Arylcycloalkyl(Methyl)amines SNDRI

[paracelsius]

I was quite intrigued reading that sinovion patent about arylcycloalkyl-methylamines that are extremely potent triple SNDR uptake inhibitors. Not arylcycloalkylamines disso. Basically move the amine of arylcyclohexylamines up one carbon for example like this:

Now looking closely it looks like 4-methylmethcathinone (mephedrone, 4MMC):

a classic triple SNDRI and releaser with its carbonyl replaced by a cyclopentyl.
Now this cyclopentyl compound above is some 300x more potent at SERT DAT NET than meth but unlike meth or meph is straightforward cocaine-like substrate reuptake inhibitor (balanced) but not releaser. Now would it also be a NMDAr antagonist? (couldnt find any info on that).. My guess is probably not... way more easier to synth than the arycylcohexylamines in 2 steps from dirt cheap para-methyl-tolunitrile!! but then again it is a STILL a phenenethylamine distant cousin, or is it?!!
EDIT: I don't trust patent literature too much..sometimes they exaggerate but it looks like they did pretty extensive SAR on this class

 

[Gaffy]

I believe making the carbon into phenylcycloisopropylamine instead of ethylamine will in turn make it both a reuptale inhibitor and a releaser, a bit like amphetamine or cathinone pyrrolidines

 

[Gaffy]

Just a little example of the many possibilitys

 

[Gaffy]

Or

 

[Gaffy]

Sekio will say it's either inactive or too bulky, I believe we'll see those when the ban will have been passed in the Netherlands

 

[paracelsius]

^ yeah sure there are tons of possibilities (have you heard of Markush enumeration like that: R1--N(R2)---R3 where R1, R2 R3 is pretty much anything you can imagine!!! google it..you can also do that but it wont take you far!..but then again for this compound class why "reinventing the wheels"?..it is already done, extensive SAR of hundred of analogs in that patent.
oh btw dont put too much trust on that swiss target prediction!!

 

[clubcard]

Swap the cyclopentyl for a cyclobutyl and the result overlays the ring-substituted amphetamines perfectly. Look at sibutramine. I did consider making this modification to PEAs but it's far too much work for a low-potency product. Now, in the case of synthetic THCs, swapping the dimethyl of the side-chain for a cyclobutyl and the product is 2 orders of magnitude stronger. Forget discoverers name, A Greek chemist, if memory serves.

 

[paracelsius]

Swap the cyclopentyl for a cyclobutyl and the result overlays the ring-substituted amphetamines perfectly. Look at sibutramine. I did consider making this modification to PEAs but it's far too much work for a low-potency product...

No actually in that case the cyclopentyl is the best (v cyclobutyl or cyclohexyl). Thats because those are more comparable to coke/tropanes than amphs. Try overlaying OP compound with troparil: quite perfect fit with the cyclopentyl overlays the pyrolidine of troparil/coke nicely. Better yet, dock the OP compound to hDAT in complex with troparil: you can't beat that. as good as it gets!

I bet anything they bind same way as coke or aryltropanes not amphs! to DAT at least. That's why they pure coke-like reuptake inhibitors, not amph-like releasers.
As for potency some of those are actually extremely (and I mean extremely) potent at both DAT-NET-SERT with OP IC50 of 3, 9 and 3nM resp compared to coke > 200nM at both 3 transporters. Same with sibutramine (OP is about 100xtimes sibutramine across all 3). The 3,4-dichloro is even more insanely potent (~0.8nM at DAT-SERT ie more than 200xcoke!!!!!).

As for synth, it is actually straightforward (ArCH2CN+BrCH2CH2CH2CH2Br+base)->1-cyano-1-arylcyclopentane) then reduce the nitrile to amine and then reductive alkylation. Tons of ways to do the last two steps. Even the first primary amine(from nitrile reduction) is quite potent I just worry it might not survive MAO first pass metabolism but who knows? My guess the first step you wont really need strong base(NaH)/inert atmosphere like they did in the patent. Simple potassium carbonate in boiling toluene will do may be with a pinch of catalytic KI to speed things up...not sure if synth talk allowed here but @ MOD: remove if that is not the case)...

here US10562878 quite extensive SAR if interested (literally several hundreds of cpds tested.. stay safe all BLighters