CN109320483A - 香豆素衍生物、其制备方法及其作为药物的用途 - Google Patents
香豆素衍生物、其制备方法及其作为药物的用途 Download PDFInfo
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- CN109320483A CN109320483A CN201710659661.9A CN201710659661A CN109320483A CN 109320483 A CN109320483 A CN 109320483A CN 201710659661 A CN201710659661 A CN 201710659661A CN 109320483 A CN109320483 A CN 109320483A
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Abstract
本发明提供式(I)表示的化合物及其药学上可接受盐、酯,其中各个符号如说明书中所定义。所述化合物或其药学上可接受的盐、酯具有GPR40受体功能调节作用,引起胰岛素释放增加。并且作为胰岛素促分泌素制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物是有用的。
Description
技术领域
本发明涉及一种新的香豆素衍生物、其制备方法及含有该衍生物的药物或药物组合物以及其作为治疗剂特别是作为GPR40激动剂在制备预防或治疗糖尿病、代谢性综合征、及其相关疾病的药物中的用途。
背景技术
糖尿病是一种能量代谢疾病,主要分为1型糖尿病(胰岛素依赖型糖尿病)和2型糖尿病(非-胰岛素依赖型糖尿病)。目前全球约有3.66亿糖尿病患者,占世界人口的6.4%,其中2型糖尿病患者约占糖尿病患者总数的90~95%。
糖尿病可以通过饮食调节和锻炼治疗。当这些不能缓解症状时,需要进行药物治疗。目前糖尿病的药物治疗方法包括:双胍类如二甲双胍,能够减少肝脏中葡萄糖的形成;磺酰脲类如格列本脲,能够刺激胰腺β细胞分泌更多的胰岛素;噻唑烷二酮类如匹格列酮,通过激活氧化物酶体增殖物激活受体γ(PPAR-γ)增强胰岛素的生物效用;α-葡萄糖苷酶抑制剂如阿卡波糖,能够抑制肠道内葡萄糖的生成;胰高血糖素样肽-1(GLP-1)类似物如利拉鲁肽,能够促进胰腺的β细胞分泌胰岛素;二肽基肽酶IV(DPP-IV)抑制剂如西格列汀,能够抑制体内GLP-1的降解。但是,现有的治疗糖尿病的方法都有一定的缺陷。例如胰岛素注射剂和磺酰脲类,可能引起低血糖和体重增加副作用;二甲双胍类、α-葡萄糖苷酶抑制剂和GLP-1类似物可能引起胃肠道副作用;PPAR-γ激动剂可能引起体重增加和水肿副作用;DPP-IV抑制剂可能引起咽上部炎、头疼和感染副作用。针对多个领域的研究正在进行,以期为市场带来更有效的新型降血糖药物。
游离脂肪酸受体(FFAR)是近几年去孤儿化的G蛋白偶联受体(GPCRs)。目前已确定的游离脂肪酸受体有G蛋白偶联受体40(GPR40)家族,包括GPR40(也称游离脂肪酸受体1,FFA1)、GPR41(也称也称游离脂肪酸受体3,FFA3)、GPR43(也称游离脂肪酸受体2,FFA2)以及其它家族的GPR84、GPR120。GPR40是在寻找新的促生长激素神经肽-甘丙肽受体(GALR)亚型时发现的孤儿型GPCR,在胰腺β细胞和分泌胰岛素的细胞系中高度表达。GPR40能结合如软脂酸,硬脂酸,油酸,亚油酸和亚麻酸等血浆中的游离脂肪酸实现多种生理机能。例如长链游离脂肪酸与GPR40结合后激活GPR40,诱导细胞内钙离子水平升高,增强葡萄糖刺激的胰岛素的分泌(GSIS)。GPR40调节剂发挥肠促胰岛素作用来促进GSIS,此外也可与多种治疗糖尿病药物联合使用。基于以上,GPR40激动剂可治疗糖尿病以及相关适应症,尤其是2型糖尿病,肥胖胰岛素抵抗,葡萄糖耐受不良,以及其他适应症。以GPR40为潜在的治疗靶点,发现和改造具有GPR40激动活性的化合物具有重要的研究价值和应用前景。
目前公开了一系列GPR40激动剂的专利申请,其中包括WO2004041266,WO2005087710,WO2005051890,WO2006083781,WO2007013689,WO2008066097,WO2009054390,WO2010085525等。
本发明涉及结构新颖的香豆素衍生物,其在体内表现出较好降血糖活性,因此所述通式(I)化合物及其可药用的盐、酯潜在的用于治疗或者预防糖尿病及相关疾病。
发明内容
权利要求通式(I)所示的化合物或其可药用的盐、酯:
其中:
X不存在或为C、O、S、NH或N(C1-C4烷基);
Y为O、CH2、S、NH或N(C1-C4烷基);
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环;
R1自为H、D、F、Cl、Br、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R2~R4相同或不同,并各自为H、F、Cl、Br、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2等;
R5~R7相同或不同并各自为H、D、F、Cl、Br、CN、CF3、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C3-C10碳环-O-、取代或未取代的C1-C6烷基-CO-、取代或未取代的C3-C10碳环-CO-、取代或未取代的C1-C6烷基-COO-、取代或未取代的C3-C10碳环-COO-、取代或未取代的C3-C10碳环-S(O)p-、取代或未取代C1-C6烷基-S(O)p-、取代或未取代C1-C6烷基-S(O)p-取代或未取代C1-C6烷基、NO2、NH2、NH(C1-C4烷基)、NH(取代或未取代的C3-C10碳环)、-N(C1-C4烷基)2、-CONH2、-CONH(C1-C4烷基)、(C1-C4烷基)CONH-、(取代或未取代的C3-C10碳环)CONH-、-CONH(取代或未取代的C3-C10碳环)、-CON(C1-C4烷基)2、取代或未取代的C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)p的杂原子的3至10元杂环基等,但不限于举例范围;
n为0、1、2、3、4、5或6;
m为0、1、2、3、4、5或6;
p在出现时为0、1或2。
根据权利要求1所述的通式(I)的化合物或其可药用的盐、酯,其是通式(II)所示的化合物或其可药用的盐、酯:
其中:
X不存在或为C、O、S、NH或N(C1-C4烷基);
Y为O、NH;
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环;
R1自为H、D、F、Cl、Br、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R2~R4相同或不同,并各自为H、F、Cl、Br、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R5~R7相同或不同并各自为H、D、F、Cl、Br、CN、CF3、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C3-C10碳环-O-、取代或未取代的C1-C6烷基-CO-、取代或未取代的C3-C10碳环-CO-、取代或未取代的C1-C6烷基-COO-、取代或未取代的C3-C10碳环-COO-、取代或未取代的C3-C10碳环-S(O)p-、取代或未取代C1-C6烷基-S(O)p-、取代或未取代C1-C6烷基-S(O)p-取代或未取代C1-C6烷基、NO2、NH2、NH(C1-C4烷基)、NH(取代或未取代的C3-C10碳环)、-N(C1-C4烷基)2、-CONH2、-CONH(C1-C4烷基)、(C1-C4烷基)CONH-、(取代或未取代的C3-C10碳环)CONH-、-CONH(取代或未取代的C3-C10碳环)、-CON(C1-C4烷基)2、取代或未取代的C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)p的杂原子的3至10元杂环基等,但不限于举例范围;
n为0、1、2、3、4、5或6;
m为0、1、2、3、4、5或6;
p在出现时为0、1或2。
根据权利要求1所述的通式(I)的化合物或其可药用的盐、酯,其是通式(III)所示的化合物或其可药用的盐、酯:
其中:
X为O、S、NH;
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环;
R1自为H、D、F、Cl、Br、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R2~R4相同或不同,并各自为H、F、Cl、Br、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-;
R5~R7相同或不同并各自为H、D、F、Cl、Br、CN、CF3、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C3-C10碳环-O-、取代或未取代的C1-C6烷基-CO-、取代或未取代的C3-C10碳环-CO-、取代或未取代的C1-C6烷基-COO-、取代或未取代的C3-C10碳环-COO-、取代或未取代的C3-C10碳环-S(O)p-、取代或未取代C1-C6烷基-S(O)p-、取代或未取代C1-C6烷基-S(O)p-取代或未取代C1-C6烷基、NO2、NH2、NH(C1-C4烷基)、NH(取代或未取代的C3-C10碳环)、-N(C1-C4烷基)2、-CONH2、-CONH(C1-C4烷基)、(C1-C4烷基)CONH-、(取代或未取代的C3-C10碳环)CONH-、-CONH(取代或未取代的C3-C10碳环)、-CON(C1-C4烷基)2、取代或未取代的C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)p的杂原子的3至10元杂环基等,但不限于举例范围;
n为0、1、2、3;
m为0、1、2、3;
p在出现时为0、1或2。
根据权利要求1-3所定义的通式(I)化合物及其可药用盐,该化合物选自:
2-(7-(苄氧基-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-1);
2-(4-甲基-7-((2-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-2);
2-(4-甲基-7-((3-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-3);
2-(4-甲基-7-((4-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-4);
2-(7-((2-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-5);
2-(7-((2-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-6);
2-(7-((3-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-7);
2-(7-((4-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-8);
2-(7-((2,4-二氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-9);
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-10);
2-(4-甲基-7-((2-硝基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-11);
2-(7-((2-氨基苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-12);
2-(7-((2,6-二氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-13);
2-(7-(苄胺基-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-14);
2-(7-((2-氟苄基)氨基)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-15);
2-(7-((4-氯苄基)氨基)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-16);
2-(7-((2-氯-6-氟苄基)氨基)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-17);
2-(4-甲基-7-((萘基-1-甲基)氨基)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-18)等,但不限于举例范围。
本发明的另一方面涉及通式(I)所述的化合物或可药用的盐、酯在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
所述的盐包通式(I)所示的化合物形成的无机盐或有机盐。
所述的酯包括通式(I)所示的化合物与醇形成的酯。
所述的无机盐包括通式(I)所示的化合物形成的Li盐、Na盐、K盐、Mg盐、Zn盐、Ca盐、Fe盐等,但不限于举例范围。
所述的有机盐包括通式(I)所示的化合物形成的氨盐、伯胺盐、仲胺盐、叔胺盐、季胺盐等,但不限于举例范围。
所述的酯包括通式(I)所示的化合物与C1-C30烷基醇、取代的C1-C30烷基醇、C3-C10碳环醇或取代的C3-C10碳环醇、多元醇(羟基数目大于等于2)等形成的酯,但不限于举例范围。
本发明的另一方面涉及通式(I)所述的化合物或可药用的盐、酯在制备GPR受体调节剂药物中的应用。
所述的GPR受体包括GPR40、GPR41、GPR43、GPR84、GPR119和GPR120等,但不限于举例范围。
本发明的另一方面涉及通式(I)所述的化合物或可药用的盐、酯在制备胰岛素分泌调节剂药物中的应用。
本发明的另一方面涉及一种药物组合物,其含有治疗有效剂量的通式(I)所述的化合物或其可药用的盐、酯及其可药用的载体、稀释剂或赋形剂。该药物组合物制备GPR40激动剂中的用途。该药物组合物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮肉、皮下、静脉、粘膜组织,或是被其他物质混合或包裹后导入机体等,但不限于举例范围。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物药物,该药物可制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式,但不限于举例范围。
发明的详细说明
除非另有说明,否则说明书和权利要求书中的术语具有下述含义。
“C1-C4烷基”可以提及例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等,但不限于举例范围。
“℃1-C6烷基”可以提及如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等,但不限于举例范围。
“C1-C30烷基”可以为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基、壬基、葵基等,但不限于举例范围。
“多元醇”可以为乙二醇、丙三醇、苯二酚、苯三酚、寡聚糖、多聚糖、多聚醇等,但不限于举例范围。
“C3-C10碳环”可以提及例如环丙烷、环丁烷、环戊烷、环己烷等饱和碳环;环丁烯、环戊烯、环己烯等不饱和碳环及苯环等芳香碳环,但不限于举例范围。
“杂环”可以提及例如5-10元杂环,构成杂环的原子除了含有碳原子外,还含有一种或两种选自N、S、O的1至4个杂原子,优选5-10元非芳香杂环或5-10元芳香杂环等。具体地,非芳香杂环例如四氢呋喃、四氢吡喃、吡咯烷基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基等;芳香杂环例如噻吩基、呋喃基、吡啶基、噻唑基、嘧啶基、吡唑基、咪唑基等,但不限于举例范围。
“杂环基”可以提及例如5-10元(单环、双环或三环)杂环基,构成杂环的原子除了含有碳原子外,还含有一种或两种选自N、S、O的1至4个杂原子,优选5-10元非芳香杂环或5-10元芳香杂环等。具体地,非芳香杂环,例如四氢呋喃、四氢吡喃、吡咯烷基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基等;芳香杂环例如噻吩基、呋喃基、吡啶基、噻唑基、嘧啶基、吡唑基、咪唑基等,但不限于举例范围。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本发明通式(I)所述化合物或其可药用的盐、酯,或其前药与其他化学组分的混合物,其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收,利于活性成分在生物体内发挥生物活性。
本发明化合物的合成方法。
可如方案一所示制备式(I)的化合物。
化合物(VI)可以通过将通式(IV)表示的化合物和通式(V)表示的化合物(分别简称化合物(IV)和化合物(V))在碱的存在下反应制备,得到的化合物(VI)进一步在碱存在下水解酯,得到化合物(I)。
方案一:
其中:W为离去基团;R为烷基例如甲基、乙基、丙基、苯基等;X,R1~R4,m,n的定义如通式(I)中所述。
W表示离去基团,可以提及例如Cl、Br、I、任选卤代的C1-C6烷基磺酰基氧基(例如,甲磺酰基氧基、乙磺酰基氧基、三氯甲磺酰基)、任选具有取代基的的C6-C10芳基磺酰基氧基(例如,苯基磺酰基氧基、对甲苯磺酰基氧基,间-硝基苯磺酰基氧基等)等。
作为所述的碱包括无机碱和有机碱,所述的无机碱可以提及例如,碱金属碳酸盐类例如碳酸钠、碳酸钾、碳酸铯等;碱金属碳酸氢盐类例如碳酸氢钾等;碱金属氢氧化物例如氢氧化锂、氢氧化钠、氢氧化钾等;所述的无机碱可以提及例如三乙胺、吡啶、二甲基吡啶、正丁基锂、叔丁基钾等。
生物学评价
以下生物学测试实施例描述解释本发明。
本发明测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常用试剂。
测试例1本发明中化合物的体内降糖活性可以通过使用如下所述的测定系统测定:
正常小鼠口服糖耐量试验(OGTT):10周龄昆明种清洁级小鼠,体重22~26g,雄性,随机分为20组,空白对照组(空白溶媒:0.5%的羧甲基纤维素),阳性药对照组(TAK-875:50mg/kg),受试化合物组(50mg/kg),每组8只,实验前小鼠禁食不禁水12小时,各组均口服灌胃给药,断尾取血,测定血糖值。然后20组小鼠分别灌胃给予空白溶媒、TAK-875、和受试化合物,30min后测定血糖值记为0min,之后立灌胃给予葡萄糖(2g/kg),并于0,15,30,60,120min测定血糖值。结果见表2。
表2:化合物对正常小鼠口服糖耐量的影响(n=8)
正常小鼠口服糖耐量试验表明:化合物I-5及I-11在体内能够明显改善正常小鼠的口服糖耐量,效果与阳性对照TAK-875相当,另外I-10和I-13也表现出较好的降血糖作用。
测试例2本发明中化合物的体外细胞毒性可以通过使用如下所述的测定系统测定:
用胰酶消化对数生长期L02细胞,用培养液吹打成单细胞悬液,以每孔8×103个细胞接种于96孔细胞培养板中,每孔200μL,每种细胞分设6个复孔;
在37℃、5%CO2、饱和湿度培养箱内培养24h后,加不同浓度的药物(0,0.1,1.0,10,20,40,60,80,100,1000μM)处理,继续培养48h;
每孔加20μL MTT溶液(5mg/mL),37℃继续孵育4h,吸弃孔内培养液,每孔加入150μL DMSO,振荡10min至充分溶解;
在酶标仪570nm波长处测定各孔吸收度。注:设空白对照,以空白对照为基数基数相对值;重复试验3次,结果如表3所示。
表2:化合物对L02细胞的细胞毒性
细胞毒性结果表明,受试化合物在测定浓度范围内均未表现出明显的细胞毒性,TAK-875在高浓度时表现出一定细胞毒性,受试化合物的细胞毒性均弱于阳性药TAK-875。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
2-(7-(苄氧基-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-1)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-1(130mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-1(220mg,白色固体),产率:81.8%。
化合物VI-1(200mg,0.57mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.57mL,1.14mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-1(150mg,白色固体),产率:81.5%;
1H NMR(500MHz,DMSO-d6)δ12.44(s,1H),7.76(d,J=8.9Hz,1H),7.53(td,J=8.2,6.2Hz,1H),7.44(d,J=8.1Hz,1H),7.37-7.30(m,1H),7.18(d,J=2.5Hz,1H),7.06(dd,J=8.9,2.6Hz,1H),5.27(s,2H),3.58(s,2H),2.37(s,3H);
13C NMR(126MHz,DMSO)δ172.03,161.37,161.24,153.68,149.42,136.74,128.95,128.52,128.32,127.05,117.16,113.94,113.20,101.84,70.28,33.12,15.45;
IR:3415.3,3110.6,3053.4,2932.6,2914.3,2860.4,2732.1,2631.9,1721.3,1690.5,1611.5,1421.8,1324.2,1281.0,1224.7,1169.0,1080.9,1001.0,906.6,821.8,779.1,749.5,695.6;
MS(ESI,m/z):323.1[M-H]-。
实施例2
2-(4-甲基-7-((2-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-2)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-2(140mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-2(213mg,白色固体),产率:76.2%。
化合物VI-2(200mg,0.55mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.55mL,1.09mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-2(143mg,白色固体),产率:77.4%;
1H NMR(500MHz,DMSO-d6)δ7.75(d,J=8.9Hz,1H),7.43(d,J=7.3Hz,1H),7.29-7.18(m,3H),7.13(d,J=2.5Hz,1H),7.06(dd,J=8.9,2.5Hz,1H),5.21(s,2H),3.58(s,2H),2.37(s,3H),2.33(s,3H);
13C NMR(126MHz,DMSO)δ172.03,161.40,153.74,149.48,137.20,134.67,130.66,129.12,128.76,127.12,126.93,126.28,117.17,113.99,113.23,101.83,69.05,33.13,18.92,15.49;
IR:3564.0,3444.3,3083.4,2930.9,2861.3,2697.7,2586.0,1716.4,1691.8,1608.7,1507.8,1388.7,1364.6,1283.3,1208.1,1174.0,1110.4,998.7,851.7,760.1;
MS(ESI,m/z):338.1[M-H]-。
实施例3
2-(4-甲基-7-((3-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-3)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-3(141mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-3(242mg,白色固体),产率:86.6%。
化合物VI-3(200mg,0.55mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.55mL,1.09mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-3(156mg,白色固体),产率:84.5%。
1H NMR(500MHz,DMSO-d63)δ12.43(s,1H),7.73(d,J=8.8Hz,1H),7.33-7.21(m,3H),7.15(d,J=6.7Hz,1H),7.06(d,J=2.2Hz,1H),7.03(dd,J=8.8,2.3Hz,1H),5.17(s,2H),3.57(s,2H),2.36(s,3H),2.32(s,3H);
13C NMR(126MHz,DMSO)δ172.02,161.37,161.28,153.68,149.43,138.16,136.64,129.15,128.85,127.05,125.40,117.14,113.92,113.19,101.81,70.32,33.11,21.41,15.44;
IR:3069.8,3012.9,2906.7,2735.1,2650.9,1720.4,1701.8,1611.1,1389.8,1364.6,1330.4,1287.4,1232.9,1180.8,1101.6,873.5,769.8;
MS(ESI,m/z):338.1[M-H]-。
实施例4
2-(4-甲基-7-((4-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-4)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-4(141mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-4(220mg,白色固体),产率:78.7%。
化合物VI-4(200mg,0.55mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.55mL,1.09mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-4(120mg,白色固体),产率:65.0%.
1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),7.74(d,J=8.9Hz,1H),7.36(d,J=7.9Hz,2H),7.20(d,J=7.8Hz,2H),7.06(d,J=2.5Hz,1H),7.03(dd,J=8.9,2.5Hz,1H),5.17(s,2H),3.57(s,2H),2.36(s,3H),2.30(s,3H);
13C NMR(126MHz,DMSO)δ172.02,161.37,161.28,153.68,149.44,137.82,133.70,129.49,128.42,127.04,117.13,113.90,113.26,101.86,70.21,33.11,21.22,15.45;
IR:3421.0,3068.9,2947.9,2932.9,2877.9,2746.5,2621.4,1724.2,1704.6,1666.3,1608.9,1431.8,1385.1,1284.1,1242.2,1174.2,1114.1,998.2,837.7,784.4;
MS(ESI,m/z):338.1[M-H]-。
实施例5
2-(7-((2-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-5)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-5(144mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-5(247mg,白色固体),产率:87.4%。
化合物VI-5(200mg,0.54mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.54mL,1.08mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-5(175mg,白色固体),产率:94.6%.
1H NMR(500MHz,DMSO-d6)δ12.44(s,1H),7.75(d,J=8.9Hz,1H),7.59(td,J=7.6,1.6Hz,1H),7.48-7.41(m,1H),7.29-7.22(m,2H),7.12(d,J=2.5Hz,1H),7.05(dd,J=8.9,2.6Hz,1H),5.26(s,2H),3.58(s,2H),2.37(s,3H);
13C NMR(126MHz,DMSO)δ172.00,161.36,161.07,153.70,149.42,131.39,131.37,131.19,131.13,127.15,125.05,125.02,117.30,114.14,113.08,101.82,64.70,64.68,33.12,15.47;
IR:3389.9,3132.1,3070.8,3050.9,2984.8,2956.6,1715.7,1611.7,1495.1,1385.6,1238.7,1170.1,1092.1,1001.6,877.3,756.7;
MS(ESI,m/z):341.1[M-H]-。
实施例6
2-(7-((2-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-6)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-6(157mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-6(217mg,白色固体),产率:73.6%。
化合物VI-6(200mg,0.52mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.52mL,1.04mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-6(165mg,白色固体),产率:89.0%.
1H NMR(500MHz,DMSO-d6)δ12.44(s,1H),7.76(d,J=8.9Hz,1H),7.63(dd,J=7.0,2.3Hz,1H),7.53(dd,J=7.4,1.7Hz,1H),7.44-7.36(m,2H),7.12(d,J=2.5Hz,1H),7.06(dd,J=8.9,2.5Hz,1H),5.27(s,2H),3.58(s,2H),2.37(s,3H);
13C NMR(126MHz,DMSO)δ172.01,161.33,161.04,153.67,149.38,134.02,133.31,130.84,130.58,129.90,127.85,127.15,117.32,114.18,113.02,101.84,67.95,33.13,15.47;
IR:3068.0,2917.2,2739.2,2621.1,1706.4,1612.6,1567.3,1438.8,1382.0,1304.0,1282.2,1220.9,1170.2,1090.5,1031.7,848.7,750.4;
MS(ESI,m/z):357.1[M-H]-。
实施例7
2-(7-((3-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-7)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-7(156mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-7(237mg,白色固体),产率:80.3%。
化合物VI-7(200mg,0.52mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.52mL,1.04mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-7(136mg,白色固体),产率:73.3%.
1H NMR(500MHz,DMSO-d6)δ12.44(s,1H),7.75(d,J=8.8Hz,1H),7.55(s,1H),7.46-7.39(m,3H),7.08(d,J=2.5Hz,1H),7.05(dd,J=8.8,2.5Hz,1H),5.24(s,2H),3.57(s,2H),2.36(s,3H);
13C NMR(126MHz,DMSO)δ172.02,161.33,160.94,153.64,149.38,139.30,133.66,130.84,128.41,127.89,127.09,126.74,117.27,114.08,113.14,101.87,69.28,33.12,15.45;
IR:3383.8,3068.5,3014.2,2930.1,2737.2,2641.0,1704.6,1616.0,1567.5,1429.5,1388.9,1366.3,1222.3,1169.0,1155.2,1096.0,1036.5,851.7,773.4;
MS(ESI,m/z):357.1[M-H]-。
实施例8
2-(7-((4-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-8)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-8(156mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-8(224mg,白色固体),产率:75.9%。
化合物VI-8(200mg,0.52mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.52mL,1.04mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-8(130mg,白色固体),产率:70.1%.
1H NMR(500MHz,DMSO-d6)δ7.74(d,J=8.9Hz,1H),7.50(d,J=8.5Hz,2H),7.46(d,J=8.5Hz,2H),7.07(d,J=2.5Hz,1H),7.03(dd,J=8.8,2.5Hz,1H),5.22(s,2H),3.57(s,2H),2.36(s,3H).
13C NMR(126MHz,DMSO)δ172.01,161.34,161.02,153.66,149.40,135.77,133.14,130.07,128.94,127.08,117.24,114.05,113.18,101.88,69.39,33.11,15.45;
IR:3381.3,3072.1,3008.6,2928.9,2743.8,2647.6,2558.9,1716.1,1698.6,1613.3,1426.9,1386.4,1332.4,1288.7,1243.4,1106.6,1007.9,877.6,809.6,783.9;
MS(ESI,m/z):357.1[M-H]-。
实施例9
2-(7-((2,4-二氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-9)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-9(183mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-9(254mg,白色固体),产率:79.1%。
化合物VI-9(200mg,0.47mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.47mL,0.95mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-9(177mg,白色固体),产率:94.8%.
1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),7.76(d,J=8.9Hz,1H),7.70(d,J=1.4Hz,1H),7.65(d,J=8.3Hz,1H),7.52-7.46(m,1H),7.12(d,J=2.0Hz,1H),7.06(dd,J=8.8,2.0Hz,1H),5.26(s,2H),3.58(s,2H),2.37(s,3H);
13C NMR(126MHz,DMSO)δ171.98,161.27,160.81,153.63,149.33,134.20,133.22,131.88,129.37,127.99,127.13,117.39,114.26,112.99,101.86,67.29,33.12,15.46;
IR:3389.1,3078.5,3009.2,2926.1,2735.8,2652.1,2538.2,1701.4,1609.7,1565.2,1512.4,1455.2,1387.5,1367.3,1287.5,1222.6,1173.5,1157.1,1094.3,1035.6,840.2,816.4,782.8,743.4;
MS(ESI,m/z):391.0[M-H]-。
实施例10
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-10)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-10(170mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-10(239mg,白色固体),产率:77.4%。
化合物VI-10(200mg,0.49mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.49mL,0.98mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-10(144mg,白色固体),产率:77.4%.
1H NMR(500MHz,DMSO-d6)δ12.44(s,1H),7.76(d,J=8.9Hz,1H),7.53(td,J=8.2,6.2Hz,1H),7.44(d,J=8.1Hz,1H),7.37-7.30(m,1H),7.18(d,J=2.5Hz,1H),7.06(dd,J=8.9,2.6Hz,1H),5.27(s,2H),3.58(s,2H),2.37(s,3H);
13C NMR(126MHz,DMSO)δ172.01,161.31,161.09,153.68,149.32,135.98,135.94,132.46,132.38,127.22,127.11,126.20,117.41,115.30,115.13,114.27,112.94,101.68,61.92,33.12,15.44;
IR:3380.7,3093.6,3010.4,2937.5,2896.8,2739.5,2642.3,1893.8,1698.8,1610.0,1509.0,1454.2,1430.6,1387.8,1361.7,1332.1,1284.3,1227.3,1177.9,1100.9,1000.2,977.6,873.2,840.0,783.8;
MS(ESI,m/z):375.0[M-H]-。
实施例11
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-11)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-11(163mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-11(253mg,白色固体),产率:83.4%。
化合物VI-11(200mg,0.49mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.49mL,0.98mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-11(154mg,白色固体),产率:80.2%.
1H NMR(500MHz,DMSO-d6)δ12.44(s,1H),8.15(d,J=7.9Hz,1H),7.80-7.74(m,3H),7.66-7.61(m,1H),7.11(d,J=2.5Hz,1H),7.06(dd,J=8.9,2.6Hz,1H),5.59(s,2H),3.57(s,2H),2.37(s,3H).
13C NMR(126MHz,DMSO)δ171.95,161.30,160.71,153.66,149.41,147.94,134.51,132.22,129.78,129.71,127.32,125.38,117.45,114.37,113.07,102.03,67.38,33.14,15.51;
IR:3461.6,3362.7,3024.8,2922.9,2852.4,1708.7,1695.6,1607.4,1507.0,1387.5,1284.0,1219.5,1167.3,1097.2,998.3,840.4,768.4;
MS(ESI,m/z):368.1[M-H]-。
实施例12
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-12)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-12(108mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-12(150mg,白色固体),产率:53.5%。
化合物VI-12(140mg,0.38mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.38mL,0.76mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-12(90mg,白色固体),产率:69.6%.
1H NMR(500MHz,DMSO-d6)δ7.74(d,J=8.9Hz,1H),7.21(dd,J=7.5,1.4Hz,1H),7.10(d,J=2.5Hz,1H),7.07-7.01(m,2H),6.69(dd,J=8.0,0.9Hz,1H),6.56(td,J=7.4,1.0Hz,1H),5.08(s,2H),3.58(s,2H),2.37(s,3H);
13C NMR(126MHz,DMSO)δ172.04,161.46,161.43,153.68,149.51,147.26,129.89,129.52,126.94,119.46,117.03,116.43,115.55,113.82,113.40,101.91,68.12,33.12,15.48;
IR:3062.6,2925.8,2851.1,1705.1,1608.9,1524.7,1284.5,1222.1,1176.3,1092.0,1032.2,859.9,788.8,728.7;
MS(ESI,m/z):338.1[M-H]-。
实施例13
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸(I-13)
化合物IV(200mg,0.76mmol)溶于10mL丙酮中,依次加入K2CO3(211mg,1.52mmol),催化量的KI和化合物V-13(158mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-13(264mg,白色固体),产率:89.1%。
化合物VI-13(200mg,0.51mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.51mL,1.02mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-13(143mg,白色固体),产率:77.0%.
1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),7.75(d,J=8.9Hz,1H),7.59-7.50(m,1H),7.19(t,J=8.0Hz,2H),7.14(d,J=2.5Hz,1H),7.04(dd,J=8.9,2.5Hz,1H),5.23(s,2H),3.58(s,2H),2.36(s,3H);
13C NMR(126MHz,DMSO)δ171.99,162.66,161.32,160.92,160.68,153.67,149.37,132.45,127.17,117.43,114.28,112.96,112.37,112.34,112.18,101.70,58.67,33.12,15.45;
IR:3149.3,3071.8,3056.7,2964.2,2852.3,1713.4,1612.2,1471.4,1387.5,1232.1,1158.7,1094.9,1052.2,1011.8,919.1,875.0,787.2,776.2;
MS(ESI,m/z):359.1[M-H]-。
实施例14
2-(7-(苄氧基)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸(I-14)
化合物IV(200mg,0.77mmol)溶于10mL丙酮中,依次加入K2CO3(212mg,1.53mmol),催化量的KI和化合物V-14(131mg,0.77mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-14(183mg,白色固体),产率:68.0%。
化合物VI-14(150mg,0.43mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.43mL,0.85mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-14(105mg,白色固体),产率:76.1%.
1H NMR(500MHz,DMSO)δ7.49(d,J=8.9Hz,1H),7.39-7.30(m,4H),7.27-7.18(m,2H),6.67(dd,J=8.8,2.3Hz,1H),6.40(d,J=2.2Hz,1H),4.37(d,J=6.0Hz,2H),3.49(s,2H),2.26(s,3H);
13C NMR(126MHz,DMSO)δ172.42,161.86,154.55,152.17,149.99,139.62,128.87,127.68,127.35,126.57,113.51,111.11,109.73,97.17,46.46,32.94,15.21;
IR:3346.0,3063.6,3028.6,2927.4,2853.6,2736.0,2630.1,2541.9,1700.9,1683.6,1625.0,1604.0,1560.9,1525.0,1421.1,1345.2,1232.0,1093.5,853.1,790.0,689.3,456.5;
MS(ESI,m/z):322.1[M-H]-。
实施例15
2-(7-((2-氟苄基)氧)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸(I-15)
化合物IV(200mg,0.77mmol)溶于10mL丙酮中,依次加入K2CO3(212mg,1.53mmol),催化量的KI和化合物V-15(144mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-15(173mg,白色固体),产率:61.2%。
化合物VI-15(150mg,0.41mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.41mL,0.82mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-15(119mg,白色固体),产率:85.9%.
1H NMR(500MHz,DMSO)δ12.33(s,1H),7.50(d,J=8.9Hz,1H),7.39(td,J=7.7,1.5Hz,1H),7.34-7.29(m,1H),7.24-7.18(m,1H),7.18-7.12(m,2H),6.68(dd,J=8.8,2.3Hz,1H),6.44(d,J=2.2Hz,1H),4.41(d,J=5.9Hz,2H),3.50(s,2H),2.27(s,3H);
13C NMR(126MHz,DMSO)δ172.38,161.84,154.55,151.92,149.97,130.01,129.98,129.54,129.47,126.65,124.85,124.83,115.79,115.62,113.67,110.92,109.90,97.06,67.47,32.91,25.57,15.20;
IR:3346.5,3081.4,3012.3,2927.3,2856.4,2734.8,2626.7,2540.3,1703.3,1682.7,1626.1,1605.5,1526.3,1345.8,1230.6,855.6,849.3,789.6,759.2,568.9;;
MS(ESI,m/z):340.1[M-H]-
实施例16
2-(7-((4-氯苄基)氧)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸(I-16)
化合物IV(200mg,0.77mmol)溶于10mL丙酮中,依次加入K2CO3(212mg,1.53mmol),催化量的KI和化合物V-16(57mg,0.76mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-16(180mg,白色固体),产率:60.9%。
化合物VI-16(150mg,0.39mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.39mL,0.78mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-16(110mg,白色固体),产率:79.1%.
1H NMR(500MHz,DMSO)δ7.48(d,J=8.9Hz,1H),7.42-7.35(m,4H),7.23(t,J=6.1Hz,1H),6.65(dd,J=8.8,2.3Hz,1H),6.39(d,J=2.2Hz,1H),4.37(d,J=6.1Hz,2H),3.49(s,2H),2.26(s,3H);
13C NMR(126MHz,DMSO)δ172.40,161.84,154.51,151.94,149.98,138.74,131.88,129.46,128.80,126.61,113.62,111.11,109.86,97.26,45.68,32.92,15.19;
IR:3321.1,3086.9,3017.1,2947.8,2897.5,2858.2,2727.8,2639.2,2560.9,1707.9,1681.9,1625.1,1603.8,1493.2,1341.3,1197.9,1156.4,1014.9,860.7,782.5,524.9;
MS(ESI,m/z):356.1[M-H]-。
实施例17
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸(I-17)
化合物IV(200mg,0.77mmol)溶于10mL丙酮中,依次加入K2CO3(212mg,1.53mmol),催化量的KI和化合物V-17(171mg,0.77mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-17(192mg,白色固体),产率:62.1%。
化合物VI-17(150mg,0.37mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.37mL,0.74mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-17(122mg,白色固体),产率:87.4%.
1H NMR(500MHz,DMSO)δ7.51(d,J=8.9Hz,1H),7.45-7.36(m,2H),7.29(ddd,J=9.5,8.1,1.3Hz,1H),6.92(t,J=5.3Hz,1H),6.72(dd,J=8.9,2.3Hz,1H),6.56(d,J=2.3Hz,1H),4.41(d,J=4.4Hz,2H),3.51(s,2H),2.28(s,3H);
13C NMR(126MHz,DMSO)δ172.37,161.88,154.59,151.77,150.01,135.42,135.37,130.95,130.87,126.63,126.13,124.10,115.21,115.03,113.68,110.85,109.89,96.79,40.43,40.27,40.10,39.93,39.77,39.60,39.43,38.64,32.93,15.24;
IR:3322.7,3082.4,3020.2,2925.0,2725.6,2627.4,1686.2,1626.0,1577.3,1527.9,1453.0,1317.5,1221.9,1195.0,975.2,849.2,784.3;
MS(ESI,m/z):374.1[M-H]-。
实施例18
2-(4-甲基-7-(萘-1-甲氧基)-2-氧代-1,2-二氢喹啉-3-)乙酸(I-18)
化合物IV(200mg,0.77mmol)溶于10mL丙酮中,依次加入K2CO3(212mg,1.53mmol),催化量的KI和化合物V-18(169mg,0.77mmol),加热回流反应过夜,反应结束后,过滤,减压浓缩滤液。残余物硅胶柱层析分离(洗脱剂体系:石油醚和乙酸乙酯),得到目标产物VI-18(160mg,白色固体),产率:52.1%。
化合物VI-18(150mg,0.37mmol)溶于6mL四氢呋喃、甲醇和水(2∶3∶1)三组分溶剂中,加入2M的氢氧化钠溶液(0.37mL,0.64mmol),室温搅拌反应2h,反应结束后,加入10mL水,滴加1M盐酸至反应液pH为3,用乙酸乙酯萃取(30mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,减压浓缩滤液,残余物硅胶柱层析分离(洗脱剂体系:二氯甲烷和甲醇),得到目标产物I-18(102mg,白色固体),产率:73.1%.
1H NMR(500MHz,DMSO)δ8.13(d,J=8.2Hz,1H),7.99-7.94(m,1H),7.87(d,J=8.1Hz,1H),7.62-7.43(m,5H),7.21(s,1H),6.73(dd,J=8.9,2.3Hz,1H),6.51(d,J=2.2Hz,1H),4.82(d,J=5.5Hz,2H),3.50(s,2H),2.28(s,3H);
13C NMR(126MHz,DMSO)δ172.41,161.89,154.65,152.31,150.04,134.42,133.91,131.56,129.02,128.11,126.70,126.65,126.31,125.90,125.72,124.06,113.47,110.99,109.74,97.09,44.74,,32.94,15.24;
IR:3333.8,3059.4,3005.9,2924.4,2865.5,2735.9,2640.3,1704.4,1685.9,1624.3,1606.1,1523.7,1508.0,1340.9,1200.9,861.5,774.9;
MS(ESI,m/z):372.1[M-H]-。
实施例19
含活性剂I-4的片剂:
按常规方法将原辅料混合,制粒,干燥,压片。
Claims (15)
1.权利要求通式(I)所示的化合物或其可药用的盐、酯:
其中:
X不存在或为C、O、S、NH或N(C1-C4烷基);
Y为O、CH2、S、NH或N(C1-C4烷基);
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环;
R1自为H、D、F、Cl、Br、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R2~R4相同或不同,并各自为H、F、Cl、Br、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2等;
R5~R7相同或不同并各自为H、D、F、Cl、Br、CN、CF3、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C3-C10碳环-O-、取代或未取代的C1-C6烷基-CO-、取代或未取代的C3-C10碳环-CO-、取代或未取代的C1-C6烷基-COO-、取代或未取代的C3-C10碳环-COO-、取代或未取代的C3-C10碳环-S(O)p-、取代或未取代C1-C6烷基-S(O)p-、取代或未取代C1-C6烷基-S(O)p-取代或未取代C1-C6烷基、NO2、NH2、NH(C1-C4烷基)、NH(取代或未取代的C3-C10碳环)、-N(C1-C4烷基)2、-CONH2、-CONH(C1-C4烷基)、(C1-C4烷基)CONH-、(取代或未取代的C3-C10碳环)CONH-、-CONH(取代或未取代的C3-C10碳环)、-CON(C1-C4烷基)2、取代或未取代的C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)p的杂原子的3至10元杂环基等,但不限于举例范围;
n为0、1、2、3、4、5或6;
m为0、1、2、3、4、5或6;
p在出现时为0、1或2。
2.根据权利要求1所述的通式(I)的化合物或其可药用的盐、酯,其是通式(II)所示的化合物或其可药用的盐、酯:
其中:
X不存在或为C、O、S、NH或N(C1-C4烷基);
Y为O、NH;
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环;
R1自为H、D、F、Cl、Br、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R2~R4相同或不同,并各自为H、F、Cl、Br、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R5~R7相同或不同并各自为H、D、F、Cl、Br、CN、CF3、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C3-C10碳环-O-、取代或未取代的C1-C6烷基-CO-、取代或未取代的C3-C10碳环-CO-、取代或未取代的C1-C6烷基-COO-、取代或未取代的C3-C10碳环-COO-、取代或未取代的C3-C10碳环-S(O)p-、取代或未取代C1-C6烷基-S(O)p-、取代或未取代C1-C6烷基-S(O)p-取代或未取代C1-C6烷基、NO2、NH2、NH(C1-C4烷基)、NH(取代或未取代的C3-C10碳环)、-N(C1-C4烷基)2、-CONH2、-CONH(C1-C4烷基)、(C1-C4烷基)CONH-、(取代或未取代的C3-C10碳环)CONH-、-CONH(取代或未取代的C3-C10碳环)、-CON(C1-C4烷基)2、取代或未取代的C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)p的杂原子的3至10元杂环基等,但不限于举例范围;
n为0、1、2、3、4、5或6;
m为0、1、2、3、4、5或6;
p在出现时为0、1或2。
3.根据权利要求1所述的通式(I)的化合物或其可药用的盐、酯,其是通式(III)所示的化合物或其可药用的盐、酯:
其中:
X为O、S、NH;
A环为取代或未取代的C3-C10碳环、取代或未取代的杂环;
R1自为H、D、F、Cl、Br、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-等;
R2~R4相同或不同,并各自为H、F、Cl、Br、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-;
R5~R7相同或不同并各自为H、D、F、Cl、Br、CN、CF3、OH、OD、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C3-C10碳环-O-、取代或未取代的C1-C6烷基-CO-、取代或未取代的C3-C10碳环-CO-、取代或未取代的C1-C6烷基-COO-、取代或未取代的C3-C10碳环-COO-、取代或未取代的C3-C10碳环-S(O)p-、取代或未取代C1-C6烷基-S(O)p-、取代或未取代C1-C6烷基-S(O)p-取代或未取代C1-C6烷基、NO2、NH2、NH(C1-C4烷基)、NH(取代或未取代的C3-C10碳环)、-N(C1-C4烷基)2、-CONH2、-CONH(C1-C4烷基)、(C1-C4烷基)CONH-、(取代或未取代的C3-C10碳环)CONH-、-CONH(取代或未取代的C3-C10碳环)、-CON(C1-C4烷基)2、取代或未取代的C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)p的杂原子的3至10元杂环基等,但不限于举例范围;
n为0、1、2、3;
m为0、1、2、3;
p在出现时为0、1或2。
4.根据权利要求1-3所定义的通式(I)化合物及其可药用盐、酯,该化合物选自:
2-(7-(苄氧基-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(4-甲基-7-((2-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(4-甲基-7-((3-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(4-甲基-7-((4-甲基苄基)氧)-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(7-((2-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(7-((2-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(7-((3-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(7-((4-氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(7-((2,4-二氯苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-2H-苯并二氢吡喃-3-)乙酸;
2-(7-(苄氧基)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸;
2-(7-((2-氟苄基)氧)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸;
2-(7-((4-氯苄基)氧)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸;
2-(7-((2-氯-6-氟苄基)氧)-4-甲基-2-氧代-1,2-二氢喹啉-3-)乙酸;
2-(4-甲基-7-(萘-1-甲氧基)-2-氧代-1,2-二氢喹啉-3-)乙酸。
5.权利要求1-4中所述的盐包括权利要求1-4中任意一项所述通式(I)所示的化合物形成的无机盐或有机盐。
6.权利要求1-4中所述的酯包括权利要求1-4中任意一项所述通式(I)所示的化合物与醇形成的酯。
7.权利要求5中所述的无机盐包括权利要求1-4中任意一项所述通式(I)所示的化合物形成的Li盐、Na盐、K盐、Mg盐、Zn盐、Ca盐、Fe盐等,但不限于举例范围。
8.权利要求5中所述的有机盐包括权利要求1-4中任意一项所述通式(I)所示的化合物形成的氨盐、伯胺盐、仲胺盐、叔胺盐、季胺盐等,但不限于举例范围。
9.权利要求6中所述的酯包括权利要求1-4中任意一项所述通式(I)所示的化合物与C1-C30烷基醇、取代的C1-C30烷基醇、C3-C10碳环醇或取代的C3-C10碳环醇、多元醇(羟基数目大于等于2)等形成的酯,但不限于举例范围。
10.权利要求1-4所述的通式(I)化合物、其可药用盐、酯在制备GPR受体调节剂药物中的应用。
11.权利要求1-4所述的通式(I)化合物、其可药用盐、酯在制备胰岛素分泌调节剂药物中的应用。
12.一种药物组合物,所述药物组合物含有治疗有效剂量的根据权利要求1-4中任意一项所述通式(I)所示的化合物、其可药用的盐、酯及可药用的载体、稀释剂或赋形剂。
13.权利要求1-4所述的通式(I)化合物、其可药用盐、酯或权利要求12所述的药物组合物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
14.权利要求13所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物或药物组合物可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮肉、皮下、静脉、粘膜组织、或是被其他物质混合或包裹后导入机体等,但不限于举例范围。
15.权利要求13所述权利要求1-4中任意一项所述通式(I)所示的化合物、其可药用的盐或酯作为活性成分制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物,该药物可制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式,但不限于举例范围。
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