Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-03-17
2003-04-22
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S909000, C514S910000, C514S878000, C514S879000
Reexamination Certificate
active
06552087
ABSTRACT:
BACKGROUND OF THE INVENTION
The preparation and use of compounds, such as N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (or N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) and salts thereof, in the treatment of depression is described in British Patent Specification 2098602. The use of compounds such as N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of Parkinson's disease is described in European Patent Number 282206. The use of compounds such as N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof in the treatment of cerebral function disorders is described in U.S. Pat. No. 4,939,175. The use of N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride in the treatment of obesity is described in European Patent Number 397831. A particularly preferred form of this compound is N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate) which is described in European Patent Number 230742. The use of N,N,-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and salts thereof for improving the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus is described in published PCT application WO95/20949.
All of the above documents are incorporated herein by reference.
The use of sibutramine as an insulin sensitiser is disclosed in WO98/11884. The use of sibutramine in lowering uric acid levels is disclosed in WO98/13033. The use of sibutramine in lowering lipid levels is disclosed in WO98,13034.
SUMMARY OF THE INVENTION
This invention relates to the (+)-enantiomer of Sibutramine, which is N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, and pharmaceutically acceptable salts thereof, to their use in the treatment of obesity and depression, to formulations containing these compounds and to methods for their preparation.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of treating any of the indications previously disclosed as being treatable by racemic sibutramine in any of the above documents comprising administering to a mammal, particularly a human, in need thereof a therapeutically effective amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-enantiomer.
In particular (+)-sibutramine is useful in the treatment of depression, obesity, Parkinson's disease, cerebral function disorders and diabetes.
The present invention provides a method of treating depression in a human which comprises administering to a human in need of antidepressant therapy, an amount of (+)-sibutramine, or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alleviate depression.
In another aspect the present invention provides a method for treating obesity or weight gain in a human which comprises administering to a human in need of a reduction in weight, an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alleviate obesity or weight gain.
In yet another aspect the present invention provides a method of treating disorders ameliorated by inhibition of neuronal monoamine reuptake in a human which comprises administering to a human in need of such treatment an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alleviate said disorders. Preferably said monoamine is dopamine. Preferably said disorder is Parkinson's disease.
In yet another aspect the present invention provides a method for treating cerebral function disorders in humans which comprises administering to a human an amount of (+)-sibutramine, or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alleviate cerebral function disorders. In a preferred embodiment the cerebral function disorder is caused by a cerebrovascular disease. In another preferred embodiment the cerebral function disorder is selected from the group consisting of senile dementia, Alzheimer's type dementia, memory loss and amnesia/amnestic syndrome. Preferably the cerebrovascular disease is selected from the group consisting of cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis and head injuries.
The above inventions provide in preferred embodiments methods of treating depression, obesity, weight gain, disorders ameliorated by inhibition of neuronal monoamine reuptake or cerebral function disorders in a human in which said amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, is sufficient to alleviate the said disease or disorder but insufficient to cause adverse effects associated with the administration of racemic sibutramine.
Examples of pharmaceutically acceptable salts of (+)-sibutramine include the hydrochloride, hydrobromide, sulphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate [e.g. (+)-tartrate, (−)-tartrate or mixtures thereof including racemic mixtures], succinate, benzoate, benzenesulphonate, camphorsulphonate, gluconate, lactate, malate, mandelate, pamoate, phosphate, p-toluenesulphonate and salts with amino acids such as glutamic acid. Preferably the salt is the hydrochloride salt.
In another aspect the present invention provides a composition for the treatment of depression in a human which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alleviate depression.
In a further aspect the present invention provides a composition for the treatment of depression in a human wherein said amount of (+)-sibutramine, or a pharmaceutically acceptable salt thereof, is sufficient to treat depression but insufficient to cause adverse effects associated with the administration of racemic sibutramine.
In another aspect the present invention provides a composition for treating obesity or weight gain in a human which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alleviate obesity or weight gain.
In a further aspect the present invention provides a composition for treating weight disorders in a human wherein said amount is sufficient to alleviate obesity or weight gain in a human but insufficient to cause adverse effects associated with administration of racemic sibutramine.
In another aspect the present invention provides a composition for the treatment of disorders ameliorated by inhibition of neuronal monoamine reuptake in a human which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alleviate said disorders.
In a further aspect the present invention provides a composition for the treatment of disorders ameliorated by inhibition of neuronal monoamine reuptake in a human wherein said amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, is sufficient to treat said disorders but insufficient to cause adverse effects associated with the administration of racemic sibutramine.
In another aspect the present invention provides a composition for treating cerebral function disorders, which comprises an amount of (+)-sibutramine or a pharmaceutically acceptable salt thereof, substantially free of its (−)-stereoisomer, said amount being sufficient to alle
Cheetham Sharon C.
Heal David John
Abbott & GmbH & Co. KG
Krass Frederick
Seshadri Tara
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