WO2017071479A1 - 一种谷氨酰胺酰基环化酶抑制剂 - Google Patents

一种谷氨酰胺酰基环化酶抑制剂 Download PDF

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WO2017071479A1
WO2017071479A1 PCT/CN2016/101995 CN2016101995W WO2017071479A1 WO 2017071479 A1 WO2017071479 A1 WO 2017071479A1 CN 2016101995 W CN2016101995 W CN 2016101995W WO 2017071479 A1 WO2017071479 A1 WO 2017071479A1
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cyclase inhibitor
glutaminyl cyclase
ring
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吴海强
刘志刚
贺震旦
郑易之
邹永东
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深圳大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms

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  • the invention relates to the field of medicinal chemistry, and in particular to a glutaminyl cyclase inhibitor.
  • Glutaminylcyclase (QC, EC 2.3.2.5) is an enzyme that catalyzes the intramolecular cyclization of N-terminal glutamine residues such as polypeptides and proteins to form pyroglutamic acid (pGlu).
  • pGlu pyroglutamic acid
  • Mammalian QC is highly conserved, has no sequence homology with papaya QC, and has significant sequence homology with bacterial aminopeptidase, so animal and plant QC have different evolutionary origins.
  • the physiological function of QC is not very clear, and may play a role in the process of plant defense against pathogenic microorganisms.
  • QC in animals has important biological functions such as changing the N-terminal chemical structure, regulating activity and enhancing stability of proteins. The key role of QC activity in the pathogenesis of many major diseases has been highly valued by people.
  • AD Alzheimer's disease
  • the main symptoms of AD include progressive memory and cognitive dysfunction. It has the characteristics of irreversible and high mortality. There is no specific treatment in clinical practice.
  • AD ⁇ -amyloid
  • a ⁇ ⁇ -amyloid cascade theory
  • Tau protein entanglement theory Tau protein entanglement theory
  • oxidative stress theory oxidative stress theory
  • biometal ion homeostasis theory mitochondria Functional failure theory and so on.
  • mitochondria Functional failure theory mitochondria Functional failure theory
  • AD pathological features are mainly A ⁇ precipitation outside the brain neurons and hyperphosphorylation of Tau protein tangles inside the neurons.
  • a ⁇ the main component of senile plaque deposition in AD patients
  • pGlu-A ⁇ has stronger neurotoxicity, faster aggregation and sedimentation rate, stronger stability, and its production is directly related to the occurrence of clinical symptoms of AD. It is a marker that is more specific than A ⁇ and more specific to the pathogenesis of AD. .
  • pGlu-A ⁇ is a product of QC enzyme catalysis, and selective inhibition of QC activity can significantly inhibit the production of pGlu-A ⁇ and the formation of senile plaque, and significantly improve the symptoms of AD such as cognitive and memory impairment.
  • the study found that the high expression of QC in the brain of AD patients is a landmark lesion in the early stage of AD. The characteristics of QC RNA can be detected in peripheral blood before the production of pGlu-A ⁇ and A ⁇ . Up. It can be seen that high expression of QC is a key factor in the pathogenesis and development of AD. QC has opened a new research direction for AD pathology and etiological anti-AD drug research. QC inhibitors are expected to become a strategic breakthrough for innovative anti-AD drug development.
  • QC is highly expressed in the pathogenesis of complex diseases such as rheumatoid arthritis, nonalcoholic hepatitis, cutaneous melanoma, and lupus erythematosus, which are related to the intrinsic immune dysfunction of the body.
  • QC inhibitors are also useful in the treatment of a variety of diseases as described above.
  • a class of linear QC inhibitor molecules is disclosed in EP1713780B1, EP2091948B1, US7304086B2, US7371871B2, US7741354B2, US7892771B2, US8129160B2, US8188094B2, US8202897B2, US8227498B2, US20080214620A1, US200880286231A1, US20090269301A1.
  • QC inhibitors such as single matrix structure, poor water solubility, poor transmembrane performance, limited activity, and complicated synthesis steps.
  • the present invention aims to provide a glutaminyl cyclase inhibitor, which aims to solve the problem that the existing QC inhibitor has a single mother structure. Poor water solubility, poor transmembrane performance, limited activity, etc.
  • a glutaminyl cyclase inhibitor wherein the structural formula is as follows:
  • the A unit is a benzene ring, a six-membered heteroaryl ring, a five-membered heteroaryl ring, a seven-membered aromatic ring, a naphthalene, an anthracene, a naphthoquinone or a polyaromatic ring system
  • R 1 is a hydrogen, a linear alkyl group, or a branched chain.
  • the B unit is a benzene ring, a six-membered heteroaryl ring, a five-membered heteroaryl ring, a seven-membered aromatic ring, a naphthalene, an anthracene, a naphthoquinone or a polyaromatic ring system, and R 2 is a hydrogen, a linear alkyl group, or a branched alkane.
  • R 2 is a hydrogen, a linear alkyl group, or a branched alkane.
  • R 3 on the imidazole ring is one of hydrogen, a linear alkyl group, a branched alkyl group, an alkoxy group, a halogen, an amine group, and a substituent thereof.
  • the glutaminyl cyclase inhibitor wherein the B unit and the C unit are ortho, meta or para at the linking position of the A unit.
  • the glutaminyl cyclase inhibitor wherein the parent core structure of the A unit and the B unit is the same or different in the same compound, and the structures of R 1 and R 2 are the same or different.
  • the glutaminyl cyclase inhibitor wherein R 1 is a single substitution or a multiple substitution at a different position.
  • the glutaminyl cyclase inhibitor wherein R 2 is a monosubstituted or polysubstituted at a different position.
  • the glutaminyl cyclase inhibitor wherein R 3 is a single substitution or a multiple substitution at a different position.
  • the glutaminyl cyclase inhibitor wherein the substitution position of R 3 is at the 2, 4 or 5 position of the imidazole ring.
  • a glutaminyl cyclase inhibitor (QC inhibitor) provided by the present invention is designed according to a crystal structure of a target enzyme protein active center, and exhibits good selectivity and specificity, and has Higher drug-forming properties; its parent structure is more abundant, water-soluble, transmembrane performance and activity higher.
  • Fig. 1 is a schematic view showing the principle of QC enzyme inhibitory activity test in the present invention.
  • the present invention provides a glutaminyl cyclase inhibitor, and the present invention will be further described in detail below in order to clarify and clarify the objects, aspects and effects of the present invention. It is understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
  • the present invention relates to a glutaminyl cyclase inhibitor (QC inhibitor) having the following structural formula:
  • the QC inhibitor of the present invention comprises three pharmacophore structural units: A, B and C, wherein the A unit is a benzene ring, a six-membered heteroaryl ring (N, S, O), and a five-membered heteroaryl ring ( C, N, S, O), seven-membered aromatic ring, naphthalene, anthracene, naphthoquinone or (hetero) polyaromatic ring system, R 1 is hydrogen, linear alkyl group, branched alkyl group, alkoxy group, Halogen, carboxyl, nitro, sulfonate, amine, phosphate, and substituents thereof (eg, hydrogen, linear alkyl, branched alkyl, alkoxy, halogen, carboxyl, nitro, sulfonate) One of a substituent of an amine group or a phosphate group; R 1 is a single substitution or a multiple substitution at a different position.
  • the B unit is a benzene ring, a six-membered heteroaryl ring (N, S, O), a five-membered heteroaryl ring (C, N, S, O), a seven-membered aromatic ring, naphthalene, anthracene, naphthoquinone or (hetero)
  • An aromatic ring system R 2 is hydrogen, a linear alkyl group, a branched alkyl group, an alkoxy group, a halogen, a carboxyl group, a nitro group, a sulfonic acid group, an amine group, a phosphoric acid group, and a substituent thereof (for example, hydrogen, straight One of a chain alkyl group, a branched alkyl group, an alkoxy group, a halogen group, a carboxyl group, a nitro group, a sulfonic acid group, an amine group or a phosphate group; R 2 is a
  • R 3 on the imidazole ring is one of hydrogen, a linear alkyl group, a branched alkyl group, an alkoxy group, a halogen, an amine group, and a substituent thereof.
  • R 3 is a single substitution or a multiple substitution at a different position.
  • the substitution position of R 3 is at the 2, 4 or 5 position of the imidazole ring.
  • linking positions of the B unit and the C unit at the A unit are ortho, meta or para.
  • the parent core structures of the A unit and the B unit are the same or different, and the structures of R 1 and R 2 are the same or different.
  • the QC inhibitors of the present invention are pharmaceutically acceptable salts, including lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, iron salts, copper salts, organic ammonium salts, hydrochloride salts, phosphate salts, acetic acid. Salt, propionate, oxalate, citrate, and the like.
  • the QC inhibitor of the invention is a new type of QC inhibitor disclosed for the first time, and has extremely important scientific significance and research value for the research of self-directed QC targeted innovation lead drug in China.
  • QC inhibitors such as QC targeted anti-AD lead drugs, treatment of QC-specific high expression-related diseases (including rheumatoid arthritis, non-alcoholic hepatitis, cutaneous melanoma, lupus erythematosus syndrome) Etc.), or a QC-related diagnostic kit.
  • QC targeted anti-AD lead drugs treatment of QC-specific high expression-related diseases (including rheumatoid arthritis, non-alcoholic hepatitis, cutaneous melanoma, lupus erythematosus syndrome) Etc.), or a QC-related diagnostic kit.
  • Example 3 QC inhibitor test for QC enzyme inhibition activity
  • the schematic diagram of the QC enzyme inhibition activity test is shown in Figure 1.
  • Enzyme activity assay was performed in a 96-well microtiter plate using 200 ul of pH 8.0 Tris buffer system: 0.3 mM NADH, 2.0 mM freshly prepared Gln-Gln, 14 mM alpha-ketoglutarate, 30 U/ml glutamate dehydrogenase, 50 mM Tris, pH 8.0 buffer, finally added 0.28 ⁇ M recombinant human QC protein and a mixture of inhibitors of different concentrations, after shaking for 30 seconds, dynamically change the absorption value of NADH at 340nm wavelength for 15min at 25 °C with a microplate reader. The data was collected every 30 seconds, and the IC 50 value of the inhibitor against QC enzyme activity was calculated according to the test results.
  • Table 1 The test results for different QC inhibitors are shown in Table 1, wherein the structural formula of the QC inhibitor is:
  • the present invention provides a glutaminyl cyclase inhibitor (QC inhibitor) which is designed according to the crystal structure of the active center of the target enzyme protein and exhibits good selectivity and specificity. It has higher drug-forming properties; its parent structure is richer, water-soluble, transmembrane performance and activity higher.
  • QC inhibitor glutaminyl cyclase inhibitor

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Abstract

本发明公开一种谷氨酰胺酰基环化酶抑制剂，其结构如式（Ｉ）。本发明所提供的一种谷氨酰胺酰基环化酶抑制剂(QC抑制剂)，其根据靶标酶蛋白活性中心晶体结构设计而成，显示出良好的选择性和专一性，具有更高的成药性；其母体结构更丰富、水溶性好、跨膜性能佳、活性更高。

Description

一种谷氨酰胺酰基环化酶抑制剂 技术领域
本发明涉及药物化学领域，尤其涉及一种谷氨酰胺酰基环化酶抑制剂。
背景技术
谷氨酰胺酰基环化酶(Glutaminylcyclase，QC，EC2.3.2.5)是一种可以催化多肽、蛋白等N端谷氨酰胺残基分子内环化反应生成焦谷氨酸(pGlu)的酶。1963年，QC首次在热带植物番木瓜(Carica papaya)乳胶中发现，后研究证实，QC在植物、动物、微生物中均有分布。哺乳动物QC具有高度保守性，与番木瓜QC之间没有任何序列同源性，而与细菌氨肽酶具有显著的序列同源性，故动物和植物QC具有不同的进化起源。在植物中，QC的生理功能并不十分明确，可能在植物防御病原微生物过程中有一定的作用。动物体内的QC具有改变蛋白等N端化学结构、调节活性、增强稳定性等重要生物学功能，QC活性增强在多种重大疾病发病机理中的关键作用日益受到人们的高度重视。
阿尔茨海默病(Alzheimer’s disease，AD)是一种常见的神经退行性疾病，是老年痴呆的主要形式，AD患者超过老年痴呆患者总数的65％以上。随全球人口老龄化的发展，AD发病率及患者人数急速 升高，流行病学调查显示，AD已成为仅次于心脑血管疾病和肿瘤的第三大世界性健康问题。AD主要症状包括进行性记忆和认知功能障碍等，具有不可逆转、高死亡率等特征，目前临床尚无特效治疗药物。
AD发病机制较为复杂，人们已从不同角度提出了众多假设，包括β-淀粉样蛋白(Aβ)级联学说、Tau蛋白缠结沉淀学说、氧化应激学说、生物金属离子稳态失衡学说、线粒体功能衰竭学说等。然而，AD确切病理机制尚不明了。基于上述学术假说的抗AD药物研究进展缓慢。
临床病理学研究已证实，AD病理学特征主要是脑部神经元外部的Aβ沉淀和神经元内部的过度磷酸化Tau蛋白缠结等。但近年来，多项体内和临床研究发现，与正常老年人脑部Aβ老年斑沉淀不同的是，AD患者脑部老年斑沉淀的主要成分并非Aβ，而是变异的Aβ，特别是N端谷氨酰胺残基分子内环合而成的pGlu-Aβ，尤其是pGlu-Aβ42/pGlu-Aβ40等，含量超过50％。pGlu-Aβ具有更强的神经毒性、更快的聚集沉淀速度、更强的稳定性，且其产生与AD临床症状的产生直接相关，是比Aβ出现更早、与AD发病更加特异的标志物。
相关研究的进一步深入显示，pGlu-Aβ是QC酶催化作用的产物，而选择性抑制QC活性可显著抑制pGlu-Aβ的产生和老年斑沉淀的形成，并明显改善认知、记忆功能损伤等AD症状。同时，研究发现AD患者脑部QC特异性高表达是AD发病早期的标志性病变，早在产生pGlu-Aβ、Aβ之前，外周血液中即可检测到QC RNA的特征性 上调。可见，QC高表达是AD发病、发展的关键促进因素，QC为AD病理及病因性抗AD药物研究开启了新的研究方向，QC抑制剂有望成为创新抗AD药物开发的战略性突破口。
此外，QC在风湿性关节炎、非酒精性肝炎、皮肤黑色素瘤、红斑狼疮综合症等多种与机体固有免疫功能失调相关复杂疾病的发病中均有特异性高表达。QC抑制剂亦可用于上述多种疾病的治疗。
当前，QC抑制剂相关研究相对较少。EP1713780B1、EP2091948B1、US7304086B2、US7371871B2、US7741354B2、US7892771B2、US8129160B2、US8188094B2、US8202897B2、US8227498B2、US20080214620A1、US200880286231A1、US20090269301A1等专利公开了一类线型QC抑制剂分子。该类QC抑制剂在结构与活性方面尚存在一定的不足之处，如母体结构单一、水溶性差、跨膜性能差、活性有限、合成步骤繁琐等。因此，进一步扩大QC抑制剂化学结构多样性，设计合成成药性更高的新QC抑制剂，并研究QC抑制剂对AD、风湿性关节炎、非酒精性肝炎、皮肤黑色素瘤、红斑狼疮综合症等疾病的治疗作用及机理，对QC高表达相关病理机理研究、病因性新药研究、QC靶向早期诊断和治疗等都具有极为重要的科学意义和应用价值。
发明内容
鉴于上述现有技术的不足，本发明的目的在于提供一种谷氨酰胺酰基环化酶抑制剂，旨在解决现有的QC抑制剂其存在母体结构单一、 水溶性差、跨膜性能差、活性有限等问题。
本发明的技术方案如下：
一种谷氨酰胺酰基环化酶抑制剂，其中，其结构式如下：
Figure PCTCN2016101995-appb-000001
其中，A单元是苯环、六元杂芳环、五元杂芳环、七元芳环、萘、蒽、萘醌或多芳环体系，R1是氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基、磷酸基及其取代物中的一种；
B单元是苯环、六元杂芳环、五元杂芳环、七元芳环、萘、蒽、萘醌或多芳环体系，R2是氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基、磷酸基及其取代物中的一种；
C单元中，咪唑环上R3是氢、直链状烷基、支链状烷基、烷氧基、卤素、胺基及其取代物中的一种。
所述的谷氨酰胺酰基环化酶抑制剂，其中，B单元和C单元在A单元的链接位置是邻位、间位或对位。
所述的谷氨酰胺酰基环化酶抑制剂，其中，在同一个化合物内，A单元和B单元的母核结构相同或不相同，R1和R2的结构相同或不相同。
所述的谷氨酰胺酰基环化酶抑制剂，其中，R1是单取代或不同位置的多取代。
所述的谷氨酰胺酰基环化酶抑制剂，其中，R2是单取代或不同位 置的多取代。
所述的谷氨酰胺酰基环化酶抑制剂，其中，R3是单取代或不同位置的多取代。
所述的谷氨酰胺酰基环化酶抑制剂，其中，R3的取代位置在咪唑环的2、4或5位。
所述的谷氨酰胺酰基环化酶抑制剂，其中，C单元中，烷基链中碳原子n＝1-4。
有益效果：本发明所提供的一种谷氨酰胺酰基环化酶抑制剂(QC抑制剂)，其根据靶标酶蛋白活性中心晶体结构设计而成，显示出良好的选择性和专一性，具有更高的成药性；其母体结构更丰富、水溶性好、跨膜性能佳、活性更高。
附图说明
图1为本发明中QC酶抑制活性测试原理示意图。
具体实施方式
本发明提供一种谷氨酰胺酰基环化酶抑制剂，为使本发明的目的、技术方案及效果更加清楚、明确，以下对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明一种谷氨酰胺酰基环化酶抑制剂(QC抑制剂)，其结构式如下：
Figure PCTCN2016101995-appb-000002
本发明的QC抑制剂，其包含三个药效团结构单元：A，B和C，其中，A单元是苯环、六元杂芳环(N、S、O)、五元杂芳环(C、N、S、O)、七元芳环、萘、蒽、萘醌或(杂)多芳环体系，R1是氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基、磷酸基及其取代物(例如氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基或磷酸基的取代物)中的一种；R1是单取代或不同位置的多取代。
B单元是苯环、六元杂芳环(N、S、O)、五元杂芳环(C、N、S、O)、七元芳环、萘、蒽、萘醌或(杂)多芳环体系，R2是氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基、磷酸基及其取代物(例如氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基或磷酸基的取代物)中的一种；R2是单取代或不同位置的多取代。
C单元中，咪唑环上R3是氢、直链状烷基、支链状烷基、烷氧基、卤素、胺基及其取代物中的一种。R3是单取代或不同位置的多取代。R3的取代位置在咪唑环的2、4或5位。C单元中，烷基链中碳原子n＝1-4，例如n为1、2、3或4。
进一步，B单元和C单元在A单元的链接位置是邻位、间位或对位。
进一步，在同一个化合物内，A单元和B单元的母核结构相同或不相同，R1和R2的结构相同或不相同。
本发明中的QC抑制剂在药学上可接受的盐，包括锂盐、钠盐、钾盐、镁盐、钙盐、铁盐、铜盐、有机铵盐、盐酸盐、磷酸盐、乙酸盐、丙酸盐、乙二酸盐、柠檬酸盐等。本发明的QC抑制剂为首次公开的新型QC抑制剂，对我国自主QC靶向创新先导药物研究具有极为重要的科学意义和研究价值。其可广泛应用于高效QC抑制剂类新药中，如QC靶向抗AD先导药物、治疗QC特异性高表达相关疾病(包括风湿性关节炎、非酒精性肝炎、皮肤黑色素瘤、红斑狼疮综合症等)的药物，或者QC相关诊断试剂盒。
实施例1：N-(3-(1H-咪唑-1-基)丙基)-3',4'-二甲氧基-[1,1'-联苯]-2-胺(MQI-1)的合成，其合成路线如下：
Figure PCTCN2016101995-appb-000003
a、3',4'-二甲氧基-[1,1'-联苯]-2-胺：将溴苯胺(5.81mmol，1当量)，3,4-二甲氧基苯硼酸(6.98mmol，1.2当量)和[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(0.35mmol，0.06当量)置于50ml圆底烧瓶中，分别加入10ml的二氧六环和10ml的2mol/L K2CO3溶液，100℃，回流3h。加入饱和NaCl溶液淬灭反应，冷却至室温，乙酸乙酯萃取三次，合并后饱和NaCl溶液洗一次，无水Na2SO4干燥，硅胶柱层析收集产物，收率为90％。
b、N-(3-溴丙基)-3',4'-二甲氧基-[1,1'-联苯]-2-胺：3',4'-二甲氧基-[1,1'-联苯]-2-胺(872.32umol，1当量)、1,3-二溴丙烷(6.11mmol，7当量)溶于6ml无水乙腈，加入无水K2CO3(1.74mmol，2当量)固体，搅拌回流过夜，蒸除溶剂，乙酸乙酯和水萃取三次，合并有机相并用饱和NaCl溶液洗一次，无水Na2SO4干燥，硅胶柱层析收集产物，收率为48％。
c、N-(3-(1H-咪唑-1-基)丙基)-3',4'-二甲氧基-[1,1'-联苯]-2-胺：咪唑(285.51umol，1当量)溶于1ml无水乙腈，加入干燥K2CO3(285.51umol，1当量)，常温搅拌15min，加入上述b中所得N-(3-溴丙基)-3',4'-二甲氧基-[1,1'-联苯]-2-胺的1ml无水乙腈溶液，回流过夜，蒸除溶剂，乙酸乙酯和水萃取三次，合并有机相并用饱和NaCl溶液洗一次，无水Na2SO4干燥，硅胶柱层析收集产物，收率为20％。
实施例2：4'-氟-N-(3-(4-甲基-1H-咪唑-1-基)丙基)-[1,1'-联苯]-2-胺(MQI-31)的合成，其合成路线如下：
Figure PCTCN2016101995-appb-000004
a、4'-氟-[1,1'-联苯]-2-胺：将溴苯胺(5.81mmol，1当量)、4-氟苯硼酸(6.98mmol，1.2当量)和[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(0.35mmol，0.06当量)置于50ml圆底烧瓶中，溶剂为10ml二氧六环和10ml 2mol/L K2CO3溶液，100℃，搅拌3h，加入饱和NaCl溶液淬灭反应，乙酸乙酯萃取三次，合并后饱和 NaCl溶液洗一次，无水Na2SO4干燥，硅胶柱层析收集产物，收率为94％。
b、N-(3-溴丙基)-4'-氟[1,1'-联苯]-2-胺：4'-氟-[1,1'-联苯]-2-胺(534.15umol，1当量)和1,3-二溴丙烷(3.74mmol，7当量)溶于4ml无水乙腈，加入无水K2CO3(1.74mmol，2当量)固体，搅拌回流过夜，蒸除溶剂，乙酸乙酯和水萃取三次，合并有机相并用饱和NaCl溶液洗一次，无水Na2SO4干燥，硅胶柱层析收集产物，收率为45％。
c、4'-氟-N-(3-(4-甲基-1H-咪唑-1-基)丙基)-[1,1'-联苯]-2-胺：4-甲基咪唑(324.48umol，1当量)溶于1ml无水乙腈，加入无水K2CO3(285.51umol，1当量)，常温搅拌15min；加入上述b中所得N-(3-溴丙基)-4'-氟[1,1'-联苯]-2-胺的1ml无水乙腈溶液，搅拌回流过夜，蒸除溶剂，乙酸乙酯和水萃取三次，合并有机相并用饱和NaCl溶液洗一次，无水Na2SO4干燥，硅胶柱层析收集产物，收率为18％。
实施例3：QC抑制剂对QC酶抑制活性测试
QC酶抑制活性测试原理示意图如图1所示。酶活测试在96孔酶标板中进行，采用200ul pH8.0Tris缓冲体系：0.3mM NADH，2.0mM新鲜制备Gln-Gln，14mMα-酮戊二酸，30U/ml谷氨酸脱氢酶，50mM Tris，pH8.0缓冲液，最后加入0.28μM重组人QC蛋白与不同浓度抑制剂的混合液，振荡30秒后以酶标仪动态检测25℃时NADH在340nm波长处15min内吸收值变化，每隔30s进行一次数据采集，根据测试结果，计算抑制剂对QC酶活抑制作用的IC50值，对于不同 QC抑制剂的测试结果如表1中所示，其中QC抑制剂的结构式为：
Figure PCTCN2016101995-appb-000005
表1
Figure PCTCN2016101995-appb-000006
综上所述，本发明所提供的一种谷氨酰胺酰基环化酶抑制剂(QC抑制剂)，其根据靶标酶蛋白活性中心晶体结构设计而成，显示出良好的选择性和专一性，具有更高的成药性；其母体结构更丰富、水溶性好、跨膜性能佳、活性更高。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。

Claims (8)

  1. 一种谷氨酰胺酰基环化酶抑制剂，其特征在于，其结构式如下：
    Figure PCTCN2016101995-appb-100001
    其中，A单元是苯环、六元杂芳环、五元杂芳环、七元芳环、萘、蒽、萘醌或多芳环体系，R1是氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基、磷酸基及其取代物中的一种；
    B单元是苯环、六元杂芳环、五元杂芳环、七元芳环、萘、蒽、萘醌或多芳环体系，R2是氢、直链状烷基、支链状烷基、烷氧基、卤素、羧基、硝基、磺酸基、胺基、磷酸基及其取代物中的一种；
    C单元中，咪唑环上R3是氢、直链状烷基、支链状烷基、烷氧基、卤素、胺基及其取代物中的一种。
  2. 根据权利要求1所述的谷氨酰胺酰基环化酶抑制剂，其特征在于，B单元和C单元在A单元的链接位置是邻位、间位或对位。
  3. 根据权利要求1所述的谷氨酰胺酰基环化酶抑制剂，其特征在于，在同一个化合物内，A单元和B单元的母核结构相同或不相同，R1和R2的结构相同或不相同。
  4. 根据权利要求1所述的谷氨酰胺酰基环化酶抑制剂，其特征在于，R1是单取代或不同位置的多取代。
  5. 根据权利要求1所述的谷氨酰胺酰基环化酶抑制剂，其特征 在于，R2是单取代或不同位置的多取代。
  6. 根据权利要求1所述的谷氨酰胺酰基环化酶抑制剂，其特征在于，R3是单取代或不同位置的多取代。
  7. 根据权利要求1所述的谷氨酰胺酰基环化酶抑制剂，其特征在于，R3的取代位置在咪唑环的2、4或5位。
  8. 根据权利要求1所述的谷氨酰胺酰基环化酶抑制剂，其特征在于，C单元中，烷基链中碳原子n＝1-4。
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