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CN-121974870-A - Benzisoselenazolone-statin bonding molecules, and preparation method and application thereof

CN121974870ACN 121974870 ACN121974870 ACN 121974870ACN-121974870-A

Abstract

The application discloses a benzisoselenazolone-statin bonding molecule, a preparation method and application thereof. The bonding molecule is formed by chemical bonding of statin pharmacophore (3, 5-dihydroxyvaleric acid or lactone structure thereof) and ebselen pharmacophore (benzisoselenazolone). The application provides a plurality of synthesis paths comprising 'connection before cyclization' and 'construction of a mother nucleus before coupling', and a plurality of specific compounds such as IA-6, IB-6, IIA-7, IIIB-5 and the like are efficiently prepared. In-vitro activity experiments show that the compounds can obviously reduce the content of Triglyceride (TG) in liver cells induced by oleic acid and palmitic acid at the cellular level, have low cytotoxicity, and have partial compound activity equivalent to that of atorvastatin. The application provides a brand new lead compound for developing a novel NASH therapeutic drug with lipid-lowering, antioxidant and anti-inflammatory dual activities.

Inventors

  • REN JIAQIANG
  • LI LIJUN
  • ZHAI TING
  • YE MENGHAN
  • SU YAOWU
  • CHEN YONG

Assignees

  • 湖北大学

Dates

Publication Date
20260505
Application Date
20260129

Claims (10)

  1. 1. Benzisoselenazolone-statin bonding molecules or pharmaceutically acceptable salts thereof, wherein the chemical structural formula of the bonding molecules is shown as formula (I) Or (II) As shown in the drawing, wherein, R 1 ,R 2 is selected from the group consisting of H, CH 3 , 、 、 、 、 、 、 、 、 、 、 Any one of them.
  2. 2. The benzisoselenazolone-statin binding molecule or a pharmaceutically acceptable salt thereof according to claim 1, wherein the benzisoselenazolone-statin binding molecule is selected from any one of the following (a) - (g): (a) Compound IA-6 has the chemical structural formula ; (B) The compound IB-6 has the chemical structural formula ; (C) The chemical structural formula of the compound IIA-7 is ; (D) Compound IIB-7 with chemical structural formula ; (E) Compound IIC-7 with chemical structural formula ; (F) The chemical structural formula of the compound IIIA-5 is ; (G) The chemical structural formula of the compound IIIB-5 is 。
  3. 3. The benzisoselenazolone-statin binding molecule or a pharmaceutically acceptable salt thereof according to claim 2, wherein the process for the preparation of compound IA-6 or IB-6 comprises the steps of: (i) Reacting IA-1 or IB-1 with thionyl chloride to generate IA-2 or IB-2; (ii) Reacting IA-2 or IB-2 with (4R-Cis) -6-aminoethyl-2, 2-dimethyl-1, 3-dioxolane-hexanoate tert-butyl ester to form amide intermediate IA-3 or IB-3; (iii) The intermediate IA-3 or IB-3 and selenium powder are subjected to cyclization reaction in the presence of cuprous iodide, phenanthroline catalysis and potassium carbonate to construct a benzisoselenazolone structure, so as to obtain a key intermediate IA-4 or IB-4; (iv) Hydrolyzing intermediate IA-4 or IB-4 under acidic condition to obtain IA-5 or IB-5; (v) Alkaline hydrolysis is carried out on IA-5 or IB-5 to finally obtain a target product IA-6 or IB-6; ; Wherein R is H or CH 3 , when R is H, the reaction formula represents the synthetic route of IA-6, I-2, I-3, I-4, I-5, I-6 are respectively corresponding to IA-2, IA-3, IA-4, IA-5, IA-6, when R is CH 3 , the reaction formula represents the synthetic route of IB-6, and I-2, I-3, I-4, I-5, I-6 are respectively corresponding to IB-2, IB-3, IB-4, IB-5, IB-6.
  4. 4. The benzisoselenazolone-statin binding molecule or a pharmaceutically acceptable salt thereof according to claim 2, wherein the process for the preparation of compound IIA-7, IIB-7 or IIC-7 comprises the steps of: (i) The method comprises the steps of (1) carrying out esterification reaction on an initial raw material IB-1 and methyl iodide in the presence of alkali to obtain an intermediate II-1; (ii) Carrying out benzyl bromination reaction on the intermediate II-1 and N-bromosuccinimide in the presence of azodiisobutyronitrile to generate an intermediate II-2; (iii) Respectively reacting the intermediate II-2 with different nucleophiles, and introducing phenoxy, anilino or naphthoxy to obtain intermediates IIA-3, IIB-3 or IIC-3; (iv) Hydrolyzing the intermediate IIA-3, IIB-3 or IIC-3 under alkaline conditions to obtain corresponding carboxylic acid intermediate IIA-4, IIB-4 or IIC-4; (v) Activating the intermediate IIA-4, IIB-4 or IIC-4, and then carrying out amidation reaction with (4R-Cis) -6-aminoethyl-2, 2-dimethyl-1, 3-dioxolane-hexanoic acid tert-butyl ester to form an amide bond to obtain the intermediate IIA-5, IIB-5 or IIC-5; (vi) The intermediate IIA-5, IIB-5 or IIC-5 and selenium powder are subjected to cyclization reaction in the presence of cuprous iodide, phenanthroline catalysis and potassium carbonate to construct a benzisoselenazolone heterocyclic structure, and the intermediate IIA-6, IIB-6 or IIC-6 is obtained; (vii) Sequentially carrying out acid catalysis and alkali catalysis to carry out two-step hydrolysis reactions, respectively breaking different acid and alkali sensitive functional groups in molecules, and finally obtaining target compounds IIA-7, IIB-7 or IIC-7 containing 3, 5-dihydroxycarboxylic acid structures; ; Wherein R is selected from 、 、 Any one of when R is When II-4, II-5, II-6, II-7 are IIA-4, IIA-5, IIA-6, IIA-7 respectively, when R is When II-4, II-5, II-6, II-7 are respectively IIB-4, IIB-5, IIB-6, IIB-7, when R is In the process, II-4, II-5, II-6 and II-7 are respectively IIC-4, IIC-5, IIC-6 and IIC-7.
  5. 5. The benzisoselenazolone-statin binding molecule or pharmaceutically acceptable salt thereof according to claim 2, wherein the method of preparation of compound IIIA-5 or IIIB-5 comprises the steps of: (i) IA-1 or IB-1 is used as a starting material, is firstly converted into acyl chloride, and then is subjected to amidation reaction with methyl paraaminobenzoate to obtain an intermediate IIIA-1 or IIIB-1; (ii) The intermediate IIIA-1 or IIIB-1 and selenium powder are subjected to cyclization reaction in the presence of cuprous iodide, phenanthroline and alkali to obtain IIIA-2 or IIIB-2; (iii) Alkaline hydrolysis is carried out on the ester intermediate IIIA-2 or IIIB-2 to obtain a corresponding carboxylic acid intermediate IIIA-3 or IIIB-3; (iv) In the presence of HATU, carrying out amidation reaction on a carboxylic acid intermediate IIIA-3 or IIIB-3 and (4R-Cis) -6-aminoethyl-2, 2-dimethyl-1, 3-dioxolane-hexanoic acid tert-butyl ester to obtain an intermediate IIIA-4 or IIIB-4; (v) Hydrolyzing the intermediate IIIA-4 or IIIB-4 under acidic conditions to produce a lactone form of the target compound IIIA-5 or IIIB-5; ; wherein R is H or CH 3 , if R is H, III-2, III-3, III-4, III-5 correspond to IIIA-2, IIIA-3, IIIA-4, IIIA-5, and if R is CH 3 , III-2, III-3, III-4, III-5 correspond to IIIB-2, IIIB-3, IIIB-4, IIIB-5.
  6. 6. An intermediate for preparing the benzisoselenazolone-statin binding molecule of claim 1 or a pharmaceutically acceptable salt thereof, comprising at least one of the following (a) - (c): (a) Compound I-5 with structural formula ; (B) Compound II-6 with structural formula ; (C) Compound III-4 with structural formula ; Wherein R 1 is selected from H or CH 3 ; R 2 is selected from 、 、 Any one of them; R 3 is selected from H or CH 3 .
  7. 7. A pharmaceutical composition comprising a benzisoselenazolone-statin binding molecule of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  8. 8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable carrier or excipient comprises at least one of polysorbate 80, poloxamer, cyclodextrin, polyethylene glycol, ethanol, ascorbic acid, sulfite, EDTA, self-microemulsions, liposomes, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, polyvinylpyrrolidone, hypromellose, starch slurry, crospovidone, sodium carboxymethyl starch, low substituted hyprolose, magnesium stearate, micro-powder silica gel, talc, polyvinyl alcohol, phthalate, water for injection, physiological saline, phosphate buffer, glycerin, polyethylene glycol.
  9. 9. Use of a benzisoselenazolone-statin binding molecule or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the manufacture of a medicament for the prevention and/or treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.
  10. 10. The use of claim 9, wherein the dosage form of the medicament comprises at least one of a tablet, a capsule, a granule, an oral liquid formulation, or an injection.

Description

Benzisoselenazolone-statin bonding molecules, and preparation method and application thereof Technical Field The application relates to the technical field of pharmaceutical chemicals, in particular to a benzisoselenazolone-statin bonding molecule, a preparation method and application thereof. Background Non-alcoholic fatty liver disease (NAFLD) and its more severe stage, non-alcoholic steatohepatitis (NASH), have become an increasingly public health problem worldwide. NASH is characterized by liver fat accumulation, inflammatory response, and hepatocellular damage, and can further develop into liver fibrosis, cirrhosis, and even hepatocellular carcinoma. At present, a specific drug aiming at the etiology treatment of the NASH is not clinically available, and the development of safe and effective therapeutic drugs is urgent. The statin is the most studied lipid-lowering drug and proved to be the most effective at present, and clinical test data show that the statin can effectively delay the disease progression of NASH. However, the chemical structure of traditional statins is primarily modified around their lipophilic parent nucleus to regulate their lipid solubility and tissue distribution. However, too strong lipophilicity may cause accumulation of the drug in non-target tissues such as muscles, thereby increasing the risk of adverse reactions such as myalgia, rhabdomyolysis, etc. (development of statin-related muscle symptoms, pharmaceutical progress, 2020,44 (4), 303-312). In addition, existing statin drugs are not specifically designed for multiple pathological mechanisms of NASH (lipid metabolic disorders, oxidative stress, inflammation), have limited antioxidant, anti-inflammatory and anti-fibrotic efficacy in NASH treatment, and lack sufficient targeting and synergy. Therefore, there is a need to design and synthesize a new class of compounds capable of simultaneously and efficiently targeting and synergistically improving NASH multiple core pathological links, and provide theory and material basis for developing next-generation efficient and safe NASH therapeutic drugs. Disclosure of Invention Ebselen (2-phenyl-1, 2-benzisoselenazol-3 (2H) -one, ebselen with chemical structural formula) Can simulate the function of glutathione peroxidase (GSH-Px), and has anti-inflammatory and antioxidant effects. The structure-activity relationship of Ebselen is that ① has a structure (benzene ring) for protecting Se-C bond, which can keep Ebselen low toxicity and avoid Se atom release, ② Se-N bond is a site for simulating glutathione peroxidase activity, and the conjugation effect of ③ carbonyl group and double bond can enhance Se atom electrophilicity. Ebselen can effectively improve various indexes related to NASH and inhibit the development of hepatic fibrosis. Based on the above, the application aims to provide a benzisoselenazolone-statin bonding molecule, and a preparation method and application thereof. The application creates a novel bonding molecule by chemical bonding between the pharmacophore of statin and the pharmacophore of Ebselen (benzisoselenazolone). The bonding molecule is expected to cooperatively exert the powerful lipid-lowering effect of statin and the powerful antioxidant and anti-inflammatory effect of Ebselen, so that the cooperative intervention on the multiple pathological pathways of NASH is realized at the molecular level, and a novel lead compound and a solution are provided for developing high-efficiency and safe NASH therapeutic drugs. For this purpose, the application provides the following technical scheme: In a first aspect, the present application provides a benzisoselenazolone-statin binding molecule or a pharmaceutically acceptable salt thereof, wherein the binding molecule has a chemical structural formula as shown in formula (I) Or (II)As shown in the drawing, wherein, R 1,R2 is selected from H, CH 3,、、、、、、、、、、Any one of them. The bonding molecule is a single bonding molecule formed by bonding statin lipid-lowering pharmacophores and ebselen (Ebselen) antioxidant/anti-inflammatory pharmacophores through a specific chemical link (Linker). Based on the structure, the bonding molecule can simultaneously exert a potent lipid-lowering effect (HMG-CoA reductase is inhibited by statin pharmacophore) and a potent antioxidant and anti-inflammatory effect (active oxygen is eliminated and inflammatory mediators are inhibited by benzisoselenazolone pharmacophore), and the bonding molecule can synergistically intervene in non-alcoholic steatohepatitis (NASH) from a plurality of key pathological links. Compared with statin drugs or Ebselen alone or by physically mixing the two, the bonding molecule or the pharmaceutically acceptable salt thereof shows that the bonding molecule formed by the chemical bonding may show more optimized tissue distribution in pharmacokinetics through computer simulation calculation and screening, and is expected to reduce side effect risks such as muscle toxi