Isoserine derivatives and their use as leukotriene antagonists

Details Isoserine derivatives and their use as leukotriene antagonists Isoserine derivatives and their use as leukotriene antagonists

1995-01-13

1996-11-19

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546180, C07D21506, C07D21518

Patent

active

055764380

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/DK93/00254, filed 5 Aug. 1993.
The present invention relates to hitherto unknown compounds useful in the human and veterinary therapy, to pharmaceutically acceptable salts thereof, to bioreversible derivatives thereof, to methods for producing said new compounds, to pharmaceutical compositions containing the new compounds, to dosage units of the compositions, and to methods of treating patients using said compositions and dosage units.
Leukotrienes, which are formed via the 5-lipoxygenase pathway of arachidonic acid metabolism, are implicated in a variety of pathophysiologic functions, such as bronchoconstriction, plasma exudation, coronary artery spasm, leukocyte chemotaxis and neutrophil degranulation.sup.1. It is therefore of considerable interest to develop compounds which inhibit 5-lipoxygenases and thereby the production of leukotrienes, or antagonize the effects of leukotrienes.
International patent application No. PCT/DK90/00201 describes a series of quinolyl methoxy substituted N-phenyl substituted isoserine (i.e. 3-amino-2-hydroxypropionic acid) derivatives with good leukotriene antagonistic activity.
Now it has surprisingly turned out that replacement of the --CH.sub.2 O-group with --CH.dbd.CH-- (trans) and concomitant substitution with halogen in the quinoline ring provides compounds with even more potent leukotriene antagonistic activity, especially in the presence of human serum albumin.
The present compounds have the general formula I ##STR1##
Y stands for --CH.dbd.CH--;
R.sub.1 is hydrogen or halogen, preferably fluorine, chlorine or bromine;
R.sub.2 is halogen, preferably fluorine, chlorine or bromine, C.sub.3, OCH.sub.3, NO.sub.2 or CF.sub.3, and n=0-3, preferably 0, 1 or 2;
A stands for an acidic group, e.g. carboxy, 1-H-tetrazolyl or a hydroxamic acid group.
Among the preferred compounds of the invention are those of formula I, in which A stands for a carboxy group.
The compounds described herein contain more centers of asymmetry and may thus give rise to diastereoisomers and optical isomers. The present invention is meant to comprehend such possible diastereoisomers as well as their racemic and resolved optically active forms.
The present salts of the compounds of formula I may be formed with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, and maleic acid.
The present salts of the compounds of formula I may also be formed with pharmaceutically acceptable, inorganic or organic bases. As examples of salts formed with pharmaceutically acceptable, non-toxic bases, mention may be made of alkali metal salts and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts, as well as salts with ammonia and suitable non-toxic amines, such as C.sub.1 -C.sub.6 -alkylamines, e.g. triethylamine, C.sub.1 -C.sub.6 alkanolamines, e.g. diethanolamine or triethanolamine, procaine, cycloalkylamines, e.g. dicyclohexylamine, benzylamines, e.g. N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-.beta.-phenethylamine, N,N'-dibenzylethylenediamine or dibenzylamine, and heterocyclic amines, e.g. morpholine, N-ethylpiperidine and the like.
Even if the present compounds are well absorbed after enteral administration, in some cases it can be advantageous to prepare suitable bioreversible derivatives of compounds of the invention, i.e. to prepare so-called prodrugs, preferably derivatives, the physiochemical properties of which leads to improved solubility at physiological pH and/or absorption of the compound in question.
Such derivatives are for instance esters of N-hydroxymethyl derivatives of compounds of the invention, such compounds being prepared by reaction of a secondary aminefunction of compounds of the invention with formaldehyde.sup.2345 followed by reaction with a suitable acidic compound or activated derivatives of suc

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