CN112839929B - Tlr8激动剂 - Google Patents
Tlr8激动剂 Download PDFInfo
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- CN112839929B CN112839929B CN201980067235.3A CN201980067235A CN112839929B CN 112839929 B CN112839929 B CN 112839929B CN 201980067235 A CN201980067235 A CN 201980067235A CN 112839929 B CN112839929 B CN 112839929B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明公开了一类结构新颖的TLR8(Toll样受体8)激动剂,具体公开了式(I)所示化合物、其药学上可接受的盐或其异构体。
Description
本申请主张如下优先权:
CN201811221301.1,申请日2018年10月19日;
CN201910161144.8,申请日2019年3月4日。
技术领域
本发明涉及结构新颖的TLR8(Toll样受体8)激动剂,具体涉及式(I)所示化合物、异构体或其药学上可接受的盐,以及式(I)所示化合物或其药学上可接受的盐在治疗病毒感染相关疾病中的应用。
背景技术
Toll样受体(Toll-like receptors,TLR)是参与非特异性免疫(天然免疫)的一类重要蛋白质分子,也是连接非特异性免疫和特异性免疫的桥梁。TLR是单个的跨膜非催化性蛋白质,主要表达于一系列免疫细胞如树突细胞、巨噬细胞、单核细胞、T细胞、B细胞、NK细胞等。Toll样受体可以识别来源于微生物的具有保守结构的分子,当微生物突破机体的物理屏障,如皮肤、粘膜等时,TLR可以识别它们并激活机体产生免疫细胞应答。如TLR1,-2,-4,-5和-6主要识别胞外的刺激,如细菌的脂多糖,脂肽、鞭毛蛋白等,而TLR3,-7,-8,和-9在细胞内涵体中起作用,吞噬和包膜溶解后结合它们的配体,可识别微生物的核酸等。
在TLR不同亚型中,TLR8具有独特的功能:TLR8主要表达于单核细胞,巨噬细胞和髓样树突细胞中。TLR8的信号通路可以被细菌单链RNA,小分子激动剂和microRNAs活化。激活TLR8后导致产生Th1极性细胞因子,如IL-12,IL-18,TNF-a和IFN-γ和各种共刺激因子如CD80,CD86。这些细胞因子能激活和放大先天免疫和适应性免疫应答,并在涉及抗病毒、抗感染、自身免疫、肿瘤等疾病方面提供有益的治疗方案。例如,关于乙型肝炎,活化肝内抗原呈递细胞和其它免疫细胞上的TLR8可以激活IL-12等细胞因子,从而能激活被病毒耗尽的特异性T细胞和NK细胞,从而重建肝内的抗病毒免疫。
VentiRX制药公司的选择性TLR8激动剂VTX-2337首次在临床上用于不同肿瘤的评价,VTX-2337给药方式为皮下注射。吉利德科学公司报道了可以口服的TLR8激动剂GS-9688,目前处于临床2期,用于慢性乙肝感染的治疗,但其结构没有公布。
发明内容
本发明提供式(I)所示化合物、异构体及其药学上可接受的盐,
其中,
带“*”碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在;
带“#”碳原子为手性碳原子,以(S)单一对映体形式或富含(S)对映体形式存在;
X选自CH和N;
Y选自CR2和N;
n选自0、1、2和3;
L选自-O-和-CR3R4-;
R1选自C1-6烷基,所述C1-6烷基任选被1、2或3个Ra取代;
R2选自H、CN、NH2、卤素、C1-6烷基、C1-6烷基-O-、NHRb、N(Rc)2、C3-6环烷基、-C(=O)Rd、-C(=O)-O-Re、-O-C(=O)-Re、-S(=O)2Rf、-S(=O)Rg;
R3和R4分别独立地选自H、卤素和C1-3烷基,所述C1-3烷基任选被1、2或3个Rh取代;
或者,R3和R4连接形成一个3-6元饱和环,所述3-6元饱和环任选被1、2或3个Ri取代;
Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh和Ri分别独立地选自F、Cl、Br、I、OH、CN、NH2、C1-6烷基、C1-6杂烷基、C3-6环烷基、3-6元杂环烷基、苯基和5-6元杂芳基,所述C1-6烷基、C1-6杂烷基、C3-6环烷基、3-6元杂环烷基、苯基和5-6元杂芳基任选被1、2或3个R取代;
所述C1-6杂烷基、3-6元杂环烷基和5~6元杂芳基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
在本发明的一些方案中,上述R2选自H和F。
在本发明的一些方案中,上述R3和R4分别独立地选自H、F、Cl、Br和CH3,所述CH3任选被1、2或3个Rh取代。
在本发明的一些方案中,上述R3和R4分别独立地选自H和F。
在本发明的一些方案中,上述Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh和Ri分别独立地选自F、Cl、Br、I、OH、CN、NH2、CH3、 所述CH3、/> 任选被1、2或3个R取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R2选自H、CN、F、Cl、Br、I、CH3、 -C(=O)CH3、-C(=O)-O-CH3、-O-C(=O)-CH3、-S(=O)2CH3、-S(=O)CH3,其他变量如本发明所定义。
在本发明的一些方案中,上述R2选自H和F,其他变量如本发明所定义。
在本发明的一些方案中,上述R3和R4分别独立地选自H、F、Cl、Br和CH3,所述CH3任选被1、2或3个Rh取代,其他变量如本发明所定义。
在本发明的一些方案中,上述R3和R4分别独立地选自H和F,其他变量如本发明所定义。
在本发明的一些方案中,上述化合物、异构体及其药学上可接受的盐,其选自
其中,
“*”、“#”、X和Y如上述所定义。
本发明还提供下式化合物、异构体及其药学上可接受的盐
本发明还提供下式化合物、异构体及其药学上可接受的盐,其选自
本发明还提供上述化合物、异构体及其药学上可接受的盐在制备治疗乙型肝炎病毒药物中的应用。
本发明还有一些技术方案是由上述各变量任意组合而来。
技术效果
本发明的化合物具有良好的的TLR8激动活性和特异选择性,对TLR8通路特异性细胞因子(IL-12p40、IFN-γ)展示出理想的诱导活性。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-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发明的范围之内。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,均包括在本发明的范围之内。
除非另有说明,术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。
除非另有说明,“(+)”表示右旋,“(-)”表示左旋,“(±)”表示外消旋。
除非另有说明,用楔形实线键和楔形虚线键/>表示一个立体中心的绝对构型,用直形实线键/>和直形虚线键/>表示立体中心的相对构型,用波浪线/>表示楔形实线键/>或楔形虚线键/>或用波浪线/>表示直形实线键/>或直形虚线键/>
除非另有说明,术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100%,并且,该异构体或对映体的含量大于等于60%,或者大于等于70%,或者大于等于80%,或者大于等于90%,或者大于等于95%,或者大于等于96%,或者大于等于97%,或者大于等于98%,或者大于等于99%,或者大于等于99.5%,或者大于等于99.6%,或者大于等于99.7%,或者大于等于99.8%,或者大于等于99.9%。
除非另有说明,术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如,其中一种异构体或对映体的含量为90%,另一种异构体或对映体的含量为10%,则异构体或对映体过量(ee值)为80%。
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。如果想得到本发明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)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H),碘-125(125I)或C-14(14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时,这种取代基可以通过其任何原子相键合,例如,吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向,其连接方向是任意的,例如,中连接基团L为-M-W-,此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成/>也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成/>所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定,环上原子的数目通常被定义为环的元数,例如,“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定,“3-6元饱和环”表示由3至6个环原子组成的环烷基、杂环烷基。所述的环包括单环,也包括螺环、并环和桥环等双环或多环体系。除非另有规定,该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述3-6元环包括3-6元、3-5元、4-6元、4-5元、5-6元环等。术语“环”还包括含有至少一个环的环系,其中的每一个“环”均独立地符合上述定义。
除非另有规定,术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基,异丁基,s-丁基和t-丁基)、戊基(包括n-戊基,异戊基和新戊基)、己基等。
除非另有规定,术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
术语“杂烷基”本身或者与另一术语联合,表示由一定数目碳原子和至少一个杂原子或杂原子团组成的,稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中,杂原子选自B、O、N和S,其中氮和硫原子任选地被氧化,氮杂原子任选地被季铵化。在另一些实施方案中,杂原子团选自-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2-、-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2N(H)-和-S(=O)N(H)-。在一些实施方案中,所述杂烷基为C1-6杂烷基;在另一些实施方案中,所述杂烷基为C1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置,包括该烷基与分子其余部分的连接位置,但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达,是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2(CH3)2、-CH2-CH2-O-CH3、-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)(CH2CH3)、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2、-CH2-S-CH2-CH3、-CH2-CH2、-S(=O)-CH3、-CH2-CH2-S(=O)2-CH3、和。至多两个杂原子可以是连续的,例如-CH2-NH-OCH3。
除非另有规定,“C3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团,其为单环和双环体系,所述C3-6环烷基包括C3-5、C4-5和C5-6环烷基等;其可以是一价、二价或者多价。C3-6环烷基的实例包括,但不限于,环丙基、环丁基、环戊基、环己基等。
除非另有规定,术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团,其1、2、3或4个环原子为独立选自O、S和N的杂原子,其余为碳原子,其中氮原子任选地被季铵化,氮和硫杂原子可任选被氧化(即NO和S(O)p,p是1或2)。其包括单环和双环体系,其中双环体系包括螺环、并环和桥环。此外,就该“3-6元杂环烷基”而言,杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
除非另有规定,本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用,术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团,其1、2、3或4个环原子为独立选自O、S和N的杂原子,其余为碳原子。其中氮原子任选地被季铵化,氮和硫杂原子可任选被氧化(即NO和S(O)p,p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定,Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况,例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12,也包括n至n+m中的任何一个范围,例如C1-12包括C1-3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等;同理,n元至n+m元表示环上原子数为n至n+m个,例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环,也包括n至n+m中的任何一个范围,例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。
缩略词清单
Pd/C | Pd/C催化剂,钯含量10w% |
DCM | 二氯甲烷 |
NH3·H2O | 氨水,含量25%~28% |
THF | 四氢呋喃 |
Boc | 叔丁氧羰基,是一种胺保护基团 |
Cbz | 苄氧羰基,是一种胺保护基团 |
DMF | Ⅳ,N-二甲基甲酰胺 |
TFA | 三氟乙酸 |
DCM | 二氯甲烷 |
PE | 石油醚 |
DMSO | 二甲亚砜 |
EtOH | 乙醇 |
MeOH | 甲醇 |
HOAc | 乙酸 |
HATU | 2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐 |
EDCI | 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐 |
HOBt | 1-羟基苯并三唑 |
Boc2O | 二叔丁基二碳酸酯 |
CbzCl | 氯甲酸苄酯 |
DIPEA | 二异丙基乙基胺 |
SiO2 | 100-200目硅胶粉,用于柱层析 |
IPA | 异丙醇 |
psi | 磅力/平方英寸,压力单位 |
SFC | 超临界流体色谱 |
p-HPLC | 制备高效液相色谱,用于化合物的纯化 |
p-TLC | 制备薄层色谱,用于化合物的纯化 |
本发明所使用的溶剂可经市售获得且不需要进一步纯化。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上,化学位移以四甲基硅烷高场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD:SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
用配有Shimadzu SIL-20A自动进样器和日本岛津DAD:SPD-M20A探测器的岛津LC20AB系统进行高效液相色谱分析,采用Xtimate C18(3m填料,规格为2.1×300mm)色谱柱。0-60AB_6分钟的方法:应用线性梯度,以100%A(A为0.0675%TFA的水溶液)开始洗脱,并以60%B(B为0.0625%TFA的MeCN溶液)结束洗脱,整个过程为4.2分钟,然后以60%B洗脱1分钟。将色谱柱再平衡0.8分钟达到100∶0,总运行时间为6分钟。10-80AB_6分钟的方法:应用线性梯度,以90%A(A为0.0675%TFA的水溶液)开始洗脱,并以80%B(B为0.0625%TFA的乙腈溶液)结束洗脱,整个过程为4.2分钟,然后以80%B洗脱1分钟。将色谱柱再平衡0.8分钟达到90∶10,总运行时间为6分钟。柱温为50℃,流速为0.8mL/min。二极管阵列检测器扫描波长为200-400nm。
在Sanpont-group的硅胶GF254上进行薄层色谱分析(TLC),常用紫外光灯照射检出斑点,在某些情况下也采用其他方法检视斑点,在这些情况下,用碘(10g硅胶中加入约1g碘并彻底混合而成)、香草醛(溶解大约1g香草醛于100mL 10%H2SO4中制得)、茚三酮(从Aldrich购得)或特殊显色剂(彻底混合25g(NH4)6Mo7O24·4H2O、5g(NH4)2Ce(IV)(NO3)6、450mL H2O和50mL浓H2SO4而制得)展开薄层板,检视化合物。采用Still,W.C.;Kahn,M.;andMitra,M.Journal of Organic Chemistry,1978,43,2923-2925.中所公开技术的类似方法,在Silicycle的40-63μm(230-400目)硅胶上进行快速柱色谱。快速柱色谱或薄层色谱的常用溶剂是二氯甲烷/甲醇、乙酸乙酯/甲醇和己烷/乙酸乙酯的混合物。
在使用Gilson UV/VIS-156检测器的Gilson-281 Prep LC 322系统上进行制备色谱分析,所采用的色谱柱为Agella Venusil ASB Prep C18(5m填料,规格为150×21.2mm)、Phenomenex Gemini C18(5m填料,规格为150×30mm)、Boston Symmetrix C18(5m填料,规格为150×30mm)或Phenomenex Synergi C18(4m填料,规格为150×30mm)。在流速约为25mL/min时,用低梯度的乙腈/水(水中含有0.05%HCl、0.25%HCOOH或0.5%NH3·H2O)洗脱化合物,总运行时间为8-15分钟。
具体实施方式
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
步骤A:将NH3·H2O(111.16克,539.14毫摩尔,122.15毫升),氰化钠(9.58克,195.47毫摩尔)溶于水28.00毫升)中,然后冰浴冷却到15摄氏度下滴加乙酸(12.23克,203.67毫摩尔,11.65毫升)。加完后,然后在15摄氏度下滴加1-10(20.00克,199.68毫摩尔,24.69毫升)。反应体系在35摄氏度下搅拌12小时,反应液用150毫升DCM萃取三次。合并的有机相用100毫升食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得到产物1-1。1H NMR(400MHz,CDCl3)δ1.69-1.64(m,2H),1.56-1.45(m,5H),1.44-1.36(m,2H),0.96(t,J=7.2Hz,3H)。
步骤B:将1-1(22.00克,174.33毫摩尔),碳酸钾(72.28克,522.98毫摩尔)溶于四氢呋喃(200.00毫升)和H2O(40.00毫升)中,然后在零摄氏度下将CbzCl(38.66克,226.62毫摩尔,32.22毫升)滴加进去。反应体系在25摄氏度下搅拌8小时。反应体系加乙酸乙酯(100毫升)和水(50毫升)并分液。将有机相分开,用100毫升食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得到粗品。粗品用硅胶柱纯化(SiO2,PE/EtOAc=1/0至20/1),得到产物1-3。1H NMR(400MHz,CDCl3)δ7.42-7.33(m,5H),5.23-5.11(m,2H),4.93(br s,1H),2.00-1.80(m,2H),1.70(s,3H),1.54-1.35(m,4H),1.00-0.92(m,3H)。LCMS(ESI)m/z·261.3[M+H]+。
步骤C:将1-3(37.00克,120.81毫摩尔)和无水氯化钴(31.37克,241.62毫摩尔)溶于甲醇(400.00毫升),在氮气保护下,将硼氢化钠(22.85克,604.05毫摩尔)于2个小时内在5-15℃下分批加入到反应液。反应体系在15摄氏度下搅拌1小时,然后加入氨水(20%,500毫升)和乙酸乙酯(1000毫升)并分液。水相再用500毫升乙酸乙酯萃取2次。合并的有机相用300毫升食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得到1-4。1H NMR(400MHz,CDCl3):δ7.31-7.20(m,5H),5.04-4.90(m,3H),2.87-2.57(m,2H),1.67-1.41(m,2H),1.31-1.08(m,7H),0.82(t,J=7.0Hz,3H)。LCMS(ESI)m/z·265.2[M+H]+。
步骤D:将Boc-L-脯氨酸(894.99毫克,4.16毫摩尔),HATU(1.73克,4.54毫摩尔)溶于乙腈(10毫升),加入DIPEA(977.77毫克,7.56毫摩尔)。然后向混合液中加入1-4(1克,3.78毫摩尔)。反应液在15摄氏度搅拌0.5小时。向反应体系加水(30毫升)和二氯甲烷(50毫升)并分液。有机相用50毫升食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得到粗品。粗品用硅胶柱纯化(SiO2,PE/EtOAc=20/1到1/1),得到1-5。
步骤E:将1-5(1.7克,3.68毫摩尔)溶于甲醇(50毫升),在氮气保护下加入Pd/C(303.57毫克)。反应液用氢气置换3次。反应体系在氢气(15psi)氛围下于25℃搅拌12小时。反应液过滤并减压除去溶剂,得到1-6。
步骤F:向化合物1-6(900毫克,2.75毫摩尔),1-7(3.5克,5.25毫摩尔)的四氢呋喃(10毫升)混合液中加入DIPEA(1.07毫克,8.25毫摩尔)。反应液加热至70摄氏度并搅拌12小时。反应液减压浓缩得粗品1-8。LCMS(ESI)m/z:491.3[M+H]+。
步骤G:将1-8(357毫克,727.05微摩尔)和2,4二甲氧基苄胺(729.40毫克,4.36毫摩尔)溶于无水二氧六环(8mL),然后加入DIPEA(281.90毫克,2.18毫摩尔)。反应液在氮气保护性升温至120摄氏度搅拌12小时。反应液减压除去溶剂后加乙酸乙酯(30毫升)溶解,然后用0.5N的稀盐酸调节pH(6~7)。用乙酸乙酯萃取三次,每次20毫升,合并有机相后用饱和食盐水(50毫升)洗涤,再用无水硫酸钠干燥,过滤浓缩得产物1-9。LCMS(ESI)m/z:622.6[M+H]+。
步骤H:将1-9(580毫克,932.82微摩尔)通过SFC拆分(分离柱:DAICEL CHIRALPAKAD(规格:250mm*30mm,粒径10μm);流动相:[0.1%NH3·H2O,IPA]40%-40%,3.5min)得到1-10(保留时间=2.276min,ee值:100%)。LCMS(ESI)m/z:622.4[M+H]+。
步骤I:将1-10(220毫克,353.83微摩尔)溶于TFA(5毫升)中,室温下搅拌反应30分钟。然后减压浓缩得粗品,再经过p-HPLC纯化得化合物l。1H NMR(400MHz,CD3OD)δ8.64(dd,J=1.2,4.4Hz,1H),8.59(br t,J=6.1Hz,1H),7.89(dd,J=1.2,8.4Hz,1H),7.80(dd,J=4.4,8.4Hz,1H),4.36-4.25(m,1H),4.06-3.93(m,1H),3.92-3.8l(m,1H),3.42-3.32(m,2H),2.52-2.36(m,1H),2.33-2.19(m,1H),2.12-1.90(m,3H),1.87-1.75(m,1H),1.55(s,3H),1.47-1.27(m,4H),0.93(t,J=7.0Hz,3H)。LCMS(ESI)m/z:372.3[M+H]+。
实施例2
步骤A:将1-5(2克,4.33毫摩尔)通过SFC拆分(分离柱:DAICEL CHIRALPAKAD-H(规格:250mm*30mm,粒径5μm);流动相:[0.1%NH3·H2O,EtOH]25%-25%,1.8min)得到单一构型2-l(保留时间=1.283min,ee值:100%)。
步骤B:将2-1(600毫克,1.30毫摩尔)溶于甲醇(20毫升),在氮气保护下加入Pd/C(60毫克)。反应液用氢气置换数次。反应体系在氢气(15psi)氛围下于25℃搅拌12小时。反应液过滤并减压除去溶剂,得到2-2。1H NMR(400MHz,DMSO-d6)δ=7.73(br d,J=4.8Hz,1H),4.17(dd,J=2.9,8.3Hz,1H),3.42(br d,J=4.0Hz,1H),3.35-3.31(m,1H),3.14-3.10(m,1H),2.98-2.88(m,1H),2.20-2.04(m,1H),1.92-1.73(m,3H),1.48-1.36(m,9H),1.28(br s,6H),0.98-0.86(m,6H)。
步骤C:向化合物2-2(83毫克,253.47微摩尔)和2-3(50.70毫克,253.47微摩尔)的THF(4毫升)混合液中加入DIPEA(65.52毫克,506.93微摩尔)。反应液加热至70摄氏度并搅拌12小时。反应液减压浓缩得粗品2-4。LCMS(ESI)m/z:492.1[M+H]+。
步骤D:将2-4(124毫克,252.53微摩尔)和2,4-二甲氧基苄胺(168.90毫克,1.01毫摩尔)溶于无水二氧六环(5mL),然后加入DIPEA(65.27毫克,505.07微摩尔)。反应液在氮气保护下升温至120摄氏度搅拌14小时。反应液倒入10毫升水中,用乙酸乙酯(10毫升)萃取两次,合并有机相后用饱和食盐水(10毫升)洗涤,再用无水硫酸钠干燥,过滤浓缩。残余物用p-TLC纯化得化合物2-5。
LCMS(ESI)m/z:622.7[M+H]+。
步骤E:将2-5(60毫克,96.50微摩尔)溶于TFA(2毫升)中,室温下搅拌反应14小时。然后减压浓缩得粗品,再经过p-HPLC纯化得化合物2。
1H NMR(400MHz,CD3OD)δ8.95(br s,1H),8.85(brt,J=6.1Hz,1H),8.67(br d,J=4.8Hz,1H),8.44(d,J=5.5Hz,1H),4.38(br d,J=7.1Hz,1H),4.14-4.02(m,1H),3.67-3.56(m,1H),3.46-3.32(m,2H),2.57-2.42(m,1H),2.37-2.24(m,1H),2.15-1.89(m,4H),1.58(s,3H),1.44-1.27(m,4H),0.96-0.86(m,3H)。LCMS(ESI)m/z:372.1[M+H]+。
实施例3
实施例3可参照实施例2的制备方法制得。在实施例2的步骤C中,用2,4-二氯喹唑啉替代2-3。
1H NMR(400MHz,CD3OD)δ8.15-7.76(m,1H),7.56(brd,J=1.2Hz,1H),7.30(d,J=8.3Hz,1H),7.23-7.04(m,1H),3.93(d,J=13.9Hz,1H),3.82-3.64(m,1H),3.42(d,J=13.9Hz,1H),3.01-2.86(m,2H),2.26-1.66(m,6H),1.52(s,3H),1.33(br s,4H),0.91(s,3H).LCMS(ESI)m/z:371.1[M+H]+。
实施例4
步骤A:在氮气保护下,向1-2(50克,396.20毫摩尔)的甲醇(300毫升)溶液中加入盐酸甲醇溶液(4摩尔/升,198.10毫升)和二氧化铂(1克,4.40毫摩尔)。反应液用氢气置换数次,然后在氢气氛围(50psi)下于25摄氏度搅拌32小时。反应液通过硅藻土过滤并用甲醇(200毫升)洗涤,滤液在45摄氏度下减压浓缩得到化合物4-1。
1H NMR(400MHz,D2O-d6)δ3.30-3.22(m,2H),1.70(m,2H),1.41(s,3H),1.31-1.23(m,4H),0.851(m,3H)步骤B:将4-1(6克,29.53毫摩尔)溶于水中(30毫升),然后加入碳酸氢钠(6.20克,73.84毫摩尔),温度保持在0到5摄氏度滴加(Boc)2O(5.37克,24.61毫摩尔)的甲醇溶液(20毫升),温度保持在0到5摄氏度搅拌2小时,然后在25摄氏度搅拌12小时。反应液加水(30毫升)和乙酸乙酯(50mL)分液,水相用乙酸乙酯/异丙醇(3:1)萃取2次,每次50毫升。合并有机相后用饱和食盐水(30毫升)洗涤,再用无水硫酸钠干燥,过滤浓缩得粗品。粗品用硅胶柱纯化(SiO2,PE/EtOAc=1/1到0/1)得到4-2。
1H NMR(400MHz,DMSO-d6)δ6.70(br t,J=5.7Hz,IH),2.87(d,J=6.1Hz,2H),1.39(s,9H),1.30-1.18(m,6H),0.91(s,3H),0.89-0.83(m,3H)
步骤C:向4-2(2.2克,9.55毫摩尔)和DIPEA(4.4克,34.05毫摩尔)的THF(40mL)溶液中加入1-7(13.89克,69.44毫摩尔),反应升温至70摄氏度搅拌12小时。反应液加水(50毫升)和乙酸乙酯(100毫升)分液。有机相分离,用饱和食盐水(30毫升)洗涤,再用无水硫酸钠干燥,过滤浓缩得粗品。粗品用硅胶柱纯化(SiO2,PE/EtOAc=10/1到0/1),得到4-3。
LCMS(ESI)m/z:394.1[M+H]+
步骤D:将4-3(1.23克,3.11毫摩尔),2,4-二甲氧基苄胺(2.53克,15.13毫摩尔),DIPEA(1.12克,9.34毫摩尔)溶于二氧六环(15毫升),氮气置换3次,然后反应液在氮气保护下于100摄氏度搅拌12小时。反应液减压浓缩除去溶剂,残余物加乙酸乙酯(20毫升)并用稀盐酸(1摩尔/升,20毫升*2)洗涤。有机相用饱和食盐水洗涤(20毫升)一次,无水硫酸钠干燥后过滤浓缩。将残余物(0.95克)通过SFC拆分(分离柱:DAICEL CHIRALCEL OD(规格:250mm*30mm,粒径10μm);流动相:[0.1%NH3·H2O,IPA]35%-35%,4.1min)得到单一构型4-5;保留时间=1.681min,ee值:99%)。
步骤E:将4-5(420毫克,353.83微摩尔)溶于TFA(2毫升)中,28摄氏度下搅拌反应30分钟。然后减压浓缩得粗品,再经过p-HPLC纯化得化合物4-6。
步骤F:将4-6溶于二氯甲烷(4毫升)中,然后冰浴冷却至10摄氏度下加入EDCI(40.06毫克,208.99微摩尔),HOBt(28.24毫克,208.99微摩尔)和DIPEA(102.99毫克,796.16微摩尔,138.68毫升)。混合物在10摄氏度下搅拌0.5小时后,冷却至-10摄氏度,然后加入(S)-N-Boc-2-羧酸吗啉(100毫克,199.04微摩尔)。反应体系在-10摄氏度下搅拌1小时。将反应液倒入20毫升水中,用15毫升二氯甲烷萃取两次。合并的有机相用20毫升水洗涤,无水硫酸钠干燥,减压除去溶剂得到粗品。粗品经p-TLC(EA∶MeOH=20/1)得到化合物4-7。
LCMS(ESI)m/z:488.5[M+H]+。
步骤G:将化合物4-7溶于三氟乙酸(1毫升)和二氯甲烷(1毫升)的混合溶剂中,反应体系在20-25摄氏度下搅拌0.5小时。减压除去溶剂得到粗品。粗品经p-HPLC纯化得到化合物4.
1HNMR(400MHz,CD3OD)δ8.39(dd,J=1.5,4.3Hz,1H),7.71-7.61(m,1H),7.56(dd,J=4.2,8.5Hz,1H),3.98-3.44(m,7H),3.00-2.81(m,2H),2.22-2.07(m,1H),1.83-1.66(m,1H),1.55-1.30(m,7H),0.93(t,J=7.1Hz,3H))。LCMS(ESI)m/z:388.1[M+H]+
实施例5,6,7可参照实施例4的制备方法制得。在实施例4的步骤F中,用其它Boc保护的氨基酸分别替代(S)-N-Boc-2-吗啉羧酸。
实施例5
1H NMR(400MHz,CD3OD)δ8.38(dd,J=1.5,4.3Hz,1H),7.70-7.61(m,1H),7.56(dd,J=4.2,8.5Hz,1H),4.02-3.88(m,2H),3.69-3.57(m,1H),3.29-3.04(m,1H),3.09(ddd,J=10.8,12.6,16.0Hz,1H),2.67-2.50(m,1H),2.36(dq,J=6.2,14.5Hz,1H),2.18-2.05(m,1H),1.86-1.65(m,1H),1.51-1.27(m,7H),1.20(t,J=7.1Hz,1H),0.98-0.84(m,3H)。LCMS(ESI)m/z:408.1[M+H]+
实施例6
1H NMR(400MHz,CD3OD)δ8.37(dd,J=1.5,4.3Hz,1H),7.76-7.62(m,1H),7.55(dd,J=4.2,8.5Hz,1H),3.86-3.61(m,2H),3.26(dd,J=2.9,10.2Hz,1H),3.06(br d,J=11.9Hz,1H),2.72-2.58(m,1H),2.20-2.07(m,1H),1.95-1.56(m,4H),1.55-1.29(m,10H),0.99-0.88(m,3H)。LCMS(ESI)m/z:386.1[M+H]+
实施例7
1H NMR(400MHz,CD3OD)δ8.38(dd,J=1.5,4.3Hz,1H),7.69-7.62(m,1H),7.56(dd,J=4.2,8.5Hz,1H),4.37(t,J=8.4Hz,1H),3.88(d,J=14.1Hz,1H),3.77-3.58(m,2H),2.65(m,J=4.3,8.9,11.2Hz,1H),2.38-2.10(m,2H),1.84-1.71(m,1H),1.53-1.28(m,8H),0.94(t,J=7.0Hz,3H)。LCMS(ESI)m/z:358.1[M+H]+
实验例1:人Toll样受体7(TLR7)和人Toll样受体8(TLR8)体外受体结合活性筛选实验
本实验所用的HEK-BlueTMhTLR7(货号:hkb-htlr7)和HEK-BlueTMhTLR8(货号:hkb-htlr8)细胞株购于InvivoGen公司。这两个细胞株由人胚肾293细胞系稳定共转染hTLR7或hTLR8和诱导表达分泌型碱性磷酸酶(SEAP)报告基因所构建的,其中分泌型胚胎碱性磷酸酶(SEAP)报告基因由IFN-β启动子调控。该启动子与NF-κB和AP-1结合位点融合,hTLR7或hTLR8激动剂会激活NF-κB和AP-1,并诱导分泌型碱性磷酸酶(SEAP)的表达和分泌。用QUANTI-BlueTM试剂检测SEAP表达量,以此来鉴定化合物对hTLR7和hTLR8受体的激动活性。
实验步骤:
1.化合物按3倍梯度加入到细胞板中,共10个浓度,每个浓度双复孔。阴性对照孔每孔加入1微升DMSO。
2.从CO2培养箱取出T150培养的细胞,弃去细胞培养上清,用杜氏磷酸盐缓冲液(DPBS)清洗细胞一次,加入约10mL培养液,然后轻拍细胞培养瓶使细胞脱壁,然后用移液器将细胞团轻轻吹打均匀。细胞计数,并将细胞悬液用培养液调整到500,000细胞/毫升。然后在含有化合物的96孔板中每孔加入100微升稀释后的细胞(50,000细胞/孔)。
3.将化合物和细胞在37℃、5%CO2培养箱共孵育24小时。
4.化合物活性检测:取20微升诱导后每个孔的细胞上清液,加入到含有180μLQUANTI-BlueTM试剂的细胞培养板中,37℃孵育1小时之后,用多功能酶标仪检测每孔在650纳米的光密度吸收值(OD650)。
5.细胞活性检测:按照ATPlite lStep说明书方法操作,荧光素酶信号(RLU)用多功能酶标仪检测。
6.数据分析:化合物活性:OD650值用GraphPad Prism软件分析,并拟合化合物剂量效应曲线,计算化合物的EC50值(半数最大效应浓度)。
实验结果:如表1所示。
表1
受试化合物 | 人TLR8 EC50(μM) | 人TLR7 EC50(μM) |
化合物1 | 0.002 | >15 |
化合物2 | 0.006 | >15 |
化合物3 | 0.032 | >15 |
化合物4 | 0.014 | >15 |
化合物5 | 0.106 | >15 |
化合物6 | 0.018 | >15 |
化合物7 | 0.015 | >15 |
结论:本发明实施例展示出理想的TLR8激动剂活性,且在TLR8和TLR7之间的具有TLR8的特异选择性。
实验例2:外周血单个核细胞实验方案
TLR8是固有免疫系统感受外源性的病原体的一类受体,能够识别外源的病毒单链RNA,引起一系列细胞因子,如TNF-α,IL-12,IFN-γ的释放以引起抗病毒免疫反应;TLR7是另外一类固有免疫系统感受外源性的病原体的一类受体,被激活后主要产生IFN-α等抗病毒细胞因子。本实验使用TLR8激动剂的潜在化合物刺激人外周血单个核细胞(hPBMC),通过检测上述TNF-α,IL-12p40,IFN-γ和IFN-α的水平来反映化合物对TLR8受体的活化作用和TLR8/TLR7的选择性。
实验步骤:
1.采集健康志愿者新鲜血液,EDTA-K2抗凝管(货号:BD-8516542)抗凝;
2.Ficoll密度梯度离心,分离中间云雾层的hPBMC细胞,含10%血清的RPMIl640(来源:Gibco,货号:224400-089)培养液洗2次,培养液重悬至10ml,Vi-cell细胞计数仪计数,调整细胞悬液浓度至2x106/mL;
3.用DMSO将化合物溶解至100mM,并分别用DMSO稀释至50mM,2mM,分别作为初始浓度,依次做X3稀释,即取前一浓度样本5μL+10μLDMSO;稀释8个梯度;再分别用培养基稀释500倍,配成化合物工作液;
4.U底96孔板中,每孔加入hPBMC悬液100μL,以及化合物工作液100μL,终浓度依次为2000nM,666.7nM,222.2nM,74.1nM,24.7nM,8.2nM,2.7nM,0.9nM,孵育24小时,收上清-20℃冻存,待检测TNF-α,IFN-gamma,IL-12p40细胞因子;另一组化合物样本终浓度依次为50μM,16.7μM,5.6μM,1.9μM,0.6μM,0.2μM,0.1μM,0.02μM,孵育24小时,收上清-20℃冻存,待检测IFN-alpha细胞因子;
5.流式细胞小球微阵列术(CBA)检测上清中IL-12p40,TNF-α,IFN-γ;酶联免疫法(ELISA)检测细胞上清中IFN-α。
6.数据分析:化合物活性:EC50值(半数最大效应浓度)用GraphPad Prism软件分析,并拟合化合物剂量效应曲线,计算化合物的EC50值。
实验结果:如表2所示。
表2
结论:本发明的实施例具有理想的TLR8通路特异性细胞因子IL-12p40,TNF-alpha和IFN-gamma诱导活性,对TLR7通路特异性细胞因子IFN-alpha的诱导活性相对较低,展示出理想的对TLR8通路激动特异选择性。
Claims (12)
1.式(I)所示化合物、异构体及其药学上可接受的盐,
其中,
带“*”碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在;
带“#”碳原子为手性碳原子,以(S)单一对映体形式或富含(S)对映体形式存在;
X选自CH和N;
Y选自CR2和N;
n选自0、1、2和3;
L选自-O-和-CR3R4-;
R1选自C1-6烷基,所述C1-6烷基任选被1、2或3个Ra取代;
R2选自H、CN、NH2、卤素、C1-6烷基、C1-6烷基-O-、NHRb、N(Rc)2、-C(=O)Rd、;
R3和R4分别独立地选自H、卤素和C1-3烷基,所述C1-3烷基任选被1、2或3个Rh取代;
5.根据权利要求4所述的化合物、异构体及其药学上可接受的盐,其中,R2选自H和F。
6.根据权利要求1-3任意一项所述的化合物、异构体及其药学上可接受的盐,其中,R3和R4分别独立地选自H、F、Cl、Br和CH3,所述CH3任选被1、2或3个Rh取代。
7.根据权利要求6所述的化合物、异构体及其药学上可接受的盐,其中,R3和R4分别独立地选自H和F。
12.根据权利要求1-11任意一项所述的化合物、异构体及其药学上可接受的盐在制备治疗乙型肝炎病毒药物中的应用。
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CN116472047A (zh) * | 2021-11-05 | 2023-07-21 | 中国医药研究开发中心有限公司 | 芳胺类衍生物及其制备方法和医药用途 |
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WO2018107200A1 (en) * | 2016-12-13 | 2018-06-21 | Beta Therapeutics Pty Ltd | Heparanase inhibitors and use thereof |
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2019
- 2019-10-18 WO PCT/CN2019/111897 patent/WO2020078455A1/zh unknown
- 2019-10-18 AU AU2019361697A patent/AU2019361697A1/en active Pending
- 2019-10-18 CN CN201980067235.3A patent/CN112839929B/zh active Active
- 2019-10-18 US US17/286,316 patent/US20210340141A1/en active Pending
- 2019-10-18 EP EP19873359.4A patent/EP3875451B1/en active Active
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WO2014076221A1 (en) * | 2012-11-16 | 2014-05-22 | Janssen R&D Ireland | Heterocyclic substituted 2-amino-quinazoline derivatives for the treatment of viral infections |
WO2016141092A1 (en) * | 2015-03-04 | 2016-09-09 | Gilead Sciences, Inc. | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds |
WO2018045144A1 (en) * | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
WO2018107200A1 (en) * | 2016-12-13 | 2018-06-21 | Beta Therapeutics Pty Ltd | Heparanase inhibitors and use thereof |
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CN112839929A (zh) | 2021-05-25 |
WO2020078455A1 (zh) | 2020-04-23 |
EP3875451A1 (en) | 2021-09-08 |
EP3875451B1 (en) | 2024-01-03 |
AU2019361697A1 (en) | 2021-05-20 |
US20210340141A1 (en) | 2021-11-04 |
EP3875451A4 (en) | 2022-07-13 |
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