2-indolinone compounds and uses thereof

Abstract

The application belongs to the technical field of biomedicine, and particularly relates to a 2-indolone compound serving as a target p38MAPK, including a compound as shown in structural formula I or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof has the activity of inhibiting p38MAPK, can serve as an inhibitor of p38MAPK, and has the activity of resisting tumors, and can effectively inhibit the growth of tumor cells.

Description

Technical Field

[0001] This invention belongs to the field of biological antitumor pharmaceutical technology, and particularly relates to a 2-indole ketone compound and its uses. Background Technology

[0002] p38 mitogen-activated protein kinase (MAPK), also known as RK or CSBP (cytokinin-specific binding protein), is a mammalian ortholog of yeast Hog1p MAP kinase. It participates in the signaling cascade controlling cytokines and stress cell responses. It responds to stress stimuli such as cytokines, ultraviolet radiation, heat shock, and osmotic shock, and participates in cell differentiation, apoptosis, and autophagy. Due to aging, persistent activation of the p38 MAPK pathway in muscle satellite cells (muscle stem cells) impairs muscle regeneration.

[0003] The p38 MAPK family consists of four identified members: p38α, p38β, p38γ, and p38δ. Extensive evidence supports p38α's role as a tumor suppressor, negatively regulating cell cycle progression at G1 / S and G2 / M channels through multiple mechanisms. However, p38α also possesses oncogenic effects, which are related to key cancer progression processes (such as invasion, inflammation, and angiogenesis) in which p38α is involved. Activation of the p38 MAPK pathway has been demonstrated in various disease models involving cancer cell invasion and migration, such as breast cancer, prostate cancer, melanoidoma, and metastatic serous ovarian cancer, making p38 a promising target for cancer therapy.

[0004] Hundreds of p38 MAPK inhibitors have been reported, but none are currently used as clinical treatments. This is likely because p38 MAPK is involved in multiple cellular activities, and its inhibition can lead to various side effects. The role of p38 MAPK in cancer is highly complex, and different systems and conditions may yield different research results. However, mounting evidence suggests that p38 MAPK inhibitors affect the proliferation, invasion, and migration of cancer cells, demonstrating significant potential for cancer treatment. Summary of the Invention

[0005] To address the aforementioned technical challenges, this invention utilizes high-throughput screening technology to design and synthesize a 2-indoleone inhibitor targeting p38MAPK. This inhibitor selectively inhibits the p38 MAPK protein and its downstream signaling pathways, exhibiting excellent anti-proliferative activity in corresponding tumor cells. Therefore, the development of such inhibitors holds great promise for future research.

[0006] The present invention addresses the above-mentioned technical problems by providing a method for preparing and applying a 2-indolone compound.

[0007] The technical problem solved by the present invention is to provide a 2-indoleone inhibitor that targets p38 MAPK.

[0008] The present invention provides compounds as shown below or pharmaceutically acceptable salts thereof:

[0009]

[0010] The compounds in this invention, or their pharmaceutically acceptable salts, have the structural formula shown in Formula I.

[0011] In this invention, the compound skeleton is indole; the 2-fluorophenyl substitution and the different skeleton structures may change the binding mode of the compound with p38, thereby causing different levels of activity.

[0012] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

[0013] Furthermore, the antitumor drug is preferably an inhibitor targeting p38 MAPK.

[0014] The antitumor drug is preferably an antitumor drug, and the corresponding tumor is a tumor with p38 MAPK overexpression characteristics.

[0015] A pharmaceutical composition comprising an effective dose of any of the compounds described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

[0016] The compounds prepared by this invention, or their pharmaceutically acceptable salts, can be used as inhibitors targeting p38 MAPK, exhibiting antitumor activity and effectively inhibiting the growth of cancer cells.

[0017] The compounds of this invention have an inhibitory effect on tumor cells with p38 MAPK overexpression. Attached Figure Description

[0018] Figure 1 The figure shows the test results of the anti-proliferative activity of the compound represented by Formula I in this invention against MDA-MB-231 and RKO cells. Detailed Implementation

[0019] The present invention will be further described below with reference to specific embodiments:

[0020] The present invention provides compounds as shown below or pharmaceutically acceptable salts thereof:

[0021]

[0022] A compound or a pharmaceutically acceptable salt thereof, with the structural formula shown in Formula I.

[0023] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

[0024] Furthermore, the antitumor drug is preferably an inhibitor targeting p38 MAPK.

[0025] The antitumor drug is preferably an antitumor drug, and the corresponding tumor is a tumor with p38 MAPK overexpression characteristics.

[0026] The present invention also provides a pharmaceutical composition comprising an effective dose of the above-described compound or a pharmaceutically acceptable salt thereof.

[0027] The compounds of the present invention can be formulated into the following forms by methods known in the art: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely dispersed powders or aerosols or sprays for inhalation, and sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral (including intravenous, intramuscular or infusion) administration.

[0028] Liquid formulations can be prepared using sterile water or water-propylene glycol solutions as solvents, or the active ingredient can be formulated in an aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavoring agents, stabilizers, and thickeners as needed.

[0029] Orally administered aqueous suspensions can be made by dispersing finely dispersed active components together with a viscous substance in water, such as natural synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other suspending agents known in the pharmaceutical field.

[0030] The pharmaceutical composition may be in unit dose form. In these forms, the composition is divided into unit doses containing an appropriate amount of the active ingredient. The unit dose form may be a packaged formulation comprising a portion of the formulation, such as boxed tablets, capsules, and powders in tubular vials or ampoules. The unit dose form may also be capsules, sachets, or tablets, or any of these packaging forms in appropriate quantities.

[0031] The active ingredient of the pharmaceutical composition of the present invention may be the compound of the present invention alone, or it may be combined with other antitumor compounds as the active ingredient.

[0032] In the treatment of tumors, the pharmaceutical compositions of the present invention can be used in combination with other antitumor drugs. For example, they can be used in combination with antiproliferative / antitumor drugs, cell growth inhibitors, anti-invasion drugs, growth factor function inhibitors, anti-angiogenic agents, and vascular damaging agents used in medical oncology.

[0033] In the treatment of tumors, such combination therapy can be achieved by administering various therapeutic components simultaneously, sequentially, or individually. Such combination products utilize compounds of the present invention within their effective dose range and other pharmaceutically active agents within their permitted dose range.

[0034] The specific embodiments of the present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the embodiments described herein.

[0035] Example 1: Synthesis of the compound

[0036] The compound was synthesized using the following reaction:

[0037]

[0038] (i) HATU, DIEA, DMF, 25°C; (ii) THF, NaOH, 40°C; (iii) HATU, DIEA, DMF, 25°C.

[0039] (1) General method for synthesizing intermediates 1-2

[0040] 2-O-indoline-6-carboxylic acid (1.77 g, 10 mmol), methyl 4-aminomethylbenzoate (1.65 g, 10 mmol), HATU (4.18 g, 11 mmol), and DIEA (2.58 g, 20 mmol) were dissolved in DMF and incubated at room temperature for 2 h. After TLC was completed, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give intermediate 1, a yellow solid (2.75 g, yield 85%).

[0041] Intermediate 1 (2.5 g, 7.7 mmol) was dissolved in 30 mL of a THF:water mixture of 2:1, and lithium hydroxide (0.74 g, 30.8 mmol) was added. The mixture was heated at 40 °C for 3 h. After the reaction was confirmed to be complete by TLC, the solution was concentrated under reduced pressure to remove THF. The pH of the solution was adjusted to acidic, and the product was precipitated and filtered to give intermediate 2, a white solid (2.09 g, yield 84%).

[0042] (2) Synthesis method of compound 1

[0043] 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) were added to 30 mL of LDM. The mixture was reacted at room temperature for 2 h, and TLC analysis showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give a yellow solid compound 1 (1.56 g, yield 83%).

[0044] Compound 1, yellow solid, yield 83%; 1 H NMR (400MHz, DMSO-d6) 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).

[0045] Experiment 1: Compound 1's anti-proliferative assay against MDA-MB-231, RKO cells

[0046] Antiproliferative activity assays were performed in MDA-MB-231, RKO cells, and the results are shown below. Figure 1 As shown.

[0047] MDA-MB-231, RKO cells were treated with compound 1, and the half-maximal inhibitory concentration (IC50) against different tumor cell types was determined. Figure 1 It can be clearly seen that the compound has significant and strong anti-proliferative activity against cells expressing p38 MAPK, with half-maximal inhibitory concentrations of 24.2±0.07μM and 21.34±0.91μM against MDA-MB-231 and RKO cells, respectively.

[0048] Based on the above experiments, this invention has obtained an inhibitor that can effectively inhibit the anti-cancer effect of p38 MAPK. This type of inhibitor can provide a good method for treating various tumors that overexpress p38 MAPK, including breast cancer. The development of such inhibitors has a broad research prospect.

[0049] The above embodiments / experimental examples are merely illustrative and not intended to limit the implementation methods. Those skilled in the art will recognize that various variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementation methods. However, obvious variations or modifications derived therefrom remain within the scope of this invention.

Claims

1. A 2-indolone compound, characterized in that: The compound is a compound with the structural formula shown in Formula I or a pharmaceutically acceptable salt thereof: 。 2. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an antitumor medicament for treating breast cancer and / or colorectal cancer.

3. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises an effective dose of a formulation of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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