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6-oxohexahydropyrimidine derivative, its preparation method and pharmaceutical application

A compound and general formula technology, applied in the field of medicinal chemistry, can solve the problems of general activity and single structure type, and achieve the effect of potential medicinal value

Active Publication Date: 2022-04-19
南京安美医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although a series of skeleton structures have been disclosed so far, hydroxyproline is still used as the skeleton for modification in the treatment of cerebral apoplexy, anemia, and cerebral ischemia. The structure type is relatively single and the activity is general.

Method used

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  • 6-oxohexahydropyrimidine derivative, its preparation method and pharmaceutical application
  • 6-oxohexahydropyrimidine derivative, its preparation method and pharmaceutical application
  • 6-oxohexahydropyrimidine derivative, its preparation method and pharmaceutical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] 3-(3,3-Dimethylbutyryl)-N-(4-(4-methylthiazol-5-yl)benzyl)-6-oxohexahydropyrimidine-4-carboxamide

[0079]

[0080] Step 1: 4-(4-Methylthiazol-5-yl)benzonitrile

[0081] Add KOAc (3.2g) and 4-methylthiazole (3.24g) to a 50ml single-necked bottle, add 15ml DMF to dissolve, add p-bromoxynil (3.0g), add Pd(OAc) 2 (16 mg), heated under reflux and stirred in an external bath, after 10 hours, TLC detected that the raw materials were completely reacted, filtered, added 50 ml of water, extracted three times with EA (20 mL×3), combined the organic phases, washed with 50 ml of saturated aqueous sodium chloride solution, anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate under reduced pressure to obtain 3.2 g of the title compound.

[0082] Step 2: (4(4-methylthiazol-5-yl)phenyl)methanamine

[0083] Add 4-(4-methylthiazol-5-yl)benzonitrile (2.0g) into a 50ml three-necked flask, add 15ml of methanol to dissolve, add Raney nickel, replace with hydroge...

Embodiment 2

[0093] N-([1,1'-biphenyl-4-methyl)-3(3,3-dimethylbutyryl)-6-oxohexahydropyrimidine-4-carboxamide]

[0094]

[0095] Step 1: N-([1,1'-biphenyl-4-methyl)-3(3,3-dimethylbutyryl)-6-oxohexahydropyrimidine-4-carboxamide]

[0096] Add the 3-(3,3-dimethylbutyryl)-6-oxahexahydropyrimidine-4-carboxylic acid (150 mg) prepared above into a 25 ml one-mouth bottle, add 5 ml of DMF, and add HBTU (250 mg) , add 1,1'-biphenyl-4-methylaminoamine (114mg), add DIPEA (240mg), stir at room temperature for 3h, LC-MS detects that the reaction is complete. Add 15ml of water, extract the aqueous phase with EA (20mL×3), combine the organic phases, wash with 50ml of saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. It was filtered and concentrated under reduced pressure to obtain 185 mg of an oily substance, which was prepared by HPLC to obtain 35 mg of the title compound (HPLC purity: 97.6%).

[0097] The rest of the reaction steps were prepared with reference to th...

Embodiment 3

[0101] 3-(3,3-Dimethylbutyryl)-N-(4-hydroxybenzyl)-6-oxohexahydropyrimidine-4-carboxamide

[0102]

[0103] Step 1: 3-(3,3-Dimethylbutyryl)-N-(4-hydroxybenzyl)-6-oxohexahydropyrimidine-4-carboxamide

[0104] Add the 3-(3,3-dimethylbutyryl)-6-oxahexahydropyrimidine-4-carboxylic acid (150 mg) prepared above into a 25 ml one-mouth bottle, add 5 ml of DMF, and add HBTU (250 mg) , add (4-hydroxyphenyl)methanamine (78.12mg), add DIPEA (240mg), stir at room temperature for 3h, LC-MS detects that the reaction is complete. Add 15ml of water, extract the aqueous phase with EA (20mL×3), combine the organic phases, wash with 50ml of saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. It was filtered and concentrated under reduced pressure to obtain 170 mg of an oily substance, which was prepared by HPLC to obtain 25 mg of the title compound (HPLC purity: 96.4%).

[0105] The rest of the reaction steps were prepared with reference to the synthesis method...

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PUM

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Abstract

The invention discloses a 6-oxohexahydropyrimidine derivative, and also discloses a preparation method of the derivative, and its use in the preparation, prevention and treatment of ischemia caused by HIF-1α deficiency leading to cerebral apoplexy and cerebral ischemia , anemia and other diseases in the drug application. The derivatives prepared by the present application can compete with HIF-1α for binding to VHL protein, and have obvious competitive inhibitory effect on HIF-1α / VHL protein-protein interaction, thereby releasing HIF-1α, which is effective for the deficiency of HIF-1α. It has a certain effect on cerebral ischemia, and has potential medicinal effects for the treatment and prevention of cerebral ischemia, stroke and anemia.

Description

technical field [0001] The invention belongs to medicinal chemistry technology, and in particular relates to a 6-oxohexahydropyrimidine derivative, its preparation method and pharmaceutical application. Background technique [0002] After cerebral ischemia, hypoxia-inducible factors-1α (HIF-1α) stimulates the expression of its target gene, vascular endothelial growth factor (VEGF), thereby promoting angiogenesis and improving cerebral hemodynamics In hypoxia, the expression of HIF-1α also increases the expression level of glucose transport enzyme-1, which promotes the transfer, utilization and glycolysis of glucose, and provides energy for brain tissue to relieve brain damage. damage; finally, HIF-1α can also play a role in brain protection by promoting the expression of erythropoietin (EPO). [0003] HIF-1 belongs to the basic helixloop-helix (bHLH) structural transcription factor family member, three α analogs (HIF-1α, HIF-2α, HIF-3α) and HIF-1β, all contain bHLH and PAS...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12C07D239/06A61K31/513A61P25/28A61P7/06
CPCA61P7/06A61P25/28C07D239/06C07D417/12
Inventor 薛鑫张海晴
Owner 南京安美医药科技有限公司