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Phenylguanidine derivates containing pyrazolo pyrimidinone, medicament composition thereof as well as preparation method and application thereof

A technology of pyrazolopyrimidone and phenylguanidine, applied in the field of phenylguanidine derivatives, can solve the problems of photosensitivity, blurred vision, light vision and the like

Inactive Publication Date: 2012-10-24
TOPHARMAN SHANGHAI CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although sildenafil has achieved remarkable clinical curative effect, because it also has different degrees of inhibitory effects on other phosphodiesterase (PDE) isozymes other than PDE5, the clinical manifestations are headache, flushing, indigestion, nasal congestion, Toxic and side effects such as blurred vision, photosensitivity, and pale vision

Method used

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  • Phenylguanidine derivates containing pyrazolo pyrimidinone, medicament composition thereof as well as preparation method and application thereof
  • Phenylguanidine derivates containing pyrazolo pyrimidinone, medicament composition thereof as well as preparation method and application thereof
  • Phenylguanidine derivates containing pyrazolo pyrimidinone, medicament composition thereof as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0164] 5-(5-Ethylamino-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one

[0165]

[0166] 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (preparation method See Bioorg.Med.Chem.; 9; 7; 2001; 1895-1900.) (2.4g, 7.3mmol) was dissolved in 50ml80% acetonitrile aqueous solution, added 0.14g 5%Pd / C and 5g ammonium formate, nitrogen protection, Stir at room temperature for 20h. Palladium charcoal was filtered off, the solvent was evaporated to dryness and washed with 50ml CH 2 Cl 2 Dissolved, washed with water (50ml) and saturated brine (50ml) respectively, anhydrous Na 2 SO 4 Drying and concentration to dryness afforded a crude white solid. Purify by silica gel column chromatography (eluent: 10% petroleum ether-ethyl acetate) to obtain 2.4 g of the title compound with a yield of 92.1%. 1 H NMR (CDCl 3 )δ: 8.31(1H,d), 7.35(1H,dd), 7.13(1H,d), 4.27(3H,s), 4.21(2H,q), 4.01(2H,q), 2.92(2H,t ), 1.85 (2H, m), 1.36 (3H, ...

preparation example 2

[0168] 5-(5-Ethylamino-2-propoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one

[0169]

[0170] According to the same method as Preparation Example 1, with 5-(5-amino-2-propoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7 (6H)-Kone (for preparation see Bioorg. Med. Chem.; 9; 7; 2001; 1895-1900.) as starting material. The crude product was purified by silica gel column chromatography with a yield of 90.3%. 1 H NMR (CDCl 3 )δ: 8.31(1H,d), 7.35(1H,dd), 7.13(1H,d), 4.27(3H,s), 4.21(2H,t), 4.01(2H,q), 2.92(2H,t ), 2.03 (2H, m), 1.85 (2H, m), 1.36 (3H, t), 1.18 (3H, t), 1.02 (3H, t).

preparation example 3

[0172] 5-(5-Benzylamino-2-propoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one

[0173]

[0174] 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (1.0g , 3.0mmol) was dissolved in 100ml methanol, slowly added dropwise benzaldehyde (0.33g, 3.1mmol), after TLC showed that the reaction ended, cooled with an ice bath, added NaBH in batches 4 (0.11 g, 3.1 mmol). After the reaction, the ethanol was evaporated to dryness, dissolved in dichloromethane (30ml), washed with water and saturated brine, anhydrous Na 2 SO 4 Dry, concentrate, and recrystallize from methanol / dichloromethane to obtain 1.05 g of the title compound, yield: 82.3%. 1 H NMR (CDCl 3 )δ: 7.55 (1H, d), 7.45-7.36 (6H, m), 7.20 (1H, d), 4.99 (2H, s), 4.16 (3H, s), 4.11 (2H, q), 2.75 (2H , t), 1.72 (2H, m), 1.31 (3H, t), 0.93 (3H, t).

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Abstract

The invention relates to the technical field of medicine, in particular to phenyl guanidine derivatives containing pyrazolopyrimidin and expressed by general formula I, and pharmaceutically acceptable salt or solvate thereof, and also relates to medicament composition containing compounds and a method for preparing the compounds. The compounds has stronger PDE5 inhibition activity than sildenafil, has higher selectivity than PDE 6 distributed on retina, and further can be applied to treating various vein dysfunctional diseases such as male erectile dysfunction.

Description

technical field [0001] The present invention relates to a class of phenylguanidine derivatives containing pyrazolopyrimidinone, pharmaceutically acceptable salts or solvates thereof, and also relates to pharmaceutical compositions containing such compounds and methods for preparing such compounds. The compound of the invention can effectively inhibit V-type phosphodiesterase (PDE5), and thus can be applied to the treatment of various vascular disorders such as male erectile dysfunction. Background technique [0002] Sildenafil (WO94 / 28902) launched by Pfizer is the first oral PDE5 inhibitor for the treatment of male erectile dysfunction. It inhibits V-type phosphodiesterase in smooth muscle cells, increasing the level of cGMP, the substrate of the enzyme, causing relaxation and vasodilation of smooth muscle, thereby increasing blood flow there and leading to erection. [0003] Subsequently, major pharmaceutical companies and research groups have developed a large number of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P43/00
CPCC07D487/04A61P15/10A61P43/00
Inventor 刘正田广辉王震辛颉张金凤朱毅沈敬山沈竞康
Owner TOPHARMAN SHANGHAI CO LTD