CN114516878A - 三环化合物及其医药用途 - Google Patents
三环化合物及其医药用途 Download PDFInfo
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- CN114516878A CN114516878A CN202111391626.6A CN202111391626A CN114516878A CN 114516878 A CN114516878 A CN 114516878A CN 202111391626 A CN202111391626 A CN 202111391626A CN 114516878 A CN114516878 A CN 114516878A
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- deuterium
- halogen
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- hydrogen
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Abstract
本公开涉及三环化合物及其医药用途。具体而言,本公开提供式I所示化合物或其可药用盐,该类化合物或其可药用盐具有NLRP3炎性体抑制活性,可用于治疗或预料NLRP3相关疾病。
Description
技术领域
本公开涉及医药领域,具体涉及一类三环化合物及其医药用途。
背景技术
NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)是一种蛋白编码基因,该蛋白属于核苷酸结合和寡聚化域样受体(nucleotide-binding and oligomerizationdomain-like receptors,NLRs)家族,也被称为“含脓素域蛋白3”(Inoue et al,Immunology,2013,139,1 1-18)。该基因编码一种蛋白,该蛋白包含一个吡啶结构域,一个核苷酸结合位点结构域(NBD)和一个富含亮氨酸的重复(LRR)基序。通过响应无菌的炎性危险信号,NLRP3与衔接蛋白、凋亡相关斑点样蛋白(ASC)以及酶原-1相互作用,形成NLRP3炎性体。之后,NLRP3炎性体的激活导致炎性细胞因子IL-1b和IL-18的释放,而当NLRP3炎性体的激活失调时,则会驱动许多疾病的发生。
研究表明,NLRP3炎性体的激活与多类疾病相关,包括:炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和自身炎症性疾病。因此,需要提供新的NLRP3炎性体通路抑制剂,来为上述疾病的治疗提供新的可选方式。
发明内容
第一方面,本公开提供式I化合物或其可药用盐,
其中,环A选自芳环或杂芳环,环B选自4-8元的碳环或杂环,环C选自3-8元的碳环或杂环;并且,环B与环A通过2个共用的原子连接,环C与环B通过1个共用的原子连接;
X选自CR5或N,Y选自O或NR6;
R1、R2独立地选自氢、氘、卤素、-OR7a、-SR7a、-C(=O)R7a、-OC(=O)R7a、-C(=O)OR7a、-C(=O)NR7aR7b、-NR7aR7b、-NR7aC(=O)R7b、-NR7aS(=O)2R7b、-S(=O)2R7a、-S(=O)2NR7aR7b、-CN、-NO2,或任选被一个或多个取代基取代的以下基团:C1-6烷基、C3-10环烷基、芳基、杂芳基、杂环基,所述取代基选自:氘、卤素、-OR8a、-SR8a、-C(=O)R8a、-OC(=O)R8a、-C(=O)OR8a、-C(=O)NR8aR8b、-NR8aR8b、-NR8aC(=O)R8b、-NR8aS(=O)2R8b、-S(=O)2R8a、-S(=O)2NR8aR8b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代;
R3和R4组成的组,与它们所连接的碳原子形成碳环、杂环、芳基或杂芳基,所述碳环、杂环、芳基或杂芳基任选被以下基团取代:氘、卤素、-OR9a、-SR9a、-C(=O)R9a、-OC(=O)R9a、-C(=O)OR9a、-C(=O)NR9aR9b、-NR9aR9b、-NR9aC(=O)R9b、-NR9aS(=O)2R9b、-S(=O)2R9a、-S(=O)2NR9aR9b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代;
R5选自氢、氘、卤素、C1-4烷基、C3-6环烷基或C3-6环烷基亚甲基,所述C1-4烷基、C3-6环烷基和C3-6环烷基亚甲基任选被一个或多个如下的取代基取代:氘、卤素、-OR5a或-NR5aR5b;
R6选自氢、氘、-CN、C1-6烷基、C3-6环烷基或C3-6环烷基亚甲基,所述C1-6烷基、C3-6环烷基或C3-6环烷基亚甲基任选被一个或多个的氘或卤素取代;
R5a、R5b独立地选自氢、氘或任选被被一个或多个的氘或卤素取代的C1-4烷基;
R7a、R7b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团:C1-4烷基、C3-6环烷基、C3-6环烷基亚甲基、芳基、杂芳基或杂环基,所述取代基选自:氘、卤素、-NH2、-OH、-CN、C1-4烷基、C1-4烷氧基、C3-6环烷基或C3-6环烷基亚甲基,上述取代基任选进一步被一个或多个的氘或卤素取代;
R8a、R8b、R9a、R9b、独立地选自氢、氘或任选被一个或多个取代基取代的以下基团:C1-4烷基、C3-6环烷基、C3-6环烷基亚甲基,所述取代基选自:氘、卤素、-NH2、-OH、-CN、C1-4烷基、C1-4烷氧基、C3-6环烷基或C3-6环烷基亚甲基,上述取代基任选进一步被一个或多个的氘或卤素取代;
在一些实施方案中,环A、环B和环C组成:
其中,R10a独立地选自氢、氘、卤素、C1-4烷基、C1-4烷氧基、C3-6环烷基或C3-6环烷基亚甲基,上述基团任选被一个或多个的氘或卤素取代;
R10b选自氢、C1-4烷基、C3-6环烷基、C3-6环烷基亚甲基,上述基团任选被一个或多个的氘或卤素取代;m为选自1-3的整数。
在一些实施方案中,环A、环B和环C组成:
其中,R10a如前述所定义;R11a为环B的取代基,R11a独立地选自氢、氘、卤素或任选被一个或多个卤素取代的C1-4烷基;n为选自0-8的整数。
在一些实施方案中,环A、环B和环C组成:
其中,R12a选自氢、氘、对甲苯磺酰基或任选被一个或多个氘或卤素取代的C1-4烷基;R13a、R13b、R13c、R13d独立地选自氢、氘或卤素。
在一些实施方案中,Y选自O。
在另一些实施方案中,Y选自NR6,R6选自氢、氘、-CN或任选被一个或多个的氘或卤素取代的C1-6烷基;优选为氢或-CN。
在一些实施方案中,式I化合物或其可药用盐选自:
其中,环D如式I化合物所定义,R12a如前述所定义。
在一些实施方案中,式I或式II-a至式II-t化合物或其可药用盐中,X选自N。
在另一些实施方案中,X选自CR5,R5选自氢、氘、卤素或C1-4烷基,所述C1-4烷基任选被一个或多个如下的取代基取代:氘、卤素、-OR5a或-NR5aR5b。
在一些实施方案中,式I或式II-a至式II-t化合物或其可药用盐中,R1和R2独立地选自氢、氘、卤素、-OR7a、-SR7a、-CN、-NO2或任选被一个或多个取代基取代的以下基团:C1-6烷基、C3-10环烷基、芳基、杂芳基、杂环基,所述取代基选自:氘、卤素、-OR8a、-SR8a、-C(=O)R8a、-OC(=O)R8a、-C(=O)OR8a、-C(=O)NR8aR8b、-NR8aR8b、-NR8aC(=O)R8b、-NR8aS(=O)2R8b、-S(=O)2R8a、-S(=O)2NR8aR8b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代;所述R8a和R8b如式I化合物所定义;
R3和R4组成的组与它们所连接的碳原子形成碳环、杂环、芳基或杂芳基,所述碳环、杂环、芳基或杂芳基任选被以下基团取代:氘、卤素、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代。
在一些实施方案中,R3和R4组成的组与它们所连接的碳原子形成3-7元的碳环或杂环,所述碳环或杂环任选被以下基团取代:氘、卤素或C1-4烷基,所述C1-4烷基任选进一步被一个或多个的氘或卤素取代。
在另一些实施方案中,R1选自氢或氘,R2选自任选被一个或多个取代基取代的以下基团:C1-6烷基、芳基、杂芳基或杂环基,所述取代基选自:氘、卤素、-OR8a、-SR8a、-C(=O)R8a、-OC(=O)R8a、-C(=O)OR8a、-C(=O)NR8aR8b、-NR8aR8b、-NR8aC(=O)R8b、-NR8aS(=O)2R8b、-S(=O)2R8a、-S(=O)2NR8aR8b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代。
在一些实施方案中,R1选自氢或氘,R2选自任选被一个或多个取代基取代的芳基或杂芳基,所述取代基选自:氘、卤素、-OR8a、-SR8a、-C(=O)R8a、-OC(=O)R8a、-C(=O)OR8a、-C(=O)NR8aR8b、-NR8aR8b、-NR8aC(=O)R8b、-NR8aS(=O)2R8b、-S(=O)2R8a、-S(=O)2NR8aR8b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代。
在一些实施方案中,R2选自:
其中,R2a、R2b独立地选自氢、氘、卤素、-OR8a、-SR8a、-C(=O)R8a、-OC(=O)R8a、-C(=O)OR8a、-C(=O)NR8aR8b、-NR8aR8b、-NR8aC(=O)R8b、-NR8aS(=O)2R8b、-S(=O)2R8a、-S(=O)2NR8aR8b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代;R2c选自氢或任选被一个或多个氘或卤素取代的C1-4烷基;
p为选自1-5的整数,q为选自1-4的整数。
在一些实施方案中,R2a、R2b独立地选自氢、氘、卤素、-OR8a、-SR8a、-NR8aR8b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代。
在另一些实施方案中,环D选自:
第二方面,本公开还提供一系列化合物或其可药用盐,选自:
第三方面,本公开还提供一种药物组合物,其包含第一或第二方面所述的化合物或其可药用盐,和至少一种药学上可接受的载体、稀释剂或者赋形剂。
在一些实施方案中,所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中,基于组合物的总重量,所述的药物组合物含有0.01-99.99%的前述化合物或其可药用的盐。在某些实施方案中,所述的药物组合物含有0.1-99.9%的前述化合物或其可药用的盐。在某些实施方案中,所述的药物组合物含有0.5%-99.5%的化合物或其可药用的盐。在某些实施方案中,所述的药物组合物含有1%-99%的化合物或其可药用的盐。在某些实施方案中,所述的药物组合物含有2%-98%的化合物或其可药用的盐。
第四方面,本公开还提供第一或第二方面所述的化合物或其可药用盐,或第三方面所述药物组合物在制备治疗与NLRP3活性相关的疾病的药物中的用途。
NLRP3活性相关的疾病包括炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病。
本公开还提供第一或第二方面所述的化合物或其可药用盐,或第三方面所述药物组合物在制备治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的药物中的用途。
所述炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病可具体选自:自身炎症发热综合征(如冷吡啉相关周期性综合征),镰状细胞性贫血症,系统性红斑狼疮,肝脏相关疾病(如慢性肝病、病毒性肝炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、酒精性肝病),炎症性关节炎相关疾病(如痛风、软骨钙化病、骨关节炎、类风湿关节炎、急性或慢性关节炎),肾脏相关疾病(如高草酸尿症、狼疮性肾炎、高血压性肾病、血液透析相关炎症、I型或II型糖尿病和其并发症(如肾病、视网膜病)),神经炎症相关疾病(如脑部感染、急性损伤、多发性硬化症,阿尔茨海默氏病和神经退行性疾病),心血管及代谢相关紊乱或疾病(如降低心血管疾病风险(CvRR)、动脉粥样硬化、I型和II型糖尿病以及相关并发症、外周动脉疾病(PAD)、急性心力衰竭和高血压),伤口愈合,疤痕形成,炎性皮肤疾病(例如痤疮、化脓性汗腺炎),哮喘,结节病,年龄相关性黄斑变性,与癌症有关的疾病/病症(例如骨髓增生性肿瘤、白血病、骨髓增生异常综合症(MDS)、骨髓纤维化、肺癌、结肠癌)。
本公开中所述化合物可药用盐选自无机盐或有机盐,本公开所述化合物可与酸性或碱性物质反应成相应盐。
另一方面,本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本公开的范围之内。
另外,本公开的化合物和中间体还可以以不同的互变异构体形式存在,并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如,质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变,如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。互变异构体的实例是在如下所示的A和B之间。
本发明中的所有化合物可以被画成A型或B型。所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。
本公开化合物可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开还包括一些与本文中记载的那些相同的,但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素,诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
除另有说明,当一个位置被特别地指定为氘(D)时,该位置应理解为具有大于氘的天然丰度(其为0.015%)至少1000倍的丰度的氘(即,至少10%的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质,或它们可使用常规技术采用氘代试剂合成,氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C1-6烷基”是指卤素或者氰基可以但不必须存在,该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
本发明所述化合物的化学结构中,键表示未指定构型,即如果化学结构中存在手性异构体,键可以为或者同时包含 两种构型。虽然为简便起见将全部上述结构式画成某些异构体形式,但是本发明可以包括所有的异构体,如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。
术语解释:
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
“烷基”指饱和的脂族烃基团,包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选一个或多个以下基团,独立地选自卤素、氘、羟基、氧代、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基,所述C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
“环烷基”指饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至8个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基、等;多环环烷基包括螺环、稠环和桥环的环烷基。
“碳环”指饱和或部分不饱和的单环或多环环状烃基团,包含3至20个碳原子,优选包含3至8个碳原子。碳环可与芳环、杂芳环、杂环、环烃进一步稠合,当其与杂芳环或杂环稠合时,稠合化学键的两端不包含杂原子。
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃基团,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选包含3至7个环原子。单环杂环烷基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“杂环烷基”非限制性实例包括:
杂环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自如卤素、氘、羟基、氧代、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基,所述C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述杂环基环可以稠合于芳环、杂芳环或环烃上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
“芳基”或“芳环”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至12元,例如苯基和萘基。
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基,所述C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述芳基环可以稠合于杂芳环、杂环或环烃上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
“杂芳基”或“杂芳环”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为6至12元,更优选为5元或6元。例如。其非限制性实例包括:咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪,等等。
含有氮原子的杂芳基的示例包括但不限于吡咯基、哌嗪基、嘧啶基、咪唑基、哒嗪基、吡嗪基、四唑基、三唑基、吡啶基、吡唑基、噁唑基或噻唑基等。
杂芳基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基,所述C1-6烷基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、C3-6环烷基、3至6元杂环烷基、C5-8环烯基、C3-6环烷氧基、3至6元杂环烷氧基、C5-8环烯氧基、C6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述杂芳基环可以稠合于芳环、杂环或环烃上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
“卤素”指氟、氯、溴或碘。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
具体实施方式
以下结合实施例进一步描述本公开中,但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。化合物的光学异构体(异构体)空间构型可进一步通过测量单晶参数的方式确认。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪,以正/负离子模式扫描,质量扫描范围为100~1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mmI.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱;
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶100~200目、200~300目或300~400目硅胶为载体,或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm,60,12g,,25g,40g,80g或其他规格)。
高压柱纯化系统使用Waters AutoP,配合使用Waters XBridge BEH C18 OBDPrep Column,5μm,19mm X 150mm或者Atlantis T3 OBD Prep Column,5μm,19mm X 150mm。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自上海泰坦科技,ABCR GmbH&Co.KG,Acros Organics,Aldrich Chemical Company,韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明,反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空,充入氢气,反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)。
实施例1
步骤1:5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪](化合物1c)的合成
将化合物1b(4.10mL,42.8mmol)和三乙胺(23.8mL,171.3mmol)的二氯甲烷(60mL)溶液冷却至0℃,加入甲磺酰氯(8.2mL,103mmol),混合物在室温搅拌1小时。冷却至室温后,加入盐水(100mL),用乙酸乙酯(100mL×2)萃取,合并的有机相用盐水(50mL×3)洗涤,用无水硫酸钠干燥后过滤,滤液在真空中浓缩得到粗品。该粗品溶于DMF(100mL)中,加入碳酸钾(19.4g,142.7mmol)和化合物1a(3g,35.7mmol)。混合物在80℃下搅拌充分反应。冷却至室温后,加入乙酸乙酯(300mL)稀释,用水(100mL)洗涤,盐水(100mL)洗涤,用无水硫酸钠干燥,过滤,滤液在真空下浓缩后,通过快速柱层析(淋洗剂:0-40%乙酸乙酯的石油醚)进行纯化得到化合物1c(0.75g,收率14%)。
LCMS:MS(ESI)m/z=151.2[M+H]+
步骤2:3'-溴-5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪](化合物1d)的合成
向化合物1c(250mg,1.67mmol)的乙腈(5mL)溶液中加入NBS(296.3mg,1.67mmol),混合物在室温下搅拌充分反应。在真空下浓缩得到残渣,直接通过快速柱层析[C-18柱,乙腈/水5-70%)]进行纯化后冻干,得到化合物1d(220mg,收率57.7%)。
LCMS:MS(ESI)m/z=229.3,231.3[M+H]+
步骤3:化合物1f的合成
将化合物1e(1g,3.856mmol)和三乙胺(1.07mL,7.72mmol)的乙醚(10mL)溶液冷却至0℃,滴加二氯亚砜(0.28mL,3.86mmol)。混合物在室温搅拌充分反应。过滤,滤饼用石油醚(50mL×2)洗涤,在真空下浓缩滤液,得到化合物1f(820mg,收率69.6%)。
1H NMR:(400MHz,CDCl3)δppm 7.39-7.30(m,15H)
步骤4:N-三苯代甲基-5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-亚磺酰胺(化合物1g)的合成
将化合物1d(460mg,2.01mmol)的四氢呋喃(10mL)溶液冷却至-78℃,在氮气下,滴加正丁基锂溶液(2.5M正己烷溶液,1mL),混合物在-78℃下搅拌10分钟后加入化合物1f(797mg,2.61mmol),混合物缓慢升至室温后搅拌充分反应。在真空下浓缩得到残渣,直接通过快速柱层析[C-18柱,乙腈/水5-95%)]进行纯化后冻干,得到化合物1g(160mg,收率17.5%)。
LCMS:MS(ESI)m/z=454.3[M+H]+
步骤5:N'-三苯代甲基-5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺脒(化合物/消旋体1h)的合成
将化合物1g(160mg,0.35mmol)的四氢呋喃(4mL)溶液冷却至0℃,加入1-氯苯并三氮唑(53.9mg,0.35mmol),混合在0℃搅拌0.5小时后加入过量的氨的四氢呋喃溶液,混合物在室温搅拌充分反应。在真空下浓缩得到残渣,直接通过快速柱层析[C-18柱,乙腈/水5-95%)]进行纯化后冻干,得到化合物(消旋体)1h(60mg,收率36.3%)。
LCMS:MS(ESI)m/z=469.4[M+H]+
步骤6:5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-胺(化合物1k)的合成
将化合物1i(150mg,0.71mmol)溶于二氧六环(2.5mL)中,加入碳酸钾(288mg,2.12mmol),1j(130mg,0.85mmol)和水(0.5mL),在氮气下加入催化剂Pd(dppf)Cl2(87.7mg,0.106mmol)。混合物在80℃下搅拌充分反应。冷却至室温后,加水(10mL)稀释,用乙酸乙酯(15mLx2)萃取,合并的有机相用盐水(15mLx2)洗,用无水硫酸钠干燥,过滤,滤液在真空下浓缩得到粗品,通过快速柱层析(淋洗剂:5-30%乙酸乙酯的石油醚)进行纯化得到化合物1k(101mg,收率58.9%)。
1H NMR:(400MHz,CDCl3)δppm 8.22(d,J=5.2Hz,1H),7.09-6.93(m,2H),6.86(s,1H),6.77(d,J=7.6Hz,1H),4.00-3.97(m,3H),2.97(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.17(t,J=7.2Hz,2H).
ES-LCMS m/z 241.2[M+H]+.
步骤7:4-(4-异氰酸基-2,3-二氢-1H-茚-5-基)-2-甲氧基吡啶(化合物1l)的合成
将化合物1k(35mg,0.146mmol)和三乙胺(17.69mg,0.175mmol)的四氢呋喃(2mL)溶液冷却至0℃,加入三光气(25.07mg,0.084mmol)后,混合物在70℃氮气下搅拌充分反应。冷却至室温后过滤,滤饼用四氢呋喃(5mL)洗,合并得分滤液在真空下浓缩得到化合物1l(38mg,收率98%)。
ES-LCMS m/z 299.1[M+MeOH+H]+.
步骤8:N'-((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰)-N-三苯代甲基-5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺脒(化合物/消旋体1m)的合成
将化合物1h(55mg,0.117mmol)的四氢呋喃(2mL)溶液冷却至0℃,加入氢化钠(60%矿物油)(5.6mg,0.14mmol),混合物在0℃氮气下搅拌0.5小时后加入化合物1l(37.4mg,0.14mmol),混合物在室温搅拌充分反应。在真空下浓缩得到残渣,直接通过快速柱层析[C-18柱,乙腈/水5-85%)]进行纯化后冻干,得到化合物(消旋体)1m(45mg,收率52%)。
LCMS:MS(ESI)m/z=737.6[M+H]+
步骤9:N'-((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰)-5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺脒(化合物/消旋体1)的合成
将化合物1m(45mg,0.061mmol)的二氯甲烷(2mL)溶液冷却至0℃,加入甲磺酸(48.9mg,0.61mmol),混合物在0℃下搅拌充分反应。在真空下浓缩得到残渣,直接通过快速柱层析[C-18柱,乙腈/水5-60%)]进行纯化后冻干,得到化合物(消旋体)1(13.5mg,收率44.7%)。
LCMS:MS(ESI)m/z=495.5[M+H]+
1H NMR:(400MHz,DMSO-d6)δ=8.16(br s,1H),8.10(d,J=5.3Hz,1H),7.39(s,1H),7.23(s,2H),7.18-7.14(m,1H),7.12-7.05(m,1H),6.95(d,J=4.8Hz,1H),6.77(s,1H),4.23-4.10(m,2H),4.01(s,2H),3.86(s,3H),2.91(t,J=7.4Hz,2H),2.77(s,2H),2.00(quin,J=7.3Hz,2H),0.78(s,4H).
实施例2
步骤1:5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺酰胺(化合物3a)的合成
在-78℃下,向四氢呋喃(50mL)中通入二氧化硫15分钟,备用。将化合物1d(350mg,1.528mmol)的四氢呋喃(3mL)冷却至-78℃,缓慢滴加正丁基锂溶液(2.5M正己烷溶液)。然后在-78℃下搅拌30秒。然后将加入上述二氧化硫的四氢呋喃溶液(2mL),混合物在-78℃下搅拌充分反应。加入水淬灭,分液,有机层用水萃取,收集并合并水相。加入二水合柠檬酸三钠(900mg,3.056mmol)。将混合物冷却至10℃后加入羟胺磺酸(259.20mg,2.292mmol)的水溶液。混合物在室温搅拌充分反应。用乙酸乙酯萃取,合并的有机相用盐水洗涤,无水硫酸钠干燥,过滤,滤液在真空中浓缩获得粗品,通过快速柱层析(淋洗剂:90-100%乙酸乙酯的石油醚)进行纯化得到化合物3a(70mg,收率19.9%)。
1H NMR:(400MHz,CDCl3)δppm 7.44(d,J=2.0Hz,1H),5.25(d,J=8.0Hz,2H),3.99(s,4H),0.83-0.80(m,2H),0.80-0.77(m,2H).
步骤2:N-((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰)-5',7'-二氢螺[环丙烷-1,6'-吡唑并[5,1-b][1,3]噁嗪]-3'-磺酰胺(化合物3)的合成
将化合物3a(35mg,0.153mmol)的四氢呋喃(2mL)溶液冷却至0℃,在氮气下加入氢化钠(60%矿物油)(24.5mg,0.61mmol)。混合物在0℃下搅拌15分钟,然后加入化合物1l(40.7mg,0.15mmol)的四氢呋喃(1mL)溶液。所得混合物在室温下氮气下搅拌充分反应。加入水(50mL)稀释,用柠檬酸(30%)将调至pH=3,用乙酸乙酯(20mLx3)萃取。合并的有机相用无水硫酸钠干燥,过滤。滤液在真空中浓缩,得到粗品,通过纯化得到化合物3(5.4mg,收率7.3%)。
LCMS:MS(ESI)m/z=496.2[M+H]+
1H NMR:(400MHz,CD3CN)δ=8.12(d,J=5.2Hz,1H),7.32(d,J=1.5Hz,1H),7.21(d,J=7.6Hz,1H),7.13(d,J=7.2Hz,1H),6.97(d,J=5.2Hz,1H),6.77(s,1H),5.50(d,J=2.0Hz,1H),5.01(dd,J=10.8Hz,J=1.8Hz,1H),4.95(s,1H),3.90(s,3H),3.41(d,J=10.4Hz,1H),2.97(t,J=7.4Hz,2H),2.91(d,J=7.6Hz,2H),2.12–2.04(m,4H),1.37–1.33(m,1H),0.99–0.95(m,1),0.82–0.77(m,2H).
生物学评价
以下结合测试例进一步描述解释本公开中,但这些测试例并非意味着限制本公开中的范围。
实验例1在人类单核细胞中的NLRP3炎症体抑制活性测定
1.实验仪器和试剂
1.1实验仪器
Plate washer:BioTek 405 Select 405TSUS Microplate Washer 96 and 384Well w/Ultrasonic(6025)(BioTek,cat#405TSUS)
Plate reader:PerkinElmer 2104 EnVision Multilabel Plate Readers
1.2实验试剂
试剂 | 供应商 |
Human IL-1b ELISA kit | BD |
Penicillin/Streptomycin | Gibco |
RPMI1640 medium | Gibco |
RPMI1640 medium | Gibco |
HEPES | Gibco |
FBS | Gibco |
Lipopolysaccharides | Sigma |
hygromycin B | Client |
Normocin | Client |
ATP | Sigma |
96 well plates,Elisa | Greiner |
96 well plates | Corning |
15mL centrifuge tube | Corning |
2.实验方案
第1天:通过密度梯度离心从人体血液中分离PBMC,用含有2%FBS的PBS清洗PBMC两次(300g离心8分钟)。然后使用人类泛单核细胞分离试剂盒和LS柱将单核细胞从PBMC中分离。细胞在4℃下与CD14-FITC染色30分钟,FACS在BD FACSVerse上运行,以分析泛单核细胞的纯度。计数并调整细胞密度至2.5x105细胞/毫升。将细胞种至96孔板中,2.5x104单核细胞/100mL悬浮液/孔。在5%CO2,37℃,孵育过夜。
第2天:预滴定测试化合物,使所有滴定点,包括DMSO对照孔包含0.1%的DMSO。去除培养基,预处理单核细胞(通过将150mL化合物(在无血清1640培养基中稀释)或DMSO添加到各自的孔中,在5%的CO2,37℃下孵育0.5小时)。然后处理细胞(通过加入含有700ng/mLLPS(最终浓度为100ng/mL)的1640(无血清)溶液25mL,在37℃下5%CO2中孵育3.5小时)。在3.5小时的孵育结束时,刺激细胞(加入25mL的40mM ATP(最终浓度将是5mM)处理45分钟)。将80mL的上清转移到新板中,并在-80℃下储存。
第3天:根据制造商的说明将上清溶液稀释20倍用于人类单核细胞IL-1b ELISA。
第3-4天:ELISA实验
1)第3天:在板中加入100mL/孔捕获抗体(用包被缓冲液稀释)。密封板,并在4℃下孵育过夜。
2)第4天:吸掉孔中液体,每次用300uL/≥洗缓冲液洗3次。最后一次洗涤后,将板反转过来,在吸水纸上吸干,以去除任何残留缓冲液。
3)在板中加入试验稀释液,≥200uL/孔。在室温中孵育1小时。
4)吸干/洗涤,如步骤2。
5)用试验稀释液制备标准和样品稀释液。
6)将每个标准品、样品和对照加入对应的孔中,100mL/孔。密封板并在室温中孵育2小时。
7)吸干/洗涤如步骤2,但要洗涤5次。
8)将检测抗体用试验稀释液稀释,加入孔中,100mL/孔。
9)密封板并在室温中孵育1小时。
10)吸干/洗涤如步骤2,但要洗涤5次。
11)将酶试剂用试验稀释液稀释,并加入孔中,100mL/孔。密封板并在室温中孵育30分钟。
12)吸干/洗涤,使用30秒-1分钟的浸泡步骤,共洗7次。
13)在每个孔中加入100mL的底物溶液。在黑暗中室温下孵育板(无板密封剂)30分钟。
14)向每孔添加50mL终止溶液。
15)在停止反应后30分钟内通过仪器Envision读取450nm的吸收值。如果波长校正可用,则从吸收度450nm中减去570nm的吸收度。
3.实验结果
化合物编号 | IL-1βinhibition(EC<sub>50</sub>)/nM |
1 | 23.6 |
Claims (10)
1.式I化合物或其可药用盐,
X选自CR5或N,Y选自O或NR6;
R1选自氢或氘;
R2选自:
R2a、R2b独立地选自氢、氘、卤素、-OR8a、-SR8a、-NR8aR8b、-CN、-NO2、C1-4烷基或C3-6环烷基,所述C1-4烷基或C3-6环烷基任选进一步被一个或多个的氘或卤素取代;
p为选自1-5的整数,q为选自1-4的整数;
R3和R4组成的组与它们所连接的碳原子形成3-7元的碳环或杂环,所述碳环或杂环任选被以下基团取代:氘、卤素或C1-4烷基,所述C1-4烷基任选进一步被一个或多个的氘或卤素取代;
R5选自氢、氘、卤素、C1-4烷基、C3-6环烷基或C3-6环烷基亚甲基,所述C1-4烷基、C3-6环烷基和C3-6环烷基亚甲基任选被一个或多个如下的取代基取代:氘、卤素、-OR5a或-NR5aR5b;
R6选自氢、氘、-CN或任选被一个或多个的氘或卤素取代的C1-6烷基;优选为氢或-CN;
R5a、R5b独立地选自氢、氘或任选被被一个或多个的氘或卤素取代的C1-4烷基;
R8a、R8b、R9a、R9b、独立地选自氢、氘或任选被一个或多个取代基取代的以下基团:C1-4烷基、C3-6环烷基、C3-6环烷基亚甲基,所述取代基选自:氘、卤素、-NH2、-OH、-CN、C1-4烷基、C1-4烷氧基、C3-6环烷基或C3-6环烷基亚甲基,上述取代基任选进一步被一个或多个的氘或卤素取代。
2.根据权利要求1所述的化合物或其可药用盐,其中,Y选自NR6,R6选自氢、氘、-CN或任选被一个或多个的氘或卤素取代的C1-6烷基;优选为氢或-CN。
4.根据权利要求1-3任一所述化合物或其可药用盐,其中,X选自CR5,R5选自氢、氘、卤素或C1-4烷基,所述C1-4烷基任选被一个或多个如下的取代基取代:氘、卤素、-OR5a或-NR5aR5b。
8.一种药物组合物,包含权利要求1-7所述的化合物或其可药用盐,和至少一种药学上可接受的载体、稀释剂或者赋形剂。
9.权利要求1-7所述的化合物或其可药用盐,或权利要求8所述的药物组合物在制备治疗与NLRP3活性相关的疾病的药物中的用途。
10.权利要求1-7所述的化合物或其可药用盐,或权利要求9所述的药物组合物在制备治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的药物中的用途。
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