CN113698352B - 1- (phenol benzyl) benzimidazole derivatives, and preparation method and application thereof - Google Patents
1- (phenol benzyl) benzimidazole derivatives, and preparation method and application thereof Download PDFInfo
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- 238000000034 method Methods 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 6
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
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- 239000003513 alkali Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical class C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 6
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- OACPOWYLLGHGCR-UHFFFAOYSA-N 2-chloro-6-fluorobenzaldehyde Chemical compound FC1=CC=CC(Cl)=C1C=O OACPOWYLLGHGCR-UHFFFAOYSA-N 0.000 description 1
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- 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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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 1- (phenol benzyl) benzimidazole derivative, and a preparation method and application thereof. The structural formula of the 1- (phenol benzyl) benzimidazole derivative is shown as formula (I), wherein R 1 Is H, one or more substituted halogen atoms (e.g. chlorine, fluorine or bromine, etc.) or trifluoromethyl, R 2 Is H or methyl. The invention also discloses a preparation method of the 1- (phenol benzyl) benzimidazole derivative, which has simple process, low price, suitability for large-scale production and stable and reliable source. The 1- (phenol benzyl) benzimidazole derivative not only has good inhibition activity on the growth of wild cancer cells, but also has strong inhibition activity on the growth of various drug-resistant cancer cell strains, is expected to be used for researching and preparing candidate drugs with potential anticancer activity, and has great development potential.
Description
Technical Field
The invention belongs to the field of chemical medicine preparation, and in particular relates to a novel tri-leaf sector-shaped 1- (phenol benzyl) benzimidazole derivative, a preparation method thereof and application thereof in preparing anticancer drugs.
Background
Cancer is the first major disease threatening human life, 1929 tens of thousands of new cancer cases worldwide in 2020, 1006 tens of thousands in men and 923 tens of thousands in women; 996 ten thousand cancer deaths occurred worldwide in 2020, with 553 ten thousand men and 443 ten thousand women. 457 ten thousand new cancer cases in China in 2020, 248 ten thousand men and 209 ten thousand women; 300 cases of cancer death, 182 for men and 118 for women. The new cancer cases in china are the first worldwide (data from global cancer report 2020) and people talk about cancer changes. More particularly, the continuous mutation of cancer genes leads to the loss of therapeutic effect and research value of the marketed therapeutic drugs or candidate drugs under investigation. The mutation of the gene results in the unavailability of effective drugs and the patient dies continuously without help. On the other hand, however, the development of drug-resistant cancer candidate drugs is becoming more difficult. Firstly, the cancer occurrence mechanism is more and more complex, the period of drug development is long, and the risk is high; secondly, development cost is high, and meanwhile, double high risks of failure and patent failure are faced, so that the cost is huge, and the cost is low; and thirdly, continuous and long-term research and development investment of manpower and financial resources is needed. The current small molecule cancer therapeutic drug is developed from early non-target treatment with larger side effect to current target cancer treatment, and the first generation of Ecritinib is developed to the third generation of Ostinib and the like, but the latter also enters a drug resistant period nowadays, and the fourth generation of target drug development also enters a strong development period, such as TQB3804 and the like, which is good in the day, and can effectively treat the cancer with drug resistant mutation of C797S. In addition to small molecule drugs, immunotherapy has been advanced in the rapid development stage for nearly 10 years, and many antibody drugs such as opdivo (drug O) and keytrua (drug K) have emerged, which take immune checkpoints such as PD1, PD-L1 and CTLA4 as immune activation targets. However, antibody drugs have the problems of narrow indication (model), insensitive curative effect, solid tumor treatment and the like. Thus, in the face of cancer attacks, it is very important and urgent to continue to find and develop small molecule drug candidates for cancer treatment.
Disclosure of Invention
It is a first object of the present invention to provide a novel class of tri-lobe-shaped 1- (phenol-based benzyl) benzimidazole derivatives.
The structural formula of the 1- (phenol benzyl) benzimidazole derivative is shown as the formula (I):
wherein R is 1 Is H, trifluoromethyl or one or more substituted halogen atoms (such as chlorine, fluorine or bromine), R 2 Is H or methyl.
A second object of the present invention is to provide a process for preparing the above-mentioned 1- (phenol-based benzyl) benzimidazole derivative, which comprises the steps of:
substrate o-fluorobenzaldehyde derivatives
With benzimidazole derivatives->
And alkali in N, N-Dimethylformamide (DMF), removing N, N-dimethylformamide after the reaction, adding water and extracting with ethyl acetate, purifying the extract to obtain final target substance->
Said R is 1 Is H, trifluoromethyl or one or more substituted halogen atoms (such as chlorine, fluorine or bromine), R 2 Is H or methyl.
Preferably, said substrate o-fluorobenzaldehyde derivative
With benzimidazole derivatives->
The ratio of the amounts of substances (moL) is 2.0-2.5:1.0, said benzimidazole derivatives +.>
The ratio of the amount (moL) of the alkali to the amount of the alkali is 1.0:2.0-4.0. The alkali is K 2 CO 3 ，Na 2 CO 3 ，K 3 PO 4 Or Cs 2 CO 3 。
Said substrate o-fluorobenzaldehyde derivatives
With benzimidazole derivatives->
And the base in N, N-dimethylformamide, the reaction conditions are preferably 60-90 ℃ for 2-6 hours.
A third object of the present invention is to provide the use of a 1- (phenol-based benzyl) benzimidazole derivative in the preparation of an anticancer drug.
A fourth object of the present invention is to provide an anticancer drug containing the 1- (phenol-based benzyl) benzimidazole derivative or its salt as an active ingredient.
The anticancer medicine is an anti-ovarian cancer, anti-lung cancer, anti-breast cancer, anti-colorectal adenocarcinoma or anti-nasopharyngeal carcinoma medicine.
The anticancer drug is used as a candidate drug for inhibiting the growth of wild type and drug-resistant cancer cell strains such as A2780, A549, MCF-7, HCT-8, CNE-1 and the like.
Preferably, the 1- (phenol benzyl) benzimidazole derivative is used as a medicament in the form of a free compound or hydrochloride, sulfate, citrate and the like thereof for anticancer treatment.
The invention discloses a novel tri-leaf sector-shaped 1- (phenol benzyl) benzimidazole derivative and a preparation method thereof, wherein the preparation method is simple in process, low in cost, suitable for large-scale production and reliable and stable in source. The 1- (phenol benzyl) benzimidazole derivative has the growth inhibition activity of wild type and drug-resistant cancer cell strains, and has great popularization and application potential.
Detailed Description
The following examples are further illustrative of the invention and are not intended to be limiting thereof.
Example 1: synthesis of Compound 1
5.6-Diphenylimidazole 30mg (0.2 mmol,1.0 eq.) 2-chloro-6-fluorobenzaldehyde 58. Mu.L (0.5 mmol,2.5 eq.) and K 2 CO 3 55mg (0.4 mmol,2.0 eq) of the mixture was reacted in DMF at 80℃for 5h, cooled to room temperature after completion, rotatedDMF was evaporated and 50mL of water was added, each time extracted with 20mL of ethyl acetate three times, the ethyl acetate extracts (organic layers) were combined and dried, and after removal of ethyl acetate, the residue was subjected to silica gel column chromatography to give 40mg of the target compound (compound 1, structural formula of which is shown in formula 1), yield: 45%.
The nuclear magnetic data of compound 1 are as follows:
1 H NMR(500MHz,CDCl 3 )δ10.50(s,1H),8.17(d,J＝1.9Hz,1H),7.76(s,1H),7.57(s,1H),7.39(td,J＝8.3,5.7Hz,1H),7.32–7.27(m,2H),7.24(s,1H),7.17–7.12(m,2H),6.75(d,J＝8.3Hz,1H),2.36(s,3H),2.36(s,3H). 13 C NMR(176MHz,CDCl 3 )δ187.10(d,J＝13.6Hz)158.88(d,J＝250.4Hz),156.42,142.46,140.13,138.47,135.00(d,J＝8.2Hz),133.66,132.63,130.46,130.23,127.82,124.75(d,J＝13.2Hz),120.96,118.29,118.17,117.65,117.08,110.26,80.37,20.69,20.22.MS-ESI(m/z):443.1(M+H) + 。
example 2: synthesis of Compound 2
The 5.6-dimethyl-benzoimidazole was replaced with benzimidazole, and the synthesis was performed in the same manner as in example 1 to obtain the target compound (compound 2, structural formula of which is shown in formula 2), yield: 67%.
The nuclear magnetic data of compound 2 are as follows:
1 H NMR(700MHz,CDCl 3 )δ10.51(s,1H),8.33(s,1H),7.82(d,J＝5.4Hz,2H),7.50–7.47(m,1H),7.40(td,J＝8.2,5.9Hz,1H),7.31(dd,J＝9.1,2.7Hz,3H),7.28(d,J＝8.3Hz,1H),7.17–7.12(m,2H),6.76(d,J＝8.4Hz,1H). 13 C NMR(176MHz,CDCl 3 )δ188.29(d,J＝13.3Hz),161.19(d,J＝255.6Hz),157.46(s),143.52(s),141.42(d,J＝6.3Hz),136.83(s),134.53(s),134.05(d,J＝4.3Hz),132.41(d,J＝10.8Hz),126.55(s),126.07(s),124.13(s),123.91(s),123.10(s),120.95(d,J＝14.1Hz),120.78(s),116.28(d,J＝22.4Hz),113.76(s),109.71(s),81.52(s).MS-ESI(m/z):415.1(M+H) + 。
example 3: cytotoxic Activity of Compounds
Under normal culture conditions, various wild-type or drug-resistant human ovarian cancer cells A2780 (taxol-resistant strain), human lung cancer cell strain A549 (cisplatin-resistant strain), human breast cancer MCF-7 (doxorubicin-resistant strain), human colorectal adenocarcinoma HCT-8 (vincristine-resistant strain) and human nasopharyngeal carcinoma CNE-1 were cultured under conditions of 10% FBS and 1% penicillin/strepavidin of RPMI or DMEM (5% CO) 2 37 c). Cell viability was calculated using the CCK8 (DOjindo, japan) method. In 384-well plate, 400-800 cancer cells and test compound at each concentration are placed in each well, blank solution is used as negative control, taxol is used as positive control, each test is repeated three times, cell proliferation after 72h is calculated, and GraphPad Prism 5 software calculates IC of the compound 50 Values.
The specific results are shown in Table 1:
table 1: cytotoxic Activity of Compounds 1 and 2 against respective tumor cells
Note that: the "-" in the above table indicates that no corresponding test was performed.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that the above-mentioned preferred embodiment should not be construed as limiting the invention, and the scope of the invention should be defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (9)
1- (phenol benzyl) benzimidazole derivative, which is characterized in that the structural formula is shown as formula (I):
wherein,,R 1 is H, trifluoromethyl or one or more substituted halogen atoms; r is R 2 Is H or methyl.
2. A process for the preparation of a 1- (phenol-based benzyl) benzimidazole derivative according to claim 1, comprising the steps of:
substrate o-fluorobenzaldehyde derivatives
With benzimidazole derivatives->
And alkali reacts in N, N-dimethylformamide, the N, N-dimethylformamide is removed after the reaction, water is added and ethyl acetate is used for extraction, and the extract is purified to obtain a final target substance +.>
Said R is 1 Is H, trifluoromethyl or one or more substituted halogen atoms; r is R 2 Is H or methyl.
3. The process according to claim 2, wherein the substrate o-fluorobenzaldehyde derivative is
With benzimidazole derivatives->
The mass ratio of the substances is 2.0-2.5:1.0, and the benzimidazole derivative is prepared by the following steps of
The ratio of the alkali to the substance is 1.0:2.0-4.0.
4. The process according to claim 2, wherein the base isK 2 CO 3 ，Na 2 CO 3 ，K 3 PO 4 Or Cs 2 CO 3 。
5. The process according to claim 2, wherein the substrate o-fluorobenzaldehyde derivative is
With benzimidazole derivatives->
And alkali in N, N-dimethylformamide, wherein the reaction condition is that the reaction is carried out for 2 to 6 hours at the temperature of 60 to 90 ℃.
6. Use of a 1- (phenol-based benzyl) benzimidazole derivative or a salt thereof according to claim 1 in the preparation of an anticancer drug.
7. The use according to claim 6, wherein the anticancer drug is an anti-ovarian, anti-lung, anti-breast, anti-colorectal adenocarcinoma or anti-nasopharyngeal carcinoma drug.
8. An anticancer drug comprising the 1- (phenol-based benzyl) benzimidazole derivative or a salt thereof according to claim 1 as an active ingredient.
9. The anticancer drug according to claim 8, wherein the anticancer drug is an anti-ovarian, anti-lung, anti-breast, anti-colorectal adenocarcinoma or anti-nasopharyngeal carcinoma drug.
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