Indanylamphetamine - A new potent MDMA analog

[ChemisTris]

psycosmo said: "I wonder what would happen of the oxygens in the MDO group were replaced with nitrogens"

I have thought about this too. Although Rhodium said it may be too polar to cross the blood-brain-barrier, and thus be inactive, i have found a referance that would suggest some potential activiy.

Medicinal agents in the series of b-phenylisopropylamine derivatives.  VI.  Benzimidazole analogs of b-phenylisopropylamine.
Piotrovskii, L. B.; Kudryashova, N. I.; Khromov-Borisov, N. V.    Inst. Eksp. Med.,  Leningrad,  USSR.
Khim.-Farm. Zh.  (1975),  9(10),  3-5.  (CA 84:30964)

Abstract
Aminopropylbenzimidazole (I, R = H) was obtained in 50% yield in 6 steps from p-O2NC6H4CH2CHMeNH2 by redn., acetylation, nitration, deacetylation, redn., and cyclization by HCO2H.  Addnl. obtained was 60% I (R = Me).  I have potential sedative activity (no data).
(my bold)

The journal is written in Russian. I don't have access to this, nor do i speak Russian, so if any Russian speaking bees are interested in this, i would love to hear more  

My next thought is the potential placement of a lipophilic group on one of the benzimidazole nitrogens. Not a bulky lipophilic group, but something small, Me or Et to make the molecule more suitable for crossing the BBB, but then the question is - will the molecule have suitable activity at the receptor.

Would anybee care to comment?
Got democracy?

http://www.dhushara.com/book/multinet/democ/wed.htm

[Rhodium]

VERY interesting... I would love someone to prove my assumption wrong about nitrogen-substituted derivatives being too polar to be active, because if that is true we have a lot of nitrogen-based analogs to try out...

[ChemisTris]

Yes, Rhodium, it would be most interesting! I originally became interested in these analogues after learning more about isosteres. I had assumed that they would posses some activity, but we really need details now.

Of the (limited) liturature i have about benzimidazole analogs, much of it is based around Dopa analogues with carboxylic acid groups, and obviously these are too polar to cross the BBB.

There is a ref where X (where X = the methylene bridge) has been replaced by C=O (this would be too polar i assume), N (again more polar), SO₂ (polar again). These are of limited value to us, but how about where X = C-Me. (all these with the N-X-N ring system). The C-Me has been prepared, but on a molecule with a COOH on it   .
The referance for all this was:
Synthesis of dopa and dopamine analogs with acidic imido-functionalities in heterocyclic ring moieties instead of the phenolic hydroxyl groups.
Schmidhammer, H.; Hohenlohe-Oehringen, K.
Inst. Organ. Pharm. Chem.,  Univ. Innsbruck,  Innsbruck,  Austria.    Sci. Pharm.  (1983),  51(1),  8-16. CA 99:140318

The abstract i have of this doesn't say much except that the were prepared through known methods.
Got democracy?

http://www.dhushara.com/book/multinet/democ/wed.htm

[Lilienthal]

The -O-CH(CH3)-O- analogs are inactive. That has been published several years ago in J. Med. Chem.

[Dr_Heckyll]

There are always surprises. The other day I ran into some compounds which had a quarternary nitrogen and still were antidepressants, i.e. get through the BBB. I wouldn't have believed it if I hadn't seen the pharmacological data with my own eyes. This is so contrary to all I would have expected. And they were active orally! In a way that was a mind-opening experience for me! I ain't say again: oh, this is too polar   ...


For every molecule there is a moron thinking it will be a great drug

[tiresias3]

Nitro groups have a plus charge on the N and may be too polar to cross the BBB, but cyclized alkenylamines attached to a phenyl such as indole are certainly not too polar to cross the BBB. 

However, these PEA's are 'Thanatos' in nature because their N (an aniline) is antiaromatic, rather than 'Eros' like the alkoxy-AMPs, with their activated phenols and such.

DMT is 'Thanatos.' 

5-carboxaldehyde-indole is a new product from Sigma-Aldrich @ $85.15 per 5 grams.  You may or may not bee interested,
"I mean, we'll take it slow, I really don't know."--Tricky

Note:  Regular indole is 3-carboxaldehyde-indole, unless I'm naming it wrong, but I think you will at least get the idea.

.

"You're schemin' on a thing that's a mirage.  I'm tryin' to tell ya'll now it's a sabotage"--the BBB's, _Ill Communication_

[Rhodium]

I get the idea. There have already been something published about 4-(N,N-dimethylethylamino)-indole compunds (they called them "iso-DMT's") and they were active, at least in in vitro assays. Very cumbersome synth though. Now, could you carry the above 5-indolecarboxaldehyde through all the usual steps without anything attaching to the very reactive indole 3-position?

[moo]

Oh, yes   . From Tihkal #48, alpha-methyltryptamine, extensions and commentary section:

"And there are five possible chain relocation, from the normal 3-position to the 2, the 4, the 5, the 6 or the 7-positions. All five "alpha-methyltryptamine" isomers are known, but only one is known to be active in man as a CNS active material. This is the 5-isomer, 5-(2-aminopropyl)indole or 5-IT, which, at 20 milligrams orally, is a long-lived stimulant producing increased heart-rate, anorexia, diuresis, and slight hyperthermia for about twelve hours."

[TheRampartLion11]

The IUPAC name for that compound is actually IAN-AMP, but who knew?

.

[gamilaraay]

[Promethium]

There is the possibility that you obtained a mixture of 4- and 5-indanylamphetamine (2-indan-4-yl-1-methyl-ethylamine and 2-indan-5-yl-1-methyl-ethylamine). J. Org. Chem., Vol. 39, No. 19, 1974, 2852 describes a procedure very similar to yours and it produced a 20:80 mix of 4- and 5-indanaldehyde. A different temperature or whatever...and your mix might have been even more unfavourable. The 4-IAP might have then modified the psychopharmacology of the 5-IAP, who knows?

I wonder, btw, why those who have apparently tried IAP (Rhodium, FractalFlower...) are not sharing their experience. Is IAP the great big secret? Basic pharmacological considerations indicate that it's some 4-6x more potent than MDMA, with a significantly longer duration of action due to the absence of the metabolically unstable methylenedioxy group.

PS: According to your write-up you used TiCl4 as catalyst, just like in the JOC paper, where it leads to the 20:80 mix, while Nichols in his JMC publication used SnCl4 and got a 98% yield. You could check the melting point of your final product, which should be 218-219 °C.