Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-17
1999-11-02
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514314, 5142355, 544128, 546165, A61K 3147, C07D21548
Patent
active
059771364
DESCRIPTION:
BRIEF SUMMARY
This invention relates to 1,2,3,4 tetrahydroquinoline derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. In particular, it relates to 1,2,3,4 tetrahydroquinoline derivatives which are potent and specific antagonists of excitatory amino acids.
Carling et al, Bioorganic and Medicinal Chemistry Letters Vol 13 pp 65-70 1993 teaches 4-substituted-2-carboxy tetrahydroquinolines having good in vitro affinity for the glycine modulatory site of the NMDA receptor complex but at best only weak in vivo activity. More particularly it teaches that such derivatives substituted at the 4 position by the group CH.sub.2 CO.sub.2 H or CH.sub.2 CONHPh have little or no in vivo activity when administered systemically (ip).
We have found a novel group of 4 substituted 2-carboxy-tetrahydroquinoline derivatives which not only have a good in vitro affinity for the strychnine insensitive glycine binding site associated with the NMDA receptor complex but also good in vivo activity when administered intravenously (iv).
Thus the present invention provides a compound of formula (I) ##STR2## or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO.sub.2 R.sub.2 or COR.sub.2 wherein R.sub.2 represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; or (CH.sub.2).sub.n R.sub.3 wherein R.sub.3 is hydroxy, COR.sub.4, NR.sub.5 R.sub.6, NHCOR.sub.7, or NHCONR.sub.8 R.sub.9 group. R.sub.5 and R.sub.6 together with the nitrogen atom to which they are attached represent a heterocyclic group; aryl or heterocyclic group; heterocyclic or cycloalkyl group;
In compounds of formula (I) the exocyclic double bond is in the trans (E) configuration.
For use in medicine the salts of the compounds of formula (I) will be physiologically acceptable thereof. Other salts however may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore, unless otherwise stated, references to salts include both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).
Suitable physiologically acceptable salts of compounds of the invention include base addition salts and where appropriate acid addition salts. Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline metal salts such as sodium, potassium, calcium, and magnesium, and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
The compounds of formula (I) and/or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.
Compounds of formula (I) and in particular the base addition salts thereof e.g. sodium salt have been found to have an advantageous profile of solubility in water.
The term alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom examples of such groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
The term optionally substituted alkyl as used herein refers to an alkyl group as defined above and which is substituted by one or more hydroxy. carboxyl, and amino groups.
The term halogen refers to a fluorine, chlorine, bromine or iodine atom.
The term aryl refers to an optionally substituted phenyl group or a 5 or 6 membered heteroaryl in which the 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from oxygen sulphur or nitrogen and 6-membered heteroaryl group containing 1 or 2 nitrogen atoms.
Examples of suitable heteroaryl groups include furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, and pyrimidinyl.
The term optionally substituted phenyl refers to a phenyl group substitu
REFERENCES:
R.W. Carling et al., "Anticonvulsant Activity of Glycine-Site NMDA Antagonists", Bioorganic& Medicinal Chemistry Letters, vol. 3, No. 1, 1993, pp. 65-70.
Bertani Barbara
Di Fabio Romano
Giacobbe Simone
Micheli Fabrizio
Glaxo Wellcome SpA
Huang Evelyn Mei
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