TWI732765B - 酪胺酸激酶抑制劑 - Google Patents
酪胺酸激酶抑制劑 Download PDFInfo
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- TWI732765B TWI732765B TW105117466A TW105117466A TWI732765B TW I732765 B TWI732765 B TW I732765B TW 105117466 A TW105117466 A TW 105117466A TW 105117466 A TW105117466 A TW 105117466A TW I732765 B TWI732765 B TW I732765B
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Abstract
本發明提供作為酪胺酸激酶抑制劑、尤其布魯頓酪胺酸激酶(Bruton tyrosine kinase,「BTK」)抑制劑,且因此適用於治療可藉由抑制BTK來治療的疾病(諸如癌症、自體免疫、發炎及血栓栓塞疾病)之化合物。亦提供含有此類化合物之醫藥組合物及製備此類化合物之方法。
Description
本申請案主張2015年6月3日申請之美國臨時申請案序號62/170,547及2015年12月28日申請之美國臨時申請案序號62/271,689之權益,其中之每一者以全文引用之方式併入本文中。
本發明提供作為酪胺酸激酶抑制劑,特定言之布魯頓酪胺酸激酶(「BTK」)抑制劑,且因此適用於治療諸如癌症、自體免疫、發炎及血栓栓塞疾病的疾病之化合物。亦提供含有此類化合物之醫藥組合物及製備此類化合物之方法。
BTK,為Tec家族非受體酪胺酸激酶之成員,對於B細胞受體下游之B細胞信號傳導至關重要。其在B細胞及其他造血細胞(諸如單核細胞、巨噬細胞及肥大細胞)中表現。其在B細胞功能之維持B細胞庫之各種態樣中起作用(參見Gauld S.B.等人,B cell antigen receptor signaling:roles in cell development and disease.Science,296:1641-2.2002)。B細胞在類風濕性關節炎中(參見Perosa F.,等人,CD20-depleting therapy in autoimmune diseases:from basic research to the clinic.J Intern Med.267:260-77.2010及Dörner T,等人Targeting B cells in immune-mediated inflammatory disease:a comprehensive review of mechanisms of action and identification of biomarkers.Pharmacol Ther.
125:464-75.2010及Honigberg,L.,等人,The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indiced arthritis.Clin.Immunol.127 S1:S111.2008)及在其他自體免疫疾病(諸如全身性紅斑性狼瘡症及癌症中)(參見Shlomchik M.J.,等人,The role of B cells in lpr/lpr-induced autoimmunity.J.Exp Med.180:1295-1306.1994;Honigberg L.A.,The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.Proc.Natl.Acad.Sci.107:13075-80.2010;及Mina-Osorio P,等人,Suppression of glomerulonephritis in lupus-prone NZB x NZW mice by RN486,a selective inhibitor of Bruton's tyrosine kinase.Arthritis Rheum.65:2380-91.2013)發揮作用。
BTK抑制劑亦存在治療過敏性疾病之潛能(參見Honigberg,L.,等人,The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indiced arthritis.Clin.Immunol.127 S1:S111.2008)。注意到不可逆抑制劑抑制小鼠中由IgE抗原複合物誘導之被動皮膚全身性過敏反應(PCA)。此等發現與在BTK-突變肥大細胞及基因剔除小鼠之情況下注意到的彼等一致且表明BTK抑制劑可適用於治療哮喘,IgE依賴性過敏性呼吸道疾病。
因此,抑制BTK之化合物將適用於諸如自體免疫疾病、發炎性疾病及癌症的疾病之治療。
其中:R1及R2獨立地為氫、烷基、烷氧基、鹵烷基或鹵基;X為-O-、-CONR-、-NRCO-或-NR-CO-NR',其中R及R'獨立地為氫或烷基;Ar為雜芳基或苯基,其中雜芳基及苯基視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代;A為-N-或-CR3-,其中R3為氫、烷基、環丙基、鹵基、鹵烷基、鹵烷氧基、烷氧基或氰基;Y為鍵或伸烷基;環Z為視情況經一個或兩個獨立地選自烷基、羥基、烷氧基及氟之取代基取代的雜環胺基;R5為式(i)、(ii)、(iii)或(iv)之基團:
其中:Ra為氫、氟或氰基;其限制條件為當Ra為氰基時,則Rb為氫且Rc不為氫;Rb為氫或烷基;及Rc為氫、羥烷基、烷氧基烷基、烷基(視情況經一個或兩個獨立地選自以下之取代基取代:羥基、羥烷基、雜芳基(視情況經一個或
兩個獨立地選自烷基及雜環基之取代基取代,其中雜環基視情況經一個或兩個獨立地選自鹵基及烷基之取代基取代)及-CONR9R10(其中R9及R10獨立地為氫或烷基,或R9及R10與其所連接之氮原子一起形成視情況經一個或兩個選自烷基及雜環基之取代基取代的雜環基))、環烷基(視情況經一個或兩個獨立地選自鹵基、烷基、烷氧基烷基及芳基之取代基取代;或其中該環烷基之兩個相鄰取代基與其所連接之碳原子一起形成雜環基)、雜環基烷基、雜環基(其中雜環基及雜環基烷基中之雜環基視情況經一個、兩個或三個取代基取代,其中視情況存在之取代基中之兩者獨立地選自烷基、烷氧基、羥基、鹵基、胺基及側氧基,且視情況存在之取代基中之一者為烷基、羥烷基、烷氧基、烷氧基烷基、醯基、鹵烷基、烷基磺醯基、烷氧羰基或雜環基,其中該雜環基經一個或兩個獨立地選自氫、烷基、鹵基、羥基及烷氧基之取代基取代)或-(伸烷基)-NR6R7(其中R6及R7獨立地為氫、烷基、鹵烷基、羥烷基、烷氧基烷基、環烷基或雜環基,其中該雜環基視情況經一個或兩個獨立地選自烷基、鹵基、羥基、羥烷基、烷氧基烷基、醯基及烷氧羰基之取代基取代;或R6及R7與其所連接之氮原子一起形成
或,其中X1、X2及X3中之一者或兩者為氮且其餘部分
為碳且環視情況經一個或兩個獨立地選自烷基、鹵烷基及鹵基之取代基取代);及/或其醫藥學上可接受之鹽,其限制條件為:當A為-N-時,則Ra為氰基且Rc為雜環胺基烷基,其中雜環胺基烷基中之雜環胺基視情況經一個或兩個獨立地選自烷基、烷氧基、羥基、鹵基、胺基及側氧基之取代基取代,且雜環胺基之氮原子經雜環基取代,其中該雜環基經一個或兩個獨立地選自氫、烷基、鹵基、羥基及烷氧基之取代基取代。
在一個實施例中,當式(I)化合物及/或其醫藥學上可接受之鹽(及本文所揭示之其任何實施例)中之R5為式(i)、(ii)或(iii)(其中Ra為氰基)之基團時,本發明化合物為BTK之可逆共價抑制劑,即其可與半胱胺酸殘基之硫醇基,特定言之與BTK之Cys481形成可逆共價鍵。
在另一實施例中,當式(I)化合物及/或其醫藥學上可接受之鹽(及本文所揭示之其任何實施例)中之R5為式(i)、(ii)或(iii)(其中Ra為氫或氟)之基團,或R5為式(iv)之基團時,本發明化合物為BTK之不可逆共價抑制劑,即其可與半胱胺酸殘基之硫醇基,特定言之與BTK之Cys481形成不可逆共價鍵。
在第二態樣中,本發明係關於包含式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽;及醫藥學上可接受之賦形劑的醫藥組合物。
(a)在第二態樣之實施例(a)中,調配物為固體口服調配物,其包含:(i)式(I)化合物及/或其醫藥學上可接受之鹽(或本文所揭示之其任一實施例);及(ii)用於在腸內釋放該化合物及/或其醫藥學上可接受之鹽的構件。
(b)在第二態樣之實施例(b)中,調配物為固體口服調配物,其包含用於在腸內自該口服調配物釋放治療有效量之式(I)化合物及/或其醫藥學上可接受之鹽(或本文所揭示之其任一實施例)的構件。
在實施例(a)或(b)內,在一個實施例中式(I)化合物及/或其醫藥學上可接受之鹽(或本文所揭示之其任一實施例)在小腸內釋放。
在實施例(a)或(b)及其中所含之實施例的又一實施例中,其中(i)式(I)化合物及/或其醫藥學上可接受之鹽(或本文所揭示之其實施例);及/或(ii)包含式(I)化合物(或本文所揭示之其實施例)及/或其醫藥學上
可接受之鹽之劑型;包覆有至少一種包衣,其中該包衣獨立地選自(當存在多於一種包衣時)腸溶衣及非腸溶延時釋放包衣,較佳地包衣為一或多種腸溶衣。
在一個實施例中,當式(I)化合物及/或其醫藥學上可接受之鹽(或本文所揭示之其實施例)及/或包含式(I)化合物及/或其醫藥學上可接受之鹽(或本文所揭示之其實施例)的劑型包覆有腸溶衣時,腸溶衣為聚合物。在另一實施例中,當式(I)化合物及/或其醫藥學上可接受之鹽及/或包含式(I)化合物及/或其醫藥學上可接受之鹽的劑型包覆有腸溶衣時,腸溶衣為陰離子聚合物,其選自聚甲基丙烯酸酯(例如聚甲基丙烯酸乙基丙烯酸酯、聚甲基丙烯酸甲基丙烯酸甲酯)、基於纖維素之聚合物(例如鄰苯二甲酸乙酸纖維素CAP、苯偏三酸乙酸纖維素CAT、丁二酸乙酸纖維素CAS、鄰苯二甲酸羥丙基甲基纖維素HPMCP、丁二酸乙酸羥丙基甲基纖維素HPMCAS)及聚乙烯衍生物(諸如聚乙酸乙烯酯鄰苯二甲酸酯PVAP)。在又一實施例中,腸溶衣在具有約4.5至約7或約5或5.5至約7之pH的胃腸道中腐蝕以釋放式(I)化合物及/或其醫藥學上可接受之鹽(或本文所揭示之其實施例)。
當採用非腸溶包衣時,可以空腹狀態投與非腸溶延時釋放劑型且延時釋放包衣可經設計以在投與之後約0.3至約3小時內或約0.5至約2小時內腐蝕、破裂或變得高度可滲透以釋放式(I)化合物(或本文所揭示之其實施例)及/或其醫藥學上可接受之鹽。
在第三態樣中,本發明係關於治療有需要之哺乳動物的可藉由抑制BTK治療之疾病的方法,該方法包含向有需要之哺乳動物投與包含治療有效量之式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽及醫藥學上可接受之賦形劑的醫藥組合物。在一個實施例中,疾病為癌症、自體免疫、發炎或血栓栓塞疾病。在一個實施例中,疾病為急性壞死性出血性腦白質炎、急性播散性腦脊
髓炎、艾迪森氏病(Addison's disease)、無γ球蛋白血症、斑禿、普禿、澱粉樣變性、僵直性脊椎炎、抗GBM/抗TBM腎炎、抗磷脂症候群(APS)、抗磷脂抗體症候群、再生不全性貧血、關節炎、自體免疫性血管性水腫、自體免疫性自主神經失調、自體免疫性肝炎、自體免疫性高脂質血症、自體免疫性免疫缺乏症、自體免疫性內耳病(AIED)、自體免疫性心肌炎、自體免疫性卵巢炎、自體免疫性胰臟炎、自體免疫性視網膜病、自體免疫性血小板減少性紫癲(ATP)、自體免疫性甲狀腺疾病、自體免疫性蕁麻疹、自體免疫性溶血性貧血(例如,溫抗體型自體免疫性溶血性貧血(warm autoimmune hemolytic anemia))、軸突及神經元神經病變、巴洛病(Balo disease)、貝切特氏病(Behcet's disease)、大皰性類天疱瘡、心肌病、卡斯特爾曼病(Castleman disease)、乳糜瀉、卻格司氏病(Chagas disease)、慢性疲勞症候群、慢性發炎性脫髓鞘多發性神經病(CIDP)、慢性復發性多灶性骨髓炎(CRMO)、徹奇-斯全司症候群(Churg-Strauss syndrome)、瘢痕性類天疱瘡/良性黏膜類天疱瘡、腹腔病、柯根氏症候群(Cogans syndrome)、冷凝集素病、先天性心傳導阻滯、柯沙奇心肌炎(coxsackie myocarditis)、CREST病、克羅恩氏病(Crohn's disease)、脫髓鞘神經病變、疱疹樣皮炎、皮肌炎、德維克氏病(Devic's disease)(視神經脊髓炎)、糖尿病、盤狀狼瘡、德雷斯勒氏症候群(Dressler's syndrome)、乾眼症、自主神經失調、子宮內膜異位、嗜酸性食道炎、嗜酸性筋膜炎、結節性紅斑、原發性混合冷球蛋白血症、伊文氏症候群(Evans syndrome)、實驗性過敏性腦脊髓炎、肌肉纖維疼痛、纖維化肺泡炎、巨細胞性動脈炎(顳動脈炎)、巨細胞性心肌炎、絲球體腎炎、古德巴士德氏症候群(Goodpasture's syndrome)、肉芽腫性多血管炎(GPA)(先前稱作韋格納氏肉芽腫病(Wegener's Granulomatosis))、格雷夫氏病(Graves' disease)、格林-巴利症候群(Guillain-Barre syndrome)、橋本氏甲狀腺炎(Hashimoto's
thyroiditis)、溶血性貧血、亨諾-許蘭紫癜(Henoch-Schonlein purpura)、妊娠疱疹、低γ球蛋白血症、特發性肺部纖維化、特發性血小板減少性紫癜(ITP)、IgA腎病、IgG4相關硬化性疾病、免疫調節脂蛋白、包涵體肌炎、發炎性腸病、間質性膀胱炎、幼年型關節炎、幼年型糖尿病(1型糖尿病)、幼年型肌炎、川崎症候群(Kawasaki syndrome)、蘭伯特-伊頓症候群(Lambert-Eaton syndrome)、白細胞碎裂性血管炎、扁平苔癬、硬化性苔癬、木質結膜炎、線性IgA疾病(LAD)、狼瘡(SLE)、狼瘡(包括狼瘡性腎炎)、萊姆病、慢性、美尼埃爾氏病(Meniere's disease)、顯微鏡下多血管炎、混合性結締組織病(MCTD)、莫倫氏潰瘍(mooren's ulcer)、穆-哈二氏病(Mucha-Habermann disease)、黏膜類天疱瘡、多發性硬化、重症肌無力、肌炎、發作性睡病、神經肌強直、嗜中性球減少症、眼部瘢痕性類天疱瘡、斜視眼陣攣肌陣攣症候群、視神經炎、奧德氏甲狀腺炎、骨關節炎、復發性風濕、PANDAS(與鏈球菌相關之兒童自體免疫性神經精神病症)、副腫瘤小腦退化、陣發性夜間血紅素尿症(PNH)、帕瑞-羅姆伯格氏症候群(Parry Romberg syndrome)、睫狀體扁平部炎(周邊葡萄膜炎)、帕-特二氏症候群(Parsonnage-Turner syndrome)、周邊神經病變、靜脈周圍腦脊髓炎、惡性貧血、天疱瘡(諸如尋常天疱瘡、落葉狀天疱瘡)、POEMS症候群、結節性多動脈炎、風濕性多肌痛、多發性肌炎、心肌梗塞後症候群、心包切開術後症候群、原發性膽汁性肝硬化、原發性硬化性膽管炎、原發性膽汁性肝硬化、孕酮皮炎、牛皮癬、牛皮癬性關節炎、牛皮癬性關節炎、純紅細胞再生障礙、壞疽性膿皮病、雷諾現象(raynauds phenomenon)、反應性關節炎、反射性交感神經失養症、萊特爾氏症候群(Reiter's syndrome)、復發性多軟骨炎、腿不寧症候群、腹膜後纖維化、風濕熱、類風濕性關節炎、類肉瘤病、施密特症候群(Schmidt syndrome)、鞏膜炎、硬皮病、休格連
氏症候群(Sjogren's syndrome)、精子及睪丸自體免疫、僵人症候群、斯蒂爾氏病(Still's disease)、亞急性細菌性心內膜炎(SBE)、蘇薩克氏症候群(Susac's syndrome)、交感性眼炎、高安氏動脈炎(Takayasu's arteritis)、顳動脈炎/巨細胞性動脈炎、血小板減少性紫癲(TTP)、托-享二氏症候群(Tolosa-Hunt syndrome)、橫貫性脊髓炎、I型、II型及III型自體免疫性多腺症候群、潰瘍性結腸炎、未分化結締組織病(UCTD)、葡萄膜炎、血管炎、水泡性皮膚病(vesiculobullous dermatosis)、白斑病、外陰疼痛或狼瘡。
在第三態樣之一個實施例中,哺乳動物罹患自體免疫疾病,例如發炎性腸病、關節炎、狼瘡(包括狼瘡性腎炎)、類風濕性關節炎、牛皮癬性關節炎、骨關節炎、斯蒂爾氏病、幼年型關節炎、糖尿病、重症肌無力、肉芽腫性多血管炎、橋本氏甲狀腺炎、奧德氏甲狀腺炎、格雷夫斯氏病、休格連氏症候群、乾眼症(包括休格連氏乾眼症及非休格連氏乾眼症)、多發性硬化、格林-巴利症候群、急性播散性腦脊髓炎、艾迪森氏病、斜視眼陣攣肌陣攣症候群、僵直性脊椎炎、抗磷脂抗體症候群、再生不全性貧血、自體免疫性肝炎、腹腔病、古德巴士德氏症候群、特發性血小板減少性紫癜、視神經炎、硬皮病、原發性膽汁性肝硬化、萊特爾氏症候群、高安氏動脈炎、顳動脈炎、自體免疫性溶血性貧血、韋格納氏肉芽腫病、牛皮癬、普禿、貝切特氏病、慢性疲勞、自主神經失調、子宮內膜異位、間質性膀胱炎、神經肌強直、硬皮病、天疱瘡(諸如尋常天疱瘡及/或落葉狀天疱瘡)、大皰性類天疱瘡、年齡相關性黃斑變性(濕性及乾性)、糖尿病黃斑水腫、角膜移植、腹主動脈瘤、黏膜類天疱瘡或外陰疼痛。
在另一實施例中,自體免疫疾病為狼瘡、尋常天疱瘡、重症肌無力、休格連氏症候群、乾眼症、多發性硬化、韋格納氏肉芽腫病、自體免疫性溶血性貧血、特發性血小板減少性紫癜、肉芽腫性多血管
炎或類風濕性關節炎。
在第三態樣之另一實施例中,哺乳動物罹患異種免疫病狀或疾病,例如移植物抗宿主疾病、移植、輸注、全身性過敏反應、過敏、I型過敏、過敏性結膜炎、過敏性鼻炎或異位性皮炎。在另一實施例中,疾病為異位性皮炎。
在第三態樣之又一實施例中,哺乳動物罹患發炎疾病,例如哮喘、闌尾炎、瞼炎、細支氣管炎、支氣管炎、滑囊炎、子宮頸炎、膽管炎、膽囊炎、結腸炎、結膜炎、膀胱炎、淚腺炎、皮炎、皮肌炎、腦炎、心內膜炎、子宮內膜炎、腸炎、小腸結腸炎、上髁炎、附睾炎、筋膜炎、纖維組織炎、胃炎、胃腸炎、肝炎、化膿性汗腺炎、喉炎、乳腺炎、腦膜炎、脊髓炎心肌炎、肌炎、腎炎、卵巢炎、睪丸炎、骨炎、耳炎、胰臟炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、靜脈炎、局部肺炎、肺炎、直腸炎、前列腺炎、腎盂腎炎、鼻炎、輸卵管炎、竇炎、口腔炎、滑膜炎、肌腱炎、扁桃腺炎、葡萄膜炎、陰道炎、血管炎或外陰炎。在此態樣之另一實施例中,哺乳動物罹患發炎皮膚疾病,其包括例如皮炎、接觸性皮炎、濕疹、蕁麻疹、紅斑座瘡及皮膚、關節或其他組織或器官中之疤痕牛皮癬性損傷。在另一實施例中,發炎疾病為哮喘或皮炎。
在第三態樣之又一實施例中,哺乳動物罹患發炎及/或自體免疫疾病,包括急性發炎及/或自體免疫疾病,其中皮質類固醇療法用作一線或二線療法或一線或二線維持療法。在一個實施例中,式(I)化合物(或本文所揭示之其任何實施例)用於以下之治療:內分泌病症:原發性或繼發性腎上腺皮質功能不全(氫皮質酮或皮質酮為首選:在適用情況下合成類似物可與鹽皮質激素結合使用;在嬰兒期中鹽皮質激素補充特別重要);先天性腎上腺增生;非化膿性甲狀腺炎;與癌症相關之高鈣血症。
風濕性病症:在以下中作為短期投與之輔助療法(使患者度過急性發作或惡化):牛皮癬性關節炎;類風濕性關節炎,包括幼年型類風濕性關節炎(所選病例可需要低劑量維持療法);僵直性脊椎炎;急性及亞急性滑囊炎;急性非特異性腱鞘炎;痛風;急性痛風性關節炎;創傷後骨關節炎;骨關節炎滑膜炎;上髁炎。
膠原蛋白疾病:在惡化期間或在以下之所選病例中作為維持療法:全身性紅斑性狼瘡症、全身性皮肌炎(多發性肌炎)、急性風濕性心臟炎。
皮膚病學疾病:天疱瘡;大皰性疱疹樣皮炎;重度多形性紅斑(史蒂芬斯-約翰遜症候群(Stevens-Johnson syndrome));剝脫性皮炎;蕈樣真菌病;重度牛皮癬;重度脂溢性皮炎。
過敏病況:控制習知治療之適當試驗難治療之重度或失能過敏病狀:季節性或常年性過敏性鼻炎;支氣管哮喘;接觸性皮炎;異位性皮膚炎;血清病;藥物過敏反應。
眼科疾病:涉及眼睛及其附件之重度急性及慢性過敏及發炎過程,諸如:過敏性角膜邊緣潰瘍、眼部帶狀疱疹、前段發炎、彌漫性後葡萄膜炎及脈絡膜炎、交感性眼炎、過敏性結膜炎、角膜炎、脈絡膜視網膜炎、視神經炎、虹膜炎及虹膜睫狀體炎。
呼吸道疾病:症狀性類肉瘤病;不可藉由其他方式管理之呂佛勒氏症候群(Loeffler's syndrome);鈹中毒;吸入性肺炎;當與合適之抗結核化學療法同時使用時之暴發性或播散性肺結核病
血液科病症:成人之特發性血小板減少性紫癜;成人之繼發性血小板減少;後天性(自體免疫)溶血性貧血;幼紅細胞減少症(RBC貧血);先天性(紅細胞系)發育不全性貧血。
贅生性疾病:用於以下之緩解性管理:成人之白血病及淋巴瘤,兒童之急性白血病。
水腫性病況:為了在特發性類型或由於紅斑性狼瘡之腎病症候群中誘導多尿或緩解蛋白尿,而無尿毒症。
胃腸疾病:為了使患者在以下中度過疾病之關鍵期:潰瘍性結腸炎、局部性腸炎。
雜項:當與合適之抗結核化學療法同時使用時具有蛛膜下阻滯及即將發生之阻滯的結核性腦膜炎;具有神經或心肌參與之旋毛蟲病。
式(I)化合物及/或其醫藥學上可接受之鹽可視情況與皮質類固醇、非皮質類固醇、免疫抑制及/或消炎劑組合用於治療上列疾病。在一個實施例中,免疫抑制劑選自干擾素α、干擾素γ、環磷醯胺、他克莫司、黴酚酸嗎啉乙酯、甲胺喋呤、氨苯碸(dapsone)、柳氮磺胺吡啶、硫唑嘌呤、抗CD20藥劑(諸如利妥昔單抗(rituximab)、奧伐木單抗(ofatumumab)、歐比托珠單抗(obinutuzumab)或維托珠單抗(veltuzumab),或其生物類似版本)、抗TNFα藥劑(諸如依那西普(entanercept)、英利昔單抗(infliximab)、戈利木單抗(golilumab)、阿達木單抗(adalimumab)或聚乙二醇化賽妥珠單抗(certolizumab pegol)或其生物類似版本)、針對配位體或其受體之抗IL6藥劑(諸如托西利單抗(tocilizumab)、賽瑞路單抗(sarilumab)、奧諾奇單抗(olokizumab)、艾爾斯里路單抗(elsililumab)、或思圖昔單抗(siltuximab))、針對配位體或其受體之抗IL17藥劑(諸如塞庫金單抗(secukinumab)、優特克單抗(ustekinumab)、布羅達單抗(brodalumab)或伊科奇單抗(ixekizumab))、針對配位體或其受體之抗IL1藥劑(諸如在利納西普(rilonacept)、康納單抗(canakinumab)或阿那白滯素(anakinra)之情況下)、針對配位體或其受體之抗IL2藥劑(諸如巴利昔單抗(basiliximab)或達利珠單抗(daclizumab))、抗CD2藥劑(諸如阿法賽特(alefacept))、抗CD3藥劑(諸如莫羅莫那-cd3)、抗CD80/86藥劑
(諸如阿巴西普(abatacept)或貝拉西普(belatacept))、抗神經鞘胺醇-1-磷酸鹽受體藥劑(諸如芬戈莫德(fingolimod))、抗C5藥劑(諸如艾庫組單抗(eculizumab))、抗整合素α4藥劑(諸如那他珠單抗(natalizumab))、抗α4β7藥劑(諸如維多珠單抗(vedolizumab))、抗mTOR藥劑(諸如西羅莫司或依維莫司)、抗鈣調神經磷酸酶藥劑(諸如他克莫司)及抗BAFF/BlyS藥劑(諸如貝利單抗(belimumab)、VAY736或布里莫德)、來氟米特及特立氟胺。較佳地,免疫抑制劑為利妥昔單抗、奧伐木單抗、歐比托珠單抗或維托珠單抗或其生物類似版本。
在第三態樣之又一實施例中,哺乳動物罹患癌症。在一個實施例中,癌症為B細胞增生性病症,例如瀰漫性大B細胞淋巴瘤、濾泡性淋巴瘤、慢性淋巴細胞性淋巴瘤(CLL)、慢性淋巴球性白血病、慢性骨髓性白血病、B細胞急性淋巴母細胞性白血病(B-ALL)、費城染色體(Philadelphia chromosome)陽性B-ALL、B細胞前淋巴球性白血病、小淋巴細胞性淋巴瘤(SLL)、多發性骨髓瘤、B細胞非霍奇金淋巴瘤(B-cell non-Hodgkin lymphoma)、淋巴漿細胞性淋巴瘤/瓦爾登斯特倫巨球蛋白血症(Waldenstrom macroglobulinemia)、脾邊緣區淋巴瘤、漿細胞骨髓瘤、漿細胞瘤、結外邊緣區B細胞淋巴瘤、結內邊緣區B細胞淋巴瘤、套細胞淋巴瘤、縱隔(胸腺)大B細胞淋巴瘤、血管內大B細胞淋巴瘤、原發性滲出性淋巴瘤、伯基特淋巴瘤(burkitt lymphoma)/白血病或淋巴瘤樣肉芽腫。
在第三態樣之又一實施例中,哺乳動物罹患血栓栓塞病症,例如心肌梗塞、心絞痛、血管成形術之後的再閉塞、血管成形術之後的再狹窄、主動脈冠狀動脈旁路之後的再閉塞、主動脈冠狀動脈旁路之後的再狹窄、中風、暫時性缺血、周邊動脈閉塞病症、肺栓塞或深靜脈血栓形成。
在第四態樣中,本發明係關於式(I)化合物(及本文中描述之其任
何實施例)及/或其醫藥學上可接受之鹽,其用作藥物。在一個實施例中,式(I)化合物及/或其醫藥學上可接受之鹽之用途係用於治療由BTK介導之疾病,例如疾病為在第三態樣及其中實施例中描述之發炎疾病、自體免疫疾病、癌症或血栓栓塞疾病。
在第五態樣中的為式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽在製造用於治療哺乳動物之疾病的藥物中之用途,其中BTK促成該疾病之病理學及/或症狀。在此態樣之一個實施例中,疾病為在第三態樣及其中實施例中描述之癌症、自體免疫、發炎或血栓栓塞疾病。
在涉及治療癌症之前述態樣中的任一者中的為其他實施例,其包含投與式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽與抗癌劑之組合。當使用組合療法時,藥劑可同時(諸如固定組合藥品)或依序投與。
其中:R1、R2、R3、X、Ar、Y及環Z如以上第一態樣中所定義;或其鹽。
其中:R1、R2、R3、X、Ar、Y及Z如以上第一態樣中所定義;在醯化反應條件下與式RcCH=C(CN)COL化合物反應,其中L為離去基,其中Rc如以上第一態樣中所定義;或(2).式(I)化合物,其中Ra為氫,A為-CR3-且其他基團如以上第一態樣中所定義:或其醫藥鹽;該方法包含使式(III)化合物:
其中:R1、R2、R3、X、Ar、Y及環Z如以上第一態樣中所定義;在醯化反應條件下與式RcRbC=CHCOL化合物反應,其中L為離去基,其中Rb及Rc如以上第一態樣中所定義;(c)視情況製備自以上步驟(1)或(2)獲得之化合物之酸加成鹽;(d)視情況製備自以上步驟(1)或(2)獲得之化合物之游離鹼。
定義:除非另外說明,否則以下在說明書及申請專利範圍中使用之術語出於本發明之目的定義且具有以下含義:「烷基」意謂一至六個碳原子之直鏈飽和單價烴基或三至六個碳原子之分支鏈飽和單價烴基,例如甲基、乙基、丙基、2-丙基、丁基(包括所有異構體形式)、戊基(包括所有異構體形式)及其類似基團。
除非另外說明,否則「伸烷基」意謂一至六個碳原子之直鏈飽和二價烴基或三至六個碳原子之分支鏈飽和二價烴基,例如亞甲基、伸乙基、伸丙基、1-甲基伸丙基、2-甲基伸丙基、伸丁基、伸戊基及其類似基團。
「烷基磺醯基」意謂-SO2R基團,其中R為如上文所定義之烷基;例如甲磺醯基、乙磺醯基及其類似基團。
「胺基」意謂-NH2。
「烷氧基」意謂-OR基團,其中R為如上文所定義之烷基;例如
甲氧基、乙氧基、丙氧基或2-丙氧基、正丁氧基、異丁氧基或第三丁氧基,及其類似基團。
「烷氧基烷基」意謂經如上文所定義之烷氧基(在一個實施例中,一個或兩個烷氧基)取代之一至六個碳原子之直鏈單價烴基或三至六個碳原子之分支鏈單價烴基,例如2-甲氧基乙基、1-甲氧基丙基、2-甲氧基丙基或3-甲氧基丙基、2-乙氧基乙基,及其類似基團。
「烷氧羰基」意謂-C(O)OR基團,其中R為如上文所定義之烷基;例如甲氧羰基、乙氧羰基及其類似基團。
「醯基」意謂-COR基團,其中R為烷基、鹵烷基或環烷基;例如乙醯基、丙醯基、環丙基羰基及其類似基團。當R為烷基時,該基團在本文中亦稱為烷基羰基。
「環烷基」意謂三至十個碳原子之環狀飽和單價烴基,其中一個或兩個碳原子可經側氧基置換;例如環丙基、環丁基、環戊基或環己基,及其類似基團。
「羧基」意謂-COOH。
「鹵基」意謂氟、氯、溴或碘;在一個實施例中氟或氯。
「鹵烷基」意謂如上文所定義之烷基,其經一個或一至五個鹵素原子(在一個實施例中氟或氯)取代,包括經不同鹵素取代之彼等,例如-CH2Cl、-CF3、-CHF2、-CH2CF3、-CF2CF3、-CF(CH3)2及其類似基團。當烷基僅僅經氟取代時,其在本發明中可稱為為氟烷基。
「鹵烷氧基」意謂-OR基團,其中R為如上文所定義之鹵烷基,例如-OCF3、-OCHF2,及其類似基團。當R為其中烷基僅僅經氟取代之鹵烷基時,其在本發明中可稱為氟烷氧基。
「羥烷基」意謂經一個或兩個羥基取代之一至六個碳原子之直鏈單價烴基或三至六個碳原子之分支鏈單價烴基,其限制條件為若存在兩個羥基,則其不皆在同一碳原子上。代表性實例包括(但不限於)
羥甲基、2-羥乙基、2-羥丙基、3-羥丙基、1-(羥甲基)-2-甲基丙基、2-羥丁基、3-羥丁基、4-羥丁基、2,3-二羥丙基、1-(羥甲基)-2-羥乙基、2,3-二羥丁基、3,4-二羥丁基及2-(羥甲基)-3-羥丙基。其他實例包括(但不限於)2-羥乙基、2,3-二羥丙基及1-(羥甲基)-2-羥乙基。
「雜環基」意謂4至10個環原子之飽和或不飽和單價單環或雙環基團(稠合雙環或橋接雙環),其中一個或兩個環原子為選自N、O及S(O)n之雜原子,其中n為0至2之整數,其餘環原子為C。另外,雜環基環中之一個或兩個環碳原子可視情況經-CO-基團置換。更特定言之,術語雜環基包括(但不限於)氧雜環丁烷基、N-吡咯啶基、N-哌啶基、高哌啶子基(homopiperidino)、2-側氧基吡咯啶基、2-側氧基哌啶基、N-嗎啉基、哌嗪基、四氫哌喃基、N-硫代嗎啉基、六氫吡咯并[1,2-a]吡嗪-6(2H)-酮-基、四氫-1H-噁唑并[3,4-a]吡嗪-3(5H)-酮-基、5,6,7,8-四氫-[1,2,4]三唑并[4,3-a]吡嗪-基、3-氧雜-8-氮雜雙環[3.2.1]辛烷-基,及其類似基團。當雜環基環不飽和時,其可含有一個或兩個環雙鍵,其限制條件為環不為芳族。
「雜環基烷基」意謂-(伸烷基)-R基團,其中R為如上文所定義之雜環基環;例如四氫呋喃基甲基、哌嗪基甲基、嗎啉基乙基及其類似基團。
「雜環胺基」意謂4至8個環原子之飽和或不飽和單價單環基團,其中一個或兩個環原子為選自N、O或S(O)n之雜原子,其中n為0至2之整數,其餘環原子為C,其限制條件為環原子中之至少一者為N。另外,雜環胺基環中之一個或兩個環碳原子可視情況經-CO-基團置換。當雜環胺基環不飽和時,其可含有一個或兩個環雙鍵,其限制條件為環不為芳族。
「雜環胺基烷基」意謂-(伸烷基)-R基團,其中R為如上文所描述之雜環胺基。
「雜芳基」意謂5至10個環原子之單價單環或雙環芳基,其中一或多個(在一個實施例中一個、兩個或三個)環原子為選自N、O及S之雜原子,其餘環原子為碳。代表性實例包括(但不限於)吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、異吲哚基、噁唑基、異噁唑基、苯并噻唑基、苯并噁唑基、喹啉基、異喹啉基、吡啶基、嘧啶基、吡嗪基、噠嗪基、三唑基、四唑基,及其類似基團。
如本文所用之「哺乳動物」意謂馴養動物(諸如狗、貓及馬),及人類。在一個實施例中,哺乳動物為人類。
本發明亦包括式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽之前藥。術語前藥意欲代表共價鍵結載劑,當向哺乳動物個體投與前藥時其能夠釋放式(I)(或本文中描述之其實施例中之任一者)之活性成分。活性成分之釋放在活體內發生。可藉由熟習此項技術者已知之技術製備前藥。此等技術一般將給定化合物中之合適官能基改質。然而,此等改質官能基活體內或藉由常規操作再生最初官能基。式(I)化合物(或本文中描述之其實施例中之任一者)之前藥包括其中羥基、胺基、羧酸或類似基團經改質之化合物。前藥之實例包括(但不限於)酯(例如乙酸酯、甲酸酯及苯甲酸酯衍生物)、式(I)化合物中之羥基或胺基官能基之胺基甲酸酯(例如N,N-二甲胺基羰基))、醯胺(例如三氟乙醯胺基、乙醯胺基及其類似基團),及其類似基團。式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽之前藥亦在本發明之範疇內。
本發明亦包括式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽之多晶形式(非晶形以及結晶)及氘化形式。
化合物之「醫藥學上可接受之鹽」意謂醫藥學上可接受且擁有母體化合物之所需藥理學活性之鹽。此類鹽包括:
用諸如以下之無機酸形成之酸加成鹽:鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似物;或用諸如以下之有機酸形成之酸加成鹽:甲酸、乙酸、丙酸、己酸、環戊丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸、蘋果酸、順丁烯二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、肉桂酸、杏仁酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羥基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦磺酸、葡庚糖酸、4,4'-亞甲基雙-(3-羥基-2-烯-1-羧酸)、3-苯基丙酸、三甲基乙酸、第三丁基乙酸、月桂基硫酸、葡萄糖酸、麩胺酸、羥基萘甲酸、水楊酸、硬脂酸、黏康酸,及其類似物;或當母體化合物中存在之酸性質子經金屬離子(例如鹼金屬離子、鹼土金屬離子或鋁離子)置換;或與有機鹼(諸如乙醇胺、二乙醇胺、三乙醇胺、緩血酸胺、N-甲基還原葡糖胺及其類似物)配位時形成之鹽。應瞭解醫藥學上可接受之鹽無毒。關於適合之醫藥學上可接受之鹽之額外資訊可見於Remington's Pharmaceutical Sciences,第17版,Mack Publishing Company,Easton,PA,1985中,其以引用的方式併入本文中。
本發明之化合物可具有不對稱中心。含有經不對稱取代之原子之本發明化合物可以光學活性或外消旋形式經分離。在此項技術中熟知如何製備光學活性形式,諸如藉由物質之解析。除非特定指示特定立體化學或異構形式,否則呈個別形式及其混合物之所有對掌性、非對映異構性、外消旋形式在本發明之範疇內。
某些式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽可以互變異構體及/或幾何異構體之形式存在。呈個別形式及其混合物之所有可能互變異構體及順式及反式異構體在本發明之範疇內。另外,如本文所用,術語烷基包括該烷基之所有可
能的異構體形式,儘管僅僅闡述幾個實例。此外,當環狀基團(諸如雜芳基、雜環基)經取代時,其包括所有位置異構體,儘管僅僅闡述幾個實例。此外,式(I)化合物(或本文中描述之其實施例中之任一者)及/或其醫藥學上可接受之鹽之所有水合形式在本發明之範疇內。
「側氧基」或「羰基」意謂=(O)基團。
「視情況(optional)」或「視情況(optionally)」意謂隨後描述之事件或情形可能發生但非必須發生,且該描述包括事件或情形發生之情況及不發生之情況。舉例而言,「視情況經烷基取代之雜環基」意謂烷基可能存在但非必須存在,且該描述包括雜環基經烷基取代之情況及雜環基不經烷基取代之情況。
「醫藥學上可接受之載劑或賦形劑」意謂適用於製備一般安全、無毒及既不生物學上亦不以其他方式非所需之醫藥組合物的載劑或賦形劑,且包括對於獸醫用途以及人類醫藥用途可接受之載劑或賦形劑。如本說明書及申請專利範圍中所使用之「醫藥學上可接受之載劑/賦形劑」包括一種及多於一種此類賦形劑。
在針對式(I)中之Rc的雜環基之定義中,片語「其中視情況存在之取代基中之兩者獨立地選自烷基、烷氧基、羥基、鹵基及側氧基,且視情況存在之取代基中之一者為烷基、環烷基、羥烷基、烷氧基烷基、醯基、鹵烷基、烷基磺醯基、烷氧羰基或雜環基」(及申請專利範圍及/或說明書中他處之類似片語)意謂當雜環基經一個取代基取代時,取代基可為所列視情況存在之取代基中的任一者。當雜環基環經兩個取代基取代時,則兩個取代基可選自烷基、烷氧基、羥基、鹵基及側氧基或兩個取代基中之一者選自烷基、烷氧基、羥基、鹵基及側氧基,且另一個取代基選自烷基、環烷基、羥烷基、烷氧基烷基、醯基、鹵烷基、烷基磺醯基、烷氧羰基及雜環基。且當雜環基環經三個取代基取代時,則兩個取代基選自烷基、烷氧基、羥基、鹵基及側氧
基且第三取代基選自烷基、環烷基、羥烷基、烷氧基烷基、醯基、鹵烷基、烷基磺醯基、烷氧羰基及雜環基。
疾病之「治療(treating/treatment)」包括:(1)預防疾病,即使得疾病之臨床症狀不會在可能曝露於或易患疾病但尚未經歷或展示疾病症狀之哺乳動物中發展;(2)抑制疾病,即使疾病或其臨床症狀之發展停滯或減少;或(3)緩解疾病,即致使疾病或其臨床症狀消退。
「治療有效量」意謂當向哺乳動物投與以用於治療疾病時,足以實現疾病之此類治療的式(I)化合物(或本文中描述之其實施例中之任一者)的量。「治療有效量」將視化合物、疾病及其嚴重性及待治療之哺乳動物之年齡、體重等而改變。
在以下實施例1-24及其中含有之實施例或亞實施例中,本發明包括:
1.一種式(I)化合物,其如以上第一態樣之第一實施例中所定義,包括其E或Z異構體,及/或其醫藥學上可接受之鹽。
2.如實施例1之化合物及/或其醫藥學上可接受之鹽,其中:R1及R2獨立地為氫、烷基、烷氧基、鹵烷基或鹵基;X為-O-、-CONR-、-NRCO-或-NR-CO-NR',其中R及R'獨立地為氫或烷基;Ar為雜芳基或苯基,其中雜芳基及苯基視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代;A為-N-或-CR3-,其中R3為氫、烷基、環丙基、鹵基、鹵烷基、
鹵烷氧基、烷氧基或氰基;Y為鍵或伸烷基;環Z為視情況經一個或兩個獨立地選自烷基、羥基、烷氧基及氟之取代基取代的雜環胺基;R5為式(i)、(ii)、(iii)或(iv)之基團:
其中:Ra為氫、氟或氰基;其限制條件為當Ra為氰基時,則Rb為氫且Rc不為氫;Rb為氫或烷基;及Rc為氫、視情況經一個或兩個獨立地選自OH之取代基取代的烷基雜芳基(視情況經一個或兩個獨立地選自烷基及雜環基之取代基取代,其中雜環基視情況經一個或兩個獨立地選自鹵基及烷基之取代基取代)及-CONR9R10(其中R9及R10獨立地為氫或烷基,或R9及R10與其所連接之氮原子一起形成視情況經一個或兩個選自烷基及雜環基之取代基取代的雜環基),視情況經一個或兩個獨立地選自鹵基、烷基及芳基之取代基取代的環烷基,羥烷基,烷氧基烷基,雜環基烷基、雜環基(其中雜環基及雜環基烷基中之雜環基視情況經一個、兩個或三個取代基取代,其中視情況存在之取代基中之兩者獨立地選自烷基、烷氧基、羥基、鹵基、胺基及側氧基,且視情況存在之取代基中之一者為烷基、羥烷基、烷氧基、烷氧基烷基、醯
基、鹵烷基、烷基磺醯基、烷氧羰基或雜環基,其中雜環基經一個或兩個獨立地選自氫、烷基、鹵基、羥基及烷氧基之取代基取代),或-(伸烷基)-NR6R7(其中R6及R7獨立地為氫、烷基、鹵烷基、羥烷基、烷氧基烷基、環烷基或雜環基,其中雜環基視情況經一個或兩個獨立地選自烷基、鹵基、羥基、羥烷基、烷氧基烷基、醯基及烷氧羰
基之取代基取代;或R6及R7與其所連接之氮原子一起形成或
,其中X1、X2及X3中之一者或兩者為氮且其餘部分為碳且環
視情況經一個或兩個獨立地選自烷基、鹵烷基及鹵基之取代基取代);及/或其醫藥學上可接受之鹽,其限制條件為:當A為-N-時,則Ra為氰基且Rc為雜環胺基烷基,其中雜環胺基烷基中之雜環胺基視情況經一個或兩個獨立地選自烷基、烷氧基、羥基、鹵基、胺基及側氧基之取代基取代,且雜環胺基之氮原子經雜環基取代,其中該雜環基經一個或兩個獨立地選自氫、烷基、鹵基、羥基及烷氧基之取代基取代。
3.如實施例1至2之化合物及/或其醫藥學上可接受之鹽,其中A為-N-。
4.如實施例1至2之化合物及/或其醫藥學上可接受之鹽,其中A為-CR3-。在實施例4之一個實施例中,R3為氫、甲基、乙基、異丙基、氟或氯。在實施例3之第二實施例中,R3為氫。
5.如實施例1至4及其中所含之實施例中任一項之化合物及/或其醫藥學上可接受之鹽,其中-X-Ar連接至苯環之4-位置處之碳,連接至環狀脲環之N的苯環之碳為位置1。
6.如實施例1至5及其中所含之實施例中任一項之化合物及/或其
醫藥學上可接受之鹽,其中X為-O-。在實施例6內,在第四實施例中,Ar為雜芳基或苯基,其中雜芳基及苯基視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代。在實施例6內,在第五實施例中,Ar為吡啶基、嘧啶基、噻吩基或吡嗪基,其視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代。在實施例6內,在第六實施例中,Ar為苯基,其中苯基視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代,較佳經一個或兩個氟取代。
7.如實施例1至6及其中所含之實施例中任一項之化合物及/或其醫藥學上可接受之鹽,其中X為-CONR-或-NRCO-。在實施例6內,在第四實施例中,Ar為雜芳基或苯基,其中雜芳基及苯基視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代。在實施例7內,在第五實施例中,Ar為吡啶基、嘧啶基、噻吩基或吡嗪基,其視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代。在實施例7內,在第六實施例中,Ar為苯基,其中苯基視情況經一個、兩個或三個獨立地選自烷基、鹵基、鹵烷基、烷氧基及羥基之取代基取代,較佳經一個或兩個氟取代。
8.如實施例1至7及其中所含之實施例中任一項之化合物及/或其醫藥學上可接受之鹽,其中R1及R2獨立地為氫或鹵基,較佳氫或氟,更佳R1及R2為氫或R1為氫且R2為氟。
9.如實施例1至8及其中所含之實施例中任一項之化合物及/或其醫藥學上可接受之鹽,其中Y為伸烷基且環Z為吡咯啶基,且在一個實施例中,吡咯啶-2-基或氮雜環丁烷-3-基。在實施例9內,在一個實施例中,Y為亞甲基。在實施例9內,在第二實施例中,在C2處連接之吡咯啶基環及在連接至Y之吡咯啶基環之碳處的立體化學為(R)或
(S)。在實施例9內的為另一實施例,其中R5為式(i)或(iv)之基團。
10.如實施例1至9及其中所含之實施例中任一項之化合物及/或其醫藥學上可接受之鹽,其中Y為一鍵且環Z為吡咯啶基或哌啶基且在C-3碳處連接至環狀脲氮,吡咯啶基或哌啶基之氮原子為位置C-1。在一個實施例中,在連接至環狀脲氮之吡咯啶基或哌啶基之碳處的立體化學為(R)。
11.如實施例1至10及其中所含之實施例中任一項之化合物及/或其醫藥學上可接受之鹽,其中Ra為氫。在實施例11內,在一個實施例中,R5為式(i)之基團。在實施例11內,在第二實施例中,R5為式(ii)或(iii)之基團。在實施例11內,在第三實施例中,R5為式(iv)之基團。在實施例11中之實施例一至三內,在一個亞實施例中,Rb及Rc為氫。在實施例11中之實施例一至三內,在另一亞實施例中,Rb為氫且Rc為烷基或-(伸烷基)-NR6R7(其中R6及R7獨立地為氫、烷基、鹵烷基、羥烷基、烷氧基烷基、環烷基或雜環基,其中雜環基環視情況經一個或兩個獨立地選自烷基、鹵基、羥基、羥烷基、烷氧基烷基、醯基及烷氧羰基之取代基取代),較佳地R6及R7獨立地為氫或烷基。
12.如實施例1至11及其中所含之實施例中任一項之化合物或其醫藥學上可接受之鹽,其中Ra為氰基。在實施例12內,在一個實施例中,R5為式(i)之基團。在實施例12內,在第二實施例中,R5為式(ii)或(iii)之基團。
(a)在實施例12中之實施例一及二內,在一個亞實施例中,Rc為環烷基,其視情況經一個或兩個獨立地選自鹵基、烷基、烷氧基烷基及芳基之取代基取代;或其中環烷基之兩個相鄰取代基與其所連接之碳原子一起形成雜環基。在一個實施例中,Rc為環丙基、1-甲基環丁
基、1-苯基環丙基、1-甲基環丙基、2,2-二氟環丙基、、
或。
(b).在實施例12中之實施例一及二內,在第二亞實施例中Rc為未經取代之烷基。在一個實施例中,Rc為異丙基或第三丁基。
(c).在實施例11中之實施例一及二內,在一個亞實施例中,Rc為-(伸烷基)-NR6R7(其中R6及R7獨立地為氫、烷基、鹵烷基、羥烷基、烷氧基烷基、環烷基或雜環基)。在另一亞實施例中,Rc為-C(CH3)2NH2、-C(CH3)2NHCH3、-C(CH3)2N(CH3)2、-C(CH3)2NHCH2CH3、-C(CH3)2NHCH(CH3)2、-C(CH3)2NH環丙基、-C(CH3)2NH(CH2)2OCH3、-C(CH3)2OCH2CH3、-C(CH3)2N(CH2CH3)(氧雜環丁烷-3-基)、-C(CH3)2N(CH3)(氧雜環丁烷-3-基)或-C(CH3)2NH(氧雜環丁烷-3-基)。
(d)在實施例12中之實施例一及二內,在另一亞實施例中,Rc為雜環基烷基,其中雜環基烷基中之雜環基視情況經一個、兩個或三個取代基取代,其中視情況存在之取代基中之兩者獨立地選自烷基、烷氧基、羥基、鹵基、胺基及側氧基,且視情況存在之取代基中之一者為烷基、羥烷基、烷氧基烷基、醯基、鹵烷基、烷基磺醯基、烷氧羰基或雜環基,其中雜環基視情況經一個或兩個獨立地選自烷基、鹵基、羥基及烷氧基之取代基取代。
在亞實施例(d)之一個亞實施例中,Rc為-C(CH3)2嗎啉-4-基、-C(CH3)2-4-(2,2,2-三氟乙基)哌嗪-1-基、-C(CH3)2-4-(1-甲基)哌啶-1-
基、、、-C(CH3)2-4-乙基-3-側氧基哌嗪-1-
基、C(CH3)2四氫哌喃-4-基、-C(CH3)2-4-甲氧羰基哌嗪-1-基、-C(CH3)2-4-(氧雜環丁烷-4-基)哌嗪-1-基、-C(CH3)2-4-(3-甲基氧雜環丁烷-4-基)哌嗪-1-基、-C(CH3)2-4-第三丁氧基羰基哌嗪-1-基、-C(CH3)2-4-乙醯基哌嗪-1-基、-C(CH3)2-4-甲氧羰基哌嗪-1-基、-C(CH3)2-哌嗪-
1-基、-C(CH3)2-3,3-二氟吡咯啶-1-基、-C(CH3)2-(S)-3-甲氧基吡咯啶-1-基、-C(CH3)2-(R)-3-甲氧基吡咯啶-1-基、-C(CH3)2-(S)-2-(甲氧基甲基)吡咯啶-1-基、-C(CH3)2-(R)-2-(甲氧基甲基)吡咯啶-1-基、
、、-C(CH3)2-4-甲基哌嗪-1-基、-C(CH3)2-4-
乙基哌嗪-1-基、-C(CH3)2-4-異丙基哌嗪-1-基、-C(CH3)2-4-(2-甲氧基乙基)哌嗪-1-基、-C(CH3)2-4-乙醯基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-3,4,5-三甲基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-3,5-二甲基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-二甲基嗎啉-4-基、-C(CH3)2-哌啶-1-基、-C(CH3)2-吡咯啶-1-基、-C(CH3)2-3-側氧基-哌嗪-1-基或-C(CH3)2-(3-側氧基-4-甲基哌嗪-1-基)。在亞實施例(d)之第二亞實施例中,Rc為雜環基烷基,其中雜環基烷基中之雜環基經另一雜環基取代,其中在另一雜環基之碳上另一雜環基經烷基取代。
(e).在實施例12中之實施例一及二內,在又一亞實施例中,Rc為視情況經一個、兩個或三個取代基取代之雜環基,其中視情況存在之取代基中之兩者獨立地選自烷基、烷氧基、羥基、鹵基、胺基及側氧基,且視情況存在之取代基中之一者為烷基、羥烷基、烷氧基烷基、醯基或雜環基。在亞實施例(e)之一個亞實施例中,Rc為3-甲基氧雜環丁烷-3-基、3-乙基氧雜環丁烷-3-基、3-氟氧雜環丁烷-3-基、3-胺基氧雜環丁烷-3-基、4-甲基哌啶-4-基、3-甲基氮雜環丁烷-3-基、1-甲基氮雜環丁烷-3-基、4-甲基-4-四氫哌喃基或1,3-二甲基氮雜環丁烷-3-
基。在另一亞實施例(f)中,Rc為、、、或
(g)在實施例12之另一亞實施例中,Rc為烷基,其視情況經一個或兩個獨立地選自羥基、羥烷基及雜芳基之取代基取代,該雜芳基經一個或兩個獨立地選自烷基及雜環基之取代基取代,其中雜環基視情況經一個或兩個獨立地選自鹵基及烷基之取代基取代。在另一實施例中,Rc為經一個或兩個羥基取代基取代之烷基。在另一實施例中,Rc為
在一亞實施例中,Rc為經雜芳基取代之烷基,該雜芳基視情況經一個或兩個獨立地選自烷基及雜環基之取代基取代,其中雜環基視情況經一個或兩個獨立地選自鹵基及烷基之取代基取代。在此亞實施例內,在另一實施例中,Rc為
在另一亞實施例中,Rc為經-CONR9R10取代之烷基,其中R9及R10獨立地為氫或烷基,或R9及R10與其所連接之氮原子一起形成視情況經一個或兩個選自烷基及雜環基之取代基取代的雜環基。在此亞實施例內的為其中R9及R10均為氫或烷基之實施例。在另一實施例中,Rc為-C(CH3)2-CONH2或-C(CH3)2-CON(CH3)2。
在另一亞實施例中,Rc為經-CONR9R10取代之烷基,其中R9及R10與其所連接之氮原子一起形成視情況經一個或兩個選自烷基及雜環基之取代基取代的雜環基。在此亞實施例內的為其中由R9及R10與其所連接之氮原子一起形成之雜環基為4-甲基哌嗪基或4-(氧雜環丁烷-3-基)哌嗪-1-基的實施例。
13.如實施例3、5、6及8至10中任一項之化合物(亦即A為-N-;-X-Ar連接至苯環之4-位置處的碳,連接至環狀脲環之N的苯環之碳為位置1;X為O;Y為一鍵;環Z為吡咯啶基或哌啶基且在C-3碳處連接至環狀脲氮,吡咯啶基或哌啶基環之氮原子為C-1;在連接至環狀氮之吡咯啶基或哌啶基之碳處的立體化學為(R)),其中R5為式(i)之基團,Ra為氰基,Rb為氫且Rc為雜環基烷基,其中雜環基烷基中之雜環基視情況經一個、兩個或三個取代基取代,其中視情況存在之取代基中之兩者獨立地選自烷基、烷氧基、羥基、鹵基、胺基及側氧基,且視情況存在之取代基中之一者為烷基、羥烷基、烷氧基、烷氧基烷基、醯基、鹵烷基、烷基磺醯基、烷氧羰基或雜環基,其中雜環基經一個或兩個獨立地選自氫、烷基、鹵基、羥基及烷氧基之取代基取代。
表1之化合物中的任一者之E或Z異構體及/或此等化合物中之任一者之醫藥學上可接受之鹽亦包括在本發明之範疇內。
本發明亦關於以下化合物:4-胺基-1-((3S)-1-(環氧乙烷-2-羰基)哌啶-3-基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;4-胺基-1-((3S)-1-(2,3-二羥基丙醯基)哌啶-3-基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;4-胺基-1-((3S)-1-(2-羥基丙醯基)哌啶-3-基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;(S)-4-胺基-1-(1-(3-羥基丙醯基)哌啶-3-基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;4-胺基-1-(((2R)-1-(環氧乙烷-2-羰基)吡咯啶-2-基)甲基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;4-胺基-1-(((2R)-1-(2,3-二羥基丙醯基)吡咯啶-2-基)甲基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;4-胺基-1-(((2R)-1-(2-羥基丙醯基)吡咯啶-2-基)甲基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;及(R)-4-胺基-1-((1-(3-羥基丙醯基)吡咯啶-2-基)甲基)-3-(4-苯氧基
苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;及/或其醫藥學上可接受之鹽。
此等化合物可根據以下闡述之流程4製備且具有與式(I)化合物相同之效用。
本發明化合物可藉由以下顯示之反應流程中描繪之方法製得。
在製備此等化合物中使用之起始物質及試劑可購自商業供應商,諸如Aldrich Chemical Co.(Milwaukee,Wis.)、Bachem(Torrance,Calif.)或Sigma(St.Louis,Mo.);或藉由熟習此項技術者已知之方法遵循在參考文獻中闡述之程序製備,該等參考文獻諸如Fieser及Fieser's Reagents for Organic Synthesis,第1-17卷(John Wiley and Sons,1991);Rodd's Chemistry of Carbon Compounds,第1-5卷及增刊(Elsevier Science Publishers,1989);Organic Reactions,第1-40卷(John Wiley and Sons,1991),March's Advanced Organic Chemistry,(John Wiley and Sons,第4版)及Larock's Comprehensive Organic Transformations(VCH Publishers Inc.,1989)。此等流程僅說明可藉由其合成本發明化合物之一些方法,且可作出對此等流程之各種修改且熟習此項技術者將參考本發明提出各種修改。可視需要使用習知技術,包括(但不限於)過濾、蒸餾、結晶、層析及其類似技術來分離及純化反應之起始物質及中間物及最終產物。可使用習知方式(包括物理常數及光譜資料)來表徵此類物質。
除非相反地說明,否則本文中描述之反應在大氣壓下在約-78℃至約150℃,或約0℃至約125℃之溫度範圍內或在約室內(或環境)溫度,例如約20℃下進行。
可如以下流程1中所說明及描述製備其中R5為式(i)之基團且其他基團如發明內容中所定義之式(I)化合物。
二鹵基雜芳基化合物(諸如4,6-二氯-5-硝基嘧啶)與式NH(PG)2(其中PG為適合之胺基保護基,諸如苯甲基)之胺之反應得到式1化合物。反應在適合之有機溶劑,諸如二噁烷、二氯甲烷及其類似物中進行。第二鹵基經其中Y及環Z如發明內容中所定義且PG1為適合之胺基保護基(諸如Boc)之式2之胺基化合物置換產生式3化合物。反應在二氯甲烷、二噁烷、四氫呋喃及其類似物中在額外鹼(諸如三乙胺)下進行。式2化合物,諸如(R)-3-胺基哌啶-1-甲酸第三丁酯、(S)-3-胺基哌啶-1-甲酸第三丁酯、(R)-3-(胺基甲基)吡咯啶-1-甲酸第三丁酯、(S)-3-(胺基甲基)吡咯啶-1-甲酸第三丁酯、(R)-2-(胺基甲基)氮雜環丁烷-1-甲酸第三丁酯及(S)-2-(胺基甲基)氮雜環丁烷-1-甲酸第三丁酯,為市售的或可藉由此項技術中熟知之方法製備。式3化合物之硝基可用諸如Zn及氯化銨之試劑在EtOAc中或用Fe或SnCl在諸如乙酸於EtOH中之溶劑
中還原得到式4化合物。
可藉由在有機溶劑(諸如二氯乙烷及其類似物)中用羰基二咪唑、光氣或光氣等效物(例如雙光氣或三光氣)在鹼(諸如三乙胺、二異丙基乙胺及其類似物)存在下加熱4來環化式4化合物以形成式5之苯并咪唑酮。移除胺基保護基PG得到式6化合物。所利用之反應條件係基於胺基保護基之性質。舉例而言,當PG為苯甲基時,其可經由使用Pd/C催化劑及其類似物用諸如乙酸之添加劑氫化來移除,得到式6化合物。使6與其中R1、R2、Ar及X係如發明內容中所定義之式7之芳基酸經由銅介導之偶合(Chan-Lam偶合),使用例如Cu(OAc)2作為催化劑在諸如DCM之溶劑中用添加劑(諸如TEMP)或氧及鹼(諸如吡啶或三乙胺)反應,得到式8化合物。式7化合物,例如(4-苯氧基苯基)酸、2-[4-(3-氟苯氧基)-苯基]-4,4,5,5-四甲基-1,3,2-二氧硼、4-(4-氟苯氧基)苯基酸、4-(3-氟苯氧基)苯基酸、4-(3,5-二氟苯氧基)-苯基酸、4-(4-氯-2-氟苯氧基)苯基-酸及4-(3-(三氟甲基)苯氧基)苯基酸,為市售的或可由苯基鹵化物,藉由鋰鹵素交換及用硼酸三異丙酯淬滅來製備。
替代地,可藉由使化合物5首先與酸7反應,接著在上文所描述之條件下移除胺基保護基來製備化合物8。在化合物8中移除胺基保護基PG1得到式9化合物。所利用之反應條件係基於胺基保護基之性質。舉例而言,當PG1為Boc時,其可在酸水解反應條件下,諸如用酸(諸如TFA、HCl及其類似物)處理來移除。
化合物9可隨後藉由此項技術中熟知之方法轉化成式(I)化合物。舉例而言,式(I)化合物可藉由以下方式製備:偶合化合物9與式10之酸或化合物10之酸衍生物(諸如酸氯化物,其中Ra、Rb及Rc係如發明內容中所描述),得到式(I)化合物。當使用化合物10時,在標準醯胺偶合條件下,諸如在HATU、DCC、碳二咪唑(CDI)及其類似物存在下
進行反應。式10化合物或其酸氯化物衍生物為市售的(例如丙烯醯氯)或其可藉由此項技術中熟知之方法製備,諸如氰基乙酸與醛(諸如異丁醛或特戊醛)之縮合產物。
其中Ra為氰基之式(I)化合物亦藉由首先將化合物9與2-氰基乙酸在標準醯胺偶合條件(諸如碳二咪唑(CDI)及其類似物)下縮合得到式11化合物來製備。式11化合物與式RcCHO(其中Rc如發明內容中所定義)之醛在標準縮合反應條件下,諸如使用鹼(諸如哌啶及其類似物)在乙酸及其類似物存在或不存在下在溶劑(諸如乙醇及其類似物)中在室溫至回流範圍內之溫度下縮合隨後得到式(I)化合物。式RcCHO化合物為市售的或其可藉由此項技術中熟知之方法製備,例如乙醛、環丙醛、異丁醛、3-甲基氧雜環丁烷-3-甲醛、2-(二甲胺基)-2-甲基丙醛、2-甲基-2-(1-哌啶基)丙醛、(2S)-2-甲醯基吡咯啶-1-甲酸第三丁酯及2-甲基-2-(嗎啉-4-基)丙醛為市售的。乙氧基-2-甲基丙醛由異丁醛,如PCT國際申請案2007142576中所描述製備。其中Rc為-(伸烷基)-NR6R7之化合物RCCHO可藉由用溴處理異丁醛以形成溴異丁醛,隨後藉由添加HNR6R7置換溴化物來製備。
替代地,化合物11亦可與RcCHO之前驅體基團縮合且隨後轉化成式(I)化合物。舉例而言,化合物11可與2-甲基-1-側氧基丙-2-基胺基甲酸第三丁酯縮合,接著移除胺基保護基得到式(I)化合物,其中Rc為2-胺基丙-2-基。縮合反應亦可藉由在鹼(諸如吡咯啶或哌啶)下在有或無氯三甲基矽烷下在二氯甲烷或其他適合之溶劑(例如二噁烷及乙醇)中添加所需醛RcCHO來進行。可如流程2中所描述製備式(I)化合物,其中R5為式(ii)-(iv)之基團。藉由遵循上文所描述之程序且用適合起始物質,諸如2-丁炔酸、乙烯磺醯氯、(E)-丙-1-烯-1-磺醯氯、1-丙炔-1-磺醯氯替代化合物9,可獲得式(I)化合物。
替代地,為了製備式(I)化合物,其中R5為式(ii)之基團,可使式
11化合物與市售氰基甲磺醯氯反應,得到氰基甲基磺醯胺,其可與式12之醛在TMSCl及吡咯啶下縮合得到式(I)之結構。
可如流程3中所描述製備式(I)化合物,其中A=CH。可首先使2,4-二氯-3-硝基吡啶與其中Y及環Z如發明內容中所定義且PG1為適合之胺基保護基(諸如Boc)之式2之胺基化合物反應。隨後與式NH(PG)2(其中PG為適合之胺基保護基,諸如4-甲氧基苯甲基)之胺在諸如DMF之溶劑中反應得到式14化合物。在標準條件下藉由用Pd/C氫化或藉由用Zn、Fe或SnCl還原來還原硝基得到式15化合物。與羰基二咪唑或光氣等效物縮合得到環狀脲16。可在此階段進行Chan-Lam偶合且如流程1中所描述完成化合物(I)之合成。
替代地,可藉由首先用酸(諸如TFA)處理以移除兩個保護基且隨後安設PG1(例如Boc)基團來製備化合物17。隨後用二甲基甲醯胺二甲基縮醛處理得到式18化合物。在如上文所描述之Chan-Lam條件下反應隨後得到化合物19。隨後藉由用酸(諸如HCl或TFA)在溶劑(諸如二氯甲烷、二噁烷、MeOH或EtOH)中處理19來去除保護基得到式20
化合物。隨後以與流程1及2中所描述之方法類似的方式準備式(I)化合物之製備。
以下流程4顯示式21、22、24及25之化合物之製備。使用諸如HATU之試劑在諸如DMF之溶劑中偶合市售之酸(諸如3-羥基丙酸或2-羥基丙酸(呈外消旋體或呈(S)或(R)異構體))與來自流程2之化合物20分別得到式21及22之化合物。在溶劑(諸如DMF)中在鹼(諸如三甲胺或二異丙基乙胺)下可向化合物20中添加丙烯醯氯得到式23化合物。用試劑(諸如四氧化鋨及N-甲基嗎啉氧化物(NMO))在丙酮及水之混合物中氧化得到式24之二醇。可由式23化合物,藉由在溶劑(諸如甲苯或二氯甲烷)中用氧化劑(諸如mCPBA)氧化或藉由第三丁基過氧化氫(TBHP)及金雞納生物鹼催化劑(夏普利斯環氧化(Sharpless epoxidation))製備化合物25。
可使用以下顯示之通用方法製備一些其他化合物。
將含芳基酸(1.0當量)、TEA(4.0當量)、Cu(OAc)2(0.50當量)、
TEMPO(1.10當量)及分子篩(4A)(500mg)之二氯甲烷(0.1mM)置放至用O2氛圍淨化及維持之100mL圓底燒瓶中。攪拌所得溶液30分鐘且隨後添加芳基酸(2.00當量)。在室溫下攪拌所得溶液隔夜。在真空下濃縮所得混合物。將殘餘物施加至用二氯甲烷/甲醇溶離之矽膠管柱上得到所需產物A。
向A(1.0當量)於二噁烷中之溶液中添加氯化氫(12M)。在85℃下在油浴中攪拌所得溶液3小時。隨後藉由添加碳酸氫鈉(飽和)淬滅反應物。用DCM/MeOH(10:1)萃取所得溶液且合併有機層。用飽和氯化鈉洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。此產生360mg(100%)B。
將B(1.0當量)、2-氰基乙酸(1.0當量)、HATU(1.5當量)、TEA(3.0當量)及N,N-二甲基甲醯胺(0.1mMol)置放至50mL圓底燒瓶中。在室溫下攪拌所得溶液2小時。用二氯甲烷萃取所得溶液且合併有機層。用6×100mL水洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。將殘餘物施加至具有二氯甲烷/甲醇之矽膠管柱上得到化合物C。
將C(1.0當量)置放至圓底燒瓶中,使C溶解於DCM中至0.2M之濃度。冷卻溶液至0℃,且添加醛(3.0當量)接著添加吡咯啶(6.0當量)及TMSCl(4.0當量)。使反應物升溫至室溫且攪拌3小時或直至消耗起始物質。添加水且分離各層。經硫酸鈉乾燥有機層,過濾且在真空中移除溶劑。藉由矽膠層析或製備型HPLC純化得到所需化合物D。醛商業地購買,藉由以下顯示之方法或藉由文獻中已知之方法(亦即經由斯溫條件(Swern conditions)或用氧化劑(諸如PCC或戴斯-馬丁高碘
烷(Dess-Martin periodinane))來氧化醇)。
向2-甲基丙醛(1.0當量)於DCM(0.2M)中之用冰浴冷卻之溶液中逐滴添加溴(1.0當量)。在1小時之後,在真空中自所得2-溴-2-甲基丙醛溶液移除大部分溶劑。在室溫下在DCM(8ml)中稀釋此物質且添加胺(2.0當量)。在攪拌隔夜之後,用鹽水(30mL)稀釋混合物且分離各層。有機層經乾燥(MgSO4),過濾且濃縮以分離所需醛,其直接用於下一步驟或在使用之前藉由矽膠層析純化。
可使用以下生物實例中描述之活體外及/或活體內分析測試BTK抑制活性、抑制劑BTK結合複合物之滯留時間及本發明化合物與BTK之Cys 481(UniprotKB序列ID Q06187)形成不可逆共價鍵或可逆共價鍵之能力。
可使用以下生物實例1、3、4及5中描述之活體外及/或活體內分析測試本發明之式(I)化合物及/或其醫藥學上可接受之鹽之BTK抑制活性。認為藉由彼等分析中的任一者之激酶抑制活性測定為在本發明範疇內之激酶抑制活性,即使任何或所有其他分析不引起激酶抑制活性之測定。
在不受任何特定機制理論束縛的情況下,在本發明化合物為可逆共價抑制劑之彼等實施例中,咸信半胱胺酸硫氫基及形成式(I)化合物(其中R5為式(i)、(ii)或(iii)之基團,其中Ra為氰基(參見式(I)))中之R5基團中之一部分碳-碳雙鍵的碳原子可形成可逆,即不穩定、共價鍵,諸如其中BTK之Cys 481攻擊本發明化合物中之上列R5基團中之
碳-碳雙鍵的缺電子碳原子以形成硫醇加成物。
在一些實施例中,烯烴之缺電子碳原子遠離連接至Ra基團(其中Ra為氰基)之碳,即連接至Rb及Rc基團(參見本發明化合物中之式(I))的碳原子。因此,在本發明化合物中Ra基團(其中Ra為氰基)與「-N-CO-、-NSO2或-N-SO-」部分及其所鍵結之烯烴部分之組合可增加烯烴之反應性以與BTK中之活性位點半胱胺酸殘基形成硫醇加成物。
作為可逆共價抑制劑之本發明化合物可以兩種不同方式與BTK結合。除上文所論述之不穩定共價結合以外,咸信其亦與BTK形成非共價結合(例如經由凡得瓦爾力結合、氫結合、疏水結合、親水結合及/或靜電電荷結合),非共價結合足以至少部分抑制BTK之激酶活性。
如本文中所揭示,不穩定共價結合發生在抑制劑中之烯烴及抑制劑與BTK具有前述非共價結合之位點處或附近的半胱胺酸481殘基硫醇側鏈之間。
如顯而易見,作為可逆共價抑制劑之本發明化合物具有半胱胺酸介導之共價結合及與BTK之非共價結合兩者。此與僅經由非共價結合抑制BTK且缺乏半胱胺酸介導之共價結合的非共價可逆抑制劑形成對比。
本發明化合物與BTK以上文所提及之兩種不同方式之結合提供具有較慢解離速率及延長之作用持續時間的可逆共價抑制劑,在一些情況下與不可逆共價抑制劑類似而不形成永久不可逆蛋白質加成物。不可逆與可逆共價抑制劑,尤其本文所揭示之化合物之間的差異可利用本文所揭示之分析確定。
一般而言,結合涉及抑制劑,當BTK呈某些組態時該等抑制劑與BTK形成穩定之可逆共價鍵且當BTK呈不同組態時(在兩種情況下在生理條件下)形成容易遭受斷裂之可逆共價鍵,而即使當BTK呈不同組態時,形成不可逆共價鍵之抑制劑與BTK之間的相互作用在生理條
件下穩定。
可逆共價鍵通常賦予與化合物在含半胱胺酸結合位點內之滯留時間相關之獨特特性。在此情形下,滯留時間係指化合物-目標複合物在不同條件下之暫時持續時間(參見Copeland RA,Pompliano DL,Meek TD.Drug-target residence time and its implications for lead optimization.Nat.Rev.Drug Discov.5(9),730-739(2006))。
當與不與BTK形成共價鍵之化合物相比時,在如本文中所揭示之可逆共價抑制劑中存在可逆共價鍵可引起延長之滯留時間。在本文所揭示之一個實施例中,作為可逆共價抑制劑之本發明化合物具有至少約1小時之滯留時間。滯留時間可使用佔有率分析在生物化學或細胞環境中量測(參見以下生物實例2及9)。另外,滯留時間可使用功能分析在規定清除時段之後量測。
在不可逆共價抑制劑中形成不可逆共價鍵之化合物共享此等延長之滯留時間特性但可仍然使用可逆性分析與可逆共價抑制劑區別。本發明化合物與BTK之Cys481形成可逆或不可逆共價鍵之能力可藉由以下生物實例2、6-8中描述之分析測定。認為藉由以下生物實例2、6-8中的任一者測定半胱胺酸殘基與本發明化合物之烯烴鍵之間的共價鍵之結合可逆性為在本發明範疇內之可逆結合,即使其他方法中的一者或兩者不引起結合可逆性之測定。
一般而言,本發明化合物將藉由提供類似效用之藥劑的任一可接受投與方式、以治療有效量投與。式(I)化合物之治療有效量可在每日約0.01至約500mg/kg患者體重範圍內,其可以單個或多個劑量投與。在一個實施例中,劑量濃度將為每日約0.1至約250mg/kg。在另一實施例中,劑量濃度將為每日約0.5至約100mg/kg。適合之劑量濃度可為每日約0.01至約250mg/kg,每日約0.05至約100mg/kg,或每
日約0.1至約50mg/kg。在此範圍內,劑量可為每日約0.05至約0.5,約0.5至約5或約5至約50mg/kg。就經口投與而言,組合物可以含有約1.0至約1000毫克活性成分,尤其約1.0、5.0、10、15、20、25、50、75、100、150、200、250、300、400、500、600、750、800、900及1000毫克活性成分之錠劑形式提供。本發明化合物,即活性成分之實際量將視許多因素而定,諸如待治療之疾病之嚴重性、個體之年齡及相對健康狀況、利用之化合物之效能、投與之途徑及形式及其他因素。
一般而言,本發明化合物將作為醫藥組合物藉由以下途徑中之任一者投與:經口、全身性(例如經皮、鼻內或藉由栓劑)或非經腸(例如肌肉內、靜脈內或皮下)投與。較佳投藥方式為使用可根據病痛程度而調整之便利日給藥方案經口投藥。組合物可採取錠劑、丸劑、膠囊、半固體、散劑、持續釋放調配物、溶液、懸浮液、酏劑、氣霧劑或任何其他適當組合物之形式。
調配物之選擇視各種因素而定,諸如藥物投與之模式(例如對經口投藥而言,呈錠劑、丸劑或膠囊形式之調配物較佳)及原料藥之生物可用性。最近,已基於生物可用性可藉由增加表面積,即降低粒徑來增加之原理研發尤其用於顯示不佳生物可用性之藥物的醫藥調配物。舉例而言,美國專利第4,107,288號描述具有尺寸介於10至1,000nm範圍內之粒子的醫藥調配物,其中活性材料負載在大分子之交聯基質上。美國專利第5,145,684號描述一種醫藥調配物之製備,其中在表面改質劑存在下將原料藥粉碎成奈米粒子(平均粒徑為400nm),且隨後將其分散於液體介質中以得到展示顯著較高之生物可用性的醫藥調配物。在胃pH下分解之藥物之生物可用性可藉由以在十二指腸內釋放藥物之調配物形式投與此類藥物來增加。
組合物一般由式(I)化合物及/或其醫藥學上可接受之鹽與醫藥學
上可接受之賦形劑之組合組成,該賦形劑諸如黏合劑、界面活性劑、稀釋劑、緩衝劑、抗黏附劑、滑動劑、親水性或疏水性聚合物、阻滯劑、穩定劑(stabilizing agents/stabilizer)、崩解劑或超級崩解劑、抗氧化劑、消泡劑、填充劑、調味劑、著色劑、潤滑劑、吸附劑、防腐劑、塑化劑或甜味劑或其混合物,其促進將式(I)化合物(或本文中揭示之其任何實施例)及/或其醫藥學上可接受之鹽處理成可在醫藥學上使用之製劑。任何熟知技術及賦形劑可在適合時及如此項技術中所理解使用,參見例如Remington:The Science and Practice of Pharmacy,第二十一版,(Pharmaceutical Press,2005);Liberman,H.A.,Lachman,L.,及Schwartz,J.B.編,Pharmaceutical Dosage Forms,第1-2卷Taylor & Francis 1990;及R.I.Mahato,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems,第二版(Taylor & Francis,2012)。
在某些實施例中,調配物可包括一或多種pH調節劑或緩衝劑,例如酸,諸如乙酸、硼酸、檸檬酸、反丁烯二酸、順丁烯二酸、酒石酸、蘋果酸、乳酸、磷酸及鹽酸;鹼,諸如氫氧化鈉、磷酸鈉、硼酸鈉、檸檬酸鈉、乙酸鈉、乳酸鈉及參羥基甲胺基甲烷;及緩衝劑,諸如檸檬酸鹽/右旋糖、碳酸氫鈉、氯化銨,及其類似物。此類用作鹼之緩衝劑可具有除鈉以外之相對離子,例如鉀、鎂、鈣、銨或其他相對離子。此類酸、鹼及緩衝劑以維持組合物之pH在可接受範圍內所需之量包括在內。
在某些實施例中,調配物亦可包括使組合物之重量莫耳滲透濃度達可接受範圍所需之量的一或多種鹽。此類鹽包括具有鈉、鉀或銨陽離子及氯離子、檸檬酸根、抗壞血酸根、硼酸根、磷酸根、碳酸氫根、硫酸根、硫代硫酸根或亞硫酸氫根陰離子之鹽;適合鹽包括氯化鈉、氯化鉀、硫代硫酸鈉、亞硫酸氫鈉及硫酸銨。
在某些實施例中,調配物亦可包括一或多種消泡劑以減少在處
理期間可引起水性分散液凝結、成品膜中之氣泡或一般損害處理之發泡。例示性消泡劑包括矽乳液或脫水山梨糖醇倍半油酸酯。
在某些實施例中,調配物亦可包括一或多種抗氧化劑,諸如非硫醇抗氧化劑,例如丁基化羥基甲苯(BHT)、抗壞血酸鈉、抗壞血酸或其衍生物及生育酚或其衍生物。在某些實施例中,需要時,抗氧化劑提高化學穩定性。亦可添加其他試劑,諸如檸檬酸或檸檬酸鹽或EDTA以減緩氧化。
在某些實施例中,調配物亦可包括一或多種防腐劑以抑制微生物活性。適合防腐劑包括含汞物質,諸如硝酸苯汞(merfen)及硫柳汞(thiomersal);穩定化二氧化氯;及四級銨化合物,諸如苯紮氯銨(benzalkonium chloride)、溴化十六烷基三甲基銨及氯化十六烷基吡錠。
在某些實施例中,調配物亦可包括一或多種黏合劑。黏合劑賦予黏著品質且包括例如海藻酸及其鹽;纖維素衍生物,諸如羧甲基纖維素、甲基纖維素(例如Methocel®)、羥丙基甲基纖維素、羥乙基纖維素、羥丙基纖維素(例如Klucel®)、乙基纖維素(例如Ethocel®)及微晶纖維素(例如Avicel®);微晶右旋糖;直鏈澱粉;矽酸鎂鋁;多醣酸;膨潤土;明膠;聚乙烯-吡咯啶酮/乙酸乙烯酯共聚物;交聯普維酮(crosspovidone);普維酮;澱粉;預膠凝化澱粉;黃蓍、糊精、糖,諸如蔗糖(例如Dipac®)、葡萄糖、右旋糖、糖蜜、甘露糖醇、山梨糖醇、木糖醇(例如Xylitab®)及乳糖;天然或合成膠,諸如阿拉伯膠、黃蓍、印度膠、伊沙普爾皮黏膠(mucilage of isapol husks)、聚乙烯吡咯啶酮(例如Polyvidone® CL、Kollidon® CL、Polyplasdone® XL-10)、松木多醣、Veegum®、聚乙二醇、聚氧化乙烯、蠟、海藻酸鈉及其類似物。
在某些實施例中,調配物亦可包括分散劑及/或黏度調節劑。分
散劑及/或黏度調節劑包括控制藥物在液體介質中或造粒方法或摻合方法中之擴散及均質性的材料。在一些實施例中,此等試劑亦促進塗佈或腐蝕基質之效用。例示性擴散促進劑/分散劑包括例如親水性聚合物、電解質、Tween®60或80、PEG、聚乙烯吡咯啶酮(PVP;商業上已知為Plasdone®)及基於碳水化合物之分散劑,諸如羥丙基纖維素(例如HPC、H--PC-SL及HPC-L)、羥丙基甲基纖維素(例如HPMC K100、RPMC K4M、HPMC K15M及HPMC K100M)、羧甲基纖維素鈉、甲基纖維素、羥乙基纖維素、羥丙基纖維素、鄰苯二甲酸羥丙基甲基纖維素、硬脂酸乙酸羥丙基甲基纖維素(HPMCAS)、非結晶纖維素、聚氧化乙烯、矽酸鎂鋁、三乙醇胺、聚乙烯醇(PVA)、乙烯基吡咯啶酮/乙酸乙烯酯共聚物(S630)、具有環氧乙烷及甲醛之4-(1,1,3,3-四甲基丁基)-苯酚聚合物(亦稱為泰洛沙泊(tyloxapol))、泊洛沙姆(poloxamer)(例如Pluronics F68®、F88®及F10®8,其為環氧乙烷與環氧丙烷之嵌段共聚物);及泊洛沙胺(poloxamine)(例如Tetronic 908®,亦稱為泊洛沙胺908®,其為由環氧丙烷及環氧乙烷依序添加至乙二胺衍生之四官能嵌段共聚物(BASF Corporation,Parsippany,N.J.))、聚乙烯吡咯啶酮K12、聚乙烯吡咯啶酮K17、聚乙烯吡咯啶酮K25或聚乙烯吡咯啶酮K30、聚乙烯吡咯啶酮/乙酸乙烯酯共聚物(S-630)、聚乙二醇(例如聚乙二醇之分子量可為約300至約6000,或約3350至約4000,或約7000至5400)、羧甲基纖維素鈉、甲基纖維素、聚山梨醇酯-80、海藻酸鈉、膠(諸如黃蓍膠及阿拉伯膠、瓜爾豆膠、三仙膠(xanthans),包括三仙膠(xanthan gum))、糖、纖維素材料(諸如羧甲基纖維素鈉、甲基纖維素、羧甲基纖維素鈉)、聚山梨醇酯-80、海藻酸鈉、聚乙氧基化脫水山梨糖醇單月桂酸酯、聚乙氧基化脫水山梨糖醇單月桂酸酯、普維酮、卡波姆(carbomer)、聚乙烯醇(PVA)、海藻酸鹽、聚葡萄胺糖及其組合。諸如纖維素或三乙基纖維素之塑化劑
亦可用作分散劑。尤其適用於脂質分散液及自乳化分散液之分散劑為二肉豆蔻醯基磷脂醯基膽鹼、來自蛋類之天然磷脂醯基膽鹼、來自蛋類之天然磷脂醯基甘油、膽固醇及肉豆蔻酸異丙酯。一般而言,在粉末填充之明膠膠囊調配物中使用約10至約70%之黏合劑含量。錠劑調配物中之黏合劑使用量隨直接壓縮、濕式造粒、碾壓或其他賦形劑(諸如本身可用作適度黏合劑之填充劑)的使用而變化。熟習此項技術之調配者可確定用於調配物之黏合劑量,但在錠劑調配物中至多90%且更通常至多70%之黏合劑使用量為常見的。
在某些實施例中,調配物亦可包括一或多種稀釋劑,稀釋劑指用於在遞送之前稀釋所關注的化合物的化合物。稀釋劑亦可用於穩定化合物,因為其可提供更穩定環境。溶解於緩衝溶液(其亦可提供pH控制或維持)中之鹽用作此項技術中之稀釋劑,包括(但不限於)磷酸鹽緩衝鹽水溶液。在某些實施例中,稀釋劑增加組合物體積以促進壓縮或形成足夠體積以供針對膠囊填充進行均質摻合。此類化合物包括例如乳糖、澱粉、甘露糖醇、山梨糖醇、右旋糖、微晶纖維素(諸如Avicel®);磷酸氫二鈣、二水合磷酸二鈣、磷酸三鈣、磷酸鈣;無水乳糖、噴霧乾燥乳糖;預膠凝化澱粉、可壓縮糖(諸如Di-Pac®(Amstar));羥丙基甲基纖維素、硬脂酸乙酸羥丙基甲基纖維素、基於蔗糖之稀釋劑、糖粉;單水合硫酸一氫鈣、二水合硫酸鈣;三水合乳酸鈣、葡萄糖結合劑;水解穀類固體、直鏈澱粉;粉末狀纖維素、碳酸鈣;甘胺酸、高嶺土;甘露糖醇、氯化鈉;肌醇、膨潤土及其類似物。
在某些實施例中,調配物亦可包括一或多種崩解劑,崩解劑包括當與胃腸液接觸時溶解及分散劑型。崩解試劑或崩解劑促進物質之分解或崩解。崩解試劑之實例包括澱粉,例如天然澱粉,諸如玉米澱粉或馬鈴薯澱粉;預膠凝化澱粉,諸如National 1551或乙醇酸澱粉
鈉,諸如Promogel®或Explotab®;纖維素,諸如木材產品;甲基結晶纖維素,例如Avicel®、Avicel® PH101、Avicel® PH 102、Avicel® PH105、Elceme® P100、Emcocel®、Vivacel®及Solka-Floc®;甲基纖維素、交聯羧甲纖維素或交聯纖維素,諸如交聯羧甲基纖維素鈉(Ac-Di-Sol®)、交聯羧甲基纖維素或交聯之交聯羧甲纖維素;交聯澱粉,諸如乙醇酸澱粉鈉;交聯聚合物,諸如交聯聚維酮、交聯聚乙烯吡咯啶酮;海藻酸鹽,諸如海藻酸或海藻酸之鹽,諸如海藻酸鈉;黏土,諸如Veegum® HV(矽酸鎂鋁)、膠(諸如瓊脂、瓜爾豆膠、槐豆膠、加拉亞膠(Karaya)、果膠或黃蓍膠);乙醇酸澱粉鈉;膨潤土;天然海綿;界面活性劑;樹脂,諸如陽離子交換樹脂;柑桔渣;月桂基硫酸鈉;月桂基硫酸鈉與澱粉之組合;及其類似物。
在某些實施例中,調配物亦可包括腐蝕促進劑。腐蝕促進劑包括控制特定材料在胃腸液中之腐蝕之材料。腐蝕促進劑通常為一般技術者已知。例示性腐蝕促進劑包括例如親水性聚合物、電解質、蛋白質、肽及胺基酸。
在某些實施例中,調配物亦可包括一或多種填充劑,填充劑包括諸如以下之化合物:乳糖、碳酸鈣、磷酸鈣、磷酸氫二鈣、硫酸鈣、微晶纖維素、纖維素粉末、右旋糖、葡萄糖結合劑、聚葡萄糖、澱粉、預膠凝化澱粉、蔗糖、木糖醇、乳糖醇、甘露糖醇、山梨糖醇、氯化鈉、聚乙二醇及其類似物。
在某些實施例中,調配物亦可包括一或多種調味劑及/或甜味劑,例如阿拉伯膠糖漿、乙醯磺胺酸K、阿力甜、大茴香、蘋果、阿斯巴甜糖、香蕉、巴伐利亞奶油漿果、黑醋栗、奶油硬糖、檸檬酸鈣、樟腦、焦糖、櫻桃、櫻桃奶油巧克力、肉桂、泡泡糖、柑橘、柑橘潘趣(punch)、柑橘奶油、棉花糖、可可、可樂、冷櫻桃、冷柑橘、賽克拉美(cyclamate)、賽拉美(cylamate)、右旋糖、桉、丁香
酚、果糖、果汁潘趣、薑、甘草次酸鹽、甘草(glycyrrhiza/licorice)糖漿、葡萄、葡萄柚、蜂蜜、異麥芽糖、檸檬、萊姆、檸檬奶油、甘草酸單銨、麥芽糖醇、甘露糖醇、楓、蜀葵、薄荷醇、薄荷奶油、混合漿果、新桔皮苷DC、紐甜、橙子、梨、桃、胡椒薄荷、胡椒薄荷奶油、粉末、樹莓、草根沙士、糖蜜酒、糖精、黃樟素、山梨糖醇、綠薄荷、綠薄荷奶油、草莓、草莓奶油、甜菊、蔗糖素、蔗糖、糖精鈉、糖精、阿斯巴甜糖、乙醯磺胺酸鉀、甘露糖醇、塔林(talin)、木糖醇、蔗糖素、山梨糖醇、瑞士奶油(Swiss cream)、塔格糖、紅橘、祝馬丁、百果糖(tutti fruitti)、香草、胡桃、西瓜、野櫻桃、冬青、木糖醇或此等調味成分之任何組合,例如大茴香-薄荷醇、櫻桃-大茴香、肉桂-橙子、櫻桃-肉桂、巧克力-薄荷、蜂蜜-檸檬、檸檬-萊姆、檸檬-薄荷、薄荷醇-桉、橙子-奶油、香草-薄荷,及其混合物。
在某些實施例中,調配物亦可包括一或多種潤滑劑及滑動劑,其為防止、減少或抑制材料之黏附或摩擦之化合物。例示性潤滑劑包括例如硬脂酸;氫氧化鈣;滑石;硬脂基延胡索酸鈉;烴,諸如礦物油;或氫化植物油,諸如氫化大豆油;高碳數脂肪酸及其鹼金屬鹽及鹼土金屬鹽,諸如鋁、鈣、鎂、鋅、硬脂酸、硬脂酸鈉、甘油、滑石、蠟、硼酸、苯甲酸鈉、乙酸鈉、氯化鈉、白胺酸、聚乙二醇(例如PEG4000)或甲氧基聚乙二醇,諸如Carbowax®;油酸鈉、苯甲酸鈉、二十二烷酸甘油酯、聚乙二醇、月桂基硫酸鎂或月桂基硫酸鈉;膠態二氧化矽,諸如Syloid®、Cab-O-Sil®;澱粉,諸如玉米澱粉、聚矽氧油、界面活性劑及其類似物。
在某些實施例中,調配物亦可包括一或多種塑化劑,其為用於軟化腸溶或延遲釋放包衣以使其不易裂之化合物。適合之塑化劑包括例如聚乙二醇,諸如PEG 300、PEG 400、PEG 600、PEG 1450、PEG 3350及PEG 800;硬脂酸;丙二醇;油酸;檸檬酸三乙酯;癸二酸二
丁酯;三乙基纖維素及三醋精。在一些實施例中,塑化劑亦可充當分散劑或濕潤劑。
在某些實施例中,調配物亦可包括一或多種增溶劑,增溶劑包括諸如以下之化合物:三醋精、檸檬酸三乙酯、油酸乙酯、辛酸乙酯、月桂基硫酸鈉、多庫酯鈉、維生素E TPGS、二甲基乙醯胺、N-甲基吡咯啶酮、N-羥乙基吡咯啶酮、聚乙烯吡咯啶酮、羥丙基甲基纖維素、羥丙基環糊精(例如Captisol®)、乙醇、正丁醇、異丙醇、膽固醇、膽汁鹽、聚乙二醇200-600、四氫呋喃聚乙二醇醚、二乙二醇單乙醚、丙二醇及二甲基異山梨糖醇及其類似物。在一個實施例中,增溶劑為維生素E TPGS及/或Captisol®或ß-羥丙基環糊精。
在某些實施例中,調配物亦可包括一或多種懸浮劑,懸浮劑包括諸如以下之化合物:聚乙烯吡咯啶酮,例如聚乙烯吡咯啶酮K112、聚乙烯吡咯啶酮K17、聚乙烯吡咯啶酮K25或聚乙烯吡咯啶酮K30;乙烯基吡咯啶酮/乙酸乙烯酯共聚物(S630);聚乙二醇,例如聚乙二醇之分子量可為約300至約6000,或約3350至約4000,或約7000至約5400;羧甲基纖維素鈉;甲基纖維素;羥丙基甲基纖維素;硬脂酸乙酸羥甲基纖維素;聚山梨醇酯-80;羥乙基纖維素;海藻酸鈉;膠,諸如黃蓍膠及阿拉伯膠、瓜爾豆膠、三仙膠,包括三仙膠;糖;纖維素材料,諸如羧甲基纖維素鈉、甲基纖維素、羧甲基纖維素鈉、羥丙基甲基纖維素、羥乙基纖維素;聚山梨醇酯-80;海藻酸鈉;聚乙氧基化脫水山梨糖醇單月桂酸酯;聚乙氧基化脫水山梨糖醇單油酸酯;普維酮,及其類似物。
在某些實施例中,調配物亦可包括一或多種界面活性劑,界面活性劑包括諸如以下之化合物:月桂基硫酸鈉、多庫酯鈉、Tween 20、60或80、三醋精、維生素E TPGS、脫水山梨糖醇單油酸酯、聚氧化乙烯脫水山梨糖醇單油酸酯、聚氧化乙烯脫水山梨糖醇單月桂酸
酯、聚山梨醇酯、泊洛沙姆、膽汁鹽、單硬脂酸甘油酯、環氧乙烷與環氧丙烷之共聚物(例如Pluronic®(BASF)),及其類似物。一些其他界面活性劑包括聚氧化乙烯脂肪酸甘油酯及植物油,例如聚氧化乙烯(60)氫化蓖麻油;及聚氧化乙烯烷基醚及烷基苯基醚,例如辛苯聚醇10、辛苯聚醇40。在一些實施例中,可包括界面活性劑以增強物理穩定性或用於其他目的。
在某些實施例中,調配物亦可包括一或多種黏度增強劑,其包括例如甲基纖維素、三仙膠、羧甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素、硬脂酸乙酸羥丙基甲基纖維素、鄰苯二甲酸羥丙基甲基纖維素、卡波姆、聚乙烯醇、海藻酸鹽、阿拉伯膠、聚葡萄胺糖,及其組合。
在某些實施例中,調配物亦可包括一或多種濕潤劑,其包括諸如以下之化合物:油酸、單硬脂酸甘油酯、脫水山梨糖醇單油酸酯、脫水山梨糖醇單月桂酸酯、三乙醇胺油酸酯、聚氧化乙烯脫水山梨糖醇單油酸酯、聚氧化乙烯脫水山梨糖醇單月桂酸酯、多庫酯鈉、油酸鈉、月桂基硫酸鈉、多庫酯鈉、三醋精、Tween 80、維生素E TPGS、銨鹽,及其類似物。
本文所揭示之醫藥製劑可藉由以下獲得:混合一或多種固體賦形劑與本文所描述之化合物中之一或多者,固體賦形劑諸如載劑、黏合劑、填充劑、懸浮劑、調味劑、甜味劑、崩解劑、分散劑、界面活性劑、潤滑劑、著色劑、稀釋劑、增溶劑、潤濕劑、塑化劑、穩定劑、穿透增強劑、濕潤劑、消泡劑、抗氧化劑、防腐劑或其一或多種組合;視情況研磨所得混合物;且在添加適合賦形劑之後視需要處理顆粒混合物,得到錠劑。
本文所揭示之醫藥製劑亦包括由明膠製成之膠囊,以及由明膠及塑化劑(諸如甘油或山梨糖醇)製成之軟性密封膠囊。膠囊亦可由聚
合物(諸如羥丙甲纖維素)製成。膠囊可含有活性成分與諸如乳糖之填充劑、諸如澱粉之黏合劑及/或諸如滑石或硬脂酸鎂之潤滑劑、及視情況選用之穩定劑之摻合物。在軟膠囊中,活性化合物可溶解或懸浮於適合之液體,諸如脂肪油、液體石蠟、脂質、增溶劑或液體聚乙二醇中。此外,可添加穩定劑。用於經口投與之所有調配物均應呈適於此類投與之劑量。
此等調配物可藉由習知藥理學技術製造。習知藥理學技術包括例如以下方法之一者或組合:(1)乾燥混合,(2)直接壓縮,(3)研磨,(4)乾燥或非水造粒,(5)濕式造粒,(6)熔融,或(7)擠壓。參見例如Lachman等人,The Theory and Practice of Industrial Pharmacy,第3版(1986)。其他方法包括例如噴霧乾燥、盤式塗佈、熔融造粒、造粒、流體化床噴霧乾燥或塗佈(例如wurster塗佈)、切向塗佈、頂部噴塗、壓片、擠壓、擠壓/滾圓,及其類似方法。
應瞭解本文中描述之固體劑型中所用的賦形劑之間存在大量重疊。因此,上文所列添加劑應僅視為例示而非限制本文中所描述之固體劑型中可包括之賦形劑類型。熟習此項技術者根據所要特定特性容易確定此類賦形劑之類型及量。
在一些實施例中,本文中描述之固體劑型為包覆腸溶包衣之經口劑型,即呈利用腸溶包衣來實現化合物在胃腸道之腸中之釋放的如本文所描述之醫藥組合物之口服劑型。「包覆腸溶包衣之」藥物及/或錠劑係指包覆有在胃中保持完整但在到達腸(在一個實施例中小腸)後溶解及釋放藥物之物質的藥物及/或錠劑。如本文所用,「腸溶包衣」為將治療活性劑核心包封為劑型或粒子之一或多種材料,諸如聚合物材料。通常,在治療活性劑自劑型釋放之前溶解大量或所有腸溶包衣材料,以便實現治療活性劑核心或粒子在小腸及/或大腸中之延遲溶解。腸溶衣論述於例如Loyd,V.Allen,Remington:The Science and
Practice of Pharmacy,第二十一版,(Pharmaceutical Press,2005;及P.J.Tarcha,Polymers for Controlled Drug Delivery,第3章,CRC Press,1991中。將腸溶衣塗覆至醫藥組合物之方法為此項技術中熟知,且包括例如美國專利公開案第2006/0045822號。
包覆腸溶包衣之劑型可為含有式(I)化合物(或其任何實施例)及/或其醫藥學上可接受之鹽之顆粒、粉末、糰粒、珠粒或粒子及/或其他賦形劑(其自身經包覆或未經包覆,其限制條件為至少錠劑或式(I)化合物經包覆)的壓縮或模製或擠壓錠劑(經包覆或未經包覆)。包覆腸溶包衣之口服劑型亦可為含有式(I)化合物(或其任何實施例)及/或其醫藥學上可接受之鹽之糰粒、珠粒或顆粒及/或其他賦形劑(其自身經包覆或未經包覆,其限制條件為其中之至少一者經包覆)之膠囊(經包覆或未經包覆)。最初用作腸溶衣之包衣之一些實例為蜂蠟及單硬脂酸甘油酯;蜂蠟、蟲膠及纖維素;及十六醇、膏膠及蟲膠以及蟲膠及硬脂酸(美國專利第2,809,918號);聚乙酸乙烯酯及乙基纖維素(美國專利第3,835,221號)。最近,使用之包衣為聚甲基丙烯酸酯之中性共聚物(Eudragit L30D)(F.W.Goodhart等人,Pharm.Tech.,第64-71頁,April,1984);甲基丙烯酸與甲基丙烯酸甲酯之共聚物(Eudragit S),或含有金屬硬脂酸鹽之聚甲基丙烯酸酯(Mehta等人 美國專利第4,728,512號及第4,794,001號)、丁二酸乙酸纖維素及鄰苯二甲酸羥丙甲纖維素之中性共聚物。
任何展示pH依賴性溶解性概況之陰離子聚合物可在本文中描述之方法及組合物中用作腸溶包衣以達成遞送至腸。在一個實施例中,遞送至小腸。在另一實施例中,遞送至十二指腸。在一些實施例中,本文中所描述之聚合物為陰離子羧酸聚合物。在其他實施例中,聚合物及其相容混合物及其一些特性包括(但不限於):蟲膠:
亦稱為純化蟲膠,其為自昆蟲之樹脂分泌物獲得之精煉產物。此包衣在pH>7之介質中溶解;丙烯酸聚合物:丙烯酸聚合物之效能(主要為其於生物流體中之溶解性)可基於取代程度及類型而變化。適合丙烯酸聚合物之實例包括甲基丙烯酸共聚物及甲基丙烯酸銨共聚物。Eudragit系列L、S及RS(由Rohm Pharma製造且已知為Evonik®)可溶解於有機溶劑、水性分散液或乾燥散劑中使用。Eudragit系列RL、NE及RS不溶於胃腸道中,但可滲透且主要用於結腸靶向。Eudragit系列L、L-30D及S不可溶於胃中且在腸中溶解且可經選擇及調配以在大於5.5或低至大於5或高達大於7之pH值下溶解。
纖維素衍生物:適合之纖維素衍生物之實例為:乙基纖維素;纖維素之偏乙酸酯與鄰苯二甲酸酐之反應混合物。效能可基於取代程度及類型而變化。鄰苯二甲酸乙酸纖維素(CAP)在pH>6中溶解。Aquateric(FMC)為基於水溶液之系統且為粒子<1μm之噴霧乾燥CAP假乳膠。Aquateric中之其他組分可包括普朗尼克(pluronics)、Tweens及乙醯化單酸甘油酯。其他適合之纖維素衍生物包括:苯偏三酸乙酸纖維素(Eastman);甲基纖維素(Pharmacoat,Methocel);鄰苯二甲酸羥丙基甲基纖維素(HPMCP);丁二酸羥丙基甲基纖維素(HPMCS);及丁二酸乙酸羥丙基甲基纖維素(HPMCAS,例如AQOAT(Shin Etsu))。效能可基於取代程度及類型而變化。舉例而言,諸如HP-50、HP-55、HP-55S、HP-55F級之HPMCP為適合的。效能可基於取代程度及類型而變化。舉例而言,適合等級之丁二酸乙酸羥丙基甲基纖維素包括(但不限於)AS-LG(LF),其在pH 5下溶解;AS-MG(MF),其在pH 5.5下溶解;及AS-HG(HF),其在較高pH下溶解。此等聚合物以顆粒或以用
於水性分散液之精細粉末形式提供;聚乙酸乙烯酯鄰苯二甲酸酯(PVAP):PVAP在pH>5中溶解,且對水蒸氣及胃液而言滲透性低得多。以上聚合物及其pH依賴性溶解性之詳細描述可見於http://pop.www.capsugel.com/media/library/enteric-coated-hard-gelatin-capsules.pdf,Professor Karl Thoma及Karoline Bechtold之標題為「Enteric coated hard gelatin capsules」之文章。在一些實施例中,包衣可含有且一般含有塑化劑及可能的此項技術中熟知的其他包衣賦形劑,諸如著色劑、滑石及/或硬脂酸鎂。適合之塑化劑包括檸檬酸三乙酯(Citroflex 2)、三醋精(三乙酸甘油酯)、乙醯基三乙基檸檬酸酯(Citroflec A2)、Carbowax 400(聚乙二醇400)、鄰苯二甲酸二乙酯、檸檬酸三丁酯、乙醯化單酸甘油酯、甘油、脂肪酸酯、丙二醇及鄰苯二甲酸二丁酯。特定言之,陰離子羧酸丙烯酸聚合物通常將含有10-25重量%塑化劑,尤其鄰苯二甲酸二丁酯、聚乙二醇、檸檬酸三乙酯及三醋精。採用諸如流化床或Wurster塗佈機或噴霧或盤包覆之習知包覆技術塗覆包衣。包衣厚度必須足以確保口服劑型直至達到腸道中之所需局部傳遞部位仍保持完整。
除塑化劑以外,可向包衣中添加著色劑、界面活性劑、抗黏附劑、消泡劑、潤滑劑(例如巴西棕櫚蠟或PEG)及其他添加劑以溶解或分散包衣材料,且以改良包衣效能及經包覆之產品。
為了加快腸衣之溶解,可塗覆腸溶聚合物(例如Eudragit L30 D-55)之一半厚度雙重包衣,且內部腸衣可在10%檸檬酸存在下具有至多pH 6.0之緩衝液,接著為標準Eudragit L 30 D-55之最終層。與無緩衝,以單層形式塗覆之類似包覆系統相比,塗覆兩層腸衣,各厚度為典型腸衣之一半,Liu及Basit能夠加快腸溶包衣溶解(Liu,F.及Basit,A.Journal of Controlled Release.147(2010)242-245)。
腸溶包衣之完整性可例如藉由微粒內藥物之降解量測。包覆腸溶包衣之劑型或糰粒可在溶解測試中首先在胃液中且單獨地在腸液中如USP中所描述測試以測定其功能。
含有所揭示之化合物的包覆腸溶包衣之錠劑及膠囊調配物可藉由此項技術中熟知之方法製得。舉例而言,含有本文所揭示之化合物的錠劑可使用側通風塗佈盤(Freund Hi-塗佈機)用含有Eudragit®、鄰苯二甲酸二乙酯、異丙醇、滑石及水之塗佈溶液來包覆腸溶衣。
替代地,可如下製備可併入錠劑或膠囊中之包含包覆腸溶包衣之糰粒的多單位劑型。
核心材料:用於單獨包覆腸溶包衣之分層糰粒的核心材料可根據不同原理構成。用活性劑(亦即式(I)化合物(包括本文所揭示之實施例)及/或其醫藥學上可接受之鹽)分層,視情況與鹼性物質或緩衝液混合之種子可用作核心材料以用於進一步處理。將用活性劑分層之種子可為單獨或以混合物形式包含不同氧化物、纖維素、有機聚合物及其他材料之水不溶性種子或單獨或以混合物形式包含不同無機鹽、糖、那普瑞爾(non-pareils)及其他材料之水溶性種子。此外,種子可包含呈晶體、聚結物、壓製品等形式之活性劑。種子之尺寸對於本發明不必要但可在大約0.1與2mm之間變化。藉由粉末或溶液/懸浮液分層,使用例如造粒或噴塗分層設備產生用活性劑分層之種子。
在種子分層之前,活性劑可與其他組分混合。此類組分可為黏合劑、界面活性劑、填充劑、崩解劑、鹼性添加劑或其他及/或醫藥學上可接受之成分(單獨或呈混合物形式)。黏合劑為例如聚合物,諸如羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)、羧甲基纖維素鈉、聚乙烯吡咯啶酮(PVP)或糖、澱粉或具有黏著特性之其他醫藥學上可接受之物質。適合之界面活性劑見於醫藥學上可接受之非離子或
離子界面活性劑(諸如月桂基硫酸鈉)之群。
替代地,視情況與適合之組分混合的活性劑可調配成核心材料。該核心材料可藉由擠壓/滾圓、球狀化或壓縮,利用習知處理設備產生。經調配之核心材料之尺寸大約在0.1與4mm之間,且例如0.1與2mm之間。製造之核心材料可進一步用包含活性劑之額外成分分層及/或用於進一步處理。
活性劑與醫藥組分混合以在最終製劑中獲得較佳處理及加工特性及活性劑之適合濃度。可使用醫藥組分,諸如填充劑、黏合劑、潤滑劑、崩解劑、界面活性劑及其他醫藥學上可接受之添加劑。
替代地,前述核心材料可藉由使用噴霧乾燥或噴霧凝結技術製備。
腸溶包衣層:在將腸溶包衣層塗覆至呈個別糰粒形式之核心材料上之前,糰粒可視情況用一或多個包含醫藥賦形劑之分離層覆蓋,醫藥賦形劑視情況包括鹼性化合物(諸如pH緩衝化合物)。此/此等分離層將核心材料與作為腸溶包衣層之外部層分離。保護活性劑之核心材料的此/此等分離層應為水溶性或在水中快速崩解。
分離層可視情況藉由塗佈或分層程序在適合設備(諸如塗佈盤、塗佈造粒機)中或在使用水及/或有機溶劑用於塗佈製程之流體化床設備中塗覆至核心材料。作為替代方案,分離層可藉由使用粉末塗佈技術塗覆至核心材料。用於分離層之材料為醫藥學上可接受之化合物,諸如糖、聚乙二醇、聚乙烯吡咯啶酮、聚乙烯醇、聚乙酸乙烯酯、羥丙基纖維素、甲基纖維素、乙基纖維素、羥丙基甲基纖維素、羧甲基纖維素鈉、腸溶包衣聚合物之水溶性鹽及其他,其單獨或以混合物形式使用。添加劑,諸如塑化劑、著色劑、顏料、填充劑、抗黏劑及抗靜電劑,諸如硬脂酸鎂、二氧化鈦、滑石,及其他添加劑亦可包括至
分離層中。
當視情況存在之分離層塗覆至核心材料時,其可構成可變厚度。分離層之最大厚度通常僅受處理條件限制。分離層可充當擴散障壁且可充當pH緩衝區。視情況塗覆之分離層對於本發明不必要。然而,分離層可改良活性物質之化學穩定性及/或新穎多單位錠劑劑型之物理特性。
替代地,分離層可藉由塗覆在核心材料上之腸溶包衣聚合物層與核心材料中之鹼性反應化合物之間的反應就地形成。因此,形成之分離層包含在腸溶包衣層聚合物與在用以形成鹽之位置中的鹼性反應化合物之間形成的水溶性鹽。
藉由使用適合之塗佈技術將一或多種腸溶包衣層塗覆至核心材料上或用分離層覆蓋之核心材料上。腸溶包衣層材料可分散或溶解於水中或適合之有機溶劑中。可使用以下中之一或多者(單獨或以組合形式)作為腸溶包衣層聚合物:例如甲基丙烯酸共聚物、鄰苯二甲酸乙酸纖維素、鄰苯二甲酸羥丙基甲基纖維素、丁二酸乙酸羥丙基甲基纖維素、聚乙酸乙烯酯鄰苯二甲酸酯、苯偏三酸乙酸纖維素、羧甲基乙基纖維素、蟲膠或其他適合之腸溶包衣聚合物之溶液或分散液。
腸溶包衣層含有醫藥學上可接受之塑化劑以獲得所需機械特性,諸如腸溶包衣層之可撓性及硬度。此類塑化劑為例如(但不限於)三醋精、檸檬酸酯、鄰苯二甲酸酯、癸二酸二丁酯、十六醇、聚乙二醇、聚山梨醇酯或其他塑化劑。
塑化劑之量關於所選腸溶包衣層聚合物、所選塑化劑及該(等)聚合物之塗覆量針對各腸溶包衣層配方最佳化,其方式為使得腸溶包衣層之機械特性,即可撓性及硬度(例如例示為(維氏硬度(Vickers hardness))得到調節,以使得若需要錠劑,則用腸溶包衣層覆蓋之糰粒之耐酸性在將糰粒壓縮成錠劑期間不顯著降低。塑化劑之量通常為
按腸溶包衣層聚合物之重量計超過5%,諸如15-50%且進一步諸如20-50%。添加劑,諸如分散劑、著色劑、顏料聚合物(例如聚(丙烯酸乙酯、甲基丙烯酸甲酯))、抗黏劑及消泡劑亦可包括至腸溶包衣層中。可添加其他化合物以增加膜厚度及減少酸性胃液至酸敏感材料中之擴散。塗覆之腸溶包衣之最大厚度通常僅受處理條件及所需溶解概況限制。
覆蓋層:用腸溶包衣層覆蓋之糰粒可視情況進一步用一或多個覆蓋層覆蓋。覆蓋層應為水溶性或在水中快速崩解。覆蓋層可藉由塗佈或分層程序在適合之設備(諸如塗佈盤、塗佈造粒機)中或在使用水及/或有機溶劑用於塗佈或分層製程之流體化床設備中塗覆至包覆腸溶包衣之分層糰粒。用於覆蓋層之材料選自醫藥學上可接受之化合物,諸如糖、聚乙二醇、聚乙烯吡咯啶酮、聚乙烯醇、聚乙酸乙烯酯、羥丙基纖維素、甲基纖維素、乙基纖維素、羥丙基甲基纖維素、羧甲基纖維素鈉及其他,其單獨或以混合物形式使用。添加劑,諸如塑化劑、著色劑、顏料、填充劑、抗黏劑及抗靜電劑,諸如硬脂酸鎂、二氧化鈦、滑石,及其他添加劑亦可包括至覆蓋層中。覆蓋層可進一步防止包覆腸溶包衣之分層糰粒之潛在聚集,此外其可防止腸溶包衣層在壓縮製程期間破裂且促進製錠製程。塗覆之覆蓋層之最大厚度通常受處理條件及所需溶解概況限制。覆蓋層亦可用作錠劑膜衣層。
軟明膠膠囊之腸溶包衣可含有乳液、油、微乳液、自乳化系統、脂質、三酸甘油酯、聚乙二醇、界面活性劑、其他增溶劑及其類似物,及其組合,以溶解活性劑。軟明膠膠囊之可撓性藉由殘餘水及塑化劑維持。此外,對於明膠膠囊,明膠可溶解於水中以使得噴塗必須在具有相對低之相對濕度的速率下實現,諸如可在流化床或Wurster中實現。此外,乾燥應在不移除殘餘水或塑化劑,致使膠囊
外殼破裂之情況下實現。針對軟明膠膠囊之腸溶包衣最佳化之市售摻合物諸如Instamodel EPD(腸溶聚合分散液),可購自Ideal Cures,Pvt.Ltd.(Mumbai,India)。在實驗室規模上,包覆腸溶包衣之膠囊可藉由以下製備:a)在燒瓶中旋轉膠囊或在最低可能溫度下在具有塑化劑之溫和加熱腸溶包衣材料溶液中浸漬膠囊或b)在實驗室規模噴霧/流化床中,且隨後乾燥。
對於水性活性劑,可尤其理想的為在乳液之水相中併入藥物。此類「油包水」乳液為藥物提供適合之生物物理學環境且可提供油-水界面,該界面可使藥物免受pH或可降解藥物之酶的不良作用。另外,此類油包水調配物可提供脂質層,其可有利地與身體之細胞中之脂質相互作用,且可增加調配物分配至細胞之膜上。此類分配可增加此類調配物中之藥物吸收至循環中且因此可增加藥物之生物可用性。
在一些實施例中,油包水乳液含有由中鏈或長鏈羧酸或其酯或醇、界面活性劑或表面活性劑構成之油相,及主要含有水及活性劑之水相。
中鏈及長鏈羧酸為在C8至C22範圍內之具有至多三個不飽和鍵(亦分枝)之彼等羧酸。飽和直鏈酸之實例為正十二烷酸、正十四烷酸、正十六烷酸、己酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕櫚酸、硬脂酸、二十烷酸、二十二烷酸、褐煤酸及蜂花酸。亦適用的為不飽和單烯烴直鏈單羧酸。此等之實例為油酸、鱈油酸及芥子酸。亦適用的為不飽和(聚烯烴)直鏈單羧酸。此等之實例為亞麻油酸、蓖麻油酸、次亞麻油酸、二十碳四烯酸及二十二碳-13-炔酸(behenolic acid)。適用之分支酸包括例如二乙醯基酒石酸。不飽和烯烴鏈亦可經羥基化或乙氧基化以防止氧化或以改變表面特性。
長鏈羧酸酯之實例包括(但不限於)來自以下之群之彼等:單硬脂酸甘油酯;單棕櫚酸甘油酯;單硬脂酸甘油酯與單棕櫚酸甘油酯之混
合物;單亞麻油酸甘油酯;單油酸甘油酯;單棕櫚酸甘油酯、單硬脂酸甘油酯、單油酸甘油酯及單亞麻油酸甘油酯之混合物;單次亞麻油酸甘油酯;單鱈油酸甘油酯;單棕櫚酸甘油酯、單硬脂酸甘油酯、單油酸甘油酯、單亞麻油酸甘油酯、單次亞麻油酸甘油酯及單鱈油酸甘油酯之混合物;乙醯化甘油酯,諸如蒸餾乙醯化單酸甘油酯;丙二醇單酯、蒸餾單酸甘油酯、硬脂醯基乳酸鈉及二氧化矽之混合物;d-α生育酚聚乙二醇1000丁二酸酯;單甘油酯及二甘油酯之混合物,諸如Atmul;硬脂醯基乳酸鈣;乙氧基化單甘油酯及二甘油酯;乳酸化單甘油酯及二甘油酯;甘油與丙二醇之乳酸羧酸酯;長鏈羧酸之乳酸酯;長鏈羧酸之聚甘油酯;長鏈羧酸之丙二醇單酯及二酯;硬脂醯基乳酸鈉;脫水山梨糖醇單硬脂酸酯;脫水山梨糖醇單油酸酯;長鏈羧酸之其他脫水山梨糖醇酯;丁二醯化單酸甘油酯;檸檬酸硬脂酯單甘油酯、庚酸硬脂酯、蠟之十六基酯、辛酸硬脂酯、C8-C30膽固醇/羊毛甾醇酯;及蔗糖長鏈羧酸酯。自乳化長鏈羧酸酯之實例包括來自以下之群之彼等:硬脂酸酯、棕櫚酸酯、蓖麻油酸酯、油酸酯、二十二烷酸酯、蓖麻油酸酯、肉豆蔻酸酯、月桂酸酯、辛酸酯及己酸酯。在一些實施例中,油相可包含長鏈羧酸或其酯或醇中之2者或多於2者之組合。在一些實施例中,可使用中鏈界面活性劑且油相可包含辛酸/癸酸三甘油酯及辛酸之C8/C10單甘油酯/二甘油酯、辛酸甘油酯或丙二醇單辛酸酯或其混合物之混合物。
可使用之醇由以上例示之羧酸之羥基形式以及硬脂醇例示。
表面活性劑或界面活性劑為可在親水性/疏水性(水/油)界面處積聚且降低界面處之表面張力的長鏈分子。因此其可穩定乳液。在本發明之一些實施例中,界面活性劑可包含:界面活性劑之Tween®(聚氧化乙烯山梨酸酯)家族、界面活性劑之Span®(脫水山梨糖醇長鏈羧酸酯)家族、界面活性劑之Pluronic®(乙烯或環氧丙烷嵌段共聚物)家
族、界面活性劑之Labrasol®、Labrafil®及Labrafac®(各為聚乙二醇化甘油酯)家族、油酸、硬脂酸、月桂酸或其他長鏈羧酸之脫水山梨糖醇酯、泊洛沙姆(聚乙烯聚丙二醇嵌段共聚物或Pluronic®)、其他脫水山梨糖醇或蔗糖長鏈羧酸酯、單酸甘油酯及二酸甘油酯、辛酸/癸酸三酸甘油酯之PEG衍生物及其混合物或以上中之兩者或多於兩者之混合物。在一些實施例中,界面活性劑相可包含聚氧化乙烯(20)脫水山梨糖醇單油酸酯(Tween 80酯活與脫水山梨糖醇單油酸酯(Span 80酸酯之混合物。
水相可視情況包含懸浮於水及緩衝液中之活性劑。
在一些實施例中,此類乳液為粗乳液、微乳液及液晶乳液。在其他實施例中,此類乳液可視情況包含滲透增強劑。在其他實施例中,可使用含有噴霧乾燥分散液或微粒或奈米粒子之囊封微乳液、粗乳液或液晶。
在一些實施例中,本文中描述之固體劑型為非腸溶延時釋放劑型。如本文所用之術語「非腸溶延時釋放」係指使得藥物之釋放可在腸道中之一些一般可預測位置實現的遞送,該位置比若不存在延遲釋放變化所實現之位置更遠。在一些實施例中,延遲釋放之方法為在經設計之持續時間之後變為可滲透、溶解、破裂及/或不再完整之包衣。呈延時釋放劑型之包衣可具有用以腐蝕之固定時間,其後藥物經釋放(適合之包衣包括聚合包衣,諸如HPMC、PEO及其類似物)或具有由以下構成之核心:超級崩解劑,或滲透劑,或水引誘劑,諸如鹽;親水性聚合物,通常聚氧化乙烯或烷基纖維素;鹽,諸如氯化鈉、氯化鎂、乙酸鈉、檸檬酸鈉;糖,諸如葡萄糖、乳糖或蔗糖或其類似物,其經由半透膜抽取水;或氣體產生劑,諸如檸檬酸及碳酸氫鈉(有或無酸,諸如檸檬酸或併入在劑型中之前述酸中的任一者)。半透膜,雖然大多不對藥物可透亦不對滲透劑可透,但對在接近恆定之
速率下滲透之水可透以進入劑型以增大壓力且在溶脹壓力超過某一臨限值之後歷經所需延遲時間破裂。藥物通過此膜之滲透率應為小於水之1/10且在一個實施例中小於水滲透率之1/100。替代地,膜可藉由歷經所需延遲時間瀝濾水性可提取物而變為多孔。
滲透劑型已描述在Theeuwes US 3,760,984中,且滲透破裂劑型描述在Baker US 3,952,741中。若採用具有不同時序之不同裝置,則此滲透破裂劑型可提供單個釋放脈衝或多個脈衝。滲透破裂之時序可藉由選擇聚合物及含有藥物及滲透劑或引誘劑之核心周圍的半滲透膜之厚度或面積來控制。當劑型中之壓力隨著額外滲透水增加時,膜伸長直至其斷裂點,且隨後藥物釋放。替代地,可藉由在膜中具有較薄、較弱區域或藉由添加較弱材料至包覆膜之區域來在膜中產生特定破裂區域。具有較高水滲透率之可用作半滲透膜之一些較佳聚合物為乙酸纖維素、乙酸丁酸纖維素、硝酸纖維素、交聯聚乙烯、醇、聚胺基甲酸酯、耐綸6、耐綸6.6及芳族耐綸。乙酸纖維素為尤其較佳聚合物。
在另一實施例中,在腸溶包衣至少部分溶解之後開始其對釋放藥物之延遲的延時包衣由在與水接觸後開始逐漸隨時間腐蝕之親水性易蝕聚合物構成。此類聚合物之實例包括纖維素聚合物及其衍生物,包括(但不限於):羥烷基纖維素、羥甲基纖維素、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、羧甲基纖維素、微晶纖維素;多醣及其衍生物;聚氧化烯,諸如聚氧化乙烯或聚乙二醇,尤其高分子量聚乙二醇;聚葡萄胺糖;聚(乙烯醇);三仙膠;順丁烯二酸酐共聚物;聚(乙烯吡咯啶酮);澱粉及基於澱粉之聚合物;麥芽糊精;聚(2-乙基-2-噁唑啉);聚(伸乙亞胺);聚胺基甲酸酯;水凝膠;交聯聚丙烯酸;及前述中之任一者之組合或摻合物。
適用於形成易蝕包衣之一些較佳易蝕親水性聚合物為聚(環氧乙烷)、羥丙基甲基纖維素及聚(環氧乙烷)與羥丙基甲基纖維素之組合。
聚(環氧乙烷)在本文中用於指未經取代之環氧乙烷之線性聚合物。聚(環氧乙烷)聚合物之分子量可在約105道爾頓至約107道爾頓範圍內。聚(環氧乙烷)聚合物之較佳分子量範圍為約2×105至2×106道爾頓且可購自The Dow Chemical Company(Midland,Mich.),稱為SENTRYR POLYOXTM水溶性樹脂,NF(國家處方集)級。當使用較高分子量之聚氧化乙烯時,亦包括促進此包衣之腐蝕或崩解的其他親水性試劑,諸如鹽或糖,如葡萄糖、蔗糖或乳糖。
延時劑型可為機械藥丸,諸如Enterion®膠囊,或pH敏感膠囊,在預編程時間之後或當其接收可傳輸之信號時或在其離開胃後其可釋放藥物。
調配物中本發明化合物之量可在熟習此項技術者採用之全部範圍內變化。通常,以重量百分比(wt%)計,調配物將含有以總調配物計,約0.01-99.99重量%之式(I)化合物,其餘部分為一或多種適合之醫藥賦形劑。在一個實施例中,化合物以約1至80重量%之含量存在。
本發明化合物可與一或多種其他藥物組合用於治療本發明化合物或其他藥物可具有效用之疾病或病狀,其中共同地藥物之組合比單獨藥物更安全或更有效。此類其他藥物可藉由因此常用之途徑且以因此常用之量與本發明化合物同時或依序投與。當本發明化合物與一或多種其他藥物同時使用時,含有此類其他藥物及本發明化合物之呈單位劑型之醫藥組合物較佳。然而,組合療法亦可包括本發明化合物及一或多種其他藥物在不同重疊時程上投與之療法。亦預期當與一或多種其他活性成分組合使用時,本發明之化合物及其他活性成分可以比各自單獨使用時之劑量低的劑量使用。
因此,本發明之醫藥組合物亦包括除本發明化合物以外,含有一或多種其他活性成分之彼等醫藥組合物。
以上組合包括本發明化合物不僅與一種其他活性化合物,而且與兩種或多於兩種其他活性化合物之組合。類似地,本發明化合物可與用於預防、治療、控制、改善本發明化合物適用之疾病或病狀或降低其風險之其他藥物組合使用。此類其他藥物可藉由因此常用之途徑且以因此常用之量與本發明化合物同時或依序投與。當本發明化合物與一或多種其他藥物同時使用時,除本發明化合物以外,含有此類其他藥物之醫藥組合物,諸如固定組合藥品較佳。因此,本發明之醫藥組合物亦包括除本發明化合物以外,亦含有一或多種其他活性成分之彼等醫藥組合物。本發明化合物與第二活性成分之重量比可改變且將視各成分之有效劑量而定。一般而言,將使用各自之有效劑量。
當個體罹患自體免疫疾病、發炎疾病或過敏疾病或處於罹患自體免疫疾病、發炎疾病或過敏疾病之風險下時,式(I)化合物及/或其醫藥學上可接受之鹽可與以下治療劑中之一或多者以任何組合使用:免疫抑制劑(例如他克莫司(tacrolimus)、環孢素、雷帕黴素、甲胺喋呤、環磷醯胺、硫唑嘌呤、巰基嘌呤、黴酚酸酯或FTY720)、糖皮質激素(例如潑尼松、乙酸可的松、潑尼龍、甲基潑尼龍、地塞米松、倍他米松、曲安西龍、倍氯米松、乙酸氟氫可的松、乙酸去氧皮質酮、醛固酮)、非類固醇消炎藥(例如水楊酸鹽、芳基烷酸、2-芳基丙酸、N-芳基鄰胺基苯甲酸、昔康、昔布或磺醯基苯胺)、Cox-2特異性抑制劑(例如伐地昔布、塞內昔布或羅非昔布)、來氟米特、金硫代葡萄糖、硫代蘋果酸金、奧若芬(aurofin)、柳氮磺胺吡啶、羥基氯奎寧、二甲胺四環素、TNF-α結合蛋白(例如英利昔單抗、依那西普或阿達木單抗)、阿巴西普(abatacept)、阿那白滯素(anakinra)、干擾素-β、干擾素-γ、介白素-2、過敏疫苗、抗組織胺、抗白三烯、β-促效劑、茶鹼或抗膽鹼激導性劑。
當個體罹患B細胞增生性病症(例如漿細胞骨髓瘤)或處於罹患B
細胞增生性病症之風險下時,個體可用式(I)化合物及/或其醫藥學上可接受之鹽與一或多種其他抗癌劑之任何組合治療。在一些實施例中,一或多種抗癌劑為促凋亡劑。抗癌劑之實例包括(但不限於)以下中之任一者:棉酚(gossyphol)、根納三思(genasense)、多酚E、氯富辛(Chlorofusin)、全反式視黃酸(ATRA)、苔蘚蟲素(bryostatin)、腫瘤壞死因子相關細胞凋亡誘導配位體(TRAIL)、5-氮雜-2'-脫氧胞苷、全反式視黃酸、小紅莓、長春新鹼(vincristine)、依託泊苷(etoposide)、吉西他濱(gemcitabine)、伊馬替尼(GleevecTM)、格爾德黴素(geldanamycin)、17-N-烯丙基胺基-17-去甲氧基格爾德黴素(17-AAG)、夫拉平度(flavopiridol)、LY294002、硼替佐米(bortezomib)、曲妥珠單抗(trastuzumab)、BAY 11-7082、PKC412或PD184352、亦稱為「太平洋紫杉醇(paclitaxel)」之TaxolTM(其為藉由增強及穩定微管形成起作用之熟知抗癌藥物)及TaxolTM之類似物(諸如TaxotereTM)。具有基本紫杉烷構架作為共用結構特徵之化合物亦已顯示由於穩定微管而具有阻滯處於G2-M期之細胞的能力,且可適用於與本文所描述之化合物組合治療癌症。
與式(I)化合物及/或其醫藥學上可接受之鹽組合使用之抗癌劑之其他實例包括有絲分裂原活化之蛋白激酶信號傳導之抑制劑,例如U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青黴素或LY294002;Syk抑制劑;mTOR抑制劑;及抗體(例如美羅華(rituxan))。
可與式(I)化合物及/或其醫藥學上可接受之鹽組合使用之其他抗癌劑包括阿德力黴素、放線菌素d、博萊黴素、長春鹼、順鉑、阿西維辛(acivicin);阿柔比星(aclarubicin);阿考達唑鹽酸鹽(acodazole hydrochloride);阿克羅寧(acronine);阿多來新(adozelesin);阿地白介素;六甲蜜胺(altretamine);安波黴素(ambomycin);阿美蒽醌乙酸
鹽;胺魯米特;安吖啶;阿那曲唑;安麯黴素;天冬醯胺酶;曲林菌素;阿紮胞苷;阿紮替派(azetepa);阿佐黴素(azotomycin);巴馬司他(batimastat);苯佐替派(benzodepa);比卡魯胺;比生群鹽酸鹽;雙奈法德二甲磺酸鹽(bisnafide dimesylate);比折來新(bizelesin);博萊黴素硫酸鹽;布喹那鈉(brequinar sodium);溴匹立明(bropirimine);硫酸布他卡因;放線菌素C(cactinomycin);卡普睾酮(calusterone);卡醋胺(caracemide);卡貝替姆(carbetimer);卡鉑;卡莫司汀;卡柔比星鹽酸鹽;卡折來新(carzelesin);西地芬戈(cedefingol);苯丁酸氮芥;西羅黴素(cirolemycin);克拉屈濱;克立那托甲磺酸鹽(crisnatol mesylate);環磷醯胺;阿糖胞苷;達卡巴嗪;道諾黴素鹽酸鹽;地西他濱(decitabine);右奧馬鉑(dexormaplatin);地紮胍寧(dezaguanine);地紮胍寧甲磺酸鹽;地吖醌(diaziquone);小紅莓;鹽酸小紅莓;曲洛昔芬(droloxifene);曲洛昔芬檸檬酸鹽;屈他雄酮丙酸鹽;達佐黴素(duazomycin);依達曲沙;依氟鳥胺酸鹽酸鹽;依沙蘆星(elsamitrucin);恩洛鉑(enloplatin);恩普胺酯(enpromate);依匹哌啶(epipropidine);表柔比星鹽酸鹽;厄布洛唑(erbulozole);依索比星鹽酸鹽;雌氮芥;雌氮芥磷酸鈉;依他噠唑(etanidazole);依託泊苷;依託泊苷磷酸鹽;埃托寧(etoprine);法屈唑鹽酸鹽;法紮拉濱(fazarabine);非瑞替尼(fenretinide);氟尿苷;氟達拉賓磷酸鹽;氟尿嘧啶;氟西他濱;磷喹酮(fosquidone);福司曲星鈉(fostriecin sodium);吉西他濱;吉西他濱鹽酸鹽;羥基脲;艾達黴素鹽酸鹽;異環磷醯胺;伊莫福新(ilmofosine);介白素II(包括重組介白素II或rIL2);干擾素α-2a;干擾素α-2b;干擾素α-n1;干擾素α-n3;干擾素β-1a;干擾素γ-1 b;異丙鉑;伊立替康鹽酸鹽;蘭瑞肽乙酸鹽;來曲唑;亮丙瑞林乙酸鹽;利阿唑鹽酸鹽;洛美曲索鈉;洛莫司汀;洛索蒽醌鹽酸鹽;馬索羅酚;美登素;二氯甲二乙胺鹽酸鹽;乙酸甲地孕
酮;乙酸甲烯雌醇;美法侖;美諾立爾;巰基嘌呤;甲胺喋呤;甲胺喋呤鈉;氯苯胺啶;美妥替哌;米丁度胺;米托卡西;米托羅米;米托潔林;米托馬星;絲裂黴素;米托司培;米托坦;米托蒽醌鹽酸鹽;黴酚酸;諾考達唑;諾加黴素;奧馬鉑;奧昔舒侖;培門冬酶;培利黴素;奈莫司汀;培洛黴素硫酸鹽;培磷醯胺;哌泊溴烷;哌泊舒凡;吡羅蒽醌鹽酸鹽;普卡黴素;普洛美坦;卟吩姆鈉;泊非羅黴素;潑尼氮芥;丙卡巴肼鹽酸鹽;嘌呤黴素;嘌呤黴素鹽酸鹽;吡唑呋喃菌素;利波腺苷;羅穀亞胺;沙芬戈;沙芬戈鹽酸鹽;司莫司汀;辛曲秦;司泊索非鈉(sparfosate sodium);司帕黴素;鍺螺胺鹽酸鹽;螺莫司汀;螺鉑;鏈黑黴素;鏈脲佐菌素;磺氯苯脲;他利黴素;替康蘭鈉;喃氟啶;替洛蒽醌鹽酸鹽;替莫泊芬;替尼泊甙;替羅昔隆;睾內酯;硫米嘌呤;硫鳥嘌呤;噻替派;噻唑呋林;替拉紮明;托瑞米芬檸檬酸鹽;曲托龍乙酸鹽;曲西立濱磷酸鹽;曲美沙特;曲美沙特葡萄糖醛酸鹽;曲普瑞林;妥布氯唑鹽酸鹽;尿嘧啶氮芥;烏瑞替派;伐普肽;維替泊芬;長春鹼硫酸鹽;長春新鹼硫酸鹽;長春地辛;長春地辛硫酸鹽;長春匹定硫酸鹽;長春甘酯硫酸鹽;長春羅新硫酸鹽;長春瑞濱酒石酸鹽;長春羅定硫酸鹽;長春利定硫酸鹽;伏羅唑;折尼鉑;淨司他丁;佐柔比星鹽酸鹽。
可與式(I)化合物及/或其醫藥學上可接受之鹽組合使用之其他抗癌劑包括:20-表-1,25二羥維生素D3;5-乙炔尿嘧啶;阿比特龍;阿柔比星;醯基富烯;腺環戊醇;阿多來新;阿地白介素;ALL-TK拮抗劑;六甲蜜胺;胺莫司汀;艾美多;阿米福汀;胺基乙醯丙酸;胺柔比星;安吖啶;阿那格雷;阿那曲唑;穿心蓮內酯;血管生成抑制劑;拮抗劑D;拮抗劑G;安他利;抗背部化形態生成蛋白質-1;抗雄激素、前列腺瘤;抗雌激素;抗新普拉通;反義寡核苷酸;阿非迪黴素甘胺酸鹽;細胞凋亡基因調節子;細胞凋亡調節子;脫嘌呤核
酸;ara-CDP-DL-PTBA;精胺酸脫胺酶;奧沙那寧;阿他美坦;阿莫司汀;阿新司坦汀1;阿新司坦汀2;阿新司坦汀3;阿紮司瓊;阿紮托新;重氮酪胺酸;巴卡丁III衍生物;巴拉諾;巴馬司他;BCR/ABL拮抗劑;苯并二氫卟酚;苯甲醯基星形孢菌素;β內醯胺衍生物;β-阿立辛;β克拉黴素B;樺木酸;bFGF抑制劑;比卡魯胺;比生群;雙氮丙啶基精胺;雙奈法德;雙特拉汀A;比折來新;比銳來特;溴匹立明;布度鈦;丁硫胺酸磺醯亞胺;鈣泊三醇;鈣磷酸蛋白C;喜樹鹼衍生物;金絲雀痘IL-2;卡培他濱;甲醯胺-胺基-三唑;羧胺三唑;CaRest M3;CARN 700;軟骨衍生抑制劑;卡折來新;酪蛋白激酶抑制劑(ICOS);栗樹精胺;殺菌肽B;西曲瑞克;克羅林;氯喹喏啉磺醯胺;西卡前列素;順卟啉;克拉屈濱;克羅米芬類似物;克黴唑;克立黴素A;克立黴素B;康柏斯達汀A4;康柏斯達汀類似物;康納京尼;卡那貝西汀816;克立那托;念珠藻環肽8;念珠藻環肽A衍生物;卡拉新A;環戊蒽醌;環普蘭姆;西匹黴素;阿糖胞苷十八烷基磷酸鹽;細胞溶解因子;昔托斯他汀;達昔單抗;地西他濱;去氫膜海鞘素B;德舍瑞林;地塞米松;右異環磷醯胺;右雷佐生;右維拉帕米;地吖醌;迪德尼B;地多西;二乙基降精胺;二氫-5-氮胞苷;9-二噁黴素;二苯基螺莫司汀;二十二烷醇;多拉司瓊;脫氧氟尿苷;曲洛昔芬;屈大麻酚;多卡米辛SA;依布硒啉;依考莫司汀;依地福新;依決洛單抗;依氟鳥胺酸;欖香烯;乙嘧替氟;表柔比星;愛普列特;雌氮芥類似物;雌激素促效劑;雌激素拮抗劑;依他噠唑;依託泊苷磷酸鹽;依西美坦;法屈唑;法紮拉濱;非瑞替尼;非格司亭;非那雄胺(fmasteride);夫拉平度;氟卓斯汀;氟斯特酮;氟達拉賓;氟道諾欣鹽酸鹽;福酚美克;福美司坦;福司曲星;福莫司汀;德卟啉釓;硝酸鎵;加洛他濱;加尼瑞克;明膠酶抑制劑;吉西他濱;麩胱甘肽抑制劑;海普法姆;海瑞古林;六
亞甲基雙乙醯胺;金絲桃毒;伊班膦酸;艾達黴素;艾多昔芬;伊決孟酮;伊莫福新;伊洛馬司他;咪唑吖啶酮;咪喹莫特;免疫刺激肽;胰島素樣生長因子-1受體抑制劑;干擾素促效劑;干擾素;介白素;碘苄胍;碘多柔比星;4-甘薯醇;伊羅普拉;伊索拉定;異苯胍唑;異海利德林B;伊他司瓊;伽斯利德;卡哈利德F;片螺素-N三乙酸鹽;蘭瑞肽;雷那黴素;來格司亭;香菇多醣硫酸鹽;立托斯坦汀;來曲唑;白血病抑制因子;白細胞α干擾素;亮丙瑞林+雌激素+孕酮;亮丙瑞林;左旋咪唑;利阿唑;線性多元胺類似物;親脂性雙醣肽;親脂性鉑化合物;立索克林醯胺7;洛鉑;蚯吲磷脂;洛美曲索;氯尼達明;洛索蒽醌;洛伐他汀;洛索立賓;勒托替康;德卟啉鎦;里斯福林;裂解肽;美坦新;麥洛坦汀A;馬立馬司他;馬索羅酚;馬斯平;基質溶素抑制劑;基質金屬蛋白酶抑制劑;美諾立爾;麥爾巴隆;美替瑞林;蛋胺酶;甲氧氯普胺;MIF抑制劑;米非司酮;米替福新;米立司亭;錯配雙鏈RNA;丙脒腙;二溴衛矛醇;絲裂黴素類似物;米托萘胺;米托毒素纖維母細胞生長因子-沙泊寧;米托蒽醌;莫法羅汀;莫拉司亭;單株抗體,人類絨毛膜促性腺激素;單磷醯基脂質A+分支桿菌細胞壁sk;莫哌達醇;多抗藥性基因抑制劑;基於多腫瘤抑制因子1之療法;芥子抗癌劑;印度洋海綿B;分支桿菌細胞壁提取物;邁瑞酮;N-乙醯地那林;經N取代之苯甲醯胺;那法瑞林;納格瑞替;納洛酮+戊唑星;納帕維;奈帕特林;那托司亭;奈達鉑;奈莫柔比星;奈立膦酸;中性內肽酶;尼魯胺;尼撒黴素;氧化氮調節劑;氮氧化物抗氧化劑;紐崔林;O6-苯甲基鳥嘌呤;奧曲肽;奧克恩;寡核苷酸;奧那司酮;昂丹司瓊;昂丹司瓊;奧拉新;經口細胞因子誘導劑;奧馬鉑;奧沙特隆;奧沙利鉑;厄諾黴素;巴拉烏胺;棕櫚醯基根瘤菌素;帕米膦酸;帕納三醇;帕諾米芬;帕拉巴汀;帕折普汀;培門冬酶;培得星;戊聚糖聚
硫酸鈉;噴司他汀;泮托唑;潘氟隆;培磷醯胺;紫蘇子醇;芬那黴素;苯乙酸酯;磷酸酶抑制劑;畢西巴尼;匹魯卡品鹽酸鹽;吡柔比星;吡曲克辛;普拉汀A;普拉汀B;纖維蛋白溶酶原活化子抑制劑;鉑錯合物;鉑化合物;鉑-三胺錯合物;卟吩姆鈉;泊非羅黴素;潑尼松;丙基雙吖啶酮;前列腺素J2;蛋白酶體抑制劑;基於蛋白質A之免疫調節劑;蛋白激酶C抑制劑;微藻蛋白激酶C抑制劑;蛋白質酪胺酸磷酸酶抑制劑;嘌呤核苷磷酸化酶抑制劑;紫紅素;派拉瑞丁;吡哆醛化血色素聚氧化乙烯結合物;raf拮抗劑;雷替曲塞;拉莫司瓊;ras法呢基蛋白質轉移酶抑制劑;ras抑制劑;ras-GAP抑制劑;去甲基化瑞替普汀;Re 186依替膦酸錸;根瘤菌素;核糖核酸酶;R.亞11瑞汀醯胺;羅穀亞胺;羅希吐鹼;羅莫肽;羅喹美克;盧比龍B1;盧伯;沙芬戈;散特平;SarCNU;塞克菲特A;沙格司亭;Sdi 1模擬物;司莫司汀;衰老衍生1;有義寡核苷酸;信號轉導抑制劑;信號轉導調節劑;單鏈抗原結合蛋白質;西佐喃;索布佐生;硼卡鈉;苯乙酸鈉;索維洛;促生長因子結合蛋白;索納明;斯帕磷酸;斯卡黴素D;螺莫司汀;斯蘭羅皮汀;海綿抑素1;角鯊胺;幹細胞抑制劑;幹細胞分裂抑制劑;斯蒂醯胺;基質溶素抑制劑;索菲欣;超活性血管活性腸肽拮抗劑;蘇拉斯塔;蘇拉明;苦馬豆素;合成葡糖胺聚糖;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他紮羅汀;替康蘭鈉;喃氟啶;碲哌喃鎓;端粒酶抑制劑;替莫泊芬;替莫唑胺;替尼泊甙;四氯十氧化物;四唑明;噻立拉斯汀;噻可拉林;血小板生成素;血小板生成素模擬物;胸腺法新;胸腺生長素受體促效劑;胸腺曲南;甲狀腺刺激激素;乙基初卟啉錫;替拉紮明;二氯化二茂鈦;特西汀;托瑞米芬;分化全能幹細胞因子;轉譯抑制劑;維甲酸;三乙醯基尿苷;曲西立濱;曲美沙特;曲普瑞林;特比司瓊;妥羅雄脲;酪胺酸激酶抑制劑;泰福斯汀;UBC抑制
劑;烏苯美司;尿生殖竇衍生之生長抑制因子;尿激酶受體拮抗劑;伐普肽;維洛林B;載體系統,紅血球基因療法;維拉雷瑣;凡拉明;維汀;維替泊芬;長春瑞濱;維夏汀;維他欣;伏羅唑;紮諾特隆;折尼鉑;亞苄維;及淨司他丁司他美。
可與式(I)化合物及/或其醫藥學上可接受之鹽組合使用之其他抗癌劑包括烷基化劑、抗代謝物、天然產物或激素,例如氮芥(例如二氯甲基二乙胺、環磷醯胺、苯丁酸氮芥等)、磺酸烷基酯(例如硫酸布他卡因)、亞硝基脲(例如卡莫司汀、洛莫司汀等)或三氮烯(達卡巴嗪等)。抗代謝物之實例包括(但不限於)葉酸類似物(例如甲胺喋呤)或嘧啶類似物(例如阿糖胞苷)、嘌呤類似物(例如巰基嘌呤、硫鳥嘌呤、噴司他汀)。
適用於與式(I)化合物及/或其醫藥學上可接受之鹽組合之天然產物之實例包括(但不限於)長春花生物鹼(例如長春鹼、長春新鹼)、表鬼臼毒素(例如依託泊苷)、抗生素(例如道諾黴素、小紅莓、博萊黴素)、酶(例如L-天冬醯胺酶)或生物反應調節劑(例如干擾素α)。
可與式(I)化合物及/或其醫藥學上可接受之鹽組合使用之烷基化劑之實例包括(但不限於)氮芥(例如二氯甲基二乙胺、環磷醯胺、苯丁酸氮芥、美法侖等)、乙烯亞胺及甲基三聚氰胺(例如六甲基三聚氰胺、噻替派)、磺酸烷基酯(例如硫酸布他卡因)、亞硝基脲(例如卡莫司汀、洛莫司汀、司莫司汀、鏈脲佐菌素等)或三氮烯(達卡巴嗪等)。抗代謝物之實例包括(但不限於)葉酸類似物(例如甲胺喋呤),或嘧啶類似物(例如氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤類似物(例如巰基嘌呤、硫鳥嘌呤、噴司他汀)。
適用於與式(I)化合物及/或其醫藥學上可接受之鹽組合之激素及拮抗劑之實例包括(但不限於)腎上腺皮質類固醇(例如潑尼松)、孕酮(例如己酸羥基孕酮、乙酸甲地孕酮、乙酸甲羥孕酮)、雌激素(例如己
烯雌酚、乙炔雌二醇)、抗雌激素(例如他莫昔芬)、雄激素(例如丙酸睪固酮、氟羥甲基睾酮)、抗雄激素(例如氟他胺)、促性腺激素釋放激素類似物(例如亮丙瑞林)。可用於本文中描述之治療或預防癌症之方法及組合物之其他藥劑包括鉑配位複合物(例如順鉑、卡鉑)、蒽醌(例如米托蒽醌)、經取代脲(例如羥基脲)、甲基肼衍生物(例如丙卡巴肼)、腎上腺皮質抑制劑(例如米托坦、胺魯米特)。
由於穩定微管藉由阻滯處於G2-M期之細胞起作用且可與本發明之BTK抑制劑化合物組合使用之抗癌劑之實例包括(但不限於)以下出售之藥物及處於研發中之藥物:厄布洛唑(亦稱為R-55104)、海兔毒素10(亦稱為DLS-10及NSC-376128)、米伏布林羥乙磺酸鹽(亦稱為CI-980)、長春新鹼、NSC-639829、迪斯德莫來(亦稱為NVP-XX-A-296)、ABT-751(Abbott,亦稱為E-7010)、阿爾托希汀(Altorhyrtin)(諸如阿爾托希汀A及阿爾托希汀C)、海綿抑素(諸如海綿抑素1、海綿抑素2、海綿抑素3、海綿抑素4、海綿抑素5、海綿抑素6、海綿抑素7、海綿抑素8及海綿抑素9)、西馬多丁鹽酸鹽(亦稱為LU-103793及NSC-D-669356)、埃博黴素(諸如埃坡黴素A、埃坡黴素B、埃坡黴素C(亦稱為去氧埃坡黴素A或dEpoA)、埃坡黴素D(亦稱為KOS-862、dEpoB及去氧埃坡黴素B)、埃坡黴素E、埃坡黴素F、埃坡黴素B N-氧化物、埃坡黴素A N-氧化物、16-氮雜-埃坡黴素B、21-胺基埃坡黴素B(亦稱為BMS-310705)、21-羥基埃坡黴素D(亦稱為去氧埃坡黴素F及dEpoF)、26-氟埃坡黴素、奧瑞他汀PE(亦稱為NSC-654663)、索布里多汀(Soblidotin)(亦稱為TZT-1027)、LS-4559-P(Pharmacia,亦稱為LS-4577)、LS-4578(Pharmacia,亦稱為LS-477-P)、LS-4477(Pharmacia)、LS-4559(Pharmacia)、RPR-112378(Aventis)、長春新鹼硫酸鹽、DZ-3358(Daiichi)、FR-182877(Fujisawa,亦稱為WS-9885B)、GS-164(Takeda)、GS-198(Takeda)、KAR-2(Hungarian
Academy of Sciences)、BSF-223651(BASF,亦稱為ILX-651及LU-223651)、SAH-49960(Lilly/Novartis)、SDZ-268970(Lilly/Novartis)、AM-97(Armad/Kyowa Hakko)、AM-132(Armad)、AM-138(Armad/Kyowa Hakko)、IDN-5005(Indena)、念珠藻環肽52(亦稱為LY-355703)、AC-7739(Ajinomoto,亦稱為AVE-8063A及CS-39.HCl)、AC-7700(Ajinomoto,亦稱為AVE-8062、AVE-8062A、CS-39-L-Ser.HCl及RPR-258062A)、維提醯胺(Vitilevuamide)、特吡萊辛(Tubulysin)A、卡納登所(Canadensol)、矢車菊黃素(亦稱為NSC-106969)、T-138067(Tularik,亦稱為T-67、TL-138067及TI-138067)、COBRA-1(Parker Hughes Institute,亦稱為DDE-261及WHI-261)、H10(Kansas State University)、H16(Kansas State University)、溫可西汀(Oncocidin)A1(亦稱為BTO-956及DIME)、DDE-313(Parker Hughes Institute)、費加諾里德B.勞力馬里得(Fijianolide B.Laulimalide)、SPA-2(Parker Hughes Institute)、SPA-1(Parker Hughes Institute,亦稱為SPIKET-P)、3-IAABU(Cytoskeleton/Mt.Sinai School of Medicine,亦稱為MF-569)、諾司卡品(Narcosine)(亦稱為NSC-5366)、納斯卡品(Nascapine)、D-24851(Asta Medica)、A-105972(Abbott)、哈米特林(Hemiasterlin)、3-BAABU(Cytoskeleton/Mt.Sinai School of Medicine,亦稱為MF-191)、TMPN(Arizona State University)、乙醯基丙酮酸二茂釩、T-138026(Tularik)、單星素(Monsatrol)、依納諾辛(Inanocine)(亦稱為NSC-698666)、3-1AABE(Cytoskeleton/Mt.Sinai School of Medicine)、A-204197(Abbott)、T-607(Tuiarik,亦稱為T-900607)、RPR-115781(Aventis)、艾榴素(Eleutherobins)(諸如脫甲基艾榴素、脫乙醯基艾榴素、異艾榴素A及Z-艾榴素)、卡瑞巴西德(Caribaeoside)、卡瑞巴林(Caribaeolin)、軟海綿素B、D-64131(Asta Medica)、D-68144(Asta Medica)、重氮醯胺
(Diazonamide)A、A-293620(Abbott)、NPI-2350(Nereus)、根薯酮內酯(Taccalonolide)A、TUB-245(Aventis)、A-259754(Abbott)、迪奧佐他汀(Diozostatin)、(-)-苯基阿夕斯丁(Phenylahistin)(亦稱為NSCL-96F037)、D-68838(Asta Medica)、D-68836(Asta Medica)、肌基質蛋白(Myoseverin)B、D-43411(Zentaris,亦稱為D-81862)、A-289099(Abbott)、A-318315(Abbott)、HTI-286(亦稱為SPA-110,三氟乙酸鹽)(Wyeth)、D-82317(Zentaris)、D-82318(Zentaris)、SC-12983(NCI)、力司弗拉司達汀(Resverastatin)磷酸鈉、BPR-OY-007(National Health Research Institutes)及SSR-250411(Sanofi)。
當個體罹患血栓栓塞病症(例如中風)或處於罹患血栓栓塞病症之風險下時,個體可用式(I)化合物與一或多種其他抗血栓栓塞劑之任何組合治療。抗血栓栓塞劑之實例包括(但不限於)以下中之任一者:血栓溶解劑(例如阿替普酶(alteplase)、阿尼普酶(anistreplase)、鏈激酶(streptokinase)、尿激酶(urokinase)或組織纖維蛋白溶酶原活化因子)、肝素、亭紮肝素(tinzaparin)、華法林(warfarin)、達比加群(dabigatran)(例如達比加群酯(dabigatran etexilate))、因子Xa抑制劑(例如方達珀魯(fondaparinux)、德拉瑞斯(draparinux)、利伐沙班(rivaroxaban)、DX-9065a、奧米沙班(otamixaban)、LY517717或YM150)、噻氯匹定(ticlopidine)、克羅匹多(clopidogrel)、CS-747(普拉格雷(prasugrel)、LY640315)、希美加群(ximelagatran)或BIBR 1048。
提供以下式(I)化合物及中間物(參考)之製備以使得熟習此項技術者能夠更清楚地理解及實踐本發明。其不應被視為限制本發明之範
疇,而僅為本發明之說明及代表。在以下化合物中在烯烴碳處之
線表示化合物以(E)及(Z)異構體之非限定混合物形式分離。
將2,4-二氯-3-硝基吡啶(8g,41.45mmol,1.00當量)、N,N-二甲基甲醯胺(50mL)、(R)-3-胺基哌啶-1-甲酸第三丁酯(8.3g,41.44mmol,1.00當量)及TEA(6.29g,62.16mmol,1.50當量)置放至100mL圓底燒瓶中。在25℃下攪拌所得溶液隔夜。用H2O稀釋所得溶液,用乙酸乙酯萃取且合併有機層。用飽和氯化鈉洗滌所得混合物且經無水硫酸鈉乾燥且濃縮。將殘餘物施加至矽膠管柱上且用乙酸乙酯/石油醚(1:1)溶離,得到8g(51%)呈黃色油狀物之(R)-3-((2-氯-3-硝基吡啶-4-基)胺基)哌啶-1-甲酸第三丁酯。
將(R)-3-((2-氯-3-硝基吡啶-4-基)胺基)哌啶-1-甲酸第三丁酯(8g,22.42mmol,1.00當量)、異丁醇(100mL)、雙[(4-甲氧基苯基)甲基]胺(5.78g,22.46mmol,1.00當量)及TEA(2.955g,29.20mmol,1.30當量)置放至250mL圓底燒瓶中。在95℃下攪拌所得溶液隔夜。冷卻反應混合物且在真空下濃縮。此產生12g(92%)呈黃色油狀物之(R)-3-((2-(雙(4-甲氧基苯甲基)胺基)-3-硝基吡啶-4-基)胺基)哌啶-1-甲酸第三丁酯。
將(R)-3-((2-(雙(4-甲氧基苯甲基)胺基)-3-硝基吡啶-4-基)胺基)哌啶-1-甲酸第三丁酯(10g,17.31mmol,1.00當量)、AcOH/MeOH(1:1,100mL)及Fe(9.69g,173.04mmol,10.00當量)置放至250mL圓底燒瓶中。在25℃下攪拌所得溶液隔夜且隨後在真空下濃縮。溶液之pH值用碳酸氫鈉調節至8.0-9.0。用二氯甲烷萃取所得溶液且用碳酸氫鈉洗滌有機層,過濾且經無水硫酸鈉乾燥,隨後在真空下濃縮得到
8.8g(92.8%)呈黃色油狀物之(R)-3-((3-胺基-2-(雙(4-甲氧基苯甲基)-胺基)吡啶-4-基)胺基)哌啶-1-甲酸第三丁酯。
將(R)-3-((3-胺基-2-(雙(4-甲氧基-苯甲基)胺基)吡啶-4-基)胺基)哌啶-1-甲酸第三丁酯(12g,19.72mmol,1.00當量,90%)、CH3CN(100mL)及CDI(5.336g,32.91mmol,1.50當量)置放至250mL圓底燒瓶中。在80℃下攪拌所得溶液隔夜。冷卻反應混合物且濃縮。將殘餘物施加至矽膠管柱上且用乙酸乙酯/石油醚(1:5)溶離得到11g(89%)呈黃色固體油狀物之(R)-3-(4-[雙[(4-甲氧基-苯基)甲基]-胺基]-2-側氧基-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯。
將(R)-3-(4-[雙[(4-甲氧基苯基)-甲基]胺基]-2-側氧基-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯(1.5g,2.61mmol,1.00當量)、二氯甲烷(30mL)及三氟乙酸(30mL)置放至50mL圓底燒瓶
中。在50℃下攪拌所得溶液4小時。溶液之pH值用碳酸氫鈉調節至9。用二氯甲烷萃取所得溶液且合併有機層且經無水硫酸鈉乾燥。在真空下濃縮所得混合物,得到0.45g(73.7%)呈淡黃色固體狀之(R)-4-胺基-1-(哌啶-3-基)-1,3-二氫-2H-咪唑并[4,5-c]吡啶-2-酮。
將(R)-4-胺基-1-(哌啶-3-基)-1,3-二氫-2H-咪唑并[4,5-c]吡啶-2-酮(1g,4.29mmol,1.00當量)、1,4-二噁烷/H2O(1:1,50mL)、Boc2O(1.03g,4.72mmol,1.03當量)及碳酸鈉(1.5g,14.15mmol,1.50當量)置放至100mL圓底燒瓶中。在25℃下攪拌所得溶液1小時,隨後用二氯甲烷萃取且合併有機層。用水及飽和氯化鈉洗滌所得有機層且隨後在真空下濃縮。將殘餘物施加至矽膠管柱上且用二氯甲烷/甲醇(30:1)溶離得到1.2g(84%)呈淡黃色固體狀之(R)-3-(4-胺基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯。
將(R)-3-(4-胺基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯(6.5g,19.50mmol,1.00當量)及DMF-DMA(50mL)置放至100mL圓底燒瓶中。在40℃下攪拌所得溶液1小時且隨後在真空下濃縮。隨後用CH2Cl2溶解所得混合物且用鹽水洗滌。合併有
機層且在真空下濃縮,且用己烷洗滌。藉由過濾收集固體得到5.0289g(66%)呈固體狀之(R,E)-3-(4-(((二甲胺基)亞甲基)胺基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯。
LC-MS m/z:389.2(M+1)
將(R)-3-(4-[雙[(4-甲氧基苯基)-甲基]胺基]-2-側氧基-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯(10g,17.43mmol,1.00當量)、二氯甲烷(100mL)、(4-苯氧基苯基)酸(7.5g,35.04mmol,2.00當量)、TEMPO(3g,19.20mmol,1.10當量)及TEA(7g,69.18mmol,4.00當量)、Cu(OAc)2(1.6g,8.81mmol,0.50當量)置放至250mL圓底燒瓶中。在25℃下在環境-壓力氧氣氛圍下攪拌所得溶液隔夜。添加(4-苯氧基苯基)酸(7.5g,35.04mmol,2.00當量)且使所得溶液在25℃下反應隔夜。將殘餘物施加至矽膠管柱上且用乙
酸乙酯/石油醚(1:3)溶離得到1.5g(12%)呈黃色固體狀之(R)-3-(4-[雙[(4-甲氧基苯基)甲基]胺基]-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯。
將(R)-3-(4-[雙[(4-甲氧基苯基)-甲基]胺基]-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯(5g,6.07mmol,1.00當量,90%)、二氯甲烷(80mL)及三氟乙酸(80mL)置放至250mL圓底燒瓶中。在50℃下攪拌所得溶液5小時。在真空下濃縮所得混合物。溶液之pH值用碳酸氫鈉調節至9。用二氯甲烷萃取所得溶液且合併有機層且經無水硫酸鈉乾燥。將殘餘物施加至矽膠管柱上且用二氯甲烷/甲醇(30:1)溶離得到1g(41%)呈淡黃色固體狀之4-胺基-3-(4-苯氧基苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮。
將4-胺基-3-(4-苯氧基苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮(79mg,0.20mmol,1.00當量)、N,N-二甲基甲醯胺(2mL)、TEA(0.082mL,1.50當量)、HATU(113mg,0.30mmol,1.50當量)及2-氰基-4,4-二甲基戊-2-烯酸(46mg,0.30mmol,3.00當量)置放至10mL圓底燒瓶中。在室溫下攪拌所得溶液2.5小時且隨後藉由添加水來淬滅。用二氯甲烷萃取所得溶液且合併有機層且在真空下濃縮。藉由製備型HPLC在以下條件(2號-分析HPLC-SHIMADZU(HPLC-10))下純化粗產物:管柱,Gemini-NX C18 AXAI封裝,21.2×150mm 5um 11nm;移動相,水及0.05% TFA及ACN(20.0% ACN直至50.0%,在8分鐘內);偵測器,254nm,得到50mg(47%)呈白色固體狀之標題化合物。LC-MS m/z:537.2(M+1)
將(R,E)-3-(4-(((二甲胺基)-亞甲基)胺基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯(200mg,0.51mmol,1.00當量)、二氯甲烷(20mL)、TEA(208mg,2.06mmol,4.00當量)、TEMPO(88.5mg,0.57mmol,1.10當量)及Cu(OAc)2(46.7mg,0.26mmol,0.50當量)置放至50mL圓底燒瓶中。在25℃下攪拌所得溶液0.5小時。添加(4-苯氧基苯基)酸(220mg,1.03mmol,2.00當量)且使所得溶液在25℃下反應隔夜。將殘餘物施加至矽膠管柱上且用二氯甲烷/乙酸乙酯(5:1)溶離得到150mg(52%)呈淡黃色固體狀之(R)-3-[4-[(E)-[(二甲胺基)亞甲基]胺基]-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-甲酸第三丁酯。
將(3R)-3-[4-[(E)-[(二甲胺基)-亞甲基]-胺基]-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-甲酸第三丁酯(150mg,0.27mmol,1.00當量)、1,4-二噁烷(6mL)及氯化氫(3mL)置放至25mL圓底燒瓶中。在50℃下攪拌所得溶液隔夜。用水淬滅反應混合物。溶液之pH用碳酸氫鈉調節至9。用二氯甲烷:CH3OH=10:1萃取所得溶液且合併有機層。用氯化鈉洗滌所得混合物且合併有機層,經無水硫酸鈉乾燥且在真空下濃縮。將殘餘物施加至矽膠管柱上且用二氯甲烷/甲醇(30:1)溶離得到80mg(74%)呈淡黃色固體狀之4-胺基-3-(4-苯氧基苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮。
將4-胺基-3-(4-苯氧基苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮(2g,4.98mmol,1.00當量)、N,N-二甲基甲醯胺(20mL)、2-氰基乙酸(402.5mg,4.73mmol,0.95當量)、HATU(2.84g,7.47mmol,1.50當量)及TEA(1.51g,14.92mmol,3.00當量)置放至
50mL圓底燒瓶中。在室溫下攪拌所得溶液1小時且隨後用水淬滅。用乙酸乙酯萃取所得溶液且合併有機層。用飽和氯化鈉洗滌有機層,經無水硫酸鈉乾燥且在真空下濃縮。將殘餘物施加至具有二氯甲烷/甲醇(30:1)之矽膠管柱上得到1.3g(56%)呈淡黃色固體狀之3-[(3R)-3-[4-胺基-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]-3-側氧基丙腈。
將3-[(3R)-3-[4-胺基-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]-3-側氧基丙腈(800mg,1.71mmol,1.00當量)、二氯甲烷(20mL)、2-甲基-2-[4-(氧雜環丁烷-3-基)哌嗪-1-基]丙醛(1.0875g,5.12mmol,3.00當量)、TMSCl(922mg,8.49mmol,4.97當量)及吡咯啶(0.607g)置放至50mL圓底燒瓶中。在室溫下攪拌所得溶液1小時。在真空下濃縮所得混合物。在以下條件(2號-分析HPLC-SHIMADZU(HPLC-10))下藉由製備型TLC純化,隨後藉由製備型HPLC純化粗產物:管柱,Gemini-NX C18 AXAI封裝,21.2×150mm 5um 11nm;移動相,水及0.05% TFA及ACN(20.0% ACN直至40.0%,在10min內);偵測器,uv 254nm),得到0.478g(42%)呈淡黃色固體狀之標題化合物。LC-MS m/z:663.3(M+1)。
將(R)-4-胺基-3-(4-苯氧基苯基)-1-(哌啶-3-基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(150mg,0.37mmol,1.00當量)、DCM-CH3OH(6mL)、TEA(113mg,1.12mmol,3.00當量)置放至100mL圓底燒瓶中。此接著為在0℃下在攪拌下在5分鐘內逐滴添加丙-2-烯醯氯(40.1mg,0.44mmol,1.20當量)。在0℃下攪拌所得溶液2小時。在真空下濃縮所得混合物。將殘餘物施加至具有二氯甲烷/甲醇(30:1)之矽膠管柱上。藉由製備型HPLC在以下條件(管柱,XBridge製備型C18 OBD管柱,5um,19×150mm;移動相,水及0.05% TFA及ACN(25.0% ACN直至45.0%在8分鐘內)下純化粗產物(100mg)。獲得54.5mg呈白色固體狀之(R)-1-(1-丙烯醯基哌啶-3-基)-4-胺基-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮之產物。LC-MS m/z:465.2(M+1)
將(R)-4-胺基-3-(4-苯氧基苯基)-1-(哌啶-3-基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(150mg,0.37mmol,1.00當量)、N,N-二甲基甲醯胺(15mL)、丁-2-炔酸(31.42mg,0.37mmol,1.00當量)、HATU(213.2mg,0.56mmol,1.50當量)、TEA(113.4mg,1.12mmol,3.00當量)置放至100mL圓底燒瓶中。在室溫下攪拌所得溶液2小時。隨後藉由添加50mL水淬滅反應物。用3×50mL二氯甲烷萃取所得溶液且合併有機層。用50mL鹽水洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。將殘餘物施加至具有二氯甲烷/甲醇(30:1)之矽膠管柱上。藉由製備型HPLC如實例3中所描述純化粗產物(100mg)獲得86.5mg(50%)呈白色固體狀之(R)-4-胺基-1-(1-(丁-2-炔醯基)哌啶-3-基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:468.2(M+1)。
將2-(哌啶-4-基)乙酸甲酯鹽酸鹽(10g,51.63mmol,1.00當量)、二氯甲烷(100mL)置放至250mL 3頸圓底燒瓶中。在0℃下攪拌所得溶液30分鐘。隨後添加三乙胺(15.65g,154.66mmol,3當量)、Boc2O(12.4g,56.82mmol,1.1當量)。使所得溶液在25℃下在攪拌下反應額外14小時。溶液之pH值用檸檬酸(3%)調節至7.0。用2×100mL水及2×100mL飽和鹽水洗滌所得混合物。將殘餘物施加至具有乙酸乙酯/石油醚(1:10)之矽膠管柱上。此產生10g(75.2%)呈無色油狀之4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸第三丁酯。
將LDA(46.7mL,3.00當量)、四氫呋喃(80mL)、4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸第三丁酯(8g,31.1mmol,1.00當量)置放至250mL 3頸圓底燒瓶中。在-78℃下攪拌所得溶液30分鐘。隨後添加CH3I(22g,155mmol,5.00當量)。使所得溶液在-78℃下在攪拌下反應額外1小時。在-78℃下添加額外LDA(46.7mL,3.00當量)且在0.5小時之後,添加CH3I(22g,155mmol,5.00當量)。在室溫下攪拌反應物16小時。隨後藉由添加200mL NH4Cl淬滅反應物。用2×200mL乙酸乙酯萃取所得溶液且合併有機層。用2×200mL水及2×200mL飽和氯化鈉洗滌所得混合物。藉由矽膠層析使用乙酸乙酯/石油醚
(1:35)純化殘餘物。此產生6g(68%)呈淡黃色油狀物之4-(1-甲氧基-2-甲基-1-側氧基丙-2-基)哌啶-1-甲酸第三丁酯。
將LiAlH4(1.6g,42.2mmol,4.00當量)、四氫呋喃(50mL)、4-(1-甲氧基-2-甲基-1-側氧基丙-2-基)哌啶-1-甲酸第三丁酯(3g,10.5mmol,1.00當量)置放至100mL 3頸圓底燒瓶中。在-78℃下攪拌所得溶液3小時。使反應混合物升溫至0℃。隨後藉由添加1.6mL水淬滅反應物,隨後添加1.6mL 15% NaOH,接著添加4.8mL H2O。過濾固體得到1.5g(83%)呈粉紅色油狀物之2-甲基-2-(1-甲基哌啶-4-基)丙-1-醇。
將草醯氯(440mg,3.47mmol,1.20當量)、二氯甲烷(50mL)置放至100mL圓底燒瓶中,在-78℃下放入DMSO(684mg,8.75mmol,3.00當量)、2-甲基-2-(1-甲基哌啶-4-基)丙-1-醇(500mg,2.92mmol,1.00當量)、TEA(1.48g,14.6mmol,5.00當量)。在-78℃下攪拌所得溶液30分鐘。使所得溶液在25℃下在攪拌下反應額外2小時。隨後藉由添加水淬滅反應物。用二氯甲烷萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。此產生385mg(88%)呈黃色油狀物之2-甲基-2-(1-甲基哌啶-4-基)丙醛。
將(R)-3-(3-(4-胺基-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-基)-3-側氧基丙腈(100mg,0.19mmol,1.00當量,90%)、二氯甲烷(50mL)、2-甲基-2-(1-甲基哌啶-4-基)丙醛(108mg,0.57mmol,3.00當量)、TMSCl(115mg,1.01mmol,5.00當量,95%)、吡咯啶(75.8mg,1.01mmol,5.00當量,95%)置放至100mL圓底燒瓶中。在室溫下攪拌所得溶液16小時。藉由製備型
HPLC在以下條件(管柱,Gemini-NX C18 AXAI封裝,21.2×150mm 5um 11nm;移動相,水及0.05% TFA及ACN(20.0% ACN直至50.0%,在8分鐘內);偵測器,254nm下純化粗產物。此產生15.5mg(12%)呈淡黃色固體狀之(R)-2-(3-(4-胺基-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(1-甲基哌啶-4-基)戊-2-烯腈。LC-MS m/z:620.3(M+1)。
在用惰性氮氣氛圍淨化且維持之250mL 3頸圓底燒瓶中,在-78℃下用乙腈(690mg,16.8mmol)處理於無水THF(20mL)中之HMPA(6.0mL)及LDA(16.8mmol)。攪拌溶液30分鐘,且逐滴添加於THF(15mL)中之(2-溴乙氧基)(第三丁基)二甲基矽烷(3.4g,14.3mmol)。繼續攪拌2小時,其後添加第二份LDA(16.8mmol,於20mL THF中)。攪拌溶液30分鐘,且逐滴添加於THF(15mL)中之(2-溴乙氧基)(第三丁基)二甲基矽烷(3.4g,14.3mmol)。使反應繼續進行2小時。添加NH4Cl飽和水溶液,且使混合物達到室溫。添加乙醚,分離各相,且用乙醚萃取水層。用鹽水洗滌合併之有機相,經Na2SO4乾燥,且濃縮。管柱層析[二氧化矽,石油醚]得到無色油狀物(3.2g,53%)。
將於甲苯(15mL)中之4-[(第三丁基二甲基矽烷基)氧基]-2-[2-[(第三丁基二甲基矽烷基)氧基]乙基]丁腈(1g,2.80mmol,1.00當量)置放至用惰性氮氣氛圍淨化且維持之250mL 3頸圓底燒瓶中。在-78℃下添加DIBAL-H(1M)(3.36mL,1.20當量)且在-78℃下在液氮浴中攪拌所得溶液1小時。添加水(0.7mL)且使混合物達到室溫。添加NaOH水溶液(0.7mL,4M)且繼續攪拌15分鐘。添加水(2.1mL)且再攪拌懸浮液15分鐘。混合物經Na2SO4乾燥且在真空下濃縮。藉由矽膠管柱用PE/EA(20:1)純化殘餘物。此產生900mg(89%)呈無色油狀之4-[(第三丁基二甲基矽烷基)氧基]-2-[2-[(第三丁基二甲基矽烷基)氧基]乙基]丁醛。
將3-[(3R)-3-[4-胺基-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]-3-側氧基丙腈(150mg,0.32mmol,1.00當量)、4-[(第三丁基二甲基矽烷基)氧基]-2-2-[(第三丁基二甲基矽烷基)氧基]乙基丁醛(346mg,0.96mmol,3.00當量)、TMSCl(173mg,1.59mmol,5.00當量)、吡咯啶(114mg,1.61mmol,5.00當量)、二氯甲烷(2mL)置放至8mL小瓶中。在室溫下攪拌所得溶液3小時。在真空下濃縮所得混合物。將殘餘物施加至具有二氯甲烷/甲醇(30:1)之矽膠管柱上。此產生120mg(46%)呈黃色固體狀之2-[[(3R)-3-[4-胺基-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]羰基]-6-[(第三丁基二甲基矽烷基)氧基]-4-[2-[(第三丁基二甲基矽烷基)氧基]乙基]己-2-烯腈。
將2-[[(3R)-3-[4-胺基-2-側氧基-3-(4-苯氧基苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]羰基]-6-[(第三丁基二甲基矽烷基)氧基]-4-[2-[(第三丁基二甲基矽烷基)氧基]乙基]己-2-烯腈(120mg,0.15
mmol,1.00當量)、三氟乙酸(1mL)、二氯甲烷(5mL)置放至25mL圓底燒瓶中。在室溫下攪拌所得溶液2小時。隨後藉由添加飽和碳酸氫鈉淬滅反應物。用3×20mL DCM/MeOH(10:1)萃取所得溶液且合併有機層。用飽和氯化鈉洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。藉由製備型TLC用DCM/MeOH(15:1)純化殘餘物。藉由製備型HPLC在以下條件(Atlantis製備型T3 OBD管柱,19×150mm 5um 10nm;移動相,水及0.1% FA及MeCN(20.0% MeCN直至50.0%,在10分鐘內);偵測器,254nm下純化粗產物。此產生7.9mg(9%)呈白色固體狀之(R)-2-(3-(4-胺基-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-6-羥基-4-(2-羥乙基)己-2-烯腈。LC-MS m/z:583.2(M+1)。
將於二氯甲烷(100mL)中之Cu(OAc)2(6.96g,38.3mmol,1.00當量)、吡啶(15.2g,192mmol,5.00當量)及4A分子篩(5g)置放至用O2氛圍淨化且維持之250mL圓底燒瓶中。攪拌所得溶液30分鐘且隨後添加2,6-二氟苯酚(5g,38.4mmol,1.00當量)及(4-溴苯基)酸
(15.4g,76.6mmol,2.00當量)。在室溫下攪拌所得溶液隔夜。在真空下濃縮所得混合物。將殘餘物施加至矽膠管柱上且用石油醚溶離。此產生5.5g(50%)呈黃色油狀物之2-(4-溴苯氧基)-1,3-二氟苯。
將於四氫呋喃(100mL)中之2-(4-溴苯氧基)-1,3-二氟苯(5.5g,19.3mmol,1.00當量)置放至用惰性氮氣氛圍淨化且維持之250mL 3頸圓底燒瓶中。在-78℃下添加nBuLi於己烷(11.6mL,1.50當量)中之2.5M溶液且攪拌所得溶液30分鐘,且隨後添加硼酸三甲酯(4.03g,38.8mmol,2.00當量)。使反應物升溫至室溫且在室溫下攪拌所得溶液3小時。隨後藉由添加氯化氫(2M)淬滅反應物。用3×150mL乙醚萃取所得溶液且合併有機層。用1×200mL氯化鈉(飽和)洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。將殘餘物施加至具有二氯甲烷/甲醇(50:1)之矽膠管柱上。此產生2.15g(45%)呈棕色固體狀之[4-(2,6-二氟苯氧基)苯基]酸。
將於二氯甲烷(50mL)中之(R,E)-3-(4-(((二甲胺基)亞甲基)胺基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯(500mg,1.29mmol,1.00當量)、TEA(521mg,5.15mmol,4.00當量)、Cu(OAc)2(117mg,0.64mmol,0.50當量)、TEMPO(221mg,1.41mmol,1.10當量)及Ms(4A)(500mg)置放至用O2氛圍淨化且維持之100mL圓底燒瓶中。攪拌所得溶液30分鐘且隨後添加[4-(2,6-二氟苯氧基)苯基]酸(644mg,2.58mmol,2.00當量)。在室溫下攪拌所得溶液隔夜。在真空下濃縮所得混合物。將殘餘物施加至具有二氯甲烷/甲醇(30:1)之矽膠管柱上。此產生490mg呈棕色固體狀之(R,E)-3-(4-(((二甲胺基)亞甲基)胺基)-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯。
向(R,E)-3-(4-(((二甲胺基)亞甲基)胺基)-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-甲酸第三丁酯(490mg,0.83mmol,1.00當量)於30mL二噁烷中之溶液中添加15mL氯化氫(12M)。在85℃下在油浴中攪拌所得溶液3小時。隨後藉由添加碳酸氫鈉(飽和)淬滅反應物。用3×100mL DCM/MeOH(10:1)萃取所得溶液且合併有機層。用1×100mL氯化鈉(飽和)洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。此產生360mg(100%)呈棕色固體狀之4-胺基-3-[4-(2,6-二氟苯氧基)苯基]-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮。
將4-胺基-3-[4-(2,6-二氟苯氧基)苯基]-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮(360mg,0.82mmol,1.00當量)、2-氰基乙酸(70mg,0.82mmol,1.00當量)、HATU(470mg,1.24mmol,1.50當量)、TEA(250mg,2.47mmol,3.00當量)、N,N-二甲基甲醯胺(10mL)置放至50mL圓底燒瓶中。在室溫下攪拌所得溶液2小時。用二氯甲烷萃取所得溶液且合併有機層。用6×100mL水洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。將殘餘物施加至具有二氯甲烷/甲醇(30:1)之矽膠管柱上。此產生260mg(63%)呈棕色固體狀之(R)-3-(3-(4-胺基-3-(4-(2,6-二氟苯氧基)苯基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-基)-3-側氧基丙腈。
遵循實例2之步驟4中之方案得到(R)-2-(3-(4-胺基-3-(4-(2,6-二氟苯氧基)苯基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(4-(氧雜環丁烷-3-基)哌嗪-1-基)戊-2-烯腈。LC-MS m/z:699.2(M+1)
將於二氯甲烷(100mL)中之Cu(OAc)2(6.96g,38.3mmol,1.00當量)、吡啶(15.2g,192mmol,5.00當量)及4A分子篩(5g)置放至用O2氛圍淨化且維持之250mL圓底燒瓶中。攪拌所得溶液30分鐘且隨後添加2,3-二氟苯酚(5g,38.43mmol,1.00當量)及(4-溴苯基)酸(15.4g,76.6mmol,2.00當量)。在室溫下攪拌所得溶液隔夜。在真空下濃縮所得混合物。將殘餘物施加至具有石油醚之矽膠管柱上。此產生3.17g(29%)呈無色油狀之1-(4-溴苯氧基)-2,3-二氟苯。
將於四氫呋喃(100mL)中之1-(4-溴苯氧基)-2,3-二氟苯(3.17g,11.12mmol,1.00當量)置放至用惰性氮氣氛圍淨化且維持之250mL 3頸圓底燒瓶中。在-78℃下添加nBuLi(6.7mL,1.50當量)之2.5M溶液且攪拌所得溶液30分鐘且隨後添加硼酸三甲酯(2.32g,22.3mmol,2.00當量)。在室溫下攪拌所得溶液3小時。隨後藉由添加HCl(2M)淬滅反應物。用3×150mL乙醚萃取所得溶液且合併有機層。用1×200mL氯化鈉(飽和)洗滌所得混合物。經無水硫酸鈉乾燥混合物且在真空下濃縮。將殘餘物施加至具有二氯甲烷/甲醇(50:1)之矽膠管
柱上。此產生1g(36%)呈白色固體狀之[4-(2,3-二氟苯氧基)苯基]酸。
向2,4-二氯-3-硝基吡啶(5g,25.9mmol)於DMF(50mL)中之溶液中添加Et3N(5.2g,51.8mmol)及(S)-2-(胺基甲基)吡咯啶-1-甲酸第三丁酯(5.4g,27.2mmol)。在室溫下攪拌所得混合物隔夜,隨後過濾且濃縮濾液至乾燥。用水(150mL)處理殘餘物且用DCM(30mL×3)萃取。用鹽水(40mL)洗滌合併之有機相,經Na2SO4乾燥,且濃縮至乾燥。所得6.9g(S)-2-(((2-氯-3-硝基吡啶-4-基)胺基)甲基)吡咯啶-1-甲酸第三丁酯不經進一步純化即在下一步驟中使用。
向(S)-2-(((2-氯-3-硝基吡啶-4-基)胺基)甲基)吡咯啶-1-甲酸第三丁酯(6.9g,19.4mmol)於i-PrOH(100mL)中之溶液中添加雙(4-甲氧基苯甲基)胺(7.5g,29.1mmol)及TEA(5.9g,58.2mmol)。使混合物回流隔夜。冷卻至室溫後,濃縮混合物至乾燥。藉由矽膠層析(溶離劑:石油醚/乙酸乙酯,5:1至2:1)純化殘餘物得到4.4g呈淡黃色固體狀之(S)-2-(((2-(雙(4-甲氧基苯甲基)胺基)-3-硝基吡啶-4-基)胺基)甲
基)吡咯啶-1-甲酸第三丁酯。
向(S)-2-(((2-(雙(4-甲氧基苯甲基)胺基)-3-硝基吡啶-4-基)胺基)甲基)吡咯啶-1-甲酸第三丁酯(4.4g,7.6mmol)於EtOH(100mL)中之溶液中添加NH4Cl(2.0g,38.1mmol)及H2O(10mL),接著分批添加Zn粉(2.5g,38.1mmol)同時攪拌。使所得混合物回流持續3小時,隨後經由矽藻土過濾。濃縮濾液得到殘餘物,其再溶解於水(50mL)中且用乙酸乙酯(100mL×3)萃取。用鹽水(400mL)洗滌合併之有機相,經Na2SO4乾燥,濃縮得到2.9g呈淡黃色固體狀之(S)-2-(((3-胺基-2-(雙(4-甲氧基苯甲基)胺基)吡啶-4-基)胺基)甲基)吡咯啶-1-甲酸第三丁酯,其直接用於下一步驟。
向(S)-2-(((3-胺基-2-(雙(4-甲氧基苯甲基)胺基)吡啶-4-基)胺基)甲基)吡咯啶-1-甲酸第三丁酯(2.9g,5.3mmol)於無水乙腈(30mL)中之溶液中分批添加CDI(2.6g,15.9mmol)。使所得混合物回流持續2小時,隨後濃縮得到殘餘物,其藉由矽膠層析用PE:EtOAc=2:1純化得到2.6g呈淡黃色固體狀之(S)-2-((4-(雙(4-甲氧基苯甲基)胺基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯啶-1-甲酸第三丁酯,其直接用於下一步驟。
向(S)-2-((4-(雙(4-甲氧基苯甲基)胺基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯啶-1-甲酸第三丁酯(7g,12.2mmol)於無水DCM(100mL)中之溶液中添加Cu(OAc)2(2.2g,12.4mmol)、TEMPO(2.1g,13.4mmol)、4A分子篩(20g)及Et3N(20g,196mmol),接著逐份添加4-苯氧基苯基酸(10.5g,48.9mmol)同時攪拌。在O2氛圍下在室溫下攪拌混合物78小時。濃縮溶劑且藉由矽膠管
柱用PE:EtOAc=2:1純化殘餘物,得到呈淡黃色固體狀之(S)-2-((4-(雙(4-甲氧基苯甲基)胺基)-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯啶-1-甲酸第三丁酯(3.2g,36%)。
使(S)-2-((4-(雙(4-甲氧基苯甲基)胺基)-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯啶-1-甲酸第三丁酯(2g,2.7mmol)溶解於TFA(10mL)中且在室溫下攪拌隔夜。濃縮反應物且用H2O(50mL)稀釋殘餘物且用EtOAc萃取。用NaOH水溶液將水相調節至pH=13且用EtOAc(2×100mL)萃取,且濃縮有機相得到870mg(S)-4-胺基-3-(4-苯氧基苯基)-1-(吡咯啶-2-基甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮,其不經進一步純化即在下一步驟中使用。
在0℃下向(S)-4-胺基-3-(4-苯氧基苯基)-1-(吡咯啶-2-基甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(200mg,0.5mmol)於DMF(10mL)中之溶液中添加Et3N(150mg,1.5mmol)、2-氰基乙酸(47mg,0.55mmol)及HATU(284mg,0.75mmol)。在0℃下攪拌30分鐘之後,將反應物傾入水(20mL)中且藉由EtOAc(30mL,兩次)萃取,濃縮有機相且藉由矽膠層析,用PE:EtOAc=1:1溶離來純化殘餘物得到70mg呈白色固體狀之(S)-3-(2-((4-胺基-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯啶-1-基)-3-側氧基丙腈。
在室溫下向(S)-3-(2-((4-胺基-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯啶-1-基)-3-側氧基丙腈(80mg,0.17mmol)、2-甲基-2-(4-(氧雜環丁烷-3-基)哌嗪-1-基)丙醛(72mg,0.34mmol)及吡咯啶(120mg,1.7mmol)於DCM(2mL)中之溶液
中緩慢逐滴添加氯(三甲基)矽烷(69mg,0.68mmol)。在30分鐘之後,用DCM(20mL)稀釋反應物且用NaHCO3水溶液(20mL)洗滌。有機層經無水Na2SO4乾燥,過濾且濃縮,得到粗殘餘物,其藉由製備型TLC純化得到呈白色固體狀之(S)-2-(2-((4-胺基-2-側氧基-3-(4-苯氧基苯基)-2,3-二氫-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯啶-1-羰基)-4-甲基-4-(4-(氧雜環丁烷-3-基)哌嗪-1-基)戊-2-烯腈(10mg,9%)。LC-MS m/z:662.8(M+1)。
在0℃下向(S)-4-胺基-3-(4-苯氧基苯基)-1-(吡咯啶-2-基甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(200mg,0.17mmol)及DIPEA(129mg,1.0mmol)於DCM(2mL)中之溶液中緩慢逐滴添加丙烯醯氯(45mg,0.50mmol)。在30分鐘之後,用DCM(20mL)稀釋反應物且用NaHCO3水溶液(20mL)洗滌。有機層經無水Na2SO4乾燥,過濾且濃縮,得到粗殘餘物,其藉由製備型TLC純化,得到70mg呈白色固體狀之(S)-1-((1-丙烯醯基吡咯啶-2-基)甲基)-4-胺基-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:455.9(M+1)。
在0℃下向(S)-4-胺基-3-(4-苯氧基苯基)-1-(吡咯啶-2-基甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(200mg,0.17mmol)及DIPEA(129mg,1.0mmol)於DCM(10mL)中之溶液中緩慢逐滴添加丁-2-炔醯氯(50mg,0.50mmol)。0.5小時之後,用DCM(20mL)稀釋反應物且用NaHCO3水溶液(20mL)洗滌。有機層經無水Na2SO4乾燥,過濾且濃縮,得到粗殘餘物,其藉由製備型TLC純化,得到50mg呈白色固體狀之(S)-4-胺基-1-((1-(丁-2-炔醯基)吡咯啶-2-基)甲基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:467.9(M+1)。
向(R)-4-胺基-3-(4-苯氧基苯基)-1-(哌啶-3-基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(154mg,0.38mmol,1.0當量)於2mL DMF中之溶液中添加二異丙基乙胺(0.2mL,1.1mmol)。添加2-氟丙-2-烯酸(51.8mg,0.580mmol),接著添加HATU(97mg,1.1mmol)。在攪拌1小時之後,直接藉由製備型HPLC(Shimadzu,C18管柱;移動相水及0.05% TFA及ACN(10%至90%,歷經20分鐘))純化物質。用飽和碳酸
氫鈉及DCM稀釋經純化之溶離份且分離各層。經MgSO4乾燥有機層,過濾且濃縮。使其溶解於最少的水及乙腈中且凍乾,得到65mg呈白色固體狀之(R)-4-胺基-1-(1-(2-氟丙烯醯基)哌啶-3-基)-3-(4-苯氧基苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:474.1(M+1)。
使用基於測徑規之激酶分析(Caliper Life Sciences,Hopkinton,MA)來量測本發明化合物之BTK激酶活性之抑制。測試化合物之連續稀釋液在室溫下與人類重組BTK(0.5nM)、ATP(16nM及磷酸受體肽基質FAM-GEEPLYWSFPAKKK-NH2(1μM)一起培育3小時。反應隨後用EDTA,最終濃度20mM終止且磷酸化反應產物在測徑規桌上型分析器(Caliper LabChip 3000)上定量。計算各化合物稀釋液之抑制%且計算產生50%抑制之濃度。此值以IC50呈現。以下提供某些本發明化合物之IC50。
化合物用於抑制BTK活性之效能可藉由使化合物結合至含有BTK之人類周邊血液單核細胞(PBMC)中之標靶來評估。BTK佔有之程度在用化合物處理細胞且經由結合(R,E)-N-(2-(4-(4-(3-(4-胺基-3-(2-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-4-側氧基丁-2-烯-1-基)哌嗪-1-基)乙基)-3-(5,5-二氟-7,9-二甲基-5H-414,514-二吡咯并[1,2-c:2',1'-f][1,3,2]二氮雜硼-2-基)丙醯胺之佔有率作為探針來偵測未佔據之BTK之後量測。
簡言之,自健康志願者獲得人類血液且各5ml分配在9個單獨15ml試管中。添加待測試效能之化合物之連續稀釋液使得最終濃度在10uM下開始且連續稀釋3倍持續總共9次連續稀釋。使化合物與血液相互作用1小時。隨後使用Ficoll自各試管分離PBMC。隨後使經分離PBMC再懸浮於1ml RPMI1640培養基中且添加佔有率探針至對於各樣品1uM之濃度持續1小時。洗滌PBMC,溶解,且藉由SDS-PAGE評估。凝膠內螢光用於量測結合至BTK之BTK佔有率探針之抑制程度。隨後,藉由西方墨點法用BTK抗體(BD Bioscience目錄號611117)測定各樣品中之總BTK。
此分析亦經修改以量測PBMC中BTK結合之耐久性。此處,持續1小時向人類全血中添加2uM濃度之化合物。使用Ficoll分離PBMC,洗滌,且在37℃下再懸浮於培養基中持續4小時或18小時。持續1小時添加佔有率探針至對於各樣品1uM之濃度,且隨後以與上文所描述相同之方式測定BTK佔有率。
B細胞受體之活化引起增加之BTK活性、鈣移動及B細胞活化(參見Honigberg L.A.,等人,Proc Natl Acad Sci U S A.107:13075-80.2010)。已顯示BTK抑制劑阻斷B細胞活化,如藉由CD69表現所量測
(參見Karp,R.,等人,Inhibition of BTK with AVL-292 Translates to Protective Activity in Animal Models of Rheumatoid Arthritis.Inflammation Research Association Meeting,Sept,2010)。在B細胞活化之後表現CD69作為全血中BTK活性之量度。將全血之等分試樣與測試化合物之連續稀釋液一起預培育30分鐘,接著用抗IgM(山羊Fab'2,50μg/ml)活化。在37℃下培育樣品隔夜且隨後根據製造商之說明用PE標記之抗CD20及APC標記之抗CD69(BD Pharmingen)染色30分鐘。隨後溶解全血且針對CD 69表現藉由FACS將在CD20表現上門控之細胞定量。基於無抑制之DMSO對照計算抑制%且繪製為隨測試化合物濃度而變,IC50值自測試化合物濃度計算。
鼠膠原蛋白誘導性關節炎(mCIA)之抑制為類風濕性關節炎之標準動物疾病模型。先前研究已經證明BTK之抑制在阻斷mCIA中有效(參見Honigberg L.A.,等人,Proc Natl Acad Sci U S A.107:13075-80.2010)。在第0天開始,DBA/1小鼠用於完全弗氏佐劑(Complete Freund's Adjuvant)中之II型膠原蛋白之乳液注射。21天後小鼠增強免疫以使疾病之發展同步。在患輕度疾病之後,動物參與研究且隨機化。給藥為經口,Q.D.,通常持續11天,測試化合物或地塞米松(0.2mg/kg)作為對照。一組僅接受媒劑。臨床計分(0-4)係基於腫脹程度及關節炎之嚴重性。所有四個腳爪之分數相加,最大分數為16。藉由Elisa在研究結束時量測各動物之抗膠原蛋白抗體及總Ig(Bolder BioPath,Boulder,CO)。
將濃度比其IC50值大10倍之本發明之化合物及/或醫藥學上可接受
之鹽添加至蛋白激酶(5nM)於含有20mM Hepes[pH 7.5]、5mM MgCl2、0.01% Triton X-100及1mM二硫蘇糖醇之緩衝液中的溶液中。在22℃下60分鐘之後,將反應物轉移至透析卡(0.1-0.5mL Slide-A-Lyzer,MWCO 10kDa,Pierce)且在22℃下用1L緩衝液(20mM Hepes[pH 7.5],5mM MgCl2,0.01% Triton X-100,及1mM二硫蘇糖醇)透析。每日兩次更換透析緩衝液直至實驗結束。每24小時自透析卡移除等分試樣且分析蛋白激酶活性。各樣品之激酶活性針對該時間點之DMSO對照校正且表示為平均值±SD。將觀測到對於Ra為氰基之本發明化合物,激酶活性將在透析時恢復,且對於Ra為氫或氟之本發明化合物將不恢復。
經本發明之化合物及/或醫藥學上可接受之鹽抑制之蛋白激酶可經受質譜分析以評估永久性不可逆共價加成物之形成。檢驗在蛋白激酶之胰蛋白酶裂解後產生之完整全蛋白或肽片段的適合分析方法一般在此項技術中已知(參見Lipton,Mary S.,Ljiljana,Pasa-Tolic,編Mass Spectrometry of Proteins and Peptides,Methods and Protocols,第二版.Humana Press.2009)。此類方法藉由觀測與對照樣品之質量加不可逆加合物之質量相對應的質量峰來鑑定永久性不可逆共價蛋白質加成物。下文描述兩種此類方法。
方法:將蛋白激酶(5μM)之質(諸如BTK)與本發明化合物(25μM,5當量)一起在室溫下在緩衝液(20mM Hepes[pH 8.0],100mM NaCl,10mM MgCl2)中培育1小時。亦製備不具有本發明化合物之對照樣品。藉由添加相等體積之0.4%甲酸停止反應,且藉由液相層析
(Microtrap C18蛋白質管柱[Michrom Bioresources],5% MeCN,0.2%甲酸,0.25mL/min;用95% MeCN、0.2%甲酸溶離)及線上ESI質譜(LCT Premier,Waters)分析樣品。蛋白激酶及任何加成物之分子量可用MassLynx反卷積軟體測定(參見專利申請案WO2014 011900及PCT/US2010/048916)。
結果:經Ra為氰基之本發明化合物抑制之蛋白激酶(諸如BTK)之高解析度完整質譜分析將揭露與在抑制劑不存在下的激酶(例如對照樣品)類似之頻譜。將不存在質譜中與激酶之分子量加化合物之分子量對應的新穎峰之形成。相反,經Ra為氫或氟之本發明化合物抑制之蛋白激酶之高解析度完整質譜分析將揭露質譜中與激酶之分子量加不可逆激酶抑制劑之分子量對應的新穎峰(例如不存在於無抑制劑之對照樣品中的峰)之形成。基於此實驗,不可逆蛋白質加合物將為熟習此項技術者顯而易見。
方法:在胰蛋白酶消化之前,將蛋白質(10-100pmol)與本發明之化合物及/或醫藥學上可接受之鹽(100-1000pmol,10當量)一起培育3小時。在化合物培育之後碘乙醯胺可用作烷基化劑。亦製備不利用本發明之化合物及/或醫藥學上可接受之鹽的對照樣品。對於胰蛋白酶消化,1μl等分試樣(3.3pmol)用10μl 0.1% TFA稀釋,隨後使用作為解吸附基質之α氰基-4-羥基肉桂酸(5mg/mol,於0.1% TFA:乙腈50:50中)或作為解吸附基質之芥子酸(10mg/mol,於0.1% TFA:乙腈50:50中)直接微C18拉鏈式傾卸至MALDI標靶上(參見PCT/US2010/048916)。
結果:經Ra為氰基之本發明化合物及/或醫藥學上可接受之鹽抑制之激酶之胰蛋白酶片段之高解析度質譜分析將揭露與在抑制劑不存在下的激酶(例如對照樣品)類似之頻譜。將不存在對照樣品中不存在
的任何經修飾肽之跡象。基於此實驗,無永久性、不可逆蛋白質加成物將為熟習此項技術者顯而易見。
相反,經Ra為氫或氟之本發明化合物抑制之激酶之胰蛋白酶片段之高解析度質譜分析將揭露含有對照樣品中不存在之經修飾肽的頻譜。基於此實驗,不可逆蛋白質加成物將為熟習此項技術者顯而易見。此外,基於準確質量及MS-MS片段化模式,可確定經修飾肽之序列,藉此限定作為共價修飾位點之半胱胺酸殘基。
以下為可用以辨別化合物是否展示自BTK之較慢解離速率或不存在解離速率(諸如若共價鍵在化合物與標靶之間形成則通常將出現)的方案。較慢解離之讀出為所關注的化合物阻斷高親和力螢光示蹤分子與激酶活性位點之結合的能力,如使用時差式螢光共振能量轉移(TR-FRET)偵測。在由50mM Hepes pH 7.5、10mM MgCl2、0.01% Triton X-100及1mM EGTA組成之緩衝液中進行實驗。
程序之第一步為以10μL之體積培育500nM BTK(Invitrogen目錄號PV3587)與1.5μM本發明化合物30分鐘。隨後藉由添加40μL緩衝液將混合物5倍稀釋。隨後向小體積384孔板(諸如Greiner目錄號784076)之孔中添加10μL體積之經稀釋激酶/化合物溶液。為了探測激酶-化合物結合相互作用之可逆性,製備含有高親和力螢光示蹤劑及與銪偶合之抗體兩者的競爭溶液。對於BTK,競爭溶液含有1.5μM示蹤劑178(Invitrogen目錄號PV5593),其為BTK之與螢光團AlexaFluor 647偶合之專用高親和力配位體。競爭溶液亦含有80nM與銪偶合之抗聚組胺酸抗體(Invitrogen目錄號PV5596),其經設計以結合BTK中之聚組胺酸純化標籤。
在將10μL競爭溶液添加至Greiner板之後,培育混合物一小時或
多於一小時以允許非共價抑制劑解離及高親和力示蹤劑結合之時間。將預期共價及緩慢解離抑制劑將阻斷示蹤劑之結合而快速解離非共價抑制劑將不抑制。使用TR-FRET在抗組胺酸抗體之銪部分與示蹤劑178之AlexaFluor 647基團之間偵測示蹤劑與BTK之結合。使用配備有過濾器及鏡子之與LANCE型TR-FRET實驗相容之Perkin Elmer Envision儀器(型號2101)評估結合。以在競爭化合物不存在下獲得之信號之百分比繪製資料。藉由自反應省略BTK獲得背景信號。若化合物為不可逆共價抑制劑,則在整個實驗過程中將完全阻斷示蹤劑與標靶之結合。若化合物為可逆共價抑制劑,則當化合物自標靶解離時,示蹤劑將結合標靶。對於耐久性量測,在清除之1、6及24小時本文所揭示之化合物之佔有率範圍顯示於以下。
開發以下方法以判定化合物與其標靶是否形成不可逆共價鍵抑或可逆共價鍵。用在比所關注化合物高之濃度的蛋白質標靶製備反應物。不可逆及可逆共價化合物均結合標靶且變為自溶液中耗盡。反應物隨後在擾動下處理,包括用5M胍鹽酸鹽變性及用胰蛋白酶消化兩者,從而破壞標靶之正確摺疊。將發現擾動使可逆共價化合物由於自標靶解離而返回至溶液中而不可逆共價化合物保持與標靶結合。化合物在溶液中之濃度在擾動之前及之後使用與串聯質譜耦接之高效液相層析(HPLC)評估。使用此技術,可展現Ra為氫或氟之不可逆共價本發明化合物在天然與擾動狀態下自溶液中耗盡,而本文所揭示之Ra為氰基之化合物在摺疊狀態下耗盡但在擾動標靶之後返回至溶液中,證明此等化合物形成可逆共價鍵。
以下為含有式(I)化合物之代表性醫藥調配物。
緊密混合以下成分且壓製成單一刻痕錠劑。
緊密混合以下成分且裝載至硬殼明膠膠囊中。
含本發明化合物(例如化合物1)之2% HPMC,含1% Tween 80之去離子水,pH 2.2,具有MSA,足量至至少20mg/mL。
前述揭示內容已經藉助於說明及實例,出於清晰性及理解的目的相當詳細地描述。因此,應理解以上描述意欲為說明性而非限定性。因此,本發明之範疇不應參考以上描述確定,但應替代地參考以下所附申請專利範圍,以及該等申請專利範圍授權之等效物之完整範疇確定。
Claims (19)
- 如請求項1之化合物及/或其醫藥學上可接受之鹽,其中R3為氫。
- 如請求項1或2之化合物及/或其醫藥學上可接受之鹽,其中-X-Ar係連接至苯環之4-位置處之碳,連接至環狀脲環之N的該苯環之碳為位置1。
- 如請求項1或2之化合物及/或其醫藥學上可接受之鹽,其中R1及R2獨立地為氫或鹵基。
- 如請求項1或2中之化合物及/或其醫藥學上可接受之鹽,其中,Y為一鍵,且環Z為哌啶基,其中該哌啶基環之3-位置處的碳原子係連接至該環狀脲環之氮原子。
- 如請求項5之化合物及/或其醫藥學上可接受之鹽,其中在連接至該環狀脲氮的該哌啶基之碳處的立體化學為(R)。
- 如請求項1之化合物及/或其醫藥學上可接受之鹽,其中R5為如請求項1所定義之式(i)之基團。
- 一種醫藥組合物,其包含如請求項1至8中任一項之化合物及/或醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑。
- 一種醫藥組成物,其包含如請求項8之化合物及/或醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑。
- 一種如請求項1至8中任一項之化合物或其(E)或(Z)異構體、及/或 前述化合物中之任一者之醫藥學上可接受之鹽的用途,其係用於製備具抑制有需要之哺乳動物中之BTK的藥劑。
- 一種如請求項1至8中任一項之化合物或其(E)或(Z)異構體、及/或前述化合物中之任一者之醫藥學上可接受之鹽的用途,用於製備在有需要之哺乳動物中治療選自下列疾病之藥劑:自體免疫疾病、發炎疾病、異種免疫病狀或疾病、血栓栓塞疾病或癌症。
- 如請求項12之用途,其中該疾病為急性壞死性出血性腦白質炎、急性播散性腦脊髓炎、自體免疫性內耳病(AIED)、自體免疫性視網膜病、軸突及神經元神經病變、慢性發炎性脫髓鞘多發性神經病(CIDP)、脫髓鞘神經病變、德維克氏病(Devic's disease)(視神經脊髓炎)、實驗性過敏性腦脊髓炎、巨細胞性動脈炎(顳動脈炎)、格林-巴利症候群(Guillain-Barre syndrome)、蘭伯特-伊頓症候群(Lambert-Eaton syndrome)、慢性美尼埃爾氏病(Meniere's disease)、重症肌無力、神經肌強直、斜視眼陣攣肌陣攣症候群、視神經炎、副腫瘤小腦退化、周邊神經病變、靜脈周圍腦脊髓炎、腿不寧症候群、僵人症候群、交感性眼炎、高安氏動脈炎(Takayasu's arteritis)、顳動脈炎/巨細胞性動脈炎、橫貫性脊髓炎、多發性硬化、自主神經失調、年齡相關性黃斑變性(濕性及乾性)、角膜移植、腦炎、腦膜炎、血管炎或全身性紅斑性狼瘡症(SLE)。
- 如請求項12之用途,其中該疾病為類風濕性關節炎、牛皮癬性關節炎、狼瘡、葡萄膜炎、重症肌無力、溫抗體型自體免疫性溶血性貧血(warm autoimmune hemolytic anemia)、韋格納氏肉芽腫病(Wegener's granulomatosis)、休格連氏病(Sjogren's disease)、休格連氏乾眼症(Sjogren's dry eye)、非休格連氏乾眼 症(non-Sjogren's dry eye disease)、牛皮癬、天疱瘡、蕁麻疹或哮喘。
- 如請求項12之用途,其中該癌症為彌漫性大B細胞淋巴瘤、濾泡性淋巴瘤、慢性淋巴細胞性淋巴瘤、慢性淋巴球性白血病、B細胞前淋巴球性白血病、小淋巴細胞性淋巴瘤(SLL)、多發性骨髓瘤、B細胞非霍奇金淋巴瘤(B-cell non-Hodgkin lymphoma)、淋巴漿細胞性淋巴瘤/瓦爾登斯特倫巨球蛋白血症(Waldenstrom macroglobulinemia)、脾邊緣區淋巴瘤、漿細胞骨髓瘤、漿細胞瘤、結外邊緣區B細胞淋巴瘤、結內邊緣區B細胞淋巴瘤、套細胞淋巴瘤、縱隔(胸腺)大B細胞淋巴瘤、血管內大B細胞淋巴瘤、原發性滲出性淋巴瘤、伯基特淋巴瘤(burkitt lymphoma)/白血病或淋巴瘤樣肉芽腫。
- 如請求項3之化合物及/或其醫藥學上可接受之鹽,其中R1及R2獨立地為氫或鹵基。
- 如請求項3之化合物及/或其醫藥學上可接受之鹽,其中環Z為哌啶基,其中該哌啶基環之3-位置處的碳原子係連接至該環狀脲環之氮原子,且Y為一鍵。
- 如請求項4之化合物及/或其醫藥學上可接受之鹽,其中,Y為一鍵,且環Z為哌啶基,其中該哌啶基環之3-位置處的碳原子係連接至該環狀脲環之氮原子。
- 如請求項6之化合物及/或其醫藥學上可接受之鹽,其中R5為如請求項1所定義之式(i)之基團。
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