Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-21
1999-11-23
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540360, A61K 31395, C07D20509
Patent
active
059901020
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to certain novel monocyclic .beta.-lactam compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of artherosclerosis.
Lipoprotein Associated Phospholipase A.sub.2 (Lp-PLA.sub.2). The sequence of the enzyme, the isolation and purification thereof, isolated nucleic acids encoding the enzyme, recombinant host cells transformed with DNA encoding the enzyme are described in patent application WO 95/00649 (SmithKline Beecham plc). Suggested therapeutic uses for inhibitors of the enzyme included artherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, Apr. 6, 1995, 549) describe the same enzyme, although calling it by the name `Platelet Activating Factor Acetyl Hydrolase` (PAF acetyl hydrolase) and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.
Lp-PLA.sub.2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA.sub.2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA.sub.2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA.sub.2 could therefore prove beneficial in the treatment of this phenomenon. A Lp-PLA.sub.2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
Lp-PLA.sub.2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA. Examples of such disorders include psoriasis.
Lp-PLA.sub.2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA.sub.2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
We have now identified a series of compounds which have been found to act as inhibitors of Lp-PLA.sub.2.
Accordingly, the present invention provides a compound of formula (I): ##STR2## in which: R.sup.1 and R.sup.2, which may be the same or different, is each selected from hydrogen, halogen or optionally substituted C.sub.(1-8) alkyl; substituted;
Compounds of formula (I) are inhibitors of Lp-PLA.sub.2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted above.
Representative examples of R.sup.1 and R.sup.2 include hydrogen
REFERENCES:
Kita et al., Tetrahedron Letters, 36(1) , pp. 115-118 (1995).
Kita et al., Chemical & Pharmaceutical Bulletin, 39(9), pp. 2225-2232 (1991).
Kametani, Chem Abs 109:6266, 1988.
Ihara, Tetrahedron, vol. 38, 2489, 1982.
Dhanak Dashyant
Hickey Deirdre Mary Bernadette
Ife Robert John
Leach Colin Andrew
Tew David Graham
Berch Mark L.
Dustman Wayne J.
King William T.
Kinzig Charles M.
SmithKline Beecham p.l.c.
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