Novel heterocyclic derivatives and pharmaceutical composition containing same

A composition and medicine technology, applied in the field of novel heterocyclic derivatives and pharmaceutical compositions containing the same, can solve the problems of no record of analgesic receptor antagonism, no record of receptor antagonism, etc.

Inactive Publication Date: 2013-06-05
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In Patent Documents 8, 9, 10, and 11, compounds having a structure similar to the compound of the present invention are described, but the analgesic effect and P2X 3 or P2X 2 / 3 Receptor antagonism Not documented
In addition, Non-Patent Document 8 describes a compound that has a structure similar to the compound of the present invention and exhibits analgesic activity, but for P2X 3 or P2X 2 / 3 Receptor antagonism not documented

Method used

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  • Novel heterocyclic derivatives and pharmaceutical composition containing same
  • Novel heterocyclic derivatives and pharmaceutical composition containing same
  • Novel heterocyclic derivatives and pharmaceutical composition containing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1843] Preparation of 1-(4-chlorobenzyl)-3-ethylamino-6-(4-isopropoxyphenylamino)benzene (I-071)

[1844] [chemical 120]

[1845]

[1846] To a mixture of 3-bromo-4-fluoro-1-nitrobenzene (1.0 g, 4.6 mmol) and DMSO (5 mL), potassium carbonate (1.01 mg, 7.3 mmol) and 4-isopropoxyaniline ( 1.03g, 6.8mmol), stirred at 100°C for 0.5 hours. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL×2). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the obtained target product was solidified with ethyl acetate and hexane to obtain 3-bromo-4-(4-isopropoxy Phenylamino)-1-nitrobenzene (0.55g, yield: 35%).

[1847] 1H-NMR(δppmTMS / DMSO-d6):1.28(6H,d,J=6.0Hz),4.61(1H,sept,J=6.0Hz),6.76(1H,d,J=9.0Hz),6.97(2H ,d,J=9.0Hz),7.19(2H,d,J=9.0Hz),8.00(1H,dd,J=8.9Hz,2.4Hz),...

Embodiment 2

[1857] Preparation of 1-(4-chlorobenzyl)-3-dimethylamino-6-(3-fluoro-4-isopropoxyphenylamino)benzene (I-123)

[1858] [chemical 122]

[1859]

[1860] To a mixture of 3-bromo-1-dimethylaminobenzene (0.3g, 1.5mmol) and THF (3mL), add 4-chlorobenzylzinc chloride (0.5MTHF solution, 6mL, 3mmol), triphenyl Phosphine (39.3mg, 0.15mmol) and palladium(II) acetate (17mg, 0.08mmol), stirred under reflux for 2 hours. Water (200 mL) was added to the reaction liquid, followed by extraction with ethyl acetate (200 mL). The extract was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 1-(4-chlorobenzyl)-3-dimethylaminobenzene (0.32 g, yield: 87 %).

[1861] 1H-NMR (δppmTMS / CDCl 3 ):2.89(6H,s),3.87(2H,s),6.48-6.59(4H,m),7.08-7.22(4H,m).

[1862]To a mixture of 1-(4-chlorobenzyl)-3-dimethylaminobenzene (120mg, 0.5m...

Embodiment 3

[1867] Preparation of 1-(4-chlorobenzyl)-3-(3-hydroxypropyloxy)-6-(3-fluoro-4-isopropoxyphenylamino)benzene (I-076)

[1868] [chem 123]

[1869]

[1870] To the mixed solution of 5-hydroxyl-2-nitrobenzaldehyde (3.0g, 18mmol) and DMF (10mL), add potassium carbonate (3.23g, 23.3mmol) and (3-bromopropoxyl (tert-butyl) Dimethylsilane (5.56g, 21.5mmol), stirred overnight at room temperature. Add water (200mL) to the reaction solution, and extract with ethyl acetate (200mL×2). The extract is washed with saturated brine (200mL), washed with Dry over anhydrous sodium sulfate, then concentrate under reduced pressure.The resulting residue is purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 5-[3-(tert-butyldimethylsilane) in the form of light yellow oil Oxy)propyloxy]-2-nitrobenzaldehyde (3.0 g, yield: 49%).

[1871] 1H-NMR(δppmTMS / DMSO-d6):0.00(6H,s),0.83(9H,s),1.92(2H,q,J=5.7Hz),3.73(2H,t,J=5.7Hz),4.21 (2H,t,J=5.7Hz),7.22(1H,d,J=2.7Hz),7.33(1H,d,J=2.7...

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Abstract

Disclosed is a novel compound that acts as an antagonist for P2X3 and/or P2X2/3 receptors. Also disclosed is a pharmaceutical composition that acts as an antagonist for P2X3 and/or P2X2/3 receptors, said composition containing: a compound represented by formula (I), a pharmacologically permitted salt thereof, or a solvate of either. In the formula, ring A represents a substituted or unsubstituted five-to-seven-membered cycloalkane, a substituted or unsubstituted five-to-seven-membered cycloalkene, or the like; C represents a carbon atom; -X- represents -N(R16)- or the like; R16 represents hydrogen, a substituted or unsubstituted alkyl, or the like; R7 represents a substituted or unsubstituted five- or six-membered heteroaryl or a substituted or unsubstituted six-to-ten-membered aryl; each of Q1 and Q2 independently represents a carbon atom or a nitrogen atom; -L- represents -O-, -S-, or the like; R6 represents a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, or the like; and R2 represents hydrogen, hydroxyl, or the like.

Description

technical field [0001] The present invention relates to compounds useful in the treatment of P2X receptors, in particular P2X 3 and / or P2X 2 / 3 Compounds for receptor-associated diseases or conditions, and pharmaceutical compositions containing the compounds. Background technique [0002] Adenosine triphosphate (ATP) is known as an intracellular energy source and a phosphorylation substrate. On the other hand, it is also known to function as an extracellular information transmission substance. Furthermore, it is known that ATP is released extracellularly from various stimuli such as cell injury, inflammation, aggressive stimulation, and decrease in blood oxygen concentration, and is released from primary sensory nerve endings together with other neurotransmitters. ATP released extracellularly transmits various extracellular information through ATP receptors (Non-Patent Document 4, Non-Patent Document 5). [0003] ATP receptors are broadly classified into ion channel-type ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/136A61K31/415A61K31/4168A61K31/42A61K31/421A61K31/426A61K31/4375A61K31/44A61K31/4412A61K31/455A61K31/47A61K31/472A61K31/4725A61K31/4965A61K31/502A61K31/505A61K31/506A61K31/513A61K31/517A61K31/535A61K31/536A61K31/5377A61K31/538A61P13/10A61P29/00A61P43/00C07C217/92C07D213/74C07D213/80C07D213/82C07D215/22C07D217/24C07D231/38C07D233/96C07D235/30C07D237/32C07D239/42C07D239/47C07D239/54C07D239/84C07D239/95C07D239/96C07D241/20C07D255/02C07D261/12C07D263/32C07D263/34C07D263/48C07D265/10C07D265/26
CPCC07D239/96C07D239/42C07D235/30C07D217/24C07C217/84C07D265/36C07D241/20C07D409/12C07D237/04C07D255/02C07D215/22C07C217/92C07D405/06C07D401/14C07D277/20C07D231/38C07C217/80C07C2101/14C07D213/82C07D265/10C07D239/95C07D237/32C07D277/34C07D213/74C07D407/06C07D261/12C07D405/12C07D233/96C07C233/25C07D263/34C07D265/26C07D413/12C07D409/06C07D277/38C07D401/12C07D263/32C07D417/14C07D263/48C07D405/14C07D239/84C07D417/12C07D213/80C07D211/72C07D239/47C07D239/54C07C233/75C07D277/28A61P13/00A61P13/10A61P29/00A61P43/00C07C2601/14C07D213/64C07D213/69C07D213/79C07D215/56C07D217/22C07D233/88C07D237/20C07D239/48C07D239/545C07D239/557C07D239/78C07D265/06C07D277/42
Inventor 甲斐浩幸远藤毅直原彩枝旭健太郎堀口透
Owner SHIONOGI & CO LTD
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