BME has also contributed to the most successful Hungarian medicine

September marked 10 years since Richter's anti-schizophrenia drug, cariprazine, was approved by the U.S. Food and Drug Administration (FDA), marking the start of a success story for the first wholly domestically developed and internationally recognised original medicine in decades. Marketed in the U.S. as Vraylar® and in Europe as Reagila®, the product, which now generates more than $3 billion in annual revenues worldwide, is well known, but less so that an important episode in its development took place at BME. László Hegedűs, associate professor with habilitation at the Faculty of Chemical Technology and Biotechnology explained how he contributed to the creation of a product that he only learned about years later.

"I had nothing to do with the discovery of the molecule itself, it was entirely the work of the researchers at Richter," the head of the Department of Organic Chemistry and Technology said at the beginning of the interview. When the company's experts contacted him and his colleagues, cariprazine was not even mentioned. They asked for help to produce an intermediate that could be used in the synthesis of a wide range of active agents related to the nervous system.

The significance of trans-4-aminocyclohexylacetic acid ethyl ester.HCl is that it ensures the proper binding of the active agent molecules to the receptors in the brain, i.e. it is a so-called spacer group. It is a well-known substance, but it has been challenging to produce. 

The original process, described by Soviet researchers, required 150 degrees Celsius and 150 bar of pressure, 

conditions that are extreme in the fine chemical industry and not necessarily easy to achieve even in a large pharmaceutical plant. In addition, you need a skeletal catalyst, called Raney® nickel, which destroys glass-lined equipment.

Of course, Richter could have bought this intermediate on the market, but that would have made the project very expensive. The company has therefore contracted BME so that the researchers find a simpler and cheaper method to achieve at least 95% purity. László Hegedűs and his late mentor, Tibor Máthé, have developed a hydrogenation technology that meets the requirements, and besides the palladium catalyst and hydrogen, it requires practically only water and very mild reaction conditions (50 °C, 4 bar).

"We submitted the research report in 2001, it was accepted, and then nothing substantial happened for a long time. Six years later, they called to discuss the way forward. At first I suddenly didn't know what that was about, I hadn't thought about the project for a long time. The first thing was to clarify who the inventors were and in what proportion," recalled the lecturer of the Faculty of Chemical Technology and Biotechnology. As it turns out, the intermediate is key to the synthesis of cariprazine, 

"like any cog in an expensive watch: a tiny element, but without it, the mechanism doesn't work".

This also shows how complex the process of developing a drug is today - in this case, it required, among others, chemical engineers with specialised knowledge of heterogeneous catalytic hydrogenation, such as László Hegedűs and his team. Once the solution is found, it is of course up to the manufacturer to scale it up and produce hundreds of kilograms of material under industrial conditions instead of just a few grams.

An interesting sidelight to the story is that the new technology has been criticised by many people precisely because it is very simple, and therefore seemingly not innovative. But the simple answer had to be found, and no one had ever been able to do it before, so the process was granted patent protection in 2014, first in Europe and then in many other parts of the world (e.g. the U.S., Canada, Japan, China). Nobody has come up with a better one since then.

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