Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-11
2001-03-27
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06207685
ABSTRACT:
STATE OF THE ART
The family of neurotoxic products or those containing neurotoxin includes products such as the organophosphates which can be found, for example, in insecticides or pesticides for domestic or industrial use, but also poison gas for use in warfare, such as soman, sarin, tabun or VX. Among the existing therapies such as polymedication to combat intoxication by such compounds, none totally prevents the appearance of neuropathological after-effects.
A subject of the invention is the use of thienylcyclohexylamine corresponding to the formula 2-methyl-1-(1-piperidinyl)-1-(2-thienyl)cyclohexane, for the preparation of a medicament intended to limit or inhibit the effects due to neurotoxic products or those containing neurotoxin in primates and in particular in man. It can be used by itself or in combination with other substances with a pharmaceutical activity capable of limiting or inhibiting the effects due to neurotoxic products or those containing neurotoxin.
Thienylcyclohexylamine as defined above, is described in Patent EP 396734. Taking into account the existence of 2 asymmetric carbons, this thienylcyclohexylamime can be in substantially pure racemic, diastereoisomeric or enantiomeric form.
The preparation of the diastereoisomers of 1-thienylcyclohexylamine consists of reacting the 2-bromothienyl-magnesium compound on 2-methylcyclo hexanone, and treating the 2-methyl-1-(2-thienyl)cyclohexanol thus obtained with NaN
3
in order to obtain the corresponding azide, reducing this azide into the amine and finally treating with 1,5-halogenopentane. The cis and trans diastereoisomers are separated by preparative chromatography on silica gel, using a hexane/ether mixture (95/5 by volume): the first fraction, corresponding to the trans compound, crystallizes at 40 -41° C., the second fraction, corresponding to the cis compound, crystallizes at 80-81° C. The enantiomers can be obtained by using optically active acids such as di-O,O′-4-toluoyltartaric acid.
BRIEF SUMMARY OF THE INVENTION
A particular subject of the invention is the use of thienylcyclohexylamine as defined above, with at least one substance chosen from anticholinergic, anticonvulsive substances and substances which reactivate cholinesterases.
A particular subject of the invention is the use of thienylcyclohexylamine as defined above, with at least one anticholinergic substance, at least one anticonvulsive substance and at least one substance which reactivates cholinesterases.
The pharmacological terms used have the standard meaning known to a person skilled in the art. Therefore, among the anticholinergic substances, the following substances can be mentioned: atropine, scopolamine, atropine N-oxide, dihexyverine and tiemonium methylsulphate. Among the anticonvulsive substances, the following substances can for example be mentioned: phenobarbital, primidone, carbamazepine, ethosuximide, phenytoin, sodium valproate, progabide, gabapentin, vigabatrin, loprazolam, benzodiazepins such as clonazepam, clobazam, diazepam and prodiazepam. Among the substances which reactivate cholinesterases, there can be mentioned pralidoxime, obidoxime, HI6.
A subject of the invention is also a use of thienylcyclohexylamine as defined above, characterized in that the thienylcyclohexylamine is combined with a reversible cholinesterase inhibitor intended to be administered before exposure to neurotoxic products or those containing neurotoxin. Among the reversible cholinesterase inhibitors, the following can be mentioned: pyridostigmine, physostigmine.
A subject of the invention is also, as a medicament, a product containing thienylcyclohexylamine as defined above, combined with at least one substance with a pharmaceutical activity capable of limiting or inhibiting the effects due to neurotoxic products or those containing neurotoxin, as well as the pharmaceutical compositions containing it.
A more particular subject of the invention is, as a medicament, a product containing thienylcyclohexylamine as defined above, in substantially pure racemic, diastereoisomeric or enantiomeric form, combined with at least one substance chosen from anticholinergic, anticonvulsive substances and substances which reactivate cholinesterases. Preferably, the product as defined above, contains thienylcyclohexylamine as defined above, combined with at least one anticholinergic substance, one anticonvulsive substance and one substance which reactivates cholinesterases.
The invention also relates to a product containing thienylcyclohexylamine and at least one substance chosen from anticholinergic, anticonvulsive substances and substances which reactivate cholinesterases as a combination product for simultaneous use, separate use or use spread over time, to limit or inhibit the effects due to neurotoxic products or those containing neurotoxin.
A subject of the invention is also a product as defined above characterized in that in addition it contains a cholinesterase inhibitor intended to be administered before exposure to neurotoxic products or those containing neurotoxin.
Thienylcyclohexylamine as defined above, can be administered at a dose comprised between 0.001 and 10 mg/kg, preferably between 0.01 and 0.1 mg/kg. The substances which are optionally combined with it such as anticholinergic, anticonvulsive substances or substances which reactivate cholinesterases, known in pharmacology, are administered at doses usually recommended in their respective pharmacological fields.
Thienylcyclohexylamine as defined above as well as the pharmaceutically active substances with which it is optionally combined, can be administered by standard administration routes such as oral, intramuscular, intraperitoneal, sub-cutaneous or intravenous. They can be administered simultaneously or separately, by identical or different administration routes. Preferably, thienylcyclohexylamine is administered by intravenous route and the pharmaceutically active substances with which it is optionally combined such as the anticholinergic, anticonvulsive substances and the substances which reactivate cholinesterases, are administered by intramuscular or intravenous route. In the case where thienylcyclohexylamine is combined with at least one of the pharmaceutically active substances as defined above, the administration of thienylcyclohexylamine can be deferred with respect to the administration of these other substances.
The administration of thienylcyclohexylamine can also be carried out from the moment of intoxication up to several hours after this intoxication. Preferably, this administration is carried out within two hours of the intoxication. More preferably, this administration can be carried out between 10 minutes and 45 minutes after intoxication.
The results shown hereafter in the experimental part illustrate the high effectiveness of the complementary administration of cis-thienylcyclohexylamine 10 to 45 minutes after intoxication.
Therefore a subject of the invention is the use described above, characterised in that 2-methyl-(1-piperidinyl)-1-(2-thienyl)cyclohexane, in substantially pure racemic, diastereoisomeric or enantiomeric form, is administered within two hours and preferably within the hour following intoxication with neurotoxic products or those containing neurotoxin.
REFERENCES:
patent: 5179109 (1993-01-01), Kamenka et al.
patent: 5604255 (1997-02-01), Rice et al.
patent: 0317953 (1989-05-01), None
patent: 9005524 (1990-05-01), None
Cross et al., Abstract to “Neuroprotective activity of chlormethiazole following transient forebrain ischemia in the gerbil”, Br. J. Pharmacol. 104(2), pp. 406-411, 1991.
D'Arbigny Pierre
Kamenka Jean-Marc
Lallement Guy
Bierman, Muserlian and Lucas
Jones Dwayne C.
Societe de Conseils de Recherches et d'Applications Scienti
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