CN114671887A - Preparation of indolinone compound and anti-tumor application thereof - Google Patents
Preparation of indolinone compound and anti-tumor application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The invention relates to preparation and application of indolinone compounds, and belongs to the technical field of antitumor medicine. The invention solves the technical problem of providing an indolinone autophagy degradation agent serving as a target BRD 4. The compound includes a compound shown below or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof has the activity of degrading BRD4 protein, and can effectively inhibit the proliferation of triple negative breast cancer, lung adenocarcinoma and acute promyelocytic leukemia cells. The compound of the invention is preferably a compound for resisting triple negative breast cancer, lung adenocarcinoma and acute promyelocytic leukemia, and the corresponding tumor type is characterized by BRD4 overexpression.
Description
Technical Field
The invention relates to preparation and application of indolinone compounds, and belongs to the technical field of antitumor medicine.
Background
Bromodomain-binding protein 4 (BRD 4) is a member of bromodomain and extra-terminal (BET) family, and can bind to acetylated histone or non-histone proteins, thereby regulating gene replication and transcription, affecting processes such as cell cycle, cell differentiation, and cell proliferation. BRD4 plays an important role in gene regulation and control networks of various malignant tumors, and can influence malignant progression of various tumors by activating transcription factors such as C-MYC and the like, and BRD4 expression up-regulation is a key target for malignant progression and poor prognosis of tumors such as leukemia, breast cancer, lung cancer, liver cancer and the like.
The invention designs and synthesizes a series of dihydroindolone autophagy degrading agents targeting BRD4 by adopting autophagy-targeting chimera (AUTAC) technology and utilizing the degradation effect of autophagy bodies on target proteins. The degradation agent can degrade BRD4 protein through an autophagy way and shows good antiproliferative activity in various tumor cells, so the degradation agent has wide research prospect aiming at the development of the degradation agent.
Disclosure of Invention
The invention solves the technical problem of providing an indolinone autophagy degradation agent serving as a target BRD 4.
The present invention provides a compound shown below or a pharmaceutically acceptable salt thereof:
wherein R is an iodine atom (I) or a bromine atom (Br)
m is 0 or 1;
n is 2 to 6;
z is 0 to 6;
x is a carbon atom (C) or an oxygen atom (O).
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Furthermore, the anti-tumor drug is preferably a degradation agent drug targeting BRD 4.
The anti-tumor medicine is preferably an anti-tumor medicine, and the corresponding tumor triple negative breast cancer, lung adenocarcinoma and acute promyelocytic leukemia are obtained.
The compound or the pharmaceutically acceptable salt thereof prepared by the invention can be used as an autophagy degrading agent targeting BRD4, has anti-tumor activity, and can effectively inhibit the growth of cancer cells. The compound has an inhibiting effect on tumor cells of triple negative breast cancer, lung adenocarcinoma and acute promyelocytic leukemia, and particularly has a good inhibiting effect on triple negative breast cancer cells.
Drawings
Table 1 shows the degradation rate of BRD4 in MDA-MB-231 cells (triple negative breast cancer cells) and the result of the anti-proliferative activity test of the BRD4 in MDA-MB-231, A549 and HL-60 cells.
TABLE 1 BRD4 degradation Rate test results and results for antitumor cell proliferation Activity of related Compounds of formula I
FIG. 1 shows that compounds 1-11 have degradation effect on BRD4 protein in HeLa cells (cervical cancer cells).
FIG. 2 shows the degradation of BRD4 protein by Compound 6 in different cell lines.
Detailed Description
The present invention provides a compound shown below or a pharmaceutically acceptable salt thereof:
wherein R is an iodine atom (I) or a bromine atom (Br)
m is 0 or 1;
n is 2 to 6;
z is 0 to 6;
x is a carbon atom (C) or an oxygen atom (O).
The following are some preferred structures of the compounds of the present invention.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Furthermore, the anti-tumor drug is preferably a degradation agent drug targeting BRD 4.
The anti-tumor medicine is preferably a medicine for treating triple negative breast cancer, lung adenocarcinoma and acute promyelocytic leukemia.
The present invention also provides a pharmaceutical composition which is a preparation comprising an effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof.
The compounds of the invention can be prepared in the following forms by methods known in the art: 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 or sterile emulsions for parenteral (including intravenous, intramuscular or infusion). The liquid formulations can be prepared using sterile water or water-propylene glycol solutions as solvents, or the active ingredient can be formulated in aqueous polyethylene glycol solutions. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents 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 compositions are divided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package including discrete quantities of the preparation, for example, tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet or it can be the appropriate number of any of these packaged forms.
The active ingredient of the pharmaceutical composition of the present invention may be only the compound of the present invention, or may be combined with other anti-tumor compounds as an active ingredient.
In the process of treating tumors, the pharmaceutical composition can be used for combined treatment with other antitumor drugs. For example, it is used in combination with antiproliferative/antitumor agents, cytostatic agents, anti-invasive drugs, growth factor function inhibitors, antiangiogenic agents, vascular damaging agents, etc. for medical oncology.
In the treatment of tumors, such combination therapy may be achieved by the simultaneous, sequential or separate administration of the various therapeutic ingredients. Such combinations employ the compounds of the present invention in an effective dosage range and the other pharmaceutically active agents in a permitted dosage range.
The following examples are provided to further illustrate the embodiments of the present invention and are not intended to limit the scope of the present invention.
EXAMPLE 1 Synthesis of preferred Compounds
Preferred compounds are synthesized using the following reaction scheme:
(i)K2CO3DMF, 80 ℃; (ii) piperidine and ethanol are refluxed; (iii) TFA, DCM, room temperature; (iv) DMF, HATU, DIPEA, room temperature; (v)TFA, DCM, room temperature; (vi) DMF, HATU, DIPEA, room temperature.
1. General Synthesis of intermediates 1 to 5
3, 5-dibromo-4-hydroxybenzaldehyde (560mg, 2.0mmol), tert-butyl 2-bromoacetate (468.1mg, 2.4mmol), and K were added to DMF (6.0mL) at 80 ℃ respectively2CO3(552mg, 4.0mmol) and the resulting reaction mixture was stirred vigorously. After completion of the reaction, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The product was purified by column chromatography on silica gel (20: 1-10: 1 petroleum ether/ethyl acetate) to afford intermediate 1.
To a solution of intermediate 1(394mg, 1.00mmol) in ethanol (5.0mL) was added 5-iodoindol-2-one (224mg, 1.30 mmol) and piperidine, which was dissolved at room temperature. After completion of the reaction, the reaction was refluxed to 80 ℃ for 3h, washed twice with ethanol and filtered to give intermediate 2(471.6mg, 74%) as a reaction mixture.
Intermediate 2(471.6mg, 0.743mmol) was dissolved in anhydrous dichloromethane (7mL) at 25 ℃. To the reaction mixture was added TFA (2 mL). After the second complete conversion, the reaction mixture was concentrated. The product was subjected to silica gel column Chromatography (CH)2Cl2MeOH ═ 5: 1 to 3: 1) to give intermediate 3.
A mixture of intermediate 3(43.3mg, 0.08mmol), HATU (37.1mg, 0.10mmol) and DIPEA (38.7mg, 0.3 mmol) was stirred in 2mL DMF at room temperature for 3h, extracted with ethyl acetate and dried over anhydrous sodium sulfate to give intermediate 4.
Intermediate 4(37.5mg, 0.05mmol) was added to anhydrous dichloromethane (2.0mL) and magnetically stirred. To the reaction mixture was added TFA (1 mL). The mixture was stirred at 25 ℃ for 3h to give intermediate 5, which was used directly in the next step.
2. General procedure for the Synthesis of Compounds 1-12
A mixture of intermediate 5(38.2mg, 0.05mmol), HATU (26.6mg, 0.07mmol), JQ1 (carboxylic acid) (20.0mg, 0.05mmol) and DIPEA (25.8mg, 0.2mmol) was stirred in 2mL DMF at room temperature for 3h, extracted with ethyl acetate, dried over anhydrous sodium sulfate and purified by silica gel column chromatography to give compounds 1-11.
Compound 1, yellow solid, yield 69%;1H NMR(600MHz，DMSO-d6)，δ(ppm)：10.86(s，2/3H)， 10.80(s，1/3H)，8.78(s，1H)，8.29-8.24(m，1H)，8.19(dt，J＝17.7，6.0Hz，1H)，8.03(s，1H)，8.00 (s，1H)，7.85(s，2/3H)，7.68(s，1/3H)，7.56(q，J＝7.9Hz，1H)，7.50-7.46(m，2H)，7.41(d，J＝8.3 Hz，2H)，6.74(d，J＝8.1Hz，1/3H)，6.68(d，J＝8.1Hz，2/3H)，4.52(dd，J＝8.3，6.0Hz，1H)，4.49 -4.39(m，2H)，3.30-3.18(m，5H)，3.14-3.06(m，1H)，2.57(s，3H)，2.38(s，3H)，1.60(s，3H)， 1.51(dq，J＝21.5，7.4，7.0Hz，4H)；13C NMR(150MHz，DMSO-d6)，δ(ppm)：169.5，167.6，166.5， 166.2，163.1，155.2，152.8，152.3，149.9，142.8，140.6，138.7，137.6，136.8，136.2，135.3，134.4， 133.7，133.6，133.5，133.3，132.3，130.7，130.2，129.9，129.6，128.5，128.2，127.1，123.1，117.8， 117.1，112.1，84.3，84.0，71.0，55.0，53.9，38.4，38.2，37.7，30.4，29.1，26.7，26.6，14.1，12.7，11.4. HR-ESI-MS[M+H]+：m/z 1029.96228。
compound 2, yellow solid, yield 58%; 1H NMR(600MHz，DMSO-d6)，δ(ppm)：10.85(s，2/3H)，10.79(s，1/3H)，8.78(s，1H)，8.21(t，J＝5.6Hz，1H)，8.18-8.14(m，1H)，8.03(d，J＝1.7Hz，1H)， 8.00(s，1H)，7.84(s，2/3H)，7.67(s，1/3H)，7.58-7.53(m，1H)，7.49-7.45(m，2H)，7.41(d，J＝ 8.3Hz，2H)，6.74(d，J＝8.1Hz，1/3H)，6.69(d，J＝8.1Hz，2/3H)，4.50(td，J＝6.1，3.0Hz，1H)， 4.45(s，2/3H)，4.42(s，4/3H)，3.28-3.17(m，4H)，3.15-3.05(m，2H)，2.57(s，3H)，2.38(s，3H)， 1.60(s，3H)，1.57-1.41(m，6H)；13C NMR(150MHz，DMSO-d6)，δ(ppm)：169.8，168.0，166.9， 166.6，163.5，155.6，153.2，152.7，150.3，143.2，141.0，139.1，138.0，137.2，136.6，135.7，134.8， 134.2，134.1，134.0，133.9，133.7，132.7，131.1，130.6，130.3，130.0，128.9，128.6，127.5，123.5， 118.2，117.5，113.2，112.5，84.7，71.4，54.4，40.8，38.8，38.1，29.3，29.1，24.2，14.5，13.1，11.8. HR-ESI-MS[M+H]+：m/z 1043.97805。
Compound 3, yellow solid, yield 71%;1H NMR(400MHz，DMSO-d6)，δ(ppm)：10.84(s，2/3H)， 10.79(s，1/3H)，8.78(s，1H)，8.23-8.11(m，2H)，8.05-7.99(m，1H)，7.85(s，2/3H)，7.68(s， 1/3H)，7.55(ddd，J＝10.0，7.5，1.7Hz，1H)，7.51-7.38(m，5H)，6.75(d，J＝8.1Hz，1/3H)6.70(d，J＝8.1Hz，2/3H)，4.57-4.48(m，1H)，4.46(s，2/3H)，4.43(s，4/3H)，3.26-3.15(m，4H)，3.14- 3.04(m，2H)，2.58(s，3H)，2.39(s，3H)，1.61(s，3H)，1.53-1.43(m，4H)，1.32(p，J＝3.6Hz，4H)；13C NMR(150MHz，DMSO-d6)，δ(ppm)：169.4，166.5，166.1，163.0，162.3，155.1，152.8，149.8， 142.8，140.6，137.6，136.8，136.2，135.3，134.4，133.5，133.3，132.3，130.7，130.1，129.9，129.6， 128.5，127.1，117.8，117.1，112.0，84.3，71.0，53.9，38.5，38.3，37.7，29.3，29.0，26.1，14.1，12.7，11.3. HR-ESI-MS[M+H]+：m/z 1057.99451。
compound 4, yellow solid, yield 64%;1H NMR(400MHz，DMSO-d6)，δ(ppm)：10.83(s，2/3H)， 10.78(s，1/3H)，8.76(s，1H)，8.30(t，J＝5.5Hz，1H)，8.22-8.11(m，1H)，8.02(s，1H)，7.98(s，1H)， 7.82(s，2/3H)，7.67(s，1/3H)，7.53(d，J＝6.4Hz，1H)，7.49-7.37(m，4H)，6.74(d，J＝8.1Hz， 1/3H)，6.69(d，J＝8.1Hz，2/3H)，4.69-4.38(m，3H)，3.62-3.47(m，4H)，3.41(s，2H)，3.28(ddd， J＝19.7，12.2，5.9Hz，4H)，2.57(s，3H)，2.38(s，3H)，1.60(s，3H)；13C NMR(150MHz， DMSO-d6)，δ(ppm)：170.2，168.0，166.9，166.9，163.5，155.5，153.2，152.7，150.2，143.2，141.0， 139.1，138.0，137.2，136.6，135.7，134.8，134.1，133.9，133.7，132.7，131.1，130.6，130.3，130.0， 128.9，128.6，127.5，123.4，118.2，117.5，113.2，112.4，84.7，84.4，71.4，69.4，69.0，54.3，39.1，38.8， 38.0，14.5，13.1，11.8.HR-ESI-MS[M+H]+：m/z 1045.95874。
compound 5, yellow solid, yield 73%;1H NMR(400MHz，DMSO-d6)，δ(ppm)：10.85(s，2/3H)， 10.79(s，1/3H)，8.79(s，1H)，8.30(s，1H)，8.13(dt，J＝20.6，5.8Hz，1H)，8.01(s，1H)，7.84(s， 2/3H)，7.69(s，1/3H)7.58-7.54(m，1H)，7.53-7.43(m，3H)，7.44-7.40(m，2H)，6.75(d，J＝8.1 Hz，1/3H)6.70(d，J＝8.1Hz，2/3H)，4.58-4.46(m，3H)，3.59-3.53(m，5H)，3.49(t，J＝5.9Hz， 2H)，3.34-3.25(m，3H)，3.18(d，J＝5.1Hz，3H)，3.09(q，J＝7.3Hz，1H)，2.59(s，3H)，2.40(s， 3H)，1.67-1.57(m，3H)；13C NMR(150MHz，DMSO-d6)，δ(ppm)：170.2，168.0，166.9，163.5， 155.5，153.2，152.7，150.2，143.2，141.0，139.1，138.0，137.2，136.6，135.7，134.8，134.2，134.1， 133.9，133.7，132.7，131.1，130.6，130.3，130.0，128.9，128.6，127.5，127.5，123.4，118.1，117.4， 113.2，112.4，84.7，84.3，71.5，70.1，70.1，69.7，69.2，54.3，54.0，46.1，39.1，38.8，38.0，14.5，13.1， 11.8，9.0.HR-ESI-MS[M+H]+：m/z 1089.98621。
compound 6, yellow solid, yield 63%;1H NMR(400MHz，CDCl3)，δ(ppm)：10.67(s，2/3H)，9.36 (s，1/3H)，8.51(s，1H)，7.77(s，1H)，7.76-7.65(m，2H)，7.54(s，1H)，7.46(dd，J＝8.2，1.7Hz，1H)， 7.43-7.37(m，2H)，7.31(dd，J＝8.6，2.7Hz，2H)，7.24(s，1H)，6.86(d，J＝8.1Hz，1/3H)，6.75(d， J＝8.1Hz，2/3H)，4.77(t，J＝8.1，6.2Hz，2/3H)，4.67(t，J＝8.1，6.2Hz，1/3H)，4.58(s，2/3H)，4.56 (s，4/3H)，3.72-3.40(m，16H)，3.40-3.18(m，2H)，2.69(s，3H)，2.41(s，3H)，1.90(t，J＝6.0Hz， 2H)，1.80(q，J＝6.0，5.6Hz，2H)，1.67(s，3H)；13C NMR(200MHz，CDCl3)，δ(ppm)：170.3，170.3，167.4，167.1，164.2，163.9，155.7，152.8，152.6，150.0，141.9，140.6，139.0，138.2，136.9，136.8， 136.5，136.5，136.1，133.8，133.5，133.4，132.9，132.1，131.9，131.8，131.1，131.1，131.0，131.0， 130.7，130.6，129.9，128.8，128.7，128.3，128.2，127.9，126.6，123.1，118.3，117.5，113.0，112.8，84.2， 84.1，71.2，71.0，70.9，70.6，70.6，70.5，70.4，70.1，70.0，69.8，69.5，69.0，54.4，38.9，38.1，37.6，37.5， 36.9，29.7，29.2，29.1，29.1，28.6，14.5，13.2，11.9.HR-ESI-MS[M+H]+：m/z 1162.04346。
compound 7, yellow solid, yield 55%;1H NMR(400MHz，DMSO-d6)，δ(ppm)：10.89(s，1H)，8.85(s， 1/3H)，8.79(s，2/3H)，8.35-8.25(m，1H)，8.18-8.09(m，1H)，8.07-8.00(m，1H)，7.86(s，1H)， 7.71-7.53(m，2H)，7.51-7.45(m，2H)，7.42(dt，J＝8.6，2.1Hz，2H)，6.77(dd，J＝8.2，3.1Hz， 1/3H)，6.72(dd，J＝8.2，3.1Hz，2/3H)，4.66-4.34(m，3H)，3.83-3.60(m，3H)，3.56(s，6H)，3.50 -3.42(m，5H)，3.33-3.20(m，4H)，2.58(s，3H)，2.39(s，3H)，1.60(s，3H)；13C NMR(150MHz， DMSO-d6)，δ(ppm)：171.4，170.2，170.2，166.8，163.5，162.8，155.5，150.3，137.2，136.2，135.7， 132.7，131.2，130.6，130.3，130.0，128.9，125.7，125.0，125.0，112.6，84.8，79.6，70.2，70.2，70.1， 70.0，69.6，68.5，61.1，54.3，49.1，39.1，38.0，36.3，31.2，14.5，13.1，11.8.HR-ESI-MS[M+H]+：m/z 1155.9938。
compound 8, yellow solid, yield 66%;1H NMR(400MHz，CDCl3)，δ(ppm)：9.15(s，4/5H)，8.52 (s，1/5H)，7.82(d，J＝1.7Hz，1H)，7.78(s，2H)，7.56(s，1H)，7.53-7.46(m，2H)，7.44-7.38(m， 2H)，7.36-7.29(m，2H)，7.26-7.21(m，1H)，6.85(d，J＝8.2Hz，1/5H)，6.76(d，J＝8.2Hz，4/5H)，4.68(t，J＝7.0Hz，1H)，4.61(s，2H)，3.86-3.64(m，10H)，3.63(d，J＝4.4Hz，5H)，3.56(ddd，J＝ 10.8，8.5，4.7Hz，4H)，3.50(q，J＝4.8Hz，2H)，3.41(dd，J＝14.7，7.2Hz，1H)，2.66(s，3H)，2.39(s， 3H)，1.66(s，3H)；13C NMR(100MHz，CDCl3)，δ(ppm)：170.7，168.6，167.4，164.0，155.8，153.0， 150.0，142.0，139.2，136.9，136.7，136.2，133.9，133.8，133.5，132.2，131.9，131.1，130.9，130.7， 130.0，128.8，128.4，123.2，118.3，112.8，84.3，71.5，70.7，70.6，70.5，70.4，70.0，69.8，54.5，39.5， 39.0，39.0，14.5，13.2，12.0.HR-ESI-MS[M+H]+：m/z 1200.0197。
compound 9, yellow solid, yield 55%;1H NMR(600MHz，CDCl3)，δ(ppm)：10.01(s，1/2H)，9.86 (s，1/2H)，8.48(s，1H)，7.78(d，J＝1.6Hz，1H)，7.75(s，1H)，7.71(t，J＝5.5Hz，1H)，7.57(dt，J＝ 24.0，5.6Hz，1H)，7.52(d，J＝5.7Hz，1H)，7.46(dd，J＝8.2，1.7Hz，1H)，7.39(d，J＝8.2Hz，2H)， 7.30(d，J＝8.6Hz，2H)，6.79(d，J＝8.1Hz，1/2H)，6.72(d，J＝8.1Hz，1/2H)，4.69(dt，J＝9.0，7.1 Hz，1H)，4.59(s，1H)，4.54(s，1H)，3.65-3.62(m，8H)，3.61-3.55(m，15H)，3.51-3.45(m，2H)， 3.42(td，J＝14.5，13.5，6.2Hz，1H)，2.66(s，3H)，2.38(s，3H)，1.64(s，3H)；13C NMR(200MHz， DMSO-d6)，δ(ppm)：170.8，168.8，167.7，167.6，167.1，164.1，164.0，155.7，153.1，152.8，150.0， 142.4，140.4，139.1，138.1，136.9，136.6，136.2，133.8，133.6，133.5，133.0，132.1，131.6，131.1，131.0，130.6，129.9，128.8，128.5，128.2，127.7，126.7，123.1，118.2，117.4，113.1，112.5，84.2，71.4， 70.4，70.2，70.0，69.8，54.4，39.4，39.0，38.8，14.5，12.0，11.8.HR-ESI-MS[M+H]+：m/z 1244.0463。
compound 10, yellow solid, yield 70%;1H NMR(400MHz，CDCl3)，δ(ppm)：10.02(s，2/3H)，9.92 (s，1/3H)，8.51(s，1H)，7.78(s，2H)，7.74-7.54(m，2H)，7.53-7.44(m，2H)，7.43-7.38(m，2H)， 7.34-7.30(m，2H)，6.83-6.79(m，2/3H)，6.72-6.69(m，1/3H)4.77-4.66(m，1H)，4.61(s， 4/3H)，4.57(s，2/3H)3.75(tt，J＝4.4，2.1Hz，1H)，3.65(t，J＝4.4Hz，8H)，3.61(q，J＝6.8，6.2Hz， 18H)，3.50(q，J＝5.6Hz，2H)，3.43(dd，J＝14.8，6.9Hz，1H)，2.68(s，3H)，2.40(s，3H)，1.66(s， 3H)；13C NMR(200MHz，CDCl3)，δ(ppm)：170.5，168.5，167.3，167.2，166.8，163.9，156.3，155.5， 152.8，152.5，149.8，142.5，140.4，138.9，137.9，136.6，136.4，136.0，133.8，133.7，133.2，133.1， 132.9，131.8，131.3，130.9，130.7，130.3，129.8，128.5，128.0，127.6，126.5，122.8，118.7，117.9， 117.1，113.0，112.3，83.8，83.7，71.1，71.0，71.0，70.4，70.3，70.3，70.3，70.2，70.2，70.1，70.0，69.7， 69.7，69.5，69.5，69.4，54.1，53.9，42.2，39.2，38.8，38.4，18.3，17.1，14.3，13.0，11.9，11.6. HR-ESI-MS[M+H]+：m/z 1288.0729。
compound 11, yellow solid, yield 57%;1H NMR(400MHz，DMSO-d6)，δ(ppm)：10.86(s，2/3H)， 10.81(s，1/3H)，8.78(s，1H)，8.16(dt，J＝13.9，5.5Hz，2H)，8.02(s，1H)，7.89(t，J＝1.9Hz，1H)， 7.87(d，J＝2.4Hz，1H)，7.47(d，J＝8.4Hz，2H)，7.44-7.33(m，3H)，6.86(d，J＝8.3Hz，1/3H)， 6.81(d，J＝8.3Hz，2/3H)，4.51(dd，J＝8.0，6.2Hz，1H)，4.45(s，2/3H)，4.43(s，4/3H)，3.50(dt，J＝ 5.7，3.4Hz，6H)，3.48-3.44(m，4H)，3.42(d，J＝6.6Hz，2H)，3.26(q，J＝4.8，3.4Hz，2H)，3.23- 3.18(m，2H)，3.18-3.08(m，2H)，2.58(s，3H)，2.39(s，3H)，1.79-1.64(m，4H)，1.60(s，3H)；13C NMR(150MHz，DMSO-d6)，δ(ppm)：169.9，168.2，167.1，166.7，166.6，163.5，162.8，155.5，153.2， 152.8，150.2，142.9，140.6，137.2，136.6，135.7，135.1，134.3，134.1，133.9，133.7，133.4，132.7， 132.2，131.1，130.6，130.3，130.0，128.9，128.8，127.7，127.2，125.3，123.4，123.0，118.2，117.5， 113.7，113.2，112.0，71.4，70.2，70.1，70.0，68.9，68.5，54.3，38.1，36.6，36.3，29.9，29.6，14.5，13.1， 11.8.HR-ESI-MS[M+H]+：m/z 1136.0391。
test example 1 Western blotting of Compounds 1 to 11
The degradation rate of BRD4 by compounds 1-11 in Hela cells was examined by immunoblotting, and the results are shown in Table 1, FIG. 1 and FIG. 2. As can be seen from the results in table 1, fig. 1, and fig. 2, compounds 4, 5, 6, 8, 9, and 11 showed better degradation of BRD4, with compound 6 showing the best degradation. And the compound 6 has good degradation effect on BRD4 in A549 (lung adenocarcinoma cells), HL-60 (acute promyelocytic leukemia cells), MDA-MB-231 (triple negative breast cancer cells), MDA-MB-436 (triple negative breast cancer cells), MDA-MB-468 (triple negative breast cancer cells) and MCF-7 (breast cancer cells) (figure 2).
Test example 2 anti-proliferation test of MDA-MB-231, A549, HL-60 cells with Compounds 1 to 11
The results of the anti-proliferative activity tests in MDA-MB-231, A549 and HL-60 cells are shown in Table 1. MDA-MB-231, A549, HL-60 cells were treated with the preferred compounds and the median inhibitory concentrations against different tumor cells were determined. As is apparent from Table 1, the series of compounds have remarkably strong antiproliferative activity on various tumor cells.
By combining the experiments, the degradation agent capable of effectively degrading BRD4 to play an anticancer role is obtained, the degradation agent can provide a good method for treating various tumors of over-expression BRD4 including triple negative breast cancer, lung adenocarcinoma and acute promyelocytic leukemia, and has a wide research prospect aiming at the development of the degradation agent.
Claims (7)
1. A compound having a structural formula as shown in formula I: the present invention provides a compound shown below or a pharmaceutically acceptable salt thereof:
wherein R is an iodine atom (I) or a bromine atom (Br)
m is 0 or 1;
n is 2 to 6;
z is 0 to 6;
x is a carbon atom (C) or an oxygen atom (O).
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the structural formula is shown as formula I.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that:
R is an iodine atom (I) or a bromine atom (Br)
m is 0 or 1;
n is 2 to 6;
z is 0 to 6;
x is a carbon atom (C) or an oxygen atom (O).
4. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor medicament.
5. Use according to claim 4, characterized in that: the anti-tumor medicine is a degradation agent medicine targeting BRD 4.
6. Use according to claim 4, characterized in that: the anti-tumor drug is a drug for treating triple negative breast cancer, lung adenocarcinoma and acute promyelocytic leukemia.
7. A pharmaceutical composition characterized by: a formulation comprising an effective amount of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
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