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Phthalimide compound used as PDE2/4 dual inhibitor and preparation method thereof

A phthalimide and dual-inhibitor technology, applied in the field of phthalimide compounds and their preparation, can solve the problem of poor pharmacokinetic properties, weak and side effects of PDEs inhibitors Effectiveness and other issues, to achieve a good effect of dual inhibitory activity

Active Publication Date: 2020-05-19
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, more and more recent studies have shown that single PDEs inhibitors often show obvious side effects and weak efficacy in clinical practice, such as the PDE4 inhibitor roflumilast, apremilast, etc. Intestinal side effects, dizziness, headache, nausea, vomiting, etc. PDE2 inhibitors have not been marketed because of their weak efficacy and poor pharmacokinetic properties, but drugs that can inhibit multiple PDE subtypes at the same time are possible One of the strategies to solve these problems

Method used

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  • Phthalimide compound used as PDE2/4 dual inhibitor and preparation method thereof
  • Phthalimide compound used as PDE2/4 dual inhibitor and preparation method thereof
  • Phthalimide compound used as PDE2/4 dual inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1: the preparation of compound a

[0025] 1. Preparation of Intermediate 2

[0026]

[0027] Add 20ml of a mixed solvent of dichloromethane and methanol (1:1) into a round bottom flask, add furfural 1.8g (20mmol) and benzylamine 2.5g (24mmol) successively under stirring, react at 45°C for 1h, then cool down to 25°C, Add 500 mg NaBH three times in 45 minutes 4 , After 3 hours of reaction, the temperature was raised to 45°C, and the reaction was stopped after 4 hours, and the solvent was evaporated to dryness under reduced pressure. Add 20ml of dichloromethane again to dissolve, wash with saturated saline and deionized water three times, evaporate the solvent under reduced pressure, and separate by column chromatography to obtain 3.4g of intermediate 2 with a yield of 79.0%.

[0028] 2. Preparation of Intermediate 4

[0029]

[0030] In a round bottom flask, add 0.98g (10mmol) of maleic acid glycoside and dissolve it in 30ml of ether solvent. After it ...

Embodiment 2

[0037] Embodiment 2: the preparation of compound b

[0038] Except for using n-butylamine instead of benzylamine, the synthesis method was the same as that of compound a in Example 1, and the total yield was 52.3%. The structural formula is as follows:

[0039]

[0040] ESI MS:383.7[M+H] +1 , 1 H-NMR(300MHz,DMSO)δ8.21-8.14(m,1H),7.93-7.80(m,2H),6.97-6.74(m,3H),4.74(s,2H),4.17-4.15(m, 1H), 3.76(s, 3H), 3.53(s, 3H), 1.91-1.67(m, 2H), 1.33-1.29(m, 6H), 0.85(s, 3H).

Embodiment 3

[0041] Embodiment 3: the preparation of compound c

[0042] Except that n-propylamine was used instead of benzylamine, the synthesis method was the same as that of compound a in Example 1, and the total yield was 48.9%. The structural formula is as follows:

[0043]

[0044] ESI MS:369.1[M+H] +1 , 1 H-NMR(300MHz,DMSO)δ8.21-8.14(m,1H),7.93-7.80(m,2H),6.97-6.74(m,3H),4.74(s,2H),4.17-4.15(m, 1H), 3.76(s, 3H), 3.52(s, 3H), 1.93-1.67(m, 2H), 1.31-1.27(m, 4H), 0.86(s, 3H).

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Abstract

The invention discloses a phthalimide compound used as a PDE2 / 4 dual inhibitor and a preparation method thereof. The general formula of the phthalimide compound is shown in the specification, and thephthalimide compound has good PDE2 / 4 dual inhibitory activity, can show more excellent pharmacodynamic properties and has small side effects compared with the traditional single PDEs inhibitor. The compound can be used for preparing medicines for treating senile dementia, depression, arthritis, asthma, chronic obstructive pulmonary diseases and the like.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a phthalimide compound as a PDE2 / 4 dual inhibitor and a preparation method thereof. Background technique [0002] Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are intracellular second messengers. They exist in many tissue cell structures, are responsible for intracellular signal transduction, participate in the regulation of various physiological processes, and play an extremely important role in the physiological activities of cells. The imbalance of cAMP and cGMP concentration will lead to the occurrence of various diseases, so how to maintain the concentration at a normal level and keep the body in a healthy state has become the focus of research. Phosphodiesterases (Phosphodiesterases, PDEs) are the only super enzyme family that can hydrolyze cAMP and cGMP in the body. The human genome encodes 11 PDE families (PDE1 to PDE11) to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48A61P25/28A61P25/24A61P19/02A61P11/00A61P11/06A61K31/4035
CPCC07D209/48A61P25/28A61P25/24A61P19/02A61P11/00A61P11/06
Inventor 黄险峰董炎华许煌高英曹依菁孔韧宋国强
Owner CHANGZHOU UNIV
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