4-MAR stereoisomers SAR

[paracelsius]

I spent the last few days trying get hold of this paper. Cant even find a doi. seems the journal start indexing 1987 and up (the paper is 1980). I would be most grateful if anybody has access to some sort of electronic version:

European Journal of Medicinal Chemistry 1980 Vol 15 Issue 2 Pages 111-117.
2. Stereochemistry studies on drugs. 8. 1-Phenyl-3-imino-perhydro-3H-oxazolo(3,4-a)pyridine with blood pressure increasing activity
By Wollweber, H; Hiltmann, R.; Stoepel, K.; Kronenberg. H. G.​

Isomers of the iminoperhydrooxazolopyridines I (R = H, 3-Me, 4-Me, 3-OMe, 4-OMe, 3-Cl, 4-Cl; R1 = H, Me) and of the iminooxazolidines II (R2, R3 = H, Me) were prepd. stereospecifically according to literature methods. The antihypotensive and central system stimulant activity of I and II is stereochem.-dependent, (-)-trans-I (R = R1 = H) being most active.

It is SAR of Aminorex (structure II R3R2 = H), 4-MAR (structure II R3 = H and R2 = Me) and cyclic homologs I in vivo! not in vitro monoamines activity data. Both cis and trans as well as their (+) and (-) enantiomers. Really very very interesting! Thanks a lot for your help.

 

[Fertile]

The image on the lest is NOT AR or 4MAR - where did that piperidine ring appear from?

 

[Skorpio]

I spent the last few days trying get hold of this paper. Cant even find a doi. seems the journal start indexing 1987 and up (the paper is 1980). I would be most grateful if anybody has access to some sort of electronic version:

It is SAR of Aminorex (structure II R3R2 = H), 4-MAR (structure II R3 = H and R2 = Me) and cyclic homologs I in vivo! not in vitro monoamines activity data. Both cis and trans as well as their (+) and (-) enantiomers. Really very very interesting! Thanks a lot for your help.

I failed with some cursory Googles.

 

[Fertile]

Well the one on the right is one of the 4 isomers, so it's not all bad.

 

[paracelsius]

@Fertile : look carefully, Structure II is actually aminorex (R2 is H and R3 is H), 4-MAR (R2 is Me and R3 is H), 3-MAR (R2 is H and R3 is Me)..etc. Structure I (R,R1 is H) is just 4-MAR with a propano bridge bewtween the 4-methyl and the N.

The reason I find that German paper interesting is they prepared and tested all possible pure stereoisomers. Not only cis and trans but also (+)cis, (-)cis, (+)trans, (-) trans...

They patented the first group (Structure I) before McNeil aminorex patent. That paper compare the 2 but I just cant get my hand on it. Guess I have go to a big Library get a hard copy but I live in a small town Canadian prairies... It is a pain to get a hard copy

@Skorpio : thanks a lot for trying. I guess only way is to get hard copy but I thought somehow somewhere there is a electronic version.

 

[plumbus-nine]

I would love to see more worthy 4-MAR related compounds to be available. The only one I've been able to source so far was 4,4'-dimethylaminorex which absolutely kicked my ass. It remains to be under my top 3 drug experiences ever. If 4-MAR is anything aline then it must be a winner, maybe the only drug of which I've only ever read positive reviews. Wonder why nobody bothers to make it anymore, heard that the precursor norephedrine became difficult to source but this would be the first time where precursor monitoring led to the disappearance of a drug(?).

 

[Fertile]

One would make the precursor from L-PAC.

 

[Fertile]

@Fertile : look carefully, Structure II is actually aminorex (R2 is H and R3 is H), 4-MAR (R2 is Me and R3 is H), 3-MAR (R2 is H and R3 is Me)..etc. Structure I (R,R1 is H) is just 4-MAR with a propano bridge bewtween the 4-methyl and the N.

The reason I find that German paper interesting is they prepared and tested all possible pure stereoisomers. Not only cis and trans but also (+)cis, (-)cis, (+)trans, (-) trans...

They patented the first group (Structure I) before McNeil aminorex patent. That paper compare the 2 but I just cant get my hand on it. Guess I have go to a big Library get a hard copy but I live in a small town Canadian prairies... It is a pain to get a hard copy

@Skorpio : thanks a lot for trying. I guess only way is to get hard copy but I thought somehow somewhere there is a electronic version.

I think it will only mediate DAT. The piperidine makes it too large to affect NET or SERT That's why bath salts are so selective and awful. DAT will manage with those long chains. Ring substitution would only alter potency and/or duration but not action.

p-Methylaminorex is a pure SERT. m-Methylaminorex is balanced NET/DAT.A 2:1 mixture of p to m is like MDMA on steroids.....

We made a LOT of analogues a decade ago.

 

[unodelacosa]

Wonder why nobody bothers to make it anymore, heard that the precursor norephedrine became difficult to source but this would be the first time where precursor monitoring led to the disappearance of a drug(?).

Yeah so it's really odd, the story of 4-MAR, in particular the case of United States of America v William Hahne in the Central District of FL circa 2004. Why it's significant is because it was put to the test finally that the U.S. made a mistake in specifically only scheduling the cis-enantiomer of 4-MAR, leaving the trans-enantiomer wide open to the research chemical loophole and the Federal Analog Act from the mid-80's. Meaning to say, this chemist down in the middle of the swamps and alligators of central Florida manage to scrap together a functional synthesis to manufacture trans-4-methylaminorex starting from PPA (Phenylpropanolamine – also known as cathinone – is what was in Dexedrine [EDIT: sorry, I meant to say "Dexatrim" – it was a weight-loss product they removed from shelves some time in the 90s]). I suspect there's confusion over this aspect of the law though, and furthermore, the precursor to it is also a precursor to methamphetamine and is pretty tightly controlled in the U.S. Idk about elsewhere, but I doubt it's much different. You see, PPA was taken out of OTC Dexetrim because it was causing cardiac issues in older folks.

The shame of it is that the synthesis that Hahne pioneered is a simple one-pot shot synthesis. I can't post the details here but just search the Erowid's Hive archive for it. I think the original post was by Bandil.

 

[Fertile]

cathine - not cathinone.

Yeah, just PPA & KOCN.

They all used it and all damaged their hearts - it's got 5ht2b affinity so it causes heart-valve damage.
3,4-MD Aminorex has no 5ht2b affinity not is it an MAOI (4MAR is but AR is not) - Dr. Dave confirmed that, so I think we can rely on the info.

 

[Tranced]

Everyone loves 4-MAR and we haven't even taken it. Welcome to bluelight I guess.

 

[Fertile]

Everyone loves 4-MAR and we haven't even taken it. Welcome to bluelight I guess.

Oh, I've taken 4-MAR a couple of times, at modest doses. 5HT2b affinity is only an issue if you use for months (their was a disaster CC AR in Germany where it was used as a weight-loss drug. I think the details are on the net.

It's a very clean stimulant (DAT>NET) with moderate SERT. It's my wife who really likes stims, so she had more. It's NOT as good as plain AR (which I have also samples) and not even close to 3,4-MDAR. MDAR takes too many steps to be attractive to producers although the development of L-PAC biosynthesis does make it simpler, Just swap benzaldehyde for piperonal and you get 3,4-MD L-PAC....

But I don't find it a practical target, or an interesting synthesis. I design drugs, I don't take them (other than prescribed) because epilepsy, aphasia and chronic pain - so I'm already a 'polydrug user', simply one who the doctor considers so damaged that it's worth the risk; I presume.

 

[Tranced]

Which class is it in? Is it a phen?

 

[Rectify]

Fertile,

You should make this:

BEATNIK
5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1,3-thiazol-2-amine

 

[unodelacosa]

Fertile,

You should make this:

BEATNIK
5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1,3-thiazol-2-amine

Mescaminothiazole?
Mescalinaminothiazole?
Trimethoxy-phenmethiazolamine?

At first, I thought you were shooting for Mescalinaminorex, which is actually kinda fun to say. It's like: MESCA-LEENA-MEENO-REX.

Interesting though. I've always wanted to try 2C-B-Aminorex…

 

[unodelacosa]

cathine - not cathinone.

Oops, yeah my bad. It's a β-hydroxy-amphetamine whilst cathinone is a β-ketone-amphetamine. However, I believe it's norephedrine that you want for this (this.(target) = the specifically unscheduled trans-4-MAR enantiomer), not norpseudoephedrine, at least according to the original post I referred to earlier, and presented here for convenience: https://chemistry.mdma.ch/hiveboard/novel/000458588.html

Yeah, just PPA & KOCN.

That's it, plus of course some HCl acid (but that's pretty much a given), and appropriate vessels – though I'm sure some significant skimping could occur here without incident.

They all used it and all damaged their hearts - it's got 5ht2b affinity so it causes heart-valve damage.

They all who? Hive "bees" from circa 2004-ish? I hadn't heard that but I've long suspected 4-MAR is cardiotoxic. Also, I wouldn't plan on using it ceaselessly nonstop for days on end, nor would I recommend that to others.

3,4-MD Aminorex has no 5ht2b affinity not is it an MAOI (4MAR is but AR is not) - Dr. Dave confirmed that, so I think we can rely on the info.

So you're saying the "ecstasy form of aminorex"—if you will, i.e., Aminorex w/a 3,4-methylenedioxy ring substitution on it—has no 5-HT2B serotonin receptor subtype affinity and is also not a monoamine oxidase inhibitor, and neither is Aminorex? However, 4-MAR meanwhile is indeed an MAOI, and that all of this has been confirmed by Dr. David Nichols?

I wonder what would happen if, whilst high on 4-MAR, a healthy person took a ~30 mg blast of DMT freebase crystal… Or even: I wonder if it would be possible to have an ayahuasca-type experience by combining 4-MAR and orally ingested DMT ? ? ? …

 

[unodelacosa]

Oh, I've taken 4-MAR a couple of times, at modest doses. 5HT2b affinity is only an issue if you use for months (their was a disaster CC AR in Germany where it was used as a weight-loss drug. I think the details are on the net.

What was it like? Did it live up to the hype people like Eleusis, aka Jeff Jenkins, ascribed to it in the late 90s on the newsgroup alt.drugs.chemistry?

It's a very clean stimulant (DAT>NET) with moderate SERT. It's my wife who really likes stims, so she had more. It's NOT as good as plain AR (which I have also samples) and not even close to 3,4-MDAR.

Ok so you're saying, for you, it goes: 3,4-MDAR > AR > 4-MAR, is that it? But it would seem to me that MDAR is more ecstasy-like, AR is more Adderall/Amphetamine-like, and 4-MAR is closer to methamphetamine. Is that at all accurate?

Goddamn, if I could just get my hands on some PPA and some KOCN safely…

MDAR takes too many steps to be attractive to producers although the development of L-PAC biosynthesis does make it simpler, Just swap benzaldehyde for piperonal and you get 3,4-MD L-PAC....

Yeah I figured it was one of those things like PMK versus BMK resulting in 3,4-MDMA and Methamphetamine, respectively. Heliotropin isn't the easiest to come by these days though, but then neither is benzaldehyde, relatively speaking and from the clandestine operator's perspective.

But I don't find it a practical target, or an interesting synthesis. I design drugs, I don't take them (other than prescribed) because epilepsy, aphasia and chronic pain - so I'm already a 'polydrug user', simply one who the doctor considers so damaged that it's worth the risk; I presume.

Perhaps, or maybe just embrace the concept of better living through chemistry, and throw in a pinch of "medicated to the one I love" for good measure. Sorry to hear of your suffering though, friend.

BTW, I assume you've already checked Google Scholar for that paper?

 

[Tranced]

So is it a phen?

 

[Fertile]

Mescaminothiazole?
Mescalinaminothiazole?
Trimethoxy-phenmethiazolamine?

At first, I thought you were shooting for Mescalinaminorex, which is actually kinda fun to say. It's like: MESCA-LEENA-MEENO-REX.

Interesting though. I've always wanted to try 2C-B-Aminorex…

Aminorex is zwittrionic with it swapping between endo & exo forms in vivo. While the exo form is a primary amine, the endo is a secondary amine, and we know secondary amines do not bind well at the 5HT2a receptor. The Nichols group DID make an NBOMe type compound but using a phenyl piperidine system but I suspect it's the chain beyond the amine that gave it high affinity despite it having a secondary amine.

So I can kind of think of several possible problems, and I wouldn't bet on it being much fun if it worked - it's duration would be about 24 hours! I always ask the simple question - Dr. Dave has a lab with about 12 workers, a huge budget and an unrivalled knowledge of 5HT2a ligands... and he hasn't touched the aminorex scaffold EVER. I even sent him the QSAR as far as we went, so he had some insights into the QSAR of ring-substituted aminorex compounds... but when I last talked to him, his response was prescient 'BE CAREFUL'.

So far wiser heads than mine have circulated our data (I presume) and neither the teams in Germany or the US have made a single AR.... absence of proof is not proof of absence, but their are many simpler targets. 2-aminobutanes would be an obvious one. The French patented a lot of them in the 1950s as diet drugs - but you end up with 2 chiral centres, which I suspect was an issue.

 

[unodelacosa]

So is it a phen?

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.