Stimulants of the Future

[Refluxer]

A photo of the tablets claimed to contain either 50 or 100 mgs of 2-benzylpiperidine surfaced:

They are huge, but the effects people claim they have show they contain a stimulant of some sort. An analysis of them would be wonderful.

 

[hussness]

^So do you know yet whether it's 2-benzylpiperidine or 2-benzylpiperazine?

 

[Refluxer]

No idea. The picture is not mine, I just found a link. If I had unrestricted access to GC/MS/NMR I'd buy some and analyze it - but I don't.

 

[Helios.]

Supposedly they are piperidine things. But there is somewhat of a language barrier going on here.

 

[fastandbulbous]

2-benzyl-pyridine.
2-piperonyl-pyridine.

Once you turn the heterocyclic ring aromatic you get a change in activity, generally to the detriment. An even better compound would be 3-benzylmorpholine which has the same phenylisopropylamine skeleton that most stimulants have, but of the pipradrol derivatives made by altering the nitrogen heterocycle ring, the morpholine derivative proved to be the most potent. This also applied to the compounds where one of the phenyl groups was replaced by a hydrogen, which includes 2-benzylpiperidine. The fact that in the case of amfonelic acid the nitrogen is in an aromatic ring makes this a weird compoiund in my eyes!

 

[Helios.]

^We've already covered the 2-morpholinyl things.

 

[fastandbulbous]

^We've already covered the 2-morpholinyl things.

Not very well then as they're actually '3-morpholinyl things' as the ring numbering starts on the oxygen, not the nitrogen.

I was simply pointing out that the morpholino derivatives of compounds containing only one aromatic ring (eg 2-benzylpiperidine) follows the same potency sequence for the different heterocyclic rings as does the compounds with 2-aromatic groups (eg. pipradrol, 2-(alpha, alpha diphenylmethyl)piperidine etc) in that the best of both groups are the morpho;ine derivatives; everybody seems dazzled by 2-benzylpiperidine yet the morpholine derivative would be a much more simple synthesis

 

[Helios.]

A lot of if has to do with availability.

As for simplicity / elegance of synthesis:

(1) Benzene or 1,3-benzodioxole + d-2-(CO2H)-piperidine + hypophosphorous acid
(2) H2N-NH2, KOH.

If you want it your way, I don't see why d-3-(CO2H)-morpholine couldn't be substituted for d-2-(CO2H)-piperidine in the above outline.

I'm not disagreeing with that which you say in any way, except my outline looks about as simple as it gets.

 

[Refluxer]

I just thought of sticking a second phenylring at the 1 position on amphetamine, i.e. 1,1-diphenyl-2-aminopropane. I realize this will make the molecule much more clumsy/bulky, but since several other stimulants have a similar structure maybe it can have activity? And you can also expand this to several other symmetric isomers.

Anyone heard about this one? I'm sure it has been examined somewhere sometime.

 

[MattPsy]

Something similar, (S)-diphenyl-2-pyrrolidinyl-methane, is a CNS stimulant active in dosage of 25mg to 100mg...

 

[vecktor]

A lot of if has to do with availability.

As for simplicity / elegance of synthesis:

(1) Benzene or 1,3-benzodioxole + d-2-(CO2H)-piperidine + hypophosphorous acid
(2) H2N-NH2, KOH.

If you want it your way, I don't see why d-3-(CO2H)-morpholine couldn't be substituted for d-2-(CO2H)-piperidine in the above outline.

I'm not disagreeing with that which you say in any way, except my outline looks about as simple as it gets.

not quite, for elegance and simplicity, commercially available 2-benzyl pyridine 1 step to 2-benzyl piperidine.

 

[Helios.]

It (the 2 phenyl amphetamine) won't have any more chiral centers.

vecktor,
yes that's even easier with some hydrogenation.

However, my dear <0,0,0> to <x,y,z> for a given time being, your way results in racemic 50/50 d/l R/S 2-benzylpiperidine while my, slightly--only slightly--more complex method, being stereospecific, spits out pure d-2-benzylpiperidine.

Availability of starting precusor compounds is always an impotant considerartion either way.

"Things should be made as simple as possible to be correct, but no simpler."--Einstein.

d-benzylpiperidine is 2x as valuable as racemice 2-benzylpiperidine.

 

[fastandbulbous]

Something similar, (S)-diphenyl-2-pyrrolidinyl-methane, is a CNS stimulant active in dosage of 25mg to 100mg...

Ah, but the heterocyclic compounds are different beasts to the amphetamines. Whereas the heterocyclic compounds are reuptake inhibitors, amphetamines cause neurotransmitter release as well as inhibiting reuptake so it's not clear cut as to what the action of 1,1-diphenyl-2-propylamine. I've thought about that several times in the past but was never able to dig up much in the way of pharmacological info. On that same basis I've also wondered about beta carbon substitution of a methyl group to give 2-phenyl-3-butylamine (alpha, beta dimethylphenethylamine); this does introduce another chiral centre though so you've then got 4 isomers possible

 

[Smyth]

The butane compounds have been looked at in the past on a paper concerning conformationally rigid meth analogs. Data extracted from the article is included in the attachment. Nothing too exciting but worth viewing for information purposes.

There's been alot of work by Rothmann on dual 5HT/DA releasers lately. A quick search on JPET will yield the relevant documentation. It seems that they are quite anorectic even though they are in no way reinforcing/rewarding. This has been attributed to activity at the 5HT2C receptor subtype. It's doubtful that these compounds represent stimulants of the future but it still represents present day research in the treatment of stimulant abuse.

 

[Helios.]

Is it just me or do DA/5HT reuptake inhibitors generally suck?

 

[Refluxer]

EDIT: I was whoozy in the head and thought I read something else.

 

[Refluxer]

I would greatly appreciate if anyone could help me find the following article on 2-DPMP:

J. Tripod, Experientia, 1954, Vol. 10, p. 261

 

[Helios.]

fastandbulbous obviously gets credit for this one:
3-benzyl-morpholine HCl.

 

[Refluxer]

Nevermind.

 

[Refluxer]

Fast and bulby:

You mentioned 2-phenyl-3,6-dimethylmorpholine earlier. Can you dig up any references as I'm interested to read some more. And how about that molecule but with 3,5 substitution instead?

EDIT: Satisfied now, huh? :D