Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-13
1999-08-31
Mach, D. Margaret M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546176, C07D21512, A61K 3147
Patent
active
059454334
DESCRIPTION:
BRIEF SUMMARY
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 antagonize the effects of leukotrienes. (1990) 645.
International patent application No. PCT/DK93/00254 (Publication No. WO94/03431) describes a series of quinolyl substituted N-phenyl substituted isoserines with leukotriene antagonistic activity.
Now we have surprisingly found that novel diol containing compounds according to general formula I are very potent antagonists, especially in the presence of human serum albumin, and with superior bioavailability and prolonged activity in vivo.
The present compounds have the general formula I ##STR2##
R.sub.1 is hydrogen or halogen, preferably fluorine or chlorine, and m is 0, 1 or 2;
The compounds described herein contain more centres of asymmetry and may thus give rise to stereoisomers. The present invention is meant to comprise all such possible stereoisomers as well as their racemic and stereo-chemical mixtures.
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.
5-Lipoxygenase inhibitors and leukotriene antagonists are of potential interest in the therapy of asthma, allergy, rheumatoid arthritis, spondylo-arthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, such as psoriasis and atopic dermatitis, chronic inflammatory bowel disease, and other inflammatory conditions, vasospasm associated with angina pectoris, pulmonary hypertension, cystic fibrosis, the adult respiratory distress syndrome, ischemic and reperfusion injury, migraine headache, etc..sup.2. The identification of specific 5-lipoxygenase inhibitors and leukotriene antagonists is thus a novel approach with very wide implications for the treatment of a diversity of clinical disorders. (1984) 79.
Leukotriene antagonists may be identified by observing the contractions elicited in preparations of guinea-pig ileum strips suspended in a physiological buffer by addition of pure leukotriene D.sub.4 (LTD.sub.4).sup.3. When the compounds of the present invention were added to the ileum preparation before addition of LTD.sub.4 a significant inhibition occurred of the specific LTD.sub.4 - induced contraction. This inhibition occurred at concentrations as low as 0.1-1 nM. On the other hand, contractions induced with histamine at 10.sup.-7 M were not inhibited by these compounds even at micromolar concentrations. butted.rgaard-Nielsen, European J. Pharmacol. 155 (1988) 1-17.
It is of importance to investigate the receptor binding properties of leukotriene antagonists in relation to their inhibition of smooth muscle contraction. Receptor binding studies may be performed with guinea-pig lung membranes in a direct competition assay between a leukotrien receptor.sup.3,4. A pIC.sub.50 value is determined as the negative H!LTD.sub.4 binding by 50%. The pIC.sub.50 values for the compounds of the present invention are equal to or higher than those for the reference compound SR3040.sup.5 (see Table I) Weichman, C. M. Kinzig, J. G. Gleason and S. T. Crooke, J. Pharmacol. Exp. Ther. 234 (1985) 316. 94/03431), Example 18.
TABLE I ______________________
REFERENCES:
Lewis et al, New Eng. J. Med., 323 (1990), pp. 645-655.
Goetzl et al, J. Clin. Immunol., 4 (1984), pp. 79-84.
Kirstein Dorte
Rachlin Schneur
Leo Pharmaceutical Products Ltd. A/S
M. Mach D. Margaret
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