CN-121990941-A - N-methylnitrosamines compound, pharmaceutical composition and application thereof

Abstract

The invention discloses an N-methyl nitrosamine compound, a pharmaceutical composition and application thereof. The compound (formula I) is an anoxia activated NO donor drug, has the characteristic of effectively releasing NO under the condition of high selectivity anoxia, thereby obviously improving the activity of myocardial cells, has excellent in-vitro and in-vivo activity, and can be used for preventing or treating myocardial anoxia injury. Meanwhile, the ether bond connecting structure improves the metabolic stability of the compound, so that the compound has the in vivo metabolic property beneficial to patent medicine.

Inventors

• GOU SHAOHUA
• YANG WANXIANG

Assignees

• 东南大学

Dates

Publication Date

20260508

Application Date

20241104

Claims (10)

1. 1. An N-methylnitrosamines compound characterized by having the structure of formula I: Wherein: the definition of Z 1 、Z 2 , X, Y satisfies any of the following conditions: (1) When Z 1 is nitro, Z 2 is hydrogen, X, Y is selected from hydrogen, halogen, C 1 -C 4 alkyl; (2) When Z 2 is nitro, Z 1 is selected from hydrogen, halogen, C 1 -C 4 alkyl, X, Y is selected from hydrogen, halogen, C 1 -C 4 alkyl.
2. 2. The N-methylnitrosamines according to claim 1, wherein in the structure: When Z 1 is nitro, Z 2 is hydrogen, X, Y is hydrogen or X, Y, and any one of them is selected from halogen and C 1 -C 4 alkyl.
3. 3. The N-methylnitrosamines according to claim 1, wherein in the structure: When Z 2 is nitro and Z 1 is hydrogen, X, Y is hydrogen or X, Y is selected from halogen and C 1 -C 4 alkyl; when Z 2 is nitro, Z 1 is selected from halogen and C 1 -C 4 alkyl, X, Y is hydrogen.
4. 4. The N-methylnitrosamines according to claim 1, wherein in the structure: When Z 1 is nitro, Z 2 is hydrogen, X, Y is hydrogen or X, Y is any one selected from fluorine, chlorine, methyl, ethyl; When Z 2 is nitro and Z 1 is hydrogen, X, Y is hydrogen or X, Y is selected from chlorine, methyl and ethyl; When Z 2 is nitro, Z 1 is selected from chlorine, bromine, methyl, ethyl, X, Y is hydrogen.
5. 5. The N-methylnitrosamines according to claim 1, characterized in that they are selected from any one of the following compounds:
6. 6. a pharmaceutical composition comprising an N-methylnitrosamine compound according to claim 1 and a pharmaceutically acceptable carrier.
7. 7. Use of an N-methylnitrosamines as defined in claim 1 or a pharmaceutical composition as defined in claim 6 for the preparation of a medicament for the prophylaxis or treatment of myocardial hypoxic injury diseases.
8. 8. The use according to claim 7, wherein the drug is a hypoxia-activated NO donor drug.
9. 9. The use according to claim 7, wherein the medicament is a medicament for improving myocardial cell viability under hypoxic conditions.
10. 10. The use according to claim 7, wherein the medicament is a medicament for the prevention or treatment of coronary heart disease.

Description

N-methylnitrosamines compound, pharmaceutical composition and application thereof Technical Field The invention relates to an N-methyl nitrosamine compound and a pharmaceutical composition and application thereof, in particular to an N-methyl nitrosamine compound for improving the activity of hypoxic myocardial cells and a pharmaceutical composition and application thereof. Background Coronary heart disease, also known as ischemic heart disease, is caused by organic stenosis or blockage of the coronary arteries, resulting in ischemia of myocardial tissue and hypoxia at the cellular level, leading to myocardial damage. Nitric Oxide (NO) donor drugs are often used to treat coronary heart disease caused by myocardial ischemia because of their ability to release free NO molecules in vivo, thereby promoting vasodilation. However, existing drugs such as nitrate generally lack selectivity, are difficult to accurately release sufficient amount of NO at the anoxic part, and are fast in vivo metabolism, so that the treatment effect is poor. CN116675620 discloses a class of NO donor compounds which can release NO through the catalysis of nitroreductase and can also release NO selectively in hypoxic cardiomyocytes, but the carbonate chain in the structure is not high in stability and easy to metabolize, and the properties of the patent medicine remain to be improved, so that the clinical application of the compounds is limited to a certain extent. Disclosure of Invention The first object of the invention is to provide an N-methylnitrosamines compound, the second object is to provide a pharmaceutical composition constructed by the compound, and the third object is to provide a pharmaceutical application of the compound and the pharmaceutical composition thereof. The N-methylnitrosamine compound has the structure of formula I: Wherein: the definition of Z 1、Z2, X, Y satisfies any of the following conditions: (1) When Z 1 is nitro, Z 2 is hydrogen, X, Y is selected from hydrogen, halogen, C 1-C4 alkyl; (2) When Z 2 is nitro, Z 1 is selected from hydrogen, halogen, C 1-C4 alkyl, X, Y is selected from hydrogen, halogen, C 1-C4 alkyl. Preferably, in the structure: When Z 1 is nitro, Z 2 is hydrogen, X, Y is hydrogen or X, Y, and any one of them is selected from halogen and C 1-C4 alkyl. Preferably, in the structure: When Z 2 is nitro and Z 1 is hydrogen, X, Y is hydrogen or X, Y is selected from halogen and C 1-C4 alkyl; when Z 2 is nitro, Z 1 is selected from halogen and C 1-C4 alkyl, X, Y is hydrogen. Preferably, in the structure: When Z 1 is nitro, Z 2 is hydrogen, X, Y is hydrogen or X, Y is any one selected from fluorine, chlorine, methyl, ethyl; When Z 2 is nitro and Z 1 is hydrogen, X, Y is hydrogen or X, Y is selected from chlorine, methyl and ethyl; When Z 2 is nitro, Z 1 is selected from chlorine, bromine, methyl, ethyl, X, Y is hydrogen. Preferably, the N-methylnitrosamines according to the invention are selected from any one of the following compounds: the preparation method of the N-methylnitrosamine compound comprises the following steps: (i) Reacting 4-hydroxy (N-methyl) aniline hemisulfate with sodium nitrite in the presence of acetic acid to obtain IM1; (ii) Dissolving a nitro benzyl alcohol derivative S1, triphenylphosphine (PPh 3) and IM1 in tetrahydrofuran, adding diisopropyl azodicarboxylate (DIAD) in nitrogen at 0 ℃, and transferring to room temperature for reaction after the addition, thus obtaining the N-methylnitrosamine compound I. Wherein in the step (i), the reaction temperature is 0 ℃, acetic acid is a solvent, and Z 1、Z2 and X, Y are defined as above. The pharmaceutical composition of the invention comprises the N-well-ball of the invention Methylnitrosamines and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be an auxiliary material widely used in the field of medicine production. Adjuvants are primarily used to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can include one or more of binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, binders, disintegrants, lubricants, anti-adherent agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners. The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional