CN117209474A - 吡咯烷衍生物、药物组合物及其在医药上的应用 - Google Patents
吡咯烷衍生物、药物组合物及其在医药上的应用 Download PDFInfo
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- CN117209474A CN117209474A CN202310674652.2A CN202310674652A CN117209474A CN 117209474 A CN117209474 A CN 117209474A CN 202310674652 A CN202310674652 A CN 202310674652A CN 117209474 A CN117209474 A CN 117209474A
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- trifluoromethyl
- hexane
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- azabicyclo
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Abstract
本发明涉及一种吡咯烷衍生物及其在医药上的应用,具体而言涉及如通式(I)所示的吡咯烷衍生物、或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或共晶,包含其的药物组合物以及本申请的化合物或组合物在制备自身免疫疾病药物中的用途。
Description
技术领域
本发明涉及一种吡咯烷衍生物、药物组合物及其在医药上的应用。
背景技术
Toll样受体(Toll-like receptors,TLR)是一类分子模式识别受体,广泛分布于不同的组织中,监视识别不同的病原体相关分子模式(PAMP)和损伤相关分子模式(DAM P),在先天免疫和获得性免疫中均扮演着重要的角色。
TLR属于I型跨膜蛋白,到目前为止已发现13个TLR家族成员,其中10个存在于人类中,TLR1、TLR2、TLR4、TLR5、TLR6、TLR10和TLR11位于细胞膜上,可以识别微生物的脂类、脂蛋白等物质;而TLR3、TLR7、TLR8和TLR9位于胞内囊泡结构(如溶酶体、内涵体和内质网等),识别微生物的核酸。
TLR7和TLR8在序列和功能上最相似,大量研究表明,TLR7/8的激活可以引发I型干扰素应答及多种炎症反应,在自身免疫性障碍如系统性红斑狼疮(SLE)的情况下,TLR7/8的异常持续激活导致疾病状态的恶化。因此,开发具有选择性和强效抑制活性化合物,通过拮抗TLR7/8抑制过度激活的免疫反应有望成为治疗自身免疫性疾病的新方法。
发明内容
本发明的目的是提供新的吡咯烷衍生物或者立体异构体、其药物组合物以及其在制备自身免疫疾病药物中的应用。
本发明的一个或多个实施方式提供通式(I)所示的化合物,或者其所有的立体异构体:
其中:
R1选自-CONHR4;
R4选自
R2选自C1-6烷基,所述烷基任选地进一步被1个或多个卤素取代
R3选自
进一步地,R2可以选自CF3。
本发明的一个或多个实施方式提供通式(I)所示的化合物,或者其立体异构体,所述化合物为以下结构之一:
本发明的一个或多个实施方式提供药物组合物,所述药物组合物包括:
通式(I)所示的化合物或者其立体异构体;
任选的一种或者多种其他活性成分;以及
药学上可接受的载体和/或赋形剂。
本发明的一个或多个实施方式还提供通式(I)所示的化合物或者其立体异构体、上述药物组合物在制备自身免疫疾病药物中的用途。
本发明的一个或多个实施方式还提供一种用于制备通式(I)化合物的中间体,或者其立体异构体、溶剂化物、代谢产物、前药、氘代物、药学上可接受的盐或共晶,其中,所述中间体选自:
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4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、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“任选地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
具体实施方式
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但不限于此。
中间体A-1:(1S,5R)--3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸
(1S,5R)-3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid
中间体A-2:(1R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸
(1R,5S)-3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid
第一步:
1-苄基-4-(三氟甲基)-2,5-二氢-1H-吡咯-3-羧酸乙酯A-1.3
ethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate
N2氛围下,将A-1.1(10g,60mmol)溶于30mL二氯甲烷(DCM)中,冰浴下滴加A-1.2(14.4g,60mmol)的二氯甲烷溶液(10mL),随后缓慢滴加三氟乙酸(684mg,6mmol)的二氯甲烷溶液(10mL),室温搅拌2h。将反应液加入30mL水中,DCM萃取三次,有机相用饱和食盐水30mL洗,无水硫酸钠干燥,旋干,硅胶柱层析纯化(乙酸乙酯:石油醚=1:10),得到目标产物1-苄基-4-(三氟甲基)-2,5-二氢-1H-吡咯-3-羧酸乙酯A-1.3(黄色油状液体,15.5g,产率86%),直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ7.34-7.24(m,5H),4.19(q,2H),3.79-3.78(m,4H),1.20(t,3H).
LC-MS m/z(ESI)=300.1[M+1]。
第二步:
3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯A-1.4
ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate
N2氛围下,将三甲基碘化亚砜(3.5g,15.8mmol)溶于10mL二甲亚砜中,冰浴下分批次加入氢化钠(633.6mg,15.8mmol)的二甲亚砜溶液(5mL),室温搅拌30分钟。随后滴加A-1.3(4.3g,14.4mmol)的二甲亚砜溶液(5mL),60℃反应5h。饱和氯化铵淬灭反应,DCM 30mL萃取,饱和食盐水30mL洗,有机相用无水硫酸钠干燥,旋干,硅胶柱层析纯化(乙酸乙酯:石油醚=1:10),得到目标产物3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯A-1.4(无色油状液体,3.5g,产率78%),直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ7.34-7.24(m,5H),4.11(q,2H),3.66(s,2H),3.08-
3.01(m,2H),2.86-2.82(m,1H),2.65-2.62(m,1H),1.82-1.79(m,2H),1.15(t,3H).
LC-MS m/z(ESI)=314.1[M+1]。
第三步:
5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯A-1.5
-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate
将A-1.4(1g,3.2mmol)溶于乙醇50mL中,随后加入Pd/C(681mg,0.64mm ol),反应体系用1atm H2置换两次,升温至60℃反应3h。硅藻土过滤,旋干溶剂,得到目标产物5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯A-1.5(无色油状液体,1g,产率88%),直接用于下一步。
1H NMR(400MHz,DMSO-d6)δ4.11(q,2H),3.20-2.75(m,5H),1.75(d,1H),1.48-1.47(m,1H),1.16(t,3H).
LC-MS m/z(ESI)=224.1[M+1]。
第四步:
(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯A-1.7
ethyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxy late
N2氛围下,将5-溴喹啉-8-甲腈A-1.6(654mg,2.9mmol)溶于1,4-二氧六环30mL中,随后加入A-1.5(804mg,3.5mmol),N2置换气三次,依次加入碳酸铯(4.3g,13.05mmol)和RuPhosPdG3(486mg,0.58mmol),N2置换气三次,升温至90℃反应2h。旋干溶剂,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干溶剂,粗产物A-1.7直接投下一步。
LC-MS m/z(ESI)=376.1[M+1],398.1[M+23].
第五步:
3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A
3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic ac id
将A-1.7的粗产品(2.02g,5.39mmol)溶于四氢呋喃溶液10mL中,将无水氢氧化锂(1.29g,53.9mmol)的水溶液10mL滴入反应液中,室温搅拌过夜。待反应结束,旋干四氢呋喃,乙酸乙酯萃取,保留水相,用2M盐酸水溶液将水相pH调至3-4,乙酸乙酯萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,真空除去溶剂。MPLC分离(乙腈:水=47:53),得到目标产物3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸化合物A(黄色固体,387mg,21%)。
1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),9.02-9.00(m,1H),8.64-8.62(m,1H),8.16(d,J=8.0Hz,1H),7.61(dd,1H),7.25(d,1H),4.05-3.77(m,4H),2.07-1.86(m,2H).
LC-MS m/z(ESI)=348.1[M+1],370.1[M+23].
第六步:
3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸中间体A-1和A-2
3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic ac id
化合物A-1和化合物A-2通过chiral prep-HPLC拆分。分析方法:手性柱Ig-3,甲醇作为流动相,流速1mL/min,中间体A-1保留时间为3.619min,中间体A-2保留时间为4.741min。
实施例1
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(吡啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物1
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1
(200mg,0.57mmol)溶于6mL N,N-二甲基甲酰胺中,随后冰浴加入HATU(260mg,0.68mmol),DIPEA(220mg,1.71mmol)低温搅拌5分钟,然后加入4-氨基吡啶1-1(54mg,0.51mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(吡啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物1(淡黄色固体,253mg,83%)。
1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.02(dd,J=4.2,1H),8.67(dd,1H),8.47(d,2H),8.19(d,1H),7.62(dd,3H),7.27(d,1H),4.13(s,2H),4.02(d,1H),3.92(d,1H),2.10(d,1H),1.80(d,1H).
19F NMR(376MHz,DMSO-d6)δ-63.88.
LC-MS m/z(ESI)=424.10[M+1].
实施例2
(1S,5R)-N-(6-氨基吡啶-2-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物2
(1S,5R)-N-(6-aminopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabic yclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(100mg,0.28mmol)溶于6mL N,N-二甲基甲酰胺中,随后冰浴加入HATU(94mg,0.33mmol),DIPEA(111mg,0.86mmol)低温搅拌5分钟,然后加入吡啶-2,6-二胺2-1(94mg,0.86mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-N-(6-氨基吡啶-2-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物2(淡黄色固体,65mg,73%)。
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.01(dd,1H),8.66(dd,1H),8.18(d,1H),7.60(dd,1H),7.36(t,1H),7.25(d,1H),7.18(d,1H),6.21(d,,1H),5.76(s,2H),4.11(q,2H),4.01–3.87(m,2H),1.96(d,1H),1.66(d,1H).
19F NMR(376MHz,DMSO-d6)δ-63.70.
LC-MS m/z(ESI)=439.10[M+1].
实施例3
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(5-吗啉吡啶-2-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物3
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(5-morpholinopyridin-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将化合物A-1(200.0mg,0.58mmol)溶解于DMF 2mL中,随后加入HATU(219.0mg,0.58mmol)和DIPEA(159.0mg,1.20.6mmol),室温搅拌10min,加入化合物3-1(103.3mg,0.58mmol),室温搅拌1h。TLC反应完毕,将反应液加入15mL水中水洗,饱和食盐水15mL洗,有机相用无水硫酸钠干燥旋干,MPLC纯化,得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(5-吗啉吡啶-2-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物3(白色固体,90mg,30.5%)。
1H NMR(400MHz,DMSO-d6)δ9.03-8.98(m,1H),8.69-8.63(m,1H),8.18(d,1H),8.04(d,1H),7.90(d,1H),7.64-7.59(m,1H),7.47-7.41(m,1H),7.26(d,1H),4.28–4.07(m,2H),3.94(s,2H),3.82–3.64(m,4H),3.17–2.97(m,4H),2.03(d,1H),1.70(d,1H).
19F NMR(376MHz,DMSO-d6)δ63.69.
LC-MS m/z(ESI)=509.2[M+1].
实施例4
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(6-吗啉吡啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物4
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-morpholinopyridin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(50mg,0.14mmol)溶于6mL N,N-二甲基甲酰胺中,随后冰浴加入HATU(65.7mg,0.173mmol),DIPEA(55.7mg,0.43mmol)低温搅拌5分钟,然后加入6-吗啉吡啶-3-胺4-1(28.4mg,0.158mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(6-吗啉吡啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物4(淡黄色固体,47mg,92%)。
1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.02(dd,1H),8.67(dd,1H),8.29(d,1H),8.19(d,1H),7.76(dd,1H),7.62(dd,1H),7.27(d,1H),6.84(d,1H),4.10(d,2H),4.05–3.95(m,2H),3.89(d,1H),3.69(t,4H),3.38(d,3H),2.10(d,1H),1.75(d,1H).
19F NMR(376MHz,DMSO-d6)δ-63.76.
LC-MS m/z(ESI)=509.20[M+1].
实施例5
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物5
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(trifluor omethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(100mg,0.28mmol)溶于6mL N,N-二甲基甲酰胺中,随后冰浴加入HATU(127mg,0.33mmol),DIPEA(108mg,0.84mmol)低温搅拌5分钟,然后加入5-(4-甲基哌嗪-1-基)吡啶-2-胺5-1(60mg,0.31mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物5(淡黄色固体,50mg,63%)。
1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),9.01(dd,1H),8.66(dd,1H),8.18(d,1H),8.03(d,1H),7.88(d,1H),7.60(dd,1H),7.41(dd,1H),7.26(d,1H),4.20–4.06(m,2H),3.94(s,2H),3.14(t,4H),2.46(t,4H),2.22(s,3H),2.03(d,1H),1.69(d,1H).
19F NMR(376MHz,DMSO-d6)δ-63.73.
LC-MS m/z(ESI)=522.20[M+1].
实施例6
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-吗啉苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物6
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-morpholinophenyl)-5-(trifluoromethyl)-3-azabic yclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(50mg,0.14mmol)溶于6mL N,N-二甲基甲酰胺中,随后冰浴加入HATU(65.7mg,0.173mmol),DIPEA(55.7mg,0.43mmol)低温搅拌5分钟,然后加入4-吗啉苯胺6-1(28.1mg,0.158mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-吗啉苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物6(淡黄色固体,36mg,87%)。
1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.01(dd,1H),8.67(dd,1H),8.18(d,1H),7.61(dd,1H),7.45(dd,2H),7.26(d,1H),6.91(d,2H),4.18–4.05(m,2H),4.00(d,1H),3.90(d,1H),3.72(t,4H),3.31(s,1H),3.05(t,3H),2.07(d,1H),1.72(d,1H).
19F NMR(376MHz,DMSO-d6)δ-63.81.
LC-MS m/z(ESI)=508.20[M+1].
实施例7
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-(吡咯烷-1-基)苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物7
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(pyrrolidin-1-yl)phenyl)-5-(trifluoromethyl)-3-az abicyclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(100mg,0.28mmol)溶于6mL N,N-二甲基甲酰胺中,随后冰浴加入HATU(127mg,0.33mmol),DIPEA(108mg,0.84mmol)低温搅拌5分钟,然后加入4-(吡咯烷-1-基)苯胺7-1(51mg,0.31mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-(吡咯烷-1-基)苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物7(淡黄色固体,70mg,88%)。
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.01(dd,1H),8.67(dd,1H),8.18(d,1H),7.61(dd,1H),7.36(dd,2H),7.25(d,1H),6.56–6.44(m,2H),4.10(q,2H),3.99(d,1H),3.89(d,1H),3.24–3.11(m,4H),2.07(d,1H),1.99–1.88(m,4H),1.70(d,1H).
19F NMR(376MHz,DMSO-d6)δ-63.76.
LC-MS m/z(ESI)=492.20[M+1].
实施例8
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-(1-甲基哌啶-4-基)苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物8
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(1-methylpiperidin-4-yl)phenyl)-5-(trifluorometh yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(100mg,0.28mmol)溶于6mL N,N-二甲基甲酰胺中,随后冰浴加入HATU(127mg,0.33mmol),DIPEA(108mg,0.84mmol)低温搅拌5分钟,然后加入4-(1-甲基哌啶-4-基)苯胺8-2(60.3mg,0.31mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-(1-甲基哌啶-4-基)苯基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物8(淡黄色固体,60mg,72%)。
1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.01(dd,1H),8.67(dd,1H),8.18(d,1H),7.61(dd,1H),7.55–7.47(m,2H),7.27(d,1H),7.23–7.16(m,2H),4.17–4.06(m,2H),4.00(d,1H),3.91(d,1H),2.90–2.81(m,2H),2.40(m,1H),2.19(s,3H),2.08(d,1H),2.02–1.90(m,2H),1.77–1.54(m,5H).
19F NMR(376MHz,DMSO-d6)δ-63.85.
LC-MS m/z(ESI)=520.20[M+1].
实施例9
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(吡啶-2-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物9
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(pyridin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将(1R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(150mg,0.43mmol)溶于6ML N,N-二甲基甲酰胺中,随后冰浴加入HATU(196mg,0.51mmol),DIPEA(166mg,1.29mmol)低温搅拌5分钟,然后加入1-(吡啶-2-基)哌啶-4-胺9-1(84mg,0.47mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(吡啶-2-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物9(淡黄色固体,141mg,8
5%)。
1H NMR(400MHz,DMSO-d6)δ9.00(dd,1H),8.63(dd,1H),8.16(d,1H),8.13–8.02(m,2H),7.59(dd,1H),7.51(m,1H),7.21(d,1H),6.85(d,1H),6.59(dd,1H),4.30–4.20(m,2H),4.00(d,1H),3.93(m,3H),3.80(d,1H),2.91(td,2H),2.00(d,1H),1.71(td,2H),1.62(d,1H),1.48–1.32(m,2H).
19F NMR(376MHz,DMSO-d6)δ-63.54.
LC-MS m/z(ESI)=507.20[M+1].
实施例10
(1S,5R)-N-(5-(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-基)吡啶-2-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物10
(1S,5R)-N-(5-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyridin-2-yl)-3-(8-cyanoqui nolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
第一步:
(1S,5R)-N-(5-溴吡啶-2-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺10-2
(1S,5R)-N-(5-bromopyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabi cyclo[3.1.0]hexane-1-carboxamide
将化合物A-1(400.0mg,1.15mmol)溶解于DMF 2mL中,随后加入HATU(438.3mg,1.15mmol)和DIPEA(595.9mg,4.61mmol),室温搅拌10min,加入10-1(199.4mg,1.15mmol),室温搅拌1h。TLC反应完毕,将反应液加入15mL水中水洗,饱和食盐水15mL洗,有机相用无水硫酸钠干燥旋干,MPLC分离(乙腈:水47:53),得到粗产物(1S,5R)-N-(5-溴吡啶-2-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物10-2(白色固体,103mg,17.9%)。
LC-MS m/z(ESI)=502.1[M+1].
第二步:
叔丁基((3R,4R)-1-(6-(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)吡啶-3-基)-4-甲氧基吡咯烷-3-基)氨基甲酸酯10-4
tert-butyl((3R,4R)-1-(6-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabic yclo[3.1.0]hexane-1-carboxamido)pyridin-3-yl)-4-methoxypyrrolidin-3-yl)carbamate
N2氛围下,将10-2(50.2mg,0.1mmol)溶于1,4-二氧六环10mL中,随后加入10-3(21.6mg,0.1mmol),N2置换气三次,依次加入碳酸铯(130.3mg,0.4mmo l)和Ruphos Pd G3(8.37mg,0.01mmol),N2置换气三次,升温至90℃反应2h。旋干溶剂,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干溶剂,得到粗产物叔丁基((3R,4R)-1-(6-(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)吡啶-3-基)-4-甲氧基吡咯烷-3-基)氨基甲酸酯10-4,直接投下一步。
LC-MS m/z(ESI)=638.3[M+1].
第三步:
(1S,5R)-N-(5-(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-基)吡啶-2-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物10
(1S,5R)-N-(5-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)pyridin-2-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将10-4的粗产品溶于二氯甲烷10mL中,加入三氟乙酸(126.0mg,1.16mmol),室温搅拌2h。待反应结束,旋干。MPLC分离(乙腈:水47:53),得到目标产物(1S,5R)-N-(5-(3R,4R)-3-氨基-4-甲氧基吡咯烷-1-基)吡啶-2-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物10(黄色固体,30mg,55.9%)。
1H NMR(400MHz,DMSO-d6)δ9.04-8.98(m,1H),8.69-8.63(m,1H),8.18(d,1H),7.88–7.80(m,1H),7.71–7.56(m,2H),7.26(d,1H),6.99-6.92(m,1H),4.23–4.07(m,2H),3.94(s,2H),3.75–3.65(m,1H),3.59-3.51(m,1H),3.48(d,1H),3.47-3.41(m,1H),3.30(s,3H),3.24-3.20(m,1H),2.99-2.95(m,1H),2.03(d,1H),1.68(d,1H).
19F NMR(376MHz,DMSO-d6)δ64.48.
LC-MS m/z(ESI)=538.2[M+1].
实施例11
(1S,5R)-3-(8-氰基喹啉-5-基)-N-(6-(吡咯烷-1-基)吡啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物11
(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide
将(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸A-1(100mg,0.28mmol)溶于5ml N,N-二甲基甲酰胺中,随后冰浴加入HATU(127mg,0.33mmol),DIPEA(180.6mg,1.4mmol)低温搅拌5分钟,然后加入6-(吡咯烷-1-基)吡啶-3-胺11-1(86mg,0.31mmol),搅拌半小时,TLC反应完毕,反应液直接浓缩,反相C18柱层析纯化(碱法),得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(6-(吡咯烷-1-基)吡啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物11(淡黄色固体,92mg,86%)。
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.02(dd,1H),8.67(dd,1H),8.24–8.14(m,2H),7.64(m,2H),7.27(d,1H),6.44(d,1H),4.16–4.06(m,2H),4.01(d,1H),3.89(d,1H),3.36-3.33(m,4H),2.10(d,1H),2.00–1.88(m,4H),1.74(d,1H).
19F NMR(376MHz,DMSO-d6)δ-63.73.
LC-MS m/z(ESI)=493.20.20[M+1].
生物测试
HEK-Blue-hTLR7/8/9细胞抑制实验
1、将HEK-Blue-hTLR7/8细胞(1×104个/孔)、HEK-Blue-hTLR9细胞(1.5×104个/孔)接种于384孔细胞培养板中,每孔体积为30μL。置于37℃,5%CO2培养箱培养4h。
2、将化合物用DMSO配制,用DMEM培养基稀释10个浓度(1:3稀释),终浓度分别为10000,3333.3,1111.1,370.4,123.5,41.2,13.7,4.6,1.5,0.5nM;R848使用DMSO配制,用DMEM培养基稀释,终浓度为0.8μM(HEK-Blue-hTLR7)、3μM(HEK-Blue-hTLR8);ODN2006使用无内毒素水配制,用DMEM培养基稀释,终浓度为1μM。
3、以DMSO处理的细胞为空白对照组,同时设立单独用Resiquimod(R848)处理的细胞为HEK-Blue-hTLR7/8的阳性对照组,单独用ODN2006处理的细胞为HEK-Blue-hTL R9的阳性对照组。以受试化合物与R848或ODN2006处理的细胞为测试组。每组设2个平行孔,放入置于37℃,5%CO2培养箱培养。
4、培养4h后,从培养箱中取出HEK-Blue-hTLR7/8的384孔板,每孔单独加入R848或者同时加入R848和稀释后的化合物。置于37℃,5%CO2培养箱培养16h;从培养箱中取出HEK-Blue-hTLR9的384孔板,每孔单独加入ODN2006或者同时加入ODN2006和稀释后的化合物。置于37℃,5%CO2培养箱培养16h。
5、培养16h后,从培养箱中取出384孔板,1000rpm离心1分钟,使用多功能酶标仪读取每个孔在620nm处的光密度值。
6、计算细胞抑制率=(1-(OD620测试组-OD620空白组)/(OD620阳性组-OD620空白组))×100%,通过曲线拟合计算半数抑制浓度(half maximal inhibitoryconcentration,IC50)。
试验结果如表1、表2和表3所示:
表1
化合物 | TLR7 IC50(nM) |
化合物1 | 32 |
化合物2 | 27 |
化合物4 | 17 |
化合物5 | 2 |
化合物6 | 9 |
化合物7 | 12 |
化合物8 | 1 |
化合物9 | 19 |
化合物10 | 4 |
化合物11 | 9 |
表2
表3
化合物 | TLR8 IC50(nM) |
化合物5 | 11 |
化合物8 | 2 |
化合物10 | 22 |
结论:本发明化合物对HEK-Blue-hTLR7/8细胞拮抗活性较好,有明显拮抗作用,同时对HEK-Blue-hTLR9细胞无明显拮抗作用。
IL-6的体内抑制实验
实验材料:化合物溶液的配制:R848用纯水配制(灭菌),最终浓度25μg/100μL;受试化合物用pH=3的柠檬酸钠缓冲液配制,最终浓度0.1mg/mL。
实验动物:C57BL/6雌鼠,购自集萃药康,6-8周龄。
实验方法:C57BL/6雌鼠随机分为空白组、对照组和实验组,每组8只。
空白组:小鼠禁食12h后取血。
对照组:小鼠禁食12h后灌胃PH=3的柠檬酸钠缓冲液,其余操作与实验组一致;
实验组:小鼠禁食12h后灌胃给予受试化合物(1mg/kg),1h后腹腔注射25μg R848(购自MCE),2h后摘眼球取血,血清室温静置30min,接着离心10min(3000rpm),取上清液,用IL-6ELISA试剂盒测量血清IL-6浓度,通过对照组和实验组IL-6血清浓度,计算IL-6抑制率。计算公式:抑制率=(C2-C3)/(C2-C1)×100%。
C1:空白组血清IL-6浓度;
C2:对照组血清IL-6浓度;
C3:实验组血清IL-6浓度。
表2:IL-6的体内抑制实验
化合物 | IL-6抑制率 |
化合物5 | >95% |
化合物8 | >85% |
结论:本发明化合物对IL-6有明显的抑制作用。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (6)
1.通式(I)所示的化合物,或者其所有的立体异构体,溶剂化物、代谢产物、前药、药学上可接受的盐或共晶:
其中:
R1选自-CONHR4;
R4选自
R2选自C1-6烷基,所述烷基任选地进一步被1个或多个卤素取代;
R3选自
2.根据权利要求1所述的式(I)所示的化合物,或者其所有的立体异构体,溶剂化物、代谢产物、前药、药学上可接受的盐或共晶:
其中,R2选自CF3。
3.根据权利要求1或2所述的化合物,或者其所有的立体异构体,所述化合物为以下结构之一:
4.一种药物组合物,所述药物组合物包括:
权利要求1-3任一项所述的化合物或者其立体异构体;
任选的一种或者多种其他活性成分;以及
药学上可接受的载体和/或赋形剂。
5.权利要求1-3任一项所述的化合物或者其立体异构体、权利要求4所述的药物组合物在制备自身免疫疾病药物中的用途。
6.一种制备通式(I)化合物的中间体,或者其立体异构体、溶剂化物、代谢产物、前药、氘代物、药学上可接受的盐或共晶,其中,所述中间体选自:
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