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CN-121971448-A - Use of benzazepine derivatives for the prevention or treatment of atherosclerosis

CN121971448ACN 121971448 ACN121971448 ACN 121971448ACN-121971448-A

Abstract

The invention discloses an application of a benzazepine derivative in preparing a medicament for preventing or treating atherosclerosis, wherein the benzazepine derivative is a compound with a chemical structure shown in a formula I or pharmaceutically acceptable salt or precursor or metabolite thereof, Formula I wherein X is halogen or H. The invention has the technical effects of remarkable plaque stabilizing effect, plaque composition improvement, plaque internal necrosis core area reduction, effective total plaque load reduction, delay/reversion of lesion progress, no dependence on lipid reduction, and filling of treatment blank, provides a brand-new plaque stabilizing treatment strategy, and is expected to solve the clinical problem of residual cardiovascular risk. And the safety is good, the organ specificity is high, and the systemic toxicity is low. Provides a new treatment paradigm, is used for old drugs, has great clinical transformation potential, can be used as supplement and enhancement of basic therapy (such as statin lipid lowering) to form a combined treatment scheme of lipid lowering and plaque stabilizing, and realizes multichannel cooperative control of atherosclerosis.

Inventors

  • Sheng Xunde
  • MIAO GUOLIN
  • ZHANG LING
  • WANG YUHUI
  • HUANG WEI
  • HAN YUFEI
  • CHEN JINGXUAN

Assignees

  • 北京大学

Dates

Publication Date
20260505
Application Date
20260123

Claims (10)

  1. 1. The application of the benzazepine derivative in preparing the medicine for preventing or treating atherosclerosis or atherosclerosis cardiovascular diseases is characterized in that the benzazepine derivative is a compound with a chemical structure shown in a formula I or pharmaceutically acceptable salt, precursor or metabolite thereof, I is a kind of Wherein X is halogen or H.
  2. 2. The method according to claim 1, wherein the benzazepine derivative is Kenpaullone.
  3. 3. The method according to claim 1, wherein the atherosclerosis or atherosclerotic cardiovascular disease is selected from one or more of coronary atherosclerosis, carotid atherosclerosis, cerebral atherosclerosis, aortic atherosclerosis, and lower limb atherosclerosis.
  4. 4. The method according to claim 3, wherein the atherosclerosis or atherosclerotic cardiovascular disease is selected from the group consisting of atherosclerosis-stable plaques and atherosclerosis-unstable plaques.
  5. 5. The method according to claim 1 to 4, wherein the composition is used for preventing or treating atherosclerosis of one or more of types I, II, III, IV, V or VI.
  6. 6. The method according to claim 1 to 4, wherein the method is used for preparing a medicament for stabilizing vulnerable atherosclerotic plaques.
  7. 7. The method according to claim 1 to 4, wherein the inhibition of plaque progression reduces lipid accumulation, inflammatory infiltrates and apoptosis.
  8. 8. The method according to claim 1 to 4, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
  9. 9. The method according to claim 1 to 4, wherein the drug is selected from the group consisting of an oral preparation or a parenteral preparation or the drug is selected from the group consisting of a capsule, a tablet, a granule, and a pill.
  10. 10. The method according to claim 1-4, wherein the drug is selected from one of oral liquid and emulsion, or one of injection, lyophilized powder for injection and inhalant.

Description

Use of benzazepine derivatives for the prevention or treatment of atherosclerosis Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of a benzazepine derivative in preventing or treating atherosclerosis. Background Benzazepine and its derivatives are an important class of heterocyclic compounds whose core structure is formed by the fusion of a benzene ring with a seven-membered nitrogen heterocycle (nitrogen-containing seven-membered ring). Such structures are widely found in a variety of drug molecules with important biological activities, such as play a role in the therapeutic field of neuropsychiatric and cardiovascular diseases. Kenpaullone is benzazepine, one of its derivatives, having the structure: IC50 < 1 μm has been demonstrated to have effects of reducing self-renewal and cell viability of breast cancer stem cells in vitro, demonstrating the potential to treat pathological pain and chronic itch in preclinical studies by modulating specific neural pathways. Atherosclerosis cardiovascular disease (Atherosclerotic cardiovascular disease, ASCVD) Is the primary cause of global death and disability, and brings heavy disease burden to society. Clinical events (such AS myocardial infarction and cerebral apoplexy) are mainly caused by unstable plaque rupture and secondary thrombosis of Atherosclerosis (AS). Although current standard treatments based on lipid lowering, anti-inflammatory and anti-platelet significantly improve patient prognosis, there is a sustained and significant "residual cardiovascular risk" (30% -40%). Currently, only lipid-lowering drugs or anti-inflammatory drugs are combined with antithrombotic drugs to delay the development of atherosclerosis, and accurate therapies for directly targeting and stabilizing the atherosclerotic plaques are lacking. The prior art does not have the application of benzazepine derivatives in preparing medicaments for treating atherosclerosis diseases. Disclosure of Invention To solve the above technical problems, the present invention provides the use of a benzazepine derivative in the preparation of a medicament for preventing or treating atherosclerosis and stabilizing atherosclerotic plaques, which is capable of delaying the progression of atherosclerotic diseases and stabilizing atherosclerotic plaques in a lipid-independent and anti-inflammatory manner. The mechanism of action is independent of lipid metabolism regulation and mainly exerts anti-atherosclerosis effects through the following pathways. The invention provides the use of a benzazepine derivative, which is a compound having the chemical structure of formula I or a pharmaceutically acceptable salt or a precursor or metabolite thereof, (Formula I). Wherein X is halogen or H. X is H, which corresponds to the absence of substitution on the benzene ring. Further, the benzazepine derivative is Kenpaullone. Kenpaullone the structural formula isKenpaullone is hereinafter sometimes abbreviated as KPL. Further, the atherosclerosis is selected from one or more of coronary atherosclerosis, carotid atherosclerosis, cerebral atherosclerosis, aortic atherosclerosis, lower limb atherosclerosis, preferably coronary atherosclerosis, carotid atherosclerosis. Further, the atherosclerosis is selected from atherosclerosis stabilized plaques or atherosclerosis unstable plaques, preferably atherosclerosis unstable plaques. Further, the atherosclerosis is more preferably atherosclerosis of normal lipid level but unstable plaque. In addition, atherosclerosis is generally classified clinically into eight types, in which early lesions of types I-III are regressive. Type IV-VI progressive lesions, wherein the type IV-V lesions are plaques with large necrotic nuclei and fibrous caps, with little calcification, can lead to lumen stenosis, type VI lesions have surface ulcers or intra-plaque hemorrhage, thrombosis, and also appear as thin and uneven fibrous caps, and the plaques are ruptured at the shoulders with the thinnest fibrous caps and the most foam cell infiltration in severe cases, and are considered to be atherosclerosis vulnerable plaques. Type VII lesions are simple calcified plaques. Type VIII lesions are fibrous plaques without a lipid core, which may be accompanied by a small amount of calcification. Type VIII lesions may result from lipid regression or changes within phase VI lesions. Based on the invention, the key pathological link of plaque instability can be directly interfered by regulating and controlling inflammatory microenvironment, reducing apoptosis cells and increasing the thickness of fibrous caps in the atherosclerosis plaque, and the formation of necrotic cores can be fundamentally inhibited by targeting the plaque microenvironment. Therefore, the medicament can be used for preventing or treating atherosclerosis I-VI, preferably one or more of I, II, III, IV, V or VI. The invention also provides application of the medi