CN114008030A - 用作nlrp3调节剂的稠合的1,2-噻唑和1,2-噻嗪 - Google Patents
用作nlrp3调节剂的稠合的1,2-噻唑和1,2-噻嗪 Download PDFInfo
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- CN114008030A CN114008030A CN202080045213.XA CN202080045213A CN114008030A CN 114008030 A CN114008030 A CN 114008030A CN 202080045213 A CN202080045213 A CN 202080045213A CN 114008030 A CN114008030 A CN 114008030A
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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Abstract
本发明涉及可用于治疗、缓解或预防一组对炎症小体途径组分活化的调节或抑制有响应的疾病、障碍和异常的新化合物。特别地,炎症小体途径组分是NLRP3炎症小体。更特别地,本发明化合物具有抑制NLRP3炎症小体的能力。此外,本发明化合物调节、特别是降低IL‑1β和/或IL‑18水平。
Description
发明领域
本发明涉及可用于治疗、减轻或预防一组对炎症小体途径组分活化的调节或抑制有响应的疾病、障碍和异常的新化合物。特别地,炎症小体途径组分来自NOD-样受体(NLR)家族,例如含热蛋白结构域的蛋白质3(NLRP3)炎症小体。更特别地,本发明化合物具有抑制NLRP3炎症小体的能力。此外,本发明化合物调节、特别是降低IL-1β和/或IL-18水平。
发明背景
炎症小体蛋白复合物是炎症信号传导的关键组分。这些复合物组装响应于多种危险信号,例如来自病原体的分子(病原体相关分子模式,PAMP)以及改变的宿主分子、无菌组织损伤产物和环境因素(危险相关分子模式,DAMP)。炎症小体家族由NALP1-14、IPAF和NAIP1-6组成,其中每个家族成员提供对不同PAMP/DAMP(包括核酸、细菌蛋白质、代谢物、蛋白质聚集物和毒素活性)的特异性(Sharma,D.&Kanneganti,T.D.The cell biology ofinflammasomes:mechanisms of inflammasome activation and regulation.J.CellBiol.213,617-629(2016))。炎症小体通常由传感器(细胞溶质模式识别受体,PRR)和称作凋亡相关斑点样蛋白的接头蛋白(包含半胱氨酸天冬氨酸蛋白酶-募集结构域(CARD)(ASC))和效应器例如蛋白酶半胱氨酸天冬氨酸蛋白酶-1组成(Broz,P.;Dixit,V.M.Inflammasomes:Mechanism of Assembly,Regulation andSignalling.Nat.Rev.Immunol.2016,16,407-420)。
NLRP3(NOD-样受体(NLR)家族,含热蛋白结构域的蛋白3)炎症小体是最佳描述的家族成员之一。它是NLR家族的三部分蛋白质,并且包含氨基末端PYRIN(PYD)结构域、核苷酸结合NACHT结构域和羧基末端富含亮氨酸重复(LRR)结构域。响应于多种物质,包括聚集的蛋白质、晶体和改变的细胞离子稳态,NLRP3传感器分子与包含半胱氨酸天冬氨酸蛋白酶活化和募集结构域(ASC,也称作PYCARD)接头蛋白的凋亡相关斑点样蛋白组装成多分子复合物。ASC蛋白聚合成大复合物(ASC斑点)导致半胱氨酸天冬氨酸蛋白酶-1效应蛋白活化,随后将前-IL1β和前-IL18裂解成其活性分泌形式,并且介导焦亡(Heneka等人,2018NatRev Neurosci)。IL-1β通过IL-1β受体发挥作用,并且诱导继发促炎信号包括IL-6和TNF-α分泌,并且在感染部位吸引和活化适应性免疫系统的细胞。NLRP3/ASC复合物可以释放到胞外环境中,在那里它们可以传播炎症。
多项遗传学和药理学证据突出了NLRP3炎症小体在人体疾病中的重要性。NLRP3功能获得性突变导致遗传的隐热蛋白相关周期性综合征(CAPS),包括穆-韦二氏综合征(MWS)、家族性寒冷性自身炎性综合征和新生儿发作性多系统炎性疾病。
与衰老相关的组织损伤产物的积累导致多种疾病中的NLRP3炎症小体活化,所述疾病包括代谢障碍、阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、动脉粥样硬化、肥胖、肺病、肝病和痛风等。
来自动物模型的大量实验证据指出过度NLRP3活化在广泛疾病中的不利作用。NLRP3-炎症小体遗传或药理学下调在以下模型中显示出保护作用:阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、脱髓鞘、病毒性脑炎、癫痫、中风、动脉粥样硬化、哮喘、变态反应性炎症、CAPS、痛风、炎性肠病、非酒精性脂肪肝病、非酒精性脂肪性肝炎、高血压、心肌梗死、草酸盐诱导的肾病、移植物抗宿主病、1型和2型糖尿病、类风湿性关节炎、骨髓增生异常综合征等(Heneka等人,Nat Rev Neurosci.2018年10月;19(10):610-621;Mangan等人,NatRev Drug Discov.2018年8月;17(8):588-606)。
由于上述原因,NLRP3炎症小体活性的调节代表了有前途的治疗方法。
目前对NLRP3-相关疾病的治疗包括靶向IL-1的生物制剂。它们是重组IL-1受体拮抗剂阿那白滞素、中和IL-1β抗体卡那奴单抗和可溶性诱饵IL-1受体列洛西普。这些方法已经证实可成功治疗CAPS,并且这些生物活性剂已用于其它IL-β相关疾病的临床试验。然而,它们的活性仅限于下游,炎症小体效应器及其在中枢神经系统(CNS)应用的生物利用度有限。
已经显示几种小分子抑制NLRP3炎症小体(Baldwin,A.G.,Brough,D.&Freeman,S.Inhibiting the inflammasome:a chemical perspective.J.Med.Chem.59,1691-1710(2016);综述在Mangan等人,Nat Rev Drug Discov.2018Aug;17(8):588-606中)。
这些包括多种化学类别,例如基于磺酰脲的化合物(格列本脲,CP 456,773(akaCRID3和MCC950)及其衍生物);非类固醇抗炎药的芬那酯类;羟基磺酰胺类似物JC-171;新硼化合物系列;包含苯并咪唑的结构Fc11a-2;聚酮化合物螺达醇(spirodalesol);丙烯酸酯和丙烯酰胺衍生物;3,4亚甲基二氧基-β-硝基苯乙烯;β-磺酰基腈分子OLT1177;CY-09;BOT-4-酮;和迈克尔受体。这些化合物的大部分具有混杂的作用方式和有限的效能。因此,需要鉴定和开发具有改善的药理学和/或生理学和/或理化特性的特异性NLRP3炎症小体。
WO9832733涉及芳基和杂芳基取代的磺酰脲,其为白细胞介素-1α和白细胞介素-1β处理和释放的有用抑制剂。
WO2016131098、WO2017/140778和WO2018215818涉及磺酰脲和相关化合物及其在治疗或鉴定响应于NLRP3抑制或NLRP3或炎症过程相关组分的活化抑制的疾病或病症。
WO2017184604、WO2017184623、WO2017184624、WO2019023145、WO2019023147和WO2019079119涉及可用于治疗病症、疾病或障碍的化学实体,其中NLRP3活性降低或增加促成个体的病症、疾病或障碍的病理学和/或症状和/或进展。
WO2018136890涉及磺酰脲和磺酰硫脲化合物及其在治疗对调节细胞因子例如IL-1β和IL-18、调节NLRP3或抑制NLRP3或炎症过程相关组分的活化有响应的疾病或病症中的用途。
WO2018225018和WO2019043610涉及NLRP3调节剂以及新抑制剂化合物在治疗疾病或病症以及治疗由NLRP3介导的疾病状态以及治疗其中牵涉白介素1β活性和白介素-18(IL-18)的疾病或病症中的用途。
WO2019008025、WO2019008029、WO2019034686、WO2019034688、WO2019034690、WO2019034692、WO2019034693、WO2019034696、WO2019034697、WO2019068772、WO2019092170、WO2019092171和WO2019092172涉及新化合物(例如磺酰脲、磺酰硫脲、亚砜亚胺脲(sulfoximine urea)和亚砜亚胺硫脲(sulfoximine thiourea)),其可用于治疗和预防医学障碍和疾病,最特别地通过NLRP3抑制。
WO2018015445涉及磺酰脲化合物或其药学上可接受的盐,其具有炎症小体抑制活性并且由此可用于治疗人或动物体的方法。
WO2020018975公开了定义为与炎症过程相关的白细胞介素-1活性抑制剂和NLRP3调节剂的磺酰亚胺酰胺(sulfonimidamide)衍生物。
WO9832733涉及芳基和杂芳基取代的磺酰脲,其为白细胞介素-1α和白细胞介素-1β加工和释放的抑制剂。
WO2020018970公开了定义为白细胞介素-1活性抑制剂的磺酰脲。
最近已破译了NLRP3炎症小体与Tau病理学之间的互相干扰。Ising等人(Nature2019年11月;575(7784):669-673)涉及在额颞痴呆(FTD)的Tau22小鼠模型中小神经胶质细胞和NLRP3炎症小体活化在tau病变发病机制中的重要作用。NLRP3炎症小体组分在Tau22小鼠中的遗传消融减少了Tau聚集/磷酸化并且改善了认知。Stancu等人(ActaNeuropathol.2019;137(4):599-617)研究了炎症小体活化在Tau病理学的朊病毒样或模板化接种中的作用。在ASC缺陷型-PS19 Tau转基因小鼠中发现了外源接种Tau病理学的显著抑制。此外,已证实NLRP3抑制剂MCC950的长期脑内施用抑制外源性接种的Tau病理学。最终,ASC缺乏也减少了PS19小鼠中非外源性接种的Tau病理学。
需要鉴定和开发具有改善的药理学和/或生理学和/或物理化学性质的特别的NLRP3炎症小体抑制剂和/或白介素活性调节剂。
本发明令人惊奇地提供了能够调节NLRP3炎症小体的式(I)化合物。因此,此类化合物有益于治疗与通常导致病理性炎症的IL-18水平改变相关的疾病或异常。
发明概述
本发明的一个目的在于提供可以用于治疗、缓解或预防一组疾病、障碍和异常的化合物,所述疾病、障碍和异常对炎症小体途径组分的活化的调节或抑制有响应。特别地,炎症小体途径组分是NLRP3炎症小体。本发明人惊奇地发现这些目的可以通过如下所述的式(I)化合物来实现。
式(I)化合物表现出高度调节或抑制炎症小体途径组分的能力,特别是其中炎症小体途径组分是NLRP3炎症小体。由于其独特的设计特征,这些化合物显示出性质例如适当的亲脂性和分子量、脑摄取和药代动力学、细胞渗透性、溶解性和代谢稳定性,从而成为治疗、缓解或预防对NLRP3炎症小体活化抑制有响应的疾病、障碍和异常的成功药物。
本发明公开了具有抑制NLRP3炎症小体能力的式(I)的新化合物。本发明提供了使用式(I)化合物或其药物组合物治疗与NLPR3炎症小体相关的疾病、障碍和异常的方法。本发明还提供了药物组合物,其包含式(I)化合物和选自药学上可接受的赋形剂、载体、稀释剂和佐剂的至少一种。本发明还提供了用于治疗、缓解或预防对炎症途径组分活化的调节或抑制有响应的疾病、障碍或异常的此类化合物。
在下列项目中概述了本发明:
1.式(I)化合物:
或其立体异构体、外消旋混合物、互变异构体、药学上可接受的盐、前药、水合物、溶剂化物和多晶型物;
其中
A选自芳基和杂芳基;其中芳基和杂芳基可以任选被取代;
R1选自氢、烷基、碳环基和杂环基;其中烷基、碳环基和杂环基可以任选被取代;
R2选自下列环系
R3选自氢、卤素、烷基、NR*R*(其中R*独立地选自H和烷基)、芳基和杂芳基,其中烷基、芳基或杂芳基可以任选被取代;
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基;其中烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基可以任选被取代;
R5选自氢、卤素、任选取代的烷基、任选取代的芳基或任选取代的杂芳基;
W选自C和N,在W是N的情况下,R4不存在;
X各自独立地选自CH2和O;
Y选自NH、O和CRR;
R各自独立地选自氢、卤素、CH3、CH2F、CHF2和CF3;
Z和Z’独立地选自C和N,条件是当m是0时,Z’是C;
m是0或1;
n是0或1;并且
p各自独立地是0、1或2。
2.项目1的化合物,其是式(Ia)化合物:
3.项目1或2的化合物,其是式(Ib)化合物:
4.项目1-3任一项的化合物,其是式(Ic)化合物:
5.项目1的化合物,其是式(Id)化合物:
其中
A选自芳基和杂芳基,其中芳基和杂芳基可以任选被取代,
R2选自下列环系
其中
X独立地选自CH2和O,
p各自独立地是1或2,
W选自C和N,在W是N的情况下,R4不存在;
R3选自任选取代的杂芳基、烷基和卤素,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,其中烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基可以任选被取代,并且
R5选自氢、任选取代的烷基和任选取代的杂芳基。
6.项目1的化合物,其是式(Ie)化合物:
其中
A选自芳基和杂芳基,其中芳基和杂芳基可以任选被取代,
R2选自下列环系
其中
X独立地选自CH2和O,
p各自独立地是1或2,
W选自C和N,在W是N的情况下,R4不存在,
R3选自任选取代的杂芳基、烷基和卤素,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,其中烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基可以任选被取代,并且
R5选自氢、任选取代的烷基和任选取代的杂芳基。
各自可以任选被取代。
8.项目1-7任一项的化合物,其中R3是任选取代的吡啶。
9.项目1-8任一项的化合物,其选自以下列表:
10.药物组合物,其包含如项目1-9任一项中所定义的化合物和任选选自药学上可接受的赋形剂、载体、稀释剂和佐剂的至少一种。
11.如项目1-9任一项中所定义的化合物或如项目10中所定义的药物组合物,其用作药物。
12.如项目1-9任一项中所定义的化合物或如项目10中所定义的药物组合物,其用于治疗、缓解或预防对炎症小体途径组分活化的调节或抑制有响应的障碍或异常。
13.用于项目12的用途的化合物或药物组合物,其还调节、特别是降低IL-1β和/或IL-18水平。
14.用于项目12或13的用途的化合物或药物组合物,其中炎症小体途径组分是NLRP3炎症小体。
15.如项目1-9任一项中所定义的化合物或如项目10中所定义的药物组合物,其用于治疗、缓解或预防对NLRP3炎症小体活化的抑制有响应的障碍或异常。
16.治疗、预防或缓解对炎症小体途径组分活化的调节或抑制有响应的障碍或异常的方法,该方法包括给需要此类治疗的个体施用有效量的如项目1-9任一项中所定义的化合物或如项目10中所定义的药物组合物。
17.项目16的方法,其中化合物还调节、特别是降低IL-1β和/或IL-18水平。
18.项目16或17的方法,其中炎症小体途径组分是NLRP3炎症小体。
19.治疗、预防或缓解对NLRP3炎症小体活化的抑制有响应的障碍或异常的方法,该方法包括给需要此类治疗的个体施用有效量的如项目1-9任一项中所定义的化合物或如项目10中所定义的药物组合物。
20.如项目1-9任一项中所定义的化合物在制备用于治疗、缓解或预防对炎症小体途径组分活化的调节或抑制有响应的障碍或异常的药物中的用途。
21.项目20的用途,其中化合物还调节、特别是降低IL-1β和/或IL-18水平。
22.项目20或21的用途,其中炎症小体途径组分是NLRP3炎症小体。
23.如项目1-9任一项中所定义的化合物在制备用于治疗、缓解或预防对NLRP3炎症小体活化的抑制有响应的障碍或异常的药物中的用途。
24.用于项目12-15任一项的用途的化合物、用于项目12-15任一项的用途的药物组合物、项目16-19任一项的方法或项目20-23任一项的用途,其中疾病、障碍或异常对IL-1β、IL-17、IL-18、IL-1a、IL-37、IL-33和Th17细胞的一种或多种的调节有响应。
25.混合物,其包含如项目1-9任一项中所定义的化合物和至少一种另外的生物活性化合物,其选自不同于项目1-9任一项中所定义的治疗剂;以及任选选自药学上可接受的载体、稀释剂、佐剂和赋形剂的至少一种。
26.项目25的混合物,其中另外的生物活性化合物选自抗-淀粉样蛋白β抗体或淀粉样蛋白β小分子抑制剂、抗-Tau抗体或Tau聚集小分子抑制剂、抗-α突触核蛋白抗体或α-突触核蛋白聚集小分子抑制剂、抗-TDP-43抗体或抗-TDP-43聚集小分子抑制剂。
27.用于项目12-15任一项的用途的化合物、用于项目12-15任一项的用途的药物组合物、项目16-19任一项的方法或项目20-23任一项的用途,其中疾病、障碍或异常选自阿尔茨海默病,帕金森病,肌萎缩性侧索硬化,脱髓鞘,病毒性脑炎,癫痫,中风,动脉粥样硬化,哮喘,变态反应性炎症,隐热蛋白相关周期性综合征(CAPS),穆-韦二氏综合征(MWS),家族性寒冷性自身炎性综合征(FCAS),新生儿发作性多系统炎性疾病(NOMID),痛风,假痛风,炎性肠病,非酒精性脂肪肝病,非酒精性脂肪性肝炎,高血压,心肌梗死,草酸盐诱导的肾病,移植物抗宿主病,1型糖尿病,2型糖尿病,类风湿性关节炎,骨髓增生异常综合征,家族性地中海热(FMF),TNF受体相关周期性综合征(TRAPS),甲羟戊酸激酶缺乏(MKD),高免疫球蛋白血症D、周期热综合征(HIDS),白细胞介素1受体缺乏(DIRA)拮抗剂,Majeed综合征,化脓性关节炎、坏疽性脓皮病和痤疮(PAPA),A20单倍剂量不足(HA20),PLCG2-相关抗体缺乏和免疫失调(PLAID),儿科肉芽肿关节炎(PGA),PLCG2-相关自身炎症、抗体缺乏和免疫失调(APLAID),具有B-细胞免疫缺陷、周期热、发育迟缓的铁粒幼细胞贫血(SIFD),慢性非细菌性骨髓炎(CNO),Sweet综合征,慢性复发性多病灶性骨髓炎(CRMO),滑膜炎、脓疱病、痤疮、骨肥大、骨炎综合征(SAPHO),多发性硬化(MS),银屑病,贝切特病,舍格伦综合征,施尼茨勒综合征,慢性阻塞性肺障碍(COPD),类固醇抵抗性哮喘,石棉肺,硅肺,囊性纤维化,运动神经元病,亨廷顿病,脑型疟,因肺炎球菌性脑膜炎导致的脑损伤,肥胖,年龄相关的黄斑变性(AMD),角膜感染,葡萄膜炎,干眼,慢性肾病,糖尿病肾病,酒精性肝病,皮肤接触过敏,晒伤,骨关节炎,系统性青少年特发性关节炎,成年发作性Still病,复发性多软骨炎,基孔肯雅病毒,罗斯河病毒,流感,HIV,冠状病毒,登革热病毒,寨卡病毒,化脓性汗腺炎(HS),肺癌转移,胰腺癌,胃癌,骨髓增生异常综合征,白血病,多肌炎,结肠炎,蠕虫感染,细菌感染,腹部主动脉瘤,伤口愈合,抑郁,心理学应激,心包炎包括德雷斯勒综合征,缺血再灌注损伤,额颞叶痴呆,HIV-相关神经认知障碍,冠状病毒相关炎性病理学和外伤性脑损伤。
28.用于项目12-15、22或25任一项的用途的化合物、用于项目12-15、22或25任一项的用途的药物组合物、项目16-19、24或27任一项的方法或项目20-24或27任一项的用途,其中疾病、障碍或异常选自阿尔茨海默病、帕金森病、隐热蛋白相关周期性综合征(CAPS)、非酒精性脂肪肝病、NASH和痛风。
29.如项目1-9任一项中所定义的化合物作为分析参比物或体外筛选工具的用途。
30.制备式(Ic)或(Id)化合物的方法,包括与式(IId)化合物在溶剂和碱的存在下发生异氰酸酯衍生物偶联反应的步骤
其中A、R2和R1如项目1-8任一项中所定义。
31.制备式(Ie)化合物的方法,包括式(IIe)化合物在溶剂和碱的存在下进行异氰酸酯衍生物偶联反应的步骤
其中A、R2和R1如项目1-8任一项中所定义。
32.如下定义的式(IId)或式(IIe)化合物:
其中A和R1如项目1-8的任一项中所定义。
定义
在本申请的含义内,应用以下定义:
“烷基”是指由碳和氢原子组成的饱和直链或支链有机部分。适合的烷基的实例具有1-6个碳原子,优选1-4个碳原子,并且包括甲基、乙基、丙基、异丙基、正丁基、叔丁基和异丁基。在本发明中,任何烷基可以任选被一个或多个(优选1或2个)以下定义为“任选取代基”的取代基取代。如果该部分是较大部分例如“烷氧基”的部分,则上述烷基的定义也适用。这同样适用于其它部分,例如环烷基、环烯基、芳基、杂芳基、杂环基等。
“Hal”或“卤素”是指F、Cl、Br和I。
“环烷基”是指饱和单环、双环或三环烃基(每个环具有3-8个环碳原子)。“环烯基”是指在一个环内具有至少一个(优选1或2)碳-碳双键的不饱和、非芳族单环、双环或三环烃基(每个环具有3-8个环碳原子)。它们的实例可以选自环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等。本发明中的任何环烷基或环烯基可以任选被一个或多个(优选1或2个)以下定义为“任选取代基”的取代基取代;所述任选取代基包括例如卤素(例如Cl、F、Br和I);卤代烷基(例如CF3、2-Br-乙基、CH2F、CH2Cl、CH2CF3或CF2CF3);羟基;氨基;羧酸酯基;酰氨基;烷基氨基;芳基氨基;烷氧基;芳氧基;硝基;叠氮基;氰基;硫代;磺酸;硫酸酯基;膦酸;磷酸酯基;和膦酸酯基。
“芳基”是指每个环中至多8个成员的稳定的单环、双环或三环碳环,其中至少一个环是如Huckel规则定义的芳族的。该术语包括包含饱和碳环或杂芳基或杂环基的多环系统,只要至少一个环是具有至多8个碳环原子的芳环。在本发明中,任何芳基可以任选被一个或多个(优选1或2个)以下定义为“任选取代基”的取代基取代。
“杂芳基”是指在其至少一个环上包含一个或多个(特别是1-4个)非碳环原子(特别是N、O或S或其任何组合)的芳基(优选在各环中具有至多8个环成员)。杂芳基环也可以与一个或多个环烃、杂环、芳基或杂芳基环稠合。杂芳基包括但不限于具有一个杂原子的5-元杂芳基(例如噻吩、吡咯、呋喃);在1,2或1,3位上具有两个杂原子的5-元杂芳基(例如唑、吡唑、咪唑、噻唑、嘌呤);具有三个杂原子的5-元杂芳基(例如三唑、噻二唑);具有四个杂原子的5-元杂芳基(例如四唑);具有一个杂原子的6-元杂芳基(例如吡啶、喹啉、异喹啉、菲、5,6-环庚烯并吡啶);具有两个杂原子的6-元杂芳基(例如哒嗪、噌啉、酞嗪、吡嗪、嘧啶、喹唑啉);和具有三个杂原子的6-元杂芳基(例如1,3,5-三嗪)。在本发明内,任何杂芳基可以任选在一个或多个碳环原子和/或杂环原子处被下文定义为“任选取代基”的取代基取代。
“杂环基”是指环中具有4-8个原子的非芳族环并且这些原子中的1-4个是杂原子(其可以独立地选自N、S和O)。杂环也可以与一个或多个环烃、杂环、芳基或杂芳基环稠合。杂环包括部分饱和和完全饱和的杂环基团。杂环系统可以通过基团的任意数量的碳原子或杂原子连接至另外的部分,并且可以均是饱和的和不饱和的。杂环部分的非限制性实例包括吡咯烷基、吡咯啉基、吡喃基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢噻吩基、吡唑啉基、二硫杂环戊二烯基、氧硫杂环戊二烯基、二烷基、二英基、嗪基、氮杂基、二氮杂基、硫氮杂基、氧杂基和硫杂基、咪唑啉基、硫代吗啉基、氧杂环丁烷基等。
涉及某些基团的“任选取代的”是指所述基团任选被一个或多个取代基取代(即,取代基可以存在或不存在)。此类“任选取代基”可以选自任选取代的烷基;任选取代的环烷基(例如任选取代的环丙基);任选取代的羟基烷基;任选取代的烷氧基(例如任选取代的烷氧基);任选取代的链烯基;任选取代的炔基;任选取代的芳基;芳氧基;任选取代的杂芳基;任选取代的杂环基;卤素(例如F、CI、Br和I);羟基;卤代烷基(例如CH2F、CHF2、CF3、2-Br-乙基、CH2CF3和CF2CF3);氨基(例如NH2、NR30H和NR30R31);烷基氨基;芳基氨基;酰基;酰氨基;CN;N3;NO2;CH2OH;CONH2;CONR32R33;CO2R32;CH2OR32;NHCOR32;NHCO2R32;烷硫基;硫酸酯基;磺酸;磺酸酯基例如烷基或芳烷基磺酰基;膦酸;磷酸酯基;膦酸酯基;单、二或三磷酸酯;三苯甲基或单甲氧基三苯甲基;R32SO;R32SO2;CF3S;和CF3SO2;三烷基甲硅烷基例如二甲基-叔丁基甲硅烷基或二苯基甲基甲硅烷基;其中R30、R31、R32和R33各自独立地选自H和任选取代的烷基。
具有一个或多个旋光碳的本发明化合物可以作为外消旋体和外消旋混合物(包括所有比例的混合物)、立体异构体(包括非对映异构体混合物和单一非对映异构体、对映异构体混合物和单一对映异构体、构象异构体的混合物和单一构象异构体),互变异构体、阻转异构体和旋转异构体存在。所有异构形式都包括在本发明中。本发明中描述的包含烯属双键的化合物包括E和Z几何异构体。本发明中还包括式(I)化合物的所有药学上可接受的盐、前药、多晶型物、水合物和溶剂化物。
术语“多晶型物”是指本发明化合物的多种结晶结构。其可以包括但不限于晶体形态(和无定形材料)和所有晶格形式。本发明的盐可以是结晶的并且可以作为一种以上的多晶型物存在。
本发明还包括盐的溶剂化物、水合物以及无水形式。对溶剂化物中包含的溶剂没有特别限制并且可以是任何药学上可接受的溶剂。实例包括水和C1-4醇(例如甲醇或乙醇)。
将“药学上可接受的盐”定义为所公开化合物的衍生物,其中母体化合物通过制备其酸或碱盐进行修饰。药学上可接受的盐的实例包括但不限于碱性残基例如胺的无机或有机酸盐;酸性残基例如羧酸等的碱盐或有机盐。药学上可接受的盐包括例如由无毒无机或有机酸形成的母体化合物的常规无毒盐或季铵盐。例如,此类常规无毒盐包括衍生自无机酸的那些,所述无机酸例如但不限于盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等;以及由有机酸制备的盐,所述有机酸例如但不限于乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、羟乙磺酸等。本发明的药学上可接受的盐可以由含有碱性或酸性部分的母体化合物通过常规化学方法合成。通常,此类盐可以通过将这些化合物的游离酸或碱形式与化学计量的适当碱或酸在水或有机溶剂或两者的混合物中反应来制备。有机溶剂包括但不限于非水介质,例如醚、乙酸乙酯、乙醇、异丙醇或乙腈。适合的盐的列表可以在Remington’sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA,1990,p.1445中找到,其公开内容以引用并入本文。
本发明化合物还可以以前药形式提供,即在体内代谢成活性代谢物的化合物。如本发明说明书的下文和权利要求书中所用,术语“前药”是指由于体内生物转化而释放活性母体药物的任何共价键合的化合物。一般性地描述前药的Goodman和Gilman的参考文献(The Pharmacological Basis of Therapeutics,第8版,McGraw-Hill,Int.Ed.1992,“Biotransformation of Drugs”,p 13-15)通过引用并入本文。
将“药学上可接受的”定义为这样一些化合物、材料、组合物和/或剂型,在合理的医学判断范围内,其适用于接触人和动物组织,而没有过度毒性、刺激性、变态反应性响应或其它问题或并发症,与合理的有益性/风险比相称。
施用于个体的化合物的“有效量”是根据合理的医学判断适合于治疗、预防或缓解疾病、障碍或异常的剂量。特定剂量水平和剂量频率可以取决于例如多种因素,包括所用的具体化合物的活性、该化合物的代谢稳定性和作用时长、施用模式和时间、排泄速率和药物组合。患者的特异性因素,例如年龄、体重、一般健康状况、性别、膳食和特定病症的严重性也可以影响所施用的量。
本发明的患者或个体通常是动物,特别是哺乳动物,更特别是人。
如本文所用,“NLRP3”是指NOD-样受体(NLR)家族,包含热蛋白结构域的炎症小体的蛋白3组分。炎症小体是胞内超分子复合体,其包含传感器分子、接头含有CARD的凋亡相关斑点-样蛋白(ASC)和效应器蛋白酶半胱氨酸天冬氨酸蛋白酶1。炎症小体传感器分子活化时,ASC自组装成螺旋状原纤维组装体,导致形成所谓的ASC斑点或pyroptosome,其作为分子平台起作用,用于通过亲近诱导的自催化活化激活原-半胱氨酸天冬氨酸蛋白酶1。活性半胱氨酸天冬氨酸蛋白酶1触发白细胞介素1(IL-1)家族蛋白的活化和释放,并且使众多细胞溶质蛋白的非常规分泌成为可能。NLRP3活化时释放的促炎介体是IL-1β、IL-18、高迁移率族蛋白B1(HMGB1)、白三烯和前列腺素。
“Tau聚集抑制剂”是指小分子化合物,其结合Tau并且直接减少Tau聚集或促进预先形成的Tau聚集物的解聚。
“α-突触核蛋白聚集抑制剂”是指小分子化合物,其结合α-突触核蛋白并且直接减少α-突触核蛋白聚集或促进预先形成的α-突触核蛋白聚集物的解聚。
“TDP-43聚集抑制剂”是指小分子化合物,其结合TDP-43并且直接减少TDP-43聚集或促进预先形成的TDP-43聚集物的解聚。
除非另有说明,否则“定义”部分中给出的定义和优选定义适用于以下描述的所有实施方案。
发明详述
下文将描述本发明化合物。应当理解,还设想了以下定义的所有可能组合。
在一个实施方案中,本发明涉及式(I)化合物:
或其立体异构体、外消旋混合物、互变异构体、药学上可接受的盐、前药、水合物、溶剂化物和多晶型物。
对于R1是氢,互变异构重排可能产生例如以下式(Ia)化合物,其是优选实施方案的主题:
式(Ia)化合物的进一步优选的实施方案是下式(Ib)化合物:
式(Ia)和(Ib)化合物的进一步优选的实施方案是下式(Ic)化合物:
如果适合,下列定义适用于式(I)、(Ia)、(Ib)和(Ic)。
其中这些环各自可以任选被取代。
A的任选取代基优选选自任选取代的C1-6烷基、卤素、羟基烷基、NHs(烷基)t(其中s和t各自可以是0、1或2,只要s+t=2;并且其中烷基是C1-10烷基)、任选取代的杂环烷基、任选取代的环烷基、卤代烷基和CN。更优选地,A的任选取代基可以是(对于基团如:如果利用取代,则取代基还可以键合至氮,例如:)、和CN。
R1选自氢、烷基和杂环基(例如氧杂环丁烷基),优选氢和烷基(例如Me);如果R1是氢,则互变异构重排是可能的。烷基和杂环基可以任选被取代。
R2选自下列环系
优选其选自以下环结构:
R3是任选取代的杂芳基,更优选任选取代的吡啶;优选的取代基是-O烷基(例如-OCH3)。R4选自氢、卤素、烷基、烷基-O-烷基、芳基和杂芳基。更优选R4选自氢和卤素。
W选自C和N。
X独立地选自CH2和O。更优选X是CH2。
Y选自NH、O和CRR,优选NH。
R各自独立地选自氢、卤素、CH3、CH2F、CHF2、CF3。
R1选自氢、烷基和杂环基,其中烷基和杂环基可以任选被取代;优选R1是氢。
m是0或1。
n是0或1。
优选选择n和m,以便得到5-或6-元环。
p各自独立地是0或1;优选至少一个p是1,并且更优选p均是1。
式(I)化合物包含下式的部分:
其优选选自
式(Ia)化合物包含下式的部分:
式(I)化合物的实例是:
式(I)化合物的优选实施方案如下:
如果适合,下列定义适用于式(I)、(Ia)、(Ib)、(Ic)、(Id)和(Ie):
A选自芳基和杂芳基,其中芳基和杂芳基可以任选被取代。优选A选自 其中这些环各自可以任选被取代。更优选A选自 其中这些环各自可以任选被取代。甚至更优选A选自其中这些环各自可以任选被取代。进一步更优选A选自其中这些环各自可以任选被取代。进一步更优选A选自其中这些环各自可以任选被取代。最优选A是可以任选被取代的
应当理解,芳基和杂芳基可以在任意可利用的位置上连接。
A的任选取代基优选选自任选取代的烷基(例如甲基或异丙基)、卤素(例如Cl、F或Br)、NHs(烷基)t(其中s和t各自可以是0、1或2,只要s+t=2)、任选取代的杂芳基、任选取代的芳基、任选取代的杂环烷基、任选取代的环烷基、-CN、-C(O)O-烷基(例如-C(O)O-甲基)、-S-烷基(例如-S-甲基)和-O-烷基(例如-O-甲基)。A的任选取代基更优选选自烷基、卤素、羟基烷基、NHs(烷基)t(其中s和t各自可以是0、1或2,只要s+t=2)、任选取代的杂芳基、任选取代的芳基、任选取代的杂环烷基、任选取代的环烷基、卤代烷基、-CN、-C(O)O-烷基、-S-烷基和-O-烷基。A的任选取代基进一步更优选选自烷基、卤素、羟基烷基、NHs(烷基)t(其中s和t各自可以是0、1或2,只要s+t=2)、任选取代的杂芳基、任选取代的芳基、任选取代的杂环烷基、任选取代的环烷基、卤代烷基、-CN、-S-烷基和-O-烷基。甚至更优选A的任选取代基选自烷基、卤素、卤代烷基、烷基-OH、NHs(烷基)t(其中s和t各自可以是0、1或2,只要s+t=2)、-CN、-C(O)O-烷基和-O-烷基。甚至更优选A的任选取代基选自-C(O)O-甲基、-CN、-Cl、-Br、-F、甲氧基、最优选A的任选取代基可以是和CN
在一个实施方案中,A的任选取代基选自任选取代的C1-6烷基、卤素、羟基烷基、NHs(烷基)t(其中s和t各自可以是0、1或2,只要s+t=2;并且其中烷基是C1-10烷基)、任选取代的杂环烷基、任选取代的环烷基、卤代烷基和CN。在进一步的实施方案中,A的任选取代基可以是和CN。
R1选自氢、烷基(例如甲基)、碳环基和杂环基(例如氧杂环丁烷基),其中烷基、碳环基和杂环基可以任选被取代。在一个实施方案中,R1选自氢、烷基和杂环基(例如氧杂环丁烷基)。优选R1是氢或烷基,更优选氢。如果R1是氢,则互变异构重排是可能的。例如在式(Ia)-(Ie)中显示了可能的互变异构体。烷基和杂环基可以任选被取代。
R2选自下列环系
优选R2选自下列环系
在一个实施方案中,R2选自下列环系
更优选R2选自下列环结构:
并且更优选R2选自
甚至更优选R2选自
R3选自氢、卤素(例如Cl、F或Br)、烷基(例如异丙基)、NR*R*(其中R*独立地选自H和烷基)例如NHMe)、芳基(例如苯基)和杂芳基(例如吡啶),其中烷基、芳基或杂芳基可以任选被取代。优选R3选自卤素、烷基、NR*R*、芳基和杂芳基,其中烷基、芳基或杂芳基可以任选被取代。更优选R3选自卤素、烷基、芳基和杂芳基,其中烷基、芳基或杂芳基可以任选被取代。在一个实施方案中,R3是任选取代的杂芳基,更优选任选取代的吡啶。优选R3是任选取代的杂芳基、异丙基、Cl、F或Br。更优选R3是任选取代的吡啶、异丙基或Br,其中吡啶例如被-O烷基(例如-OCH3)取代。最优选R3是任选取代的吡啶。
R3的杂芳基优选是吡啶。
R3部分的杂芳基的优选取代基是-O烷基(例如-OCH3)。
R4选自氢、卤素(例如氟)、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,其中烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基可以任选被取代。更优选R4选自氢和卤素。甚至更优选R4是氢或氟,最优选R4是氢。在一个实施方案中,R4选自氢、卤素、烷基、烷基-O-烷基、芳基和杂芳基,例如R4可以选自氢和卤素。
R5选自氢、卤素、任选取代的烷基(例如异丙基)、任选取代的芳基和任选取代的杂芳基,优选R5选自氢、任选取代的烷基和任选取代的杂芳基,更优选氢、异丙基或任选取代的吡啶,其中吡啶优选被-O烷基(例如-OCH3)取代,更优选R5是异丙基或
R5部分的芳基和杂芳基的优选取代基是-O烷基(例如-OCH3)。
W选自C和N,优选W是C。更优选地,当W是C时,R4是氢。在W是N的情况下,R4不存在。
X各自独立地选自CH2和O。更优选X是CH2。
Y选自NH、O和CRR,优选Y是NH。
Z和Z’独立地选自C和N,条件是当m是0时,Z’是C。优选地,Z和Z’是C。
R各自独立地选自氢、卤素、CH3、CH2F、CHF2、CF3,优选R是氢。
m是0或1。
n是0或1。
优选选择n和m,以便得到5-或6-元环。
p各自独立地是0、1或2,优选1或2;更优选至少一个p是1,并且甚至更优选p均是1。在一个实施方案中,p各自独立地是0或1,优选至少一个p是1。
其中X独立地选自CH2和O,
p各自独立地是1或2,并且
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基。
在该实施方案中,优选X是CH2,至少一个p是1,并且R4选自氢和卤素。在该实施方案中,更优选X是CH2,p均是1,并且R4选自氢和F(氟)。
其中X独立地选自CH2和O,并且
p各自独立地是1或2。
在该实施方案中,优选X是CH2,并且至少一个p是1,并且更优选p均是1。
其中X独立地选自CH2和O,
p各自独立地是1或2,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,并且
R3是任选取代的杂芳基、烷基和卤素。
在该实施方案中,优选X是CH2,至少一个p是1,并且更优选p均是1,R3是任选取代的杂芳基、异丙基、Cl、F或Br,并且R4选自氢和卤素。在该实施方案中,更优选X是CH2,p均是1,R3是任选取代的吡啶、异丙基或Br,其中吡啶优选被-O烷基(例如-OCH3)取代,并且R4是氢或F(氟)。
其中W选自C和N,在W是N的情况下,R4不存在,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,并且
R5是氢、任选取代的烷基或任选取代的杂芳基。
本发明的进一步的实施方案涉及下式(Id)化合物:
或其立体异构体、外消旋混合物、互变异构体、药学上可接受的盐、前药、水合物、溶剂化物和多晶型物,
其中
A选自芳基和杂芳基,其中芳基和杂芳基可以任选被取代,
R2选自下列环系
其中
X各自独立地选自CH2和O,
p各自独立地是1或2,
W选自C和N,在W是N的情况下,R4不存在,
R3选自任选取代的杂芳基、烷基和卤素,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,并且
R5选自氢、任选取代的烷基或任选取代的杂芳基。
A的任选取代基优选选自任选取代的烷基、卤素、羟基烷基、NHs(烷基)t(其中s和t各自可以是0、1或2,只要s+t=2)、任选取代的杂环烷基、任选取代的环烷基、卤代烷基、CN、烷基和烷氧基。更优选A的任选取代基选自任选取代的烷基,优选甲基或异丙基;卤素,优选Cl、F或Br;CN;烷基羧基,优选甲基羧基;和烷氧基,优选甲氧基。此外,烷基可以任选被OH或卤素取代,优选Cl、F或Br。甚至更优选A的任选取代基是甲基羧基、CN、Cl、Br、F、甲氧基、
优选R2选自如下环结构
优选X是CH2。
优选至少一个p是1,并且更优选p均是1。
优选R3选自任选取代的杂芳基、异丙基、Cl、F和Br。更优选R3选自任选取代的吡啶、异丙基和Br,其中吡啶优选被-O烷基(例如-OCH3)取代。
优选R4选自氢和卤素,优选氢或F(氟)。更优选R4是氢。
优选W是C。更优选当W是C时,R4是氢。
其中
X独立地选自CH2和O,
p各自独立地是1或2,并且
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基。
优选X是CH2,至少一个p是1,并且R4选自氢和卤素。
更优选X是CH2,p均是1,并且R4选自氢和F(氟)。
其中X独立地选自CH2和O,并且
p各自独立地是1或2。
优选X是CH2,并且至少一个p是1,并且更优选p均是1。
其中X选自CH2和O,
p各自独立地是1或2,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,并且
R3选自任选取代的杂芳基、烷基和卤素。
优选X是CH2,至少一个p是1,并且更优选p均是1,R3选自任选取代的杂芳基、异丙基、Cl、F和Br,并且R4选自氢和卤素。
更优选X是CH2,p均是1,R3是任选取代的吡啶、异丙基或Br,其中吡啶优选被-O烷基(例如-OCH3)取代,并且R4是氢或F(氟)。
其中W选自C和N,在W是N的情况下,R4不存在,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,并且
R5是氢、任选取代的烷基或任选取代的杂芳基。
优选W是C,R4选自氢和卤素,并且R5是氢、异丙基或任选取代的吡啶,其中吡啶优选被-O烷基(例如-OCH3)取代。
式(Id)化合物是
鉴定了下列对映异构体。显示了洗脱峰*:
本发明的进一步的实施方案涉及下式(Ie)化合物:
或其立体异构体、外消旋混合物、互变异构体、药学上可接受的盐、前药、水合物、溶剂化物和多晶型物,
其中
A选自芳基和杂芳基,其中芳基和杂芳基可以任选被取代,
R2选自下列环系
其中
X独立地选自CH2和O,
p各自独立地是1或2,
W选自C和N,在W是N的情况下,R4不存在,
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基,
R3选自任选取代的杂芳基、烷基和卤素,并且
R5选自氢、任选取代的烷基和任选取代的杂芳基。
在式(Id)化合物方面给出的优选定义在本文中适用。
优选的式(Ie)化合物是
本发明还设想了本文公开的实施方案、优选实施方案和更优选实施方案的任意组合。
本发明还涉及药物组合物,其包含式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物和任选至少一种药学上可接受的赋形剂、载体、稀释剂和/或佐剂。
在一个实施方案中,药物组合物包含式(Id)化合物和任选至少一种药学上可接受的赋形剂、载体、稀释剂和/或佐剂。
在进一步的实施方案中,药物组合物包含式(Ie)化合物和任选至少一种药学上可接受的赋形剂、载体、稀释剂和/或佐剂。
上述对式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物所定义的实施方案在本文中也适用并且可以彼此相互组合。
本发明涉及治疗、缓解或预防疾病、障碍或异常的方法,包括对有需要的患者施用治疗有效量的如本文所定义的式(I)化合物、特别是式(Ic)、(Id)或(Ie)化合物的步骤。
本发明涉及如本文所定义的式(I)化合物、特别是式(Ic)、(Id)或(Ie)化合物,其用作药物。
本发明涉及如本文所定义的式(I)化合物,特别是式(Ic)、(Id)或(Ie)化合物,其用于治疗、缓解或预防对炎症小体途径组分的调节或抑制有响应的疾病、障碍或异常和/或用于调节、特别是降低IL-1β和/或IL-18水平。
本发明涉及治疗、缓解或预防对炎症小体途径组分的调节或抑制有响应的疾病、障碍或异常和/或用于调节、特别是降低IL-1β和/或IL-18水平的方法,通过向有需要的患者施用治疗有效量的如本文定义的式(I)化合物、特别是式(Ic)、(Id)或(Ie)化合物来进行。
在一个实施方案中,本发明涉及治疗、预防或缓解对炎症小体途径组分的调节或抑制有响应的疾病、障碍或异常的方法,通过向有需要的患者施用治疗有效量的如本文定义的式(I)化合物、特别是式(Ic)、(Id)或(Ie)化合物来进行。
优选疾病、障碍或异常响应于炎症小体途径组分的调节,特别是响应于炎症小体途径组分的抑制。优选炎症小体途径组分是NLRP3炎症小体。
在一个实施方案中,本发明涉及治疗、预防或缓解对调节、特别是降低IL-1β和/或IL-18水平有响应的疾病、障碍或异常的用途或方法。
换言之,本发明涉及治疗、预防或缓解对调节、特别是降低IL-1β和/或IL-18水平有响应的疾病、障碍或异常的方法,通过给有需要的患者施用治疗有效量的如本文所定义的式(I)化合物、特别是式(Ic)、(Id)或(Ie)化合物来进行。
更优选疾病、障碍或异常选自阿尔茨海默病,帕金森病,肌萎缩性侧索硬化,脱髓鞘,病毒性脑炎,癫痫,中风,动脉粥样硬化,哮喘,变态反应性炎症,隐热蛋白相关周期性综合征(CAPS),穆-韦二氏综合征(MWS),家族性寒冷性自身炎性综合征(FCAS),新生儿发作性多系统炎性疾病(NOMID),痛风,假痛风,炎性肠病,非酒精性脂肪肝病,非酒精性脂肪性肝炎,高血压,心肌梗死,草酸盐诱导的肾病,移植物抗宿主病,1型糖尿病,2型糖尿病,类风湿性关节炎,骨髓增生异常综合征,家族性地中海热(FMF),TNF受体相关周期性综合征(TRAPS),甲羟戊酸激酶缺乏(MKD),高免疫球蛋白血症D、周期热综合征(HIDS),白细胞介素1受体缺乏(DIRA)拮抗剂,Majeed综合征,化脓性关节炎、坏疽性脓皮病和痤疮(PAPA),A20单倍剂量不足(HA20),PLCG2-相关抗体缺乏和免疫失调(PLAID),儿科肉芽肿关节炎(PGA),PLCG2-相关自身炎症、抗体缺乏和免疫失调(APLAID),具有B-细胞免疫缺陷、周期热、发育迟缓的铁粒幼细胞贫血(SIFD),慢性非细菌性骨髓炎(CNO),Sweet综合征,慢性复发性多病灶性骨髓炎(CRMO),滑膜炎、脓疱病、痤疮、骨肥大、骨炎综合征(SAPHO),多发性硬化(MS),银屑病,贝切特病,舍格伦综合征,施尼茨勒综合征,慢性阻塞性肺障碍(COPD),类固醇抵抗性哮喘,石棉肺,硅肺,囊性纤维化,运动神经元病,亨廷顿病,脑型疟,因肺炎球菌性脑膜炎导致的脑损伤,肥胖,年龄相关的黄斑变性(AMD),角膜感染,葡萄膜炎,干眼,慢性肾病,糖尿病肾病,酒精性肝病,皮肤接触过敏,晒伤,骨关节炎,系统性青少年特发性关节炎,成年发作性Still病,复发性多软骨炎,基孔肯雅病毒,罗斯河病毒,流感,HIV,冠状病毒,登革热病毒,寨卡病毒,化脓性汗腺炎(HS),肺癌转移,胰腺癌,胃癌,骨髓增生异常综合征,白血病,多肌炎,结肠炎,蠕虫感染,细菌感染,腹部主动脉瘤,伤口愈合,抑郁,心理学应激,心包炎包括德雷斯勒综合征,缺血再灌注损伤,额颞叶痴呆,HIV-相关神经认知障碍,冠状病毒相关炎性病理学和外伤性脑损伤。
优选疾病、障碍或异常选自阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、脱髓鞘、病毒性脑炎、癫痫、中风、动脉粥样硬化、哮喘、变态反应性炎症、隐热蛋白相关周期性综合征(CAPS)、痛风、炎性肠病、非酒精性脂肪肝病、非酒精性脂肪性肝炎(NASH)、高血压、心肌梗死、草酸盐诱导的肾病、移植物抗宿主病、1型糖尿病、2型糖尿病、类风湿性关节炎、骨髓增生异常综合征、抗嗜中性粒细胞胞质抗体相关血管炎(AAV)、狼疮肾炎、抗肾小球基膜(GMB)病、IgA肾病、肾小球肾炎(GN)、系统性红斑狼疮(SLE)、局灶性节段性肾小球硬化、微小病变疾病(MCD)、银屑病关节炎和遗传性阵发性回归热(HRF)。
优选疾病、障碍或异常选自阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、脱髓鞘、病毒性脑炎、癫痫、中风、动脉粥样硬化、哮喘和变态反应性炎症、隐热蛋白相关周期性综合征(CAPS)、痛风、炎性肠病、非酒精性脂肪肝病、非酒精性脂肪性肝炎(NASH)、高血压、心肌梗死、草酸盐诱导的肾病、移植物抗宿主病、1型和2型糖尿病、类风湿性关节炎和骨髓增生异常综合征。
更优选疾病、障碍或异常选自阿尔茨海默病、帕金森病、隐热蛋白相关周期性综合征(CAPS)、非酒精性脂肪肝病、NASH、类风湿性关节炎和痛风。
甚至更优选疾病、障碍或异常选自阿尔茨海默病、帕金森病、隐热蛋白相关周期性综合征(CAPS)、类风湿性关节炎和痛风。
在一个实施方案中,本发明涉及如本文所定义的式(I)化合物,特别是式(Ic)、(Id)或(Ie)化合物,其用于通过调节炎症小体途径组分、特别是通过调节NLRP3炎症小体来治疗、缓解或预防tau病变。
在一个实施方案中,本发明涉及如本文所定义的式(I)化合物,特别是式(Ic)、(Id)或(Ie)化合物,其用于治疗、缓解或预防IL-18和/或IL-1β相关疾病或异常,通过调节炎症小体途径组分、特别是通过调节NLRP3炎症小体来进行。个体的IL-18和/或IL-1β水平通常由于施用如本文定义的式(I)化合物、特别是式(Ic)、(Id)或(Ie)化合物而降低。
IL-18和/或IL-1β相关疾病和异常可以选自慢性阻塞性肺病(COPD),输血相关肺损伤,支气管肺发育不良(BPD),急性呼吸窘迫综合征(ARDS),小儿自身炎性疾病或病症,Still病,特别是成年型Still病或青少年Still病,青少年类风湿性关节炎(JRA),青少年特发性关节炎(JIA),全身性青少年发作型特发性关节炎(SoJIA),全身性青少年特发性关节炎(sJIA),间质性肺病(ILD),巨噬细胞活化综合征(MAS)包括原发性,继发性和复发性MAS,噬血细胞性淋巴组织细胞增生症(HLH),与穿孔蛋白中的遗传缺陷相关的家族性(遗传性)噬血细胞性淋巴组织细胞增生症(FHLH),munc 13-4和18-2,synthaxin 11,免疫缺陷例如切-东二氏综合征(CHS),格里西里综合征(GS),X-连锁淋巴组织增生综合征(XLP2),X-连锁凋亡蛋白缺陷(XIAP)抑制剂,与感染病症特别是疱疹病毒例如EBV和其它病原体相关的获得性噬血细胞性淋巴组织细胞增生症,与NLRC4突变相关的自身炎性综合征,巨细胞动脉炎(GCA),化脓性关节炎、坏疽性脓皮病和痤疮和痤疮(PAPA),肺结节病,心力衰竭,缺血性心脏病,干眼病(DED),角膜炎,角膜溃疡和擦伤,虹膜炎,青光眼,舍格伦综合征,自身免疫性葡萄膜炎,贝切特病,结膜炎,变态反应性结膜炎,2型糖尿病,实体器官和血液干细胞移植,缺血再灌注损伤,家族性地中海热(FMF),肿瘤坏死因子受体1-相关周期性综合征(TRAPS),超-lgD综合征(甲羟戊酸激酶基因突变),痛风,施尼茨勒综合征,韦格纳肉芽肿也称作具有多血管炎的肉芽肿(GPA),桥本甲状腺炎,克罗恩病,早发性炎性肠病(EOIBD),非常性EOIBD(VEOIBD),婴儿IBD,新生儿IBD,溃疡性结肠炎和Blau综合征(NOD-2突变)。
NLRP3炎症小体的调节显然有益于具有导致病理性炎症的改变的IL-18水平的疾病、障碍和异常。
上述如对式(I)化合物例如式(Ia)、(Ib)、(Ic)、(Id)或(Ie)化合物所定义的实施方案在本文中适用并且可以彼此组合。
本发明涉及如本文所定义的式(I)化合物,特别是式(Ic)、(Id)或(Ie)化合物,其是个体的NLRP3炎症小体活性调节剂和/或IL-18和/或IL-1b水平的调节剂。
本发明涉及药物组合物,其包含如本文所定义的式(I)化合物,特别是式(Ic)、(Id)或(Ie)化合物和至少一种另外的生物活性化合物,所述另外的生物活性化合物不同于式(I)化合物,特别是式(Ic)、(Id)或(Ie)化合物;以及任选药学上可接受的赋形剂、载体、稀释剂或佐剂的至少一种的组合。
特别地,另外的生物活性化合物可以用于治疗靶向不同病理机制的疾病、障碍或异常,例如抗-淀粉样蛋白β抗体、抗-Tau抗体、淀粉样蛋白β小分子抑制剂、Tau聚集小分子抑制剂、抗-α突触核蛋白抗体或α-突触核蛋白聚集小分子抑制剂、抗-TDP-43抗体或抗-TDP-43聚集小分子抑制剂等。当本发明化合物与另外的生物活性化合物组合使用时,每种化合物的剂量可以不同于如果该化合物用作单一疗法的剂量。
本发明涉及式(I)化合物,特别是式(Ic)、(Id)或(Ie)化合物作为分析参比物或体外筛选工具的用途。本发明化合物可以用作分析参比物或体外筛选工具,其用于表征具有活化的NLRP3炎症小体的细胞以及测试靶向NLRP3炎症小体的化合物。
本发明涉及获得式(I)化合物、特别是式(Ic)、(Id)或(Ie)化合物的方法。在进一步的实施方案中,该方法优选适合于获得式(Id)或(Ie)化合物。
在一个实施方案中,该方法包括将用于制备式(Ic)或(Id)化合物的式(IId)化合物在溶剂和碱的存在下进行异氰酸酯衍生物偶联反应的步骤
其中A、R2和R1如上述所定义。
偶联反应使用适合的溶剂在强碱性条件下进行。碱优选是NaH、三乙胺或吡啶。溶剂优选是THF、DCM或CHCl3。
偶联优选在室温(rt)进行。
优选该方法包括将用于制备式(Id)化合物的式(IId)化合物在溶剂和碱的存在下进行异氰酸酯衍生物偶联反应的步骤。
在一个实施方案中,该方法包括将用于制备式(Ie)化合物的式(IIe)化合物在溶剂和碱的存在下进行异氰酸酯衍生物偶联反应的步骤。
其中A、R2和R1如上述所定义。
偶联反应使用适合的溶剂,在强碱条件下进行。碱优选是NaH、三乙胺或吡啶。溶剂优选是THF、DCM或CHCl3。
偶联优选在室温(rt)进行。
本发明进一步涉及如下所定义的式(IId)和(IIe)化合物:
其中A和R1如上述所定义。
本发明还设想了本文公开的实施方案、优选实施方案和更优选实施方案的任意组合。
药物组合物
虽然本发明化合物可以单独施用,但是优选根据标准药物实践将其配制成药物组合物。因此,本发明还提供了药物组合物,其包含治疗有效量的式(I)化合物任选与药学上可接受的载体、稀释剂、佐剂或赋形剂的混合物。
药学上可接受的载体、稀释剂、佐剂和赋形剂是制药领域众所周知的,并且描述在例如下列文献中:Remington’s Pharmaceutical Sciences,第15或第18版(AlfonsoR.Gennaro,ed.;Mack Publishing Company,Easton,PA,1990);Remington:the Scienceand Practice of Pharmacy第19版(Lippincott,Williams&Wilkins,1995);Handbook ofPharmaceutical Excipients,第3版(Arthur H.Kibbe,ed.;Amer.Pharmaceutical Assoc,1999);Pharmaceutical Codex:Principles and Practice of Pharmaceutics第12版(Walter Lund ed.;Pharmaceutical Press,London,1994);The United StatesPharmacopeia:The National Formulary(United States Pharmacopeial Convention);Fiedler’s“Lexikon der Hilfstoffe”第5版Cantor Verlag Aulendorf 2002;“TheHandbook of Pharmaceutical Excipients”,第4版,American PharmaceuticalsAssociation,2003;和Goodman和Gilman's:the Pharmacological Basis ofTherapeutics(Louis S.Goodman和Lee E.Limbird,eds.;McGraw Hill,1992),其公开内容通过引用并入本文。
载体、稀释剂、佐剂和药用赋形剂可以根据预期的施用途径和标准药学实践进行选择。这些化合物必须在对其接受者无害的意义上是可接受的。
可用于配制本发明的药物组合物的药学上有用的赋形剂可以包括例如媒介物、溶剂(例如一元醇,例如乙醇、异丙醇,和多元醇,例如乙二醇)、食用油(例如大豆油、椰子油、橄榄油、红花油和棉籽油)、油酯(例如油酸乙酯和肉豆蔻酸异丙酯)、粘合剂(例如羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、预胶化淀粉及其组合)、增溶剂、增稠剂、稳定剂、崩解剂(例如羧甲基纤维素钙(CMC-Ca)、羧甲基纤维素钠(CMC-Na)、交联PVP(例如交联聚维酮、或XL)、海藻酸、海藻酸钠、瓜尔胶、交联CMC(交联羧甲基纤维素钠,例如)、羧甲基淀粉-Na(淀粉羟乙酸钠)(例如或),优选交联PVP和/或交联羧甲基纤维素钠)、助流剂(例如胶体SiO2(例如200)、三硅酸镁、粉状纤维素、滑石粉及其组合)、润滑剂(例如硬脂酸镁、硅酸铝或硅酸钙、硬脂酸、氢化蓖麻油、滑石粉、山嵛酸甘油酯、硬脂酸富马酸钠及其组合)、缓冲剂、乳化剂、润湿剂、助悬剂、甜味剂、着色剂、矫味剂、包衣剂、防腐剂、抗氧化剂、加工助剂、药物递送修饰剂和增强剂(例如磷酸钙)、硬脂酸镁、滑石粉、单糖、二糖、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、右旋糖、羟丙基-β-环糊精、聚乙烯吡咯烷酮、低熔点蜡和离子交换树脂。
对于载体没有特别限制并且将取决于施用途径以及药物组合物的形式(即固体、液体等)。适合的载体包括但不限于多元醇,例如甘露醇、山梨醇、木糖醇;二糖,例如乳糖、蔗糖、右旋糖和麦芽糖;多糖,例如麦芽糖糊精和葡聚糖;淀粉,例如玉米淀粉;纤维素,例如微晶纤维素、羧甲基纤维素钠、低取代羟丙基纤维素、羟乙基纤维素、羟丙基纤维素或其混合物;环糊精和无机试剂,例如磷酸二钙、磷酸氢钙;羟基磷灰石、磷酸三钙、滑石粉和二氧化硅。优选微晶纤维素、蔗糖和/或乳糖作为载体。也可以使用它们的组合。载体还可以包括蛋白质和细胞穿透肽,应当取决于施用途径和靶标进行选择。
对稀释剂没有特别限制并且将取决于施用途径以及药物组合物的形式(即固体、液体等)。稀释剂包括例如水、乙醇、丙二醇和甘油,以及它们的组合。
佐剂为一种添加剂,其本身几乎没有药理作用或没有药理作用,但如果将它们与本发明化合物一起施用,则增加本发明化合物的功效或效力。
本发明化合物的施用(递送)途径包括但不限于以下的一种或多种:口服(例如作为片剂、胶囊或作为可摄入溶液)、局部、粘膜(例如作为鼻喷雾剂或用于吸入的气雾剂)、鼻、非肠道(例如通过可注射形式)、胃肠道、脊柱内、腹膜内、肌内、静脉内、子宫内、眼内、皮内、颅内、气管内、阴道内、脑室内、脑内、皮下、眼科(包括玻璃体内或前房内)、透皮、直肠、口腔、硬膜外和舌下。
例如,这些化合物可以以片剂、胶囊剂、小珠(ovules)、酏剂、溶液剂或混悬剂的形式口服施用,它们可以包含矫味剂或着色剂,用于立即、延迟、修饰、持续、脉冲或控制-释放应用。
片剂可以包含赋形剂,例如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙和甘氨酸,崩解剂,例如淀粉(优选玉米、马铃薯或木薯淀粉)、淀粉羟乙酸钠、交联羧甲基纤维素钠和某些复合硅酸盐,以及制粒粘合剂,例如聚乙烯吡咯烷酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、蔗糖、明胶和阿拉伯胶。此外,可以包含润滑剂,例如硬脂酸镁、硬脂酸、山嵛酸甘油酯和滑石粉。相似类型的固体组合物也可用作明胶胶囊剂中的填充剂。在这方面优选的赋形剂包括乳糖、淀粉、纤维素、奶糖,例如乳糖或高分子量聚乙二醇。对于水性混悬剂和/或酏剂,该试剂可以与多种甜味剂或矫味剂、着色物质或染料、与乳化剂和/或助悬剂和与稀释剂例如水、乙醇、丙二醇和甘油及其组合合并。
如果本发明化合物通过非肠道施用,则此类施用的实例包括以下的一种或多种:静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内或皮下施用化合物;和/或使用输液技术。对于非肠道施用,化合物可以以无菌水溶液的形式使用,该水溶液可以包含其它物质,例如足够的盐或葡萄糖以使溶液与血液等渗。如有必要,水溶液应适当缓冲(优选pH为3-9)。在无菌条件下制备适合的非肠道制剂易于通过本领域技术人员众所周知的标准制药技术完成。
如所示的,本发明化合物可以鼻内或通过吸入施用,并且以干粉吸入器或气雾剂喷雾形式便利地从加压容器、泵、喷雾器或雾化器中递送,其中使用适合的抛射剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟烷烃例如1,1,1,2-四氟乙烷(HFA134AT)或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA)、二氧化碳或其它适合的气体。在加压气雾剂的情况下,剂量单位可以通过配备阀门以递送计量的量来确定。加压容器、泵、喷雾器或雾化器可以包含活性化合物的溶液或混悬液,例如使用乙醇和抛射剂的混合物作为溶剂,其中可以另外包含润滑剂,例如三油酸山梨坦。用于吸入器或吹入器的胶囊和药筒(例如由明胶制成)可以配制成包含化合物和适合的粉末基质(例如乳糖或淀粉)的粉末混合物。
可选择的是,本发明化合物可以以栓剂或阴道栓剂的形式施用,或者可以以凝胶、水凝胶、洗剂、溶液剂、乳膏剂、软膏剂或散粉的形式局部应用。本发明化合物也可以经皮肤或透皮施用,例如,通过使用皮肤贴剂。
它们也可以通过肺或直肠途径施用。它们也可以通过眼途径施用。对于眼科用途,可以将化合物配制成在等渗、pH调节的无菌盐水中的微粉化混悬剂,或优选配制成等渗、pH调节的无菌盐水中的溶液剂,任选与防腐剂例如苄扎氯铵组合。可选择的是,可以将它们配制在软膏剂中,例如凡士林。
对于局部应用于皮肤,可以将本发明化合物配制成适合的软膏剂,其包含悬浮或溶解在例如与以下一种或多种的混合物中的活性化合物:矿物油、液体凡士林、白凡士林、丙二醇、乳化蜡和水。可选择的是,可以将它们配制成悬浮或溶解在例如以下一种或多种的混合物中的适合的洗剂或乳膏剂:矿物油、单硬脂酸山梨坦、聚乙二醇、液体石蜡、聚山梨酯60、鲸蜡酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苄醇和水。
通常,临床医师将确定最适合单个个体的实际剂量。任何特定个体的特定剂量水平和剂量频率可能会有所不同,并且将取决于多种因素,包括所用特定化合物的活性、该化合物的代谢稳定性和作用时长、年龄、体重、一般健康状况、性别、膳食、施用方式和时间、排泄速率、药物组合、特定病症的严重程度以及接受疗法的个体。
本发明化合物施用于人(体重约70kg)的建议剂量为每单位剂量0.1mg-1g,优选1mg-500mg活性成分。单位剂量可以例如每天施用1-4次。剂量将取决于施用途径。应当理解,可能有必要根据患者的年龄和体重以及待治疗病症的严重程度对剂量进行常规变化。精确的剂量和施用途径最终将由主治医师或兽医决定。
要求保护的化合物可以单独或与一种或多种另外的生物活性化合物组合用于治疗、缓解或预防所述疾病、障碍或异常。特别地,另外的生物活性化合物可以是用于治疗靶向不同病理机制的疾病、病症或异常的化合物,例如阿尔茨海默病中的抗-淀粉样蛋白β抗体和/或抗-Tau抗体或Tau聚集小分子抑制剂、抗-α突触核蛋白抗体或α-突触核蛋白聚集小分子抑制剂、抗-TDP-43抗体或抗-TDP-43聚集小分子抑制剂等。当本发明化合物与针对相同疾病、障碍或异常的另外的生物活性化合物组合使用时,每种化合物的剂量可以与单独使用该化合物时的剂量不同。
上述涉及的组合可以便利地以药物制剂的形式使用。此类组合的各个组分可以通过任何便利的途径以单独或组合的药物制剂依次或同时施用。当依次施用时,可以首先施用本发明化合物或另外的生物活性化合物。当施用同时进行时,该组合可以以在相同或不同的药物组合物中的形式施用。当在同一制剂中组合时,可以理解,这两种化合物必须是稳定的并且彼此和与制剂的其它组分相容。当单独配制时,它们可以以任何便利的制剂形式提供,便利地以本领域对此类化合物已知的方式提供。
可以按照对于本领域技术人员而言本身已知的方式制备本发明的药物组合物,例如Remington’s Pharmaceutical Sciences,第15版,Mack Publishing Co.,New Jersey(1975)中所述。
可以治疗、缓解或预防的疾病、障碍或异常的实例包括但不限于阿尔茨海默病,帕金森病,肌萎缩性侧索硬化,脱髓鞘,病毒性脑炎,癫痫,中风,动脉粥样硬化,哮喘和变态反应性炎症,隐热蛋白相关周期性综合征(CAPS),穆-韦二氏综合征(MWS),家族性寒冷性自身炎性综合征(FCAS),新生儿发作性多系统炎性疾病(NOMID),痛风,假痛风,炎性肠病,非酒精性脂肪肝病,非酒精性脂肪性肝炎,高血压,心肌梗死,草酸盐诱导的肾病,移植物抗宿主病,1型和2型糖尿病,类风湿性关节炎,骨髓增生异常综合征,家族性地中海热(FMF),TNF受体相关周期性综合征(TRAPS),甲羟戊酸激酶缺乏(MKD),高免疫球蛋白血症D和周期热综合征(HIDS),白细胞介素1受体缺乏(DIRA)拮抗剂,Majeed综合征,化脓性关节炎、坏疽性脓皮病和痤疮(PAPA),A20单倍剂量不足(HA20),PLCG2-相关抗体缺乏和免疫失调(PLAID),儿科肉芽肿关节炎(PGA),PLCG2-相关自身炎症、抗体缺乏和免疫失调(APLAID),具有B-细胞免疫缺陷、周期热、发育迟缓的铁粒幼细胞贫血(SIFD),慢性非细菌性骨髓炎(CNO),Sweet综合征,慢性复发性多病灶性骨髓炎(CRMO)和滑膜炎、脓疱病、痤疮、骨肥大、骨炎综合征(SAPHO),多发性硬化(MS),银屑病,贝切特病,舍格伦综合征和施尼茨勒综合征,慢性阻塞性肺障碍(COPD),类固醇抵抗性哮喘,石棉肺,硅肺,囊性纤维化,运动神经元病,亨廷顿病,脑型疟,因肺炎球菌性脑膜炎导致的脑损伤,肥胖,年龄相关的黄斑变性(AMD),角膜感染,葡萄膜炎和干眼,慢性肾病,糖尿病肾病,酒精性肝病,皮肤接触过敏,晒伤,骨关节炎,系统性青少年特发性关节炎,成年发作性Still病,复发性多软骨炎,基孔肯雅和罗斯河病毒,流感,HIV,登革热病毒,寨卡病毒,化脓性汗腺炎(HS),肺癌转移,胰腺癌,胃癌,骨髓增生异常综合征,白血病,多肌炎,结肠炎,蠕虫感染,细菌感染,腹部主动脉瘤,伤口愈合,抑郁,心理学应激,心包炎包括德雷斯勒综合征,缺血再灌注损伤,额颞叶痴呆,HIV-相关神经认知障碍和外伤性脑损伤;优选疾病、障碍或异常选自阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、脱髓鞘、病毒性脑炎、癫痫、中风、动脉粥样硬化、哮喘和变态反应性炎症、CAPS、痛风、炎性肠病、非酒精性脂肪肝病、非酒精性脂肪性肝炎、高血压、心肌梗死、草酸盐诱导的肾病、移植物抗宿主病、1型和2型糖尿病、类风湿性关节炎和骨髓增生异常综合征。
本发明化合物可以用作分析参比物或体外筛选工具,其用于表征具有活化的NLRP3炎症小体的细胞或测试靶向NLRP3炎症小体的化合物。
本发明化合物也可以以与至少一种另外的生物活性化合物和/或药学上可接受的载体和/或稀释剂和/或赋形剂和/或佐剂的混合物形式提供。该化合物和/或另外的生物活性化合物优选以治疗有效量存在。
另外的生物活性化合物的性质将取决于混合物的预期用途。另外的生物活性物质或化合物可以通过与本发明化合物相同或相似的机制或通过不相关的作用机制或通过多种相关和/或不相关的作用机制发挥其生物效应。
本发明还包括本发明化合物的所有适合的同位素变体。将本发明化合物的同位素变体定义为这样一种变体:其中至少一个原子被具有相同原子序数但原子量不同于通常在自然界中发现的原子量的原子所替代。可以掺入本发明化合物的同位素的实例包括氢、碳、氮、氧、硫、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、17O、18O、35S、18F和36Cl。例如,本发明的某些同位素变体例如是这样一些同位素:其中掺入放射性同位素,例如3H或14C,它们可用于药物和/或底物组织分布研究。氚化即3H和碳-14,即14C同位素特别优选,这归因于其易于制备和可检测性。18F-标记的化合物特别适合于成像应用,例如PET。此外,用同位素、例如氘即2H取代可以提供某些治疗优势,因为代谢稳定性更高,例如,体内半衰期增加或剂量需求降低,因此在某些情况下可能是优选的。本发明化合物的同位素变体通常可以通过常规方法制备,例如通过示例性方法或通过在下文实施例和制备例中所述的制备方法,使用适合的试剂的适当同位素变体。
可以通过使用公知的制备步骤,例如,下列方案中所示的通用方法的那些,由本领域技术人员合成本发明化合物。给出这些方法仅用于示例目的,而不应视为限定。
可以使用氨和适合的溶剂由商购可获得的氯磺酰基衍生物合成磺酰胺。在碱性条件下,在适合的溶剂中,可以实现对磺酰胺部分进行适当的(例如TBDMS、TBDPS)保护。可以使用通用氯化剂(例如Ph3PCl2、PCl5、SOCl2),然后进行氨处理。衍生物可以在不进行分离的情况下进行脱保护步骤,然后是分子内闭环(单罐法),得到苯并[d]异噻唑-3-酮1-氧化物衍生物。在强碱性条件下用适当的异氰酸酯,应用适合的溶剂处理可以在纯化后得到期望的脲衍生物,为外消旋混合物。如果期望,可以通过手性超临界流体色谱法(SFC)分离对映异构体,得到期望的单一对映异构体。
可以使用氨和适合的溶剂由商购可获得的氯磺酰基衍生物合成磺酰胺。在碱性条件下,在适合的溶剂中,可以实现对磺酰胺部分进行适当的(例如TBDMS、TBDPS)保护。可以使用通用氯化剂(例如Ph3PCl2、PCl5、SOCl2),然后进行胺处理。衍生物可以在不进行分离的情况下进行脱保护步骤,然后是分子内闭环(单罐法),得到保护的苯并[d]异噻唑-3-酮1-氧化物衍生物。使用适合的溶剂在酸性条件下脱保护,然后用适合的异氰酸酯,应用适合的溶剂在强碱性条件下处理可以在纯化后得到期望的脲衍生物,为外消旋混合物。如果期望,可以通过手性超临界流体色谱法(SFC)分离对映异构体,得到期望的单一对映异构体。
制备例
制备例1
将3-(氯磺酰基)噻吩-2-甲酸甲酯(5.0g,20.77mmol)在THF(500mL)中的溶液冷却至-20℃,并且使氨气缓慢地通过溶液吹扫30分钟。然后将反应混合物在室温搅拌30分钟。反应完成后,除去固体。使反应混合物通过布氏漏斗过滤,并且减压浓缩滤液,得到粗产物。然后将粗产物与乙醚(2×20mL)一起研磨,使得到的固体通过布氏漏斗过滤,并且干燥,得到3-氨磺酰基噻吩-2-甲酸甲酯(1.8g,39%),为无色结晶固体。
MS:220.1[(M-H)]-
制备例2-14
按照制备例1的方法,使用下表中所示的适合的试剂,制备下列化合物。
表1:
制备例15
将2-氨磺酰基烟酸甲酯(0.5g,2.31mmol)在DCM(20mL)中的溶液冷却至0℃,并且加入三乙胺(0.97mL,6.9444mmol),然后加入TBDMSCl(0.418g,2.77mmol)。将反应混合物在室温搅拌16小时。反应完成后,用水稀释反应混合物,并且用DCM(2×50mL)萃取。分离有机相,用水(50mL)洗涤,然后用饱和盐水溶液(50mL)洗涤,经Na2SO4干燥,随后过滤。减压浓缩滤液,得到粗产物。通过快速色谱法纯化粗产物(中性氧化铝;在石油醚中的0-50%乙酸乙酯)。采集纯的级分,并且真空浓缩,得到标题的2-(N-(叔丁基二甲基甲硅烷基)氨磺酰基)烟酸甲酯(0.48g,63%),为灰白色固体。
MS:331.27(M+H)+。
制备例16-34
按照制备例15的方法,使用下表中所示的适合的试剂,制备下列化合物。
表2:
制备例35
向Ph3PCl2(0.581g,1.74mmol)在CHCl3(15mL)中的混悬液中加入三乙胺(0.61mL,4.36mmol),并且将混合物在室温搅拌10分钟。然后将反应混合物冷却至0℃,缓慢地加入制备例19(0.480g,1.4545mmol)在CHCl3中的溶液,并且将混合物搅拌20分钟。然后将反应混合物冷却至-20℃,并且用氨气吹扫5分钟。在0℃将混合物温热30分钟。30分钟后,形成混悬液,并且通过过滤除去固体。减压蒸发滤液,得到粗的2-(N’-(叔丁基二甲基甲硅烷基)亚氨氨磺酰基(sulfamidimidoyl))烟酸甲酯,为灰白色固体(0.470g粗品)。尽管化合物被PPh3O污染,但是不经进一步纯化直接将其用于下一步。
制备例36-54
按照制备例35的方法,使用下表中所示的适合的试剂,制备下列化合物。
表3
制备例55
在0℃向搅拌的制备例37(1.4g,4.18mmol)在MeOH(15mL)中的溶液中滴加2NNaOH溶液(10.45mL,20.92mmol),并且将混合物在室温搅拌1小时。反应完成后,用盐水溶液(25mL)稀释反应混合物,并且用乙酸乙酯(2×100mL)萃取。分离有机层,并且经Na2SO4干燥,过滤,并且蒸发,得到1-((叔丁基二甲基甲硅烷基)氨基)-3H-1,4-噻吩并[2,3-d]异噻唑-3-酮1-氧化物(900mg,粗品),为灰白色泡沫状固体。将粗化合物不经进一步纯化用于下一步。
MS:189.16[(M-TBDMS)]+
制备例56
在0℃向搅拌的制备例55(0.9g,2.97mmol)在1,4-二烷(15mL)中的溶液中滴加在1,4-二烷中的4M HCl(2.97mL,11.90mmol),并且将混合物搅拌25分钟。反应完成后,减压蒸发反应混合物,得到粗化合物。通过Grace自动化纯化(二氧化硅24g柱,用MeOH在DCM中的混合物(1-10%)梯度洗脱)纯化粗化合物。减压浓缩采集的纯级分,得到1-((叔丁基二甲基甲硅烷基)氨基)-3H-1,4-噻吩并[2,3-d]异噻唑-3-酮1-氧化物(380mg,2步总计68%),为灰白色结晶固体。
1H NMR(400MHz,DMSO-d6)δ=8.24(s,2H),8.14(d,1H),7.41(d,1H)。
MS:189.1[(M+H)]+
制备例57
在0℃向搅拌的制备例40(350mg,0.9mmol)在1,4-二烷(5mL)中的溶液中滴加1MHCl的二烷溶液(0.5mL),并且将混合物在室温搅拌1小时。反应完成后,减压蒸发反应混合物,并且通过Grace自动化纯化(二氧化硅12g柱,用MeOH在DCM中的混合物(1-10%)梯度洗脱)纯化残余物。减压浓缩采集的纯级分,得到1-氨基-3-氧代-3H-1,4-苯并[d]异噻唑-6-甲酸甲酯1-氧化物(60mg,2步总计40%),为黄色固体。
1H-NMR,(400MHz,DMSO-d6)δ=8.43(d,1H),8.36-8.38(dd,1H),8.25(s,2H),7.96(d,1H),3.94(s,3H)。
MS:239.06[(M-H)]+
制备例58和59
按照制备例57的方法,使用下表中所示的适合的试剂,制备下列化合物。
表4:
制备例60
在室温向搅拌的制备例35(0.47g粗品)在甲醇(5mL)中的溶液中缓慢地加入NH4OH溶液(8mL),并且将混合物加热至回流3小时。反应完成后,减压蒸发溶剂,得到粗产物。通过Grace自动化纯化器(SiO2,12g柱;在DCM中的0-5%甲醇)纯化粗产物。采集纯的级分,并且减压浓缩,得到1-氨基-3H-1,4-异噻唑并[5,4-b]吡啶-3-酮1-氧化物(0.15g,57%)。
MS:184.18(M+H)+。
制备例61-75
按照制备例60的方法,使用下表中所示的适合的试剂,制备下列化合物。
表5:
实施例
所有试剂和溶剂均得自商业来源,并且无需进一步纯化即可使用。用Bruker400MHz-AVANCE III HD NMR和Bruker 500MHz-AVANCE III HD NMR光谱仪在氘代溶剂中记录1H-NMR光谱。化学位移(δ)以百万分率和耦合常数(J值)以赫兹报告。自旋多重性由以下符号表示:s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)、bs(宽单峰)。用WaterACQUITY SQD2 UPLC/MS系统得到质谱。使用Agilent 7890B气相色谱仪和5977A质谱仪采集GC-MS数据。色谱法使用硅胶(Acme:硅胶60,0.063-0.2mm)和具体实施例中所示的适合溶剂进行。快速纯化使用Biotage Isolera one或Reveleris X2具有KP-NH SNAP柱(Biotage)或Reveleris二氧化硅柱(Grace)和具体实施例中所示的溶剂梯度进行。薄层色谱法(TLC)在硅胶板(Merck)上进行,使用UV检测。
实施例1
步骤A:
在0℃向搅拌的按照文献方法(ACS Med.Chem.Lett.2017年5月1日;8(6):672-677)制备的1-氨基-3H-1,4-苯并[d]异噻唑-3-酮1-氧化物在THF(8mL)中的溶液中缓慢地加入NaH(60%)(26.0mg,0.659mmol),并且将混合物搅拌15分钟。在0℃向反应混合物中滴加商购可获得的4-异氰酰基-1,2,3,5,6,7-六氢-s-引达省(0.109g,0.549mmol)在THF(4mL)中的溶液,并且将混合物在室温搅拌1小时。反应完成后,用饱和NH4Cl溶液(15mL)使反应猝灭,并且用EtOAc(2×40mL)萃取混合物。经Na2SO4干燥有机相,过滤,并且减压蒸发滤液,得到粗产物。通过快速色谱法(SiO2,230-400目;在DCM中的0-3%甲醇)纯化粗产物。采集纯的化合物级分,并且减压浓缩,得到外消旋标题化合物实施例1(0.075g,93.68%),为灰白色固体。
1H-NMR,(400MHz,DMSO-d6)δ=8.07-8.05(d,1H),7.68-7.6(m,3H),6.85(s,1H),2.79-2.75(t,4H),2.67-2.64(t,4H),1.95-1.88(m,4H)。
MS:381.9(M+H)+。
实施例2-29
按照实施例1的方法,使用下表中所示的适合的试剂,制备下列化合物。可以用DCM或CHCl3代替THF溶剂,用三乙胺或吡啶代替NaH。
表6:
实施例30
在室温向搅拌的实施例9(15mg,0.034mmol)在干四氢呋喃(0.2mL)中的溶液中加入2M MeMgBr的THF溶液(0.05mL,0.01mmol),并且将混合物搅拌1小时。反应完成后,向反应混合物中加入饱和NH4Cl溶液(1mL),并且用EtOAc(2×5mL)萃取混合物。经Na2SO4干燥有机层,过滤,并且真空蒸发。通过Grace自动化纯化器(SiO2 4g柱;在DCM中的0-10%MeOH梯度洗脱)纯化所得残留物。蒸发采集的纯化合物级分,并且真空干燥,得到1-(1,2,3,5,6,7-六氢-s-引达省-4-基)-3-(6-(2-羟基丙-2-基)-1-氧化-3-氧代-3H-1,4-苯并[d]异噻唑-1-基)脲(4.4mg,29%),为灰白色固体。
1H-NMR,(500MHz,DMSO-d6)δ=8.20(d,1H),8.00(bs,1H),7.70(dd,1H),7.52(d,1H),6.81(s,1H),5.23(s,1H),2.78-2.54(m,8H),1.92-1.88(m,4H),1.45(s,3H),1.43(s,3H)。
MS:440.51(M+H)+
实施例31
按照实施例30的方法,使用下表中所示的适合的试剂,制备下列化合物。
表7:
对映异构体的分离:
使外消旋混合物通过SFC进行手性分离,得到纯对映异构体。
SFC方法:
柱名:Chiralpak IC(4.6*250)mm,5μm;
共溶剂:40%
共溶剂名:在甲醇中的0.5%DEA
注射体积:10μL
流速:4mL/分钟
出口压力:100巴
温度:30℃
第一个洗脱峰(Rt=3.34):
减压蒸发级分,并且将得到的残留物与乙醚一起研磨以除去二乙胺污染物,得到实施例1a,为灰白色固体,手性纯度为99.97%。
1H-NMR,(400MHz,DMSO-d6)δ=8.06-8.04(m,1H),7.86(s,1H),7.61-7.5(m,3H),6.80(s,1H),2.77-2.74(t,4H),2.68-2.66(m,4H),1.98-1.87(m,4H)。
MS:382.28(M+H)+。
第二个洗脱峰(Rt=4.36):
减压蒸发级分,并且将得到的残留物与乙醚一起研磨以除去二乙胺污染物,得到实施例1b,为灰白色固体,手性纯度为97.76%。
1H-NMR,(400MHz,DMSO-d6)δ=8.07-8.05(m,1H),7.99(s,1H),7.61-7.54(m,3H),6.81(s,1H),2.77-2.74(t,4H),2.67-2.65(m,4H),1.91-1.878(m,4H)。
MS:382.33(M+H)+。
实施例32-64
按照实施例1的手性分离,得到对映异构纯化合物。可以使用不同的柱类型、洗脱液、温度、压力和流速。
表8:
生物学测定描述
NLRP3抑制测定
以下测定可以用于使用常规刺激剂尼日利亚菌素(Invivogen)或尿酸单钠晶体(MSU)(Invivogen)测定测试化合物对NLRP3炎症小体的抑制活性。
细胞培养
在补充有10%热灭活FCS和50U/mL青霉素-链霉素(Life Technologies)的RPMI1640Glutamax培养基中培养人单核细胞样细胞。
基于负选择,使用leucosep管和来自Miltenyi的经典单核细胞分离试剂盒从人血液中分离HMDM(人单核细胞衍生的巨噬细胞)。
NLRP3炎症小体活化测定将人单核细胞样细胞以每孔75000个接种在96孔板中,并且用10ng/mL PMA(肉豆蔻酸乙酸佛波醇酯)分化为巨噬细胞过夜。第二天,加入包含10ng/mL LPS(脂多糖)的培养基。LPS引发3小时后,在用3.75μM的尼日利亚菌素或150μg/mL的MSU进行NLRP3炎症小体刺激3小时之前30分钟加入浓度范围为100μM-6nM的测试化合物。
将原代人单核细胞衍生的巨噬细胞(HMDM)以每孔30000个接种在96孔板中,并且用10ng/mL人M-CSF(巨噬细胞集落刺激因子)分化为巨噬细胞。在DIV 8(体外天)加入包含10ng/mL LPS的培养基。LPS引发3小时后,在用2.5μM的尼日利亚菌素或150μg/mL的MSU进行NLRP3炎症小体刺激3小时之前30分钟加入浓度范围为10μM-128pM的测试化合物。
IL-1β的测定
为了进行IL-1β定量,使用AlphaLISA试剂盒,按照制造商的说明(Perkin ElmerAlphaLISA AL220F)分析上清液。
IC50
使用GraphPad Prism 8测定IC50(对应于50%抑制的浓度)。
测定下列实施例化合物:
说明:+++IC50<1μM;++IC50 1<x<10μM;+IC50 10<x<30μM。
测试化合物显示抑制人单核细胞样细胞和HMDM细胞中IL-1β释放,使用MSU或尼日利亚菌素作为活化剂。
Claims (24)
1.式(I)化合物:
或其立体异构体、外消旋混合物、互变异构体、药学上可接受的盐、前药、水合物、溶剂化物和多晶型物;
其中
A选自芳基和杂芳基;其中芳基和杂芳基可以任选被取代;
R1选自氢、烷基、碳环基和杂环基;其中烷基、碳环基和杂环基可以任选被取代;
R2选自下列环系
R3选自氢、卤素、烷基、NR*R*(其中R*独立地选自H和烷基)、芳基和杂芳基,其中烷基、芳基或杂芳基可以任选被取代;
R4选自氢、卤素、烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基;其中烷基、烷基-O-烷基、碳环基、杂环基、芳基和杂芳基可以任选被取代;
R5选自氢、卤素、任选取代的烷基、任选取代的芳基或任选取代的杂芳基;
W选自C和N,在W是N的情况下,R4不存在;
X各自独立地选自CH2和O;
Y选自NH、O和CRR;
R各自独立地选自氢、卤素、CH3、CH2F、CHF2和CF3;
Z和Z’独立地选自C和N,条件是当m是0时,Z’是C;
m是0或1;
n是0或1;并且
p各自独立地是0、1或2。
8.权利要求1-7任一项的化合物,其中R3是任选取代的吡啶。
10.药物组合物,其包含如权利要求1-9任一项中所定义的化合物和任选的选自药学上可接受的赋形剂、载体、稀释剂和佐剂的至少一种。
11.如权利要求1-9任一项中所定义的化合物或如权利要求10中所定义的药物组合物,其用作药物。
12.如权利要求1-9任一项中所定义的化合物或如权利要求10中所定义的药物组合物,其用于治疗、缓解或预防对炎症小体途径组分活化的调节或抑制有响应的障碍或异常。
13.用于权利要求12的用途的化合物或药物组合物,其还调节、特别是降低IL-1β和/或IL-18水平。
14.用于权利要求12或13的用途的化合物或药物组合物,其中炎症小体途径组分是NLRP3炎症小体。
15.如权利要求1-9任一项中所定义的化合物或如权利要求10中所定义的药物组合物,其用于治疗、缓解或预防对NLRP3炎症小体活化抑制有响应的障碍或异常。
16.用于权利要求12-15任一项的用途的化合物或用于权利要求12-15任一项的用途的药物组合物,其中疾病、障碍或异常对IL-1β、IL-17、IL-18、IL-1a、IL-37、IL-33和Th17细胞的一种或多种的调节有响应。
17.混合物,其包含如权利要求1-9任一项中所定义的化合物和至少一种另外的生物活性化合物,其选自与如权利要求1-9任一项中所定义的化合物不同的治疗剂;以及任选的选自药学上可接受的载体、稀释剂、佐剂和赋形剂的至少一种。
18.权利要求17的混合物,其中另外的生物活性化合物选自抗-淀粉样蛋白β抗体或淀粉样蛋白β小分子抑制剂、抗-Tau抗体或Tau聚集小分子抑制剂、抗-α突触核蛋白抗体或α-突触核蛋白聚集小分子抑制剂、抗-TDP-43抗体或抗-TDP-43聚集小分子抑制剂。
19.用于权利要求12-15任一项的用途的化合物或用于权利要求12-15任一项的用途的药物组合物,其中疾病、障碍或异常选自阿尔茨海默病,帕金森病,肌萎缩性侧索硬化,脱髓鞘,病毒性脑炎,癫痫,中风,动脉粥样硬化,哮喘,变态反应性炎症,隐热蛋白相关周期性综合征(CAPS),穆-韦二氏综合征(MWS),家族性寒冷性自身炎性综合征(FCAS),新生儿发作性多系统炎性疾病(NOMID),痛风,假痛风,炎性肠病,非酒精性脂肪肝病,非酒精性脂肪性肝炎,高血压,心肌梗死,草酸盐诱导的肾病,移植物抗宿主病,1型糖尿病,2型糖尿病,类风湿性关节炎,骨髓增生异常综合征,家族性地中海热(FMF),TNF受体相关周期性综合征(TRAPS),甲羟戊酸激酶缺乏(MKD),高免疫球蛋白血症D、周期热综合征(HIDS),白细胞介素1受体缺乏(DIRA)拮抗剂,Majeed综合征,化脓性关节炎、坏疽性脓皮病和痤疮(PAPA),A20单倍剂量不足(HA20),PLCG2-相关抗体缺乏和免疫失调(PLAID),儿科肉芽肿关节炎(PGA),PLCG2-相关自身炎症、抗体缺乏和免疫失调(APLAID),具有B-细胞免疫缺陷、周期热、发育迟缓的铁粒幼细胞贫血(SIFD),慢性非细菌性骨髓炎(CNO),Sweet综合征,慢性复发性多病灶性骨髓炎(CRMO),滑膜炎、脓疱病、痤疮、骨肥大、骨炎综合征(SAPHO),多发性硬化(MS),银屑病,贝切特病,舍格伦综合征,施尼茨勒综合征,慢性阻塞性肺障碍(COPD),类固醇抵抗性哮喘,石棉肺,硅肺,囊性纤维化,运动神经元病,亨廷顿病,脑型疟,因肺炎球菌性脑膜炎导致的脑损伤,肥胖,年龄相关的黄斑变性(AMD),角膜感染,葡萄膜炎,干眼,慢性肾病,糖尿病肾病,酒精性肝病,皮肤接触过敏,晒伤,骨关节炎,系统性青少年特发性关节炎,成年发作性Still病,复发性多软骨炎,基孔肯雅病毒,罗斯河病毒,流感,HIV,冠状病毒,登革热病毒,寨卡病毒,化脓性汗腺炎(HS),肺癌转移,胰腺癌,胃癌,骨髓增生异常综合征,白血病,多肌炎,结肠炎,蠕虫感染,细菌感染,腹部主动脉瘤,伤口愈合,抑郁,心理学应激,心包炎包括德雷斯勒综合征,缺血再灌注损伤,额颞叶痴呆,HIV-相关神经认知障碍,冠状病毒相关炎性病理学和外伤性脑损伤。
20.用于权利要求12-15任一项的用途的化合物或用于权利要求12-15任一项的用途的药物组合物,其中疾病、障碍或异常选自阿尔茨海默病、帕金森病、隐热蛋白相关周期性综合征(CAPS)、非酒精性脂肪肝病、NASH和痛风。
21.权利要求1-9任一项中所定义的化合物作为分析参比物或体外筛选工具的用途。
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CN113166081A (zh) * | 2018-11-13 | 2021-07-23 | 诺华股份有限公司 | 用于治疗与nlrp活性相关的病症的化合物和组合物 |
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CA3051839A1 (en) | 2017-02-17 | 2018-08-23 | Bristol-Myers Squibb Company | Antibodies to alpha-synuclein and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017140778A1 (en) * | 2016-02-16 | 2017-08-24 | The University Of Queensland | Sulfonylureas and related compounds and use of same |
WO2020102100A1 (en) * | 2018-11-13 | 2020-05-22 | Novartis Inflammasome Research, Inc. | Compounds and compositions for treating conditions associated with nlrp activity |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0964849T3 (da) | 1997-01-29 | 2003-08-25 | Pfizer | Sulfonyl-urinstofderivater og deres anvendelse ved regulering af interleukin-1-aktivitet |
CA2975192A1 (en) | 2015-02-16 | 2016-08-25 | The University Of Queensland | Sulfonylureas and related compounds and use of same |
EP3445749B1 (en) | 2016-04-18 | 2022-12-21 | Novartis AG | Compounds and compositions for treating conditions associated with nlrp activity |
EP3872070A1 (en) | 2016-04-18 | 2021-09-01 | Novartis AG | Compounds and compositions for treating conditions associated with nlrp activity |
EP3272739A1 (en) | 2016-07-20 | 2018-01-24 | NodThera Limited | Sulfonyl urea derivatives and their use in the control of interleukin-1 activity |
AU2018210525B2 (en) | 2017-01-23 | 2022-06-02 | Genentech, Inc. | Chemical compounds as inhibitors of interleukin-1 activity |
BR112019024831A2 (pt) | 2017-05-24 | 2020-06-09 | The University Of Queensland | composto, sal, solvato ou pró-droga, composição farmacêutica, método de tratamento ou prevenção de uma doença, método para inibir o nlrp3 |
WO2018225018A1 (en) | 2017-06-09 | 2018-12-13 | Cadila Healthcare Limited | Novel substituted sulfoximine compounds |
US11370776B2 (en) | 2017-07-07 | 2022-06-28 | Inflazome Limited | Sulfonylureas and sulfonylthioureas as NLRP3 inhibitors |
MA56075A (fr) | 2017-07-07 | 2022-04-06 | Inflazome Ltd | Nouveaux composés de sulfonamide carboxamide |
EP3658538B1 (en) | 2017-07-24 | 2023-04-19 | Novartis AG | Compounds and compositions for treating conditions associated with nlrp activity |
MX2020000911A (es) | 2017-07-24 | 2020-09-10 | Novartis Ag Star | Compuestos y composiciones para tratar afecciones asociadas con la actividad nlrp. |
KR20200041918A (ko) | 2017-08-15 | 2020-04-22 | 인플라좀 리미티드 | 신규한 설폰아마이드 카복스아마이드 화합물 |
US11542255B2 (en) | 2017-08-15 | 2023-01-03 | Inflazome Limited | Sulfonylureas and sulfonylthioureas as NLRP3 inhibitors |
EP3668843A1 (en) | 2017-08-15 | 2020-06-24 | Inflazome Limited | Sulfonylureas and sulfonylthioureas as nlrp3 inhibitors |
TW201910316A (zh) | 2017-08-15 | 2019-03-16 | 愛爾蘭商英弗雷佐姆有限公司 | 新穎化合物 |
US11773058B2 (en) | 2017-08-15 | 2023-10-03 | Inflazome Limited | Sulfonamide carboxamide compounds |
EP3668862A1 (en) | 2017-08-15 | 2020-06-24 | Inflazome Limited | Novel sulfonamide carboxamide compounds |
US11518739B2 (en) | 2017-08-15 | 2022-12-06 | Inflazome Limited | Sulfonamide carboxamide compounds |
WO2019043610A1 (en) | 2017-08-31 | 2019-03-07 | Cadila Healthcare Limited | NEW SUBSTITUTED SULFONYLUREA DERIVATIVES |
US11623922B2 (en) | 2017-10-03 | 2023-04-11 | Inflazome Limited | Compounds |
US11718631B2 (en) | 2017-10-17 | 2023-08-08 | Novartis Ag | Sulphonamides and compositions thereof for treating conditions associated with NLRP activity |
PE20210050A1 (es) | 2017-11-09 | 2021-01-08 | Inflazome Ltd | Nuevos compuestos de sulfonamida carboxamida |
WO2019092172A1 (en) | 2017-11-09 | 2019-05-16 | Inflazome Limited | Novel sulfonamide carboxamide compounds |
EP3707137A1 (en) | 2017-11-09 | 2020-09-16 | Inflazome Limited | Novel sulfonamide carboxamide compounds |
CN112437683A (zh) | 2018-07-20 | 2021-03-02 | 豪夫迈·罗氏有限公司 | 用作白细胞介素-1 活性抑制剂的磺酰脲类化合物 |
EP3823974A1 (en) | 2018-07-20 | 2021-05-26 | F. Hoffmann-La Roche AG | Sulfonimidamide compounds as inhibitors of interleukin-1 activity |
-
2020
- 2020-06-22 CN CN202080045213.XA patent/CN114008030A/zh active Pending
- 2020-06-22 EP EP20734185.0A patent/EP3986879A1/en active Pending
- 2020-06-22 US US17/621,457 patent/US20220378801A1/en active Pending
- 2020-06-22 WO PCT/EP2020/067388 patent/WO2020254697A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017140778A1 (en) * | 2016-02-16 | 2017-08-24 | The University Of Queensland | Sulfonylureas and related compounds and use of same |
WO2020102100A1 (en) * | 2018-11-13 | 2020-05-22 | Novartis Inflammasome Research, Inc. | Compounds and compositions for treating conditions associated with nlrp activity |
Non-Patent Citations (2)
Title |
---|
MAXIMILIAN BREMERICH等: "Additions to N-Sulfinylamines as an Approach for the Metal-free Synthesis of Sulfonimidamides: O-Benzotriazolyl Sulfonimidates as Activated Intermediates", ANGEW. CHEM. INT. ED., vol. 58, pages 19014 - 19020 * |
YANTAO CHEN等: "Saccharin Aza Bioisosteres-Synthesis and Preclinical Property Comparisons", ACS MEDICINAL CHEMISTRY LETTERS, vol. 8, pages 672 - 677, XP055722909, DOI: 10.1021/acsmedchemlett.7b00137 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113166081A (zh) * | 2018-11-13 | 2021-07-23 | 诺华股份有限公司 | 用于治疗与nlrp活性相关的病症的化合物和组合物 |
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