Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-07-22
2000-11-14
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548183, A61K 31426, C07D41712
Patent
active
061471003
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel pyrrolidine derivatives having activity of inhibiting cytosolic phospholipase A.sub.2, and the pharmaceutical composition for inhibiting the cytosolic phospholipase A.sub.2 which contains a novel pyrrolidine derivative as an active ingredient.
BACKGROUND ART
Phospholipase A.sub.2 (PLA.sub.2) is a protein capable of specifically hydrolyzing the ester bond at the sn-2-position of phospholipids, and includes cytosolic PLA.sub.2 (cPLA.sub.2) and secretory type PLA.sub.2 (sPLA.sub.2) which are clearly distinguishable from each other. It is known that cPLA.sub.2 can selectively hydrolyze phospholipids which is esterified with arachidonic acid 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 leulotrienes which are endobiotic substances known to be participating in the onset of inflammation. These inflammation inducers are produced through a series of processes, so called, "arachidonate cascade". Therefore, it is assumed that the inhibition of the release of arachidonic acid would suppress the production of various substances involved in inflammation and is useful for the prevention or treatment of inflammatory diseases. Examples of such diseases include rheumatoid arthritis, asthma, inflammatory bowel diseases, injury due to ischemic reperfusion, allergic rhinitis, psoriasis, and the like. The compounds having thiazolidinedion and pyrrolidine rings are disclosed in WO97/41120, WO97/41121, EP-780389-A1, JP 7-138258 (A1), and EP-528734-A1. However, there is no description about the cytosolic phospholipase A.sub.2 inhibitory activity therein. WO97/05135 discloses the cytosolic phospholipase A.sub.2 inhibitor but not compounds of the present invention.
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 possess potent cPLA.sub.2 inhibitory activity. Thus, the present invention provides I) a compound of the formula (I): ##STR2## wherein R.sup.1 is hydrogen atom, lower alkyl, optionally substituted aryl, aryl fused with a non-aromatic hydrocarbon ring or a non-aromatic heterocyclic ring, optionally substituted aralkyl, optionally substituted arylcarbonyl, or optionally substituted heteroaryl; Z is --S--, --SO--, --O--, --OCH.sub.2 --, --CONH--, CONHCH.sub.2 --, --N(R.sup.16)-- (wherein R.sup.16 is hydrogen atom, alkyl, or aralkyl), or a bond; X.sup.1 is --(CH.sub.2).sub.q --CO-- (wherein q is an integer of 0 to 3), --(CH.sub.2).sub.r --CO--N(R.sup.17)-- (wherein R.sup.17 is hydrogen atom or lower alkyl, and r is an integer of 0 to 3), --CH.sub.2 NSO.sub.2 --, --(CH.sub.2).sub.s --N(R.sup.18)--CO-- (wherein R.sup.18 is hydrogen atom or lower alkyl, s is an integer of 0 to 3), --CH.sub.2 NHCOCH.sub.2 O--, --CH.sub.2 N(R.sup.19)COCH.dbd.CH-- (wherein R.sup.19 is hydrogen atom or lower alkyl), --(CH.sub.2 NHCS--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 OCH.sub.2 --, --CH.sub.2 --N(R.sup.20)--CH.sub.2 -- (wherein R.sup.20 is hydrogen atom, lower alkyl, or acyl), alkylene, alkenylene, or a bond; X.sup.2 is optionally substituted arylene, optionally substituted heteroarylene, heterocyclediyl, --C.tbd.C--, or a bond; X.sup.3 is alkylene, alkenylene, or a bond; A, B, and E are each independently oxygen atom or sulfur atom; D is hydrogen atom or hydroxy lower alkyl; Y.sup.1 is --(CH.sub.2).sub.m CO--, --(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--, --(CH.sub.2).sub.n NHCO--, --(CH.sub.2).sub.n NHSO.sub.2 --, or a bond; m is an integer of 0 to 3; n is an integer of 1 to 3; Y.sup.2 is a substituent represented by the formula: ##STR3## wherein R.sup.2 and R.sup.3 are both hydrogen atoms or one is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl, and the other is hydrogen atom or lower alkyl; R.
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Ohtani Mitsuaki
Seno Kaoru
Watanabe Fumihiko
Gerstl Robert
Shionogi & Co. Ltd.
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