Those old ass sulfone downers, sulfonal, trional, tetronal

[Limpet_Chicken]

Ok, started a thread on these years back, never got going though really, aside from some interesting stuff from hammilton and co.

What I'm wondering...is has ANYBODY actually tried any of these.

I have looked all over, and I cannot find a single bioassay report. other than some accounts of the general properties of sulfonal, trional and tetronal in some medical books I have dated from around the time these first came into use. And a warning in a very old book on forensic toxicology, which warns that a phenyl substituted analog, or might have been diphenyl...one of these was inactive, the other 'rankest poison', and indicating it to be of an exceedingly virulent nature, yet does not elaborate.

 

[sekio]

from ze Martindale Extra Pharmacopiea 1941

Sulfonal
Dose. 5 to 20 grains (0.3 to 1.2g), in cachets or suspended in mucilage. Should be finely powdered and followed by hot fluid. Unless in solution the dose should be given 1-2 hours before sleep is desired.
In colorless crystals or powder, tasteless and odorless. M.p. about 126deg.
Soluble. 1 in 450 of water, 1 in 15 of boiling water, 1 in 80 of alcohol, freely in hot alcohol. 1 in 90 of ether, 1 in 3 of chloroform
Antidotes. Empty stomach by emetic or stomach tube. Keep patient lying down and warm, but keep roused. Give sodium bicarbonate in dilute solution freely. Stimulants e.g. hot strong coffee, strychnine 1/8grain, or caffeine sodium benzoate 2grains., hypodermically. Nikethamide 5 to 15ml of 25% solution, IV. Dextrose IV. Artificial respiration and inhalation of oxygen with 7% CO2 if needed. Lumbar puncture and drainage may be needed to remove the poison in the spinal cord (ed note: fuck me)
Uses. Sulfonal is a hypnotic and is used for producing prolonged sleep in psychiatric cases and in nervous insomnia, especially when chloral is contraindicated. It is slow in taking effect and is best given in hot milk 3-4 hours before retiring. The sleep produced lasts from 6 to 8 hours and the effect of the drug may carry over into the next day, with vertigo, lassitude, drowsiness, and depression. Since it is very slowly absorbed and excreted it is cumulative and must not be used continuously. It does not produce tolerance (ed. note: yeah right) but it may cause a habit, symptoms of which are general lethargy, mental, moral and muscular weakness (ed. LOL), loss of nutrition, and dyspepsia. It may sometimes give rise to skin eruptions and hematoporphyrin in the urine. Sulphonal has only feeble analgesic properties and is of no value in insomnia due to pain.

Methylsulfonal.
Dose. 5 to 20 grains (0.3 to 1.2gm), as for sulfonal. Max single dose 15 grains, max in 24 hours 30 grains.
Crystalline scales or powder, m.p. about 77deg.
Soluble. 1 in 320 of water, 1 in 12 of alcohol, and in ether.
Antidotes. As for sulfonal
Uses. Has a stronger hypnotic action than sulphonal and produces sleep in half to one hour. Methylsulphonal is more effective in sleeplessness connected with neurasthenia and organic brain disease, but is useless in insomnia due to pain, and in morphine and cocaine habits. Toxic symptoms are the same as sulphonal but there is less danger of cumulative effect.

 

[Hammilton]

never tried them, but the synthesis is fairly simple. Wouldn't be hard to give it a shot.

You can see how these are basically meprobamate analogues. I'd like to see more substitution patterns explored. I assume many have been, I just haven't bothered trolling through patents to find them. It'd be interesting if you stuck Seconal's 5,5-disubstitution pattern on there what you'd get.

The thioketo analogues of barbiturates are significantly more potent than their keto analogues. I wonder if that would hold for meprobamate analogues. Wonder if they'd have stability issues.

What someone really needs to make are selone analogues and then tellurone (?) analogues. By this point they'll be so fucking lonely that they'll need the drugs to cope. Imagine how horrible that smell would be!

 

[ebola?]

This is great. That excerpt reads like it's from 1890, not 1941!

ebola

 

[sekio]

never tried them, but the synthesis is fairly simple.

I wouldn't want to try though, given one component is ethylmercaptan (natural gas odorant). A good fume hood would be mandatory if you wanted to go out in public after conducting your synthesis...

I also am not too sure about the rather... delayed effects. Probably due to very high fat solubility. It seems like it would be of the same class of sedatives as e.g. chloral hydrate, or phenobarbital, in that it's certainly useful for getting knocked the fuck out but not so great for either safety or subjective "good times", like e.g. secobarbital.

 

[Limpet_Chicken]

Yeah, mercaptans....gahh.....


I would not be willing to attempt the synthesis of the selenone or tellurone. Thioketones are beastly as it is. Read of the properties of thioacetone. A release from a sealed fume hood setup, that was not even WEIGHABLE, was apparently sufficient to evacuate an area for miles around. Given the propensity of selenium xyz to stink worse than the sulfur derivative, and its a fair bet the tellurium compounds are worse yet. I would not wish to be the poor bastard doing that synthesis. Thiols are fair game though. Been contemplating testing them as a demethylating reagent in opiate alkaloids. Apparently its absolutely stellar. If guaranteed to make your neighbors want you crucified by the nadgers

I've had people cross the street to avoid me before after working with thiols.


Not that one would live to report of it for long, but I bet the polonium compounds would be truly heinous.

 

[Hammilton]

Sulfonmethane has a predicted logP of 0.662

Secobarbital analogue has a predicted LogP of 3.009

Big difference! If it wasn't metabolized quickly it'd hang around for a long time. That reactive propenyl group may make it more readily metabolized. Actually,

I assume that the inability to metabolize coupled with the high lipophilicity of the phenyl-substituted analogue mentioned in Limpet's previous thread on these is the basis for the comments made about it. Propynyl might be useful, too, though a lot of compounds with that substitution have negative effects on the liver. It works for 1-ethynylcyclohexanol, though.

 

[Limpet_Chicken]

Sulfonal apparently acts quite quickly, within as little as a half hour after a per os dose, apparently producing some 8 hours good sleep.

(source-sorry I cannot link it, it is a hard copy book, MacGregor Robertson-the household physician, vol II, dated late 1800s. No info on trional or tetronal in there though, sulfonal itself was brand new, the newest sedative available at the time.

Bearing in mind, they were using carbon tet medicinally, ethyl bromide and iodide as inhalational anaesthetics, treating teething babies with mercury and chalk or blue pill, etc., plenty of antimony, mercury, arsenic and the like in use, (hell...they even treated piles with HNO3...no thanks!)

Great books if anyone gets a chance to get hold of a copy (I have both volumes I and II....all leather bound, with marbled inlays, wonderfully archaic chemistry and colorful language of the times, and in the ones I have, their former owner's personal handwritten notes on paper, between various pages, all in old fashioned cursive, although difficult to read. Quite the pride of my library )


I wonder if the series produced antagonist or inverse agonist effects at GABAa with the big bulky phenyls not fitting the binding site in a correct orientation to allow the active, agonist-bound conformation to stabilize. Resulting in a convulsant. Wouldnt be the first time a pharmacophore did that. Look at fluorothyl for instance, a convulsant fluoroether volatile anaesthetic -like gas

 

[Hammilton]

Not likely. Phenyl substitutions are tolerated, see phenobarbital, and the diphenyl analogue. No wonder that one want used in humans.

Dimethyl might make for an antagonist, though. I believe alkyl substitutions need to be at least ethyl to be agonists. See bemegride.

 

[ae789b4]

(I tried to post this some time ago but something went wrong and I was to lazy to type it all out again)

This is a bit of a weird first post but you have to start some were. I have been researching old sedative hypnotics recently, I was planning to make a thread on these in general and will at some point I have lots of data on various chloral analogues.

I am not sure how much of this has been posed here before but its interesting any way. According to page 301-313 Synthetic Organic Chemistry: (For Honours & Post-Graduate Students of …(found this on google books and the end of the title has been cropped off) and also Analytical Chemistry: (Comprehensively Covering the UGC Syllabus) page a5- a11 for these sulphones to be active both sulphone gropes must be attached to the same carbon which must it self be bonded to another methyl or longer chain. increasing the length of the diethyl groups reduces or removes sedative activity, no comment is made as to weather dimethyl is active, adding another methyl to the central carbon increases activity (sufonmethane itself) and increasing one or both of these side chains to ethyl also increases potency.

As such it appears there is relatively little scope for analogues however propyl or isopropyl on the central carbon and either one or two methyls instead of ethyls on the sulphone groups may be more active. Adding halogens and or doable/ triple bonds may also improve activity as it dose for many similar depressants. I would make and test some analogues but there is no way that I am going to make ethanethiol in my house without a fume cabinet. These are certainly interesting compounds but and I whould like to try them at some point despite the toxicity none of them are illegal in the uk but sulfonmethane trional and tetronal are illegal in the us. These are however total unsuitable for the rc market as they are far to poisonous. Even more toxic than ethanol which is saying something.

 

[Limpet_Chicken]

Heh yes. Keep those kinds of nasty, fuming stinking chalcogen-ols in a glove box, IMO, if your going to try it at home. Made that mistake with thioacetone once and oh boy....glad I only made an absolutely miniscule quantity of the stuff. NOT pleasant, and it spreads worse, and faster than gonorrhea at a frat party piss-up.

Thiols aren't so bad as that though, they are at least containable, if sufficient care is taken.