CN114591308A - 一类glp-1r受体激动剂化合物及其用途 - Google Patents
一类glp-1r受体激动剂化合物及其用途 Download PDFInfo
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- CN114591308A CN114591308A CN202110334388.9A CN202110334388A CN114591308A CN 114591308 A CN114591308 A CN 114591308A CN 202110334388 A CN202110334388 A CN 202110334388A CN 114591308 A CN114591308 A CN 114591308A
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Abstract
本发明涉及一类GLP‑1R受体激动剂化合物及其用途。具体地,本发明公开了下式(I)表示的化合物或其药学上可接受的盐。所述化合物可以用于通过激活GLP‑1R受体来治疗代谢性相关疾病,如糖尿病和非酒精性脂肪肝病。
Description
本申请要求于2020年12月03日向中国专利局提交的名称为“一类GLP-1R受体激动剂化合物及其用途”,申请号为202011406013.0的发明专利申请的优先权权益,在此以引用方式并入本文中。
技术领域
本发明涉及药物合成领域,具体而言,涉及一类GLP-1R受体激动剂化合物及其用途。
背景技术
GLP-1受体(GLP-1Receptor,GLP-1R),是一种7次跨膜的G蛋白偶联受体B家族(分泌素家族)中的胰高血糖素受体亚家族,它广泛分布于胰腺及胰腺外组织,如中枢神经系统、心血管、胃肠道、肺、肾脏、甲状腺、皮肤、淋巴细胞、间充质干细胞等。
胰高血糖素样肽-1(GLP-1)是GLP-1R受体的天然配体,是一种多肽化合物。其有两种形式,分别为GLP-1(7-37)和GLP-1(7-36)酰胺,这两者仅有一个氨基酸序列不同,GLP-1约80%的循环活性来自GLP-1(7-36)酰胺。GLP-1由胰高血糖素原基因表达,在胰岛α细胞中,胰高血糖素原基因的主要表达产物是胰高血糖素,而在肠黏膜的L细胞中,前激素转换酶(PC1)将胰高血糖素原剪切为其羧基端的肽链序列,即GLP-1。GLP-1与GLP-1R受体结合可促进胰岛素的合成与分泌,同时也刺激β细胞增殖,抑制其凋亡。
GLP-1主要通过以下几方面发挥降糖作用。
1)保护胰岛β细胞的作用
GLP-1可作用于胰岛β细胞,促进胰岛素基因的转录、胰岛素的合成和分泌,并可刺激胰岛β细胞的增殖和分化,抑制胰岛β细胞凋亡,增加胰岛β细胞数量。
此外,GLP-1还可作用于胰岛α细胞,强烈地抑制胰高血糖素的释放,并作用于胰岛δ细胞,促进生长抑素的分泌,生长抑素又可作为旁分泌激素参与抑制胰高血糖素的分泌。
研究证明,GLP-1可通过多种机制明显地改善2型糖尿病动物模型或患者的血糖情况,其中,促进胰岛β细胞的再生和修复,增加胰岛β细胞数量的作用尤为显著。
2)葡萄糖浓度依赖性降糖作用
GLP-1具有葡萄糖浓度依赖性降糖作用,只有在血糖水平升高的情况下,GLP-1才发挥降糖作用,而在血糖水平正常时,则不会使其进一步降低。
3)减轻体重
GLP-1是通过多种途径产生降低体重的作用,包括抑制胃肠道蠕动和胃液分泌,抑制食欲及摄食,延缓胃内容物排空。GLP-1还可作用于中枢神经系统(特别是下丘脑),从而使人体产生饱胀感和食欲下降。
诺和诺德公司近日公布的索马鲁肽(一种修饰的长效GLP-1多肽)临床3期结果表明,在所有随机化患者中,肥胖患者治疗68周后,索马鲁肽2.4mg治疗组从平均基线体重105.3公斤下降14.9%、安慰剂组体重下降2.4%;索马鲁肽2.4mg组有86.4%的患者体重减轻≥5%、安慰剂组为31.5%。
正因为GLP-1通过作用于GLP-1R受体能显著改善代谢类疾病,国内外很多公司都研发了各种修饰或未修饰的GLP-1短效(一天三次)或长效(一天一次、一周一次)多肽药物,这包括:艾塞那肽、利拉鲁肽、阿必鲁肽、度拉糖肽、贝那鲁肽、利司那肽、索马鲁肽等。
然而,将GLP-1多肽及其修饰物应用于临床也面临着很多问题,天然的GLP-1极易被体内的二肽基肽酶Ⅳ(DPP-Ⅳ)降解,其血浆半衰期不足2分钟,必须持续静脉滴注或持续皮下注射才能产生疗效,这大大限制了GLP-1的临床应用。而修饰的GLP-1虽然能够延长半衰期,但口服生物利用度低,在口服用药方面仍然存在非常大的挑战,因此迫切需要开发能够口服的小分子GLP-1R受体激动剂药物。
WO2018109607公布了如下通式化合物及一个候选药物PF-06882961及Ref-01(原文献中化合物4A-01及3A-01,在下文中用作对照化合物)。
出乎意料的是,相比于PF-06882961及Ref-01,本发明中绝大多数化合物在显示很好活性的同时,还显示了更好的体内药代性质,更适合作为药物开发。
WO2019239371公开了如下通式化合物及以下化合物Ref-02(原文献中实施例1,在下文中用作对照化合物)。
出乎意料的是,相比于化合物Ref-02,本发明中的化合物不但活性高,而且也显示了更优良的药代性质。
发明内容
本发明的技术目的是提供一类具有GLP-1R受体激动活性的化合物。
根据本发明的一个方面,本发明提供了一种以下式(I)表示的化合物或其药学上可接受的盐,
其中,
A是苯基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基;
R1选自-H、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基、-C6-10芳基或含有选自O或N中的一个或两个杂原子的-C5-10杂芳基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基可以被0-3个F取代;
下标m是0、1、2或3的整数;
R2、R3各自独立选自-H、氘、C1-6烷基;或者R2、R3与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的杂环烷基;
L选自-O-、-S-、-NR11-或-C(R11R12)-;所述R11、R12为氢或-C1-6烷基;
R4选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
下标n是0、1或2的整数;
R5选自-H、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
下标o是0、1或2的整数;
R6、R7各自独立地选自-H、氘、-C1-6烷基;或者R6、R7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基;或者R6与其相连的碳原子以及B环一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基;
R8选自-C1-3烷基、-亚甲基C3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基;其中,所述-C1-3烷基、亚甲基C3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代;
Z选自N或CR13;
R9选自氢、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
下标p是0、1或2的整数;
R10选自-COOH或羧基等排体;
R13选自氢、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
所述卤素选自F、Cl和Br。
优选地,本发明化合物具有如下式(II)所示的结构:
其中,
A是苯基或吡啶基;
R1选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基、所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基可以被0-3个F取代;
下标m是0、1或2的整数;
R2、R3各自独立地选自-H、氘、C1-6烷基;
R4选自卤素、-CN、-OH、氘、-C1-6烷基或-C1-6烷氧基;
下标n是0或1的整数;
R5选自卤素、-OH、-C1-6烷基或-C1-6烷氧基;
下标o是0或1的整数;
R6、R7各自独立地选自-H、氘、C1-6烷基;或者R6、R7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基;
R8选自-C1-3烷基、-亚甲基C3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基;其中,所述-C1-3烷基、亚甲基C3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代;
Z选自N或CR13;
R13选自氢、卤素、-CN、-OH、氘、-C1-6烷基或-C1-6烷氧基。
进一步优选地,本发明化合物具有如下式(III)所示的结构:
其中,
R1选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基、所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基可以被0-3个F取代;
下标m是1或2的整数;
A是苯基、吡啶基;
R4选自卤素、-OH、氘、-C1-6烷基或-C1-6烷氧基;
下标n是0或1的整数;
R5选自卤素、-OH、-C1-6烷基或-C1-6烷氧基;
下标o是0、1或2的整数;
R8选自-C1-3烷基、-亚甲基C3-6环烷基或-亚甲基C4-6杂环烷基。
更进一步优选地,本发明化合物具有如下式(IV)所示的结构:
其中,
R1选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基、所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基可以被0-3个F取代;
下标m是1或2的整数;
A是苯基、吡啶基;
R4选自卤素、-OH、氘、-C1-6烷基或-C1-6烷氧基;
下标n是0或1的整数;
R5选自-C1-6烷基;
下标o是0或1的整数。
更进一步优选地,由式(IV)表示的本发明化合物结构中,所述R1选自-F、-Cl、-Br、-CN、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;
优选地,所述m是2;
优选地,所述A是苯基;
优选地,所述R4选自-F、-Cl;
更进一步优选地,下标o是0。
更进一步优选地,根据本发明的所述化合物选自以下化合物之一:
根据本发明的另一个方面,本发明提供了一种药物组合物,所述药物组合物包括治疗有效量的根据本发明上述式(I)至式(IV)表示的化合物或其药学上可接受的盐作为活性成分,以及药学上可接受的辅料。
根据本发明的另一个方面,本发明提供了上述化合物或其药学上可接受的盐,或上述药物组合物作为活性成分在制备用于通过激活GLP-1R受体来治疗代谢相关疾病的药物中的用途。
在具体实施方式中,所述代谢相关疾病选自葡萄糖耐受不良、高血糖症、血脂异常、1型糖尿病(T1D)、2型糖尿病(T2D)、高甘油三酯血症、综合征X、胰岛素抵抗、葡萄糖耐量降低(IGT)、糖尿病性血脂异常、高脂血症,动脉硬化,动脉粥样硬化、高血压、肥胖症、非酒精性脂肪肝、非酒精性脂肪肝炎、肝纤维化、肝硬化、嗜睡等疾病中的任一种。
有益效果
本发明合成一类新型的GLP-1R受体激动剂化合物,通过药理实验证实该类化合物对GLP-1R受体具有很好的激动活性,因此可以用于GLP-1R受体相关代谢疾病的治疗。此外,本发明的化合物还显示出优异的药物代谢性质。
具体实施方式
以下,将详细地描述本发明。在进行描述之前,应当理解的是,在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义,而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上,根据与本发明的技术方面相应的含义和概念进行解释。因此,这里提出的描述仅仅是出于举例说明目的的优选实例,并非意图限制本发明的范围,从而应当理解的是,在不偏离本发明的精神和范围的情况下,可以由其获得其他等价方式或改进方式。
根据本发明,如果无另外说明,这里引用的所有术语具有与那些本领域的熟练人员理解本发明相同的含义。
如本文所用的术语“盐”是指含阳离子和阴离子的化合物,其可通过可接受质子部位的质子化和/或可供质子部位的去质子化来产生。值得注意的是,可接受质子部位的质子化导致形成阳离子类物质,其电荷通过生理阴离子的存在而平衡,而可供质子部位的去质子化导致形成阴离子类物质,其电荷通过生理阳离子的存在而平衡。
术语“药学上可接受的盐”指所述盐是药学上可接受的。药学上可接受的盐的例子包括但不限于:(1)酸加成盐,与无机酸形成,如盐酸、氢溴酸、硫酸、硝酸、磷酸等等;或与有机酸形成,如羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4对甲苯磺酸、樟脑酸、十二烷基硫酸、葡萄糖酸、谷氨酸、水杨酸、顺式-已二烯二酸等等;或(2)碱加成盐,和上述无机酸的任一种的共轭碱形成,其中共轭碱包含选自Na+、K+、Mg2+、Ca2+、NHxR4-x +中的阳离子组分,其中NHxR4-x +(R是C1-4烷基,下标x是选自0、1、2、3或4的整数)表示季铵盐中的阳离子。应该理解,所有涉及药学上可接受的盐都包括相同酸加成盐的本文中所定义的溶剂加成形式(溶剂化物)或晶体形式(多晶型物)。
术语“C1-M烷基”是指包含1-M个碳原子的烷基,例如其中M是具有下列数值的整数:2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30。例如术语“C1-6烷基”是指含有1-6个碳原子的烷基。烷基的例子包括但不限于低级烷基,包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或戊基、异戊基、新戊基、己基、庚基和辛基。
术语“C3-M环烷基”是指包含3-M个碳原子的环烷基,例如其中M是具有下列数值的整数:4、5、6、7、8。例如术语“C3-6环烷基”是指含有3-6个碳原子的环烷基。环烷基的例子包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“芳香基”指芳族体系,可以是单环或原本稠合的或连接在一起的多芳环,从而使至少一部分稠合或连接的环形成共轭的芳系。芳基基团包括但不限制于:苯基、萘基、四氢萘基。芳基可被任选取代,如可被1-4个选自下组的基团所取代的芳基或杂环:卤素、-CN、-OH、-NO2、氨基、烷基、环烷基、链烯基、炔基、烷氧基、芳氧基、取代的烷氧基、烷基羰基、烷基羧基、烷基氨基或芳硫基。
术语“取代”指参考基团可以被一个或多个额外基团所取代,额外基团单独地且独立的选自于,烷基,环烷基,芳基,杂芳基,杂脂环烃,羟基,烷氧基,烷硫基,芳硫基,烷亚砜基,芳亚砜基,烷砜基,芳砜基,氰基,卤基,羰基,硫代羰基,硝基,卤烷基,氟烷基和氨基,包括单取代和双取代的氨基基团及其被保护的衍生物。
本发明所提供的由式(I)表示的化合物或其药学上可接受的盐,和包含该化合物的药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。例如其制剂配方的单位剂量中包含0.05-200mg式(I)的化合物或其药学上可接受的盐,优选地,制剂配方的单位剂量中包含0.1mg-100mg式(I)的化合物。
本发明的由式(I)表示的化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为0.01-200mg/kg体重,一次性服用,或0.01-100mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
本发明中,术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化,如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。
典型的配方是通过混合本发明的式(I)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的,包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。
所用的特定载体、稀释剂或赋形剂,将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言,安全的溶剂是无毒性含水溶剂诸如水,以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使该药物以可被接受的形式制造或使用。
本发明所述的如式(I)的化合物与至少一种其它药物的组合使用时,两种药物或多种药物可以分开使用也可以组合使用,优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式,分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中,本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质,或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等;粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等;湿润剂如甘油等;崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等;溶液阻滞剂如石蜡等;吸收促进剂如季铵化合物等;吸附剂如高岭土、膨润土等;润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下,该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料,其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其药物组合物之外,该液态剂型可含有本领域中常用的惰性稀释剂,诸如水或其他溶剂;增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺;油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等);甘油;四氢糠基醇;聚乙二醇与脱水山梨糖醇的脂肪酸酯;或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外,该组合物也可包括赋形剂,诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言,除了本发明的由通式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物之外,可进一步含有载剂诸如悬浮剂,如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶,或这些物质中几种的混合物等。
本发明的由式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物可采用其它局部给药剂型给药,包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液,亦意欲涵盖于本发明的范围内。
此外,本公开还涵盖了试剂盒(例如制药包装)。提供的试剂盒可以包含本文所述的药物组合物或化合物和容器(例如,药瓶、安瓿、瓶子、注射器和/或分装包装或其它合适的容器)。在一些实施方式中,提供的试剂盒可以任选地进一步包括第二容器,其包含用于稀释或悬浮本文所述的药物组合物或化合物的药用赋形剂。在一些实施方式中,设置在第一容器和第二容器中的本文所述的药物组合物或化合物组合形成一个单元剂量形式。
在某些实施方式中,本文所述试剂盒进一步包括包含于试剂盒中的用于使用所述化合物或药物组合物的用法说明。本文所述的试剂盒还可以包括管理机构(如美国食品药品监督管理局(FDA))所要求的信息。在某些实施方式中,在试剂盒中包括的信息为处方信息。在某些实施方式中,试剂盒和用法说明提供用于治疗需要其的受试者的增殖性疾病和/或预防需要其的受试者的增殖性疾病。本文所述的试剂盒可以包含一种或多种额外的药物制剂作为单独的组合物。
以下结合具体的实施例对本发明作进一步详细的说明,但本发明不限于以下实施例,实施例是为了更好的阐释本发明的某些具体体现而不能被解释为以任何方式限定本发明的范围。实施例中未注明的条件为常规条件。除非特别说明,以下实施例中使用的试剂和仪器均为市售可得产品。
以下实施例中化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定使用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQadvantage MAX)。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例中无特殊说明,反应的温度为室温,为20℃-30℃。
实施例中采用的柱层析的洗脱机体系包括有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,D:丙酮和石油醚体系,溶剂的体积比例根据化合物的极性不同而进行调节。
实验中所用缩写语:D:氘;h:小时;min:分钟;EA:乙酸乙酯;DMF:N,N-二甲基酰胺;ml:毫升;mmol:摩尔;Cs2CO3:碳酸铯;PdCl2(dtbpf):[1,1'-双(二苯基膦基)二茂铁]二氯化钯;Boc:叔丁氧羰基;THF:四氢呋喃;DCM:二氯甲烷;DIPEA:二异丙基乙胺;TFA:三氟醋酸;TEA:三乙胺;THF:四氢呋喃;TBD:1,5,7-三氮杂二环[4.4.0]癸-5-烯;N:摩尔每升。
实施例1:化合物1的制备
按照如下路线利用起始原料1-1制备化合物1。
步骤1:中间体1-3的合成
将原料1-1(1.25g,9.0mmol)溶于二氧六环(10mL)中,加入中间体1-2(3.00g,9.0mmol),Cs2CO3(4.42g,13.5mmol),Pd(dppf)Cl2(0.40g,5.4mmol),加热至100℃反应过夜。反应完全后,冷至室温,加入10mL水和20mL EA萃取,干燥浓缩有机相,柱层析得中间体1-3(1.90g,76%)。
1H NMR(400MHz,CDCl3):7.20-7.09(m,2H),6.91-6.89(m,2H),5.85(brs,1H),4.08(brs,2H),3.64(t,J=8.0Hz,2H),2.47(brs,2H),1.50(s,9H);
MS m/z(ESI):276.1[M+1].
步骤2:中间体1-4的合成
将中间体1-3(400mg,1.45mmol)加入甲醇(6.0mL)中,加入5%Pd/C(80mg,20%),室温反应过夜。反应完全后,过滤,滤液浓缩得到氢化产物1-4(320mg,75%)。
1H NMR(400MHz,CDCl3):7.12-7.05(m,2H),6.87(t,J=8.0Hz,1H),6.80(t,J=8.0Hz,1H),4.23(brs,2H),3.09-3.02(m,1H),2.83(brs,2H),1.84-1.81(m,2H),1.65-1.59(m,2H),1.49(s,9H);
步骤3:中间体1-6的合成
将中间体1-4(320mg,1.15mmol)、取代的苄溴化合物1-5(247mg,1.15mmol)溶于乙腈(10ml)中,加入碳酸钾(319mg,2.31mmol),室温反应过夜。反应完成后,浓缩,加入10mL水,用EA萃取两次,无水硫酸钠干燥,浓缩得到白色固体粗品1-6(370mg,78%)
1H NMR(400MHz,CDCl3):7.64(t,J=8.0Hz,1H),7.52(d,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),7.21-7.15(m,2H),7.02(t,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),5.21(s,2H),4.24(brs,2H),3.16-3.10(m,1H),2.82(brs,2H),1.83-1.80(m,2H),1.66-1.59(m,2H),1.48(s,9H).
步骤4:中间体1-7的合成
将中间体1-6(350mg,0.85mmol)加入DCM(20mL)中,加入TFA(2.0mL),室温反应2.0h。反应完全后,浓缩,加入EA,用饱和碳酸氢钠水溶液调pH到8,分液,有机相干燥浓缩得中间体1-8(270mg),无需纯化直接投入下一步反应.
步骤5:中间体1-9的合成
将中间体1-7(270mg,0.87mmol)、氯代物1-8(205mg,0.69mmol,参照WO2018109607合成)溶于二氧六环(6mL)中,加入DIPEA(393mg,3.0mmol),加热到50℃反应,反应结束后,加入H2O(5mL)和EA(15mL)萃取,干燥浓缩,柱层析纯化得中间体1-9(200mg,40%)。
1H NMR(400MHz,CDCl3):8.18(s,1H),7.98(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.65(t,J=8.0Hz,1H),7.54(d,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),7.24-7.16(m,2H),7.01(t,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),5.26-5.23(m,1H),5.20(s,2H),4.76-4.61(m,3H),4.44-4.40(m,1H),4.00(s,2H),3.95(s,3H),3.07-2.98(m,3H),2.77-2.75(m,1H),2.50-2.45(m,1H),2.35-2.28(m,2H),1.85-1.83(m,2H),1.76-1.71(m,2H).
MS m/z(ESI):569.2[M+1].
步骤6:化合物1的合成
将中间体1-9(100mg,0.17mmol)加入MeCN/THF(4mL/4mL)的混合溶剂中,加入0.97N六元二环胍(TBD)(0.4mL),室温反应过夜。继续补加0.97N TBD(1.0mL)反应2h。浓缩溶剂,加入水(6.0mL),用1N柠檬酸水溶液调体系pH到5-6,加入EA(10mL),萃取得有机相,干燥浓缩,柱层析纯化得化合物1(70mg,72%)
1H NMR(400MHz,DMSO-d6):12.74(brs,1H),8.28(s,1H),7.96(d,J=8.0Hz,1H),7.80-7.74(m,3H),7.65(t,J=8.0Hz,1H),7.22(t,J=8.0Hz,2H),7.08(d,J=8.0Hz,1H),6.97(d,J=8.0Hz,1H),5.25(s,2H),5.10(s,1H),4.82-4.79(m,1H),4.69-4.65(m,1H),4.51-4.48(m,1H),4.39-4.36(m,1H),4.04-3.94(m,1H),3.82-3.79(m,1H),3.01-2.89(m,3H),2.70-2.68(m,1H),2.45-2.43(m,1H),2.24-2.18(m,2H),1.70-1.60(m,4H).
MS m/z(ESI):555.1[M+1].
实施例2:化合物2的制备
按照实施例1类似的合成方式,用起始原料(3-氟-2-羟基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物2。
1H NMR(400MHz,DMSO-d6):8.19(s,1H),7.84(d,J=8.0Hz,1H),7.74-7.66(m,3H),7.58(d,J=8.0Hz,1H),7.06-6.96(m,3H),5.08(s,2H),5.01-4.99(m,1H),4.74-4.68(m,1H),4.58-4.55(m,1H),4.42-4.40(m,1H),4.29-4.27(m,1H),3.87(d,J=16.0Hz,1H),3.72(d,J=16.0Hz,1H),2.90-2.87(m,1H),2.76-2.63(m,3H),2.35-2.30(m,1H),2.04-1.91(m,2H),1.51-1.39(m,4H).
MS m/z(ESI):573.1[M+1].
实施例3:化合物3的制备
按照实施例1类似的合成方式,除了在实施例1中的步骤3中采用1-(溴甲基)-4-氯-2-氟苯替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外,以与实施例1中相同的方法制备得化合物3。
1H NMR(400MHz,DMSO-d6):8.19(s,1H),7.74(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.51-7.47(m,2H),7.44(d,J=8.0Hz,1H),7.11-7.08(m,2H),7.01(d,J=8.0Hz,1H),6.87-6.84(m,1H),5.06(s,2H),5.01-4.99(m,1H),4.74-4.70(m,1H),4.58-4.55(m,1H),4.42-4.40(m,1H),4.29-4.27(m,1H),3.87-3.75(m,2H),2.95-2.92(m,1H),2.79-2.70(m,2H),2.68-2.64(m,1H),2.35-2.31(m,1H),2.11-2.00(m,2H),1.60-1.55(m,4H).
MS m/z(ESI):564.2[M+1].
实施例4:化合物4的制备
按照实施例1和3的类似合成方式,用起始原料(3-氟-2-羟基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物4。
1H NMR(400MHz,DMSO-d6):12.74(brs,1H),8.28(s,1H),7.82(d,J=8.0Hz,1H),7.67(d,J=8.0Hz,1H),7.54-7.52(m,2H),7.36(d,J=8.0Hz,1H),7.13-7.04(m,3H),5.08(s,2H),4.83-4.77(m,1H),4.67-4.64(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),4.04-3.92(m,2H),3.80-3.77(m,1H),2.95-2.90(m,1H),2.84-2.73(m,3H),2.43-2.40(m,1H),2.09-2.00(m,2H),1.58-1.41(m,4H).
MS m/z(ESI):582.0[M+1].
实施例5:化合物5的制备
按照实施例1和3的类似合成方式,用起始原料(2-羟基-3-甲氧基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物5。
MS m/z(ESI):594.1[M+1].
实施例6:化合物6的制备
按照实施例1和3的类似合成方式,用起始原料(2-羟基-3-甲氧基苯基)苯硼酸替换1-1(2-羟基苯基)制备得到化合物6。
1H NMR(400MHz,DMSO-d6):12.71(brs,1H),8.27(s,1H),7.81(d,J=8.0Hz,1H),7.79-7.54(m,3H),7.38(d,J=8.0Hz,1H),7.23-7.21(m,1H),6.98(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),5.17(s,2H),5.10-5.05(m,1H),4.77-4.71(m,1H),4.62-4.58(m,1H),4.49-4.45(m,1H),4.38-4.36(m,1H),3.92-3.88(m,1H),3.77-3.74(m,1H),3.06-3.02(m,1H),2.95-2.93(m,1H),2.81-2.79(m,1H),2.67-2.63(m,1H),2.41-2.36(m,1H),2.13-2.00(m,4H),1.60-1.58(m,2H).
MS m/z(ESI):582.2[M+1].
实施例7:化合物7的制备
将30mg化合物4溶解于5mL甲醇中,加入6mg Pd/C,室温氢化过夜,过滤浓缩得到化合物7(29mg)。
MS m/z(ESI):548.2[M+1].
实施例8:化合物8的制备
按照实施例1类似的合成方式,除了在实施例1中的步骤3中采用1-(溴甲基)-2-氟-4-氟苯替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外,以与实施例1中相同的方法制备得化合物8。
1H NMR(400MHz,DMSO-d6):12.77(brs,1H),8.28(s,1H),7.82(d,J=8.0Hz,1H),7.66-7.60(m,2H),7.37-7.32(m,1H),7.20-7.09(m,4H),6.95-6.92(m,1H),5.13(s,2H),5.05-4.99(m,1H),4.82-4.77(m,1H),4.67-4.64(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96-3.92(m,1H),3.81-3.77(m,1H),3.00-2.97(m,1H),2.87-2.84(m,2H),2.71-2.69(m,1H),2.44-2.40(m,1H),2.22-2.10(m,2H),1.67-1.58(m,4H).
MS m/z(ESI):548.2[M+1].
实施例9:化合物9的制备
按照实施例1类似的合成方式,除了在实施例1中的步骤3中采用2-(溴甲基)-5-氯吡啶替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外,以与实施例1中相同的方法制备得化合物9。
1H NMR(400MHz,DMSO-d6):12.83(brs,1H),8.66(s,1H),8.35-8.39(m,2H),8.10-8.05(m,1H),7.90-7.83(m,1H),7.66-7.56(m,2H),7.21-7.14(m,2H),7.01(d,J=8.0Hz,1H),5.21(s,2H),5.12-5.05(m,1H),4.82-4.75(m,1H),4.67-4.60(m,1H),4.53-4.49(m,1H),4.38-4.36(m,1H),4.00-3.87(m,1H),3.76-3.74(m,1H),3.01-2.86(m,3H),2.71-2.65(m,1H),2.44-2.22(m,2H),1.95-1.89(m,1H),1.77-1.63(m,4H).MS m/z(ESI):547.2[M+1].
实施例10:化合物10的制备
按照实施例1类似的合成方式,除了在实施例1中的步骤3中采用4-氯-1-(1-氯乙基)-2-氟苯替代化合物1-5(4-(溴甲基)-3-氟苯腈)以外,以与实施例1中相同的方法制备得化合物10。
1H NMR(400MHz,DMSO-d6):12.71(brs,1H),8.30(s,1H),7.84(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,1H),7.48-7.44(m,2H),7.31(d,J=8.0Hz,1H),7.19(d,J=8.0Hz,1H),7.06(t,J=8.0Hz,1H),6.87(t,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),5.65(q,J=8.0Hz,1H),5.12-5.10(m,1H),4.74-4.70(m,1H),4.51-4.48(m,1H),4.40-4.37(m,1H),4.04-3.99(m,1H),3.87-3.75(m,1H),2.98-2.90(m,3H),2.72-2.70(m,1H),2.43-2.41(m,1H),2.35-2.30(m,2H),1.68-1.65(m,4H),1.61(d,J=8.0Hz,3H).
MS m/z(ESI):578.2[M+1].
实施例11:化合物11的制备
按照实施例1类似的合成方式,制备得化合物11。
1H NMR(400MHz,DMSO-d6):12.72(brs,1H),8.28(s,1H),7.78(d,J=8.0Hz,1H),7.72(s,1H),7.64(d,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),7.22-7.18(m,2H),7.06(d,J=8.0Hz,1H),6.96-6.93(m,1H),5.15(s,2H),5.10-5.05(m,1H),4.81-4.77(m,1H),4.67-4.63(m,1H),4.50-4.48(m,1H),4.37-4.33(m,1H),4.02-3.93(m,2H),3.82-3.80(m,1H),3.00-2.88(m,3H),2.69-2.65(m,1H),2.43-2.39(m,1H),2.22-2.16(m,2H),1.70-1.61(m,4H).
MS m/z(ESI):580.2[M+1].
实施例12:化合物12的制备
按照实施例1类似的合成方式,制备得化合物12。
1H NMR(400MHz,DMSO-d6):12.77(brs,1H),8.29(s,1H),7.83(d,J=8.0Hz,1H),7.68(d,J=8.0Hz,1H),7.43-7.40(m,1H),7.19-7.17(m,2H),7.11-7.05(m,3H),6.92-6.90(m,1H),5.10(s,2H),4.81-4.79(m,1H),4.67-4.63(m,1H),4.37-4.36(m,1H),4.04-3.84(m,3H),3.02-2.97(m,1H),2.89-2.84(m,2H),2.73-2.65(m,1H),2.43-2.40(m,1H),2.33(s,3H),2.22-2.16(m,2H),1.69-1.60(m,4H).
MS m/z(ESI):544.2[M+1].
实施例13:化合物13的制备
按照实施例1类似的合成方式,制备得化合物13。
1H NMR(400MHz,DMSO-d6):12.72(brs,1H),8.28(s,1H),7.81(d,J=8.0Hz,1H),7.67(d,J=8.0Hz,1H),7.61-7.53(m,2H),7.39(d,J=8.0Hz,1H),7.22-7.18(m,1H),7.05-7.02(m,1H),6.77-6.73(m,1H),5.17(s,2H),5.08-5.05(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.51-4.46(m,1H),4.39-4.35(m,1H),3.96-3.93(m,1H),3.81-3.78(m,1H),2.99-2.97(m,1H),2.84-2.68(m,3H),2.40-2.38(m,1H),2.19-2.14(m,2H),1.66-1.63(m,4H);
MS m/z(ESI):582.2[M+1].
实施例14:化合物14的制备
按照实施例1类似的合成方式,制备得化合物14。
1H NMR(400MHz,DMSO-d6):12.67(brs,1H),8.28(s,1H),7.82(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.59-7.51(m,2H),7.38(d,J=8.0Hz,1H),7.13-7.09(m,1H),7.04-7.00(m,2H),5.13(s,2H),5.09-5.07(m,1H),4.83-4.76(m,1H),4.67-4.63(m,1H),4.50-4.48(m,1H),4.38-4.36(m,1H),4.04-4.02(m,1H),4.00-3.95(m,1H),3.92-3.85(m,1H),3.00-2.96(m,1H),2.85-2.80(m,2H),2.72-2.70(m,1H),2.45-2.41(m,1H),2.22-2.21(m,2H),1.66-1.62(m,4H)
MS m/z(ESI):582.2[M+1].
实施例15:化合物15的制备
按照实施例1类似的合成方式,制备得化合物15。
1H NMR(400MHz,DMSO-d6):12.72(brs,1H),8.29(s,1H),7.83(d,J=8.0Hz,1H),7.67(s,1H),7.41(d,J=12.0Hz,1H),7.30-7.22(m,2H),7.05(d,J=8.0Hz,1H),6.93-6.90(m,1H),6.58-6.56(m,1H),6.32(d,J=8.0Hz,1H),5.84(brs,1H),5.11-5.10(m,1H),4.86-4.80(m,1H),4.70-4.67(m,1H),4.51-4.50(m,1H),4.36-4.33(m,3H),4.04-3.99(m,2H),3.86-3.83(m,1H),3.05-3.02(m,1H),2.92-2.85(m,1H),2.75-2.70(m,2H),2.42-2.34(m,3H),1.83-1.77(m,2H),1.60-1.55(m,2H).
MS m/z(ESI):563.2[M+1].
实施例16:化合物16的制备
按照实施例1类似的合成方式,制备得化合物16。
MS m/z(ESI):577.2[M+1].
实施例17:化合物17的制备
按照实施例1类似的合成方式,制备得化合物17。
MS m/z(ESI):580.2[M+1].
实施例18:化合物18的制备
按照实施例1类似的合成方式,制备得化合物18。
1H NMR(400MHz,DMSO-d6):8.24(s,1H),7.83(d,J=8.0Hz,1H),7.68(d,J=8.0Hz,1H),7.57-7.54(m,1H),7.42-7.39(m,1H),7.30-7.28(m,1H),7.02-6.99(m,1H),6.95-6.90(m,3H),5.07(s,2H),4.77-4.70(m,2H),4.61-4.57(m,2H),4.48-4.44(m,2H),4.33-4.30(m,2H),2.98-2.94(m,3H),2.67-2.65(m,1H),2.62-2.56(m,3H),2.40-2.35(m,2H).
MS m/z(ESI):565.2[M+1].
实施例19:化合物19的制备
按照实施例1类似的合成方式,制备得化合物19。
MS m/z(ESI):564.2[M+1].
实施例20:化合物20的制备
按照实施例1类似的合成方式,制备得化合物20。
1H NMR(400MHz,DMSO-d6):12.74(brs,1H),8.24(s,1H),7.80(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.47-7.44(m,4H),7.33-7.31(m,4H),7.23-7.20(m,2H),7.06-7.00(m,1H),5.14(s,2H),4.91-4.88(m,1H),4.68-4.62(m,1H),4.54-4.50(m,1H),4.45-4.40(m,3H),4.34-4.31(m,1H),2.59-2.55(m,1H),2.30-2.34(m,1H).
MS m/z(ESI):557.1[M+1].
实施例21:化合物21的制备
按照实施例1类似的合成方式,制备得化合物21。
MS m/z(ESI):563.2[M+1].
实施例22:化合物22的制备
按照实施例1类似的合成方式,制备得化合物22。
MS m/z(ESI):565.2[M+1].
实施例23:化合物23的制备
按照实施例1类似的合成方式,制备得化合物23。
MS m/z(ESI):590.2[M+1].
实施例24:化合物24的制备
按照实施例1类似的合成方式,制备得化合物24。
MS m/z(ESI):508.1[M+1].
实施例25:化合物25的制备
按照实施例1类似的合成方式,制备得化合物25。
MS m/z(ESI):602.2[M+1].
实施例26:化合物26的制备
按照实施例1类似的合成方式,制备得化合物26。
MS m/z(ESI):566.2[M+1].
实施例27:化合物27的制备
按照实施例1类似的合成方式,制备得化合物26。
MS m/z(ESI):566.2[M+1].
实施例28:化合物28的制备
按照实施例1类似的合成方式,制备得化合物28。
MS m/z(ESI):578.2[M+1].
实施例29:化合物29的制备
按照实施例1类似的合成方式,制备得化合物29。
MS m/z(ESI):578.2[M+1].
实施例30:化合物30的制备
按照实施例1类似的合成方式,制备得化合物30。
MS m/z(ESI):592.2[M+1].
测试实施例1:GLP-1R cAMP Assay活性试验
本实验旨在验证本发明化合物对GLP-1R受体的激动活性。
主要试剂:
cAMP Detection Kit,Cisbio(Cat#62AM4PEJ) |
1M HEPES,Invitrogen(Cat#15630-106) |
1X HBSS,Invitrogen(Cat#14025) |
BSA,Sigma(Cat#B2064-100G) |
IBMX,Sigma(Cat#I5879) |
7-37,Hao Yuan(Cat#HY-P0055) |
培养基:
靶点 | 宿主细胞系 | 克隆 |
GLP-1R | HEK293 | N/A |
主要耗材与仪器:
OptiPlate-384,White,PerkinElmer(Cat#6007290); |
384well plate for Echo,Labcyte(Cat#P-05525); |
EnVision,PerkinElmer; |
Vi-cell counter,Beckman(Cat#Vi-CELL<sup>TM</sup>XR Cell Viability Analyzer) |
实验方法:
a)化合物源板的准备:
使用Bravo在DMSO中从100uM开始4倍稀释化合物,共10点。
使用Bravo在DMSO中从500nM开始4倍稀释参比化合物多肽GLP-1(7-37),共10点。
b)细胞悬浮液的制备:
1)在37℃水浴中快速解冻1小瓶GLP-1R细胞。
2)将细胞悬浮液转移到15ml锥形管中的10ml HBSS中。
3)在室温下以1000rpm离心细胞5分钟以沉淀细胞
4)轻轻吸出上清液,小心不要吸出细胞。
5)轻弹沉淀使细胞松弛,然后将细胞沉淀重悬于10ml HBSS中。使用无菌移液器上下移液以清除团块。
6)计数细胞的浓度并确定Vi-cell上的细胞活力。
7)将GLP-1R细胞以2.0xE5/mL细胞的浓度重新悬浮在测试缓冲液中。
8)将10μLGLP-1R细胞转移到OptiPlate-384孔板中。
c)化合物的转移:
1)使用Echo Transfer将100nL化合物转移到OptiPlate-384板上。
2)以1000rpm旋转平板5秒钟。
d)激动剂的HTRF cAMP分析:
1)在添加检测试剂之前,将板在室温下孵育30分钟。
2)使用电动多通道移液器分别添加10μL检测试剂。
3)用TopSeal-A膜覆盖384孔板,并在室温下孵育60分钟。
卸下TopSeal-A,在EnVision上阅读。
具体测试数据见下表1。
表1
结论:本发明中的化合物显示了很好的GLP-1R受体激动活性。
测试实施例2:大鼠药代动力学评价:
以大鼠为受试动物,测试了大鼠灌胃给予化合物后不同时刻血浆中药物浓度。研究本发明化合物在大鼠体内药物代谢动力学行为,评价其药物代谢特征。每组实施例选用3只体重相近的大鼠,口服给予剂量为10mg/kg,单次给药。动物给药后在15min、30min、1h、2h、4h、6h、8h、12h、24h时间点采集血液。采用LC-MS/MS分析方法检测血浆中化合物含量,方法的定量下限均为20ng/mL。使用代谢动力学数据分析软件WinNonlin 7.0对血浆中的浓度数据进行统计,利用非房室模型法(NCA)计算药代参数,具体见下表2。
实验方案:
实验药品:本发明化合物及对照化合物。
药物配置:取一定量药物,加入2%Klucel LF+0.1%Tween 80水溶液,配制成呈澄清溶液或均匀悬浮液。
给药:大鼠禁食过夜后灌胃给药,给药剂量为10mg/kg。
操作:大鼠灌胃给药,于给药前及给药后15min、30min、1h、2h、4h、6h、8h、12h、24h尾静脉采血,置于肝素化样品管中,4℃,3500转/分钟离心10分钟分离血浆,于-20℃保存,给药后2小时进食。
测定药物灌胃给药后大鼠血浆中待测化合物的含量:血浆样品室温解冻后分别取50μL,加入130μL的内标工作液(1000ng/mL,乙腈,甲苯磺丁脲),涡旋约1min后,4℃,13000rpm条件下离心10min。取50μL上清液与100μL 50%乙腈水混合后进样LC/MS/MS分析。
药代动力学参数结果见表2。
表2:大鼠药物代谢数据
结论:相比于对照化合物PF-06882961及Ref-01、Ref-02,本发明的化合物吸收更好,血液中药物的暴露量更高,具有非常优异的药物代谢性质。
测试实施例3:食蟹猴药代动力学评价
以食蟹猴为受试动物,测试了食蟹猴静注与口服给予化合物后不同时刻血浆中药物浓度。研究本发明化合物在食蟹猴体内药物代谢动力学行为,评价其药物代谢特征。每组实施例选用2只体重相近的食蟹猴,静注给予剂量为1mg/kg,口服给予剂量为50mg/kg,单次给药。
给药时食蟹猴周龄:约2-4周岁;体重:给药开始时3.0-4.6kg;4只;性别:雄性。
静脉组:取配制终浓度为0.5mg/mL的供试品用于静脉给药,配制溶剂为5%DMSO+45%PEG400+50%水,制剂呈澄清溶液。
口服组:取配制终浓度为10mg/mL的供试品用于口服给药,配制溶剂为5%DMSO+45%PEG400+50%水,制剂呈均一混悬溶液。
动物给药后在5min、15min、30min、1h、2h、4h、7h、12h、24h时间点采集血液。采用LC-MS/MS分析方法检测血浆中化合物含量,方法的定量下限均为20ng/mL。使用代谢动力学数据分析软件WinNonlin 7.0对血浆中的浓度数据进行统计,利用非房室模型法(NCA)计算药代参数,具体见下表3。
测定药物给药后食蟹猴血浆中待测化合物的含量:血液样本采集后放置于标记好的冰浴离心管中,迅速离心分离出血浆,离心条件:4000转/分钟,10分钟,4℃,血浆置于-40℃以下条件保存待测。
药代动力学参数结果见表3。
结论:相比于对照化合物PF-06882961,在相同制剂和给药剂量下,在食蟹猴中,本发明化合物具有明显更优的药代性质。口服本发明化合物后,具有更高的血液暴露量,24小时后仍然具有很高的血药浓度,口服生物利用度明显更好,适合口服给药。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种以下式(I)表示的化合物或其药学上可接受的盐,
其中,
A是苯基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基;
R1选自-H、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基、-C6-10芳基或含有选自O或N中的一个或两个杂原子的-C5-10杂芳基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基可以被0-3个F取代;
下标m是0、1、2或3的整数;
R2、R3各自独立选自-H、氘、C1-6烷基;或者R2、R3与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的杂环烷基;
L选自-O-、-S-、-NR11-或-C(R11R12)-;所述R11、R12为氢或-C1-6烷基;
R4选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
下标n是0、1或2的整数;
R5选自-H、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
下标o是0、1或2的整数;
R6、R7各自独立地选自-H、氘、-C1-6烷基;或者R6、R7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基;或者R6与其相连的碳原子以及B环一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基;
R8选自-C1-3烷基、-亚甲基C3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基;其中,所述-C1-3烷基、亚甲基C3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代;
Z选自N或CR13;
R9选自氢、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
下标p是0、1或2的整数;
R10选自-COOH或羧基等排体;
R13选自氢、卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基;所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基可以被0-3个F取代;
所述卤素选自F、Cl和Br。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述化合物或其药学上可接受的盐具有如下式(II)所示的结构:
其中,
A是苯基或吡啶基;
R1选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基、所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基可以被0-3个F取代;
下标m是0、1或2的整数;
R2、R3各自独立地选自-H、氘、C1-6烷基;
R4选自卤素、-CN、-OH、氘、-C1-6烷基或-C1-6烷氧基;
下标n是0或1的整数;
R5选自卤素、-OH、-C1-6烷基或-C1-6烷氧基;
下标o是0、1或2的整数;
R6、R7各自独立地选自-H、氘、C1-6烷基;或者R6、R7与其相连的碳原子一起组成3-6元环烷基或含有选自O或N中的一个或两个杂原子的3-6元杂环烷基;
R8选自-C1-3烷基、-亚甲基C3-6环烷基或-亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基;其中,所述-C1-3烷基、亚甲基C3-6环烷基、亚甲基含有选自O或N中的一个或两个杂原子的C4-6杂环烷基可以被选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基或含有选自O或N中的一个或两个杂原子的5-6元杂芳基中的一个或多个取代;
Z选自N或CR13;
R13选自氢、卤素、-CN、-OH、氘、-C1-6烷基或-C1-6烷氧基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述化合物或其药学上可接受的盐具有如下式(III)所示的结构:
其中,
R1选自卤素、-CN、-OH、氘、-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基、所述-C1-6烷基、-C1-6烷氧基、-C2-6烯基、-C2-6炔基可以被0-3个F取代;
下标m是1或2的整数;
A是苯基、吡啶基;
R4选自卤素、-OH、氘、-C1-6烷基或-C1-6烷氧基;
下标n是0或1的整数;
R5选自卤素、-OH、-C1-6烷基或-C1-6烷氧基;
下标o是0、1或2的整数;
R8选自-C1-3烷基、-亚甲基C3-6环烷基或-亚甲基C4-6杂环烷基。
6.根据权利要求4所述的化合物或其药学上可接受的盐,其特征在于,下标o是0。
8.一种药物组合物,所述药物组合物包括治疗有效量的根据权利要求1至7中任意一项所述的化合物或其药学上可接受的盐作为活性成分,以及药学上可接受的辅料。
9.根据权利要求1至4中任意一项所述的化合物或其药学上可接受的盐或根据权利要求8所述的药物组合物作为活性成分在制备用于通过激活GLP-1R受体来治疗代谢相关疾病的药物中的用途。
10.根据权利要求9所述的用途,其中,所述代谢相关疾病选自葡萄糖耐受不良、高血糖症、血脂异常、1型糖尿病(T1D)、2型糖尿病(T2D)、高甘油三酯血症、综合征X、胰岛素抵抗、葡萄糖耐量降低(IGT)、糖尿病性血脂异常、高脂血症,动脉硬化,动脉粥样硬化、高血压、肥胖症、非酒精性脂肪肝、非酒精性脂肪肝炎、肝纤维化、肝硬化、嗜睡等疾病中的任一种。
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WO2023111144A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
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