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Dibenzothiazepine Derivatives and Use Thereof

a technology of dibenzothiazepine and derivatives, applied in the field of bipolar disorders, mood disorders, anxiety disorders, etc., can solve the problems of high treatment compliance, low remission rate, safety and tolerability

Inactive Publication Date: 2011-06-30
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compound demonstrates potential for enhanced treatment of depressive phases of bipolar disorder, mood stabilization, and reduced side effects, offering a more effective and safer therapeutic option compared to existing medications.

Problems solved by technology

Although some current drugs have acute efficacy, remission rates are still low.
Safety and tolerability are still issues since approximately 75% of patients experience side effects, and treatment compliance is a major issue.

Method used

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  • Dibenzothiazepine Derivatives and Use Thereof
  • Dibenzothiazepine Derivatives and Use Thereof
  • Dibenzothiazepine Derivatives and Use Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1a

2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine

[0101]Scheme A shows one method of preparing 2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (VI).

[0102]Thus, in a five-step process: 5-fluoro-2-mercapto-benzoic acid ethyl ester may be reacted with 1-fluoro-2-nitrobenzene to form 5-fluoro-2-(2-nitro-phenylsulfanyl)-benzoic acid ethyl ester; the ethyl ester may be converted to 5-fluoro-2-(2-amino-phenylsulfanyl)-benzoic acid ethyl ester; the aminophenyl compound may be cyclized to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, and that may be then reacted with piperazine to form the title compound.

Step 1:

[0103]To a solution of ethyl 5-fluoro-2-mercaptobenzoate (I) (25.0 g, 124.9 mmol) and 1-fluoro-2-nitrobenzene (13.2 mL, 124.9 mmol) in acetone (700 mL) was added K2CO3 (34.5 g, 249.7 mmol) at ambient temperature. The yellow suspension was heated to reflux (60° C.) for 5 hours. The reaction mix...

example 1b

2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine

[0108]Scheme B shows another contemplated method of preparing 2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine.

[0109]Thus, in a three-step process: 2,2′-disulfanediyldianiline may be reacted with 2-bromo-5-fluoro-benzoic acid, as shown, to form 2-(2-amino-phenylsulfanyl)-5-fluoro-benzoic acid; the benzoic acid may be cyclized, as shown, to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, and that may be reacted with piperazine to form the title compound.

Synthesis of 2-fluorodibenzo[b,f][1,4]thiazepin-11(10H)-one

[0110]

[0111]A suspension of nickel bromide (5 mmol, 1.09 g), bipyridyl (5 mmol, 0.78 g) and zinc dust (200 mmol, 13.08 g) in 200 mL dry acetonitrile was magnetically stirred, treated with 2,2′-disulfanediyldianiline (52 mmol, 12.92 g) and heated in an oil bath set at 75° C. for 30 min after reaching maximum internal temperature. At the end...

example 1c

2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine

[0114]Scheme C shows another contemplated method of preparing 2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine.

[0115]Thus, 1-chloro-2-nitrobenzene may be reacted with 4-fluorobenzenethiol in the presence of a base to form 1-nitro-2-phenylsulfanyl-(4-fluorobenzene). The nitrofluorobenzene may be reduced to 1-amino-2-phenylsulfanyl-(4-fluorobenzene) which can converted (for example, as shown) to [2-(4-fluoro-phenylsulfanyl)-phenyl]-carbamic acid phenyl ester. Such an ester may be cyclized as shown to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, which can then be reacted with piperazine to form the title compound.

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Abstract

Compounds the following formula: wherein Z is as described in the specification, pharmaceutically acceptable salts thereof, compositions comprising the same, and methods of treating bipolar disorder, an anxiety disorder, a mood disorder or schizophrenia or other psychotic disorder with said compounds.

Description

FIELD OF THE INVENTION[0001]The present invention relates to methods of treating bipolar disorders, mood disorders, anxiety disorders, and schizophrenia and other psychotic disorders, and to compounds suitable for use in such treatments, pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the such compounds, processes for preparing the such compounds and prodrugs thereof.BACKGROUND OF THE INVENTION[0002]A number of drugs have been approved to treat bipolar disorder and schizophrenia (e.g., anticonvulsants and atypical antipsychotics), and treatment of mania has been achieved with several atypical antipsychotics (e.g., risperidone, olanzapine and quetiapine). Other compounds have been used for the clinical treatment of major depressive disorder (e.g., reboxetine and desimpramine) as well as bipolar depression (quetiapine). However, improvement in therapy is still desired in terms of achieving better remission rates, more effective treatment of depression...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/554C07D417/04A61P25/18A61P25/22
CPCC07D281/16A61K31/554C07D417/04A61P25/00A61P25/18A61P25/22A61P25/24
Inventor BROWN, DEANWESOLOWSKI, STEVENWIDZOWSKI, DANDAMEWOOD, JAMES R.PIERSON, JR., M. EDWARDWOOD, MICHAELEDWARDS, PHILIPHULSIZER, JAMESSHENVI, ASHOKKUMAR BHIKKAPPAMUIR, JAMES CAMPBELL
Owner ASTRAZENECA AB
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