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Inhibitors of D-amino acid oxidase

An aryl, alkyl technology, applied in the field of D-amino acid oxidase inhibitors, can solve problems such as improving or enhancing learning, memory or cognition, etc. that are not mentioned

Inactive Publication Date: 2010-01-27
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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  • Inhibitors of D-amino acid oxidase
  • Inhibitors of D-amino acid oxidase
  • Inhibitors of D-amino acid oxidase

Examples

Experimental program
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Embodiment approach

[0131] In another exemplary embodiment, the compound of the invention has a structure selected from:

where Z, A, R 4 , R 6 , R 1 and R 2 as defined in formula (I). In the above structures, each stereocenter marked with an asterisk "*" or "**" is independently racemic or as defined. In one example, a stereocenter marked with "*" has the (R)-configuration. In another example, a stereocenter marked with a "*" has the (S)-configuration. R 1 and R 2 Together with the atoms to which they are attached, optionally bonded to form a 3- to 7-membered ring.

[0132] In one embodiment, R 1 and R 2 combine to form substituted or unsubstituted cyclopropane rings. Exemplary compounds according to this embodiment have structures selected from the following formulae:

where R 30 and R 31 is a member independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted he...

Embodiment 1

[0298] The title compound was synthesized from cyclopentanone according to general methods 1A, 1B and 1C. In the last step, 1.5 g (7.48 mmol) of ethyl (E)-3-(2-chlorocyclopent-1-enyl)acrylate were cyclized. The crude product was purified by flash chromatography (0-50% EtOAc / heptane) to provide 418 mg (31%, last step) of 1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 2-Carboxylic acid ethyl ester. 1 H NMR (400MHz, CDCl 3 )δppm 1.34(t, J=7.13Hz, 3H), 2.38-2.48(m, 2H), 2.59-2.65(m, 2H), 2.69-2.75(m, 2H), 4.30(q, J=7.13Hz, 2H), 6.67 (d, J = 1.37 Hz, 1H), 8.78 (brs, 1H); LCMS-MS (ESI+) 179.9 (M+H).

[0299] According to General Procedure 7, ethyl 1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate ( 100mg, 0.56mmol) to synthesize the title compound. The crude product was purified by flash chromatography (0-100% EtOAc / heptane) to give 61 mg (73%) of 1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-2- Carboxylic acid (1). 1 H NMR (400MHz, CD 3 OD) δppm2.35-2.44 (m, 2H), 2.54-2.61 (m, 2H), 2...

Embodiment 2

Synthesis of Pyrrole Analogs Using 4-Substituted Fused Cyclopentanes

2.1.) Synthesis of methyl 4-oxo-1,4,5,6-tetrahydrocyclopentadieno[b]pyrrole-2-carboxylate

2.1.a) Synthesis of methyl 5-formyl-1H-pyrrole-2-carboxylate

[0300] To 1,2-dichloroethane (40 mL), DMF (13.6 mL, 176 mmol) was added. The mixture was cooled to 0 °C, and phosphorus oxychloride (16.4 mL, 176 mmol) was added dropwise over 5 minutes. The resulting solution was stirred for 15 minutes. To this solution was added methyl 1H-pyrrole-2-carboxylate (20 g, 160 mmol) in dichloroethane (80 mL) dropwise at 0 °C (ca. 1 h). The cooling bath was removed, and the reaction mixture was heated to reflux for about 1 hour, then allowed to cool to room temperature. EtOAc (250 mL) in ice water (400 mL) was added and the organic layer was separated. with NaHCO 3 The solution neutralized the aqueous layer, then eluted with EtOAc (4 x 100 mL). with dilute NaHCO 3 solution, brine washed organic layer and combined organic ...

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Abstract

The present invention provides novel inhibitors of the enzyme D-amino acid oxidase. The compounds of the invention are useful for treating or preventing diseases and / or condition, wherein modulation of D-serine levels, and / or its oxidative products, is effective in ameliorating symptoms. The invention further provides methods of enhancing learning, memory and / or cognition. For example, the invention provides methods for treating or preventing loss of memory and / or cognition associated with neurodegenerative diseases, such as Alzheimer's disease. The invention further provides methods for preventing loss of neuronal function characteristic of neurodegenerative diseases. In addition, methods are provided for the treatment or prevention of neuropsychiatric diseases (e.g., schizophrenia) and for the treatment or prevention of pain and ataxia.

Description

[0001] Cross References to Related Applications [0001] Under 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Patent Application No. 60 / 885,588, filed January 18, 2007, which is incorporated herein by reference in its entirety for all purposes. technical field [0002] The present invention relates to enzyme inhibitors, especially inhibitors of D-amino acid oxidase (DAAO). 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 peripheral nervous system. The role of D-serine as a neurotransmitter is at the N-methyl-D-aspartate (NMDA) selective subtype of glutamate receptors - ion channels expressed in neurons, here called NMDA receptors Body - is important in the activation. [0004] NMDA receptors mediate many physiological functions. NMDA receptors are complex ion channels containing multiple protein subunits th...

Claims

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Application Information

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IPC IPC(8): C07D209/42C07D491/04C07D495/04A61K31/403A61P25/00
CPCC07D495/04C07D491/04C07D209/52C07D209/94C07D487/04C07D209/42G01N21/253G01N21/255G01N21/3151A61P21/00A61P21/02A61P25/00A61P25/04A61P25/06A61P25/16A61P25/18A61P25/28A61P43/00A61K31/403
Inventor M·L·R·赫弗南Q·K·方R·J·福格尔桑S·C·霍普金斯C·O·奥格布M·索克瑞K·L·斯皮尔
Owner SEPACOR INC
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