TWI822724B - 唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型 - Google Patents
唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型 Download PDFInfo
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- TWI822724B TWI822724B TW108102825A TW108102825A TWI822724B TW I822724 B TWI822724 B TW I822724B TW 108102825 A TW108102825 A TW 108102825A TW 108102825 A TW108102825 A TW 108102825A TW I822724 B TWI822724 B TW I822724B
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Abstract
本發明係關於(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型;其製備方法,含有該等結晶型之醫藥組合物,由該等結晶型製備之醫藥組合物及其作為藥品、尤其作為CXCR7受體調節劑之用途。
Description
本發明係關於新穎結晶型(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺(此後亦稱為「化合物」):、用於製備該化合物之方法、包含該結晶型之醫藥組合物、由該結晶型製備之醫藥組合物及其作為CXCL11/CXCL12受體CXCR7之調節劑的用途、尤其用於治療癌症、自體免疫疾病、發炎性疾病、移植排斥或纖維化之用途。本發明進一步關於在癌症(尤其腦腫瘤,包括惡性神經膠瘤、多形性神經膠質母細胞瘤;神經胚細胞瘤;胰臟癌,包括胰腺癌/胰臟管腺癌;胃腸癌,包括結腸癌、肝細胞癌、胃癌;卡波西氏肉瘤(Kaposi's sarcoma);白血病,包括成人T細胞白血病;淋巴瘤;肺癌;乳癌;橫紋肌肉瘤;前列腺癌;食道鱗癌;口腔鱗狀細胞癌;子宮內膜癌;甲狀腺癌,包括乳突甲狀腺癌;轉移癌;肺轉移;皮膚癌,包括黑色素瘤及轉移性黑色素瘤;膀胱癌;多發性骨髓瘤;骨肉瘤;頭頸癌;及腎癌,包括腎透明細胞癌、轉移性腎透明細胞癌)之治療中,作為藥品與一或多種治療劑及/或放射療法及/或針對性療法組合之該結晶型。
趨化介素受體係一組G蛋白偶合受體(GPCR),其以高親和力連接肽趨化介素配體。趨化介素受體之主要功能係在靜止狀態下以及在發炎期間引導白血球向淋巴器官及組織運輸,但亦已發現特定趨化介素受體對非造血細胞及其祖細胞之作用。
CXCR7 (別名ACKR3、別名RDC1、別名CMKOR1、別名GPR159)具有兩種已知趨化介素配體:CXCL12 (別名基質細胞衍生衍生因子1、SDF-1;別名前B細胞生長刺激因子,PBSF)及CXCL11 (別名l-TAC、別名INF-y-誘導型T細胞a化學吸引因子)。
基質衍生化學吸引因子CXCL12參與免疫監測及發炎反應之調節。CXCL12係由骨髓基質細胞、內皮細胞、心臟、骨骼肌、肝、腦、腎、實質細胞分泌且對幹細胞增殖、存活及造血細胞/祖細胞向骨髓回歸起重要作用(Rankin SM等人; Immunol let. 2012, 145(1-2):47-54)。CXCL12亦將骨髓衍生祖細胞召集至形成血管分佈之位點。此外,其在致癌作用中起主導作用。CXCL12促使內皮祖細胞及骨髓衍生抑制細胞召集至腫瘤位點,以及促使其他骨髓衍生細胞之召集。此外,CXCL12調節與腫瘤進程相關之血管生成/血管形成且在將循環腫瘤細胞種入轉移位點中起關鍵作用。除趨化性功能外,亦已顯示CXCL12調節腫瘤細胞增殖、移動性及存活(Kryczek I等人; Cancer Res. 2005, 65(2):465-72; Teicher BA等人; Clin Can Res. 2010, 16(11):2927-31; Domanska UM等人; European J of Cancer. 2013, 49(1):219-30)。
除CXCR7外,CXCL12連接且激活CXCR4 (別名引信蛋白、別名白血球衍生七次跨膜域受體;LESTR、別名D2S201E、別名七次跨膜片段受體、別名HM89、別名脂多醣相關蛋白3;lap3、別名LPS相關蛋白3),而CXCL11連接且激活CXCR3 (別名GPR9、別名CD183)。
因此,CXCR7與其配體CXCL12及CXCL11 (此後稱為CXCR7軸)之相互作用參與將承載受體之細胞引導至身體之具體位置,尤其引導至發炎、免疫損傷及免疫功能障礙之位點,且亦與組織損傷、細胞凋亡、細胞生長及血管抑制之誘導相關。CXCR7及其配體經上調且在包括以下之不同病理性情況中得到高度表現:癌症、自體免疫疾病、發炎、感染、移植排斥、纖維化及神經退化。
癌症係全世界死亡之主要原因。腫瘤由異常增殖惡性癌細胞構成,亦由功能支持微環境構成。此腫瘤微環境由細胞、細胞外基質組分及信號傳導分子之複合陣列構成,且藉由基質與腫瘤細胞之間改變的通信建立。隨著腫瘤尺寸擴大,其引發不同因子產生,該等因子可幫助腫瘤生長,諸如血管生成因子(促進血管向內生長),或可幫助避開宿主免疫反應襲擊。CXCL12係生成於腫瘤中之該血管生成及免疫調節因子。
本結晶CXCR7調節劑可單獨或以組合形式適用於癌症,其中CXCL11/CXCL12受體CXCR7之表現與癌症之疾病進程相關(其中包括胰臟癌、胰腺癌、乳癌、荷爾蒙抗性前列腺癌、腎細胞癌、子宮頸癌、子宮頸內上皮腫瘤、乳突甲狀腺癌、膀胱癌、尤文氏肉瘤(Ewing's sarcoma)、結腸癌、大腸直腸癌、肺癌、肺腺癌、非小細胞肺癌、腦脊髓膜瘤、MALT淋巴瘤、皮膚鱗狀細胞癌、神經-內分泌腫瘤、鼻咽癌、多形性神經膠質母細胞瘤、星狀細胞瘤、神經膠瘤、肝細胞癌、雌激素陽性乳癌、骨肉瘤、膽囊癌、腎腫瘤及腎細胞癌)。CXCR7亦表現於以下中:血癌、腺癌、腦轉移癌、多發性骨髓瘤、頭頸癌、原發性皮膚黑色素瘤、黑色素瘤、轉移性黑色素瘤、橫紋肌肉瘤、垂體腺瘤、口腔鱗狀細胞癌、口腔腫瘤、淋巴質漿細胞淋巴瘤、成人T細胞白血病、腦腫瘤、食道鱗癌、食道癌、卵巢癌、淋巴瘤、病毒引發性腫瘤、耳鼻喉癌、伯奇氏淋巴瘤(Burkitt's lymphoma)、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、甲狀腺癌、子宮頸鱗狀細胞癌、子宮內膜癌、神經胚細胞瘤、胃腸癌、淋巴球增生性疾病、乳房外佩吉特氏病(extramammary paget disease)、急性骨髓白血病、急性淋巴性白血病、胃癌、神經鞘腫瘤及絨毛膜癌、惡性胸膜間皮瘤、神經鞘瘤、腦脊髓膜瘤、彌散性大B細胞淋巴瘤、口腔白斑病、卡波西氏肉瘤及齒槽橫紋肌肉瘤(審查參見Sun等人; Cancer Metastasis Rev. 2010, 29(4), 709-722)。
本CXCR7調節劑可單獨或以組合形式適用於疾病,其中已顯示使用siRNA、shRNA、微RNA、過度表現、CXCR7敲除動物、CXCR7促效劑、CXCR7拮抗劑、抗體或奈米抗體之CXCR7調節作為單一試劑在實驗疾病模型中改變腫瘤生長,或在包括以下之疾病中與細胞毒性療法組合:肝細胞癌(Xue TC等人; Exp Ther Med. 2012, 3(1):117-123; Zheng等人; Journal of Experimental and Clinical Cancer Research. 2010, 11;29:31)、卡波西氏肉瘤(Raggo C等人; Cancer Res. 2005, 65(12):5084-95)、T細胞白血病(Jin Z等人; Int J Cancer. 2009, 125(9):2229-35)、淋巴瘤(Burns JM 等人; J Exp Med. 2006, 203(9):2201-13)、肺癌、乳癌(Miao Z等人; PNAS. 2007, 104(40):15735-40)、胃癌(De-Min M等人; World J Surg Oncol. 2016, 14(1):256-266)、橫紋肌肉瘤(Grymula K等人; Int J cancer. 2010, 127(11):2554-68)、前列腺癌(Wang J等人; J Biol Chem. 2008, 283(7):4283-94)、胰腺癌(Shakir M等人; Pancreas. 2015, 44(4):528-34)、食道鱗癌(Zhou SM等人; Oncol Rep. 2016, 35(6):3453-9)、子宮內膜癌(Long P等人; Tumour boil. 2016, 37(6):7473-80)、乳突甲狀腺癌(Zhang H等人; Tumour boil. 2016, 37(2):2415-23)、口腔鱗狀細胞癌(Chen N等人; Tumour boil. 2016, 37(1):567-75)、肺轉移(Goguet-Surmenian等人; Br J Cancer. 2013, 109(6):1579-85)、黑色素瘤(McConnell AT等人; Br J Dermatol. 2016, doi: 10.1111/bjd.14720)、膀胱癌(Liu L等人; Mol Med Rep. 2013, 8(1):140-6)、多發性骨髓瘤(Azab AK等人; Blood. 2014, 124(12):1905-14)、骨肉瘤(Zhang Y等人; Oncol Rep. 2014, 32(3):965-72)、結腸癌(Wang HX等人; Mol Clin Oncol. 2015, 3(6):1229-1232)、IV級星狀細胞瘤(Walters MJ等人; Br J Cancer. 2014, 110(5):1179-88)、頭頸癌(Maussang D等人; J Biol Chem. 2013, 288(41):29562-72)、神經胚細胞瘤(Liberman J等人; Plos One. 2012, 7(8):e43665)及神經膠質母細胞瘤(Liu Y; Anticancer Res. 2015, 35(1):53-64; Walters MJ等人; Br J Cancer. 2014, 110(5):1179-88; Ebsworth K等人; J Clin Oncol. 2012, 30(15) e13580);改變腫瘤相關性血管(Miao Z等人; PNAS. 2007, 104(40):15735-40);且減少腫瘤細胞接種(Grymula K等人; Int J cancer. 2010, 127(11):2554-68)。
本CXCR7調節劑可單獨或以組合形式適用於疾病,其中已顯示CXCR7調節(例如,使用siRNA、shRNA、微RNA、過度表現、CXCR7敲除動物、CXCR7促效劑、CXCR7拮抗劑、抗體或奈米抗體)調整白血球轉移(Berahovich RD等人; Immunology. 2014, 141(1):111-22)且促進髓磷脂/神經元修復(Williams JL等人; J Exp Med. 2014, 5; 211(5):791-9; Gottle P等人; Ann Neurol. 2010, 68(6):915-24),在以下實驗疾病模型中提供有益效用:發炎性、自體免疫及髓鞘脫失疾病,包括多發性硬化及自體免疫腦脊髓炎(Cruz-Orengo L等人; J Neuroinflammation. 2011, 6; 8:170; Bao J等人; Biochem Biophys Res Commun. 2016 Jan 1; 469(1):1-7),格巴二氏症候群(Guillain-Barré syndrome)或自體免疫神經炎(Brunn A等人; Neuropathol Appl Neurobiol. 2013, 39(7):772-87)、風濕性關節炎(Watanabe K等人; Arthritis Rheum. 2010, 62(11):3211-20)、急性肺炎/急性肺損傷(Ngamsri KC等人; J Immunol. 2017, 198(6):2403-2413; Petty JM等人; J Immunol. 2007, 178(12):8148-57)、氣喘(Gasparik V等人; ACS Med Chem Lett. 2012 Jan 12; 3(1):10-4; Chang HC等人; Immunology. 2017 DOI: 10.1111/imm.12881);緩解慢性缺氧性肺性高血壓(Sartina E等人; Pediatr Res. 2012, 71(6):682-8);肺纖維化(Cao Z等人; Nat Med. 2016,; 22(2):154-62);及動脈粥狀硬化(Zhao D等人; Biochemistry. 2015, 17; 54(45):6806-14; Ma W.等人; Biochem Pharmacol. 2014, 1; 89(1):99-108)。
此外,已指出CXCR7參與心臟幹細胞轉移(Chen D等人; Sci Rep. 2015, 5:16813)、慢性同種異體移植物血管病變(Thomas MN等人; Transpl Int. 2015, 28(12):1426-35)、發炎性腸病(Werner L等人; Theranostics. 2013, 3(1):40-6)、慢性鼻竇炎(Patadia M等人; Am J Rhinol Allergy. 2010, 24(1):11-6)、人類肺血管疾病(Rafii S等人; Nat Cell Biol. 2015, 17(2):123-36)及嚴重子癲前症之發展(Lu J等人; Exp Mol Pathol. 2016, 100(1):184-91);且改善基於間葉幹細胞之療法對腎缺血/再灌注損傷之有益效用(Liu H等人; Plos One. 2012, 7(4):e34608)且引發類抗焦慮劑行為(Ikeda Y等人; Cell. 2013, 5; 155(6):1323-36)。除上文提及之疾病外,CXCR7調節劑可適用於治療腎同種異體移植物排斥、全身性紅斑狼瘡、骨關節炎、肺血管疾病、急性腎衰竭、包括大腦缺血之缺血、慢性同種異體移植物排斥、急性冠狀動脈綜合症、受損中樞神經系統;高血脂病、HSC移植、高血壓、肺性高血壓、滋賀-毒素相關性溶血性尿毒症候群、HIV/AIDS;硬化、壓力相關性疾病、增生性糖尿病視網膜病變、西尼羅病毒腦炎(West Nile virus encephalitis)、血管損傷、肺纖維化、子宮內膜異位、自體免疫甲狀腺炎、脈絡膜新血管形成相關性疾病、再生不全性貧血、薛格連氏病(Sjögren's disease)及白斑症。
機械地,最新研究已提供愈來愈多之證據證明激活CXCL12路徑係腫瘤經由多重互補作用對習知療法及生物試劑具有抗性之潛在機制:(i)藉由直接促進癌細胞存活、入侵及癌症幹細胞及/或腫瘤引發之細胞表型;(ii)藉由召集「末端基質」 (亦即,骨髓衍生細胞)以促進免疫抑制、腫瘤再生及轉移;及(iii)藉由直接促進血管生成或使用旁分泌方式(Duda DG等人: CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?; Clin Cancer Res; 2011, 17(8); 2074-80),其最近討論了臨床前及臨床數據,該等數據支持包括CXCR7調節劑之抗CXCL12試劑在癌症治療中作為敏化劑對抗現有療法之潛在用途。此外,內皮細胞上CXCR7表現中之改善似乎對自體免疫疾病中之發炎性滲入至關重要。CXCL12及CXCL11係發炎性免疫反應中之關鍵配體:(i)藉由作用於細胞轉移、細胞黏著及細胞存活(Kumar R等人; Cell Immunol. 2012, 272(2):230-41);(ii)藉由驅使細胞之分化、成熟及極化,亦即,巨噬細胞(Ma W.等人; Biochem Pharmacol. 2014, 1; 89(1):99-108)、CD4+ T細胞(Zohar Y等人; J Clin Invest. 2014, 124(5):2009-22)、少突神經膠質細胞祖細胞(Gottle P等人; Ann Neurol. 2010, 68(6):915-24);(iii)藉由參與回歸過程(Lewellis SW等人; J Cell Biol. 2013, 4; 200(3):337-55)。因此,標靶CXCR7且因此調節其配體之含量將對各種自體免疫及發炎性疾病之病因起決定性作用。Sanchez-Martin等人(Trends Mol Med. 2013, 19(1):12-22)最近論述了CXCR7在疾病中之失調且強調以下事實:此受體係用於治療自體免疫疾病及炎症之有趣治療目標。
因此,本CXCR7拮抗劑可單獨或與一或多種治療劑及/或化學療法及/或放射療法及/或免疫療法組合使用;特定而言,與化學療法、放射療法、EGFR抑制劑、芳香酶抑制劑、諸如尤其PD1及/或PDL1封鎖及/或CTLA4封鎖之免疫療法、或其他標靶療法組合;用於預防/防治或治療諸如以下之癌症:癌;腺癌;神經內分泌腫瘤;皮膚癌,包括黑色素瘤及轉移性黑色素瘤;肺癌,包括非小細胞肺癌;轉移性癌症;肺轉移癌;膀胱癌,包括泌尿膀胱癌;尿道上皮細胞癌;腎癌,包括腎細胞癌;轉移性腎細胞癌、轉移性腎透明細胞癌;胃腸癌,包括結腸癌、大腸直腸腺瘤、大腸直腸腺癌、大腸直腸癌、轉移性大腸直腸癌、家族性腺瘤息肉病(FAP)、食道癌、口腔鱗狀細胞癌;胃癌、膽囊癌、膽管癌、肝細胞癌;胰臟癌,諸如胰腺癌或胰臟管腺癌;子宮內膜癌;卵巢癌;子宮頸癌;神經胚細胞瘤;前列腺癌,包括抗閹割前列腺癌;腦腫瘤,包括腦轉移、惡性神經膠瘤、多形性神經膠質母細胞瘤、神經管胚細胞瘤、腦脊髓膜瘤;乳癌,包括三陰性乳癌;口腔腫瘤;鼻咽腫瘤;胸癌;頭頸癌;白血病,包括急性骨髓白血病、成人T細胞白血病;甲狀腺癌,包括乳突甲狀腺癌;絨毛膜癌;尤文氏肉瘤;骨肉瘤;橫紋肌肉瘤;卡波西氏肉瘤;淋巴瘤,包括伯奇氏淋巴瘤、MALT淋巴瘤;原發性眼內B細胞淋巴瘤、多發性骨髓瘤及病毒誘導性腫瘤;及涉及CXCR7及/或CXCL12及/或CXCL11介導性轉移、趨化性、細胞黏著、跨內皮轉移、細胞增殖及/或存活之疾病。
具體而言,自參考文獻得知CXCR7在腦腫瘤、惡性神經膠瘤及多形性神經膠質母細胞瘤中之潛在作用。包括CXCR7調節劑之CXCL12路徑的調節劑已作為與化療劑或放射療法組合用於治療腦癌之潛在治療劑而得到提及。舉例而言,Hattermann等人(Cancer research 2010, 70 (8):3299-3308)教示CXCL12 「刺激防止喜樹鹼及替莫唑胺誘發性細胞凋亡且CXCR7拮抗劑降低CXCL12之抗細胞凋亡作用」。作者總結,「CXCR7在星狀細胞瘤/神經膠質母細胞瘤中係CXCL12之功能受體,且調和針對藥物誘發性細胞凋亡之抗性」。此外,Hattermann等人(Oncol Rep. 2012, 27: 1348-1352)教示「CXCL12消除替莫唑胺之抗增殖效果」。作者亦教示此效果可能由CXCR7特異性拮抗劑幾乎完全消除,「表明CXCL12之抗細胞凋亡效果主要由CXCR7調和」。Ebsworth等人(Neuro Oncol (2013) 15 (suppl 3):iii37-iii61. ET-023)教示在神經膠質母細胞瘤之大鼠模型中,當與放射療法組合投與時,CXCR7拮抗劑顯著延長存活時間。其他研究(例如,Ebsworth K等人; J Clin Oncol. 2012, 30(15) e13580; Walters MJ等人; Br J Cancer. 2014, 110(5):1179-88)支持此發現,該等研究揭示與放射療法組合之CXCR7的體內抑制在另一神經膠質母細胞瘤之大鼠模型中使存活時間顯著延長。此外,Liu SC等人(Neuro-Oncology 2014; 16(1):21-28)教示照射後CXCL12之抑制作用在大鼠中抑制原生腦腫瘤中之腫瘤再生。Liu SC等人(Neuro Oncol. 2013, 16(1):21-8)亦教示相較於單獨照射,照射後腦轉移模型中CXCL12之抑制作用抑制腫瘤生長且延長壽命。Calatozzolo C等人(Cancer Biol Ther. 2011, 11(2), 1-12)教示在體外實驗中,CXCR7拮抗劑顯示完全抑制神經膠瘤增生。
具體而言,已在參考文獻中描述CXCR7於胰腺腫瘤中之作用。Shakir等人(Pancreas. 2015, 44(4):528-34)觀察到,在與CXCL12相互作用時,CXCR4及CXCR7激活促進更激進行為之下游蛋白酶。此外,CXCR7及CXCl12之表現與腫瘤組織學等級相關(Liu Z等人; World J Surg Oncol. 2014, 12:348)。此等發現由Heinrich EL等人(J Transl Med. 2012, 10:68)證實。因此,CXCR7調節劑可能適用於治療胰腺癌。
CXCR7調節劑亦可能適用於治療乳突甲狀腺癌。Liu Z等人(J Surg Res. 2014, 191(2):379-88)描述CXCR7傳訊RNA及蛋白質含量在乳突甲狀腺癌中顯著提高且與腫瘤進程相關。CXCR7可能調節參與S-G2相轉移之增殖、細胞週期、細胞凋亡、侵入及細胞週期調節性蛋白質的表現。敲除乳突甲狀腺癌細胞中之CXCR7抑制細胞增殖及侵入、誘發S相捕獲且促進細胞凋亡。Zhang H等人(Tumor Biol. 2016, 37(2):2415-23)進一步證明CXCR7影響乳突甲狀腺癌細胞之生長且參與乳突甲狀腺癌之腫瘤形成,其或許係藉由調節血管新生VEGF或IL-8導致的血管生成而進行。甲狀腺癌中CXCR7軸之表現及功能係由Zhu X等人(Int J Oncol. 2016, 48(6):2321-9)證實。
CXCR7調節劑亦可能適用於治療肺癌:使用過度表現與RNA干預之組合,Miao Z等人(PNAS. 2007, 104(40):15735-40)確定CXCR7促進形成自乳癌細胞及肺癌細胞之腫瘤的生長且促進實驗性肺轉移。Iwakiri S等人(Iwakiri S等人; Cancer. 2009, 115(11):2580-93)觀察到,CXCR7之較高表現與病理I階段非小細胞肺癌中之早期及轉移性再生有關。
CXCR7調節劑亦可適用於治療肝細胞癌:據報道,肝細胞癌組織中之CXCR7表現增加。敲除CXCR7表現顯著抑制肝細胞癌細胞侵入、黏著及血管生成。此外,CXCR7表現之下調使肝細胞癌之異種移植模型中的腫瘤生長減弱(Zheng K等人; J Exp Clin Cancer Res. 2010, 29:31)。Monnier J等人(Eur J Cancer. 2012, 48(1):138-48)亦觀察到,在408個人類肝細胞癌之群組中,相較於正常肝對照物,CXCR7在腫瘤中明顯更高。人類肝細胞癌部分上的免疫組織化學染色證明癌症組織中之CXCR7表現更高。在肝細胞癌細胞株中使用CXCR7之RNAi,Xue TC等人(Exp Ther Med. 2012, 3(1):117-123)觀察到,CXCR7下調使腫瘤生長減少,且減少裸鼠中肺轉移之數目。此外,組織微陣列顯示,具有高CXCR7表現之HCC易於轉移至肺。下調CXCR7抑制了具有高度轉移可能性之人類肝細胞癌細胞的生長及肺轉移。
CXCR7調節劑亦可適用於治療轉移性結腸癌:Guillemot等人(Br J Cancer. 2012, 107(12):1944-9)觀察到,在注射大腸直腸癌細胞之後,用CXCR7拮抗劑治療之小鼠的肺轉移顯著減少。Wang HX等人(Mol Clin Oncol. 2015, 3(6):1229-1232)研究結腸癌樣品中之CXCR7表現,且觀察到相較於正常結腸組織中之CXCR7含量,結腸腫瘤中之CXCR7含量明顯更高。此外,相較於非轉移性腫瘤,淋巴結轉移性結腸腫瘤呈現明顯更高之CXCR7表現。
亦報導CXCR7表現於腦轉移中(Salmaggi等人; Cancer Biol Ther.2009, 8:17, 1-7)。作者總結,CXCL12/CXCR4/CXCR7路徑可能係進一步研究之有趣目標,該等研究探究此等分子在轉移性細胞之侵入及增殖中的作用。
具體而言,自參考文獻得知CXCR7對發炎性髓鞘脫失疾病之作用。CXCR7表現於整個成年小鼠大腦之各種區域中,且其表現在針對多發性硬化症之小鼠模型中經上調(Banisadr G等人; J Neuroimmune Pharmacol. 2016 Mar; 11(1):26-35)。血腦障(BBB)處CXCL12經改變之表現形式參與多發性硬化症且與疾病之嚴重程度相關(McCandless EE等人; Am J Pathol. 2008, 172(3):799-808)。已顯示CXCR7拮抗作用在小鼠中之實驗性自體免疫腦脊髓炎中有效。彼等最新研究有力表明CXCR7在多發性硬化症中經由互補機制成為疾病調節分子:(i)藉由經由BBB處之CXCL12重新分配促使白血球進入血管周空間中(Cruz-Orengo L等人; J Neuroinflammation. 2011, 6; 8:170; Cruz-Orengo L等人; J Exp Med. 2011, 14; 208(2):327-39)且調節CXCR4介導之整合素的活化(Hartmann TN等人; J Leukoc Biol. 2008,; 84(4):1130-40) (ii)藉由直接影響微膠質細胞趨化性(Bao J等人; Biochem Biophys Res Commun. 2016 Jan 1; 469(1):1-7)且影響發炎性單核細胞,促使其進入大腦(Douglas SD等人; J Leukoc Biol. 2017; 102: 1155-1157) (iii)藉由經由提高CXCL12之含量促進髓鞘再生,該CXCL12促進CXCR4介導之少突神經膠質細胞祖細胞成熟(Williams JL等人; J Exp Med. 2014, 5; 211(5):791-9; Gottle P等人; Ann Neurol. 2010, 68(6):915-24)。最近,Chu等人(Neuroscientist. 2017, 23(6): 627-648)評述標靶軸CXCL12/CXCR4/CXCR7對於髓鞘脫失疾病之重要性,此係因為其在促進少突神經膠質細胞祖細胞之轉移、增殖及分化中之中心作用。因此,在治療學上,CXCR7拮抗作用可能預防炎症且在髓鞘脫失成人CNS中促進髓磷脂修復。
具體而言,自參考文獻得知CXCR7在風濕性關節炎中之潛在作用。據報導,CXCR7表現於滑膜中之內皮細胞上。此外,在風濕性關節炎患者之滑液組織中發現CXCL12及CXCL11 mRNA之含量提高(Ueno等人; Rheumatol Int. 2005, 25(5):361-7)。顯示CXCL12在CD4+ T細胞及滑膜中之單核細胞累積中起中心作用(Nanki T等人; J Immunol. 2000, 165(11):6590-8; Blades MC等人; Arthritis Rheum. 2002 Mar; 46(3):824-36)。此外,CXCL12經由其促血管生成功能及其對蝕骨細胞召集及分化之作用而參與風濕性關節炎過程。此外,包括CXCR7調節劑之CXCL12路徑的調節劑已作為治療風濕性關節炎之潛在治療劑而提出。Villalvilla等人(Expert Opin Ther Targets. 2014, 18(9):1077-87)最近論述支持抗CXCL12試劑在風濕性關節炎治療中之潛在用途的臨床前及臨床資料。Watanabe等人(Arthritis Rheum. 2010, 62(11):3211-20)教示在預防及治療上,CXCR7抑制劑減少小鼠膠原蛋白誘發性關節炎模型中之疾病臨床症狀及血管生成。
具體而言,CXCR7參與若干發炎性疾病。舉例而言,CXCL12及CXCL11參與急性及慢性肺部發炎過程,諸如慢性阻塞性肺病(Petty JM等人; J Immunol. 2007, 178(12):8148-57; Porter JC等人; J Immunol. 2008, 180(3):1866-77)。發現CXCL12在人類及動物模型之肺中經上調(Phillips RJ等人; J Clin Invest. 2004, 114(3):438-46)。已顯示肺中CXCR7之敲除及抗CXCL12試劑使氣喘模型中之肺炎及氣道過度活性減弱(Gasparik V等人; ACS Med Chem Lett. 2012 Jan 12; 3(1):10-4; Lukacs NW等人; Am J Pathol. 2002, 160(4):1353-60)。顯示CXCR7拮抗作用或CXCL12封鎖使肺炎減弱,使小鼠之急性肺部損傷中的肺部上皮障壁穩定(Ngamsri KC等人; J Immunol. 2017, 198(6):2403-2413; Konrad FM等人; Cell Death Dis. 2017, 8 (5))。Cao等人(Nat Med. 2016,; 22(2):154-62)教示在肺部損傷後,CXCR7調節劑在肺纖維化之小鼠模型中「促進肺泡修復且減少纖維化」。亦描述肝纖維化中CXCR7之作用(Ding BS等人; Nature. 2014, 505(7481):97-102)。
亦報導,CXCL12及CXCL11在發炎性腸病中經上調(Koelink PJ等人; Pharmacol Ther. 2012, 133(1):1-18)。發現CXCR7在發炎性腸病中之周邊血液T細胞上經上調(Werner L等人; J Leukoc Biol. 2011, 90(3):583-90)。作者假設「提高發炎性腸病病人之周邊血液中CXCR7之表現可能使T細胞向黏膜發炎之位點的流入增加」 (Werner L等人; Theranostics. 2013, 3(1):40-6)。在發炎性腸病之小鼠模型中,CXCL12路徑之調節劑可能減少T細胞之滲入且減少組織損傷(Mikami S等人; J Pharmacol Exp Ther. 2008, 327(2):383-92; Xia XM等人; PLoS One. 2011, 6(11):e27282)。
亦在皮損幹癬皮膚中發現CXCL12及CXCL11之含量提高(Chen SC等人; Arch Dermatol Res. 2010, 302(2):113-23; Zgraggen S等人; PLoS One. 2014, 9(4):e93665)。Zgraggen等人教示封鎖CXCL12在兩種不同類牛皮癬皮膚炎症模型中改善慢性皮膚炎症之過程。
如全身性紅斑狼瘡(SLE)之若干其他自體免疫疾病顯示經改變之CXCR7/CXCR4表現,其與SLE B細胞之受損CXCL12促進性轉移有關(Biajoux V等人; J Transl Med. 2012, 18; 10:251)。此外,在多個狼瘡之鼠類模型中,腎炎性腎中之CXCL12經顯著上調。Wang等人(J Immunol. 2009, 182(7):4448-58)教示作用於CXCL12軸係狼瘡中之較佳治療目標,而CXCR4拮抗劑顯著改善疾病、延長存活時間且減弱腎炎及淋巴腺增生。
在來自自體免疫患者之甲狀腺中及動物模型中發現CXCL12及CXCR4經上調(Armengol MP等人; J Immunol. 2003, 170(12):6320-8)。Liu等人(Mol Med Rep. 2016, 13(4):3604-12)教示阻斷CXCR4在小鼠中減少自體免疫甲狀腺炎之嚴重性,減少淋巴細胞滲入及自動抗體生成。
Virani等人(Virani S等人; AJRI. 2013, 70:386-397)教示封鎖CXCL12限制子宮內膜異位病灶中之血管生成。
CXCR7調節劑之生物特性亦包括(但不限於)任何由其配體CXCL11、CXCL12、BAM22及其關聯肽連接及/或控制之生理性功能及/或細胞功能。因此,CXCL12損耗使癌細胞對體內化學療法敏感,且CXCL12治療阻礙結腸癌轉移(Duda等人; Clin. Cancer Res. 2011 17(8) 2074-2080; Naumann等人; Plos One. 2010, 5(2) e9175)。CXCR7亦係CXCL11之受體(別名小型可誘導細胞因子子族b,成員11;scyb11,別名干擾素-γ-可誘導蛋白質9;ip9,別名小型可誘導細胞因子子族b,成員9b,scyb9b)且因此CXCR7活性之調節劑亦可用於指示CXCL11相關性病理學(Rupertus K等人; Clin Exp Metastasis. 2014, 31(4):447-59; Zohar Y等人; J Clin Invest. 2014, 124(5):2009-22; Antonelli A等人; Thyroid. 2013, 23(11):1461-9)。CXCR7亦用作類鴉片肽BAM22及其關聯肽(肽E、肽BAM12、BAM14、BAM18)之受體,且因此CXCR7活性之調節劑亦很可能用於指示類鴉片肽相關性病理學(Ikeda等人; Cell. 2013, 155, 1323-1336)。亦已顯示,CXCR7用作CXCl11及CXCL12之清除受體。因此,已顯示CXCR7標靶改變CXCl11及CXCL12局部濃度,使CXCl11及CXCL12濃度梯度解禁。
自WO2016/040515得知特定異㗁唑化合物,其係SMYD蛋白質阻斷劑,其中在WO2016/040515之化合物中,用特定(環)烷基取代基而非本發明之苯基取代基取代異㗁唑環;且哌啶部分不攜載羧醯胺取代基。自WO2006/087543、WO2005/026149及J. Med. Chem 2014, 57(14), 6060-6082得知特定吡咯化合物作為抗菌劑。自WO2005/032490得知環狀二胺作為因子Xa抑制劑。WO2004/050024揭示吡咯啶化合物作為趨化介素受體調節劑。
本發明提供新穎結晶型(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺,其係CXCR7受體之調節劑,亦即,其用作CXCR7受體拮抗劑,且用於預防或治療對CXCL12受體及/或CXCL11受體之活化作出回應之疾病,尤其係癌症。在癌症之預防或治療中,該結晶型亦可與一或多種化學療法試劑及/或放射療法及/或標靶療法組合使用。
1)本發明之第一實施例係關於化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型;
其特徵係:
a. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、8.2°及18.3° (尤其3.6°、7.2°、8.2°、8.7°及18.3°;尤其3.6°、7.2°、8.2°、8.7°、9.1°、10.8°、13.9°、17.0°、17.5°及18.3°);或
b. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.7°、8.5°及10.9° (尤其6.7°、8.5°、10.9°、13.2°及14.5°;尤其6.7°、8.5°、10.9°、13.2°、14.1°、14.5°、16.0°、17.4°、18.4°及20.8°);或
c. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:8.2°、17.9°及21.0° (尤其6.8°、8.2°、14.1°、17.9°及21.0°;尤其6.8°、8.2°、8.8°、14.1°、16.0°、17.9°、21.0°及24.1°)。
應理解,實施例1)之結晶型包含呈游離鹼(亦即,不呈鹽形式)之結晶型的化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺。此外,該等結晶型可包含非配位及/或配位溶劑。配位溶劑在本文中用作結晶溶合物之術語。類似地,非配位溶劑在本文中用作物理吸附或物理捕獲溶劑之術語(Polymorphism in the Pharmaceutical Industry (R. Hilfiker編, VCH, 2006), 第8章: U.J. Griesser: The Importance of Solvates之定義)。特定而言,結晶型1係無水物,亦即,其不包含配位水,但可包含非配位溶劑,諸如異丙醇、甲醇、乙醇及/或水。特定而言,結晶型2係無水物,亦即,其不包含配位水,但可包含非配位溶劑,諸如異丙醇、甲醇、乙醇及/或水。特定而言,結晶型3係二水合物,亦即,其包含約2當量之配位水,且可包含額外非配位溶劑,諸如水。
2)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、8.2°及18.3°;其中該結晶型之特徵尤其係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、7.2°、8.2°、8.7°及18.3°。
3)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、8.2°及18.3°;或關於實施例2)之該結晶型,其中該結晶型之特徵尤其係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、7.2°、8.2°、8.7°、9.1°、10.8°、13.9°、17.0°、17.5°及18.3°。
4)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、8.2°及18.3°;或關於實施例2)或3)之該結晶型,其基本上顯示如圖1中描繪之X射線粉末繞射圖案。
5)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、8.2°及18.3°;或關於實施例2)至4)中任一者之該結晶型,如藉由示差掃描熱量測定法(例如,藉由使用如本文所述之方法)測定,其在約259℃處具有吸熱現象。
6)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、8.2°及18.3°;或關於實施例2)至5)中任一者之該結晶型,其中該形式係藉由以下獲得:
a) 將10 mg化合物與1 mL甲醇混合,或將20 mg化合物與1 mL約3:1甲醇與乙腈之混合物混合;
b) 藉由以0.1℃/min之勻速升溫加熱至約65℃以溶解化合物;
c) 藉由使用0.1℃/min之勻速降溫將混合物冷卻至約20℃;且
d) 過濾且乾燥產物(例如,在室溫下且在約10毫巴之減壓下持續4小時)。
7)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:3.6°、8.2°及18.3°;或關於實施例2)至6)中任一者之該結晶型,其中該結晶型係無水物(亦即,其不含配位水)。
8)另一實施例係關於實施例1之化合物的結晶型,其特徵係:
a. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.7°、8.5°、10.9°、13.2°及14.5°;或
b. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.8°、8.2°、14.1°、17.9°及21.0°。
9)另一實施例係關於實施例1)或8)之化合物的結晶型,其特徵係:
a. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.7°、8.5°、10.9°、13.2°、14.1°、14.5°、16.0°、17.4°、18.4°及20.8°;或
b. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.8°、8.2°、8.8°、14.1°、16.0°、17.9°、21.0°及24.1°。
10)另一實施例係關於實施例1)或8)之化合物的結晶型,其特徵係:
a. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.7°、8.5°、10.9° (尤其6.7°、8.5°、10.9°、13.2°及14.5°);或關於實施例9)之該結晶型,其基本上顯示如圖2中描繪之X射線粉末繞射圖案;或
b. 在X射線粉末繞射圖中,於以下折射角2q處存在峰:8.2°、17.9°、21.0° (尤其6.8°、8.2°、14.1°、17.9°及21.0°);或關於實施例9)之該結晶型,其基本上顯示如圖3中描繪之X射線粉末繞射圖案。
11)另一實施例係關於實施例1之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.7°、8.5°、10.9°、13.2°、14.5° (尤其6.7°、8.5°、10.9°、13.2°、14.1°、14.5°、16.0°、17.4°、18.4°及20.8°)。
12)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.7°、8.5°及10.9°;或關於實施例8)至11)中任一者之該結晶型,其中該結晶型係無水物(亦即,其不含配位水)。
13)另一實施例係關於實施例1之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.8°、8.2°、14.1°、17.9°、21.0° (尤其6.8°、8.2°、8.8°、14.1°、16.0°、17.9°、21.0°及24.1°)。
14)另一實施例係關於實施例1)之化合物的結晶型,其特徵係在X射線粉末繞射圖中,於以下折射角2q處存在峰:8.2°、17.9°及21.0°;或關於實施例8)至10)或13)中任一者之該結晶型,其中該結晶型係二水合物(亦即,其含有約2當量之配位水;其中應理解,該約2當量之配位水相當於化合物之結晶型具有約6.9%之水含量(例如,如藉由GVS/吸水實驗測定)。
進一步揭示呈結晶型4之(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺,該形式之特點尤其係在X射線粉末繞射圖中,於以下折射角2q處存在峰:6.4°、8.3°、16.7°、18.0°及23.2° (尤其6.4°、8.3°、8.9°、13.6°、14.1°、15.4°、16.7°、18.0°及23.2°);且其基本上顯示如圖4中描繪之X射線粉末繞射圖案。特定而言,結晶型4可包含額外配位或非配位溶劑,諸如THF及/或水。
為避免任何質疑,上文實施例之一無論何時提及「在X射線粉末繞射圖中,於以下折射角2θ處之峰」,該X射線粉末繞射圖均藉由使用組合Cu Kα1與Kα2輻射獲得,無Kα2剝離;且應理解,如本文提供之2θ值的準確度係在+/- 0.1-0.2°範圍內。尤其在本發明實施例及申請專利範圍中指定峰之折射角2theta (2θ)時,給出之2q值應理解為自該值減0.2°至該值加0.2° (2θ +/- 0.2°)之區間;且較佳自該值減0.1°至該值加0.1° (2θ +/- 0.1°)。
當複數形式用於化合物、固體、醫藥組合物、疾病及其類似物時,此亦欲意謂單個化合物、固體或其類似者。
術語「對映異構性增濃」在本發明之上下文中理解為意謂尤其至少90 wt%,較佳至少95 wt%,且最佳至少99 wt%化合物以該化合物之對映異構體形式存在。應理解,化合物係以對映異構性增濃之絕對(3S,4S)-構形存在。
術語「基本上純」在本發明之上下文中理解為意謂尤其至少90 wt%,較佳至少95 wt%,且最佳至少99 wt%化合物之晶體以本發明之結晶型存在,尤其以本發明之單一結晶型存在。
當例如在X射線粉末繞射圖中定義峰之存在時,常用途徑係根據S/N比(S = 訊號,N = 雜訊)進行。根據此定義,當陳述峰必須存在於X射線粉末繞射圖時,應理解X射線粉末繞射圖中之峰係藉由具有大於x (x數值大於1),通常大於2,尤其大於3之S/N比(S=訊號,N=雜訊)定義。
在陳述分別如圖1至圖4中所描繪,結晶型基本上顯示X射線粉末繞射圖案之上下文中,術語「基本上」意謂至少該等圖示中描繪之圖的主峰(亦即,相較於圖中強度最高峰,具有大於10%,尤其大於20%之相對強度之彼等峰)必須存在。然而,熟習X射線粉末繞射之技術者將認識到X射線粉末繞射圖中之相對強度因較佳定向效應可經受較強強度變化。
除非用於溫度,否則置於數值「X」之前的術語「約」在本申請案中指代自X減X之10%至X加X之10%的區間,且較佳指代自X減X之5%至X加X之5%的區間。在溫度之特定情況下,置於溫度「Y」之前的術語「約」在本申請案中指代溫度Y減10℃至Y加10℃之區間,較佳指代Y減5℃至Y加5℃之區間,尤其指代Y減3℃至Y加3℃之區間。室溫意謂約25℃之溫度。當在本申請案中使用術語n等效表達,其中n係數值時,其意謂且在本申請案之範疇中n指代約值n,較佳n指代確定數值n。
每當字組「之間」或「至」用於描述數值範圍時,應理解指定範圍之端點明確包括在範圍內。舉例而言:若溫度範圍描述為介於40℃與80℃之間(或40℃至80℃),則此意謂端點40℃及80℃包括在範圍內;或若變量定義為介於1與4之間(或1至4)的整數,則此意謂變量係整數1、2、3或4。
表達%w/w係指與所考慮組合物之總重量相比之重量百分比。同樣,表達v/v係指所考慮兩種組分之體積比。表達「vol」表示體積(以L為單位,例如,溶劑)/重量(以kg為單位,例如,反應物)。舉例而言,7 vol表示7公升(溶劑)/kg (反應物)。
實施例1)至14)中任一者之化合物的結晶型,尤其基本上純結晶型可用作藥品,例如,以醫藥組合物形式用於腸內或非經腸投與。
15)因此,另一實施例係關於實施例1)至14)中任一者之化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型作為藥品之用途。
實施例1)至14)中任一者之化合物的結晶固體,尤其基本上純結晶固體可用作單一組分或用作與化合物之其他結晶型或非晶型之混合物。
醫藥組合物之製造可以任何熟習此項技術者將熟悉之方式實現(參見例如Remington,The Science and Practice of Pharmacy
, 第21版(2005), 第5部分, “Pharmaceutical Manufacturing” [由Lippincott Williams & Wilkins出版]),其藉由將本發明之結晶型(視情況與其他治療有價值的物質組合)引入蓋倫投藥劑型以及適合、無毒、惰性、醫藥學上可接受之固體或液體載劑材料及必要時常見醫藥佐劑。
16)本發明之另一實施例係關於醫藥組合物,其包含實施例1)至14)中任一者之化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型作為活性成分,及至少一種醫藥學上可接受之載劑材料。
實施例16)之該醫藥組合物尤其適用於預防或治療與CXCR7受體或其配體相關之疾病或病症。
17)本發明之另一實施例係關於實施例14)之醫藥組合物,其中該醫藥組合物呈錠劑形式。
18)本發明之另一實施例係關於實施例14)之醫藥組合物,其中該醫藥組合物呈膠囊形式。
19)本發明之另一實施例係關於實施例1)至14)中任一者之化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型[尤其實施例2)至實施例7)中任一者之結晶型]在製造醫藥組合物中之用途,其中該醫藥組合物包含化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺作為活性成分及至少一種醫藥學上可接受之載劑材料。
為避免任何質疑,實施例19)指代實施例1)至14)中任一者之結晶型[尤其實施例2)至7)中任一者之結晶型],其適合用作/用作化合物之最終分離步驟(例如,以滿足醫藥製造之純度要求),然而實施例17)之最終醫藥組合物可能含有或可能不含該結晶型(例如,此係因為化合物之最初結晶型在製造過程期間進一步轉化且/或溶解於醫藥學上可接受之載劑材料中;因此,在最終醫藥組合物中,化合物可以非晶型、以另一結晶型或以溶解形式或類似形式存在)。
20)因此,本發明之另一實施例係關於一種醫藥組合物,其包含化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺作為活性成分,其中該醫藥組合物係使用實施例1)至14)中任一者之化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型[尤其實施例2)至7)中任一者之結晶型]及至少一種醫藥學上可接受之載劑材料製造。
21) 本發明之另一實施例係關於實施例20)之醫藥組合物,其中該醫藥組合物呈膠囊形式。
22)本發明之另一實施例係關於實施例1)至14)中任一者之化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型,其用於預防/防治或治療與CXCR7受體或其配體相關之疾病或病症。
23)本發明之另一實施例係關於實施例1)至14)中任一者之化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺之結晶型,其用於製備用於預防/防治或治療與CXCR7受體或其配體相關之疾病或病症的藥品。
如實施例1)至14)中任一項定義之化合物的結晶型適用於預防/防治或治療與CXCR7受體或其配體相關之病症,尤其係與CXCR7受體之功能異常、或藉由CXCR7傳訊之配體的功能異常、或藉由其其他受體(CXCR4及CXCR3)傳訊之CXCR7配體 (CXCL12及CXCL11)的功能異常相關之病症。
該等與CXCR7受體或其配體相關之疾病或病症尤其選自由以下組成之群:
· 癌症(尤其腦腫瘤,包括惡性神經膠瘤、多形性神經膠質母細胞瘤;神經胚細胞瘤;胰臟癌,包括胰腺癌/胰臟管腺癌;胃腸癌,包括結腸癌、肝細胞癌及胃癌;卡波西氏肉瘤(Kaposi's sarcoma);白血病,包括成人T細胞白血病;淋巴瘤;肺癌;乳癌;橫紋肌肉瘤;前列腺癌;食道鱗癌;口腔鱗狀細胞癌;子宮內膜癌;甲狀腺癌,包括乳突甲狀腺癌;轉移癌;肺轉移;皮膚癌,包括黑色素瘤及轉移性黑色素瘤;膀胱癌;多發性骨髓瘤;骨肉瘤;頭頸癌;及腎癌,包括腎透明細胞癌、轉移性腎透明細胞癌);
· 發炎性疾病(尤其慢性鼻竇炎、氣喘、慢性阻塞性肺病、動脈粥狀硬化、心肌炎及類肉瘤病;尤其慢性鼻竇炎、氣喘及動脈粥狀硬化);
· 自體免疫病症(尤其(發炎性)髓鞘脫失疾病;多發性硬化症(MS);格巴二氏症候群(Guillain Barré syndrome);風濕性關節炎(RA);發炎性腸病(IBD,尤其包含克羅恩氏病(Crohn's disease)及潰瘍性結腸炎);全身性紅斑狼瘡(SLE);狼瘡性腎炎;間質性膀胱炎;乳糜瀉;自體免疫腦脊髓炎;骨關節炎;及I型糖尿病;尤其具有發炎部分之自體免疫病症,諸如(發炎性)髓鞘脫失疾病、多發性硬化症、格巴二氏症候群、風濕性關節炎、發炎性腸病、全身性紅斑狼瘡、狼瘡性腎炎及自體免疫腦脊髓炎);
· 移植排斥(尤其腎同種異體移植物排斥、心同種異體移植物排斥及由造血幹細胞移植導致的移植物抗宿主疾病);及
· 纖維化(尤其肝纖維化、肝硬化、肺纖維化,尤其自發性肺纖維化)。
該等與CXCR7受體或其配體相關之疾病或病症尤其係癌症、自體免疫病症(尤其具有發炎性部位之自體免疫病症)及纖維化。
此外,其他與CXCR7受體或其配體相關之疾病或病症係涉及以下之疾病:CXCR7及/或CXCL12及/或CXCL11介導之轉移、趨化性、細胞黏著、跨內皮轉移、細胞增殖及/或存活。
此外,其他與CXCR7受體或其配體相關之特定疾病或病症係增生性糖尿病視網膜病變;西尼羅病毒腦炎(West Nile virus encephalitis);肺血管疾病、急性腎衰竭、包括大腦缺血之缺血、急性冠狀動脈綜合症、受損中樞神經系統、高血脂病、高血壓、肺部高血壓、滋賀毒素相關性溶血性尿毒症症候群、子癲前症、血管損傷、HIV/AIDS、血管生成及腦部及神經元功能異常(諸如阿茲海默氏症(Alzheimer's disease)之發炎部位)、壓力相關性疾病(諸如焦慮、抑鬱及創傷後壓力病症)及涉及類鴉片受體之疾病、子宮內膜異位、自體免疫甲狀腺炎、脈絡膜血管新生相關性疾病、再生不全性貧血、薛格連氏病(Sjögren's disease)及白斑症。在子實施例中,該與CXCR7受體或其配體相關之另一特定疾病或病症係肺性高血壓。
術語「癌症」指代所有種類之癌症,諸如癌瘤;腺癌;白血病;肉瘤;淋巴瘤;骨髓瘤;轉移性癌症;腦腫瘤;神經胚細胞瘤;胰臟癌;胃腸癌;肺癌;乳癌;前列腺癌;子宮內膜癌;皮膚癌;膀胱癌;頭頸癌;神經內分泌腫瘤;卵巢癌;子宮頸癌;口腔腫瘤;鼻咽腫瘤;胸癌;及病毒誘發性腫瘤。
術語尤其指代腦腫瘤,包括腦轉移、惡性神經膠瘤、多形性神經膠質母細胞瘤、神經管胚細胞瘤、腦脊髓膜瘤;神經胚細胞瘤;胰臟癌,包括胰腺癌/胰臟管腺癌;胃腸癌,包括結腸癌、大腸直腸癌、大腸直腸腺癌、轉移性大腸直腸癌、家族性腺瘤息肉症(FAP)、胃癌、膽囊癌、膽管癌、肝細胞癌;卡波西氏肉瘤(Kaposi's sarcoma);白血病,包括急性骨髓性白血病、成人T細胞白血病;淋巴癌,包括伯奇氏淋巴瘤(Burkitt's lymphoma)、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、MALT淋巴瘤及原發性眼內B細胞淋巴瘤;肺癌,包括非小細胞肺癌;乳癌,包括三陰性乳癌;橫紋肌肉瘤;前列腺癌,包括抗閹割前列腺癌;食道鱗癌;(口腔)鱗狀細胞癌;子宮內膜癌;甲狀腺癌,包括乳突甲狀腺癌;轉移癌;肺轉移;皮膚癌,包括黑色素瘤及轉移性黑色素瘤;膀胱癌,包括泌尿膀胱癌、尿道細胞癌;多發性骨髓瘤;骨肉瘤;頭頸癌;及腎癌,包括腎細胞癌、腎透明細胞癌、轉移性腎細胞癌、轉移性腎透明細胞癌;以及神經內分泌腫瘤;卵巢癌;子宮頸癌;口腔腫瘤;鼻咽腫瘤;胸癌;絨毛膜癌;尤文氏肉瘤(Ewing's sarcoma);及病毒誘發性腫瘤。
術語「癌症」尤其指代惡性神經膠瘤,尤其多形性神經膠質母細胞瘤、神經胚細胞瘤;胰臟癌,尤其胰臟管腺癌;卡波西氏肉瘤;成人T細胞白血病、淋巴瘤;肺癌;乳癌;橫紋肌肉瘤;前列腺癌;食道鱗癌;(口腔)鱗狀細胞癌;子宮內膜癌;乳突甲狀腺癌;轉移癌;肺轉移;黑色素瘤;膀胱癌;多發性骨髓瘤;骨肉瘤;胃腸癌,尤其結腸癌、肝細胞癌及胃癌;頭頸癌;及腎透明細胞癌。較佳地,術語「癌症」指代惡性神經膠瘤,尤其多形性神經膠質母細胞瘤;胰臟癌,尤其胰臟管腺癌;乳突甲狀腺癌;肝細胞癌;肺癌;乳癌;轉移癌;肺轉移;黑色素瘤;結腸癌;頭頸癌;及腎透明細胞癌。
如實施例1)至14)中任一者定義之化合物的結晶型可尤其適用作治療劑,其用於預防/防治或治療如先前定義之癌症,該癌症係轉移癌/形成轉移之癌症。
如實施例1)至14)中任一者定義之化合物的結晶型可尤其適用作治療劑,其用於預防/防治或治療癌症。其可用作單一治療劑或與一或多種化學治療劑及/或放射療法及/或標靶療法組合。在子實施例中,當式(I)化合物與一或多種化學治療劑及/或放射療法及/或標靶療法組合用於預防/防治或治療癌症時,該癌症尤其係惡性神經膠瘤,尤其多形性神經膠質母細胞瘤;胰臟癌,尤其胰臟管腺癌;乳突甲狀腺癌;肺轉移;黑色素瘤;肺癌;轉移癌;肝細胞癌;乳癌;大腸結腸癌;或頭頸癌。此類組合治療可同時、分開或在一段時間內進行。
因此,本發明亦關於包含醫藥學上可接受之載劑材料及以下的醫藥組合物:
· 如實施例1)至14)中任一項定義之化合物的結晶型;
· 及一或多種細胞毒性化學治療劑。
因此,本發明進一步關於一種套組,其包含
· 醫藥組合物,該組合物包含醫藥學上可接受之載劑材料及如實施例1)至14)中任一項定義之化合物的結晶型;
· 及如何與化學療法及/或放射療法及/或標靶療法組合使用該醫藥組合物以預防或治療癌症(尤其惡性神經膠瘤、尤其多形性神經膠質母細胞瘤)之說明。
術語「放射療法」或「放射線療法」或「放射線腫瘤學」指代電離放射線預防(輔助療法)及/或治療癌症之醫療用途;包括外部及內部放射療法。
術語「標靶療法」指代用一或多種抗腫瘤劑,諸如對特定類型之癌細胞或基質細胞起作用之小分子或抗體,預防/防治(輔助療法)及/或治療癌症。一些標靶療法阻斷某些酶、蛋白質或與癌細胞之生長及擴散有關之其他分子的活動。其他類型之標靶療法幫助免疫系統殺滅癌細胞(免疫療法);或直接將毒性物質投遞至癌細胞且將其滅殺。尤其適用於與本發明之化合物組合之標靶療法的實例係免疫療法,尤其標靶程式性細胞死亡受體1 (PD-1受體)或其配體PD-L1之免疫療法(Feig C等人, PNAS 2013)。
當與式(I)化合物組合使用時,術語「標靶療法」尤其指代諸如以下之試劑:
a) 表皮生長因子受體(EGFR)抑制劑或阻斷抗體(例如,吉非替尼(Gefitinib)、埃羅替尼(Erlotinib)、阿法替尼(Afatinib)、埃克替尼(Icotinib)、拉帕替尼(Lapatinib)、帕尼單抗(Panitumumab)、紮魯目單抗(Zalutumumab)、尼妥珠單抗(Nimotuzumab)、馬妥珠單抗(Matuzumab)及西妥昔單抗(Cetuximab));
b) B-RAF抑制劑(例如威羅菲尼(Vemurafenib)、索拉菲尼(Sorafenib)、達拉菲尼(Dabrafenib)、GDC-0879、PLX-4720、LGX818);
c) 芳香酶抑制劑(例如依西美坦(Exemestane)、來曲唑(Letrozole)、阿那曲唑(Anastrozole)、氟氯唑(Vorozole)、福美坦(Formestane)、法屈唑(Fadrozole);
d) 免疫查核點抑制劑(例如,抗PD1抗體,諸如帕博利珠單抗(Pembrolizumab) (蘭布魯珠單抗(Lambrolizumab),MK-3475)、納武單抗(Nivolumab)、皮地利珠單抗(Pidilizumab)、AMP-514/MED10680;小分子抗PD1試劑,諸如例如WO2015/033299、WO2015/044900及WO2015/034820中揭示之化合物;抗PD1L抗體,諸如BMS-936559、阿特珠單抗(atezolizumab) (MPDL3280A)、MEDI4736、阿維單抗(avelumab) (MSB0010718C);抗PDL2,諸如AMP224、抗CTLA-4抗體,諸如伊匹木單抗(ipilimumab)、替西木單抗(tremilmumab);
e) 疫苗方式(例如樹狀細胞疫苗、肽或蛋白質疫苗(例如使用gp100肽或MAGE-A3肽);
f) 再次引入經遺傳修飾以分泌免疫調節因子,諸如顆粒球單核細胞群落刺激因子(GMCSF)基因轉染之腫瘤細胞疫苗(GVAX)或Fms相關之酪胺酸激酶3 (Flt-3)配位體基因轉染之腫瘤細胞疫苗(FVAX)或基於Toll樣受體增強之GM-CSF腫瘤之疫苗(TEGVAX)的患者來源或同種異體(非自身)癌細胞;
g) 基於T細胞之授受性免疫療法,包括嵌合抗原受體(CAR)工程改造之T細胞(例如CTL019);
h) 基於細胞因子或免疫細胞因子之療法(例如,干擾素α、干擾素β、干擾素γ、介白素2、介白素15);
i) Toll樣受體(TLR)促效劑(例如,雷西莫特(resiquimod)、咪喹莫特(imiquimod)、葡萄糖吡喃基脂A、CpG寡聚脫氧核苷酸);
j) 沙利多邁(Thalidomide)類似物(例如來那度胺(Lenalidomide)、泊馬多胺(Pomalidomide));
k) 吲哚-2,3-二氧酶(IDO)及/或色胺酸-2,3-二氧酶(TDO)抑制劑(例如NLG919/吲哚莫德(Indoximod)、1MT (1-甲基色胺酸)、INCB024360);
l) T細胞共激受體之活化劑(例如抗淋巴細胞活化基因3 (LAG-3)抗體(諸如BMS-986016);抗T細胞免疫球蛋白黏蛋白-3 (TIM-3)抗體、抗CD137/4-1BB抗體(例如BMS-663513/優魯單抗(urelumab))、抗殺傷細胞免疫球蛋白樣受體(KIR),例如利魯單抗(Lirilumab) (IPH2102/BMS-986015);抗OX40/CD134 (腫瘤壞死因子受體超家族,第4成員)、抗OX40-配體/CD252;抗葡萄糖皮質素誘發性TNFR族相關性基因(GITR) (諸如TRX518)、抗CD40 (TNF受體超家族第5成員)抗體(諸如CP-870,893);抗CD40-配體抗體(諸如BG9588);抗CD28抗體);
m) 結合腫瘤特異性抗原之分子以及T細胞表面標記物,諸如雙特異性抗體或抗體片段、諸如設計之錨蛋白重複蛋白質(DARPINS)之抗體模擬性蛋白質、雙特異性T細胞銜接子(BITE,例如AMG103、AMG330);
n) 標靶群落刺激因子-1受體(CSF-1R)之抗體或小分子量抑制劑(例如,RG7155或PLX3397)。
當與如實施例1)至14)中任一者定義之化合物的結晶型組合使用時,諸如彼等d)處所列之免疫查核點抑制劑及尤其標靶程式性細胞死亡受體1 (PD-1受體)或其配體PD-L1之彼等物係較佳的。
術語「化學療法」指代用一或多種細胞毒性抗腫瘤劑(「細胞毒性化學治療劑」)治療癌症。化學療法常常結合諸如放射線療法或手術之其他癌症治療使用。該術語尤其指代藉由殺死迅速分裂(大部分癌細胞之主要特性之一)之細胞來起作用的習知化學治療劑。化學療法可每次使用一種藥物(單劑化學療法)或一次使用若干藥物(組合化學療法或多化學療法)。使用僅僅在曝光時方轉變成細胞毒活性之藥物的化學療法稱為光化學療法或光動力療法。
如本文所用,術語「細胞毒性化學治療劑」或「化學治療劑」指代誘發細胞凋亡或壞死性細胞死亡之活性抗腫瘤劑。當與式(I)化合物組合使用時,該術語尤其指代習知細胞毒性化學治療劑,諸如:
a) 烷化劑(例如二氯甲二乙胺、氯芥苯丁酸、環磷醯胺、依弗醯胺(ifosfamide)、鏈脲黴素、卡氮芥、洛莫斯汀(lomustine)、米爾法蘭(melphalan)、白消安(busulfan)、達卡巴嗪(dacarbazine)、替莫唑胺、噻替派(thiotepa)或六甲蜜胺(altretamine);尤其替莫唑胺);
b) 鉑藥物(例如順順鉑、卡鉑或奧沙利鉑);
c) 抗代謝藥物(例如5-氟脲嘧啶、卡培他賓(capecitabine)、6-硫醇嘌呤、胺甲喋呤、吉西他濱(gemcitabine)、阿糖胞苷(cytarabine)、夫達拉濱(fludarabine)或培美曲塞(pemetrexed));
d) 抗腫瘤抗生素(例如道諾微素、阿黴素、表柔比星(epirubicin)、依達比星(idarubicin)、放線菌素-D、博萊微素(bleomycin)、絲裂黴素-C或米托蒽醌(mitoxantrone));
e) 有絲分裂抑制劑(例如紫杉醇、多西他塞(docetaxel)、伊沙匹隆(ixabepilone)、長春花鹼、長春新鹼、長春瑞濱(vinorelbine)、長春地辛或雌莫斯汀(estramustine));或
f) 拓樸異構酶抑制劑(例如依託泊苷(etoposide)、替尼泊苷(teniposide)、拓樸替康(topotecan)、伊立替康(irinotecan)、二氟替康(diflomotecan)或伊洛替康(elomotecan))。
當與實施例1)至14)中任一者定義之化合物的結晶型結合使用時,較佳細胞毒性化學治療劑係上述烷化劑(尤其二氯甲二乙胺、氯芥苯丁酸、環磷醯胺、依弗醯胺、鏈脲黴素、卡氮芥、洛莫斯汀、米爾法蘭、白消安、達卡巴嗪、3-甲基-(三氮烯-1-基)咪唑-4-羧醯胺(MTIC)及其前體藥,諸如尤其替莫唑胺、噻替派(thiotepa)、六甲蜜胺;或此等化合物之醫藥學上可接受之鹽;尤其替莫唑胺);及有絲分裂抑制劑(尤其紫杉醇、多西他塞、伊沙匹隆、長春花鹼、長春新鹼、長春瑞濱、長春地辛、雌莫斯汀;或此等化合物之醫藥學上可接受之鹽;尤其紫杉醇)。與式(I)化合物結合使用之最佳細胞毒性化學治療劑係常規用於治療多形性神經膠質母細胞瘤之彼等物,尤其替莫唑胺。放射療法同樣較佳。
化學療法可在治癒意圖下給與或其可旨在延長生命或減輕症狀。
a) 組合形式化學療法係使用藥物與其他癌症治療法,諸如放射線療法或手術。
b) 誘導化學療法係使用化學治療藥物之第一線癌症治療。此類型化學療法用於治癒意圖。
c) 鞏固化學療法在緩解後給與,以延長整體無疾病時間且提高整體存活。投與之藥物與實現緩解之藥物相同。
d) 加強化學療法與鞏固化學療法一致,但使用與誘導化學療法不同之藥物。
e) 組合化學療法涉及同時用許多不同藥物治療患者。該等藥物之機制及副作用不同。最大優點係對任一藥劑形成抗性之機率降至最低。此外,藥物可常以較低劑量使用,降低毒性。
f) 新輔助化學療法在諸如手術之局部治療前給與,且經設計以縮小原發性腫瘤。其亦給與具有高風險微轉移疾病之癌症。
g) 輔助化學療法在局部治療(放射療法或手術)後給與。其可在幾乎無癌症存在之證據但存在復發風險時使用。其亦可用於殺死已擴散至其他身體部分之任何癌細胞。此等微轉移瘤可用輔助化學療法治療且可降低由此等散播性細胞引起之復發速率。
h) 維持化學療法係重複低劑量治療以延長緩解。
i) 補救性化學療法或緩解性化學療法在無治癒意圖下給與,但僅降低腫瘤負荷及增加預期壽命。對於此等方案,一般預期更佳毒性型態。
當與實施例1)至14)中任一者定義之化合物的結晶型結合使用時,諸如上文a)、b)、c)、d)、e)及尤其g)及/或h)處所列之彼等化學療法的預防性或治癒性形式(或準用:放射療法)係較佳的。
在提及投與類型時,「同時」在本申請案中意謂相關投與類型在於在大致相同時間投與兩種或更多種活性成分及/或治療;其中應瞭解,同時投與將使受試者同時暴露於兩種或更多種活性成分及/或治療。在同時投與時,該兩種或更多種活性成分可以固定劑量組合投與,或以相當非固定劑量組合(例如,藉由在大致相同時間使用以相同投與途徑投與之兩種或更多種不同醫藥組合物)投與或藉由使用兩種或更多種不同投與途徑之非固定劑量組合投與;其中該投與使受試者基本上同時曝露於兩種或更多種活性成分及/或治療。
當提及投藥類型時,「固定劑量組合」在本申請案中意謂相關投藥類型在於投與包含兩種或更多種活性成分之一種單一醫藥組合物。
當提及投與類型時,「分開」在本申請案中意謂相關投與類型在於在不同時間點投與兩種或更多種活性成分及/或治療;其中應理解,分開投與將產生受試者同時曝露於兩種或更多種活性成分及/或治療之治療階段(例如,至少1小時,尤其至少6小時,尤其至少12小時);其中該「分開投與」可在某些情況下亦涵蓋受試者曝露於兩種或更多種活性成分及/或治療之僅一者下持續特定時間段(例如,至少12小時,尤其至少一日)之治療階段。因此,分開投與尤其指代其中一種活性成分及/或治療例如一日一次地給予,且另一者例如一日兩次、一日三次、每隔一日地給予之情況,其中該投與類型之結果在於,在基本上整個治療時段期間,受試者同時曝露於兩種或更多種活性成分及/或治療。分開投與亦指代以下情況:其中以基本上長於一日(諸如每日一次或兩次)投與(例如其中例如一日一次或兩次地給予一種活性成分及/或治療,且一週一次地給予另一者)之頻率給予活性成分及/或治療之至少一者。舉例而言,當與放射療法組合使用時(例如一週或兩週),本發明如實施例1)至14)中任一者定義之化合物的結晶型將可能「分開」使用。
「在一段時間內」投與在本申請案中意謂在不同時間相繼投與兩種或更多種活性成分及/或治療。該術語尤其係指其中活性成分及/或治療之一者的整個投與在另一/其他活性成分及/或治療之投與開始前完成的投與方法。以此方式,可投與活性成分及/或治療之一者達若干個月,接著投與其他活性成分及/或治療。
「在一段時間內」投與亦涵蓋其中如實施例1)至14)中任一者定義之化合物的結晶型將用於初始化學治療或放射治療或標靶療法(例如引導性化療)結束後方開始之治療的情況,其中該治療視情況將與進一步/進行性化學治療或放射治療或標靶治療組合(例如,與鞏固化學療法、加強化學療法、輔助化學療法或維護化學療法組合;或與其放射療法等效療法組合);其中該進一步/進行性化學治療或放射治療或標靶療法將與使用如實施例1)至14)中任一者定義之化合物的結晶型之治療同時或分開進行。
自體免疫病症可定義為包含(發炎性)髓鞘脫失疾病;多發性硬化症(MS);格巴二氏症候群;風濕性關節炎(RA);發炎性腸病(IBD,尤其包含克羅恩氏病及潰瘍性結腸炎);全身性紅斑狼瘡(SLE);狼瘡性腎炎;間質性膀胱炎;乳糜瀉;自體免疫腦脊髓炎;骨關節炎;及I型糖尿病。此外,自體免疫疾病進一步包含諸如以下之病症:牛皮癬;牛皮癬關節炎;抗磷脂質症候群;甲狀腺炎,諸如橋本氏甲狀腺炎(Hashimoto's thyroiditis);淋巴球性甲狀腺炎;重症肌無力症;眼色素層炎;上鞏膜炎;鞏膜炎;川崎氏病;葡萄膜視網膜炎;後段葡萄膜炎;與貝切特氏病相關之眼色素層炎;眼色素膜腦膜炎症候群;過敏性腦脊髓炎;特異性疾病,諸如鼻炎、結膜炎、皮膚炎;及感染後字體免疫疾病,包括風濕性發熱及感染後腎小球性腎炎。在子實施例中,自體免疫病症尤其指代具有發炎性部位之自體免疫病症,其中特定實例係(發炎性)髓鞘脫失疾病、多發性硬化症(MS)、格巴二氏症候群、風濕性關節炎(RA)、發炎性腸病(IBD,尤其包含克羅恩氏病及潰瘍性結腸炎)、全身性紅斑狼瘡(SLE)、狼瘡性腎炎及自體免疫腦脊髓炎。
發炎性疾病可定義為尤其包含慢性鼻炎以及氣喘、慢性阻塞性肺病(COPD)、動脈粥狀硬化、心肌炎、乾眼病、類肉瘤病、發炎性疾病及急性肺損傷。
移植排斥可定義為包含移植器官之排斥,諸如腎、肝、心、肺、胰、角膜及皮膚;由造血幹細胞移植導致的移植物抗宿主疾病;慢性同種異體移植物排斥及慢性同種異體移植物血管病變。
纖維化可定義為尤其包含肝纖維化、肝硬化、肺纖維化、自發性肺纖維化、腎纖維化、心肌內膜纖維化及關節纖維化。
如實施例1)至14)中任一者定義之化合物的結晶型亦適用於防治或治療腫瘤之方法,其包含投與有效量之該結晶型,其中該有效量使腫瘤特性改變,且其中該改變係藉由調整CXCL11/CXCL12受體路徑實現;其中該防治或治療可視情況與習知化學治療或放射治療結合進行(在該情況下,腫瘤尤其係惡性神經膠瘤,尤其多形性神經膠質母細胞瘤)。該組合治療可同時、分開及/或在一段時間內進行。
如實施例1)至14)中任一者定義之化合物的結晶型亦適用於改變免疫反應之方法,其包含投與有效量之該結晶型,其中該有效量改變發炎性疾病,且其中該反應係藉由CXCL11/CXCL12受體路徑調整。
本發明亦關於用於製備呈對映異構性增濃形式之化合物的方法,且關於用於製備且表示實施例1)至14)中任一者之化合物的結晶型之特徵的方法。該等方法描述於下文實驗部分之程序中。
實驗程序:
所有溫度係以℃陳述。以不進一步純化之接收狀態使用商購之初始材料。除非另外指明,否則所有反應均在氮氣或氬氣之氛圍下於烘乾玻璃器皿中進行。化合物藉由矽膠急驟管柱層析法或藉由製備型HPLC純化。本發明中所述化合物之特徵係藉由LC-MS資料(滯留時間tR
以分鐘給出;獲自質譜之分子量以g/mol給出)表示,其使用下文所列條件。在本發明化合物呈現為構形異構體之混合物的情況下,尤其在其LC-MS譜中可見,給出最大量構像之滯留時間。
NMR頻譜學
Bruker Avance II光譜儀配備有400 MHz (1
H) Ultrashield™磁鐵及BBO 5mm探頭或PAXTI 1mm探頭,或Bruker Avance III HD Ascend 500 MHz (1
H),配備有DCH冷凍探針之磁鐵。相對於由NMR溶劑之不完全氘化產生之質子共振,化學位移(δ)係以百萬分之一(ppm)報導,例如,二甲亞碸δ(H) 2.49 ppm,氯仿δ(H) 7.24 ppm。縮寫s
、d
、t
、q
及m
分別指代單峰、雙峰、三峰、四峰、多峰且br
指代寬峰。偶合常數J
係以Hz報導。
質量控制(QC)分析性LC-MS:裝置及條件:
泵:Waters Acquity Binary, Solvent Manager,MS:Waters SQ Detector,DAD:Acquity UPLC PDA Detector,ELSD:Acquity UPLC ELSD。管柱:來自Waters之Acquity UPLC CSH C18 1.7 µm 2.1×50 mm或Acquity UPLC HSS T3 C18 1.8 µm 2.1×50 mm,在60℃下於Acquity UPLC Column Manager中保持恆溫。溶離劑:A1: H2O + 0.05% FA;B1: AcCN + 0.045% FA。方法:梯度:在2.0分鐘內,2% B 98% B。流速:1.0 mL/min。偵測:UV 214nm及ELSD,及MS,tR係以分鐘給出。
分析性LC-MS裝置:
二元梯度泵Agilent G4220A或與質譜分析偵測(單一四極質量分析器,Thermo Finnigan MSQPlus或等效裝置)相當。條件:
方法 A ( 酸性條件 )
:管柱:Zorbax SB-aq (3.5 μm,4.6 × 50 mm);條件:MeCN [溶離劑A];水 + 0.04% TFA [溶離劑B];梯度:在1.5分鐘內,95% B ® 5% B (流速:4.5毫升/分鐘)。偵測:UV/Vis + MS。
製備型LC-MS裝置:
二元梯度泵Gilson 333/334或與質譜分析偵測(單一四極質量分析器,Thermo Finnigan MSQPlus或等效裝置)相當。條件:
方法 B ( 鹼性條件 )
:管柱:Waters XBridge C18 (10 μm,30 × 75 mm);條件:MeCN [溶離劑A];水 + 0.5% NH4
OH (25% aq.) [溶離劑B];梯度:在6.5分鐘內,95% B ® 5% B (流速:75毫升/分鐘)。偵測:UV/Vis + MS。對掌性分析性層析法 裝置:
HPLC
:具有Dionex DAD-3000 UV偵測器之Dionex HPG-3200SD泵。
SFC
:CO2
供應:Aurora Fusion A5 Evolution;泵:Agilent G4302A;UV偵測器:Agilent G1315C。條件:
HPLC
:管柱:ChiralPak AY-H,5 mm,250×4.6 mm或Regis (R,R) Whelk-O1 250×4.6mm,5µm;溶離劑:A:Hept,0.05% DEA,B:乙醇,0.05% DEA,流速0.8至1.2毫升/分鐘。
SFC
管柱:Regis (R,R) Whelk-O1,4.6×250 mm,5µM;溶離劑:A:60% CO2
,B:40% DCM/EtOH/DEA 50:50:0.1對掌性製備型層析法 裝置:
HPLC :具有
Dionex DAD-3000 UV偵測器之2 Varian SD1泵。
SFC
:CO2
供應:Maximator DLE15-GG-C;泵:2 SSI HF CP 300;UV偵測器:Dionex DAD-3000。條件:
HPLC
:管柱:ChiralPak IA、IB、IC、IE或IF,5 mm,20×250 mm或Regis (R,R) Whelk-O1,21.1×250mm,5µm;溶離劑:A (0%至90% Hept)與B (10%至100% EtOH,0.1% DEA)之合適混合物,流速:16、23或34毫升/分鐘之合適流速。
SFC
:管柱:Regis (R,R) Whelk-O1,30×250 mm,5µm或ChiralPak IC,30×250 mm,5µm;溶離劑A (60%至80% CO2
)與B (30%至40%之DCM/EtOH/DEA 50:50:0.1)之合適混合物,流速160毫升/分鐘。X 射線粉末繞射 (XRPD) 分析 XRPD 方法 1 :
以反射模式(成對2θ/θ)在配備有用CuKα-輻射操作之Lynxeye偵測器的Bruker D8 Advance X射線繞射儀上收集X射線粉末繞射圖案。通常,以40kV/40mA運行X射線管。在呈2θ之3 - 50°掃描範圍內,運用0.02° (2θ)之步長及76.8秒之步時間。發散狹縫固定設為0.3。將粉末微微按入具有0.5 mm深度之矽單晶樣本夾持器中,且在量測期間,樣本在其自身平面上旋轉。使用Cu Kα1與Kα2組合輻射報導繞射資料,無Kα2剝離。如習知記錄之X射線粉末繞射圖案之一般情況,如本文提供之2θ值的準確度係在+/- 0.1-0.2°範圍內。XRPD 方法 2 :
以反射模式在配備有自動XYZ階段、用於自動樣本放置之雷射視訊顯微鏡及用CuKα-輻射操作之Vantec-500偵測器的Bruker D8 GADDS-HTS繞射儀上收集X射線粉末繞射圖案。通常,以40 kV/40 mA運行X射線管。X射線光學由與0.5 mm針孔準直儀耦聯之單個Göbel多層鏡組成。通常,單一框架係在180秒內記錄,其使用4°處之θ1及16°處之θ2的測角器位置及20 cm之偵測器距離。框架整合於5-35° 2θ範圍內。在不研磨的情況下按原樣使用粉末以平板樣品形式製備在環境條件下操作之樣本。將大約5-10 mg樣本輕按於玻璃片上以獲得平滑表面。在量測時間內不移動樣本。使用Cu Kα1與Kα2組合輻射報導繞射資料,無Kα2剝離。如習知記錄之X射線粉末繞射圖案之一般情況,如本文提供之2θ值的準確度係在+/- 0.1-0.2°範圍內。重力蒸氣吸附 (GVS) 分析
在25℃下以步進模式操作之多樣本儀器SPS-100n (Projekt Messtechnik, Ulm, 德國)上進行量測。允許樣本在40% RH下平衡,隨後開始預定義之濕度程序(應用40-0-95-0-95-40% RH,5%ΔRH之步進及每步24小時最大平衡時間)。使用約20至30 mg之各樣本。根據歐洲藥典技術指南(European Pharmacopeia Technical Guide,1999,第86頁)進行吸濕性分類,例如,輕微吸濕性:質量增加小於2%且等於或大於0.2% 質量/質量;吸濕性:質量增加小於15%且等於或大於2% 質量/質量。考慮首先吸附掃描中之40%相對濕度與80%相對濕度之間質量變化。示差掃描熱量測定法
在具有34位置自動取樣器之Mettler Toledo STARe System (DSC822e模組,具有陶瓷感測器之量測單元及STAR軟體9.20版)上收集DSC資料。使用經鑑定之銦校準儀器之能量及溫度。除非另外陳述,否則通常在自動穿孔鋁盤上將1-5 mg之各樣本以10℃ min-1
自20℃加熱至280℃。在樣本上以20 mL min-1
維持氮氣吹掃。峰值溫度以熔點報導。熱重力分析 (TGA)
在具有34位置自動取樣器之Mettler Toledo STARe System (TGA851e模組及STAR軟體9.20版)上收集TGA資料。除非另外陳述,否則通常在自動穿孔鋁盤上約5 mg之各樣本以10℃ min-1
自30℃加熱至250℃。在樣本上以10 mL min-1
維持氮氣吹掃。峰值溫度以熔點報導。縮寫 ( 如上文或下文中使用 ) :
aq. 水性
Boc 丁氧基羰基
d 日
DCM 二氯甲烷
DEA 二乙胺
DIPEA 二異丙基-乙基胺,Hünig's鹼,乙基-二異丙基胺
DMF 二甲基甲醯胺
DMSO 二甲亞碸
Et 乙基
EtOAc 乙酸乙酯
EtOH 乙醇
FC 急驟層析
h 小時
HATU 六氟磷酸2-(7-氮雜-1H-苯并三唑-1-基)-1,1,3,3-四 甲基鎓
Hept 庚烷
HPLC 高效液態層析
HV 高度真空條件
LC-MS 液態層析-質譜分析法
Me 甲基
MeCN 乙腈
MeOH 甲烷
mL 毫升
min 分鐘
Nr 數目
Ph 苯基
prep. 製備型
rpm 轉數/分鐘
RT 室溫
s 秒
sat. 飽和的
SFC 超臨界液態層析
tBu 第三丁基
TEA 三乙胺
TFA 三氟乙酸
THF 四氫呋喃
T3
P 丙基磷酸酐
tR
滯留時間參考實例 1 : (3S,4S)-1- 環丙基甲基 -4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -3- 羧酸 (1- 嘧啶 -2- 基 - 環丙基 )- 醯胺 4-((S)-1- 苯基 - 乙基胺基 )-5,6- 二氫 -2H- 吡啶 -1,3- 二羧酸 1- 第三丁酯 3- 乙酯
在配備有Dean-Stark分離器及回流冷凝器之乾燥燒瓶中,將4-側氧基哌啶-1,3-二羧酸-1-第三丁酯3-乙酯(10 g,37 mmol)溶解於甲苯(150 mL)中。添加(S)-(-)-α-甲基苄胺(6.71 g,55.4 mmol)及單水合對二甲苯磺酸 (0.36 g,1.85 mmol)且將混合物加熱至回流持續3小時。隨後將混合物冷卻至RT,使用飽和NaHCO3
水溶液(3 × 100 mL)洗滌三次,且在MgSO4
上乾燥,過濾且在減壓下濃縮以產生如黃色厚油之產物。LC-MS方法A:tR
= 1.01分鐘;[M+H]+
= 375.18 .1
H NMR (400 MHz, CDCl3
)δ
: 9.28 (d,J
= 7.4 Hz, 1 H), 7.25-7.38 (m, 5 H), 4.63 (m,
1 H), 4.19 (q,J
= 7 Hz, 2 H), 4.07 (s, 2 H) 3.46-3.38 (m, 1 H) 3.33-3.26 (m, 1 H), 2.43-35 (m, 1 H), 2.09-1.99 (m, 1 H), 1.50 (d,J
= 7.4 Hz, 3 H), 1.43 (s, 9 H) , 1.29 (t, J = 7.0 Hz, 3 H)。(3R,4S)-4-((S)-1- 苯基 - 乙基胺基 )- 哌啶 -1,3- 二羧酸 1- 第三丁酯 3- 乙酯
在-15下於N2
下將氫硼化鈉(1.43 g,37.85 mmol)溶解於THF (100 mL)中。在20分鐘內逐滴添加TFA (10.7 mL,0.14 mmol)。在-14至-18℃下於10分鐘內添加4-((S)-1-苯基-乙基胺基)-5,6-二氫-2H-吡啶-1,3-二羧酸1-第三丁酯3-乙酯(10.5 g,28 mmol)。在0℃下攪拌所得混合物持續60分鐘。仔細添加冰水(100 mL)且在RT下攪拌反應混合物持續10分鐘。添加3 M aq. NaOH溶液以使混合物達至pH 11。用DCM (2 × 100 mL)提取反應混合物,用鹵水(2 × 100 mL)洗滌組合之有機層,在MgSO4
上乾燥,且在減壓下蒸發溶劑。使用庚烷/EtOAc系統(1:0至4:1)作為溶離劑在120 g矽膠上藉由FC純化所得油以獲得呈微黃油(9.5 g)之標題產物。標題化合物係由~10 %之對應(3S,4R)-異構體污染。LC-MS方法A:tR
= 0.71分鐘;[M+H]+
= 377.33.1
H NMR (400 MHz, CDCl3
)δ
: 7.31-7.41 (m, 5 H), 4.14-4.27 (m, 3 H), 4.02 (q,J
= 6.6 Hz, 1 H), 3.74-3.85 (m, 3 H), 3.00-3.10 (m, 2 H), 2.89-2.94 (m, 2 H), 1.88 (m, 1 H), 1.60-1.65 (m, 1 H), 1.42-1.46 (m, 11 H), 1.28-1.38 (m, 3 H)。(3R,4S)-4- 胺基 - 哌啶 -1,3- 二羧酸 1- 第三丁酯 3- 乙酯
在H2
下於活性炭(1 g)上將(3R,4S)-4-((S)-1-苯基-乙基胺基)-哌啶-1,3-二羧酸1-第三丁酯3-乙酯(9.6 g,25.5 mmol)於MeOH (250 mL)中之溶液添加至Pd(OH)2
20%懸浮液中。在RT下攪拌混合物持續18小時。使懸浮液濾過Celite,且在真空下濃縮過濾物以獲得呈微黃油(5.65 g)之標題產物。標題化合物含有~10 %之對應(3S,4R)-異構體。LC-MS方法A:tR
= 0.54分鐘;[M+H]+
= 273.26.1
H NMR (400 MHz, CDCl3
)δ
: 4.56-4.65 (m, 1 H), 4.40-4.65 (m, 2 H), 4.04-4.30 (m, 3 H), 3.59-3.72 (m, 1 H), 3.01-3.21 (m, 2 H), 2.51-2.68 (m, 2 H), 1.98-2.11 (m, 1 H), 1.73-1.77 (m, 1 H), 1.46 (m, 8 H), 1.26-1.39 (m, 3 H)。(3R,4S)-4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -1,3- 二羧酸 1- 第三丁酯 3- 乙酯
在RT下,向(3R,4S)-4-胺基-哌啶-1,3-二羧酸1-第三丁酯3-乙酯(12.15 g,27.2 mmol)於DCM (200 mL)中之溶液添加5-(2,4-二氟苯基)異㗁唑-3-羧酸(6.1 g,26.3 mmol)。隨後,添加TEA (15.2 mL,109 mmol),隨後係T3P 50%於DCM中(32.4 mL,54.4 mmol)。在RT下攪拌反應混合物持續24小時。用飽和NaHCO3
水溶液(2 × 100 mL)洗滌反應混合物兩次。在MgSO4
上乾燥有機層且進行蒸發。使用庚烷/EtOAc系統(1:0至85:15)作為溶離劑在100 g矽膠上藉由FC純化粗製殘餘物以獲得呈白色粉末之標題化合物(10.25 g);標題化合物含有~10%之對應(3S,4R)-異構體;LC-MS方法A:tR
= 1.15分鐘;[M+H]+
= 480.1.1
H NMR (400 MHz, CDCl3
)δ
: 7.96-8.00 (m, 1 H), 7.81-7.89 (m, 1 H), 6.98-7.13 (m, 2 H), 4.54-4.62 (m, 1 H), 4.42-4.52 (m, 1 H), 3.97-4.28 (m, 2 H), 3.14-3.21 (m, 1 H), 2.88-3.08 (m, 2 H), 2.03-2.18 (m, 1 H), 1.78-1.87 (m, 1 H), 1.58 (s, 2 H), 1.48-1.52 (m, 9 H), 1.28-1.37 (m, 3 H)。(3S,4S)-4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -1,3- 二羧酸 1- 第三丁酯 3- 乙酯
將乙醇鈉(3.225 g,45 mmol)添加至(3R,4S)-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-1,3-二羧酸1-第三丁酯3-乙酯(3.6 g,7.5 mmol)於EtOH (40 mL)與EtOAc (20 mL)之混合物中的溶液中。在RT下攪拌混合物1日。用飽和NH4
Cl水溶液(25 mL)處理反應混合物。添加DCM (50 mL)。分離有機相,且用DCM提取三次aq.層(3 × 50 mL)。在MgSO4
上乾燥組合之有機層,過濾且濃縮。使用鹼性條件(方法B)藉由製備型LC-MS純化粗製殘餘物。獲得呈無色粉末之標題化合物(1.91 g),其含有~10 %之對應(3S,4R)-異構體。
藉由含有~10% (3R,4R)-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-1,3-二羧酸1-第三丁酯3-乙酯之(3S,4S)-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-1,3-二羧酸1-第三丁酯3-乙酯的混合物之對掌性製備性獲得對映異構性純標題化合物,其使用管柱ChiralPak IC,5 mm,30×250 mm;使用A (80%CO2
)與B (50% DCM,20% MeOH,0.1% DEA)之混合物作為溶離劑,及160毫升/分鐘之流速。對掌性HPLC:tR
= 3.29分鐘。LC-MS方法A: tR
= 1.06分鐘;[M+H]+
= 480.08.1
H NMR (400 MHz, CDCl3
)δ
: 8.90-8.94 (m, 1 H), 8.04-8.10 (m, 1 H), 7.57-7.62 (m, 1 H), 7.31-7.38 (m, 1 H), 7.11-7.16 (m, 1 H), 4.23-4.32 (m, 1 H), 4.05-4.13 (m, 1 H), 4.03 (q,J
= 7.1 Hz, 2 H), 3.92-3.97 (m, 1 H), 2.80-3.06 (m, 2 H), 2.61-2.69 (m, 1 H), 1.77-1.81 (m, 1 H), 1.48-1.58 (m, 1 H), 1.40-1.46 (m, 9 H), 1.08 (t,J
= 7.1 Hz, 3 H)。(3S,4S)-4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -1,3- 二羧酸 1- 第三丁酯
將(3S,4S)-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-1,3-二羧酸1-第三丁酯3-乙酯(4.98 g,10.7 mmol)溶解於THF (80 mL)中。隨後,添加aq. 1M NaOH溶液(20 mL,20 mmol),且在RT下攪拌混合物3小時。使用2M aq. HCl溶液(10 mL)使反應混合物酸化至約pH = 3,且使用DCM提取三次(3 × 50 mL)。在MgSO4
上乾燥組合之有機相,過濾且濃縮。獲得呈白色粉末之標題化合物(4.56 g);LC-MS方法A tR
= 0.99分鐘;[M+H]+
= 452.33.1
H NMR (400 MHz, DMSO-d6)δ
: 12.51 (s, 1 H), 8.90 (d,J
= 8.8 Hz, 1 H), 8.07 (td,J 1
= 8.6 Hz,J 2
= 6.4 Hz, 1 H), 7.60 (m, 1 H), 7.34 (td,J 1
= 8.5 Hz,J 2
= 2.2 Hz, 1 H), 7.15 (d,J
= 2.9 Hz, 1 H), 4.26 (m, 1 H), 4.04-4.17 (m, 1 H), 3.92-3.95 (m, 1 H), 2.79-3.01 (m, 2 H), 2.60 (td,J 1
= 11.0 Hz,J 2
= 4.0 Hz, 1 H), 1.75-1.82 (m, 1 H), 1.36-1.54 (m, 10 H)。(3S,4S)-4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }-3-(1- 嘧啶 -2- 基 - 環丙基胺甲醯基 )- 哌啶 -1- 羧酸第三丁酯
向(3S,4S)-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-1,3-二羧酸1-第三丁酯(400 mg,0.88 mmol)於DMF (15 mL)中之溶液中添加鹽酸1-(嘧啶-2-基)環丙-1-胺(171 mg,0.975 mmol)、DIPEA (0.805 mL,4.61 mmol)及HATU (404 mg, 1.06 mmol)。在RT下攪拌反應混合物4小時。蒸發揮發物,且使用鹼性條件(方法B)藉由製備型LC-MS純化粗製混合物以產生標題化合物(419 mg);LC-MS方法A tR
=0.95分鐘;[M+H]+
= 568.97。1
H NMR (500 MHz, DMSO-d6)δ
: 8.62 (d,J
= 8.6 Hz, 1 H), 8.53 (d,J
= 4.8 Hz, 3 H), 8.08 (d,J
= 6.4 Hz, 1 H), 7.34 (d,J
= 2.4 Hz, 1 H), 7.19-7.21 (m, 1 H), 7.17 (d,J
= 3.0 Hz, 1 H), 3.92-4.1 (m, 2 H) 3.63 (m, 1 H), 3.35-3.45 (m, 1 H), 3.15-3.26 (m, 2 H), 2.75-2.92 (m, 1H), 1.42-154 (m, 4 H), 1.22-1.44 (m, 11 H)。鹽酸 (3S,4S)-4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -3- 羧酸 (1- 嘧啶 -2- 基 - 環丙基 )- 醯胺
將(3S,4S)-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-3-(1-嘧啶-2-基-環丙基胺甲醯基)-哌啶-1-羧酸第三丁酯(419 mg,0.74 mmol)溶解於二㗁烷(10 mL)中。逐滴添加於二㗁烷中之HCl 4M (5 mL,20 mmol)中。在RT下攪拌混合物1小時。蒸發溶劑,且在HV上乾燥殘餘物以獲得呈白色粉末之標題粗製化合物(365 mg)。LC-MS方法A: tR
= 0.64分鐘;[M+H]+
= 469.17。1
H NMR (400 MHz, DMSO-d6)δ
: 9.38-9.41 (m, 1 H), 9.27-9.29 (m, 1 H), 9.00 (d,J
= 8.5 Hz, 1 H), 8.93 (s, 1 H), 8.57 (d,J
= 4.8 Hz, 2 H), 8.06 (q,J
= 7.8 Hz, 1 H), 7.59 (t,J
= 10.5 Hz, 1 H), 7.31-7.39 (m, 2 H), 7.25 (t,J
= 4.8 Hz, 1 H), 4.27 (d,J
= 9.8 Hz, 1 H), 3.34 (m, 2 H), 3.07-3.20 (m, 3 H), 2.03 (m, 1 H), 1.86-1.89 (m, 1 H), 1.51 (m, 1 H), 1.37-1.41 (m, 1 H), 1.03-1.11 (m, 2 H)。(3S,4S)-1- 環丙基甲基 -4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -3- 羧酸 (1- 嘧啶 -2- 基 - 環丙基 )- 醯胺
在RT下向鹽酸(3S,4S)-4-{[5-(2,4-二氟-苯基)-異㗁唑-3-羰基]-胺基}-哌啶-3-羧酸甲酯(200 mg,0.396 mmol)於DCM (20 mL)中之懸浮液中添加環丙烷甲醛(0.03 mL,0.396 mmol),隨後添加DIPEA (0.2 mL,1.2 mmol)及三乙醯氧基硼氫化鈉(221 mg,1 mmol)。在RT下攪拌反應混合物2小時。用飽和NaHCO3
水溶液處理反應混合物兩次(50 mL)。在MgSO4
上乾燥有機相且蒸發。在鹼性條件下(方法B)藉由製備型LC-MS純化粗製殘餘物以產生呈無色固體之標題化合物(148 mg);對掌性HPLC: tR
= 2.42分鐘;LC-MS方法A: tR
= 0.69 分鐘;[M+H]+
= 523.04。1
H NMR (400 MHz, DMSO-d6)δ
: 8.57 (d,J
= 8.4 Hz, 1 H), 8.51 (d,J
= 4.7 Hz, 2 H), 8.47 (s, 1 H), 8.08 (dd,J 1
= 8.2 Hz,J 2
= 15.7 Hz, 1 H), 7.59 (t,J
= 9.8 Hz, 1 H), 7.34 (t,J
= 8.3 Hz, 1 H), 7.12-7.23 (m, 2 H), 3.95-4.06 (m, 1 H), 3.14 (d,J
= 10.0 Hz, 1 H), 2.99 (d,J
= 10.3 Hz, 1 H), 2.72 (t,J
= 9.3 Hz, 1 H), 2.18-2.27 (m, 2 H), 2.12 (t,J
= 11.4 Hz, 1 H), 2.01 (t,J
= 11.5 Hz, 1 H), 1.85 (d,J
= 11.0 Hz. 1 H), 1.54-1.66 (m, 1 H), 1.45-1.51 (m, 1 H), 1.31-1.41 (m, 1 H), 1.04-1.16 (m, 2 H), 0.79-0.90 (m, 1 H), 0.49 (d,J
= 7.6 Hz, 2 H), 0.10 (d,J
= 4.1 Hz, 2 H)。II. 生物分析 活體外分析
根據以下實驗方法確定化合物對CXCR7受體之拮抗作用。
該分析使用來自invitrogen之Tango CXCR7-bla
U2OS細胞株。此等細胞含有與TEV蛋白酶位點連接之人類趨化介素受體CXCR7,及穩定整合於Tango GPCR-bla
U2OS親本細胞株中之Gal4-VP16轉錄因子。在UAS反應元之控制下,此親本細胞株穩定表現β抑制蛋白/TEV蛋白酶融合蛋白及β內醯胺酶報導基因。在配體結合及受體活化時,將蛋白酶標記β抑制蛋白分子召集至藉由蛋白酶分裂位點在C端連接至轉錄因子之CXCR7。蛋白酶使轉錄因子自CXCR7分離,其移位至細胞核且激活β內醯胺酶之表現。FRET啟用之基質允許偵測β內醯胺酶表現。
使用0.05%胰朊酶-EDTA使Tango CXCR7-bla
U2OS細胞自培養皿分離且在生長介質(McCoy's 5A 90% (v/v)、滲出之FCS 10% (v/v)、0.1mM NEAA、25mM HEPES (pH 7.3)、1 mM丙酮酸鈉、P/S 1% (v/v) 50 μg/mL潮黴素、100 μg/mL遺傳黴素、200 μg/mL博萊黴素)中收集,減速旋轉且再懸浮於介質(McCoy's 5A 90% (v/v)、滲出之FCS 1% (v/v)、0.1 mM NEAA、25 mM HEPES (pH 7.3)、P/S 1% (v/v))中。將10'000個細胞/孔(30 μL)接種於384孔盤中(黑色內壁,透明底部)。再37℃/5% CO2
下培養該盤24小時。將測試化合物溶解為10 mM於DMSO中,且連續稀釋於DMSO中達至劑量反應曲線之最終濃度的500×。隨後,以1:100將化合物稀釋於分析介質中,達至最終濃度之5×。將10微升/孔之稀釋化合物添加至分析盤中,且在37℃下培養15分鐘。其後,將CXCL12/SDF1-α稀釋於分析介質中,達至最終濃度之5× (其受體活化之EC80值),且將10微升/孔添加至分析盤中。促效劑使受體活化,且因此使β抑制蛋白召集。用作拮抗劑之化合物削弱此活化。在37℃下培養該盤22小時。將10微升/孔之偵測試劑(LiveBLAzerTM
-FRET B/G (CCF4-AM)基質)轉移至分析盤,且在室溫下避光培養該盤2小時。測定螢光計數(掃描1: Ex 409/20 nm,Em 460/30 nm,掃描2:Ex 409/20 nm,Em 530/30 nm)。計算之發射比係用於IC50
測定。所計算之IC50
值可視日常細胞分析效能而變動。此類變動為熟習此項技術者已知。來自若干量測之平均IC50
值給定為幾何平均值。在此分析中,測試參考實例1之化合物以具有3 nM之IC50
。III. 實例 實例 1 : 呈結晶型 1 之 (3S,4S)-1- 環丙基甲基 -4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -3- 羧酸 (1- 嘧啶 -2- 基 - 環丙基 )- 醯胺
在標準HPLC瓶中,將1 mL MeOH添加至10 mg化合物(例如,如獲自參考實例1)中,藉由以0.1℃/分鐘之勻速升溫加熱至65℃溶解懸浮液,同時使用Crystal 16器件(Crystallization Systems, NL)以500 rpm使用磁棒攪拌。隨後,以0.1℃/分鐘之勻速降溫使溶液冷卻至20℃。所獲固體係呈結晶型1之化合物。
或者,在標準HPLC瓶中,將1mL MeOH/MeCN 3/1添加至20 mg化合物(例如,如獲自參考實例1)中,藉由以0.1℃/分鐘之勻速升溫加熱至65℃溶解懸浮液,同時使用Crystal 16器件(Crystallization Systems, NL)以500 rpm使用磁棒攪拌。隨後,以0.1℃/分鐘之勻速降溫使溶液冷卻至20℃。所獲固體係呈結晶型1之化合物。 實例 2 : 呈結晶型 2 之 (3S,4S)-1- 環丙基甲基 -4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -3- 羧酸 (1- 嘧啶 -2- 基 - 環丙基 )- 醯胺
將呈形式1之100 mg化合物懸浮於1 mL DCM中,且在室溫下用置於4 mL玻璃瓶中之磁性攪拌棒輕柔攪拌。1週後,分離固體,且固體係呈結晶型2之化合物。
或者,在標準HPLC瓶中,將1mL MeOH/MeCN 3/1添加至10 mg化合物(例如,如獲自參考實例1)中,藉由以0.1℃/分鐘之勻速升溫加熱至40℃溶解懸浮液,同時使用Crystal 16器件(Crystallization Systems, NL)以500 rpm使用磁棒攪拌。隨後,以0.1℃/分鐘之勻速降溫使溶液冷卻至20℃。所獲固體係呈結晶型2之化合物。 實例 3 : 呈結晶型 3 之 (3S,4S)-1- 環丙基甲基 -4-{[5-(2,4- 二氟 - 苯基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -3- 羧酸 (1- 嘧啶 -2- 基 - 環丙基 )- 醯胺
在4 mL玻璃瓶中,將50mg呈形式2之化合物懸浮於0.4 mL水中,且在振盪器上於室溫下輕柔搖晃。1日後,當以濕狀態量測時,所獲固體係呈結晶型3之化合物。結晶型3係二水合物。 實例 4 : 呈結晶型 4 之 (3S,4S)-1- 環丙基甲基 -4-{[5-(2,4- 二氟 - 丙基 )- 異㗁唑 -3- 羰基 ]- 胺基 }- 哌啶 -3- 羧酸 (1- 嘧啶 -2- 基 - 環丙基 )- 醯胺
在4 mL玻璃瓶中,將10 mg化合物溶解於3 mL THF中,且允許在環境條件下蒸發。在固體完全蒸發後(3日後),所量測之固體係呈結晶型4之化合物。
或者,將呈形式2之10 mg化合物懸浮於0.02 mL THF/H2
O 9/1中,且使小瓶在RT封閉。6日後,所獲固體係呈結晶型4之化合物。
圖1顯示如自實例1獲得之呈結晶型1之化合物的X射線粉末繞射圖。當與圖中強度最高峰比較時,用方法1圖量測之X射線繞射顯示具有相對強度之峰,該相對強度在指定折射角2θ處係以下百分比(相對峰強度於括弧內給出) (報導選自範圍3-40° 2θ之具有明顯強度之峰):3.6° (53%)、7.2° (31%)、8.2° (68%)、8.7° (46%)、9.1° (6%)、10.8° (50%)、13.9° (9%)、17.0° (26%)、17.5° (12%)、18.3° (100%)。
圖2顯示如自實例2獲得之呈結晶型2之化合物的X射線粉末繞射圖。當與圖中強度最高峰比較時,用方法1量測之X射線繞射圖顯示具有相對強度之峰,該相對強度在指定折射角2θ處係以下百分比(相對峰強度於括弧內給出) (報導選自範圍3-40° 2θ之具有明顯強度之峰):6.7° (46%)、8.5° (100%)、10.9° (19%)、13.2° (15%)、14.1° (13%)、14.5° (31%)、16.0° (16%)、17.4° (20%)、18.4° (16%)、20.8° (14%)。
圖3顯示如自實例3獲得之呈結晶型3之化合物的X射線粉末繞射圖。當與圖中強度最高峰比較時,用方法2量測之X射線繞射圖顯示具有相對強度之峰,該相對強度在指定折射角2θ處係以下百分比(相對峰強度於括弧內給出) (報導選自範圍3-40° 2θ之具有明顯強度之峰):6.8° (26%)、8.2° (100%)、8.8° (11%)、14.1° (27%)、16.0° (16%)、17.9° (31%)、21.0° (26%)、24.1° (17%)。
圖4顯示如自實例4獲得之呈結晶型4之化合物的X射線粉末繞射圖。當與圖中強度最高峰比較時,用方法2量測之X射線繞射圖顯示具有相對強度之峰,該相對強度在指定折射角2θ處係以下百分比(相對峰強度於括弧內給出) (報導選自範圍3-40° 2θ之具有明顯強度之峰):6.4° (100%)、8.3° (38%)、8.9° (12%)、13.6° (20%)、14.1° (9%)、15.4° (14%)、16.7° (28%)、18.0° (32%)、23.2° (42%)。
為避免任何質疑,上文所列峰描述圖1至圖4中所示X射線粉末繞射之實驗結果。應理解,與上文所列峰相反,僅要求一系列特徵峰完全且明確表示本發明呈各別結晶型之化合物的特點。
在圖1至圖4之X射線繞射圖中,折射角2theta (2q)繪製於橫軸上,且計數繪製於縱軸上。
Claims (16)
- 如請求項5之化合物(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺的結晶型,其 可藉由以下獲得:a)將10mg(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺與1mL甲醇混合,或將20mg(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺與1mL 3:1甲醇與乙腈之混合物混合;b)藉由以0.1℃/分鐘之勻速升溫加熱至65 +/- 5℃溶解(3S,4S)-1-環丙基甲基-4-{[5-(2,4-二氟-苯基)-異唑-3-羰基]-胺基}-哌啶-3-羧酸(1-嘧啶-2-基-環丙基)-醯胺;c)藉由使用0.1℃/分鐘之勻速降溫將該混合物冷卻至20 +/- 3℃,及d)過濾且乾燥產物。
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