CN102503894B - 5-substituted methylene imidazolidine-2, 4-diketone derivative as well as pharmaceutical composition and application thereof - Google Patents
5-substituted methylene imidazolidine-2, 4-diketone derivative as well as pharmaceutical composition and application thereof Download PDFInfo
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- CN102503894B CN102503894B CN201110364739.7A CN201110364739A CN102503894B CN 102503894 B CN102503894 B CN 102503894B CN 201110364739 A CN201110364739 A CN 201110364739A CN 102503894 B CN102503894 B CN 102503894B
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- dione
- imidazolidine
- benzylidene
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Abstract
本发明同时公开了具有通式Ⅰ结构的化合物或其药学上可接受的盐，其中R1、R2、R3的定义同说明书的定义。本发明同时也公开了包含作为活性成分Ⅰ的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体、赋形剂或稀释剂组成的药物组合物，特别是作为治疗糖尿病的药物方面的用途。
The present invention also discloses a compound with the general formula I structure or a pharmaceutically acceptable salt thereof, wherein the definitions of R1, R2 and R3 are the same as those in the description. The present invention also discloses a pharmaceutical composition comprising the compound as the active ingredient I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, excipients or diluents, especially as a therapeutic Medicinal use in diabetes.
Description
技术领域 technical field
本发明属于有机化学药物合成技术领域，涉及治疗糖尿病的化学药物的合成，更具体地说，是一类新的5-取代亚甲基咪唑烷-2,4-二酮类衍生物及其制备方法，以及含有它们的药物组合物和作为药物的用途。 The invention belongs to the technical field of organic chemical drug synthesis, and relates to the synthesis of chemical drugs for treating diabetes, more specifically, a new class of 5-substituted methylene imidazolidine-2,4-dione derivatives and their preparation methods, as well as pharmaceutical compositions containing them and their use as medicines. the
背景技术 Background technique
糖尿病及其慢性并发症对人类健康的危害是十分严重的，随着生物环境的改善在全世界的发病率有逐年增高的趋势，降血糖是最重要的治疗手段，由于需要长期服药，对疗效和副作用具有很高的要求，因此，新型降糖药一直是人们开发的重点。最近，蛋白酪氨酸磷酸酯酶1B（PTP1B）抑制剂被发现具有良好的降糖作用。 Diabetes and its chronic complications are very serious hazards to human health. With the improvement of the biological environment, the incidence rate in the world is increasing year by year. Hypoglycemia is the most important treatment. and side effects have very high requirements, therefore, new hypoglycemic agents have been the focus of people's development. Recently, inhibitors of protein tyrosine phosphatase 1B (PTP1B) were found to have favorable hypoglycemic effects. the
PTP1B是蛋白酪氨酸磷酸酯酶家族中最具代表性的成员，该酶通过调节细胞内酪氨酸的磷酸化水平来控制细胞的成长、分化、代谢；细胞迁移、基因转录、离子通道开闭、免疫反应、细胞凋亡以及成骨发育也受到PTP1B的调控。PTP1B在胰岛素信号传导链中起负向调节作用，阻碍细胞中糖原的合成，使血液中血糖浓度升高，最终导致糖尿病。因此，PTP1B已经成为研制糖尿病药物的靶酶。PTP1B 特异性抑制剂有望提高胰岛素的敏感性，有效地治疗2型糖尿病、胰岛素抵抗和肥胖症。 PTP1B is the most representative member of the protein tyrosine phosphatase family. This enzyme controls the growth, differentiation, and metabolism of cells by regulating the phosphorylation level of tyrosine in cells; cell migration, gene transcription, and ion channel opening. Closure, immune response, apoptosis, and osteogenesis are also regulated by PTP1B. PTP1B plays a negative regulatory role in the insulin signal transduction chain, hinders the synthesis of glycogen in cells, increases blood sugar concentration, and eventually leads to diabetes. Therefore, PTP1B has become a target enzyme for the development of diabetes drugs. PTP1B-specific inhibitors are expected to improve insulin sensitivity and effectively treat type 2 diabetes, insulin resistance, and obesity. the
目前已发现的PTP1B的抑制剂主要可以分为三类：第一类是无机小分子类化合物，这类化合物以钒酸钠为代表，但是其选择性非常低，对所有的PTPs都有较强的抑制性，所以该类化合物没有开发的前景，也不可能应用到临床治疗当中。第二类为天然产物，近些年来国内外关于天然产物中的PTP1B抑制剂分离、鉴定和筛选取得了飞速进展，如黄酮类和萜类化合物表现出有效的抑制活性。第三类就是有机化合物，该类物质大多通过有机合成和组合化学的方法进行得到，再对化合物的取代基团进行修饰，最后得到较理想的PTP1B抑制剂。此类抑制剂主要包括：抗敏寡核苷酸类抑制剂、噻吩类抑制剂、一元羧酸类抑制剂、1,2,5-异噻唑烷酮类、1,2,5-噻二唑烷酮类以及研究不多的变构抑制剂（苯并呋喃磺酰胺类化合物）。由于分子量太大（>500Da）、带电荷较高和亲脂系数高等因素，使这些抑制剂的成药性降低。因此，寻找高度专一性、高效、低毒的PTP1B抑制剂仍是很大的挑战。 The PTP1B inhibitors that have been discovered so far can be mainly divided into three categories: the first category is inorganic small molecule compounds, such compounds are represented by sodium vanadate, but their selectivity is very low, and they have strong effects on all PTPs. Inhibition, so this type of compound has no prospect of development, and it is impossible to apply it to clinical treatment. The second category is natural products. In recent years, rapid progress has been made in the isolation, identification and screening of PTP1B inhibitors in natural products at home and abroad, such as flavonoids and terpenoids showing effective inhibitory activity. The third category is organic compounds, which are mostly obtained through organic synthesis and combinatorial chemistry, and then the substituent groups of the compounds are modified to finally obtain a more ideal PTP1B inhibitor. Such inhibitors mainly include: anti-sensitive oligonucleotide inhibitors, thiophene inhibitors, monocarboxylic acid inhibitors, 1,2,5-isothiazolidinones, 1,2,5-thiadiazole Alkanones and less studied allosteric inhibitors (benzofuran sulfonamides). Due to factors such as large molecular weight (>500Da), high charge and high lipophilic coefficient, the druggability of these inhibitors is reduced. Therefore, it is still a great challenge to find highly specific, highly effective, and low-toxic PTP1B inhibitors. the
我们前期工作发现了两个具有降糖活性的化合物（5-(4-苄氧基苄亚甲基)咪唑烷-2,4-二酮，5-(4-(2-氯苄氧基)苄亚甲基)咪唑烷-2,4-二酮）。在此基础上，我们利用计算机辅助设计先进手段，优化结构，设计、合成了咪唑烷-2,4-二酮类化合物，并且测定了对PTP1B的抑制活性和对四氧嘧啶致高血糖模型小鼠的降糖活性。本模型是典型的抗糖尿病药物动物筛选模型（参见：陈建国，梅松，付颖，胡欣，王茵。四氧嘧啶致小鼠高血糖模型的研究。卫生毒理学杂志，2004, 18(2)：99-101。），能够保证筛选结果的准确有效性。 Our previous work found two compounds with hypoglycemic activity (5-(4-benzyloxybenzylmethylene)imidazolidine-2,4-dione, 5-(4-(2-chlorobenzyloxy) benzylidene) imidazolidine-2,4-dione). On this basis, we used advanced computer-aided design methods to optimize the structure, design and synthesize imidazolidine-2,4-dione compounds, and determined the inhibitory activity on PTP1B and the effect on alloxan-induced hyperglycemia models. Hypoglycemic activity in mice. This model is a typical animal screening model for anti-diabetic drugs (see: Chen Jianguo, Mei Song, Fu Ying, Hu Xin, Wang Yin. Research on the model of hyperglycemia in mice induced by alloxan. Journal of Health Toxicology, 2004, 18(2) : 99-101.), which can ensure the accuracy and validity of the screening results. the
目前未见以咪唑烷-2,4-二酮为母核的PTP1B抑制剂的报道。该类抑制剂具有很好的创新性。 So far, there are no reports of PTP1B inhibitors with imidazolidine-2,4-dione as the core. Such inhibitors are highly innovative. the
发明内容 Contents of the invention
本发明的一个目的是提供了5-苄亚甲基咪唑烷-2,4-二酮类衍生物及其药学上可接受的盐。 One object of the present invention is to provide 5-benzylidene imidazolidine-2,4-dione derivatives and pharmaceutically acceptable salts thereof. the
本发明的另一个目的是提供制备具有通式Ⅰ的化合物或其药学上可接受的盐的方法。 Another object of the present invention is to provide a process for preparing the compound of general formula I or a pharmaceutically acceptable salt thereof. the
本发明的再一个目的是提供含有通式Ⅰ化合物或其药学上可接受的盐作为有效成分，以及一种或多种药学上可接受的载体、赋形剂或稀释剂的药用组合物，及其在降糖方面的应用。 Another object of the present invention is to provide a pharmaceutical composition containing a compound of general formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers, excipients or diluents, and its application in hypoglycemia. the
现结合本发明的目的对本发明内容进行具体描述。 The content of the present invention will now be specifically described in conjunction with the purpose of the present invention. the
具有通式Ⅰ结构的化合物或其药学上可接受的盐： A compound with a general formula I structure or a pharmaceutically acceptable salt thereof:
Ⅰ Ⅰ
其中R1为: 苯环、取代苯环（不包括4-羟基苯基，4-苄氧基苯基，4-(2-氯苄氧基)苯基）、芳杂环、取代芳杂环、C1-5烷基或-C3-6环烷基； Where R 1 is: benzene ring, substituted benzene ring (excluding 4-hydroxyphenyl, 4-benzyloxyphenyl, 4-(2-chlorobenzyloxy)phenyl), aromatic heterocycle, substituted aromatic heterocycle , C 1 - 5 alkyl or -C 3 - 6 cycloalkyl;
R2为: 氢原子、苄基、取代苄基、C1-5烷基、-C3-6环烷基或CH2R4，其中R4为芳杂环、取代芳杂环； R 2 is: hydrogen atom, benzyl, substituted benzyl , C 1-5 alkyl, -C 3-6 cycloalkyl or CH 2 R 4 , wherein R 4 is an aromatic heterocycle or a substituted aromatic heterocycle;
R3为: 氢原子、苄基、取代苄基、C1-5烷基、-C3-6环烷基或CH2R5，其中R5为芳杂环、取代芳杂环。 R 3 is: hydrogen atom, benzyl, substituted benzyl , C 1-5 alkyl, -C 3-6 cycloalkyl or CH 2 R 5 , wherein R 5 is an aromatic heterocycle or a substituted aromatic heterocycle.
本发明优选通式Ⅰ化合物或其药学上可接受的盐，其中 The present invention is preferably a compound of general formula I or a pharmaceutically acceptable salt thereof, wherein
R1为: 苯环、取代苯环（不包括4-羟基苯基，4-苄氧基苯基，4-(2-氯苄氧基)苯基）、芳杂环（如呋喃）、取代芳杂环（如5-乙酰氧甲基呋喃）、C1-4烷基、-C4-6环烷基； R 1 is: benzene ring, substituted benzene ring (excluding 4-hydroxyphenyl, 4-benzyloxyphenyl, 4-(2-chlorobenzyloxy)phenyl), aromatic heterocycle (such as furan), substituted Aromatic heterocycle (such as 5-acetoxymethylfuran), C 1 - 4 alkyl, -C 4 - 6 cycloalkyl;
R2为: 氢原子、苄基、取代苄基、C1-4烷基、-C4-6环烷基、CH2R4，其中R4为芳杂环（如呋喃、吡啶）、取代芳杂环（如取代呋喃、取代吡啶）； R 2 is: hydrogen atom, benzyl, substituted benzyl, C 1 - 4 alkyl, -C 4 - 6 cycloalkyl, CH 2 R 4 , wherein R 4 is an aromatic heterocycle (such as furan, pyridine), substituted Aromatic heterocycles (such as substituted furans, substituted pyridines);
R3为: 氢原子、苄基、取代苄基、C1-4烷基、-C4-6环烷基、CH2R5，其中R5为芳杂环（如呋喃、吡啶）、取代芳杂环（如取代呋喃、取代吡啶）。 R 3 is: hydrogen atom, benzyl, substituted benzyl, C 1 - 4 alkyl, -C 4 - 6 cycloalkyl, CH 2 R 5 , where R 5 is an aromatic heterocycle (such as furan, pyridine), substituted Aromatic heterocycles (such as substituted furans, substituted pyridines).
本发明另一优选的通式Ⅰ化合物或其药学上可接受的盐其中， Another preferred compound of general formula I of the present invention or a pharmaceutically acceptable salt thereof wherein,
R1为: 苯环、取代苯环（不包括4-羟基苯基，4-苄氧基苯基，4-(2-氯苄氧基)苯基）、芳杂环（如呋喃）、取代芳杂环（如5-乙酰氧甲基呋喃）、C1-3烷基、环己烷基； R 1 is: benzene ring, substituted benzene ring (excluding 4-hydroxyphenyl, 4-benzyloxyphenyl, 4-(2-chlorobenzyloxy)phenyl), aromatic heterocycle (such as furan), substituted Aromatic heterocycle (such as 5-acetoxymethylfuran), C 1 - 3 alkyl, cyclohexane;
R2为: 氢原子、苄基、取代苄基、C1-3烷基、环己烷基、CH2R4，其中R4为芳杂环（如呋喃、吡啶）、取代芳杂环（如取代呋喃、取代吡啶）； R 2 is: hydrogen atom, benzyl, substituted benzyl, C 1-3 alkyl, cyclohexane, CH 2 R 4 , wherein R 4 is aromatic heterocycle (such as furan, pyridine), substituted aromatic heterocycle ( Such as substituted furan, substituted pyridine);
R3为: 氢原子、苄基、取代苄基、C1-3烷基、环己烷基、CH2R5，其中R5为芳杂环（如呋喃、吡啶）、取代芳杂环（如取代呋喃、取代吡啶）； R 3 is: hydrogen atom, benzyl, substituted benzyl, C 1-3 alkyl, cyclohexane, CH 2 R 5 , wherein R 5 is aromatic heterocycle (such as furan, pyridine), substituted aromatic heterocycle ( Such as substituted furan, substituted pyridine);
本发明优选所述的通式Ⅰ化合物或其药学上可接受的盐所代表的化合物如下： The compound represented by the preferred compound of general formula I or its pharmaceutically acceptable salt in the present invention is as follows:
I-1：5-(4-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-1: 5-(4-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-2：1-对氯苄基-5-(4-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-2: 1-p-chlorobenzyl-5-(4-(p-chlorobenzyloxy) benzyl methylene) imidazolidine-2,4-dione
I-3：1,3-二（对氯苄基）-5-(4-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-3: 1,3-bis(p-chlorobenzyl)-5-(4-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-4：5-(4-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-4: 5-(4-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-5：1-苯丙基-5-(4-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-5: 1-phenylpropyl-5-(4-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-6：1,3-二（苯丙基）-5-(4-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-6: 1,3-bis(phenylpropyl)-5-(4-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-7：5-(4-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-7: 5-(4-(acetophenoneoxy)benzylidene)imidazolidine-2,4-dione
I-8：1-苯乙酮基-5-(4-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-8: 1-acetophenonyl-5-(4-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
I-9：1,3-二（苯乙酮基）-5-(4-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-9: 1,3-bis(acetophenonyl)-5-(4-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
I-10：5-(4-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-10: 5-(4-(Pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
I-11：1-吡啶甲基-5-(4-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-11: 1-pyridylmethyl-5-(4-(pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
I-12：1,3-二（吡啶甲基）-5-(4-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-12: 1,3-bis(pyridylmethyl)-5-(4-(pyridylmethoxy)benzylidene)imidazolidine-2,4-dione
I-13：5-(4-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-13: 5-(4-(Ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-14：1-乙氧羰基甲基-5-(4-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-14: 1-ethoxycarbonylmethyl-5-(4-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-15：1,3-二（乙氧羰基甲基）-5-(4-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-15: 1,3-bis(ethoxycarbonylmethyl)-5-(4-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-16：5-(3-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-16: 5-(3-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-17：1-对氯苄基-5-(3-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-17: 1-p-chlorobenzyl-5-(3-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-18：1,3-二（对氯苄基）-5-(3-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-18: 1,3-bis(p-chlorobenzyl)-5-(3-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-19：5-(3-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-19: 5-(3-(Phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-20：1-苯丙基-5-(3-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-20: 1-phenylpropyl-5-(3-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-21：1,3-二（苯丙基）-5-(3-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-21: 1,3-bis(phenylpropyl)-5-(3-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-22：5-(3-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-22: 5-(3-(Acetophenonoxy)benzylidene)imidazolidine-2,4-dione
I-23：1-苯乙酮基-5-(3-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-23: 1-acetophenonyl-5-(3-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
I-24：1,3-二（苯乙酮基）-5-(3-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-24: 1,3-bis(acetophenonyl)-5-(3-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
I-25：5-(3-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-25: 5-(3-(Pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
I-26：1-吡啶甲基-5-(3-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-26: 1-pyridylmethyl-5-(3-(pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
I-27：1,3-二（吡啶甲基）-5-(3-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-27: 1,3-bis(pyridylmethyl)-5-(3-(pyridylmethoxy)benzylidene)imidazolidine-2,4-dione
I-28：5-(3-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-28: 5-(3-(Ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-29：1-乙氧羰基甲基-5-(3-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-29: 1-ethoxycarbonylmethyl-5-(3-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-30：1,3-二（乙氧羰基甲基）-5-(3-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-30: 1,3-bis(ethoxycarbonylmethyl)-5-(3-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-31：5-(2-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-31: 5-(2-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-32：1-对氯苄基-5-(2-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-32: 1-p-chlorobenzyl-5-(2-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-33：1,3-二（对氯苄基）-5-(2-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-33: 1,3-bis(p-chlorobenzyl)-5-(2-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
I-34：5-(2-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-34: 5-(2-(Phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-35：1-苯丙基-5-(2-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-35: 1-phenylpropyl-5-(2-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-36：1,3-二（苯丙基）-5-(2-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-36: 1,3-bis(phenylpropyl)-5-(2-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
I-37：5-(2-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-37: 5-(2-(Acetophenonoxy)benzylidene)imidazolidine-2,4-dione
I-38：1-苯乙酮基-5-(2-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-38: 1-acetophenonyl-5-(2-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
I-39：1,3-二（苯乙酮基）-5-(2-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-39: 1,3-bis(acetophenonyl)-5-(2-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
I-40：5-(2-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-40: 5-(2-(Pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
I-41：1-吡啶甲基-5-(2-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-41: 1-pyridylmethyl-5-(2-(pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
I-42：1,3-二（吡啶甲基）-5-(2-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-42: 1,3-bis(pyridylmethyl)-5-(2-(pyridylmethoxy)benzylidene)imidazolidine-2,4-dione
I-43：5-(2-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-43: 5-(2-(Ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-44：1-乙氧羰基甲基-5-(2-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-44: 1-ethoxycarbonylmethyl-5-(2-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-45：1,3-二（乙氧羰基甲基）-5-(2-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-45: 1,3-bis(ethoxycarbonylmethyl)-5-(2-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
I-46：5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-46: 5-(5-Acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
I-47：1-苄基-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-47: 1-Benzyl-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
I-48：1，3-二（呋喃甲基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-48: 1,3-bis(furanmethyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
I-49：1-呋喃甲基-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-49: 1-furylmethyl-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
I-50：1，3-二（呋喃甲基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-50: 1,3-bis(furanmethyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
I-51：1-吡啶甲基-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-51: 1-pyridylmethyl-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
I-52：1，3-二（吡啶甲基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮。 I-52: 1,3-bis(pyridylmethyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione.
本发明所述通式Ⅰ化合物，其中药学上可接受的盐系指通式Ⅰ化合物与酸成盐，包括无机酸和有机酸；与碱成盐，碱为碱金属的氢氧化物。例如与氢氧化钠，氢氧化钾，氢氧化钙，碳酸钠等碱性化合物所形成的药学上可接受的盐，如相应的钠盐，钾盐或钙盐等等；与适宜有机碱，如甲胺、三乙胺、葡甲胺、碱性氨基酸等生成的药学上可接受的盐；以及与各种无机酸，例如，盐酸、硫酸、硝酸、磷酸等，或有机酸，例如，甲酸、乙酸、柠檬酸、草酸、富马酸、马来酸、氨基酸等等所生成的药学上可接受的盐。 The pharmaceutically acceptable salt of the compound of general formula I in the present invention means that the compound of general formula I forms a salt with an acid, including inorganic acid and organic acid; it forms a salt with a base, and the base is an alkali metal hydroxide. For example, pharmaceutically acceptable salts formed with basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and sodium carbonate, such as corresponding sodium salts, potassium salts, or calcium salts, etc.; and suitable organic bases, such as The pharmaceutically acceptable salts of methylamine, triethylamine, meglumine, basic amino acids, etc.; and various inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as formic acid, Pharmaceutically acceptable salts formed from acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, amino acids, etc. the
本发明所述通式Ⅰ化合物通过以下步骤合成：The compound of general formula I of the present invention is synthesized through the following steps:
以醛和咪唑烷-2，4-二酮为起始原料，在哌啶催化条件下，加热反应制备得5-取代亚甲基咪唑烷-2，4-二酮。然后在丙酮溶剂中，以碳酸钾作为缚酸剂，和各种氯化物反应，制备得各种取代的化合物I： Using aldehyde and imidazolidine-2,4-dione as starting materials, under the condition of piperidine catalysis, heat reaction to prepare 5-substituted methylene imidazolidine-2,4-dione. Then in acetone solvent, potassium carbonate is used as an acid-binding agent to react with various chlorides to prepare various substituted compounds I:
其中，各取代基团的定义同上文所述。 Wherein, the definition of each substituent group is the same as above.
本发明进一步公开了包含作为活性成分的通式Ⅰ化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体、赋形剂或稀释剂组成的药物组合物。该药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。 The present invention further discloses a pharmaceutical composition comprising the compound of general formula I or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparations, liquid oral preparations, injections and other dosage forms. the
本发明的系列化合物还可以通过非肠道形式给药。优选的非肠道给药形式为注射剂给药。所述固体及液体口服制剂包括：片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖浆剂、颗粒剂、口服溶液剂、注射剂等等。 The series of compounds of the present invention can also be administered parenterally. The preferred form of parenteral administration is injection. The solid and liquid oral preparations include: tablets, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, syrups, granules, oral solutions, injections and the like. the
药物组合物以及单元剂型中含有的活性成份（通式Ⅰ化合物）的量可以根据患者的病情、医生诊断的情况特定的加以应用，所用的化合物的量或浓度在一个较宽的范围内调节，通常，活性化合物的量范围为组合物的0.5％～90％（重量），另一优选的范围为0.5%-70%。 The amount of the active ingredient (compound of general formula I) contained in the pharmaceutical composition and the unit dosage form can be specifically applied according to the patient's condition and the situation diagnosed by the doctor, and the amount or concentration of the compound used can be adjusted within a wide range. Generally, the amount of active compound is in the range of 0.5% to 90% by weight of the composition, another preferred range is 0.5% to 70%. the
本发明化合物的药物组合物制备如下：使用标准和常规的技术，使本发明化合物与制剂学上可接受的固体或液体载体结合，以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质，其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉剂等等。 Pharmaceutical compositions of the compounds of this invention are prepared by bringing into association a compound of this invention with a pharmaceutically acceptable solid or liquid carrier, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques. Forming agents combined to prepare microparticles or microspheres. Solid dosage forms include tablets, dispersible granules, capsules, sustained-release tablets, sustained-release pellets, and the like. A solid carrier can be at least one substance, which may act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, disintegrating agent and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, talc, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic materials such as methylcellulose, microcrystalline cellulose, Low melting point paraffin, polyethylene glycol, mannitol, cocoa butter, etc. Liquid dosage forms include solvents, suspensions such as injections, powders and the like. the
本发明通式I化合物的（典型1-52化合物）抑酶活性通过以下方式测定： The (typical 1-52 compound) inhibitory enzyme activity of the general formula I compound of the present invention is determined by the following methods :
材料：PTP1B酶及其底物购自Sigma-Aldrich公司。 Materials: PTP1B enzyme and its substrate were purchased from Sigma-Aldrich Company.
方法：以PTP1B为酶，以胰岛素受体(Thr-Arg-Asp-Ile-Tyr[PO3H2]-Glu-Thr-Asp-Tyr-Tyr)中pTyr1146附近序列对应的磷酸基肽为底物。应用孔雀绿试剂，通过PTP底物的去磷酸化，测定自由磷酸基团。简言之，在40μL缓冲液 (25 mM Tris-HCl, PH7.4, 50mM NaCl, 5mM DTT, and 2.5mM EDTA)中，加入0.15μg GST-SHP2- PTP，80μM的待测化合物（典型1-52）或者DMSO，室温孵化30 min。PTP底物浓度逐渐增加到0.1mM，30℃ 孵化30 min。最后，加入50μl孔雀绿溶液，15min后测定吸光度OD620，以DMSO空白为参照计算倍性变化。 Method: PTP1B was used as the enzyme, and the phosphopeptide corresponding to the sequence near pTyr 1146 in the insulin receptor (Thr-Arg-Asp-Ile-Tyr[PO 3 H 2 ]-Glu-Thr-Asp-Tyr-Tyr) was used as the base thing. Free phosphate groups are measured by dephosphorylation of a PTP substrate using malachite green reagent. Briefly, 0.15 μg of GST-SHP2-PTP, 80 μM of the compound to be tested (typically 1- 52) or DMSO, incubate at room temperature for 30 min. The PTP substrate concentration was gradually increased to 0.1 mM, and incubated at 30°C for 30 min. Finally, 50 μl malachite green solution was added, the absorbance OD 620 was measured 15 minutes later, and the ploidy change was calculated with DMSO blank as reference.
通式I化合物在80 μM时对PTP1B的抑制活性（倍性变化）
通式I化合物I-8在不同浓度时对PTP1B的抑制活性（倍性变化）
结论：本发明通式I化合物具有抑制PTP1B酶的活性。 Conclusion: the compound of general formula I of the present invention has the activity of inhibiting PTP1B enzyme.
本发明通式I化合物（典型1-52化合物）的动物活性通过以下方式测定： The animal activity of the general formula I compound (typical 1-52 compound) of the present invention is determined by the following method :
材料：四氧嘧啶，白色粉末，Sigma 公司产品，注射时以生理盐水新鲜配制成15mg/ml。0.1ml/20g体重，相当于75mg/kg。 Material: Alloxan, white powder, product of Sigma Company, freshly prepared with normal saline for injection at 15mg/ml. 0.1ml/20g body weight, equivalent to 75mg/kg. the
血糖试剂盒：中生北控生物公司产品。 Blood glucose kit: product of Zhongsheng Beikong Biological Co., Ltd. the
动物：健康ICR小鼠，雌雄各半，体重20～24g。 Animals: Healthy ICR mice, half male and half male, weighing 20-24 g. the
方法：动物禁食16小时后尾静脉注射75mg/kg四氧嘧啶。48小时后禁食6小时用毛细管自小鼠球后静脉丛取血，离心分离血清，用葡萄糖氧化酶法测定血清葡萄糖含量。选择血糖值高于300mg/dl的小鼠，再按照测得的血糖含量平均分为7组，分别为模型、阳性（达美康80mg/kg）和各给药组。给药3天，于末次给药后1和24小时禁食取血，测定血糖含量。 Methods: Animals were fasted for 16 hours and injected with 75 mg/kg alloxan into tail vein. After 48 hours of fasting for 6 hours, blood was collected from the retrobulbar venous plexus of the mice with a capillary tube, the serum was separated by centrifugation, and the serum glucose content was determined by the glucose oxidase method. Select the mice whose blood sugar value is higher than 300mg/dl, and then divide them into 7 groups according to the measured blood sugar content, which are model, positive (Dameikang 80mg/kg) and each administration group. After 3 days of administration, fasting was taken 1 and 24 hours after the last administration, and blood was taken to measure the blood sugar level. the
通式I化合物药后1 h对四氧嘧啶致高血糖模型小鼠血糖含量的影响
注：** 与模型组相比p<0.01 Note: ** Compared with the model group, p<0.01
通式I化合物药后24h对四氧嘧啶致高血糖模型小鼠血糖含量的影响
注：** 与模型组相比p<0.01 Note: ** Compared with the model group, p<0.01
结果表明：本通式I化合物（典型1-52化合物）具有明显的降血糖活性。 The results show that the compound of general formula I (typical 1-52 compound) has obvious hypoglycemic activity. the
附图说明 Description of drawings
图1为通式I化合物的结构式图。 Figure 1 is a structural formula diagram of the compound of general formula I. the
具体实施方式：Detailed ways:
下面结合实施例对本发明做进一步的说明，实施例仅为解释性的，决不意味着它以任何方式限制本发明的范围，本发明的化合物经高效液相色谱（HPLC），薄层色谱（TLC），熔点（m.p.）进行检测，随后可以采用核磁共振（1HNMR/13CNMR）等更进一步确证其结构。其中羟基苯甲醛和咪唑烷-2,4-二酮有市售。 Below in conjunction with embodiment the present invention will be further described, embodiment is only explanatory, in no way means that it limits the scope of the present invention in any way, compound of the present invention is through high performance liquid chromatography (HPLC), thin-layer chromatography ( TLC), melting point (mp) for detection, and then nuclear magnetic resonance ( 1 HNMR/ 13 CNMR) can be used to further confirm its structure. Among them, hydroxybenzaldehyde and imidazolidine-2,4-dione are commercially available.
实施例1Example 1
5-羟基苄亚甲基咪唑烷-2，4-二酮的制备(Ⅱ) Preparation of 5-Hydroxybenzylmethyleneimidazolidine-2,4-dione (Ⅱ)
在250 mL圆底烧瓶中加入6.11 g（50 mmol）羟基苯甲醛和5.5 g（55 mmol）咪唑烷-2,4-二酮，加入10 mL哌啶，烧瓶上方安装回流冷凝管和干燥管，烧瓶置于油浴中使反应液与油浴面相平，加热到130 ℃ 并保持30分钟；产生大量气泡并微沸；冷却后加入60℃蒸馏水200 mL，用玻璃棒搅拌至固体溶解，得到红色溶液以及黄色絮状不溶物，过滤除去不溶物质，待滤液冷却至室温后，把滤液转移到烧杯中，边搅拌边逐滴加入20 mL 10 N HCl 溶液；室温下静置12 h后，用布氏漏斗抽滤得到黄色沉淀，并用冷水完全冲洗三﹑四次，干燥后得到黄色固体，分别为： Add 6.11 g (50 mmol) hydroxybenzaldehyde and 5.5 g (55 mmol) imidazolidine-2,4-dione into a 250 mL round bottom flask, add 10 mL piperidine, install a reflux condenser and a drying tube above the flask, Place the flask in an oil bath to make the reaction solution level with the oil bath surface, heat to 130°C and keep for 30 minutes; a large number of bubbles are generated and slightly boiled; after cooling, add 200 mL of distilled water at 60°C, stir with a glass rod until the solid dissolves, and obtain a red color Solution and yellow flocculent insoluble matter, filter to remove insoluble matter, after the filtrate is cooled to room temperature, transfer the filtrate to a beaker, add 20 mL of 10 N HCl solution drop by drop while stirring; The yellow precipitate was obtained by suction filtration through a Schneider funnel, and was washed three or four times with cold water, and the yellow solid was obtained after drying, which were respectively:
II-1：5-(4-羟基苄亚甲基)咪唑烷-2,4-二酮（8.11 g，79.5 %），m.p.316~318 ℃。1H-NMR(DMSO-d6,400Hz), δ:11.089(s, 1H, N1H);10.299(s, 1H, N3H); 9.856(s, 1H, OH); 7.469(d, 2H, J=8.4Hz, Ar-H); 6.767(q, 2H, J=8.4Hz, Ar-H); 6.346(s, 1H, Ar-CH). MS (m/z): 203.0(M－1); 205.0(M＋1); 409.0(2M＋1). II-1: 5-(4-hydroxybenzylidene)imidazolidine-2,4-dione (8.11 g, 79.5 %), mp316~318 ℃. 1 H-NMR(DMSO-d 6 ,400Hz), δ :11.089(s, 1H, N 1 H); 10.299(s, 1H, N 3 H); 9.856(s, 1H, OH); 7.469(d, 2H, J= 8.4Hz, Ar-H); 6.767(q, 2H, J =8.4Hz, Ar-H); 6.346(s, 1H, Ar-CH). MS ( m/z ): 203.0(M－ 1); 205.0(M+1); 409.0(2M+1).
II-2：5-（3-羟基苄亚甲基）咪唑烷-2，4-二酮（7.93 g，77.7 %），m.p.298~300 ℃。1H-NMR（DMSO-d6，400Hz）δ：11.184（1H,s,N3H）, 10.425(1H,s,N1H),9.466(1H,s,OH),7.181(1H,t,J=7.6Hz,ArH),7.050(1H,d,J=8.0Hz,ArH),6.924(1H,s,ArH)，6.732(1H,m,ArH),6.292(1H,s,ArCH). MS m/z:203.1（M-1）,407.1(2M-1). II-2: 5-(3-hydroxybenzylidene)imidazolidine-2,4-dione (7.93 g, 77.7 %), mp298~300 ℃. 1 H-NMR (DMSO-d 6 , 400Hz) δ: 11.184 (1H, s, N 3 H), 10.425 (1H, s, N 1 H), 9.466 (1H, s, OH), 7.181 (1H, t ,J=7.6Hz,ArH),7.050(1H,d,J=8.0Hz,ArH),6.924(1H,s,ArH),6.732(1H,m,ArH),6.292(1H,s,ArCH). MS m/z :203.1(M-1),407.1(2M-1).
II-3：5-(2-羟基苄亚甲基)咪唑烷-2,4-二酮（8.45 g，82.8 %），m.p.327~329 ℃。1H-NMR(DMSO-d6, 400Hz), δ: 11.120(s, 1H, N1H); 10.246(s, 1H, N3H); 10.039(s, 1H, OH); 7.525(d, 1H, J=7.6Hz, Ar-H); 7.144(m, 1H, Ar-H); 6.828(m, 2H, Ar-H); 6.659(s, 1H, =CH). MS m/z:203.1（M-1）。 II-3: 5-(2-hydroxybenzylidene)imidazolidine-2,4-dione (8.45 g, 82.8 %), mp327~329 ℃. 1 H-NMR(DMSO-d 6 , 400Hz), δ : 11.120(s, 1H, N 1 H); 10.246(s, 1H, N 3 H); 10.039(s, 1H, OH); 7.525(d, 1H, J= 7.6Hz, Ar-H); 7.144(m, 1H, Ar-H); 6.828(m, 2H, Ar-H); 6.659(s, 1H, =CH). MS m/z :203.1 (M-1).
实施例2Example 2
对氯氯苄与5-(4-对羟基苄亚甲基)咪唑烷-2,4-二酮反应步骤：混合的5-[4-对羟基苄亚甲基]咪唑烷-2,4-二酮（4.08g，20mmol），对氯氯苄（3.24 g，20 mmol），K2CO3（2.76g，20mmol）和丙酮（120mL）回流24 h，TLC检测原料反应完毕，停止反应；冷却后过滤除去无机盐；滤液经过减压蒸馏得到粗品，用少量溶剂溶解后经过硅胶柱分离纯化，依次得到I-1：白色固体（0.46g，14.00 %），m.p.255~258℃；I-2：浅黄色固体（0.62 g，27.15 %），m.p.167~168 ℃；I-3：白色固体（0.56 g，28.83 %），m.p.129~132 ℃。 p-Chlorobenzyl chloride and 5-(4-p-hydroxybenzylidene) imidazolidine-2,4-dione reaction steps: Mixed 5-[4-p-hydroxybenzylidene] imidazolidine-2,4- Diketone (4.08g, 20mmol), p-chlorobenzyl chloride (3.24 g, 20 mmol), K 2 CO 3 (2.76g, 20mmol) and acetone (120mL) were refluxed for 24 h, TLC detected that the reaction of the raw materials was complete, and the reaction was stopped; cooling After that, the inorganic salt was removed by filtration; the filtrate was distilled under reduced pressure to obtain the crude product, which was dissolved in a small amount of solvent and purified by silica gel column to obtain I-1: white solid (0.46g, 14.00%), mp255~258°C; I-2: Pale yellow solid (0.62 g, 27.15 %), mp167~168 ℃; I-3: white solid (0.56 g, 28.83 %), mp129~132 ℃.
化合物结构及谱图解析如下： The compound structure and spectrum analysis are as follows:
I-1: 5-[4-(对氯苄氧基) 苄亚甲基]咪唑烷-2,4-二酮 I-1 : 5-[4-(p-chlorobenzyloxy)benzylidene]imidazolidine-2,4-dione
谱图解析： Spectrum analysis:
1H-NMR(DMSO-d6, 400Hz), δ: 10.654(s, 1H, N3H); 9.895(s, 1H, N1H); 7.499(s, 2H, J=8.8Hz, Ar-H); 7.381-7.415(m, 2H, Ar-H); 7.303(d, 2H, J=8.4Hz, Ar-H); 6.786(d, 2H, J=8.8Hz, Ar-H); 6.502(s, 1H, =CH); 4.641(s, 2H, OCH2). MS (m/z): 329.0(M＋1)；346.2(M＋NH4)。 1 H-NMR(DMSO-d6, 400Hz), δ : 10.654(s, 1H, N 3 H); 9.895(s, 1H, N 1 H); 7.499(s, 2H, J =8.8Hz, Ar-H ); 7.381-7.415(m, 2H, Ar-H); 7.303(d, 2H, J =8.4Hz, Ar-H); 6.786(d, 2H, J =8.8Hz, Ar-H); 6.502(s , 1H, =CH); 4.641(s, 2H, OCH 2 ). MS ( m/z ): 329.0 (M+1); 346.2 (M+NH 4 ).
I-2: 1-对氯苄基-5-[4-(对氯苄氧基) 苄亚甲基]咪唑烷-2,4-二酮 I-2 : 1-p-chlorobenzyl-5-[4-(p-chlorobenzyloxy)benzylidene]imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 9.867(s, 1H, N3H); 7.310-7.434(m, 9H, Ar-H); 6.680-6.734(m, 2H, Ar-H); 6.429(s, 1H, =CH); 4.938(s, 2H, ArCH2); 4.720(t, 2H, J=6.4Hz, OCH2). MS (m/z): 452.0(M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 9.867(s, 1H, N 3 H); 7.310-7.434(m, 9H, Ar-H); 6.680-6.734(m, 2H, Ar-H); 6.429(s, 1H, =CH); 4.938(s, 2H, ArCH 2 ); 4.720(t, 2H, J =6.4Hz, OCH 2 ). MS ( m/z ): 452.0(M -1).
I-3: 1,3-二(对氯苄基)-5-[4-(对氯苄氧基)苄亚甲基]咪唑烷-2,4-二酮 I-3 : 1,3-bis(p-chlorobenzyl)-5-[4-(p-chlorobenzyloxy)benzylidene]imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.419-7.474 (m, 6H, Ar-H); 7.333 (d, 2H, J=8.4Hz, Ar-H); 7.108-7.145 (m, 4H, Ar-H); 6.930(d, 2H，J=8.8Hz, Ar-H); 6.744(s, 1H, =CH); 6.593(d, 2H, Ar-H); 5.151(s, 2H, OCH2); 4.714(s, 4H, ArCH2). MS (m/z): 577.0(M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 7.419-7.474 (m, 6H, Ar-H); 7.333 (d, 2H, J =8.4Hz, Ar-H); 7.108- 7.145 (m, 4H, Ar-H); 6.930(d, 2H, J =8.8Hz, Ar-H); 6.744(s, 1H, =CH); 6.593(d, 2H, Ar-H); 5.151( s, 2H, OCH 2 ); 4.714 (s, 4H, ArCH 2 ). MS ( m/z ): 577.0 (M-1).
实施例3-28Example 3-28
参照实施例2的操作，区别在于用不同结构的卤代化合物与实施例1的产物经取代反应，得到下述通式I的化合物 With reference to the operation of Example 2, the difference is that the product of Example 1 is replaced with a halogenated compound of different structure to obtain the compound of the following general formula I
上述各化合物的氢谱和质谱的测定结果见下面的描述。 The measurement results of the hydrogen spectra and mass spectra of the above compounds are described below.
I-4：5-(4-(苯丙氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-4: 5-(4-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.519(s, 1H, N3H); 9.864(s, 1H, N1H); 7.485(d, 2H, J=8.4Hz, Ar-H); 7.143-7.284(m, 5H, Ar-H); 6.773(t, 2H, J=7.2Hz, Ar-H); 6.453(s, 1H, =CH); 3.486(t, 2H, J=7.2Hz, OCH2); 2.586(t, 2H, J=7.2Hz, PhCH2); 1.823-1.896(m, 2H, PhCH2CH2). MS(m/z): 323.3(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.519(s, 1H, N 3 H); 9.864(s, 1H, N 1 H); 7.485(d, 2H, J =8.4 Hz, Ar-H); 7.143-7.284(m, 5H, Ar-H); 6.773(t, 2H, J =7.2Hz, Ar-H); 6.453(s, 1H, =CH); 3.486(t, 2H, J =7.2Hz, OCH 2 ); 2.586(t, 2H, J =7.2Hz, PhCH 2 ); 1.823-1.896(m, 2H, PhCH 2 CH 2 ). MS(m/z): 323.3(M +1).
I-5：1-苯丙基-5-(4-(苯丙氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-5: 1-phenylpropyl-5-(4-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.422(s, 1H, NH); 7.635(d, 2H, J=8.6Hz, Ar-H); 7.401(m, 4H, Ar-H); 7.258(m, 6H, Ar-H); 6.852(m, 2H, Ar-H); 6.606(s, 1H, =CH); 4.358(m, 4H, CH2); 2.775(m, 4H, CH2); 1.811(m, 4H, CH2). MS(m/z): 441.5(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.422(s, 1H, NH); 7.635(d, 2H, J =8.6Hz, Ar-H); 7.401(m, 4H, Ar-H); 7.258(m, 6H, Ar-H); 6.852(m, 2H, Ar-H); 6.606(s, 1H, =CH); 4.358(m, 4H, CH 2 ); 2.775(m , 4H, CH 2 ); 1.811(m, 4H, CH 2 ). MS(m/z): 441.5(M+1).
I-6: 1,3-二（苯丙基）-5-(4-(苯丙氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-6: 1,3-bis(phenylpropyl)-5-(4-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.641(d, 2H, J=8.6Hz, Ar-H); 7.410(m, 6H, Ar-H); 7.288(m, 9H, Ar-H); 6.902(m, 2H, Ar-H); 6.614(s, 1H, =CH); 4.025(m, 6H, CH2); 2.668(m, 6H, CH2); 2.058(m, 6H, CH2). MS(m/z): 559.5(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 7.641(d, 2H, J =8.6Hz, Ar-H); 7.410(m, 6H, Ar-H); 7.288(m, 9H, Ar-H); 6.902(m, 2H, Ar-H); 6.614(s, 1H, =CH); 4.025(m, 6H, CH 2 ); 2.668(m, 6H, CH 2 ); 2.058( m, 6H, CH2 ). MS (m/z): 559.5 (M+1).
I-7：5-(4-(苯乙酮氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-7: 5-(4-(acetophenoneoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.730(s, 1H, N3H); 9.919(s, 1H, N1H); 8.068(d, 2H, J=7.2Hz, Ar-H); 7.724(t, 1H, J=7.6Hz, Ar-H); 7.528-7.606(m, 4H, Ar-H); 6.813(d, 2H, J=8.8Hz, Ar-H); 6.548(s, 1H, =CH); 5.096（s, 2H, OCH2). MS(m/z): 323.2(M+1); 340.2(M+ NH4); 321.0(M－1); 662.2(2M+ NH4)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.730(s, 1H, N 3 H); 9.919(s, 1H, N 1 H); 8.068(d, 2H, J =7.2 Hz, Ar-H); 7.724(t, 1H, J =7.6Hz, Ar-H); 7.528-7.606(m, 4H, Ar-H); 6.813(d, 2H, J =8.8Hz, Ar-H ); 6.548(s, 1H, =CH); 5.096(s, 2H, OCH 2 ). MS(m/z): 323.2(M+1); 340.2(M+ NH 4 ); 321.0(M－1); 662.2 (2M+ NH4 ).
I-8：1-苯乙酮基-5-(4-(苯乙酮氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-8: 1-acetophenonyl-5-(4-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 9.643(s, 1H, N3H); 8.090(t, 2H, J=7.2Hz, Ar-H); 7.676-7.753(m, 3H, Ar-H); 7.610(q, 3H, J=7.6Hz, Ar-H); 7.442(t, 2H, J=8.4Hz, Ar-H); 7.104(d, 2H, J=8.4Hz, Ar-H); 6.807(s, 1H, =CH); 6.587(d, 2H, J=8.8Hz, Ar-H); 5.230 (s, 2H, ArCOCH2); 5.140(s, 2H, OCH2). MS (m/z): 441.0 (M＋1); 458.0(M＋NH4); 439.0(M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 9.643(s, 1H, N 3 H); 8.090(t, 2H, J =7.2Hz, Ar-H); 7.676-7.753( m, 3H, Ar-H); 7.610(q, 3H, J =7.6Hz, Ar-H); 7.442(t, 2H, J =8.4Hz, Ar-H); 7.104(d, 2H, J =8.4 Hz, Ar-H); 6.807(s, 1H, =CH); 6.587(d, 2H, J =8.8Hz, Ar-H); 5.230 (s, 2H, ArCOCH 2 ); 5.140(s, 2H, OCH 2 ). MS ( m/z ): 441.0 (M+1); 458.0 (M+ NH4 ); 439.0 (M-1).
I-9：1,3-二（苯乙酮基）-5-(4-(苯乙酮氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-9: 1,3-bis(acetophenonyl)-5-(4-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 8.093 (t, 2H, J=7.2Hz, Ar-H); 7.947 (t, 2H, J=7.2Hz, Ar-H); 7.556-7.755 (m, 9H, Ar-H); 7.493 (t, 2H, J=7.6Hz, Ar-H); 7.203(d, 2H，J=8.8Hz, Ar-H); 6.854(s, 1H, =CH); 6.784(d, 2H, J=8.8Hz, Ar-H); 5.404 (s, 2H, COCH2); 5.243 (s, 2H, COCH2); 5.112(d, 4H, OCH2). MS (m/z): 559.0 (M＋1); 576.0(M＋NH4)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 8.093 (t, 2H, J =7.2Hz, Ar-H); 7.947 (t, 2H, J =7.2Hz, Ar-H) ; 7.556-7.755 (m, 9H, Ar-H); 7.493 (t, 2H, J =7.6Hz, Ar-H); 7.203(d, 2H, J =8.8Hz, Ar-H); 6.854(s, 1H, =CH); 6.784(d, 2H, J =8.8Hz, Ar-H); 5.404 (s, 2H, COCH 2 ); 5.243 (s, 2H, COCH 2 ); 5.112(d, 4H, OCH 2 ). MS ( m/z ): 559.0 (M+1); 576.0 (M+ NH4 ).
I-10：5-(4-(吡啶甲氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-10: 5-(4-(Pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.256 (s, 1H, N3H); 9.834 (s, 1H, N1H); 8.453 (s, 1H, Ar-H); 7.930 (m, 1H, Ar-H); 7.655 (m, 3H, Ar-H); 7.412(d, 1H，J=8.8Hz, Ar-H); 6.977(d, 2H, J=8.8Hz, Ar-H); 6.702(s, 1H, =CH); 5.414 (s, 2H, CH2). MS (m/z): 296.3 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 10.256 (s, 1H, N 3 H); 9.834 (s, 1H, N 1 H); 8.453 (s, 1H, Ar-H ); 7.930 (m, 1H, Ar-H); 7.655 (m, 3H, Ar-H); 7.412(d, 1H, J =8.8Hz, Ar-H); 6.977(d, 2H, J =8.8Hz , Ar-H); 6.702(s, 1H, =CH); 5.414 (s, 2H, CH2 ). MS ( m/z ): 296.3 (M+1).
I-11：1-吡啶甲基-5-(4-(吡啶甲氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-11: 1-pyridylmethyl-5-(4-(pyridinemethoxy) benzyl methylene) imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.175 (s, 1H, N3H); 8.465 (d, 2H, J=8.4Hz, Ar-H); 7.950 (m, 1H, Ar-H); 7.735 (m, 1H, Ar-H); 7.641(m, 3H，Ar-H); 7.402(m, 1H，Ar-H); 7.302(d, 2H，J=8.6Hz, Ar-H); 6.944(d, 2H, J=8.2Hz, Ar-H); 6.668(s, 1H, =CH); 5.458 (s, 2H, CH2) ; 4.772 (s, 2H, CH2). MS (m/z): 387.5 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 10.175 (s, 1H, N 3 H); 8.465 (d, 2H, J =8.4Hz, Ar-H); 7.950 (m, 1H, Ar-H); 7.735 (m, 1H, Ar-H); 7.641(m, 3H, Ar-H); 7.402(m, 1H, Ar-H); 7.302(d, 2H, J =8.6Hz , Ar-H); 6.944(d, 2H, J =8.2Hz, Ar-H); 6.668(s, 1H, =CH); 5.458 (s, 2H, CH 2 ) ; 4.772 (s, 2H, CH 2 ). MS ( m/z ): 387.5 (M+1).
I-12：1,3-二（吡啶甲基）-5-(4-(吡啶甲氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-12: 1,3-bis(pyridylmethyl)-5-(4-(pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 8.447 (m, 3H, Ar-H); 7.969 (m, 1H, Ar-H); 7.728 (m, 2H, Ar-H); 7.657(m, 3H，Ar-H); 7.422(m, 1H，Ar-H); 7.317(m, 4H，Ar-H); 6.987(d, 2H, J=8.8Hz, Ar-H); 6.687(s, 1H, =CH); 5.447 (m, 2H, CH2) ; 4.774 (m, 2H, CH2); 4.705 (m, 2H, CH2). MS (m/z): 478.5 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 8.447 (m, 3H, Ar-H); 7.969 (m, 1H, Ar-H); 7.728 (m, 2H, Ar-H ); 7.657(m, 3H, Ar-H); 7.422(m, 1H, Ar-H); 7.317(m, 4H, Ar-H); 6.987(d, 2H, J =8.8Hz, Ar-H) ; 6.687(s, 1H, =CH); 5.447 (m, 2H, CH 2 ) ; 4.774 (m, 2H, CH 2 ); 4.705 (m, 2H, CH 2 ). MS ( m/z ): 478.5 ( M+1).
I-13：5-(4-(乙氧羰基甲氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-13: 5-(4-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.727(s, 1H, N1H); 9.923(s, 1H, N3H); 7.526(d, 2H, J=8.8Hz, Ar-H); 6.811(d, 2H, J=8.4Hz, Ar-H); 6.544(s, 1H, =CH); 4.293(s, 2H, Ar-O-CH2); 4.158(q, 4H, J=7.2Hz, OCH2); 1.210(m, 3H, CH3). MS (m/z): 291.2(M＋1); 308.2(M＋NH4); 598.0(2M＋NH4); 289.0(M－1); 579.0(2M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.727(s, 1H, N 1 H); 9.923(s, 1H, N 3 H); 7.526(d, 2H, J =8.8Hz , Ar-H); 6.811(d, 2H, J =8.4Hz, Ar-H); 6.544(s, 1H, =CH); 4.293(s, 2H, Ar-O-CH 2 ); 4.158(q, 4H, J =7.2Hz, OCH 2 ); 1.210(m, 3H, CH 3 ). MS ( m/z ): 291.2(M+1); 308.2(M+NH 4 ); 598.0(2M+NH 4 ); 289.0(M－1 ); 579.0(2M-1).
I-14：1-乙氧羰基甲基-5-(4-(乙氧羰基甲氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-14: 1-ethoxycarbonylmethyl-5-(4-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.858(s, 1H, N3H); 7.635(d, 2H, J=9.2Hz, Ar-H); 6.984(d, 2H, J=8.8Hz, Ar-H); 6.876(s, 1H, =CH); 4.849(s, 2H, Ar-O-CH2); 4.304(s, 2H, N1-CH2); 4.162(q, 4H, J=7.2Hz, OCH2); 1.217(m, 6H, CH3). MS (m/z): 377.2(M＋1); 394.2(M＋NH4); 770.0(2M＋NH4); 375.0(M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.858(s, 1H, N 3 H); 7.635(d, 2H, J =9.2Hz, Ar-H); 6.984(d, 2H , J =8.8Hz, Ar-H); 6.876(s, 1H, =CH); 4.849(s, 2H, Ar-O-CH 2 ); 4.304(s, 2H, N 1 -CH 2 ); 4.162( q, 4H, J =7.2Hz, OCH 2 ); 1.217(m, 6H, CH 3 ). MS ( m/z ): 377.2(M+1); 394.2(M+NH 4 ); 770.0(2M+NH 4 ); 375.0(M -1).
I-15：1,3-二（乙氧羰基甲基）-5-(4-(乙氧羰基甲氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-15: 1,3-bis(ethoxycarbonylmethyl)-5-(4-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.282(d, 2H, J=8.4Hz, Ar-H); 6.962(d, 2H, J=8.4Hz, Ar-H); 6.876(s, 1H, =CH); 4.809(s, 2H, Ar-O-CH2); 4.382(s, 2H, N1-CH2); 4.284(s, 2H, N3-CH2); 4.163(q, 4H, J=7.2Hz，OCH2); 3.885(q, 2H, J=7.2Hz, OCH2);1.207(t, 6H, J=7.2Hz, CH3); 1.001(m, 3H, CH3). MS (m/z): 480.2(M＋NH4); 942.0(2M＋NH4)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 7.282(d, 2H, J =8.4Hz, Ar-H); 6.962(d, 2H, J =8.4Hz, Ar-H); 6.876(s, 1H, =CH); 4.809(s, 2H, Ar-O-CH 2 ); 4.382(s, 2H, N 1 -CH 2 ); 4.284(s, 2H, N 3 -CH 2 ); 4.163(q, 4H, J =7.2Hz, OCH 2 ); 3.885(q, 2H, J =7.2Hz, OCH 2 ); 1.207(t, 6H, J =7.2Hz, CH 3 ); 1.001(m, 3H , CH 3 ). MS ( m/z ): 480.2 (M+NH 4 ); 942.0 (2M+NH 4 ).
I-16：5-(3-(对氯苄氧基) 苄亚甲基)咪唑烷-2，4-二酮 I-16: 5-(3-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.025(s, 1H, N3H); 9.036(s, 1H, N1H); 7.502(s, 1H, Ar-H); 7.401(d, 2H,J=8.4Hz,Ar-H); 7.350(d, 2H, J=8.4Hz, Ar-H); 7.105(d, 2H, J=8.8Hz, Ar-H);6.805(s,1H,Ar-H);6.536(s, 1H, =CH); 5.022(s, 2H, OCH2). MS (m/z): 329.5(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.025(s, 1H, N 3 H); 9.036(s, 1H, N 1 H); 7.502(s, 1H, Ar-H) ; 7.401(d, 2H, J =8.4Hz, Ar-H); 7.350(d, 2H, J =8.4Hz, Ar-H); 7.105(d, 2H, J =8.8Hz, Ar-H);6.805 (s, 1H, Ar-H); 6.536(s, 1H, =CH); 5.022(s, 2H, OCH 2 ). MS ( m/z ): 329.5 (M+1).
I-17：1-对氯苄基-5-(3-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-17: 1-p-chlorobenzyl-5-(3-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.014(s, 1H, N3H);7.562(m, 1H, Ar-H); 7.401(m, 2H, Ar-H); 7.358(m, 2H, Ar-H); 7.302(m, 4H, Ar-H); 7.152(m, 2H, Ar-H); 6.889(m, 1H, Ar-H); 6.629(s, 1H, =CH); 5.325(m, 4H, CH2). MS (m/z): 452.0(M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.014(s, 1H, N 3 H);7.562(m, 1H, Ar-H); 7.401(m, 2H, Ar-H) ; 7.358(m, 2H, Ar-H); 7.302(m, 4H, Ar-H); 7.152(m, 2H, Ar-H); 6.889(m, 1H, Ar-H); 6.629(s, 1H , =CH); 5.325 (m, 4H, CH 2 ). MS ( m/z ): 452.0 (M-1).
I-18：1,3-二（对氯苄基）-5-(3-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-18: 1,3-bis(p-chlorobenzyl)-5-(3-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.474 (m, 1H, Ar-H); 7.413 (d, 2H, J=8.8Hz, Ar-H); 7.345 (m, 4H, Ar-H); 7.306(m,6H，Ar-H); 7.104(d,2H，J=8.4Hz,Ar-H); 6.828(m,1H，Ar-H);6.625(s, 1H, =CH);5.147(m,6H,CH2). MS (m/z): 578.5(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 7.474 (m, 1H, Ar-H); 7.413 (d, 2H, J =8.8Hz, Ar-H); 7.345 (m, 4H, Ar-H); 7.306(m,6H, Ar-H); 7.104(d,2H, J =8.4Hz,Ar-H); 6.828(m,1H, Ar-H);6.625(s, 1H , =CH); 5.147 (m, 6H, CH 2 ). MS ( m/z ): 578.5 (M+1).
I-19：5-(3-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-19: 5-(3-(Phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.415(s, 1H, N3H); 9.126(s, 1H, N1H); 7.625(d, 1H, J=8.8Hz, Ar-H); 7.484(m, 2H, Ar-H); 7.284(m, 3H, Ar-H); 7.128(t, 2H, J=7.2Hz, Ar-H); 6.926(t, 1H, J=7.2Hz, Ar-H); 6.429(s, 1H, =CH); 4.364(t, 2H, J=7.6Hz, OCH2); 3.058(t, 2H, J=7.2Hz, PhCH2); 1.823-1.896(m, 2H, PhCH2CH2). MS(m/z): 323.5(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.415(s, 1H, N 3 H); 9.126(s, 1H, N 1 H); 7.625(d, 1H, J =8.8 Hz, Ar-H); 7.484(m, 2H, Ar-H); 7.284(m, 3H, Ar-H); 7.128(t, 2H, J =7.2Hz, Ar-H); 6.926(t, 1H , J =7.2Hz, Ar-H); 6.429(s, 1H, =CH); 4.364(t, 2H, J =7.6Hz, OCH 2 ); 3.058(t, 2H, J =7.2Hz, PhCH 2 ) ; 1.823-1.896 (m, 2H, PhCH2CH2 ) . MS (m/z): 323.5 (M+1).
I-20：1-苯丙基-5-(3-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-20: 1-phenylpropyl-5-(3-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.258(s, 1H, NH); 7.664(d, 2H, J=8.8Hz, Ar-H); 7.425(m, 4H, Ar-H); 7.285(m, 6H, Ar-H); 6.935(m, 2H, Ar-H); 6.614(s, 1H, =CH); 4.325(m, 8H, CH2); 2.725(m, 4H, CH2). MS(m/z): 441.5(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.258(s, 1H, NH); 7.664(d, 2H, J =8.8Hz, Ar-H); 7.425(m, 4H, Ar-H); 7.285(m, 6H, Ar-H); 6.935(m, 2H, Ar-H); 6.614(s, 1H, =CH); 4.325(m, 8H, CH 2 ); 2.725(m , 4H, CH 2 ). MS (m/z): 441.5 (M+1).
I-21：1,3-二（苯丙基）-5-(3-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-21: 1,3-bis(phenylpropyl)-5-(3-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.485(d, 2H, J=8.4Hz, Ar-H); 7.452(m, 6H, Ar-H); 7.139(m, 9H, Ar-H); 6.911(m, 2H, Ar-H); 6.606(s, 1H, =CH); 4.126(m, 6H, CH2); 2.669(m, 6H, CH2); 2.102(m, 6H, CH2). MS(m/z): 559.3(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 7.485(d, 2H, J =8.4Hz, Ar-H); 7.452(m, 6H, Ar-H); 7.139(m, 9H, Ar-H); 6.911(m, 2H, Ar-H); 6.606(s, 1H, =CH); 4.126(m, 6H, CH 2 ); 2.669(m, 6H, CH 2 ); 2.102( m, 6H, CH2 ). MS (m/z): 559.3 (M+1).
I-22：5-(3-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-22: 5-(3-(Acetophenoneoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.658(s, 1H, N3H); 9.926(s, 1H, N1H); 8.025(d, 2H, J=8.4Hz, Ar-H); 7.716(t, 1H, J=8.2Hz, Ar-H); 7.506(m, 4H, Ar-H); 6.818(d, 2H, J=8.8Hz, Ar-H); 6.557(s, 1H, =CH); 5.028（s, 2H, OCH2). MS(m/z): 323.6(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.658(s, 1H, N 3 H); 9.926(s, 1H, N 1 H); 8.025(d, 2H, J =8.4 Hz, Ar-H); 7.716(t, 1H, J =8.2Hz, Ar-H); 7.506(m, 4H, Ar-H); 6.818(d, 2H, J =8.8Hz, Ar-H); 6.557(s, 1H, =CH); 5.028(s, 2H, OCH2 ). MS(m/z): 323.6(M+1).
I-23：1-苯乙酮基-5-(3-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-23: 1-acetophenonyl-5-(3-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 9.669(s, 1H, N3H); 8.074(t, 2H, J=7.6Hz, Ar-H); 7.698(m, 3H, Ar-H); 7.658(q, 3H, J=8.0Hz, Ar-H); 7.417(t, 2H, J=8.6Hz, Ar-H); 7.158(d, 2H, J=8.6Hz, Ar-H); 6.857(s, 1H, =CH); 6.574(d, 2H, J=8.6Hz, Ar-H); 5.241 (s, 2H, ArCOCH2); 5.174(s, 2H, OCH2). MS (m/z): 441.0 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 9.669(s, 1H, N 3 H); 8.074(t, 2H, J =7.6Hz, Ar-H); 7.698(m, 3H, Ar-H); 7.658(q, 3H, J =8.0Hz, Ar-H); 7.417(t, 2H, J =8.6Hz, Ar-H); 7.158(d, 2H, J =8.6Hz, Ar-H); 6.857(s, 1H, =CH); 6.574(d, 2H, J =8.6Hz, Ar-H); 5.241 (s, 2H, ArCOCH 2 ); 5.174(s, 2H, OCH 2 ) . MS ( m/z ): 441.0 (M+1).
I-24：1,3-二（苯乙酮基）-5-(3-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-24: 1,3-bis(acetophenonyl)-5-(3-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 8.018(t, 2H, J=8.4Hz, Ar-H); 7.997 (t, 2H, J=7.6Hz, Ar-H); 7.574-7.757 (m, 9H, Ar-H); 7.487 (t, 2H, J=8.0Hz, Ar-H); 7.215(d, 2H，J=8.4Hz, Ar-H); 6.842(s, 1H, =CH); 6.774(d, 2H, J=8.2Hz, Ar-H); 5.417 (s, 2H, COCH2); 5.274 (s, 2H, COCH2); 5.141(d, 4H, OCH2). MS (m/z): 559.0 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 8.018(t, 2H, J =8.4Hz, Ar-H); 7.997 (t, 2H, J =7.6Hz, Ar-H) ; 7.574-7.757 (m, 9H, Ar-H); 7.487 (t, 2H, J =8.0Hz, Ar-H); 7.215(d, 2H, J =8.4Hz, Ar-H); 6.842(s, 1H, =CH); 6.774(d, 2H, J =8.2Hz, Ar-H); 5.417 (s, 2H, COCH 2 ); 5.274 (s, 2H, COCH 2 ); 5.141(d, 4H, OCH 2 ). MS ( m/z ): 559.0 (M+1).
I-25：5-(3-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-25: 5-(3-(Pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.105 (s, 1H, N3H); 9.788 (s, 1H, N1H); 8.395 (s, 1H, Ar-H); 7.958 (m, 1H, Ar-H); 7.633 (m, 3H, Ar-H); 7.418(d, 1H，J=8.4Hz, Ar-H); 6.968(d, 2H, J=8.4Hz, Ar-H); 6.747(s, 1H, =CH); 5.584 (s, 2H, CH2). MS (m/z): 296.6 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 10.105 (s, 1H, N 3 H); 9.788 (s, 1H, N 1 H); 8.395 (s, 1H, Ar-H ); 7.958 (m, 1H, Ar-H); 7.633 (m, 3H, Ar-H); 7.418(d, 1H, J =8.4Hz, Ar-H); 6.968(d, 2H, J =8.4Hz , Ar-H); 6.747(s, 1H, =CH); 5.584 (s, 2H, CH2 ). MS ( m/z ): 296.6 (M+1).
I-26：1-吡啶甲基-5-(3-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-26: 1-pyridylmethyl-5-(3-(pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.258 (s, 1H, N3H); 8.469 (d, 2H, J=8.8Hz, Ar-H); 7.879 (m, 1H, Ar-H); 7.802 (m, 1H, Ar-H); 7.587(m, 3H，Ar-H); 7.419(m, 1H，Ar-H); 7.475(d, 2H，J=8.4Hz, Ar-H); 6.892(d, 2H, J=8.6Hz, Ar-H); 6.629(s, 1H, =CH); 5.685 (s, 2H, CH2) ; 4.741 (s, 2H, CH2). MS (m/z): 387.3 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 10.258 (s, 1H, N 3 H); 8.469 (d, 2H, J =8.8Hz, Ar-H); 7.879 (m, 1H, Ar-H); 7.802 (m, 1H, Ar-H); 7.587(m, 3H, Ar-H); 7.419(m, 1H, Ar-H); 7.475(d, 2H, J =8.4Hz , Ar-H); 6.892(d, 2H, J =8.6Hz, Ar-H); 6.629(s, 1H, =CH); 5.685 (s, 2H, CH 2 ) ; 4.741 (s, 2H, CH 2 ). MS ( m/z ): 387.3 (M+1).
I-27：1,3-二（吡啶甲基）-5-(3-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-27: 1,3-bis(pyridylmethyl)-5-(3-(pyridylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 8.425 (m, 3H, Ar-H); 7.996 (m, 1H, Ar-H); 7.746 (m, 2H, Ar-H); 7.635(m, 3H，Ar-H); 7.458(m, 1H，Ar-H); 7.258(m, 4H，Ar-H); 6.638(d, 2H, J=8.4Hz, Ar-H); 6.586(s, 1H, =CH); 5.367 (m, 2H, CH2) ; 4.445 (m, 2H, CH2); 4.256 (m, 2H, CH2). MS (m/z): 478.6 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 8.425 (m, 3H, Ar-H); 7.996 (m, 1H, Ar-H); 7.746 (m, 2H, Ar-H ); 7.635(m, 3H, Ar-H); 7.458(m, 1H, Ar-H); 7.258(m, 4H, Ar-H); 6.638(d, 2H, J =8.4Hz, Ar-H) ; 6.586(s, 1H, =CH); 5.367 (m, 2H, CH 2 ) ; 4.445 (m, 2H, CH 2 ); 4.256 (m, 2H, CH 2 ). MS ( m/z ): 478.6 ( M+1).
I-28：5-(3-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-28: 5-(3-(Ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.745(s, 1H, N1H); 9.986(s, 1H, N3H); 7.528(d, 2H, J=8.4Hz, Ar-H); 6.745(d, 2H, J=8.8Hz, Ar-H); 6.547(s, 1H, =CH); 4.305(s, 2H, Ar-O-CH2); 4.206(q, 4H, J=8.0Hz, OCH2); 1.045(m, 3H, CH3). MS (m/z): 291.7(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.745(s, 1H, N 1 H); 9.986(s, 1H, N 3 H); 7.528(d, 2H, J =8.4Hz , Ar-H); 6.745(d, 2H, J =8.8Hz, Ar-H); 6.547(s, 1H, =CH); 4.305(s, 2H, Ar-O-CH 2 ); 4.206(q, 4H, J =8.0Hz, OCH2 ); 1.045(m, 3H, CH3 ). MS ( m/z ): 291.7(M+1).
I-29：1-乙氧羰基甲基-5-(3-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-29: 1-ethoxycarbonylmethyl-5-(3-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.756(s, 1H, N3H); 7.358(d, 2H, J=8.8Hz, Ar-H); 6.876(d, 2H, J=8.6Hz, Ar-H); 6.736(s, 1H, =CH); 4.825(s, 2H, Ar-O-CH2); 4.377(s, 2H, N1-CH2); 4.174(q, 4H, J=7.6Hz, OCH2); 1.222(m, 6H, CH3). MS (m/z): 377.8(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.756(s, 1H, N 3 H); 7.358(d, 2H, J =8.8Hz, Ar-H); 6.876(d, 2H , J =8.6Hz, Ar-H); 6.736(s, 1H, =CH); 4.825(s, 2H, Ar-O-CH 2 ); 4.377(s, 2H, N 1 -CH 2 ); 4.174( q, 4H, J =7.6Hz, OCH2 ); 1.222(m, 6H, CH3 ). MS ( m/z ): 377.8(M+1).
I-30：1,3-二（乙氧羰基甲基）-5-(3-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-30: 1,3-bis(ethoxycarbonylmethyl)-5-(3-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.566(d, 2H, J=8.8Hz, Ar-H); 6.986(d, 2H, J=8.8Hz, Ar-H); 6.848(s, 1H, =CH); 4.816(s, 2H, Ar-O-CH2); 4.385(s, 2H, N1-CH2); 4.276(s, 2H, N3-CH2); 4.176(q, 4H, J=8.0Hz，OCH2); 3.876(q, 2H, J=7.6Hz, OCH2);1.212(t, 6H, J=7.6Hz, CH3); 1.336(m, 3H, CH3). MS (m/z): 480.4(M＋NH4)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 7.566(d, 2H, J =8.8Hz, Ar-H); 6.986(d, 2H, J =8.8Hz, Ar-H); 6.848(s, 1H, =CH); 4.816(s, 2H, Ar-O-CH 2 ); 4.385(s, 2H, N 1 -CH 2 ); 4.276(s, 2H, N 3 -CH 2 ); 4.176(q, 4H, J =8.0Hz, OCH 2 ); 3.876(q, 2H, J =7.6Hz, OCH 2 ); 1.212(t, 6H, J =7.6Hz, CH 3 ); 1.336(m, 3H , CH 3 ). MS ( m/z ): 480.4 (M+NH 4 ).
I-31：5-(2-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-31: 5-(2-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.017(s, 1H, N3H); 9.156(s, 1H, N1H); 7.425(s, 1H, Ar-H); 7.396(d, 2H,J=8.0Hz,Ar-H); 7.302(d, 2H, J=8.8Hz, Ar-H); 7.125(d, 2H, J=8.4Hz, Ar-H);6.805(s,1H,Ar-H);6.687(s, 1H, =CH); 5.013(s, 2H, OCH2). MS (m/z): 329.4(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.017(s, 1H, N 3 H); 9.156(s, 1H, N 1 H); 7.425(s, 1H, Ar-H) ; 7.396(d, 2H, J =8.0Hz, Ar-H); 7.302(d, 2H, J =8.8Hz, Ar-H); 7.125(d, 2H, J =8.4Hz, Ar-H);6.805 (s, 1H, Ar-H); 6.687(s, 1H, =CH); 5.013(s, 2H, OCH 2 ). MS ( m/z ): 329.4 (M+1).
I-32：1-对氯苄基-5-(2-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-32: 1-p-chlorobenzyl-5-(2-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.022(s, 1H, N3H);7.584(m, 1H, Ar-H); 7.475(m, 2H, Ar-H); 7.364(m, 2H, Ar-H); 7.362(m, 4H, Ar-H); 7.253(m, 2H, Ar-H); 6.902(m, 1H, Ar-H); 6.593(s, 1H, =CH); 5.286(m, 4H, CH2). MS (m/z): 452.4(M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.022(s, 1H, N 3 H);7.584(m, 1H, Ar-H); 7.475(m, 2H, Ar-H) ; 7.364(m, 2H, Ar-H); 7.362(m, 4H, Ar-H); 7.253(m, 2H, Ar-H); 6.902(m, 1H, Ar-H); 6.593(s, 1H , =CH); 5.286 (m, 4H, CH 2 ). MS ( m/z ): 452.4 (M-1).
I-33：1,3-二（对氯苄基）-5-(2-(对氯苄氧基)苄亚甲基)咪唑烷-2，4-二酮 I-33: 1,3-bis(p-chlorobenzyl)-5-(2-(p-chlorobenzyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.492 (m, 1H, Ar-H); 7.443 (d, 2H, J=8.0Hz, Ar-H); 7.426 (m, 4H, Ar-H); 7.358(m,6H，Ar-H); 7.058(d,2H，J=8.8Hz,Ar-H); 6.873(m,1H，Ar-H);6.639(s, 1H, =CH);5.156(m,6H,CH2). MS (m/z): 578.3(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 7.492 (m, 1H, Ar-H); 7.443 (d, 2H, J =8.0Hz, Ar-H); 7.426 (m, 4H, Ar-H); 7.358(m,6H, Ar-H); 7.058(d,2H, J =8.8Hz,Ar-H); 6.873(m,1H, Ar-H);6.639(s, 1H , =CH); 5.156 (m, 6H, CH 2 ). MS ( m/z ): 578.3 (M+1).
I-34：5-(2-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-34: 5-(2-(Phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.425(s, 1H, N3H); 9.109(s, 1H, N1H); 7.639(d, 1H, J=8.6Hz, Ar-H); 7.483(m, 2H, Ar-H); 7.259(m, 3H, Ar-H); 7.134(t, 2H, J=7.6Hz, Ar-H); 6.936(t, 1H, J=7.6Hz, Ar-H); 6.426(s, 1H, =CH); 4.326(t, 2H, J=8.0 Hz, OCH2); 3.056(t, 2H, J=7.6Hz, PhCH2); 1.896(m, 2H, PhCH2CH2). MS(m/z): 323.6(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.425(s, 1H, N 3 H); 9.109(s, 1H, N 1 H); 7.639(d, 1H, J =8.6 Hz, Ar-H); 7.483(m, 2H, Ar-H); 7.259(m, 3H, Ar-H); 7.134(t, 2H, J =7.6Hz, Ar-H); 6.936(t, 1H , J =7.6Hz, Ar-H); 6.426(s, 1H, =CH); 4.326(t, 2H, J =8.0 Hz, OCH 2 ); 3.056(t, 2H, J =7.6Hz, PhCH 2 ) ; 1.896 (m, 2H, PhCH2CH2 ) . MS (m/z): 323.6 (M+1).
I-35：1-苯丙基-5-(2-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-35: 1-phenylpropyl-5-(2-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.159(s, 1H, NH); 7.692(d, 2H, J=8.6Hz, Ar-H); 7.445(m, 4H, Ar-H); 7.293(m, 6H, Ar-H); 6.905(m, 2H, Ar-H); 6.605(s, 1H, =CH); 4.362(m, 8H, CH2); 2.705(m, 4H, CH2). MS(m/z): 441.7(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.159(s, 1H, NH); 7.692(d, 2H, J =8.6Hz, Ar-H); 7.445(m, 4H, Ar-H); 7.293(m, 6H, Ar-H); 6.905(m, 2H, Ar-H); 6.605(s, 1H, =CH); 4.362(m, 8H, CH 2 ); 2.705(m , 4H, CH 2 ). MS (m/z): 441.7 (M+1).
I-36：1,3-二（苯丙基）-5-(2-(苯丙氧基)苄亚甲基)咪唑烷-2，4-二酮 I-36: 1,3-bis(phenylpropyl)-5-(2-(phenylpropoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.365(d, 2H, J=8.8Hz, Ar-H); 7.469(m, 6H, Ar-H); 7.145(m, 9H, Ar-H); 6.893(m, 2H, Ar-H); 6.622(s, 1H, =CH); 4.445(m, 6H, CH2); 2.775(m, 6H, CH2); 2.152(m, 6H, CH2). MS(m/z): 559.5(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 7.365(d, 2H, J =8.8Hz, Ar-H); 7.469(m, 6H, Ar-H); 7.145(m, 9H, Ar-H); 6.893(m, 2H, Ar-H); 6.622(s, 1H, =CH); 4.445(m, 6H, CH 2 ); 2.775(m, 6H, CH 2 ); 2.152( m, 6H, CH2 ). MS (m/z): 559.5 (M+1).
I-37：5-(2-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-37: 5-(2-(Acetophenoneoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ:10.693(s, 1H, N3H); 9.896(s, 1H, N1H); 8.078(d, 2H, J=8.8Hz, Ar-H); 7.825(t, 1H, J=8.8Hz, Ar-H); 7.553(m, 4H, Ar-H); 6.863(d, 2H, J=8.2Hz, Ar-H); 6.442(s, 1H, =CH); 5.253（s, 2H, OCH2). MS(m/z): 323.4(M+1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ :10.693(s, 1H, N 3 H); 9.896(s, 1H, N 1 H); 8.078(d, 2H, J =8.8 Hz, Ar-H); 7.825(t, 1H, J =8.8Hz, Ar-H); 7.553(m, 4H, Ar-H); 6.863(d, 2H, J =8.2Hz, Ar-H); 6.442(s, 1H, =CH); 5.253(s, 2H, OCH2 ). MS(m/z): 323.4(M+1).
I-38：1-苯乙酮基-5-(2-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-38: 1-acetophenonyl-5-(2-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 9.639(s, 1H, N3H); 8.125(t, 2H, J=7.8Hz, Ar-H); 7.863(m, 3H, Ar-H); 7.753(q, 3H, J=8.6Hz, Ar-H); 7.452(t, 2H, J=8.8Hz, Ar-H); 7.206(d, 2H, J=8.8Hz, Ar-H); 6.863(s, 1H, =CH); 6.485(d, 2H, J=8.8Hz, Ar-H); 5.266 (s, 2H, ArCOCH2); 5.147(s, 2H, OCH2). MS (m/z): 441.3 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 9.639(s, 1H, N 3 H); 8.125(t, 2H, J =7.8Hz, Ar-H); 7.863(m, 3H, Ar-H); 7.753(q, 3H, J =8.6Hz, Ar-H); 7.452(t, 2H, J =8.8Hz, Ar-H); 7.206(d, 2H, J =8.8Hz, Ar-H); 6.863(s, 1H, =CH); 6.485(d, 2H, J =8.8Hz, Ar-H); 5.266 (s, 2H, ArCOCH 2 ); 5.147(s, 2H, OCH 2 ) . MS ( m/z ): 441.3 (M+1).
I-39：1,3-二（苯乙酮基）-5-(2-(苯乙酮氧基)苄亚甲基)咪唑烷-2，4-二酮 I-39: 1,3-bis(acetophenonyl)-5-(2-(acetophenonyloxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 8.036(t, 2H, J=8.8Hz, Ar-H); 7.856 (t, 2H, J=7.6Hz, Ar-H); 7.577-7.732 (m, 9H, Ar-H); 7.453 (t, 2H, J=8.6Hz, Ar-H); 7.233(d, 2H，J=8.3Hz, Ar-H); 6.856(s, 1H, =CH); 6.776(d, 2H, J=8.6Hz, Ar-H); 5.443 (s, 2H, COCH2); 5.263 (s, 2H, COCH2); 5.425(d, 4H, OCH2). MS (m/z): 559.3 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 8.036(t, 2H, J =8.8Hz, Ar-H); 7.856 (t, 2H, J =7.6Hz, Ar-H) ; 7.577-7.732 (m, 9H, Ar-H); 7.453 (t, 2H, J =8.6Hz, Ar-H); 7.233(d, 2H, J =8.3Hz, Ar-H); 6.856(s, 1H, =CH); 6.776(d, 2H, J =8.6Hz, Ar-H); 5.443 (s, 2H, COCH 2 ); 5.263 (s, 2H, COCH 2 ); 5.425(d, 4H, OCH 2 ). MS ( m/z ): 559.3 (M+1).
I-40：5-(2-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-40: 5-(2-(Pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.125 (s, 1H, N3H); 9.763 (s, 1H, N1H); 8.365 (s, 1H, Ar-H); 7.986 (m, 1H, Ar-H); 7.639 (m, 3H, Ar-H); 7.458(d, 1H，J=8.8Hz, Ar-H); 6.993(d, 2H, J=8.2Hz, Ar-H); 6.785(s, 1H, =CH); 5.563 (s, 2H, CH2). MS (m/z): 296.3 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 10.125 (s, 1H, N 3 H); 9.763 (s, 1H, N 1 H); 8.365 (s, 1H, Ar-H ); 7.986 (m, 1H, Ar-H); 7.639 (m, 3H, Ar-H); 7.458(d, 1H, J =8.8Hz, Ar-H); 6.993(d, 2H, J =8.2Hz , Ar-H); 6.785(s, 1H, =CH); 5.563 (s, 2H, CH2 ). MS ( m/z ): 296.3 (M+1).
I-41：1-吡啶甲基-5-(2-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-41: 1-pyridylmethyl-5-(2-(pyridinemethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.236 (s, 1H, N3H); 8.492 (d, 2H, J=8.6Hz, Ar-H); 7.886 (m, 1H, Ar-H); 7.836 (m, 1H, Ar-H); 7.563(m, 3H，Ar-H); 7.435(m, 1H，Ar-H); 7.396(d, 2H，J=8.4Hz, Ar-H); 6.982(d, 2H, J=8.8Hz, Ar-H); 6.636(s, 1H, =CH); 5.688 (s, 2H, CH2) ; 4.744 (s, 2H, CH2). MS (m/z): 387.6 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 10.236 (s, 1H, N 3 H); 8.492 (d, 2H, J =8.6Hz, Ar-H); 7.886 (m, 1H, Ar-H); 7.836 (m, 1H, Ar-H); 7.563(m, 3H, Ar-H); 7.435(m, 1H, Ar-H); 7.396(d, 2H, J =8.4Hz , Ar-H); 6.982(d, 2H, J =8.8Hz, Ar-H); 6.636(s, 1H, =CH); 5.688 (s, 2H, CH 2 ) ; 4.744 (s, 2H, CH 2 ). MS ( m/z ): 387.6 (M+1).
I-42：1,3-二（吡啶甲基）-5-(2-(吡啶甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-42: 1,3-bis(pyridylmethyl)-5-(2-(pyridylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 8.463 (m, 3H, Ar-H); 7.993 (m, 1H, Ar-H); 7.748(m, 2H, Ar-H); 7.639(m, 3H，Ar-H); 7.460(m, 1H，Ar-H); 7.258(m, 4H，Ar-H); 6.695(d, 2H, J=8.4Hz, Ar-H); 6.584(s, 1H, =CH); 5.396 (m, 2H, CH2) ; 4.475 (m, 2H, CH2); 4.254 (m, 2H, CH2). MS (m/z): 478.4 (M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d 6 , 400Hz), δ : 8.463 (m, 3H, Ar-H); 7.993 (m, 1H, Ar-H); 7.748(m, 2H, Ar-H ); 7.639(m, 3H, Ar-H); 7.460(m, 1H, Ar-H); 7.258(m, 4H, Ar-H); 6.695(d, 2H, J =8.4Hz, Ar-H) ; 6.584(s, 1H, =CH); 5.396 (m, 2H, CH 2 ) ; 4.475 (m, 2H, CH 2 ); 4.254 (m, 2H, CH 2 ). MS ( m/z ): 478.4 ( M+1).
I-43：5-(2-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-43: 5-(2-(Ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.775(s, 1H, N1H); 9.987(s, 1H, N3H); 7.536(d, 2H, J=8.8Hz, Ar-H); 6.743(d, 2H, J=8.4Hz, Ar-H); 6.550(s, 1H, =CH); 4.312(s, 2H, Ar-O-CH2); 4.214(q, 4H, J=8.6Hz, OCH2); 1.046(m, 3H, CH3). MS (m/z): 291.5(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.775(s, 1H, N 1 H); 9.987(s, 1H, N 3 H); 7.536(d, 2H, J =8.8Hz , Ar-H); 6.743(d, 2H, J =8.4Hz, Ar-H); 6.550(s, 1H, =CH); 4.312(s, 2H, Ar-O-CH 2 ); 4.214(q, 4H, J =8.6Hz, OCH2 ); 1.046(m, 3H, CH3 ). MS ( m/z ): 291.5(M+1).
I-44：1-乙氧羰基甲基-5-(2-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-44: 1-ethoxycarbonylmethyl-5-(2-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.747(s, 1H, N3H); 7.363(d, 2H, J=8.4Hz, Ar-H); 6.876(d, 2H, J=8.4Hz, Ar-H); 6.763(s, 1H, =CH); 4.841(s, 2H, Ar-O-CH2); 4.377(s, 2H, N1-CH2); 4.163(q, 4H, J=7.8Hz, OCH2); 1.228(m, 6H, CH3). MS (m/z): 377.9(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.747(s, 1H, N 3 H); 7.363(d, 2H, J =8.4Hz, Ar-H); 6.876(d, 2H , J =8.4Hz, Ar-H); 6.763(s, 1H, =CH); 4.841(s, 2H, Ar-O-CH 2 ); 4.377(s, 2H, N 1 -CH 2 ); 4.163( q, 4H, J =7.8Hz, OCH2 ); 1.228(m, 6H, CH3 ). MS ( m/z ): 377.9(M+1).
I-45：1,3-二（乙氧羰基甲基）-5-(2-(乙氧羰基甲氧基)苄亚甲基)咪唑烷-2，4-二酮 I-45: 1,3-bis(ethoxycarbonylmethyl)-5-(2-(ethoxycarbonylmethoxy)benzylidene)imidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.565(d, 2H, J=8.4Hz, Ar-H); 6.982(d, 2H, J=8.4Hz, Ar-H); 6.847(s, 1H, =CH); 4.828(s, 2H, Ar-O-CH2); 4.376(s, 2H, N1-CH2); 4.277(s, 2H, N3-CH2); 4.176(q, 4H, J=8.8Hz，OCH2); 3.882(q, 2H, J=7.8Hz, OCH2);1.251(t, 6H, J=7.6Hz, CH3); 1.325(m, 3H, CH3). MS (m/z): 480.5(M＋NH4)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 7.565(d, 2H, J =8.4Hz, Ar-H); 6.982(d, 2H, J =8.4Hz, Ar-H); 6.847(s, 1H, =CH); 4.828(s, 2H, Ar-O-CH 2 ); 4.376(s, 2H, N 1 -CH 2 ); 4.277(s, 2H, N 3 -CH 2 ); 4.176(q, 4H, J =8.8Hz, OCH 2 ); 3.882(q, 2H, J =7.8Hz, OCH 2 ); 1.251(t, 6H, J =7.6Hz, CH 3 ); 1.325(m, 3H , CH 3 ). MS ( m/z ): 480.5 (M+NH 4 ).
实施例17Example 17
5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮的制备(I-46) Preparation of 5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione (I-46)
在250 mL圆底烧瓶中加入8.4 g （50 mmol）5-乙酰氧甲基-2-呋喃甲醛和5.5 g（55 mmol）咪唑烷-2,4-二酮，加入10 mL哌啶，烧瓶上方安装回流冷凝管和干燥管，烧瓶置于油浴中使反应液与油浴面相平，加热到130 ℃ 并保持30分钟；产生大量气泡并微沸；冷却后加入60℃蒸馏水200 mL，用玻璃棒搅拌至固体溶解，得到红色溶液以及黄色絮状不溶物，过滤除去不溶物质，待滤液冷却至室温后，把滤液转移到烧杯中，边搅拌边逐滴加入20 mL 10 N HCl 溶液；室温下静置12 h后，用布氏漏斗抽滤得到黄色沉淀，并用冷水完全冲洗三﹑四次，干燥后得到黄色固体： Add 8.4 g (50 mmol) of 5-acetoxymethyl-2-furfuraldehyde and 5.5 g (55 mmol) of imidazolidine-2,4-dione into a 250 mL round bottom flask, add 10 mL of piperidine, and Install the reflux condenser and drying tube, place the flask in an oil bath so that the reaction solution is level with the oil bath surface, heat to 130°C and keep for 30 minutes; a large number of bubbles are generated and slightly boiled; after cooling, add 200 mL of distilled water at 60°C, and use a glass Stir with a stick until the solid dissolves to obtain a red solution and yellow flocculent insoluble matter, remove the insoluble matter by filtration, transfer the filtrate to a beaker after the filtrate is cooled to room temperature, and add 20 mL of 10 N HCl solution drop by drop while stirring; After standing still for 12 h, filter with Buchner funnel to obtain yellow precipitate, and rinse with cold water three or four times, and obtain yellow solid after drying:
I-46：5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮（10.69 g，85.5 %），m.p.257~259 ℃； I-46: 5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione (10.69 g, 85.5%), m.p.257~259 ℃;
1H-NMR(DMSO-d6,400Hz),δ:9.735(s,1H,NH);7.574(d,1H,J=7.1Hz,CH);6.471(d,1H,J=6.7Hz,CH);6.253(s,1H,NH);5.956(s,2H,CH2);2.453(s,3H,CH3). MS (m/z): 249.0(M－1);251.0(M＋1)。 1 H-NMR(DMSO-d 6 ,400Hz), δ :9.735(s,1H,NH);7.574(d,1H, J =7.1Hz,CH);6.471(d,1H, J =6.7Hz,CH ); 6.253 (s, 1H, NH); 5.956 (s, 2H, CH 2 ); 2.453 (s, 3H, CH 3 ). MS ( m/z ): 249.0 (M-1); 251.0 (M+1).
实施例18Example 18
氯苄与I-46反应步骤：混合的I-46（5g，20mmol），氯苄（2.53 g，20 mmol），K2CO3（2.76g，20mmol）和丙酮（120mL）回流24 h，TLC检测原料反应完毕，停止反应；冷却后过滤除去无机盐；滤液经过减压蒸馏得到粗品，用少量溶剂溶解后经过硅胶柱分离纯化，依次得到I-47：白色固体（1.18g，17.32 %），m.p.212~214℃； Reaction procedure of benzyl chloride and I-46: Mixed I-46 (5g, 20mmol), benzyl chloride (2.53 g, 20 mmol), K 2 CO 3 (2.76g, 20mmol) and acetone (120mL) were refluxed for 24 h, TLC Detect the completion of the raw material reaction, stop the reaction; filter to remove the inorganic salt after cooling; the filtrate is distilled under reduced pressure to obtain the crude product, which is dissolved in a small amount of solvent and purified through silica gel column separation and purification to obtain I-47 in turn: white solid (1.18g, 17.32%), mp212~214℃;
I-48：浅黄色固体（2.41 g，28.52 %），m.p.206~208 ℃。 I-48: light yellow solid (2.41 g, 28.52%), m.p.206~208 ℃.
化合物结构及谱图解析如下： The compound structure and spectrum analysis are as follows:
I-47：1-苄基-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-47: 1-Benzyl-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.852(s, 1H, NH); 7.524(m, 1H, Ar-H); 7.362(d, 1H, J=8.8Hz, Ar-H); 7.256(m, 1H, Ar-H); 7.218(d, 1H, J=8.8Hz, Ar-H); 7.082(d, 1H, J=8.8Hz, Ar-H); 6.802(s, 1H, =CH); 6.748(s, 1H, =CH), 5.548(s, 1H, =CH), 5.014(m, 2H, CH2), 2.257(s, 3H, CH3). MS (m/z): 341.1(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.852(s, 1H, NH); 7.524(m, 1H, Ar-H); 7.362(d, 1H, J =8.8Hz, Ar -H); 7.256(m, 1H, Ar-H); 7.218(d, 1H, J =8.8Hz, Ar-H); 7.082(d, 1H, J =8.8Hz, Ar-H); 6.802(s , 1H, =CH); 6.748(s, 1H, =CH), 5.548(s, 1H, =CH), 5.014(m, 2H, CH 2 ), 2.257(s, 3H, CH 3 ). MS ( m /z ): 341.1(M+1).
I-48: 1，3-二（苄基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-48 : 1,3-bis(benzyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.310-7.302(m, 5H, Ar-H); 7.253(m, 1H, Ar-H); 7.214(m, 4H, Ar-H); 6.725(s, 1H, =CH); 6.705(s, 1H, =CH); 5.762(s, 1H, =CH);5.183(s, 2H, CH2); 5.057(s, 2H, CH2); 4.958(s, 2H, CH2);2.257(s,3H,OCH3). MS (m/z): 429.5(M－1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 7.310-7.302(m, 5H, Ar-H); 7.253(m, 1H, Ar-H); 7.214(m, 4H, Ar- H); 6.725(s, 1H, =CH); 6.705(s, 1H, =CH); 5.762(s, 1H, =CH);5.183(s, 2H, CH 2 ); 2 ); 4.958(s, 2H, CH 2 ); 2.257(s, 3H, OCH 3 ). MS ( m/z ): 429.5(M-1).
实施例19-20Example 19-20
参照实施例18的操作，区别在于用不同结构的卤化物与I-46反应，得到下述通式的化合物： With reference to the operation of Example 18, the difference is to react with halides of different structures and I-46 to obtain the compound of the following general formula:
上述各化合物的氢谱和质谱的测定结果见下面。 The measurement results of the hydrogen spectrum and mass spectrum of each of the above-mentioned compounds are shown below.
I-49：1-（2-呋喃甲基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-49: 1-(2-furylmethyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.746(s, 1H, NH); 7.632(d, 1H,J=8.2Hz, =CH); 7.396(d, 1H, J=8.2Hz, =CH); 6.528(d, 1H,J=8.0Hz, =CH); 6.425(d, 1H, J=7.2Hz, =CH); 6.405(d, 1H, J=7.8Hz, =CH);5.025(s, 2H, CH2), 4.251(s, 2H, CH2),2.202(s, 3H, CH3). MS (m/z): 331.3(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.746(s, 1H, NH); 7.632(d, 1H, J =8.2Hz, =CH); 7.396(d, 1H, J = 8.2Hz, =CH); 6.528(d, 1H, J =8.0Hz, =CH); 6.425(d, 1H, J =7.2Hz, =CH); 6.405(d, 1H, J =7.8Hz, =CH ); 5.025(s, 2H, CH2 ), 4.251(s, 2H, CH2 ), 2.202(s, 3H, CH3 ). MS ( m/z ): 331.3 (M+1).
I-50：1，3-二（2-呋喃甲基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-50: 1,3-bis(2-furanmethyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 7.632(d, 1H,J=8.2Hz, =CH); 7.396(d, 1H, J=8.2Hz, =CH); 6.528(d, 1H,J=8.0Hz, =CH); 6.425(d, 1H, J=7.2Hz, =CH); 6.405(d, 1H, J=7.8Hz, =CH);5.025(s, 2H, CH2), 4.251(s, 2H, CH2),2.202(s, 3H, CH3). MS (m/z): 411.2(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 7.632(d, 1H, J =8.2Hz, =CH); 7.396(d, 1H, J =8.2Hz, =CH); 6.528( d, 1H, J =8.0Hz, =CH); 6.425(d, 1H, J =7.2Hz, =CH); 6.405(d, 1H, J =7.8Hz, =CH);5.025(s, 2H, CH 2 ), 4.251(s, 2H, CH 2 ), 2.202(s, 3H, CH 3 ). MS ( m/z ): 411.2(M+1).
I-51：1-（3-吡啶甲基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-51: 1-(3-pyridylmethyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.256(s, 1H, NH); 8.562(m,1H,ArH); 8.324(d, 1H, J=8.3Hz, ArH);7.428(m, 1H,ArH); 7.328(m, 1H,ArH);6.475(d, 1H, J=7.2Hz, =CH); 6.415(d, 1H, J=7.8Hz, =CH); 6.243(d, 1H, J=7.5Hz, =CH);5.574(s, 2H, CH2), 5.251(s, 2H, CH2),2.213(s, 3H, CH3). MS (m/z): 342.2(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.256(s, 1H, NH); 8.562(m,1H,ArH); 8.324(d, 1H, J =8.3Hz, ArH); 7.428(m, 1H,ArH); 7.328(m, 1H,ArH);6.475(d, 1H, J =7.2Hz, =CH); 6.415(d, 1H, J =7.8Hz, =CH); 6.243( d, 1H, J =7.5Hz, =CH);5.574(s, 2H, CH 2 ), 5.251(s, 2H, CH 2 ),2.213(s, 3H, CH 3 ). MS ( m/z ): 342.2 (M+1).
I-52：1，3-二（3-吡啶甲基）-5-（5-乙酰氧甲基呋喃-2-基）亚甲基咪唑烷-2，4-二酮 I-52: 1,3-bis(3-pyridylmethyl)-5-(5-acetoxymethylfuran-2-yl)methyleneimidazolidine-2,4-dione
谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 8.595(m,2H,ArH); 8.324(m, 2H,ArH);7.618(m, 2H,ArH); 7.375(m,2H,ArH);7.305(d, 1H, J=7.8Hz, =CH); 6.772(d, 1H, J=7.6Hz, =CH); 6.528(d, 1H, J=7.5Hz, =CH);5.605(s, 2H, CH2), 5.259(s, 2H, CH2), 5.104(s, 2H, CH2),2.228(s, 3H, CH3). MS (m/z): 433.5(M＋1)。 Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 8.595(m,2H,ArH); 8.324(m, 2H,ArH);7.618(m, 2H,ArH); 7.375(m,2H ,ArH);7.305(d, 1H, J =7.8Hz, =CH); 6.772(d, 1H, J =7.6Hz, =CH); 6.528(d, 1H, J =7.5Hz, =CH);5.605 (s, 2H, CH 2 ), 5.259(s, 2H, CH 2 ), 5.104(s, 2H, CH 2 ), 2.228(s, 3H, CH 3 ). MS ( m/z ): 433.5(M+1) .
实施例21Example 21
化合物I-48成草酸盐：取上述I-48产物1.0g，溶于30ml无水乙醇，加热至回流，加入等摩尔草酸，保温反应45分钟。降至室温，静置12小时。减压浓缩至析出白色固体，停止浓缩，冷却，过滤，干燥，即得其草酸盐，m.p.158-160℃。谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 11.025(s, 2H, OH); 7.308(m, 5H, Ar-H); 7.257(m, 1H, Ar-H); 7.218(m, 4H, Ar-H); 6.730(s, 1H, =CH); 6.702(s, 1H, =CH); 5.764(s, 1H, =CH);5.175(s, 2H, CH2); 5.052(s, 2H, CH2); 4.955(s, 2H, CH2);2.252(s,3H,OCH3). MS (m/z): 429.5(M－1)。 Formation of compound I-48 into oxalate: Take 1.0 g of the above-mentioned I-48 product, dissolve it in 30 ml of absolute ethanol, heat to reflux, add equimolar oxalic acid, and keep the reaction for 45 minutes. Cool to room temperature and let stand for 12 hours. Concentrate under reduced pressure until a white solid is precipitated, stop concentrating, cool, filter, and dry to obtain its oxalate, mp158-160°C. Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 11.025(s, 2H, OH); 7.308(m, 5H, Ar-H); 7.257(m, 1H, Ar-H); 7.218 (m, 4H, Ar-H); 6.730(s, 1H, =CH); 6.702(s, 1H, =CH); 5.764(s, 1H, =CH);5.175(s, 2H, CH2 ); 5.052(s, 2H, CH2 ); 4.955(s, 2H, CH2 ); 2.252(s, 3H, OCH3 ). MS ( m/z ): 429.5 (M-1).
实施例22Example 22
化合物I-49成盐酸盐：取上述I-49产物1.0g，溶于约80ml无水甲醇中，冰浴冷却至10℃，搅拌下滴加浓盐酸，调至PH1-2。减压蒸尽溶剂，加入无水乙醇，加热至回流，保温反应10min，趁热过滤，滤液室温静置，析出白色固体，过滤，干燥，即得化合物I-49的盐酸盐，m.p.239-241℃。谱图解析：1H-NMR(DMSO-d6, 400Hz), δ: 10.744(s, 1H, NH); 7.630(d, 1H,J=8.4Hz, =CH); 7.396(d, 1H, J=8.6Hz, =CH); 6.526(d, 1H,J=8.4Hz, =CH); 6.422(d, 1H, J=7.6Hz, =CH); 6.406(d, 1H, J=8.0Hz, =CH);5.027(s, 2H, CH2), 4.253(s, 2H, CH2),2.204(s, 3H, CH3). MS (m/z): 331.3(M＋1)。 Compound I-49 into hydrochloride: Take 1.0 g of the above-mentioned I-49 product, dissolve it in about 80 ml of anhydrous methanol, cool in an ice bath to 10°C, add concentrated hydrochloric acid dropwise under stirring, and adjust to pH 1-2. Evaporate the solvent under reduced pressure, add absolute ethanol, heat to reflux, keep warm for 10 minutes, filter while it is hot, leave the filtrate at room temperature, and precipitate a white solid, filter and dry to obtain the hydrochloride of compound I-49, mp239-241 ℃. Spectrum Analysis: 1 H-NMR(DMSO-d6, 400Hz), δ : 10.744(s, 1H, NH); 7.630(d, 1H, J =8.4Hz, =CH); 7.396(d, 1H, J = 8.6Hz, =CH); 6.526(d, 1H, J =8.4Hz, =CH); 6.422(d, 1H, J =7.6Hz, =CH); 6.406(d, 1H, J =8.0Hz, =CH ); 5.027(s, 2H, CH2 ), 4.253(s, 2H, CH2 ), 2.204(s, 3H, CH3 ). MS ( m/z ): 331.3 (M+1).
实施例23 Example 23
片剂制备方法如下： Tablets are prepared as follows:
处方 用量/片 Prescription Dosage/tablet
I-2 100 mg I-2 100 mg
微晶纤维素 20 mg Microcrystalline Cellulose 20 mg
淀粉 40 mg Starch 40 mg
乳糖 100 mg Lactose 100 mg
聚维酮 8 mg Povidone 8 mg
羧甲基淀粉钠 10 mg Sodium carboxymethyl starch 10 mg
硬脂酸镁 qs Magnesium stearate qs
微粉硅胶 qs Micropowder silica gel qs
总计 约280 mg； A total of about 280 mg;
工艺：将活性成分辅料分别过100目筛，称取处方量的主药和辅料（一半羧甲基淀粉钠）充分混合，加入聚乙烯吡咯烷酮水溶液适量制软材，过24目筛，制得湿颗粒于50-60℃烘箱中干燥约2-3小时，将剩余羧甲基淀粉钠，硬脂酸镁和微粉硅胶与颗粒混合均匀，整粒，测定中间体含量，用Φ9 mm浅冲压片。 Process: pass the active ingredients and auxiliary materials through a 100-mesh sieve, weigh the main drug and auxiliary materials (half carboxymethyl starch sodium) of the prescription amount and mix them well, add an appropriate amount of polyvinylpyrrolidone aqueous solution to make a soft material, and pass through a 24-mesh sieve to obtain wet Dry the granules in an oven at 50-60°C for about 2-3 hours, mix the remaining sodium carboxymethyl starch, magnesium stearate and micropowder silica gel with the granules evenly, sizing the granules, measuring the content of intermediates, and punching tablets with a diameter of Φ9 mm.
实施例24 Example 24
胶囊的制备如下： Capsules are prepared as follows:
处方 用量/囊 Prescription Dosage/capsule
I-3 100 mg I-3 100 mg
微晶纤维素 20mg Microcrystalline Cellulose 20mg
乳糖 60mg Lactose 60mg
羧甲基淀粉钠 6 mg Sodium carboxymethyl starch 6 mg
羟丙甲纤维素 5 mg Hypromellose 5 mg
微粉硅胶 5 mg Micronized silica gel 5 mg
硬脂酸镁 qs Magnesium stearate qs
滑石粉 qs Talc powder qs
总计 200 mg； Total 200 mg;
工艺：将活性成分辅料分别过100目筛，称取处方量的主药和辅料充分混合，加入羟丙甲纤维素溶液适量制软材，过24目筛，制得湿颗粒于50-60℃烘箱中干燥约2-3小时，将硬脂酸镁和滑石粉与颗粒混合均匀，整粒，测定中间体含量，用2号胶囊灌装。 Process: pass the active ingredients and auxiliary materials through a 100-mesh sieve, weigh the main drug and auxiliary materials in the prescription amount and mix them well, add an appropriate amount of hypromellose solution to make a soft material, pass through a 24-mesh sieve, and prepare wet granules at 50-60 °C Dry in an oven for about 2-3 hours, mix the magnesium stearate and talcum powder with the granules evenly, sizing the granules, measure the content of intermediates, and fill them with No. 2 capsules.
实施例25Example 25
口服溶液剂的制备（每瓶量） Preparation of oral solution (amount per bottle)
I-4 200 mg I-4 200 mg
甘露醇 100 mg Mannitol 100 mg
柠檬酸 20 mg Citric acid 20 mg
橙味香精 10 mg Orange flavor 10 mg
阿斯巴甜 10 mg Aspartame 10 mg
尼泊金 qs Paraben qs
蒸馏水 100ml； Distilled water 100ml;
工艺：取蒸馏水10ml，称取处方量的柠檬酸、甘露醇、橙味香精、阿斯巴甜、样品搅拌使溶解， 加入防腐剂后，灌装于瓶中。 Process: Take 10ml of distilled water, weigh the prescribed amount of citric acid, mannitol, orange flavor, aspartame, stir the sample to dissolve, add preservatives, and fill in bottles.
实施例26Example 26
颗粒剂,每袋含： Granules, each bag contains:
I-5 100 mg I-5 100 mg
乳糖 730 mg Lactose 730 mg
甘露醇 150 mg Mannitol 150 mg
糖精钠 5 mg Sodium Saccharin 5 mg
香精 5 mg Fragrance 5 mg
2％羟丙甲纤维素（水） qs； 2% hypromellose (water) qs;
工艺：将主药与辅料分别过100目筛，充分混合，然后称取处方量辅料与主药充分混合。再加入粘合剂制软材，14目筛制粒，55℃干燥，16目筛整粒，测定袋重包装。 Process: Pass the main drug and auxiliary materials through a 100-mesh sieve respectively, mix them thoroughly, then weigh the prescription amount of auxiliary materials and mix them fully with the main drug. Then add soft material made of binder, granulate with 14 mesh sieve, dry at 55°C, granulate with 16 mesh sieve, measure bag weight and pack.
实施例27Example 27
注射液的制备 Preparation of Injection
I-6 50 mg I-6 50 mg
磷酸二氢钠 10 mg Sodium dihydrogen phosphate 10 mg
柠檬酸 20 mg Citric acid 20 mg
氯化钠 90 mg Sodium chloride 90 mg
注射用水 50 ml； Water for injection 50 ml;
工艺：取注射用水50ml，称取处方量的柠檬酸、磷酸二氢钠、氯化钠搅拌使溶解，加入样品搅拌溶解，用0.1mol/L的盐酸或氢氧化钠调pH值为4.0-7.0，加入0.1%的活性炭吸附20分钟。先用045μm滤膜滤过，再用022μm精滤。按每安剖2毫升灌装，105℃高温灭菌30分钟即得注射液。 Process: Take 50ml of water for injection, weigh the prescribed amount of citric acid, sodium dihydrogen phosphate, and sodium chloride and stir to dissolve, add the sample and stir to dissolve, adjust the pH value to 4.0-7.0 with 0.1mol/L hydrochloric acid or sodium hydroxide , add 0.1% activated carbon to adsorb for 20 minutes. First filter with 045μm filter membrane, and then use 022μm fine filter. Fill in 2 ml per aliquot, and sterilize at 105°C for 30 minutes to obtain the injection.
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| xian-chao cheng et al..synthesis of novel imidazolidine-2,4-dione derivatives as potential antidiabetic agents.《asian journal of chemistry》.2011,第23卷(第9期),4114-4116. * |
| xian-chaochengetal..synthesisofnovelimidazolidine-2 4-dione derivatives as potential antidiabetic agents.《asian journal of chemistry》.2011 |
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