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CN-118027004-B - Triazole compound for protecting brain tissue and preparation method thereof

CN118027004BCN 118027004 BCN118027004 BCN 118027004BCN-118027004-B

Abstract

The invention provides a triazole compound for protecting brain tissues and a preparation method thereof, belongs to the technical field of biological medicines, provides a triazole compound shown as a formula (I) and chiral isomer, enantiomer, diastereoisomer, geometric isomer, free form or pharmaceutically acceptable salt, hydrate, solvate or ester thereof, and also provides a preparation method thereof, compared with the prior art, the triazole compound is prepared by splicing a lactone ring-opening product of butylphthalide and ligustrazine through triazole, and the triazole compound is novel and can be used for protecting brain tissues.

Inventors

  • TIAN YU
  • SUN GUIBO
  • SHANG HAI
  • YE JINGXUE
  • WANG MIN

Assignees

  • 中国医学科学院药用植物研究所

Dates

Publication Date
20260508
Application Date
20240112

Claims (6)

  1. 1. A triazole compound for protecting brain tissue, characterized by any one of the following structural formulas: 、 、 、 、 、 、 、 、 、 、 、 、 、 。
  2. 2. the method for preparing triazole-based compound according to claim 1, comprising the steps of: (1) Alkaline hydrolysis of butylphthalide or halogen substituted butylphthalide is adopted, pH is regulated, concentration is carried out, and chloroacetyl chloride, 4-dimethylaminopyridine and triethylamine are added for reaction to obtain an intermediate 1; (2) Dissolving the intermediate 1 obtained in the step (1) with propargylamine, and adding O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroboric acid and N, N-diisopropylethylamine to react to obtain an intermediate 2; (3) Initiating ligustrazine by benzoyl peroxide, and carrying out bromination reaction with NBS to obtain an intermediate 3; (4) Dissolving the intermediate 3 obtained in the step (3), and adding sodium azide to react to obtain an intermediate 4; (5) Dissolving the intermediate 2 obtained in the step (2) and the intermediate 4 obtained in the step (4), and adding a catalyst to react to obtain an intermediate 5; (6) The intermediate 5 obtained in the step (5) and a substituted compound undergo substitution reaction under the action of a catalyst to obtain the triazole compound; The intermediate 1 is Wherein the intermediate 2 is ; The intermediate 3 is Wherein the intermediate 4 is Wherein the intermediate 5 is Wherein X is H, I or Br.
  3. 3. The process according to claim 2, wherein the base used in step (1) is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide and calcium hydroxide; the hydrolysis condition in the step (1) is that the temperature is kept at 55-65 ℃ for 1.5-3h, or the temperature is kept at 55-65 ℃ for 30-45min, the target pH value for regulating the pH value in the step (1) is 3-4, the adopted reagent is one or more selected from dilute hydrochloric acid, dilute sulfuric acid and dilute nitric acid, the concentration method in the step (1) is to add an extractant for extraction, the extractant is one or two selected from ethyl acetate and diethyl ether, the molar use ratio of chloroacetyl chloride, 4-dimethylaminopyridine and triethylamine to butylphthalide or halogen substituted butylphthalide in the step (1) is 1.4-1.6:0.08-0.12:1.4-1.6:1, the molar use ratio of propargylamine to intermediate 1 in the step (2) is 1.1-1.3:1, and the molar use ratio of O-benzotriazol-N, N, N ', N' -tetramethyl urea tetrafluoro-N, N-isopropyl-1.2:1.8:1.
  4. 4. The preparation method according to claim 2, wherein the molar ratio of benzoyl peroxide to ligustrazine in step (3) is 0.08-0.12:1, the molar ratio of NBS to ligustrazine in step (3) is 0.25-0.35:1, the molar ratio of sodium azide to intermediate 3 in step (4) is 1.15-1.25:1, and the reaction conditions in step (4) are that microwaves are used for 55-70min at 55-65 ℃.
  5. 5. The preparation method according to claim 2, wherein the molar ratio of the intermediate 2 to the intermediate 4 in the step (5) is 1:0.9-1.1, the catalyst in the step (5) comprises thiophene-2-carboxylic acid cuprous (I), the molar ratio of the substituted compound to the intermediate 5 in the step (6) is 1.4-1.6:1, the substituted compound in the step (6) is selected from morpholine, N-methylpiperazine, piperazine, diethylamine and dimethylamine, and the condition of the substituted reaction in the step (6) is that the substituted reaction is carried out for 100-140min at 60-70 ℃ or is carried out for 50-65min at 60-70 ℃.
  6. 6. A pharmaceutical composition comprising the triazole compound of claim 1 or a pharmaceutically acceptable salt.

Description

Triazole compound for protecting brain tissue and preparation method thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a triazole compound for protecting brain tissues and a preparation method thereof. Background The traditional Chinese medicine composition is used for treating cerebral apoplexy, and is mainly used for relieving symptoms by providing medicines with the effects of reducing blood pressure, resisting platelet aggregation, resisting anticoagulation and the like, but has an insignificant treatment effect and cannot effectively prevent cerebral apoplexy from occurring and recurrence, and meanwhile, no specific medicine can completely cure cerebral apoplexy at present, the disease condition can be relieved only through a series of treatments, and the effect of the medicine for treating cerebral apoplexy is limited. Therefore, the adoption of medicaments for treating cerebral apoplexy is always one of important subjects of researches of technicians in the field, n-butylphthalide, NBP) is referred to as butylphthalide for short, commonly referred to as apigenin A, is a main component of celery volatile oil, is a levorotatory body of butylphthalide separated from volatile oil of celery seeds of plants in Umbelliferae by researchers of Chinese medical science institute, is a chemical medicament taking 'ischemic cerebral apoplexy treatment' as a main indication, covers an action mechanism of two medicaments for improving cerebral blood flow and protecting brain tissues, and can play a unique treatment role for patients with ischemic cerebral apoplexy. Although butylphthalide can have therapeutic effect on a plurality of pathological links of cerebral ischemia, the butylphthalide has poor water solubility and overall curative effect. The patent application CN106928155A designs and prepares 3 azide ligustrazine and butylphthalide spliced compounds on the basis of butylphthalide, and ligustrazine (TMP) is an alkaloid extracted from rhizoma ligustici wallichii of the Umbelliferae and is one of the effective components for treating cardiovascular and cerebrovascular diseases. Pharmacological studies prove that the ligustrazine has the effects of dilating blood vessels, increasing arterial blood flow, inhibiting platelet aggregation, reducing platelet activity and the like, and has the characteristics of complete absorption and wide distribution in vivo. However, ligustrazine has poor lipid solubility, rapid metabolism, short half-life, and is easy to accumulate poisoning because frequent clinical administration is required to maintain effective therapeutic concentration of the drug, so that the application of ligustrazine is limited. The invention patent CN106928155B discloses a tetramethylpyrazine butylphthalide split compound, a preparation method thereof and application thereof in medicines, wherein the tetramethylpyrazine butylphthalide split compound has the following structural general formula I, and the tetramethylpyrazine butylphthalide split compound is prepared by taking phthalic anhydride and tetramethylpyrazine as starting raw materials and performing bromination, nucleophilic addition, catalytic dehydration, ester hydrolysis, reduction and esterification reaction; the invention provides a pharmaceutical composition, which is prepared from a ligustrazine butylphthalide split compound serving as a medicinal active ingredient and a pharmaceutically acceptable carrier, excipient, diluent, auxiliary agent, vector or combination thereof, wherein the ligustrazine butylphthalide split compound prepared by the invention has good inhibition effect on platelet aggregation induced by Adenosine Diphosphate (ADP) in vitro and has good in vivo pharmacokinetic property, and can be used for preventing and treating cardiovascular and cerebrovascular diseases and complications thereof. In implementing the invented embodiments, the inventors found that at least the following drawbacks exist in the background art: The invention mainly adopts the Bern turbidimetry to test the inhibition activity of a target compound on Adenosine Diphosphate (ADP) -induced rabbit platelet aggregation to evaluate the platelet aggregation inhibition activity of the compound, however, the current platelet aggregation inhibition drugs are more in selection, and meanwhile, the unique cerebral apoplexy treatment effect and protection effect of butylphthalide per se are not obviously highlighted, so that the unique effects of butylphthalide on ischemic cerebral apoplexy treatment and prevention are exerted in the background art, and the compound with the brain tissue protection effect still needs to be further developed on the basis of butylphthalide so as to well prevent and treat cerebral apoplexy. Disclosure of Invention Aiming at the defect of the prior art that a compound for efficiently protecting brain tissues is lacking, the triazole ring is further introduced t