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Substituted pyrrole-4-alkylamine compounds and application thereof

A technology for compounds, uses, and applications in the fields of medicinal chemistry and pharmacotherapeutics

Active Publication Date: 2018-09-21
SHANGHAI LEADO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are few domestic studies, but foreign pharmaceutical companies have developed a series of pyrimidinedione TRPA1 inhibitors, and the TRPA1 channel has also become a research hotspot for new analgesics

Method used

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  • Substituted pyrrole-4-alkylamine compounds and application thereof
  • Substituted pyrrole-4-alkylamine compounds and application thereof
  • Substituted pyrrole-4-alkylamine compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0142] Preparation of 2-bromo-1-(2-fluorophenyl)ethan-1-one (intermediate II-1)

[0143]

[0144] Dissolve 3.5 g of 2-fluoroacetophenone in 60 ml of ethyl acetate, add 11.3 g of copper bromide, and then heat to 80° C. to react overnight. After the reaction was complete, the reaction liquid was cooled to room temperature, suction filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography to obtain the compound of formula II-1, 5.2 g of yellow oil, with a yield of 95%.

[0145] 1 H NMR (400MHz, CDCl 3 )δ7.94(td, J=7.6,1.8Hz,1H),7.63–7.55(m,1.8Hz,1H),7.27(dd,J=11.3,3.8Hz,1H),7.18(dd,J=11.5 ,8.6Hz,1H),4.53(d,J=2.4Hz,2H).

Embodiment 2

[0147] Preparation of 2-[2-(2-fluorophenyl)-2-oxoethyl]malononitrile (intermediate III-1)

[0148]

[0149]Dissolve 5 grams of intermediate II-1 in 40 milliliters of ethanol, add 1.52 grams of malononitrile, stir until fully dissolved, slowly add 1.3 grams of potassium hydroxide in 40 milliliters of aqueous solution, dropwise for about 1 hour, and then place The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into an equal volume of water, stirred thoroughly, filtered with suction, and the filter cake was retained to obtain the compound of formula III-1, 4.2 g of a white solid compound, with a yield of 91%.

[0150] 1 H NMR (400MHz, CDCl 3 )δ8.02(td, J=7.7,1.8Hz,1H),7.71–7.60(m,1H),7.32(dd,J=15.9,8.2Hz,1H),7.23(dd,J=11.5,8.4Hz ,1H),4.39(t,J=6.6Hz,1H),3.76(dt,J=11.9,5.9Hz,2H).

Embodiment 3

[0152] Preparation of 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (intermediate IV-1)

[0153]

[0154] 2 g of intermediate III-1 were dissolved in 40 ml of hydrochloric acid in ethyl acetate, and the reaction was stirred overnight at room temperature. After the reaction was complete, the solvent was distilled off under reduced pressure to obtain the compound of formula IV-1, 2.1 g of white solid, with a yield of 96%.

[0155] 1 H NMR (400MHz, DMSO-d 6 )δ7.72(td, J=7.9,1.7Hz,1H),7.42–7.23(m,3H),6.91(d,J=2.5Hz,1H).

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PUM

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Abstract

The invention relates to substituted pyrrole-4-alkylamine compounds and application thereof. The invention particularly provides application of compounds shown in a formula I, or optical isomers thereof, or racemates thereof, or solvates thereof, or pharmaceutically acceptable salts thereof; the compounds as well as the optical isomers, the racemates, the solvates and the pharmaceutically acceptable salts thereof are used for preparing pharmaceutical compositions or preparations; the pharmaceutical compositions or preparations are used for (a) inhibiting a transient receptor potential channelprotein, and (b) treating diseases related to the transient receptor potential channel protein; in the formula, the definition of all groups is shown in the description. The formula I is shown in thedescription.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a substituted pyrrole-4-alkylamine compound and its application. Background technique [0002] In 1999, Jaquemar et al. first isolated ankyrin-like transmembrane protein (ankyrin-like protein) in human lung fibroblasts. In 2003, Story et al. found that a protein called ANKTM1 was expressed in mouse dorsal root ganglia. Ankyrin, which was found to be a member of the TRP ion channel family through sequence analysis, namely TRPA1. TRPA1 has 6 transmembrane proteins, its N-terminus and C-terminus are both in the cell, the hydrophilic region of the S5-S6 transmembrane domain forms a pore, and its specific structure is that there are at least 14 ankyrin repeats at its N-terminus. TRPA1 is mainly distributed in the primary sensory neurons of the dorsal root nerve, trigeminal nerve and vagus nerve, and is expressed in both peptidergic and non-peptidergic neur...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D207/48C07D409/12A61P29/00A61P25/00A61P11/00A61P1/00A61P11/06A61P11/14A61P13/02A61P17/04A61K31/4439A61K31/4709A61K31/40A61K31/4025
CPCA61P1/00A61P11/00A61P11/06A61P11/14A61P13/02A61P17/04A61P25/00A61P29/00C07D207/48C07D401/12C07D409/12
Inventor 王友鑫曲振林张玲玲
Owner SHANGHAI LEADO PHARMATECH CO LTD
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