Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-11
1999-08-17
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548253, A61K 3141, C07D40504
Patent
active
059394471
DESCRIPTION:
BRIEF SUMMARY
SCOPE OF THE INVENTION
This invention covers certain benzopyran compounds which have activity as leukotriene antagonists and are active metabolites of an anti-asthma drug named pranlukast.
AREA OF THE INVENTION
Substituted benzopyran compound which have activity as leukotriene antagonists are known in the art. For example U.S. Pat. No. 4,780,469 which corresponds to Japanese patent 1741466 and EP patent EP O 173 516-A discloses a class of benzopyrans which are described as antagonists of the leukotrienes, particularly the peptido-leukotrienes LTC.sub.4, LTD.sub.4, and LTE.sub.4. As such, these compounds are useful for treating a host of diseases associated with modification of the metabolic pathway which has these leukotrienes as intermediates. An example of such diseases is asthma.
This invention relates to an benzylhydroxybenzopyran and arylhydroxybenzopyran as illustrated by Formula I and II respectively. ##STR1##
Formula I is named nzopyran.
Formula II is named 5-yl-4H-1-benzopyran.
This invention also relates to an essentially pure preparation of a compound of formula I or II, or a pharmaceutical composition of one and/or the other in combination with a pharmaceutically acceptable excipient. It also relates to a method for manufacturing a medicarnent for treating a disease such as asthma using fornula I or II, or an essentially pure form thereof. These compounds are useful in treating asthma. Hydrates, solvates, tautomeric forms, isomers and polymorphs of these compounds are also included with the scope of this invention.
DETAILED DESCRIPTION OF THE INVENTION
These two compounds may be prepared by synthetic chemistry means or can be obtained by extracting them from biological samples collected from mammals which have been given the compound an (pranlukast). A synthetic process for one of the compounds is given below; the other can be isolated from biological sources as further described below. The compound named in the preceeding sentence can be made by the chemistries set out in U.S. Pat. No. 4,780,469 which corresponds to Japanese patent 1741466 and EP patent EP O 173 516-A.
The benzylic hydroxylation (Formula (I)) of pranlukast appears to be a major route of metabolism in humans. This metabolism results in measurable plasma concentrations in humans. Results from a human radiolabel study suggests that 98.4% of the administered radiolabel is recovered in feces arylhydroxy and benzylhydroxy metabolic pathways appear to be the two major metabolitic routes of pranlukast metabolism in humans and when considering the poor absorption of pranlukast, the quantities of these metabolites measured in feces may represent the total of absorbed and metabolized parent.
In incubations of liver microsomes from rats or mice, the arylhydroxy and benzylhydroxy metabolites are detectable when using high concentrations of pranlukast (50 uM), but hydrolysis of the amide bond in the center of the molecule is the predominant metabolic pathway in these rodent incubations. Liver microsomes from dogs form the arylhydroxy species and only very small amounts of the benzyl species.
The arylhydroxy and benzylhydroxy metabolites are measurable in human plasma, but only limited data are available from the single radiolabelled study. The arylhydroxy metabolite appears to be sulfated in humans but there is no evidence for sulfation of the benzylhydroxy metabolite. From an evaluation of a battery of human liver microsomes, it was evident that some human livers have enhanced activity towards benzylic hydroxylation. It appears that benzylic and aryl hydroxylation are performed by different P450 enzymes but which enzyme(s) is currently not known.
As regards the pharmacological activity of Formula I and II both have been found to be active in assays predictive of utility in treating asthma and other diseases which can be treated by pranlukast.
It will be recognized that both compounds may exist in both racemic and optically active forms. Both forms are to be considered to be within the scope of the present invention.
Pharmaceutically
REFERENCES:
patent: 5596103 (1997-01-01), Johnson et al.
Annan Blanche W.
Gorycki Peter D.
Kuo George Y.
Kanagy James M.
Kinzig Charles M.
Ramsuer Robert W.
SmithKline Beecham Corporation
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