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Sigma receptor inhibitors

A technology of isomers and solvates, applied in the direction of anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve the problems of no given or implied effect, etc.

Inactive Publication Date: 2007-08-08
LAB DEL DR ESTEVE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

No action of these compounds on sigma receptors is given or implied

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0229] Synthesis of 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethyl)-1-phenyl-1H-indazole (1)

[0230] Step 1: Synthesis of ethyl 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetate

[0231]

[0232] To (1,5,6,7-tetrahydro-1-phenyl-4H-indazol-4-ylidene)acetate E / Z isomer mixture (1,6g, 5,67mmol) in 50mL To the solution in EtOH was added Pd-C (150 mg, 10%) and the resulting solution was stirred on a Parr hydrogenator under nitrogen atmosphere (50 psi) for 18 hours. The reaction mixture was purged with nitrogen, filtered using Celite and the solvent was evaporated under reduced pressure to give ethyl 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetate ( 1,60 g, 5,63 mmol, 99%, oil).

[0233] 1 H RMN (300MHz, CDCl 3 ): δ1,29(t,J=7,2Hz,3H), 1,48(m,1H), 1,73(m,1H), 1,98(m,2H), 2,45(dd, J=15,4Hz, J'=8,0Hz,1H), 2,68(m,3H), 3,26(m,1H), 4,20(q,J=7,2Hz,2H), 7 , 31(m, 1H), 7, 41-7, 52(m, 5H).

[0234] Step 2: Synthesis of 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)ethan...

Embodiment 2

[0247] Synthesis of 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethyl)-1-phenyl-1H-indazole oxalate (2)

[0248]

[0249] To 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethyl)-1-phenyl-1H-indazole (380 mg, 1,22 mmol) in 4 mL of acetone Add HO to the solution 2 CCO 2 H.2H2 O (156 mg, 1,23 mmol) to give 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethyl)-1-phenyl-1H-indazole oxalate (318 mg, 0,79 mmol, 65%, white solid).

[0250] m.p.=150-151℃

[0251] 1 H RMN (300MHz, DMSO-d 6 , TFA): δ1,36(m,1H), 1,60(m,1H), 1,71-1,93(m,3H), 2,04(m,1H), 2,56-2, 77(m, 3H), 3,03(m, 2H), 3,21(m, 2H), 3,44(d, J=12,7Hz, 2H), 3,62(t, J=11, 6Hz, 2H), 3,92(m, 2H), 7,29(m, 1H), 7,38-7,49(m, 4H), 7,62(s, 1H), 9,69(m , 1H).

Embodiment 3

[0253] 1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-4-(2-(4-phenylpiperidin-1-yl)ethyl)-1H-indazole ( 3) Synthesis of

[0254]Step 1: Synthesis of 1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one

[0255]

[0256] A mixture of 1-(3,4-dichlorophenyl)hydrazine hydrochloride (6,78 g, 31,8 mmol) and anhydrous sodium acetate (2,60 g, 31,8 mmol) in n-BuOH (20 mL) was slowly added to 2 - A solution of ((dimethylamino)methylene)cyclohexane-1,3-dione (5,32 g, 31,8 mmol) in n-BuOH (100 mL) and acetic acid (5 mL). The resulting mixture was heated to reflux for 2 hours and the reaction was monitored using TLC. The solvent was evaporated under reduced pressure, the residue was diluted with AcOEt and washed with H 2 O washing. The solvent was then evaporated under reduced pressure and the crude product was purified using silica gel chromatography to give 1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one (5,0 g, 17,79 mmol, 56%, orange solid).

[0257] 1 H RMN (300M...

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PUM

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Abstract

The invention relates to compounds having pharmacological activity towards the sigma receptor, and more particularly to pyrazole derivatives of formula (I) and to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use therapy and prophylaxis, in particular for the treatment of psychosis or pain.

Description

field of invention [0001] The present invention relates to compounds having pharmacological activity at sigma receptors, in particular certain pyrazole derivatives, processes for the preparation of these compounds, pharmaceutical compositions containing said compounds and their use in the treatment and prevention, especially in psychosis or use in the treatment of pain. Background of the invention [0002] Research on new therapeutic agents has been greatly facilitated in recent years by a better understanding of the structures of proteins and other biomolecules associated with target diseases. An important class of these proteins are the sigma receptors, which are cell surface receptors of the central nervous system (CNS) and may be involved in the dysphoric, hallucinogenic and cardiostimulatory effects of opioids. From biological and functional studies of sigma-receptors, there is already evidence that sigma-receptor ligands may be useful in the treatment of psychosis and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/54C07D401/06C07D403/06A61K31/4439A61K31/454A61K31/4725A61K31/496A61K31/5377A61K31/55A61P29/00A61P25/22A61P37/06C07D491/10A61K31/541C07D417/06
CPCC07D491/10C07D231/56C07D401/06C07D403/06A61P25/22A61P29/00A61P37/06
Inventor 若尔迪·科尔韦拉阿霍纳玛莉亚·罗萨·库韦莱斯-阿尔蒂森特约尔格·霍莱兹丹尼尔·马蒂内-莫尔莫大卫·韦诺-多梅内克
Owner LAB DEL DR ESTEVE SA
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