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REALLY the best MXE replacement

i did check and as far as I can tell, nobody ever patented or produced a paper that is the ethoxy homologue of MXE, CMXE or related. Someone DID make the meta-ethoxy derivative of PCP though, but only as a reference standard. They did NOT make the ortho or para ethoxy....

So maybe their IS some paper, unreferenced, in which meta-ethoxy PCP was considered, but nobody ever made it.

I would certainly like to know the biosteric minimum of the NMDA receptor.
 
BTW finally I've found the patent based on the paper in European Journal of Medicinal Chemistry paper that REALLY did a good job on detailing swapping the cyclohexyl moiety for a 4-thiane and the stereochemistry of derivatives that place a methyl side-chain at the spot where ketamine & MXE place the ketone moiety. It really explores the QSAR. Nor DAT data, sadly.

US6342511B1

Phencyclidine derivatives, preparation method and pharmaceutical compositions containing same.

I think it's important to remember that some of there replace the ketone moiety seen in of ketamine & MXE with a chiral methyl group. I've already mentioned that the cyclohexane can be replaced by a 4-thiane. MOST laws based on Markush structural definitions require a cyclohexyl. For that reason, I'm pretty sure that the thiane analogues of K & MXE would be the best targets to go for... You are changing the molecule the least you can so less chance of a nasty shock.

That said, I cannot find any examples of these whereas the 2-chloro-5-methoxy derivative of MXE (or MXM i.e. the methylamine homologue) are known, Anyone interested might be able to use the names in the patents to find papers that give some sort of explanation of why they issued a patent that covers so FEW novel compounds. I maintain that they found distinct clinical advantages over ketamine, thought they might have 'the next big thing' and secured their intellectual property rights. I COULD be utterly wrong but I've seen lots of patents and by that ear, most covered every damned homologue they could make.

Like why always -Cl? Not -F, --Br, -I or a pseudohalogen. I did post a decent reference that shows why the -Cl is the best option (I think) but it's open to some interpretation.
 
Relpacing Cl with trifluoromethyl gives some interesting compounds. Trifluoromethyl is about the same size (van der Waal radius, but more electronegative)
 
Ah - the -F & -CF3 are both known but the duration is supposed to be much (x2-x3) longer from reports. I guess since all the patents refer to possible medicines, the designers concluded that a K replacement would want a similar duration.

BTW I checked and nowhere is MXE referenced in any patent or paper. Did you actually do that so it was possible to patent? It may seem a small thing, but I was pretty impressed.
 
MXE is mentioned in loads of peer reviewed journal papers. The fact that it's also a UN controlled narcotic, doesn't bode well for it to be takrn up as a pharmacutical medicine. I did notice though, that the S-isomer of ketaminewas patented as a new drug, so why not methoxetamine.

BTW, the ketone group on the cyclohexyl ring was (I think) to give a metabolic tag, for enzymes to latch onto and reduce it's half life (why PCPhas a fucking long half life). Adding a chiral methyl group isn't polar enough to reduce the half life. Now a chiral hydroxyl group ismuch more what's required (or even a chiral methoxy group, for a bit longer half life. Quite certain changing the methoxycarbonyl of methylphenidate to a methoxy or even a plain carbonyl would increase the halflife.
 
Oh I didn't think that a chiral -CH3 was a practical replacement. I was noting that such a different substitution worked and indeed had a higher affinity. Was MXE a UN controlled narcotic BEFORE you decided it was the next K analogue to go for?

I know you are no fan of PCP. You mentioned it's long duration and the fact that it was too stimulating. I concluded that the 3 key elements for a 'euphoric' compound of that class was the NMDA/DAT ratio and the rate of dynamic change of concentration and metabolism (to active metabolite & for elimination).

I mean, if you ever extracted methadone freebase from juice and vaped it, you would notice that it produces an utterly different experience.
 
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