Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-06-28
1990-10-23
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548517, 549318, 514471, C07D30760, C07D40512, A61K 3140, A61K 31365
Patent
active
049652834
DESCRIPTION:
BRIEF SUMMARY
The invention relates to esters of which the acid component is an amino acid radical and the alcoholic component is the radical of a 4-alkoxy-5-arylhydroxymethyl-2(5H)-furanone, that is amino acid esters of the general formula I ##STR1## wherein the oxygen atoms at C-5 and C-.alpha. assume relatively to each other the threo position and wherein chlorine or bromine atom, a lower alkyl group having 1 to 3 C atoms, a perfluoro lower alkyl having 1 to 3 C atoms, the difluoromethoxy or nitro group, phenylalanine, proline, 5-oxoproline, glutamic acid, glutamine, asparaginic acid, asparagine, methionine, glycine, .beta.-alanine, 4-aminobutyric acid, 2-methylalanine or a 1-amino-1-cycloalkane carboxylic acid having a 3-7-member cycloalkyl radical, replaced by the radical R.sup.5, and the benzyloxycarbonyl radical (Z) or the tert. butoxycarbonyl radical (BOC),
The invention further relates to a process for the preparation of the aforementioned amino acid esters; the latter can be obtained by different combination of the individual process steps as desired in the form of racemates, mixtures of diastereomers or enantiomers or in the form of pure diastereomers or enantiomers. (For the definition of the terms "racemate", "diastereomers" and "enantiomers" cf. Roempps Chemie-Lexikon, 8th Edition, Vol. 2, page 928/929, Franckh'sche Verlagshandlung, Stuttgart 1981).
The invention further relates to pharmaceutical preparations which contain at least one of the compounds according to the invention and to the use of the compounds according to the invention as therapeutic agents and in the treatment of convulsions and diseases of the epileptic group in hot-blooded animals and in humans and the use of said compounds in the preparation of anticonvulsives and antiepileptics.
The compounds of the general formula I contain in their alcoholic component, i.e. the 5-arylhydroxymethyl-2(5H)-furanone substructure, two centres of asymmetry at the carbon atoms C-5 and C-.alpha. at which due to the threo configuration of the adjoining oxygen atoms the relative configuration is defined but not the absolute configuration. Consequently, the two following isomers of the general formulae Ia and Ib can occur: ##STR2## The corresponding erythro compounds with 5-S, .alpha.-S and 5-R, .alpha.-R configuration are not the subject of this invention.
When the compounds of the general formulae I are esters of an achiral amino acid the isomers Ia and Ib are enantiomeric compounds. If however the compounds of the general formula I are esters of a chiral L- or D-amino acid then (at least) one new centre of asymmetry is added and leads to (at least) 4 diastereomers, that is to (L)-Ia and (L)-Ib as well as (D)-Ia and (D)-Ib, depending on whether L- or D-amino acid is used for the esterification.
The subject of the invention includes all compounds of the general formula Ia, Ib, (L)-Ia, (L)-Ib, (D)-Ia and (D)-Ib and the respective mixtures of Ia with Ib, of (L)-Ia with (L)-Ib and of (D)-Ia with (D)-Ib but not mixtures of L-amino acid esters with D-amino acid esters.
The compounds of the general formula I are novel and are distinguished by anticonvulsive and antiepileptic effectiveness.
A whole number of compounds of very different chemical constitution are known which have anticonvulsive and antiepileptic effectiveness (cf. for example Erhart/Ruschig, Arzneimittel, Vol. 1, p. 177 et seq., Verlag Chemie, Weinheim, 1972), to which belong in particular the active substances carbamazepine, diazepam, diphenylhydantoin, ethosuximide, phenobarbital and valproic acid. All these known anticonvulsives/antiepileptics have chronic-toxic side effects to varying degrees, including exanthema, depressive states, paranoia, megaloblastic anemia, damage to blood-forming bone marrow, liver damage and others. Many of these active substances are sparingly soluble in water; this leads to difficulties in preparing an intravenous or parenteral form of administration and embodies the risk of inadequate bioavailability after oral administration.
There was therefore a need for availabili
REFERENCES:
patent: 3541214 (1970-11-01), Heusser et al.
patent: 4855320 (1989-08-01), Chatterjee et al.
Chatterjee Shyam S.
Klessing Klaus
Berch Mark L.
Chang Celia
Dr. Willmar Schwabe GmbH & Co.
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