Practical MXE replacement

[fastandbulbous]

Is that required for NMDA antagonism, or some serotonin action, or some unknown magic factor?

Nope, plain unsubstituted aromatic ring compounds are NMDA antagonists. On the other hand, look at how many SSRI compounds have an aromatic alkoxy group...

 

[Fertile]

I think I mentioned it before but Parke Davis patented ketamine and so using google patent, I looked at all patents that referenced the ketamine patent and I found one really unusual patent. As you know, patents are costly and so lawyers usually try to make a patent that covers as many different compounds a possible.

So I was REALLY surprised to discover that they issued a patent for just 1 compound namely: 2-(2-chloro-5-methoxyphenyl)-2-(methylamino)cyclohexan-1-one i.e. 5-methoxy ketamine. They didn't cover any other (pseudo)halogens, only -Cl. They didn't cover any other N-substitutions even though it was known that the N-ethyl is more potent and they only used a ketone even though it was known that the group is mainly space-filling and so methyl side-chains produce more potent products (but longer duration, twice as many enantiomers and tricky preparation).

I haven't seen anyone trying to swap the ketone for a methylene. This would make the ring more rigid and wouldn't introduce an extra optical centre... but I expect that is HARD chemistry.

So did I just miss 5-MeO ketamine (or it's N-ethyl homologue)? Have they been on the market and subsequently banned? I don't keep up with RCs any more. The quality seems very low indeed.

 

[fastandbulbous]

N-ethylnorketamine was surprisingly shite, in my experience.

 

[Morpheus God of morphine]

I read that mxe is and Serotonin reuptake inhibitor and nmda antagonist and has no opiate affinity. so curious has this changed, this was on a binding assessment posted here a while back

 

[fastandbulbous]

I read that mxe is and Serotonin reuptake inhibitor and nmda antagonist and has no opiate affinity. so curious has this changed, this was on a binding assessment posted here a while back

Yep, surprised me as well. The opiate type effects must be a mixture of NMDA antagonist and SSRI actiity. I can see how that combination could be mistaken for it.

 

[Fertile]

Purely for it's simplicity:

2 hosted at ImgBB

Image 2 hosted in ImgBB

ibb.co

I developed pyrophenidone (effects identical to MDPV) at the same time but I noted that JUST an N-pyrrolidine produced a decent DRI so figured it was possible to optimise DRI OR NMDA properties. I never tried ring-modification if the above compound but as it is, it's a really interesting trip. I touched the tip of my fingers with the tips of my wife's fingers and at once we both lost the ability to feel where one of us ended and the other began.

A meta methoxy does not work. An ortho -Cl does work but the chemistry is more complex (hence the idiot French adding an ortho methoxy that turned out to be toxic. I would love to know if adding a p-Me to the beta aromatic would increase DRI although the NMDA/DRI balance is just about perfect as it is. Only if and ortho -Cl on the alpha carbon increases NMDA activity would I consider it.

I THINK someone added an ortho -F but I do not know if this was the best or merely the most convenient to make.

I also found what is without a doubt the simplest, safest, cheapest and highest yielding reductive amination so you can make isophenidine in 1 step.

US Patent Application WO2007124920A1 'Process for the preparation of [4(s,r)-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalen-1-ylidene]methylamine' Example 5.

Yield for isophenidine is 100% i.e. the product is pure enough to be used as is.

Why was this not a huge Hit? Well at the time the people in the lab had just bought 250L of piperidine so they figured out the (toxic) methoxyphenidine to use up the piperidine. Quite a few people spotted the 1,2-diphenylethylamine class of NMDA antagonist/DRI and newer and more complex compounds were marketed. In short, my own team buried it because they would have made a loss.

What it tells us is important. The QSAR is more like that of PCP than of ketamine. The N-isopropyl is the most potent monosubstituted PCP analogue. The meta methoxy derivative of isophenidine was not tested but m-methoxy & m-hydroxy derivatives PCP are considered to be very good (the latter also seems to display MOR activity). The m-hydroxy would also overlay the phenol of dextranophal & gives insights into optical activity.

BUT the key thing about isophenidine is that it is made from 2 VERY cheap precursors and the synthesis uses simple and cheap reagents. So maybe you might want to ring-substitute, but:

1,2-Diphenylethanone AKA Desoxybenzoin (CAS 207-193-2)
Isopropylamine Hydrochloride (CAS 15572-56-2)

I mean, 8A-PDHQ, MK-801 (dizocilpine), NEFA & N-methylhexahydrofluorenamine (PD-137889) all provide an decent training set to find the exact position of the N: relative to the aromatic and lanicemine shows possible modification of the beta aromatic, methoxyphenidine possible modification of the alpha aromatic. I take it we are looking for something with the appropriate NMDA antagonist : DRI ratio?

If one wishes to start with the simplest, isophenidine looks like a good prototype for quantum 3DQSAR calculations.

 

[fastandbulbous]

Purely for it's simplicity:

2 hosted at ImgBB

Image 2 hosted in ImgBB

ibb.co

I developed pyrophenidone (effects identical to MDPV) at the same time but I noted that JUST an N-pyrrolidine produced a decent DRI so figured it was possible to optimise DRI OR NMDA properties. I never tried ring-modification if the above compound but as it is, it's a really interesting trip. I touched the tip of my fingers with the tips of my wife's fingers and at once we both lost the ability to feel where one of us ended and the other began.

A meta methoxy does not work. An ortho -Cl does work but the chemistry is more complex (hence the idiot French adding an ortho methoxy that turned out to be toxic. I would love to know if adding a p-Me to the beta aromatic would increase DRI although the NMDA/DRI balance is just about perfect as it is. Only if and ortho -Cl on the alpha carbon increases NMDA activity would I consider it.

I THINK someone added an ortho -F but I do not know if this was the best or merely the most convenient to make.

I also found what is without a doubt the simplest, safest, cheapest and highest yielding reductive amination so you can make isophenidine in 1 step.

US Patent Application WO2007124920A1 'Process for the preparation of [4(s,r)-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalen-1-ylidene]methylamine' Example 5.

Yield for isophenidine is 100% i.e. the product is pure enough to be used as is.

Why was this not a huge Hit? Well at the time the people in the lab had just bought 250L of piperidine so they figured out the (toxic) methoxyphenidine to use up the piperidine. Quite a few people spotted the 1,2-diphenylethylamine class of NMDA antagonist/DRI and newer and more complex compounds were marketed. In short, my own team buried it because they would have made a loss.

What it tells us is important. The QSAR is more like that of PCP than of ketamine. The N-isopropyl is the most potent monosubstituted PCP analogue. The meta methoxy derivative of isophenidine was not tested but m-methoxy & m-hydroxy derivatives PCP are considered to be very good (the latter also seems to display MOR activity). The m-hydroxy would also overlay the phenol of dextranophal & gives insights into optical activity.

BUT the key thing about isophenidine is that it is made from 2 VERY cheap precursors and the synthesis uses simple and cheap reagents. So maybe you might want to ring-substitute, but:

1,2-Diphenylethanone AKA Desoxybenzoin (CAS 207-193-2)
Isopropylamine Hydrochloride (CAS 15572-56-2)

I mean, 8A-PDHQ, MK-801 (dizocilpine), NEFA & N-methylhexahydrofluorenamine (PD-137889) all provide an decent training set to find the exact position of the N: relative to the aromatic and lanicemine shows possible modification of the beta aromatic, methoxyphenidine possible modification of the alpha aromatic. I take it we are looking for something with the appropriate NMDA antagonist : DRI ratio?

If one wishes to start with the simplest, isophenidine looks like a good prototype for quantum 3DQSAR calculations.

How does m-OH PCP give insights into optical activity, as it's not optically active itself, or is this one of those annoying frequent 'senior moments'?

 

[Fertile]

How does m-OH PCP give insights into optical activity, as it's not optically active itself, or is this one of those annoying frequent 'senior moments'?

Optical activity of the amine function. Sorry for not being clear. I really don't know if one isomer is responsible for all the activity or if one is NMDA antagonist & the other DRI.

Diphenidine was nicked straight from a patent but I forget where it is - haven't seen it for years. I was simply asked to produce a K alternative outside the arylcyclohexylamine law the UK introduced. I knew full well it was intended to be a lead compound but the boss evidently had a huge number of orders so I get my sample... and on the same day it's being sold on the site. All further research of little interest as it was 'good enough'.

But those senior moments do kick in. I now have a periodic table on the wall because I cannot remember the (official) MW of each element. When I say official, I mean the number derived from the stable isotopes. All that used to be in my head....

Right now I would be happy just to find my pencil.

 

[fastandbulbous]

Optical activity of the amine function. Sorry for not being clear. I really don't know if one isomer is responsible for all the activity or if one is NMDA antagonist & the other DRI.

Diphenidine was nicked straight from a patent but I forget where it is - haven't seen it for years. I was simply asked to produce a K alternative outside the arylcyclohexylamine law the UK introduced. I knew full well it was intended to be a lead compound but the boss evidently had a huge number of orders so I get my sample... and on the same day it's being sold on the site. All further research of little interest as it was 'good enough'.

But those senior moments do kick in. I now have a periodic table on the wall because I cannot remember the (official) MW of each element. When I say official, I mean the number derived from the stable isotopes. All that used to be in my head....

Right now I would be happy just to find my pencil.

I have days I'd be happy to find my trousers!

 

[Fertile]

https://i2-prod.liverpoolecho.co.uk/incoming/article24861308.ece/ALTERNATES/s810/0_Madchester-Teenagers-wearing-Joe-Bloggs-clothing-Manchester-1989.jpg

Check out these bad boys, like a skirt on each leg.
But seriously - places like B&Q sell those single use outfits people wear while painting ad decorating. You could just have dispenser. Every day, new trousers. Like some wonderful dream.

 

[fastandbulbous]

https://i2-prod.liverpoolecho.co.uk/incoming/article24861308.ece/ALTERNATES/s810/0_Madchester-Teenagers-wearing-Joe-Bloggs-clothing-Manchester-1989.jpg

Check out these bad boys, like a skirt on each leg.
But seriously - places like B&Q sell those single use outfits people wear while painting ad decorating. You could just have dispenser. Every day, new trousers. Like some wonderful dream.

I've had single day use underwear, courtesy of the NHS, anything like that sounds like the stuff of (semi translucent) nightmares!

 

[Fertile]

Well, I'm from Madchester, our kid, so around 88 lots of wannabees wore the most S T U P I D clothing on earth. I've also ended up on a secure psychiatric ward so I have some idea of how horrible it is. A prison with pot plants. 28 days and I saw someone in a white coat for ohh.... 5 minutes tops. All they do is put you somewhere out of sight.

 

[izo]

bring out a perkin-elmer top and youve got some merch you can sell to the science chicks. make it a push up and they get a nobel price. thats the way they like it, aha aha. twats!

 

[Mjäll]

What if one were to place ethoxy or isopropoxy instead of methoxy?

Has the drug EXE been produced? Would it work?

 

[izo]

Optical activity of the amine function. Sorry for not being clear.

irrelevant. whats your point fertile?

 

[Fertile]

irrelevant. whats your point fertile?

It was a private joke with K.

 

[izo]

private joker, go on.

 

[fastandbulbous]

What if one were to place ethoxy or isopropoxy instead of methoxy?

Has the drug EXE been produced? Would it work?

Well, the ethoxy group should still fit in the receptor (from what I can see), and it has the oxygen, with lone pair electrons, to give it the serotonogic activity. No idea if the isopropoxy is too large.

 

[Fertile]

Well if it fits, it will work. The body will deprotect the ethoxy faster and more completely than the methoxy. I don't know if you tried the 3-OH homologue of MXE... because I imagine it will tend towards that.

But I've mentioned before that Parke Davis patented the 2-chloro-5-methoxy analogue of ketamine. The patent for that 1 compound. No other ethers, no other (pseudo))halogens. My guess is that they thought it so much better than K, they patented it as fast as they could as they expected others to discover it.

For some reason I thought RC makers had already made it, but apparently not.

1

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ibb.co

I'm no good at names - maybe just call it FXB?

 

[izo]

you cant get into big company data. so go on and on.