CN115960075A - Caffeic acid derivative and preparation method and application thereof - Google Patents
Caffeic acid derivative and preparation method and application thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 33
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of medicines, and relates to a caffeic acid derivative, a preparation method thereof and application thereof in preparing a medicine for treating nonalcoholic steatohepatitis (NASH). Animal test results show that the compound can obviously reduce glutamic-pyruvic transaminase (ALT) and glutamic-oxalacetic transaminase (AST) of mice, improve liver functions of the mice and can be used for treating NASH.
Description
Technical Field
The invention relates to a caffeic acid derivative, a preparation method thereof and application of the caffeic acid derivative as a medicine for treating nonalcoholic steatohepatitis (NASH).
Background
Non-alcoholic fatty liver disease (NAFLD) is a metabolic stress liver disease closely related to insulin resistance and genetic predisposition, and the disease spectrum includes non-alcoholic liver steatosis, non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis, hepatocellular carcinoma (HCC), and the like. The therapeutic goals of NASH are to delay, arrest, reverse the progression of the disease, improve clinical outcome, including reducing the incidence of cirrhosis and its complications, reducing the need for liver transplantation, improving survival rates, improving quality of life, and the like. However, the current intervention measures can benefit some patients by changing the life style (diet, exercise intervention and the like) to reduce weight, and no effective and safe NASH treatment medicine is confirmed by clinical tests. Even in patients with NASH complicated with liver fibrosis who undergo weight loss surgery, the degree of liver fibrosis in more than 50% of patients is not improved or even worsened, and therefore drug treatment for liver damage in NASH patients is important. Some key factors in the research and development process of the NASH new medicine are updated rapidly, china and the Food and Drug Administration (FDA) issue clinical research guidelines for the research and development of the NASH medicine to ask for comments, but the research and development of the NASH medicine are challenged due to complex disease pathogenesis, large patient heterogeneity and the like, although more than 50 treatment medicines are in the clinical research and development stage at present, the success rate of clinical trials is low, the clinical treatment requirements of patients in the field are not met, and a plurality of key pending problems still exist.
The pathogenesis of NASH has not been elucidated to date. Most scholars previously supported the theory of further damage to the liver caused by oxygen stress and lipid peroxidation centered on the mitochondrial Reactive Oxygen Species (ROS), i.e., "secondary hit". In recent years, NASH drugs based on various new theories and new targets have been gradually introduced into clinical research, but the complex pathogenesis, disease heterogeneity, diagnostic disorder, and choice of therapeutic endpoints thereof, etc., provide great challenges for the development of new NASH drugs.
The Farnesoid X Receptor (FXR) agonist drug obeticholic acid (OCA) from Intercept as the drug of the first globally filed application for the treatment of NASH was rejected by the Food and Drug Administration (FDA) in 6 months of 2020, since the expected benefit based on the surrogate histopathological test endpoint was not determined and the therapeutic benefit did not exceed the potential risk (increased LDL-C side effects). In 5 months 2020, GENFIT announced a phase III clinical failure of its peroxisome proliferator-activated receptor (PPAR) agonist GFT-505 (elafinidor), and stopped the development of this drug in the NASH field. Gilidder also announced phase III clinical failure of its GS-4997 (selonsertib).
The lead Guangshu et al (CN 102503932B) reported a gas signal molecule donor, and a series of compounds were synthesized by introducing a hydrogen sulfide releasing group to the structure of the compound, and had significant anti-inflammatory and/or anti-tumor activities. However, there is no disclosure and/or teaching in this patent document that the compounds can be used to treat non-alcoholic steatohepatitis.
Elena Garnie et al (JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,2017, 32 (1), 1012-1028) disclose the use OF caffeic acid derivatives as STAT3 and NF-kB inhibitors, and as useful in the treatment OF cancer. However, this journal reference also does not disclose and/or teach the compounds useful for the treatment of non-alcoholic steatohepatitis.
Therefore, the development of a new compound for treating nonalcoholic steatohepatitis, in particular to an anti-NASH medicine with independent intellectual property rights in China, has important economic benefits and social benefits.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: a caffeic acid derivative is provided, which can be used for treating non-alcoholic steatohepatitis (NASH).
In a first aspect of the present invention, there is provided a compound of formula I and pharmaceutically acceptable salts thereof, having the structure:
wherein: x is selected from NH and S.
Preferably, the compound of formula I has the following structure:
preferably, the pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromide, phosphate, sulphate, acetate, oxalate, tartrate, citrate, trifluoroacetate, methanesulphonate, ethanesulphonate, p-toluenesulphonate or salicylate;
in another aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Preferably, the pharmaceutical composition is an oral formulation, an intravenous or intramuscular injection formulation, a topical administration formulation, an inhalation formulation.
Preferably, the pharmaceutical composition is a tablet, a capsule, a sustained release agent, a controlled release agent, an injection powder, an injection solution, a suspension, an emulsion, a micro-pill, a powder, a micro-emulsion, a targeted preparation, an inhalant.
Another aspect of the present invention provides a process for preparing a compound of formula I, comprising the steps of:
dissolving a compound 1 and a compound 2 in an organic solvent, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine, stirring at room temperature for reaction, detecting by TLC (thin layer chromatography), performing reduced pressure spin-drying on the solvent after the reaction is finished, adding water, extracting for three times by using dichloromethane, combining organic layers, drying by using anhydrous sodium sulfate, filtering, concentrating, and purifying the obtained residue by using a silica gel column chromatography to obtain an intermediate;
adding the intermediate into anhydrous methanol containing sodium methoxide, stirring for reaction, detecting by TLC, adding dichloromethane after the reaction is finished, washing with 1M diluted hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying the obtained residue by silica gel column chromatography to obtain the compound of formula I.
In another aspect, the present invention relates to a compound of formula I and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a medicament for treating non-alcoholic steatohepatitis, wherein the compound of formula I has the following structure:
wherein: x is O, S, NH.
Preferably, the compound or the pharmaceutical composition comprising the same is capable of reducing alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST).
Defining:
in certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt, which is well known in the art. Examples of pharmaceutically acceptable salts are forms which form salts with compounds such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, acetic, oxalic, maleic, tartaric, citric, succinic or malonic, acetic, propionic, glycolic, pyruvic, oxalic, lactic, trifluoroacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic acid and the like.
The "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, isotonicity agents, and absorption delaying agents, and the like. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides a new caffeic acid derivative, widens the range of the existing NASH-resistant compound, and can be continuously optimized as a lead compound;
(2) The compound of the invention can effectively reduce alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) and improve the liver function of mice.
Drawings
FIG. 1 is a graph showing the trend of the compound of the present invention on alanine Aminotransferase (ALT) after CAS-1 administration;
FIG. 2 shows the trend of the compound CAS-1 of the present invention towards aspartate Aminotransferase (AST) after administration;
FIG. 3 is a graph showing the trend of the compound of the present invention on alanine Aminotransferase (ALT) after CAS-2 administration;
FIG. 4 shows the trend of the compound CAS-2 of the present invention towards aspartate Aminotransferase (AST) after administration.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are provided to better illustrate the present invention and are not intended to limit the scope of the present invention. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 Synthesis of the Compound CAS-1
Diacetyl caffeic acid (compound 1, 2.64g) and compound 2 (2.26 g) were dissolved in chloroform (50 ml), followed by addition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 3.8 g) and 4-dimethylaminopyridine (DMAP, 122 mg), reaction stirred at room temperature for 24 hours, TLC detection, after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, each was extracted three times with 100ml of dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was subjected to silica gel column chromatographyPurification (dichloromethane: methanol = 10) gave 3.15g of product. The above compound was added to 50ml of anhydrous methanol containing 1.6g of sodium methoxide, stirred for 24 hours, checked by TLC, and after the reaction was completed, 50ml of dichloromethane was added, followed by washing with 20ml of 1M diluted hydrochloric acid 2 times. Dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 10) to obtain 2.31g of a product. 1 H NMR(400MHz,DMSO-d 6 )δ9.46(s,1H),9.43(s,1H),7.50(d,1H),6.67-7.30(m,7H),6.30(d,1H),5.65(s,1H)。MS(ESI)m/z:388.99[M+H] + 。
EXAMPLE 2 Synthesis of the Compound CAS-2
Diacetyl caffeic acid (compound 1,2.64g) and compound 3 (2.25 g) were dissolved in chloroform (50 ml), followed by addition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 3.8 g) and 4-dimethylaminopyridine (DMAP, 122 mg), stirred at room temperature for 24 hours, checked by TLC, after the reaction was completed, the solvent was dried under reduced pressure, 50ml of water was added, extracted three times with 100ml of dichloromethane respectively, after the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 10) to give 3.07g of a product. The above compound was added to 50ml of anhydrous methanol containing 1.6g of sodium methoxide, stirred for 24 hours, checked by TLC, and after the reaction was completed, 50ml of dichloromethane was added, followed by washing 2 times with 20ml of 1M diluted hydrochloric acid each time. Dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 10) to obtain 2.12g of a product. 1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),9.45(s,1H),9.24(s,1H),6.67-7.44(m,8H),6.33(d,1H),5.69(s,1H)。MS(ESI)m/z:387.02[M+H] + 。
EXAMPLE 2 inhibitory Activity of the Compounds of the present invention against alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST)
C57BL/6J mice are selected, males are randomly grouped, the animals except a normal group (a control group) are continuously fed with high-fat feed for 10 weeks, gavage is started after 10 weeks, CAS-1 or CAS-230.0mg/kg (a low dose group), CAS-1 or CAS-260.0mg/kg (a high dose group) or physiological saline with the same volume (a normal control and a model) is administered, the administration is performed once a day after 3 times, fasting is performed for 12 hours, then blood is taken from orbital venous plexus behind the mice, and the content change of ALT and AST in serum is determined by a blood biochemical analyzer.
The results are shown in FIGS. 1 to 4. Wherein: control group means normal mice; db/db represents a group which was continuously fed with the high fat diet for 10 weeks, but was not administered; db/db + CAS-1 (low) means a group that was continuously fed with high fat diet for 10 weeks and was gavaged with CAS-1 or CAS-230.0mg/kg, 1 time/d; db/db + CAS-1 (low) means a group that was continuously fed with high fat diet for 10 weeks and was gavaged with CAS-1 or CAS-260.0mg/kg, 1 time/d. Data are expressed as X ± SEM (n = 7-9). Represents db/m mice compared to model group, { P } <0.01; db/db mice, # P <0.05, # P <0.01, compared to control groups. Multiple comparisons were analyzed by two-way analysis of variance and Dunnett's test.
As can be seen from FIGS. 1 to 4, the compound of the present invention can significantly reduce the levels of glutamic-pyruvic transaminase (FIG. 1, FIG. 3) and glutamic-oxalacetic transaminase (FIG. 2, FIG. 4) and improve the liver function of db/db mice, which indicates that the compound of the present invention has a certain therapeutic effect on NASH, can be used for preparing a drug for treating or preventing NASH, and provides more options for clinical treatment of NASH.
Claims (10)
1. A compound of formula I or a pharmaceutically acceptable salt thereof, having the structure:
wherein: x is selected from NH and S.
2. A compound of formula I according to claim 1, having the structure:
3. the pharmaceutically acceptable salt of the compound of formula I according to claim 1 or 2, characterized in that: the pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromide, phosphate, sulphate, acetate, oxalate, tartrate, citrate, trifluoroacetate, methanesulphonate, ethanesulphonate, p-toluenesulphonate or salicylate.
4. A process for preparing a compound of formula I, comprising the steps of:
dissolving a compound 1 and a compound 2 in an organic solvent, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine, stirring at room temperature for reaction, detecting by TLC (thin layer chromatography), performing reduced pressure spin-drying on the solvent after the reaction is finished, adding water, extracting for three times by using dichloromethane, combining organic layers, drying by using anhydrous sodium sulfate, filtering, concentrating, and purifying the obtained residue by using a silica gel column chromatography to obtain an intermediate;
adding the intermediate into anhydrous methanol containing sodium methoxide, stirring for reaction, detecting by TLC, adding dichloromethane after the reaction is finished, washing with 1M diluted hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying the obtained residue by silica gel column chromatography to obtain the compound of formula I.
5. A pharmaceutical composition comprising a compound of formula I as described in any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, wherein: the pharmaceutical composition is an oral preparation, an intravenous or intramuscular injection preparation, a topical administration preparation and an inhalation preparation.
7. The pharmaceutical composition of claim 5, wherein: the pharmaceutical composition is tablets, capsules, sustained release agents, controlled release agents, injection powder injections, injection solutions, suspensions, emulsions, micro-pills, powders, micro-emulsions, targeted preparations and inhalants.
8. The use of a compound of formula I and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment of non-alcoholic steatohepatitis, wherein the compound of formula I has the structure:
wherein: x is selected from O, S, NH.
9. Use according to claim 8, characterized in that: the compound of formula I has the following structure:
10. use according to claim 8 or 9, said compound being capable of reducing alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST).
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