Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-29
2001-02-13
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06187807
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a novel composition containing optically pure (S)(−)-amisulpride or a pharmaceutically acceptable salt thereof.
This composition possesses antipsychotic properties useful in the treatment of positive, negative, affective or cognitive symptoms of schizophrenia, dysthymia, autism, tardive dyskinesia induced by neuroleptics, Tourette disease(tics), manic or depressive symptoms in patients with bipolar disorders, sudden attacks of delirium, migraine and drug addiction while inducing therapeutic effects at doses lower and with a higher safety ratio than the racemic mixture of amisulpride or its salts.
This invention also relates to a method of treatment utilizing this composition in the therapeutical indications described above.
Amisulpride, belonging to the benzamide series, is described in U.S. Pat. No. 4,401,822 to Thominet et al. Amisulpride is known for its antiapomorphine activity. Chemically, the (S)(−) isomer is (S)-(−)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide, referred thereafter as (S)(−)-amisulpride.
At the present time, amisulpride is available only as a racemic mixture, hereinafter called (R,S)-amisulpride. (R,S)-Amisulpride is mainly used in the treatment of acute and chronic schizophrenic disorders, in which positive symptoms (such as delusions, hallucinations, thought disorders) and/or negative symptoms (such as blunted affect, emotional and social withdrawal) are prominent. More particularly (R,S)-amisulpride is used for treating patients having predominant primary negative symptoms. (R,S)-Amisulpride is also used in the treatment of depressive disorders such as dysthimia.
Pharmacological profile of (R,S)-amisulpride is well described in H.Schoemaker et al.,
The Journal of Pharmacology and Experimental Therapeutics
, 280 (1997), 83-97 and Gh. Perrault et al.,
The Journal of Pharmacology and Experimental Therapeutics
, 280 (1997), 73-82. In particular, it is reported how this pharmacological profile is distinct from that of classical neuroleptics such as haloperidol and from that of another benzamide, remoxipride. It is characterizd by a preferential blockade of D
2
and D
3
receptors with presynaptic and limbic selectivity.
According to these properties (R,S)-amisulpride has certain advantages over other antipsychotics (neuroleptic agents). (R,S)-amisulpride shows a clinical efficacy against negative, positive, affective or cognitive symptoms of schizophrenia, a low propensity to produce extrapyramidal side effects and a good general tolerance.
SUMMARY OF THE INVENTION
It has been now discovered that the (S)(−) enantiomer of amisulpride, of formula:
or pharmaceutically salts thereof are effective antipsychotic agents with a qualitatively similar pharmacological profile, while inducing therapeutical effect at lower doses and showing a higher safety ratio than (R,S)-amisulpride. Novel compositions containing optically pure (S)(−)-amisulpride or any acceptable salt thereof, which have antipsychotic activity while inducing therapeutic effect at lower doses and showing a higher safety ratio than (R,S)-amisulpride are also disclosed.
Also included within the present invention are novel compositions containing optically pure (S)(−) enantiomer of amisuipride or any acceptable salt thereof, which are useful in the treatment of negative, positive, affective and cognitive symptoms of schizophrenic disorders, dysthymia, autism, tardive dyskinesia induced by neuroleptics, Tourette disease, manic or depressive symptoms, migraine headaches, sudden attacks of delirium, but also in weaning drug addicts.
DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses a method of treatment capable of eliciting antipsychotic properties, which comprises administering to a patient suffering from psychotic disorders and/or depressive disorders, an amount of (S)(−)-amisulpride or a pharmaceutically salt thereof, substantially free of its (R)(+)-stereoisomer, sufficient to alleviate schizophrenic symptoms while allowing to avoid or strongly reduce risks of appearance of side effects associated with (R,S) -amisulpride.
The present invention also emcompasses a composition adapted for the treatment of a patient in need of antipsychotic and/or antidepressive therapy, containing (S)(−)-amisulpride or a pharmaceutically salt thereof, substantially free of its (R)(+)-stereoisomer, which have antipsychotic activity while allowing to avoid or strongly reduce risks of appearance of side effects associated with the racemic mixture of (R,S)-amisulpride.
Pure (S)(−)-amisulpride shows an increased therapeutic potency as compared to the racemic mixture that could have been expected for an active enantiomer of a racemic mixture. In addition, after ingestion of the same dose of (S)(−)-amisulpride or (R,S)-amisulpride, occurrence of side effects is comparable. Therefore, the safety ratio of (S)(−)-amisulpride is markedly increased as compared to the racemic mixture.
As a result, a composition according to the invention allows the dose of active substance to be reduced by about 2-fold in comparison with the traditional dosage of the racemic mixture, while side effects can be markedly reduced.
As used in the present application, the term “substantially free of the (R)(+) stereoisomer” means that the composition contains at least 90% by weight of (S)(−)-amisulpride and 10% by weight or less of (R)(+)-amisulpride. In the most preferred embodiment the term “substantially free of the (R)(+) stereoisomer” means that the composition contains at least 99% by weight of (S)(−)-amisulpride and 1% by weight or less of (R)(+)-amisulpride.
The term “eliciting antipsychotic properties” means relief from the symptoms associated with psychotic disorders and/or depressive disorders, which include but is not limited to schizophrenia and dysthimia.
The term “side effect” as used in the present application includes but is not limited to extrapyramidal side effects.
The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Among acids may be mentioned inclusively but not in a limiting manner, inorganic or organic acids such as hydrochloric, hydrobromic, sulphuric, phosphoric, oxalic, acetic, tartaric, citric, or methane sulphonic acid. Especially preferred among these acids are the tartaric acids and particularly the [S-(R*,R*)]-2,3-dihydroxybutanedioic acid (Chemical abstract registry number: 147-71-7), hereinafter called D-(−)-tartaric acid.
The preferred salt of (S)(−)-amisulpride is the D-(−)-tartrate of (S)(−)-amisulpride.
The synthesis of the (S)(−)-amisulpride can be performed by the following method:
2-methoxy-4-amino-5-mercaptobenzoic acid is treated with ethylsulfate to provide the 5-ethylthiobenzoic acid which is then oxidized to provide the 2-methoxy-4-amino-5-ethylsulphonyl benzoic acid. This acid is then reacted with (S)-(−)-1-ethyl-2-aminomethylpyrrolidine. This reaction is carried out by activating either the acid moiety or the amino moiety by means known in the art.
Thus the acid moiety may be converted into the corresponding acyl halide, alkyl ester, reactive ester, aryl ester, N-hydroxyimide ester of a carbonic acid or a haloformic ester, azide, hydrazide, azolide, acid isothiocyanate, trichloroacetophenone, or triphenylphophine derivative. Alternatively, the acid moiety is left intact and the amine activated by reaction with phosphorus chloride, phosphorus oxychloride, a dialkyldiaryl-, or orthophenylenechloro_phosphite, an alkyl- or aryldichlorophosphite, or the formation of an isothiocyanate of the amine or a substituted urea or sulphamide.
The activated compound is then reacted with the unactivated component by means well-known in the art. In a further embodiment the free acid and the free amine may be reacted together in the presenc
Miget Joël
Perrault Ghislaine
Schoemaker Hans
Criares Theodore J.
Foley & Lardner
Kim Jennifer
Sanofi-Synthelabo
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