CN108164506A - 一种dpp-4酶抑制剂及其制备和应用 - Google Patents
一种dpp-4酶抑制剂及其制备和应用 Download PDFInfo
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- CN108164506A CN108164506A CN201810106027.7A CN201810106027A CN108164506A CN 108164506 A CN108164506 A CN 108164506A CN 201810106027 A CN201810106027 A CN 201810106027A CN 108164506 A CN108164506 A CN 108164506A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
Abstract
本发明涉及一种DPP‑4抑制剂及其制备和应用,具体地,本发明公开了如式A所示的结构全新的氨基酸衍生物,及其制备方法和作为DPP‑4抑制剂的用途。本发明的化合物表现出很好DPP‑4抑制作用,有作为抗糖尿病药物的应用价值。
Description
技术领域
本发明属于医药领域,具体地,本发明涉及一类新颖的DPP-4抑制剂氨基酸衍生物,及其制备方法和应用。
背景技术
糖尿病是一种长期慢性疾病,影响了全球超过3亿人口的健康。世界卫生组织(WHO)预测,至2030年,糖尿病将会成为世界第7大致死疾病。
人体内存在一种能调节血糖的多肽,称为胰高血糖样多肽-1(glucagon-likepeptide 1,GLP-1),GLP-1能刺激胰岛素的分泌,从而起到使血糖水平回归正常的作用。人体口服摄取的葡萄糖有50%-70%通过GLP-1/胰岛素通路代谢。因此,GLP-1是一种重要的降糖多肽。但是GLP-1在体内的半衰期极其短暂,大约只有2min。原因是人体内有一种二肽肽酶4(dipeptidyl peptidase 4,DPP-4)能迅速降解GLP-1,使之失活。因此,通过抑制DPP-4酶的活性,能提高体内GLP-1浓度,延长其半衰期,从而起到降血糖的目的。
目前市场上在售的DPP-4抑制剂有很多副作用,如血糖控制不稳,发生低血糖等,有的甚至有心血管疾病和长期肾病的风险,因此,本领域仍然需要研发一类效能更高和安全性更好的DPP-4抑制剂。
发明内容
本发明的一个目的是提供一种效能更高和安全性更好的新型DPP-4抑制剂氨基酸衍生物。
本发明的另一目的是提供上述新型DPP-4抑制剂的制备方法。
本发明的另一目的是提供上述新型DPP-4抑制剂的用途。
本发明第一方面提供了式A化合物或其药学上可接受的盐,或其光学异构体,
其中:
R1选自下组:取代或未取代的苯基、取代或未取代的C3-C6环烷基、取代或未取代的5-10元饱和或不饱和杂环基;其中,所述的杂环基是指环的骨架上具有1-3个选自N、O或S的杂原子;其中,所述取代是指被选自下组的一个或多个(例如1个、2个、3个)取代基所取代:羟基、酯基(COOC1-C6烷基、COO苯基或被C1-C6烷基、C1-C6烷氧基或卤代的C1-C6烷基取代的COO苯基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基;
R2选自下组:取代或未取代的3-10元饱和杂环基、取代或未取代的3-10元不饱和杂环基;其中,所述的杂环基是指环的骨架上至少含有1个N原子和任选的0-2个选自N、O或S的杂原子;其中,所述取代是指被选自下组的一个或多个(例如1个、2个、3个)取代基所取代:酯基(COOC1-C6烷基、COO苯基或被C1-C6烷基、C1-C6烷氧基或卤代的C1-C6烷基取代的COO苯基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基。
在另一优选例中,R1选自下组:取代或未取代的苯基、取代或未取代的咪唑基、取代或未取代的三唑基、取代或未取代的呋喃基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的吡啶基、取代或未取代的苯并吡咯基;其中,所述取代是指被选自下组的一个或多个(例如1个、2个、3个)取代基所取代:羟基、酯基(COOC1-C6烷基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基。
在另一优选例中,R1选自下组:
在另一优选例中,R2选自下组:取代或未取代的4-6元饱和杂环基;其中,所述的杂环基是指环的骨架上至少含有1个N原子;其中,所述取代是指被选自下组的一个或多个(例如1个、2个、3个)取代基所取代:酯基(COOC1-C6烷基、COO苯基或被C1-C6烷基、C1-C6烷氧基或卤代的C1-C6烷基取代的COO苯基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基。
在另一优选例中,R2选自下组:
其中,R3为C1-C6烷基、苯基或被C1-C6烷基、C1-C6烷氧基或卤代的C1-C6烷基取代的苯基。
在另一优选例中,所述化合物选自下组:
本发明第二方面提供了第一方面所述的化合物的制备方法,所述方法包括以下步骤:
(i)在惰性溶剂中,在碱性条件下,在缩合剂作用下将式a-1化合物与R2NH2进行反应,从而形成式a-2化合物;
(ii)在酸性溶液中,将式a-2化合物进行脱保护反应,从而形成式A化合物。
在另一优选例中,步骤(i)中,所述惰性溶剂选自下组:二氯甲烷、DMSO、DMF、四氢呋喃,或其组合。
在另一优选例中,步骤(i)中,所述缩合剂选自下组:2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)。
在另一优选例中,步骤(i)中,所述碱选自下组:三乙胺(TEA)、DIPEA,或其组合。
在另一优选例中,步骤(i)中,所述反应在不加热条件下进行;较佳地,反应温度为20℃-35℃。
在另一优选例中,步骤(ii)中,所述酸性溶液为含有三氟醋酸或氯化氢的溶液。较佳地,为含有三氟醋酸或氯化氢的二氯甲烷或四氢呋喃溶液。较佳地,其中,三氟醋酸或氯化氢:二氯甲烷或四氢呋喃的比例为1:10。
本发明第三方面提供了一种药物组合物,所述的药物组合物包括:(i)本发明第一方面所述的化合物或其药学上可接受的盐,或其光学异构体;以及(ii)药学上可接受的载体。
本发明第四方面提供了一种本发明第一方面所述化合物或其药学上可接受的盐,或其光学异构体的用途,或本发明第三方面所述组合物的用途,1)用于制备DPP-4酶抑制剂;2)用于制备与DPP-4酶的活性或表达量相关的疾病的药物。
在另一优选例中,所述的与DPP-4酶的活性或表达量相关的疾病为糖尿病。
本发明第五方面提供了一种DPP-4酶抑制剂,其包含本发明第一方面所述的化合物或其药学上可接受的盐,或其光学异构体;或本发明第三方面所述的组合物。
本发明还提供了一种治疗方法,所述方法包括步骤:向有需要的患者施用本发明第一方面所述的化合物或其药学上可接受的盐或本发明第三方面所述的药物组合物。
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,意外地发现了一类结构新颖的氨基酸衍生物,其具有优异的DPP-4抑制活性,可用于抗糖尿病作用。基于上述发现,发明人完成了本专利。
术语
在本发明中,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、胺基、C1-C4烷基(优选C1-C2烷基)、苯基或5-7元杂环基。
术语“C1-C6烷基”指具有1至6个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基、或类似基团;优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。术语“C1-C4烷基”和“C1-C2烷基”具有类似的含义。
术语“C3-C6环烷基”指在环上具有3至6个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、或类似基团。
术语“C1-C6烷氧基”指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基、或类似基团。
术语“C1-C6酰基”指具有“-CO-(C1-C6烷基)”结构的基团,非限制性地包括甲基酰基、乙基酰基、丙基酰基、异丙基酰基、丁基酰基、异丁基酰基、仲丁基酰基、叔丁基酰基、或类似基团。
术语“5-10元饱和或不饱和杂环基”或“3-10元饱和或不饱和杂环基”是指在环上含有1至3个选自N、O和S中的杂原子的饱和、部分不饱和或完全不饱和的5-10元或3-10元环基。术语“5-7元杂环基”是指在环上含有1至3个选自N、O和S中的杂原子的饱和、部分不饱和或完全不饱和的5-7元环基。上述杂环基可选自:呋喃、吡咯、噻唑、咪唑、三唑、吡啶、哌啶、哌嗪、吗啉、苯并吡啶、苯并咪唑或类似基团。
术语“卤素”指F、Cl、Br和I。术语“卤代的”是基团指被选自F、Cl、Br和I的一个或多个所取代。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
本发明化合物
本发明化合物包括具有如本发明式A所示结构的化合物。具体地,本发明化合物优选为如下化合物:
本发明化合物还包括式A化合物的药学上可接受的盐,具体地,为式A化合物与无机酸或有机酸反应形成常规的药学上可接受的盐。例如,常规的药学上可接受的盐可通过式A化合物与无机酸或有机酸反应制得;其中,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等;所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等。或者为式A化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐等;或者为式A化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐等。
本发明化合物还包括式A化合物的各种光学异构体,例如R型或S型、D型或L型。
制备方法
本发明化合物可以通过本领域常规合成方法获得,也可以按照本发明提供的制备方法制得。本发明的制备方法包括以下步骤:
(i)在惰性溶剂中,在碱性条件下,在缩合剂作用下将式a-1化合物与R2NH2进行反应,从而形成式a-2化合物;
(ii)在酸性溶液中,将式a-2化合物进行脱保护反应,从而形成式A化合物。
在另一优选例中,步骤(i)中,所述惰性溶剂选自下组:二氯甲烷、DMSO、DMF、四氢呋喃,或其组合。
在另一优选例中,步骤(i)中,所述缩合剂选自下组:2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)。
在另一优选例中,步骤(i)中,所述碱选自下组:三乙胺(TEA)、DIPEA,或其组合。
在另一优选例中,步骤(i)中,所述反应在不加热条件下进行;较佳地,反应温度为20℃-35℃。
在另一优选例中,步骤(ii)中,所述酸性溶液为含有酸的有机溶剂。较佳地,所述酸选自下组:三氟醋酸、氯化氢等。所述有机溶剂选自下组:二氯甲烷溶、四氢呋喃等。较佳地,其中酸和有机溶剂的比例为1:10。
DPP-4抑制剂
如本文所用,术语“DPP-4抑制剂”指能够用于抑制二肽肽酶4的化合物。
药物组合物及其用途
本发明化合物具有优异的二肽肽酶4抑制活性,因此,其可用于制备用于治疗与二肽肽酶4相关的疾病的药物。
本发明提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体。
本发明所述的“活性成分”是指本发明化合物,即所述的式A化合物或其药学上可接受的盐,或其光学异构体。
本发明所述的“活性成分”和药物组合物可用作DPP-4酶抑制剂。
“安全有效量”指的是:活性成分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活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“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的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。
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。
在另一优选例中,本发明式A化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中,本发明式A化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分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)等。
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,活性成分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。
所述的固体剂型还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,这种组合物中活性成分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。
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。除了活性成分外,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。
除了活性成分外,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。
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。
本发明化合物或药物组合物可用于制备DPP-4酶抑制剂。
本发明化合物或药物组合物可用于制备治疗与DPP-4酶的活性或表达量相关的疾病的药物。
本发明的提供了一种DPP-4酶抑制剂,其包含选自本发明的化合物,以及任选地一种或多种药学上可接受的载体。
本发明的主要优点
1.本发明提供了一类结构新颖的以式A为代表的氨基酸衍生物。这类化合物的合成路线设计合理,原料易得,适于应用。
2.本发明提供的氨基酸衍生物可以用于DPP-4抑制剂及治疗糖尿病。
3.本发明提供的氨基酸衍生物有较高的活性,最低IC50值可≤1nM。
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。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1体外测定氨基酸类化合物对人DPP-4抑制活性
使用DMSO溶解表1中的各个化合物(终浓度<10mM),将化合物溶解在缓冲液中(20mM Tris,pH 7.4;20mM KCl;0.1mg/mL BSA)。将人DPP-4蛋白(终浓度0.1nM)加入上述溶液中,孵育10分钟。使用AP-AFC(终浓度10μM)激活反应。反应终体积为100μL。使用酶标仪(激发光400nm;吸收光505nm)读取吸收率。采用SPSS软件,根据标准数学模型计算半数抑制率(IC50)。
表1
注:表中A为IC50≤1nM,B为1nM<IC50≤10nM,C为10nM<IC50≤200nM。
实施例2(S)-1-(胺基-3-(1H-咪唑-4-基)-3-甲酸乙酯哌啶酰胺(l-h-3et)
将L型N-叔丁基氧羰基组氨酸与3-甲酸乙酯哌啶溶解在二氯甲烷中并加入HATU和三乙胺在室温下搅拌8小时。使用薄层色谱板检测反应,待反应完成后,真空旋转蒸发去除溶剂。所得粗产品使用硅胶柱分离得到(S)-1-(N-叔丁氧羰基-胺基-3-(1H-咪唑-4-基)-3-甲酸乙酯哌啶酰胺。将(S)-1-(N-叔丁氧羰基-胺基-3-(1H-咪唑-4-基)-3-甲酸乙酯哌啶酰胺溶解于三氟乙酸:二氯甲烷=1:10的溶液中,室温搅拌反应3小时,检测反应结束后。往反应液中添加二氯甲烷及饱和碳酸氢钠溶液,中和反应液并分离有机相。有机相干燥后,真空旋转蒸发除去溶剂,得到题目所述化合物。1H NMR(400MHz,甲醇-d4)δ8.90(br.s.,1H),7.49(br.s.,1H),4.81(br.s.,1H),4.18-4.29(m,1H),4.07-4.18(m,2H),3.98(br.s.,1H),3.79(d,J=14.48Hz,1H),3.66-3.74(m,1H),3.49(d,J=12.52Hz,1H),2.36-2.62(m,1H),2.08(br.s.,1H),1.72-1.89(m,2H),1.57(br.s.,1H),1.30-1.46(m,1H),1.11-1.30(m,3H)。
实施例3(S)-1-(胺基-3-(1H-咪唑-4-基)-3-甲酸哌啶酰胺(l-h-3h)
将l-h-3et溶解于浓度为1N的氢氧化钠溶液中,并室温搅拌8小时。使用薄层色谱板检测反应。待反应完成后,使用浓度为1N的盐酸溶液中和反应液。真空旋转蒸发去除溶剂得粗产品。粗产品使用无水甲醇进行重结晶,收集溶剂相,浓缩后得到题目所述产品。1HNMR(400MHz,甲醇-d4)δ8.90(br.s.,1H),7.49(br.s.,1H),4.81(br.s.,1H),4.18-4.29(m,1H),3.98(br.s.,1H),3.79(d,J=14.48Hz,1H),3.66-3.74(m,1H),3.49(d,J=12.52Hz,1H),2.36-2.62(m,1H),2.08(br.s.,1H),1.72-1.89(m,2H),1.57(br.s.,1H),1.30-1.46(m,1H)。
实施例4(S)-1-(胺基-3-(1H-咪唑-4-基)-4-甲酸乙酯哌啶酰胺(l-h-4et)
使用实施例2中所述方法得到题目所述产品,不同点在于:3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ8.90(br.s.,1H),7.47(br.s.,1H),4.42(d,J=12.91Hz,1H),4.24(d,J=12.91Hz,1H),4.14(d,J=6.65Hz,2H),3.94(d,J=13.30Hz,1H),3.86(d,J=12.91Hz,1H),3.69(br.s.,1H),3.06(t,J=11.74Hz,1H),2.88(t,J=12.33Hz,1H),2.66(br.s.,1H),1.97(d,J=11.74Hz,2H),1.47-1.75(m,2H),1.18-1.34(m,3H)。
实施例5(S)-1-(胺基-3-(1H-咪唑-4-基)-4-甲酸哌啶酰胺(l-h-4h)
使用实施例3中所述方法得到题目所述产品。不同点在于:用实施例4制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ8.90(br.s.,1H),7.47(br.s.,1H),4.42(d,J=12.91Hz,1H),4.24(d,J=12.91Hz,1H),3.94(d,J=13.30Hz,1H),3.86(d,J=12.91Hz,1H),3.69(br.s.,1H),3.06(t,J=11.74Hz,1H),2.88(t,J=12.33Hz,1H),2.66(br.s.,1H),1.97(d,J=11.74Hz,2H),1.47-1.75(m,2H)。
实施例6(R)-1-(胺基-3-(1H-咪唑-4-基)-3-甲酸乙酯哌啶酰胺(d-h-3et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸构型为d构型。1HNMR(400MHz,甲醇-d4)δ8.90(s.,1H),7.49(s.,1H),4.81(m,1H),4.18-4.29(m,1H),4.07-4.18(q,2H),3.98(br.s.,1H),3.79(d,J=14.48Hz,1H),3.66-3.74(m,1H),3.49(d,J=12.52Hz,1H),2.36-2.62(m,1H),2.08(br.s.,1H),1.72-1.89(m,2H),1.57(br.s.,1H),1.30-1.46(m,1H),1.11-1.30(br,q,J=1.00Hz,3H)。
实施例7(R)-1-(胺基-3-(1H-咪唑-4-基)-3-甲酸哌啶酰胺(d-h-3h)
使用实施例3中所述方法得到题目所述产品。不同点在于:用实施例6制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ8.90(s.,1H),7.49(s.,1H),4.81(m,1H),4.18-4.29(m,1H),3.98(m,1H),3.79(d,J=14.48Hz,1H),3.66-3.74(m,1H),3.49(d,J=12.52Hz,1H),2.36-2.62(m,1H),2.08(br.s.,1H),1.72-1.89(m,2H),1.57(m,1H),1.30-1.46(m,1H)。
实施例8(R)-1-(胺基-3-(1H-咪唑-4-基)-4-甲酸乙酯哌啶酰胺(d-h-4et)
使用实施例6中所述方法得到题目所述产品,不同点在于:3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ8.88(br.s.,1H),7.49(br.s.,1H),4.81(br.s.,1H),4.08-4.22(m,2H),3.88-4.07(m,1H),3.60-3.88(m,2H),3.51(d,J=9.39Hz,1H),3.18(d,J=10.96Hz,1H),2.42-2.61(m,1H),2.07(br.s.,1H),1.73-1.89(m,2H),1.68(d,J=15.26Hz,1H),1.56(br.s.,1H),1.14-1.30(m,3H)。
实施例9(R)-1-(胺基-3-(1H-咪唑-4-基)-4-甲酸乙酯哌啶酰胺(d-h-4h)
使用实施例3中所述方法得到题目所述产品。不同点在于:用实施例8制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ8.89(s.,1H),7.48(s.,1H),4.81(br.s.,1H),3.88-4.07(m,1H),3.60-3.88(m,2H),3.51(d,J=9.39Hz,1H),3.18(d,J=10.96Hz,1H),2.42-2.61(m,1H),2.07(br.s.,1H),1.73-1.89(m,2H),1.68(d,J=15.26Hz,1H),1.56(br.s.,1H)。
实施例10(S)-1-胺基-3-苯基-3-甲酸乙酯哌啶酰胺(l-p-3et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类用L-苯丙氨酸代替组氨酸。1H NMR(400MHz,甲醇-d4)δ7.16-7.45(m,5H),4.70(br.s.,1H),4.27(d,J=11.74Hz,1H),4.05(m,2H),3.34-3.54(m,1H),3.11-3.25(m,1H),2.87-3.11(m,2H),2.66-2.87(m,1H),2.35(br.s.,1H),1.83(d,J=11.74Hz,1H),1.54(br.s.,2H),1.34(d,J=11.74Hz,1H),1.26(m,3H)。
实施例11(S)-1-胺基-3-苯基-3-甲酸哌啶酰胺(l-p-3h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例10制得的产品代替实施例2制得的产品。。1H NMR(400MHz,甲醇-d4)δ7.16-7.45(m,5H),4.70(br.s.,1H),4.27(d,J=11.74Hz,1H),3.34-3.54(m,1H),3.11-3.25(m,1H),2.87-3.11(m,2H),2.66-2.87(m,1H),2.35(br.s.,1H),1.83(d,J=11.74Hz,1H),1.54(br.s.,2H),1.34(d,J=11.74Hz,1H)。
实施例12(S)-1-胺基-3-苯基-4甲酸乙酯哌啶酰胺(l-p-4et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为L-苯丙氨酸代替组氨酸,3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ7.09-7.37(m,5H),4.60-4.78(m,1H),4.15-4.42(m,1H),3.94-4.15(m,2H),3.05-3.18(m,2H),2.79-3.05(m,2H),2.35-2.47(m,1H),1.88-2.23(m,1H),1.72(br.s.,1H),1.39-1.58(m,2H),1.36(br.s.,1H),1.17(br.q,J=1.00Hz,3H)。
实施例13(S)-1-胺基-3-苯基-4-甲酸哌啶酰胺(l-p-4h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例12制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ7.00-7.30(m,5H),4.16-4.68(m,1H),3.43-4.06(m,1H),3.01-3.14(m,1H),2.74-3.01(m,3H),2.07-2.34(m,1H),1.92(br.s.,1H),1.78(br.s.,1H),1.55-1.73(m,1H),1.51(br.s.,1H),1.22-1.47(m,1H)。
实施例14(R)-1-胺基-3-苯基-3-甲酸乙酯哌啶酰胺(d-p-3et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为D-苯丙氨酸代替组氨酸。1H NMR(400MHz,甲醇-d4)δ7.18-7.47(m,5H),4.69(br.s.,1H),4.29-4.47(m,1H),4.02-4.20(m,1H),3.67(br.s.,2H),2.90-3.20(m,3H),2.39-2.57(m,1H),1.80(br.s.,1H),1.71(br.s.,1H),1.49-1.66(m,2H),1.46(br.s.,1H),1.16-1.36(m,3H)。
实施例15(R)-1-胺基-3-苯基-3-甲酸哌啶酰胺(d-p-3h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例14制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ7.13-7.43(m,5H),4.19-4.35(m,1H),3.51-3.74(m,1H),3.19(br.s.,2H),3.04(br.s.,1H),2.29-2.58(m,1H),1.99(br.s.,1H),1.74(br.s.,1H),1.65(br.s.,1H),1.53(br.s.,1H),1.36(br.s.,1H),1.23(br.s.,1H)。
实施例16(R)-1-胺基-3-苯基-4甲酸乙酯哌啶酰胺(d-p-4et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为D-苯丙氨酸代替组氨酸,3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ7.09-7.37(m,5H),4.60-4.78(m,1H),4.15-4.42(m,1H),3.94-4.15(m,2H),3.05-3.18(m,2H),2.79-3.05(m,2H),2.35-2.47(m,1H),1.88-2.23(m,1H),1.72(br.s.,1H),1.39-1.58(m,2H),1.36(br.s.,1H),1.17(br.q,J=1.00Hz,3H)。
实施例17(R)-1-胺基-3-苯基-4-甲酸哌啶酰胺(d-p-4h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例16制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ7.00-7.30(m,5H),4.16-4.68(m,1H),3.43-4.06(m,1H),3.01-3.14(m,1H),2.74-3.01(m,3H),2.07-2.34(m,1H),1.92(br.s.,1H),1.78(br.s.,1H),1.55-1.73(m,1H),1.51(br.s.,1H),1.22-1.47(m,1H)。
实施例18(S)-1-(胺基-3-(1-羟基苯基-4-基)-3-甲酸乙酯哌啶酰胺(l-y-3et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为L-酪氨酸代替组氨酸。1H NMR(400MHz,甲醇-d4)δ6.96-7.15(m,2H),6.75(br.s.,2H),4.22-4.78(m,2H),4.02-4.18(m,2H),3.34-3.84(m,2H),2.87-3.09(m,2H),2.78(s,2H),2.29-2.68(m,2H),1.40-1.97(m,2H),1.13-1.35(m,3H)。
实施例19(S)-1-(胺基-3-(1-羟基苯基-4-基)-3-甲酸哌啶酰胺(l-y-3h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例18制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ6.91-7.13(m,2H),6.74(br.s.,2H),4.00(br.s.,1H),3.53(d,J=11.35Hz,1H),2.74-2.84(m,4H),1.92-2.11(m,1H),1.84(br.s.,1H),1.47-1.76(m,2H),1.42(br.s.,1H),1.28(d,J=16.43Hz,1H)。
实施例20(S)-1-(胺基-3-(1-羟基苯基-4-基)-4-甲酸乙酯哌啶酰胺(l-y-4et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为L-酪氨酸代替组氨酸,3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ7.10(t,J=8.41Hz,2H),6.75-6.88(m,2H),4.59(br.s.,1H),4.28(t,J=12.72Hz,1H),4.13(d,J=5.87Hz,2H),2.91-3.17(m,2H),2.75-2.86(m,5H),2.40-2.64(m,1H),1.86(t,J=13.30Hz,1H),1.50-1.77(m,2H),1.07-1.35(m,3H)。
实施例21(S)-1-(胺基-3-(1-羟基苯基-4-基)-4-甲酸哌啶酰胺(l-y-4h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例20制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ6.89-7.10(m,2H),6.71(br.s.,2H),3.08(d,J=11.35Hz,1H),2.58-2.71(m,1H),2.23(d,J=10.56Hz,1H),2.02(br.s.,1H),1.76-1.97(m,2H),1.63(d,J=11.35Hz,2H),1.30(d,J=16.04Hz,4H)。
实施例22(R)-1-(胺基-3-(1-羟基苯基-4-基)-3-甲酸乙酯哌啶酰胺(d-y-3et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为D-酪氨酸代替组氨酸。1H NMR(400MHz,甲醇-d4)δ6.98(t,J=9.39Hz,2H),6.53-6.81(m,2H),4.50(br.s.,1H),4.26(d,J=19.17Hz,1H),4.02(d,J=6.26Hz,2H),2.81-3.10(m,2H),2.71(br.s.,5H),2.30-2.57(m,2H),1.27-1.49(m,2H),1.15(br.s.,2H)。
实施例23(R)-1-(胺基-3-(1-羟基苯基-4-基)-3-甲酸哌啶酰胺(d-y-3h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例22制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ6.92-7.15(m,2H),6.74(d,J=7.43Hz,2H),2.88-3.16(m,2H),2.78(br.s.,6H),1.95(br.s.,1H),1.68-1.84(m,1H),1.54(br.s.,1H),1.39(br.s.,1H)。
实施例24(R)-1-(胺基-3-(1-羟基苯基-4-基)-4-甲酸乙酯哌啶酰胺(d-y-4et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为D-酪氨酸代替组氨酸,3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ7.07(t,J=8.41Hz,2H),6.72-6.85(m,2H),4.59(br.s.,1H),4.28(t,J=12.72Hz,1H),4.11(d,J=5.87Hz,2H),2.88-3.14(m,2H),2.77-2.88(m,5H),2.40-2.64(m,1H),1.86(t,J=13.30Hz,1H),1.50-1.77(m,2H),1.07-1.35(m,3H)。
实施例25(R)-1-(胺基-3-(1-羟基苯基-4-基)-4-甲酸哌啶酰胺(d-y-4h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例24制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ7.00-7.21(m,2H),6.77(d,J=6.65Hz,2H),4.60(br.s.,1H),3.52(br.s.,1H),2.87-3.14(m,2H),2.75-2.84(m,4H),2.28-2.52(m,1H),1.86(d,J=11.35Hz,1H),1.64(d,J=15.65Hz,1H),1.55(br.s.,1H)。
实施例26(S)-1-(胺基-3-(吲哚基-3-基)-3-甲酸乙酯哌啶酰胺(l-w-3et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为L-色氨酸代替组氨酸。1H NMR(400MHz,甲醇-d4)δ7.51-7.65(m,1H),7.43(br.s.,1H),7.05-7.30(m,3H),4.25-4.48(m,1H),4.04-4.21(m,2H),2.99-3.18(m,1H),2.82-2.92(m,2H),2.27-2.79(m,1H),1.57-1.84(m,1H),1.50(d,J=12.52Hz,1H),1.14-1.31(m,3H)。
实施例27(S)-1-(胺基-3-(吲哚基-3-基)-3-甲酸哌啶酰胺(l-w-3h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例26制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ7.39-7.59(m,1H),7.31(br.s.,1H),6.87-7.14(m,3H),4.48-4.62(m,1H),3.91-4.35(m,1H),2.93-3.15(m,2H),2.77(br.s.,2H),2.34-2.64(m,1H),2.07-2.31(m,1H),1.54-1.84(m,2H),1.24-1.54(m,2H)。
实施例28(S)-1-(胺基-3-(吲哚基-3-基)-4-甲酸乙酯哌啶酰胺(l-w-4et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为L-色氨酸代替组氨酸,3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ10.63(br.s.,1H),7.51(dd,J=7.43,19.56Hz,1H),7.37(dd,J=8.22,13.69Hz,1H),7.20(br.s.,1H),7.00-7.15(m,2H),4.64(br.s.,1H),4.15(t,J=15.26Hz,1H),3.97-4.11(m,2H),2.76-2.94(m,1H),2.67(br.s.,1H),2.30-2.46(m,1H),2.27(br.s.,1H),1.69(d,J=11.74Hz,2H),1.48(d,J=12.52Hz,1H),1.25-1.44(m,2H),1.20(d,J=6.26Hz,3H),0.74-0.93(m,1H)。
实施例29(S)-1-(胺基-3-(吲哚基-3-基)-4-甲酸哌啶酰胺(l-w-4h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例28制得的产品代替实施例2制得的产品。。1H NMR(400MHz,甲醇-d4)δ7.52(dd,J=7.04,19.96Hz,1H),7.30-7.44(m,1H),7.21(br.s.,1H),6.95-7.14(m,2H),4.65(br.s.,1H),4.02-4.28(m,1H),3.62(d,J=8.61Hz,1H),3.31(br.s.,2H),2.69(d,J=12.13Hz,1H),2.16-2.41(m,2H),1.62-1.82(m,2H),1.62-1.82(m,2H)。
实施例30(R)-1-(胺基-3-(吲哚基-3-基)-3-甲酸乙酯哌啶酰胺(d-w-3et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为D-色氨酸代替组氨酸。1H NMR(400MHz,甲醇-d4)δ7.47-7.62(m,1H),7.38(br.s.,1H),7.20-7.28(m,1H),7.09-7.20(m,1H),7.06(br.s.,1H),4.63(br.s.,1H),4.34(t,J=12.33Hz,1H),3.93-4.16(m,2H),2.98-3.20(m,1H),2.60-2.90(m,1H),2.43(br.s.,1H),1.72(br.s.,1H),1.55-1.69(m,1H),1.48(br.s.,2H),1.37(d,J=7.04Hz,2H),1.28(br.s.,1H),1.21(t,J=6.30Hz,3H)。
实施例31(R)-1-(胺基-3-(吲哚基-3-基)-3-甲酸哌啶酰胺(d-w-3h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例30制得的产品代替实施例2制得的产品。。1H NMR(400MHz,甲醇-d4)δ7.52(d,J=19.96Hz,1H),7.34(d,J=7.04Hz,1H),7.13(br.s.,1H),7.08(br.s.,1H),7.01(br.s.,1H),3.31(br.s.,4H),3.03(br.s.,2H),1.58-1.78(m,2H),1.47(t,J=15.46Hz,2H),1.31-1.39(m,1H),1.28(br.s.,1H)。
实施例32(R)-1-(胺基-3-(吲哚基-3-基)-4-甲酸乙酯哌啶酰胺(d-w-4et)
使用实施例2中所述方法得到题目所述产品,不同点在于:氨基酸种类为D-色氨酸代替组氨酸,3-甲酸乙酯哌啶用4-甲酸乙酯哌啶代替。1H NMR(400MHz,甲醇-d4)δ7.51(dd,J=7.24,18.98Hz,1H),7.32-7.45(m,1H),7.21(br.s.,1H),7.13(d,J=7.83Hz,1H),7.06(br.s.,1H),4.65(br.s.,1H),4.14-4.24(m,1H),3.98-4.10(m,2H),3.48(d,J=13.30Hz,1H),2.68(br.s.,1H),2.15-2.42(m,1H),1.61-1.78(m,2H),1.33-1.59(m,2H),1.28(br.s.,2H),1.20(d,J=5.87Hz,3H),0.88(d,J=8.61Hz,1H)。
实施例33(R)-1-(胺基-3-(吲哚基-3-基)-4-甲酸哌啶酰胺(d-w-4h)
使用实施例3中所述方法得到题目所述产品,不同点在于:用实施例32制得的产品代替实施例2制得的产品。1H NMR(400MHz,甲醇-d4)δ7.49-7.65(m,1H),7.30-7.40(m,1H),7.21(br.s.,1H),7.08-7.17(m,1H),7.05(br.s.,1H),4.62(br.s.,2H),2.48-3.10(m,2H),1.60-1.78(m,5H),1.49(d,J=19.96Hz,3H)。
通过上述类似的方法,合成了表2所述化合物:
表2
通过实施例1的方法实验证明:表2化合物的人DPP-4抑制活性IC50<500nM。
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)
1.式A化合物或其药学上可接受的盐,或其光学异构体,
其中:
R1选自下组:取代或未取代的苯基、取代或未取代的C3-C6环烷基、取代或未取代的5-10元饱和或不饱和杂环基;其中,所述的杂环基是指环的骨架上具有1-3个选自N、O或S的杂原子;其中,所述取代是指被选自下组的一个或多个取代基所取代:羟基、酯基(COOC1-C6烷基、COO苯基或被C1-C6烷基、C1-C6烷氧基或卤代的C1-C6烷基取代的COO苯基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基;
R2选自下组:取代或未取代的3-10元饱和杂环基、取代或未取代的3-10元不饱和杂环基;其中,所述的杂环基是指环的骨架上至少含有1个N原子和任选的0-2个选自N、O或S的杂原子;其中,所述取代是指被选自下组的一个或多个取代基所取代:酯基(COOC1-C6烷基、COO苯基或被C1-C6烷基、C1-C6烷氧基或卤代的C1-C6烷基取代的COO苯基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基。
2.如权利要求1所述的化合物或其药学上可接受的盐,或其光学异构体,其特征在于,R1选自下组:取代或未取代的苯基、取代或未取代的咪唑基、取代或未取代的三唑基、取代或未取代的呋喃基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的吡啶基、取代或未取代的苯并吡咯基;其中,所述取代是指被选自下组的一个或多个取代基所取代:羟基、酯基(COOC1-C6烷基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基。
3.如权利要求1所述的化合物或其药学上可接受的盐,或其光学异构体,其特征在于,R1选自下组:
4.如权利要求1所述的化合物或其药学上可接受的盐,或其光学异构体,其特征在于,R2选自下组:取代或未取代的4-6元饱和杂环基;其中,所述的杂环基是指环的骨架上至少含有1个N原子;其中,所述取代是指被选自下组的一个或多个取代基所取代:酯基(COOC1-C6烷基、COO苯基或被C1-C6烷基、C1-C6烷氧基或卤代的C1-C6烷基取代的COO苯基)、羧基(COOH)、C1-C6酰基、酰胺基(CONH2)、硝基、氰基、异氰基、脲基、硫脲基、卤素、胺基(NH2)、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、C3-C6环烷基。
5.如权利要求1所述的化合物或其药学上可接受的盐,或其光学异构体,其特征在于,所述化合物选自下组:
6.如权利要求1所述的化合物的制备方法,其特征在于,所述方法包括以下步骤:
(i)在惰性溶剂中,在碱性条件下,在缩合剂作用下将式a-1化合物与R2NH2进行反应,从而形成式a-2化合物;
(ii)在酸性溶液中,将式a-2化合物进行脱保护反应,从而形成式A化合物。
7.一种药物组合物,其特征在于,所述的药物组合物包括:(i)如权利要求1所述的化合物或其药学上可接受的盐,或其光学异构体;以及(ii)药学上可接受的载体。
8.一种如权利要求1所述化合物或其药学上可接受的盐,或其光学异构体的用途,或如权利要求7所述组合物的用途,其特征在于,1)用于制备DPP-4酶抑制剂;2)用于制备与DPP-4酶的活性或表达量相关的疾病的药物。
9.如权利要求8所述的用途,其特征在于,所述的与DPP-4酶的活性或表达量相关的疾病为糖尿病。
10.一种DPP-4酶抑制剂,其特征在于,其包含如权利要求1所述的化合物或其药学上可接受的盐,或其光学异构体;或如权利要求7所述的组合物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109608524A (zh) * | 2018-11-09 | 2019-04-12 | 李泉 | 一种兼具dpp-4抑制及glp1r激活活性的多肽衍生物、制备和应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004076433A1 (en) * | 2003-02-28 | 2004-09-10 | Aic | Dipeptidyl peptidase inhibitors |
WO2004076434A1 (en) * | 2003-02-28 | 2004-09-10 | Aic | Dipeptidyl peptidase inhibitors |
CN101318925A (zh) * | 2007-06-04 | 2008-12-10 | 上海恒瑞医药有限公司 | 吡咯烷并四元环类衍生物、其制备方法及其在医药上的用途 |
CN101786978A (zh) * | 2009-01-23 | 2010-07-28 | 上海阳帆医药科技有限公司 | 2-氨基丙酸衍生物 |
CN102453001A (zh) * | 2010-10-22 | 2012-05-16 | 中国医学科学院药物研究所 | 硫代吗啉类化合物及其制备方法和用途 |
-
2018
- 2018-02-02 CN CN201810106027.7A patent/CN108164506B/zh not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004076433A1 (en) * | 2003-02-28 | 2004-09-10 | Aic | Dipeptidyl peptidase inhibitors |
WO2004076434A1 (en) * | 2003-02-28 | 2004-09-10 | Aic | Dipeptidyl peptidase inhibitors |
CN101318925A (zh) * | 2007-06-04 | 2008-12-10 | 上海恒瑞医药有限公司 | 吡咯烷并四元环类衍生物、其制备方法及其在医药上的用途 |
CN101786978A (zh) * | 2009-01-23 | 2010-07-28 | 上海阳帆医药科技有限公司 | 2-氨基丙酸衍生物 |
CN102453001A (zh) * | 2010-10-22 | 2012-05-16 | 中国医学科学院药物研究所 | 硫代吗啉类化合物及其制备方法和用途 |
Non-Patent Citations (3)
Title |
---|
ACS: "774172-63-3/rn or 1177103-26-2/rn or 1290194-22-7/rn or 1290218-91-5/rn or 1306130-25-5/rn or 1307178-65-9/rn or 1562433-57-1/rn or 1562651-92-6/rn or 1910245-27-0/rn or 1919525-41-9/rn or 1939459-18-3/rn or 1939632-00-4/rn", 《STN ON THE WEB》 * |
朱燕云等: "两个 α-氨基酸类二肽肽酶Ⅳ抑制剂的合成", 《合成化学》 * |
韩蓓等: "甘氨酰胺类DPP-IV抑制剂的设计、合成及体外活性研究", 《药学学报》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109608524A (zh) * | 2018-11-09 | 2019-04-12 | 李泉 | 一种兼具dpp-4抑制及glp1r激活活性的多肽衍生物、制备和应用 |
CN109608524B (zh) * | 2018-11-09 | 2022-06-03 | 北京志道生物科技有限公司 | 兼具dpp-4抑制及glp1r激活活性的多肽衍生物、制备和应用 |
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