CN-122010896-A - Bicyclol derivative, pharmaceutical composition thereof, preparation method and application thereof

Abstract

The invention discloses a bicyclo-ethanol derivative formula (I) or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition and application thereof, in particular application of the medicament in liver disease treatment.

Inventors

• PAN XIANDAO
• SUN HUA
• WANG LIN
• ZHANG LINGZHI
• SHEN LONGYING
• GAO CHEN
• Lin Xueman
• ZHAO TIANTIAN

Assignees

• 中国医学科学院药物研究所

Dates

Publication Date

20260512

Application Date

20241112

Claims (10)

1. 1. A class of bicyclo-alcohol derivatives having the following general formula (I): (I) Wherein: x is S, O; R 1 is H; R 2 is C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, aryl; Aryl is substituted or unsubstituted phenyl, furyl, thienyl, isoxazolyl, pyrimidinyl, pyrazinyl, naphthyl, chromonyl, quinolinyl, isoquinolinyl or pyridyl, the substituents on the phenyl ring being selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy; Or R 1 ＝R 2 ,R 1 、R 2 is H, methyl or morpholino.
2. 2. The bicyclol derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein, C 1-4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; c 1-4 alkoxy means methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy.
3. 3. The bicyclol derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein the benzene ring substituents are para, meta, ortho, and the number of substituents is mono-, di-or poly-substituted.
4. 4. A bicyclol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein said compound is selected from the group consisting of:
5. 5. A process for the preparation of a bicyclo-alcohol derivative according to any one of claims 1-4, characterized in that the process for the preparation of said compound is as follows: The reaction step a is that bicyclic alcohol is oxidized in oxidant to form bicyclic aldehyde, and the reaction step b is that substituted thiosemicarbazide or semicarbazide corresponding to the bicyclic aldehyde is condensed to obtain the compound shown in the general formula (I), X, R 1、 R 2 is defined in any one of claims 1-4.
6. 6. A pharmaceutical composition comprising a bicyclol derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
7. 7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is selected from the group consisting of injection, tablet, capsule, pill, powder, and paste.
8. 8. The pharmaceutical composition according to claim 7, wherein said pharmaceutical composition is selected from the group consisting of a controlled release dosage form, a sustained release dosage form, and various microparticle delivery systems.
9. 9. Use of a bicyclo-alcohol derivative according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of liver related diseases.
10. 10. The use according to claim 9, wherein said liver-related disorder is selected from the group consisting of hepatitis a, hepatitis b, hepatitis c, drug-induced liver disease, alcoholic liver disease, non-alcoholic liver disease, autoimmune liver disease, liver fibrosis in the progression of liver disease, cirrhosis, liver failure.

Description

Bicyclol derivative, pharmaceutical composition thereof, preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a novel bicyclo-ethanol derivative and salts thereof, a pharmaceutical composition containing the same, and application of the bicyclo-ethanol derivative and salts thereof in medicines for treating liver diseases. Background The natural product library is a structural framework and a bioactive source spring which are found to have diversity, and the structural frameworks can be directly applied to the structural optimization of innovative medicaments. Chronic liver disease is a common disease that seriously jeopardizes human health worldwide, including viral hepatitis, alcoholic hepatitis, non-alcoholic liver disease, autoimmune hepatitis, and drug-induced liver injury. China is the large country of liver diseases. The number of patients with liver injury and liver inflammation caused by various reasons in China is numerous, viral hepatitis is the main factor, statistics is provided, and the annual direct economic loss of chronic hepatitis (including liver fibrosis, liver cirrhosis, liver cancer and liver failure caused by later stage) in China reaches 9000 hundred million RMB. In recent years, the incidence of drug-induced liver diseases, alcoholic and non-alcoholic fatty liver diseases, and autoimmune liver diseases has also been on the rise year by year. Searching for safe and effective medicaments for preventing and treating liver diseases is always a hotspot in research and development of pharmaceutical companies in various institute of world. Bicyclol (Bicyclol), trade name of Barcenox, chemical name 4,4 '-dimethoxy-5, 6,5',6 '-dimethylenedioxy-2' -hydroxymethyl-2-methoxycarbonyl biphenyl. The structure of the bicyclo alcohol is derived from schisandrin which is an active ingredient of Chinese medicine schisandra chinensis, and researches show that schisandrin has obvious effect of reducing serum transaminase. The marketing of the bicyclo-ethanol creates huge economic and social benefits for the country and benefits the majority of hepatopathy patients. But the bicyclo-ethanol has poor water solubility and low bioavailability, and limits the clinical application to a certain extent. Sun Piaoyang and the like to synthesize dicyclo alcohol glycoside derivatives, improving the water solubility of dicyclo alcohol, wang Faping and the like to synthesize dicyclo alcohol adefovir dipivoxil, improving the antiviral activity of the derivatives, su Xian and the like to synthesize dicyclo alcohol amino acid esters, improving the water solubility of dicyclo alcohol, li Chuanbo and the like to synthesize dicyclo alcohol phosphate, improving the water solubility and liver protection effect, liu Lian and the like to synthesize dicyclo alcohol acetylcysteine esters, testing the antitumor activity of the dicyclo alcohol acetylcysteine esters, wu Song and the like to synthesize dicyclo alcohol methylenemorpholine derivatives and salts thereof, testing the liver cell protection effect and increasing the water solubility. These derivatives mostly improve the water solubility of the bicyclic alcohol with little research on liver protection. The semicarbazone can be complexed with heavy metal ions (such as copper ions, chromium ions and the like) to form a complex, so that the heavy metal is discharged out of the body, and the semicarbazone has a good liver protection effect. Disclosure of Invention The invention solves the technical problems that the compound with the general formula (I) and the pharmaceutically acceptable salt thereof are obtained by firstly oxidizing the bicyclic alcohol serving as a raw material and then condensing the bicyclic alcohol with substituted thiosemicarbazide or semicarbazide, and the preparation method, the pharmaceutical composition and the application thereof in medicaments for treating liver diseases. In order to solve the technical problems of the invention, the invention provides the following technical scheme: according to a first aspect of the present invention there is provided a bicyclol derivative of the general formula: Wherein: x is S, O; R 1 is H; R 2 is C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, aryl; The aryl is substituted or unsubstituted phenyl, furyl, thienyl, isoxazolyl, pyrimidinyl, pyrazinyl, naphthyl, chromonyl, quinolinyl, isoquinolinyl or pyridyl, the substituent on the benzene ring is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or R 1＝R2,R1、R2 is H, methyl or morpholino ring. The C1-4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl; The C1-4 alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. The positions of the substituent groups of the benzene ring are para position, meta position and ortho position, and the number of the substituent groups is monos