REALLY the best MXE replacement

[Fertile]

GB Patent 1202834 'NOVEL CYCLOHEXANONE COMPOUNDS AND PROCESS MEANS FOR THE PRODUCTION THEREOF' by Parke Davis (no name of chemist given)

That covers 2-Amino-2-(2-chloro-5-methoxyphenyl)cyclohexan-1-one - Compound 1

 

[izo]

do you have any reason why this is the best mxe replacement? i dont think that this compound is not worthwhile but just wanted to ask. dont think that the o-chloro interferes much during receptor binding with the other phenyl substituent but im not sure of it.

why not simply go for the 3-ethoxy homolog of mxe?

 

[Fertile]

OK well I've gone through about 180 patents just concerning ketamine analogues and 2 things strike me. In all of those patents, only a -Cl or an -OCH3 are at the 2 position. So I figured that their had to be SOMETHING about those 2. Their is, metabolism:

Halogen Substitution Influences Ketamine Metabolism by Cytochrome P450 2B6: In Vitro and Computational Approaches

Ketamine is analgesic at anesthetic and subanesthetic doses, and used recently to treat depression. Biotransformation mediates ketamine effects, influencing both systemic elimination and bioactivation. CYP2B6 is the major catalyst of hepatic ketamine ...

www.ncbi.nlm.nih.gov

Of course the methoxy can be deprotected and gluconated.

Then I noticed the patent I listed. In a patent people will attempt to cover as many analogues as possible to prevent so-called 'me too' drugs. Patents are VERY costly so issuing a patent for a very limited number of compounds only makes sense if you are rushing to ensure that YOU get the patent.

Again, looking through all the patents they tried just about every modification (within the rule I have given) so bridging the cyclohexane and a huge number of different amine substituents were all made & tested and the results are there for anyone willing to put in the effort.

They first tried the 2-chloro-3-methoxy and 2-chloro-3-hydroxy homologues and noted it's ED50 (for anesthesia). Then they performed further studies which lead to the patent I have reverenced with 2-Cl-5-OCH3. So why not take a look at the ED50 of ketamine and the ED50 of this stuff. Oh, and also compare it to the examples in which they placed the chloro next to the methoxy or hydroxy. It shows that the -Cl being para to the -OCH3 produces the highest activity by a large margin.

Nobody had the tools to check affinity or docking for the class at the time. Things like MK-801 came along a generation later. I'm quite prepared to hear about peoples theory as to why it is so potent, but I'm happy to note that the makers considered it worth a patent and the ED50 seems to have been tested in the same manner.

 

[izo]

ok thx.

 

[Fertile]

All I can say is that from VERY early on, only ortho -Cl & -OCH3 were patented. You would expect them to patent others if it would allow a 'me too' drug but they didn't. But then they tested 2-chloro-3-methoxy and it wasn't any good so they tried 2-chloro-5-methoxy and that DID work.

I cannot think myself into the mind of a research chemist but the way that they did everything to ensure patent rights (issuing patent for very limited number of compounds) combined with a known method of HIDING patent rights (getting GB patent but not US patent) shows they intended to make it their next product.

I talked to Dan and he told me that US researchers often didn't have access to Canadian Patents... and NEVER access to GB patents. Why GB? Because it's the same language (give or take). NOBODY could claim in court that a patent existed.... and they couldn't argue over details of a translation.

I know it seems minor, but also consider that the compound I refer to is COMPOUND 1 in the patent. Generally speaking (and especially of that era) one put the most significant compound(s) first.

Nowhere EVER has someone patented the ethoxy. If it was a reasonable substitute, it WOULD have been patented.

Of course, one needs 1-bromo-2-chloro-5-methoxy benzene as a precursor. It isn't cheap. But 2-bromo-1-chloro-4-methoxybenzene isn't used commercially, so the costs of.... well, what IS the product called? You tell me. But it isn't used commercially so it isn't as cheap as the K or MXE precursors.

name hosted at ImgBB

Image name hosted in ImgBB

ibb.co

I'm sure the N-methyl, N-ethyl & N-isopropyl will all work fine. Maybe even replacing the -Cl with a -CF3 would be OK... but the KEY is that 2,5 disubstitution (with the 5 being methoxy) will work.

I'm still surprised that nobody has yet produced simple tiletamine analogues. If they will make deschloroketamine, why not the methyl homologue of tiletamine? Since it's already made commercially, it's going to be the cheapest BY FAR.

 

[izo]

All I can say is that from VERY early on, only ortho -Cl & -OCH3 were patented. You would expect them to patent others if it would allow a 'me too' drug but they didn't. But then they tested 2-chloro-3-methoxy and it wasn't any good so they tried 2-chloro-5-methoxy and that DID work.

yea this is really odd. i know some patents also from parke davis where they also only patented only one compound but the usual way is a patent filled with up to hundreds of compounds ala pfizers patent from where they took ab-fubinaca.

Nowhere EVER has someone patented the ethoxy. If it was a reasonable substitute, it WOULD have been patented.

ok, maybe i dont get it but if it isnt a viable substitute where is the mxe patent in the first place?

 

[Fertile]

Well I'm happy that someone else took that long journey. So often people don't recognize that 1 patent reference is derived from hundreds of patents. Parke Davis were going through something of a rut so each patent had to count. An I know this because Dan Lednicer talked me through Upjohn patents. Put simply. if they didn't see a product, they didn't patent (and he RAN their lab at the time). As it is, the WHOLE company was sold for alprazolam

If something was a potential substitute, it would ne patented. I cannot believe that other (pseudo)halides were not tested to avoid the 'me too' atmosphere. They felt an o-Cl was pretty much vital.

Why? I don't know, but if you read about the medicinal chemists involved,, safe to say they KNEW their work.

That is a key element - knowing people at least as able had the time to check.

 

[izo]

As it is, the WHOLE company was sold for alprazolam

dont get it, you mean upjohn? why?

They felt an o-Cl was pretty much vital.

you mean the invention and decision to use ketamine medicinally? well o-Cl is pretty much the best option, the most and best controllable ach for non recreational purposes id say. dont know if there is something to it but i think it has something to do with electron repulsion between the o-Cl and the ketone and right electronegativity of the Cl. just an idea...

safe to say they KNEW their work.

thats safe to assume, id say.^

 

[Fertile]

Indeed I do mean Upjohn - if you look at Upjohn's output in the 1970s, there were MANY truly great novel compounds but nothing that had any medical advantage.

The patents initially go for the o-Cl and it's actually later papers that mention the deschloro. So I can only presume they had something related in which the o-Cl was vital. I couldn't find anything in the papers the K patent reference, so I'm guessing one would have to check all the patents by Calvin L Stevens. But then a Belgian patent was issued at the same time and so one might have to search through them.

Having patents online is wonderful and Pubchem is excellent for finding substructures but it's just not as good as Reaxys. Reaxys rarely gave a reference that was not available.

But F&B originally found the paper in which PCP, K & diphenidine are ALL compared. It's a late 1960s paper from an institution i.e. no patents attached but even then people were trying to find the bond-angle between the N: and the aryl. If memory serves, 109.5 degrees is the 'magic angle'. Well, I know MK-801 has that angle, so it's possible to find.

 

[izo]

MK-801

this is still the most potent non competetive nmda antagonist up until today, right? it is 40 years old, after all.

 

[Fertile]

But MK-801 doesn't appear to have any DRI activity. The trip reports are not very positive. There are others like 8A-PDHQ which while appearing to have a lower affinity than PCP, it almost as potent as MK-801.

Now 8A might be a reasonable target - it's a matter of what precursors are available.

 

[izo]

The trip reports are not very positive.

ah ok, didnt knew yet, would suspect it to be rather strange.

There are others like 8A-PDHQ which while appearing to have a lower affinity than PCP, it almost as potent as MK-801.

ok, seems to be a rather good compound, as is the saturated indole derivate from the following patent:

1962 - Saturated quinoline and indole derivatives US3035059

it's a matter of what precursors are available.

and thats a matter of your budget/ the potential of your idea.


any idea about these compounds? if not, make them in small batches, test them in small groups and sell them via starwait out of the easter islands...

 

[Fertile]

he second one is the most likely to work.... but it has 3 chiral centres.

That's the problem with them all and why disubstitution of the aromatic is also the most practical next step. But 8A-PDHQ might be interesting.... since I suspect the aryl can be substituted.

 

[Xorkoth]

I would say that the reports on MK-801 overall do not sound very positive, but they are extremely interesting, and I remember reading one more recent one (which could mean anytime in the last 10 years because time is weird), where the author really liked it. It sounds like a very weird drug.

Certainly not an MXE replacement at all, though.

 

[Fertile]

The duration and lack of DRI makes MK-801 something I'm happy to read about but not to take. The thing is - it looks like the researchers were looking for a new antidepressant (at least it references papers on tricyclic antidepressants with a similar structure).

It's a drug that's crying out for a sacrificial moiety to reduce duration. I'm also aware people have died after taking it and it WAS for sale some years ago, so why aren't their MORE experiences?

It sounds like it emulates schizophrenia's positive symptoms quite well.

 

[Fertile]

BTW anyone making K or MXE would switch to CMXE (chloro MXE? I dunno) by swapping 1-bromo-2-chlorobenzene (CAS 249-303-1) for 2-bromo-1-chloro-4-methoxybenzene (CAS 2732-80-1). The latter isn't an off-the-shelf precursor but their is a German patent from 1970 that provides a very simple route to it. The cost from the few places that do sell it is very low for such a rare compound suggesting it's 1 step from something very common.

Now bridging the cyclohexane would get around the laws in nations that use Markush structures to make whole classes illegal (even before they have ever been made) but that would also need quite an unusual precursor. I mean, if it means the stuff is an order of magnitude stronger then MAYBE and even then, you MAY have more problems because you have to resolve the enantiomers.

 

[fastandbulbous]

do you have any reason why this is the best mxe replacement? i dont think that this compound is not worthwhile but just wanted to ask. dont think that the o-chloro interferes much during receptor binding with the other phenyl substituent but im not sure of it.

why not simply go for the 3-ethoxy homolog of mxe?

Yep, the ethoxy group will fit in the NMDA receptor just as well as the methoxy of mxe. DMXE is ok, but it requires an atom with lone pairs to act as a SRI. Apparently replacing the methoxy group with a fluoro group is quite successful (fluorine has 3 lone pairs, oxygen has 2). Makes me think that nitrogen would work as well, but aromatic amines just scream NO to me, as they generally end up as something nasty (like in nomifensine - a DRI/NRI, but causes problems with liver toxicity)

 

[Fertile]

Did you read the patent up the thread? I did check over 100 patents and for whatever reason, they stick to -Cl at ortho or meta, -OCH3 at meta or if disubstituted, 2-chloro-5-methoxy. Absence of proof isn't proof of absence but why wouldn't they cover ALL the practical K alternatives in the patents? They go to HUGE lengths to cover all possible amines, so it wasn't complexity of availability of unusual precursors.

Not arguing, just asking. You may well have seen papers I have not. If you have reference to other aryl-alkyl ethers being used, I would love to read it. If you have tried the ethoxy than that is also good enough for me.

 

[Mjäll]

Yep, the ethoxy group will fit in the NMDA receptor just as well as the methoxy of mxe. DMXE is ok, but it requires an atom with lone pairs to act as a SRI. Apparently replacing the methoxy group with a fluoro group is quite successful (fluorine has 3 lone pairs, oxygen has 2). Makes me think that nitrogen would work as well, but aromatic amines just scream NO to me, as they generally end up as something nasty (like in nomifensine - a DRI/NRI, but causes problems with liver toxicity)

DMXE feels serotonergic to me, but i'd love not worrying about combinations.

 

[fastandbulbous]

Did you read the patent up the thread? I did check over 100 patents and for whatever reason, they stick to -Cl at ortho or meta, -OCH3 at meta or if disubstituted, 2-chloro-5-methoxy. Absence of proof isn't proof of absence but why wouldn't they cover ALL the practical K alternatives in the patents? They go to HUGE lengths to cover all possible amines, so it wasn't complexity of availability of unusual precursors.

Not arguing, just asking. You may well have seen papers I have not. If you have reference to other aryl-alkyl ethers being used, I would love to read it. If you have tried the ethoxy than that is also good enough for me.

Nah, just my view after looking atthepharmacophore and proteinstructure of the NMDA receptor. It worked when coming up with the structure of mxe in the first place, but hey, no one is infallable (or at age 33, tbey ail you to abig wooden cross - just my bit ofx.as joy!!)