CN112375112B - Benzimidazole derivative BI361 and preparation method and application thereof - Google Patents
Benzimidazole derivative BI361 and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a benzimidazole derivative BI361 and a preparation method thereof, wherein the chemical name of the benzimidazole derivative BI361 is {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl ] -1H-benzo [ d ] imidazole-4-yl } (piperidine-1-yl) methanone. The benzimidazole derivative and the pharmaceutically acceptable salt, solvate and hydrate thereof have excellent antitumor in-vitro and in-vivo activities on MCF-7, SK-BR-3, HCT116, U-118MG, U-87MG and MDA-MB-468, and have good application prospects in preparation of antitumor drugs.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a benzimidazole derivative BI361 as well as a preparation method and application thereof.
Background
Malignant tumor is a common disease and frequently encountered disease seriously threatening human health, and the death rate of the tumor in China has increased 29.42% in recent 20 years. In the middle-aged and senior population, between the ages of 35 and 59, tumors have been the first cause of death of various types. And (3) displaying data: the disease rate of tumors in China is about 200/10 ten thousands of people, more than 220 thousands of new cases are generated every year, and more than 600 thousands of patients are treated. The tumor treatment method includes operation treatment, radiotherapy and chemotherapy. Currently, chemotherapy remains the primary means of clinical treatment of tumors. The search for anti-tumor drugs is one of the hot spots in the research of new drugs. In recent years, benzimidazole compounds have attracted much attention because of their excellent biological activity, and have become a focus of research for researchers in biology and chemistry. The indications include: peptic ulcer, parasitic infection, bacterial infection, viral infection, tumor, etc., and particularly, has the effect of selectively inhibiting glioblastoma and other tumors. The inventors have surprisingly found that {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl ] -1H-benzo [ d ] imidazol-4-yl } (piperidin-1-yl) methanone has a certain antitumor activity, and have proposed an invention relating to {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl ] -1H-benzo [ d ] imidazol-4-yl } (piperidin-1-yl) methanone or a pharmaceutically acceptable salt, solvate, or prodrug or stereoisomer or tautomer or metabolite of the compound.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention provides a benzimidazole derivative BI361 which is chemically named as {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl ] -1H-benzo [ d ] imidazole-4-yl } (piperidine-1-yl) methanone and has inhibitory activity on proliferation of MCF-7, SK-BR-3, HCT116, U-118MG, U-87MG and MDA-MB-468 six tumor cells.
The technical scheme is as follows: in order to achieve the technical object, the invention provides a benzimidazole derivative BI361, which is chemically named as {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl ] -1H-benzo [ d ] imidazol-4-yl } (piperidin-1-yl) methanone, and the structural formula of which is shown as follows:
the invention further provides a preparation method of the benzimidazole derivative BI361, which comprises the following steps:
s1: placing 1H-1, 3-benzobisoxazole-4-carboxylic acid, methanol and sulfuric acid into a reaction bottle, carrying out oil bath reflux, stirring overnight, adjusting the pH value to be neutral by using a sodium bicarbonate saturated solution, filtering, collecting solids and drying to obtain a compound (1), namely 1H-1, 3-benzobisoxazole-4-carboxylic acid methyl ester;
s2: placing the compound 1, ACN and BSA into a 250mL occlusion reaction bottle, and stirring for 15-20 minutes at 80-85 ℃; to CH at room temperature3CN to which TMSOTf and [3,4, 5-tris (acetoxy) oxopentan-2-yl group were added]Mixing the above solutions at 80-85 deg.C for 2.5-3 hr, vacuum concentrating, and adding NaHCO3The solution was dissolved and extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was eluted with ethyl acetate/petroleum ether (1:1) on a silica gel column to give compound (2), methyl 1- {3, 4-bis (acetoxy) -5- [ (acetoxy) methyl]Oxazol-2-yl } -1H-1, 3-benzobisoxazole-4-carboxylic acid methyl ester;
s3: me was added to a solution of piperidine and THF in an ice bath3Al, then adding a THF solution of the compound (2); the resulting solution was stirred under reflux in an oil bath overnight and the filtrate was concentrated in vacuo to give compound (3), i.e., {5- [4- (dimethylcarbamoyl) -1H-1, 3-benzodiazol-1-yl]-3- [ (4-methylphenyl) carbonyl]Oxazol-2-yl } methyl 4-methylbenzoate;
s4: adding NH to the compound (3)3The methanol solution is stirred at room temperature overnight and then concentrated in vacuo and the crude product is purified by flash preparative high performance liquid chromatography to give compound (4), i.e. {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl]-1H-benzo [ d]Imidazol-4-yl } (piperidin-1-yl) methanone.
Preferably, in step S1, the ratio of the 1H-1, 3-benzodiazole-4-carboxylic acid, methanol and sulfuric acid is 10 to 50 g: 20-100 mL: 5-50 mL.
In step S2, the ratio of the amounts of compound 1, ACN, BSA, TMSOTf and methyl [3,4, 5-tris (acyloxy) oxopentan-2-yl ] acetate was: 3-9 g: 100-350 mL: 3-20 g: 3-20 g: 2-30 g, the reaction temperature is 60-100 ℃, and the reaction time is 60-180 minutes.
In the step S3, the reaction temperature is 0-60 ℃, and piperidine, THF and Me are used3The dosage ratio of Al to the compound (2) is 1-5 g: 30-100 mL: 3-20 mL: 1-5 g.
In step S4, Compound (3), NH3-the amount ratio of sodium methoxide: 1-5 g: 50-100 mL. The mobile phase gradient elution conditions for purification by preparative chromatography are as follows: h2O(0.5％NH3·H2O)：CH3CN＝1:2～5:1。,
The invention further provides the application of the novel benzimidazole derivative in preparing an antitumor agent.
The present invention also provides a pharmaceutical composition comprising a compound as set forth in claim 1 above and a pharmaceutically acceptable carrier.
More particularly, the invention provides the use of the compound or the pharmaceutical composition in the preparation of medicaments.
Meanwhile, the invention also provides application of the novel benzimidazole derivative BI361 or pharmaceutically acceptable salt, solvate or prodrug or stereoisomer or tautomer or metabolite of the compound in preparation of antitumor agents.
Finally, the invention provides the application of the novel benzimidazole derivative BI361 or the pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or metabolite of the compound in preparing the medicine for treating tumors by combining with one or more anticancer drugs.
Has the advantages that: the invention discloses a benzimidazole derivative BI361, and adopts an MTT method to evaluate the inhibition activity of the benzimidazole derivative BI361 on the proliferation of 6 tumor cells including MCF-7, SK-BR-3, HCT116, U-118MG, U-87MG and MDA-MB-468, and calculates the IC for inhibiting the proliferation of the six tumor cells50The value and the result show that the prepared novel benzimidazole derivative BI361 has an inhibiting effect on the tumor cells and can be used for preparing an anti-tumor preparation.
Drawings
FIG. 1 is a scheme of synthesis of benzimidazole derivatives,wherein: i) sulfuric acid, methanol; ii) BSA, TMSOTf, acetonitrile; iii) piperidine, Me3Al, THF; iv) ammonia-methanol.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of methyl 1H-1, 3-benzobisoxazole-4-carboxylate (Compound 1)
30g of 1H-1, 3-benzodiazole-4-carboxylic acid, 80mL of methanol and 20mL of sulfuric acid were placed in a 250mL round-bottom flask. The resulting solution was oil-bathed at reflux and stirred overnight. Adjusting the pH value to be neutral by using a saturated solution of sodium bicarbonate. The solid was collected by filtration and dried. 27.5g (84% yield) of Compound 1 are obtained as a yellow solid. The compound 1 was characterized by LC-MS, with the following results:
LC-MS:(ES,m/z):177.2[M+H]+
EXAMPLE 2 preparation of methyl 1- [3, 4-bis (acetoxy) -5- [ (acetoxy) methyl ] oxazol-2-yl ] -1H-1, 3-benzobisoxazole-4-carboxylic acid methyl ester (Compound 2)
5g of Compound 1, 150mL of ACN and 5.77g of BSA were placed in a 250mL closed round bottom flask and stirred at 85 ℃ for 15 minutes. Then 20mL CH at room temperature3CN was added 8.20g of TMSOTf and 9.94g of [3,4, 5-tris (acetoxy) oxopentan-2-yl group]Methyl acetate solution. The above solutions were mixed and stirred at 85 ℃ for 2.5 h. Concentrated in vacuo using 100mL NaHCO3The solution was dissolved and extracted with 100mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was eluted with ethyl acetate/petroleum ether (1:1) on a silica gel column. 8.4g (68% yield) of Compound 2 are obtained as a yellow oil.
LC-MS:(ES,m/z):435.1[M+H]+
EXAMPLE 3 preparation of methyl [5- [4- (dimethylcarbamoyl) -1H-1, 3-benzoxadiazol-1-yl ] -3- [ (4-methylphenyl) carbonyl ] oxazol-2-yl ] methyl 4-methylbenzoate (Compound 3)
13.8mL Me were added to a solution of 1.96g piperidine and 40mL THF in an ice bath over 5 minutes3Al, then 4g of a solution of Compound 2 in 5mL of THF, mixing the above solutions, stirring overnight under reflux in an oil bath, filtering off the solid, and concentrating the filtrate in vacuo. 4.5g of Compound 3 are obtained as a yellow oil. The compound 3 was characterized by LC MS, with the following results:
LC-MS:(ES,m/z):488.2[M+H]+
EXAMPLE 4 preparation of {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl ] -1H-benzo [ d ] imidazol-4-yl } (piperidin-1-yl) methanone (Compound 4)
4g of Compound 3, 50mL NH3The methanol solution was stirred at room temperature overnight and then concentrated in vacuo. The crude product was purified by flash preparative high performance liquid chromatography under the following conditions: c18A column; mobile phase: h2O(0.5％NH3·H2O)：CH3CN is 1:0, increasing to H2O(0.5％NH3·H2O)：CH3CN 2:1, within 30 minutes; detector, UV 254 nm. 554.4mg (19% yield) of Compound 4 were obtained as a white solid.
ESI-MS and the like were performed on the prepared Compound 4, and the results were as follows:
LC-MS:(ES,m/z):362.25[M+H]+
1H-NMR:(300MHz,DMSO-d6,ppm):δ8.50(s,1H),7.80(d,J＝8.1Hz,1H),7.30(t,J＝7.5Hz,1H),7.15(d,J＝7.2Hz,1H),5.89(d,J＝6.3Hz,1H),5.49(d,J＝6.6Hz,1H),5.23(d,J＝4.8Hz,1H),5.12(t,J＝5.1Hz,1H),4.42-4.36(q,1H),4.14-4.10(q,1H),3.98(d,d,J＝3.3Hz,1H),3.66-3.58(m,4H),3.10(t,J＝4.8Hz,2H),1.59(s,4H),1.42(s,2H).
[α]＝-17.560(C＝0.41g/100mL,T＝24.8℃,MeOH)
experimental example 5 evaluation of antitumor cell proliferation Activity of Compound 4.
(1) And (3) testing a sample:
the compounds 4 of the invention were all formulated to the desired concentration in media containing 0.1% DMSO.
(2) Cell lines:
MCF-7 (human breast cancer cells, ATCC: HTB-22), SK-BR-3 (human breast cancer cells, ATCC: HTB-30), HCT116 (human colon cancer cells, ATCC: CCL-247), U-118MG (human brain astrocytoma, ATCC: HTB-15), U-87MG (human brain astrocytoma, ATCC: HTB-14), and MDA-MB-468 (human breast cancer cells, ATCC: HTB-132)6 tumor cells were purchased from American Standard culture Collection (ATCC).
(3) Main instruments and materials
Ultra-pure water instrument: MILLIPORE Direct-Q3;
an autoclave: HVE-50, Hirayama corporation;
digital display constant temperature water bath: HH-4, Kyowa electric appliances, Inc.;
an ultra-clean bench: VS-1300-U clean bench, Suzhou Antai air technology, Inc.;
a cell incubator: HF151UVCO2 incubator, shanghai li cheng;
low-temperature centrifuger: shanghai' an pavilion scientific instrument factory
An enzyme-labeling instrument: ELx800 Biotek Inc
A flat plate oscillator: ZD-9556, Taicang scientific and educational facilities;
96-well cell culture plate, 25cm2Culture bottles: corning Costar corporation;
2mL of frozen tubes: corning Costar corporation;
(4) primary reagent
RPMI-1640 medium: gibco corporation; DMEM medium: gibco corporation;
l-15 Medium: gibco corporation; McCoy's 5A medium: gibco corporation;
MEM medium: gibco corporation; PBS buffer: gibco corporation;
fetal bovine serum: gibco corporation; 0.25% pancreatin solution: hyclone company;
MTT (thiazolidine blue): sigma, dissolving in PBS solution to make 5mg/mL solution, filtering, sterilizing, and storing in dark place;
doxorubicin (ADR): beijing Huafeng Union technologies, Inc. DMSO, DMSO: dimethyl sulfoxide, Sigma corporation;
(5) test method
The MCF-7 and U-118MG cells adopt DMEM culture medium, the U-87MG cells adopt MEM culture medium, the MDA-MB-468 cells adopt L-15 culture medium, the HCT116 cells adopt McCoy's 5A culture medium, and other cells adopt RPMI-1640 culture medium. The culture medium contains 10% of extinguishant fetal calf serum and 80 U.mL-1Penicillin and 0.08 mg/mL-1Streptomycin.
MCF-7, SK-BR-3, HCT116, U-118MG, U-87MG and MDA-MB-468 cells in logarithmic growth phase with good growth state are divided into 1 × 104The cells were plated at a density of 100. mu.l/well in 96-well plates. Placing at 37 ℃ and 5% CO2Culturing in an incubator for 12 hours to adhere to the wall. Adding a compound 4 which is to be detected and is dissolved in a culture medium after sterilization treatment into a drug-added cell hole according to a preset concentration gradient, wherein each hole is 200 mu l, adding an equal volume of the culture medium into a blank cell hole, adding an equal volume of Adriamycin (ADR) dissolved in the culture medium into a control cell hole according to the preset concentration gradient, and paralleling 6 holes. At 37 deg.C, 5% CO2After 48 hours of incubation in an incubator, 10. mu.l of 5mg/mL MTT solution was added to each well, and the mixture was further incubated at 37 ℃ with 5% CO2The culture was carried out in an incubator for 4 hours. The supernatant was carefully aspirated, 150. mu.l of DMSO was added to each well to dissolve the purple residue (formazan), the plate was shaken for 10 minutes to dissolve the precipitate completely, and the O.D. value (absorbance) was measured on a microplate reader at a wavelength of 570 nm.
The inhibition rate of the sample on tumor cells at each sample concentration was calculated according to the formula "relative survival rate ═ D blank containing drug (D)/(D control-D blank) × 100%".
The experiment was repeated 3 times in parallel and the inhibition rate was plotted against the compound concentration to calculate the IC of compound 4 of the invention50(median effective inhibitory concentration) value. While doxorubicin (ADR) was used as a positive control drug.
(6) Results of the experiment
TABLE 1 Compound 4BI361 antitumor cell proliferation Activity (IC)50±SDμM)
As shown in Table 1, the test results of the compound 4 on the proliferation activity of the tumor cells are shown, and the results show that the prepared novel benzimidazole derivative has an inhibitory effect on the tumor cells and can be used for preparing an anti-tumor preparation.
Claims (10)
1. A benzimidazole derivative BI361, chemically named {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl ] -1H-benzo [ d ] imidazol-4-yl } (piperidin-1-yl) methanone, and pharmaceutically acceptable salts of the compound.
2. The method of preparing the benzimidazole derivative BI361 of claim 1, comprising the steps of:
s1: placing 1H-1, 3-benzobisoxazole-4-carboxylic acid, methanol and sulfuric acid into a reaction bottle, carrying out oil bath reflux, stirring overnight, adjusting the pH value to be neutral by using a sodium bicarbonate saturated solution, filtering, collecting solids and drying to obtain a compound (1), namely 1H-1, 3-benzobisoxazole-4-carboxylic acid methyl ester;
s2: placing the compound (1), ACN and BSA into a 250mL occlusion reaction bottle, and stirring for 15-20 minutes at 80-85 ℃; to CH at room temperature3CN to which TMSOTf and [3,4, 5-tris (acetoxy) oxopentan-2-yl group were added]Mixing the above solutions at 80-85 deg.C for 2.5-3 hr, vacuum concentrating, and adding NaHCO3The solution was dissolved and extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was eluted with a 1:1 mixture of ethyl acetate/petroleum ether on a silica gel column to give compound (2), methyl 1- {3, 4-bis (acetoxy) -5- [ (acetoxy) methyl]Oxazol-2-yl } -1H-1, 3-benzobisoxazole-4-carboxylic acid methyl ester;
s3: me was added to a solution of piperidine and THF in an ice bath3Al, then adding a THF solution of the compound (2); the resulting solution was stirred under reflux in an oil bath overnight and the filtrate was concentrated in vacuo to give compound (3), i.e., {5- [4- (dimethylcarbamoyl) -1H-1, 3-benzodiazol-1-yl]-3- [ (4-methylphenyl) carbonyl]Oxazol-2-yl } methyl 4-methylbenzoate;
s4: adding NH to the compound (3)3-methanol solutionStirring overnight at room temperature, then concentrating in vacuo and purifying the crude product by flash preparative high performance liquid chromatography to give compound (4), i.e., {1- [ tetrahydro-3, 4-dihydroxy-5- (hydroxymethyl) furan-2-yl]-1H-benzo [ d]Imidazol-4-yl } (piperidin-1-yl) methanone.
3. The method for preparing the benzimidazole derivative BI361 according to claim 2, wherein in step S1, the ratio of 1H-1, 3-benzodiazole-4-carboxylic acid to methanol to sulfuric acid is 10-50 g: 20-100 mL: 5-50 mL.
4. The method of claim 2, wherein in step S2, compound (1), ACN, BSA, TMSOTf, and methyl [3,4, 5-tris (acetoxy) oxopentan-2-yl ] acetate are used in a ratio of: 3-9 g: 100-350 mL: 3-20 g: 3-20 g: 2-30 g.
5. The method for preparing the benzimidazole derivative BI361 as claimed in claim 2, wherein the reaction temperature is 0-60 ℃ in step S3, piperidine, THF, Me3The dosage ratio of Al to the compound (2) is 1-5 g: 30-100 mL: 3-20 mL: 1-5 g.
6. The method for preparing the benzimidazole derivative BI361 as claimed in claim 2, wherein in step S4, compound (3), NH3-the amount ratio of sodium methoxide: 1-5 g: 50-100 mL; the mobile phase gradient elution conditions for purification by preparative chromatography are as follows: in 30 minutes, the mobile phase is composed of a mixture containing 0.5% NH3·H2H of O2O：CH3CN =1:0 increased to 0.5% NH3·H2H of O2O：CH3CN=2:1。
7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
8. Use of a compound according to claim 1, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament.
9. Use of the benzimidazole derivative BI361 of claim 1 or a pharmaceutically acceptable salt of the compound for the preparation of an antitumor agent.
10. Use of the benzimidazole derivative BI361 of claim 1, or a pharmaceutically acceptable salt thereof, in combination with one or more anti-cancer agents for the preparation of a medicament for the treatment of tumors.
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| Antitumor and antiviral effect of riboside of benzimidazole derivatives;Mizutani, Hiroko等;《Japan. J. Med. Sci. & Biol.》;19601231;第13卷;第147-153页 * |
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