Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-07-10
1992-03-24
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514490, 514849, 546133, 546 63, A01N 9342
Patent
active
050989090
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a method of treatment of cough and/or bronchoconstriction in mammals, including humans, and to the use of compounds in the preparation of a medicament for the treatment of cough and/or bronchoconstriction.
GB 2125398A, EP-A-200444, EP-A-247266, EP-A-235878, EP-A-67770, EP-A-158265, EP-A-158532 and EP-A-254584 disclose classes of compounds which are 5-HT.sub.3 receptor antagonists, useful in the treatment of inter alia migraine, cluster headache and trigeminal neuralgia. GB 2153821A describes a further class of 5HT.sub.3 receptor antagonists.
It has now been discovered that 5HT.sub.3 receptor antagonists, such as certain of the above classes of compounds, are of potential use in the treatment of cough and/or bronchoconstriction, such as that arising as a result of asthma.
Cough is useful when it effectively expels secretions i.e. when it is a productive cough. Dry or unproductive cough has no useful effect. Unproductive cough may arise from effects such as cancer (primary or secondary) affecting sensory nerves in the larynx or larger bronchi, from asthma--especially childhood asthma--and in the early or later stages of coryza. Unproductive cough may also occur due to infiltration of the cough centre in the brain by tumour. Cough may also occur without known cause.
Treatment of cough by drugs is unsatisfactory.
Peripheral stimulation of sensory nerves in the larynx (which can cause cough) can be blocked by local anaesthetics such as lignocaine, but the only effective form of therapy for dry and painful cough used clinically is provided by the opiates (morphine, codiene, and methadone etc.).
Accordingly, the present invention provides a method of treatment of cough and/or bronchoconstriction in mammals, including humans, which method comprises the administration to the mammal in need of such treatment, an effective amount of a 5-HT.sub.3 receptor antagonist, such as a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof:
X is a group of formula (a), (b), (c), (d) or (e): ##STR1## wherein
R.sub.a to R.sub.d are selected from hydrogen, halogen or hydroxy;
R.sub.1 is hydrogen and R.sub.2 is hydrogen or C.sub.1-4 alkyl; or
R.sub.1 and R.sub.2 together are a bond;
R.sub.3 to R.sub.7 are independently hydrogen or C.sub.1-6 alkyl; and
R.sub.4 together with R.sub.2 may be C.sub.2-7 polymethylene when R.sub.1 is hydrogen;
either R.sub.8 is C.sub.1-6 alkoxy;
R.sub.9 is hydrogen;
R.sub.10 is amino or C.sub.1-7 alkanoylamino; and
R.sub.11 is halo or C.sub.1-6 alkylthio; or
R.sub.8 is hydrogen;
R.sub.9 is halo, C.sub.1-6 alkoxy or C.sub.1-6 alkyl;
R.sub.10 is hydrogen or C.sub.1-6 alkoxy; and
R.sub.11 is halo, C.sub.1-6 alkoxy or C.sub.1-6 alkyl;
L is CH or N;
Y is NH or O, with the proviso that Y is NH when X is (e) and R.sub.8 is C.sub.1-6 alkoxy;
Z is a group of formula (f), (g) or (h): ##STR2## wherein
n is 2 or 3;
p and q are independently 1 to 3; and
R.sub.12 or R.sub.13 is methyl or ethyl; a group of formula (d) or (e); ##STR3## wherein
R.sub.12 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 alkenyl, phenyl or phenyl-C.sub.1-3 alkyl; and
one of the groups represented by R.sub.13, R.sub.14 and R.sub.15 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.2-6 alkenyl or phenyl-C.sub.1-3 alkyl and each of the other groups, which may be the same or different, is hydrogen or C.sub.1-6 alkyl.
In formula (I):
Examples of moieties in alkyl or alkyl containing groups in R.sub.1 to R.sub.11 include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.
Suitable examples of R.sub.2 and R.sub.4 when joined include C.sub.2, C.sub.3, C.sub.4, C.sub.5 or C.sub.6 polymethylene, preferably C.sub.2, C.sub.3, C.sub.4 or C.sub.5 polymethylene.
R.sub.a to R.sub.d are preferably selected from hydrogen, fluoro, chloro and hydroxy, most preferably hydrogen. R.sub.b may be 5-, 6- or 7-chloro or fluoro.
When X is of sub-formula (a), R.sub.1 and R.sub.3 are preferably both hydrogen and one or both of R.sub.2 and R.sub.4 (most preferably both)
REFERENCES:
Chemical Abstracts, vol. 109, p. 696, 1988, 1902422.
Br. J. Pharmacol., vol. 87, No. 2, Feb. 1986, The Macmillan Press Ltd.; H. E. Connor et al.: "5-carboxamidotryptamine is a selective agonist at 5-hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats", pp. 417-426, see the abstract.
J. Physiol. (London), vol. 365, 1985 (GB), D. J. Armstrong et al.: "MDL 72222 (a 5-HT abtagonist) antagonizes the pulmonary depressor and respiratory chemoreflexes evoked by phenylbiguanide in anaesthetized rabbits", p. 104P.
Chest, vol. 92, No. 5, Nov. 1987, M. Cazzola et al.: "Ketanserin, a new blocking agent of serotonin S.sub.2 -receptors. Respiratory functional effects in chronic obstruction of the airways", pp. 863-866, see the abstract.
Allgemeine und Spezielle Pharmakologie und Toxikologie, 3rd edition, Bibliographisches Institut, Mannheim (DE), 1980, p. 151.
Beecham Group p.l.c.
Carr Deborah D.
Dees Jos,e G.
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