Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-09-30
2000-06-06
Berca, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540359, 540360, C07D20509, A61K 31395
Patent
active
060718994
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 atherosclerosis.
Lipoprotein Associated Phospholipase A.sub.2 (Lp-PLA.sub.2) was formerly known Platelet Activating Factor Acetyl Hydrolase (PAF acetyl hydrolase). 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 atherosclerosis, 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 and suggest that it may have potential as a therapuetic protein for regulating pathological inflammatory events.
It has been shown that 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. An 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 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, myocardial infarction, reperfusion injury 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 or C.sub.(1-8) alkyl; cycloalkylC.sub.(1-6) alkyl each of which may be optionally substituted;
Compounds of formula (1) 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.
Suitably, R.sup.1 and R.sup.2 is each selected from hydrogen, methyl or ethyl. Preferably, R.sup.1 and R.sup.2 is each hydrogen or one of R.sup.1 and R.sup.2 is hydrogen and the other of R.sup.1 and R.sup.2 is methyl (to give a trans-methyl). More preferably, R.sup.1 and R.sup.2 is each hydrogen.
Representative examples of R.sup.
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Dhanak Dashyant
Hickey Deirdre Mary Bernadette
Ife Robert John
Leach Colin Andrew
Tew David Graham
Berca Mark L.
Kanagy James M.
Kinzig Charles M.
SmithKline Beecham p.l.c.
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