Synthesis and pharmacological studies of 4,4-disubstituted piperidines: a new class of compounds with potent analgesic properties

[AlsoTapered]

Library Genesis

libgen.pm

Page 398, section 11.4 4-Pipedidinols in the book 'Opiate Analgesics - Chemistry and Receptors' by Casy & Parfitt

A large number of compounds were tested and although the book incorrectly identifies the MOST potent example as being:

2-[1-[2-(2-chlorophenyl)ethyl]-4-hydroxypiperidin-4-yl]-N-(2-methoxyphenyl)-N-prop-2-enylpropanamide

With an ED50 of 0.07 mg/kg compared to 3.4 mg/kg for morphine in animal models i.e. around x48 morphine, it represents a facile target BUT what is actually of MORE value is the detail that both the A & B aromatics are substituted. The A-aromatic possesses an O-methoxy although the O-ethoxy was almost equipotent. The B-aromatic has an O-chloro moiety. Now the former substitution is also seen in diphenpipenol ((S) isomer is x105 morphine), an MT-45 derivative that is 118 times more potent than the parent compound.

The important question is WHY. I strongly believe it's because the o-methoxy fixes the rotation of the A-aromatic. So the question is, has someone applied this lesson to, say, fentanyl? The answer is yes they have.

Library Genesis

libgen.pm

Compound 3 is O-methoxy fentanyl.

Is it more potent than the parent compound? Yes, 4 times as active, from the VERY limited study.

From which we can deduce that keeping the rotation of the A-aromatic relative to the nearby piperidine or piperizine (i.e. the moiety containing the basic nitrogen) is key to increasing MOR affinity.

 

[Hexenstahl]

Even though this subject is at this point in time way too complex for me to understand, I'm going to order that book because that is exactly what I was always looking for: an encyclopedia of opioids with an emphasis on the neurological and chemical aspects of this substance class. Strange how amazon doesn't offer this book though. I'll see where I can buy a physical copy of it and start reading it as soon as my knowledge in chemistry has become advanced enough. Thanks for this thread. Without it I wouldn't have discovered this amazing treasure trove of a book

EDIT:
holy mother of God, the hardcover version costs 300€!!! Are these people on crack??? I always knew textbooks are expensive, but knowledge souldn't be THIS expensive!

 

[AlsoTapered]

There are free .PDF versions available on-line.

BTW note in the first paper that R3 i.e. one of the two 4-substituants of the piperidine was only one of 3 moieties:

1 - H
2 - OH
3 - OCOCH2CH3

And the -OH examples were all, by far, the MOST active. But they did not try alkyls, ethers or a methoxy ester. So it seems highly likely that such modifications would have significantly increased activity. It's important to note that while 3-methyl fentanyl was known, 4-methyl fentanyl was only tested a few years later. Neither had the 4-methoxy nor the 4-methoxymethyl - both KNOWN to be much more active. Why they didn't try the methyl ester I don't know but suspect that it represented a 'magic methyl' i.e. to test the formate ester would have required a totally different synthetic methodology.

But it I've learnt one thing, it's that medicinal chemists OFTEN do not look at papers from other nations. The Swiss evidently DID look at the Japanese work but the unusual opioid they found was likely to develop molecular probes rather than facile medicines.

It's also worth noting that while the book specifies the N-ethyl homologue (amide) being the most potent, PubChem suggests that the N-allyl amide is a lot more potent.

(Z)-but-2-enedioic acid;2-[1-[2-(2-chlorophenyl)ethyl]-4-hydroxypiperidin-4-yl]-N-(2-methoxyphenyl)-N-prop-2-enylpropanamide

(Z)-but-2-enedioic acid;2-[1-[2-(2-chlorophenyl)ethyl]-4-hydroxypiperidin-4-yl]-N-(2-methoxyphenyl)-N-prop-2-enylpropanamide | C30H37ClN2O7 | CID 54586957 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities...

pubchem.ncbi.nlm.nih.gov

In fact the affinity data suggests that it could be 2 orders of magnitude more potent. This modification was tried with fentanyl and reduced potency but in this case I suggest that the pi-bonding represents a 'fragment' of an extra aromatic ring showing that the Swiss work was DEEPLY influence by said Japanese work i.e. 3 aromatics are represented.

2-[1-[2-(2-chlorophenyl)ethyl]-4-hydroxypiperidin-4-yl]-N-(2-methoxyphenyl)-N-prop-2-enylpropanamide

 

[AlsoTapered]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

BTW above is a link to the most potent of the series according to PubChem.

It ALSO lends further data inferring that U-93951, the U-47700 derivative IS indeed a lot more potent than the parent compound. It the U-77891 N-substituent (which is compatible) were also added, the final compound could well be several hundred times more potent than morphine.

 

[Hexenstahl]

There are free .PDF versions available on-line.

I've only been able to find this https://z-lib.is/book/opioid-analgesics but this edition seems to be from 1986. Doesn't matter as it is too early for me to read that book anyway. By the time my knowledge has advanced enough I have probably saved enough money to buy the hardcover version lol.

Edit:
I just noticed that the 1986 edition is the only edition that exists lol, so it shouldn't be an issue. I'm gonna download it and let my local library print those pages and bind them for me.

 

[AlsoTapered]

You hardly imagine that such a book to be a best seller. 2000 copies were printed and they still haven't sold them all - but given that the book was essentially the practical part of a masters qualification in medicinal chemistry, it apparently took 2 people eight years...

 

[Hexenstahl]

I mean if the intention behind such an astronomically high price was to serve as a kind of barrier to make sure only a certain type of people would get the information, then I would understand it, but if the intention was to simply make money then I really don't understand it because these kind of books really don't sell well. In that case it would have made more sense for the authors with all their extensive knowledge in the chemistry of opioids to found a pharmaceutical company specializing in the manufacture and marketing of this tasty substance class. Oh well...

 

[AlsoTapered]

No - I doubt the authors, printers or publishers ever intended to make a profit. But it's aimed at specialist libraries - essentially 1 copy to each university that offered a post-graduate course in medicinal chemistry. Still QUITE costly but imagine that every year 8 students read the book and have done since 1987 (before the internet was common). In those terms it's doing what it's meant to do.

I don't think university libraries are inaccessible to the public. They may not let you take books home but nobody should have trouble accessing a physical copy.

But that book is sort of the 'easy' one.

The real masterwork was 'Opiates' by Lenz, Evans, Walters and Hopfinger which is about three times the size and came out in 1986. And you won't be surprised to learn that it was ALSO part of a masters qualification.

Again, before the internet and only buyers were expected to be university libraries.

BUT both of them have turned up on Scribd.

Neither the authors nor the printers are actively preventing digital copies being shared. The publishers and wholesalers MAY have a few copies left in storage... but essentially they are historic works. I imagine ALL of the authors are retired by now.