Use of ONS to protect Open Research: the case of the Ugi approach to Praziquantel

As we were collecting reactions from The Synaptic Leap for the Reaction Attempts project, Andrew Lang noticed that there might be a quick synthetic route to praziquantel via a Ugi reaction. I researched it further and found a paper (Kim et al 1998) where Ugi product 1 was indeed converted to racemic praziquantel via the Pictet-Spegler cyclization.


Using Beilstein Crossfire the only synthesis of 1 I found involves a multi-step amidation strategy. But this compound should be accessible in one step from commercially available starting materials via a Ugi reaction (shown above). Since all the starting materials are liquids we have some flexibility with solvent choice. Khalid first tried it in methanol EXP258 a few weeks ago but did not get a precipitate. He was going to monitor it by NMR next to see if the problem was high solubility of the Ugi product or with the reaction itself.

It was therefore with great interest that I read Mat Todd's report this morning on The Synaptic Leap that a German patent had been issued on this Ugi strategy to praziquantel. (TSL didn't provide a means of leaving a comment so I edited the page - which made me the author of that post but actually Mat wrote it)

I have often mentioned during my talks that Open Notebook Science could be used not only in a defensive manner to claim academic priority - but also as an offensive tactic to block patent applications. A company attempting to prevent the commercial exploitation of rival inventions has a few options. Where applicable, it can buy up an existing patent pool with the intention of sitting on it. For new inventions, it can do research and try to file patents before their competitors. But this is a costly process and it may make more sense to simply publish the inventions to create disclosed prior art, thereby blocking patent applications of their competitors.

But - as I and many others have discussed - the current publication system is not optimally suited for the purpose of simply disclosing and communicating science. Not only is it generally slow but the traditional article format requires a narrative of some sort - rarely can single experiments be published. This means that much (if not most) of research done by an individual or group will never be disclosed.

For these reasons I think that keeping an easily discoverable Open Notebook for projects designed to block patent submission by competitors makes a lot of sense - both economically and from a workflow perspective. Since researchers already have to keep a lab notebook, making it public doesn't impose the added time that writing an article or patent will require.

In this specific example of praziquantel we were too late. But if we had recorded this experiment a few years ago it might have worked to block Domling's patent. Now, it isn't clear to me that EXP258 would have been enough to do that. The strategy to make praziquantel via a Ugi reaction was clearly stated but the experiment was not conclusive. However, since Domling reported that methanol worked I am sure that we would have had the "reduced to practice" evidence in the notebook shortly.

Above I used a company as an example of a party motivated to disclose inventions to protect their interests. In our case it would not be a company but rather the entire Open Science community. It is in our best interest to keep our scientific territory as unencumbered by patents as possible. Keeping Open Notebooks might be one of the simplest means of ensuring that.

Consider a humanitarian organization that might want to manufacture praziquantel. I haven't researched it but presumably the Domling patent was filed in a number of countries beside Germany. In order to consider using the Ugi strategy, the organization would now have to deal with the patent holder. This might be the factor that makes this route untenable. Patents have proven to be problematic for humanitarian aid - even in the simple case of providing food.

But all is not lost. In addition to offering a simple 2-step synthesis of praziqantel, the Ugi route offers an easy way to make large libraries of analogs. Optimally we would like to work with someone who has experience with docking praziquantel. It might be interesting to screen not only the praziquantel analogs but also the uncyclized Ugi products themselves. When we did this for malarial enoyl reductase inhibitors (D-EXP005) we found that we did not need to cyclize to obtain compounds predicted to bind. This ultimately led to active compounds.