In the late 1960s a German group studied ethylsulfonyl groups as potential bioisosteres for both esters and ketones. The ethylsulfonyl replaced the esters in pethidine & prodine but more interesting to me is that it also replaced the ketone in ketobemidone - sulfonylbemidone, I suppose. I'm fairly confident that this isn't going to lead to people rushing out to make them - it's quite a lot of effort. I note from 3,3-dimethyl pethidine & 3,3-dimethyl prodine are as potent as the trans isomers of the monomethyl analogues. Likewise, a 3,3 dimethyl moiety on the piperidine ring of propiram also provided the most active (except for adding a 4-phenyl - that overlays fentanyl). Even non-rigid analogues like Dimethylaminopivalophenone (which overlays 3,3-dimethyl pethidine) was the only active member of the class. Adding a S=O spacer to the metofoline's 4-chlorophenylethyl to produce a [(chlorophenyl)sulfinyl]ethyl increases activity by at least an order of magnitude.
Bioisosteres are an interesting concept and without doubt provide potential alternatives. About the most interesting fact was that the sulfonylethyl and sulfonyl-N-propyl are equipotent but the latter is more toxic. If you throw all of those into Reaxys, you will get a whole heap of refs. On a cautionary note, none of them have been trialled in humans and luckily, the low potency (compared with the fentanyl class) does not make them targets of gray markets (well, maybe the 3,3-dimethyl-4-phenyl derivative of metopholine will be some x120 morphine but no WAY is that a simple target.
I'm not listed refs but it is ALL on the Eunoia disc so the people with that 4.7 Gb DVD (almost full) have all of the papers. I'm kind of concerned that dubious people are just looking to make millions in 1 deal. Carfentanil is NOT a good option. It's killed people I know. Interestingly, sufentanil has a truly VAST TI and is inherently a very safe options and the 2-thienyl can be swapped with a 2-furanyl so the product is a)unlisted (but in 1970s ICI patents) & b)novel c)not currently looked out for - apparently x1500 M isn't enough!
So it seems a good move to look at the current situation and wonder why such awful agents represent most of the market. We all know that replacing the N-methyl of levorphanol with an N-phenyl ethyl, an N-(2-thienyl)-ethyl, N-(2-furanyl)-ethyl exist with the latter being x8 (levorphanol) x30 (2-thienyl) & 2-(2-furanyl) x60 have truly VAST TIs. Adding a beta-hydroxy (like the beta-hydroxy fentanyls) also doubles potency.
So, I just posted this with a view to pointing out that the people ordering the stuff have no idea of medicinal chemistry and the Chinese producers aren't very imaginative. Butorphanol can have the -CH3 swapped for an N-2-(2-furanyl)-ethyl in 2 simple steps... but does this reduce the damages opioids are causing or do people simply keep upping the dose to push that TI?
I don't know - I just know that 95% of compounds aren't on the web but they are on the Eunoia Disc so people looking through that will see the massive number of papers and patents... but I presume people who have it are NOT clandestine drug designers - it's just a comprehensive list (2 years of Reaxys research) of everything known (until 2016).
Can we influence the market to push safer alternatives? Should we be producing exhaustive lists with TI data? I don't know - but the data is ALL in 1 place and available to all (well, dozens of discs were produced and so the data isn't controlled).
Bioisosteres are an interesting concept and without doubt provide potential alternatives. About the most interesting fact was that the sulfonylethyl and sulfonyl-N-propyl are equipotent but the latter is more toxic. If you throw all of those into Reaxys, you will get a whole heap of refs. On a cautionary note, none of them have been trialled in humans and luckily, the low potency (compared with the fentanyl class) does not make them targets of gray markets (well, maybe the 3,3-dimethyl-4-phenyl derivative of metopholine will be some x120 morphine but no WAY is that a simple target.
I'm not listed refs but it is ALL on the Eunoia disc so the people with that 4.7 Gb DVD (almost full) have all of the papers. I'm kind of concerned that dubious people are just looking to make millions in 1 deal. Carfentanil is NOT a good option. It's killed people I know. Interestingly, sufentanil has a truly VAST TI and is inherently a very safe options and the 2-thienyl can be swapped with a 2-furanyl so the product is a)unlisted (but in 1970s ICI patents) & b)novel c)not currently looked out for - apparently x1500 M isn't enough!
So it seems a good move to look at the current situation and wonder why such awful agents represent most of the market. We all know that replacing the N-methyl of levorphanol with an N-phenyl ethyl, an N-(2-thienyl)-ethyl, N-(2-furanyl)-ethyl exist with the latter being x8 (levorphanol) x30 (2-thienyl) & 2-(2-furanyl) x60 have truly VAST TIs. Adding a beta-hydroxy (like the beta-hydroxy fentanyls) also doubles potency.
So, I just posted this with a view to pointing out that the people ordering the stuff have no idea of medicinal chemistry and the Chinese producers aren't very imaginative. Butorphanol can have the -CH3 swapped for an N-2-(2-furanyl)-ethyl in 2 simple steps... but does this reduce the damages opioids are causing or do people simply keep upping the dose to push that TI?
I don't know - I just know that 95% of compounds aren't on the web but they are on the Eunoia Disc so people looking through that will see the massive number of papers and patents... but I presume people who have it are NOT clandestine drug designers - it's just a comprehensive list (2 years of Reaxys research) of everything known (until 2016).
Can we influence the market to push safer alternatives? Should we be producing exhaustive lists with TI data? I don't know - but the data is ALL in 1 place and available to all (well, dozens of discs were produced and so the data isn't controlled).
