311 |
20 | 23.58 | 3.7696 |
21 | 24.72 | 3.5988 |
22 | 25.24 | 3.5261 |
23 | 26.86 | 3.3168 |
24 | 27.39 | 3.2533 |
25 | 28.43 | 3.1370 |
26 | 29.06 | 3.0699 |
27 | 29.55 | 3.0206 |
28 | 30.05 | 2.9714 |
29 | 31.05 | 2.8777 |
30 | 32.22 | 2.7758 |
31 | 33.49 | 2.6734 |
32 | 34.80 | 2.5762 |
33 | 36.02 | 2.4917 |
此游離酸母體材料之差示掃描熱量測定(DSC)熱分析圖與先前DSC設備相同,且示於圖8。使用以10℃/分鐘之加熱速率加熱至最終溫度300℃在略有波紋的鋁盤中進行實驗。此化合物在DSC中具有簡單的單次熔融事件,其中起始溫度為166.6℃,峰值溫度為173.8℃且熔融焓為68 J/g,之後在高於200℃下熱分解。在分解事件之前,化合物藉由TGA損失展現可忽略的重量損失。熟習此項技術者將認識到,吸熱之起始溫度、峰值溫度及焓可視實驗條件而變化。
此游離酸母體材料之熱解重量分析(TGA)熱分析圖與先前TGA設備相同,且示於圖9。在N
2吹掃下及使用以10℃/分鐘之加熱速率加熱至最終溫度200℃在敞口鋁盤中進行實驗。在分解事件之前,化合物在190℃下展現1.3%重量損失。
方法 B ( 經由對映選擇性途徑 ) (
R)-(2-((3,5-
二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸 步驟 1 : (
S)-
甲磺酸 4-(2-(( 雙 ( 苯甲氧基 ) 磷醯基 ) 胺基 )-1-(( 甲磺醯基 ) 氧基 )-2- 側氧基乙基 ) 苯酯 用熱風槍加熱500 mL圓底燒瓶約5分鐘,同時用氮氣吹掃。冷卻至室溫後,將NaH (於礦物油中60%分散液,1.089 g,27.2毫莫耳)及THF (120 mL)饋入燒瓶。將混合物冷卻至0℃且添加二磷酸四苯甲酯(7.99 g,14.85毫莫耳),接著經約3分鐘逐份添加(
S)-甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(4.0 g,12.37毫莫耳)。在0℃下在氮氣氣球(balloon)下攪拌反應混合物。在0℃下在2小時之後,LCMS分析展示無剩餘起始材料。將反應混合物小心地倒入10%檸檬酸水溶液(200 mL)中且劇烈攪拌。藉由過濾收集所得沈澱物,用水(3 x 50 mL),接著用Et
2O (3 x 50 mL)沖洗,且在高真空下乾燥至恆重,以得到呈白色固體狀的(
S)-甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(6.57 g,11.26毫莫耳,產率91%)。LCMS m/z = 584.0 [M+H]
+。
1H NMR (400 MHz, DMSO-d
6) δ 10.48 (br s, 1H), 7.69 - 7.57 (m, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.22 (m, 10H), 6.11 (s, 1H), 5.13 - 4.96 (m, 3H), 4.96 - 4.88 (m, 1H), 3.40 (s, 3H), 3.28 (s, 3H)。對掌性SFC:100% ee。
步驟 2 : (
R)-
甲磺酸 4-(2-(( 雙 ( 苯甲氧基 ) 磷醯基 ) 胺基 )-1-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2- 側氧基乙基 ) 苯酯 在0℃下,向2-(二甲胺基)-4-乙基-6-巰基吡啶-3,5-二甲腈(480 mg,2.066毫莫耳)於THF (20 mL)中之溶液中添加NaH (83 mg,2.066毫莫耳)。在0℃下攪拌所得混合物30分鐘,隨後在0℃下逐滴添加至(
S)-甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(1266 mg,2.170毫莫耳)於DCM (1 mL)中之溶液中。使混合物升溫至室溫,攪拌1小時且用氯化銨淬滅。水層用DCM萃取且經硫酸鈉乾燥。用MeOH濕磨殘餘物,以得到呈灰白色固體狀的(
R)-甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(908 mg,1.198毫莫耳,58%產率)。LCMS m/z = 720.2 [M+H]
+。
1H NMR (400 MHz, DMSO-d
6) δ 10.56 (d,
J= 10.8 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.48 - 7.39 (m, 2H), 7.37 - 7.29 (m, 8H), 7.29 - 7.23 (m, 2H), 5.81 (s, 1H), 5.09 - 4.86 (m, 4H), 3.39 (s, 3H), 3.27 (s, 6H), 2.76 (q,
J= 7.6 Hz, 2H), 1.21 (t,
J= 7.6 Hz, 3H),混雜有約25%起始甲磺酸酯。對掌性HPLC:99.3% ee。
方法 C ( 甘胺酸鹽之對映選擇性合成 ) (
R)-(2-((3,5-
二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸甘胺酸鹽 步驟 1 : (S)- 甲磺酸 4-(2- 胺基 -1- 羥基 -2- 側氧基乙基 ) 苯酯 將H
2O (400 mL),隨後2,2-雙(羥乙基)-(亞胺基參)-(羥甲基)-甲烷(10.8 g,51.4毫莫耳)饋入配備有頂置式攪拌的1 L JLR,且在夾套溫度設定為20℃之情況下攪拌3分鐘。隨後,將由β-菸鹼醯胺腺嘌呤二核苷酸磷酸二鈉鹽(NADP+,二鈉) (500 mg)、酮還原酶(1.50 g)及H
2O (15 mL)製成之溶液饋入JLR且攪拌所得溶液5分鐘。添加甲磺酸4-(2-胺基-2-側氧乙醯基)苯酯(50.0 g,206毫莫耳)、H
2O (100 mL),隨後添加異丙醇(63.4 mL,822毫莫耳)且將反應物加熱至30℃。在攪拌24小時之後,將反應物冷卻至0℃且添加1 N NaOH水性溶液(25.0 mL)。將所得漿液在0℃下保持23小時,隨後藉由真空過濾過濾出所沈澱之固體。經分離之固體用H
2O洗滌兩次(每次用250 mL洗滌),隨後用三級丁基甲基醚(250 mL)洗滌。在真空下乾燥之後,所要產物(S)-甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯分離為白色至灰白色固體(45.0 g,184毫莫耳,89%產率)。
LCMS m/z = 246.0 [M+H]
+。
1H NMR: (400 MHz, DMSO-d6) δ ppm 7.54 - 7.49 (m, 2H), 7.42 (br s, 1H), 7.33 - 7.28 (m, 2H), 7.21 (br s, 1H), 6.13 (d, J = 4.9 Hz, 1H), 4.89 (d, J = 4.9 Hz, 1H), 3.37 (s, 3H)。對掌性HPLC:>99% ee。
步驟 2 : (S)- 甲磺酸 4-(2- 胺基 -1-(( 甲磺醯基 ) 氧基 )-2- 側氧基乙基 ) 苯酯 將(S)-甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯(2.57 g,10.5毫莫耳)及N,N-二甲基乙醯胺(10.3 mL)饋入配備有頂置式攪拌的100 mL JLR且在夾套溫度設定為20℃之情況下攪拌。隨後,添加1-甲基咪唑(1.51 g,18.4毫莫耳)且使反應物冷卻至0℃。向黃色溶液中緩慢添加作為於N,N-二甲基乙醯胺(5.12 mL)中之溶液的甲磺酸酐(2.56 g,14.7毫莫耳),同時保持反應溫度<5℃。隨後,使反應物升溫至20℃且在該溫度下攪拌21小時。完成後,將反應物冷卻至0℃,藉由歷經1小時添加H
2O (26 mL),隨後歷經2小時添加5%硫酸鈉水性溶液(51.5 mL)淬滅。攪拌所得漿液20小時,隨後藉由真空過濾收集固體。經分離之固體用H
2O洗滌兩次(每次用25 mL洗滌),隨後用三級丁基甲基醚洗滌兩次(每次用15 mL洗滌)。在真空下乾燥之後,所要產物(S)-甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯分離為白色固體(3.14 g,9.71毫莫耳,93%產率)。
LCMS m/z = 324.0 [M+H]
+。
1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (s, 1H), 7.63 - 7.54 (m, 3H), 7.41 (d, J = 7.8 Hz, 2H), 5.91 (s, 1H), 3.41 (s, 3H), 3.26 (s, 3H)。
步驟 3 : (S)- 甲磺酸 4-(2-(( 二甲氧基磷醯基 ) 胺基 )-1-(( 甲磺醯基 ) 氧基 )-2- 側氧基乙基 ) 苯酯 將四氫呋喃(200 ml)、接著將(S)-甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(40 g,124毫莫耳)饋入配備有頂置式攪拌之經氮氣沖洗的1 L JLR,隨後在夾套溫度設定為20℃之情況下攪拌約5分鐘。隨後,使漿液冷卻至0℃且將氯-二甲基磷酸酯(20 mL,186毫莫耳)饋入容器。在攪拌1小時之後,緩慢添加三級丁醇鋰於四氫呋喃(272 mL,272毫莫耳)中之1 M溶液,同時保持反應溫度<5℃。將反應物攪拌約1小時且經由HPLC分析確定為未完成的。將額外的氯-二甲基磷酸酯(6.3 mL,58毫莫耳)饋入反應物中,接著緩慢添加三級丁醇鋰於四氫呋喃(37.1 mL,37.1毫莫耳)中之1 M溶液。攪拌反應物30分鐘,隨後經由緩慢添加10%檸檬酸水性溶液(w/w,40 mL)淬滅,同時保持反應溫度<5℃。攪拌反應物約15分鐘,隨後饋入額外的10%檸檬酸水性溶液(w/w,80 mL),同時保持反應溫度<5℃。使溫度升高至20℃且在該溫度下保持約30分鐘。隨後,使反應混合物冷卻至0℃且保持大約14小時。經由真空蒸餾將反應物濃縮至約300 mL總體積。將異丙醇(380 mL)饋入反應物且在20℃下攪拌反應物2小時。經由真空蒸餾將反應物濃縮至約520 mL總體積,隨後添加H
2O (80 mL)及異丙醇(80 mL),且將反應物冷卻至0℃。在攪拌19小時之後,將產物漿液轉移至過濾乾燥器中。使用氮氣壓力過濾掉母液。用H
2O (400 mL)沖洗反應器,隨後轉移至過濾乾燥器以洗滌經分離之固體。氮氣壓力用於推動洗滌產物濾餅。用異丙醇(400 mL)沖洗反應器,隨後轉移至過濾乾燥器以洗滌經分離之固體。氮氣壓力用於推動洗滌產物濾餅。隨後,用三級丁基甲基醚(200 ml)洗滌產物固體。經分離之固體在氮氣下乾燥23小時,隨後在20℃下真空乾燥21小時,以得到呈白色固體狀的所要產物(S)-甲磺酸4-(2-((二甲氧基磷醯基)胺基)-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(35.1 g,81毫莫耳,產率66%)。
LCMS m/z = 454.1 [M+Na]
+。
1H NMR (400 MHz, DMSO-d6) δ ppm 10.28 (br s, 1H), 7.60 - 7.68 (m, 2H), 7.44 - 7.51 (m, 2H), 6.07 (s, 1H), 3.67 (d,
J= 12 Hz, 3H), 3.57 (d,
J= 12 Hz, 3H), 3.43 (s, 3H), 3.30 (s, 3H)。對掌性HPLC:>99% ee。
步驟 4 : (R)- 甲磺酸 4-(1-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(( 二甲氧基磷醯基 ) 胺基 )-2- 側氧基乙基 ) 苯酯 將H
2O (338 mL)及碳酸鈉(5.18 g,48.9毫莫耳)饋入配備有頂置式攪拌之經氮氣沖洗的1 L JLR,隨後在20℃下攪拌。用額外的H
2O (42.0 mL)沖洗反應容器之壁,隨後攪拌混合物10分鐘。饋入丙酮(170 mL),接著饋入2-(二甲胺基)-4-乙基-6-巰基吡啶-3,5-二甲腈(22.7 g,98.0毫莫耳)及額外的丙酮(42.0 mL)。攪拌混合物約1小時,隨後一次性添加(S)-甲磺酸4-(2-((二甲氧基磷醯基)胺基)-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(42.2 g,98.0毫莫耳)。攪拌反應物2小時,隨後藉由真空過濾收集所沈澱之固體。經分離之固體用H
2O洗滌兩次(每次用126 mL洗滌),隨後用異丙醇洗滌兩次(每次用210 mL洗滌),隨後用三級丁基甲基醚(420 mL)洗滌,且用氮氣流吹乾15小時。隨後,產物濾餅用三級丁基甲基醚(336 mL)再漿化。在混合約10分鐘之後,將固體過濾至乾燥且用額外的三級丁基甲基醚(126 mL)沖洗。在真空下乾燥之後,收集所要產物(R)-甲磺酸4-(1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-((二甲氧基磷醯基)胺基)-2-側氧基乙基)苯酯,以得到灰白色固體(50.6 g,88.0毫莫耳,產率90%)。
LCMS m/z = 568.1 [M+H]
+。
1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 - 10.43 (m, 1H), 7.55 - 7.66 (m, 2H), 7.36 - 7.48 (m, 2H), 5.81 (br s, 1H), 3.64 (d,
J= 12 Hz, 3H), 3.52 (d,
J= 12 Hz, 3H), 3.42 (s, 3H), 3.37 (s, 6H), 2.77 (q,
J= 8 Hz, 2H), 1.21 (t,
J= 8 Hz, 3H)。對掌性HPLC:>99% ee。
步驟 5 : (
R)-(2-((3,5-
二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸 DMF 半溶劑合物 將二氯甲烷(250 mL)及(R)-甲磺酸4-(1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-((二甲氧基磷醯基)胺基)-2-側氧基乙基)苯酯(65.0 g,115毫莫耳)饋入經氮氣吹掃之2 L JLR,隨後用額外的二氯甲烷(100 mL)洗滌容器壁以產生均勻的棕色溶液。冷卻此溶液至0℃後,饋入碘基三甲基矽烷(42.1 mL,309毫莫耳),同時保持內部溫度<5℃。在0℃下攪拌所得褐色反應混合物1小時。反應混合物之HPLC分析指示反應為未完成的,因此饋入額外的碘基三甲基矽烷(3.12 mL,22.9毫莫耳)。攪拌13分鐘後,藉由添加約50% DMF淬滅溶液(91 mL)來淬滅反應物,同時保持內部溫度<5℃ (注意:藉由添加H
2O (3.30 mL,183毫莫耳)至無水DMF (179 mL)來製備DMF淬滅溶液)。將反應混合物保持在0℃下3分鐘,隨後用於二氯甲烷(6.50 mL)中漿化的(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸DMF半溶劑合物(165 mg)結晶接種,且保持在0℃下約30分鐘。隨後,經由逐份添加二氯甲烷(650 mL)進一步稀釋稀漿液,隨後在0℃下攪拌約30分鐘。緩慢饋入剩餘的約50% DMF淬滅溶液(91 mL),同時保持內部溫度<5℃。添加完成時,夾套溫度以2℃/分鐘之速率升高至20℃且保持在20℃下約45分鐘。用二氯甲烷(650 mL)進一步稀釋反應漿液且攪拌12小時。藉由真空過濾收集經沈澱之固體,隨後用二氯甲烷洗滌兩次(每次用325 mL洗滌)。固體在20℃下用乙酸乙酯(325 mL)再漿化約2.5小時,藉由真空過濾分離,隨後經真空乾燥以得到呈白色至灰白色的產物(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸DMF半溶劑合物(58.4 g,101毫莫耳,89%產率)。1H NMR展示產物:DMF比率為1:0.8。
LCMS m/z = 540.0 [M+H]
+。
1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 - 12.19 (br s, 1 H), 9.75 (br d,
J= 9.5 Hz, 1 H), 7.96 (s, 0.8 H, DMF), 7.58 - 7.65 (m, 2 H), 7.31 - 7.46 (m, 2 H), 5.80 (br s, 1 H), 3.42 (s, 3 H), 3.37 (m, 6 H), 2.90 (s, 2.8 H, DMF), 2.74 (m, 4.8 H,包括DMF), 1.21 (t,
J= 7.5 Hz, 3 H)。對掌性HPLC:>99% ee。
步驟 6 : (
R)-(2-((3,5-
二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸甘胺酸鹽 該製程在一對16 L JLR中進行,標註為容器A及容器B,其各自配備有頂置式攪拌。將微米尺寸甘胺酸(71.5 g,0.952莫耳)、二氯甲烷(9 L)及甲醇(896.5 mL)饋入容器A,且將相同饋料重複饋入容器B。在25℃下攪拌混合物。隨後,歷經至少15分鐘將(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸DMF半溶劑合物(137.5 g,0.238莫耳)於乙酸乙酯(1.1 L)中的漿液饋入容器A。用乙酸乙酯(550 mL)沖洗漿液容器,隨後將此沖洗液轉移至反應器中。將漿液饋入及乙酸乙酯沖洗對容器B重複。容器A及容器B中之結晶用(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸甘胺酸鹽(5.5 g)接種。在接種後,對於各反應器,將緩慢添加於乙酸乙酯(1.1 L)中之(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸DMF半溶劑合物(137.5 g,0.238莫耳)、乙酸乙酯(550 mL)容器沖洗,及沖洗液轉移至容器A及容器B的過程重複三次。在25℃下攪拌漿液隔夜且反應完成。將容器A及B兩者之漿液混合物清空至配備有濾紙之不鏽鋼盤形過濾器中。使用真空壓力過濾掉母液。容器A及容器B各自用乙酸乙酯(3.3 L)沖洗,隨後轉移至盤形過濾器以洗滌經分離之固體且過濾。用乙酸乙酯沖洗容器A及容器B重複第二次。真空壓力用於推動洗滌產物濾餅。在真空下在50℃下乾燥經分離之固體直至LOD分析產生<1%,以得到呈白色固體狀的(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸甘胺酸鹽(1101 g,1.791莫耳,92.5%產率)。1H NMR展示產物:甘胺酸比率為1:1。
LCMS m/z = 540.2 [M+H]
+。
1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (br d,
J= 7.50 Hz, 1 H), 7.66 (br d,
J= 8.0 Hz, 2 H), 7.36 (br d,
J= 8.0 Hz, 2H), 5.80 (s, 1 H), 3.48 (s, 2 H), 3.41 (s, 3 H), 3.34 (s, 7 H), 2.74 (q,
J= 7.5 Hz, 3 H), 1.19 (t,
J= 7.5 Hz, 3 H)。對掌性HPLC:>99% ee。
實例1之結晶化合物,即與(R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸之甘胺酸化合物(1:1)。
此材料之X射線粉末繞射(XRPD)圖案示於圖1,且在下表I中給出繞射角及晶格面距的概述。使用X'celerator
TM即時多條(Real Time Multi-Strip;RTMS)偵測器在Si零背景晶圓(Si zero-background wafer)上在PANanalytical X'Pert Pro繞射儀上進行XRPD分析。獲取條件包括:Cu K
α輻射;波長(λ):1.5405980 Å;產生器張力:45 kV;產生器電流:40 mA;步長:0.0167°2θ。入射光束側之組態:10 mm可程式化發散狹縫、0.02 rad索勒狹縫(Soller slit)、防散射狹縫(0.5°)及10 mm光束遮罩。繞射光束側之組態:10 mm可程式化防散射狹縫組裝體(X'celerator模組)及0.02 rad索勒狹縫。
表I
繞射角及晶格面距之XRPD概述
峰 # | 繞射角 [°2θ] | 晶格面距 [Å] |
1 | 5.42 | 16.3027 |
2 | 5.78 | 15.2672 |
3 | 7.44 | 11.8749 |
4 | 9.59 | 9.2110 |
5 | 10.56 | 8.3679 |
6 | 10.81 | 8.1745 |
7 | 11.55 | 7.6557 |
8 | 13.04 | 6.7854 |
9 | 14.46 | 6.1218 |
10 | 14.84 | 5.9641 |
11 | 15.56 | 5.6903 |
12 | 16.25 | 5.4518 |
13 | 17.01 | 5.2072 |
14 | 18.32 | 4.8394 |
15 | 18.82 | 4.7116 |
16 | 19.00 | 4.6665 |
17 | 19.20 | 4.6182 |
18 | 19.60 | 4.5246 |
19 | 20.49 | 4.3310 |
20 | 20.99 | 4.2287 |
21 | 21.18 | 4.1924 |
22 | 21.54 | 4.1216 |
23 | 21.69 | 4.0934 |
24 | 22.34 | 3.9755 |
25 | 22.65 | 3.9233 |
26 | 23.20 | 3.8313 |
27 | 23.95 | 3.7127 |
28 | 24.42 | 3.6426 |
29 | 24.99 | 3.5610 |
30 | 25.17 | 3.5354 |
31 | 26.22 | 3.3958 |
32 | 26.54 | 3.3559 |
在40 mL/分鐘N
2吹掃下,此材料之差示掃描熱量測定(DSC)熱分析圖於配備有自動取樣器及冷凍冷卻系統之TA Instruments Discovery差示掃描量熱計上記錄且示於圖2。使用以10℃/分鐘之加熱速率加熱至最終溫度200℃在略有波紋的鋁盤中進行實驗。此化合物在DSC中具有簡單的單次熔融事件,其中起始溫度為183.6℃,峰值溫度為188.8℃且熔融焓為64 J/g。熔融焓之確定由於熔融後立即熱分解而為不可靠的。在分解事件之前,化合物藉由TGA損失展現可忽略的重量損失。熟習此項技術者將認識到,吸熱之起始溫度、峰值溫度及焓可視實驗條件而變化。
此材料之熱解重量分析(TGA)熱分析圖於TA Instruments Discovery熱解重量分析儀上記錄且示於圖3。在N
2吹掃下及以10℃/分鐘之加熱速率加熱至最終溫度200℃在敞口鋁盤中進行實驗。在分解事件之前,化合物在160℃下展現0.3%重量損失。
關於XRPD、DSC及TGA之上述參數中的一般要點中的每一者適用於本申請案中進行之XRPD、DSC及TGA分析中的每一者。另外,在此情況下所報導之所有XRPD數據中,數據具有加或減0.2之精確性。
步驟 7 : (
R)-(2-((3,5-
二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸甘胺酸鹽單水合物 將(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸DMF半溶劑合物(1.5 g,2.54毫莫耳)及乙酸乙酯(37.5 mL)饋入裝配有頂置式攪拌之50 mL JLR。在攪拌的同時,將反應器夾套以1℃/分鐘加熱至50℃且保持在50℃下95分鐘。將2 M甘胺酸於水中之溶液(2.67毫莫耳甘胺酸)裝載至附著之10 mL劑量單元。歷經90分鐘將2 M甘胺酸水溶液(1.33 mL)饋入反應混合物。在饋入之後,將混合物保持60分鐘,隨後以0.25℃/分鐘使其冷卻至5℃。使反應混合物在5℃下保持60分鐘。隨後,反應混合物程式化隔夜完成兩個溫度循環,以1℃/分鐘加熱至50℃,保持在50℃下,以0.25℃/分鐘冷卻至5℃且在5℃下保持60分鐘。使反應混合物在5℃下保持4.5天且隨後經由一次性過濾漏斗過濾。用乙酸乙酯(2 x 9 mL)沖洗反應固體之濕餅兩次且過濾。將固體置於25℃下真空烘箱中隔夜且乾燥以產生呈白色固體狀的(
R)-(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸水合甘胺酸鹽(1.55 g,2.45毫莫耳)。
1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (s, 1 H), 7.65 (br d,
J= 7.5 Hz, 2 H), 7.36 (br d,
J= 7.5 Hz, 2 H), 5.79 (br s, 1 H), 3.40 (s, 6 H), 3.35 (br s, 9 H), 2.74 (q,
J= 7.0 Hz, 2 H), 1.19 (t,
J= 7.0 Hz, 3 H)。對掌性HPLC:>99% ee。
實例1之單水合甘胺酸鹽的X射線粉末繞射(XRPD)圖案示於圖4,且在下表II中給出繞射角及晶格面距的概述。
表II
實例1單水合甘胺酸鹽的XRPD繞射角及晶格面距之概述
峰# | 繞射角[°2θ] | 晶格面距[Å] |
1 | 5.13 | 17.2011 |
2 | 5.75 | 15.3532 |
3 | 7.27 | 12.1458 |
4 | 9.28 | 9.5245 |
5 | 10.26 | 8.6117 |
6 | 10.61 | 8.3277 |
7 | 11.52 | 7.6772 |
8 | 12.87 | 6.8726 |
9 | 13.86 | 6.3858 |
10 | 14.56 | 6.0794 |
11 | 15.43 | 5.7389 |
12 | 16.31 | 5.4293 |
13 | 17.32 | 5.1171 |
14 | 18.52 | 4.7872 |
15 | 19.15 | 4.6299 |
16 | 19.89 | 4.4604 |
17 | 20.84 | 4.2586 |
18 | 21.23 | 4.1824 |
19 | 22.11 | 4.0168 |
20 | 22.55 | 3.9404 |
21 | 23.13 | 3.8421 |
22 | 23.83 | 3.7305 |
23 | 24.13 | 3.6847 |
24 | 25.47 | 3.4942 |
25 | 26.06 | 3.4171 |
26 | 27.91 | 3.1941 |
27 | 28.65 | 3.1137 |
28 | 29.05 | 3.0716 |
29 | 29.90 | 2.9860 |
30 | 30.42 | 2.9363 |
31 | 30.82 | 2.8990 |
32 | 31.34 | 2.8522 |
33 | 32.91 | 2.7196 |
34 | 33.38 | 2.6825 |
35 | 36.72 | 2.4456 |
此水合甘胺酸鹽材料之差示掃描熱量測定(DSC)熱分析圖與先前DSC設備相同,且示於圖5。使用以10℃/分鐘之加熱速率加熱至最終溫度250℃在略有波紋的鋁盤中進行實驗。此化合物具有自40至140℃之廣吸熱脫水事件,繼而出現急劇熔融吸熱,起始溫度為175.5℃、峰值溫度為179.3℃且熔融焓為52 J/g。熔融焓之確定由於熔融後立即熱分解而為不可靠的。熟習此項技術者將認識到,吸熱之起始溫度、峰值溫度及焓可視實驗條件而變化。
此水合甘胺酸鹽材料之熱解重量分析(TGA)熱分析圖與先前TGA設備相同,且示於圖6。在N
2吹掃下及以10℃/分鐘之加熱速率加熱至最終溫度250℃在敞口鋁盤中進行實驗。化合物在分解事件之前展現40至140℃之3.0%重量損失,其指示單水合物形態形式。
實例 2
(R)- 甲磺酸 4-(2- 胺基 -1-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2- 側氧基乙基 ) 苯酯 步驟 1 : 甲磺酸 4-(2- 胺基 -2- 側氧乙醯基 ) 苯酯 在氮氣下在室溫下歷經1分鐘向甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯(50 g,204毫莫耳)於乙腈(3000 mL)中的經攪拌懸浮液中以一次饋料添加二氧化錳(248 g,2854毫莫耳)。在70℃下加熱反應混合物16小時且隨後在80℃下加熱48小時。將反應混合物冷卻至室溫,經由矽藻土過濾,且用乙腈(2000 mL)洗滌矽藻土床。在減壓下濃縮濾液,以得到44 g呈灰白色固體狀的所要粗產物。藉由UPLC MS對材料之分析指示,46.67%曲線下面積對應於產物質量,且48.26%曲線下面積對應於起始材料質量。粗產物/起始材料混合物如下文所描述使用PCC進行氧化反應。
在氮氣下在室溫下藉由以一次饋料與矽藻土混合,向含有甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯及甲磺酸4-(2-胺基-2-側氧乙醯基)苯酯(42.0 g,86毫莫耳)之混合物於四氫呋喃(THF) (2.4 L)中的經攪拌溶液中添加PCC (18.53 g,86毫莫耳)。在室溫下攪拌反應混合物2小時。反應混合物經由矽藻土過濾且用(2000 mL) THF洗滌矽藻土床。在真空中濃縮濾液,以得到呈深褐色固體狀的粗產物。將粗產物溶解於100 mL甲醇及150 mL DCM之混合物中且吸收至400 g二氧化矽(60至120目)上。所得材料經由4 kg二氧化矽(230至400目)過濾且用(3000 mL)乙酸乙酯洗滌二氧化矽床。在真空中濃縮濾液以得到呈灰白色固體狀的甲磺酸4-(2-胺基-2-側氧乙醯基)苯酯(26 g,52%)。LCMS m/z = 244.0 [M+H]
+。
1HNMR (400 MHz, DMSO-d6) δ ppm 8.37 (br s, 1H), 8.13-8.09 (m, 2H), 8.06 (br s, 1H), 7.58-7.54 (m, 2H), 3.49 (s, 3H)。
步驟 2 : (S)- 甲磺酸 4-(2- 胺基 -1- 羥基 -2- 側氧基乙基 ) 苯酯 將甲磺酸4-(2-胺基-2-側氧基乙醯基)苯酯(5.0 g,20.56毫莫耳)及異丙醇(10 mL)饋入配備有過大攪拌棒之500 mL圓底燒瓶。向所得混合物中添加80 mL β-菸鹼醯胺腺嘌呤二核苷酸磷酸二鈉鹽(NADP+,二鈉) (100 mg,20.56毫莫耳)於0.1 M KPi pH 7.0緩衝液中的1.25 mg/mL溶液,隨後添加SynBio酮還原酶序列ID S00000617 (300 mg,20.56毫莫耳)。在室溫下劇烈攪拌所得漿液。總計46小時之後,水層飽和有固體KCl且用EtOAc (200 mL)稀釋混合物。因此形成乳液,經由Celite®墊過濾混合物,且用大量EtOAc (3 x 75 mL)沖洗,得到澄清的相異層。用鹽水洗滌有機層且用EtOAc (2 x 75 mL)反萃取經合併之水層。經合併之有機物經Na
2SO
4乾燥,過濾且在減壓下濃縮。在高真空下乾燥殘餘物至恆重,以得到呈白色固體狀的(S)-甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯(4.40 g,87%產率)。LCMS m/z = 246.0 [M+H]
+。
1HNMR: (400 MHz, DMSO-d6) δ ppm 7.54 - 7.49 (m, 2H), 7.42 (br s, 1H), 7.33 - 7.28 (m, 2H), 7.21 (br s, 1H), 6.13 (d, J = 4.9 Hz, 1H), 4.89 (d, J = 4.9 Hz, 1H), 3.37 (s, 3H)。對掌性HPLC:>99% ee。
步驟 3 : (S)- 甲磺酸 4-(2- 胺基 -1-(( 甲磺醯基 ) 氧基 )-2- 側氧基乙基 ) 苯酯 歷經約1分鐘向(S)-甲磺酸4-(2-胺基-1-羥基-2-側氧基乙基)苯酯(4.3 g,17.53毫莫耳)於二氯甲烷(DCM) (40 mL)中的冷(0℃)懸浮液中添加Ms-Cl (1.639 mL,21.04毫莫耳),隨後歷經約3分鐘添加TEA (3.67 mL,26.3毫莫耳)。2小時之後,LCMS展示約15%起始材料(3小時之後無額外進展),因此使反應混合物再冷卻至0℃且添加額外部分的Ms-Cl (0.410 mL,5.26毫莫耳)及TEA(1.222 mL,8.77毫莫耳)。移除冰浴且使反應物升溫至室溫。在額外30分鐘之後,反應混合物用NaHCO
3飽和水溶液(50 mL)淬滅且劇烈攪拌。過濾所得懸浮液/乳液,且依序用水(3 x 30 mL)及乙醚(3 x 30 mL)沖洗固體,且在高真空下乾燥至恆重,以得到呈淺灰白色固體狀的(S)-甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(4.44 g,78%產率)。LCMS m/z = 324.0 [M+H]
+。
1HNMR (400 MHz, DMSO-d6) δ ppm 7.86 (s, 1H), 7.63 - 7.54 (m, 3H), 7.41 (d, J = 7.8 Hz, 2H), 5.91 (s, 1H), 3.41 (s, 3H), 3.26 (s, 3H)。
步驟 4 : (R)- 甲磺酸 4-(2- 胺基 -1-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2- 側氧基乙基 ) 苯酯 向2-(二甲胺基)-4-乙基-6-巰基吡啶-3,5-二甲腈(1.437 g,6.19毫莫耳)於乙酸乙酯(50 mL)中的懸浮液中添加iPr
2EtN (1.350 mL,7.73毫莫耳)。在室溫下攪拌橙色懸浮液。30分鐘後,添加(S)-甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(2.0 g,6.19毫莫耳)於乙酸乙酯(30 mL)中的懸浮液且在室溫下攪拌所得橙色懸浮液。在4小時之後,用刮勺刮擦燒瓶內部,其起始產物沈澱。將所得懸浮液再攪拌30分鐘,隨後冷卻至0℃。沈澱物藉由使用過濾漏斗過濾收集,依序用冷(0℃) EtOAc (2 x 20 mL)、水(2 x 10 mL)、冷(0℃) EtOAc(2 x 20 mL)沖洗,隨後乙醚(2 x 10 mL)沖洗。在高真空下乾燥固體48小時以得到呈灰白色固體狀的(R)-甲磺酸4-(2-胺基-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(1.37 g,48.2%產率)。LCMS m/z = 460.2 [M+H]
+。
1H NMR (400 MHz, DMSO-d
6) δ ppm 7.96 (s, 1H), 7.62 (d,
J= 8.8 Hz, 2H), 7.42 - 7.31 (m, 3H), 5.66 (s, 1H), 3.39 (s, 3H), 3.33 (s, 6H), 2.75 (q,
J= 7.8 Hz, 2H), 1.20 (t,
J= 7.8 Hz, 3H)。
實例 3 (2-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2-(4-(( 甲磺醯基 ) 氧基 ) 苯基 ) 乙醯基 ) 胺基磷酸 在0℃下,向甲磺酸4-(2-((雙(苯甲氧基)磷醯基)胺基)-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(77.34 g,107毫莫耳)於乙腈(1 L)中的溶液中添加碘基三甲基矽烷(34 mL,247毫莫耳)且使混合物升溫至室溫。在室溫下攪拌反應混合物30分鐘。用1.2 L 10%偏亞硫酸氫鈉淬滅反應物。形成沈澱物且攪拌黏稠混合物。過濾混合物且用1 L水洗滌所收集之固體。在真空下在過濾器漏斗中乾燥隔夜。將所得固體懸浮於2 L醚中且攪拌30分鐘。過濾混合物且將所收集固體乾燥,以得到呈灰白色固體狀的(2-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲磺醯基)氧基)苯基)乙醯基)胺基磷酸(32 g,59.3毫莫耳,55.2%產率)。LCMS m/z = 540.0 [M+H]
+。
1H NMR (400 MHz, DMSO-d
6) δ ppm 9.48 (s, 1H), 7.66 (d,
J= 8.5 Hz, 2H), 7.35 (d,
J= 8.5 Hz, 2H), 5.81 (s, 1H), 3.40 (s, 3H), 3.34 (s, 6H), 2.74 (q,
J= 7.6 Hz, 2H), 1.20 (t,
J= 7.6 Hz, 3H) (未觀測到2個磷酸酯質子)。
實例 4 甲磺酸 4-(2- 胺基 -1-((3,5- 二氰基 -6-( 二甲胺基 )-4- 乙基吡啶 -2- 基 ) 硫基 )-2- 側氧基乙基 ) 苯酯 向2-(二甲胺基)-4-乙基-6-巰基吡啶-3,5-二甲腈(2.0 g,8.61毫莫耳)於乙酸乙酯(50 mL)中的黃色懸浮液中依序一次性添加DIEA (1.880 mL,10.76毫莫耳)及甲磺酸4-(2-胺基-1-((甲磺醯基)氧基)-2-側氧基乙基)苯酯(2.78 g,8.61毫莫耳)。在室溫下攪拌混合物24小時。藉由過濾收集固體,用乙酸乙酯、水及更多乙酸乙酯沖洗。乾燥固體,得到3.50 g淡黃色固體。將固體材料懸浮於30 mL水中且攪拌1小時。藉由過濾收集固體,用水沖洗,且乾燥,以得到呈淡黃色固體狀的甲磺酸4-(2-胺基-1-((3,5-二氰基-6-(二甲胺基)-4-乙基吡啶-2-基)硫基)-2-側氧基乙基)苯酯(3.09 g,76%)。LCMS m/z = 460.0 [M+H]
+。
1H NMR (400 MHz, DMSO-d
6) δ ppm 7.97 (s, 1H), 7.65 - 7.59 (m, 2H), 7.41 - 7.34 (m, 3H), 5.65 (s, 1H), 3.40 (s, 3H), 3.33 (s, 6H), 2.75 (q,
J= 7.6 Hz, 2H), 1.20 (t,
J= 7.6 Hz, 3H)。
生物資料 DNMT1 閃爍近接分析 ( Scintillation Proximity Assay , SPA)- 分析 A ( 全長人類 DNMT1)此分析以信號增大型式使用閃爍近接技術來評估化合物之效能。利用全長人類DNMT1、半甲基化DNA雙螺旋
*及氚化SAM監測活性。分析盤創建由以下參數組成:將500 nL化合物之11pt 3倍連續稀釋液壓至96孔Costar盤(#3884)中。在分析當天製備之分析緩衝液混合物由以下組成:20 mM Tris pH 7.5、1 mM DTT、1 mM EDTA及5%甘油。隨後,製備2X酶混合物,其由分析緩衝液中30 nM DNMT1蛋白(全長人類DNMT,內部製得)組成。最後製備2X受質混合物,且其由分析緩衝液中160 nM 40聚體(40 mer)半甲基化DNA
*、0.48 µM
3H-SAM及2.92 µM冷SAM組成(最後添加
3H-SAM)。批量製備淬滅物(1 mM SAH)且在-20℃下冷凍直至使用時間。使用多注式(multichannel)電子吸液管將10 μL之2X受質混合物添加至整個盤中。在添加之間振盪盤至少10秒以確保混合。接著,使用多注式吸液管將20 μL 2x淬滅混合物添加至管柱12 (振盪盤)。使用多注式電子吸液管將10 μL 2x酶混合物添加至整盤,開始於管柱11且移動至管柱10 (最後為管柱12以避免預淬滅攜帶)。在遮蓋盤的情況下,使盤在振盪器上培育30分鐘。在培育期結束時,將20 μL淬滅混合物添加至除管柱12之外的所有孔(振盪盤),隨後添加稀釋於無DNA酶水中的20 μL 3 mg/mL PerkinElmer PEI PVT SPA珠粒(目錄# RPNQ0097),且使其振盪至少30分鐘。用透明密封件密封盤且以500 rpm離心1分鐘。在MicroBeta (PerkinElmer,讀取
3H (1分鐘/孔)上讀取盤。
使用Microsoft Excel分析數據至Vi/Vo且使用GraFit擬合數據。針對各盤內之不受抑制(DMSO)及經預淬滅對照組標準化反應。使用三參數對數擬合分析劑量-反應曲線,其中Y
最小值限於0且結果表述為IC
50值。
最終分析條件:20 mM Tris (Hampton Research-HR-937-06),pH 7.5;1 mM DTT (Invitrogen-P2325);1 mM EDTA (Invitrogen-AM9260G);5%甘油(Teknova - G1796);0.02% Pluronic F127 (Life Technologies-P6866);15 nM DNMT1 (全長人類DNMT1 - GSK內部製得);240 nM
3H-SAM (PerkinElmer-NET155H001MC);1460 nM冷SAM (New England Biolabs-B9003S)及80 nM 40-聚體半甲基化DNA寡核苷酸(Integrated DNA Technologies-定製);1 mM SAH (Sigma A9384)及再懸浮於中水之1 mg/mL PEI PVT SPA珠粒(PerkinElmer RPNQ0097)。
* 40聚體me-DNA寡聚物雙螺旋:
5'-CCTCTTCTAACTGCCAT(Me-dC)GATCCTGATAGCAGGTGCATGC-3'
5'-GCATGCACCTGCTATCAGGATCGATGGCAGTTAGAAGAGG-3'
DNMT1 閃爍近接分析 (SPA)- 分析 B ( 人類截短 DNMT1 (601-1600))此分析以信號增大型式使用閃爍近接技術來評估化合物之效能。利用人類截短DNMT1 (601-1600)、單一半甲基化CpG位點寡核苷酸及氚化SAM來監測活性。分析盤創建由以下參數組成:將10 mM化合物(11點,3倍連續稀釋液)以100 nL/孔(100X於100% DMSO中)壓至Griener白色LV 384孔盤(#784075)中。在分析當天製備之分析緩衝液混合物由以下組成:鹼性緩衝液:(500 mM Hepes,ph 8,1 M MgCl2,預先製備,在室溫下作為儲備物儲存)、10% NP40-Surfact AMPS、10%超純BSA 50 mg/ml及2 M DTT (DL-二硫蘇糖醇)。隨後,製備由以下組成之2X酶混合物:DNMT1蛋白(截短人類DNMT1-601-1600,以16.876 μM儲備濃度內部製得),向分析緩衝液混合物中添加。最後製備2X受質混合物,且其由以下組成:1 mM 40-聚體半甲基化DNA寡核苷酸、12.5 μM 3H-SAM (腺苷-L-甲硫胺酸-S-[甲基-3H]特異性活性55-85 Ci/毫莫耳)及32 mM S-腺苷-L-甲硫胺酸溶液(使其在添加至受質混合物之前於無核酸酶H2O中稀釋至1 mM),向分析緩衝液混合物中添加(最後添加3H-SAM)。使用Thermo Multidrop combi將5 μL分析緩衝液混合物分配至僅管柱18中。接著,使用Thermo Multidrop combi將5 μL 2X酶混合物分配至管柱1-17、19-24中。隨後,使用Thermo Multidrop combi將5 μL 2X受質混合物分配至整個盤。將盤堆疊且頂盤上蓋盤下培育40分鐘。在培育步驟之25分鐘左右處將淬滅混合物製成,該混合物由以下組成:32 mM S-腺苷-L-甲硫胺酸& PerkinElmer PEI PS成像珠粒(目錄#RPNQ0098)於無核酸酶H2O中的溶液(10mg/ml)。在使用之前,使淬滅混合物渦旋以獲得溶液中之珠粒。在培育40分鐘之後,使用Thermo Multidrop combi將10 μL淬滅混合物分配至整個盤。用透明密封件密封盤且以1000 rpm/1分鐘離心且黑暗調適30分鐘。在Viewlux (PerkinElmer,613 nm發射濾光器(emission filter),300秒雙暴露(dual-exposure),(總讀取時間10分鐘))上讀取盤。
使用Abase資料庫分析數據。針對各盤內之不受抑制(DMSO)及低對照組標準化反應。使用四參數對數擬合分析劑量-反應曲線且結果表述為pIC
50值。
最終分析條件:50 mM HEPES (Teknova-H1035),pH 8.0;2 mM MgCl2 (Sigma-M1028);1 mM DTT (Sigma-D5545);0.01% NP40界面活性劑Amps (Themo Scientific-28324);0.01% BSA (Ambion-AM2618);40 nM DNMT1 (截短人類DNMT1 (601-1600-GSK內部製得);100 nM 3H-SAM (American Radiolabeled Chemicals公司-ART 0288);900 nM冷SAM (New England Biolabs-B9003S)及200 nM 40-聚體半甲基化DNA寡核苷酸(Integrated DNA Technologies-43334514)。
固體化合物在禁食模擬腸液中之溶解度在室溫下平衡4小時後,在pH 6.5下測定固體化合物於禁食模擬腸液(FaSSIF)中之溶解度(使用描述於Sou, T.;Bergström, C. A. S. Automated assays for thermodynamic (equilibrium) solubility determination.
Drug Discovery Today: Technologies2018,
27, 11-19中的程序)。將1 ml FaSSIF緩衝液(3 mM牛膽酸鈉、0.75 mM卵磷脂於pH 6.5磷酸鈉緩衝液中)添加至4 ml小瓶中之人工稱重的1 mg固體化合物。所得懸浮液在室溫下以900 rpm振盪4小時,且隨後轉移至Multiscreen HTS 96孔溶解度濾盤以分離殘餘固體及濾液。使用DMSO中已知濃度之化合物的單點校準藉由HPLC-UV進行濾液中化合物濃度的定量。除了化合物,測試一組3種已知溶解度之內標(分別為2、20及140 µg/ml之Atovaquone、Nimesulide及Warfarin)以評估過程之適用性。分析之動態範圍為1至1000 µg/ml。
結果
aDNMT1全長
bDNMT1截短
化合物 | 結構 | DNMT1 IC 50(nM) | 大鼠口服生物可用性(%) | FaSSIF溶解度(µg/mL) |
實例1 | 16139 a | > 1000 | ||
實例2 | 54 a | 40 | 1 | |
實例3 | 5209 a | > 1000 | ||
實例4 | 107 a | < 1 | ||
參考化合物1 | 89 a | < 1 | ||
參考化合物2 | 156 a | 2.7 | ||
參考化合物3 | 631 b | |||
參考化合物4 | 79 b | 6.1 | 4 |
藥物動力學研究 :所有研究均根據關於實驗室動物之照護、福利及處理之GSK政策(GSK Policy on the Care, Welfare and Treatment of Laboratory Animals)進行且由GSK的機構動物照護及使用委員會(Institutional Animal Care and Use Committee)或由研究進行之機構的倫理審查過程審查。在非交叉設計中,藥物動力學研究針對實例2使用非禁食雄性威斯達韓(Wistar Han)大鼠,n=3/劑量途徑,且針對參考化合物4,非禁食雄性史泊格多利(Sprague-Dawley)大鼠,n=2/劑量途徑進行。化合物在5% DMA/15% Solutol中製備為溶液且以60分鐘IV輸注及PO管飼形式投與。在給藥前至給藥後24小時之多個時間點連續收集血液樣品且藉由LC/MS/MS定量分析物。藉由比較自PO給藥獲得之劑量標準化曲線下面積(dose normalized Area Under the Curve,DNAUC)與自IV途徑獲得之DNAUC來計算生物可用性百分比[(PO DNAUC/IV DNAUC)*100]。
活體內小鼠研究 - 方法 :將懸浮於50%基質膠(BD Biosciences)/50%杜爾貝科氏磷酸鹽緩衝鹽水(Dulbecco's phosphate-buffered saline,DPBS)中之SKM-1細胞(3.8 x 10
6)植入8至11週齡雌性NOD.CB17-Prkdc<scid>1NCrCrl小鼠中。用數位測徑規量測腫瘤,且根據腫瘤尺寸(P值> 0.9085)分層區組(stratified block)隨機分為處理組,其中功效或PK/PD研究之平均腫瘤體積分別為219或1076 mm
3。GSK4172239A每週調配於無菌水中。每週兩次量測小鼠之體重及腫瘤尺寸。在隨機分組後當天開始給藥。動物每天兩次(BID)經由經口管飼(PO)以22、67或200 mg/kg給藥實例1。在研究期間,未超出兩次連續量測≥ 2,500 mm
3的最大腫瘤負荷。對於PK/PD研究,在第20次給藥(10天)之後兩小時採集腫瘤、血液及骨髓。對於PK,將血液與水50:50混合,同時將腫瘤以1:4稀釋度在無菌水中均質化(全向手持均質器(Omni hand-held homogenizer))。用乙腈沈澱兩種樣品,且藉由HPLC-MS/MS (Waters Acquity uPLC, Sciex API5000)測定實例4之濃度。使用整體DNA甲基化(5-甲基胞嘧啶) LC-MS/MS分析評估SKM-1腫瘤及小鼠骨髓樣品。使用Quick-DNA Miniprep套組(Zymo Research)根據製造商說明書分離DNA。對於各樣品,根據製造商說明書,將DNA降解酶Plus (Zymo Research)添加至1,250 ng DNA以自基因體DNA釋放個別核苷。將經降解酶處理之DNA (10 μl)與190 μl乙腈/水/氫氧化銨(90:10:0.1)溶液合併,該溶液含有100 ng/ml 2'-去氧胞苷-13C,15N2 (Toronto Research Chemicals)及10 ng/ml 5-甲基-2'-去氧胞苷-13C,15N2 (Toronto Research Chemicals)標記之標準物。使HPLC-MS/MS方法最佳化以定量2'-去氧胞苷及5-甲基-2'-去氧胞苷。分離分析物及經標記標準物,其藉由在Waters Acquity UPLC上使用Acquity BEH Amide,1.7 μm,2.1×50 mm
2管柱進行親水性相互作用液相層析(HILIC),隨後在Sciex API5000上採用陽離子渦輪噴霧電離(turbo spray ionization)進行MS/MS分析。2'-去氧胞苷及5-甲基-2'-去氧胞苷之濃度使用由純2'-去氧胞苷(Sigma-Aldrich)及5-甲基-2'-去氧胞苷(Santa Cruz Biotechnology)產生之標準曲線測定。相對於總胞嘧啶濃度標準化5-甲基胞嘧啶之濃度以測定5-甲基胞嘧啶百分比。相對於媒劑對照物標準化來自經處理樣品之值。
活體內小鼠研究 - 結果 : 實例 1 呈現活體內活性。在攜有皮下SKM-1人類急性骨髓白血病(AML)異種移植物之免疫功能不全的小鼠中評估實例1。動物每天兩次(BID)經由經口管飼(PO)以22、67或200 mg/kg給藥實例1。為檢驗藥物動力學(PK)及藥效動力學(PD)變化,在第20次給藥(10天;n=5隻動物/組)後兩小時採集腫瘤、血液及骨髓。藥物動力學評估所揭露藥物暴露(量測為外消旋活性部分實例4)在血液及腫瘤中為劑量成比例的且大致相等。另外,使用基於LC-MS/MS之5-甲基胞嘧啶分析整體評估抑制DNMT1的機制結果,即DNA甲基化降低。與媒劑相比,實例1之所有劑量下的整體DNA甲基化減少,其中在200 mg/kg組中觀測到腫瘤之最大變化為49%且骨髓為47%。在後續研究中,為檢驗抗腫瘤功效,在處理下每週兩次量測腫瘤體積(n=10隻動物/組)持續≥4週。在第22天與媒劑相比時,其中最後一天媒劑組含有9隻動物,實例1誘導腫瘤體積之劑量依賴性降低,其中腫瘤生長抑制範圍在22 mg/kg組中之平均35%至200 mg/kg組中之明顯消退。
圖1為實例1之化合物之甘胺酸鹽的X射線粉末繞射。
圖2為實例1之化合物之甘胺酸鹽的差示掃描熱量測定。
圖3為實例1之化合物之甘胺酸鹽的差示掃描熱量測定。
圖4為實例1之化合物之甘胺酸鹽單水合物的X射線粉末繞射。
圖5為實例1之化合物之甘胺酸鹽單水合物的差示掃描熱量測定。
圖6為實例1之化合物之甘胺酸鹽單水合物的熱解重量分析。
圖7為實例1化合物之X射線粉末繞射。
圖8為實例1之化合物的差示掃描熱量測定。
圖9.實例1之化合物的熱解重量分析。
Claims (18)
- 如請求項4之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物,其中該醫藥學上可接受之鹽為甘胺酸鹽。
- 如請求項5之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物,其中該醫藥學上可接受之鹽為無水物。
- 如請求項6之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物,其中該醫藥學上可接受之鹽為無水結晶甘胺酸鹽。
- 如請求項7之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物,其中該無水結晶甘胺酸鹽提供實質上如表1中所闡明之XRPD圖案: 表I 繞射角及晶格面距之XRPD概述
峰 # 繞射角[°2θ] 晶格面距[Å] 1 5.42 16.3027 2 5.78 15.2672 3 7.44 11.8749 4 9.59 9.2110 5 10.56 8.3679 6 10.81 8.1745 7 11.55 7.6557 8 13.04 6.7854 9 14.46 6.1218 10 14.84 5.9641 11 15.56 5.6903 12 16.25 5.4518 13 17.01 5.2072 14 18.32 4.8394 15 18.82 4.7116 16 19.00 4.6665 17 19.20 4.6182 18 19.60 4.5246 19 20.49 4.3310 20 20.99 4.2287 21 21.18 4.1924 22 21.54 4.1216 23 21.69 4.0934 24 22.34 3.9755 25 22.65 3.9233 26 23.20 3.8313 27 23.95 3.7127 28 24.42 3.6426 29 24.99 3.5610 30 25.17 3.5354 31 26.22 3.3958 32 26.54 3.3559 - 如請求項7之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物,其中該無水結晶甘胺酸鹽提供實質上如圖1之XRPD圖案。
- 如請求項7之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物,其中該無水結晶甘胺酸鹽提供具有代表性繞射峰之XRPD圖案。
- 一種醫藥組合物,其包含如請求項1至10中任一項之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物及一或多種醫藥學上可接受之賦形劑。
- 一種如請求項1至10中任一項之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物的用途,其用於製造供治療與不當DNMT1活性相關之疾病用的藥劑。
- 如請求項12之用途,其中與不當DNMT1活性相關之該疾病為癌症、癌前症候群或β血紅素病變(haemoglobinopathy)病症。
- 如請求項13之用途,其中該癌症為骨髓發育不良症候群(MDS)、急性骨髓白血病(AML)、大腸直腸癌(CRC)、淋巴瘤(例如,非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma))、黑色素瘤、腎癌、胃癌、非小細胞肺癌(NSCLC)或乳癌。
- 如請求項13之用途,其中該β血紅素病變病症為鐮狀細胞疾病、鐮狀細胞貧血或β地中海貧血。
- 一種組合,其包含如請求項1至10中任一項之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物,及一或多種其他活性劑。
- 一種如請求項4至10中任一項之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物的用途,其用於製造供治療鐮狀細胞疾病、鐮狀細胞貧血或β地中海貧血用的藥劑。
- 一種如請求項4至10中任一項之化合物或其前藥或其醫藥學上可接受之鹽、立體異構體或水合物的用途,其用於製造供治療骨髓發育不良症候群(MDS)、急性骨髓白血病(AML)、大腸直腸癌(CRC)、非霍奇金氏淋巴瘤(NHL)、黑色素瘤或乳癌用的藥劑。
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- 2022-02-24 IL IL305427A patent/IL305427A/en unknown
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IL305427A (en) | 2023-10-01 |
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AR124975A1 (es) | 2023-05-24 |
EP4301733A1 (en) | 2024-01-10 |
CA3212345A1 (en) | 2022-09-09 |
KR20230154230A (ko) | 2023-11-07 |
CL2023002577A1 (es) | 2024-01-26 |
CN116917273A (zh) | 2023-10-20 |
BR112023017296A2 (pt) | 2023-11-14 |
US11771711B2 (en) | 2023-10-03 |
CO2023011641A2 (es) | 2023-09-18 |
JP2024509529A (ja) | 2024-03-04 |
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