Amidino guanido substituted aromatic heterocyclic copmound and synthesis and use thereof

A technology of aromatic heterocycles and compounds, which can be used in medical preparations containing active ingredients, organic chemistry, pharmaceutical formulations, etc., and can solve the problems of high price of peptide inhibitors.

Inactive Publication Date: 2011-10-26
任建东 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Peptide inhibitors are expensive and need to b...

Method used

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  • Amidino guanido substituted aromatic heterocyclic copmound and synthesis and use thereof
  • Amidino guanido substituted aromatic heterocyclic copmound and synthesis and use thereof
  • Amidino guanido substituted aromatic heterocyclic copmound and synthesis and use thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: Synthesis of amidino-substituted aromatic heterocyclic compounds

[0036] (1) Grind p-nitrobenzaldehyde, p-aminobenzoic acid and NAY zeolite evenly, under solvent-free conditions, cool to room temperature after microwave irradiation for 10 minutes, add methanol to dissolve, remove NAY zeolite by filtration, and concentrate the filtrate under reduced pressure to obtain (E)-4-(4-Nitrobenzimino)benzoic acid.

[0037] (2) Dissolve (E)-4-(4-nitrobenzimino)benzoic acid in anhydrous methanol, carefully add sodium borohydride at 0°C, react at room temperature for 2 hours, add water to the reaction solution, Adjust the pH to 6 with formic acid, extract with dichloromethane / methanol, and separate and purify with polyamide or silica gel to obtain 4-(4-nitrobenzylamino)benzoic acid.

[0038] (3) a. Under ice-bath conditions, feed dry HCl gas into methanol and make it saturated, add 6-cyano-2-naphthol, react overnight at room temperature, generate methyl 6-hydroxy-2-n...

Embodiment 2

[0042] Embodiment 2: BApNA (N-benzoyl-DL-arginine p-nitroaniline hydrochloride) assays the inhibitory activity of compound (III) to trypsin

[0043] experimental method:

[0044] Take a 96-well plate, and add 50 μl of compound (III) aqueous solution (0.061, 0.122, 0.245, 0.489, 0.977, 1.953, 3.906, 7.813 μg / ml) and 50 μl of human trypsin solution (0.1 mg / ml) into each well successively. ml) and 100 μl BApNA solution (prepared to a 0.5 mg / ml solution with pH 7.4, 0.05M Tris-HCl buffer), in the other 3 wells, replace compound (III) with 50 μl deionized water, and the addition of the remaining reagents Same as above, as a non-inhibition control, incubate the 96-well plate at 37°C for 10 min, then add 20 μl of glacial acetic acid to terminate the reaction, and immediately measure the absorbance at 405 nm using a microplate reader. Calculate the inhibitory rate of compound (III) to trypsin at different concentrations according to the absorbance value, and the calculation formula i...

Embodiment 3

[0053] Embodiment 3: the protective effect of compound (III) on mice with acute pancreatitis

[0054] experimental method:

[0055] (1) Survival rate survey:

[0056] Get 40 KM mice and divide them into 4 groups randomly (n=10): control group, acute pancreatitis model group, acute pancreatitis model+compound (III) administration group, acute pancreatitis model+nafamostat The medicine group, wherein the preparation method of the model group is: 1 time per hour, 2 consecutive intraperitoneal injections of L-arginine (each dose is 4g / kg) to the mice to induce acute pancreatitis; the control group is only injected with normal saline; In pancreatitis model+compound (III) administration group, acute pancreatitis model+nafamostat administration group, compound (III) and nafamostat were injected intraperitoneally 1h after the last L-arginine injection. Medicine, the dose is 10mg / kg. The survival of each group was observed within 72 hours after administration.

[0057] (2) Enzyme a...

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Abstract

The invention relates to an amidino guanido substituted aromatic heterocyclic compound represented by the general formula (I), wherein, R1, R2 may represent the same or different groups, and may be substituted at any position of the hetero-aromatic ring, and may be represented as: -O-R3, -S-R3, -COOR3, -COR3, -O-COR3, -NH-COR3 and groups shown in the description, m represents a natural number such as 0, 1 or 2; R3 represents a hydrogen atom, linear alkyl or branched alkyl, substituted or non-substituted aromatic group or aromatic heterocyclic ring; R4 and R5 represent a hydrogen atom, linear alkyl or branched alkyl, aromatic group or aromatic heterocyclic ring; A ring represent a cycloaliphatic ring, aromatic ring, aromatic heterocyclic ring or fused heterocycle; X and Y represent carbon, nitrogen, oxygen, sulfur and the like and can be any position on the ring; B represents -COO-, -CONH-, -OCO-, -NHCO- or the like, and n represents a natural number such as 0, 1 or 2. The compound disclosed in the invention has stable property, can inhibit tryptic activity proved by pharmacology experiments, and can be used for preparing medicines for treating acute or chronic pancreatitis.

Description

[technical field] [0001] The invention relates to the technical field of medicine, and relates to a class of amidinoguanidine-substituted aromatic heterocyclic compounds capable of inhibiting the activity of human trypsin and uses of the compounds. [Background technique] [0002] Acute pancreatitis (AP) is a common disease in abdominal surgery, and the incidence of severe pancreatitis has gradually increased in recent years. Because it greatly disturbs the physiology and obviously damages various important organs, the mortality rate is very high. Sometimes it can cause sudden death. The mortality rate of severe pancreatitis is 20%, and those with complications can be as high as 50%. The etiology of AP is complex, and the pathogenesis has not yet been fully elucidated, and clinically there is still a lack of specific therapeutic drugs. The treatment of acute pancreatitis is one of the greatest challenges facing modern gastroenterology. The design and development of drugs ...

Claims

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Application Information

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IPC IPC(8): C07C257/18A61K31/245A61P1/18
Inventor 田伏洲任建东何菱余蓉骆助林王瑞丰
Owner 任建东
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