阅读说明：本技术 一种金刚烷甲酰胺类化合物及其制备方法和应用 (Adamantane formamide compound and preparation method and application thereof ) 是由 翁建全 温亚龙 孔瑶蕾 楼涛 于 2019-11-05 设计创作，主要内容包括：本发明公开了一种金刚烷甲酰胺类化合物及其制备方法和应用,金刚烷甲酰胺类化合物即N-(3-卤代-4-取代苯基-2-氮杂环丁酮-1-基)金刚烷甲酰胺类化合物。它将1-金刚烷甲酰腙、卤代乙酰氯溶于有机溶剂中,冰浴条件下反应,TLC监测至反应结束后,反应液经后处理制得目标产物金刚烷甲酰胺类化合物。本发明提供的化合物,其制备方法简单。本发明将所得的化合物用DNA松散实验进行Top1抑制活性的测试,DNA松散实验结果表明,50μM浓度下,本发明所得的金刚烷甲酰胺类化合物均对Top1均表现出一定程度的抑制活性,其中化合物Ib、Ii、In、Ip、Is、Iu的抑制活性为“++”,化合物Im的活性最好,其对Top1抑制活性显示为“+++”,可作为药物先导进行进一步优化。(The invention discloses an adamantane carboxamide compound, a preparation method and an application thereof, wherein the adamantane carboxamide compound is an N- (3-halogeno-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamide compound. Dissolving 1-adamantane formylhydrazone and halogenated acetyl chloride in an organic solvent, reacting under an ice bath condition, monitoring by TLC (thin layer chromatography) until the reaction is finished, and carrying out post-treatment on the reaction solution to obtain the target product adamantane carboxamide compound. The compound provided by the invention is simple in preparation method. The obtained compound Is tested for the Top1 inhibitory activity by using a DNA loose test, and the result of the DNA loose test shows that the adamantane carboxamide compounds obtained by the invention all show a certain degree of inhibitory activity to Top1 under the concentration of 50 mu M, wherein the inhibitory activity of compounds Ib, Ii, In, Ip, Is and Iu Is '++', the compound Im has the best activity, and the inhibitory activity to Top1 Is '++', and the compound can be further optimized as a drug lead.)

1. An adamantane carboxamide compound, i.e.N- (3-halo-4-substituted phenyl-2-azetidinon-1-yl) adamantanecarboxylThe amine compound is characterized by having a structure shown as a formula (I):

in the formula (I), H on a benzene ring is mono-substituted or not substituted by a substituent R; n is 0 or 1, and n =0 represents that H on the benzene ring is not substituted; n =1, represents H on the phenyl ring monosubstituted by a substituent R; the substituent R is C1-C4 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, halogen, nitro or pyridyl; the substituent X is halogen.

2. An adamantane carboxamide compound as claimed in claim 1, where substituent R is methyl, t-butyl, methoxy, trifluoromethyl, Cl, Br, nitro or pyridyl; and the substituent X is Cl or Br.

3. An adamantane carboxamide compound according to claim 1, where R (n) is hydrogen, 2-methoxy, 4-methyl, 4-tert-butyl, 2-bromo, 2-methyl, 3-bromo, 3-methoxy, 4-trifluoromethyl, 4-chloro, 3-nitro, 2-chloro, a pyridine ring; x is Cl or Br.

4. A preparation method of adamantane carboxamide compounds as claimed in claim 1, characterized in that 1-adamantane formylhydrazone as shown in formula (II) and halogenated acetyl chloride as shown in formula (III) are dissolved in organic solvent, reaction is carried out under ice bath condition, TLC monitoring is carried out until the reaction is finished, and the reaction solution is post-treated to obtain adamantane carboxamide compound as shown in formula (I)N- (3-halo-4-substituted phenyl-2-azetidinon-1-yl) adamantanecarboxamides;

in the formula (II), H on a benzene ring is mono-substituted or not substituted by a substituent R; n is 0 or 1, and n =0 represents that H on the benzene ring is not substituted; n =1, represents that H on the phenyl ring is substituted by a substituent R; the substituent R is C1-C4 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, halogen, nitro or pyridyl; in the formula (III), the substituent X is halogen.

5. The method for preparing adamantane carboxamide compound according to claim 4, characterized in that the molar ratio of 1-adamantane formylhydrazone shown in formula (II) to the halogenated acetyl chloride shown in formula (III) is 1:1 to 5, preferably 1: 1.0 to 3.0.

6. The process for preparing adamantanamides and their use according to claim 4, wherein said organic solvent isN,N-dimethylformamide, acetone or tetrahydrofuran, preferablyN,N-dimethylformamide; the mass ratio of the 1-adamantane formylhydrazone shown in the formula (II) to the organic solvent is 1: 50-80, and preferably 1: 60-70.

7. The method for preparing adamantane carboxamide compound according to claim 4, characterized in that the reaction time under ice bath condition is 5-20 h, preferably 8-14 h.

8. The process for producing adamantanecarboxamides according to claim 4, characterized by the following steps: adding a certain amount of ice water into the reaction liquid, separating out a solid product, carrying out suction filtration and washing, and recrystallizing the obtained crude product to obtain the compound shown in the formula (I)N- (3-halo-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamides.

9. The preparation method of the adamantane carboxamide compound according to claim 8, characterized in that the mass ratio of 1-adamantane formylhydrazone shown in formula (II) to ice water in the post-treatment process is 1: 300-700, preferably 1: 450-580; the recrystallization solvent is one or more of ethanol, ethyl acetate and dichloromethane.

10. Use of adamantanamides as claimed in claim 1 as Top1 inhibitors.

Technical Field

The invention relates to an adamantane formamide compound and a preparation method and application thereof, in particular to an adamantane formamide compoundN- (3-halogeno-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamide compounds and synthesis methods and applications thereof.

Background

Adamantane has unique chemical and physical properties, and has been widely used in the fields of medicine (chemical reviews, 2013, 113(5): 3516. about.3604), pesticides (chemical agents, 2016, 38(03): 224. about.230), photovoltaic Materials (Tetrahedron, 2013, 69(48): 10357. about.10360), surfactants (Materials today communications, 2015, 5(1): 23-31), catalysts (petrochemical, 1992, 1(1): 55-62), lubricants (Journal of tribology, 2013, 1(2): 33), etc., as "New generation fine chemicals raw Materials", wherein in the field of medicine, adamantane derivatives are reported to have antitumor (Investigational New Drugs, 2009, 27 (6. about.594. about.about.12), antiviral (Journal of Diseases, 1989, 159, 2. about.430), lipophilic Drugs (1987. about.about.about.12), lipophilic Drugs (biomedical agents, 3512. about.about.23. about.23), lipophilic Drugs (1987. about.about.23. about.23), lipophilic Drugs (1987. about.23. about.12), and more particularly, lipophilic Drugs (biomedical Drugs) with improved stability, such as pharmacological Drugs (anti-11. about. about.7. about.

The nitrogen-containing heterocyclic compound has the characteristics of high target specificity and good environmental compatibility due to the similar alkaloid structure in organisms, and has become the mainstream research field for creating new medicaments. As an important member of nitrogen-containing heterocycles, 2-azetidinone derivatives and derivatives thereof have been receiving attention from drug developers because of their wide biological activities, and have been drawing wide attention in the fields of medicine (European Journal of Medicinal Chemistry, 2010, 45: 5541-5560) and agricultural chemicals (ActaPoloniae Pharmaceuticala, 2016(73): 93-106). Among them, the applications in anticancer (Heterocyclic Communications, 2001(7): 83-90; Chinese science: Chemistry, 2018, 48(07): 751-.

In addition, the hydrazide skeleton is also an important potential drug lead structure. Hydrazide compounds have been reported to have a wide range of biological and physiological activities such as anti-tumor (Bioorganic Medicinal Chemistry, 2007, 15(1), 288-. Therefore, research on the synthesis method and biological performance of the hydrazide structural unit-containing compound is receiving more and more attention from drug developers.

Because the adamantane derivatives, the 2-azetidinone derivatives and the acylhydrazine compounds have good biological activity. In order to find a novel medicine lead structure, the invention adopts a method of splicing active substructures to combine the three structures, designs and synthesizes a series of structuresNThe- (3-halogeno-4-substituted phenyl-2-azetidinone-1-yl) adamantane formamide compound is expected to have better biological activity.

Series designed and synthesized by the inventionNThe research on the structure and the biological activity of the- (3-halo-4-substituted phenyl-2-azetidinone-1-yl) adamantane formamide compounds is not reported in documents.

Disclosure of Invention

In order to solve the above technical problems in the prior art, the present invention provides a method for manufacturing a semiconductor deviceN- (3-halogeno-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamide compound, synthetic method and application thereofNThe- (3-halo-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamides are simple to prepare and exhibit certain topoisomerase I (Top 1) inhibitory activity.

An adamantane carboxamide compound as described, i.e.N- (3-halo-4-substituted phenyl-2-nitrogen)The heterocyclic butanone-1-yl) adamantane formamide compound is characterized in that the structure is shown as the formula (I):

in the formula (I), H on a benzene ring is mono-substituted or not substituted by a substituent R; n is 0 or 1, and n =0 represents that H on the benzene ring is not substituted; n =1, represents that H on the phenyl ring is substituted by a substituent R; the substituent R is C1-C4 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, halogen, nitro or pyridyl; the substituent X is halogen.

The adamantane formamide compound is characterized in that a substituent R is methyl, tert-butyl, methoxy, trifluoromethyl, Cl, Br, nitro or pyridyl; and the substituent X is Cl or Br.

The adamantane carboxamide compound is characterized in that R (n) is hydrogen, 2-methoxy, 4-methyl, 4-tert-butyl, 2-bromo, 2-methyl, 3-bromo, 3-methoxy, 4-trifluoromethyl, 4-chloro, 3-nitro, 2-chloro or pyridine ring; x is Cl or Br.

The preparation method of the adamantane carboxamide compound is characterized in that 1-adamantane formylhydrazone shown in formula (II) and halogenated acetyl chloride shown in formula (III) are dissolved in an organic solvent, the reaction is carried out under the ice bath condition, TLC (thin layer chromatography) is used for monitoring until the reaction is finished, and the reaction solution is subjected to post-treatment to prepare the compound shown in formula (I)N- (3-halo-4-substituted phenyl-2-azetidinon-1-yl) adamantanecarboxamides;

，

in the formula (II), H on a benzene ring is mono-substituted or not substituted by a substituent R; n is 0 or 1, and n =0 represents that H on the benzene ring is not substituted; n =1, represents that H on the phenyl ring is substituted by a substituent R; the substituent R is C1-C4 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, halogen, nitro or pyridyl; in the formula (III), the substituent X is halogen.

The preparation method of the adamantane formamide compound is characterized in that the molar ratio of the 1-adamantane formylhydrazone shown in the formula (II) to the halogenated acetyl chloride shown in the formula (III) is 1: 1-5, and preferably 1: 1.0-3.0.

The preparation method of the adamantane carboxamide compound is characterized in that the organic solvent isN,N-dimethylformamide, acetone or tetrahydrofuran, preferablyN,N-dimethylformamide; the mass ratio of the 1-adamantane formylhydrazone shown in the formula (II) to the organic solvent is 1: 50-80, and preferably 1: 60-70.

The preparation method of the adamantane carboxamide compound is characterized in that the reaction time under the ice bath condition is 5-20 hours, preferably 8-14 hours.

The preparation method of the adamantane carboxamide compound is characterized by comprising the following post-treatment steps: adding a certain amount of ice water into the reaction liquid, separating out a solid product, carrying out suction filtration and washing, and recrystallizing the obtained crude product to obtain the compound shown in the formula (I)N- (3-halo-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamides.

The preparation method of the adamantane carboxamide compound is characterized in that the mass ratio of 1-adamantane formylhydrazone shown in the formula (II) to ice water in the post-treatment process is 1: 300-700, preferably 1: 450-580; the recrystallization solvent is one or more of ethanol, ethyl acetate and dichloromethane.

The adamantane carboxamide compound is applied as a Top1 inhibitor.

Compared with the prior art, the invention has the beneficial effects that:

the invention provides a novelNThe- (3-halo-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamide compounds are simple to prepare, and the obtained compounds show certain Top1 inhibitory activity. The synthesized compounds were tested for Top1 inhibitory activity in the examples of the present invention using DNA loose assay, which showed 22 new compounds shown in the examples of the present invention at a concentration of 50. mu.MGlu' sNThe- (3-halo-4-substituted phenyl-2-azetidinone-1-yl) adamantane carboxamides all show a certain degree of inhibitory activity on Top1, wherein the inhibitory activity of the compounds Ib, Ii, In, Ip, Is and Iu Is '+++, the inhibitory activity of the compound Im Is the best, and the inhibitory activity on Top1 Is' +++, and the compounds can be further optimized as a drug lead.

Detailed Description

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.