Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-05-16
1998-12-15
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514214, 5142245, 5142295, 514279, 540476, 540477, 540577, 540578, 540579, 544 14, 544 56, 544 99, 546 27, 546 28, 546 29, 546 31, 546 34, 546 35, C07D49122, A61K 31475
Patent
active
058497315
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/02791 filed Sep. 26, 1996.
TECHNICAL FIELD
The present invention relates to novel indole derivatives and medical applications thereof.
BACKGROUND ART
Nowadays, opioid receptors are classified into three types, .mu., .delta., and .kappa.. Among these, .delta. opioid receptors have been researched only for a short time, and ligands selective to this receptor, especially alkaloid agonists have not yet been found and developed. Accordingly, .delta. opioid receptors have been lacking in research as compared with the other opioid receptors. Recently, among pharmacological actions relating to .delta. opioid receptors, antitussive action and analgesic action are attracting attentions.
Codeine, which is known as a typical antitussive capable of surely stopping coughing, acts on .mu. opioid receptors while essentially causing severe side effects such as drug dependence, respiratory depression, constipation, and suppression of CNS. There is, therefore, a demand for highly active antitussives which are free from .mu. opioidergic side effects as shown in codeine, and can be safely used. In recent years, although some .kappa. opioid agonists were reported as showing antitussive activity, removal of aversion and psychotomimetic could not be achieved in many cases. Additionally, due to their agonistic properties on the opioid receptors, removal of suppression of CNS is still a problem to be solved. Lately, although some .delta. opioid antagonists were also reported as showing antitussive activity, they required improvement in antitussive activity for practical use.
Meanwhile, .mu. opioid agonists represented by morphine have been used as analgesics. The use of such agonists is, however, allowed only under strict management in view of the above-mentioned side effects. Further, in .kappa. agonists, the above-mentioned side effects, i.e. aversion and psychotomimetic are also problems to be solved. Moreover, no alkaloid .delta. agonist has yet been developed, and its potential as an analgesic has not yet been clarified.
DISCLOSURE OF INVENTION
Accordingly, the object of the present invention is to provide .delta. opioid ligands (agonists and antagonists) which have a novel chemical structure, can be used as antitussives and analgesics, and are free from the above-described severe side effects such as drug dependence, respiratory depression, constipation, and suppression of CNS.
The Inventors earnestly conducted research to obtain the above-mentioned ideal .delta. ligands, and found that indole derivatives represented by the following general formula (I) and pharmacologically acceptable acid addition salts thereof exhibit strong antitussive or analgesic activities as .delta. ligands. ##STR2## atoms, a cycloalkylalkyl having 4 to 7 carbon atoms, a cycloalkenylalkyl having 5 to 7 carbon atoms, an aryl having 6 to 12 carbon atoms, an aralkyl having 7 to 13 carbon atoms (herein, "aralkyl" stands for "arylalkyl" and "arylalkenyl"), an alkenyl having 3 to 7 carbon atoms, a furan-2-yl-alkyl (herein, the alkyl has 1 to 5 carbon atoms), or a thiophene-2-yl-alkyl (herein, the alkyl has 1 to 5 carbon atoms); alkanoyloxy having 1 to 5 carbon atoms; alkanoyloxy having 1 to 5 carbon atoms, or an aralkyloxy having 7 to 13 carbon atoms; one of the carbon atoms may be replaced with a nitrogen atom, an oxygen atom, or a sulfur atom); chloro, bromo, iodo, nitro, an alkyl having 1 to 5 carbon atoms, an alkoxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, phenyl, a hydroxyalkyl having 1 to 3 carbon atoms, isothiocyanato, SR.sup.6, SOR.sup.6, SO.sub.2 R.sup.6, (CH.sub.2).sub.p OR.sup.6, (CH.sub.2).sub.p CO.sub.2 R.sup.6, SO.sub.2 NR.sup.7 R.sup.8, CONR.sup.7 R.sup.8, (CH.sub.2).sub.p NR.sup.7 R.sup.8, or (CH.sub.2).sub.p N(R.sup.7)COR.sup.8 (wherein p is an integer from 0 to 5; R.sup.6 is an alkyl having 1 to 5 carbon atoms; each of R.sup.7 and R.sup.8 is individually hydrogen, an alkyl having 1 to 5 carbon atoms, or a cycloalkylalkyl having 4 to 7 carbon atoms; and among the ab
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Endo Takashi
Kawai Koji
Maeda Masayuki
Nagase Hiroshi
Sakami Satoshi
Rao Deepak R.
Shah Mukund J.
Toray Industries Inc.
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