4-MAR stereoisomers SAR

[Fertile]

If by that you mean does it have a phenyl group, then yes. If you're asking if it's a phenethylamine, then no. It is a CNS stimulant drug of the 2-amino-5-aryl oxazoline class.

I replied to the IMAGE you supplied. Adding a 2,5-dimethoxy and ESPECIALLY a p=Br just meant the body will be deprived on it's main metabolic pathway. People have made p-F 4MAR and the duration is just toooooo long.

So we tried the p-Methyl AR first - because that provides a sacrificial moiety so duration goes down. It also significantly made the compound almost totally SERT selective. Then we made the m-methyl and that was DAT>NET>>SERT. So a 2:1 mixture of the two was an excellent MDMA substitute, but not elegant. Thus having proven the biosteric minimum WOULD fit an MD moiety, we made the 34-MD derivative of aminorex. NOT 4 methylaminorex. Because I am reliably informed (Dr. Dave) that it's an MAOI and so we stayed WELL clear.

If you know 4MAR is a significant MAOI, you would respect the fact that if it's also modulating monoamine release - it's an accident waiting to happen.

PLAIN aminorex is the better scaffold. But it has 5HT2b affinity (as does 4MAR) - so while fine on an occasional basis, long-term use is likely to lead to COPD. Both AR 4MAR have caused COPD in thousands of people. so it's only safe if it's going to be used occasionally. Straight stimulants lead to binges, entactogents rarely.

Read the story of the Florida lab busted for making 4MAR. They had all been using daily for months, they all had COPD, specifically heart valve damage.

So I repeat - people have looked into this scaffold, it's a possible MDMA replacement but as I have already stated - too complex synthetically.

But by all means, provide a facile synthesis and we will continue.

 

[unodelacosa]

I replied to the IMAGE you supplied.

Yeah I was replying to someone else in the thread.

But by all means, provide a facile synthesis and we will continue.

Piperonal substitution for benzaldehyde w/your aforementioned L-PAC method sounds promising …

Read the story of the Florida lab busted for making 4MAR. They had all been using daily for months, they all had COPD, specifically heart valve damage.

Really? I read that case pretty closely. I don't recall any mentions of COPD. I'll look again for some new sources, but if you have any links, they would be appreciated.

I wonder if it's possible to avoid the cardiotoxic effects by taking a 5-HT2B receptor blocker? …

And just how much of an MAOI is 4-MAR?

 

[Fertile]

https://thorax.bmj.com/content/thoraxjnl/26/3/262.full.pdf

https://www.ahajournals.org/doi/full/10.1161/01.cir.99.1.156

Drug-Induced Pulmonary Hypertension: The First 50 Years

Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization Group 1 pulmonary hypertension (PH) characterized by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have...

meridian.allenpress.com

An orally available, highly selective 5-hydroxytryptamine 2B (5-HT2B) receptor antagonist ameliorating pulmonary and dermal fibrosis

Background: 5-hydroxytryptamine (5-HT) is well known as a stimulator of tissue fibrosis and a significant role of peripheral 5-HT2B receptors in human fibrosis has been suggested. The pro-fibrotic effects of the 5-HT2B receptor are believed to be mediated through activation of the TGF-β/Smad...

erj.ersjournals.com

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051517

So how do we do this - say to people 'take drug A so drug B doesn't kill you'?

Unless the dose-response curves match, you cannot just mix it in. How likely do you think it is that the DR curves & therapeutic windows will match?

The L-PAC was just me extemporising. The investment in time as much as money would be the issue. I think L-PAC synthesis is neat and it's currently legal, but not for long, I fear. It would take a HUGE investment and not many people have the skillset to setup the modified bioreaction at scale, scale & telescope the synthesis of the product in a practical time.

If you can go from L-PAC directly to 4-MAR.... THAT is where their is a fortune to be made.

 

[plumbus-nine]

I wonder how the 4-mar's can be MAOIs and triple releasers in one molecule and yet to be pretty safe on their own. Hell I has some venlafaxine on my system when first trying 4,4'-DMAR because I was young and ignorant about unknown drugs but it went out fine, there was some hangover which didn't occur with the drug alone but in theory a MAOI + SNRI should kill you, doesn't it? Interesting to read about that plain 4-mar is a MAOI as well! I would love to sample it one day. A shame that these superior stims have mostly vanished (or were never popular to begin with?)

 

[Fertile]

I wonder how the 4-mar's can be MAOIs and triple releasers in one molecule and yet to be pretty safe on their own. Hell I has some venlafaxine on my system when first trying 4,4'-DMAR because I was young and ignorant about unknown drugs but it went out fine, there was some hangover which didn't occur with the drug alone but in theory a MAOI + SNRI should kill you, doesn't it? Interesting to read about that plain 4-mar is a MAOI as well! I would love to sample it one day. A shame that these superior stims have mostly vanished (or were never popular to begin with?)

Considering how little reaches the market, their are an alarming number of autopsy reports. I grant you, these people were likely doing 500mg+ a day, but the COD was never fully established in any of the cases. 'Drug Intoxication' has always been the go to phrase.

So how dangerous? Dunno - but statisticians will, I feel, regard 4MAR as being a lot more risky (per dose) than say MDMA.

But 4MAR is mainly a stim so people WILL go on runs or binges and use huge amounts. I remember the DEA file of the only 4MAR bulk dealer they ever followed (or at least reported on following). A 22 YO who was found dead in a motel - only drug in system 4MAR.

But you cannot put a CI on a single case. But it seems dealers who also use are killed by the stuff. I think there are also 2 Israeli cases of dealers found dead - COD '4MAR intoxication;. Well II say that but my Yiddish is very poor. I can bless a wedding, but that's about it so Google Translate MAY be inaccurate.

If you design this stuff - the safety of this stuff is on you. That's why I wanted U47700 to be pills. i got ignored. People died. I quit the company for it.

 

[paracelsius]

What I think is overlooked with the oxazolines is that you don't have to be limited to analogs with(meth)amphetamine monoamines releasing. imo they'd make extremely good pyros-like reuptake inhibitors. That's why I am trying hard AF to get my hand on that paper Eur J Med Chem 1980, 15(2), 111-17. but so far no success. I live in the shittiest place when it comes to access to Univ literature hard copies!

Keep in mind the AR-type oxazolines (OP structure II with alfa-methyl or H and bunch of ring subst analogs RCs..etc) are amphetamine-type monoamines releasers SNDRAs not reuptake inhibitors SNDRIs like cocaine, pyros or phenidates..etc.

If you look at cathinones SAR, increasing alfa-alkyl size (from methyl to propyl, butyl, pentyl, hexyl etc) you go from releaser to reuptake inhibitor. Quite general SAR. The bigger the substituent the more reuptake inhibitor v releaser. So is increasing size of the N-substituent (N-Me->N-ethyl->Pyrrolidine) go from releaser SNDRA (eg mephedrone) to SNDRI (eg MDPV). Now why am I saying all that?

Well look at OP structure I very closely. As I said it is just 4-MAR with bigger alfa-alkyl (R2) and N-substituents(R3) joined together. Another way to look at it: It is just a cyclized version of the reverse ester of methylphenidate levophacetoperane , with the COCH3 replaced with C=NH.

So I expect these compounds to be cocaine, phenidate or pyros-like SDNRI stimulants (no I am pretty sure of that. We know they are stimulants according to that paper at least, just by what mechanism?? (If only I get my hand on that paper!!). I don’t know about selectivity ratios DAT-NET-SERT inhibition of these compounds. But I am pretty sure they too big to be transporter substrate but rather reuptake inhibitors stimulants. Way more potent than cocaine for sure.

Synth is actually straightforward one step from commercial phenyl-piperidinyl carbinol, a little bit more difficult than boiling eggs if one knows what hes doing. Granted the chiral carbinol is no cheap. but no synthesis talk allowed on BL.

 

[Fertile]

What I think is overlooked with the oxazolines is that you don't have to be limited to analogs with(meth)amphetamine monoamines releasing. imo they'd make extremely good pyros-like reuptake inhibitors. That's why I am trying hard AF to get my hand on that paper Eur J Med Chem 1980, 15(2), 111-17. but so far no success. I live in the shittiest place when it comes to access to Univ literature hard copies!

Keep in mind the AR-type oxazolines (OP structure II with alfa-methyl or H and bunch of ring subst analogs RCs..etc) are amphetamine-type monoamines releasers SNDRAs not reuptake inhibitors SNDRIs like cocaine, pyros or phenidates..etc.

If you look at cathinones SAR, increasing alfa-alkyl size (from methyl to propyl, butyl, pentyl, hexyl etc) you go from releaser to reuptake inhibitor. Quite general SAR. The bigger the substituent the more reuptake inhibitor v releaser. So is increasing size of the N-substituent (N-Me->N-ethyl->Pyrrolidine) go from releaser SNDRA (eg mephedrone) to SNDRI (eg MDPV). Now why am I saying all that?

Well look at OP structure I very closely. As I said it is just 4-MAR with bigger alfa-alkyl (R2) and N-substituents(R3) joined together. Another way to look at it: It is just a cyclized version of the reverse ester of methylphenidate levophacetoperane , with the COCH3 replaced with C=NH.

So I expect these compounds to be cocaine, phenidate or pyros-like SDNRI stimulants (no I am pretty sure of that. We know they are stimulants according to that paper at least, just by what mechanism?? (If only I get my hand on that paper!!). I don’t know about selectivity ratios DAT-NET-SERT inhibition of these compounds. But I am pretty sure they too big to be transporter substrate but rather reuptake inhibitors stimulants. Way more potent than cocaine for sure.

Synth is actually straightforward one step from commercial phenyl-piperidinyl carbinol, a little bit more difficult than boiling eggs if one knows what hes doing. Granted the chiral carbinol is no cheap. but no synthesis talk allowed on BL.

What's the DOI. Always refer to DOIs.

I come up with a hypertensive when when I search for Eur J Med Chem 1980, 15(2), 111-17

 

[paracelsius]

Of course but that is exactly my frustration. That journal start indexing 1987 and up so cant find any doi at all only that bits that you mention. But I found that FR patent FR3718M from same German Bayer guys for the specific (-)trans II. Tested it in mice, rats, rabbits, cats and humans. Looks like a potent stimulant to me. In humans they tried 15-30 mg doses. But anyway I found those compounds quite interesting. might make them my next project. thanks for trying tho.

 

[Fertile]

So it's the same as GB Patent 995964A.

Yeah, so it's about midway between mazindol, aminorex & levophacetoperane.

I found papers that show making the 5-membered ring of mazindol a 6-membered ring using an extra -CH2-, the compounds are about x10 more potent. I will dig it out for you. I have to tell you that we failed to find the precursors to Levophacetoperane when we tried and this puppy requires even more work.

So yeah, I totally see that it's a target, but why not go for clofenciclan? I mean, that's shorter acting - more like coke, but it's a much easier target. There are many much easier targets.

By all means go ahead, it is pure research, but long ago I realized that 3 steps... 4 at the outside... that's about the limit because yields get so low, workup gets so complex (side products) and then people don't like totally novel things. Trust me - Isophenidine is 1 step, cheap, really good and it's gone NOWHERE. You just can't tell. But Isophenidine failing only cost $2500... this would be a lot more.

It was never assigned a CAS number.

 

[paracelsius]

Yeah I think same patent family. Here is another one US3,496,185 (different Co tho) Same idea but using Pipradol to get OP II with a diphenyl instead.
Sure clofenciclan certainly easier target but it looks like a pure DRIs, isnt it? maybe with a dash with NMDA. Pure DRIs are not especially enjoyable Just make compulsive weird behaviors like weird sex, compulsive gambling or strange things like that!
Oh BTW that (-)trans compound last about 4-5 hours in humans which is nice. ARs in general have just unbelievebly long duration! I hate that.
"Sure clofenciclan certainly easier target": No I take that back, I mean the ureido route to oxazolines with aminoalcohols and cyanate is even easier than meth shake'nbake if one knows what hes doing.

 

[Fertile]

Like cocaine, you mean? Yeah, it's just like coke.

BTW the p-Cl of mazindol is most certainly to increase SERT activity so it is less stimulating. It will also increase duration.

 

[unodelacosa]

So how do we do this - say to people 'take drug A so drug B doesn't kill you'?

Ha! That's a good point. Thank you, btw, for sharing those links and the info. Much obliged.

Unless the dose-response curves match, you cannot just mix it in. How likely do you think it is that the DR curves & therapeutic windows will match?

Yeah you're right. I guess I'm just a little bit crestfallen to learn this news about a drug I've always wanted to dabble with, but it's hard to hold confidence in this compound as being a worthwhile exploration given the inherent danger it would pose to the health of the user. (le sigh).

The L-PAC was just me extemporising.

Well done, then.

The investment in time as much as money would be the issue. I think L-PAC synthesis is neat and it's currently legal, but not for long, I fear. It would take a HUGE investment and not many people have the skillset to setup the modified bioreaction at scale, scale & telescope the synthesis of the product in a practical time.

If you can go from L-PAC directly to 4-MAR.... THAT is where their is a fortune to be made.

Indeed. Although PPA + KOCN refluxed and quenched with HCl = easy bake oven one-pot synth. A lot easier than messing around with cyanogen bromide anyway, in my opinion.
Thanks again for the links and info

 

[paracelsius]

What exactly was the problem with isophenidine?

Like cocaine, you mean?

minus the euphoria

 

[Fertile]

Indeed. Although PPA + KOCN refluxed and quenched with HCl = easy bake oven one-pot synth. A lot easier than messing around with cyanogen bromide anyway, in my opinion.
Thanks again for the links and info

Well you are going to have to convert L-MDPAC to MDPPA and since 50% of your product will be cis, it won't react. So dig out the patent on resolving the trans isomers. You can oxidize back to L-MDPAC and run it through again.

Sounds easy, ay? It's not. Only when done at scale... and you still end up with an MAOI...

So BrCN it is.

We found out the hard way.

 

[paracelsius]

It is strange there is no info at all about the D and L isomers of plain Aminorex anywhere (expect the OP paper that I am still trying get my hands on)..
I am pretty sure one will be better than the other just like S-(meth)amph is the "good" enantioner and L-(meth)amph the "shitty".

Aminorex contains one chiral carbon and the available information indicates that it has only been evaluated as a racemic mixture ......... doi:10.1021/acschemneuro.8b00415.

Maybe I guess interest drops after it was pulled from the market but then again effects of different stereoisomers of the 4-MAR derivatives have been extensively studied! Couldnt be synth reasons: it is no more harder separate the S and R than with S and R meth(amph) maybe via the tartrate..

 

[Fertile]

I think I just performed an energy minimization of dexamphetamine and tried overlaying both of the aminorex isomers to find the active. Like phenmetrazine and other related stimulants, they all place the N: (nitrogen lone-pair) in the same port. That seems to be the key. of course with aminorex, it's the imine,

Aminorex actually exists in a mesoionic state with the imine<->secondary amine & amine<-->imine exist. That IS mentioned in the original patent but not later. I've often wondered if that is because in physiological conditions, one form predominates.

 

[paracelsius]

The amino tautomer forms predominate exclusively both in solution and solid state (by IR). There are bunch of studies on that question amino-oxazolines v iminooxazolidines tautomerism (have to check my notes). N-3 substituted are the ones existing in the imino-oxazolidine form. So energy minimization would make more sense with the amino form. But some of those software can take into account possible tautomerism, no?

Yeah I think only isomer is responsible for activity. Especially with MA releasers, it is pretty general only one enantiomer is responsible for activity as far as monoamines release is concerned. The relative position of the charged N is critical. But that hasnt been done for Aminorex tho so one can only speculate.

I mean for one it would make it safer. I mean dextroaminorex (or levoaminorex) v the racemate but as I said it hasn't been done afaik..expect that old German OP paper.
Usually the other "shitty" isomer is responsible for off-target troubles like 5HT2b and other cardiovascular issues. Like with S and R-meth(amph), or phenmetrazines ...etc

edit: imo patents are mentioning both tautomers just in case someone come along and claim the other tautomer as a different compound. Patent lawyers are good at that bullshit! I mean recent challenge to psylocibin patents were thrown out. I mean for fck sake how can you claim shit that is known for ages?? Absolutely nothing novel. I guess you can if you have money!

 

[unodelacosa]

So BrCN it is.

Just to be sure we're on the same page, you do know I'm referring to this synthesis, right? → https://chemistry.mdma.ch/hiveboard/novel/000458588.html

It looks pretty legit to me, forming a urea intermediary and resolving it w/HCl. It also seems to be enantiomerically specific, producing (unscheduled) trans-4-methylaminorex instead of (scheduled) cis-4-methylaminorex. The upshot of this in the U.S. is that—at least on the federal level—only cis-4-methylaminorex has been scheduled, and the govt. failed to apply successfully the 1986 Analogue Act in the 2004 case in the Middle District of Florida, United States of America v William Hahne.

We found out the hard way.

What do you mean by this, and who is "we" in the above statement?

 

[Fertile]

No - not the 4-methyl derivative. It's an MAOI as I have mentioned. How do I know - I asked Dr. David Nichols. I don't know he knows but he didn't suggest, he stated suggesting personal experience.

The 'we' is me and other people who would not thank me for mentioning them.

 

[unodelacosa]

No - not the 4-methyl derivative. It's an MAOI as I have mentioned. How do I know - I asked Dr. David Nichols.

I've searched for this but found nothing about 4-MAR being an MAOI. I concede it certainly seems to be cardiotoxic.

I don't know he knows but he didn't suggest, he stated suggesting personal experience.

@paracelsius – can you weigh in on this for us, please? In this post you state that aminorex and 4-methylaminorex are both not MAOIs. And I could've sworn I read somewhere that 4-methylaminorex turned out not to be significantly neurotoxic. It just has a really long duration of effects and likely a long half life to elimination, plus a sketchy cardiotoxicity profile.

The 'we' is me and other people who would not thank me for mentioning them.

Ok then, fair enough.

I'd like to see data on the degree these compounds inhibit monoamine oxidase and what the relative viability of the compound might be for the inclusion w/some orally ingested DMT to form a 4-MAR-huasca experience…