Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity

A compound and pharmacy technology are applied in the field of triazole derivatives and pharmaceutical compositions containing the same with analgesic effect, can solve the problems such as the method of changing pyrazole group to aniline group which are not recorded or recorded, and achieve excellent analgesic effect. effect of pain

Active Publication Date: 2013-06-12
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, Patent Document 14 does not describe the method of using the pyrazolyl group on the triazine ring as a leaving group to change it to an anilino group.
[0012] Non-Patent Documents 9, 10, 11, and 12 describe a method of changing a pyrazolyl group as a leaving group to an anilino group, but there is no description of changing a pyrazolyl group substituted on a triazine ring to an anilino group. method

Method used

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  • Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity
  • Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity
  • Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1299] Preparation of 6-(ethylthio)-1-(4-fluorobenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione

[1300]

[1301] Add isopropyl isocyanate (8.2mL, 84mmol) and DBU (12.6mL, 84mmol) to the mixture of S-ethylthiourea hydrobromide (14.8g, 80mmol) and DMF (75mL) under ice cooling ), stirred for 6 hours under ice cooling. Under ice cooling, 1,1'-carbonyldiimidazole (15.57 g, 96 mmol) and DBU (18.0 mL, 120 mmol) were added to the reaction solution, and the mixture was further stirred for 2 hours. After the reaction, 2 mol / L hydrochloric acid (240 mL) was added over about 50 minutes under ice cooling, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 6-(ethylthio)-3-isopropyl-1,3,5-triazine as a light brown solid -2,4(1H,3H)-dione (12.29g, yield: 71%).

[1302] 1H-NMR (δppm TMS / DMSO-d6): 1.27 (6H, t, J=7.2 Hz)), 1.33 (6H, d, J=6.9 Hz)...

Embodiment 2

[1306] 1-(4-Fluorobenzyl)-6-(4-isopropoxyphenylamino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione (I-0133) Preparation

[1307]

[1308] Under microwave irradiation, at 230°C, 6-(ethylthio)-1-(4-fluorobenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H, A mixture of 3H)-dione (0.323 g, 1 mmol) and 4-isopropoxyaniline (0.907 g, 6 mmol) and 1-methyl-2-pyrrolidone (1 mL) was stirred for 30 minutes. After the reaction, water (100 mL) was added, and extraction was performed with ethyl acetate (100 mL). After drying the extract with anhydrous sodium sulfate, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained target product was precipitated in ethyl acetate and hexane to obtain 1-(4-fluorobenzyl)-6-(4-isopropoxyphenylamino)-3-isopropyl as a colorless solid -1,3,5-triazine-2,4(1H,3H)-dione (0.21g, yield: 51%).

[1309] Melting point: 176-177°C

[1310] 1H-NMR(δppm TMS / CDCl 3 ): 1.34 (6H, d, J =...

Embodiment 3

[1312] 6-(3-Chloro-4-isopropoxyphenylamino)-1-(4-chlorobenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H )-Diketone preparation (I-0228)

[1313]

[1314] At 90 ℃, 1-(4-chlorobenzyl)-6-(ethylsulfanyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-di A mixture of ketone (0.60 g, 1.78 mmol), 3-chloro-4-isopropoxyaniline (0.99 g, 5.3 mmol) and acetic acid (10 mL) was stirred for 6 hours. After the reaction, the reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (100 mL). The extract was washed with saturated aqueous sodium bicarbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate / hexane) purification. The obtained target product was precipitated in diethyl ether and hexane to obtain 6-(3-chloro-4-isopropoxyphenylamino)-1-(4-chlorobenzyl)-3- as a colorless s...

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PUM

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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 exhibits analgesic activity or acts to ameliorate urinary problems, said composition containing: a compound represented by formula (I), a pharmacologically permitted salt thereof, or a solvate of either. In the formula, Rh and Rj together form a bond; Ra and Rb, and / or Rd and Re, together form an oxo or the like; Rc represents hydrogen, a substituted or unsubstituted alkyl, or the like; -Rf represents -(CR4aR4b) n -R2; R4a and R4b represent hydrogen, a substituted or unsubstituted alkyl, or the like; R2 represents a substituted or unsubstituted cycloalkyl or the like; n represents an integer from 1 to 4; -Rg represents -X-R3; -X- represents -O-, -S-, or the like; and R3 represents a substituted or unsubstituted cycloalkyl or the like.

Description

Technical field [0001] The present invention relates to the treatment of P2X receptors, especially P2X 3 And / or P2X 2 / 3 A compound for a receptor-related disease or disorder, and a pharmaceutical composition containing the compound, which has analgesic effect and urinary dysfunction improvement effect. Background technique [0002] Adenosine triphosphate (ATP) is widely known as an energy source and phosphorylation substrate in cells. On the other hand, it is also known to function as an information transmitting substance outside the cell. Furthermore, it is also known that ATP is released to the outside of the cell due to various stimuli such as cell damage, inflammation, aggression stimulus, and decrease in blood oxygen concentration, and is released from the end of the primary sensory nerve together with other neurotransmitters to the outside of the cell. . The ATP released outside the cell transmits various extracellular information via ATP receptors (Non-Patent Document 4 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D251/46A61K31/53A61K31/5377A61K31/55A61P13/10A61P25/04A61P43/00C07D401/06C07D401/12C07D401/14C07D403/06C07D403/12C07D405/06C07D405/12C07D409/06C07D413/06C07D413/12C07D413/14C07D417/06C07D417/12C07D417/14
CPCA61P13/00A61P13/10A61P25/02A61P25/04A61P29/00A61P43/00C07D251/46C07D251/52C07D401/06C07D401/12C07D401/14C07D403/04C07D403/06C07D403/12C07D405/06C07D405/12C07D405/14C07D409/06C07D413/06C07D413/12C07D413/14C07D417/06C07D417/12C07D417/14A61K31/53
Inventor 甲斐浩幸龟山贵之堀口透旭健太郎远藤毅藤井康彦新谷拓也中村健一郎直原彩枝长谷川刚大原美穗多田幸男牧利克饭田圣
Owner SHIONOGI & CO LTD
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