The Story of Azithromycin

Izum azitromicina, djelatne tvari makrolidnog antibiotika Sumameda (tržišna marka u Hrvatskoj), pripada me?u najveća dostignuća u hrvatskoj znanstvenoj povijesti. S aspekta komercijalizacije znanstvenih istraživanja vjerojatno je najveće. Ovaj izum ujedno je i velik doprinos znanosti, medicini i poboljšanju kvalitete života na globalnoj razini. Iznimno terapijsko djelovanje učinilo je azitromicin jednim od najuspješnijih antibiotika na svjetskoj razini. Za nastanak azitromicina zaslužni su znanstvenici PLIVINA Istraživačkog instituta - dr. sc. S. Dokić, mr. sc. G. Kobrehel, dr. sc. G. Lazarevski i dr. sc. Z. Tamburašev. Azitromicin je prvi predstavnik nove klase 15-eročlanih makrolida, nazvane azalidi po dušiku uvedenom u eritromicinski prsten. Dobiven je u nekoliko sintetskih koraka: oksimacijom eritromicina A, Beckmannovom pregradnjom dobivena oksima eritromicina A s aromatskim sulfokloridima, zatim redukcijom iminoetera eritromicina A te konačno metiliranjem u eritromicinski prsten uvedenoga dušika. Današnje je uobičajeno kemijsko ime za azitromicin 9-deokso-9a-aza-9a-metil-9a-homoeritromicin A. U ovom je radu, u povodu tridesete godišnjice jugoslavenske patentne prijave za azitromicin, dan pregled istraživanja koja su dovela do izuma azitromicina te radova i patenata koji su ta istraživanja opisali i učinili dostupnima svjetskoj javnosti. Opisani su i pregovori te sklapanje ugovora izme?u PLIVE, farmaceutske tvrtke vlasnika patenta i Pfizera, jedne od vodećih svjetskih farmaceutskih tvrtki, kojoj je PLIVA licencirala izum. Taj prvi i do sada najuspješniji primjer transfera znanja i tehnologije u Hrvatskoj, koji se dogodio još u drugoj polovici prošlog stoljeća, Svjetska organizacija za intelektualno vlasništvo (WIPO) na svojim internetskim stranicama navodi kao dobar primjer komercijalizacije rezultata istraživanja i proaktivne strategije licenciranja.The invention of azithromycin (1, Figure 1), the active pharmaceutical ingredient of the antibiotic Sumamed (Croatian brand name by PLIVA; Zithromax by Pfizer in the USA) belongs among the great achievements in the history of science in Croatia. From the viewpoint of commercialization of research results, it may have been one of the greatest. In addition to contributing to science and to medicine, azithromycin has also brought about an improvement in the quality of life on the global level. Owing to its exceptional therapeutic properties, it has come to be one of the most successful antibiotics worldwide. Marking the 30th anniversary of the azithromycin Yugoslav patent application, this paper gives an overview of the research that led to its discovery and comes with a list of papers and patents through which the drug has been made known to the public (Table 1, Figures 4 and 6). The invention was due to the scientists from the Research Institute of the pharmaceutical company PLIVA in Zagreb, Croatia, D. Sc. S. Đokić, M. Sc. G. Kobrehel, D. Sc. G. Lazarevski, and D. Sc. Z. Tamburašev (Figure 3). Azithromycin became the first representative of the new class of 15-membered macrolides known as azalides after the introduction of nitrogen in the macrocycle of erythromycin A (2, Figure 1). Its synthesis involved several steps (Figure 2): oximation of erithromycin A, Beckmann rearrangement of erythromycin A oxime with aromatic sulphochlorides, reduction of the produced erithromycin A iminoether, and final methylation of the nitrogen introduced in the macrocycle of erythromycin A. Because of inadequate analytical support in the late 1970s and early 1980s, the precise structure of the LD product (Figure 5) in the Beckmann rearrangement step of azithromycin synthesis was confirmed only later as 7 and not 6 as assumed (Figure 5). Today, azithromycin is known under the common chemical name of 9-deoxo-9a-aza-9a-methyl-homoerythromycin A. This paper also deals with the negotiations and signing of a contract between PLIVA, Croatian pharmaceutical company, the patent holder, and Pfizer, one of the world largest pharmaceutical companies in the field of proprietary research. The dihydrate form of azithromycin is also discussed. The azithromycin (i.e. Sumamed and Zithromax) story, which dates from the second half of the last century, can be considered as the first and foremost example of successful knowledge and technology transfer in Croatia ever. On their web pages, the World Intellectual Property Organization (WIPO) reports the PLIVA azithromycin story as a case study and excellent example of proactive licensing strategy. For the discovery of azithromycin, in addition to receiving numerous awards, in the year 2000, PLIVA\u27s scientists D. Sc. S. Đokić and M. Sc. G. Kobrehel, together with the representatives from the US-based Pfizer, were granted the honorable titles of "Heroes of Chemistry 2000" by the American Chemical Society (ACS), a non-profit association of American chemists and chemical engineers, and the largest association of scientists in the world. This high award is rightly taken to be also recognition of the achievement of PLIVA\u27s entire team working on azithromycin. The success of azithromycin has placed PLIVA among the few pharmaceutical companies in the world that have developed their own blockbuster drug, and has entitled Croatia to join a small group of nations that have developed a new antibiotic

Antalarmin

In the mol­ecule of the title compund [systematic name: N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethyl­phen­yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine], C24H34N4, the pyrrolopy­rimidine ring system is nearly planar, its five- and six-membered rings forming a dihedral angle of 5.3 (2)°. The benzene ring is nearly orthogonal to the central ring system. The N atom carrying the ethyl and n-butyl groups is flattened pyramidal