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CN-121991015-A - Compound, pharmaceutical composition and application thereof in preparation of drugs for treating cardiovascular and cerebrovascular diseases

CN121991015ACN 121991015 ACN121991015 ACN 121991015ACN-121991015-A

Abstract

The invention discloses a compound, a pharmaceutical composition and application thereof in preparing medicines for treating cardiovascular and cerebrovascular diseases, and belongs to the technical field of medicines. The invention provides a flavonoid compound for treating cardiovascular and cerebrovascular diseases and a pharmaceutical composition thereof, wherein the flavonoid compound can obviously reduce cerebral infarction area of mice in a model group and can be used for treating cardiovascular and cerebrovascular diseases.

Inventors

  • PEI GANG
  • LIU XI
  • DONG XIAOXU
  • HUANG SHICHAO
  • XIA PENG

Assignees

  • 上海东西智荟生物医药有限公司

Dates

Publication Date
20260508
Application Date
20251107
Priority Date
20241108

Claims (20)

  1. 1. A compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, wherein the compound has the structure shown in the formula: The compound of the formula I, R 1 is selected from hydrogen, deuterium, halogen, hydroxy, amino, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkylamino; r 2 、R 3 is each independently selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, fmoc-aminoacyl, aminoacyl or a group having one of the following formulas: Wherein each R 4 、R 5 is independently selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof, and mixtures thereof, wherein R 1 is selected from OH, F, cl, br, I; Each of said R 2 、R 3 is independently selected from the group consisting of an alkyl group of C 1 -C 6 or a group having one of the following formulas: 、 Wherein each R 4 、R 5 is independently selected from hydrogen, deuterium, or CH 3 ;R 6 is selected from H, a substituted or unsubstituted aliphatic side chain, or a substituted or unsubstituted aromatic side chain.
  3. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, wherein each R 2 、R 3 is independently selected from an alkyl group of H, C 1 -C 4 or a group of one of the following formulae: 、 Wherein each R 4 、R 5 is independently selected from hydrogen, deuterium, or CH 3 ;R 6 is selected from the side chain of the alpha position of one of the natural amino acids.
  4. 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, wherein R 1 is selected from fluoro, hydroxy; The R 2 is selected from alkyl of C 1 -C 4 or a group having one of the following formulas: 、 Wherein R 4 、R 5 is independently selected from hydrogen or CH 3 ;R 6 is hydrogen, and R 3 is hydrogen.
  5. 5. A compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, wherein the compound has the structure shown in the formula: The compound of the formula II is shown in the specification, R 1 is selected from hydrogen, deuterium, halogen, hydroxy, amino, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkylamino; r 2 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, fmoc-aminoacyl, aminoacyl or a group having one of the following general formulae: Wherein each R 4 、R 5 is independently selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl.
  6. 6. The compound of claim 5, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof, and mixtures thereof, wherein R 1 is selected from fluoro, hydroxy; The R 2 is selected from alkyl of C 1 -C 4 or a group having one of the following formulas: 、 Wherein each R 4 、R 5 is independently selected from hydrogen or CH 3 ;R 6 is hydrogen.
  7. 7. A compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, wherein the compound is any one of formulas II-a, II-b, II-c, II-d, II-e, II-f: formula II-a; formula II-b; formula II-c; Formulas II-d; Formulas II-e; Formula II-f.
  8. 8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or tautomer thereof, and mixtures thereof, and a pharmaceutically acceptable carrier or diluent.
  9. 9. A pharmaceutical composition comprising a compound of formula II-a or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, and a pharmaceutically acceptable carrier or diluent; Formula II-a.
  10. 10. A pharmaceutical composition comprising a compound of formula II-b or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, and a pharmaceutically acceptable carrier or diluent; Formula II-b.
  11. 11. A pharmaceutical composition comprising a compound of formula II-d or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, and a pharmaceutically acceptable carrier or diluent; formula II-d.
  12. 12. The pharmaceutical composition according to any one of claims 8 to 11, wherein the pharmaceutical composition is in a single dosage form comprising between 0.03mg and 300mg of the compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, and a pharmaceutically acceptable carrier or diluent.
  13. 13. The pharmaceutical composition according to any one of claims 8 to 12, wherein the mass percentage of the compound or pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof and mixtures thereof in the pharmaceutical composition is 1 to 99wt%.
  14. 14. The pharmaceutical composition according to any one of claims 8 to 13, wherein the compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof or mixture thereof in the pharmaceutical composition has a drug loading concentration of 0.01 to 10 mg/mL.
  15. 15. The pharmaceutical composition according to any one of claims 8 to 14, further comprising an agent selected from at least one of the following: A combination drug; other therapeutic agents for cerebrovascular diseases; therapeutic agents for cardiovascular diseases.
  16. 16. The pharmaceutical composition according to any one of claims 15, wherein the other therapeutic agent for cerebrovascular disease is selected from any one, two or more of the following: A therapeutic agent for cerebrovascular diseases characterized by inhibiting or reducing or alleviating brain inflammation; A therapeutic agent for cerebrovascular diseases characterized by inhibiting or reducing or alleviating cerebral infarction volume; a therapeutic agent for cerebrovascular diseases characterized by inhibiting or reducing or alleviating a decrease in cerebral blood flow; a therapeutic agent for cerebrovascular diseases characterized by inhibiting or reducing or alleviating flow interruption of cerebral blood flow; Therapeutic agent for cerebrovascular diseases characterized by inhibiting or reducing or alleviating cerebrovascular rupture.
  17. 17. The pharmaceutical composition according to claim 15 or 16, wherein the combination is selected from any one, two or more of the following: A combination drug with an anti-cerebral thrombosis effect; A combination drug having an antiplatelet effect; A combination drug having thrombolytic effect; a combination drug with antioxidant effect; A combination drug having an anticoagulant effect; A combination drug with cholesterol reducing effect.
  18. 18. The pharmaceutical composition according to any one of claims 15 to 17, wherein the combination drug or other therapeutic agent for cerebrovascular disease or therapeutic agent for cardiovascular disease comprises any one, two or more of butylphthalide, edaravone, dexcamphol, aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, heparin, warfarin, dabigatran, apixaban, rivaroxaban and atorvastatin.
  19. 19. The pharmaceutical composition according to any one of claims 8 to 18, wherein the dosage form of the pharmaceutical composition is selected from one or more of a powder, a tablet, a pill, a capsule, a sustained release agent, a controlled release agent, an injection, an infusion or a suspension.
  20. 20. The pharmaceutical composition according to claim 8-18, wherein the pharmaceutical composition is in the form of an injection, and the pharmaceutical composition further comprises a solvent.

Description

Compound, pharmaceutical composition and application thereof in preparation of drugs for treating cardiovascular and cerebrovascular diseases Technical Field The invention belongs to the field of pharmacy, and in particular relates to a compound, a pharmaceutical composition and application thereof in preparing medicaments for treating cardiovascular and cerebrovascular diseases. Background Cardiovascular and cerebrovascular diseases are commonly called diseases of heart blood vessels and cerebral blood vessels, are diseases of which tissue injury is caused by insufficient blood supply due to blood vessel blockage, comprise myocardial infarction, chronic heart failure, coronary heart disease, ischemic cerebral apoplexy, peripheral arterial vascular disease, deep vein thrombosis, pulmonary embolism and the like, and are the first cause of death worldwide. It was counted that about 1790 ten thousand people die from cardiovascular and cerebrovascular diseases in 2016, accounting for 31% of the total number of deaths worldwide, with 85% of them dying from heart disease and stroke. Cerebral stroke (stroke), also known as "stroke", is an acute cerebrovascular disease, which is a disease in which brain tissue is damaged due to sudden rupture of cerebral blood vessels or failure of blood to flow into the brain due to vessel occlusion, and includes ischemic and hemorrhagic strokes, wherein the ischemic stroke accounts for 85%. Aiming at ischemic cerebral apoplexy, the main treatment strategies at present are firstly to improve cerebral blood circulation, including intravenous injection thrombolytic enzyme, arterial thrombus taking, anticoagulation and the like, and secondly to protect nerve tissues by removing free radicals, resisting oxidative damage and the like through neuroprotective agents such as Edaravone (ED) and butylphthalide (NBP). Under the current treatment strategies, the mortality rate of ischemic stroke remains high, and better treatment schemes are needed. But only the blood supply in the ischemic area is restored as soon as possible, so that the nerve function defect after ischemia can be reduced to the maximum extent. Thrombolytic therapy, although capable of rapidly restoring blood supply to ischemic areas, is critical to restoring nerve function by promoting the establishment of collateral circulation and the generation of new blood vessels because of its narrow time window and limited clinical application. The collateral circulation in the early stage of ischemic cerebral stroke depends on the opening of the original vascular network, which varies from person to person, and is difficult to intervene, whereas the collateral circulation establishment in the later stage depends on the generation of new blood vessels (angiogenisis). The new blood vessel can help blood flow to bypass the blocking section to reach brain tissue, improve blood flow perfusion in ischemic area, reduce infarct area, and promote neuron remodeling and function recovery. Therefore, we developed entirely new compounds based on mechanisms that promote angiogenesis. Disclosure of Invention The invention provides a novel compound, which can improve blood flow perfusion in an ischemic area and reduce infarct size by promoting angiogenesis, thereby achieving the purpose of preventing or treating cardiovascular diseases or cerebrovascular diseases, in particular ischemic cerebral apoplexy. Based on this: it is an object of the present invention to provide a novel compound having a prophylactic or therapeutic effect on cardiovascular diseases or cerebrovascular diseases, particularly cerebral apoplexy; It is a second object of the present invention to provide the use of a compound for the prevention or treatment of cardiovascular or cerebrovascular diseases, in particular cerebral stroke; the third object of the present invention is to provide a pharmaceutical composition containing the above-mentioned compound having a preventive or therapeutic effect on cardiovascular diseases or cerebrovascular diseases, particularly cerebral apoplexy; The fourth object of the present invention is to provide the use of the above pharmaceutical composition for preventing or treating cardiovascular diseases or cerebrovascular diseases, particularly cerebral apoplexy; Based on the above aims, the invention aims to solve the core problem that the existing medicines are unsatisfactory in treatment effect. [1. Compounds of formula I ] In a first aspect, the present invention provides a compound or a pharmaceutically acceptable salt, ester, hydrate, solvate or tautomer thereof, and mixtures thereof, having the structure shown below: R 1 is selected from hydrogen, deuterium, halogen, hydroxy, amino, substituted or unsubstituted C 1-C6 alkyl, substituted or unsubstituted C 1-C6 alkoxy, substituted or unsubstituted C 1-C6 alkylamino; R 2、R3 is each independently selected from hydrogen, deuterium, substituted or unsubstituted C 1-C6 alkyl, fmoc-aminoacyl, a