CN115611944A - 不对称gpr84拮抗剂及其用途 - Google Patents
不对称gpr84拮抗剂及其用途 Download PDFInfo
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- CN115611944A CN115611944A CN202110801592.7A CN202110801592A CN115611944A CN 115611944 A CN115611944 A CN 115611944A CN 202110801592 A CN202110801592 A CN 202110801592A CN 115611944 A CN115611944 A CN 115611944A
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Abstract
本发明公开了一种不对称GPR84拮抗剂及其用途,该GPR84拮抗剂结构如式I所示,式中,各取代基的定义如说明书和权利要求书中所述。本发明的式I化合物,具有GPR84的拮抗活性,可以竞争性地抑制GPR84激动剂引起的受体的激活效应,能够用于治疗与GPR84高表达或兴奋性过高相关的多种疾病,如多发性硬化症、炎症性肠病、器官纤维化、关节炎等。
Description
技术领域
本发明涉及一类G蛋白偶联受体84(G protein-coupled receptor 84,简称GPR84)的配体分子。本发明所涉及的配体分子具有GPR84的拮抗活性,可以竞争性的抑制GPR84激动剂引起的受体的激活效应,可用于治疗与GPR84高表达或兴奋性过高相关的多种疾病,如多发性硬化症、炎症性肠病、器官纤维化、关节炎等。
背景技术
GPR84是2001年发现的一种G蛋白偶联受体,偶联Gi通路,可被链长为C9-C14的中链脂肪酸(MCFAs)激活,GPR84激活后可抑制腺苷酸环化酶,使得cAMP的产生减少。GPR84在多种组织或器官中表达,如心脏、肺、肾、肝脏、骨髓、脂肪等,特别是在与先天免疫系统有关的髓系细胞中表达广泛,包括外周血中的单核细胞、巨噬细胞和嗜中性粒细胞,以及中枢神经系统中的小胶质细胞。在生理条件下,GPR84在白细胞和脂肪细胞中的表达较低,但急性炎症刺激(如脂多糖LPS、TNFα、或者与众多疾病相关的炎症反应)可诱导GPR84表达显著上调。GPR84激活可以增强巨噬细胞的吞噬作用,促进免疫细胞的趋化作用,增加促炎型细胞因子(IL-12p40)的分泌,从而放大机体的炎症反应;而GPR84的敲除会导致巨噬细胞中促炎性细胞因子(IL-1,IL-6和TNF)的分泌减少,同时T细胞中Th2细胞因子(IL-4,IL-5,IL-13)的分泌增加。以上研究证实了GPR84在机体代谢调节与免疫反应中的促炎作用,后续研究揭示GPR84与多种炎症和代谢性疾病发生发展过程相关,如多发性硬化症(multiplesclerosis,MS,Glia 2007,55,790-800)、炎症性肠病(inflammatory bowel disease,IBD,J.Med.Chem.2020,63,13526-13545)、器官纤维化(J.Clin.Med.2020,9,4,Am.J.Pathol.2018,188,1132-1148)、关节炎(Curr.Opin.Clin.Nutr.Metab.Care 2011,14,322-327)等。因此,GPR84是治疗上述疾病的潜在靶点,而GPR84拮抗剂则有望用于治疗这些疾病。
至今为止,GPR84拮抗剂只有比利时Galapagos公司和加拿大Liminal公司的专利报道。Galapagos公司的化合物具有四氢异喹啉并嘧啶酮(或吡啶酮)的结构母核(WO2013092791,WO2014095798,WO2015197550,WO2016169911),代表性化合物GLPG1205为高活性的GPR84负向变构剂(J.Med.Chem.2020,63,13526-13545),曾作为治疗炎症性肠病的候选药物进入Ⅱ期临床研究,但因其疗效与安慰剂组无显著差异而试验终止。该化合物正进行第二个Ⅱ期临床评估,用于特发性肺纤维化的治疗。Liminal公司的PBI-4050和PBI-4547为非选择性GPR84拮抗剂,它们结构分别为3-正戊基苯乙酸钠和3,5-二正戊基苯乙酸钠,均为脂肪酸的类似物,对GPR84的拮抗活性在微摩尔级别,同时对脂肪酸受体GPR40和GPR120都有激动活性。PBI-4050用于治疗特发性肺纤维化的临床Ⅱ期试验已经完成,目前正进行治疗症的Ⅱ/Ⅲ期临床研究;PBI-4547正作为非酒精性脂肪肝炎的候选药物进行Ⅰ期临床研究。
南发俊等报道一类具有磷酸二酯结构的高活性GPR84拮抗剂(WO2018161831),其中的两个酯基均为三环结构,代表性化合物XYF573c对DSS诱导的小鼠肠炎症状具有显著的缓解作用,疗效优于同剂量下的柳氮磺胺吡啶。此外,组织分布研究显示XYF573c能够选择性分布于肠道(AUC0-8h=24447.42h*ng/mL,口服:5mg/kg),而在外周血中暴露量相对较低(AUC0-8h=666.53h*ng/mL,口服:5mg/kg),因此XYF573c主要通过作用于肠道免疫细胞中上调的GPR84,抑制GPR84介导的炎症反应而起到治疗肠炎的效果,而其在外周血中的分布表明它也能部分通过抑制外周免疫细胞的迁移而起效。此类GPR84拮抗剂靶向肠道分布的特性表明其适合炎症性肠病的治疗,但它们较差的口服吸收限制了它们在治疗器官纤维化、多发性硬化症、关节炎等疾病中应用。
化合物的口服吸收与脂水分配系数(如CLogP、ALogP)密切相关,具有较好类药性的化合物的CLogP需小于5(Lipinski类药五规则),而XYF573c的CLogP为6.419,仍有较大的优化空间。原GPR84拮抗剂的磷酸二酯结构中,两个酯基均为强亲脂性的三环结构,这种对称的结构特征不仅限制了化合物化学空间的拓展,也极大阻碍了化合物类药性质(如CLogP、ALogP等)的优化。
发明内容
本发明的目的在于提供一种新型的GPR84的拮抗剂及其制备方法和用途。
本发明的第一方面,提供一种通式(I)所示的化合物,或其对映异构体、非对映异构体、外消旋体、或其药学上可接受的盐,
式中,Y为O或S;
Z为H,或以下金属的离子:Li、Na、K、Ca、Mg、Cu、Fe、Zn、Al、Mn,或以下碱的共轭酸:NH3、精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇、咪唑;
L1为无、O、S、-CH=CH-、-CO-、-C(=CH2)-、取代或未取代的C1~C6亚烷基、-NH-、-N(C1~C4烷基)-、C3~C6环烷基或C3~C6杂环烷基,所述取代是指具有选自下组的一个或多个取代基:C1~C6烷基、C1~C6烷氧基、卤素、羟基;
L2为无、CH;
环A、B各自独立地为C6-C10芳环、C3-C10环烷烃环、C3-C10杂环烷烃环、C3-C10杂芳环;
n1、n2各自独立地为0、1、2、3或4;R1、R2各自独立地为-OH、-SH、-NH2、F、Cl、Br、I、-CrH2r-L7-CsH2s+1、-CrH2r-N(CtH2t+1)-CsH2s+1、取代或未取代的C1~C6烷基,上述取代是指具有选自下组的一个或多个取代基:卤素、羟基、氨基、-COOC1~C6烷基、-COOH;L7各自独立地为O、S、NH,各r独立地为0、1、2、3、4、5或6,各s独立为0、1、2、3、4、5或6,各t独立为1、2、3、4、5、或6;
L3、L4各自独立地为O、无、-O(C1~C10亚烷基)-、-O(C1~C10亚烷基)NH-、-O(C1~C10亚烷基)O-、-CONH-、-OCO-、-NH-、-NHCOO-、-N(C1~C6烷基)-、或C1~C10亚烷基;
R3为H、OH、NH2、SH、-COOH、取代或未取代的C1~C10烷基、取代或未取代的C2~C10烯基、取代或未取代的C2~C10炔基、取代或未取代的3-12元环烷烃环、取代或未取代的C6-C14芳环、取代或未取代的氨基、取代或未取代的4-10元杂环烷烃环、取代或未取代的4-10元杂芳环、胆酸、石胆酸、去氧胆酸、异石胆酸、异去氧胆酸、鹅去氧胆酸、熊去氧胆酸、α-鼠胆酸、β-鼠胆酸、γ-鼠胆酸、ω-鼠胆酸;上述取代是指具有选自下组的1、2、3、4、5或6个取代基:氨基、C1~C10烷基、卤素、C6-C10芳环、C1~C6烷氧基、3-12元环烷烃环、-O-CpH2p-O-CqH2q+1、硝基、氧代(=O)、羟基、羧基、-C(O)OC1~C6烷基、-O-C6-C10芳环;其中,各p独立地为1、2、3、4、5或6,各q独立为1、2、3、4、5或6;
在另一优选例中,环A、B各自独立地为苯环、C3-C6环烷烃环、C3-C6杂环烷烃环、C3-C6杂芳环。
在另一优选例中,环A、B各自独立地为苯环、噻吩环、吡咯环、呋喃环、环己烷环、环戊烷环或环庚烷环。
在另一优选例中,L1独立地为无、CH2、O、S、-CO-、-NH-;L2独立地为无、CH。
在另一优选例中,n1为0、1或2;R1为为F、Cl、Br、I、甲氧基、乙氧基、正丙氧基、异丙氧基。
在另一优选例中,n2为0、1或2;R2为F、Cl、Br、I、甲氧基、乙氧基、正丙氧基、异丙氧基。
在另一优选例中,L3为O或S。
在另一优选例中,L4为O、无、-NH-、-OCH2NH-、-OCH2CH2NH-、-OCH2CH2CH2NH-、-N(C1~C4烷基)-、-CH2-或-CH2CH2-。
在本发明中,如-O(C1~C10亚烷基)-、-O(C1~C10亚烷基)NH-、-CONH-、-OCO-、-NHCOO-、-OCH2NH-、-OCH2CH2NH-、-OCH2CH2CH2NH-等基团的连接方式没有特别的限制,自左向右,或者自右向左与相连的原子或基团,如C、P、R3相连接,例如对于P-L4-R3,当L4为-CONH-,表示P-CONH-R3或R3-CONH-P。在另一优选例中,当L4定义为上述基团时,上述基团左端与P相连,右端与R3相连接。
在另一优选例中,R3为取代或未取代的C1~C10烷基、取代或未取代的C2~C10烯基、取代或未取代的C2~C10炔基、取代或未取代的3-12元环烷烃环、取代或未取代的C6-C14芳环、取代或未取代的氨基、取代或未取代的4-10元杂环烷烃环、取代或未取代的4-10元杂芳环、胆酸、石胆酸、去氧胆酸、异石胆酸、异去氧胆酸、鹅去氧胆酸、熊去氧胆酸、α-鼠胆酸、β-鼠胆酸、γ-鼠胆酸、ω-鼠胆酸;上述取代是指具有选自下组的1、2、3、4或5个取代基:氨基、C1~C10烷基、卤素、C6-C10芳环、C1~C6烷氧基、3-12元环烷烃环、-O-CpH2p-O-CqH2q+1、硝基、氧代(=O)、羟基、羧基、-COOC1~C6烷基、-O-苯环,其中,各p独立地为1、2或3,各q独立为1、2或3。
在另一优选例中,所述化合物为实施例中制备的任一化合物。
本发明的第二方面,提供第一方面所述的化合物的制备方法,包括以下步骤:
以式S1化合物、式S2化合物和式S3化合物为原料,反应获得具有式P1所示结构的化合物,
其中,R1、R2、R3、L1、L2、L4、L5、Y、n1、n2、环A、B的定义如前所示;
L3为O;
各X1独立地为二甲氨基、乙氨基、二异丙基氨基;
X2为氰乙基、烯丙基、叔丁基、苄基。
本发明的第三方面,提供第一方面所述的化合物的制备方法,包括以下步骤:
以式S1化合物、式S3化合物和式S4化合物为原料,反应获得具有式P1所示结构的化合物,
其中,R1、R2、R3、L1、L2、L4、L5、Y、n1、n2、环A、B的定义如前所示;
L3为O或CH2;
各X独立地为F、Cl、Br或I。
本发明的第四方面,提供第一方面所述的化合物的制备方法,包括以下步骤:
以式S1化合物和式S5化合物为原料,反应获得具有式P1所示结构的化合物,
其中,R1、R2、R3、L1、L2、L4、L5、Y、n1、n2、环A、B的定义如前所示;
L3为O或CH2;
各X独立地为F、Cl、Br或I。
本发明的第五方面,提供一种药物组合物,包含:
第一方面所述的通式(I)所示的化合物,或其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐;和
药学上可接受的载体。
本发明的第六方面,提供第一方面所述的化合物或其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或第五方面所述的药物组合物用途,所述用途为:
(i)用于制备GPR84拮抗剂;
(ii)用作GPR84拮抗剂;
(iii)用于制备治疗GPR84受体高表达或兴奋性过高所导致的相关疾病的药物。
在另一优选例中,所述疾病为多发性硬化症、炎症性肠病、纤维化、神经退行性疾病或关节炎。
本发明的第七方面,提供一种用于治疗GPR84受体高表达或兴奋性过高所导致的相关疾病的方法,向有需要的患者给予本发明的化合物或药学上可接受的盐。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
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示出化合物XYF573c与LSX472a在ICR小鼠中的组织分布。
具体实施方式
本申请的发明人经过广泛而深入地研究,研发出一种新型结构的GPR84的拮抗剂,磷酸二酯的一个酯基为三环片段,另一酯基衍生为多种结构类型,如(环)烷基或取代(环)烷基、芳基或取代芳基、胆酸衍生物等。本申请的化合物能够竞争性地抑制GPR84的激动剂引起的该受体的激活,可用于制备治疗因GPR84受体高表达或兴奋性过高所导致的相关疾病的药物,所述疾病包括多发性硬化症、炎症性肠病、纤维化、关节炎等。此外,这种非对称结构的改造突破了原有对称磷酸二酯类GPR84拮抗剂的结构特征,在保持GPR84拮抗活性的基础上降低了化合物的CLogP,使其具有更好的口服吸收和脏器分布特性,利于开发治疗器官纤维化、关节炎、多发性硬化症,以及炎症性肠病等疾病的药物。在此基础上,完成了本发明。
术语
本发明中,C6-C10是指具有6-10个碳原子,C3-C6是指具有3-6个碳原子,依此类推。
本发明中,除非另有说明,芳环、环烷烃环、烷基、烯基、炔基等术语与本领域熟练人员所熟悉的意义相同。例如,烷基是指饱和的线性或支链烃基;例如-CH3或-CH(CH3)2;亚烷基是指饱和烃基从形式上消去两个一价氢剩余的部分,包括但不限于亚甲基(-CH2-)、亚乙基(-CH2CH2-)等。烷氧基是指-O-(烷基),包括但不限于-OCH3、-OCH2CH3等。环烷烃环、环烷基是指饱和的环状烃基,例如环己基。杂环烷基、杂环烷烃环是指包含至少一个(如1、2、3或4个)杂原子(选自:N、O或S)的饱和的环状烃基。杂芳环、杂芳基是指包含至少一个(如1、2、3或4个)杂原子(选自:N、O或S)的芳环。
除非另外说明,本文所述的芳环、杂芳环、环烷烃环、烷基、亚烷基、烷氧基、环烷基、杂环烷基等同时包括取代的和未取代的,可能的取代基包括,但不限于:C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、羟基、卤素、巯基、氰基、硝基、羧基和羧酸酯基等。
GPR84拮抗剂
本发明提供的GPR84拮抗剂,为具有前述所示式I结构的化合物。
本发明还提供其药学上可接受的盐,包括式I化合物与无机碱或有机碱类化合物反应而得到的盐。得自无机碱的盐包括但不局限于:铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括但不局限于伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇、咪唑等。
本发明的主要优点为:
发明人研发出一种新型结构的GPR84的拮抗剂,磷酸二酯的一个酯基为三环片段,另一酯基衍生为多种结构类型,如(环)烷基或取代(环)烷基、芳基或取代芳基、胆酸衍生物等。这种改造有助于拓展GPR84拮抗剂的化学空间,降低CLogP,使其具有更好的口服吸收和脏器分布特性,从而有助于GPR84相关疾病的治疗。
综上,本发明所提供的化合物能够较好地保持对GPR84的拮抗活性,同时口服吸收更优,且具有更特异的靶组织分布特性,因而具有更好的开发前景。
制备方法
式I化合物可通过下述路线一至路线五中的任何一种来实现:
路线一:
第一步反应在二氯甲烷或乙腈中进行;所用活化试剂为4,5-二氰基咪唑或二异丙氨基四氮唑盐或N-甲基咪唑;反应温度为20℃~60℃;反应时间约需1~24h;反应完成后用饱和NaHCO3、Na2CO3溶液中和,以AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取,浓缩物经柱层析纯化。第二步反应在二氯甲烷或N,N-二甲基甲酰胺中进行,所用活化剂为四氮唑,反应时间约需1~24h,之后加入氧化剂氧化,所用氧化剂为叔丁基过氧化氢或间氯过氧苯甲酸,反应时间约0.3~2h,饱和Na2SO3淬灭,以AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取,浓缩物经柱层析纯化。第三步反应在二氯甲烷中进行,根据保护基X2不同所用条件为催化氢化或碱催化,催化氢化所用催化剂为Pd/C或Pd(OH)2/C加常压氢气;碱催化所用碱为三乙胺或1,8-二氮杂二环十一碳-7-烯(DBU),反应时间约需0.3~1h,反应完成后过滤除去不溶物,加稀盐酸中和,以AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取,浓缩物经柱层析得目标产物,所得产物用NMR等方法来确认。
其中,R1、R2、R3、L1、L2、L4、L5、Y、n1、n2、环A、B的定义如前所示;L3为O;各X1独立地为二甲氨基、乙氨基、二异丙基氨基;X2为氰乙基、烯丙基、叔丁基、苄基。
路线二:
反应在吡啶中进行;反应温度为60℃~100℃;反应时间约需1~24h;反应完成后冷却至室温,加入S3后在60℃~100℃反应1~24h,反应完成后加水淬灭,以AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取,浓缩物经柱层析纯化得目标产物,所得产物用NMR等方法来确认。其中,R1、R2、R3、L1、L2、L4、L5、Y、n1、n2、环A、B的定义如前所示;L3为O、S、NH或CH2;各X独立地为F、Cl、Br或I。
路线三:
反应在吡啶中进行;反应温度为60℃~100℃;反应时间约需1~24h;反应完成后以H2O淬灭,用AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取,饱和食盐水洗,经干燥后,低温减压除去溶剂,浓缩物经柱层析得目标产物,所得产物用NMR等方法来确认。
其中,R1、R2、R3、L1、L2、L4、L5、Y、n1、n2、环A、B的定义如前所示;L3为O或CH2;各X独立地为F、Cl、Br或I。
路线四:
原料P1溶于乙酸乙酯中,加入碱(M的共轭碱、M的氢氧化物或M的碳酸化合物)的水溶液洗涤两次,水层用乙酸乙酯反萃,乙酸乙酯层浓缩,粗品用硅胶柱层析得产物P2。
M为以下金属的阳离子:Li、Na、K、Ca、Mg、Cu、Fe、Zn、Al、Mn,或以下碱的共轭酸:NH3、精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇、咪唑等;
其中,R1、R2、R3、L1、L2、L4、L5、Y、n1、n2、环A、B的定义如前所示;
L3为O或CH2。
路线五:
反应在N,N-二甲基甲酰胺(DMF)中进行,所用活化剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl),二甲氨基吡啶(DMAP),所用碱为三乙胺或N,N-二异丙基乙胺,常温下反应时间约为6~24h,反应结束后低温减压除去溶剂,以乙酸乙酯提取,水相反萃三次,饱和食盐水洗涤,有机相浓缩后经柱层析得目标产物,所得产物用NMR等方法来确认。
其中,R1、R2、R3、R4、L1、L2、L4、Y、n1、n2、环A、B的定义如前所示;
L5独立地为无、-(CH2)m-、-(CH2)m-CH=CH-、-(CH2)m-C≡C-、-(C2H4O)m-、-(CH2)m-NH-、-(CH2)m-O-,各m独立地为0-10的整数;
R4为C1-C10取代或未取代的烷基,取代或未取代的C6-C10芳环、C3-C10环烷烃环、C3-C10杂环烷烃环、C3-C10杂芳环、胆酸、石胆酸、去氧胆酸、异石胆酸、异去氧胆酸、鹅去氧胆酸、熊去氧胆酸、α-鼠胆酸、β-鼠胆酸、γ-鼠胆酸、ω-鼠胆酸;所述取代是指具有选自下组的一个或多个取代基:C1~C6烷基、C1~C6烷氧基、卤素、羟基;
L3为O或CH2。
用途
式I化合物作为GPR84的拮抗剂,能够竞争性的抑制GPR84的激动剂引起的该受体的激活,可用于制备治疗因GPR84受体高表达或兴奋性过高所导致的相关疾病的药物,所述疾病包括多发性硬化症、炎症性肠病、器官纤维化、关节炎等。
药物组合物
本发明的药物组合物含有治疗有效量的式I化合物或其药学上可接受的盐,以及含有一种或多种可药用的载体。
“可药用的载体”、“药学上可接受的载体”或“药学上可用的载体”是指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活性成分(式I化合物或其药学上可接受的盐)以及它们之间相互掺和,而不明显降低活性成分的药效。可药用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)、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。
本发明的化合物和药物组合物可以是多种形式,可以通过如胶囊、片剂、颗粒剂、溶液状、粉剂、散剂或糖浆等形式口服给药或以注射剂的形式非口服给药,本发明的化合物和药物组合物可以存在于适宜的固体或液体载体中和适宜的用于注射或滴注的消毒器具中。上述制剂可通过常规制药方法制备。
本发明的化合物和药物组合物可用于哺乳动物临床使用,包括人和动物,可以通过口、鼻或胃肠道等途径给药。最优选的给药途径为口服。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
下述实施例中,NMR用Bruker生产的AVANCE III 400M仪器测定,NMR定标:δH7.26ppm(CDCl3),2.50ppm(DMSO-d6),3.15ppm(CD3OD);试剂主要由上海化学试剂公司提供;TLC薄层层析硅胶板由山东烟台会友硅胶开发有限公司生产,型号HSGF 254;化合物纯化使用的正相柱层析硅胶为山东青岛海洋化工厂分厂生产,型号zcx-11,200-300目。
实施例1
化合物LSX448的制备
中间体G1M的合成。原料G1(200mg,0.78mmol),4,5-二氰基咪唑(184mg,1.56mmol)溶于干燥的二氯甲烷中,于20℃氩气保护下向其中滴加双(二异丙基氨基)(2-氰基乙氧基)膦(0.495ml,1.56mmol),20℃下反应5h后加饱和NaHCO3调pH至7,浓缩,二氯甲烷萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(PE:AcOEt=15:1~10:1),得中间体G1M(280mg,78%,无色液体)。
化合物LSX448的合成。中间体G1M溶解于干燥的二氯甲烷,加入四氮唑(43mg,0.63mmol)和G2(0.097ml,0.63mmol),反应4h,加入过氧叔丁醇(70%in water)(0.094ml,0.63mmol),反应1h,加饱和亚硫酸钠溶液中和,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(PE:AcOEt=10:1~2:1)得中间体G1N,将其重新以干燥的二氯甲烷溶解,加入1,8-二氮杂二环十一碳-7-烯(0.094ml,0.63mmol),反应30mins,加入1mol/L HCl调pH至7,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(DCM:MeOH=15:1~10:1),旋干溶剂得目标化合物LSX448(35mg,10%,白色固体)。1H NMR(d6-DMSO,400MHz):δ7.46(d,J=7.2Hz,1H),7.31-7.20(m,6H),7.08(d,J=7.2Hz,1H),3.87(m,2H),3.83(s,3H),1.45(m,2H),1.24-1.14(m,10H),0.78(t,J=7.6Hz,3H)。
用同样的方法合成了以下化合物
实施例2
化合物LSX442的制备
原料G1(200mg,0.78mmol)溶于干燥的吡啶(5mL),氩气保护下滴加重蒸的POCl3(0.078mL,0.86mmol),80℃下反应过夜,第二天冷却至室温后向体系中滴加G3(290mg,2.34mmol),滴毕体系升温至80℃反应6h后回到室温后加水淬灭,加入1mol/L盐酸调pH至7,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(DCM:MeOH=15:1~10:1),旋干溶剂得目标化合物LSX442(40mg,12%,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.46(d,J=7.2Hz,1H),7.29-7.04(m,9H),6.78(d,J=8.4Hz,2H),3.83(s,3H),3.67(s,3H)。
用同样的方法合成了以下化合物
实施例3
化合物LSX432的制备
原料G1(200mg,0.78mmol)溶于干燥的吡啶(5mL),氩气保护下滴加G5(0.480mL,2.34mmol),80℃下反应过夜,回到室温后加水淬灭,加入1mol/L盐酸调pH至7,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(DCM:MeOH=15:1~10:1),旋干溶剂得目标化合物LSX432(120mg,35%,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.43(d,J=7.2Hz,1H),7.39–7.10(m,6H),7.05(d,J=7.2Hz,1H),3.83(s,3H),1.49–1.35(m,4H),1.30–1.03(m,10H),0.89–0.79(m,3H).
实施例4
化合物LSX419的制备
中间体G1M(368mg,0.78mmol)溶解于干燥的二氯甲烷,加入过氧叔丁醇(70%,水中)(0.094ml,0.63mmol),反应1h,加饱和亚硫酸钠溶液中和,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析,(PE:AcOEt=10:1~2:1),得中间体G1N以干燥二氯甲烷溶解,加入1,8-二氮杂二环十一碳-7-烯(0.094ml,0.63mmol),反应30分钟,加入1mol/L HCl调pH至7,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(DCM:MeOH=15:1~10:1),旋干溶剂得目标化合物LSX419(120mg,18%,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.49(d,J=7.2Hz,1H),7.38–7.24(m,5H),7.20(dd,J=7.2,1.2Hz,1H),7.13(dd,J=7.2,1.2Hz,1H),3.85(s,3H),3.44(dp,J=20.0,6.8Hz,2H),1.15(d,J=6.8Hz,12H)。
实施例5
化合物LSX784的制备
中间体G1M(920mg,0.78mmol)溶解于干燥的二氯甲烷,加入四氮唑(107mg,1.575mmol)和G6(0.242ml,1.575mmol),反应4h,加入过氧叔丁醇(70%,水中)(0.235ml,1.575mmol),反应1h,加饱和亚硫酸钠溶液中和,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(PE:AcOEt=10:1~2:1),得中间体以干燥二氯甲烷溶解,加入1,8-二氮杂二环十一碳-7-烯(0.235ml,1.575mmol),反应30分钟,加入1mol/L HCl调pH至7,乙酸乙酯萃取,水相反萃三次后饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,硅胶柱层析(DCM:MeOH=15:1~10:1),旋干溶剂得中间体以氯化氢乙酸乙酯溶液溶解,常温下反应2h后低温减压除去溶剂,真空干燥后加入胆酸(122mg,0.298mmol),EDCI(86mg,0.448mmol),DMAP(109mg,0.892mmol),以N,N-二甲基甲酰胺和三乙胺为溶剂,常温反应2d后减压除去溶剂,浓缩后硅胶柱层析(DCM:MeOH:AcOH=10:1:0.1~5:1:0.1)得到LSX784(16mg,1.05%,白色固体)。1H NMR(400MHz,DMSO-d6)δ7.46(d,J=7.6Hz,1H),7.38–7.17(m,6H),7.13–7.06(m,1H),4.31(d,J=4.4Hz,1H),4.16–4.06(m,1H),4.00(d,J=3.2Hz,1H),3.94–3.80(m,5H),3.80–3.74(m,1H),3.67–3.55(m,1H),3.09(q,J=6.8Hz,2H),2.28–2.06(m,2H),2.07–1.91(m,1H),1.86–1.70(m,4H),1.72–1.57(m,4H),1.49–1.09(m,15H),1.04–0.77(m,12H),0.59(s,3H).
实施例6
(1)实验目的
进行本发明化合物的GPR84拮抗活性测试。
(2)材料来源
人源GPR84细胞系,通过在HEK293细胞系中转染编码GPR84和Gα16蛋白的质粒得到。荧光染料Fluo-4 AM购自Invitrogen公司。
(3)测试原理
细胞内Ca2+离子是一种非常重要的G蛋白偶联受体信号通路第二信使,当与Gα16蛋白偶联的GPR84和激动剂结合后,细胞内的Ca2+离子浓度能够显著增加。Fluo-4是一种Ca2+离子特异性荧光探针,能够和Ca2+离子定量结合并发出荧光。因此采用荧光检测法,在96孔或384孔平底微孔板中检测化合物的激动活性或拮抗活性。
GPR84拮抗剂对受体抑制效应的检测:GPR84细胞经荧光染料Fluo-4孵育后,加入不同浓度的拮抗化合物孵育一段时间,使其占据激动剂与GPR84的结合位点(拮抗结合位点),再加入一定浓度的激动剂(6-n-octylaminouracil,6-OAU),与拮抗化合物竞争结合位点,同时用波长为485nm的光源激发并于525nm波段检测细胞内钙离子浓度变化引起的染料荧光强度的改变,用GraphPad PRISM软件进行计算得到化合物的半数抑制浓度(IC50)。
(4)实验过程
配制HBSS:0.4g/L KCl(5.4mM),0.12g/L Na2HPO4·12H2O(0.3mM),0.06g/L KH2PO4(0.4mM),0.35g/L NaHCO3(4.2mM),0.14g/L CaCl2(1.3mM),0.10g/L MgCl2·6H2O(0.5mM),0.05g/L MgSO4(0.6mM),8.0g/L NaCl(137mM),称取上述各成分并用超纯水溶解,用盐酸或NaOH溶液调节pH至7.4,过滤,4℃保存一个月。
配制钙流缓冲液:首先配制560mM D-葡萄糖(100X)水溶储存液,250mM 1,2-二苯基-4-(2-苯亚硫酰)乙基-3,5-吡唑烷二酮(1000X)储存液。然后在100mL HBSS中加BSA(0.5g),560mM的D-葡萄糖储存液(1mL)和250mM 1,2-二苯基-4-(2-苯亚硫酰)乙基-3,5-吡唑烷二酮储存液(100μL),使终浓度分别为0.5%BSA,5.6mM D-葡萄糖,250μM 1,2-二苯基-4-(2-苯亚硫酰)乙基-3,5-吡唑烷二酮,混匀,现配现用。
配制染料:将2mM Fluo-4 AM(1000X,购自Invitrogen公司)的DMSO溶液(1μL)与的3%Cremophor EL(100X,购自SigmaAldrich公司)的PBS溶液(10μL)混合,之后加入1mL钙流缓冲液混匀。
将细胞按4×104个/孔的密度接种于96孔板中,培养24h后,去除培养液,每孔加入40μL Fluo-4 AM荧光染液于37℃培养箱中孵育40mins。吸弃染料后,加入50μL待测化合物,室温孵育10分钟后,用Flex Station III微孔板检测仪加入25μL 6-OAU(稀释后的有效浓度在该激动剂的EC80左右)进行刺激,并实时读取细胞内钙离子流的变化引起的Fluo-4 AM染料荧光强度的变化值(激发波长485nm,检测波长525nm)。
(5)实验结果
表1.化合物的IC50与LogP
a IC50:*1–10μM;**0.1–1μM;***<0.1μM
b CLogP值由美国CambridgeSoft公司ChemBioDraw软件(版本号Ultra 12.0)计算得到。计算使用的结构均为化合物的游离酸形式。
c ALogP值由美国公司Maestro软件(版本号11.2)计算得到。所有化合物均以pH=7时的电离状态进行计算,其中化合物LSX431因为其磷酰胺氮原子的质子化使得ALogP与CLogP的数据相差较大。
(6)结果分析
表1结果表明,本发明的化合物IC50值均小于10μM,部分化合物的IC50值介于0.1–1μM之间,部分化合物的IC50值甚至小于100nM,表明本发明的化合物能够用作GPR84拮抗剂。此外,与现有化合物XYF573c相比(IC50=26.2nM,CLogP=6.419,ALogP=6.80),其中有24个化合物的CLogP介于5–6,有30个化合物的CLogP<5,42个化合物的ALogP介于5-6,18个化合物的ALogP<5,较XYF573c的CLogP和ALogP明显降低。
实施例7
(1)实验目的
进行本发明化合物XYF573c与LSX472a在ICR小鼠中的组织分布实验,比较它们在血浆、器官中的分布与口服暴露量(AUC0-8h)。
(2)材料来源
ICR小鼠购自上海市实验动物研究中心。
(3)测试原理
应用LC-MS检测化合物在ICR小鼠的血浆及其各器官中的浓度。
(4)实验过程
小鼠在实验期间禁食12h以上,自由饮水,给药2h后提供食物。
化合物XYF573c与LSX472a均为口服,剂量为5mg/kg,溶剂为DMSO/0.5%HPMC=5/95,v/v,N=3。
口服给药0.5h、2h和8h后,分别取约20μL小鼠心脏血、门静脉血浆或20mg肝、肺、和回肠的组织于洁净的离心管中,加入200μL MeOH/ACN(50/50,v/v),并在涡流混合器中旋转1分钟,混合物在15000rpm下离心5分钟并取20μL上清液与20μL ACN/water(1/1,v/v)混合并以LC-MS进行定量分析。
AUC0-8h的数值是依据化合物在0.5h、2h和8h的浓度用梯形法计算得到。
(5)实验结果
cLogP的降低对改善化合物口服吸收至关重要。本发明的化合物LSX472a的cLogP为5.51,较XYF573c下降了0.9,这种改变也表现为LSX472a的口服暴露量(Plasma AUC0-8h)较XYF573c提高了13倍(图1和表1)。不仅如此,LSX472a在肠道(如回肠Ileum)中的暴露量还较XYF573c明显增加。因此,本发明对GPR84拮抗剂的结构拓展,改善了此类化合物的类药性,增加了其口服吸收,还有助于改善化合物的靶组织分布。
表1化合物XYF573c与LSX472a的口服暴露量
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)
1.一种通式(I)所示的化合物,或其对映异构体、非对映异构体、外消旋体、或其药学上可接受的盐,
式中,Y为O或S;
Z为H,或以下金属的离子:Li、Na、K、Ca、Mg、Cu、Fe、Zn、Al、Mn,或以下碱的共轭酸:NH3、精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇、咪唑;
L1为无、O、S、-CH=CH-、-CO-、-C(=CH2)-、取代或未取代的C1~C6亚烷基、-NH-、-N(C1~C4烷基)-、C3~C6环烷基或C3~C6杂环烷基,所述取代是指具有选自下组的一个或多个取代基:C1~C6烷基、C1~C6烷氧基、卤素、羟基;
L2为无、CH;
环A、B各自独立地为C6-C10芳环、C3-C10环烷烃环、C3-C10杂环烷烃环、C3-C10杂芳环;
n1、n2各自独立地为0、1、2、3或4;R1、R2各自独立地为-OH、-SH、-NH2、F、Cl、Br、I、-CrH2r-L7-CsH2s+1、-CrH2r-N(CtH2t+1)-CsH2s+1、取代或未取代的C1~C6烷基,上述取代是指具有选自下组的一个或多个取代基:卤素、羟基、氨基、-COOC1~C6烷基、-COOH;L7各自独立地为O、S、NH,各r独立地为0、1、2、3、4、5或6,各s独立为0、1、2、3、4、5或6,各t独立为1、2、3、4、5、或6;
L3、L4各自独立地为O、无、-O(C1~C10亚烷基)-、-O(C1~C10亚烷基)NH-、-O(C1~C10亚烷基)O-、-CONH-、-OCO-、-NH-、-NHCOO-、-N(C1~C6烷基)-、或C1~C10亚烷基;
R3为H、OH、NH2、SH、-COOH、取代或未取代的C1~C10烷基、取代或未取代的C2~C10烯基、取代或未取代的C2~C10炔基、取代或未取代的3-12元环烷烃环、取代或未取代的C6-C14芳环、取代或未取代的氨基、取代或未取代的4-10元杂环烷烃环、取代或未取代的4-10元杂芳环、胆酸、石胆酸、去氧胆酸、异石胆酸、异去氧胆酸、鹅去氧胆酸、熊去氧胆酸、α-鼠胆酸、β-鼠胆酸、γ-鼠胆酸、ω-鼠胆酸;上述取代是指具有选自下组的1、2、3、4、5或6个取代基:氨基、C1~C10烷基、卤素、C6-C10芳环、C1~C6烷氧基、3-12元环烷烃环、-O-CpH2p-O-CqH2q+1、硝基、氧代(=O)、羟基、羧基、-C(O)OC1~C6烷基、-O-C6-C10芳环;其中,各p独立地为1、2、3、4、5或6,各q独立为1、2、3、4、5或6;
2.如权利要求1所述的化合物,其特征在于,L1独立地为无、CH2、O、S、-CO-、-NH-;
L2独立地为无、CH。
3.如权利要求1所述的化合物,其特征在于,R3为取代或未取代的C1~C10烷基、取代或未取代的C2~C10烯基、取代或未取代的C2~C10炔基、取代或未取代的3-12元环烷烃环、取代或未取代的C6-C14芳环、取代或未取代的氨基、取代或未取代的4-10元杂环烷烃环、取代或未取代的4-10元杂芳环、胆酸、石胆酸、去氧胆酸、异石胆酸、异去氧胆酸、鹅去氧胆酸、熊去氧胆酸、α-鼠胆酸、β-鼠胆酸、γ-鼠胆酸、ω-鼠胆酸;上述取代是指具有选自下组的1、2、3、4或5个取代基:氨基、C1~C10烷基、卤素、C6-C10芳环、C1~C6烷氧基、3-12元环烷烃环、-O-CpH2p-O-CqH2q+1、硝基、氧代(=O)、羟基、羧基、-COOC1~C6烷基、-O-苯环,其中,各p独立地为1、2或3,各q独立为1、2或3。
8.一种药物组合物,其特征在于,包含:
如权利要求1所述的通式(I)所示的化合物,或其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐;和
药学上可接受的载体。
9.如权利要求1所述的通式(I)所示的化合物或其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或权利要求8所述的药物组合物用途,其特征在于,所述用途为:
(i)用于制备GPR84拮抗剂;
(ii)用作GPR84拮抗剂;
(iii)用于制备治疗GPR84受体高表达或兴奋性过高所导致的相关疾病的药物。
10.如权利要求9所述的用途,其特征在于,所述疾病为多发性硬化症、炎症性肠病、纤维化、神经退行性疾病或关节炎。
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