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NMDA receptor antagonists for the treatment of neuropsychiatric disorders

A technology for mental disorders and nerves, applied in the field of NMDA receptor blockers, can solve problems such as hindering the use of NMDA receptor blockers

Inactive Publication Date: 2012-10-31
EMORY UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Although NMDA receptor antagonists are useful in the treatment of many very challenging conditions, to date, dose-limiting side effects have hindered the clinical use of NMDA receptor antagonists for these conditions
Thus, although glutamate antagonists have the potential to treat many serious diseases, the severity of the side effects has led many to give up hope that better tolerated NMDA receptor antagonists can be developed (Hoyte L et al. (2004) Curr.Mol.Med.4(2):131-136; Muir, K.W. and Lees, K.R. (1995) Stroke 26:503-513; Herrling, P.L., ed. (1997) "Excitatory amino acid clinical results with antagonists (clinical results of excitatory amino acids as antagonists) "Academic Press; Parsons et al. (1998) Drug News Perspective II (Drug News Perspective II Edition): 523-569)

Method used

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  • NMDA receptor antagonists for the treatment of neuropsychiatric disorders
  • NMDA receptor antagonists for the treatment of neuropsychiatric disorders
  • NMDA receptor antagonists for the treatment of neuropsychiatric disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 and 2

[0746] Examples 1 and 2. N-(4-{3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}- Phenyl)-methanesulfonamide (compound 1) and N-(4-{3-[2-(3,4-dichloro-phenylamino)-ethylamino]-2-(S)-hydroxy-propane oxy}-phenyl)-methanesulfonamide (compound 2).

[0747]

[0748]Step (i). 3-(4-Nitro-phenoxy)-2-(S)-propylene oxide (i-1). 4-Nitrophenol (6.6 mmol) was dissolved in 5 ml dry DMF. Cesium fluoride (19.9 mmol) was added to the reaction. The reaction mixture was stirred at room temperature for 1 hour and (S)-glycidyl m-nitrobenzenesulfonate (6.6 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 24 hours. Water (150 mL) was added and the solution was extracted with ethyl acetate. Dilute the organic phase in MgSO 4 dried and evaporated. The residue was purified by column chromatography using ethyl acetate:hexane (50:50) solvent system to give the desired product i-1. This step can be replaced by (R)-glycidyl m-nitrobenzenes...

Embodiment 3

[0756] Example 3.6-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzoxazol-2-one (Compound 3).

[0757]

[0758] Step (i). 6-(2-(S)-oxiranylmethoxy)-3H-benzoxazol-2-one (ii-1). 5-Hydroxy-benzoxazole (310 mg) and cesium carbonate (780 mg) were combined in 6 mL of N,N-dimethylformamide. The reaction was stirred at room temperature for 1 hour. (S)-Glycidyl m-nitrobenzenesulfonate (520 mg) was added and the reaction was stirred overnight at room temperature. React with NH 4 Quenched with aqueous Cl and extracted with ethyl acetate. The organic layer was washed with NH 4 Cl aqueous solution and NaCl aqueous solution were washed, separated, and in Na 2 SO 4 Dry on top. Filtration, removal of solvent, and absorption onto silica gel. Elution with an ethyl acetate / methanol mixture (4:1) followed by removal of the solvent gave 445 mg of a yellow oily solid.

[0759] Step (ii). 6-{3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-3H-benzoxazo...

Embodiment 4

[0763] Example 4. 4-{3-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(S)-hydroxy-propoxy}-phenol (compound 4).

[0764]

[0765] Step (i). 3-(4-tert-Butyldimethylsilyloxy-phenoxy)-2-(S)-propylene oxide (iii-1). 4-(tert-Butyldimethylsiloxy)phenol (1.45 g, 6.25 mmol) in 5 ml dry THF was added dropwise to a suspension of NaH (0.158 g, 6.25 mmol) in 5 ml THF. After stirring at room temperature for 2 hours, glycidyl nitrobenzenesulfonate (1.30 g, 5 mmol) was added to the reaction mixture, and then 15-crown-5 (25 mol%) was added. After stirring for 24 hours, the reaction was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and brine, then dried over sodium sulfate and evaporated. The product was purified by column chromatography using EtOAc:hexane (1:9) (yield: 1.06 g 76%). 1 H NMR (400MHz, CDCl 3 )δ0.17 (6H, s), 0.98 (9H, s), 2.75 (1H, dd, J = 2.4, 4.4Hz), 2.89 (1H, q, J = 4.4Hz), 3.33-3.36 (1H, m ), 3.90 (1H, dd, J = 5.6, 10.8 Hz...

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Abstract

Provided are pharmaceutical compositions and methods of treatment or prophylaxis of certain neuropsychiatric conditions, in particular mood disorders. The compounds are of the general Formula I-V as described herein.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 61 / 127,098, filed May 9, 2008. field of invention [0003] The present invention provides NMDA receptor blockers for treating neuropsychiatric disorders, including depression, anxiety and other related diseases, including pH-sensitive NMDA receptor blockers. Background of the invention [0004] Glutamate and aspartate play a dual role in the central nervous system, namely as essential amino acids and as the most important excitatory neurotransmitters (hereinafter referred to as excitatory amino acids or EAA). There are at least four classes of EAA receptors: NMDA, AMPA (2-amino-3-(methyl-3-hydroxyoxazol-4-yl)propionic acid), kainate, and metabotropic receptors. These EAA receptors regulate many signaling events that affect all physiological brain functions. For example, NMDA receptor antagonists have been reported to produce analgesic ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61K31/4465A61P25/24
CPCA61K31/496A61K31/4465A61P25/00A61P25/22A61P25/24A61P43/00
Inventor 雷蒙德·J·汀莱蒂尼斯蒂芬·F·泰纳利斯
Owner EMORY UNIVERSITY
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