Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-24
2000-09-19
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514326, 514444, 514849, 514850, A61K 31445, A61K 3138
Patent
active
061212903
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a method of treating cough in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of an inhibitor of GABA uptake.
BACKGROUND OF THE INVENTION
Gamma-amino-butyric acid (GABA) is a major inhibitory neurotransmitter of the central and peripheral nervous systems and is released into the synapse on nerve stimulation where it can modulate the activity of other neurons. For most neurotransmitters, including GABA, neurotransmission is terminated by the rapid uptake of neurotransmitter via specific, high-affinity transporters located in the presynaptic terminal and/or surrounding glial cells. Kanner, B. I., et al., Critical Review of Biochemistry; CRC press; Boca Raton, Fla., 1987; Vol. 22, pp 1-38.
Compounds which inhibit GABA uptake have been shown to be useful in the treatment of anxiety, epilepsy, muscular and movement disorders and mental and emotional disorders (in U.S. Pat. No. 4,383,999), as well as demonstrating potent anticonvulsant effects (Yunger, L. M., et al., J. Pharm. Exp. Ther. 1985, 110, 418-427).
Presently, GABA uptake inhibitors are not known as having utility as anti-tussive agents.
SUMMARY OF THE INVENTION
This present invention resides in the discovery that compounds which inhibit GABA uptake have a therapeutic effect on treating cough in a mammal, including a human.
DETAILED DESCRIPTION OF THE INVENTION
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
Compounds which inhibit GABA uptake are used in pharmaceutical compositions as anti-tussive agents.
Illustrative and preferred among the compounds that have GABA uptake inhibitory activity are the following. ##STR1## which is (R)-1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid. This compound is disclosed in U.S. Pat. No. 4,383,999, as having GABA uptake inhibitory activity. ##STR2## which is (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid and which is disclosed in Anderson et al., J. Med. Chem. 36, (1993) 1716-1725 as having GABA uptake inhibitory activity. ##STR3## which is known as guvacine and which is disclosed in Krogsgaard-Larsen, Molecular & Cellular Biochemistry 31, 105-121 (1980) as having GABA uptake inhibitory activity.
Persons skilled in the art can readily determine if a compound is an inhibitor of GABA uptake by known methods such as those described in U.S. Pat. No. 4,383,999 and Ali, F. E., et al. J. Med. Chem. 1985, 28, 653-660. All such compounds are included within the scope of this invention.
By the term "treating" as used herein is meant prophylactic or therapeutic therapy.
By the term "inhibit GABA uptake" as used herein includes the uptake of GABA by the GABA nerve terminal, glial cells and any GABA cell surface transporter.
Compounds of the invention that inhibit GABA uptake were tested for their ability to inhibit cough in the general assay described in Forsberg, et al., Respiration 59: 72-76 (1992), with the following exceptions. Citric acid was nebulized for only one minute to the animals. Coughs were determined by examination of the flow signal and observation of the test animals.
The following compounds, described in Ali, F. E., et al. J. Med. Chem. 1985, 28, 653-660 as potent inhibitors of GABA uptake, were tested for in vivo potency as anti-tussive agents.
Compound 1--N-(4,4-diphenyl-3-butenyl)-3-pyrrolidineacetic acid [compound (1b) in Ali, F. E., et al. J. Med. Chem. 1985, 28, 653-660].
Compound 2--3-piperidinecarboxylic acid [compound (2a) in Ali, F. E. et al. J. Med. Chem. 1985, 28, 653-660].
Compound 3--(R)-N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid [compound (R)-(2b) in Ali, F. E., et al. J. Med. Chem. 1985, 28, 653-660].
Compound 4--1,2,5,6-tetrahydro-3-pyridinecarboxylic acid [compound (3a) in Ali, F. E., et al. J. Med. Chem. 1985, 28,
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Bondinell William E.
Kotzer Charles J.
Underwood David C.
Dustman Wayne J.
Henley III Raymond
King William T.
Kinzig Charles M.
SmithKline Beecham Corporation
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