CN112920241B - Benzimidazole derivative BI308 and preparation method and application thereof - Google Patents
Benzimidazole derivative BI308 and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title abstract 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 9
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 9
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
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- 150000001875 compounds Chemical class 0.000 claims description 23
- 150000001556 benzimidazoles Chemical class 0.000 claims description 19
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- 239000000243 solution Substances 0.000 claims description 16
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/052—Imidazole radicals
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention discloses a benzimidazole derivative BI308 and a preparation method thereof, wherein the chemical name of the benzimidazole derivative BI308 is methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl ] -1H benzo [ d ] imidazole-4-carboxylate. 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 biological medicines, and particularly relates to a benzimidazole derivative BI308 and 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 risen 29.42% in nearly 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. 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 inventor unexpectedly finds that methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl ] -1H benzo [ d ] imidazole-4-carboxylate has certain antitumor activity, and proposes the invention related to methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl ] -1H benzo [ d ] imidazole-4-carboxylate or 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 BI308 which is chemically named as methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl ] -1H benzo [ d ] imidazole-4-carboxylate 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 purpose, the invention provides a benzimidazole derivative BI308, which is chemically named as methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl ] -1H-benzo [ d ] imidazole-4-carboxylate, and the structural formula of which is shown as follows:
the invention further provides a preparation method of the benzimidazole derivative BI308, which comprises the following steps:
s1: putting 1H-1, 3-benzobisoxazole-4-carboxylic acid, methanol and sulfuric acid into a round bottom flask, refluxing in an oil bath, stirring overnight, adjusting the pH value to be neutral by using a saturated solution of sodium bicarbonate, filtering, collecting a solid, and drying to obtain a compound (1), namely 1H-1, 3-benzobisoxazole-4-carboxylic acid methyl ester.
S2: placing compound (1), ACN and BSA in a 250mL closed round-bottom flask, stirring at 80-85 deg.C for 10-15 min, and adding 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 NaHCO3Dissolving the solution, and extracting with ethyl acetate; combining the organic layers, drying over anhydrous sodium sulfate, and concentrating under vacuum; the residue was eluted with ethyl acetate/petroleum ether (1:1) on a silica gel column to give the compound (2), methyl 1- [3, 4-bis (acetoxy) -5- [ (acetoxy) methyl]Oxazol-2-yl]-1H-1, 3-benzodiazole-4-carboxylic acid methyl ester;
s3: reacting compound (2) with NH3Methanol solution into round-bottomed flask, in chamberAfter stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and the resulting residue was purified by flash preparative high performance liquid chromatography to give compound (3), i.e., methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl]-1H benzo [ d]Imidazole-4-carboxylic acid esters.
Preferably, in step S1, the use amount ratio of 1H-1, 3-benzodiazole-4-carboxylic acid, methanol and sulfuric acid is 1-5 g: 20-60 mL: 0.5-5 mL.
In step S2, the compound (1), ACN, BSA, TMSOTf, and methyl [3,4, 5-tris (acetoxy) oxypentan-2-yl ] acetate were used in the following ratios: 0.3-0.9 g: 10-35 mL: 0.3-2 g: 0.3-2 g: 0.2-3 g, the reaction temperature is 60-100 ℃, and the reaction time is 60-180 minutes.
In step S3, Compound (2), NH3-the ratio of the amount of methanol: 1-5 g: 10-60 mL, and the mobile phase gradient elution conditions for purifying the prepared chromatogram are as follows: h2O(1％NH4HCO3): ACN is 10: 1-1: 10. The invention further provides application of the benzimidazole derivative in preparing an antitumor agent.
The present invention also provides a pharmaceutical composition comprising a compound as set forth in claim 1 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 benzimidazole derivative BI308 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 benzimidazole derivative BI308 or the pharmaceutically acceptable salt, solvate or prodrug or stereoisomer or tautomer or metabolite of the compound in combination with one or more anti-cancer medicaments in preparing the medicaments for treating tumors.
Has the advantages that: the invention discloses a benzimidazole derivative BI308 and a preparation method thereofEvaluating the proliferation activity of 6 tumor cells of MCF-7, SK-BR-3, HCT116, U-118MG, U-87MG and MDA-MB-468 by MTT method, and calculating the IC for inhibiting the proliferation of six tumor cells50The value and the result show that the prepared benzimidazole derivative BI308 has an inhibition effect on the tumor cells and can be used for preparing an anti-tumor preparation.
Drawings
Fig. 1 is a scheme for the synthesis of benzimidazole derivatives, wherein: i) sulfuric acid, methanol; ii) BSA, TMSOTf, acetonitrile; iii) 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)
3.24g of 1H-1, 3-benzodiazole-4-carboxylic acid, 50mL of methanol and 2.2mL of sulfuric acid were placed in a 250mL round-bottomed flask, and the resulting solution was refluxed in an oil bath 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. 2.9g (yield 82%) of Compound 1 are obtained as a yellow solid. Compound 1 was characterized by LC-MS as follows:
LC-MS:(ES,m/z):177.1[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)
581mg of Compound 1, 15mL of ACN and 670mg of BSA were placed in a 50mL closed round bottom flask and stirred at 85 ℃ for 15 minutes. 866mg TMSOTf and 955mg [3,4, 5-tris (acetoxy) oxopentan-2-yl ] are subsequently added at room temperature]Methyl acetate solution. The above solutions were mixed and stirred at 85 ℃ for 2.5 h. Cooled to room temperature and then treated with 20mL NaHCO3The solution was quenched and extracted several times with 5mL of 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. 1.15g (yield 88%) of Compound 2 are obtained as a yellow oil. Compound 2 was characterized by LC-MS as follows:
LC-MS:(ES,m/z):435.2[M+H]+
EXAMPLE 3 preparation of methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl ] -1H-benzo [ d ] imidazole-4-carboxylate (Compound 3)
2.63g Compound 2 and 50mL NH3The methanol solution was placed in a 100mL round bottom flask. After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The resulting residue was purified by flash preparative high performance liquid chromatography under the following conditions: chromatography column, C18-an OBD; mobile phase, water (1% NH)4HCO3): ACN ═ 9:1, added to water (1% NH)4HCO3): ACN 1:5 over 30 minutes; detector, UV 254 nm. 1.1251g (yield 60%) of Compound 3 are obtained as a yellow solid.
ESI-MS and the like were performed on the prepared Compound 3, and the results were as follows:
LC-MS:(ES,m/z):309.15[M+H]+
H-NMR:(300MHz,CD3OD,ppm)δ:8.67(s,1H),8.06(dd,J＝8.3,1.2Hz, 1H),7.99(dd,J＝7.7,1.2Hz,1H),7.44(t,J＝7.9Hz,1H),6.05(d,J＝5.7Hz,1H), 4.48(t,J＝5.5Hz,1H),4.32(dd,J＝5.4,3.6Hz,1H),4.17(q,J＝3.3Hz,1H),4.01 (s,3H),3.91(dd,J＝12.1,2.9Hz,1H),3.82(dd,J＝12.1,3.3Hz,1H).
experimental example 4 evaluation of antitumor cell proliferating activity by Compound 3.
(1) And (3) testing a sample:
the compounds 3 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 are DMEM medium, the U-87MG cells are MEM medium, the MDA-MB-468 cells are L-15 medium, the HCT116 cells are McCoy's 5A medium, and the other cells are MCCoy's 5A mediumRPMI-1640 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 3 which is to be detected and is subjected to sterilization treatment and dissolved in a culture medium 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 a 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 3 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 3 BI308 antitumor cell proliferation Activity (IC)50±SDμM)
As shown in Table 1, the test results of the compound 3 on the proliferation activity of the tumor cells are shown, and the results show that the prepared benzimidazole derivative has an inhibition effect on the tumor cells and can be used for preparing an anti-tumor preparation.
Claims (9)
1. A benzimidazole derivative BI308, chemically named methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl ] -1H-benzo [ d ] imidazole-4-carboxylate, and pharmaceutically acceptable salts thereof.
2. The process for preparing the benzimidazole derivative BI308 of claim 1, comprising the steps of:
s1: putting 1H-1, 3-benzobisoxazole-4-carboxylic acid, methanol and sulfuric acid into a flask, refluxing in an oil bath, and stirring overnight; adjusting the pH value to be neutral by using a saturated solution of sodium bicarbonate; the solid was collected by filtration and dried; 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 blocking reaction bottle, and stirring for 10-15 minutes at 80-85 ℃; to CH at room temperature3CN to which TMSOTf and [3,4, 5-tris (acetoxy) oxopentan-2-yl group were added]A methyl acetate solution; mixing the above solutions at 80-85 deg.C, stirring for 2.5-3h, vacuum concentrating, and adding NaHCO3Dissolving the solution, and extracting with ethyl acetate; the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo; eluting the residue with ethyl acetate/petroleum ether on silica gel column to obtain compound (2), i.e. methyl 1- [3, 4-bis (acetoxy) -5- [ (acetoxy) methyl]Oxazol-2-yl]-1H-1, 3-benzodiazole-4-carboxylic acid methyl ester;
s3: reacting compound (2) with NH3-methanol solution into round bottom flask, after stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and the resulting residue was purified by flash preparative high performance liquid chromatography to give compound (3), methyl 1- [ (2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl]-1H benzo [ d]Imidazole-4-carboxylic acid esters.
3. The method for preparing the benzimidazole derivative BI308 according to claim 2, wherein in step S1, the ratio of 1H-1, 3-benzodiazole-4-carboxylic acid to methanol to sulfuric acid is 1-5 g: 20-60 mL: 0.5-5 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 the following ratios: 0.3-0.9 g: 10-35 mL: 0.3-2 g: 0.3-2 g: 0.2 to 3 g.
5. The method for preparing the benzimidazole derivative BI308 according to claim 2, wherein in step S3, the compound (2), NH3-the ratio of the amount of methanol: 1-5 g: 10-60 mL, and the mobile phase gradient elution conditions for purification by preparative chromatography are as follows: within 30min, the mobile phase contains 1% NH4HCO3Water (2): ACN =9:1 increase to 1% NH4HCO3Water (2): ACN =1: 5.
6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
7. Use of a compound of claim 1, or a pharmaceutical composition of claim 6, in the manufacture of a medicament.
8. Use of the benzimidazole derivative BI308 or a pharmaceutically acceptable salt thereof of claim 1, in the preparation of an anti-tumor agent.
9. Use of the benzimidazole derivative BI308 or a pharmaceutically acceptable salt thereof of claim 1, in combination with one or more anticancer agents for the preparation of a medicament for the treatment of tumors.
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