CN117304033A - Caffeic acid derivative and preparation method thereof, pharmaceutical composition and application - Google Patents

Caffeic acid derivative and preparation method thereof, pharmaceutical composition and application Download PDF

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CN117304033A
CN117304033A CN202210701582.0A CN202210701582A CN117304033A CN 117304033 A CN117304033 A CN 117304033A CN 202210701582 A CN202210701582 A CN 202210701582A CN 117304033 A CN117304033 A CN 117304033A
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cancer
hydrogen
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谢平
季鸣
焦晓臻
杜婷婷
刘晓宇
金晶
王哲
李文萱
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Abstract

The invention belongs to the technical field of medicines, and discloses a caffeic acid derivative, a preparation method thereof, a pharmaceutical composition and application thereof. In particular to a compound of a formula (I) or an isomer thereof and pharmaceutically acceptable salts thereof, and a preparation method thereof. A novel pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier. The invention also discloses application of the compounds in preventing and/or treating immune disorder, inflammation, neurodegenerative diseases, aging and/or tumor. The tumor comprises glioma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid carcinoma, head and neck tumor, cervical cancer, ovarian cancer, pancreatic cancer, prostatic cancer, colon cancer, rectal adenocarcinoma, leukemia and lymphoma.

Description

Caffeic acid derivative and preparation method thereof, pharmaceutical composition and application
Technical Field
The invention relates to a caffeic acid derivative, pharmaceutically acceptable salts, polycrystal and eutectic crystals, precursors or derivatives/probes with the same biological functions, a preparation method of the caffeic acid derivative, a pharmaceutical composition containing the caffeic acid derivative and the polycrystal and the eutectic crystals, and application of the caffeic acid derivative, the polycrystal and the eutectic crystals as medicines for preventing/treating tumors, treating autoimmune diseases, inflammatory diseases, neurodegenerative diseases and anti-aging, and belongs to the technical field of medicines.
Background
The World Health Organization (WHO) cancer research institute 2021 issued global cancer reports, and based on the cancer data issued by the world health organization, the total number of new cancers in 2020 of our country was 4,568,754, and the number of deaths from cancer was 3,002,899. China is the first people in the world, and the number of new cancer patients is higher than the global average in compound annual growth rate. The number of new-born patients in China reaches 480 ten thousand in 2022 and 520 ten thousand in 2025.
The current medical community has demonstrated that: inflammation is closely related to the occurrence and development of cancer. For example, infection with helicobacter pylori in the stomach tends to increase the risk of gastric cancer, nasopharyngeal carcinoma is associated with herpes virus infection, and liver cancer is associated with hepatitis virus infection; systemic inflammation such as obesity and depression is also related to the incidence of tumors and poor curative effect of anticancer treatment; at the same time, the clinical treatment effect of the tumor is affected to different degrees by the inflammatory response induced by the treatment. Although some anti-inflammatory agents (aspirin, statins) can significantly reduce the incidence of cancer and the risk of death; however, some pro-inflammatory cytokines or stimulators may promote immune cell penetration into the infected tissue, thereby significantly enhancing the effect of tumor treatment, suggesting that inflammation is a "double-edged sword". How to regulate inflammation to improve the effect of cancer treatment remains an important scientific problem in the current international frontier field. (Huakan Zhao, lei Wu, guifang Yan et al Inflammation and tumor progression: signaling pathways and targeted interaction. Signal Transmission TargetTher.2021,6 (1): 263.).
The caffeic acid compound widely exists in active natural products, has various biological activities such as antibiosis, antioxidation, anti-inflammatory, anti-tumor and the like, has very wide research prospect, is used for long-term research on structural optimization and anti-tumor activity of the natural products and structure-activity relation research for treating autoimmune diseases and anti-inflammatory, is helpful for finding out a lead with stronger tumor inhibition activity, higher activity for treating autoimmune diseases and inflammatory diseases and lower toxic and side effects than the original natural products aiming at structural modification of the natural products, and further becomes an anti-tumor and anti-inflammatory immune medicament.
The potential targets of the caffeic acid derivatives designed in the invention are summarized as follows:
endothelial Growth Factor Receptor (EGFR): mutant activation of EGFR is an important factor in causing abnormal biological activity in tumor cells, wherein the T790M mutation in EGFR is a change in one base pair from cytosine (C) to thymine (T), i.e., substitution of threonine at 790 in EGFR tyrosine kinase function with methionine, which can cause EGFR to be re-activated, resulting in resistance to Tyrosine Kinase Inhibitors (TKIs). We have found that the compound binds well to the protein after the mutated protein is docked with such natural products and derivatives by computer aided design (discovery studio), suggesting that: such derivatives may be candidates for screening for this target.
The PI3K/Akt/mTOR signaling pathway is used as one of important intracellular signaling pathways, plays a key role in inhibiting apoptosis and promoting proliferation in cells by influencing the activation states of various downstream effector molecules, and is closely related to the occurrence and development of various human tumors.
Cyclin dependent kinase CDK2: CDK2 is a member of the protein kinase family, relying on binding to cyclin to perform a key function in the progression of the cell cycle. The different CDK cyclin complexes phosphorylate specific target proteins to trigger the smooth progression of the cell cycle phases. In the absence of cyclin or CDK inhibitors, they lose activity, arrest of cell proliferation, and even die. CDKs regulate the operation of the cell cycle by modulating target protein phosphorylation.
Caspase-3 is a Caspase protein that interacts with both Caspase-8 and Caspase-9. Encoded by the casp3 gene. Elevated levels of caspase-3, p17 fragments in blood are a marker of recent myocardial infarction. There are studies now showing that caspase-3 may play an important role in embryonic and hematopoietic stem cell differentiation, apoptosis. Studies have shown that the expression level of caspase-3 in patients with head and neck cancer and breast cancer is abnormally increased, so that the expression is reduced, and the occurrence and development of cancer can be reduced to a certain extent.
Histone-lysine N-methyltransferase EZH2: EZH2 is an enzyme encoded by the human EZH2 gene. Two transcript variants of the gene have been identified as encoding different subtypes; genetic sequence alterations are essentially different from epigenetic modification abnormalities. Because once a DNA sequence is mutated, it is difficult to repair the gene or to eliminate the mutated gene product. But epigenetic modification abnormalities can potentially be reversed by their associated chromatin modification enzyme inhibitors. Therefore, it is important to define the action mechanism of epigenetic modification enzymes in tumor cells, and thus provide a corresponding therapeutic means for preventing epigenetic modification variation. Currently five drugs in total are in clinical phase I/II studies for EZH2 inhibitors.
Histone deacetylase (histone deacetylase, HDAC): is a protease and plays an important role in structural modification of chromosome and regulation and control of gene expression. In general, acetylation of histones facilitates dissociation of DNA from the histone octamers, relaxing the nucleosome structure, allowing specific binding of various transcription factors and co-transcription factors to DNA binding sites, activating transcription of genes. Within the nucleus, histone acetylation is in dynamic equilibrium with histone deacetylation processes and is regulated by histone acetyltransferase (histone acetyltransferase, HAT) and histone deacetylase (histone deacetylase, HDAC) together.
Cancer immunotherapy is an increasingly effective cancer treatment strategy, T cells play a key role in immunotherapy, a plurality of immune checkpoints are treasures to be discovered, and after the therapeutic effects of CTLA-4 and PD-1/PD-L1 monoclonal antibodies are confirmed, the monoclonal antibodies compete strongly on the tracks, so that the immune checkpoints should be focused on other immune checkpoints, and the functions of the immune checkpoints determine the therapeutic effects of the immunotherapy.
T cell survival and development is affected by TCR signaling, which is dependent on Src Family Kinases (SFKs). Lck is an important member of SFK and is expressed in most of the life cycle of T cells. Furthermore, lck plays an important role in activating TCR signaling pathways to activate T cells. CSK is a key regulator of SFK, its phosphorylation on Lck (Tyr 505) deactivates Lck, which inhibits T cell activation by TCR. Thus, CSK and p-Lck (Tyr 505) may be effective targets for future immunomodulatory treatments.
IDO-1, indoleamine 2, 3-dioxygenase, a key enzyme that breaks down tryptophan, is expressed in a variety of tumor cells, mediating tumor-induced immunosuppression.
TIM-3 is a class of T cell surface inhibitory molecules capable of causing failure of T cells during cancer and chronic viral infection. It is only up-regulated in cd4+ helper T cell 1 (Th 1) and cd8+ cytotoxic T cells, participating in synergistic inhibition. TIM-3, when activated, inhibits effector T cell activity and causes peripheral tolerance.
VISTA, also known as B7-H5, is expressed primarily in hematopoietic cells, the expression of which is regulated by antigen presenting cells and T cells in bone marrow.
KIR kills cell immunoglobulin-like receptors, and expresses receptors on NK cells and parts of T cell surfaces, and can specifically recognize cell surface MHC-class I molecules, thereby exerting an immunomodulatory effect.
LAG-3, lymphocyte activating gene 3 protein, is one kind of immunonegative regulating molecule distributed in activated T cell, NK cell and dendritic cell and capable of combining with MHC-II molecule, and has the functions of maintaining stable internal environment and participating in immunoregulation, and is closely related to tumor development and development.
4-1BB, also known as CD137, is a member of the TNF family expressed on the surface of activated T cells, an inducible T cell surface receptor, and 4-1BB and its ligand are another important costimulatory molecules beyond the CD28/B7 costimulatory signaling pathway.
ACAT1 belongs to a specific thiolase superfamily, and has a Chinese name of acetoacetyl CoA sulfurylase, also called Acetyl CoA Acetyl Transferase (ACAT), and reports that ACAT1 is expressed in tumor cells to usually represent an abnormal state and plays a vital role in the occurrence and development of tumors. The up-regulation mechanism of ACAT1 activity in different human cancer cells is worth studying. High expression of ACAT1 reduces its overall survival; the excessive expression of ACAT1 in MDA-MB-231 human breast cancer cells can lead ketone body to be reused to drive the progress and metastasis of tumor, so that the research on the modification of caffeic acid natural products with ACAT1 as a target point can possibly find novel antitumor drugs.
The antioxidant and anti-inflammatory immunity aspects are related as follows:
because caffeic acids are widely present in the polyphenols secondary metabolites of plants, they have very strong antioxidant and anti-inflammatory properties. The activity of the compound for removing 1, 1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radical is 2-3 times of that of vitamin C and E, and the activity of the compound for removing superoxide anion free radical is 10-30 times of that of vitamin C and E. In terms of anti-inflammatory effect, it has anti-inflammatory activity against carrageenan-induced rat plantar swelling inflammation model. The mechanism can inhibit interleukin-8 (IL-8) production by eliminating intracellular ROS, inhibiting p38 cascade phosphorylation and up-regulating nuclear factor kB (nuclear factor kappa-B, NF-kB) signal pathway, thereby playing an anti-inflammatory role. In addition, the inflammatory response of tissues can be reduced by regulating and controlling the mitogen-activated protein kinase/ERK/c-Jun amino terminal kinase signal pathway, so that the novel therapeutic agent for treating rheumatoid arthritis can be obtained. Meanwhile, has stronger liver function protection effect, and can effectively reduce CCl 4 Induced acute liver injury produces TNF- α, IL-6 and IL-1 β inflammatory factors, the mechanism of which is through nuclear factor E-2 related factor 2 (nuclear factor erythroid-related factor 2, nrf 2) mediated antioxidant and inhibition of activation of Nod-like receptor family thermal protein domain 3 inflammatory bodies for protection of acute liver injury. Such compounds may also reduce Methotrexate (MTX) induced hepatotoxicity by increasing B-cell lymphoma-2 (Bcl 2) expression and inhibiting cyclooxygenase-2, inducible nitric oxide synthase, bax (Bcl 2 associted x, bax) and caspases 3, 9 mediated inflammatory responses. Neurodegenerative disease A Pathological studies of Alzheimer's disease and Parkinson's disease have shown that chronic oxidative stress and inflammatory responses can lead to neuronal damage. Based on the strong antioxidant and anti-inflammatory effects of the phenylacrylic acid, the phenylacrylic acid has good nervous system protecting effect. Some clinical and preclinical studies have shown that caffeic acid natural products exhibit good therapeutic effects on alzheimer's disease and parkinson's disease. Can improve hypomnesis and death of hippocampal cells after transient global cerebral ischemia by increasing Bcl2, superoxide dismutase 2 and platelet-endothelial cell adhesion molecule CD31 expression, and reducing endothelin-1 expression to improve spatial memory, and prevent CA1 pyramidal cell death after bilateral common carotid artery occlusion. Prevention of saturated Free Fatty Acid (FFA) -induced lipotoxicity by activating SIRT 1-mediated mitochondrial function by reducing ROS production and increasing mitochondrial mass and mitochondrial membrane potential, alleviating oxidative stress and mitochondrial dysfunction; significantly reducing pro-apoptotic protein Bax expression, thereby reducing mitochondrial-mediated caspase-dependent apoptosis.
Although caffeic acid natural products have been demonstrated to have a variety of biologically active effects as above, their exact mechanism of action and structure-activity relationship need to be studied further, their structural derivatives need to be synthesized, and their mode of action and diseases useful for treatment, especially against inflammation-related, tumor, autoimmune diseases, neurodegenerative diseases, aging, etc.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide caffeic acid derivatives with excellent therapeutic effect and low toxicity, which have anti-inflammatory, anti-tumor, anti-autoimmune, neurodegenerative and anti-aging activities, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, polymorphs thereof or co-crystals thereof.
Another technical problem to be solved by the present invention is to provide a process for the preparation of such compounds.
Yet another technical problem underlying the present invention is to provide pharmaceutical compositions containing such compounds.
Still another technical problem to be solved by the present invention is to provide the use of such compounds for the preparation of medicaments for the anti/prophylaxis of tumors, and for the treatment of immune-related diseases, inflammatory diseases, neurodegenerative diseases and anti-aging.
In order to solve the technical problems of the invention, the following technical scheme is adopted:
a compound of formula (I) or an isomer thereof and a pharmaceutically acceptable salt thereof;
R 1 and R is 2 Independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, trihalogen C 1-6 Alkyl, trihalogen C 1-6 Alkoxy, C 1-6 An alkoxymethyleneoxy group;
Or R is 1 And R is 2 Selected from-O (CH) 2 ) n O-and is linked to its substituted phenyl group to form a ring; n is selected from 1, 2 or 3;
R 3 and R is 4 Independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, trihalogen C 1-6 Alkyl, trihalogen C 1-6 An alkoxy group;
R 5 selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxymethyl group, C 0-6 An alkylamino group;
R 6 selected from hydrogen, hydroxy, C 1-6 Alkyl, C 0-6 Alkylamino, C 1-6 Alkylcarbonyloxy, C 1-6 Alkoxycarbonyl, o=;
R 7 ，R 8 ，R 9 independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylamine sulfonic acidAcyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, trihalogen C 1-6 Alkyl, trihalogen C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, C 1-5 Alkanoyl, C 1-6 An alkoxymethyleneoxy group; or R is 8 And R is 9 Selected from-O (CH) 2 ) n’ O-and is linked to its substituted phenyl group to form a ring; n' is selected from 1, 2 or 3;
trihaloC 1-6 Alkyl and trihalogen C 1-6 The trihalogen in the alkoxy group means that the halogen contains 3 halogens including F 3 C 1-6 Alkyl, br 3 C 1-6 Alkyl, cl 3 C 1-6 Alkyl, I 3 C 1-6 Alkyl, F 2 BrC 1-6 Alkyl, F 2 ClC 1-6 Alkyl, F 2 IC 1-6 Alkyl, FBr 2 C 1-6 Alkyl group FCl 2 C 1-6 Alkyl, FI 2 C 1-6 Alkyl, clBr 2 C 1-6 Alkyl, ICl 2 C 1-6 Alkyl group ClI 2 C 1-6 An alkyl group; f (F) 3 C 1-6 Alkoxy, br 3 C 1-6 Alkoxy, cl 3 C 1-6 Alkoxy, I 3 C 1-6 Alkoxy, F 2 BrC 1-6 Alkoxy, F 2 ClC 1-6 Alkoxy, F 2 IC 1-6 Alkoxy, FBr 2 C 1-6 Alkoxy group FCl 2 C 1-6 Alkoxy, FI 2 C 1-6 Alkyl, clBr 2 C 1-6 Alkoxy, ICl 2 C 1-6 Alkoxy group ClI 2 C 1-6 An alkoxy group;
preferably F 3 C 1-4 Alkyl, br 3 C 1-4 Alkyl, cl 3 C 1-4 Alkyl, I 3 C 1-4 Alkyl, F 2 BrC 1-4 Alkyl, F 2 ClC 1-4 Alkyl, F 2 IC 1-4 Alkyl, FBr 2 C 1-4 Alkyl group FCl 2 C 1-4 Alkyl, FI 2 C 1-4 Alkyl, clBr 2 C 1-4 Alkyl, ICl 2 C 1-4 Alkyl group ClI 2 C 1-4 An alkyl group; f (F) 3 C 1-4 Alkoxy, br 3 C 1-4 Alkoxy, cl 3 C 1-4 Alkoxy, I 3 C 1-4 Alkoxy, F 2 BrC 1-4 Alkoxy, F 2 ClC 1-4 Alkoxy, F 2 IC 1-4 Alkoxy, FBr 2 C 1-4 Alkoxy group FCl 2 C 1-4 Alkoxy, FI 2 C 1-4 Alkyl, clBr 2 C 1-4 Alkoxy, ICl 2 C 1-4 Alkoxy group ClI 2 C 1-4 An alkoxy group;
most preferably F 3 C、F 3 CCH 2 、Br 3 C、Br 3 CCH 2 、Cl 3 C、Cl 3 CCH 2 、I 3 C、I 3 CCH 2 、F 2 BrC、F 2 BrCCH 2 、F 2 ClC、F 2 ClCCH 2 、F 2 IC、F 2 ICCH 2 、FBr 2 C、FBr 2 CCH 2 、FCl 2 C、FCl 2 CCH 2 、FI 2 C、FI 2 CCH 2 、ClBr 2 C、ClBr 2 CCH 2 、ICl 2 C、ICl 2 CCH 2 、ClI 2 C、ClI 2 CCH 2 ；F 3 CO、F 3 CCH 2 O、Br 3 CO、Br 3 CCH 2 O、Cl 3 CO、Cl 3 CCH 2 O、I 3 CO、I 3 CCH 2 O、F 2 BrCO、F 2 BrCCH 2 O、F 2 ClCO、F 2 ClCCH 2 O、F 2 ICO、F 2 ICCH 2 O、FBr 2 CO、FBr 2 CCH 2 O、FCl 2 CO、FCl 2 CCH 2 O、FI 2 CO、FI 2 CCH 2 O、ClBr 2 CO、ClBr 2 CCH 2 O、ICl 2 CO、ICl 2 CCH 2 O、ClI 2 CO、ClI 2 CCH 2 O；
X is selected from O;
y is selected from O, NH, S, sulfoxide, sulfone;
z is selected from CH 2 ，NH，O；
p is selected from 0 or 1.
In embodiments of the derivatives of formula (I):
preferred R 1 ，R 2 Independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, carboxy, C 1-4 Alkyl, C 1-4 Alkoxy, trihalogen C 1-4 Alkyl, trihalogen C 1-4 Alkoxy, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, C 1-3 Alkanoyl, C 1-4 An alkoxymethyleneoxy group;
Preferred R 1 ，R 2 Or is selected from-O (CH) 2 ) n’ O-and is linked to its substituted phenyl group to form a ring; n is selected from 1, 2 or 3;
preferred R 3 And R is 4 Independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, trihalogen C 1-4 Alkyl, trihalogen C 1-4 An alkoxy group;
preferred R 5 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxymethyl group, C 0-4 An alkylamino group;
preferred R 6 Selected from hydrogen, hydroxy, C 1-4 Alkyl, C 0-4 Alkylamino, C 1-4 Alkylcarbonyloxy, C 1-4 Alkoxycarbonyl, o=;
preferred R 7 ，R 8 ，R 9 Independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, carboxy, C 1-4 Alkyl, C 1-4 Alkoxy, trihalogen C 1-4 Alkyl, trihalogen C 1-4 Alkoxy, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, C 1-3 Alkanoyl, C 1-4 An alkoxymethyleneoxy group which is selected from the group consisting of,
preferred R 8 And R is 9 Or is selected from-O (CH) 2 ) n’ O-and is linked to its substituted phenyl group to form a ring; n' is selected from 1, 2 or 3;
preferably X is selected from O;
preferred Y is selected from O, NH, S, sulfoxide, sulfone;
preferred Z is selected from CH 2 ，NH，O；
Preferably p is selected from 0 or 1.
In embodiments of the derivatives of formula (I):
more preferably R 1 ，R 2 Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylsulfonyl, amino, carboxyl, methyl, ethyl, methoxy, ethoxy, trihalo C 1-2 Alkyl, trihalogen C 1-2 Alkoxy, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propionyl, butyryl, pentanoyl, isobutyryl, 2-methylbutanoyl, C 1-2 An alkoxymethyleneoxy group;
more preferably R 1 ，R 2 Or is selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
more preferably R 3 And R is 4 Independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, ethoxycarbonyl, C 1-2 Alkylcarbonyloxy, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, methyl, ethyl, methoxy, ethoxy, trihalo C 1-2 Alkyl, trihalogen C 1-2 An alkoxy group;
more preferably R 5 Selected from hydrogen, C 1-2 Alkyl, C 1-2 Alkoxymethyl group, C 0-2 An alkylamino group;
more preferably R 6 Selected from hydrogen, hydroxy, C 1-2 Alkyl, o=, C 0-2 Alkylamino, C 1-2 Alkoxycarbonyl group, C 1-2 Alkylcarbonyloxy;
more preferably R 7 ，R 8 ，R 9 Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylsulfonyl, amino, carboxyl, methyl, ethyl, methoxy, ethoxy, trihalo C 1-2 Alkyl, trihalogen C 1-2 Alkoxy, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propionyl, butyryl, pentanoyl, isobutyryl, 2-methylbutanoyl, C 1-2 An alkoxymethyleneoxy group;
more preferably R 8 And R is 9 Or is selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
more preferably X is selected from O;
more preferably Y is selected from O, NH, S, sulfoxide, sulfone;
more preferably Z is selected from CH 2 ，NH，O；
More preferably p is selected from 0 or 1.
In embodiments of the derivatives of formula (I):
most preferred R 1 ，R 2 Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, carboxyl, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, formyl, acetyl, propionyl, butyryl, valeryl, isobutyryl, methoxymethyleneoxy;
most preferred R 1 ，R 2 Or is selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
most preferred R 3 And R is 4 Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy;
Most preferred R 5 Is selected from the group consisting of hydrogen,methyl, ethyl, methoxymethyl, amino;
most preferred R 6 Selected from hydrogen, hydroxy, methyl, ethyl, O=, amino, C 1-2 Alkylcarbonyloxy;
most preferred R 7 ，R 8 ，R 9 Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, carboxyl, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, formyl, acetyl, propionyl, butyryl, valeryl, isobutyryl, methoxymethyleneoxy;
most preferred R 8 And R is 9 Or is selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
most preferably X is selected from O;
most preferably Y is selected from O, NH, S, sulfoxide, sulfone;
most preferably Z is selected from CH 2 ，NH，O；
Most preferably p is selected from 0 or 1.
Most preferred compounds include, but are not limited to, the following
In the present invention, the term "halogen" means fluorine, chlorine, bromine, iodine.
According to the invention, the compounds of formula (I) may exist in the form of isomers, the compounds of formula (I) being linked to R 5 ，R 6 The carbon configuration of the group may be either the R or S configuration.
The present invention includes all possible stereoisomers as well as mixtures of two or more isomers.
If cis/trans isomers are present, the present invention relates to both cis and trans forms and mixtures of these forms, and if desired the individual isomers can be isolated according to conventional methods or prepared by stereoselective synthesis.
The invention also discloses a method for preparing the compound, which comprises the following route steps:
preparation of Compounds of formula (I)
i, condensation; i': substitution; ii, hydrolyzing; iii, substitution;
A. the compound of formula (III) is prepared in the presence of an organic base such as pyridine, piperidine, diisopropylamine, ethylenediamine, triethylamine, N, N-diisopropylethylamine, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, etc. under alkaline conditions; the preparation method comprises the following steps of carrying out condensation reaction on carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBt) and other condensing agents in methylene dichloride, tetrahydrofuran, N, N-dimethylformamide and other solvents at the temperature of 10-30 ℃ and a compound of formula (IV) to generate a compound of formula (V); or reacting the compound of formula (III ') with the compound of formula (IV') under the conditions of organic base n-butyllithium, tert-butyllithium, LHMDS, naHMDS, LDA and the like for 1-10h at-100-10 ℃ to generate the compound of formula (V);
B. The compounds of formula (V) are prepared under acidic conditions such as hydrochloric acid, sulfuric acid, nitric acid, camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, pyridinium hydrofluoric acid; or basic conditions, organic bases such as pyridine, piperidine, diisopropylamine, ethylenediamine, triethylamine, N-diisopropylethylamine, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, and the like; removing the protecting group by hydrogenation reaction to obtain a compound of formula (VI);
C. compounds of formula (VI) in organic bases such as pyridine, piperidine, diisopropylamine, ethylenediamine, and the like; inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate and the like under alkaline conditions in acetonitrile, N, N-dimethylformamide and other solvents, and carrying out substitution reaction with the compound of the formula (VII) at 20-70 ℃ to obtain the compound of the formula (I);
wherein R is 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 ，R 7 ，R 8 ，R 9 X, Y, Z, p are as defined in any one of claims 1 to 6; y' is selected from t-butyldimethylsilyloxy, t-butyldiphenylsiloxy, trimethylsiloxy, triethylsiloxy, benzyloxy, p-methoxy Yangji, methoxymethyleneoxy, benzyloxycarbonyloxy, t-butoxycarbonyloxy; y' is selected from OH, NH 2 SH; m is selected from: hydroxy, chloro, bromo, iodo, p-toluenesulfonyl, methanesulfonyl.
The compounds of formula (I) or isomers thereof and pharmaceutically acceptable salts thereof include: hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, salicylate, amino acid, medlar, maleate, tartrate, fumarate, citrate, lactate, sodium, potassium, calcium, magnesium, lithium, ammonium salts and salts of organic bases capable of providing physiologically acceptable cations, such as salts of methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris (2-hydroxyethyl) amine. All salts of the present invention can be prepared by conventional methods. In addition, during the preparation of solvates of the compound of formula (I) and salts thereof, different crystallization conditions may give rise to polycrystals or co-crystals.
In yet another aspect, the invention relates to a pharmaceutical composition comprising an effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are typically present in the pharmaceutical compositions thereof in an amount of 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, cutaneous, vaginal, rectal, etc.
The dosage form may be a liquid, solid or semi-solid dosage form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like.
The compound of the invention can be prepared into common preparations, slow release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the preparation of the compounds of the present invention into tablets, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
In order to make the administration unit into a capsule, the compound of the present invention as an active ingredient may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used to prepare the tablets of the compounds of the invention may also be used to prepare capsules of the compounds of the invention.
For the preparation of the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture may be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator may be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol, glucose, etc. can be added as propping agent for preparing lyophilized powder for injection.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
According to the present invention, the compound of formula (I) or an isomer thereof and a pharmaceutically acceptable salt thereof show excellent effects in anti-tumor, anti-inflammatory, treatment of autoimmune diseases, neurodegenerative diseases. Thus can be used as an anti-tumor, anti-inflammatory, autoimmune disease treatment, neurodegenerative disease treatment and anti-aging agent for animals, preferably mammals, especially humans. The compound can be used for preparing medicines for preventing and/or treating tumors. The tumor is selected from glioma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, head and neck tumor, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer or rectal adenocarcinoma, leukemia and lymphoma. Can be used for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, psoriasis, various dermatitis and spinal cord lateral sclerosis, inflammatory diseases such as multiple vasculitis, reflux esophagitis and the like, and neurodegenerative diseases such as senile dementia, parkinsonism and the like.
The dosage of the pharmaceutical composition of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, the suitable daily dosage of the compounds of the present invention will range from 0.001 to 150mg/Kg of body weight, preferably from 0.1 to 100mg/Kg of body weight, more preferably from 1 to 70mg/Kg of body weight, and most preferably from 2 to 30mg/Kg of body weight. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
THE ADVANTAGES OF THE PRESENT INVENTION
The compound is a derivative of caffeic acid, has better combination with a plurality of target proteins and better bioavailability, and can be used for treating various human malignant tumors and preventing tumors, wherein the tumor diseases are lung cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, bladder cancer, breast cancer, ovarian cancer, glioma, leukemia, lymphoma, head and neck cancer and the like. Has better effect in the treatment of inflammation, autoimmune diseases, neurodegenerative diseases and aging.
Detailed Description
The following examples and experiments on pharmaceutical activity are intended to further illustrate the invention, but are not meant to limit the invention in any way.
The following examples serve to illustrate the invention without however limiting it.
The starting materials used are known compounds or are prepared according to known methods.
Step A:
(536 mg,2 mmol) of double MOM-protected caffeic acid, (559 mg,2.2 mmol) 4-tert-butylpolyethyleneoxy-3-methoxyphenol (known), (575 mg,3 mmol) EDCI,10mg DMA P in 20mL dichloromethane, triethylamine (0.56 mL,4 mmol) dropwise at 0deg.C for 10h, ethyl acetate and water were added, the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated to give 0.63g of compound 31 as yellow solidified oil in 62.4% yield.
1 H NMR(500MHz,CDCl 3 )δ7.79(s,1H),7.42(s,1H),7.19(s,2H),6.83(d,J＝8.5Hz,1H),6.69(s,1H),6.63(dd,J＝8.6,2.7Hz,1H),6.49(d,J＝15.9Hz,1H),5.27(d,J＝5.3Hz,4H),3.79(s,3H),3.54(s,3H),3.52(s,3H),1.00(s,9H),0.16(s,6H).
13 C NMR(101MHz,CDCl 3 ) Delta 165.8,151.2,149.5,147.5,146.0,145.1,142.7,128.7,123.8,120.6,116.2,115.9,115.8,113.6,106.2,95.6,94.8,56.4,56.3,55.6,25.7,18.5, -4.6. (256 mg,2 mmol) cinnamic acid, (559 mg,2.2 mmol) 4- ((tert-butylmethyliminosyl) oxy) 3-methoxyaniine as starting material, compound 32, 590mg of a white solid was obtained by condensation reaction using a similar procedure to that for the preparation of compound 31, in 76.8% yield.
1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝16.0Hz,1H),7.58(d,J＝2.6Hz,2H),7.47–7.39(m,3H),6.84(d,J＝8.5Hz,1H),6.71(d,J＝2.7Hz,1H),6.67–6.58(m,2H),3.80(s,3H),1.00(s,9H),0.17(s,6H).
13 C NMR(101MHz,CDCl 3 ) Delta 165.7,151.2,146.4,145.0,142.7,134.3,130.7,129.0,128.3,120.6,117.5,113.2,106.2,77.4,77.3,77.1,76.7,55.6,25.7,18.5, -4.6. (56 mg,2 mmol) of (E) -3- (3, 4-bis (methoxymethoxy) phenyl) acrylic acid (known), (490 mg,2.2 mmol) of 4- ((tert-butyl ethyl) oxy) aniline as a starting material gave compound 33, 650mg of a white solid in 68.4% yield by condensation reaction using a similar procedure to that for the preparation of compound 31.
1 H NMR(500MHz,CDCl 3 )δ7.84(d,J＝15.9Hz,1H),7.57(d,J＝8.8Hz,2H),6.97(d,J＝8.8Hz,2H),6.87(d,J＝8.6Hz,1H),6.73(d,J＝2.7Hz,1H),6.67(dd,J＝8.6,2.7Hz,1H),6.51(d,J＝15.9Hz,1H),3.89(s,3H),3.83(s,3H),1.04(s,9H),0.20(s,6H).
13 C NMR(101MHz,CDCl 3 )δ166.0,161.7,151.2,146.1,145.1,142.6,130.0,127.0,120.6,114.8,114.5,113.2,106.2,77.4,77.3,77.1,76.7,55.6,55.5,25.8,18.5,-4.6.
A three-necked flask was charged with (8.93 g,28.3 mmol) of 2-t-butyldimethylsilyloxy-5-bromoanisole, dropwise adding (1.6M, 17.7mL,28.3 mmol) of N-BuLi under the protection of argon at-78℃for 0.5h, followed by dropwise adding a 10mL anhydrous THF solution of the compound (E) -3- (3, 4-bis (methoxymethoxy) phenyl) -N-methoxy-N-methylcarbamide (3.5 g,11.3 mmol) (known), reacting at this temperature for 0.5h,20mL of saturated ammonium chloride slowly dropwise adding the reaction solution, concentrating the major part of THF, adding 300mL of EA,50mL of water, extracting with 100mL of EA in water, combining the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and subjecting the mixture to column chromatography (PE: EA=15:1) to obtain compound 34,4.2g pale yellow solid in a yield of 76.4%.
Starting with (780 mg,2.5 mmol) of 2-tert-butyldimethylsilyloxy-5-bromoanisole, (251 mg,1 mmol) of the compound (E) -3- (3, 4-dimthoxyphenyl) -N-methoxy-N-methylacrylamide (known), compound 35, 372mg of a pale yellow solid was obtained in 86.9% yield by a similar procedure to the preparation of compound 34.
1 H NMR(400MHz,CDCl 3 )δ7.76(d,J＝15.6Hz,1H),7.57-7.61(m,2H),7.41(d,J＝15.6Hz,1H),7.24(dd,d,J＝1.6Hz,8Hz,1H),7.16(m,1H),6.91(t,J＝8Hz,2H),3.96(s,3H),3.93(s,3H),3.90(s,3H),1.01(s,9H),0.20(s,6H)；
13 C NMR(100MHz,CDCl 3 )δ189.0,151.4,149.9,149.3,144.1,132.6,128.2,123.0,122.7,120.3,119.9,111.9,111.2,110.2,56.1,55.6,25.7,18.6,-4.5.
Using (780 mg,2.5 mmol) of 2-t-butyldimethylsilyloxy-5-bromoanisole, (192 mg,1 mmol) of N-methoxy-N-methylcinnamamide as a starting material, the procedure was similar to the preparation of compound 34, affording compound 36, 346mg of a pale yellow solid in 93.9% yield.
1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝15.6Hz,1H),7.53-7.66(m,5H),7.40-7.42(m,3H),6.92(d,J＝8.4Hz,2H),3.90(s,3H),1.01(s,9H),0.20(s,6H)；
13 C NMR(100MHz,CDCl 3 )δ188.9,151.4,150.1,144.0,135.2,132.3,130.4,129.0,128.4,122.8,121.9,120.3,111.8,55.6,25.7,18.6,-4.5.
Using (780 mg,2.5 mmol) of 2-t-butyldimethylsilyloxy-5-bromoanisole, (192 mg,1 mmol) of (E) -3- (4-fluorogenyl) -N-methoxy-N-methylacrylamide as a starting material, the procedure was similar to the preparation of compound 34 to give compound 37, 350mg of a pale yellow solid in 90.7% yield.
1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝15.6Hz,1H),7.53-7.66(m,3H),7.40-7.42(m,3H),6.92(d,J＝8.4Hz,2H),3.90(s,3H),1.01(s,9H),0.20(s,6H)；
And (B) step (B):
(500 mg,1 mmol) of Compound 31 in THF, tetrabutylammonium fluoride (1.5 mL,1.5 mmol) was added at 0deg.C, the reaction was stopped by adding saturated ammonium chloride after 30min, ethyl acetate was added, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed (PE: EA=5:1) to give 0.35g of Compound 41 as a yellow solid in 89.7% yield.
1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝15.9Hz,1H),7.42(s,1H),7.18(s,2H),6.90(d,J＝8.5Hz,1H),6.70(d,J＝2.6Hz,1H),6.65(dd,J＝8.5,2.6Hz,1H),6.49(d,J＝15.9Hz,1H),5.68(s,1H),5.27(d,J＝4.2Hz,4H),3.85(s,3H),3.53(s,3H),3.52(s,3H).
13 C NMR(101MHz,CDCl 3 )δ166.1,149.6,147.5,146.7,146.1,143.8,143.4,128.7,123.8,116.2,115.8,115.8,114.4,113.8,105.3,95.6,95.1,77.4,77.1,76.8,56.4,56.3,56.0.
(500 mg,1.3 mmol) of Compound 32 as a starting material, the compound 42, 340mg of a pale yellow solid was obtained by hydrolysis in a yield of 96.6% by using a similar operation to that of Compound 41.
1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝15.8Hz,1H),7.59(m,2H),7.52–7.37(m,4H),6.98–6.88(m,1H),6.73(s,1H),6.70–6.66(m,1H),6.62(d,J＝16.0Hz,1H),5.50(s,1H),3.89(s,4H).
(470 mg,1.1 mmol) of Compound 33 was used as a starting material, and compound 43, 320mg of a pale yellow solid was obtained by hydrolysis in a yield of 94.1% by using a similar operation to that for preparation of Compound 41.
1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝15.9Hz,1H),7.54(d,J＝8.7Hz,2H),6.93(t,J＝8.7Hz,3H),6.72(d,J＝2.6Hz,1H),6.67(dd,J＝8.5,2.6Hz,1H),6.48(d,J＝15.9Hz,1H),5.49(s,1H),3.89(s,3H),3.86(s,3H).
(4 g,8.2 mmol) of the compound 34 was used as a starting material, and the compound 44,2.9g of a pale yellow solid was obtained by hydrolysis in a yield of 94.5% by using a similar operation to that of the preparation of the compound 41.
1 H NMR(400MHz,CDCl 3 )δ7.73(d,J＝15.6Hz,1H),7.63-7.65(m,2H),7.47(m,1H),7.42(d,J＝15.6Hz,1H),7.26-7.28(m,1H),7.19(d,J＝8.8Hz,1H),7.00(d,J＝8Hz,1H),5.29(s,2H),5.29(s,2H),3.99(s,3H),3.56(s,3H),3.53(s,3H)；
13 C NMR(100MHz,CDCl 3 )δ188.6,150.3,149.3,147.4,146.9,143.8,131.2,129.6,123.8,123.7,120.4,116.2,113.7,110.5,95.6,95.2,56.4,56.2；
Starting from (60 mg,0.14 mmol) of compound 35, using similar operating procedures for preparing compound 41, compound 45 was obtained as a pale yellow solid, 35mg, yield 80%.
Starting from compound 36 (60 mg,0.16 mmol), compound 46, 35mg of a pale yellow solid was obtained in 85.3% yield using similar procedure for the preparation of compound 41.
Starting from compound 37 (60 mg,0.16 mmol), compound 47, 36mg as a pale yellow solid was obtained in 82.7% yield using similar procedure for preparing compound 41.
Example 1:
and C, operation:
a50 mL round bottom flask was charged with (50 mg,0.17 mmol) of Compound 41, (73 mg,0.2 mmol) of (S) -3- (3, 4-dimethoxyphenyl) -2-methylpropyl 4-methylparaben-zene sulfonate, (85 mg,0.26 mmol) of cesium carbonate, 5mL of acetonitrile was added, the reflux reaction was continued for 4h, TLC showed complete, after cooling, 80mg of crude product was obtained by filtration, dissolved in 5mL of tetrahydrofuran, 0.3mL of concentrated hydrochloric acid was added, after stirring for 1h, 60mg of Compound 1 was obtained by concentration, and the yield was 71.4%.
1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝15.9Hz,1H),7.09(d,J＝2.0Hz,1H),7.03(dd,J＝8.2,2.0Hz,1H),6.89(d,J＝2.1Hz,1H),6.85(d,J＝7.9Hz,2H),6.80(d,J＝1.1Hz,2H),6.73–6.67(m,2H),6.36(d,J＝15.9Hz,1H),5.97–5.86(m,2H),4.16(d,J＝10.8Hz,2H),3.88–3.84(m,9H),3.09(d,J＝10.8Hz,2H),1.78(m,1H),1.26(d,J＝7.8Hz,3H)；
Example 2:
using the procedure similar to example 1, starting from (50 mg,0.13 mmol) of Compound 41, (60 mg,0.22 mmol) 2-bromo-N- (3, 4-dimethoxyphenyl) acetate, compound 2 was obtained in a yield of 78.1% as a yellow solid of 50 mg.
1 H NMR(400MHz,Methanol-d 4 )δ7.71(d,J＝15.9Hz,1H),7.34(d,J＝2.5Hz,1H),7.14–7.06(m,3H),7.01(dd,J＝8.3,2.1Hz,1H),6.97–6.91(m,2H),6.89–6.83(m,1H),6.83–6.78(m,1H),6.44(d,J＝15.9Hz,1H),4.66(s,2H),3.93(s,4H),3.82(d,J＝7.7Hz,7H).
13 C NMR(151MHz,Methanol-d 4 )δ167.6,166.4,149.1,148.2,147.7,147.5,147.3,146.3,145.5,144.6,130.2,126.5,123.0,115.5,115.1,113.9,112.7,112.3,111.8,110.5,106.1,70.4,57.2,55.5,55.3,55.0.
Example 3:
using the procedure similar to example 1, starting from (50 mg,0.14 mmol) compound 41, (60 mg,0.22 mmol) 2-bromo-N- (3, 4-dimethoxyphenyl) acetate, compound 3 was obtained in 45mg of a yellow solid in 69.4% yield.
1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝15.8Hz,1H),7.23-7.26(m,3H),7.14–7.06(m,3H),7.01(dd,J＝8.3,2.1Hz,1H),6.97–6.91(m,2H),6.89–6.83(m,1H),6.83–6.78(m,1H),6.44(d,J＝15.9Hz,1H),4.66(s,2H),3.93(s,4H),3.82(d,J＝7.7Hz,7H).
Example 4:
using the procedure similar to example 1, starting from (50 mg,0.13 mmol) of Compound 41, (60 mg,0.22 mmol) 2-bromo-N- (4-methoxyphenyl) acetamide, compound 4 was obtained in a yield of 83.3% as a yellow solid, 50 mg.
1 H NMR(400MHz,Methanol-d 4 )δ7.71(d,J＝15.9Hz,1H),7.34(d,J＝2.5Hz,1H),7.14–7.06(m,3H),7.01(dd,J＝8.3,2.1Hz,1H),6.97–6.91(m,2H),6.89–6.83(m,1H),6.83–6.78(m,1H),6.44(d,J＝15.9Hz,1H),4.66(s,2H),3.93(s,3H),3.82(s,3H).
Example 5:
using the procedure similar to example 1, starting from (150 mg,0.40 mmol) of Compound 44, (120 mg,0.44 mmol) 2-bromo-N- (3, 4-dimethoxyphenyl) acetate, compound 5 was obtained in the form of a yellow solid with a yield of 78.2%.
1 H NMR(400MHz,CD 3 OD)δ7.77(dd,J＝8.4,2.0Hz,1H),7.73–7.65(m,2H),7.52(d,J＝15.4Hz,1H),7.36(d,J＝2.5Hz,1H),7.24–7.06(m,3H),6.93(d,J＝8.7Hz,1H),6.82(d,J＝8.1Hz,1H),4.78(s,1H),4.00(s,2H),3.83(s,2H),3.82(s,2H).
13 C NMR(151MHz,d-DMSO)δ187.6,166.0,151.9,149.4,149.0,146.0,145.5,144.6,132.4,132.1,126.8,123.1,122.5,118.7,116.1,116.0,113.0,112.5,111.7,111.6,104.9,68.3,56.1,55.8.
Example 6:
using the procedure similar to example 1, starting from (150 mg,0.48 mmol) compound 45, (180 mg,0.66 mmol) 2-bromo-N- (3, 4-dimethoxyphenyl) acetate, compound 6 was obtained in the form of a yellow solid in 74.1% yield.
1 H NMR(400MHz,Acetone-d 6 )δ7.93–7.79(m,1H),7.79–7.67(m,3H),7.47(d,J＝10.6Hz,2H),7.35(d,J＝8.7Hz,1H),7.21(d,J＝7.9Hz,2H),7.08–6.97(m,1H),6.91(d,J＝8.7Hz,1H),4.76(s,2H),4.02(s,3H),3.88(d,J＝7.1Hz,6H),3.79(d,J＝6.6Hz,6H).
13 C NMR(151MHz,acetone)δ187.2,165.5,151.8,151.5,149.9,149.7,149.4,146.1,143.8,133.2,131.9,131.8,128.1,123.3,122.5,119.4,114.2,112.2,111.5,111.5,111.4,110.8,104.9,104.8,69.1,55.5,55.5,55.3,55.2,55.1,29.3.
Example 7:
using the procedure similar to example 1, starting from (150 mg,0.59 mmol) compound 46, (180 mg,0.66 mmol) 2-bromo-N- (3, 4-dimethoxyphenyl) acetate, compound 7, 200mg of a yellow solid was obtained in 75.8% yield.
1 H NMR(500MHz,Acetone-d 6 )δ9.13(s,1H),7.94–7.70(m,5H),7.46(s,4H),7.29–7.14(m,2H),6.91(d,J＝8.5Hz,1H),4.77(s,2H),4.03(s,3H),3.86–3.69(m,7H).
13 C NMR(151MHz,acetone)δ192.6,187.3,165.6,165.5,151.8,151.7,149.9,149.8,149.4,146.1,143.4,137.7,135.2,132.8,131.9,131.9,131.8,130.3,129.3,128.9,128.5,128.3,128.1,127.3,126.7,123.4,122.8,121.8,114.3,114.1,112.2,111.5,111.4,111.4,104.9,104.8,55.6,55.5,55.1.
Example 8:
Using the procedure similar to example 1, starting from (150 mg,0.5 mmol) compound 43, (180 mg,0.66 mmol) 2-bromo-N- (3, 4-dimethoxyphenyl) acrylamide, and recrystallising twice, compound 8 was obtained in the form of a yellow solid with a yield of 65%.
1 H NMR(500MHz,Acetone-d 6 )δ9.20(s,1H),7.94–7.70(m,5H),7.46(s,4H),7.29–7.14(m,1H),6.95(d,J＝8.5Hz,1H),4.79(s,2H),4.02(s,3H),3.85–3.69(m,6H).
Example 9:
using the procedure similar to example 1, starting from (150 mg,0.42 mmol) of Compound 44, (152 mg,0.66 mmol) 2-bromo-N- (4-fluorophenyl) acetamide, compound 9 was obtained in the form of a pale yellow solid, 100mg, yield 54.6%.
1 H NMR(400MHz,Acetone-d 6 )δ9.05(s,1H),8.30(s,1H),8.05(s,1H),7.63(d,J＝8.6Hz,2H),7.48(d,J＝15.5Hz,1H),7.06(d,J＝2.1Hz,1H),6.95(d,J＝9.0Hz,2H),6.89–6.78(m,4H),4.63(s,2H),3.97(s,3H).
Example 10:
using the procedure similar to example 1, starting from (150 mg,0.55 mmol) of Compound 47, (180 mg,0.66 mmol) 2-bromo-N- (3, 4-dimethoxyphenyl) acetate, compound 10, 150mg of a pale yellow solid was obtained in 58.6% yield.
1 H NMR(400MHz,Acetone-d 6 )δ9.03(s,1H),8.35(s,1H),8.05(s,1H),7.63(d,J＝8.6Hz,2H),7.48(d,J＝15.5Hz,1H),7.06(d,J＝2.1Hz,1H),6.95(d,J＝9.0Hz,2H),6.89–6.78(m,4H),4.65(s,2H),3.86(s,3H).
Example 11:
using the procedure similar to example 1, starting from (150 mg,0.42 mmol) compound 44, (113 mg,0.54 mmol) 2-amino-N- (3, 4-dimethoxyphenyl) acetate, compound 11 was obtained in the form of a pale yellow solid, 150mg, and 75% yield.
1 H NMR(400MHz,Acetone-d 6 )δ8.99(s,1H),8.23(s,1H),8.06(s,1H),7.63(d,J＝8.6Hz,2H),7.48(d,J＝15.5Hz,1H),7.06(d,J＝2.1Hz,1H),6.95(d,J＝9.0Hz,2H),6.89–6.78(m,2H),4.98(s,2H),3.76(s,3H).
Example 12:
using the procedure similar to example 1 except for acidification, starting from (150 mg,0.52 mmol) 3-fluoro-4-hydroxyphenyl (E) -3- (4-methoxyphenyl) acrylate, (180 mg,0.66 mmol) 2-bromoN- (3, 4-dimethoxyphenyl) acrylate, compound 12 was obtained in a yield of 72% as a yellow solid without acidification.
ESI + C 26 H 24 FNO 7 ,481.2.
Example 13:
using the procedure similar to example 1, starting from (150 mg,0.42 mmol) of Compound 44, (180 mg,0.66 mmol) 2-bromo-N- (4-methoxyphenyl) acetamide, compound 13, 120mg of a pale yellow solid was obtained in 63.8% yield.
1 H NMR(400MHz,CD 3 OD)δ7.78(dd,J＝8.4,2.0Hz,1H),7.77–7.63(m,2H),7.52(d,J＝15.4Hz,1H),7.42(m,2H),7.36(d,J＝2.5Hz,1H),7.24–7.06(m,3H),6.93(d,J＝8.7Hz,1H),6.82(d,J＝8.1Hz,1H),4.78(s,2H),3.83(s,3H),3.80(s,3H).
Example 14:
using the procedure similar to example 1 except for using (107 mg,0.42 mmol) of (E) -3- (3, 4-dichlorophenyl) -1- (4-hydroxyphenyl) prop-2-en-1-one, (180 mg,0.66 mmol) of 2-bromoo-N- (4-methoxyphenyl) acetate as starting material, compound 14 was obtained in 85.2% yield as 150mg of light yellow solid.
1 H NMR(400MHz,CD 3 OD)δ7.80(dd,J＝8.4,2.0Hz,1H),7.79–7.65(m,2H),7.52(d,J＝15.4Hz,1H),7.44(m,3H),7.39(d,J＝2.5Hz,1H),7.27–7.08(m,3H),6.93(d,J＝8.7Hz,1H),6.87(d,J＝8.1Hz,1H),4.88(s,2H),3.85(s,3H).
Example 15:
using the procedure similar to example 1, starting from (150 mg,0.42 mmol) compound 44, (126 mg,0.48 mmol) N- (benzol [ d ] [1,3] dioxo-5-yl) -2-bromoacetoamide, compound 15, 160mg of a pale yellow solid was obtained in 81.6% yield.
1 H NMR(400MHz,CD 3 OD)δ9.85(brs,1H),7.98(dd,J＝8.8,2.0Hz,1H),7.82–7.69(m,2H),7.52(d,J＝15.4Hz,1H),7.44(m,2H),7.39(d,J＝2.5Hz,1H),7.27–7.08(m,2H),6.93(d,J＝8.6Hz,1H),6.87(d,J＝8.8Hz,1H),6.00(s,2H),4.88(s,2H),3.85(s,3H).
Example 16:
using the procedure similar to example 1, starting from (150 mg,0.42 mmol) compound 44, (133 mg,0.44 mmol) 2-bromo-N- (3, 4, 5-trimethoxyphenyl) acetoamide, compound 16 was obtained as a pale yellow solid in 70.8% yield.
ESI + C 27 H 27 NO 9 ,509.2
Example 17:
starting with (170 mg,0.42 mmol) of (E) -3- (3, 4-bis (methoxymethoxy) phenyl) -1- (4-hydroxy-3, 5-dimethoxyphenyl) prop-2-en-1-one, (180 mg,0.66 mmol) of 2-bromoo-N- (4-methoxyphenyl) acrylamide, the procedure similar to example 1 was followed to give compound 17, 136mg as a pale yellow solid in 45.7% yield.
ESI + C 26 H 25 NO 8 ,407.2
Example 18:
using the procedure similar to example 11, starting from (150 mg,0.42 mmol) compound 44, (108 mg,0.52 mmol) N' - (3, 4-dimthoxyphenyl) ethane-1,2-diamine, compound 18 was obtained in the form of a pale yellow solid, yield 66.7%.
ESI + C 26 H 28 N 2 O 6 ,464.2
Example 19:
using the procedure analogous to example 1 starting from (150 mg,0.42 mmol) compound 44, (92 mg,0.43 mmol) 2-bromo-N-phenylacetamide, compound 19, 160mg of a pale yellow solid was obtained in 90.9% yield.
1 H NMR(400MHz,CD 3 Cl 3 )δ7.87(m,1H),7.73–7.65(m,3H),7.52(m,2H),7.36(m,2H),7.24–7.06(m,3H),6.93(d,J＝8.7Hz,1H),6.82(d,J＝8.1Hz,1H),4.78(s,1H),4.12(s,2H).
Example 20:
using (50 mg,0.17 mmol) of (E) -3- (benzol [ d ] [1,3] dioxal-5-yl) -1- (4-hydroxy-3-methoxyphenyl) prop-2-en-1-one, (92 mg,0.43 mmol) of 2-bromo-N-phenylacetamide as a material, the procedure of example 1 was followed to give compound 20, 40mg of a pale yellow solid in 54.8% yield.
ESI + C 25 H 21 NO 6 ,431.2
Pharmacological experiments
Experimental example 1, caffeic acid derivative ACAT1 target IC 50 Measurement
Method (one)
Screening method of ACAT1 small molecule inhibitor
ACAT1 can catalyze the reversible formation of acetoacetyl-coa from two molecules of acetyl-coa. The activity is measured by the reaction of ACAT1 catalyzed substrate acetoacetyl-CoA and CoA to produce product acetoacetyl-CoA. Based on the specific absorption of acetoacetyl-CoA in a specific spectrum, the effect on ACAT1 enzyme activity is reflected by detecting an increase or decrease in the specific spectrum absorption.
The ACAT1 recombinant protein is expressed and purified by escherichia coli, and the concentration of the obtained ACAT1 recombinant protein is 1mg/ml. When ACAT1 small molecule inhibitor screening was performed, 50mM Tris-HCl (pH 8.1) and 20mM MgCl was used as buffer 2 40mM KCl. In 200. Mu.l of the enzyme catalytic system, 1. Mu.l of ACAT1 recombinant protein, 25. Mu.M of substrate acetyl CoA was added, 100. Mu.M of CPM probe was added, and small molecule inhibitors of different concentrations were added, respectively. Detection was performed by means of a microplate reader (Biotek Synergy H1) using 355nm excitation light and 460nm emission light, and inhibitor IC was performed using software Prism 7.0 50 Is calculated by the computer.
(II) results
The results of the in vitro screening for the effect on ACAT1 activity are shown in table 1. Experimental results show that the compounds 2 and 6 have better inhibition activity on ACAT 1.
TABLE 1 in vitro target screening results
Experimental example 2 determination of pyruvate kinase Activity of caffeic acid derivative
Method (one)
Screening method of pyruvate kinase small molecule regulator
Principle of: pyruvate Kinase (PK) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate in the presence of Adenosine Diphosphate (ADP), pyruvate is converted to lactate by reduced coenzyme I (NADH) in the presence of LDH, and if the label fluoresces on NADH, the fluorescent NADH becomes fluorescent NAD.
Two recombinant protein pyruvate kinase subtypes: PKLR (15501-H07E) and PKM2 (11430-H07E) were purchased from Beijing Yiqiao Shenzhou technologies Co., ltd. For PK activity screening, 100mM Tris HCl (pH 8.0) was used as buffer, 100mM KCl,10mM MgCl 2 . In 200. Mu.l of the enzyme catalytic system, various substrates and enzymes were added to a final concentration of ADP (0.6 mM), PEP (0.5 mM), NADH (180 mM), FBP (10 mM) and LDH (8 units), respectively, and small molecule inhibitors were additionally added at different concentrations. The change in absorbance at 340nm was detected by a microplate reader (Biotek synergy H1), and the inhibition or activation activity was calculated using software Prism 7.0.
(II) results
The effect of the compounds on pyruvate kinase activity in vitro is shown in Table 2. The results show that the tested compounds have no significant effect on PKLR and PKM2 enzyme activity.
TABLE 2 in vitro pyruvate kinase screening results
Compounds of formula (I) PKLR (OD value) PKM2 (OD value)
1 0.878519 1.00625
2 1.063608 0.853333
5 0.966111 0.855833
6 1.429614 1.109167
7 1.497393 0.929167
。

Claims (10)

1. A compound of formula (I) or an isomer thereof and a pharmaceutically acceptable salt thereof
R 1 And R is 2 Independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, trihalogen C 1-6 Alkyl, trihalogen C 1-6 Alkoxy, C 1-6 An alkoxymethyleneoxy group;
or R is 1 And R is 2 Selected from-O (CH) 2 ) n O-and is linked to its substituted phenyl group to form a ring; n is selected from 1, 2 or 3;
R 3 and R is 4 Independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, trihalogen C 1-6 Alkyl, trihalogen C 1-6 An alkoxy group;
R 5 selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxymethyl group, C 0-6 An alkylamino group;
R 6 selected from hydrogen, hydroxy, C 1-6 Alkyl, C 0-6 Alkylamino, C 1-6 Alkylcarbonyloxy, C 1-6 Alkoxycarbonyl, o=;
R 7 ，R 8 ，R 9 independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, carboxy, C 1-6 Alkyl, C 1-6 Alkoxy, trihalogen C 1-6 Alkyl, trihalogen C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonyloxy, C 1-5 Alkanoyl, C 1-6 An alkoxymethyleneoxy group; or R is 8 And R is 9 Selected from-O (CH) 2 ) n’ O-and is linked to its substituted phenyl group to form a ring; n' is selected from 1, 2 or 3;
x is selected from O;
y is selected from O, NH, S, sulfoxide, sulfone;
z is selected from CH 2 ，NH，O；
p is selected from 0 or 1.
2. A compound according to claim 1, or an isomer thereof, and a pharmaceutically acceptable salt thereof, characterized in that:
R 1 And R is 2 Independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, trihalogen C 1-4 Alkyl, trihalogen C 1-4 Alkoxy, C 1-4 An alkoxymethyleneoxy group;
or R is 1 And R is 2 Selected from-O (CH) 2 ) n O-and is linked to its substituted phenyl group to form a ring; n is selected from 1, 2 or 3;
R 3 and R is 4 Independently selected from the group consisting of hydrogen,fluorine, chlorine, bromine, hydroxy, dimethylamino, cyano, nitro, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, trihalogen C 1-4 Alkyl, trihalogen C 1-4 An alkoxy group;
R 5 selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxymethyl group, C 0-4 An alkylamino group;
R 6 selected from hydrogen, hydroxy, C 1-4 Alkyl, C 0-4 Alkylamino, C 1-4 Alkylcarbonyloxy, C 1-4 Alkoxycarbonyl, o=;
R 7 ，R 8 ，R 9 independently selected from hydrogen, halogen, hydroxy, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, carboxy, C 1-4 Alkyl, C 1-4 Alkoxy, trihalogen C 1-4 Alkyl, trihalogen C 1-4 Alkoxy, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonyloxy, C 1-3 Alkanoyl, C 1-4 An alkoxymethyleneoxy group; or R is 8 And R is 9 Selected from-O (CH) 2 ) n’ O-and is linked to its substituted phenyl group to form a ring; n' is selected from 1, 2 or 3;
x is selected from O;
y is selected from O, NH, S, sulfoxide, sulfone;
z is selected from CH 2 ，NH，O；
p is selected from 0 or 1.
3. A compound according to claim 2, or an isomer thereof, and a pharmaceutically acceptable salt thereof, characterized in that:
R 1 and R is 2 Independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, ethoxycarbonyl, C 1-2 Alkylcarbonyloxy, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, methyl, ethyl, methoxy, ethoxy, trihalo C 1-2 Alkyl, trihalogen C 1-2 Alkoxy, C 1-2 Alkoxy groupA methyleneoxy group; or R is 1 And R is 2 Selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
R 3 and R is 4 Independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, ethoxycarbonyl, C 1-2 Alkylcarbonyloxy, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, methyl, ethyl, methoxy, ethoxy, trihalo C 1-2 Alkyl, trihalogen C 1-2 An alkoxy group;
R 5 selected from hydrogen, C 1-2 Alkyl, C 1-2 Alkoxymethyl group, C 0-2 An alkylamino group;
R 6 selected from hydrogen, hydroxy, O=, C 1-2 Alkyl, C 0-2 Alkylamino, C 1-2 Alkylcarbonyloxy, C 1-2 An alkoxycarbonyl group;
R 7 ，R 8 ，R 9 independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylsulfonyl, amino, carboxyl, methyl, ethyl, methoxy, ethoxy, trihalo C 1-2 Alkyl, trihalogen C 1-2 Alkoxy, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propionyl, butyryl, pentanoyl, isobutyryl, 2-methylbutanoyl, C 1-2 An alkoxymethyleneoxy group;
or R is 8 And R is 9 Selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
x is selected from O;
y is selected from O, NH, S, sulfoxide, sulfone;
z is selected from CH 2 ，NH，O；
p is selected from 0 or 1.
4. A compound according to claim 3, or an isomer thereof, and a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitroMethoxycarbonyl, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methoxymethyleneoxy;
or R is 1 And R is 2 Selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
R 3 and R is 4 Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methoxycarbonyl, methylamino, methanesulfonyl, dimethylaminesulfonyl, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy;
R 5 Selected from hydrogen, methyl, ethyl, methoxymethyl, amino;
R 6 selected from hydrogen, hydroxy, methyl, ethyl, O=, amino, C 1-2 Alkylcarbonyloxy;
R 7 ，R 8 ，R 9 independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano, nitro, methylamino, methylsulfonyl, dimethylaminesulfonyl, amino, carboxyl, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, formyl, acetyl, propionyl, butyryl, valeryl, isobutyryl, methoxymethyleneoxy;
or R is 8 And R is 9 Selected from-OCH 2 O-，-OCH 2 CH 2 O-and is linked to its substituted phenyl group to form a ring;
x is selected from O;
y is selected from O, NH, S, sulfoxide, sulfone;
z is selected from CH 2 ，NH，O；
p is selected from 0 or 1.
5. The compound according to any one of claims 1 to 4, or an isomer thereof, and a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
6. A compound according to any one of claims 1 to 5, or an isomer thereof, and a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt comprises: hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, acetate, trifluoroacetate, salicylate, amino acid, medlar, maleate, tartrate, fumarate, citrate, lactate, sodium, potassium, calcium, magnesium, lithium, ammonium or salts of organic bases capable of providing physiologically acceptable cations.
7. A process for the preparation of a compound according to any one of claims 1 to 6, comprising the steps of:
i, condensation; i': substitution; ii, hydrolyzing; iii, substitution;
A. the compound of the formula (III) and the compound of the formula (IV) are subjected to condensation reaction under alkaline conditions, or the compound of the formula (III ') and the compound of the formula (IV') are subjected to substitution reaction under alkaline conditions to generate the compound of the formula (V);
B. removing the protecting group of the compound of formula (V) under acidic conditions, alkaline conditions or by hydrogenation reaction to obtain a compound of formula (VI);
C. the compound of the formula (VI) and the compound of the formula (VII) are subjected to substitution reaction under alkaline conditions to obtain the compound of the formula (I);
wherein R is 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 ，R 7 ，R 8 ，R 9 X, Y, Z, p are as defined in any one of claims 1 to 6; y' is selected from t-butyldimethylsilyloxy, t-butyldiphenylsiloxy, trimethylsiloxy, triethylsiloxy, benzyloxy, p-methoxy Yangji, methoxymethyleneoxy, benzyloxycarbonyloxy, t-butoxycarbonyloxy; y' is selected from OH, NH 2 SH; m is selected from: hydroxy, chloro, bromo, iodo, p-toluenesulfonyl, methanesulfonyl.
8. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 6 or an isomer thereof and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 6 or an isomer thereof and a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prophylaxis and/or treatment of tumors, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, anti-aging.
10. Use according to claim 9, characterized in that the tumor is selected from glioma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, head and neck tumor, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer or rectal adenocarcinoma, and leukemia and lymphoma; autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, psoriasis, various dermatitis and spinal cord lateral sclerosis, inflammatory diseases include multiple vasculitis, reflux esophagitis, and neurodegenerative diseases include senile dementia and parkinson's disease.
CN202210701582.0A 2022-06-21 2022-06-21 Caffeic acid derivative and preparation method thereof, pharmaceutical composition and application Pending CN117304033A (en)

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