A new class of products in which the phenol group of salicylic acid is linked to alkanoyl moieties bearing nitrooxy functions has been synthesized and studied for their polyvalent actions. The products were stable in acid and neutral media, while they were hydrolyzed in human serum. Their half-lives were dependent upon the structure of alkanoyl moieties. The products showed anti-inflammatory activities similar to aspirin when tested in the carrageenan-induced paw edema assay in the rat. Interestingly, unlike aspirin, they showed reduced or no gastrotoxicity in a lesion model in rats at equimolar doses. A number of them were able to inhibit platelet aggregation induced by collagen in human platelet-rich plasma. All of the products were capable of relaxing rat aortic strips precontracted with phenylephrine in a concentration-dependent manner. Selected members of this new class of nonsteroidal anti-inflammatory drugs might represent possible safer alternatives to aspirin in different clinical settings.

A series of (nitrooxyacyloxy)methyl esters of aspirin were synthesized and evaluated as new NO-donor aspirins. Different amounts of aspirin were released in serum from these products according to the nature of nitrooxyacyloxy moiety present. In the aromatic series, there is a rather good linear correlation between the amount of aspirin released and the potencies of the products in inhibiting platelet aggregation induced by collagen. Both the native compounds and the related nitrooxy-substituted acid metabolites were able to relax rat aorta strips precontracted with phenylephrine, in keeping with a NO-induced activation of the sGC as a mechanism that underlies the vasodilator effect. The products here described are new improved examples of NO-donor aspirins containing nitrooxy groups. They could represent an alternative to the use of aspirin in a variety of clinical applications.

SummaryA new series of water-soluble (R-benzoyloxy) methyl esters of aspirin bearing at the benzoyl ring both alkyl chains containing nitric oxide (NO)-releasing nitrooxy groups and solubilizing moieties, was synthesized, and the products evaluated as true aspirin pro-drugs. Most products are solid substances and all posses good water solubility. They are quite stable in acid solutions (pH=1) and less stable at physiological pH. In human serum they are immediately metabolized by esterases, producing a mixture of aspirin (ASA), salicylic acid (SA), and of the related NO-donor benzoic acids, with other minor products. Due to aspirin release, the pro-drugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. The simple NO-donor benzoic acids 28 and 48, studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum, did not trigger antiaggregatory activity when tested at 300 µM concentration. Only 28 displays quite potent NO-dependent vasodilatatory action. For two selected pro-drugs, 38 and 49, in vivo gastrotoxicity and anti-inflammatory properties are also reported: their anti-inflammatory activities are similar to that of aspirin when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity the two pro-drugs was lower than that of aspirin in a lesion model in rats.

A redetermination of the crystal structure of minodronic acid monohydrate was carried out in order to provide accurate atomic coordinates and geometry information, whose knowledge is fundamental to elucidate the presumed polymorphism of the compound at room temperature.

A very efficient, cost-effective, and easily scalable process for the synthesis of lofexidine hydrochloride (1), an alpha 2-adrenergic receptor agonist used for treating opioid withdrawal is presented. Process development allows the preparation of lofexidine hydrochloride (1) through a one-pot amidation/imidazoline ring formation reaction, starting from ethyl 2-(2,6-dichlorophenoxy)­propionate (13) and ethylenediamine (5) by the action of titanium isopropoxide. The required intermediate ethyl 2-(2,6-dichlorophenoxy)­propionate (13) can efficiently be obtained through O-alkylation of 2,6-dichlorophenol (2) with ethyl 2-chloropropionate (12) using potassium carbonate as an acid-scavenger agent.