WO2023109859A1

WO2023109859A1 - Stilbene compound and application thereof in prevention and/or treatment for central nervous system-related diseases

Info

Publication number: WO2023109859A1
Application number: PCT/CN2022/138972
Authority: WO
Inventors: 陈明; 马志龙; 贾剑敏
Original assignee: 上海泽德曼医药科技有限公司
Priority date: 2021-12-15
Filing date: 2022-12-14
Publication date: 2023-06-22

Abstract

Provided are a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof. The compound can efficiently penetrate a blood-brain barrier, inhibit an inflammatory response of the central nervous system, can be used for preventing and/or treating central nervous system-related diseases or conditions, inhibit secretion of cytokines, inhibit activation of glial cells, and inhibit glutamic acid concentration in vivo. Provided is a potential drug for preventing and/or treating central nervous system-related diseases.

Description

Stilbene compounds and their use in the prevention and/or treatment of diseases related to the central nervous system

The present invention claims the patent application number 202111537597.X submitted to the State Intellectual Property Office of China on December 15, 2021, entitled "Compounds for the Prevention or Treatment of Central Nervous System-related Diseases" and filed on December 17, 2021. The patent application No. 202111555173.6, filed with the State Intellectual Property Office of China on the 1st, is the priority of the earlier application titled "Compounds for the Prevention or Treatment of Central Nervous System Related Diseases". The entirety of the prior application is incorporated by reference into the present application.

technical field

The present disclosure relates to stilbene compounds, especially the use of such compounds in the prevention and/or treatment of diseases related to the central nervous system, and belongs to the field of medicine.

Background technique

The central nervous system (Central Nervous System, CNS) is the main part of the nervous system, which includes the spinal cord located in the spinal canal and the brain located in the cranial cavity. Or the brain and spinal cord and the connections between them. In the central nervous system, a large number of nerve cells come together to organically form a network or circuit. The main functions of the central nervous system are to transmit, store and process information, generate various mental activities, and dominate and control the behavior of animals.

Central nervous system diseases can be roughly divided into two categories. The first category is brain diseases caused by brain damage, such as Parkinson's disease, Alzheimer's disease and brain tumors, etc.; the second category is motor and sensory dysfunction caused by spinal cord injuries. wait. Microglia, as macrophages in the brain, are one of the key players in central nervous system immunity. They are distributed throughout the parenchyma, accounting for about 10% to 20% of the total number of glial cells in the brain. Experimental and epidemiological evidence has shown that the activation of microglia is associated with neurodegenerative diseases, such as stroke, Alzheimer's disease, cognitive dysfunction, etc.

The blood-brain barrier maintains a relatively stable environment in the nervous system by restricting compounds from entering the central nervous system, and protects nerve cells from harmful substances. However, the blood-brain barrier also restricts the pathways needed for compounds carried by the blood and nutrients necessary for normal metabolism to reach the central nervous system. The existence of this limitation makes it difficult for many drugs to enter the central nervous system, which has become a key bottleneck in the current drug treatment of central nervous system diseases. Therefore, the development of drugs that can effectively penetrate the blood-brain barrier and treat diseases related to the central nervous system is of great significance for the prevention and treatment of such diseases.

Contents of the invention

In order to improve the above technical problems, the present disclosure provides the use of the compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicines:

Wherein, the drug is used for at least one of the following purposes:

(1) Prevention and/or treatment of diseases or conditions related to the central nervous system;

(2) Inhibit the secretion of cytokines;

(3) inhibit the activation of glial cells;

(4) Inhibit the concentration of glutamate in the body.

According to an embodiment of the present disclosure, the compound represented by the formula (I) may be an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1), that is, 5-[( E)-2-Styryl]-2-isopropyl-1,3-benzenediol:

The present disclosure also provides the use of the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, which is used for at least one of the following uses:

(2) Inhibit the secretion of cytokines;

(3) inhibit the activation of glial cells;

(4) Inhibit the concentration of glutamate in the body.

The present disclosure also provides a method for preventing and/or treating central nervous system-related diseases or disorders, comprising administering a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to patients in need of patients.

The present disclosure also provides a method for inhibiting cytokine activity, comprising administering the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to a patient in need.

The present disclosure also provides a method for inhibiting glial cell activation, comprising administering the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to a patient in need.

The present disclosure also provides a method for inhibiting glutamic acid concentration in vivo, comprising administering the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof to a patient in need.

The present disclosure also provides a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, which is used for at least one of the following purposes:

(2) Inhibit the secretion of cytokines;

(3) inhibit the activation of glial cells;

(4) Inhibit the concentration of glutamate in the body.

The present disclosure also provides a pharmaceutical composition, which comprises a compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the drug The composition is used for at least one of the following purposes:

(2) Inhibit the secretion of cytokines;

(3) inhibit the activation of glial cells;

(4) Inhibit the concentration of glutamate in the body.

The present disclosure also provides the use of the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is used to inhibit the concentration of glutamic acid in the body.

According to an embodiment of the present disclosure, the cytokines may include, but are not limited to, at least one selected from the following: TNF-α, IL-1β, IL-6, and IL-10.

According to an embodiment of the present disclosure, the glial cells may be glial cells present in the central nervous system, including but not limited to at least one selected from the following: astrocytes, oligodendrocytes cells and microglia.

According to an embodiment of the present disclosure, the drug or pharmaceutical composition may be selected from cytokine inhibitors, such as TNF-α inhibitors and interleukin inhibitors; wherein, the interleukins may be selected from, for example, IL-1β , IL-6 or IL-10.

According to an embodiment of the present disclosure, the drug or pharmaceutical composition may be selected from activation inhibitors of glial cells.

According to an embodiment of the present disclosure, the drug or pharmaceutical composition may be selected from inhibitors of glutamate concentration in vivo.

According to an embodiment of the present disclosure, the drug or pharmaceutical composition may be selected from therapeutic or preventive agents for central nervous system-related diseases or disorders.

According to an embodiment of the present disclosure, the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof and its medicine or pharmaceutical composition can treat the disease or disease by passing through the blood-brain barrier. Prophylactic or therapeutic effects, as well as inhibition of cytokine secretion, glial cell activation and glutamate concentration.

According to an embodiment of the present disclosure, the pharmaceutically acceptable salt may be selected from addition salts of compounds of formula (I) or formula (I-1) with bases.

According to an embodiment of the present disclosure, the central nervous system-related disease or disorder may be a disease or disorder associated with secretion of cytokines and/or activation of glial cells.

According to an embodiment of the present disclosure, the central nervous system-related disease or disease may be a disease or disease related to central nervous system inflammation, which includes but is not limited to one selected from the following: neuroinflammation, neurodegenerative Disease, stroke, epilepsy, traumatic brain injury, shock, HIV dementia, glaucoma, multiple sclerosis.

As an example, said neurodegenerative disease is selected from Alzheimer's disease, cognitive impairment, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, spinal muscular atrophy, Parkinson's disease, Huntington's Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, ataxia telangiectasia, amyotrophic lateral sclerosis.

According to an embodiment of the present disclosure, the central nervous system (CNS) includes the brain and spinal cord.

In the context of this disclosure, "secretion" (such as "secretion of a cytokine") and "release" (such as "release of a cytokine") have the same meaning and are used interchangeably.

Beneficial effect

The applicant unexpectedly found that the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof can efficiently penetrate the blood-brain barrier, inhibit the inflammatory response of the central nervous system, and can be used to prevent and/or Treat diseases or conditions related to the central nervous system, inhibit the secretion of cytokines, inhibit the activation of glial cells, and inhibit the concentration of glutamate in the body.

Description of drawings

Fig. 1 is a broken line graph of changes in brain tissue drug concentration after intraperitoneal injection of the test compound in rats in Example 1.

FIG. 2 is a line graph of the inhibitory rate of the test compound on TNF-α in Example 2.

Fig. 3 is a line graph of the inhibition rate of glutamate by the test compound in Example 3.

Fig. 4 is a histogram of the inhibitory rate of the test compound in Example 4 to rat glial cell cytokines.

Detailed ways

The technical solution of the present disclosure will be further described in detail in conjunction with specific embodiments below. It should be understood that the following examples are only for illustrating and explaining the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above contents of the present disclosure are covered within the intended protection scope of the present disclosure.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

The test compound described in the following examples is the compound shown in the following formula (I-1):

Example 1

After intraperitoneal injection of the test compound in rats, the concentration of the drug in the brain tissue was determined

18 rats were randomly divided into three groups A, B and C, and 10 mg/kg of the test compound was injected intraperitoneally respectively, and the rats in groups A, B and C were killed by decapitation at 15 min, 1.5 h and 6 h after administration, respectively. Quickly dissect and collect brain tissue, and after precise weighing, prepare 50% (g/ml) homogenate by adding 1 g of tissue to 2 ml of normal saline, take 1 ml of homogenate and centrifuge at 3000 rpm for 15 min, take 200 μL of supernatant, add 400 μL of acetonitrile ( Contain internal standard 5μg/ml) to precipitate protein, then centrifuge at 12000rpm for 15min, and inject the supernatant after passing through a microporous membrane. The RP-HPLC method was used to measure and calculate the drug concentrations at different time points, and the results are shown in Figure 1. The concentration of the test compound in the rat brain tissue showed a trend of first increasing and then decreasing with time, indicating that the test compound could effectively break through the blood-brain barrier and enter the brain tissue.

Example 2

Inhibition experiments of test compounds on tumor necrosis factor-α (TNF-α) in microglial cell lines

Rat primary microglial cells (3.5×10 ⁴ cells/well) were cultured in DMEM medium containing 2% fetal bovine serum in a 96-well plate, and a drug group and a control group were respectively set up. Take out the medium from the well, add the drug-containing medium containing different concentrations of the test compound (0.01 μM, 0.1 μM, 1 μM, 10 μM) in the drug group, add blank medium in the control group, and continue to cultivate for 30 minutes. Add 100ng/mL lipopolysaccharide (LPS) to stimulate, continue to culture for 48h, measure the TNF-α level released by the cells according to the standard method of TNF-α ELISA kit, and obtain the inhibition of TNF-α by the test compound The results are shown in Figure 2. The inhibition rate of TNF-α increases with the increase of the concentration of the test compound, and can reach an inhibition rate of more than 98%.

Example 3

Inhibition experiments of test compounds on glutamate in microglial cell lines

Rat primary microglial cells (3.5×10 ⁴ cells/well) were cultured in 96-well plates with phenol red-free and serum-free DMEM medium containing 2 mM glutamine, and drug groups and control groups were set up, respectively. Take out the medium from the well, add the drug-containing medium containing different concentrations of the test compound (0.01 μM, 0.1 μM, 1 μM, 10 μM) in the drug group, add blank medium in the control group, and continue to cultivate for 30 minutes. Add 100ng/mL lipopolysaccharide (LPS) to stimulate, continue to culture for 48h, use the fluorescence detection method to measure the glutamate level in the cells respectively, and obtain the inhibitory rate of the test compound on glutamate, the results are shown in Figure 3. The inhibitory rate to glutamic acid increases with the increase of the concentration of the test compound, which can effectively inhibit glutamic acid.

Example 4

Inhibition experiments of test compounds on nerve cell cytokines

Rat primary microglial cells were cultured in DMEM medium containing 2% fetal bovine serum in 4 culture dishes, and

drug groups

1 and 2 and

control groups

1 and 2 were set up respectively. Take out the culture medium, add the culture medium containing 5μM test compound in the medication group, add the blank culture medium in the control group, after continuing to cultivate for 48h, use R&D Systems DuoSet ELISA to measure the IL-1β level in the medication group 1 and the control group 1 respectively, The levels of IL-6 in the medication group 2 and the control group 2 were measured, and the inhibitory rate of the test compound on IL-1β and IL-6 was obtained. The results are shown in FIG. 4 . The compound disclosed in the present disclosure has a high inhibitory rate on both IL-1β and IL-6.

The implementation manners of the technical solution of the present disclosure have been described as examples above. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included within the protection scope of the claims of the present application.

Claims

Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicaments:

Wherein, the drug is used for at least one of the following purposes:

(1) Prevention and/or treatment of diseases or conditions related to the central nervous system;

(2) Inhibit the secretion of cytokines;

(3) inhibit the activation of glial cells;

(4) Inhibit the concentration of glutamate in the body;

Preferably, the compound represented by the formula (I) is an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1):
The use according to claim 1, characterized in that the cytokine is selected from at least one of the following: TNF-α, IL-1β, IL-6 and IL-10.
The use according to claim 1 or 2, wherein the glial cells are glial cells present in the central nervous system, including but not limited to at least one selected from the following: astrocytes cells, oligodendrocytes, and microglia.
The use according to any one of claims 1 to 3, characterized in that the drug is selected from the group consisting of cytokine inhibitors, inhibitors of glial cell activation, inhibitors of glutamate concentration in the body, central nervous system Therapeutic and/or preventive agents for related diseases or conditions;

The cytokine inhibitor is a TNF-α inhibitor or an interleukin inhibitor; wherein the interleukin is selected from IL-1β, IL-6 and IL-10;

Preferably, the medicament has a preventive and/or therapeutic effect on the disease or condition by penetrating the blood-brain barrier, and has an inhibitory effect on the secretion of cytokines, the activation of glial cells and the concentration of glutamate.
The use according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt is selected from the addition salts of compounds represented by formula (I) or formula (I-1) and bases .
According to the use according to any one of claims 1 to 5, the diseases or disorders related to the central nervous system are diseases or disorders related to the secretion of cytokines and/or the activation of glial cells.
According to the use according to any one of claims 1 to 6, the central nervous system-related disease or disease is a disease or disease related to central nervous system inflammation, which includes but is not limited to one selected from the following : Neuroinflammation, neurodegenerative disease, stroke, epilepsy, traumatic brain injury, shock, HIV, dementia, glaucoma, and multiple sclerosis;

Preferably, the neurodegenerative disease is selected from Alzheimer's disease, cognitive impairment, cerebellar atrophy, multiple sclerosis, primary lateral sclerosis, spinal muscular atrophy, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, ataxia-telangiectasia, and amyotrophic lateral sclerosis.
According to the use according to any one of claims 1 to 7, the central nervous system includes brain and spinal cord.
A pharmaceutical composition comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, the compound represented by the formula (I-1) or a pharmaceutically acceptable salt thereof, and Pharmaceutically acceptable excipients, wherein the pharmaceutical composition is used for at least one of the following purposes:

(1) Prevention and/or treatment of diseases or conditions related to the central nervous system;

(2) Inhibit the secretion of cytokines;

(3) inhibit the activation of glial cells;

(4) Inhibit the concentration of glutamate in the body.
The pharmaceutical composition according to claim 9, characterized in that, the pharmaceutical composition is selected from the group consisting of cytokine inhibitors, inhibitors of glial cell activation, inhibitors of glutamate concentration in vivo, and central nervous system-related A therapeutic or preventive agent for a disease or condition;

The cytokine inhibitor is a TNF-α inhibitor or an interleukin inhibitor; wherein, the interleukin can be selected from IL-1β, IL-6 and IL-10;

Preferably, the pharmaceutical composition has a preventive or therapeutic effect on the disease or disorder by penetrating the blood-brain barrier, and has an inhibitory effect on the secretion of cytokines, the activation of glial cells and the concentration of glutamate.