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Synthesis of Acetylsalicylic Acid and First Clinical Studies

The Invention of Acetylsalicylic Acid Despite the undoubted benefits of sodium salicylate in the treatment of pain, fever, and inflammatory disorders, there were several problems with the practical handling of the compound. These included an unpleasant sweetish taste and, in particular, irritation ofthe stomach, often associated with nausea and vomiting. Another side effect was hearing

Ailhur Eichengtün (1B67 -1349) Felix HofImann (1B68-1946) Figure 1.1 Arthur Eichengrun and Felix Hoffmann.

Felix Hoffmann (Figure 1.1) was the chemist working on this issue in Eichengriin's group, and it was he who originally worked out a new technology of the acetylation reaction of salicylate (and other natural products such as guaiacole, cinchonine, and morphine). He was the first to produce chemically pure and stable ASA on August 10, 1897, according to his handwritten notes in the laboratory diary (Figure 1.2).

Two other individuals have to be mentioned in this context: Heinrich Dreser, head of the Department of Pharmacology at Bayer, and Carl Duisberg, the then head of the research and later president of the Bayer Company. Dreser was not interested in this kind of research. Initially, he was also not informed by the pharmacists about the successful clinical testing of the new compound, although according to his contract with Bayer, the pharmacists should have had reported this finding to him. He was probably not amused to hear about these results. According to Eichengriin [15] and other sources, he did everything to block the further development of the compound. Duisberg, the key manager in charge, emphatically supported the activities of Eichengriin and Hoffmann. The further development and clinical introduction of aspirin as an antipyretic analgesic, eventually resulting in the worldwide spread of the compound, is his merit. The new drug received the trade name "aspirin," which is composed from "acetic" and "spireic acid," a former name of o-hydroxybenzoic acid (salicylic acid), originally prepared from S. ulmaria, the richest natural source of salicylates.

The first description of the pharmacology of aspirin was published in 1899 by Dreser [16]. The names ofthe inventors Hoffmann and Eichengriin were not mentioned in this paper. Dreser considered aspirin as a better tolerable prodrug of the active principal salicylic acid. This was basically correct even from today's viewpoint for the symptoms the substance was supposed to be used at the time. According to Eichengriin [15], Dreser had nothing to do with the invention. Interestingly, it was neither Eichengriin nor Hoffmann but Dreser who had the financial benefits from the discovery. According to a contract with Bayer, the products invented under the direction of EichengrUn had to be patented in Germany to get a royalty for the inventor from the company [15]. Acetylsalicylic acid was registered on February 1,1899 under the trade name "Aspirin" by the Imperial Patent Bureau (Kaiserliches Patentamt) in Berlin and a few weeks later introduced as a tablet (1 tablet = 5 gr(ain) 325 mg) in Germany. However, the compound did not receive recognition as a substance to be patented in Germany. Aspirin was patented in 1900 exclusively in the United States (Figure 1.3). This patent expired in 1917. In 1918, afterthe World War I ended, Bayer's assets were considered enemy property, confiscated by the US government, and auctioned in the United States the same year [17]. It took Bayer about 80 years to buy back the rights of the trade name "Aspirin."

A recent article raised doubts about Hoffmann as the inventor of aspirin and ascribed this merit to EichengrUn [18]. EichengrUn was Jewish and lost the fruits of his scientific research, including the invention of several other products in addition to aspirin, such as acetate silk, because of political reasons during the Nazi regime after 1933. Eichengrün was interned in 1944 in a concentration camp and remained there until the end of World War II. In 1949, the year of his death, Eichengrün stated in an article, published in the German scientific journal Die Pharmazie, that it was he and Felix Hoffmann who should be considered as the inventors of aspirin. Though Hoffmann was probably the person who designed and did the experiments eventually resulting in pure and chemically stable ASA - additionally evidenced by the (obviously undisputed) sole mention of his name on the patent application in 1900 (Figure 1.3) - one should also ascribe a significant contribution to Eichengruün.

Further Attempts to Make Acetylsalicylic Acid At this point, it should be noted that Hoffmann was not the first person who tried to chemically synthesize ASA. In 1853, Frenchman Charles Frédéric Gerhardt from Straßburg (Alsace) described the synthesis of a new compound from acetyl chloride and sodium salicylate, which he named Salicylate acétique (see Ref. [19]).

Figure 1.2 Laboratory record of Dr Felix Hoffmann for August 10, 1897.

This publication of Gerhardt was used by several authors to ascribe the invention of ASA to him (e.g., [1, 20]). This appears not to be correct for several reasons. His preparation of ASA was impure, due to the insufficient technical procedure used by him [12], and rather a labile, intermediate raw product of the reaction between acetyl chloride (prepared by him by a suboptimal procedure) and sodium salicylate. The chemical structure was not determined. Because of inappropriate processing ofthe raw product, Gerhardt only obtained salicylic acid as a stable end product. He concluded that acetylated salicylic acid is unstable and in water immediately breaks down to salicylic acid and acetate. Both statements are wrong and do not qualify Gerhardt for the claim to have invented the synthesis of ASA [7].

In 1859, H. von Gilm, a pharmacist from Innsbruck (Austria), reported the synthesis of ASA as did Karl Kraut 10 years later in 1869. Again, these preparations were impure - see also comments in the patent application of Hoffmann (Figure 1.3). During the following 20 years, there were apparently no further attempts to improve the synthetic procedure to obtain ASA as a pure, chemically stable compound.

Thus, the origin of ASA, in contrast to the natural product salicylic acid, was exclusively in organic chemistry. From the point of view of an organic chemist, the substance had no obvious practical benefit, and there were definitely no ideas or even concepts about its possible use as a therapeutic agent. Thus, ASA probably would have suffered the fate of several hundreds of chemicals before and many thousands thereafter - a product of chemical synthesis, principally easy to make but more difficult to generate in pure and chemically stable form and without any practical significance. On the contrary, Hoffmann and Eichengriin, combined their knowledge about the chemistry of a natural product with synthetic chemistry with the intention to make a new drug out of it with improved pharmacological properties. These studies would probably not have been done without the support of the Bayer Company. Therefore, the company had good reason to celebrate the 100th anniversary of the compound, which in the meantime became the most popular drug in the world [18].

In this context, an interesting comparison with the discovery of prostacyclin can be made. Its chemical structure and a suggested (later confirmed) enzymatic synthetic pathway were originally described in 1971 by Pace-Asciak and Wolfe. These authors considered this (labile) product as just another prostaglandin, in addition to dozens of already known compounds, which was possibly overlooked by earlier investigators because of its low biological activity. This was tested at that time in bioassay experiments using the rat stomach strip. It also remained uncertain whether the compound was synthesized at all in the intact stomach wall and, if so, was released in biologically active amounts [21].

A completely different approach was followed by the group around Sir John Vane. The group's work on prostacyclin started with the discovery of a biological effect - inhibition of platelet aggregation - of an enzymatic product made from prostaglandin endoperoxides on artery walls. This prostaglandin, originally named PGX, differed in its biological behavior from all other known prostaglandins [22]. PGX was later identified as the already known enzymatic product of prostaglandin endoperoxides, described by Pace-Asciak and Wolfe, and was renamed as prostacyclin (PGI2). Despite the originality and merits of Pace-Asciak and Wolfe regarding the detection of biosynthetic pathways of natural prostacyclin and its chemical structure, the medical history of prostacyclin starts with the work of Vane's group, which was the first to discover the biological significance of prostacyclin for control of hemostasis.

The Introduction of Acetylsalicylic Acid into the Clinics Kurt Witthauer, a specialist in internal medicine in a city hospital (Diakonie Krankenhaus - still existent!) in Halle/Saale (Germany), and Julius Wolgemuth [23] from Berlin published the first clinical investigations on aspirin in 1899. Witthauer began his report as follows:

"... Nowadays, certain courage is necessary to recommend a new drug. Almost every day those are thrown on the market and one has to have an excellent memory to keep all the new names and brands in mind. Many drugs appear, are praised and recommended by companies and certain authors but after a short time have disappeared without any further comments [24]."

The author also did not forget to instruct his readers that he did this study with "not little distrust."

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