CN101434601A - 2-furyl-1H-benzimidazole-4-acidamide type derivative - Google Patents
2-furyl-1H-benzimidazole-4-acidamide type derivative Download PDFInfo
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- CN101434601A CN101434601A CNA2008100409253A CN200810040925A CN101434601A CN 101434601 A CN101434601 A CN 101434601A CN A2008100409253 A CNA2008100409253 A CN A2008100409253A CN 200810040925 A CN200810040925 A CN 200810040925A CN 101434601 A CN101434601 A CN 101434601A
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- furyl
- benzimidazole
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Abstract
The invention discloses a derivative of 2-furyl-1H-benzimidazole-4-amide with the chemical structural formula shown on the lower right. The derivative has good effect on resistance to coxsackie B3 virus and can be prepared into new anti-virus medicaments.
Description
Technical field:
The present invention relates to a kind of organic compound, particularly a kind of 2-furyl-1H-benzoglyoxaline-4-acidamide type derivative, they have good antiviral effect (coxsackie B 3 viruses), can be applicable to antiviral.
Background technology:
Step into 21 century, along with standard of living constantly improves, people more and more pay attention to healthy, are used to simultaneously to prevent and to treat the R and D development of disease medicament more and more faster.The development of biological medicine shows continuous development and the application of new technology in the research and development field of medicine.Show that according to the study 60%～65% epidemic infectious diseases is caused by virus infection.We know that the research and development of new drug always develop round the generation and the variation of disease, and therefore, the research and development of novel antiviral medicine have become the focus and the trend of new drug development.
J.Med.Chem. (1990,33:814-819) reported the series compound of following structure, and pointed out that it has good antitumous effect.
In the formula: R is
Report has synthesized the series compound of following structure among the patent US6100283, and points out that they are good PARP[poly (ADP-ribose) polysaccharases] inhibitor, have good anticancer effect.
More than two pieces of documents illustrated that all benzoglyoxaline-4-acidamide type derivative has good biological activity.Though the influence of 2 bit substituents in the benzimidazole structure to the property of medicine has been discussed in these two pieces of articles, the modification of 4 bit substituents do not discussed the influence of the compound property of medicine.
Bioorganic and Medicinal Chemistry Letters (2005,15:267-269), reach CN1634918 and reported following structural series compound, and point out that it has good anti-coxsackie B 3 viral effects.
In the formula: X is
Or
Y is
-CH
2CH
2OH or
Wherein R can represent F, Cl, Br, CH respectively
3, OH, NO
2Or H.
Summary of the invention:
The present invention seeks to introduce furyl in benzoglyoxaline parent 2-position, introducing has good bioactive intermediate group on the acyl group of benzoglyoxaline 4-position simultaneously, makes they and proteinic avidity strengthen, and has better antiviral biological activity.The present invention has designed and synthesized a series of compounds, and its antiviral (coxsackie B 3 viruses) effect is tested, and they have good antiviral effect.
The chemical structure of a kind of 2-furyl of the present invention-1H-benzoglyoxaline-4-acidamide type derivative is as follows:
In the formula: X is F, Cl, Br, CH
3, OH, NO
2Or H;
Y be H,
Or
Wherein R is F, Cl, Br, CH
3, OH, NO
2Or H.
2-furyl of the present invention-1H-benzoglyoxaline-4-acidamide type derivative has:
(L) -2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-(1 - hydroxymethyl-2 - hydroxyethyl-nitrophenyl))
Amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-(1 - methyl-2 - hydroxyethyl-chlorophenyl)) - amide,
2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-o-fluorophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-
Benzimidazole -4 - (N-o-chlorophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-o-bromophenyl)
Amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-fluorophenyl) amide, 2 - (5 - nitro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-chlorophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-
Bromophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-p-fluorophenyl) amide, 2 - (5 - nitro
-2 - furyl)-1H-benzimidazole -4 - (N-p-chlorophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazol-
Yl -4 - (N-p-bromophenyl)-amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-o-methyl-phenyl) acid
Amine, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-o-hydroxyphenyl) amide, 2 - (5 - nitro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-o-nitrophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-
O-phenyl)-amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-phenyl-methyl) amide, 2 - (5 - nitro
-2 - furyl)-1H-benzimidazole -4 - (N-inter-hydroxyphenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzo
Imidazole -4 - (N-nitrophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-meta-phenyl) acid
Amine, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-methyl-phenyl) amide, 2 - (5 - nitro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-p-hydroxyphenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-
P-nitrophenyl) amide, 2 - (5 - nitro-2 - furyl)-1H-benzimidazole -4 - (N-p-phenyl) amide, (L) -2 - (2 -
Furyl)-1H-benzimidazole -4 - (N-(1 - hydroxymethyl-2 - p-nitrophenyl-hydroxyethyl)) amide, 2 - (2 - furyl
Yl)-1H-benzimidazole -4 - (N-(1 - methyl-2 - hydroxyethyl-chlorophenyl)) - amide, 2 - (2 - furyl)-1H-benzo
Imidazole -4 - (N-o-fluorophenyl) amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-o-chlorophenyl) amide, 2 - (2 -
Furyl)-1H-benzimidazole -4 - (N-o-bromophenyl)-amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-fluorophenol
Phenyl)-amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-chlorophenyl) amide, 2 - (2 - furyl)-1H-phenyl
Benzimidazole -4 - (N-bromophenyl)-amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-p-fluorophenyl) amide,
2 - (2 - furyl)-1H-benzimidazole -4 - (N-p-chlorophenyl) amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-
-Bromophenyl)-amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-o-methyl-phenyl) amide, 2 - (2 - furyl
Yl)-1H-benzimidazole -4 - (N-o-hydroxyphenyl) amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-o-
Phenyl)-amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-o-phenyl) amide, 2 - (2 - furyl)-1H-benzo
Imidazole -4 - (N-phenyl-methyl) amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-room hydroxyphenyl) amide,
2 - (2 - furyl)-1H-benzimidazole -4 - (N-nitrophenyl) amide, 2 - (2 - furyl)-1H-benzimidazole
-4 - (N-meta-phenyl) amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-methyl-phenyl) amide, 2 - (2 - furyl
Yl)-1H-benzimidazole -4 - (N-p-hydroxyphenyl) amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-nitro
Phenyl)-amide, 2 - (2 - furyl)-1H-benzimidazole -4 - (N-p-phenyl) amide, (L) -2 - (5 - fluoro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-(1 - hydroxymethyl-2 - p-nitrophenyl-hydroxyethyl)) amide, 2 - (5 - fluoro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-(1 - methyl-2 - hydroxyethyl-chlorophenyl)) - amide, 2 - (5 - fluoro-2 - furyl)-1H-
Benzimidazole -4 - (N-o-fluorophenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-o-chlorophenyl)
Amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-o-bromophenyl)-amide, 2 - (5 - fluoro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-fluorophenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-chloroperbenzoic
Phenyl)-amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-bromophenyl)-amide, 2 - (5 - fluoro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-p-fluorophenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-p-chloro
Phenyl)-amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-p-bromophenyl)-amide, 2 - (5 - fluoro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-o-methyl-phenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-
O-hydroxyphenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-o-nitrophenyl) amide, 2 - (5 -
Fluoro-2 - furyl)-1H-benzimidazole -4 - (N-o-phenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole
-4 - (N-phenyl-methyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-inter-hydroxyphenyl) amide,
2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-nitrophenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-phenyl
Benzimidazole -4 - (N-meta-phenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-methyl-phenyl) acid
Amine, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-p-hydroxyphenyl) amide, 2 - (5 - fluoro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-p-nitrophenyl) amide, 2 - (5 - fluoro-2 - furyl)-1H-benzimidazole -4 - (N-
-Phenyl)-amide, (L) -2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-(1 - hydroxymethyl-2 - nitrophenyl
Hydroxyethyl)) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-(1 - methyl-2 - hydroxyethyl-chlorophenyl)) -
Amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-o-fluorophenyl) amide, 2 - (5 - chloro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-o-chlorophenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-o-bromo-
Phenyl)-amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-fluorophenyl) amide, 2 - (5 - chloro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-chlorophenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-Br-
Phenyl)-amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-p-fluorophenyl) amide, 2 - (5 - chloro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-p-chlorophenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-p-bromo
Phenyl)-amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-o-methyl-phenyl) amide, 2 - (5 - chloro-2 - furosemide
Furans yl)-1H-benzimidazole -4 - (N-o-hydroxyphenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-
O-nitrophenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-o-phenyl)-amide, 2 - (5 - chloro -2 -
Furyl)-1H-benzimidazole -4 - (N-phenyl-methyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole
-4 - (N-inter-hydroxyphenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-nitrophenyl) amide,
2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-meta-phenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazol-
Yl -4 - (N-methyl-phenyl) amide, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-p-hydroxyphenyl) acyl
Amine, 2 - (5 - chloro-2 - furyl)-1H-benzimidazole -4 - (N-p-nitrophenyl) amide, 2 - (5 - chloro-2 - furyl
Yl)-1H-benzimidazole -4 - (N-p-phenyl) amide, (L) -2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-(1 -
Hydroxymethyl-2 - p-nitrophenyl-hydroxyethyl)) amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-(1 - methyl-
-2 - Hydroxyethyl p-chlorophenyl)) - amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-o-fluorophenyl) amide,
2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-o-chlorophenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzo
Imidazole -4 - (N-o-bromophenyl)-amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-fluorophenyl) amide,
2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-chlorophenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzo
Imidazole -4 - (N-bromophenyl)-amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-p-fluorophenyl) amide,
2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-p-chlorophenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzo
Imidazole -4 - (N-p-bromophenyl)-amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-o-methyl-phenyl) acid
Amine, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-o-hydroxyphenyl) amide, 2 - (5 - bromo-2 - furyl
Yl)-1H-benzimidazole -4 - (N-o-nitrophenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-
O-phenyl)-amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-phenyl-methyl) amide, 2 - (5 - bromo - 2 -
Furyl)-1H-benzimidazole -4 - (N-room hydroxyphenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole
-4 - (N-nitrophenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-meta-phenyl) amide, 2 - (5 -
Bromo-2 - furyl)-1H-benzimidazole -4 - (N-methyl-phenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazol-
Yl -4 - (N-p-hydroxyphenyl) amide, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-p-nitrophenyl) acyl
Amine, 2 - (5 - bromo-2 - furyl)-1H-benzimidazole -4 - (N-p-phenyl) amide, (L) -2 - (5 - methyl-2 - furyl
Yl)-1H-benzimidazole -4 - (N-(1 - hydroxymethyl-2 - p-nitrophenyl-hydroxyethyl)) amide, 2 - (5 - methyl - 2 - furyl
Yl)-1H-benzimidazole -4 - (N-(1 - methyl-2 - hydroxyethyl-chlorophenyl)) - amide, 2 - (5 - methyl - 2 - furyl
Yl)-1H-benzimidazole -4 - (N-o-fluorophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-
O-chlorophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-o-bromophenyl)-amide, 2 - (5 - methyl
-2 - furyl)-1H-benzimidazole -4 - (N-fluorophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazol-
Yl -4 - (N-chlorophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-bromophenyl) amide,
2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-p-fluorophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-
Benzimidazole -4 - (N-p-chlorophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-p-bromophenyl)
Amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-o-methyl-phenyl) amide, 2 - (5 - methyl - 2 - furosemide
Furans yl)-1H-benzimidazole -4 - (N-o-hydroxyphenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole
-4 - (N-o-nitrophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-o-phenyl)-amide,
2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-phenyl-methyl) amide, 2 - (5 - methyl - 2 - furyl
Yl)-1H-benzimidazole -4 - (N-inter-hydroxyphenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-
Nitrophenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-meta-phenyl) amide, 2 - (5 - methyl
-2 - furyl)-1H-benzimidazole -4 - (N-methyl-phenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzo
Imidazole -4 - (N-p-hydroxyphenyl) amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-p-nitrophenyl)
Amide, 2 - (5 - methyl - 2 - furyl)-1H-benzimidazole -4 - (N-p-phenyl) amide, (L) -2 - (5 - hydroxy-2 - furyl
Yl)-1H-benzimidazole -4 - (N-(1 - hydroxymethyl-2 - p-nitrophenyl-hydroxyethyl)) amide, 2 - (5 - hydroxy-2 - furyl
Yl)-1H-benzimidazole -4 - (N-(1 - methyl-2 - hydroxyethyl-chlorophenyl)) - amide, 2 - (5 - hydroxy-2 - furyl
Yl)-1H-benzimidazole -4 - (N-o-fluorophenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-
O-chlorophenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-o-bromophenyl)-amide, 2 - (5 - hydroxy-
-2 - furyl)-1H-benzimidazole -4 - (N-fluorophenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazol-
Yl -4 - (N-chlorophenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-bromophenyl) amide,
2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-p-fluorophenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-
Benzimidazole -4 - (N-p-chlorophenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-p-bromophenyl)
Amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-o-methyl-phenyl) amide, 2 - (5 - hydroxy-2 - furosemide
Furans yl)-1H-benzimidazole -4 - (N-o-hydroxyphenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole
-4 - (N-o-nitrophenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-o-phenyl)-amide,
2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-phenyl-methyl) amide, 2 - (5 - hydroxy-2 - furyl
Yl)-1H-benzimidazole -4 - (N-inter-hydroxyphenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-
Nitrophenyl phenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-meta-phenyl) amide, 2 - (5 -
Hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-methyl-phenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-phenyl
Benzimidazole -4 - (N-p-hydroxyphenyl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-p-nitrophenyl
Yl) amide, 2 - (5 - hydroxy-2 - furyl)-1H-benzimidazole -4 - (N-p-phenyl) amide.
...
The preparation method of a kind of 2-furyl of the present invention-1H-benzoglyoxaline-4-acidamide type derivative is as follows:
With 2-glycyl-3-nitrobenzoic acid is starting raw material; process ammonia is separated, Hoffman degrades, reduction preparation 2; 3-diaminobenzoic acid; then 2; the condensation under the neutralized verdigris effect of 3-diaminobenzoic acid and furfural gets 2-furyl-1H-benzoglyoxaline-4-carboxylic acid; last 2-furyl-1H-benzoglyoxaline-4-carboxylic acid and thionyl chloride effect obtain acyl chlorides, obtain final a series of product 2-pyridyl-1H-benzoglyoxaline-4-acidamide type derivative with the amine condensation again.
A kind of 2-furyl of the present invention-1H-benzoglyoxaline-4-acidamide type derivative is to introduce furyl in the 2-position of benzoglyoxaline parent, obtains after one of benzoglyoxaline 4-position acyl group introducing has the group of good antiviral activity simultaneously.Therefore, they and proteinic avidity are strengthened, and have had better antiviral biological activity.The result that its anti-coxsackie B 3 virus activities are tested shows that the biological activity of this novel derivative and anti-coxsackie B 3 virus activities are good.The result is as shown in the table:
In the table: "-" expression sample is at maximal non-toxic dosage nonreactive coxsackie B 3 virus activities.
IC
50Expression is to viral half-inhibition concentration.
RBV is a ribavirin, claims ribavirin (Ribavirin) again, virazole
As seen from the above table, compare with the antiviral activity of common drug virazole, 2-furyl-1H-benzoglyoxaline-4-acidamide type derivative has better anti-coxsackie B 3 virus activities, has very outstanding selectivity index simultaneously.
Description of drawings:
(L)-2-that Fig. 1 obtains for embodiment 4 (5-nitro-2-furyl)-1H-benzoglyoxaline-4-(N-(1-methylol-2-p-nitrophenyl hydroxyethyl)) acid amides
1The HNMR nuclear magnetic spectrogram.
[2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-(the adjacent fluorophenyl of the N-) acid amides] that Fig. 2 obtains for embodiment 6
1The HNMR nuclear magnetic spectrogram.
Embodiment:
Embodiment 1:2,3-diaminobenzoic acid synthetic
The first step, 2-glycyl-3-nitrobenzoic acid synthetic
The adjacent dibenzoic acid acid anhydride of 30g3-nitro is added in the strong aqua of 45ml, be heated to 60 ℃, be incubated 2 hours.The needle crystal that acidifying is separated out gets white solid, filters, and drying obtains product 2-glycyl-3-nitrobenzoic acid 29.4g.
Second step, 2-amino-3-nitrobenzoic acid synthetic
The bromine of 13.9g is added in the aqueous solution of 100ml of 7.3g sodium hydroxide.And then adding 17g2-glycyl-3-nitrobenzoic acid.Heating, reaction system is separated out a large amount of red solid.Filter, acidifying gets yellow product, the dry 2-amino-3-nitrobenzoic acid 13.7g that gets.Thick product can get yellow needle-like crystal with recrystallization.
The 3rd step, 2,3-diaminobenzoic acid synthetic
2-amino-3-nitrobenzoic acid of 3g is joined in the methyl alcohol of 30ml, splash into equimolar 20% aqueous sodium hydroxide solution, raw material is dissolved fully, add the Raney Ni of 0.2g, reflux.Splash into 80% hydrazine hydrate (about 1.5eq * 1.1) then to yellow completely dissolve, filtered while hot is fallen Raney Ni.Mother liquor concentrates acidifying redness 2,3-diaminobenzoic acid 2.3g, and thick product further separates purification with column chromatography.
Synthesizing of embodiment 2:2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-carboxylic acid
With 1g 2, the 3-diaminobenzoic acid is dissolved in the 50ml methyl alcohol, under agitation splashes into the methanol solution that 20ml is dissolved with 1.85g 5-nitryl furfural.Then with neutralized verdigris (Cu (Ac)
2H
2O) aqueous solution 30ml splashes in the top reaction system, reflux 2 hours.Filtered while hot, the mixed solution dissolving filter cake with 50ml methyl alcohol and concentrated hydrochloric acid splashes into excessive sodium sulfide solution, is heated to boiling.Filtered while hot is fallen copper sulfide precipitation, mother liquor concentrate thick product.Column chromatography purification gets 2-(5-nitrofuran base)-1H-benzoglyoxaline-4-carboxylic acid, productive rate about 65%.Product structure is identified:
1HMNR(DMSO，400MHz)δ：7.28-7.32(t，1H)，7.81-7.83(d，1H)，7.87-7.89(d，3H).MS：M+＝273.
Synthesizing of embodiment 3:2-(2-furyl)-1H-benzoglyoxaline-4-carboxylic acid
Press embodiment 2 method Synthetic 2s-(2-furyl)-1H-benzoglyoxaline-4-carboxylic acid, productive rate about 63%.
Product structure is identified:
1HMNR(DMSO，400MHz)δ：6.89-6.91(m，1H)，7.24-7.28(t，1H)，7.30-7.34(t，1H)，7.67-7.69(d，1H)，7.77-7.81(d，2H).
Embodiment 4:(L)-2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-(N-(1-methylol-2-p-nitrophenyl hydroxyethyl)) acid amides synthetic
0.5g 2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-carboxylic acid is added 5ml sulfur oxychloride, reflux 1 hour.After reaction finishes, steam unnecessary sulfur oxychloride, it is standby that suspension liquid is made in the tetrahydrofuran (THF) stirring of adding 25ml.With (L)-2-amino-1-p-nitrophenyl-1, ammediol (1.1eq) is dissolved in the 30ml tetrahydrofuran (THF), under agitation splashes into the acyl chlorides suspension liquid for preparing.Stirring at room, reaction is spent the night.Filter out inorganic salt, solvent evaporated obtains (L)-2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-(N-(1-methylol-2-p-nitrophenyl hydroxyethyl)) acid amides, and thick product can use column chromatography purification, productive rate about 93%.
Product structure is identified:
1HMNR(DMSO，400MHz)δ：3.59-3.60(m，1H)，3.65-3.67(t，1H)，4.16-4.22(q，1H)，5.07-5.08(t，1H)，5.27-5.28(t，1H)，6.16-6.17(d，1H)，7.35-7.39(t，1H)，7.53-7.54(d，1H)，7.72-7.75(m，2H)，7.77-7.79(m，2H)，8.00-8.01(d，1H)，8.05-8.07(d，3H)，10.04-10.06(d，2H)，14.05(s，1H).
Synthesizing of embodiment 5:2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-(N-(1-methyl-2-rubigan hydroxyethyl))-acid amides
Get 0.5g 2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-carboxylic acid and add 5ml sulfur oxychloride, reflux 1 hour.After reaction finishes, steam unnecessary sulfur oxychloride, it is standby that suspension liquid is made in the tetrahydrofuran (THF) stirring of adding 25ml.2-amino-1-rubigan-1-propyl alcohol (1.1eq) is dissolved in the 30ml tetrahydrofuran (THF), under agitation splashes into the acyl chlorides suspension liquid.Stirred overnight at room temperature filters out inorganic salt, and solvent evaporated obtains 2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-(N-(1-methyl-2-rubigan hydroxyethyl)) acid amides, and thick product can use column chromatography purification, productive rate about 92%.
Product structure is identified:
1HMNR(DMSO，400MHz)δ：1.06-1.08(d，3H)，4.24-4.32(m，1H)，4.85-4.86(d，1H)，5.73(s，1H)，7.28-7.30(d，1H)，7.35-7.39(t，1H)，7.43-7.45(d，2H)，7.51-7.52(d，1H)，7.70-7.72(d，1H)，7.84-7.85(d，1H)，7.90-7.92(d，1H)，8.16(s，1H)，9.87-9.88(d，1H)，13.91(s，1H).
Synthesizing of embodiment 6:2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-(the adjacent fluorophenyl of N-) acid amides
Get 0.2g2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-carboxylic acid and add 5ml sulfur oxychloride, reflux 1 hour.After reaction finishes, steam unnecessary sulfur oxychloride, it is standby that suspension liquid is made in the tetrahydrofuran (THF) stirring of adding 25ml.Adjacent fluoroaniline (1.1eq) is dissolved in the 15ml methylene dichloride, under agitation splashes into the acyl chlorides suspension liquid.Stirred overnight at room temperature, solvent evaporated, ethyl acetate extraction.Solvent evaporated gets 2-(5-nitro-2-furyl)-1H-benzoglyoxaline-4-(the adjacent fluorophenyl of N-) acid amides, and thick product is further purified productive rate about 91% with column chromatography.
Product structure is identified:
1HMNR(DMSO，400MHz)δ：7.13-7.19(m，1H)，7.23-7.27(t，1H)，7.36-7.41(t，1H)，7.50-7.54(m，2H)，7.85-7.87(d，1H)，7.94-7.95(d，1H)，8.05-8.07(d，1H)，8.57-8.61(t，1H)，12.19-12.20(d，1H)，14.25(s，1H).
Embodiment 7:(L)-2-(2-furyl)-1H-benzoglyoxaline-4-(N-(1-methylol-2-p-nitrophenyl hydroxyethyl)) acid amides synthetic
Press synthetic (the L)-2-(2-furyl) of embodiment 4 methods-1H-benzoglyoxaline-4-(N-(1-methylol-2-p-nitrophenyl hydroxyethyl)) acid amides, productive rate about 90%.
Product structure is identified:
1HMNR(DMSO，400MHz)δ：3.57-3.60(m，1H)，3.64-3.69(m，1H)，4.16-4.21(q，1H)，5.18(s，1H)，5.26-5.29(d，1H)，5.96-6.12(d，1H)，6.86-6.87(d，1H)，7.09-7.15(d，1H)，7.27-7.32(m，1H)，7.36-7.37(m，1H)，7.63-7.72(m，2H)，7.73-7.76(m，2H)，8.04-8.06(d，2H)，9.89-10.11(d，1H)，13.55(s，1H).
Synthesizing of embodiment 8:2-(2-furyl)-1H-benzoglyoxaline-4-(N-(1-methyl-2-rubigan hydroxyethyl))-acid amides
Press embodiment 5 method Synthetic 2s-(2-furyl)-1H-benzoglyoxaline-4-(N-(1-methyl-2-rubigan hydroxyethyl)) acid amides, productive rate about 92%.
Product structure is identified:
1HMNR(DMSO，400MHz)δ：1.03-1.05(d，2H)，1.08-1.25(t，1H)4.26-4.31(m，1H)，4.83-4.84(d，1H)，5.77(s，1H)，6.78-6.82(d，1H)，7.19-7.23(m，1H)，7.27-7.29(t，1H)，7.31-7.35(t，2H)，7.44-7.47(d，2H)，7.64-7.66(d，1H)，7.83-7.85(d，1H)，8.00(s，1H)，10.01-10.03(d，1H)，13.42(s，1H).
Synthesizing of embodiment 9:2-(2-furyl)-1H-benzoglyoxaline-4-(the adjacent fluorophenyl of N-) acid amides
Press embodiment 6 method Synthetic 2s-(2-furyl)-1H-benzoglyoxaline-4-(the adjacent fluorophenyl of N-) acid amides, productive rate about 93%.
Product structure is identified:
1HMNR(DMSO，400MHz)δ：6.85-6.87(d，1H)，7.14-7.20(m，1H)，7.22-7.26(t，1H)，7.33-7.36(m，1H)，7.38-7.41(m，1H)，7.43-7.49(m，1H)，7.77-7.82(t，1H)，7.99-8.01(d，1H)，8.04-8.06(d，1H)，8.48-8.62(t，1H)，11.86-12.33(d，1H)，13.75(s，1H).
Claims (1)
1. 2-furyl-1H-benzoglyoxaline-4-acidamide type derivative is characterized in that chemical structural formula is as follows:
In the formula: X is F, Cl, Br, CH
3, OH, NO
2Or H;
Y be H,
Or
Wherein R is F, Cl, Br, CH
3, OH, NO
2Or H.
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| WO2010078830A1 (en) * | 2009-01-08 | 2010-07-15 | 上海交通大学 | Benzimidazole-4-carboxamide derivatives, their preparation methods, pharmaceutical compositions and their uses |
| US8362268B2 (en) | 2008-05-30 | 2013-01-29 | University Of Notre Dame Du Lac | Anti-bacterial agents from benzo[d]heterocyclic scaffolds for prevention and treatment of multidrug resistant bacteria |
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| CN1272333C (en) * | 2004-11-18 | 2006-08-30 | 上海交通大学 | 2-pyridyl-1H-benzimidazole-4-amide derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8362268B2 (en) | 2008-05-30 | 2013-01-29 | University Of Notre Dame Du Lac | Anti-bacterial agents from benzo[d]heterocyclic scaffolds for prevention and treatment of multidrug resistant bacteria |
| US9617249B2 (en) | 2008-05-30 | 2017-04-11 | University Of Notre Dame Du Lac | Benzoheterocyclic anti-bacterial agents |
| WO2010078830A1 (en) * | 2009-01-08 | 2010-07-15 | 上海交通大学 | Benzimidazole-4-carboxamide derivatives, their preparation methods, pharmaceutical compositions and their uses |
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