Platelet aggregation inhibitors, preparation

Recently, Picciola et al. (81FES1037) prepared some 2iT-indazole derivatives containing a phenylalkanoic acid residue with potential antiinflammatory activity (693). M.G. 18755 (R = CHMeC02H, R = R = R = H) and its lysine salt, M.G. 18334, showed greater activity than ibuprofen, and the homologous butyric acid derivative M.G. 18860 showed good activity as a platelet aggregation inhibitor. 

The patent literature covers many pyridazine derivatives claimed as blood platelet aggregation inhibitors and antithrombotic agents. The interest has been focused mainly on 6-aryl-4,5-dihydro-3(2//)-pyridazinones. In these compounds the aryl substituent has been varied within a wide range. Thus, dihydro-pyridazinones bearing a substituted or heterocycle-fused phenyl group at C-6 (60, R R2,R3 = H, alkyl Ar = substituted Ph) [34, 110-112,205-233] as well as various heteroaryl substituted congeners (61, R1, R2, R3 = H, alkyl Ar = pyridyl, thienyl, pyrrolyl, pyrazolyl) [234-241] have been prepared in search of novel antithrombotics. 

The first published scheme for the preparation of the platelet-aggregation inhibitor ticlopidine describes the alkylation of the thienopyridine (10-1) with 2,a-dichoro-toluene (10-2) to give the ternary salt (10-3). Reaction of that product with sodium borohydride selectively reduces the charged ring to give ticlopidine (10-4) [10]. 

Ozaki and co-workers prepared an extensive series of 5-aryl(heteroaryl)-4-oxazolecarboxylic acid methyl esters 368 (20 compounds) from acylation of methyl isocyanoacetate, followed by in situ cyclization (Scheme 1.100). These compounds were elaborated further and evaluated as blood platelet aggregation inhibitors. 

In the preparation of a platelet aggregation inhibitor 4.71 on a scale of 123.9 kg, both the bromide 4.69a and the iodide 4.69b could be coupled with the piperidine 4.70 in the presence of carbon monoxide to introduce the desired amide linkage (Scheme 4.28). While the bromide 4.69a required somewhat specific conditions for good yields, the carbonylative coupling of the iodide 4.69b did not. 

Watanuki S, KogoY, Moritomo H, Tsukamoto I, Kaga D, OkudaT, Hirayama F, Moritani Y, Takasaki J (2005) Preparation of quinolone derivatives as platelet aggregation inhibitors WO Patent 009971, 3 Feb 2005... 

A neolignan isolated by the Merck group from the plant Piperfutokadsurae, was the first natural product discovered as a potent inhibitor of the binding of [3H ]PAF to rabbit platelet membrane preparation with an IC50 close to 0.1 /iM [268]. Named kadsurenone (26), it was also shown to be a specific and potent inhibitor of PAF-induced rabbit platelet aggregation with an IC50 value of 0.99 juM. 

Several novel diadenosine 5, 5" -P-l,P-4-tetraphosphate (AppppA) analogues (94 95) and an adenosine tetraphosphate analogue (%) have been prepared as competitive inhibitors of ADP-induced platelet aggregation. Among the various analogues, the P-2, P-3-monochloromethylene AppCHClppA was found to be particularly active. 

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