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Fused heterocyclic inhibitors of D-amino acid oxidase

A compound, the technology of heterocycloalkyl, applied in the field of fused heterocyclic inhibitors of D-amino acid oxidase, can solve the problems of improving or enhancing learning, memory or cognition etc. which are not mentioned

Inactive Publication Date: 2009-08-19
SEPACOR INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

None of the above references mentioned improving or enhancing learning, memory or cognition

Method used

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  • Fused heterocyclic inhibitors of D-amino acid oxidase
  • Fused heterocyclic inhibitors of D-amino acid oxidase
  • Fused heterocyclic inhibitors of D-amino acid oxidase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

Synthesis of Fused Thiophenepyrrole Analogs

1.1. Synthesis of intermediate product aldehyde

1.1.a) Synthesis of 4-(4-chlorobenzyl)thiophene-2-carbaldehyde

[0257] Pd(OAc) 2 (144mg, 0.64mmol) and triphenylphosphine (TPP) (136mg, 0.5 2 mmol) solution mixture was weighed into a vial, dissolved in acetonitrile, and transferred into a solution containing 4-chlorobenzyl diethyl phosphate (Org. Lett. 2005, 7, 4875-4878; 3.08g, 11.6mmol), 5-methyl Acylthiophen-3-ylboronic acid (2.0g, 12.8mmol), K 3 PO 4 (2.72g, 12.8mmol) and a stir bar in a 40mL Wheaton vial. Nitrogen was bubbled through the mixture. The vial was tightly sealed, heated to 90 °C, and stirred vigorously for 16 h. The reaction was diluted with water and extracted with dichloromethane (DCM) (3 x 100 mL). The combined extracts were washed with brine, passed through Na 2 SO 4 Dry, filter and concentrate. Purification by flash chromatography (Isco CombiFlash) (0-20% Heptane / EtOAc) gave 4-(4-chlorobenzyl)th...

Embodiment 2

Synthesis of Fused Pyrrole Analogs

2.1. Synthesis of intermediate product aldehyde

2.1.a) Synthesis of 4-phenethyl-furan-2-carbaldehyde

[0357] Under a flow of argon, flush 4-bromo-2-furfural (1.50 g, 8.57 mmol), PdCl 2 (PhCN) 2 (197 mg, 0.514 mmol) and CuI (65.0 mg, 0.343 mmol) as a solid mixture for 1 min. HP (tert-butyl) 3 BF 4 (298 mg, 1.03 mmol) and diisopropylamine (1.80 mL, 12.9 mmol) in dioxane (9 mL) were added to the solid mixture, followed by phenylacetylene (1.13 mL, 10.3 mmol). The reaction was stirred at room temperature under argon atmosphere for 15 h before being filtered through a plug of silica gel with EtOAc. The solution was then concentrated in vacuo and chromatographed on silica gel to give 4-phenylethynyl-furan-2-carbaldehyde as a colorless oil (1.54 g, 92%). R f = 0.35 (1:9 Heptane / EtOAc); 1 H NMR (400MHz, CDCl 3 ) δ ppm 9.68 (d, J = 0.5 Hz, 1H) 7.90 (s, 1H) 7.48-7.55 (m, 2H) 7.35-7.40 (m, 3H) 7.33 (d, J = 0.7 Hz, 1H).

[0358] To...

Embodiment 3

[0446] To a cooled (0 °C) solution of methyl-2-pyrrolecarboxylate (8.00 g, 63.9 mmol) in DMF (320 mL) was added NaH (60% by weight, 5.10 g, 128 mmol). After 20 min, benzyl bromide (11.4 mL, 95.9 mmol) was added and the reaction was allowed to warm to room temperature. Stirring was continued for 2 hours, then saturated NH 4 Quenched with aqueous Cl (0.5 L). The mixture was extracted 3 times with EtOAc and washed with H 2 The combined organic layers were washed with O (3x) and brine, passed over MgSO 4 Dry, filter and concentrate in vacuo to yield a yellow oil. The crude product was chromatographed on silica gel (0 to 10% EtOAc in heptane, 25 min) to give methyl 1-benzyl-1H-pyrrole-2-carboxylate as a colorless oil (7.75 g, 56%) . R f = 0.48 (25:75 Heptane / EtOAc); 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.28-7.34 (m, 2H) 7.23-7.27 (m, 1H) 7.09-7.13 (m, 2H) 7.01 (dd, J = 4.0, 1.8Hz, 1H) 6.88-6.91 (m, 1H) 6.19 (dd, J=4.0, 2.6 Hz, 1H) 5.57 (s, 2H).

[0447] To a solution of methy...

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Abstract

This invention provides novel inhibitors of the enzyme D-amino acid oxidase as well as pharmaceutical compositions including the compounds of the invention. Also provided are methods for the treatment and prevention of neurological disorders, such as neuropsychiatric and neurodegenerative diseases, as well as pain, ataxia and convulsion. The compounds of the invention have the general structure wherein Q is a member selected from O, S, CR and N, X and Y are members independently selected from CR, O, S, N and NR.

Description

[0001] Cross References to Related Applications [0001] Under 35 U.S.C. §119(e), this application claims U.S. Provisional Patent Application No. 60 / 806,391 filed June 30, 2006, U.S. Provisional Patent Application No. 60 / 842,465 filed September 5, 2006, and 2007 4 Priority to U.S. Provisional Patent Application No. 60 / 914,293, filed May 26, each of which is incorporated herein by reference in its entirety for all purposes. technical field [0002] The present invention relates to enzyme inhibitors and methods of treating diseases and disorders wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidation products and NMDA receptor activity is effective in the nervous system of a mammalian subject , and with a reduction in undesired side effects. Background technique [0003] The enzyme D-amino acid oxidase (DAAO) metabolizes D-amino acids, especially D-serine in vitro at physiological pH. DAAO is expressed in the mammalian brain and periphery. T...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D491/04C07D495/04C07D513/04A61K31/381A61K31/407A61K31/429A61K31/4162A61P25/00
Inventor J·M·多尔西S·C·霍普金斯R·J·福格尔桑M·L·黑弗南M·L·约翰斯J·B·佩拉莱斯Q·K·方C·O·奥戈希S·W·约翰斯M·苏奎M·A·瓦尔尼K·L·斯皮尔
Owner SEPACOR INC
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