CN115894283A - 一种曲尼司特衍生物及其制备方法和用途 - Google Patents
一种曲尼司特衍生物及其制备方法和用途 Download PDFInfo
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- CN115894283A CN115894283A CN202111110277.6A CN202111110277A CN115894283A CN 115894283 A CN115894283 A CN 115894283A CN 202111110277 A CN202111110277 A CN 202111110277A CN 115894283 A CN115894283 A CN 115894283A
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- pharmaceutically acceptable
- acceptable salt
- tranilast
- disease
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Abstract
Description
技术领域
本发明涉及医药领域,具体涉及一种曲尼司特衍生物、制备方法及其用途,包含其的药物组合物及其用于预防或治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病中的用途。
背景技术
曲尼司特是一种不同于H1,H2受体竞争类抗组胺药的新型抗变态反应药物,其化学名为N-(3,4-二甲氧基肉桂酰)邻氨基苯甲酸,结构如下所示:
曲尼司特具有稳定肥大细胞和嗜碱性粒细胞细胞膜的作用,防止其脱颗粒。从而抑制组胺和5-羟色胺等过敏性反应物质的释放,对于lgE抗体引起的大白鼠皮肤过敏反应和实验性哮喘有显著抑制作用,是一种针对过敏性疾病发生机制的病因治疗性药物。临床主要用于治疗支气管哮喘,过敏性鼻炎,特异性皮炎,疤痕疙瘩或增生性疤痕。
此外,有研究人员进一步发现曲尼司特还可特异性抑制NLRP3炎症小体,从而能够阻断肥胖的发生和发展,预防和治疗II型糖尿病,还能够治疗NLPR3炎症小体的激动剂尿酸盐结晶堆积导致的腹膜炎和痛风以及NLPR3突变导致的Muckle Wells综合征。
曲尼司特溶解度不高,极难溶于水,难溶于甲醇、乙醇、乙酸乙酯,在光条件下易降解、产生毒副作用。曲尼司特已知剂型包括片剂,胶囊剂,颗粒剂等口服固体制剂。口服曲尼司特从消化道通过门静脉被吸收到肝脏中后,药物被代谢,只有一部分药物被运送至局部部位,生物利用度降低。为维持有效的血药浓度,需要服用大量药物,容易引发副作用。外用制剂可以直接应用于局部皮肤,能够控制血中药物的浓度,减小副作用发生的概率,对特异性皮炎,疤痕疙瘩或增生性疤痕的治疗是有利的。
因此,需要进一步发现具有良好疗效、副作用小、具有更好的药代动力学性质的、适于成药的曲尼司特衍生物。
发明内容
本发明的目的在于提供一种疗效良好、副作用小、稳定性好、药代动力学性质更好并且适于成药的新型曲尼司特衍生物。
本发明的目的是由以下技术方案来达到的,
在第一方面,本发明提供式I所示化合物或其药学上可接受的盐,
式中
R1和R2分别独立地选自CH3、CH2D、CHD2或CD3;
R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13分别独立地选自氢或氘;
条件是式I化合物中至少含有一个氘原子。
在优选的实施方式中,氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
在优选的实施方式中,式I化合物含有1至25个氘原子,或者式I化合物含有3至15个氘原子,或者式I化合物含有6至9个氘原子。
在优选的实施方式中,R11、R12、R13中至少一个为氘。
在优选的实施方式中,R3、R4、R5、R6、R7、R8、R9和R10为氢,R11、R12、R13中至少一个为氘。
在具体的实施方式中,R1、R2分别独立地选自CH3、CH2D、CHD2或CD3。
在具体的实施方式中,R3、R4、R5、R6、R7、R8、R9、R10、R11、R12和R13为氢,R1、R2分别独立地选自CH3、CH2D、CHD2或CD3。
在具体的实施方式中,R1、R2分别独立地选自CH3或CD3。
在具体的实施方式中,R1、R2相同。
在具体的实施方式中,R1、R2均为CD3。
在具体的实施方式中,式I所示化合物如下所示:
优选地,式I所示化合物如下所示:
在第二方面,本发明提供一种药物组合物,包含第一方面所述的化合物或其药学上可接受的盐以及任选的药学上可接受的辅料。
在优选的实施方式中,所述药物组合物还含有另外的治疗药物,所述的另外的治疗药物为治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病的药物。
在优选的实施方式中,所述过敏性疾病包括但不限于:支气管哮喘、过敏性鼻炎、特异性皮炎;
所述皮肤或结缔组织过度增生相关疾病包括但不限于疤痕疙瘩、增生性疤痕;
所述NLRP3炎症小体相关疾病包括但不限于:代谢综合症、动脉粥样硬化、MuckleWells综合征、家族性寒冷型自身炎症综合征、慢性婴儿神经皮肤关节综合征、痛风、肠炎、肝炎、硅肺、紫外线所诱导的皮肤晒伤、腹膜炎、脓毒血症、阿尔海默症、帕金森症或抑郁症;进一步地,上述NLRP3炎症小体相关疾病为二型糖尿病、尿酸盐结晶堆积诱导的腹膜炎、尿酸盐结晶堆积诱导的痛风、高脂食物诱导的肥胖或瘦素缺失引起的肥胖、NLRP3突变所导致的MuckleWells综合征。
在优选的实施方式中,所述的药物组合物的剂型为:口服制剂、注射制剂和透皮贴剂。
在第三方面,本发明提供第一方面所述的化合物或其药学上可接受的盐或第二方面所述的药物组合物在制备治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病中的用途。
在具体的实施方式中,所述过敏性疾病包括但不限于支气管哮喘、过敏性鼻炎、特异性皮炎;
所述皮肤或结缔组织过度增生相关疾病包括但不限于疤痕疙瘩、增生性疤痕;
所述NLRP3炎症小体相关疾病包括但不限于包括但不限于代谢综合症、动脉粥样硬化、Muckle Wells综合征、家族性寒冷型自身炎症综合征、慢性婴儿神经皮肤关节综合征、痛风、肠炎、肝炎、硅肺、紫外线所诱导的皮肤晒伤、腹膜炎、脓毒血症、阿尔海默症、帕金森症或抑郁症;进一步地,上述NLRP3炎症小体相关疾病为二型糖尿病、尿酸盐结晶堆积诱导的腹膜炎、尿酸盐结晶堆积诱导的痛风、高脂食物诱导的肥胖或瘦素缺失引起的肥胖、NLRP3突变所导致的MuckleWells综合征。
在第四方面,本发明提供一种治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病的方法,包括对需要该治疗的哺乳动物,优选人类,给予治疗有效量的第一方面所述的化合物或其药学上可接受的盐、或第二方面所述的药物组合物的步骤。
在优选的实施方式中,所述过敏性疾病包括但不限于支气管哮喘、过敏性鼻炎、特异性皮炎;
所述皮肤或结缔组织过度增生相关疾病包括但不限于疤痕疙瘩、增生性疤痕;
所述NLRP3炎症小体相关疾病包括但不限于包括但不限于代谢综合症、动脉粥样硬化、Muckle Wells综合征、家族性寒冷型自身炎症综合征、慢性婴儿神经皮肤关节综合征、痛风、肠炎、肝炎、硅肺、紫外线所诱导的皮肤晒伤、腹膜炎、脓毒血症、阿尔海默症、帕金森症或抑郁症;进一步地,上述NLRP3炎症小体相关疾病为二型糖尿病、尿酸盐结晶堆积诱导的腹膜炎、尿酸盐结晶堆积诱导的痛风、高脂食物诱导的肥胖或瘦素缺失引起的肥胖、NLRP3突变所导致的MuckleWells综合征。
在第五方面,本发明涉及式I化合物或其药学上可接受的盐、或包含式I化合物或其药学上可接受的盐的药物组合物,用于治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病,或用于制备治疗过敏性疾病、皮肤或结缔组织过度增生相关的疾病或NLRP3炎症小体相关疾病的药物;
式中
R1和R2分别独立地选自CH3、CH2D、CHD2或CD3;
R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13分别独立地选自氢或氘;
条件是式I化合物中至少含有一个氘原子。
在优选的实施方式中,所述过敏性疾病包括但不限于支气管哮喘、过敏性鼻炎、特异性皮炎;
所述皮肤或结缔组织过度增生相关疾病包括但不限于疤痕疙瘩、增生性疤痕;
所述NLRP3炎症小体相关疾病包括但不限于包括但不限于代谢综合症、动脉粥样硬化、Muckle Wells综合征、家族性寒冷型自身炎症综合征、慢性婴儿神经皮肤关节综合征、痛风、肠炎、肝炎、硅肺、紫外线所诱导的皮肤晒伤、腹膜炎、脓毒血症、阿尔海默症、帕金森症或抑郁症;进一步地,上述NLRP3炎症小体相关疾病为二型糖尿病、尿酸盐结晶堆积诱导的腹膜炎、尿酸盐结晶堆积诱导的痛风、高脂食物诱导的肥胖或瘦素缺失引起的肥胖、NLRP3突变所导致的MuckleWells综合征。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了将曲尼司特和氘代曲尼司特(实施例1样品)制剂口服给予大鼠后的血浆药物浓度-时间曲线。
具体实施方式
发明人经过广泛而深入的研究,出乎意料地获得了一类曲尼司特的氘代衍生物,与曲尼司特原型药物相比,本发明的氘代衍生物在成药性、药物颜色、稳定性、药代动力学以及毒性方面有极大的改善,从而能够获得疗效良好、副作用小、患者顺应性好、药代动力学性质更好并且适于成药的新型药物。在此基础上完成了本发明。
特别地,发明人在实验过程中出乎意料的发现:本发明制备得到的氘代曲尼司特为白色固体。中国药典(2015年版)第359页中记载曲尼司特为淡黄色或淡黄绿色固体,制备得到的曲尼司特片剂也为淡黄色或淡黄绿色片剂。流行病学调查显示有大量人群因手术、创伤等而存在疤痕疙瘩或增生性疤痕,不仅影响美观,而且严重影响患者的心理健康。谭欢等的《瘢痕疙瘩患者128例生活质量评估及影响因素分析》、李慧君等的《成年瘢痕患者心理状况调查及影响因素分析》、Balci DD等的《DLQI scores in patients with keloids andhypertrophic scars:a prospective case control study》采用了皮肤病生活质量指数(dermatology life quality index,DLQI)等量表对瘢痕疙瘩患者的生活质量进行评估,并指出疤痕疙瘩在美容形象学上的改变对患者生活质量的影响比疼痛、骚痒等自觉症状所带来的影响更为深远,更不容忽视。暴露部位(如头部、面部、耳部、颈部、前臂、小腿)的皮损,因其无法遮盖,就算是单发皮损,也可影响患者的容貌形象,令患者心理更加敏感,更容易产生“病耻感”,更害怕与人相处,害怕被人议论,从而影响患者的生活质量。
经大量的临床研究以及药理研究证实曲尼司特可以用于瘢痕疙瘩、增生性瘢痕的治疗,可以抑制瘢痕成纤维细胞胶原的合成。针对瘢痕疙瘩、增生性瘢痕的治疗,膏剂、贴剂等局部给药剂型有着起效快、全身毒副作用小的优势。但曲尼司特为淡黄色或淡黄绿色固体,即使制成膏剂或贴剂,成药后药物还是会带有颜色。瘢痕疙瘩、增生性瘢痕的患者本就心理敏感、脆弱,心理上难以接受有色药物涂抹于患处。
而本发明制备得到的曲尼司特衍生物为无色固体,有利于制备成无色的膏剂、贴剂等局部施用剂型,能够大幅度的提高疤痕疙瘩或增生性疤痕患者的顺应性。
本发明的氘代化合物
本领域已知氘代可能改变化合物,特别是具备药学活性的化合物的某种特性。然而,相比于未氘代的化合物,氘代会造成特性上有利的改变,还是不利的改变,或者是没有改变是无法合理预知的。例如,氘取代对代谢速率的影响已在部分药物上得到报道(例如,参见Blake,MI等人,J Pharm Sci,1975,64:367-91;Foster,AB,Adv Drug Res,1985,14:1-40;Kushner,DJ等人,Can J Physiol Pharmacol,1999,79-88;Fisher,MB等人,Curr OpinDrug Discov Devel,2006,9:101-109),结果是可变且不可预测的。对于一些化合物,氘代造成体内代谢清除降低。对于其他化合物,没有改变代谢。对于有些化合物,已证明代谢清除增加。氘效果的可变性还导致专家质疑或抛弃了氘修饰作为可行的药物设计策略以抑制有害代谢的想法(参见Foster第,35页和Fisher第,101页处)。
即使当氘原子结合到代谢物的已知位点时,氘修饰对药物的代谢特性的作用也是不可预测的。只有实际制备并检测了氘代药物,才能确定代谢速率是否以及怎样区别于非氘代的对应物。例如参见Fukuto等人(J.Med.Chem.,1991,34,2871-76)。很多药物有多个可能发生代谢反应的位点。需要氘取代的位点以及使对代谢的影响可见的必要的氘化程度,如果有的话,对每一药物都是不同的。
在本文,“本发明的曲尼司特衍生物”、“本发明的氘代化合物”或“氘代曲尼司特”具有相同的含义。这些术语均是指式I所示化合物或其药学上可接受的盐,
式中,R1-R13具有如上所述的定义。
本发明的氘代化合物中至少含有一个氘原子,因此,本发明的氘代化合物中氘同位素含量至少大于天然氘同位素含量。在具体的实施方式中,氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
本发明的氘代化合物可以在任何可以氘代的位置发生氘代。例如,在具体的实施方式中,本发明的氘代化合物含有1至25个氘原子,或者3至15个氘原子,或者6至9个氘原子。
本发明的氘代化合物包括在任何可以氘代的位置发生氘代的化合物。例如,在具体的实施方式中,本发明的化合物包括以下化合物:
在优选的实施方式中,本发明的氘代化合物如下所示:
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
在本文中,用于描述或限定多个取代基“分别独立地选自”某可选范围时表示各取代基在该可选范围内互不影响地进行选择。本领域技术人员会理解,当描述多个取代基“分别独立地选自”某可选范围时,等同于分别描述了各取代基选自该可选范围。例如,在具体的实施方式中,“R1、R2分别独立地选自CH3、CH2D、CHD2或CD3”等同于“R1选自CH3、CH2D、CHD2或CD3”和“R2选自CH3、CH2D、CHD2或CD3”。
本发明的药物组合物及其应用
在本发明的氘代化合物的基础上,本发明提供了包含所述氘代化合物或其药学上可接受的盐以及任选的药学上可接受的辅料或赋形剂的药物组合物。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有10-300mg本发明化合物/剂,更佳地,含50-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的氘代化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。
除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,药物组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。相应地,可以将本发明的药物组合物制备为口服、注射和透皮贴剂剂型。
基于现有技术,本领域技术人员可以知晓本发明的氘代化合物或药物组合物可以用于治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病。
在具体的实施方式中,所述过敏性疾病包括但不限于:支气管哮喘、过敏性鼻炎、特异性皮炎;
皮肤或结缔组织过度增生相关疾病包括但不限于疤痕疙瘩、增生性疤痕;
所述NLRP3炎症小体相关疾病包括但不限于包括:代谢综合症、动脉粥样硬化、Muckle Wells综合征、家族性寒冷型自身炎症综合征、慢性婴儿神经皮肤关节综合征、痛风、肠炎、肝炎、硅肺、紫外线所诱导的皮肤晒伤、腹膜炎、脓毒血症、阿尔海默症、帕金森症或抑郁症;进一步地,上述NLRP3炎症小体相关疾病为二型糖尿病、尿酸盐结晶堆积诱导的腹膜炎、尿酸盐结晶堆积诱导的痛风、高脂食物诱导的肥胖或瘦素缺失引起的肥胖、NLRP3突变所导致的MuckleWells综合征(参见CN 108938617 A,该份文献的全部内容通过引用纳入本文)。
本发明中,氘代化合物可以单独给药,或者与其它药学上可接受的化合物联合给药。因此,本发明的药物组合物还可含有另外的治疗药物,所述的另外的治疗药物为治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病的药物。
有益效果:
1.本发明提供了一种新的曲尼司特衍生物;
2.本发明的曲尼司特衍生物具备优异的溶解度、吸湿性、稳定性、活性以及药效学/药代动力学特性;
3.本发明的曲尼司特衍生物的光稳定性显著增强,更有利于药物的储存,且能降低有光分解杂质引起的药物毒副作用;
4.本发明的曲尼司特衍生物毒性显著降低;
5.中国药典(2015年版)第359页中记载曲尼司特为淡黄色或淡黄绿色固体,制备得到的曲尼司特片剂也为淡黄色或淡黄绿色片剂。而本发明的曲尼司特衍生物为无色固体,更有利于制备成膏剂、贴剂等局部施用剂型,能够大幅度的提高患者的顺应性。
6.本发明的曲尼司特衍生物的药代动力学特性良好,有利于延长药物的作用时间。
以下结合具体实施案例对本发明的技术方案进一步描述,但以下实施案例不构成对本发明的限制,所有依据本发明的原理和技术手段采用的各种施用方法,均属于本发明范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例
材料与方法
除非另有说明,本申请的实施例中使用的原料(如曲尼司特等)都是市场上直接买到,未经进一步纯化直接使用的。
DCM为二氯甲烷;MeOH为甲醇;THF为四氢呋喃;LAH为氢化铝锂;MW为微波;DMSO为二甲亚砜。
本申请中纯度及杂质测定的实验条件如下:
1、色谱柱:Agilent Pursuit C18,3um,4.6*150mm;
2、流动相:0.1%三氟乙酸(流动相A):乙腈(流动相B);
3、流速:1.0ml/min,波长:215nm,柱温:35℃,进样量:10μl;
并按照如下梯度进行洗脱:
时间(min) | A% | B% |
0 | 90 | 10 |
20 | 15 | 85 |
实施例1.N-(3,4-二氘代甲氧基肉桂酰)邻氨基苯甲酸的制备
步骤1、N-(3,4-二羟基肉桂酰)邻氨基苯甲酸(2)
向5L三口瓶中加入化合物1(210g,641mmol,1.0eq.)和CH2Cl2(3150mL),机械搅拌氮气保下滴加BBr3(482.2g,1920mmol,3.0eq.)。控制反应温度10-15℃,滴加用时约50min,随后25-28℃下反应16h。滴加MeOH(250mL)淬灭反应,控制内温10-15℃,用时约30min。随后继续在冰水浴中搅拌1.5h,过滤,滤饼用DCM(300mL)洗涤,40℃真空干燥1h得砖红色固体252g。将粗产物转移至5L三口瓶中,加入丙酮(1500mL)和纯化水(800mL),搅拌5min后固体全部溶解。一次性倒入纯化水(800mL),搅拌40min后析出黄色固体。再滴加纯化水(200mL),滴加用时约15min。加完室温下搅拌1.5h,随后冰水浴中搅拌1h。过滤,滤饼用冰水浴预冷的丙酮/水(1/1.5300mL)淋洗。40℃鼓风干燥12h,随后50℃真空干燥8h得黄色固体2(138.2g,71.9%)。
1H NMR(400MHz,DMSO-d6)δ13.59(brs,1H),11.26(s,1H),9.54(s,1H),9.14(s,1H),8.65–8.55(m,1H),8.00(dd,J=7.9,1.5Hz,1H),7.69–7.56(m,1H),7.45(d,J=15.5Hz,1H),7.21–7.12(m,1H),7.09(d,J=2.0Hz,1H),7.01(dd,J=8.2,2.0Hz,1H),6.78(d,J=8.1Hz,1H),6.52(d,J=15.5Hz,1H)。
步骤2、N-(3,4-二氘代甲氧基肉桂酰)邻氨基苯甲酸氘代甲酯(化合物3)
向2L三口瓶中加入化合物2(60.0g,200mmol,1.0eq.)和DMF(550mL),磁力搅拌溶解。随后加入K2CO3(166.2g,1200mmol,6.0eq.)和NaI(6.0g,40mmol,0.2eq.),搅拌10min后加入TsOCD3(193.5g,1020mmol,5.1eq.)并用DMF(50mL)洗称量瓶。室温25-28℃下反应30h。加入EtOAc(600mL)稀释反应液,垫硅藻土过滤,用EtOAc(600mL)淋洗。滤液用纯化水(1500mL)洗,水相用EtOAc(300mL)萃取。合并有机相,用5%NaCl水溶液(4*900mL)洗涤,Na2SO4干燥。过滤,25℃旋蒸,浓缩过程中析出固体。蒸至总体积约200mL时滴加石油醚(600mL),用时约1h。加完室温下搅拌12h,随后氮气保护下冰水浴中搅拌30min。过滤,滤饼用石油醚/乙酸乙酯(4:1 100mL)淋洗。40℃真空干燥4h得黄色固体化合物3(61.8g,87.9%)。
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.59–8.40(m,1H),7.96(dd,J=7.9,1.7Hz,1H),7.70–7.60(m,1H),7.58(d,J=15.5Hz,1H),7.38(d,J=2.0Hz,1H),7.25(dd,J=8.4,1.9Hz,1H),7.23–7.18(m,1H),7.00(d,J=8.3Hz,1H),6.83(d,J=15.5Hz,1H).
步骤3、N-(3,4-二氘代甲氧基肉桂酰)邻氨基苯甲酸(化合物4)
向250mL三口瓶中加入化合物3(2.110g,6.0mmol,1.0eq.)、THF(18mL)和MeOH(18mL),随后加入LiOH·H2O(2.110g,6.0mmol,1.0eq.)的H2O(6mL)溶液,25-28℃下反应3h。加入H2O(30mL)和CH2Cl2(50mL),搅拌后静置分液。水相用CH2Cl2(50mL)洗,有机相用H2O(15mL)萃取。合并水相,搅拌下加入6M HCl(3mL),析出白色固体,过滤,滤饼用H2O(30mL)洗涤,50℃鼓风干燥13h,得1.72g类白色固体化合物4。
1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.67–8.60(m,1H),8.01(dd,J=7.9,1.7Hz,1H),7.66–7.58(m,1H),7.57(d,J=15.6Hz,1H),7.38(d,J=1.9Hz,1H),7.25(dd,J=8.4,1.9Hz,1H),7.21–7.13(m,1H),7.00(d,J=8.3Hz,1H),6.80(d,J=15.6Hz,1H)。MS(ESI):m/z:334.1[M+H]+,356.1[M+Na]+。HPLC:99.0%。
实施例2.溶解度测定实验
将至少100mg的粉末与2ml的水混合,制备浓度大于50mg/ml的混合物。样品室温搅拌超过12小时,离心,直至上清液澄清,取上清液作为供试样品溶液。以在80%乙腈中制备的标准溶液作参比,通过HPLC测定供试样品溶液。测定结果,曲尼司特的盐在室温下水中的溶解度在以下表1中列出。
表1.溶解度实验结果
实施例的盐 | 室温下水中的溶解度(ug/ml) |
曲尼司特 | 23.8 |
实施例1样品 | 87.2 |
从表1中可知,实施例1样品的溶解度相对于曲尼司特有了较大的改善,更有利于制备成药物制剂。
实施例3.光稳定性实验
取制备得到的曲尼司特、本发明实施例1样品适量,置玻璃平皿中,于光照条件(4500lux±500lux)下放置数天,分别于各时间点取样。采用“材料与方法”部分所述的纯度及杂质测定的实验条件,分别考察2个样品在不同条件下的单杂含量和总杂含量,结果见表2。
表2.光照稳定性实验结果
表2中所述的“单杂”是指相对保留时间(RRT)为0.62±0.02处的杂质;所述的“总杂”是指样品中存在的所有杂质。
通过上表2可以看出,实施例1样品在光照条件下的最大单杂的含量基本未增加,而曲尼司特最大单杂含量增加了近1倍。可见,本申请所述的氘代曲尼司特相对于曲尼司特光稳定性良好,成药性良好和便于药物储存,从而降低药物的毒副作用。
此外,实施例1的样品未经专门纯化,而曲尼司特样品是经专门纯化的市售购得的标准品。因此,二者在原始总杂质含量方面存在显著差异。
实施例4.制剂的制备
将曲尼司特、实施例1样品(氘代曲尼司特)按照表3所示的组成制备制剂。
表3
制备方法:
1)将处方量的羧甲基纤维素钠溶解于总重80%的水中;
2)将上述曲尼司特/实施例1样品加入至上述体系中,分散均匀;
3)将上述溶液采用高剪切机剪切约2min;
4)将高剪切后溶液采用高压均质机均质,400~900bar压力下,均质15min得混悬液。
实施例5.毒性实验
有文献记载,以雄性小鼠作为试验对象,曲尼司特的急性毒性LD50值为780mg/kg,现通过以下试验方法考察实施例1样品的急性毒性。
动物种属及等级:ICR小鼠,SPF级;
性别和数量:雄性,16只;
体重:20~22g;
来源:浙江维通利华实验动物技术有限公司;
许可证号:SCXK(浙)2019-0001;
质量合格证号:20200617Abzz0619000207;
实验过程:各组小鼠以1mL注射器准确抽取相应量给药制剂经灌胃给药;根据当日体重计算给药量,经灌胃给予ICR小鼠受试物实施例1样品,观察实施例1样品在小鼠上引起的毒性反应,连续观察14天,动物体重以均数±标准差表示。各给药组与溶媒组进行比较,采用student t检验,实验结果如下表4。
表4
对以上死亡动物进行大体解剖观察,无肉眼可见的明显病变。
通过表5可以发现,经灌胃给予ICR小鼠受试物实施例1样品,给药剂量为780mg/kg时未出现小鼠死亡,给药剂量为1500mg/kg时仅有2只小鼠死亡,说明实施例1样品较曲尼司特的毒性更小,更有利于成药。
实施例6.药代动力学研究
对曲尼司特/氘代曲尼司特(实施例1样品)进行了SD大鼠口服药代动力学研究。
动物种属及等级:SD大鼠,SPF级;
性别和数量:雄性,10只;
体重:200~220g;
来源:浙江维通利华实验动物技术有限公司;
许可证号:SCXK(浙)2019-0001;
质量合格证号:2004030063;
试验过程:15只动物随机分为3组,分别口服曲尼司特和氘代曲尼司特制剂(参见实施例4制剂1、制剂2),给药剂量为10mg/kg,给药后大约0.5、1、2、4、8、10、24h依次采集血样至K2EDTA抗凝管中,并于冰上暂存,60min内完成离心(2-8℃,8000rpm离心5min),收集血浆转移至离心管中,并于≤-15℃条件下保存。
样品检测与数据处理:采用已开发的LC-MS/MS方法对血浆样品进行检测,获得血药浓度数据并计算药代动力学参数,包括但不限于Tmax,Cmax,AUC等等。详细数据见下表所示。
表4.SD大鼠口服给药后血浆中曲尼司特/氘代曲尼司特的药代动力学参数
制剂1(曲尼司特) | 制剂2(实施例1样品) | ||
<![CDATA[t<sub>1/2</sub>]]> | h | 3.18 | 3.35 |
<![CDATA[T<sub>max</sub>]]> | h | 0.50 | 1.00 |
<![CDATA[C<sub>max</sub>]]> | ng/mL | 19618.00 | 11837.60 |
<![CDATA[AUC<sub>last</sub>]]> | h*ng/mL | 90453.37 | 65673.49 |
<![CDATA[AUC<sub>inf</sub>]]> | h*ng/mL | 93530.44 | 71369.90 |
Vz_F_obs | mL/kg | 514.10 | 777.59 |
Cl_F_obs | mL/h/kg | 113.39 | 157.00 |
<![CDATA[MRT<sub>last</sub>]]> | h | 4.49 | 4.49 |
通过上述的SD大鼠给药后血浆中曲尼司特、氘代曲尼司特的药代动力学参数分析,我们发现氘代曲尼司特较曲尼司特的半衰期(t1/2)长,能够持续长时间释放,制备成缓释药物的成药前景好;最大血药浓度(Cmax)相对较低,能够有效避免药物的突释及药物突释相关的毒副作用,有着更好的安全性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
2.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R1、R2分别独立地选自CH3、CH2D、CHD2或CD3。
3.如权利要求2所述的化合物或其药学上可接受的盐,其特征在于,R3、R4、R5、R6、R7、R8、R9、R10、R11、R12和R13为氢,R1、R2分别独立地选自CH3、CH2D、CHD2或CD3。
4.如权利要求3所述的化合物或其药学上可接受的盐,其特征在于,R1、R2分别独立地选自CH3或CD3。
5.如权利要求4所述的化合物或其药学上可接受的盐,其特征在于,R1、R2相同。
6.如权利要求5所述的化合物或其药学上可接受的盐,其特征在于,R1、R2均为CD3。
8.一种药物组合物,包含权利要求1-7中任一项所述的化合物或其药学上可接受的盐以及任选的药学上可接受的辅料。
9.权利要求1-7中任一项所述的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备治疗过敏性疾病、皮肤或结缔组织过度增生相关疾病或NLRP3炎症小体相关疾病药物中的用途。
10.如权利要求9所述的用途,其特征在于,所述过敏性疾病包括但不限于支气管哮喘、过敏性鼻炎、特异性皮炎;
所述皮肤或结缔组织过度增生相关疾病包括但不限于疤痕疙瘩、增生性疤痕;
所述NLRP3炎症小体相关疾病包括但不限于代谢综合症、动脉粥样硬化、Muckle Wells综合征、家族性寒冷型自身炎症综合征、慢性婴儿神经皮肤关节综合征、痛风、肠炎、肝炎、硅肺、紫外线所诱导的皮肤晒伤、腹膜炎、脓毒血症、阿尔海默症、帕金森症或抑郁症;进一步地,上述NLRP3炎症小体相关疾病为二型糖尿病、尿酸盐结晶堆积诱导的腹膜炎、尿酸盐结晶堆积诱导的痛风、高脂食物诱导的肥胖或瘦素缺失引起的肥胖、NLRP3突变所导致的MuckleWells综合征。
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