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Bring Me More Cute Ring Systems

Here’s a paper from the Carreira group at the ETH, in collaboration with Roche, that falls into a category I’ve always enjoyed. I put these under the heading of “Synthetic routes into cute functionalized ring systems”, and you can see my drug-discovery bias showing clearly.
Med-chem people like these kinds of molecules. (I have a few of them drawn here, but all the obvious variations are in the paper, too). They aren’t in all the catalogs (yet), they’re in no one’s screening collection, and they have a particular kind of shape that might not be covered by anything else we already have in our files. There’s no reason why something like this might not be the core of a bunch of useful compounds – small saturated nitrogen heterocycles fused to other rings sure do show up all over the place.
azaspiros
And the purpose of this sort of paper matches a drug discovery person’s worldview exactly: here’s a reasonable way into a large number of good-looking compounds that no one’s ever screened, so go to it. (Here’s an earlier paper from Carreira in the same area). The chemistry involved in making this things is good, solid stuff: it’s not cutting-edge, but it doesn’t have to be. It’s done on a reasonable scale, and it certainly looks like it would work just fine. I can understand why readers from other branches of organic chemistry would skip over a paper like this. No theoretical concerns are addressed in the syntheses, no natural products are produced, no new catalysts are developed, and no new reactions are discovered. But new scaffolds are being made, and for a medicinal chemist, that’s more than enough right there. This is chemistry that does just what it needs to do, quickly, and gets out of the way, and I wouldn’t mind seeing a paper or two like this every time I open up my RSS feeds.

18 comments on “Bring Me More Cute Ring Systems”

  1. molecular architect says:

    Amen!

  2. Overthetop says:

    Agreed. A couple years ago I made scores of azetidine analogs almost identical to these for a project I was on. I couldn’t find any literature on them, so I had to devise all my routes. A nice little paper like this would have saved me a lot of time and effort.

  3. Mike says:

    We (at unnamed pharma co.) have been looking at related spirocyclic compounds ourselves and following Carriera’s work in this area or a while now. I suspect most med chem outfits are doing so too. These are ideal scaffolds to use when operating in crowded IP space.

  4. Flat Ring says:

    Once upon a time, I submitted a manuscript detailing a facile synthesis for a class of functionalized pyrazinones used in one of our med. chem. programs. The paper got rejected because the synthetic chemistry did not provide anything new and exciting to the reviewers. To them it was just a boring old heterocycle made with basic organic chemistry. To our program it was a useful, novel heterocycle with a handle for further elaboration. My guess is my reviewers were academics. We still live with two different worlds of organic synthesis, but I do think we are converging.

  5. Anonymous says:

    “These are ideal scaffolds to use when operating in crowded IP space.”
    …except that their discovery crowds the IP space further!

  6. The Aqueous Layer says:

    I didn’t look, but I wonder if Roche and EC patented the synthetic routes to these intermediates, boxing out the competition from using those particular routes in potential clinical candidates without obtaining a license…
    We’ve looked into ‘different’ looking monomers such as a variety of spirocycles as well. Synthonix has a nice collection of commercial available monomers as well. Depending on the scaffold, we found that some of them can be pretty sensitive to ring opening under the acidic conditions used to form HCl salts.

  7. Anonymous says:

    Anyone else found that azetidines like to open in acidic solution though? So what’s good for IP may not be good for PO…. (that’s one for you DMPK scientists out there)

  8. Anonymous says:

    I, too, like to use these azetidines for SAR studies, and have come to appreciate the growing commercial availability of these molecules. We have also found some of them to be sensitive to acidic conditions. Same can be said for oxetanes…

  9. Bunsen Honeydew says:

    @6: I’ve been following this Carreira/Roche work since it came out and I have to wonder if Synthonix is a start-up created by Carreira and/or Roche. I looked some time ago and couldn’t find anything conclusive.

  10. milkshake says:

    I think Synthonix are an independent CRO.
    I run into stability problems with 3-amino-substituted azetidines. As long as the 3-substituent was a tertiary amine, they were well behaved, both as a free base and bis-hydrochloride. I even distilled them. But 3-(cyclopropylamino)-azetidine polymerized on me as a free base every time

  11. daen says:

    A slight tangent, Derek, but what do you use for your RSS feeds? I was less than chuffed when Google Reader got kicked to the kerb, and I don’t find Feedly to be quite an adequate replacement.

  12. Biotech Chemist says:

    You could try the http://theoldreader.com/ it mimics Google Reader’s format pretty well. It’s servers are a bit slow but still probably the best I’ve found so far.

  13. anonchemist says:

    Maybe useful for fragment based screening? Could “grow” in 3D from the core (as opposed to flat, heteroaromatic fragments).

  14. jm says:

    But should we be using the fruits of prison labor?

  15. efdm says:

    Hey, I worked with these compounds in Carreira’s group during my early years. I was trying to synthesize Thalidomid-derivatives with these oxetanes as ketone-surrogates, but I failed. I guess the synthesis of these compounds got outsourced to a start-up somewhere in the basements of ETH Zurich…

  16. Paul says:

    Speaking of rings…
    1-methyl piperazine (aka N-methyl piperazine), along with 19 other compounds, has been identified as a natural chemical produced by human skin that disables mosquitos’ sense of smell.
    http://www.rsc.org/chemistryworld/2013/09/mosquito-repellents-confuse

  17. daen says:

    @12: Thank you, the Old Reader is much better — I hate the way Feedly refuses to use the whole width of the screen. It’s like reading a newspaper through a zoetrope — very distracting.

  18. Stiv says:

    Personally, I prefer Inoreader to the Old Reader – take a look at it:
    https://www.inoreader.com/

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