CN111741947B - 4-甲基二氢嘧啶酮化合物及其药物用途 - Google Patents
4-甲基二氢嘧啶酮化合物及其药物用途 Download PDFInfo
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Abstract
本发明涉及具有RORγ拮抗剂活性的4‑甲基二氢嘧啶酮化合物或其可药用盐、包含它的药物组合物、以及其药物用途。提供了式(1)或(2)的化合物或其可药用盐、包含它的药物组合物、以及其药物用途。
Description
技术领域
本发明涉及具有RORγ拮抗剂活性的4-甲基二氢嘧啶酮化合物或其可药用盐,包含它的药物组合物,以及其药物用途。
背景技术
RORγ(即类维生素A相关孤儿受体γ)是一种核受体,其对Th17细胞的分化和激活很重要。还已知RORγt作为RORγ的剪接变异体(非专利文献1)。RORγ和RORγt的区别仅在于它们的N端结构域,并共享相同的配体结合结构域和DNA结合结构域。据报道,RORγ在除Th17细胞以外的其它组织中也表达(非专利文献1)。
抑制RORγ可以抑制Th17细胞的分化和激活。Th17细胞中产生的IL-17涉及多种趋化因子、细胞因子、金属蛋白酶和其它炎性介质的诱导和嗜中性粒细胞的迁移,因此,抑制IL-17可以导致抑制这样的诱导和迁移(非专利文献2和3)。已知的是,Th17细胞涉及自身免疫性疾病(如类风湿性关节炎、银屑病、炎性肠病(如克罗恩病和溃疡性结肠炎)、多发性硬化、系统性红斑狼疮(SLE)、贝切特氏病、结节病、原田病、强直性脊柱炎、葡萄膜炎、风湿性多肌痛、I型糖尿病、移植物抗宿主病、局限性脱发和白癜风)、变应性疾病、干眼症、纤维化(如肺纤维化和原发性胆汁性肝硬化)和癌症(如恶性黑素瘤和前列腺癌)。
脂肪组织中的RORγ与脂肪生成的调节相关,抑制RORγ可以改善胰岛素耐受性(非专利文献4)。已知脂肪组织涉及代谢性疾病(如肝脂肪变性)。
还已知的是IL-17和Th17细胞涉及缺血、心肌病、高血压和牙周炎。
例如,关于类风湿性关节炎,据报道施用抗IL-17抗体可以改善与胶原诱导性关节炎有关的肿胀和关节破坏(非专利文献5)。还据报道,在使用IL-17缺陷小鼠的实验中可以改善与胶原诱导性关节炎有关的肿胀和关节破坏(非专利文献6)。
关于银屑病,据报道,施用抗IL-17抗体在临床试验中有效治疗银屑病(非专利文献7)。抗IL-17抗体已经投放市场用于银屑病(非专利文献8)。
关于炎性肠病如克罗恩病和溃疡性结肠炎,衍生自RORγ-KO小鼠的T细胞的适应性转移在通过T细胞的适应性转移诱导的结肠炎模型中不会增加粘膜中的IL-17,由此可以抑制结肠炎的发病(非专利文献9)。还据报道,抗IL-23抗体,一种针对激活Th17细胞的IL-23的抗体,在临床试验中有效治疗克罗恩病(非专利文献20)。
关于多发性硬化,在RORγ-KO小鼠中可以抑制小鼠实验性自身免疫性脑脊髓炎模型(其是多发性硬化的动物模型)的疾病状态(非专利文献10)。还据报道,抗IL-17A抗体在临床试验中可以改善复发缓解型多发性硬化的MRI观察结果(非专利文献21)。
关于系统性红斑狼疮,据报道,施用抗IL-17抗体可以抑制RORγt-KO小鼠中GBM肾炎模型(其是肾小球肾炎的动物模型)的发病(非专利文献11)。施用抗IL-17抗体还潜在地抑制了与SLE相关的肾炎(非专利文献12)。
关于强直性脊柱炎,据报道,施用抗IL-17抗体有效治疗强直性脊柱炎(非专利文献13)。
关于葡萄膜炎,据报道,施用抗IL-17抗体有效治疗与贝切特氏病、结节病和原田病相关的葡萄膜炎(非专利文献7)。
关于风湿性多肌痛,目前在风湿性多肌痛的临床试验中评估了抗IL-17抗体的功效。
关于I型糖尿病,施用抗IL-17抗体可以在NOD小鼠模型(其是I型糖尿病模型)中抑制疾病状态的进展(非专利文献14)。目前在临床试验中评估了抗IL-17A抗体的功效(非专利文献22)。
关于移植物抗宿主病,据报道,在小鼠移植模型中,转染RORγ-KO-小鼠衍生细胞可以改善存活率和在宿主中的排斥(非专利文献19)。
关于局限性脱发,目前在临床试验中评估了抗IL-17A抗体的功效(非专利文献25)。
关于白癜风,在患者血清和病理组中分别识别出IL-17和Th17细胞的增加(非专利文献39)。
关于变应性疾病,如哮喘,在OVA致敏模型中在RORγ-KO小鼠中表现出嗜酸性肺炎减弱、CD4+淋巴细胞数量减少和Th2细胞因子/趋化因子水平降低,这随后可以抑制变应性反应(非专利文献15)。目前在特应性皮炎的临床试验中评估了抗IL-17A抗体的功效(非专利文献23)。目前在哮喘的临床试验中评估了抗IL-23抗体的功效(非专利文献24)。
关于干眼症,据报道,Th17细胞在干眼症的动物模型中增加,目前在干眼症患者的临床试验中评估了抗IL-17抗体的功效(非专利文献16)。
关于纤维化,在博来霉素诱导的肺纤维化模型(其是肺纤维化的动物模型)中,施用抗IL-17抗体可以抑制肺部的炎症和纤维化,并延长动物的生存期(非专利文献17)。
关于原发性胆汁性肝硬化,据报道,Th17细胞在患有原发性胆汁性肝硬化的患者的病变区域中增加,目前在临床试验中评估了抗IL-23抗体的功效(非专利文献18)。
关于恶性黑素瘤,目前在临床试验中评估了抗IL-17抗体的功效(非专利文献26和27)。
关于前列腺癌,认识到抗IL-17抗体治疗在Pten-null小鼠中减少了微创性前列腺癌的形成(非专利文献33)。
关于胰岛素耐受性,在RORγ KO小鼠中可以抑制通过喂饲高脂饮食诱导的胰岛素耐受性(非专利文献4)。
关于肝脂肪变性,认识到抗IL-17抗体在酒精性肝病模型中改善了病理组织上的脂肪变性(非专利文献34)。
关于非酒精性脂肪肝病,认识到抗IL-17抗体治疗在高脂饮食诱导的非酒精性脂肪肝病模型中改善了肝功能、减轻了肝脂质蓄积、抑制了枯否细胞活化并且降低了促炎细胞因子水平(非专利文献35)。
关于缺血和心肌病,据报道,IL-17A通过调节心肌细胞凋亡和嗜中性粒细胞浸润来促进心肌的缺血/再灌注损伤。认识到抗IL-17A抗体治疗或IL-17A敲除降低梗死面积、改善心脏功能,并由此改善缺血/再灌注损伤(非专利文献36)。
关于高血压,据报道,采用针对IL-17A或IL-17RA的抗体的治疗抑制了通过施用血管紧张素II造成的血压升高(非专利文献37)。
关于牙周炎,在实验性牙周炎模型中认识到Th17细胞或IL-17的增加。据报道,采用RORγ拮抗剂、GSK805或抗IL-17A抗体的治疗减轻了模型中的骨质流失(非专利文献38)。
基于这些发现,RORγ拮抗剂被认为有益于预防或治疗自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症(如恶性黑素瘤和前列腺癌)、代谢性疾病、缺血、心肌病、高血压和牙周病。
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发明内容
本发明提供了具有RORγ拮抗剂活性的4-甲基二氢嘧啶酮化合物或其可药用盐、包含它的药物组合物以及其医药用途。本发明的一个方面包括以下说明性实施方案:
[项目1]
式(1)或(2)的化合物:
或其可药用盐。
[项目2]
如项目1所述的化合物,其中该化合物是式(1)的化合物:
或其可药用盐。
[项目3]
如项目1所述的化合物,其中该化合物是式(2)的化合物:
或其可药用盐。
[项目4]
包含如项目1至3任一项所述的化合物或其可药用盐以及可药用载体的药物组合物。
[项目5]
包含如项目1至3任一项所述的化合物或其可药用盐的RORγ拮抗剂。
[项目6]
选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病的治疗或预防剂,包含如项目1至3任一项所述的化合物或其可药用盐。
[项目7]
拮抗RORγ的方法,包括向哺乳动物施用治疗有效量的如项目1至3任一项所述的化合物或其可药用盐。
[项目8]
治疗或预防选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病的方法,包括向哺乳动物施用治疗有效量的如项目1至3任一项所述的化合物或其可药用盐。
[项目9]
如项目1至3任一项所述的化合物或其可药用盐在制备RORγ拮抗剂中的用途。
[项目10]
如项目1至3任一项所述的化合物或其可药用盐在制备选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病的治疗或预防剂中的用途。
[项目11]
如项目1至3任一项所述的化合物或其可药用盐,用于RORγ拮抗剂。
[项目12]
如项目1至3任一项所述的化合物或其可药用盐,用于治疗或预防选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病。
[项目13]
商业包装,其包含如项目4所述的药物组合物和关于该药物组合物的包装插页,所述插页描述了该药物组合物可用于治疗或预防选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病。
[项目14]
试剂盒,其包含如项目4所述的药物组合物和关于该药物组合物的包装插页,所述插页描述了该药物组合物可用于治疗或预防选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病。
[项目15]
式(1)的化合物的一种晶型:
显示了粉末X射线衍射谱图,其具有选自7.4 ± 0.2°、9.9 ± 0.2°、10.5 ±0.2°、11.4 ± 0.2°、11.6 ± 0.2°、13.4 ± 0.2°、14.2 ± 0.2°、17.4 ± 0.2°、18.3 ±0.2°、18.7 ± 0.2°和19.4 ± 0.2°的用CuKα辐射测得的衍射角(2θ)的任意三个或更多个峰。
[项目16]
式(1)的化合物的一水合物:
。
[项目17]
式(1)的化合物的一水合物的一种晶型:
显示了粉末X射线衍射谱图,其具有选自4.2 ± 0.2°、9.7 ± 0.2°、13.7 ±0.2°、14.0 ± 0.2°、15.2 ± 0.2°、15.4 ± 0.2°、16.9 ± 0.2°、18.8 ± 0.2°、20.5 ±0.2°、21.9 ± 0.2°和22.4 ± 0.2°的用CuKα辐射测得的衍射角(2θ)的任意三个或更多个峰。
附图说明
[图1]
图1显示了晶型A的粉末X射线衍射谱图。纵轴显示衍射强度(cps:计数/秒),横轴显示衍射角2θ(°)。
[图2]
图2显示了晶型A的差示扫描量热法(DSC)曲线。纵轴显示热流(瓦特/克),横轴显示温度(℃)。
[图3]
图3显示了晶型B的粉末X射线衍射谱图。纵轴显示衍射强度(cps:计数/秒),横轴显示衍射角2θ(°)。
[图4]
图4显示了晶型B的DSC曲线。纵轴显示热流(瓦特/克),横轴显示温度(℃)。
[图5]
图5显示了晶型C的粉末X射线衍射谱图。纵轴显示衍射强度(cps:计数/秒),横轴显示衍射角2θ(°)。
[图6]
图6显示了晶型C的DSC曲线。纵轴显示热流(瓦特/克),横轴显示温度(℃)。
[图7]
图7显示了晶型D的粉末X射线衍射谱图。纵轴显示衍射强度(cps:计数/秒),横轴显示衍射角2θ(°)。
[图8]
图8显示了晶型D的TG-DTA曲线。纵轴的上部显示重量(克),纵轴的下部显示温度(℃),横轴显示温度(℃)。
[图9]
图9显示了晶型D的DSC曲线。纵轴显示热流(瓦特/克),横轴显示温度(℃)。
[图10]
图10显示了晶型E的粉末X射线衍射谱图。纵轴显示衍射强度(cps:计数/秒),横轴显示衍射角2θ(°)。
[图11]
图11显示了晶型E的TG-DTA曲线。纵轴的上部显示重量(克),纵轴的下部显示温度(℃),横轴显示温度(℃)。
[图12]
图12显示了晶型E的DSC曲线。纵轴显示热流(瓦特/克),横轴显示温度(℃)。
具体实施方式
下面显示了本文中所用术语的定义。
“式(1)的化合物”和“式(2)的化合物”任选还分别被称为“化合物(1)”和“化合物(2)”。“化合物(1)或化合物(2)(,)或其可药用盐”是指化合物(1)或化合物(2)或化合物(1)或化合物(2)的可药用盐,并意在包括任意的化合物(1)的可药用盐和化合物(2)的可药用盐。
术语“可药用盐”可以是本领域中已知的不具有过度毒性的任何盐。具体而言,其包括例如与无机酸的盐、与有机酸的盐、与无机碱的盐和与有机碱的盐。各种形式的可药用盐在本领域中是公知的,并例如列举在以下参考文献中:
(a)Berge等人, J. Pharm. Sci., 66, p1-19 (1977);
(b)Stahl等人, “Handbook of Pharmaceutical Salts: Properties,Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002);
(c)Paulekuhn等人, J. Med. Chem., 50, p6665-6672 (2007)。
根据已知方法,化合物(1)或化合物(2)可以与无机酸、有机酸、无机碱或有机碱反应以获得其各自的可药用盐。
与无机酸的此类盐包括例如与氢氟酸、氢氯酸、氢溴酸、氢碘酸、硝酸、磷酸和硫酸的盐。优选的盐包括与氢氯酸、硝酸、硫酸、磷酸和氢溴酸的盐。
与有机酸的此类盐包括例如与乙酸、己二酸、藻酸、4-氨基水杨酸、脱水亚甲基柠檬酸、苯甲酸、苯磺酸、樟脑酸、樟脑-10-磺酸、碳酸、柠檬酸、依地酸、乙-1,2-二磺酸、十二烷基磺酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、葡糖醛酸、葡庚糖酸、乙醇酰基阿散酸、羟基萘甲酸、2-羟基-1-乙磺酸、乳酸、乳糖酸、苹果酸、马来酸、扁桃酸、甲磺酸、甲基硫酸、甲基硝酸、亚甲基双(水杨酸)、半乳糖二酸、萘-2-磺酸、2-萘甲酸、1,5-萘二磺酸、油酸、草酸、双羟萘酸、泛酸、果胶酸、苦味酸、丙酸、多聚半乳糖醛酸、水杨酸、硬脂酸、琥珀酸、鞣酸、酒石酸、茶氯酸(teoclic acid)、硫氰酸、三氟乙酸、对甲苯磺酸、十一烷酸、天冬氨酸和谷氨酸的盐。优选的盐包括与草酸、马来酸、柠檬酸、富马酸、乳酸、苹果酸、琥珀酸、酒石酸、乙酸、三氟乙酸、苯甲酸、葡糖醛酸、油酸、双羟萘酸、甲磺酸、苯磺酸、对甲苯磺酸和2-羟基-1-乙磺酸的盐。
与无机碱的此类盐包括例如与锂、钠、钾、镁、钙、钡、铝、锌、铋和铵的盐。优选的盐包括与钠、钾、钙、镁和锌的盐。
与有机碱的此类盐包括例如与槟榔碱、甜菜碱、胆碱、氯苄咪唑、乙二胺、N-甲基葡糖胺、N-苄基苯乙胺、三(羟甲基)甲基胺、精氨酸和赖氨酸的盐。优选的盐包括与三(羟甲基)甲基胺、N-甲基葡糖胺和赖氨酸的盐。
化合物(1)或化合物(2)或其可药用盐可以以溶剂合物形式存在。
术语“溶剂合物”是指与溶剂分子配位的化合物(1)或化合物(2)或其可药用盐,并包括水合物。此类溶剂合物优选是可药用的溶剂合物,并包括化合物(1)或化合物(2)或其可药用盐的水合物、乙醇合物和与二甲基亚砜的溶剂合物。
具体而言,此类溶剂合物包括化合物(1)或化合物(2)的半水合物、一水合物、二水合物或单乙醇合物,或化合物(1)或化合物(2)的盐酸盐的一水合物或二盐酸盐的2/3乙醇合物。优选的溶剂合物包括化合物(1)的一水合物。此类溶剂合物可以根据已知方法获得。
化合物(1)或化合物(2)或其可药用盐可以用同位素原子如2H、3H、14C和35S来标记。
例如,化合物(1)或化合物(2)的任何氢原子包括氕1H(H)、氘2H(D)和氚3H(T)。
化合物(1)或化合物(2)或其可药用盐优选是基本纯化的化合物(1)或化合物(2)或其可药用盐。更优选的是具有80%或更高的纯度的化合物(1)或化合物(2)或其可药用盐。
化合物(1)或化合物(2)或其可药用盐的优选晶型包括化合物(1)的晶型,其显示具有在任意的7.4 ± 0.2°、9.9 ± 0.2°、10.5 ± 0.2°、11.4 ± 0.2°、11.6 ± 0.2°、13.4 ± 0.2°、14.2 ± 0.2°、17.4 ± 0.2°、18.3 ± 0.2°、18.7 ± 0.2°或19.4 ±0.2°的用CuKα辐射测得的衍射角(2θ)处的至少3个峰,例如至少3、4或5个峰的粉末X射线衍射谱图。化合物(1)的更优选的晶型可以显示具有在7.4 ± 0.2°、9.9 ± 0.2°和13.4 ±0.2°的2θ处的峰的粉末X射线衍射谱图。化合物(1)的更优选的晶型可以显示具有在7.4 ±0.2°、9.9 ± 0.2°、13.4 ± 0.2°、18.7 ± 0.2°和19.4 ± 0.2°的2θ处的峰的粉末X射线衍射谱图。
化合物(1)或化合物(2)或其可药用盐的另一优选晶型包括化合物(1)的一水合物的晶型,其显示具有在任意的4.2 ± 0.2°、9.7 ± 0.2°、13.7 ± 0.2°、14.0 ± 0.2°、15.2 ± 0.2°、15.4 ± 0.2°、16.9 ± 0.2°、18.8 ± 0.2°、20.5 ± 0.2°、21.9 ± 0.2°或22.4 ± 0.2°的用CuKα辐射测得的衍射角(2θ)处的至少3个峰,例如至少3、4或5个峰的粉末X射线衍射谱图。化合物(1)的一水合物的更优选的晶型可以显示具有在4.2 ± 0.2°、9.7 ± 0.2°和16.9 ± 0.2°的2θ处的峰的粉末X射线衍射谱图。化合物(1)的一水合物的进一步优选的晶型可以显示具有在4.2 ± 0.2°、9.7 ± 0.2°、13.7 ± 0.2°、15.2 ±0.2°和16.9 ± 0.2°的2θ处的峰的粉末X射线衍射谱图。
粉末X射线衍射谱图中衍射角(2θ)的误差范围优选为± 0.2°、更优选± 0.1°、进一步优选± 0.05°。
根据药物制剂领域中的已知方法,本文中的药物组合物可以通过例如将化合物(1)或化合物(2)或其可药用盐与至少一种或多种可药用载体以合适的量混合来制备。化合物(1)或化合物(2)或其可药用盐在该药物组合物中的含量(在本文中也称为“治疗有效量”)根据剂型和剂量而不同,并例如为该组合物的0.1至100重量%。
化合物(1)或化合物(2)或其可药用盐的剂型包括口服制剂,如片剂、胶囊剂、颗粒剂、粉剂、锭剂、糖浆剂、乳剂和混悬剂,以及肠胃外制剂,如外用制剂、栓剂、注射剂、眼药水、鼻用制剂和肺部制剂。
术语“可药用载体”包括用于配制材料的各种常规的有机或无机载体物质,如固体制剂中的赋形剂、崩解剂、粘合剂、流化剂和润滑剂;液体制剂中的溶剂、增溶剂、悬浮剂、张度剂、缓冲剂和安抚剂;以及半固体制剂中的基料(bases)、乳化剂、润湿剂、稳定剂、稳定化剂、分散剂、增塑剂、pH调节剂、吸收促进剂、胶凝剂、防腐剂、填料、助溶剂、增溶剂和悬浮剂。防腐剂、抗氧化剂、着色剂或甜味剂也可以任选用作添加剂。
此类“赋形剂”包括例如乳糖、绵白糖、D-甘露醇、D-山梨醇、玉米淀粉、糊精、微晶纤维素、结晶纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素和阿拉伯树胶。
此类“崩解剂”包括例如羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、羟丙基甲基纤维素和结晶纤维素。
此类“粘合剂”包括例如羟丙基纤维素、羟丙基甲基纤维素、聚维酮、结晶纤维素、绵白糖、糊精、淀粉、明胶、羧甲基纤维素钠和阿拉伯树胶。
此类“流化剂”包括例如轻质无水硅酸和硬脂酸镁。
此类“润滑剂”包括例如硬脂酸镁、硬脂酸钙和滑石。
此类“溶剂”包括例如纯净水、乙醇、丙二醇、聚乙二醇(macrogol)、芝麻油、玉米油和橄榄油。
此类“增溶剂”包括例如丙二醇、D-甘露醇、苯甲酸苄酯、乙醇、三乙醇胺、碳酸钠和柠檬酸钠。
此类“悬浮剂”包括例如苯扎氯铵、羧甲基纤维素、羟丙基纤维素、丙二醇、聚维酮、甲基纤维素和单硬脂酸甘油酯。
此类“张度剂”包括例如葡萄糖、D-山梨醇、氯化钠和D-甘露醇。
此类“缓冲剂”包括例如磷酸氢钠、乙酸钠、碳酸钠和柠檬酸钠。
此类“安抚剂”包括例如苄醇。
此类“基料”包括例如水、动物油或植物油如橄榄油、玉米油、花生油、芝麻油和蓖麻油、低级醇如乙醇、丙醇、丙二醇、1,3-丁二醇和苯酚、高级脂肪酸及其酯、蜡、高级醇、多元醇、烃类如白矿脂、液体石蜡和石蜡、亲水矿脂、精制羊毛脂、吸水软膏、含水羊毛脂、亲水性软膏、淀粉、普鲁兰多糖、阿拉伯树胶、黄蓍胶、明胶、右旋糖酐、纤维素衍生物如甲基纤维素、羧甲基纤维素、羟乙基纤维素和羟丙基纤维素、合成聚合物如羧基乙烯基聚合物、聚丙烯酸钠、聚乙烯醇和聚乙烯基吡咯烷酮、丙二醇、聚乙二醇如聚乙二醇200至600,以及其任意两种或更多种的组合。
此类“防腐剂”包括例如对羟基苯甲酸乙酯、氯丁醇、苄醇、脱氢乙酸钠和山梨酸。
此类“抗氧化剂”包括例如亚硫酸钠和抗坏血酸。
此类“着色剂”包括例如食用染料,如食品红2号和3号、食品黄4号和5号、以及β-胡萝卜素。
此类“甜味剂”包括例如糖精钠、甘草酸二钾和阿斯巴甜。
本文中的药物组合物可以经口施用或肠胃外施用,如局部、直肠、静脉内、肌内和皮下施用于除人类外的哺乳动物,如小鼠、大鼠、仓鼠、豚鼠、兔子、猫、狗、猪、牛、马、绵羊和猴子,以及人类。剂量可以根据要施用的受试者、疾病、症状、剂型、施用路线等等而不同。例如,在经口施用于成年患者时,化合物(1)或化合物(2)的剂量(有效成分)通常为每天大约0.01毫克至大约1克,其可以一次施用或以分割量施用数次。
还可使用试剂盒,如用于给药、治疗和/或预防的试剂盒,包装,如包装的商品,和一组和/或一箱药品,其包含含有作为有效成分或活性剂的化合物(1)或化合物(2)或其可药用盐的药物组合物以及关于该组合物的书面材料,指示该组合物可以或应当用于治疗和/或预防。这样的试剂盒、包装和药品组可以包含一个或多个装有药物组合物或一种或多种有效成分和用于该组合物的其它药物或药品(或成分)的容器。这样的试剂盒、包装和药品组的实例包括商业试剂盒、商业包装和商业药品组,以便适当地用于治疗和/或预防预期的疾病。这样的试剂盒、包装和药品组中包含的书面材料包括注意事项或包装插页,其形式由政府组织指定,其规范了药物产品或生物产品的制造、使用或销售,这确保获得政府组织对涉及施用于人类的产品的制造、使用或销售的批准。试剂盒、包装和药品组可以包括包装的产品以及构造用于适当的施用步骤并构造以便能够实现更优选的医学治疗和/或预防(包括治疗和/或预防预期疾病)的结构。
化合物(1)或化合物(2)或其可药用盐具有RORγ拮抗作用,并可用于RORγ拮抗剂。
术语“具有RORγ拮抗剂活性”、“具有RORγ拮抗作用”或“拮抗RORγ”是指拮抗、优选特异性拮抗RORγ的功能,以消除或降低其活性,并包括例如根据下文测试实施例1中描述的条件拮抗、优选特异性拮抗RORγ的功能。
术语“RORγ拮抗剂”是指拮抗RORγ的功能的任何物质,优选特异性拮抗RORγ的功能的任何物质。
术语“RORγ”优选为“人RORγ”。
化合物(1)或化合物(2)或其可药用盐具有RORγ拮抗作用,并预期有效针对涉及RORγ的功能的疾病。
具体而言,化合物(1)或化合物(2)或其可药用盐预期可用于治疗或预防选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病。
术语“自身免疫性疾病”是指其中受试者的免疫系统对其甚至正常的细胞和组织过度反应并攻击以引起症状的疾病的通用名称,并具体包括类风湿性关节炎、银屑病、炎性肠病如克罗恩病和溃疡性结肠炎、多发性硬化、系统性红斑狼疮(SLE)、贝切特氏病、结节病、原田病、强直性脊柱炎、葡萄膜炎、风湿性多肌痛、I型糖尿病、移植物抗宿主病、局限性脱发和白癜风。
术语“变应性疾病”是指源于其中针对特定抗原的免疫反应过度发生的病症的疾病,并具体包括特应性皮炎、变应性鼻炎如花粉过敏、变应性结膜炎、变应性胃肠炎、哮喘如支气管哮喘和小儿哮喘、食物过敏、药物过敏和荨麻疹。
术语“纤维化”是指纤维结缔组织增多的病症,并具体包括肺纤维化和原发性胆汁性肝硬化。
术语“癌症”具体包括恶性黑素瘤和前列腺癌。
术语“代谢性疾病”是指代谢转换异常引起的疾病,或包括代谢异常作为构成发病机制的因素的疾病,并包括例如糖尿病如I型糖尿病和II型糖尿病、肝脂肪变性和非酒精性脂肪肝病。
本文中所用的术语“治疗”还包括改善症状、防止变得严重、保持缓解、防止病情恶化和防止复发。
本文中所用的术语“预防”是指抑制症状的发病机制。
化合物(1)或化合物(2)或其可药用盐具有以下证明过的性质:
(i)高代谢稳定性,参照测试实施例2;
(ii)有益的药代动力学特征,包括有利的血浆半衰期,参照测试实施例5;
(iii)诱导药物代谢酶如CYP3A4的潜能低,参照测试实施例3;
(iv)有利的高溶解度,参照测试实施例4;和
(v)持续和/或潜在的药理作用,参照测试实施例6和7。
这些性质使得化合物(1)或化合物(2)或其可药用盐特别有利。例如,化合物(1)或化合物(2)或其可药用盐:
(i)表现出持续的药理作用,这可使得能够降低给药频率或延长给药间隔,这可以有利地影响患者依从性,并由此改善总体治疗结果;
(ii)表现出药物代谢酶如CYP3A4的低诱导作用,这可能导致被此类酶代谢的联合用药的代谢降低,由此本化合物可能更适于同时服用多种治疗药物的患者;和
(iii)可能具有基于高溶解度的有利经口生物利用度,并由此即使在高给药量下也可以表现出血浆浓度的剂量依赖性增加和/或在吸收过程中表现出小的个体差异。
只要本文中公开的实施方案与说明书的另一部分中公开的另一实施方案相容,这些实施方案中的任意两个或更多个的组合也意在包括在本发明中。
在如下的实施例中说明了制备化合物(1)或化合物(2)或其可药用盐的方法。然而,制备化合物(1)或化合物(2)或其可药用盐的方法并非意在限于此。
如果需要的话,可以通过已知方法如蒸馏、重结晶和柱色谱法分离和/或提纯每个步骤中获得的各化合物,但是各反应可以在没有分离和/或提纯的情况下任选继续进行至按顺序的步骤。
室温在本文中是指未经控制的温度,并且作为一个实施方案包括1℃至40℃。
实施例
用四甲基硅烷作为内标在CDCl3或DMSO-d6中测量1H-NMR谱,所有δ值以ppm为单位显示。谱图数据中的符号含义如下。
s:单峰
d:双峰
t:三峰
q:四峰
dd:双重双峰
ddd:双重双重双峰
brs:宽单峰
m:多重峰
J:耦合常数。
[实施例1]
3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸的合成
步骤1
(S)-2-甲基-丙烷-2-亚磺酸[1-(4-溴-3-氯-苯基)-乙-(E)-叉基]-酰胺
将1-(4-溴-3-氯-苯基)-乙酮(60.0克)和(S)-(-)-2-甲基-丙烷-2-亚磺酸酰胺(37.3克)在环戊基甲基醚(257毫升)中混合。向反应溶液中添加原钛酸四乙酯(70.3克),并将反应溶液在100℃下搅拌5小时。在室温下向反应溶液中添加40w/v%乳酸铵水溶液(308毫升),该混合物用乙酸乙酯萃取。所得有机层用水和盐水洗涤,并随后经硫酸镁干燥。通过过滤器除去硫酸镁,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 =1:4 → 2:3)提纯。所得残余物用正己烷/乙醚固化,将沉淀固体过滤以获得标题化合物(70.6克)。
步骤2
(R)-3-(4-溴-3-氯-苯基)-2-异丙基-3-((S)-2-甲基-丙烷-2-亚磺酰氨基)丁酸甲酯
在氩气下将二异丙胺(12.4毫升)与四氢呋喃(89.1毫升)混合。在-78℃下向反应溶液中逐滴添加2.66M 正丁基锂/正己烷溶液(33.5毫升),并将反应溶液在冰冷却下搅拌5分钟。向反应溶液中逐滴添加3-甲基-丁酸甲酯(11.7毫升)在四氢呋喃(44.5毫升)中的混合溶液,并将反应溶液在-78℃下搅拌1小时。向反应溶液中逐滴添加(S)-2-甲基-丙烷-2-亚磺酸[1-(4-溴-3-氯-苯基)-乙-(E)-叉基]-酰胺 (15.0克)在四氢呋喃(44.5毫升)中的混合溶液,并将反应溶液搅拌2小时。向反应溶液中添加乙酸(5.1毫升)在四氢呋喃(25.4毫升)中的混合溶液,并在室温下搅拌该混合物。向反应溶液中添加1M柠檬酸单钠水溶液(100毫升),分离各层。所得有机层用水(100毫升,两遍)洗涤。合并的水层用乙酸乙酯(100毫升,两遍)萃取。合并的有机层用1M柠檬酸单钠水溶液(100毫升)、水(100毫升,两遍)和盐水洗涤,并随后经硫酸镁干燥。通过过滤器除去硫酸镁,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 = 1:4 → 3:2)提纯以获得标题化合物(18.0克)。
步骤3
(S)-2-甲基-丙烷-2-亚磺酸[(R)-1-(4-溴-3-氯-苯基)-2-羟甲基-1,3-二甲基-丁基}酰胺
在氩气下将(R)-3-(4-溴-3-氯-苯基)-2-异丙基-3-((S)-2-甲基-丙烷-2-亚磺酰氨基)丁酸甲酯(18.0克)在甲苯(39.7毫升)中混合。在-78℃下向反应溶液中逐滴添加1M二异丁基氢化铝/甲苯溶液(59.1毫升),并将反应溶液在-78℃下搅拌2小时。随后,将反应溶液逐渐升温至0℃,随后搅拌30分钟。在-78℃下向反应溶液中添加甲醇(39毫升)。在冰冷却下向反应溶液中添加30w/v%的L-酒石酸水溶液(75毫升)和乙酸乙酯(300毫升),并分离各层。所得水层用乙酸乙酯(100毫升)萃取。合并的有机层用30w/v%的L-酒石酸水溶液(80毫升,两遍)、水(80毫升,两遍)和盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物与甲苯共沸以获得标题化合物的粗产物(18.5克)。
步骤4
(R)-3-氨基-3-(4-溴-3-氯-苯基)-2-异丙基-丁-1-醇
将(S)-2-甲基-丙烷-2-亚磺酸[(R)-1-(4-溴-3-氯-苯基)-2-羟甲基-1,3-二甲基-丁基}酰胺(18.5克)在甲醇(79.5毫升)中混合。在冰冷却下向反应溶液中逐滴添加2M的氯化氢/甲醇溶液(39.8毫升),并将反应溶液搅拌1.5小时。减压浓缩反应溶液,并向残余物中添加10w/v%的碳酸钠水溶液(50.0毫升)。反应溶液用乙酸乙酯(80毫升)萃取。所得水层用乙酸乙酯萃取(两遍)。合并的有机层用10w/v%的碳酸钠水溶液(50毫升)、水(50毫升)和盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后将减压浓缩的所得有机层经硫酸镁干燥。通过过滤器除去硫酸镁,随后减压浓缩滤液。所得残余物与甲苯共沸以获得标题化合物的粗产物(15.7克)。
步骤5
3-{3-[(R)-1-(4-溴-3-氯-苯基)-2-羟基甲基-1,3-二甲基-丁基]脲基}双环[1.1.1]戊烷-1-甲酸甲酯
将3-(甲氧基羰基)双环[1.1.1]戊烷-1-甲酸(4.00克)和甲苯(47.0毫升)在氮气下混合,并在室温下向其中添加叠氮磷酸二苯酯(5.58毫升)和三乙胺(3.60毫升)。将反应溶液在120℃下搅拌50分钟。在冰冷却下经15分钟将反应溶液缓慢地逐滴添加到(R)-3-氨基-3-(4-溴-3-氯-苯基)-2-异丙基-丁-1-醇 (9.77克)在四氢呋喃(47.0毫升)中的溶液中。将反应溶液在室温下搅拌1小时。向反应溶液中添加10w/v%的柠檬酸水溶液(100毫升)并分离各层。所得有机层用水(60毫升)洗涤。合并的水层用乙酸乙酯萃取(两遍)。合并的有机层用10w/v%的柠檬酸水溶液(60毫升)、水(60毫升)、10w/v%的碳酸钠水溶液(60毫升)、水(60毫升)和盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 = 7:13 → 100:0)提纯以获得标题化合物(8.34克)。
步骤6
3-[(S)-4-(4-溴-3-氯-苯基)-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基]-双环[1.1.1]戊烷-1-甲酸甲酯
在氮气下将3-{3-[(R)-1-(4-溴-3-氯-苯基)-2-羟基甲基-1,3-二甲基-丁基]脲基}双环[1.1.1]戊烷-1-甲酸甲酯(10.0克)和氯仿(68.4毫升)混合,并在室温下向其中添加(二乙酰氧基碘代)苯(6.06克)和2,2,6,6-四甲基哌啶-1-氧自由基(0.267克)。将反应溶液在室温下搅拌3.5小时,随后在室温下向其中添加10w/w%的亚硫酸钠水溶液(50毫升)。分离各层。所得水层用氯仿萃取(两遍)。合并的有机层用水(50毫升)和盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物与甲苯共沸。将所得残余物与甲苯(213毫升)混合,随后在室温下向其中添加五氟苯胺三氟甲磺酸盐(0.307克)。将反应溶液在100℃的温热下搅拌2小时,并随后在室温下向其中添加亚硫酸钠(880毫克)和10w/v%的碳酸钠水溶液(50毫升)。分离各层。所得水层用乙酸乙酯萃取(两遍)。合并的有机层用水(50毫升)和盐水洗涤,并随后经硫酸镁干燥。通过过滤器除去硫酸镁,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 = 1:4 → 3:2)提纯。所得残余物用正己烷固化,并将沉淀固体过滤以获得标题化合物(6.35克)。
步骤7
3-{(S)-4-[4-(2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸甲酯
在氩气下将3-[(S)-4-(4-溴-3-氯-苯基)-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基]-双环[1.1.1]戊烷-1-甲酸甲酯(5.23克)、反式-2-叔丁基-环丙基-三氟硼酸钾(2.79克)、[1,1'-双(二-叔丁基-膦基)二茂铁]二氯化钯(II)(0.729克)、碳酸铯(10.9克)、甲苯(112毫升)和水(11.2毫升)混合,并将该混合物在100℃下搅拌2小时。在室温下向反应溶液中添加水(50毫升),分离各层。所得水层用乙酸乙酯萃取(两遍)。合并的有机层用水(50毫升,两遍)和盐水洗涤,并随后经硫酸镁干燥。随后,向其中添加活性炭,并将该混合物在室温下搅拌1小时。通过过滤器除去硫酸镁和活性炭,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 = 1:9 → 1:1)提纯。将所得残余物与甲醇混合,并在室温下向其中添加活性炭。通过过滤器除去活性炭,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 = 1:4 → 1:1)提纯以获得标题化合物的非对映异构体混合物(3.70克)。用手性制备柱提纯获得标题化合物(0.344克)。
制备柱的提纯条件显示如下。
制备设备:循环制备型液相色谱仪LC-92XX NEXT SERIES, Japan AnalyticalIndustry Co., Ltd.
柱:Daicel CHIRALPAK IA 2.0 cmφ×25 cmL
流动相:正己烷:2-丙醇 = 93:7
流量:10.0 mL/min
检测:UV (220 nm)。
用手性柱进行测量显示所得标题化合物的保留时间为 8.3分钟(标题化合物的非对映异构体的保留时间为7.6分钟),纯度为99%。手性柱的分析条件显示如下。
测量设备:HPLC系统, Shimadzu Corporation, 高效液相色谱仪Prominence
柱:Daicel CHIRALPAK IA-3 0.46 cmφ×15 cmL
柱温:40℃
流动相:正己烷:2-丙醇 = 93:7
流量:1.0 mL/min
检测:UV (220 nm)。
步骤8
3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸
在氮气下将3-{(S)-4-[4-(2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸甲酯(49.1克)、四氢呋喃(246毫升)和甲醇(246毫升)混合,并在室温下向其中添加2N氢氧化钠水溶液(101毫升)。将反应溶液在室温下搅拌24小时30分钟。减压浓缩反应溶液,并向残余物中添加水(400毫升)和1N盐酸(250毫升)。随后,向其中添加乙酸乙酯(900毫升)并分离各层。所得水层用乙酸乙酯(100mL×2)萃取,有机层用水(250毫升)和盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。
将所得残余物和乙腈(1000毫升)混合,并将该混合物在85℃的温热下搅拌1小时15分钟。随后,将该混合物在室温下搅拌13小时15分钟,随后将所得固体过滤以获得标题化合物的晶体(晶型A;44.7克)。
将以类似方式获得的标题化合物的晶体(29.7毫克)、乙酸乙酯(297微升)和甲醇(891微升)混合。固体完全溶解,随后用旋转蒸发仪减压浓缩溶剂,获得标题化合物的另一种晶体(晶型B)。
将以类似方式获得的上述两种晶体(各10.0毫克)和乙酸异丁酯(80微升)混合,并将所得浆料在室温下搅拌一周,随后将所得固体过滤以获得标题化合物的另一种晶体(晶型C),其用于后续程序中的晶种。
将在类似于上文所述的反应中获得的粗晶体(2.00克)和乙酸异丁酯(10毫升)混合并在90℃下搅拌。在粗晶体完全溶解后,在47℃的内部温度下向该混合物中添加晶种,并将该混合物搅拌1小时。在大约45℃的内部温度下,将正庚烷(30毫升)添加到反应溶液中,并将该混合物搅拌2小时。将该混合物在室温下搅拌24小时。将沉淀固体过滤以获得标题化合物(晶型C;1.7克)。
通过单晶X射线结构分析确定标题化合物的不对称碳的绝对构型。
(中间体1的合成)
反式-2-叔丁基-环丙基-三氟硼酸钾
在氮气下将2-(反式-2-叔丁基-环丙基)-4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷(8.03克)、甲醇(200毫升)和水(40毫升)混合,并在室温下向其中添加氟化氢钾(14克)。将反应溶液在100℃下搅拌7小时。随后,将该溶液在室温下静置整夜,并随后减压浓缩。所得残余物与甲苯共沸。将所得残余物和乙腈(120毫升)混合并在60℃下搅拌2小时。通过过滤器除去所得固体,随后减压浓缩滤液。将所得残余物和乙醚(80毫升)混合并在室温下搅拌。将沉淀固体过滤以获得标题化合物(2.86克)。
[实施例1A]
3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸的替代合成
步骤1
(4S,5S)-2-((E)-3,3-二甲基-1-丁烯基)-[1,3,2]二氧杂环戊硼烷-4,5-二甲酸双-二甲基酰胺
将2M二溴硼烷-二甲硫醚配合物/甲苯溶液(1250毫升)在甲苯(1169毫升)中混合。在水冷却下向反应溶液中逐滴添加3,3-二甲基-1-丁炔(338毫升)45分钟。将反应溶液在水冷却下搅拌2.5小时。通过将冰添加到水浴中来冷却反应溶液,防止延迟放热。在冰冷却下将反应溶液逐滴添加到8N氢氧化钾水溶液(969毫升)和水(2922毫升)的混合溶液中30分钟。将甲苯(1461毫升)和四氢呋喃(292毫升)添加到水层中,并在冰冷却下向其中逐滴添加6N盐酸(417毫升)20分钟。向其中添加氯化钠(584克),并将有机层分离。
将有机层与甲苯(1581毫升)混合并向其中添加L-酒石酸-N,N,N',N'-四甲基酰胺(562克)。将反应溶液在130℃的加热下搅拌2小时。将有机层分离并减压浓缩。用过滤器除去浓缩过程中沉淀的固体,并减压浓缩滤液以获得标题化合物的粗产物(599克)。
步骤2
(1R,2R)-2-叔丁基环丙基硼酸
在氩气下将1.1M二乙基锌/正己烷溶液(1892毫升)在甲基叔丁基醚(838毫升)中混合。在用干冰-丙酮冷却下向反应溶液中逐滴添加氯碘甲烷(301毫升)35分钟。在用干冰-丙酮冷却下将反应溶液搅拌30分钟。随后,在用干冰-丙酮冷却下向其中添加L-酒石酸-N,N,N',N'-四甲基酰胺(70.8克),并将该混合物搅拌20分钟。在用干冰-丙酮冷却下向反应溶液中逐滴添加(4S,5S)-2-((E)-3,3-二甲基-1-丁烯基)-[1,3,2]二氧杂环戊硼烷-4,5-二甲酸双-二甲基酰胺(222克)在甲基叔丁基醚(838毫升)中的混合溶液30分钟。在用干冰-乙腈冷却下将反应溶液搅拌4.5小时。随后,在用干冰-乙腈冷却下经10分钟向其中添加30w/v%的柠檬酸水溶液(1438毫升)。向反应溶液中添加乙酸乙酯(1047毫升)和氯化钠(335克),有机层用水(1047毫升)和25w/v%的氯化钠水溶液(1047毫升)洗涤并随后经硫酸镁干燥。用过滤器除去硫酸镁,随后减压浓缩滤液以获得粗产物(82.6克)。
将所得粗产物(82.6克)与8N氢氧化钾水溶液(87毫升)和水(150毫升)混合。在冰冷却下将反应溶液逐滴添加到6N盐酸(117毫升)中1小时。在冰冷却下将反应溶液搅拌1小时。将沉淀固体过滤以获得标题化合物(68.8克)。
步骤3
4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸甲酯
在氩气下将碳酸钾(1329克)在水(1600毫升)中混合。向该反应中添加甲苯(4800毫升)、4-溴-3-氯苯甲酸甲酯(800克)、(1R,2R)-2-叔丁基环丙基硼酸(1454克)和双(三苯基膦)二氯化钯(II)(112克),并将反应溶液在80℃的加热下搅拌4.5小时。将反应溶液冷却至室温。在60℃的加热下向反应溶液中添加0.5N氢氧化钾水溶液(3200毫升),并将该混合物搅拌2小时。将有机层分离,随后用甲苯(1200毫升)萃取水层。合并的有机层用水(3200毫升)洗涤,随后向其中添加硅藻土(800克)。将该混合物在室温下搅拌1小时。用过滤器除去硅藻土,随后减压浓缩滤液。向所得残余物中添加异丙醇(2000毫升),并将该混合物减压浓缩以获得标题化合物的粗产物(1061克)。
步骤4
4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸
将4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸甲酯(1061克)在异丙醇(4600毫升)中混合。向反应溶液中添加2N的氢氧化钠水溶液(4000毫升),并将反应溶液在室温下搅拌整夜。向反应溶液中添加活性炭(160克),并将该混合物搅拌30分钟。在用硅藻土过滤后,在冰冷却下向滤液中添加2N盐酸(4100毫升)。该滤液用乙酸乙酯(4800毫升)萃取。水层用乙酸乙酯(1200毫升)萃取,合并的有机层用饱和氯化钠水溶液(1600毫升)洗涤,并随后经硫酸镁干燥。用过滤器除去硫酸镁,随后减压浓缩滤液。向所得残余物中添加乙腈(1600毫升),并将该混合物减压浓缩以获得标题化合物的粗产物(920克)。
步骤5
4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸
将4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸(920克)在乙腈(7200毫升)和水(4000毫升)中混合。在67℃的内部温度的加热下搅拌反应溶液,确认4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸完全溶解。随后,向反应溶液中添加水(3700毫升),并向其中添加晶种。将该混合物在60℃的加热下搅拌6小时,并随后搅拌整夜,缓慢冷却至室温。将沉淀固体过滤以获得标题化合物(518克)。在这一步骤中,使用晶种以有效地获得晶体,但是可以在类似于这一步骤的程序中在没有晶种的情况下获得该晶体。
步骤6
4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸(S)-苯乙胺盐
将4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸(790克)在乙酸异丙酯(7900毫升)中混合。在87℃的内部温度的加热下向该混合物中逐滴添加(S)-(-)-苯乙胺(417克)10分钟。随后,向其中加入晶种。在83℃的加热下将该混合物搅拌2小时,并随后搅拌整夜,缓慢冷却至室温。将沉淀固体过滤以获得标题化合物(1087克)。在这一步骤中,使用晶种以有效地获得晶体,但是可以在类似于这一步骤的程序中在没有晶种的情况下获得该晶体。
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步骤7
4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸(S)-苯乙胺盐
将4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸(S)-苯乙胺盐(1087克)在乙酸异丙酯(7600毫升)中混合。向反应溶液中添加(S)-(-)-苯乙胺(35.2克)。将该混合物在83℃的加热下搅拌2小时并随后搅拌整夜,缓慢冷却至室温。将沉淀固体过滤以获得标题化合物(1044克)。
步骤8
4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸
将4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸(S)-苯乙胺盐(1044克)在乙腈(5200毫升)和水(3800毫升)中混合。向其中添加2N盐酸(1470毫升),并将该混合物在80℃的加热下搅拌2小时并随后搅拌整夜,缓慢冷却至室温。随后,向其中逐滴添加水(4200毫升)1小时,随后将该混合物在室温下搅拌2小时。将沉淀固体过滤以获得标题化合物(697克)。
步骤9
4-((1R,2R)-2-叔丁基环丙基)-3-氯-N-甲氧基-N-甲基苯甲酰胺
将4-((1R,2R)-2-叔丁基环丙基)-3-氯苯甲酸(1000克)在N-甲基吡咯烷酮(5000毫升)中混合。向反应溶液中添加N,O-二甲基羟胺盐酸盐(540克)、1-羟基苯并三唑一水合物(60.6克)和碳酸氢钠(465克)。在冰冷却下向该混合物中添加N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(1099克),并将该混合物搅拌1小时。将该混合物在室温下搅拌1小时,并随后向其中添加环戊基甲基醚(5000毫升)和水(2500毫升)。水层用环戊基甲基醚(400毫升)萃取,合并的有机层用水(2500毫升)和20w/v%的氯化钠水溶液(2500毫升)洗涤,并随后经硫酸钠干燥。用过滤器除去硫酸钠,并随后减压浓缩。向所得残余物中添加环戊基甲基醚(3000毫升),并将该混合物减压浓缩以获得标题化合物的粗产物(1356克)。
步骤10
1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]乙酮
将4-((1R,2R)-2-叔丁基环丙基)-3-氯-N-甲氧基-N-甲基苯甲酰胺(1356克)在四氢呋喃(5900毫升)中混合。在冰冷却下向反应溶液中逐滴添加3M甲基氯化镁/四氢呋喃溶液(1700毫升)2小时,随后将该混合物搅拌1小时。向反应溶液中添加异丙醇(117毫升),随后向其中逐滴添加2N盐酸(5900毫升)。向其中加入甲苯(6000毫升),有机层用20w/v%的氯化钠水溶液(6000毫升)和水(3600毫升)洗涤。随后,该溶液经硫酸钠干燥。用过滤器除去硫酸钠,并随后减压浓缩。向所得残余物中添加环戊基甲基醚(3500毫升),并将该混合物减压浓缩以获得标题化合物的粗产物(1193克)。
步骤11
(S)-2-甲基-丙烷-2-亚磺酸{1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]乙-(E)-叉基}酰胺
将1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]乙酮(207克)和(S)-(-)-2-甲基-丙烷-2-亚磺酸酰胺(116克)在环戊基甲基醚(1000毫升)中混合。向反应溶液中添加原钛酸四乙酯(335毫升),并将反应溶液在110℃的加热下搅拌3小时。在水冷却下向反应溶液中添加甲醇(1000毫升),并将该混合物搅拌10分钟。在30℃或更低的内部温度下向其中逐滴添加28w/w%的氨水溶液(100毫升)、L-乳酸(178毫升)和水(1000毫升)的混合水溶液15分钟。将该混合物在室温下搅拌4小时,并随后静置整夜。向水层中加入环戊基甲基醚(1000毫升),合并的有机层用25w/v%的氯化钠水溶液(1000毫升)洗涤并随后经硫酸钠干燥。用过滤器除去硫酸钠,随后减压浓缩滤液。向残余物中添加正己烷(400毫升),并将该混合物减压浓缩。额外向残余物中添加正己烷(400毫升),随后将该混合物减压浓缩。随后,向其中添加二甲基亚砜(500毫升),并将该混合物减压浓缩。向残余物中添加二甲基亚砜(500毫升),并在室温下向该混合物中逐滴添加水(50毫升)。将该混合物在室温下搅拌30分钟,随后向其中逐滴添加水(150毫升)。将该混合物在室温下搅拌12小时,并随后将沉淀固体过滤以获得标题化合物(261克)。
步骤12
(R)-3-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-异丙基-3-((S)-2-甲基-丙烷-2-亚磺酰氨基)丁酸甲酯
在氮气流下将2M二异丙基酰胺锂/四氢呋喃/正庚烷/乙苯溶液(740毫升)在四氢呋喃(786毫升)中混合。在-78℃的冷却下向反应溶液中逐滴添加3-甲基丁酸甲酯(224毫升)在四氢呋喃(524毫升)中的混合溶液45分钟,并将反应溶液在-78℃的冷却下搅拌2小时30分钟。向反应溶液中逐滴添加(S)-2-甲基-丙烷-2-亚磺酸{1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]乙-(E)-叉基}酰胺(261克)在四氢呋喃(393毫升)中的混合溶液40分钟,并将反应溶液搅拌4小时。在5分钟内向反应溶液中连续逐滴添加甲醇(131毫升)和水(131毫升),并将该混合物在室温下搅拌14小时。在水冷却下向反应溶液中添加水(786毫升),并将该混合物分离。水层用甲苯(1048毫升)萃取。合并的有机层连续用1N硫酸(1309毫升)、水(786毫升)、5w/v%的碳酸氢钠水溶液(786毫升)和25w/v%的氯化钠水溶液(786毫升)洗涤并随后经硫酸钠干燥。用过滤器除去硫酸钠,并随后减压浓缩。向所得残余物中添加甲苯(262毫升),并将该混合物减压浓缩以获得标题化合物的粗产物(348克)。
步骤13
(S)-2-甲基-丙烷-2-亚磺酸[(R)-1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-羟基甲基-1,3-二甲基-丁基}酰胺
在-78℃的冷却下在氮气流下向1M二异丁基氢化铝/甲苯溶液(2932毫升)中逐滴添加(R)-3-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-异丙基-3-((S)-2-甲基-丙烷-2-亚磺酰氨基)丁酸甲酯(348克)在甲苯(1392毫升)中的混合溶液1小时。将反应溶液在-78℃的冷却下搅拌2小时。在20℃或更低的内部温度下,在冰冷却下将反应溶液添加到柠檬酸一水合物(622克)在水(2088毫升)中的混合溶液中。将该混合物在室温下搅拌15小时,并随后分离。水层用甲苯(1044毫升)萃取。合并的有机层连续用水(1740毫升)和25w/v%的氯化钠水溶液(1740毫升)洗涤,随后经硫酸钠干燥。用过滤器除去硫酸钠,随后减压浓缩滤液以获得标题化合物的粗产物(645克)。
步骤14
(R)-3-氨基-3-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-异丙基-丁-1-醇盐酸盐
将(S)-2-甲基-丙烷-2-亚磺酸[(R)-1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-羟基甲基-1,3-二甲基-丁基}酰胺(327克)在甲苯(1309毫升)中混合。在冰冷却下向反应溶液中逐滴添加2M氯化氢/甲醇溶液(740毫升)20分钟,并将该混合物在水冷却下搅拌2小时。减压浓缩反应溶液,并向残余物中添加二异丙醚(250毫升)。将该混合物减压浓缩,随后向残余物中添加二异丙醚(4155毫升)。将该混合物在加热至90℃下搅拌6小时。将反应溶液搅拌8小时,缓慢冷却至室温,并随后将沉淀固体过滤以获得标题化合物(195克)。
步骤15
3-{3-[(R)-1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-羟基甲基-1,3-二甲基-丁基]脲基}双环[1.1.1]戊烷-1-甲酸甲酯
在氩气流下将3-(甲氧基羰基)双环[1.1.1]戊烷-1-甲酸(63.8克)在甲苯(761毫升)中混合,并经5分钟或更长时间在水冷却下向其中逐滴添加三乙胺(57.5毫升)。经7分钟或更长时间在水冷却下向其中逐滴添加叠氮磷酸二苯酯(89毫升),并将该混合物搅拌30分钟。将该混合物在加热至100℃的情况下搅拌1小时30分钟。将反应溶液在冰冷却下经37分钟逐滴添加到悬浮液中,所述悬浮液通过以下步骤来制备:将(R)-3-氨基-3-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-异丙基-丁-1-醇盐酸盐(117克)与四氢呋喃(819毫升)混合并随后在水冷却下经5分钟或更短时间向该混合物中逐滴添加三乙胺(47.9毫升)。将该混合物在冰冷却下搅拌30分钟,并随后在室温下搅拌1小时30分钟。在冰冷却下经15分钟或更长时间向该混合物中逐滴添加1N盐酸(1170毫升),随后分离该混合物。有机层连续用水(585毫升)、5w/v%的碳酸氢钠水溶液(585毫升,两遍)、水(585毫升)和25w/v%的氯化钠水溶液(585毫升)洗涤,随后经硫酸钠干燥。用过滤器除去硫酸钠,随后减压浓缩滤液。向所得残余物中添加环戊基甲基醚,并将该混合物减压浓缩。将该程序重复两遍以获得标题化合物的粗产物(192克)。
步骤16
3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸甲酯
在氮气流下将(二乙酰氧基碘代)苯(111克)和2,2,6,6-四甲基哌啶-1-氧自由基(2.44克)在乙酸(632毫升)中混合,并在室温下向该混合物中逐滴添加3-{3-[(R)-1-[4-((1R,2R)-2-叔丁基环丙基)-3-氯-苯基]-2-羟基甲基-1,3-二甲基-丁基]脲基}双环[1.1.1]戊烷-1-甲酸甲酯(158克)和2,2,6,6-四甲基哌啶-1-氧自由基(2.44克)在环戊基甲基醚(632毫升)中的混合溶液20分钟。将反应溶液在室温下搅拌17小时,随后在水冷却下向其中逐滴添加三氟乙酸(94毫升)9分钟。将反应溶液在室温下搅拌3小时30分钟,随后在水冷却下向其中添加10w/w%的亚硫酸钠水溶液(474毫升)。将该混合物搅拌45分钟。向该混合物中添加正庚烷(790毫升),并将该混合物分离。水层用正庚烷(474毫升)萃取。合并的有机层用水(790毫升,两遍)洗涤并随后经硫酸钠干燥。用过滤器除去硫酸钠,随后减压浓缩滤液。向所得残余物中添加甲苯,并将该混合物减压浓缩。将该程序重复两遍。向所得残余物中添加异丙醇,并将该混合物减压浓缩。将该程序重复三遍以获得标题化合物的粗产物(197克)。
步骤17
3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸
在氮气流下将3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸甲酯(197克)在异丙醇(437毫升)中混合,并在水冷却下向该混合物中逐滴添加2N的氢氧化钠水溶液(376毫升)12分钟。将反应溶液在室温下搅拌3小时,随后向其中添加正庚烷(730毫升)。将该混合物分离。水层用正庚烷(730毫升)洗涤。在甲基叔丁基醚(730毫升)中混合水层,并在冰冷却下向其中逐滴添加2N盐酸(584毫升)。随后,将该混合物分离。有机层用水(438毫升,两遍)洗涤并随后经硫酸钠干燥。用过滤器除去硫酸钠,随后减压浓缩滤液。向所得残余物中添加乙腈,并将该混合物减压浓缩以获得标题化合物的粗产物(152克)。
在氮气流下在乙腈(2127毫升)中混合所得粗产物,并将该混合物在90℃的加热下搅拌6小时。将反应溶液搅拌17小时,缓慢冷却至室温,随后将沉淀固体过滤以获得标题化合物的晶型A(110克)。
在乙酸异丁酯(659毫升)中混合所得粗晶体并在105℃的加热下搅拌。在粗晶体完全溶解后,进行热过滤。过滤器用乙酸异丁酯(200毫升)洗涤,并在105℃的加热下搅拌滤液以使沉淀固体完全溶解。在50℃的加热下将反应溶液搅拌3小时,缓慢冷却,随后向该溶液中加入晶种。在45℃的加热下将反应溶液搅拌1小时50分钟,缓慢冷却。在55℃的加热下向反应溶液中逐滴添加正庚烷(2601毫升)56分钟,并随后将该混合物搅拌2小时。将反应溶液搅拌18小时,缓慢冷却至室温,随后将沉淀固体过滤以获得标题化合物的晶型C(153克)。
将3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸(50.0毫克)在甲苯(0.1毫升)和正庚烷(0.1毫升)中混合,并将该混合物在80℃的加热下搅拌以使固体完全溶解。向该混合物中加入晶种,并将反应溶液搅拌6小时,缓慢冷却至室温。随后,将沉淀固体过滤以获得标题化合物的晶型B(45.0毫克)。
将3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸(9.71克)在丙酮(87.5毫升)和水(29毫升)中混合,并将该混合物在70℃的加热下搅拌2小时以使固体完全溶解。将反应溶液在42.5℃的加热下搅拌2小时,缓慢冷却。将反应溶液搅拌15小时,缓慢冷却至室温,随后将沉淀固体过滤以获得标题化合物的晶型D(7.52克)。
将标题化合物的晶体(晶型D;50.0毫克)在丙酮(0.375毫升)和水(0.125毫升)中混合,并将该混合物在58℃的加热下搅拌直到固体完全溶解。将反应溶液搅拌8天,冷却至室温,随后将所得固体过滤以获得标题化合物的另一种晶体(晶型E;18.6毫克),其在下面的程序中用于晶种。
将3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸(500毫克)在丙酮(3.6毫升)和水(0.9毫升)中混合,并将该混合物在70℃的加热下搅拌以使固体完全溶解。在50℃的加热下,将晶种添加到反应溶液中,并将反应溶液搅拌1小时。在50℃的加热下,向其中添加水(3毫升),并将该混合物搅拌2小时。将反应溶液搅拌3小时,缓慢冷却至室温,随后将沉淀固体过滤以获得标题化合物的晶型E(483毫克)。
[实施例2]
3-{(S)-5-((S)-仲丁基)-4-[4-(2-叔丁基-环丙基)-3-氯-苯基]-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸的合成
步骤1
(S)-2-[(R)-1-(4-溴-3-氯-苯基)-1-((S)-2-甲基-丙烷-2-亚磺酰氨基)-乙基]-3-甲基戊酸乙酯
在氩气下将2M二异丙基酰胺锂/四氢呋喃/正庚烷/乙苯溶液(45毫升)在四氢呋喃(45毫升)中混合。在-78℃的冷却下向反应溶液中逐滴添加(S)-3-甲基-戊酸乙酯(12.9克)在四氢呋喃(30毫升)中的混合溶液,并将反应溶液在-78℃下搅拌2小时。向反应溶液中逐滴添加(S)-2-甲基-丙烷-2-亚磺酸[1-(4-溴-3-氯-苯基)-乙-(E)-叉基]-酰胺(15.0克)在四氢呋喃(40毫升)中的混合溶液,并将反应溶液在-78℃的冷却下搅拌2小时。向反应溶液中添加饱和氯化铵水溶液,并在室温下搅拌该混合物。将反应溶液的层分离,水层用乙酸乙酯萃取(两遍)。合并的有机层用盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(甲苯:乙酸乙酯 = 4:1)提纯以获得标题化合物的非对映异构体的混合物(8.9克)。
步骤2
(S)-2-甲基-丙烷-2-亚磺酸[(1R,3S)-1-(4-溴-3-氯-苯基)-2-羟基甲基-1,3-二甲基-戊基}酰胺
在氩气下在-78℃的冷却下向1M二异丁基氢化铝/甲苯溶液(202毫升)中逐滴添加(S)-2-[(R)-1-(4-溴-3-氯-苯基)-1-((S)-2-甲基-丙烷-2-亚磺酰氨基)-乙基]-3-甲基戊酸乙酯(24.3克)在甲苯(100毫升)中的混合溶液。将反应溶液在-78℃的冷却下搅拌2小时25分钟。在-78℃的冷却下向反应溶液中添加甲醇(24.5毫升)。在-78℃的冷却下向反应溶液中添加饱和(+)-酒石酸钾钠水溶液(250毫升),并将该混合物在室温下搅拌2小时。将反应溶液的层分离,水层用甲苯(300毫升)萃取。合并的有机层用饱和(+)-酒石酸钾钠水溶液(200毫升)、水(200毫升)和盐水(200毫升)洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物与甲苯共沸以获得标题化合物的非对映异构体的粗混合物(24.7克)。
步骤3
(S)-2-[(R)-1-氨基-1-(4-溴-3-氯-苯基)-乙基]-3-甲基-戊-1-醇
将2-甲基-丙烷-2-亚磺酸[(1R,3S)-1-(4-溴-3-氯-苯基)-2-羟基甲基-1,3-二甲基-戊基}酰胺(24.7克)在甲苯(124毫升)中混合。在冰冷却下向反应溶液中逐滴添加2M氯化氢/甲醇溶液(50.4毫升),并且在用水浴冷却下将反应溶液搅拌3小时。在冰冷却下向反应溶液中添加4N氢氧化钠水溶液(25毫升)。在冰冷却下通过添加2N氢氧化钠水溶液将反应溶液的pH值调节至12。将反应溶液的层分离,水层用甲苯(200毫升)萃取。合并的有机层用盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物与甲苯共沸以获得标题化合物的非对映异构体的粗混合物(19.5克)。
步骤4
3-{3-[(1R,3S)-1-(4-溴-3-氯-苯基)-2-羟基甲基-1,3-二甲基-戊基]脲基}双环[1.1.1]戊烷-1-甲酸甲酯
在氩气下将3-(甲氧基羰基)双环[1.1.1]戊烷-1-甲酸(5.2克)和甲苯(50毫升)混合,并在室温下向其中添加叠氮磷酸二苯酯(7.2毫升)和三乙胺(4.6毫升)。将反应溶液在110℃的加热下搅拌1小时。在冰冷却下经10分钟将反应溶液逐滴添加到(S)-2-[(R)-1-氨基-1-(4-溴-3-氯-苯基)-乙基]-3-甲基-戊-1-醇(9.8克)在四氢呋喃(50毫升)中的溶液中。将反应溶液在室温下搅拌4小时。向反应溶液中添加N,N,N'-三甲基乙二胺(1.0毫升),并减压浓缩该溶液。向所得残余物中添加10%的柠檬酸水溶液,并用乙酸乙酯萃取该混合物(两遍)。合并的有机层用盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 = 1:1)提纯以获得标题化合物(10.4克)。
步骤5
3-[(S)-4-(4-溴-3-氯-苯基)-5-((S)-仲丁基)-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基]-双环[1.1.1]戊烷-1-甲酸甲酯
在氩气下将3-{3-[(1R,3S)-1-(4-溴-3-氯-苯基)-2-羟基甲基-1,3-二甲基-戊基]脲基}双环[1.1.1]戊烷-1-甲酸甲酯(10.4克)和二氯甲烷(100毫升)混合,并在室温下向其中添加(二乙酰氧基碘代)苯(7.3克)和2,2,6,6-四甲基哌啶-1-氧自由基(0.323克)。将反应溶液在室温下搅拌16.5小时。随后,在冰冷却下向其中添加硫代硫酸钠(0.954克)和水(40毫升)以及饱和碳酸氢钠水溶液的混合溶液。将反应溶液的层分离,水层用氯仿萃取(两遍)。合并的有机层用饱和碳酸氢钠水溶液和盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物与甲苯共沸。将所得残余物在甲苯(100毫升)中混合,并在室温下向其中添加五氟苯胺三氟甲磺酸盐(0.345克)。将反应溶液在110℃的温热下搅拌3小时。减压浓缩反应溶液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 =1:2)提纯以获得标题化合物(4.6克)。
步骤6
3-{(S)-5-((S)-仲丁基)-4-[4-(2-叔丁基-环丙基)-3-氯-苯基]-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸甲酯
在氩气下将3-[(S)-4-(4-溴-3-氯-苯基)-5-((S)-仲丁基)-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基]-双环[1.1.1]戊烷-1-甲酸甲酯(4.6克)、反式-2-叔丁基-环丙基-三氟硼酸钾(2.4克)、[1,1'-双(二-叔丁基-膦基)二茂铁]二氯化钯(II)(0.62克)、碳酸铯(9.4克)、甲苯(50毫升)和水(5毫升)混合。将反应溶液在100℃的加热下搅拌3.5小时。在用水浴冷却下向反应溶液中添加1-吡咯烷二硫代甲酸铵(0.69克),并将该混合物搅拌50分钟。在室温下向反应溶液中添加额外的1-吡咯烷二硫代甲酸铵(0.69克),并将该混合物搅拌20分钟。通过硅藻土过滤不溶性物质。将滤液分离,所得水层用乙酸乙酯萃取(两遍)。合并的有机层用盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。所得残余物通过硅胶柱色谱法(乙酸乙酯:正己烷 = 1:2)提纯以获得非对映异构体混合物(3.5克)。所得非对映异构体混合物(0.84克)用手性制备柱提纯以获得标题化合物(0.29克)。
制备柱的提纯条件显示如下。
制备设备:循环制备型液相色谱仪LC-9225 NEXT SERIES, Japan AnalyticalIndustry Co., Ltd.
柱:Daicel CHIRALPAK IA 2.0 cmφ×25 cm
流动相:己烷:2-丙醇 = 93:7
流量:10.0 mL/min
检测:UV (220 nm)。
用手性柱进行测量显示所得标题化合物的保留时间为10.0分钟(标题化合物的非对映异构体的保留时间为9.4分钟),纯度为99%。手性柱的分析条件显示如下。
测量设备:HPLC系统, Shimadzu Corporation, 高效液相色谱仪Prominence
柱:Daicel CHIRALPAK IA-3 0.46 cmφ×15 cm
柱温:40℃
流动相:己烷:2-丙醇 = 95:5
流量:1.0 mL/min
检测:UV (220 nm)。
步骤7
3-{(S)-5-((S)-仲丁基)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸
将3-{(S)-5-((S)-仲丁基)-4-[4-(2-叔丁基-环丙基)-3-氯-苯基]-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸甲酯(0.287克)、四氢呋喃(2毫升)和甲醇(2毫升)混合,并在室温下向其中添加2N氢氧化钠水溶液(0.58毫升)。将反应溶液在室温下搅拌18小时。将反应溶液浓缩,向所得残余物中添加1N盐酸和水。用乙酸乙酯萃取该混合物(两遍)。合并的有机层用盐水洗涤,随后经硫酸钠干燥。通过过滤器除去硫酸钠,随后减压浓缩滤液。向所得残余物中添加乙腈(1.5毫升)和水(10毫升),并在室温下搅拌该混合物。将沉淀固体过滤以获得标题化合物(0.268克)。
通过单晶X射线结构分析确定标题化合物的不对称碳的绝对构型。
[实施例3]
3-{(S)-4-[4-((1R,2R)-2-叔丁基-环丙基)-3-氯-苯基]-5-异丙基-4-甲基-2-氧代-3,4-二氢-2H-嘧啶-1-基}双环[1.1.1]戊烷-1-甲酸的结晶多晶型物
对标题化合物的晶型A至E进行了X射线粉末衍射(XRD)、热重分析和差示热分析(TG-DTA)的同时测量以及差示扫描量热法(DSC)。各测量的测量设备和条件如下所示。
粉末X射线衍射法:
测量设备:X'pert-PRO-MPD(Spectris Co., Ltd.)
测量条件:X射线, Cu/45 kV/40 mA, 通过透射法分析。
热重分析和差示热分析的同时测量:
测量设备:TGA/SDTA851e/SF(Mettler Toledo International Inc.)
测量条件:加热速率5℃/min。
差示扫描量热法:
测量设备:DSC Q2000(TA Instruments Japan Inc.)
测量条件:加热速率10℃/min。
各晶型的各测量结果如下所示。
A.晶型A
XRD数据显示在图1中。各个峰的衍射角2θ和衍射强度如下所示。
DSC数据显示在图2中。DSC曲线上的吸热峰的焓为68.5 J/g,吸热温度为195℃,外推起始温度为193℃。
B.晶型B
XRD数据显示在图3中。各个峰的衍射角2θ和衍射强度如下所示。
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DSC数据显示在图4中。DSC曲线上的吸热峰的焓为76.0 J/g,吸热温度为230.2℃,外推起始温度为229.6℃。
C.晶型C
XRD数据显示在图5中。各个峰的衍射角2θ和衍射强度如下所示。
DSC数据显示在图6中。
D.晶型D
XRD数据显示在图7中。各个峰的衍射角2θ和衍射强度如下所示。
TG-DTA数据显示在图8中。脱水造成的重量降低率为3.6%。该值对应于标题化合物的一水合物的理论含水量,晶型D被认为是标题化合物的一水合物。
DSC数据显示在图9中。DSC曲线上的吸热峰的焓为118.4 J/g,吸热温度为128.0℃,外推起始温度为118.9℃。
E.晶型E
XRD数据显示在图10中。各个峰的衍射角2θ和衍射强度如下所示。
TG-DTA数据显示在图11中。熔融造成的重量降低率为3.9%。该值对应于标题化合物的一水合物的理论含水量,晶型E被认为是标题化合物的一水合物。
DSC数据显示在图12中。DSC曲线上的吸热峰的焓为138.1 J/g,吸热温度为125.9℃,外推起始温度为115.0℃。
[测试实施例1]
针对RORγ转录活性的抑制效果的体外检测
通过测试化合物的报告基因检测来评估针对RORγ转录活性的抑制效果。
基于人RORγ(Genbank注册号NM_005060.3)和小鼠RORγ(Genbank注册号NM_011281.2)的序列获得编码人和小鼠RORγ配体结合结构域(LBD)的cDNA(LBD序列:对于人RORγ,从Ser253至Lys518;对于小鼠RORγ,从Ile251至Lys516)。
将人和小鼠RORγ的LBD cDNA插入pFA-CMV载体(Agilent Technologies, Inc.),其表达GAL4-DNA结合结构域融合蛋白。所得质粒在下文中被分别称为pFA/hRORγ质粒和pFA/mRORγ质粒。
将pFA/hRORγ质粒或pFA/mRORγ质粒瞬时共转染到含有pG5-Luc的中国仓鼠卵巢细胞(CHO细胞)(Promega)中,报告质粒以GAL4依赖方式表达荧火虫荧光素酶。
TransIT(注册商标)CHO转染试剂盒(Mirus)用于共转染CHO细胞与质粒。在检测前一天,将CHO细胞悬浮在含有10%(v/v)胎牛血清的HAM F-12营养培养基中并以每225 cm2细胞培养瓶5.5×106个细胞接种。将72 μL的TransIT(注册商标)CHO试剂添加到含有1.55 mL的Opti-MEM的2毫升管中,并随后在室温下混合并温育10分钟。将50.4 μL含有300 ng的pFA/hRORγ质粒、12000 ng的pG5-Luc质粒和11700 ng的pcDNA3.1质粒的质粒溶液添加到该管中并轻轻混合。在小鼠检测的情况下,取而代之,添加含有300 ng的pFA/mRORγ质粒、12000 ng的pG5-Luc质粒和11700 ng的pcDNA3.1质粒的质粒溶液。将该混合物在室温下温育10分钟。随后向各管中加入12 μL的CHO Mojo试剂,并轻轻混合。将该混合物在室温下温育10分钟。将所得转染试剂施用于细胞培养物。在37℃、5% CO2下温育4小时后,通过胰蛋白酶处理收获质粒转染的CHO细胞。将收集的细胞重新悬浮在培养基中并以8,000个细胞/35μL/孔接种到白色384孔板中。将该板在室温下静置1小时,随后在37℃、5% CO2下温育3小时。将测试化合物溶解在二甲基亚砜(DMSO)中以获得10 mM的浓度。各溶液用DMSO连续稀释并在临使用前用培养基进一步稀释。以6种不同浓度将测试化合物溶液添加到该板中的细胞中。DMSO的最终浓度为0.2%(v/v)。在添加测试化合物之后,将细胞在37℃、5% CO2下温育2天。
用CellTiter-Glo(Promega)通过发光法测试细胞活力。在添加测试化合物后两天,将40 μL的CellTiter-Glo各自添加到384孔板中。在添加后十分钟,用微孔板读板机(microplate reader)测量各个孔的发光。将用单独的0.2% DMSO处理过的细胞中的发光计数定义为100%,并基于单独的0.2% DMSO的值以百分比形式(对照的%)计算用测试化合物处理后的细胞活力。当细胞活力为70%或更低时,测试化合物被评估为具有细胞毒性。
使用SteadyLite HTS报告基因检测系统(Perkin Elmer)以细胞内荧光素酶活性形式检测RORγ转录活性。用扩增(Extension)缓冲液(10 mM Tricine,0.2%(w/v)牛血清白蛋白,0.02%(v/v) Tween-20)将StedyLite试剂稀释2.5倍以获得荧光素酶底物溶液。在添加测试化合物后两天,将40 μL的荧光素酶底物溶液各自添加到384孔板中。在室温下温育10分钟后,用微孔板读板机测量各个孔的发光。将衍生自用单独的0.2% DMSO处理的媒介物-对照孔中的发光计数的荧光素酶活性定义为100%,并作为基于媒介物-对照的值的百分比(对照的%)计算用测试化合物处理后的荧光素酶活性。通过曲线拟合计算测试化合物的EC50值。从数据分析中排除在观察到细胞毒性时的测试化合物浓度下的发光计数。
结果显示在下表中。
[测试实施例2]
体外代谢稳定性的评估
A.在肝微粒体中的代谢稳定性
(1)测试溶液的制备
通过用乙腈将测试物质的10 mM DMSO溶液稀释100倍来制备测试溶液。
(2)采用肝微粒体的代谢稳定性研究
用磷酸钾缓冲液(pH 7.4)将人和动物肝微粒体(SEKISUI XENOTECH;人(H2610)、大鼠(R1000)、小鼠(M1000)、猴子(P2000)、狗(D1000))调节至在反应体系中0.2 mg/mL。随后,将制备的1%的测试物质溶液添加到反应体系中。向其中添加NADPH生成体系(根据非专利文献28的方法制备),并启动代谢反应。在指定时间,向其中添加0.1%甲酸-乙腈/水(3:1),终止该反应。
(3)通过LC/MS分析
通过离心(1400 g,20分钟)分离反应终止后的样品,随后通过LC/MS(UPLC-SQD(waters))测量上清液以计算未反应物质的残余比。
B.在肝细胞中的代谢稳定性
(1)测试溶液的制备
通过用乙腈将测试物质的10 mM DMSO溶液稀释20倍来制备测试溶液。
(2)采用肝细胞的代谢稳定性研究
用William培养基E(SIGMA;W1878)将人和动物的冷冻保存的肝细胞(BIOIVT;人(IVT-X008000)、大鼠(IVT-M00005)、猴子(IVT-M00305)、狗(IVT-M00205))调节至每毫升细胞悬浮液1×106个细胞,随后将其添加到96孔板中。随后,将制备的1%的测试物质溶液添加到反应体系中,并启动代谢反应。在指定时间,向其中添加0.1%甲酸-乙腈,终止该反应。
(3)通过LC/MS分析
通过离心(1400 g,20分钟)分离反应终止后的样品,随后通过LC/MS(UPLC-SQD(waters))测量上清液以计算未反应物质的残余比。
结果显示在下表中。
[测试实施例3]
测量诱导CYP3A4的潜力
根据所附协议用核受体活化试剂盒(PURACYP;DPX2-96-002)评价诱导CYP3A4的潜力。
用随附核受体活化试剂盒(PURACYP;DPX2-96-002)的物质进行以下实验。
测量方法具体显示如下。在96孔板上接种DPX2细胞并用CO2培养箱温育24小时。通过向培养基中添加0.1%的测试化合物的DMSO溶液(1、3、10 mM)或作为阳性对照的利福平(10 mM)来制备化合物补充培养基。在接种后24小时用抽吸器移除96孔板上的培养基,并向其中添加制备的化合物补充培养基。在添加化合物后48小时,向培养基中添加CellTiter-Fluor,并且将该混合物用CO2培养箱温育1小时。随后,通过荧光法测量细胞活力。将ONE-Glo添加到该混合物中,并且将该混合物用CO2培养箱温育5分钟。随后,通过发光测定来测量报告活性。通过比较所得报告活性与DMSO对照样品来计算诱导率。由以下方程计算阳性对照的%。
结果显示在下表中。
[测试实施例4]
溶解度测量
将测试物质的10 mM DMSO 溶液(10微升)添加到96孔板中,并用离心蒸发器(Genevac HT-4X)将该混合物浓缩并干燥。在蒸发后向孔中添加200 μL的各溶剂(JP1、JP2、FaSSIF、FeSSIF)(参见非专利文献29和30)。将该混合物在室温下以2500 rpm摇振4小时。随后,将该混合物分两部分用MultiScreen PCF过滤器(MERCK Millipore;MSSLBPC)过滤以获得样品(50和100微升)。从第二次过滤获得的样品中收集40 μL,并向其中添加乙腈(300微升)。在将该混合物离心(4000 g,5分钟)后,通过LC-UV/MS(UPLC-Premier (waters))测量上清液的一部分。
结果显示在下表中。
[测试实施例5]
大鼠药代动力学(PK)检测和血浆浓度测量
(1)大鼠PK研究
将测试物质(0.3 mg/kg)的DMSO溶液(0.1 mL/kg)施用于雄性大鼠(7周龄),并在指定时间(5、10、15、30分钟,1、2、4、8、25小时)收集血液。收集血液后的样品通过离心分离(11000 g,5分钟)以获得血浆。
(2)血浆浓度的测量
将双倍体积的乙腈/水(9:1)的混合溶液添加到(1)中获得的血浆样品中,以便从该混合物中提取蛋白质。提取后的样品通过离心分离(11000 g,5分钟),并通过LC/MSMS(Nexera (Shimadzu)-QTrap5500 (AB SCIEX))测量上清液。同时测量校准曲线,并计算血浆浓度。
由血浆浓度曲线中消除阶段的两个点来计算消除速率常数(Kel),并由消除速率常数计算半衰期(T1/2)。
Kel = -(ln Conc1 - ln Conc2)/(t1-t2)
T1/2 = 0.693/Kel。
结果显示在下表中。
[测试实施例6]
测试物质对抗原致敏小鼠血浆中的IL-17产生的效果
在抗原致敏小鼠中评估了测试物质对血浆中的IL-17产生的效果。根据非专利文献31进行抗原致敏。九周龄的雌性C57BL/6J小鼠(Japan Charles River K.K.)用作测试动物。
将通过等比混合3 mg/mL的髓鞘少突胶质细胞糖蛋白(MOG;ANASPEC)和4 mg/mL的弗氏完全佐剂(CFA;Chondrex)制备的乳液在双侧腹部处以50 μL/部位的量皮下施用于小鼠(第1天)。以200 μL/头的量腹膜内施用1 μg/mL的百日咳毒素(PTX;List BiologicalLaboratories)(第1和3天)。在第8天收集血液。
在施用乳液后,每天一次进行给药持续7天(第1至7天)。将0.5%(w/v)的甲基纤维素(MC)以10 mL/kg的量经口施用于正常组(正常小鼠)和媒介物组(抗原致敏小鼠),并将悬浮在0.5%(w/v) MC中的0.03 mg/mL或0.1 mg/mL的测试物质以10 mL/kg的量经口施用于化合物给药组。
通过离心分离血液,随后用Quantikine(注册商标)Mouse IL-17 ELISA试剂盒(R&D systems, Inc.)测量血浆中的IL-17浓度。
正常组的IL-17浓度被认为是0%,媒介物组的IL-17浓度被认为是100%。由以下方程计算化合物给药组的IL-17浓度百分比(对照的%)。
对照的% = (a-b)/(c-b)×100
a:化合物给药组的IL-17浓度
b:正常组的IL-17浓度
c:媒介物组的IL-17浓度。
随后,由以下方程计算IL-17浓度降低50%时的化合物剂量(ED50)。
ED50 = 10{log(A/B)×(50-D)/(C-D)+log(B)};条件是在D = 50的情况下ED50 = B,在D > 50的情况下ED50 > B
A:较低剂量组的给药量(即0.3 mg/kg)
B:较高剂量组的给药量(即1 mg/kg)
C:在较低剂量组的对照的%
D:在较高剂量组的对照的%。
结果显示在下表中。
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[测试实施例7]
测试物质对细胞因子刺激的正常小鼠的血浆中的IL-17产生的效果
在正常小鼠中评估了测试物质对血浆中的IL-17产生的效果。根据非专利文献32进行评估。九周龄的雌性C57BL/6J小鼠(Japan Charles River K.K.)用作测试动物。
将通过以1.5 μg/mL的最终浓度混合重组小鼠IL-1β/IL-1F2蛋白质(R&Dsystems,INC.)和重组小鼠IL-23蛋白质(R&D systems,INC.)制备的混合溶液在尾静脉处以200 μL/头的量静脉内施用于所有组。在施用细胞因子溶液后2小时收集血液。
在施用细胞因子溶液之前28小时进行施用。将0.5%(w/v)甲基纤维素(MC)和悬浮在0.5%(w/v) MC中的0.1 mg/mL的测试物质以0.2 mL/头的单一量分别经口施用于媒介物组和化合物给药组。
通过离心分离血液,随后用Quantikine(注册商标)Mouse IL-17 ELISA试剂盒(R&D systems, Inc.)测量血浆中的IL-17浓度。
媒介物组的IL-17浓度被认为是100%,并由以下方程计算化合物给药组对媒介物组的IL-17浓度百分比。结果显示在下表中。
% = a/b×100
a:化合物给药组的IL-17浓度
b:媒介物组的IL-17浓度。
[制剂实施例]
本发明中的制剂实施例包括例如以下制剂。然而,本发明并非意在限于这些制剂实施例。
制剂实施例1(胶囊剂的制备)
1)实施例1化合物 30 mg
2)微晶纤维素 10 mg
3)乳糖 19 mg
4)硬脂酸镁 1 mg。
将成分1)、2)、3)和4)混合以填充到明胶胶囊中。
制剂实施例2(片剂的制备)
1)实施例1化合物 10 g
2)乳糖 50 g
3)玉米淀粉 15 g
4)羧甲基纤维素钙 44 g
5)硬脂酸镁 1 g。
将成分1)、2)和3)的全部量以及30克的成分4)与水组合,真空干燥,并随后造粒。将所得粒料与14克的成分4)和1克的成分5)混合,并用压片机压片。以这种方式,获得每片包含10 mg的实施例1化合物的1000片片剂。
工业可利用性
式(1)或(2)的化合物或其可药用盐预期可用于治疗或预防自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病。
Claims (8)
1.式(1)或(2)的化合物:
或其可药用盐。
2.根据权利要求1所述的化合物,其中所述化合物是式(1)的化合物:
或其可药用盐。
3.根据权利要求1所述的化合物,其中所述化合物是式(2)的化合物:
或其可药用盐。
4.药物组合物,其包含根据权利要求1至3任一项所述的化合物或其可药用盐,以及可药用载体。
5.RORγ拮抗剂,其包含根据权利要求1至3任一项所述的化合物或其可药用盐。
6.用于选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病的治疗或预防剂,其包含根据权利要求1至3任一项所述的化合物或其可药用盐。
7.根据权利要求1至3任一项所述的化合物或其可药用盐在制备RORγ拮抗剂中的用途。
8.根据权利要求1至3任一项所述的化合物或其可药用盐在制备用于选自自身免疫性疾病、变应性疾病、干眼症、纤维化、癌症、代谢性疾病、缺血、心肌病、高血压和牙周病的疾病的治疗或预防剂中的用途。
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CA3087994A1 (en) | 2019-09-06 |
CL2020002187A1 (es) | 2020-12-18 |
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EP3760616A1 (en) | 2021-01-06 |
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RU2020131402A (ru) | 2022-03-24 |
KR20200126973A (ko) | 2020-11-09 |
US10899717B2 (en) | 2021-01-26 |
EP3760616A4 (en) | 2021-11-03 |
JP7282546B2 (ja) | 2023-05-29 |
SG11202007117RA (en) | 2020-08-28 |
AR114270A1 (es) | 2020-08-12 |
BR112020016785A2 (pt) | 2021-02-09 |
AU2019228915A1 (en) | 2020-07-02 |
US20210363110A1 (en) | 2021-11-25 |
PE20210550A1 (es) | 2021-03-17 |
IL276323A (en) | 2020-09-30 |
TW202000650A (zh) | 2020-01-01 |
CN111741947A (zh) | 2020-10-02 |
JP2019151623A (ja) | 2019-09-12 |
PH12020551341A1 (en) | 2021-06-21 |
CO2020011860A2 (es) | 2021-01-18 |
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