CN112876352A - 一种gpr120蛋白受体抑制剂及其制备和应用 - Google Patents
一种gpr120蛋白受体抑制剂及其制备和应用 Download PDFInfo
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Abstract
本发明提供了一种GPR120蛋白受体抑制剂及其制备和应用,具体地,本发明提供了一种如下式I所示的化合物,或其药学上可接受的盐。所述的化合物具有优异的GPR120蛋白抑制活性。
Description
技术领域
本发明涉及小分子蛋白抑制剂领域,具体地,本发明提供了一种具有GPR120蛋白调节作用的化合物的制备和应用。
背景技术
GPR120,G蛋白偶联受体,通过与不饱和长链脂肪酸如α-亚油酸结合而引起细胞内信号传导,从而诱导各种生物学反应。据报道,GPR120及其配体的作用可促进胰高血糖素样肽1(“GLP-1”)的分泌,从而降低胃肠道细胞系中的血糖水平。已经发现,作为肽激素的GLP-1可以根据血糖水平诱导胰岛素分泌。还建议使用GLP-1延缓II型糖尿病中β细胞的凋亡。
GPR120在脂肪细胞中表达。已经发现通过脂肪分化诱导越来越表达GPR120。另外,已经报道了GPR120及其配体的作用抑制了脂肪分化细胞中的脂解。已知高血脂水平是胰岛素耐药性的原因之一,因此,预期通过GPR120激动剂抑制脂解会降低血液中的游离脂肪酸水平以使血脂水平正常化,并可能导致胰岛素抵抗的改善。
GPR120也在垂体中表达,并且据报道,GPR120配体抑制促肾上腺皮质激素的分泌。促肾上腺皮质激素促进其下游的糖皮质激素分泌,以诱导作用,例如促进肝脏中糖异生,对肌肉和周围组织中的葡萄糖摄取的抑制作用,在脂肪组织中的脂解或脂肪酸或甘油的释放。因此,认为GPR120即使在中枢也通过对促肾上腺皮质激素分泌的抑制作用而表现出降血糖作用或降血脂作用。
最近,已显示GPR120在小鼠和人类的肥胖中起作用。用高脂饮食喂养的GPR120基因敲除小鼠出现肥胖,葡萄糖耐受不良和脂肪肝,脂肪细胞分化和脂肪形成减少,肝脂肪形成增加。在这项研究中,这类小鼠的胰岛素抵抗与胰岛素信号传导减少和脂肪组织炎症增加有关。在人类中,肥胖个体中GPR120在脂肪组织中的表达明显高于瘦的个体。
GPR120也已经显示出在炎症中起作用。用omega-3脂肪酸治疗的野生型小鼠抑制巨噬细胞诱导的组织炎症并增强全身胰岛素敏感性。但是,在GPR120基因敲除小鼠中未观察到这种作用。
根据以上描述,具有GPR120激动剂活性的化合物被认为可用作治疗和/或预防糖尿病,肥胖症,高脂血症,脂肪肝(包括非酒精性脂肪性肝炎或NASH)的药物,和炎症相关疾病。
综上所述,本领域迫切需要开发新型的GPR120蛋白受体抑制剂。
发明内容
本发明的目的是提供一种新型的GPR120蛋白受体抑制剂。
本发明的第一方面,提供了一种如下式I所示的化合物,或其药学上可接受的盐:
其中,
n为0、1、2或3;
m为0、1或2;
p为1或2;
R1和R2选自下组:H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基;或两个位于相邻碳原子上的R1与相连的碳原子共同构成C6-C10芳基;
X选自下组:CH或N;且所述的X为CH时,R2可以位于X上;
Y选自下组:取代或未取代的C1-C2亚烷基;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基。
在另一优选例中,所述的式I化合物具有如下式II所示的结构:
其中,R3和R4各自独立地选自下组:H、C1-C4烷基。
在另一优选例中,所述的式I化合物具有如下式III所示的结构:
其中,R1选自下组:H、卤素、CN、C1-C6烷基、C3-C6环烷基;
R3和R4各自独立地选自下组:H、C1-C4烷基。
在另一优选例中,所述的式I化合物具有如下式IV所示的结构:
其中,R2选自下组:H、C1-C6烷基。
在另一优选例中,R1和R2选自下组:H、卤素、CN、取代或未取代的C1-C4烷基、取代或未取代的环丙基;或两个位于相邻碳原子上的R1与相连的碳原子共同构成C6-C10芳基;
所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C4烷基、C1-C4烷氧基、卤代的C1-C4烷氧基、C3-C6环烷基。
在另一优选例中,所述的式I化合物选自下组:
本发明的第二方面,提供了一种药物组合物,所述的药物组合物包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物;(2)药学上可接受的载体。
本发明的第三方面,提供了如本发明第一方面所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物或本发明第二方面所述的药物组合物的用途,其用于制备预防和/或治疗与GPR120蛋白受体的活性或表达量相关的疾病的药物组合物。
在另一优选例中,所述的疾病选自下组:糖尿病,高脂血症,肥胖和炎症相关疾病。
在另一优选例中,所述的疾病选自下组:糖尿病,肥胖,高脂血症,NASH或炎症相关疾病。
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
本发明人经过长期而深入的研究,设计并合成了一类新型GPR120蛋白受体抑制剂。在此基础上,发明人完成了本发明。
术语
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
定义
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C2-C6烯基指具有2-6个碳原子的直链或支链的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C2-C6炔基是指具有2-6个碳原子的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环或螺环形式。
如本文所用,术语“C1-C8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基;例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环形式,例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
除非特别说明,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
式I化合物
本发明提供了一种如下式I所示的化合物,其立体异构体或其互变异构体,或其药学上可接受的盐、水合物或溶剂化物:
其中,
n为0、1、2或3;
m为0、1或2;
p为1或2;
R1和R2选自下组:H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基;或两个位于相邻碳原子上的R1与相连的碳原子共同构成C6-C10芳基;
X选自下组:CH或N;且所述的X为CH时,R2可以位于X上;
Y选自下组:取代或未取代的C1-C2亚烷基;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基。
优选的式I化合物为本申请实施例中所示的具体化合物。
式I化合物的制备
本发明还提供了一种制备如本发明第一方面所述化合物的方法,包括步骤:
在适当的溶剂中,用醇Ia与酚Ib反应,得到化合物Ic,脱保护后得到式I化合物,其中,LG为离去基团,优选为C1-C4烷基。
药物组合物和施用方法
由于本发明化合物具有优异的GPR120的抑制活性,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预防和/或治疗与GPR120信号通路相关的疾病(例如,癌症)。
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及药学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1-2000mg本发明化合物/剂,更佳地,含有10-200mg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(如吐温)、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、肠胃外(静脉内、肌肉内或皮下)。
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、蔗糖和阿拉伯胶;(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。
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。
联合给药时,所述药物组合物还包括与一种或多种其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种可与本发明的化合物同时、分开或顺序地给药。
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20~500mg。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。
实施例1
3-(4-((2-异丙基-5-甲基苄基)氧基)-3-甲基苯基)丙酸
步骤1:(2-异丙基-5-甲基苯基)甲醇的合成
将2-异丙基-5-甲基苯甲醛(100mg,0.62mol)的THF(5mL)溶液冷却至-78℃。在该温度下加入LAH(1.0M的THF溶液,0.8mL,0.8mmol),并使反应升温至室温。将反应倒入冰水混合物中,并用乙酸乙酯(20mL*2)萃取。合并的有机层用盐水(10mL)洗涤,用硫酸钠干燥,过滤并浓缩。残余物通过柱色谱法纯化,得到标题化合物,为黄色油状物(80mg,80%收率)。MS(ESI):m/z 165.5(M+H)+。
步骤2:3-(4-(((2-异丙基-5-甲基苄基)氧基)-3-甲基苯基)丙酸甲酯的合成
(2-异丙基-5-甲基苯基)甲醇(80mg,0.49mmol),3-(4-羟基-3-甲基苯基)丙酸甲酯(105mg,0.54mmol)和PPh3(140mg,0.54mmol)的溶液在氮气气氛下于0℃在无水THF(10mL)中搅拌。在5分钟内向该混合物中滴加DIAD(0.15mL,0.54mmol),并将反应在室温下搅拌12小时。用水(10mL)洗涤反应,并用CH2Cl2(20mL*2)萃取。合并的有机层用盐水(10mL)洗涤,用硫酸镁干燥,过滤并浓缩。残余物通过快速色谱纯化,得到标题化合物(70mg,42%),为黄色固体。MS(ESI):m/z 341.5(M+H)+。
步骤3:3-(4-((2-异丙基-5-甲基苄基)氧基)-3-甲基苯基)丙酸的合成
加入3-(4-(((2-异丙基-5-甲基苄基氧基)-3-甲基苯基)丙酸甲酯(70mg,0.21mmol)在THF(5mL)和水(1mL)中的溶液。24mg,1.0mmol)。将混合物在室温搅拌5小时。用0.1N HCl中和该溶液,并用乙酸乙酯(20mL*2)萃取。合并的有机层用盐水(10mL)洗涤,用硫酸镁干燥,过滤并浓缩。残余物通过快速色谱纯化,得到标题化合物(30mg,45%),为黄色固体。MS(ESI):m/z 327.5(M+H)+。1HNMR(DMSO-d6,400MHz)12.00(s,br,1H),7.00-7.40(m,5H),6.70(d,J=7.8Hz,1H),5.20(s,2H),2.70-2.80(m,1H),2.50-2.70(m,4H),2.10(s,3H),1.00-1.20(m,6H)。
以下化合物根据与实施例1类似的方法制备:
生物测试例GPR120 TANGO分析
为了进行GPR120 TANGO测试,将TANGO细胞在补充有10%FBS的DMEM中,以10000个细胞/孔的密度铺板在96孔细胞培养板中过夜。在随后一日(第2天),将测试的化合物与细胞预孵育1小时,然后将GPCR 120激动剂添加到每个孔中,并将细胞再孵育48小时。使用读板仪(Infinite 200,Tecan)观察TANGO细胞的荧光,并计算IC50。
下表中列出了结果,当IC50小于100nM时,活性范围表示为+++。当测得的IC50为100-500nM情况下,记录活性范围为++;当IC50大于500nM时,记录活性范围为+。
结果显示,本发明化合物具有优异的GPR120半数抑制活性。
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)
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,
R1和R2选自下组:H、卤素、CN、取代或未取代的C1-C4烷基、取代或未取代的环丙基;或两个位于相邻碳原子上的R1与相连的碳原子共同构成C6-C10芳基;
所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C4烷基、C1-C4烷氧基、卤代的C1-C4烷氧基、C3-C6环烷基。
7.一种药物组合物,其特征在于,包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物;(2)药学上可接受的载体。
8.如权利要求1所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物或如权利要求7所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗与GPR120蛋白受体的活性或表达量相关的疾病的药物组合物。
9.如权利要求8所述的用途,其特征在于,所述的疾病选自下组:糖尿病,高脂血症,肥胖和炎症相关疾病。
10.如权利要求8所述的用途,其特征在于,所述的疾病选自下组:糖尿病,肥胖,高脂血症,NASH或炎症相关疾病。
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