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CN-118221701-B - Double-response low-drug-resistance nitric oxide donor, and preparation method and application thereof

CN118221701BCN 118221701 BCN118221701 BCN 118221701BCN-118221701-B

Abstract

The invention relates to the technical field of pharmaceutical chemistry, and discloses a double-response low-resistance nitric oxide donor, a preparation method and application thereof, wherein the low-resistance nitric oxide donor is 5-mononitroisosorbide oxalate diester, the preparation method adopts the reaction of 5-mononitroisosorbide with oxalyl chloride or oxalic acid under the action of a catalyst to obtain the low-resistance nitric oxide donor, and the product of the preparation method has high purity and high yield. The donor can realize double responses of different speeds in normal tissues and disease microenvironment, thereby reducing side effects on the normal tissues, reducing the generation of active nitrogen, reducing the nitrification and inactivation of related biological enzymes and avoiding the organism from generating drug resistance to the nitric oxide donor. Has good stability and long half-life period, can be used for preparing medicaments for treating cardiovascular diseases and glaucoma related diseases, and has good popularization and application values.

Inventors

  • JIA FAN
  • FU GUOSHENG
  • JI JIAN
  • JIN QIAO

Assignees

  • 浙江大学医学院附属邵逸夫医院
  • 浙江大学

Dates

Publication Date
20260508
Application Date
20240318

Claims (10)

  1. 1. A dual-response low-resistance nitric oxide donor, wherein the low-resistance nitric oxide donor is a 5-mononitroisosorbide oxalate diester having the following structural formula:
  2. 2. The method for preparing a dual-response low-resistance nitric oxide donor according to claim 1, wherein the method one or the method two are adopted: the method comprises the following steps of reacting 5-mononitroisosorbide with oxalyl chloride under the action of a catalyst to obtain the low-drug-resistance nitric oxide donor; The second method specifically comprises the step of reacting 5-mononitroisosorbide with oxalic acid under the action of a catalyst to obtain the low-drug-resistance nitric oxide donor.
  3. 3. The method of preparing a dual-response low-resistance nitric oxide donor according to claim 2, wherein in method one the molar ratio of 5-mononitroisosorbide to oxalyl chloride is 0.5:1-3:1; in the second method, the molar ratio of the 5-mononitroisosorbide to oxalic acid is 0.5:1-3:1.
  4. 4. The method for preparing a dual-response low-resistance nitric oxide donor according to claim 2, wherein the solvent used in the first or second method is selected from any one or more of dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, dioxane or dimethyl sulfoxide.
  5. 5. The preparation method of the dual-response low-drug-resistance nitric oxide donor according to claim 2, wherein in the first method, the catalyst is selected from any one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, trimethylamine, benzimidazole, 4-dimethylaminopyridine and pyridine, and the molar ratio of the catalyst to oxalyl chloride is 0.1-5:1; and/or in the second method, the catalyst is selected from one or more of dicyclohexylcarbodiimide, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, N-hydroxysuccinimide and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, and the molar ratio of the catalyst to oxalic acid is 0.1-5:1.
  6. 6. The method for preparing the double-response low-resistance nitric oxide donor according to claim 2, wherein in the first method, oxalyl chloride is added in a dropwise manner, the reaction temperature is-20-0 ℃ in the dropwise process, the dropwise time is 0.5-3 hours, and the temperature is raised to-5-25 ℃ after the dropwise process is completed and the reaction time is more than 0.5 hours.
  7. 7. The method for preparing the dual-response low-drug-resistance nitric oxide donor according to claim 2, wherein the method II comprises the step of adding 5-mononitroisosorbide to react after oxalic acid is activated with a catalyst to obtain the low-drug-resistance nitric oxide donor.
  8. 8. The method for preparing a dual-response low-resistance nitric oxide donor according to claim 7, wherein the activation temperature is below 25 ℃, the reaction temperature after activation is 20-45 ℃ and the reaction time is more than 8 hours.
  9. 9. Use of a dual-response low-resistance nitric oxide donor according to claim 1 for the preparation of a medicament for the treatment or prevention of cardiovascular diseases.
  10. 10. A medicament for the treatment or prophylaxis of cardiovascular disease comprising the dual-responsive low-resistance nitric oxide donor of claim 1.

Description

Double-response low-drug-resistance nitric oxide donor, and preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to a dual-response low-drug-resistance nitric oxide donor, and a preparation method and application thereof. Background Nitric Oxide (NO) is an important endogenous gas signal molecule in a human body, and can widely participate in various physiological processes of a living body due to higher biological activity, so that an important regulation effect is exerted. The nitric oxide molecules have important roles in maintaining cardiovascular homeostasis, nerve signal transduction, natural immune response and the like. Recent researches also show that the nitric oxide is closely related to the tumor, and the nitric oxide with a certain concentration has remarkable effects in regulating and controlling tumor drug resistance, hypoxia, apoptosis and the like. Aiming at the problem of low in vivo concentration of endogenous nitric oxide caused by abnormal metabolism under pathological conditions, the research and development of exogenous nitric oxide donor medicaments have been widely focused. The design and synthesis of nitric oxide donor drugs are of great significance in basic research and clinical application. For example, nitric oxide donors such as 5-mononitroisosorbide, nitroglycerin, and dinitrate isosorbide have been used clinically for the treatment of cardiovascular diseases as first-line medications. Under physiological conditions, the nitric oxide donor medicine releases nitric oxide through cell metabolism to exert the physiological effect of nitric oxide, and is one of the leading edge and the hot spot of the research in the biomedical field in recent years. For example, CN107459482A discloses a nitric oxide donor, a preparation and application thereof, which discloses a chemical formula of the following structure,R 2 is H, C-C8 cycloalkyl, or C1-6 alkyl optionally substituted with 1-2 substituents selected from C1-4 alkoxy, -S (O) 2 -OH, and hydroxy, wherein N is attached to the benzene ring of the fluorophore molecule, which compounds are useful as nitric oxide donors for diseases related to hypertension and the like. CN104119295A discloses a phenothiazine nitric oxide donor, a preparation method and application thereof, and a compound structural formula isN=0, 1 or 2;R 1 is hydrogen, halogen, C1-C4 branched or straight chain alkyl, halogenated C1-C4 branched or straight chain alkyl, R 2 is hydrogen, C1-C4 branched or straight chain alkyl. The compound is used as a pharmaceutical composition of active ingredients and can be used as an anti-tumor drug for preparing drugs for treating breast cancer, lung cancer and gastric cancer. Nitric oxide itself is unstable and cannot be used directly in many medical settings. Nitric oxide donor drugs achieve effective transport in vivo by loading nitric oxide and extend the half-life of nitric oxide to some extent. However, most NO donors today are still not stable, and the half-life under physiological conditions is generally varied from seconds to hours, often requiring low temperature storage and transport, which is a great nuisance for storage and biomedical applications of NO donors. On the other hand, the half-life period of nitric oxide in vivo is only 3-6 seconds, and the diffusion radius is only 40-200 mu m, so that the nitric oxide donor is required to be better converted into NO at a focus part to play a role. In addition, many nitric oxide donors can easily induce the organism to generate drug resistance to NO after being used, and the physiological effect of NO is greatly reduced after being re-dosed. This is mainly due to the fact that high levels of reactive oxygen species in the disease microenvironment will convert NO to reactive nitrogen species, which oxidize or nitrify the biological enzymes of the nitric oxide donor drug metabolism, causing its inactivation and the loss of the ability to produce NO. This problem is usually only handled clinically by stopping the patient, which increases the risk of patient-related diseases. Even with such therapies, patients induce greater resistance after several cycles, often requiring longer withdrawal periods with concomitant higher doses, which can increase drug-related toxic side effects. Therefore, the development of the low-drug-resistance nitric oxide donor has important significance in disease treatment and also has wide application prospect. Disclosure of Invention Aiming at the problems of poor stability, short half-life and easy generation of drug resistance of a nitric oxide donor in the prior art, the invention provides a double-response low-drug-resistance nitric oxide donor which has stable performance and long half-life, can be slowly hydrolyzed under the action of esterase of normal tissues, avoids burst release of nitric oxide and reduces the occurrence of drug resistance. The nitri