Aspirin prodrugs

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... 

N. M. Nielsen, H. Bundgaard, Evaluation of Glycolamide Esters and Various Other Esters of Aspirin as True Aspirin Prodrugs , J. Med. Chem. 1989, 32, 727-734. 

H. Bundgaard, N. M. Nielsen, A. Buur, Aspirin Prodrugs Synthesis and Hydrolysis of 2-Acetoxybenzoate Esters of Various V-(Hydroxyalkyl)amides , Int. J. Pharm. 1988, 44, 151-158. 

A new class of compounds, 2-alkylidenebenzo-l,3-dioxin-4-ones 237, was synthesized <2001TL5231> for which the members act as a prodrug for aspirin and have proved to be useful intermediates in the synthesis of a completely new class of aspirin prodrugs. 

One of the first prodrugs, aspirin, is cleaved to the active agent, salcylic acid, in the liver as well as various other tissues. Despite the advent of numerous newer agents for the alleviation of the pain and inflammation characteristic of inflammatory diseases, aspirin remains the most widely used drug for this 108... 

The chemistry of 1,3-dioxins containing four double bonds is poorly developed. A few examples of nucleophilic additions have been demonstrated. The proton-catalyzed addition of alcohol or carboxylic acid nucleophiles to anhydro derivatives of acetylsalicylic acid - new prodrugs of aspirin - was reported to give the C-2 O-substituted 1,3-dioxanes in 41-60% yield (Equation 19) <2001TL5231, 2003CRC265>. 

Prodrugs are drug substances that are biotransformed in the body to active metabolites and chemotherapeutic agents. Examples include sulfasalazine to sul-fapyridine, phenylbutazone to oxy-phenbutazone, aspirin to salicylate, and heta-cillin to ampicillin. In some cases, such as aspirin (ester) and hetacillin (amide), hydrolysis in water releases the active drug moiety contained within the basic structure of the prodrug. 

Preparations from plant materials containing salicylate have been used to treat pain and fever (Stone, 1763) from ancient times into the nineteenth century, when synthetic salicylic acid was synthesized in Germany and used for the same purposes. Acetyl salicylate, aspirin, synthesized as a prodrug for salicylate, was introduced by Bayer in 1899 (Dreser, 1899) and is still widely used to treat pain, fever, and inflammation. In low doses aspirin is also used by many to reduce the incidence of heart attacks by an antithrombotic effect (Antiplatelet Trialists Collaboration, 1994). Eventually, other drugs with therapeutic effects similar to those of aspirin were introduced, including indomethacin, ibuprofen, and naproxen. These... 

Aspirin and sulindac were excluded from the regression. The activity of aspirin was underestimated, probably because of its additional acetylating potential, and sulindac activity was overestimated, which can be explained by its prodrug character. 

Aspirin, one of the most widely used drugs in the United States (estimated annual consumption of 10-20 thousand tons), also has a prodrug background. The antifebrile... 

Figure 2.1 Acetylsalicylic acid 1 (Aspirin , Bayer) is much more than a prodrug of salicylic acid. Its major contribution to biological activity comes from a unique mechanism of action the activated acetyl group is transferred to a serine hydroxyl group in the binding site of cyclooxygenase. Merbaphen 2 (Novasurol , Bayer) was the first example of an organomercurial diuretic some analogs with less severe side effects were the therapeutic standard from about 1920 to 1950.

Codeine is usually administered in combination with acetaminophen or aspirin (Table 7-7). A prodrug, codeine depends on the cytochrome P-450 system for metabolism to the active compound, morphine. Patients deficient in cytochrome P-450 (up to 10% of whites) receive less analgesic efficacy. Analgesic effects of codeine occur as early as 20 minutes after oral ingestion and reach a maximum after 60 to 120 minutes. Because the potential for addiction is extremely low when used in recommended doses for treatment of acute ocular pain, codeine has gained... 

Oral administration of aspirin can result in gastrointestinal bleeding. The bleeding has been attributed to local irritation due to the acidic nature of the carboxylic acid substituent. In an attempt to reduce the gastric irritation of aspirin, acylal prodrugs were synthesized. In vitro, the prodrugs generated rapidly aspirin and in a... 

H) with water and hence behaves as a prodrug for aspirin, reaction with alcohols and carboxylic acids results in addition to the methylene function (Scheme 48) <01TL523I>. 

An attempt is made to synthesise a polymer that will act as a controlled delivery device in targeting specific areas, such as the colon, over an extended period of time. The polymers being synthesised, polyanhydride esters, are composed of alkyl chains linked by ester bonds to aromatic moieties, specifically salicylic acid - the active component of aspirin. With the medicinal properties attributed to salicyclic acid and the ease of metabolism, the incorporation of this compound into a polymer backbone yields a polymeric prodrug that may have potential in a variety of applications, in particular, inflammatory bowel disease. For these reasons, a synthetic scheme that yields the desired polyanhydride esters is designed. Characterisation of the polymers is performed and presented along with preliminary in vitro and possible... 

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