Carbazolypiperines as GABA uptake inhibitors

Details Carbazolypiperines as GABA uptake inhibitors Carbazolypiperines as GABA uptake inhibitors

1997-10-21

2000-06-06

Chang, Ceila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546200, A61K 31445, C07D40106

Patent

active

06071932&

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel substituted carbazole derivatives, to methods for their preparation, to pharmaceutical compositions containing them and to their use in the clinical treatment of abnormal functioning of the .gamma.-aminobutyric acid neurotransmission system.


BACKGROUND OF THE INVENTION

.gamma.-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS) (for review see Enna, 1983, Biochem. Pharmacol., 30, 907-15; Enna and Mohler, 1987, Raven Press, New York, 265-79; Lloyd and Morselli, 1987, Medical Biology, 65, (2-3), 159-65; Krogsgaard-Larsen, 1988, Medical Res. Reviews, 8, 1, 27-56; Schwartz, 1988, Biochem. Pharmacol. 27, 3369-76). GABA has been estimated to be present in 60-70% of all synapses within the CNS (Fahn, 1976, Raven Press, New York, 169-83). A reduction in GABA neurotransmission has been implicated in the etiology of a variety of neurological disorders including epilepsy Krogsgaard-Larsen et al., 1988, Medical Res. Reviews, 8, 1, 27-56; Loscher, 1985, Epilepsy and GABA Receptor Agonists: Basic and Therapeutic Research. L. E. R. S. Monograph. Vol. 3, G. Bartholoni, L. Bossi, K. G. Lloyd, P. L. Morselli (Eds.), Raven Press, New York, 109-18); Enna, 1981, Biochem. Pharmacol., 30, 907-14 and Neuropharmacology of Central Nervous System GABA and Behavioral Disorders, G. Palmer (Ed.). Academic Press, New York 1981, 507-25; Rebak et al., 1979, Science, 205, 211-13; Ross and Craig, 1981, J.Neurochem. 36, 1006).
The GABA uptake system has traditionally been classified as either neuronal or glial GABA uptake carriers, on the basis of pharmacological selectivity for specific GABA uptake inhibitors (for review see: Krogsgaard-Larsen, 1988, Medical Res. Reviews, 8, 1, 27-56; Schousboe et al., 1991, GABA Mechanisms in Epilepsy, G. Tunnicliff, B. U. Raess (Eds.) Wiley-Liss, New York, 165-87).
Several investigators (Gaustella et al., 1990, Science, 249, 1303-1306; Clark et al., 1992, Neuron 9, 337-348; Borden et al., 1992, J.Biol. Chem. 267, 21098-21104; Liu et al., 1993, J.Biol.Chem. 268, 2106-2112) have recently cloned, and sequenced, four subtypes of the rat and mouse GABA uptake carrier, whose pharmacology cannot be totally explained by the traditional neuronal and glial GABA uptake carriers. Gaustella et al., (1990, Science, 249, 1303-1306) and Nelson et al. (1990, FEBS Lett. 269, 181-184) reported on the cloning of GAT-1, which appears to be a neuronal GABA uptake carrier due to its high sensitivity to nipecotic acid (Gaustella et al., 1990, Science, 249, 1303-1306), and lipophilic nipecotic acid based compounds and distribution within the central nervous system (CNS) (Radian et al., 1990, J.Neurosci. 10, 1319-1330; Mabjeesh et al., 1992, J.Biol.Chem. 267, 2563-68). GAT-1 is not present outside the CNS (Nelson et al., 1990, FEBS Lett. 269, 181-184; Liu et al., 1992, FEBS. Lett. 305, 110-114). GAT-2 was initially cloned by Lopez-Corruera (1992, J.Biol.Chem. 267, 17491-17493) and is present in the CNS, kidney and liver, and has a pharmacology resembling the glial GABA uptake carrier characterized in primary cell culture. GAT-3 which was initially cloned by Liu et al., (1993, J.Biol.Chem. 267, 2106-2112), appears to be under developmental control, as GAT-3 mRNA is highly expressed in neonatal brain, but weakly expressed in adult brain. GAT-3 is also present in kidney and liver. GAT-4 (Liu et al., 1993, J.Biol.Chem. 268, 2106-2112; also termed GAT-B by Clark et al., (1992, Neuron 9, 337-348) and GAT-3 by Borden et al., (1992, J.Biol.Chem. 267, 21098-21104)), cDNA hybridized only in the CNS, and the mRNA for GAT-4 is highly enriched in the brain stem, but not present in the cerebellum or cerebral cortex. While GAT-4 has been shown to transport .beta.-alanine, it appears to have neuronal localization (Clarke et al., 1992, Neuron 9, 337-348).
The distribution of GAT-1, closely resembles the previously reported distribution of .sup.3 H-Tiagabine receptor autoradiography (Suzdak et al., 1994, Brain Research, 647(2), 231-41

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Hagen et al. "Synthesis of 6-substituted beta-carbolines that behave as . . . " CA 106:196295, 1987.

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