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Organic nitrite donor ketal type prodrug as well as preparation method and medical application thereof

A pharmacy and drug technology, applied in the application of myocardial ischemia and pulmonary arterial hypertension drugs, the preparation of prevention or treatment of cerebral ischemia, the preparation of organic nitrite donor ketal-type prodrugs, can solve the problem of damage, unproductive Ischemic protection, protein nitration, etc.

Active Publication Date: 2022-08-05
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although sodium nitrite has shown good effects in treating various animal ischemic diseases, it can be rapidly metabolized after entering the human circulation, and its half-life is only 25-30 minutes
In addition, large doses of sodium nitrite did not produce ischemic protection
The reason may be that high-concentration sodium nitrite produces a large amount of NO in a short period of time, and superoxide anion free radicals reaction to generate peroxynitrite (ONOO - ), leading to toxic side effects such as protein nitration and DNA damage
Furthermore, if sodium nitrite is given frequently, it may cause excessive Na + Ingestion, adverse cardiovascular effects

Method used

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  • Organic nitrite donor ketal type prodrug as well as preparation method and medical application thereof
  • Organic nitrite donor ketal type prodrug as well as preparation method and medical application thereof
  • Organic nitrite donor ketal type prodrug as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of (E)-2-nitromethyl-3-phenyl-1-(3-(trifluoromethyl)phenyl)prop-2-ene-1-ketal (Compound I)

[0034]

[0035] (a) put (NH 4 ) 2 S 2 O8 , p-amyl alcohol and dibenzylamine were placed in Schlenk flasks, 3-trifluoromethyl Propiophenone was added respectively, N 2 Replace, and react at 120°C for 24-30h; the reaction solution gradually changes from white to yellow. After the reaction was completed, water was added to quench, then extracted with ethyl acetate (100 mL), the organic layer was washed three times with water and saturated brine each, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate=100 / 1, v / v) separation and purification to obtain compound IV. Product IV was a colorless oil in 75% yield. 1 H NMR (300MHz, CDCl 3 )δ8.00(s, 1H), 7.92(d, J=7.7Hz, 1H), 7.81(d, J=7.6Hz, 1H), 7.60(t, J=7.7Hz, 1H), 7.43(d, J=4.2Hz, 4H), 7.40-7.34(m, 1H), 7.16(s, 1H), 2.29(s, 3H). 13 C...

Embodiment 2

[0039] Example 2: Plasma stability test of ketal-type prodrug (Compound I)

[0040] 1. Test method

[0041] A certain concentration (200 μM) of compound I and compound VI were dissolved in bovine plasma (5% DMSO assisted solubilization), incubated at 37.4 °C, and samples were taken at regular intervals, and the peak areas of the two compounds were recorded by HPLC, so as to carry out the analysis. For comparison, Compound VI is a positive control.

[0042] 2. Test results

[0043] The result is as figure 2 shown. The results showed that Compound VI was rapidly degraded in plasma, and the degradation was completed within 2 hours; the ketal prodrug I significantly improved the plasma stability of the original drug. Compound I has good stability, and only 7.8% degraded within 24h; These results suggest that the ketal-type prodrug has better plasma stability and is significantly stronger than compound VI.

Embodiment 3

[0044] Example 3: Stability of a ketal-type prodrug (Compound I) in the presence of a nucleophile.

[0045] 1. Test method

[0046] Equal concentrations of N-acetylcysteine ​​(200 μM) were co-incubated with Compound VI and Compound I at 37.4° C., and the concentration of each compound was determined at each time point using the same method described above.

[0047] 2. Test results

[0048] like image 3 As shown, compound VI can be gradually degraded with time, while compound I has better stability and hardly degrades in the presence of nucleophile. The above results prove that the protection of the carbonyl group in the α,β-unsaturated ketone structure of compound I can effectively reduce its ability to be attacked by nucleophiles and improve the stability.

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Abstract

The invention relates to the field of medicinal chemistry, in particular to an organic nitrite donor ketal type prodrug containing a 1-nitromethyl-2-phenylethylene skeleton, a preparation method of the prodrug and medical application of a medicinal composition of a compound I in prevention or treatment of cerebral ischemia, myocardial ischemia and pulmonary arterial hypertension. Compared with a previously designed and synthesized organic nitrite donor compound VI, the ketal type prodrug I of the organic nitrite donor has better plasma stability, and the strategy of the ketal type prodrug I can further improve the played ischemia protection effect and improve the survival rate of oxygen-glucose deprivation / reperfusion (OGD / R) primary neuronal cells. Meanwhile, the pharmacokinetic study shows that the ketal prodrug type donor has a better pharmacokinetic behavior. In addition, the prodrug strategy can significantly reduce MCAO rat cerebral infarction volume and cerebral water content, accelerate rat ischemic brain tissue endothelial cell proliferation, and promote angiogenesis.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a kind of organic nitrite containing 1-nitromethyl-2-phenylethylene skeleton The preparation method of the donor ketal type prodrug (compound I), the pharmaceutical composition containing the ketal type prodrug (compound I) and its medical use, especially in the preparation of prevention or treatment of cerebral ischemia, myocardial ischemia and Use of pulmonary arterial hypertension drugs. Background technique [0002] In recent years, studies have shown that sodium nitrite (NaNO 2 ) has a very good therapeutic and protective effect on some cardiovascular and cerebrovascular diseases, especially ischemic diseases. Clinical studies have shown that intravenous infusion of low-dose sodium nitrite is indeed effective and well tolerated in patients with acute ischemic stroke. It disappears after the medicine. [0003] Myocardial ischemia is one of the main inducing factors of ...

Claims

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Application Information

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IPC IPC(8): C07D317/16A61K31/357A61P9/12A61P9/10A61P9/06
CPCC07D317/16A61P9/12A61P9/10A61P9/06Y02P20/55
Inventor 黄张建张奕华孙涛吴建兵
Owner CHINA PHARM UNIV
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