Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-28
1999-09-21
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514369, 514376, 548226, 548227, C07D41712, C07D41714, C07D41312, A61K 31425, A61K 3142, A61K 3144
Patent
active
059556161
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel pyrrolidine derivatives having an activity of inhibiting cytosolic phospholipase A.sub.2, and pharmaceutical compositions for inhibiting the cytosolic phospholipase A.sub.2 which contain a novel pyrrolidine derivative as an active ingredient.
BACKGROUND ART
Phospholipase A.sub.2 (PLA.sub.2) is a protein capable of specifically hydrolyzing 2-acyl ester bond(s) of phospholipids, and includes cytosolic PLA.sub.2 (cPLA.sub.2) and secretory type PLA.sub.2 (sPLA.sub.2) which are clearly distinguishable.
It is known that cPLA.sub.2 can selectively hydrolyze phospholipids containing arachidonic acid which is esterified at the 2-position. Accordingly, the prevention of cPLA.sub.2 activity would inhibit the release of arachidonic acid from phospholipids. Arachidonic acid is a precursor of prostaglandins and leukotrienes, which are biological substances known to be participating in the onset of inflammation. These inflammatory substances are produced through a series of processes so called "arachidonate cascade". Therefore, the inhibition of the release of arachidonic acid would suppress the activity of various substances involved in inflammation and is useful in the prevention or treatment of inflammatory diseases. Examples of such disease include rheumatoid arthritis, asthma, inflammatory bowel disease, injury due to ischemic reperfusion, allergic rhinitis, and psoriasis.
However, there have not been provided any substances which have highly specific activity of inhibiting cPLA2 and are clinically applicable. It has been disclosed that compounds having phenoxy group between thiazolidione and pyrrolidine rings, which pyrrolidine ring is substituted at the N-atom with benzoxazole, etc., are effective on non-insulin dependent diabetes, or the like. See, Japanese Patent Publication (KOKAI) No. 213913/1993 corresponding to France Patent Application, Priority Claiming No. 9110430, Priority date: Aug. 20, 1991. However, there is no description about compounds having phospholipase A.sub.2 inhibitory activity in the said literature.
DISCLOSURE OF INVENTION
The present inventors have intensively studied for developing specific cPLA.sub.2 inhibitors and found that certain kinds of novel pyrrolidine derivatives, especially those having partial structure of thiazolidinedione or oxazolidinedione, possess a potent cPLA.sub.2 inhibitory activity. Thus, the present invention provides a compound of the formula I: ##STR2## wherein A and B are independently O or S; E is O or S; X.sub.1 is --CO--, --CONH--, --CH.sub.2 NHSO.sub.2 --, --CH.sub.2 NHCO--, --CH.sub.2 NHCS--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 OCH.sub.2 --, alkylene, alkenylene or a single bond; X.sub.2 is optionally substituted arylene, optionally substituted indol-diyl or a single bond; D is hydrogen or hydroxyalkyl; Y.sub.1 is --(CH.sub.2).sub.m CO--, --(CH.sub.2).sub.n NHCO--, --(CH.sub.2).sub.n NHSO.sub.2 --, --(CH.sub.2).sub.m CONH--, --(CH.sub.2).sub.m CSNH--, --(CH.sub.2).sub.m SO.sub.2 --, --(CH.sub.2).sub.m COO--, or a single bond; m and n are an integer of 0 to 3; Y.sub.2 is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkenylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclic group or optionally substituted amino; Z is --S--, --SO--, --O--, --NH--, --CONH--, --CONHCH.sub.2 -- or a single bond; R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted aralkyl, or a pharmaceutically acceptable salt or a hydrate thereof, provided that when X.sub.1 is --CH.sub.2 O--, Y.sub.1 is not a single bond; Y.sub.1 binds to the pyrrolidine ring at 1- or 2-position, X.sub.1 binds to any positions other than the one to which Y.sub.1 binds (provided that when Y.sub.1 is at the 2-position, X.sub.1 binds to the 1-position), and Z binds to any o
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Kato Toshiyuki
Ohtani Mitsuaki
Seno Kaoru
Watanabe Fumihiko
Higel Floyd D.
Shionogi & Co. Ltd.
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