14-OH dihydrocodeine and tilidine analogs

[haribo1]

The compound 14-OH dihydrocodeine is not an illegal drug in the UK. Oxidtion yields the potent oxycodone but the drug itself isn't listed. Now, as far as I can tell, it's not much more potent than straight DHC BUT, the 14-cinnamyl ester is 50x codeine in potency (and likewise isn't controlled). The question is, with the 6-OH being a secondary alcohol and the 14 being a tertiary alcohol, can the 14 alone be esterified alone? Or, for that matter, can the 6-OH be removed. The 14 cinnamyl of oxycodone is 80x codeine and I'm wondering about this unusual branch. We don't have a general analog act in the UK. Phenethylamines are bunched up together, but not opiates.
That being said, I woulder if one could obtain this widely used intermediate.

14-hydroxy nor dihydrocodeine would have even more scope. N-phenylethyl AND a 14 cinnamyl would surely be an interesting thing to mess about with.

Oh, and while on the subject. The phenyl piperidine esters & reversed esters are banned on-bloc but the ketone ones are not. Only ketobemidone is specifically mentioned. Replacing the N-methyl with a beta -OH phenyl propane group would be interesting, or adding a gamma double-bond. In the pethidine series, a gamma = bond and a para -NO2 yieldes a product 29x that of the parent. So, doing both as well as adding a meta -OH to the phenyl ring should be interesting.

I really, really wish someone could come up with a automated tool that would estimate the potency of opiates automatically. I mean, we know more about the SAR of this series better than any other class of medication AFAIK....

Thankyou for sitting through this ramble...

Oh, ast point. Tilidine is unusual in that it's a prodrug. It has to lose one or both of the N-methyl grroups to become active. So, making the analog already 1 methyl short would be legal and I would assume stronger. Also, reversed ester time? or even a ketone? I think it's worth considering...

 

[haribo1]

I cannot find any papers discussing the SAR of the tilidine class but the N-desmethyl appears to be the most potent. It's a codeine potency class of opiate, but the reversed ester or the ketone might yield something of more interest. The fact that it's active at all is a minore miracle. It doesn't follow the morphine rule. I know that the double-bond is important in activity...

Of course there are 4 isomers but only one is active. How DID it get invented? What were they looking for?

 

[morphiquet]

when you look at the structure of tilidine you find that it is quite similar to methylphenidate and i am convinced that it has been discovered in line with these dopamine-reuptake-inhibitors
(i am also convinced that tilidine itself does inhibit dopamine- and possibly na-reuptake, from personal experiences; i haven't found any drug that is more effective in motivating and helping you to learn, ie for tests). %)

 

[fastandbulbous]

^ In that it contains a phenethylamine skeleton yes, but methylphenidate has the amine incorporated into a heterocyclic ring. If anything, the stimulant it most reminds me of is fencamfamine (which itself has some opiate activity) or possibly cypenamine (trans 2-phenylcyclopentylamine).

Possibly that would also be why the above two stimulants have also been dished out to people suffering from the start of senile dementia, to facilitate memory retention

 

[resorcinol]

14-OH-dihydrocodeine sounds like it would be a pretty decent drug, probably somewhere betwenn hydrocodone and oxycodone.

Man would I love to be able to try it.

 

[morphiquet]

@fast&bulbous: tilidine has all functional molecular subunits in exact the same positions as does methylphenidate -> sec. amine (in nortilidine, the active metabolite); the carbonyl-moiety and the phenyl-ring.

i rather think that it's just the other way round: the reason that methylphenidate is not an opiate is its lacking tertiary carbon and possibly the double-bond of tilidine.

 

[mad_scientist]

Interesting that bisnortilidine is a mu-opioid full agonist too, very unusual for a primary amine to be an active opioid. Only other example I know of is dezocine, and thats one of those yucky mixed agonist-antagonists.

Must make for some messy pharmacokinetics when the parent drug is inactive but both the primary and secondary metabolites are full agonists, I'd imagine the effects of tilidine will vary markedly between individuals depending on how active their metabolic enzymes are.

 

[fastandbulbous]

i rather think that it's just the other way round: the reason that methylphenidate is not an opiate is its lacking tertiary carbon and possibly the double-bond of tilidine.

As mad scientist's post indicates, tilidine is an unusual compound that doesn't follow the rough & ready rule for the structure of opiates. Also, methylphenidate requires the heterocyclic ring so that ti binds to the dopamine transporter in an non transportable way (like pipradrol/desoxypipradrol, cocaine etc) Ones that get transported generally cause some dopamine efflux in the process as well.

Other than that, reducing the ester to a methyl generally vastly reduces mu agonist activity in the agonists based on pethedine whereas ethylphenidate has only a fraction of the activity of methylphenidate

 

[haribo1]

The published synthesis of tilidine is old, Old, OLD school. The route would be easily adapted for nortilidine, but then how strong IS nortilidine? It's just such an unusual opioid and the little I can find on research is in some odd language (not Russian)

 

[mad_scientist]

From what I could find on PubMed, both nortilidine and bisnortilidine are mu-opioid full agonists, nothing about comparative potency from what I could find, but they estimated that 30-40% of an oral dose of tilidine would be converted into nortilidine, and if we assume that tilidine itself is inactive, then since its used in a dose of 50-100mg, this would suggest nortilidine will be active in the 15-30mg range. So not bad, comparable to oxycodone perhaps?

 

[haribo1]

^Thats the range that codeine becomes active. Oxycodone is active at more like 5mg. Any thoughts on a reversed ester (or indeed a ketone) of tilidine?

 

[mad_scientist]

Yeah I know oxycodone is active at 5mg, but its not really fun until 20mg or so...

Whats the advantage of a reversed ester? Apart from changing the legal status, it wouldn't do much to the activity I don't think. Ketone might be a go though, propanoyl seems much better then ethyl ester if you compare say pethidine and ketobemidone.

I'd be curious about other substitutions on the nitrogen, or on the aromatic ring for that matter. Anyone got any references on the SAR of tilidine analogues? Difficult finding decent SAR reviews for the older drugs.

 

[haribo1]

^With the phenyl piperidine opioids, the reversed esters are the strongest. Ketobemidone has that meta -OH AND is an NMDA agonist (so is bemidone, so I guess the meta -OH does it?) Ketobemidone without the -OH is WEAK. MPPP on the other hand...