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  • N&PD Moderators: Skorpio | someguyontheinternet

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.
 
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.
 

I just wanted to highlight Scheme 4 & Scheme 5 in the above paper. It strikes me that they are general enough for people to test various aromatic ring substitutions and monoamine substituents.

I may be wrong but it seems that as long as all water is abstracted in the workup of the reaction of Scheme 4, the product could be used directly in Scheme 5 making it a one-pot process. I am somewhat surprised that they only state a yield of 91% in Scheme 4.

Assuming one can access the homologues of the intermediate used in Scheme 4 (such as swapping the o-chlorobenzene with 2-chloro-5-methoxybenzene) and that imine formation will work equally well with ethylamine, those two changes would result in the compound referenced earlier in this thread. I suggest that the name @fastandbulbous suggested, CMXE seems a good option. It's compact, describes it's relation to MXE and cannot be confused with any other RC.

As the person posted, the way Parke Davis & Company (headquartered in the US) sought and obtained a GB patent rather than a US patent IS somewhat unexplained. Sadly too much time has passed for there to be anyone likely to know who is contactable. It's one of those odd little things that do turn up from time to time.

FYI in 2022 77 metric tonnes of ketamine were produced and in bulk (>10Kg), the prices ranged from $350-$500/Kg. The price has tumbled over the years because their are chemists whose entire business model is to find the cheapest route to a specific target and to patent that route. Then, any large scale manufacturer who wishes to use the improved route has to pay a royalty.


But bear in mind that ketamine has a chiral centre and that the subjective effects of (S) ketamine and (R) ketamine are totally different. The few people I know who have sampled pure (R) ketamine declare it's effects to be somewhat similar to cocaine.

WO2020212510A1 - Synthetic methods of preparing esketamine - Google Patents

The present invention is directed to methods for the asymmetric synthesis of esketamine. The present invention is further directed to key intermediates in the asymmetric esketamine synthesis. In one embodiment, the invention is an asymmetric synthesis of esketamine comprising the conversion of...
patents.google.com
Now esketamine will eventually go through that same synthetic optimization. At the moment esketamine appears to be a much more expensive medicine likely because it is still under patent. No competition and so why invest on optimization when patients will pay the high 'ticker price'.

Certainly I was unable to find ANY information on the bulk API trading of the drug. It's almost certain that chemists will be quietly working on more facile routes to esketamine. The sample I happened upon was produced via fractional crystallization and may have not met the EE required of the medical product and I didn't ask how efficient the separation was. When only a small sample is required, techniques unsuited to scaling may be employed.

Of the patents I read, none of them were really suited to scaling.


<EDIT>FYI the BNF price for esketamine50mg/2mL injectable ampoules £26.31 (hospitals only). BNF price for ketamine 100mg/2mL £14.31 i.e. as an adjunct to general anesthesia. an equipotent dose formulation of esketamine costs twice as much as racemic ketamine. If anyone has bulk pricing data, I would love to know</EDIT>
 
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Yes.

A closer look at all the routes to >98% EE esketamine appear to be quite inefficient. The patent holder is, to nobody's surprise, Parke Davis & Company and ad best as I can make out, it takes 3-4 partial crystallizations to produce >98% EE esketamine.

Of course, who knows what manufacturers do with the waste (R) ketamine. I have read posts in which people mention an unspecified cocaine-like drug with a duration that would match (R) ketamine but no proof.

But IF someone is just throwing it away, someone will push it as a cheap new synthesis (likely with bladder damage). I don't like cocaine or substances with similar activity but at the moment, if esketamine is produced from the racemic product, there may end up with TONS of 'waste' and someone will work it out.
 
As for my mental health, dissos (ketamine included) are super disruptive. But that is just me.
 
Rectify said:
As for my mental health, dissos (ketamine included) are super disruptive. But that is just me.
Click to expand...

They are certainly a class deserving of respect. Last Saturday I was discussing K with a friend who noted that above 600mg in a day, they suffered a significant hangover. Now I'm someone who will stop after one line but my friend mentioned that he had been witness to people who were regularly consuming multiple grams per day. Tolerance apparently being the issue.

It's also a concern that many vendors appear to not have a firm grasp of the QSAR of the class and quite a few unexpected and not very active analogues have turned up.

As @fastandbulbous noted, while CMXE is recorded as being highly active (in animal models at least), it does require a costly precursor. So I've come to the conclusion that in spite of the huge potential profits, low production cost is still more important than producing the best agent.

The irony is that isophenidine is dirt cheap but since it's chemically unrelated to K, it may be that customers would not accept it.
 
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