Re PiHKAL #81: Hydroxyl analogues

[Belisarius]

For some time I've been fascinated by this statement from Shulgin's entry for FLEA:

Just how general might this concept be, that an N-hydroxyl analog of an active amine shall be of similar action and duration as the parent drug? What if it really were a generality! What havoc it would wreak in the pharmaceutical industry! If I could patent the concept, then I would be able to make parallel best sellers to all of the primary and secondary amines out there in the industry. Perhaps 90% of all the commercially available drugs that are concerned with the human mental state are amines. And a goodly number of these are primary or secondary amines. And each and every one of these could be converted to its N-hydroxyl analogue, effectively by-passing the patent protection that the originating corporation so carefully crafted. An example, just for fun. A run-away best seller right now is an antidepressant called fluoxetine, with the trade name Prozac. I will make a small wager that if I were to synthesize and taste N-hydroxy-N-methyl-3-phenyl-3-((a,a,a-trifluoro-p-tolyl)oxy)propylamine, I would find it to be an active antidepressant. Remember, Mr. Eli Lilly and Company; you read about it first, right here!

link:
http://www.erowid.org/library/books_online/pihkal/pihkal081.shtml

My question for those in the know is: just how general do you think the principle is that hydroxylated analogues of amines are--or should be--equipotent and similar in action to the originals? Has this been true in the studies you've read or known about? As he mentioned, there are a huge number of amines out there; if hydroxy analogues could double their number, it might be a major find.

Thoughts?

 

[tathra]

check also the HOT compounds, the hydroxy analogues of the 2ct series.

it seems to work for psychedelic phenethylamines, but i'm not so sure you could broadly apply it to every psychoactive amine. but hey, who knows. its definately worht looking into

 

[fastandbulbous]

I think as a generalization it holds true. The only problem is (as far as I can gather) that even at room temp conditions, it doesn't take much for the nitrogen to loose the OH group and have it replaced by a hydrogen atom.

There's a case of somebody in the UK who'd gone for synthesising N-hydroxy DOB as a way to get around the Misuse of Drugs Act, but when the forensic labs got it, they reported that the sample contained some DOB as well as the hydroxy compound. Last ref I saw about it was that they were appealing, saying that the storage conditions, or the labs handling of it had caused it to change to DOB. I'll try and find the refs for anyone interested in the legal situation.

Although the N-hydroxy DOB doesn't seem to be the most stable compound in the world, I can't remember Shulgin making any comments about the HOT series or any of the other N-hydroxy derivatives.

PS Obviously it wont apply to any drug that's a tertiary amine

 

[anhalonium9]

very interesting....

 

[tathra]

fastandbulbous

HOT-7

EXTENSIONS AND COMMENTARY: There is a working hypothesis that has been growing in substance over the last few years in this strange and marvelous area of psychedelic drugs. It all was an outgrowth of the rather remarkable coincidence that I had mentioned in the discussion that followed MDOH. There, an assay of what was thought to be MDOH gave a measure of activity that was substantially identical to MDA, and it was later found out that the material had decomposed to form MDA. So, MDA was in essence rediscovered. But when the true, valid, and undecomposed sample of MDOH was actually in hand, and assayed in its own rights, it was found to have a potency that really was the same as MDA. So, the working hypothesis goes something like this:

AN N-HYDROXY AMINE HAS APPROXIMATELY THE SAME POTENCY AND THE SAME ACTION AS ITS N-HYDROGEN COUNTERPART.

Maybe the N-hydroxy compound reduces to the N-H material in the body, and the latter is the intrinsically active agent. Maybe the N-H material oxidizes to the N-hydroxy material in the body, and the latter is the intrinsically active agent. Either direction is reasonable, and there is precedent for each. The equivalence of MDA and MDOH was the first suggestion of this. And I have made a number of NH vs. NOH challenges of this hypothesis. The interesting 2C-T-X series has provided a number of amines that are amenable to N-hydroxylation, and this is the first of them. And, after all, if you put a hydroxy (HO) group on a thio material (T), you have a HOT compound.

So, as far as nomenclature is concerned, the family of N-hydroxy analogues of N-H amines is known as the HOT family.

How does HOT-7 compare with 2C-T-7? They are almost identical. The same range of dose (centering on 20 milligrams) and if anything, perhaps slightly less long lived. Lets try some other N-hydroxys!

 

[Smyth]

^^ Interesting case F&B. I would like to know how this washed with the LE. At least in principle, it appeared that the chemist had innocent intentions.

 

[fastandbulbous]

At least in principle, it appeared that the chemist had innocent intentions.

No he didn't, he was trying to get 'round the Misuse of Drugs Act classifications; that said, I feel sorry for the bloke - convicted of manufacturing a class A drug because he didn't read up on hydroxylamine derivative stability

 

[Smyth]

Yeah, he was probably quashed by the case against him like a pedestrian trying to stop a moving vehicle. It is written all over PIHKAL with FLEA or MDOH, one need only drag up the reference to see what fragile risky water he was sailing in.

That said, this shows that it is much better to spend money in R&D of novel compounds not covered in the MDA than it is to wittingly do something illegal and lose $1000's of lab & the hassle of going to court and possibly losing your job in the process of it. The excitment of this is that you may even find something better in the process. And good discoveries could last you a lifetime.