CN117430561A - 一种gpr139受体激动剂及其制备方法 - Google Patents
一种gpr139受体激动剂及其制备方法 Download PDFInfo
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- CN117430561A CN117430561A CN202210834434.6A CN202210834434A CN117430561A CN 117430561 A CN117430561 A CN 117430561A CN 202210834434 A CN202210834434 A CN 202210834434A CN 117430561 A CN117430561 A CN 117430561A
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- compound
- pharmaceutically acceptable
- alkyl
- acceptable salt
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
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Abstract
本发明提供了一种如式(I)所示的化合物,或其在药学上可接受的盐,其中,R1、R2、R3、R4和R5等具有说明书中给出的定义。此外,本发明还提供了所述化合物及其药学上可接受的盐的制备方法,以及其在制备GPR139受体相关疾病的药物中的应用。
Description
技术领域
本发明涉及药物化学领域。具体地,本发明涉及一类G蛋白偶联受体139(GProtein-coupled Receptor 139,简称GPR139)的配体分子。
背景技术
G蛋白偶联受体139(G Protein-coupled Receptor 139,简称GPR139)是Gloriam等于2005年首次发现(Biochim Biophys Acta 2005;1722:235-246),也被称为GPCR12,PGR3,KOR3L,GPRg1。GPR139主要表达在中枢神经***(CNS)中的缰核、纹状核、丘脑、下丘脑和垂体中,其氨基酸序列在不同物种中具有高度保守性如人GPR139蛋白序列与小鼠、鸡和斑马鱼的同源性分别为96%,92%和70%。GPR139受体表达在细胞表面时,由N-端片段、7个穿膜片段和C-端片段组成,其中N-端片段由26个氨基酸组成,并含有一个半胱氨酸。Wang等报道,GPR139受体和多巴胺受体D2共表达于鼠脑的不同组织中,并通过体外细胞实验证实GPR139能促进多巴胺受体D2的激动剂产生钙流信号,且该钙流信号既能被多巴胺受体D2的拮抗剂,也能被GPR139的拮抗剂所抑制(Frontiers in Neuroscience,March 2019,Volume13,Article 281)。此外,Nepomuceno等证实GPR139能通黑色皮质素受体3或5(MC3/MC5)起协同作用。这些结果表明,GPR139能与细胞表面其它受体形成异源二聚体发挥生理作用。此外,我们的实验已证实GPR139受体能通过N-端的半胱氨酸形成同源二聚体。
不同研究团队在寻找GPR139的配体,包括激动剂和拮抗剂,的同时,Liu等报告了L-苯丙氨酸和L-色氨酸为GPR139内源性激动剂(Mol Pharmacol 2015;88:911-925)。
现有的研究表明,GPR139受体具有重要的生理功能,是抗焦虑、抗抑郁、抗精神***,治疗帕金森综合症,治疗药物和酒精滥用,治疗代谢相关疾病的潜在药物靶点。相关GPR139的结构、表达、药理、生理功能信息为设计和合成全新的GPR139激动剂提供了坚实的基础。
发明内容
在本发明的第一方面,提供了一种如式(I)所示的化合物,或其药学上可接受的盐,
其中,L1选自下组:无,或
R1选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基;
环A为C3-10碳环基,或3-10元杂环基;
其中,所述的碳环基或杂环基,各自任选地被选自下组的取代基取代:卤素、氧基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基;
并且,所述的碳环基和杂环基包括并环、桥环和螺环结构。
在部分实施方式中,所述化合物具有式(II)所示的结构:
其中,虚线键代表可为单键或双键;
W选自下组:C、N;
X选自下组:C=O或CR2;其中,R2选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4氨基烷基;
Y选自下组:CH、NR3;其中,R3选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4氨基烷基、C1-4烷氧基、C1-4卤代烷氧基;
Z选自下组:CR4,其中,R4选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基;
D选自下组:N、CH;
E选自下组:CR5、N、NR6,其中,R5选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基;R6选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4氨基烷基、C1-4烷氧基、C1-4卤代烷氧基;
或者,R2、R3、R4、R5中任意相邻的两个,即R2和R3、R3和R4或R4和R5,和其相连的碳原子,共同形成取代或未取代的C5-7碳环或5-7元杂环;
L1、R1的定义如前所述。
在部分实施方式中,所述的R1选自下组:-OCF3。
在部分实施方式中,所述的环A具有选自下组的结构:
在部分实施方式中,所述的化合物选自下组:
在本发明的第二方面,提供了一种如本发明第一方面所述的化合物、或其药学上可接受的盐的制备方法,包括步骤:
或者
其中,R’选自下组:氢、C1-4烷基;
R1、L1、环A的定义如前所述。
在本发明的第三方面,提供了一种药物组合物,其特征在于,包括如本发明第一方面所述的化合物、或其药学上可接受的盐;和药学上可接受的载体。
在本发明的第四方面,提供了一种如本发明第三方面所述的药物组合物的制备方法,其特征在于,包括步骤:将本发明第一方面所述的化合物、或其药学上可接受的盐,与药学上可接受的载体进行混合,从而形成药物混合物。
在本发明的第五方面,提供了一种如本发明第一方面所述的化合物、或其药学上可接受的盐,或者如本发明第三方面所述的药物组合物的用途,其特征在于,用于制备治疗GPR139受体相关疾病的药物。
在另一优选例中,所述GPR139受体相关疾病包括焦虑症、抑郁症、帕金森综合症、药物及酒精滥用。
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。
具体实施方式
发明人经过广泛而深入的研究,出乎意料地发现本发明化合物具有优异的GPR139受体激动活性,从而进行了一系列合成和生物活性测试。在此基础上完成了本发明。
本发明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,或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂,均为市售产品。
除非另有定义,本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不用于限制本发明。
术语
本发明的术语“包括”和“具有”以及它们任何变形,意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块,而是可选地还包括没有列出的步骤,或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤。
在本发明中提及的“多个”是指两个或两个以上。“和/或”,描述关联对象的关联关系,表示可以存在三种关系,例如,A和/或B,可以表示:单独存在A,同时存在A和B,单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本发明所述化合物中,当任何变量在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环***的线表示所指的键可连接到任何能取代的环原子上。如果环***为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C8烷基”中“C1-C8”的定义包括以直链或支链排列的具有1、2、3、4、5、、或8个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
本文所用术语“烷氧基”代表烷基-氧基基团,其中烷基的定义如上所示。
正如本领域技术人员所理解的,本文中所用“卤素”意指包括氯、氟、溴和碘。
本文所用术语“卤代烷基”代表其中有一个或多个氢原子被卤素取代的烷基基团,其中烷基的定义如上所示。
本文所用术语“卤代烷氧基”代表有一个或多个氢原子被卤素取代的烷基-氧基基团,其中烷基的定义如上所示。
活性成分
在本发明中,提供了一种可有效激动GPR139受体的活性成分。该活性成分为通式(I)所示的化合物,该活性成分可有效预防、治疗和/或缓解GPR139相关疾病。
试验表明,本发明的活性成分可有效地激动GPR139受体,从而预防、治疗和/或缓解GPR139相关疾病。
应理解,本发明的活性成分包括通式(I)所示的化合物、或其药学上可接受的盐、或其前药。应理解,本发明的活性成分还包括通式(I)化合物的晶型、无定形化合物、以及氘代化合物等形式。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
通常,在制备流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0℃~80℃,优选0℃~50℃)下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
下面的通用制备路线可以用于合成本发明式(I)结构的化合物。
或者
其中,R’、R”、R”’、R1、R2、R3、R4、R5和R6的定义如前所述。
药物组合物和施用方法
由于本发明化合物具有优异的GPR139受体激动活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与GPR139相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-3000(活性剂量范围3-30mg/kg)mg本发明化合物/剂,更佳地,含有10-2000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是: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化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受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。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选6~600mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
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,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。本发明中用到的起始原料未经特别说明,均为商业购买。
实施例
实施例1
化合物NRB104的制备
第一步:
将含有2-碘苯胺(1000mg,4.57mmol),3-丁炔-1-醇(560mg,7.99mmol),三乙胺(700mg,6.92mmol),钯(PPh3)4(530mg,0.459mmol)和碘化铜(170mg,0.893mmol)的20mL水溶液于80℃搅拌2小时,然后用150mL的水稀释,再用乙酸乙酯(3x100mL)萃取。用150mL的盐水洗有机相,然后用无水硫酸钠干燥。过滤后进行浓缩,得到800mg的中间体4-(2-氨基苯基)丁-3-炔-1-醇。
第二步:
往9.0mL水中加入1mL的硫酸,然后再加入4-(2-氨基苯基)丁-3-炔-1-醇(800mg,4.96mmol),冷却到0℃,在0℃滴入4mL含有亚硝酸钠NaNO2(520mg,7.537mmol,1.52equiv)的水溶液。混合物在室温搅拌过夜,将悬液冷却至0℃,过滤后用2mL水洗,得到400mg的中间体3-(2-羟乙基)-1H-噌啉-4-酮。
第三步:
将含有3-(2-羟乙基)-1H-噌啉-4-酮(400mg,2.17mmol,1equiv),碘甲烷(360mg,2.54mmol)和碳酸钾(440mg,3.18mmol)的5mLDMF溶液于室温搅拌12h,用C18反相柱进行纯化,得到100mg的中间体3-(2-羟乙基)-1-甲基噌啉-4-酮。
第四步:
往含有3-(2-羟乙基)-1-甲基噌啉-4-酮(100mg,0.490mmol)和高碘酸钠(420mg,1.96mmol)的1mL乙腈溶液中加入1.5mL水,1mL乙酸乙酯,混匀后加入三氯化钌(55mg,0.244mmol),然后于室温搅拌48小时。反应混合物于真空浓缩后,用C18反相柱进行纯化,得到30mg中间体(1-甲基-4-氧代噌啉-3-基)乙酸。
第五步:
将含有(1-甲基-4-氧代噌啉-3-基)乙酸(30.0mg,0.137mmol),羟基苯并***(23.0mg,0.170mmol)和二异丙基乙胺(55.0mg,0.426mmol)的1mLDMF于室温搅拌15分钟,然后加入(1S)-1-[4-(三氟甲氧基)苯基]乙胺(30.0mg,0.146mmol,)和EDCI(40mg,0.209mmol),室温搅拌2小时。用制备型HLPC纯化上述混合物,得到终产品化合物NRB104:2-(1-甲基-4-氧代噌啉-3-基)-N-[(1S)-1-[4-(三氟甲氧基)苯基]乙基]乙酰胺。
1H NMR(300MHz,DMSO-d6)δ8.54(d,J=7.8Hz,1H),8.12(d,J=8.1Hz,1H),7.89–7.85(m,1H),7.74(d,J=8.7Hz,1H),7.51–7.46(m,3H),7.32(d,J=8.1Hz,2H),5.00–4.89(m,1H),4.07(s,3H),3.60(s,2H),1.38(d,J=7.0Hz,3H).
实施例2
化合物NRB103的制备
第一步:
将含有2,3-二溴吡啶(2.00g,8.44mmol)的1,4-二氧六环溶液于110℃搅拌过夜,浓缩后得到1.4g中间体3-溴-2-肼基吡啶。
第二步:
将含有3-溴-2-肼基吡啶(1.40g,7.45mmol)的5.0mL原甲酸三甲酯溶液于105℃搅拌4小时,然后减压浓缩,再加入原甲酸三甲酯,于110℃搅拌过夜,混合物进行减压浓缩,得到1g的中间体8-溴-[1,2,4]***并[4,3-a]吡啶。
第三步:
将含有8-溴-[1,2,4]***并[4,3-a]吡啶(600mg,3.03mmol),氰乙酸乙酯(415mg,3.67mmol),叔丁醇钾(853mg,7.61mmol)和1,1'-双二苯基膦二茂铁二氯化钯(223mg,0.304mmol)的6mL1,4-二氧六环溶液于70℃搅拌4小时。真空去除溶剂,然后用硅胶层析纯化,得到200mg的中间体乙基2-氰基-2-{[1,2,4]***并[4,3-a]吡啶-8-基}乙酸酯(200mg,14%)。
第四步:
将乙基2-氰基-2-{[1,2,4]***并[4,3-a]吡啶-8-基}乙酸酯(200mg,0.869mmol)溶于1mLDMSO中,加入0.5mL盐水,于120℃处理2小时,再用乙酸乙酯(3x8mL)抽提。用盐水洗有机相,再用硫酸钠干燥,过滤浓缩后得到中间体2-{[1,2,4]***并[4,3-a]吡啶-8-基}乙腈。
第五步:
将含有2-{[1,2,4]***并[4,3-a]吡啶-8-基}乙腈(100mg,0.564mmol),EDCI(162mg,0.847mmol),羟基苯并***(91.6mg,0.678mmol)的1mLDMF溶液用N,N-二异丙基乙胺(146mg,1.130mmol)于室温反应30分钟,然后滴加(1S)-1-[4-(三氟甲氧基)苯基]乙胺(140mg,0.682mmol),室温反应1.5小时,再用反相层析柱纯化,得到终产品化合物NRB103:2-{[1,2,4]***并[4,3-a]吡啶-8-基}-N-[(1S)-1-[4-(三氟甲氧基)苯基]乙基]乙酰胺。
1H NMR(400MHz,DMSO-d6)δ9.25(d,J=2.0Hz,1H),8.77(d,J=6.4Hz,1H),8.45(d,J=6.8Hz,1H),7.48(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),7.18(d,J=6.8Hz,1H),6.95–6.89(m,1H),4.98–4.95(m,1H),3.88(s,2H),1.39(d,J=7.0Hz,3H).
实施例3
化合物NRB105的制备
第一步:
往10mL含有2-肼吡啶(1.00g,9.16mmol)的甲醇中加入丁炔二酸二甲酯(1.56g,11.0mmol),室温反应3小时。混合物浓缩成1g的中间体1,4-二甲基(2Z)-2-[2-(吡啶-2-基)肼-1-亚基]丁二酸酯。
第二步:
将1,4-二甲基(2Z)-2-[2-(吡啶-2-基)肼-1-亚基]丁二酸酯(1.00g,3.98mmol)溶于10mL的乙酸中,室温搅拌后在140℃进行微波照射40分钟。反应物倒入50mL水中,然后用乙酸乙酯抽提(3x80mL)。用盐水洗有机相,然后用硫酸钠干燥,过滤浓缩后制成1.2g的中间体2-{4-氧代吡啶并[2,1-c][1,2,4]三嗪-3-基}乙酸甲酯。
第三步:
将(1S)-1-[4-(三氟甲氧基)苯基]乙胺(122mg,0.593mmol)溶于13mL的二甲苯中,加入三甲基铝(256.8mg)于0℃反应30分钟,然后加入2-{4-氧代吡啶并[2,1-c][1,2,4]三嗪-3-基}乙酸甲酯(130mg,0.634mmol),于110℃反应6小时,再于140℃搅拌6小时。将反应物进行真空浓缩后用反相柱进行纯化,得到终产品化合物NRB105:2-{4-氧代吡啶并[2,1-c][1,2,4]三嗪-3-基}-N-[(1S)-1-[4-(三氟甲氧基)苯基]乙基]乙酰胺。
1H NMR(400MHz,DMSO-d6)δ8.74(d,J=7.2Hz,1H),8.58(d,J=8.0Hz,1H),7.95–7.91(m,1H),7.82(d,J=9.2Hz,1H),7.47(d,J=8.8Hz,2H),7.42–7.34(m,1H),7.31(d,J=8.4Hz,2H),4.99–4.96(m,1H),3.85(s,2H),1.38(d,J=6.9Hz,3H).
实施例4
化合物NRB115的制备
第一步:
往6mL含有叔丁氧羰基氨基乙酸(300mg,1.713mmol)的二氯甲烷溶液中加入(1S)-1-[4-(三氟甲氧基)苯基]乙胺(316.24mg,1.541mmol),羟基苯并***(462.83mg,3.425mmol),和EDCI(656.58mg,3.425mmol),于室温搅拌16小时。反应物用乙酸乙酯(3x40mL)和水(80mL)抽提。有机相用真空浓缩,然后硅胶柱纯化,得到300mg的中间体{[(1S)-1-(4-三氟甲氧基-苯基)-乙基氨基甲酰基]-甲基}-氨基甲酸叔丁酯。
第二步:
将{[(1S)-1-(4-三氟甲氧基-苯基)-乙基氨基甲酰基]-甲基}-氨基甲酸叔丁酯(300mg,1.713mmol)加到盐酸中(4mL,0.773mmol),于室温搅拌2小时。反应物经真空浓缩后得到175mg的2-氨基-N-[(1S)-1-(4-三氟甲氧基-苯基)-乙基]-乙酰胺。
第三步:
往含2-氨基-N-[(1S)-1-(4-三氟甲氧基-苯基)-乙基]-乙酰胺(175mg,0.667mmol)的3mL吡啶溶液中加入化合物5(82.16mg,0.667mmol),三氯氧磷(0.093mL,1.001mmol),于室温搅拌1小时。反应物用乙酸乙酯(3x50 mL)和饱和碳酸氢钠(100mL)抽提。真空干燥后用10mL甲醇结晶,得到终产品化合物NRB115(D15)。
1H NMR(400MHz,DMSO-d6)δ8.84(d,J=5.1Hz,1H),8.66(d,J=4.2Hz,1H),8.51(d,J=7.6Hz,1H),8.02(dt,J=15.3,7.6Hz,2H),7.65–7.58(m,1H),7.45(d,J=8.4Hz,2H),7.31(d,J=8.1Hz,2H),4.98(t,J=6.9Hz,1H),3.98(dd,J=11.9,8.1Hz,2H),1.38(d,J=7.0Hz,3H).
实施例5
化合物NRB118的制备
第一步:
往含2H-噌啉-3-酮(300mg,2.053mmol)的5mL二甲基甲酰胺溶液中加入氯乙酸甲酯(267.31mg,2.463mmol),碳酸钾(851.04mg,6.158mmol),于室温搅拌4小时。反应物用乙酸乙酯(3x40 mL)和饱和氯化钠(100mL)抽提。真空浓缩分离有机相,然后用硅胶柱纯化得到200mg中间体(3-氧代-3H-噌啉-2-基)-乙酸甲酯。
第二步:
往含(3-氧代-3H-噌啉-2-基)-乙酸甲酯(200mg,0.917mmol)的四氢呋喃(3mL)溶液中加入氢氧化锂(115.38mg,2.750mmol,1mL H2O)时。真空浓缩分离有机相,然后用1M盐酸酸化,再用乙酸乙酯(5x30mL)和水(100mL)抽提。真空浓缩,得到80mg的中间体(3-氧代-3H-噌啉-2-基)-乙酸。
第三步:
往含有(3-氧代-3H-噌啉-2-基)-乙酸(80mg,0.392mmol)的二甲基甲酰胺(3mL)溶液中加入化合物5(80.39mg,0.392mmol),羟基苯并***(105.89mg,0.784mmol),三乙胺(203mg,2.32mmol)和EDCI(150.21mg,0.784mmol),于室温搅拌1小时。反应物用乙酸乙酯(3x30mL)和水(80mL)抽提。分离有机相,用饱和氯化钠(80mL)洗,真空浓缩后,用硅胶柱纯化得到终产品化合物NRB118(D18):2-(3-氧代噌啉-2-基)-N-[(1S)-1-{4-[(三氟甲基)氧基]苯基}乙基]乙酰胺。
1H NMR(400MHz,DMSO-d6)δ8.79(d,J=7.6Hz,1H),7.55(d,J=9.0Hz,1H),7.48(dd,J=8.5,4.2Hz,3H),7.36–7.24(m,5H),5.04(s,2H),4.95(dd,J=14.1,7.0Hz,1H),1.40(d,J=7.0Hz,3H).
实施例6
本发明化合物的GPR139受体活性测定
1.实验方法
HEK293细胞生长在含DMEM完全培养基(含有谷氨酰胺、丙酮酸钠、青霉素/链霉素、10%胎牛血清)的10cm培养皿中,于37℃,5%CO2培养箱中培养至90%汇合度。然后传代,每周1:5传代两次。细胞传代时,首先完全吸去培养基,用4mL的DPBS洗一次,加3mL的胰酶消化液,轻摇匀。至细胞裂开时,吸去胰酶消化液,加5mL的DMEM完全培养基。用吸管吹打分散细胞后各加入1mL的分散细胞液至5个新的10cm培养皿中,然后各补加7mL的DMEM完全培养基,混匀后放置37℃,5%CO2培养箱中培养。
在转染细胞的当天,按照适当的密度消化细胞到一个10cm培养皿中,加入6mL的DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES、胎牛血清),于37℃,5%CO2培养箱中培养5小时。取一个50mL的无菌离心管A,加1mL无血清DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES),再加10μg的GPR139 DNA,混合均匀。取另一个50mL的无菌离心管B,加1mL无血清DMEM培养基(含有谷氨酰胺、丙酮酸钠、HEPES),再加60μL的Fugene HD转染试剂,混合均匀。从离心管B中取1mL的Fugene HD转染试剂,加入到离心管A中,混合均匀,并于室温放置20分钟。加2mL DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES、胎牛血清)至离心管A中,混合均匀,然后取出离心管A中的混合物(4ml),加到上述10cm培养皿的细胞中(共10mL液体),混匀后置37℃,5%CO2培养箱中培养20-24小时。
第二天,用胰酶消化液消化转染后的细胞,加适当的DMEM/F12培养基(含有谷氨酰胺、丙酮酸钠、HEPES、青霉素/链霉素、胎牛血清),将细胞接种于Matrigel包被的384-孔板中,细胞密度为6.67×106cells/mL,30μL/孔。将384-孔板置37℃,5%CO2培养箱中培养。
第三天,加10μL/孔FLIPR染料(稀释于含有Pluronic和Probenicid的HEPES溶液中)至384-孔细胞板中,于37℃,5%CO2培养箱中培养40分钟。加入稀释后的化合物到细胞板中,在FLIPR读板仪中读取钙流信号。
用XL-fit软件进行数据分析,并得到每个化合物的EC50值。
1.实验结果
表1、GPR139 FLIPR细胞钙流信号检测化合物的EC50值
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 (9)
1.如式(I)所示的化合物,或其药学上可接受的盐,
其中,L1选自下组:无,或
R1选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基;
环A为C3-10碳环基,或3-10元杂环基;
其中,所述的碳环基或杂环基,各自任选地被选自下组的取代基取代:卤素、氧基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基;
并且,所述的碳环基和杂环基包括并环、桥环和螺环结构。
2.如权利要求1所述的化合物,或其药学上可接受的盐,其特征在于,所述化合物具有式(II)所示的结构:
其中,虚线键代表可为单键或双键;
W选自下组:C、N;
X选自下组:C=O或CR2;其中,R2选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4氨基烷基;
Y选自下组:CH、NR3;其中,R3选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4氨基烷基、C1-4烷氧基、C1-4卤代烷氧基;
Z选自下组:CR4,其中,R4选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基;
D选自下组:N、CH;
E选自下组:CR5、N、NR6,其中,R5选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基;R6选自下组:氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4氨基烷基、C1-4烷氧基、C1-4卤代烷氧基;
或者,R2、R3、R4、R5中任意相邻的两个,即R2和R3、R3和R4或R4和R5,和其相连的碳原子,共同形成取代或未取代的C5-7碳环或5-7元杂环;
L1、R1的定义如权利要求1中所述。
3.如权利要求1所述的化合物,或其药学上可接受的盐,其特征在于,所述的R1选自下组:-OCF3。
4.如权利要求1所述的化合物,或其药学上可接受的盐,其特征在于,所述的环A具有选自下组的结构:
5.如权利要求1所述的化合物,或其药学上可接受的盐,其特征在于,所述的化合物选自下组:
6.如权利要求1-5任一项所述的化合物、或其药学上可接受的盐的制备方法,包括步骤:
或者
其中,R’选自下组:氢、C1-4烷基;
R1、L1、环A的定义如权利要求1中所述。
7.一种药物组合物,其特征在于,包括如权利要求1-5任一项所述的化合物、或其药学上可接受的盐;和药学上可接受的载体。
8.如权利要求7所述的药物组合物的制备方法,其特征在于,包括步骤:将权利要求1-5任一项所述的化合物、或其药学上可接受的盐,与药学上可接受的载体进行混合,从而形成药物混合物。
9.如权利要求1-5任一项所述的化合物、或其药学上可接受的盐,或者如权利要求7所述的药物组合物的用途,其特征在于,用于制备治疗GPR139受体相关疾病的药物。
在另一优选例中,所述GPR139受体相关疾病包括焦虑症、抑郁症、帕金森综合症、药物及酒精滥用。
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