CN117720525A - 2-indolone compound and application thereof - Google Patents
2-indolone compound and application thereof Download PDFInfo
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- CN117720525A CN117720525A CN202311729406.9A CN202311729406A CN117720525A CN 117720525 A CN117720525 A CN 117720525A CN 202311729406 A CN202311729406 A CN 202311729406A CN 117720525 A CN117720525 A CN 117720525A
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- pharmaceutically acceptable
- acceptable salt
- p38mapk
- inhibitor
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Abstract
The invention belongs to the technical field of biomedicine, and particularly relates to a 2-indolone compound serving as a targeting p38MAPK, which comprises a compound shown in a structural formula I or pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof has the activity of inhibiting p38MAPK, can be used as an inhibitor of p38MAPK, has anti-tumor activity, and can effectively inhibit the growth of tumor cells.
Description
Technical Field
The invention belongs to the technical field of biological antitumor pharmacy, and particularly relates to a 2-indolone compound and application thereof.
Background
p38 mitogen-activated protein kinase is a class of mitogen-activated protein kinase (MAPK), also known as RK or CSBP (cytokinin-specific binding protein), a mammalian ortholog, yeast Hog1p MAP kinase, which is involved in the signaling cascade to control cytokines and stress cell responses. It responds to stress stimuli such as cytokines, uv light irradiation, heat shock and osmotic shock, and is involved in cell differentiation, apoptosis and autophagy. Sustained activation of the p38MAPK pathway in muscle satellite cells (muscle stem cells) impairs muscle regeneration due to aging.
The p38MAPK family consists of 4 established members: p38α, p38β, p38γ, and p38δ. Much evidence supports the role of p38α as a tumor suppressor, down regulating cell cycle progression at G1/S and G2/M channels through a variety of mechanisms. But p38α also has carcinogenesis, which is related to key processes of cancer progression (such as invasion, inflammation and angiogenesis) in which p38α participates. Activation of the p38MAPK pathway has been shown to be involved in the invasion and migration of cancer cells in a variety of disease models, such as breast cancer, prostate cancer, melanoma-like, metastatic serous ovarian cancer, and the like, which makes p38 a hot target for the treatment of cancer.
There are hundreds of p38MAPK inhibitors reported so far, but no inhibitors are currently used as clinical therapeutic drugs. This is probably due to the involvement of p38MAPK in various cellular activities, and inhibition of p38MAPK may lead to various side effects. The role of p38MAPK in cancer is quite complex and different systems and conditions may lead to different findings. However, there is growing evidence that p38MAPK inhibitors have a great potential for cancer treatment, with an impact on proliferation, invasion, and migration of cancer cells.
Disclosure of Invention
In order to solve the technical problems, the invention designs and synthesizes the 2-indolone inhibitor targeting the p38MAPK through a high-throughput screening technology. The inhibitor can selectively inhibit p38MAPK proteins and downstream signal channels and has good antiproliferative activity in corresponding tumor cells, so that the inhibitor has wide research prospect for the development of the inhibitor.
The preparation and application of the 2-indolone compound in the invention solve the technical problems,
the invention solves the technical problem of providing a 2-indolone inhibitor serving as a targeting p38 MAPK.
The present invention provides a compound as shown below or a pharmaceutically acceptable salt thereof:
the structural formula of the compound or the pharmaceutically acceptable salt thereof is shown as the formula I.
The compound skeleton in the invention is indole; the substitution of 2-fluorophenyl groups and the difference in the backbone structure may alter the binding pattern of the compound to p38, thereby leading to a difference in the magnitude of the activity.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Furthermore, the antitumor drug is preferably an inhibitor drug targeting the p38 MAPK.
The antitumor drug is preferably an antitumor drug, and the corresponding tumor is a tumor with the characteristic of over-expression of p38 MAPK.
A pharmaceutical composition comprising an effective dose of a formulation of a compound of any one of the above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient formulation.
The compound or the pharmaceutically acceptable salt thereof prepared by the invention can be used as an inhibitor of targeted p38MAPK, has anti-tumor activity, and can effectively inhibit the growth of cancer cells.
The compound has an inhibiting effect on tumor cells with the characteristic of over-expression of p38 MAPK.
Drawings
FIG. 1 is a graph showing the results of the anti-proliferative activity test of the compound of formula I according to the present invention on MDA-MB-231, RKO cells
Detailed Description
The invention is further illustrated by the following description of specific embodiments:
the present invention provides a compound as shown below or a pharmaceutically acceptable salt thereof:
the structural formula of the compound or the pharmaceutically acceptable salt thereof is shown in the formula I.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Furthermore, the antitumor drug is preferably an inhibitor drug targeting the p38 MAPK.
The antitumor drug is preferably an antitumor drug, and the corresponding tumor is a tumor with the characteristic of over-expression of p38 MAPK.
The present invention also provides a pharmaceutical composition which is a formulation comprising an effective amount of the above compound or a pharmaceutically acceptable salt thereof.
The compounds of the present invention may be prepared by methods known in the art in the form of: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or sprays for inhalation, sterile aqueous or oily solutions or suspensions for parenteral (including intravenous, intramuscular or infusion) or sterile emulsions.
Sterile water or water-propylene glycol solutions may be used as solvents to prepare liquid formulations, and the active ingredient may also be formulated in aqueous polyethylene glycol solutions. Aqueous solutions for oral administration may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired.
Aqueous suspensions for oral use can be prepared by dispersing the finely divided active component in water together with viscous materials such as natural synthetic gums, resins, methylcellulose, carboxymethylcellulose and other suspending agents known in the pharmaceutical arts.
The pharmaceutical composition may be in unit dosage form. In these forms, the composition is divided into unit doses containing appropriate amounts of the active component. The unit dosage form may be a packaged formulation, including discrete amounts of formulation, such as a boxed tablet, capsule, and powder in a vial or ampoule. The unit dosage form may also be a capsule, cachet or tablet or it may be the appropriate number of any of these packaged forms.
The active ingredients of the pharmaceutical composition of the present invention may be only the compound of the present invention, or may be combined with other antitumor compounds as active ingredients.
In the course of treatment of tumors, the pharmaceutical composition of the present invention may be used in combination with other antineoplastic agents. For example, in combination with antiproliferative/antineoplastic agents for medical oncology, cytostatic agents, anti-invasive agents, inhibitors of growth factor function, antiangiogenic agents, vascular damaging agents, etc.
In the treatment of tumors, such combination therapy may be achieved by simultaneous, sequential or separate administration of the various therapeutic ingredients. Such combination products employ the compounds of the invention in an effective dosage range and other pharmaceutically active agents in a permitted dosage range.
The following describes the invention in more detail with reference to examples, which are not intended to limit the invention thereto.
Example 1 Synthesis of Compounds
The compounds were synthesized using the following reaction scheme:
(i)HATU，DIEA，DMF，25℃；(ii)THF，NaOH，40℃；(iii)HATU,DIEA，DMF，25℃。
(1) Synthesis method of intermediate 1-2
2-oxoindoline-6-carboxylic acid (1.77 g,10 mmol), methyl 4-aminomethylbenzoate (1.65 g,10 mmol), HATU (4.18 g,11 mmol), DIEA (2.58 g,20 mmol) were dissolved in DMF and after completion of TLC, ethyl acetate extraction and concentration under reduced pressure gave intermediate 1 as a yellow solid (2.75 g, 85% yield) purified by column chromatography (dichloromethane: methanol=30:1).
Intermediate 1 (2.5 g,7.7 mmol) was dissolved in 30ml hf: water = 2:1, lithium hydroxide (0.74, 30.8 mmol) was added thereto, and the mixture was heated at 40℃for 3 hours. After completion of the TLC detection reaction, THF was removed by concentration under reduced pressure, pH of the solution was adjusted to be acidic, and the product was precipitated and suction-filtered to give intermediate 2 as a white solid (2.09 g, yield 84%).
(2) Synthesis method of compound 1
To 30mL of MF was added intermediate 2 (1.5 g,4.8 mmol), 4-aminotetrahydropyran (0.48 g,4.8 mmol), HATU (2.0 g,5.28 mmol) and DIEA (1.24 g,9.6 mmol), and the reaction was allowed to proceed at room temperature for 2h, and TLC detection showed the completion of the reaction. Concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=30:1) to give compound 1 (1.56 g, yield 83%) as a yellow solid.
Compound 1, yellow solid, yield 83%; 1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),9.07(t,J＝6.0Hz,1H),8.24(d,J＝7.7Hz,1H),7.80(d,J＝8.3Hz,2H),7.50(d,J＝7.7Hz,1H),7.37(d,J＝8.2Hz,2H),7.32–7.26(m,2H),4.50(d,J＝6.0Hz,2H),3.98(qd,J＝8.5,7.2,4.8Hz,1H),3.87(d,J＝12.1Hz,2H),3.54(s,2H),3.43–3.35(m,2H),1.74(d,J＝12.4Hz,2H),1.57(qd,J＝11.9,4.5Hz,2H)。
test one Compound 1 anti-proliferation assay against MDA-MB-231, RKO cells
The results of the anti-valorized activity assay in MDA-MB-231, RKO cells are shown in FIG. 1.
MDA-MB-231, RKO cells were treated with Compound 1 and half inhibition concentrations for different tumor cells were determined. As is evident from FIG. 1, the compound has significantly stronger antiproliferative activity on cells expressing p38MAPK, and half inhibition concentrations on MDA-MB-231 and RKO cells are 24.2+ -0.07 μM and 21.34+ -0.91 μM, respectively.
By combining the experiments, the inhibitor capable of effectively inhibiting the p38MAPK to play an anticancer role is obtained, and the inhibitor can provide a good method for treating various tumors including breast cancer, which are over-expressed with the p38MAPK, and has a very wide research prospect aiming at the development of the inhibitor.
The above examples/experiments are only examples for clarity of illustration and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (6)
1. A 2-indolone compound, characterized in that: the structural formula of the compound is shown in a formula I or pharmaceutically acceptable salt thereof:
2. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the structural formula is shown in formula I.
3. Use of a compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor medicament.
4. Use according to claim 3, characterized in that: the antitumor drug is an inhibitor drug targeting the p38 MAPK.
5. Use according to claim 4, characterized in that: the antitumor drug is a drug for treating tumors with the characteristic of over-expression of p38 MAPK.
6. A pharmaceutical composition characterized by: the pharmaceutical composition comprises an effective dose of a formulation of a compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311729406.9A CN117720525A (en) | 2023-12-15 | 2023-12-15 | 2-indolone compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311729406.9A CN117720525A (en) | 2023-12-15 | 2023-12-15 | 2-indolone compound and application thereof |
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| Publication Number | Publication Date |
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| CN117720525A true CN117720525A (en) | 2024-03-19 |
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| CN202311729406.9A Pending CN117720525A (en) | 2023-12-15 | 2023-12-15 | 2-indolone compound and application thereof |
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| Country | Link |
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| CN (1) | CN117720525A (en) |
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2023
- 2023-12-15 CN CN202311729406.9A patent/CN117720525A/en active Pending
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