Ureido-containing benzimidazole derivative as well as preparation method and application thereof

A technology of benzimidazoles and benzimidazoles, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of not directly inhibiting the activity of HIPK2 kinase, and achieve good market application prospects

Active Publication Date: 2021-05-25
SHIJIAZHUANG YILING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Literature (J Am Soc Nephrol, 2017, 28, 2133) and patent WO2018129274 disclose that a class of oxadiazole (general formula VII) HIPK2 inhibitors can improve unilateral ureteral ligation and Tg26 mice by inhibiting the interaction between HIPK2 and SMAD3 Model of renal fibrosis, but this compound does not directly inhibit the kinase activity of HIPK2

Method used

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  • Ureido-containing benzimidazole derivative as well as preparation method and application thereof
  • Ureido-containing benzimidazole derivative as well as preparation method and application thereof
  • Ureido-containing benzimidazole derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082]Example 1 1- (2-morpholine ethyl) -3- (4- (1-phenyl-2- (trifluoromethyl) -1H-benzimidazol-5-yl) phenyl) urea (6A)2)

[0083]1, prepotten 4-bromo-2-nitro-N-aniline (3)

[0084]

[0085]It will be prepared from 1 and 2 to 1 and 2, 2-fluoro-5-bromide (4.4 g, 20 mmol) and aniline (2.2 mL, 24 mmol) are added to a microwave tube containing 15 ml of water, reacted at 120 ° C. 4h. After cooling, extract 3 times with ethyl acetate, washed with EtOAc (EtOAc)2SO4Dry and put it for 4 h. The coherent organic solvent was separated by hydracene column chromatography with petroleum ether. It was found to be 4.92 g of orange crystals, and the product 3 was very similar to the raw material 1, even with the minimal petroleum ether with polarity, the displacement value is still very similar. It is difficult to get a pure product, directly into the next reaction.

[0086]2. Preparation of 5-bromo-1-phenyl-2- (trifluoromethyl) -1H-benzimidazole (4b)

[0087]

[0088]In a 50 ml of three-necked, iron powder (0.4 g, 7....

Embodiment 2

[0098]Example 2 1- (4- (2-methyl-1-phenyl-1H-benzimidazol-5-yl) phenyl) -3- (2-morpholine ethyl) urea (6a)1)

[0099]

[0100]1, prepare 4-bromo-2-nitro-N-aniline (3)

[0101]

[0102]2-fluoro-5-bromide (4.4 g, 20 mmol), aniline (2.2 mL, 24 mmol) were added to a microwave tube equipped with 15 ml of water at 120 ° C for 4 h. After cooling, extract 3 times with ethyl acetate, washed with EtOAc (EtOAc)2SO4Dry and put it for 4 h. The coherent organic solvent was separated by hydracene column chromatography with petroleum ether. It was found to be 4.92 g of orange crystals, and the product 3 was very similar to the raw material 1, even with the minimal petroleum ether with polarity, the displacement value is still very similar. It is difficult to get a pure product, directly into the next reaction.

[0103]2,5-bromo-2-methyl-1-phenyl-1H-benzimidazole (4a)

[0104]

[0105]In a 50 ml of three-necked, iron powder (0.4 g, 7.2 mmol), 20 ml of glacial acetic acid was added, and 2-3 drop of concentrated hydrochlo...

Embodiment 3

[0114]Example 3 1- (4- (2-methyl-1-phenyl-1H-benzimidazole-5-yl) phenyl) -3- (3-morpholopropyl) urea (6b)1)

[0115]

[0116]Compound 6b1Preparation method reference 6A2, Yellow oil, yield: 63.0%.1H NMR (500MHz, DMSO-D6: δ8.59 (S, 1H), 7.82 (D, J = 1.4 Hz, 1H), 7.73-7.64 (M, 2H), 7.63-7.52 (m, 5H), 7.53-7.46 (m, 2H), 7.45 (DD, J = 8.4, 1.6 Hz, 1H), 7.16 (D, J = 8.4 Hz, 1H), 6.23 (S, 1H), 3.61 (S, 4H), 3.14 (DD, J = 12.7, 6.6 Hz 2H), 2.46 (S, 3H), 2.64 (S, 2H).13C NMR (125MHz, DMSO-D6): Δ155.60,152.38,143.54,140.04,136.06,135.59,135.06,134.04,130.49,129.18,127.48,127.31,121.63,118.42,116.20,110.51,66.64,58.32,53.70,36.43,14.67.HRMS (ESI) m / Z Calcd for [c28Hide31N5O2+ H]+: 470.2478; Found: 470.2964 [M + H]+.

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Abstract

The invention discloses a ureido-containing benzimidazole derivative, whose structural general formula is shown as a formula (I). The invention also discloses a preparation method of the compound and application of the compound in the preparation of medicines for resisting chronic kidney diseases. The derivative is an inhibitor of selective homologous domain interacting protein kinase-2 (HIPK2), can lower the protein level of the HIPK2 at the same time to play a dual role, has an inhibition effect on the HIPK2 kinase and protein level, a fibrosis signal molecule smad3 and an inflammation signal molecule I[kappa]B-alpha phosphorylation level, can adjust the fibrosis and inflammation processes at the same time, and has a good market application prospect as chronic kidney disease treatment medicines.

Description

Technical field[0001]The present invention relates to the field of pharmaceutical synthesis, and more particularly to a urea-benzene-imidazole derivative and a preparation method thereof.Background technique[0002]Chronic Nephrology (CKD) is a type of disease, including diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, IgA nephropathy, pyelonephritis, allergic purpura, red spotted, gout, nephrotic syndrome, polycystic kidney Wait. The incidence of CKD and (especially) have a trend of growth increasingly year-on-year. The incidence of CKD is positively correlated with the age of patients, and has already had a low age. However, CKD has a low awareness rate in the ordinary population, lacks effective prevention and treatment means in clinical practice.[0003]There is more incentives for CKD, with diabetes, hypertension, obesity, infection, etc. The CKD caused by different incentives has the same pathological changes, namely, kidney fibrosis with inflammation. Clinicall...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/10A61K31/4178A61K31/5377A61K31/4184A61P3/10A61P13/12
CPCC07D235/10A61P3/10A61P13/12A61K31/4178A61K31/4184A61K31/5377A61K31/17C07C275/18C07C275/20
Inventor 李乾斌胡高云王泽瑜陈卓
Owner SHIJIAZHUANG YILING PHARMA
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