Heterocyclic compounds, their preparation and use

Details Heterocyclic compounds, their preparation and use Heterocyclic compounds, their preparation and use

1998-01-21

1999-08-31

Huang, Evelyn Mei

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

5142282, 514254, 514292, 544 60, 544126, 544361, 546 87, A61K 31535, A61K 3144, C07D41304, C07D47104

Patent

active

059454172

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. 371 national application of PCT/DK96/00331 filed Jul. 31, 1996 published as WO 97/05137 on Feb. 13, 1997 and claims priority under 35 U.S.C. 119 of Danish application 0868/95 filed Jul. 31, 1995, the contents of which are fully incorporated herein by reference.
The present invention relates to a method of treating a disease in the central nervous system via the metabotropic glutamate receptor system, the a medicament for treating said diseases, novel therapeutic active compositions comprising these compounds.
Recent molecular biological studies have clearly established the existence of two major types of glutamate receptors in the central nervous system namely the ionotropic and the metabotropic glutamate receptors. The latter is characterised by being G-protein-linked to changes in second messenger formation and modulation of ion channel function, (Meldrum, B. (1991) Epilepsy Res. 10, 55-61, Chapman, A. (1991) in Excitatory Amino Acids p. 265-286, Blackwell scientific publ. ltd., Oxford).
At present 8 different subtypes of the metabotropic glutamate receptors are described (MGluR.sub.1 to MGluR.sub.8) and in addition some spliced variants of the subtypes are reported.
The Metabotropic glutamate receptor subtypes MGluR.sub.1 and MGluR.sub.5 are coupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, C. F. (1991) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J. J. and Krogsgaard Larsen, P. Med. Res. Rev. 10,55-94, Thomsen, C. and Suzdak, P. (1993) Eur. J. Pharmacol. 245 ,299), while the others are coupled to cyclic AMP formation (Schoepp, D. D., Johnson, B. G. and Monn, J. A. (1992) J. Neurochem. 58, 1184-1186, Cartmell et al. (1992) J. Neurochem. 58, 1964-1966, Manzoni, O. et al. (1992) Eur. J. Pharmacol. 225, 357-358).
Compounds such as L-glutamate, quisqualate and ibotenate are known to act as non-selective agonists on the metabotropic glutamate receptors, while selective ionotropic glutamate receptor agonists such as NMDA, AMPA and kainate have little effect on these receptors.
Recently a few compounds without activity at the ionotropic glutamate receptors but with activity at the metabotropic receptors have been identified.
These comprise trans-ACPD (trans 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid), the partial agonist L-AP3 (L-2-amino-3-phosphonopropionic acid) (Palmer, E., Monaghan, D. T. and Cotman, C. W. (1989) Eur. J. Pharmacol. 166, 585-587, Desai, M. A. and Conn, P. J. (1990) Neurosci. Lett. 109, 157-162, Schoepp, D. D. et al. (1991), J. Neurochem. 56, 1789-1796, Schoepp D. D. and Johnson B. G. (1989), J. Neurochem. 53,1865-1613), L-AP4 (L-2-amino4-phosphonobutyrate) which is an agonist at the MGluR.sub.4 receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) and some of the isomers of CCG (2-(carboxycyclopropyl)glycines) especially L-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107, 539-543).
Very few selective antagonists at the metabotropic glutamate receptors have been reported, however some phenylglycine derivatives S-4CPG (S-4-carboxyphenyl glycine), S-4C3HPG (S-4-carboxy-3-hydroxyphenyl glycine) and S-MCPG (S-alpha methyl4-carboxyphenyl glycine) have been reported to antagonise trans ACPD stimulated phosphoinositide hydrolysis and thus possibly acting as antagonists at the metabotropic glutamate receptors at the subtypes MGluR.sub.1 and MGluR.sub.5 (Thomsen, C. and Suzdak, P, (1993) Eur. J. Pharmacol. 245, 299).
Literature evidence suggests that compounds selective for the metabotropic glutamate receptors either as agonists or antagonists are useful in the treatment of different neurological diseases.
The use of compounds active at the metabotropic glutamate receptors for the treatment of epilepsy is corroborated by investigations of the influence of trans-ACPD in the formation of convulsions (Sacaan and Schoepp, (1992), Neurosci. lett. 139, 77) and that phosphoinositide hydrolysis mediated via MGluR is increased after kindling experiments in rats (Akiyama et al. (1992),Brain

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Blackburn et al., "(+)11-Amino-2,6-Dimethyl-1,2,3,4-Tetrahydro-6H Quinindolin-1-One, A Novel GABA.sub.A Modulator With Potential Anxiolytic Activity", Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 2., pp. 279-284.
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