CN117085014A - 恩那度司他晶型及用途 - Google Patents
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Abstract
本发明涉及恩那度司他晶型及用途。本申请首次公开了恩那司他用于制备治疗库欣病药物的用途。并首次公开了恩那司他晶型II及其制备方法。与现有的晶型N2和晶型N21相比,晶型II对库欣病具有更加显著的治疗效果。
Description
技术领域
本发明属于医药技术领域,更特别地,涉及恩那度司他的晶型及其制备方法和用途。
背景技术
库欣综合征(Cushing syndrome)是由于机体长期接受过多糖皮质激素所导致的一组症候群,根据病因可分为促肾上腺皮质激素(ACTH)依赖性和非依赖性。ACTH非依赖性主要是由肾上腺腺瘤、肾上腺腺癌、肾上腺大结节增生及少数原发色素性结节状肾上腺皮质病所导致;ACTH依赖性占Cushing综合征的70-80%,其中60-70%为垂体腺瘤所致,又称库欣病(Cushing’s didisease,CD)。肿瘤过度分泌ACTH引起高皮质醇血症进而引起向心性肥胖、高血压、糖耐量受损、血脂紊乱、凝血障碍、骨质疏松、精神异常等一系列多系统紊乱症候群,而这一系列并发症使患者的死亡率比一般人群高4倍。
流行病学调查显示库欣病的人群发病率为2-3人/百万/年。库欣病起病隐匿、发展迅速,难以控制,给临床诊断和治疗带来了极大的挑战,也给患者家庭乃至社会带来了沉重的负担。
未经治疗的库欣病预后不良,常由于严重的心血管并发症及代谢异常使得致残率和致死率成倍增加,5年生存率仅为约50%。持续的高皮质醇血症除了导致高血压、糖尿病外,亦可导致高脂血症、代谢综合征、凝血功能异常、骨质疏松、低钾血症、抑郁、焦虑及认知功能损害等,使得患者的生活质量低下。
及时正确的诊断和治疗,能降低患者的死亡率,提高患者的生活质量,避免心脑血管事件的发生,对库欣综合征患者有重大意义。
治疗方面,库欣病的治疗有手术治疗、放射治疗、药物治疗三种方法。
经蝶手术被认为是首选的治疗方法,经蝶手术的治疗目标在于完全切除垂体病灶、达到正常的皮质醇水平而不致引起垂体功能低下。由于手术显微镜的发展及神经导航等技术的广泛应用,目前95%的垂体腺瘤可以经蝶手术切除,具有创伤小、并发症少、恢复快、费用低等优点,通常,经蝶手术治疗库欣病可以实现较高的缓解率。经蝶手术的常见并发症有新发垂体功能低下(约10%的患者),以及永久性尿崩症、脑脊液漏和静脉血栓栓塞(VTE)等。对于手术后疗效不佳的患者,可考虑再次经蝶手术或者放射治疗及药物治疗。
治疗的药物包括两类:
A、作用于肾上腺的药物,通过抑制皮质醇合成发挥作用,如酮康唑、美替拉酮、依托咪酯等;
B、主要作用于垂体的药物,通过抑制分泌发挥作用,代表药物有帕瑞肽、卡麦角林、赛庚啶、罗格列酮等。最近,有学者指出,酪氨酸激酶抑制剂(吉非替尼可能会应用于库欣病的治疗。
经有效的治疗后,库欣病患者致残率及致死率可显著下降,进而达到基本与正常人持平的生存率水平。
但是,目前的治疗,无法有效控制库欣病,或具有较大的安全性隐患,因此临床上亟待开发新的药物用于进一步的治疗。
醛固酮为盐皮质激素受体(下文中也称为“MR”)特异性配体,是肾素-血管紧张素-醛固酮系统(RAAS)中的媒介物之一。醛固酮过去被认为主要在肾上腺中产生、作用于肾脏的远端肾小管而对钠和水的代谢加以调节的盐皮质激素。但是,在最近的研究中发现醛固酮在心脏、血管、脑等多种组织中产生,也广泛分布于心血管等组织中,还认识到醛固酮不仅是高血压的恶化因子,而且对心血管组织显示出多种障碍性作用(心脏纤维化及坏死、儿茶酚胺的作用增强、压力感受器反应的降低等)的危险激素。
对于与醛固酮及其受体相关的心血管系统疾病而言,阻断该激素作用的手段是有效的治疗方法。对MR具有亲和性、阻断其受体功能的MR拮抗剂(例如依普利酮或螺内酯)已经被应用于高血压治疗。此外,在大规模临床试验(RALES及EPHESUS实验)中,确认了通过MR拮抗剂与ACE抑制剂等常用治疗剂的并用,使得重症心力衰竭患者由心脏疾病导致的住院率及死亡率显著降低,并显著改善了急性心肌梗塞患者的预后。
另一方面,MR拮抗剂(例如螺内酯或依普利酮)具有特有的严重副作用(例如高钾血症),此外,对于螺内酯而言,伴有女性化乳房、月经异常、勃起功能障碍等的情况也不在少数。因此,在对与醛固酮相关的疾病的治疗中,期望开发出副作用少、安全性更高的化合物。作为从该观点出发的替代性方案(即,用于阻断或减弱醛固酮的效果的其他方案),提出了醛固酮合成酶抑制剂。
醛固酮合成酶为细胞色素P450酶,作为催化从11-去氧皮质酮(即,醛固酮前体)至醛固酮的一系列反应的酶而为人们所知。醛固酮合成酶主要在肾上腺皮质球状带中表达,血浆中的醛固酮受到肾上腺中的该酶活性的调节。此外,在心血管系统、肾、脂肪组织、脑等肾上腺以外的部位中也确认到了醛固酮的表达,在各器官局部产生的醛固酮与器官功能障碍有关。
有报道称,醛固酮合成酶抑制剂在使用酶及培养细胞的研究中能抑制醛固酮的产生,在使用各种实验动物模型的研究中具有抑制醛固酮产生的效果及治疗效果。此外,已确认了醛固酮合成酶抑制剂在高血压患者及原发性醛固酮症患者中显示出降低血浆中及尿中的醛固酮水平的作用及降压作用。总之,找到阻碍醛固酮的生物合成途径的手段是用于确立与醛固酮相关的各种疾病的有效治疗方法的可实现性高的方案。
醛固酮合成酶由醛固酮合成酶基因(CYP11B2)编码,CYP11B2和11-β羟化酶基因(CYP11B1)有95%完全相同的核苷酸序列,它们前后排列于人类8号染色体上(8q24),中间仅间隔40kb,二者总长均约为7kb,均含排列顺序完全相同的9个外显子和8个内含子。它们编码的蛋白质,有93%的氨基酸序列完全相同。CYP11B1基因编码11-β羟化酶(11β-hydroxylase)参与11-脱氧皮质酮生成皮质酮的羟化反应;同时,在肾上腺皮质的束状带,11-脱氧皮质酮最终在11-β羟化酶的作用下生成皮质醇。所以,CYP11B2和CYP11B1基因与库欣病的发病相关性成为研究的焦点。
2013年,FDA授予奥西卓司他(Osilodrostat)治疗库欣氏综合征的孤儿药资格;2020年1月获EMA批准上市,2020年3月获FDA批准上市。
Osilodrostat是一种皮质醇合成抑制剂。它抑制11β-羟化酶(CYP11B1),该酶负责肾上腺皮质醇生物合成的最后一步。在过表达人CYP11B1、肾上腺素和肾上腺素还原酶的中国仓鼠肺细胞系V79-4中,Osilodrostat剂量依赖性地抑制人CYP11B1的活性,IC50值为2.5±0.1nM(n=4)。
日本烟草及其子公司Akros Pharma和Torii开发了恩那度司他(Enarodustat,Enaroy;JTZ-951;SAL-0951),一种具有口服活性的小分子低氧诱导因子脯氨酰羟化酶结构域(HIF-PHD)抑制剂,刺激生成的内源性EPO(促红细胞生成素),用于潜在的治疗与慢性肾病相关的贫血。日本烟草公司及其子公司Torii也在研究该药物用于II型糖尿病的潜在治疗。
2019年12月,中国上市公司深圳信力泰药业正在大中华区研究恩那度司他,用于治疗与慢性肾病相关的贫血。
2020年6月,在中国提交了IND。2020年8月,获得了用于与慢性肾病相关的贫血的临床试验默示许可。2023年6月,获得在中国的上市许可。
2020年9月,日本烟草在日本获得了恩那度司他2mg和4mg片剂的生产和销售批准,用于治疗与慢性肾病相关的贫血。同年12月在日本上市销售。
恩那度司他,化学名:2-[[7-氧代-5-(2-苯乙基)-3H-[1,2,4]三唑并[1,5-a]吡啶-8-羰基]氨基]乙酸,分子式:C17H16N4O4,分子量:340.34,为白色结晶性粉末,熔点187℃,化学结构如下:
在发明专利:三唑并吡啶化合物及其作为脯氨酰基羟化酶抑制剂和红细胞生成素产生诱导剂的作用,公开号CN102471337A中,对恩那度司他及其合成路线做了描述,但是,并未给出其晶型相关衍射数据。
所描述的合成路线如下:
步骤116-10
将步骤116-9中获得的化合物(0.050g)和甲醇(3ml)进行混合,然后将混合物加热至60℃。将溶液冷却到室温并搅拌一天。固体通过过滤收集,得到标题化合物(0.031g,61%)。
1H-NMR(DMSO-D6)δ:3.12(t,2H,J=7.9Hz),3.40(t,3H,J=7.9Hz),4.22(d,2H,J=5.2Hz),6.79(s,1H),7.21-7.29(m,5H),8.58(s,1H),9.84(t,1H,J=5.2Hz),12.97(s,1H),14.22(s,1H)。
但是此专利文件中并未公开的所得到的化合物的晶型信息。
发明专利CN110214139A,用于生产三唑并吡啶化合物的方法,公开了恩那度司他及其药用盐的合成方法,虽然公开了化合物为晶体(本申请成为晶型I),并公开了结晶溶剂为2-丙醇和水(体积比330:83,说明书0260段)但是同样未公开其具体的XRPD衍射数据。
发明专利CN 115197210 A,对于恩那度司他的晶型做了深入细致的研究,得出结论:发明专利CN102471337A中得到的恩那度司他的晶型(说明书0986段)为N2,而CN110214139A中得到的晶型(说明书0260段)为N21。并公开了晶型N21的XRPD衍射数据,如下:
在衍射角2θ为5.6±0.2°,8.5±0.2°,10.4±0.2°,11.3±0.2°,11.5±0.2°,12.0±0.2°,13.4±0.2°,14.0±0.2°,14.2±0.2°,15.5±0.2°,17.1±0.2°,17.9±0.2°,18.6±0.2°,18.9±0.2°,19.5±0.2°,20.0±0.2°,20.4±0.2°,21.1±0.2°,22.8±0.2°,23.8±0.2°,25.1±0.2°,25.8±0.2°,26.9±0.2°,27.4±0.2°,28.1±0.2°,28.6±0.2°,29.1±0.2°,31.6±0.2°,32.1±0.2°,33.9±0.2°,37.0±0.2°和37.8±0.2°处具有特征峰。
但是迄今为止,并未有任何现有文献或专利公开恩那度司他其他的医药用途。
发明内容
发明人通过对恩那度司他晶型的研究,本申请首先公开一种恩那度司他晶型II,经X射线衍射法(XRPD)确证,在XRPD图谱上2θ角为9.3°的位置具有最强特征峰,相对强度为100%。
进一步地,本发明所述的恩那度司他晶型II,在XRPD图谱上2θ角约为23.8°的位置上具有特征峰,相对强度为33.0%。
进一步地,本发明所述的恩那度司他晶型II,在XRPD图谱上2θ角约为13.0°,13.9°,14.2°,16.3°,20.5°,20.8°,25.7°,27.0°的位置上具有特征峰,相对强度大于10%。
进一步地,本发明所述的恩那度司他晶型II,在XRPD图谱上2θ角约为17.9°,20.3°,21.2°,21.9°,22.9°,25.4°,30.0°,32.1°的位置上具有特征峰,相对强度大于5%。
进一步地,本发明所述的恩那度司他晶型II,具有如附图1所示的XRPD图谱。
本发明所述恩那度司他晶型II的XRPD数据见表1。
表1恩那度司他晶型II的XRPD数据如下:
2θ(°) | 强度% | 2θ(°) | 强度% |
9.3 | 100.0 | 25.4 | 8.1 |
23.8 | 33.0 | 21.9 | 7.6 |
13.0 | 14.6 | 20.3 | 6.8 |
16.3 | 13.7 | 22.9 | 6.6 |
13.9 | 13.6 | 21.2 | 6.1 |
20.5 | 13.6 | 32.1 | 6.0 |
27.0 | 13.4 | 30.0 | 5.4 |
14.2 | 12.2 | 17.9 | 5.3 |
25.7 | 11.8 | 30.9 | 4.7 |
20.8 | 11.5 |
。
特别的,由于XRPD测量的误差,上述所述2θ角可能存在±0.1°,甚至±0.2°的误差。
本申请其次公开晶型II的制备工艺,如下:
步骤1)将恩那度司他加入到混合溶剂中,升温,保持回流;
步骤2)将步骤1)体系冷却,析出晶体II;
步骤3)减压干燥,得到固态的晶型II。
其中,步骤1)所述溶剂为水和二甲基亚砜的混合物,混合物比例为水:二甲基亚砜=2-5:1。
步骤1)所述升温的步骤,其升温温度最低为80℃。
其中步骤2)所述冷却温度为60-65℃。
最后,本申请公开恩那度司他晶型II或其他晶型用于制备治疗库欣病药物的用途。其给药途径为口服。
所述恩那度司他通过抑制醛固酮合成酶或11β-羟化酶起效。
根据本发明的恩那度司他的晶型II需要进一步制备成具体的制剂形式。特别是固体,半固体和液体剂型,特别是固体剂型,例如片剂,胶囊。这样的剂型可以包含至少一种选自以下的赋形剂:填充剂(例如乳糖),粘合剂(例如微晶纤维素),崩解剂(例如交联羧甲基纤维素钠),润滑剂(例如硬脂酸镁),表面活性剂。
此外,药物组合物可以任选地包含选自着色剂,溶剂,抗微生物剂,调味剂和嗅觉调节剂的至少一种其他赋形剂。片剂可以用含有例如聚乙烯醇或聚乙二醇的常规包衣。所述药物组合物可以制备成几乎任何固体剂型,例如片剂,胶囊剂,散剂,丸剂或颗粒剂。优选的剂型是片剂或包衣片剂。片剂或包衣片剂可优选通过将恩那度司他与至少一种药学上可接受的赋形剂混合并将混合物进行压片,然后任选包衣来制备。
附图说明:
图1本发明中恩那度司他的晶型II的XRPD。
具体实施方式
通过以下实验进一步说明本发明的有益效果。但并不局限于下述实施例,本领域的技术人员在本发明基础上所作的,不脱离本发明实质内容的等同替代或变换,亦均在本发明的保护范围之内。
对比例1:按中国专利CN110214139A,说明书0260段,制备恩那度司他晶型N21,按中国专利CN102471337A,制备恩那度司他晶型N2。
实施例1恩那度司他晶型II的制备
取恩那度司他10g置于水(20ml)和二甲基亚砜(10ml)的混合溶液在80℃下搅拌,直至晶体溶解。将溶液冷却至60℃,搅拌2小时,析出晶体。析出的晶体通过过滤收集。将获得的湿晶体在减压下干燥,以得到恩那度司他晶体(8.9g,产率89%)。
其XRPD测试结果如附图1所示。为晶型II。
实施例2恩那度司他晶型II的制备
取恩那度司他10g置于水(30ml)和二甲基亚砜(10ml)的混合溶液在85℃下搅拌,直至晶体溶解。将溶液冷却至60℃,搅拌2小时,析出晶体。析出的晶体通过过滤收集。将获得的湿晶体在减压下干燥,以得到恩那度司他晶体(9.2g,产率92%)。经XRPD测试为晶型II。
实施例3恩那度司他晶型II的制备
取恩那度司他10g置于水(50ml)和二甲基亚砜(10ml)的混合溶液在90℃下搅拌,直至晶体溶解。将溶液冷却至65℃,搅拌3小时,析出晶体。析出的晶体通过过滤收集。将获得的湿晶体在减压下干燥,以得到恩那度司他晶体(8.1g,产率81%)。经XRPD测试为晶型II。
实施例4恩那度司他晶型II的制备
取恩那度司他10g置于水(50ml)和二甲基亚砜(10ml)的混合溶液在90℃下搅拌,直至晶体溶解。将溶液冷却至60℃,搅拌3小时,析出晶体。析出的晶体通过过滤收集。将获得的湿晶体在减压下干燥,以得到恩那度司他晶体(8.5g,产率85%)。经XRPD测试为晶型II。
实施例5恩那度司他晶体对醛固酮合成酶和类固醇11β-羟化酶的体外抑制活性(参照CN 102459223 B)
NCI-H295R细胞在75cm2细胞培养容器中、于37℃、95%空气-5%二氧化碳环境中在Dulbeoco氏改良Eagle’Ham F-12培养基(DME/F12)中生长,该培养基补充有Ultroser SF血清、胰岛素、转铁蛋白、亚硒酸盐和抗生素。为了形成菌落,随后将细胞转移至24孔培养容器中。将它们在此于DME/F12培养基中培养24小时,该培养基补充有0.1%牛血清代替Ultroser SF。通过将细胞在DME/F12培养基中培养72小时开始试验,该培养基补充有0.1%牛血清和不同晶型恩那度司他0.5%羧甲基纤维素钠混悬液,其中不加入细胞刺激物。恩那度司他加入的浓度范围在0.2纳摩尔至20毫摩尔。
根据生产商说明书,采用放射免疫分析方法,通过获自商业的特异性单克隆抗体测定醛固酮、皮质醇在培养基中的分泌。
可以通过加入实验化合物抑制某些类固醇激素的释放从而用于测定对各个酶的抑制作用。
化合物对酶活性的剂量依赖性抑制可以通过抑制曲线进行计算,以IC50为特征,所得IC50数据如表2所示。
表2恩那度司他不同晶型对于醛固酮合成酶和11β-羟化酶的抑制作用(均值,n=3,单位:nmol/L)
如上表数据可见,相对于现有恩那度司他晶型N21和N2,晶型II具有更好的醛固酮合成酶和11β-羟化酶抑制效果。
实施例6:不同晶型恩那度司他在嗅球切除大鼠中的活性(参照CN103596573 B施行)
双侧嗅球切除术(OBX)是慢性抑郁症的动物模型,其证实了下丘脑-垂体-肾上腺(HPA)轴在维持动态平衡中的关键作用。
OBX对HPA轴产生干扰并带来模型动物慢性抑郁症的行为和生理变化。在手术恢复后,OBX动物显示出体重急剧增加,并伴随其他特征性生理变化,如食物摄入量增加、抑郁发作、血清钠浓度和皮质甾醇水平升高。这些症状与库欣氏综合症有关。即OBX模型,切实模拟了库欣氏综合症的病症。
为了研究恩那度司他的活性,我们使用了双侧嗅球切除(OBX)大鼠的动物模型,其产生在库欣氏综合症中所见的所有上述症状。
实验步骤如下:
测试样品的制备:将不同晶型恩那度司他粉碎,粒径大约20um左右,将其以0.2g/ml的浓度混悬于0.5%的羧甲基纤维素钠水溶液中,制成混悬液。
雄性Wistar大鼠采用氯胺酮(80mg/kg)麻醉,并通过连至水泵的钝头皮下注射针头以手术方式吸出嗅球,而不破坏额叶。手术后动物恢复2周的时间。
用不同晶型,不同剂量水平的恩那度司他进行长期治疗,持续14天,每日灌胃给药一次。
模型对照组给予等体积的0.5%的羧甲基纤维素钠水溶液。
正常对照组为未经OBX手术的正常动物,给予正常饮食,不给药。
在手术前14天,开始治疗(0天),前7天,前14天分别称量各组动物体重,以判断药物对于模型动物体重的影响。
在治疗开始(0天),7天,14天,分别记录各组动物实物摄取量,以判断药物对于模型动物食物摄取量的影响。
在治疗的最后一天,抽血测定血清皮质甾醇。皮质甾醇是在啮齿类动物中发现的主要糖皮质激素,并且它是人体中发现的皮质醇激素的等效物。
表3:不同晶型恩那度司他对嗅球切除大鼠体重的影响(n=3,单位:g)
OBX模型动物与正常对照组中体重增加相比较,体重增长显著。所述不同晶型恩那度司他在10、20和40mg/kg的剂量下显著抑制OBX诱发的体重增加,尤其以晶型II最为显著。
表4:不同晶型恩那度司他对嗅球切除大鼠食物摄取量的影响(n=3,以克/天计)
时间 | 1天治疗 | 7天治疗 | 14天治疗 |
正常对照组 | 17.3±0.4 | 18.4±0.1 | 18.8±0.5 |
模型对照组 | 24.4±0.2 | 27.4±0.2 | 31.2±0.4 |
恩那度司他晶型N21(10mg/kg) | 23.4±0.3 | 26.3±0.4 | 28.3±0.6 |
恩那度司他晶型N21(20mg/kg) | 23.5±0.1 | 25.8±0.5 | 27.1±0.8 |
恩那度司他晶型N21(40mg/kg) | 22.9±0.7 | 25.6±0.1 | 27.9±0.1 |
恩那度司他晶型N2(10mg/kg) | 22.1±0.6 | 25.1±0.6 | 27.3±0.7 |
恩那度司他晶型N2(20mg/kg) | 22.6±0.1 | 24.4±0.2 | 26.1±0.4 |
恩那度司他晶型N2(40mg/kg) | 21.7±0.2 | 24.4±0.5 | 25.9±0.9 |
恩那度司他晶型II(10mg/kg) | 21.1±0.5 | 24.6±0.8 | 24.0±0.7 |
恩那度司他晶型II(20mg/kg) | 21.4±0.9 | 23.5±0.1 | 24.1±0.9 |
恩那度司他晶型II(40mg/kg) | 20.6±0.8 | 22.4±0.2 | 23.5±0.3 |
。
在手术恢复的14天后监测所有试验动物的食物摄入量。与正常对照组相比较,在OBX对照组中的动物表现出食物摄入量增加。用不同晶型恩那度司他治疗14天,食物摄入量显著降低,趋于正常,尤以晶型II为佳。
表5:在嗅球切除大鼠中不同晶型恩那度司他对血清钠和皮质甾醇浓度的影响(n=3)
动物分组 | 血清皮质甾醇水平(ug/ml) | 血清钠浓度(mEq/l) |
正常对照组 | 18.7±0.5 | 13.1±0.7 |
模型对照组 | 49.5±0.9 | 38.7±0.8 |
恩那度司他晶型N21(10mg/kg) | 34.5±0.5 | 36.7±0.7 |
恩那度司他晶型N21(20mg/kg) | 34.7±0.3 | 35.8±0.2 |
恩那度司他晶型N21(40mg/kg) | 33.6±0.2 | 34.1±0.9 |
恩那度司他晶型N2(10mg/kg) | 33.4±0.1 | 35.2±0.6 |
恩那度司他晶型N2(20mg/kg) | 33.9±0.8 | 34.7±0.1 |
恩那度司他晶型N2(40mg/kg) | 30.1±0.7 | 31.5±0.3 |
恩那度司他晶型II(10mg/kg) | 28.7±0.7 | 29.7±0.1 |
恩那度司他晶型II(20mg/kg) | 28.6±0.8 | 29.1±0.9 |
恩那度司他晶型II(40mg/kg) | 25.4±0.8 | 28.8±0.3 |
。
OBX模型动物表现出血液中皮质甾醇过度分泌。在所有剂量下用不同晶型恩那度司他治疗的动物显著地降低了血液中皮质甾醇的水平。OBX诱发血清醛固酮增加,并进一步诱发血清钠浓度增加,其在不同剂量水平下,被不同晶型恩那度司他显著降低,尤其以恩那度司他晶型II最为显著,说明恩那度司他具有作为库欣病治疗药物的潜力,尤其是晶型II。
上述研究显示不同晶型恩那度司他在治疗由嗅球切除大鼠证实的内源性因素诱发的库欣氏综合症病症(即体重增加、食量增加、皮质醇分泌过多和血清钠增加)中的疗效。因此,所述不同晶型恩那度司他在治疗和处理库欣氏综合症和皮质醇血症的所有其他病症中是有效的,尤其是晶型II。
Claims (10)
1.恩那度司他用于制备治疗库欣病药物的用途,其特征在于,所述恩那度司他化学结构如下:
2.如权利要求1所述的用途,其特征在于,所述恩那度司他的晶型为晶型N21。
3.如权利要求1所述的用途,其特征在于,所述恩那度司他的晶型为晶型N2。
4.如权利要求1所述的用途,其特征在于,所述恩那度司他的晶型为晶型II。
5.如权利要求4所述的用途,其特征在于,所述晶型II,经X射线衍射法确证,在XRPD图谱上2θ角为9.3°±0.2°的位置具有最强特征峰,相对强度为100%。
6.如权利要求4所述的用途,其特征在于,所述晶型II,经X射线衍射法确证,在XRPD图谱上2θ角为23.8°±0.2°的位置具有强特征峰,相对强度为33.0%。
7.如权利要求4所述的用途,其特征在于,所述晶型II,经X射线衍射法确证,具有如附图1所述的XPRD谱图。
8.如权利要求4-7所述的任一用途,其特征在于,所述恩那度司他晶型II的制备方法如下:
步骤1)将恩那度司他加入到水和二甲基亚砜混合溶剂中,升温至80℃或以上,保持回流;
步骤2)将步骤1)体系冷却至60-65℃,析出晶体II;
步骤3)减压干燥,得到固态的晶型II。
9.如权利要求1-7所述的任一用途,其特征在于,所述药物的给药途径为口服。
10.如权利要求1-7所述的任一用途,其特征在于,所述药物通过抑制醛固酮合成酶或11β-羟化酶起效。
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