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Capsaicin receptor agonists

A technology of compounds and salts, applied in the field of probes for the detection and localization of capsaicin receptors in the treatment of conditions related to capsaicin receptor activation

Inactive Publication Date: 2007-01-03
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therapy with the N-methyl-D-aspartate antagonist ketamine or the α(2)-adrenergic agonist clonidine reduces acute or chronic pain, Dosage can be reduced, but these preparations are often unbearable due to side effects

Method used

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  • Capsaicin receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0271] Preparation of Representative Capsaicin Receptor Agonists of Formulas Ia and Ib

[0272] A. (7-Bromo-quinazolin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine (Compound 1)

[0273] 1.7-Bromo-4-chloro-quinazoline

[0274]

[0275] 7-Bromo-3H-quinazolin-4-one (1.24 g, 0.0055 mol) in POCl 3 The solution was refluxed for 3.5 hours. Remove excess POCl under reduced pressure 3 , and the residue was partitioned between EtOAc and saturated NaHCO 3 between solutions. The EtOAc layer was dried and the solvent was removed under reduced pressure to afford 7-bromo-4-chloro-quinazoline as a yellow solid.

[0276] 2. (7-Bromo-quinazolin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine

[0277]

[0278] A mixture of 7-bromo-4-chloro-quinazoline (200 mL, 0.821 mmol) and 2-amino-5-trifluoromethyl-pyridine (239 mg, 1.48 mmol) was heated at 230°C for 2 minutes. Cool and partition the solid residue between ethyl acetate (EtOAc) and 10% NaOH. Dry the EtOAc layer (Na 2 SO ...

Embodiment 2

[0318] Preparation of Additional Representative Capsaicin Receptor Agonists of Formulas Ia and Ib

[0319] Routine modifications can be used to alter the starting materials and use additional steps to make other compounds provided in this specification, including those of Ia and Ib in the table below. In Table Ia, the compound has an EC of less than 1 micromolar when tested for capsaicin receptor agonist activity as described in Example 7. 50 .

[0320] Table Ia

[0321] Representative capsaicin receptor agonists

[0322]

[0323]

[0324]

[0325] Table Ib

[0326] Representative capsaicin receptor agonists

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

Embodiment 3

[0335] Preparation of Representative Capsaicin Receptor Agonists of Formula II

[0336] A. 5-fluoro-1-propyl-1H-benzimidazol-2-ylmethyl-(2,4-dichloro-benzyl)-(2-ethoxy-naphthalen-1-ylmethyl )-amine (compound 55)

[0337] 1. (2,4-dichloro-benzyl)-(2-ethoxy-naphthalen-1-ylmethyl)-amine

[0338]

[0339] 2,4-Dichlorobenzylamine (500 mg, 2.81 mL) was dissolved in 2-ethoxy-1-naphthaldehyde (569 mg, 2.84 mL), acetic acid (6 drops) and tetrahydrofuran (THF) (25 ml) solution. Sodium triacetoxyborohydride (903 mL, 4.26 mmol) was added in portions, and the mixture was heated at 50°C overnight. The solvent was removed under reduced pressure, and the remaining residue was dissolved in EtOAc (25 mL) and 1N NaOH (25 mL). The organic layer was removed and the aqueous solution was extracted with an additional 25 mL of EtOAc. The two organic extracts were combined and washed with brine (50 mL). Take Na 2 SO 4The combined extracts were dried and the remaining solvent was r...

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Abstract

The present invention provides capsaicin receptor agonists, these compounds are ligands useful for modulating the activity of VR1 in vivo or in vitro, especially for the treatment of humans, domesticated companion animals and livestock susceptible to capsaicin receptor activation status. The present invention also provides pharmaceutical compositions and methods of using these compounds for the treatment of these conditions, and methods of using these ligands for receptor localization studies.

Description

technical field [0001] This invention relates to capsaicin receptor agonists and to the use of such compounds for the treatment of conditions associated with capsaicin receptor activation. The invention further relates to the use of these compounds as probes for the detection and localization of capsaicin receptors. Background technique [0002] Painful or nociceptive stimuli are mediated by the peripheral terminals of a specific group of sensory neurons called nociceptors. A variety of physical and chemical stimuli induce activation of these neurons in mammals, leading to the recognition of potentially noxious stimuli. However, inappropriate or excessive activation of nociceptive receptors can produce debilitating acute or chronic pain. [0003] Neuropathic pain involves the transmission of pain messages in the absence of stimuli, typically caused by damage to the nervous system. In most cases, such pain occurs as a result of sensitization of the peripheral and central n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94C07D401/12C07D417/12C07D471/04C07D475/04C07D409/12C07D215/44C07D235/14C07D213/56A61K31/517A61K31/519A61K31/4985A61K31/4375A61K31/4706A61K31/506C07D475/06
CPCC07D401/12C07D471/04C07D239/94C07D409/12C07D417/12C07D215/44C04B35/632C07D475/06A61P3/04A61P11/06A61P11/14A61P11/16A61P13/02A61P13/10A61P17/02A61P25/04A61P29/00A61P43/00
Inventor R·鲍克他瓦特沙拉姆C·A·布卢姆H·布里尔曼T·M·考德威尔D·N·科特赖特K·J·霍杰茨J·M·彼得松X·郑
Owner NEUROGEN
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