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Nitrogen-containing ring derivative inhibitor as well as preparation method and application thereof

A compound and cycloalkyl technology, which is applied in the field of nitrogen-containing ring derivative inhibitors and their preparation, can solve problems such as loss of taste

Pending Publication Date: 2021-05-11
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Taste effects, including altered taste and partial loss of taste, were infrequent and mostly mild in nature at all dose levels, with no patients reporting complete loss of taste

Method used

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  • Nitrogen-containing ring derivative inhibitor as well as preparation method and application thereof
  • Nitrogen-containing ring derivative inhibitor as well as preparation method and application thereof
  • Nitrogen-containing ring derivative inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0236] 4-(4-Chlorobenzyl)-7-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-(2,2,2-trifluoromethyl)-4,7- Dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

[0237]

[0238] The first step: the preparation of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propionitrile

[0239]

[0240] A solution of LiHMDS in tetrahydrofuran (26.3 mL, 26.3 mmol) was cooled to -78°C and acetonitrile (1.43 mL, 27.5 mmol) was slowly added dropwise. After the mixture was stirred at -78°C for 1 hour, a solution of methyl tetrahydro-2H-pyran-4-carboxylate (3.6 g, 25.0 mmol) in tetrahydrofuran (12 mL) was slowly added dropwise. After the mixture was stirred at -78°C for 1 hour, the dry ice bath was removed and slowly returned to ambient temperature. The mixture was poured into ice water (250 mL) and extracted three times with methyl tert-butyl ether. The aqueous phase was cooled to 0°C and the pH was adjusted to around 3 with 6M HCl. Extracted with ethyl acetate three times, combined the organic phases, dried and conce...

Embodiment 2

[0263] 4-(4-Chlorobenzyl)-5-fluoro-7-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-(2,2,2-trifluoroethyl)-4 ,7-Dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

[0264]

[0265] The first step: the preparation of 1,1-diethyl-1-methylmethane tricarboxylic acid

[0266]

[0267] In a 100 mL round bottom flask was added magnesium turnings (1.3 g, 53 mmol) and 8.0 mL of ethanol. 0.5 mL of carbon tetrachloride was added, and the mixture was refluxed under argon for 1 hour. The reaction mixture thickened and turned white. Diethyl malonate (8.0 g, 50 mmol) was added to 10 mL of ethanol and heated for an additional 3 hours to give a dark green solution. The solution was cooled to room temperature and 6.0 mL of methyl chloroformate was added to 10 mL of THF. Heating was continued for over an hour and then stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride, then extracted with 225 mL of ethyl acetate. The organic layer was dried over anhydro...

Embodiment 3

[0289] 4-(2-((5-Methoxypyridin-2-yl)amino)-2-oxoethyl)-7-oxo-2-(tetrahydro-2H-pyran-4-yl)- N-(2,2,2-Trifluoroethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

[0290]

[0291]For the synthesis of Example 3, refer to the method of Example 2, and replace Example 2-5 with Example 2-3 to obtain the target compound (15 mg, 68% yield).

[0292] MS m / z(ESI): 499.9[M+H] + .

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Abstract

The invention relates to a nitrogen-containing ring derivative inhibitor as well as a preparation method and an application thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and uses of the compound as a P2X3 inhibitor in treatment of P2X3 receptor dysfunction diseases, especially in treatment of neurogenic diseases.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a nitrogen-containing cyclic derivative inhibitor and a preparation method and application thereof. Background technique [0002] P2X receptors (P2X receptors) or P2X purinoreceptors (P2X purinoreceptors) are a family of cation-permeable ATP ligand-gated ion channels that can bind to extracellular ATP. P2X receptors have seven subunits, exist in the form of homotrimers or heterotrimers, are mainly expressed in the nerve terminals (pre- and postsynaptic) of the nervous system, and regulate synaptic transmission. P2X3 receptor, a member of the P2X family, is a key sensory receptor for sensing upper airway stimuli and triggering the cough reflex, and is thought to play a key role in the sensitisation of specific sensory nerves, involved in pain and cough, and involved in In the perception of bone cancer pain, blocking P2X3 can inhibit the signaling stimulation of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D487/14C07D513/14C07D498/14A61K31/519A61P11/14A61P11/00A61P13/00A61P15/00A61P25/00A61P29/00A61P13/10A61P35/00
CPCC07D487/04C07D487/14C07D513/14C07D498/14A61P11/14A61P11/00A61P13/00A61P15/00A61P25/00A61P29/00A61P13/10A61P35/00
Inventor 肖华玲刘强黄举蔡家强
Owner SHANGHAI HANSOH BIOMEDICAL
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