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Compound containing benzomorpholone-biphenyl skeleton as well as preparation method and application thereof

A technology of benzomorpholone and skeleton compounds, which is applied in the field of medicinal chemistry, can solve the problems of lack of oral activity and low selectivity, and achieve the effects of simple synthesis method, vasodilation and high yield

Active Publication Date: 2021-08-03
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In 1971, the first angiotensin Ⅱ polypeptide analog, saraxin, was discovered, which can competitively inhibit AT 1 receptor, but low selectivity and lack of oral activity prompted the development of non-peptide angiotensin II type 1 receptor blockers

Method used

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  • Compound containing benzomorpholone-biphenyl skeleton as well as preparation method and application thereof
  • Compound containing benzomorpholone-biphenyl skeleton as well as preparation method and application thereof
  • Compound containing benzomorpholone-biphenyl skeleton as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1, the preparation of compound I-1

[0041] 2-Hydroxy-4-nitroaniline (0.50g, 3.25mmol), sodium carbonate (1.09g, 12.98mmol), benzyltriethylammonium chloride (0.74g, 3.25mmol) were dissolved in 20mL ethanol, in Under the condition of ice bath, slowly add the mixture of chloroacetyl chloride and ethanol dropwise, and continue to stir for 40min after dropping. Subsequently, the reaction bottle was moved to an oil bath, and after reflux reaction for 2 h, the reaction was complete as monitored by TLC. The solid matter in the reaction system was removed by filtration while hot, and the residue was recrystallized with ethanol after rotary evaporation to remove the solvent. Intermediate 2 was obtained by suction filtration under reduced pressure, purple needle-like crystals, and the yield was 93%. 1 H NMR (400MHz, DMSO-d 6 )δ11.15(s,1H),7.89(dt,J=8.9,2.7Hz,1H),7.81(d,J=2.7Hz,1H),7.20(dd,J=8.9,2.7Hz,1H), 4.83(s,2H). 13 C NMR (101MHz, DMSO-d 6 )δ164.25, 149.15, 14...

Embodiment 2

[0046] Embodiment 2, the synthesis of compound I-22

[0047] Intermediate 4-1 was prepared in the same manner.

[0048] Add compound 4-1 (300mg, 0.77mmol), isonicotinic acid (0.93mmol), triethylamine (0.93mmol), 1-hydroxybenzotriazole (125.32mg, 0.93mmol), 15mL to a 25mL round bottom flask Anhydrous N,N-dimethylformamide, stirred overnight at room temperature. After the reaction was terminated, 10 mL of water was added to the system, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed to obtain 5-22, a white solid, with a yield of 90%.

[0049] Compound 5-22 was dissolved in 10 mL of methanol, and then 10 mL of 1 mol / L sodium hydroxide aqueous solution was added dropwise. After heating to reflux for 3 hours, the reaction solution changed from turbid to clear, and TLC detected that the reaction was complete. The methanol was distilled off under reduced pressure, and then 10 mL of water was added ...

Embodiment 3

[0050] Embodiment 3, the synthesis of compound I-24.

[0051] Intermediate 2 was prepared in the same manner.

[0052] Dissolve 2-triphenyltetrazolium-4'-bromomethylbiphenyl (0.91g, 1.64mmol) in 20mL of acetonitrile, then add sodium carbonate (0.28g, 1.97mmol), stir at reflux for 30min, and then add compound 2 (0.32g, 1.64mmol), after the reaction was complete, filtered, the filtrate was concentrated and then separated by column chromatography to obtain the intermediate biphenyl condensation product 3-2: pale yellow solid, the yield was 82%.

[0053] To 20mL ethanol: water (V:V=3:1) mixed solvent, add compound 3-2 (0.81g, 1.20mmol) and zinc powder (0.38g, 5.98mmol), ammonium chloride (0.32g, 5.98mmol ), stirring at reflux for 2h, the reaction was complete. After the reaction solution was filtered while it was hot, the ethanol was removed by rotary evaporation, and then 10 mL of water was added, and the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution. A large ...

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a compound with a benzomorpholone-biphenyl skeleton as well as a preparation method and application thereof. The compound has a structural general formula (I) as shown in the specification. The preparation method of the compound is simple and reliable, and the total yield is more than 40%. Preliminary pharmacological experiments show that the compound has a certain relaxation effect on in-vitro artery blood vessels of rats, can inhibit proliferation of mouse embryo fibroblasts (NIH-3T3) and expression of type I collagen to a certain extent, and can be used for development of anti-hypertension drugs and anti-myocardial fibrosis drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of compounds containing a benzomorpholone-biphenyl skeleton, a preparation method and its application as an active ingredient of a drug for lowering blood pressure and resisting myocardial fibrosis. [0002] technical background [0003] Angiotensin Ⅱ type 1 receptor blockers (ARBs) have been clinically used to control cardiovascular diseases for several years, and are widely used in the treatment of hypertension and anti-fibrosis drugs. In antihypertensive aspects, compared with other antihypertensive drugs, ARBs have better curative effect and higher safety, and have the pharmacological characteristics of high efficiency, high specificity, less side effects, high compliance, and protective effects on various organs . In terms of anti-myocardial fibrosis (MF), ARBs can effectively reverse hypertensive cardiac remodeling and reduce or prevent the occurrence of MF. Compa...

Claims

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Application Information

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IPC IPC(8): C07D265/36C07D413/10C07D413/14C07D413/12A61P9/12A61P9/00A61P9/08
CPCC07D265/36C07D413/10C07D413/14C07D413/12A61P9/12A61P9/00A61P9/08
Inventor 施秀芳安义平李秀君张振中于震强陈海歌朱超然郭璇
Owner ZHENGZHOU UNIV
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