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Noncardiotoxic pharmaceutical compounds

A compound and pharmaceutical technology, applied in the field of novel non-cardiotoxic compounds and pharmaceutical compositions, can solve problems such as difficulty in formulation and limitation of application

Inactive Publication Date: 2009-05-13
唐纳德·L·巴尔博
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the difficulty of formulation and the complexity of metabolism of imipramine-N-oxide in plasma limit its application

Method used

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  • Noncardiotoxic pharmaceutical compounds
  • Noncardiotoxic pharmaceutical compounds
  • Noncardiotoxic pharmaceutical compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0082] According to a preferred embodiment of the present invention, a compound having the following general formula and a pharmaceutically acceptable salt thereof:

[0083]

[0084] In the formula, R 1 and R 2 independently hydrogen, alkyl of about 1-7 carbon atoms, aryl, aralkyl and cycloalkyl of about 3-6 carbon atoms, Y is (CH 2 ) n , wherein n is 0-2, Z is alkyl, alkoxy, alkoxy, aryloxy, or alkylaryloxy, wherein m is about 0-4, R 3 Groups selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl Oxy, substituted or unsubstituted indole, substituted or unsubstituted phenothiazine, substituted or unsubstituted dibenzoxazepine , substituted or unsubstituted dibenzothiazepines , substituted or unsubstituted oxaphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted dihy...

Embodiment 1

[1430] Synthesis of [3-(10,11-dihydro-dibenzo[b,f]azepine -5-yl)-propyl]-methyl-diethyl phosphoramidate

[1431]

[1432] Compound No. E1413

[1433] Desipramine hydrochloride (1 eq, 0.5 g) was added dropwise to a stirred solution of potassium carbonate (2 eq, 0456 g) in anhydrous DMF at 0°C. Diethyl chlorophosphate (1.2 equivalents, 0.33 mL) dissolved in anhydrous DMF was added dropwise to the above mixture, and stirred at room temperature for 12 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic layer was separated, washed with brine solution, and dried over anhydrous sodium sulfate. The dried material was concentrated and purified by column chromatography to obtain a pale yellow liquid (yield: 0.33 g), which was analyzed by HPLC (purity 93.1%). FTIR, MS and 1 H NMR spectrum and empirical general formula C 22 h 31 N 2 o 3 The structure specified by P is consistent.

Embodiment 2

[1435] Synthesis of [3-(10,11-dihydro-dibenzo[b,f]azepine -5-yl)-propyl]-methyl-carbamate methyl ester

[1436]

[1437] Compound No. E1414

[1438] Desipramine hydrochloride (1 eq, 0.3 g) was added dropwise to a stirred solution of potassium carbonate (2 eq, 0.27 g) in anhydrous DMF at 0°C. Methyl chloroform (1.2 eq, 0.1 ml) dissolved in anhydrous DMF was added dropwise to the above mixture, and stirred at room temperature for 6 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic layer was separated, washed with brine solution, and dried over anhydrous sodium sulfate. The dried material was concentrated and purified by column chromatography to obtain a pale yellow liquid (yield: 0.18 g), which was analyzed by HPLC (purity 97.7%). FTIR, MS and 1 H NMR spectrum and empirical general formula C 20 h 24 N 2 o 2 The specified structure is consistent.

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Abstract

The present invention relates to novel noncardiotoxic compounds and pharmaceutical compositions useful in the treatment of a variety of disorders including the treatment of depression, allergies, psychoses, cancer and gastrointestinal disorders. In particular, the present invention describes pharmaceutical compositions that mitigate life-threatening arrhythmias such as torsade de pointes. Torsade de pointes is a particular cardiac problem associated with many therapeutic agents and has been implicated as a possible cause of sudden death, particularly in those individuals with a past history of disturbances of cardiac rhythm, myocardial infarction, congenital repolarization abnormalities and cardiac risk factors such as hyperlipidemia and age. This arrhythmia is a variant of paroxysmal ventricular tachycardia associated with a prolonged QTc interval or prominent U waves on the ECG. Torsade de pointes is potentially lethal because it can progress to ventricular fibrillation, life-threatening arrhythmias or precipitate sudden death.

Description

[0001] Cross References to Related Applications [0002] This patent application claims previously filed co-pending provisional applications 60 / 600,699 (filed August 11, 2004) and 60 / 673,545 (filed April 21, 2005), each entitled "Non-Cardiotoxic Pharmaceutical Compositions" priority, the entire contents of which are incorporated herein by reference. Background of the invention [0003] The present invention relates to novel non-cardiotoxic compounds and pharmaceutical compositions useful in the treatment of a variety of diseases, including depression, allergies, psychosis, infections, cancer and gastrointestinal disorders. The compounds and pharmaceutical compositions of the present invention are useful for the prevention and / or reduction of severe cardiac conduction and cardiac rhythm disturbances and cardiac arrhythmias such as torsades de pointes leading to sudden cardiac death. [0004] It is estimated that in the United States alone, the incidence of sudden cardiac death...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/675C07F9/59
Inventor 唐纳德·L·巴尔博
Owner 唐纳德·L·巴尔博
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