Compounds and inhibitors of phospholipases

#This application takes priority from PCT Application PCT/AU01/00898, filed 24 Jul. 2001, which takes priority from Australian Patent Application PQ8965/00, filed 24 Jul. 2000 and Australian Patent Application PR1669/00, filed 24 Nov. 2000.

#The present invention relates generally to new inhibitors of secretory phospholipases A2 and to methods of making them. The invention discloses compounds that all bear a common chiral carbon atom attached to three different substititents that, in combination, provide (a) a calcium-binding chelating domain and (b) a hydrogen-bonding donor for the catalytic histidine of the enzyme (e.g. His48 in type IIa secretory phospholipase A2), and (c) from one to three hydrophobic moieties that occupy the substrate-biniding active site of the enzyme. In particular compounds of this invention have the same absolute configuration at their common chiral carbon atom. Many, though not all, of the compounds described can be derived simply from chiral precursors such as L- and/or D-amino acids, including uncommon and lipidic amino acids. Alternative synthetic methods can employ precursors that are not amino acids. Compounds of this invention can be used in the treatment of inflammatory diseases.

#Human non-pancreatic secretory phospholipases A2 (sPLA2) are enzymes of 14 kD in size that effect ester hydrolysis of phospholipids at the sn-2 (or 2-acyl) position of 3-sn-phosphoglycerides to release a lysophospholipid and a fatty acid (ruzanski, W., et al, Immunology Today, 1991, 12, 143-146; Dennis, E. A., Trends Biochem., Sci., 1997, 22, 1-2; Murakami, M., et al, J. Biol. Chem., 274, 44, 31435-31444 Predominantly, the fatty acid released is arachidonic acid. When arachidonic acid is produced, it may be acted upon by other enzymes, including cyclooxygenases and lipoxygenases and transformed into inflammatory mediators such as platelet activating factor, prostalgandins, thromboxanes, lipoxins, lysophosphatides and leukotrienes (see Pnizanski supra). The presence of elevated levels of sPLA2 enzymes at sites of injury or inflammation has been demonstrated in a wide range of diseases and inflammatory conditions and the levels of enzyme activity have been correlated with the severity of the pathology (see Pruzanski supra). Compounds that inhibit the activity of sPLA2 might therefore prevent the formation of inflammatory mediators and could potentially alleviate symptoms associated with inflammatory conditions.

#FIG. 1 graphically depicts the extrapolated Dixon plot to give an IC50 value for compounds (62) and (68)

#FIG. 2 depicts structural representations of a number of compounds of the invention.

#The terms “salts”, “derivatives” and “prodrugs” includes any pharmaceutically acceptable salt, ester, hydrate, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof. Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, funaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicyclic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylanmonium. Also, basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

#However, it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts and prodrugs and derivatives can be carried out by methods known in the art. For example, metal salts can be prepared by reaction of a compound of the invention with a metal hydroxide. An acid salt can be prepared by reacting an appropriate acid with a compound of the invention.

#The compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.