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Imidazole derivatives and their use as trpv4 inhibitors

A technology of base imidazole and drug, applied in the field of imidazole derivatives and their use as TRPV4 inhibitors, can solve the problems of uncontrolled inflammatory reaction in the lung and increased expression of TRPV4, etc.

Active Publication Date: 2021-07-06
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

TRPV4 expression is elevated in an acute lung injury model, leading to an uncontrolled inflammatory response in the lung, study demonstrates

Method used

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  • Imidazole derivatives and their use as trpv4 inhibitors
  • Imidazole derivatives and their use as trpv4 inhibitors
  • Imidazole derivatives and their use as trpv4 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1: 10-(4-(4-(6-N,N-dimethylformamido-8-isopropylamino-9H-purin-9-yl)-piperidin-1-yl)- Phenyl)-9,9-dimethyl-9,10-dihydroacridine

[0105] Take 51mg (0.14mmol) 4-(6-N, N-dimethylformamido-8-isopropylamino-9H-purin-9-yl) piperidine hydrochloride, 51mg (0.14mmol) 10- (4-Bromophenyl)-9,9-dimethyl-9,10-dihydroacridine, 3.1mg (0.01mmol) palladium acetate, 8.2mg (0.03mmol) 2-(di-tert-butylphosphine) Benzene, 135mg (0.42mmol) cesium carbonate dissolved in 1ml 1,4-dioxane, under nitrogen protection, heated to 100°C, stirred for 18 hours, stopped the reaction, filtered with diatomaceous earth, collected the filtrate, evaporated the solvent under reduced pressure , 60 mg of the product was isolated by column chromatography (yield 70.4%). 1 H-NMR (CHLOROFORM-D, 400MHz): δ8.62 (s, 1H), 7.44 (dd, J=7.6, 1.6Hz, 2H), 7.20 (q, J=8.9Hz, 4H), 6.94 (dtd, J=25.4, 7.3, 1.5Hz, 4H), 6.33(dd, J=8.1, 1.1Hz, 2H), 4.58(br, 1H), 4.39(m, 2H), 3.99(d, J=12.1Hz, 2H ), 3.20(s, 3H), 3.11-2.97...

Embodiment 2

[0106] Example 2: 10-(4-(4-(6-chloro-8-isopropylamino-9H-purin-9-yl)-piperidin-1-yl)-phenyl)-9,9-di Methyl-9,10-dihydroacridine

[0107] The method is the same as in Example 1, 45mg (0.14mmol) 4-(6-chloro-8-isopropylamino-9H-purin-9-yl) piperidine hydrochloride and 51mg (0.14mmol) 10-(4-bromo Phenyl)-9,9-dimethyl-9,10-acridine was reacted to obtain 42 mg of white solid (53.7% yield). 1 H-NMR (d-DMSO, 400MHz): δ8.27(s, 1H), 7.44(dd, J=7.8, 1.5Hz, 2H), 7.36(d, J=7.5Hz, 1H), 7.25(d, J=9.0Hz, 2H), 7.15(d, J=9.0Hz, 2H), 6.99-6.93(m, 2H), 6.89-6.83(m, 2H), 6.22(dd, J=8.2, 1.2Hz, 2H ), 4.54(m, 1H), 4.23-4.14(m, 1H), 4.00(d, J=12.4Hz, 2H), 2.96-2.73(m, 4H), 1.87(d, J=13.3Hz, 2H) , 1.58(s, 6H), 1.27(d, J=6.6Hz, 6H); ESI-MS(m / z): 578.28[M+H] +

Embodiment 3

[0108] Example 3: 10-(4-(4-(2-isopropylamino-5-methanesulfonyl-1H-benzimidazol-1-yl)-piperidin-1-yl)-phenyl)-9 , 9-Dimethyl-9,10-dihydroacridine

[0109] The method is the same as in Example 1, 80mg (0.21mmol) 4-(2-isopropylamino-5-methylsulfonyl-1H-benzimidazol-1-yl) piperidine hydrochloride and 78mg (0.21mmol) 10- (4-Bromophenyl)-9,9-dimethyl-9,10-dihydroacridine was reacted to obtain 76 mg of white solid (57.4% yield). 1 H-NMR (d-DMSO, 400MHz): δ8.01 (d, J=1.7Hz, 1H), 7.57 (dd, J=8.4, 1.7Hz, 1H), 7.38 (d, J=8.7Hz, 2H) , 7.34(d, J=8.4Hz, 1H), 6.97(d, J=8.8Hz, 2H), 4.41(br, 1H), 4.28(dq, J=13.2, 6.5Hz, 1H), 4.11(t, J=12.2 Hz, 1H), 3.87(d, J=12.7Hz, 2H), 3.04(s, 3H), 2.92(t, J=11.7Hz, 2H), 2.54 (qd, J=12.4, 3.8Hz, 2H), 1.98(d, J=10.3Hz, 2H), 1.71(s, 6H), 1.35(d, J=6.4Hz, 6H); ESI-MS(m / z): 620.31[M+H] +

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Abstract

The present invention relates to formula (I) imidazole derivatives and pharmaceutically acceptable salts, isomers, prodrugs and pharmaceutical compositions thereof, this type of compound is the vanilloid type 4 transient receptor potential channel (TRPV4) Inhibitors. The invention also discloses the preparation of the compound and its application as a medicine, especially as a medicine for acute lung injury.

Description

technical field [0001] The present invention relates to compounds capable of inhibiting vanilloid type 4 transient receptor potential channels and pharmaceutically acceptable salts, isomers, prodrugs and pharmaceutical compositions thereof, as well as their preparation and their application as medicines, especially It is used as a drug for acute lung injury. Background technique [0002] Transient receptor potential channels (TRP channels) are an important class of cation channels located on the cell membrane. It was first discovered in the visual system of Drosophila. The mutant Drosophila only produced transient rather than continuous spikes to continuous light stimulation, so it was named transient receptor potential channel. So far, a variety of TRP channels have been discovered in many organisms such as fruit flies, worms and mammals. In mammals, 28 TRP channel subtypes have been found. According to the homology of amino acid sequence, the 28 discovered mammalian TRP...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/00C07D401/14C07D471/04A61K31/52A61K31/473A61P11/00
CPCA61P11/00C07D401/14C07D471/04C07D473/00
Inventor 郑志兵艾崇毅李松周辛波肖军海钟武李行舟樊士勇张文娟肖典谢菲
Owner ACADEMY OF MILITARY MEDICAL SCI