Phenampromide analogues

[Fertile]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

You will notice that ALL of the fentanyl analogues can be readily applied to phenampromide with the papers/patents on propiram are valuable.

I am the first to admit that it's the (S) enthiomer that is responsible for the opioid activity but it's quite possible to add the methoxymethyl & 2-thienyl moieties of sufentanil but the more I look, the more I realize that the optimal amide is the propenyl. I've looked into dozens of others and all are less potent.

But other than prhenampromide has a chiral centre (that can be removed from the precursor rather rather than the final product which cuts cost a lot.

You may also notice that the 3,3-dimethyl (why would ANYONE make the monomethyl when multiple examples show that the 3,3-dimethyl is almost as active (only the MW lowers it from x2) and also the aromatics follow those of fentanyl.

Now the 1 item I lack is the synthesis of the 3,3-dimethyl-4-phenyl piperidine. I have looked and looked but with no use.

So a little calculation shows that it's possible to reach about x850 M in potency, isn't controlled by by name and isn't watched. In fact it HAS been sold in Europe.
It's all very well to produce the MOST active, but it's cost per dose that matters. That is why I keep telling people to keep on working with Dimethylaminopivalophenone. After all:

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

But altering the amine destroys activity, removal of dimethyl destroys activity and so a diampromide homologue is about the best one could hope for.... i.e. not much.

 

[Fertile]

BTW of course phenampromide has a chiral centre so introducing a second is going to make 75% of the compound inactive.
Fentanyl is achiral and so is sufentanil which makes them both reasonable targets.

But the phenylpropanamide moiety does seem to produce the most active compounds.

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

So far I have found 3 classes of compound that are based on the phenylpropanamide moiety. Interesting that the pendant aromatic for the cyclic example is only 1 methylene from the phenylpropanamide. Now I THINK that the methyl side-chain is to increase duration (N-benzyl groups are rapidly hydrolised). One aspect that hasn't seemingly been tested is the optical activity of said side-chain.

Let's not forget that (R) alpha methyl fentanyl IS significantly more potent than the (S) so it would seems quite reasonable to assume that since the benzene ends up in a different position, chiral activity is possible.

As for the N-methyl of the spirane. Papers suggest that it behaves like the 4 group of fentanyl so a methoxymethyl is MUCH more potent but it's only in 1 paper and until I find comparative energy-minimization, I have no idea. If it works, the phenylpropanamide moiety must work in an unusual manner.

But this covers 1000s of compounds including brophine - and I'm not sure if that p-Br is needed. I think the researchers looking for 'biases agonists' just included it and so the makers kept in. Certainly paperwork suggests a p-Me in that position LOWERS activity.

But what do they all share? They are achiral. I have a compound some x150 M that seems legal everywhere and from what I can tell, the racemic mix is x150 BUT you would need to either produce chiral intermediates or find a way to resolve - and that isn't a minor problem.

 

[Fertile]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

OK the above is about x150M in (wo)man. That MAY seem an odd way of putting it, but their are other opioids which have been shown to work as decent analgesics for one gender and worse than useless (increased pain) in the other. I refer to gender in a purely genetic sense. I'm not turning this into some gender politics agenda.

I just mean whoever you are - 1mg of the above is as potent at 150mg of morphine. That's the racemic mixture.

BUT it has taught me that an extra N in a scaffold provides 2 different minimum-energy conformations and of course a slightly different bond angle.

I rediscovered U-47700 simply by knowing an ex-Upjohn chemist (who also found BDPC) and so was able to predict U-78891 (specifically the need for the 3,4-dibromo over the slightly smaller 3,4-dichloro) before I read the patents.
But U-78891 is likely a HUGE opening for someone. I mean, it's x75 morphine (so don't eyeball it), it's orally active but still has an impressive rush is taken parenterally.

So the KEY here is obtaining (5S,6R)-N,1-dimethyl-1-azaspiro[4.5]decan-6-amine. But if you have that - it's easier to make then fentanyl. Oh, and their is a modification to U-47700 that makes it x25M. I know ONLY 25 xM doesn't sound amazing - but I defy anyone to tell the difference between the analogue and oxycodone. That makes it worth about $1.50/Mg which is quite impressive.

But I don't post my KEY find. It took 10 years to find a way to convert naloxone into N-2-(2-furyl)ethyl) oxymorphone which means legal to buy precursor and 2 steps to a compound that is around x250M... but with that oxycodone duration.