Already available anilines for amide formation

[tscmacdonald]

While we're waiting for our new amines (issue #123), I had a look through the inventory for anilines we already have that may be worth trying. Here's a list, together with clogP values of the final triazolopyrazine (as calculated with chemdraw):

Thoughts on these? I think the 2-methyl-3-chloro aniline might be interesting, as we know the 3-chloro is active. Also, it seems to have a lower clogP than the unmethylated version, which is surprising. Can anyone tell me why? Is this just an artefact of the "c" part of logP? Also of potential interest are the brominated compounds. They're a bit greasier than the chlorinated ones, but not excessively so (I suspect they might be metabolised more quickly, though).

[mattodd]

The top row compounds are interesting. The meta/Me can be compared with what you've already made and the para/N-Me is a good comparison with MMV670246 (inactive) and MMV669105 (active) - see amide section on wiki (http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series). If you can find a reference that says that aromatic bromides are OK as drugs then we can explore the bottom set, but one must ask why we see such structure so rarely?

My offline suggestion of using pyrrolidine was a bad one - been done: MMV669022 (inactive).

[tscmacdonald]

I think I might make the 2-methyl-3-chloro compound, as it'll be an interesting comparison if nothing else (although I suspect the sterics might disrupt whatever the chlorine seems to be binding to). The parachloro N-Me might be worth looking into, but given the inactivity of the parachloro compound I don't know if it's worth bothering with; waiting for N-Me compounds of primary amines we know to work is perhaps more sensible.

I haven't found much information on aromatic bromides as drugs, which seems to confirm that they're generally a bad idea. For the sake of learning if nothing else, can anyone else add to that?

Finally, it occurred to me that this series of aryl chloride amides might cause troubles when we try to couple a hydrazone with with the pyrazine chloride, but not the aryl chloride on the amide linkage: Has this been considered?

[sabinllm]

Bromphenriramine, bromfenac, mebrofenin, flusalan, bromazepam, brimonidine... they all contain aromatic bromides. There's nothing "particularly" wrong about adding a bromine to your molecule, aside from adding MW and logP

[mattodd]

...but beware of the hidden details: from wikipedia: "Bromfenac was formerly marketed in the United States by Wyeth-Ayersthttp://en.wikipedia.org/wiki/Wyeth-Ayerstin an oral formulation called Duract for short-term relief of pain (less than 10 days at a time). It was brought to market in July, 1997, and was withdrawn June 22, 1998 following numerous reports of hepatotoxicityhttp://en.wikipedia.org/wiki/Hepatotoxicityin patients who had taken the medication for longer than the recommended 10-day period. " Can you either spot patterns in such things (do the other Br-containing drugs have similar "asterisks" or find an academic source that says yes/no to aromatic bromides in drugs? 2-methyl-3-chloro - go for it in the meantime. If you start it, remember to create a dedicated Issue with context and tags.

On 11 February 2014 21:47, sabinllm notifications@github.com wrote:

Bromphenriramine, bromfenac, mebrofenin, flusalan, bromazepam, brimonidine... they all contain aromatic bromides. There's nothing "particularly" wrong about adding a bromine to your molecule, aside from adding MW and logP

Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/151#issuecomment-34743306 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

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[alintheopen]

Hey Tom, Nice suggestions. Have a wee think about why one chloride could be more reactive than the other one. ;)

On Tuesday, February 11, 2014, Mat Todd notifications@github.com wrote:

...but beware of the hidden details: from wikipedia: "Bromfenac was formerly marketed in the United States by Wyeth-Ayersthttp://en.wikipedia.org/wiki/Wyeth-Ayerstin an oral formulation called Duract for short-term relief of pain (less than 10 days at a time). It was brought to market in July, 1997, and was withdrawn June 22, 1998 following numerous reports of hepatotoxicityhttp://en.wikipedia.org/wiki/Hepatotoxicityin patients who had taken the medication for longer than the recommended 10-day period. " Can you either spot patterns in such things (do the other Br-containing drugs have similar "asterisks" or find an academic source that says yes/no to aromatic bromides in drugs? 2-methyl-3-chloro - go for it in the meantime. If you start it, remember to create a dedicated Issue with context and tags.

On 11 February 2014 21:47, sabinllm notifications@github.com<javascript:_e(%7B%7D,'cvml','notifications@github.com');> wrote:

Bromphenriramine, bromfenac, mebrofenin, flusalan, bromazepam, brimonidine... they all contain aromatic bromides. There's nothing "particularly" wrong about adding a bromine to your molecule, aside from adding MW and logP

Reply to this email directly or view it on GitHub< https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/151#issuecomment-34743306

.

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.aujavascript:_e(%7B%7D,'cvml','matthew.todd@sydney.edu.au');| W http://sydney.edu.au/science/chemistry/research/todd.html

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments.

Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/151#issuecomment-34744692 .

[tscmacdonald]

...well done, self. So, our desired product is definitely favoured (although I'm not sure how much by; some playing with temperatures might be in order). I think I'll start making the 2-methyl compound tomorrow. Issues going up!

[mattodd]

This analysis is complete, and a link to this issue has been installed in the wiki http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Synthesis_of_the_Amide-Linked_Series so closing.