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Aryloxy-and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

一种苯并、取代基的技术，应用在四氢苯并氮杂衍生物领域，能够解决起效慢、不良副作用等问题

Inactive Publication Date: 2010-03-31
ALBANY MOLECULAR RESEARCH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are several known difficulties with the use of SSRI therapy, including slow onset of action, adverse side effects, and the existence of a sizable non-responsive population to SSRI therapy

Method used

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  • Aryloxy-and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
  • Aryloxy-and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
  • Aryloxy-and heteroaryloxy-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

Example 1 -(+)-2-Methyl-5-(naphthalen-2-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c ] Aza Preparation of tartrate

[0135] Step A: To a solution of 3-bromobenzaldehyde (75.5 g, 408 mmol) in methanol (500 mL) was added methylamine (40% in water, 38 g, 490 mmol) and iodine (1 g, 3.9 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes. Sodium borohydride (23.2 g, 614 mmol) was added in portions. The mixture was stirred at 0°C for 5 hours. The solvent was removed and the residue was dissolved in water and dichloromethane. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give benzylamine (80 g, crude product) as a pale yellow oil: 1 H NMR (CDCl 3 , 500MHz) δ7.48(s, 1H), 7.38(d, J=8.0Hz, 1H), 7.24(d, J=8.0Hz, 1H), 7.19(t, J=8.0Hz, 1H), 3.72( s, 1H), 2.46(s, 3H); ESI MS m / z200[M+H] + .

[0136] Step B: A solution of benzylamine (26.4 g, 131 mmol), acrylic acid (9.5 g, 131 mmol) and pyridine (150 mL) from S...

Embodiment 2

[0146] According to the method of step J and step K of embodiment 1, from (-)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro- 1H-Benzo[c]azepine -5-phenol and 4-chlorophenol to prepare the compound. (+)-5-(4-chlorophenyl)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Tartrate (AUC HPLC>99%) is a white solid: melting point 106-108°C; 1 H NMR (CD 3 OD, 500MHz) δ9.18(d, J=5.0Hz, 1H), 8.20-8.17(m, 2H), 8.07(d, J=8.0Hz, 1H), 7.80(dd, J=8.7, 3.8Hz, 1H), 7.66(d, J=7.9Hz, 1H), 7.25(d, J=9.0Hz, 2H), 7.05(d, J=9.0Hz, 2H), 5.73(d, J=7.6Hz, 1H) , 4.92-4.84(m, 1H), 4.52-4.46(m, 1H), 4.42(s, 3H), 3.90-3.80(m, 1H), 3.56-3.50(m, 1H), 2.86(s, 3H) , 2.46-2.37 (m, 2H); ESI MS m / z 366 [M+H].

Embodiment 3

[0147] According to the method of step J and step K of embodiment 1, from (-)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro- 1H-Benzo[c]azepine -5-phenol and p-cresol to prepare the compound. (+)-2-Methyl-8-(pyridazin-3-yl)-5-(p-tolyloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Tartrate (AUC HPLC>99%) is a white solid: melting point 104-106°C; 1 H NMR (CD 3 OD, 500MHz) δ9.18(d, J=5.0Hz, 1H), 8.20-8.18(m, 2H), 8.08(d, J=8.6Hz, 1H), 7.80(dd, J=8.7, 3.8Hz, 1H), 7.66(d, J=7.9Hz, 1H), 7.06(d, J=9.0Hz, 2H), 6.93(d, J=9.0Hz, 2H), 5.69(d, J=7.7Hz, 1H) , 4.96-4.88(m, 1H), 4.55-4.52(m, 1H), 4.43(s, 3H), 3.98-3.93(m, 1H), 3.60-3.58(m, 1H), 2.93(s, 3H) , 2.54-2.35 (m, 2H); ESI MS m / z 346 [M+H].

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Abstract

The aryloxy- and heteroaryloxy-substituted tetrahydrobenzazepine derivative compounds of the present invention are represented by formulae (I) (A-E) having the following structure where the carbon atom designated * is in the R or S configuration and the substituents X and R<1>-R<9> are as defined herein.

Description

[0001] This application claims the benefit of US Provisional Patent Application Serial No. 60 / 917,200, filed May 10, 2007, which is hereby incorporated by reference in its entirety. field of invention [0002] The present invention relates to compounds, compositions, methods and the use of said compounds in combination therapy for the treatment of various neurological diseases and psychological disorders. In particular, the present invention relates to such compounds, compositions and methods, wherein the compounds are novel aryloxy and heteroaryloxy substituted tetrahydrobenzazepines derivative. Background of the invention [0003] It is well known that the neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) regulate various biological processes, and that decreased levels of DA, NE and 5-HT are associated with various neurological diseases related to its physiological phenomena. Considerable effort has been devoted to devising methods for modulating...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/55C07D223/16
CPCC07D401/14C07D223/16C07D403/04C07D471/04C07D401/04A61P13/00A61P15/00A61P15/10A61P21/00A61P25/00A61P25/02A61P25/04A61P25/06A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P25/34A61P3/04A61P3/10A61K31/55
Inventor S·刘Y·A·杨A·桑班达姆B·F·莫利诺R·E·奥尔森
Owner ALBANY MOLECULAR RESEARCH INC
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