Application of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidyl] amino} methyl) phenyl] in treatment of chronic atrophic gastritis

Abstract

The invention discloses an application of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl] amino} methyl) phenyl] in treating chronic atrophic gastritis, which is mainly used for recovering blood supply of gastric mucosa, accelerating repair after gastric mucosa injury and maintaining the function of gastric mucosa barrier by relaxing arteries under gastric mucosa, and has the advantages of being capable of treating chronic atrophic gastritis, and capable of treating chronic atrophic gastritis. The N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl] amino} methyl) phenyl] has the advantages that the effective treatment effect is achieved, a new thought is provided for the treatment of chronic atrophic gastritis, and a new application of the N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl] amino} methyl) phenyl] medicine for treating chronic atrophic gastritis is also provided.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to the use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] in treating chronic atrophic gastritis. Background Art

[0002] Gastric cancer is the second leading cause of cancer-related death worldwide. Gastric cancer incidence and mortality rates in my country are among the highest in the world, making it a serious health hazard. Chronic atrophic gastritis, a precancerous condition, is an independent risk factor for gastric cancer, providing a foundation for its development. Helicobacter pylori (Hp) infection plays a crucial role in the development and progression of CAG. Although Hp eradication can prevent or delay gastric mucosal atrophy and reduce the risk of gastric cancer, the current Hp infection rate in my country is as high as 40% to 60%, making proactive screening and eradication of all Hp-infected individuals unrealistic. Furthermore, the increasing prevalence of Hp drug resistance has limited its effectiveness. Furthermore, for Hp-infected populations (children and the elderly), the risk of adverse reactions to Hp eradication drugs is increased, necessitating comprehensive assessment and individualized management. Therefore, while striving to improve the effectiveness of Hp eradication therapy, we must also explore new intervention strategies, which are crucial for the prevention and treatment of gastric cancer.

[0003] Current clinical medications for the treatment of chronic atrophic gastritis primarily protect the gastric mucosa, improve gastric motility, and provide nutritional supplements, but their efficacy in treating the disease pathology is limited. The effective blood supply function of the submucosal microvessels of the digestive tract plays a key role in maintaining normal mucosal barrier function and histological structure. In chronic atrophic gastritis, dysfunction of the submucosal microvessels’ blood supply function may, on the one hand, lead to a decrease in the ability to clear inflammatory mediators, resulting in their local accumulation; on the other hand, it may lead to a decrease in the ability to repair gastric mucosal damage in the chronic inflammatory area. Both of these factors will further aggravate the damage to gastric mucosal cells and the loss of mucosal barrier function, thereby promoting the progression of chronic atrophic gastritis. Therefore, dysfunction of the submucosal microvascular function may be an important basis for the refractory nature of chronic atrophic gastritis. There is an urgent need for a drug that restores the function of the submucosal microvessels to provide a new therapeutic approach for the clinical prevention and treatment of refractory chronic atrophic gastritis. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] in the preparation of a medicament for treating chronic atrophic gastritis.

[0005] In order to achieve the above object, the present invention provides the following technical solutions: The use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] in the preparation of a drug for treating chronic atrophic gastritis is characterized in that the structure of the N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] is as shown in Formula I: .

[0006] Preferably, the N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] is used to treat chronic atrophic gastritis by relaxing human gastric submucosal arterioles.

[0007] Preferably, the N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] is used to treat chronic atrophic gastritis by reducing interleukin-1-β.

[0008] Preferably, the present invention uses the N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] in the preparation of a compound for improving mucosal damage in mice with chronic atrophic gastritis.

[0009] The beneficial effects of the present invention are as follows: the present invention discloses the use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] in the preparation of a drug for treating chronic atrophic gastritis, which mainly achieves an effective therapeutic effect by dilating gastric submucosal arterioles, restoring gastric mucosal blood supply, accelerating the repair of gastric mucosal damage, and maintaining the function of the gastric mucosal barrier, and provides a new idea for the treatment of chronic atrophic gastritis. It also provides a new use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] for treating chronic atrophic gastritis, which is different from the limited therapeutic effects of the drugs currently used in the clinic for treating chronic atrophic gastritis, which mainly act on gastric mucosal protection, improve gastric motility, and are nutritional supplements. The present invention seeks new drug targets from a different perspective, not only providing new therapeutic drugs for the treatment of chronic atrophic gastritis, but also broadening the pharmaceutical uses of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl]. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to make the purpose, technical solutions and beneficial effects of the present invention more clear, the present invention provides the following drawings for illustration: Figure 1N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] can induce endothelium-dependent relaxation of human gastric submucosal microvessels; Figure 2 N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] has the effect of alleviating chronic atrophic gastritis in mice (A: gastric mucosal verification score; B: interleukin-1-β content in gastric tissue). DETAILED DESCRIPTION

[0011] The present invention will be further described below with reference to the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it. However, the embodiments are not intended to limit the present invention.

[0012] Example 1 A method for dilating human gastric submucosal arterioles in vitro using N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] is provided, wherein the specific steps are as follows: A. Surgically resected gastric mucosal tissue was placed in Krebs-Henseleit (KH) solution, which contains: 118 mM sodium chloride, 4.7 mM potassium chloride, 1.18 mM magnesium sulfate, 25 mM sodium bicarbonate, 1.2 mM potassium dihydrogen phosphate, 1.6 mM calcium chloride, and 11.1 mM D-glucose.

[0013] B. Under a microscope, the adipose connective tissue surrounding the gastric submucosal artery was carefully dissected using forceps and scissors. Two segments of gastric submucosal artery, 1.5 to 2 mm in length, were removed. The vessels were secured using two tungsten wires (40 μm diameter) in a 5 mL bath of KH solution in a Danish microvascular tension meter. One tungsten wire was connected to the tension transducer, and the other to the vascular fine-tuning device. During the experiment, the bath temperature was maintained at approximately 37°C, and a gas mixture (95% O₂ + 5% CO₂) was continuously pumped in. The pH was maintained between 7.35 and 7.45. The isolated vessels were normalized to an initial tension equal to 0.9 times the vessel diameter at 100 mmHg. The fixed vessels were allowed to stabilize in KH solution for 20 minutes. After normalization, subsequent experiments were performed.

[0014] C. After mounting arterioles, vessels were allowed to stabilize at zero tension for 20 minutes before normalization. After the equilibration period, arterial endothelial integrity was assessed by maximal precontraction with 5 μM norepinephrine (NE) followed by relaxation with carbachol (CCh, 100 μM). After washing, N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] was added at concentrations of 0.5 μM, 1 μM, 2 μM, 3 μM, 4 μM, and 5 μM for the experiment.

[0015] D. The test results were statistically analyzed using Graphpad software. The results are as follows: Figure 1 Statistical results showed that N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] could relax human gastric submucosal arterioles in a dose-dependent and endothelium-dependent manner.

[0016] Example 2 A method for alleviating chronic atrophic gastritis in mice using N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] is provided, wherein the specific steps are as follows: A. Six-week-old BALB / c mice were randomly divided into a control group and an experimental group. The control group received N-methyl-N'-nitro-N-nitrosoguanidine (120 μg / mL) in the drinking water and 2% sodium salicylate and 20 mmol sodium deoxycholate by oral gavage. The experimental group received the aforementioned modeling agents and, in addition, received N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] (5 mg / kg / day) by oral gavage. All mice were treated for 16 weeks. At the end of the experiment, mice were sacrificed by cervical dislocation. Gastric tissues were fixed, sectioned, and stained with hematoxylin and eosin for evaluation of inflammatory scores. N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] significantly reduced the inflammatory score in gastric tissue of mice with chronic atrophic gastritis.

[0017] B. The gastric tissues of the mice in the control and experimental groups were homogenized, and the supernatant of the homogenate was tested for interleukin-1-β using an enzyme-linked immunosorbent assay (ELISA) kit. N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] was shown to significantly reduce the interleukin-1-β content in the gastric tissues of mice with chronic atrophic gastritis.

[0018] The above-described embodiments are merely preferred embodiments for the purpose of fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are within the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

Claims

1. Use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] in the preparation of a medicament for treating chronic atrophic gastritis, characterized in that: The structure of the N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] is shown in Formula I: 。 2. The use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] according to claim 1 in the preparation of a medicament for treating chronic atrophic gastritis, characterized in that: The N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl] can treat chronic atrophic gastritis by relaxing the submucosal arterioles of the human stomach.

3. Use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] according to claim 1 in the preparation of a medicament for treating chronic atrophic gastritis, characterized in that: The N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl]amino}methyl)phenyl]-1 ...

4. Use of N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] according to claim 1 in the preparation of a medicament for treating chronic atrophic gastritis, characterized in that: The invention relates to an application of the N-[3-chloro-4-({[2-(methylamino)-6-(2-pyridyl)-4-pyrimidinyl]amino}methyl)phenyl] in preparing a method for improving mucosal damage in mice with chronic atrophic gastritis.

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