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Pyrazolo[3,4-d]pyrimidinone compounds and their application in the preparation of phosphodiesterase ⅸ inhibitors

A 4-d, pyrazolo technology, applied in the application field of pyrazolo [3, preparation of phosphodiesterase IX inhibitors, can solve the problems of low bioavailability, asymmetric synthesis, molecules containing hand shapes, etc. Achieve broad application prospects, easy operation, and low cost

Active Publication Date: 2011-11-30
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although PDE9 inhibitors have entered phase III clinical trials as drugs for the treatment of Alzheimer's disease (AD), these inhibitors still have many shortcomings, such as molecules containing hand shapes, requiring asymmetric synthesis, and low bioavailability.

Method used

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  • Pyrazolo[3,4-d]pyrimidinone compounds and their application in the preparation of phosphodiesterase ⅸ inhibitors
  • Pyrazolo[3,4-d]pyrimidinone compounds and their application in the preparation of phosphodiesterase ⅸ inhibitors
  • Pyrazolo[3,4-d]pyrimidinone compounds and their application in the preparation of phosphodiesterase ⅸ inhibitors

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment one: the synthesis of compound W-1

[0056]

[0057] Formula (6)

[0058]In a 50mL round-bottom flask, add isopropanol (10mL), 1-(2-chlorophenyl)-6-chloro-pyrazolo[3,4-d]pyrimidin-4-one (0.4mmol, 0.1g), 2-amino-N-phenylpropanamide (0.48mmol, 0.08g), triethylamine (0.4mmol, 0.04g), and then heated to reflux, and the reaction was terminated after monitoring the completion of the reaction. After cooling to room temperature and concentrating, a colorless and transparent oil was obtained. The crude product was separated and purified by column chromatography (DCM:MeOH=25:1) to obtain 0.07 g of a white solid, with a yield of 41%.

[0059] 1 H NMR (300MHz, CDCl 3 )δ: 10.80(s, 1H), 8.64(br s, 1H), 8.13(s, 1H), 7.51-7.46(m, 2H), 7.35-7.24(m, 6H), 7.06(d, J=6.3 Hz, 2H), 4.56-4.49(m, 1H), 1.52(d, J=7.3Hz, 3H).ESI-MS: m / z=407[M-H] -

[0060] After identification, its structure is shown in formula (6).

Embodiment 2

[0061] Embodiment two: the synthesis of compound W-2

[0062]

[0063] Formula (7)

[0064] The synthesis method is the same as W-1, the raw materials are isopropanol (10mL), 1-(2-chlorophenyl)-6-chloro-pyrazolo[3,4-d]pyrimidin-4-one (0.4mmol, 0.1 g), 2-amino-N-(4-methoxyphenyl)propanamide (0.48mmol, 0.09g), triethylamine (0.4mmol, 0.04g). The crude product was separated and purified by column chromatography (DCM:MeOH=25:1) to obtain 0.08 g of a white solid with a yield of 45%.

[0065] 1 H NMR (300MHz, CDCl 3 )δ: 10.57(s, 1H), 8.14(s, 1H), 8.13(br s, 1H), 7.52-7.29(m, 4H), 7.11-6.77(m, 5H), 4.55-4.46(m, 1H ), 3.78(s, 3H), 1.52(d, J=6.9Hz, 3H) 13 C ESI-MS: m / z=437[M-H] - .

[0066] After identification, its structure is shown in formula (7).

Embodiment 3

[0067] Embodiment three: the synthesis of compound W-3

[0068]

[0069] Formula (8)

[0070] The synthesis method is the same as W-1, the raw materials are isopropanol (10mL), 1-phenyl-6-chloro-pyrazolo[3,4-d]pyrimidin-4-one (0.4mmol, 0.1g), 2- Amino-N-(4-methoxyphenyl)propanamide (0.48mmol, 0.09g), triethylamine (0.4mmol, 0.04g). The crude product was separated and purified by column chromatography (DCM:MeOH=25:1) to obtain 0.07 g of a white solid with a yield of 41%.

[0071] . 1 H NMR (300MHz, DMSO-d 6 )δ: 10.67(s, 1H), 10.17(br s, 1H), 8.06(d, J=6.3Hz, 3H), 7.54(d, J=9.0Hz, 2H), 7.36-7.23(m, 3H) , 7.11(d, J=6.3Hz, 1H), 6.89(d, J=9.0Hz, 2H), 4.55-4.46(m, 1H), 3.71(s, 1H).ESI-MS: m / z=403 [M-H] - .

[0072] After identification, its structure is shown in formula (8).

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Abstract

The invention discloses pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of a phosphodiesterase IX inhibitor. The structure of the compounds is shown as a formula (1); in the formula, when R' is 2-chlorophenyl, R refers to phenyl, substituted phenyl, benzyl, substituted benzyl, 3-methylpyridine, 1-phenylethyl, diphenylmethyl or CHCH3CONHR1, wherein R1 refers to phenyl ormethyl, methoxyl, ethoxyl, isopropoxy, methylthio, NHCOCH3 or NCH3CH3 substituted phenyl; when R' is phenyl, R refers to CHCH3CONHR2, wherein R2 refers to methoxyl or ethoxyl substituted phenyl; and when R' is methyl, R refers to 4-methoxy-benzyl, diphenylmethyl or N-(2-amino-cyclohexyl)-4-methoxy-benzenesulfonamide. The pyrazolo[3,4-d]pyrimidone compounds have activity of inhibiting phosphodiesterase IX, can serve as the phosphodiesterase IX inhibitor, can be used for preparing the phosphodiesterase IX inhibitor, and have wide application prospect. The compounds are shown as the formula (1).

Description

Technical field: [0001] The present invention relates to a class of phosphodiesterase IX inhibitors (PDEIX Inhibitors), in particular to a class of novel 6-position N-substituted pyrazolo[3,4-d]pyrimidinone compounds and their use in the preparation of phosphodiesters Use of Enzyme IX Inhibitors. Background technique: [0002] Phosphodiesterase is a superfamily of enzymes widely present in organisms. It is an important part of cell signaling pathways and can selectively degrade the important second messengers in cells, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate. (cGMP), thus playing an important physiological role. [0003] Phosphodiesterase IX is the ninth member of the phosphodiesterase family. It has a high affinity for cGMP and can specifically hydrolyze cGMP. Widely distributed in the human body, especially highly expressed in the colon, kidney, small intestine, spleen and brain. Its messenger RNA is highly expressed in the base of the b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P3/10A61P25/28A61P13/00A61P9/00A61P3/04
Inventor 万一千罗海彬孟飞刘培庆朱新海文丹邵咏贤张淳黄杰辉
Owner SUN YAT SEN UNIV
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