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Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

A technology of compounds and isomers, applied in the field of vanilloid receptors, can solve problems such as nerve cell death and nerve function damage

Active Publication Date: 2008-03-12
AMOREPACIFIC CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, treatment of primary cultures of afferent neurons with vanilloid receptor agonists such as capsaicin resulted in impairment of neuronal function and further neuronal cell death

Method used

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  • Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
  • Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
  • Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0362] Example 1: N-{4-[3-(4-tert-butylbenzyl)ureidomethyl]-2-vinylphenyl}methanesulfonamide

[0363]

[0364] Step 1: tert-Butyl (4-nitrobenzyl)carbamate

[0365] 4-Nitrobenzylamine HCl (1 g, 5.302 mmol, 1 eq.) was placed in a 100 ml round bottom flask and dissolved in saturated solution (NaHCO 3 :CH 2 Cl 2 = 1:1). To this solution was added di-tert-butyl dicarbonate (3.66ml, 15.906mmol, 3eq.) and stirred for 3 hours. After the completion of the reaction was confirmed by TLC, the reaction solution was extracted with dichloromethane, washed with water (2 times) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained liquid was subjected to column chromatography (n-hexane / ethyl acetate=10 / 1) to yield a light green solid (1.3171 g).

[0366] IR (KBr flake precipitate, cm -1 ): 3330, 3080, 301, 2984, 2916, 1687, 1513;

[0367] 1 H NMR (400MHz, CDCl 3 ): 8.11(d, 2H, J=8.4Hz), 7.37(d, 2H, J=8.4Hz), 4.99(bs, 1H), 4.37(d, 2H, J...

Embodiment 2

[0389] Example 2: N-{4-[3-(4-tert-butylbenzyl)ureidomethyl]-2-fluoro-6-vinylphenyl}methanesulfonamide

[0390]

[0391] Step 1: 4-Aminomethyl-2-fluoro-6-iodoaniline

[0392]A 50 ml double necked round bottom flask was filled with argon and a solution of 4-amino-3-fluoro-5-iodo-benzonitrile (84.4 mg, 0.322 mmol, 1 eq.) in tetrahydrofuran was placed in the flask, followed by cooling to 0 ℃. To this solution was added borane-THF complex solution (1.0 M in THF, 0.64 ml, 0.644 mmol, 2 eq.). The temperature of the reaction mixture was raised to room temperature. The reaction mixture was heated and refluxed. After the completion of the reaction was confirmed by TLC, 5% HCl was added to the solution and stirred for 20 minutes. The resulting solution was basified using 1N KOH, extracted with ether, washed with brine, passed through Na 2 SO 4 dry. The resulting liquid was concentrated under reduced pressure to yield a light yellow solid (78.4 mg, 80.5%).

[0393] IR (KBr flak...

Embodiment 3

[0414] Example 3: N-{4-[3-(4-tert-butylbenzyl)ureidomethyl]-2-ethynyl-6-fluorophenyl}methanesulfonamide

[0415]

[0416] Step 1: tert-Butyl (4-amino-3-fluoro-5-trimethylsilylethynylbenzyl)carbamate

[0417] (4-Amino-3-fluoro-5-iodobenzyl)carbamate tert-butyl ester (100 mg, 0.273 mmol, 1 eq.), dichloro(di-triphenylphosphine), palladium (9.8 mg, 0.014 mmol, 0.05 eq.) and copper iodide (2.6 mg, 0.014 mmol, 0.05 eq.) in THF were placed in a 25 ml two necked round bottom flask and stirred at room temperature for 30 minutes. To this solution were added triethylamine (114.2 µl, 0.819 mmol, 3 eq.) and (trimethylsilyl)ethynyl (50.2 µl, 0.355 mmol, 1.3 eq.) and heated to reflux overnight. The reaction solution was concentrated under reduced pressure and subjected to column chromatography (n-hexane / ethyl acetate=5 / 1) to yield a brown liquid (84.0 mg, 91.4%).

[0418] IR (NaCl, pure, cm -1 ): 3459, 3360, 2965, 2148, 1698;

[0419] 1 H NMR (400MHz, CDCl 3 ): 7.00(d, 1H, J=0.8Hz),...

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Abstract

This present invention relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receotor 1; VR1; TRPV1 )antagonist; and a pharmaceutical composition containing the same. The present invention provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, and heart disease.

Description

technical field [0001] The present invention relates to novel compounds as vanilloid receptor (vanilloid receptor 1; VR1; TRPV1) antagonists, isomers thereof or pharmaceutically acceptable salts thereof; and pharmaceutical compositions comprising the same. Background technique [0002] As diseases associated with the activity of vanilloid receptors (Nagy et al., 2004, Eur.J.Pharmacol.500, 351-369), pain such as acute pain, chronic pain, neuropathic pain, postoperative pain, rheumatic Arthralgia, osteoarthritis, postherpetic neuralgia, neuralgia, headache and migraine (Petersen et al., 2000, Pain, 88, pp125-133; Walker et al., 2003, J.Pharmacol.Exp.Ther., 304 , pp56-62); nerve-related diseases such as neuropathy, HIV-related neuropathy, nerve damage, neurodegeneration and stroke (Park et al., 1999, Arch.Pharm.Res.22, pp432-434; Kim et al., 2005, J. Neurosci.25(3), pp662-671); Diabetic neuropathy (Kamei et al., 2001, Eur.J.Pharmacol.422, pp83-86); Urgency; Irritable bowel syn...

Claims

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Application Information

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IPC IPC(8): C07C275/24A61K31/17
Inventor 金熙斗徐永钜朴亨根吴禹泽朴雪邻金珠贤张美贞朴永镐申松锡金善映金镇官郑然守李玘和崔镇圭林庆珉高现珠牟周炫金星日禹柄英
Owner AMOREPACIFIC CORP
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