Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-14
1999-06-15
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142348, 544119, 544354, A61K 31495, A61K 31535, C07D24144, C07D40112
Patent
active
059122455
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new acid amides, a process for the preparation thereof, pharmaceutical compositions comprising the same, the use of the said compounds for the treatment of diseases and for the preparation of pharmaceutical compositions suitable for the treatment of diseases.
According to an aspect of the present invention there are provided new acid amides of the formula ##STR2## wherein R.sup.1 represents hydrogen or nitro, lower alkyl or lower alkenyl optionally carrying a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, di(lower alkyl)amino, phenyl-lower alkoxycarbonyl and a 5- to 6-membered saturated heteroring containing 1 or 2 nitrogen and/or oxygen atom(s); or 6-membered saturated heterocyclic group containing optionally 1 or 2 additional nitrogen atoms and/or oxygen atom(s), said ring optionally carrying a hydroxy or a hydroxy-lower alkyl group.
The invention encompasses all of the possible mesomers, tautomeric forms and stereoisomers of the acid amides of the formula (I) and the mixtures thereof.
The compounds of the formula (I) are AMPA and kainate antagonists.
The term "lower" in respect of the alkyl and alkenyl groups means 1-6 and 2-6 carbon atoms, respectively.
The term "alkyl" used throughout the specification and claims refers to straight or branched ones such as methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, n-hexyl etc. Suitably "alkenyl" may include straight or branched ones such as vinyl, allyl, methallyl, butenyl or the like. The term "halogen atom" encompasses all the four halogen atoms, such as fluorine, chlorine, bromine and iodine. As "5- to 6-membered heterorings" saturated heterocyclic rings are mentioned, which contain as heteroatom 1 or 2 nitrogen and/or oxygen atom(s) (e.g. pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, izoxazolidinyl, oxazolidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, tetrahydro-2H-1,3-oxazinyl, tetrahydro-1H-1,2-oxazinyl or morpholinyl).
Preferred representatives of the compounds according to the invention are the following derivatives: 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-N-(2-piperidinoethyl)-6-quinoxaline sulfonamide, N,N-bis(2-hydroxyethyl)-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide and pharmaceutically acceptable salts thereof.
Those compounds of the formula (I), wherein R.sup.2 and R.sup.3 stand for basic groups, can form acid addition salts with pharmaceutically acceptable acids (e.g. hydrogen halides, sulfuric acid, maleic acid, fumaric acid, citric acid). From those compounds of the formula (I), wherein R.sup.2 and R.sup.3 represent hydrogen or alkyl, salts can be formed with mineral bases (such as sodium or potassium hydroxide), whereby the acid amides are converted into salts in form of lactimes.
According to a further aspect of the present invention there is provided a process for the preparation of acid amides of the formula (I), which comprises reacting an acid chloride of the formula ##STR3## wherein R.sup.1 is as stated above, with an amine of the formula ##STR4## wherein R.sup.2 and R.sup.3 are as stated above, and optionally converting the thus-obtained compound of the formula (I) into a pharmaceutically acceptable salt.
The reaction of the acid chlorides of the formula (II) with the amines of the formula (III) is carried out in a polar solvent, preferably water or ethanol, at a temperature between -10.degree. C. and +100.degree. C., preferably at room temperature. The reaction time varies between 1 hour and 72 hours, preferably between 3 and 8 hours.
The product can be isolated from the reaction mixture by a method known per se. If the product separates from the reaction mixture in crystalline form, the crystals are filtered off. If the product does not separate from the reaction mixture as a consequence of the amine of the formula (III) applied in excess, the amine is bound with a mineral or organic acid (e.g. hydrogen chloride or acetic acid) added to the reaction mixture in excess, and then the separated product is filtered off. The pr
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Blasko Gabor
Fekete Marton
Gaal Laszlo
Makara Gabor
Reiter Jozsef
Bernhardt Emily
Egis Gyogyszergyar Rt.
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