Theoretical Triazolobenzodiazepines

[Phenpsycho]

Hi all~

So a specific topic that has been playing on my curiosity for awhile now is the chemistry/synthesis of triazolobenzos. While comparing the ridiculously exhaustive list of regular benzos to the list of them you see a huge gap in variances between the two. I've been trying to find an explanation all over the web but haven't been successful so i'm posting this thread to hopefully find an answer.

Is there a specific limitation to the synthesis of analogs in this new class that makes it impossible to create lam versions of all the pams? I know they've done it for clonazepam, flunitrazepam, oxazepam, flutoprazepam, flubromazepam etc. so why hasn't anybody made a version for example of diazepam or phenazepam, could it be they just wouldn't be very impressive or that it would be too costly to synthesize them?

Also when I was searching around the web I came across fluclorazolam:

It's still a theoretical molecule that hasn't been produced before and it seems strange to me that it hasn't considering how popular etizolam, clonazolam and the other RC triazolobenzos have become. Does anyone have any guesses about how highly the effects of it would rate?

If there is limitations to what can and can't be synthesized I would also be interested in hearing about what new ones could exist in the future.

 

[Tryptamite]

I think phenazolam exists ad the triazolo version of phenazepam

 

[adder]

There is no limitation in the synthetic route that would make certain substitution patterns in the classic 1,4-benzodiazepines impossible to apply in triazolobenzodiazepines, though properly substituted substrates may be more or less readily available, e.g. among aryl halides aryl chlorides are generally the cheapest while aryl fluorides and bromides are generally more expensive. Anyway, the fact that you don't see more triazolobenzodiazepines on the market does not mean more haven't been synthesized and assayed. Nowadays when scientists look for a compound with action at a specific target, they want to hit a lead compound with certain properties that can be tuned via structure modification to find the compound with the most favourable profile, so a lot of inferior analogues get dropped in this process and you never see them on the market. In case of benzodiazepines I think there's a lot of them available, some like diazepam, lorazepam or clonazepam have well-grounded positions on the market being gold standards in certain situations, there is no point in changing chloro to fluoro and making another one being more expensive to make and not having any advantage over the cheaper one already available. Among benzodiazepines there are actually many alternatives for one condition, for instance anxiety, many benzodiazepines available for anxiety, but bromazepam for example is more expensive to synthesize than diazepam. Drug business works like any other with respect to costs and profits, if it made sense for some company to push bromazepam or some other benzodiazepine more heavily, I'm sure they would have done it.

As an example of a benzodiazepine that has been recently assayed as an improved replacement of one used for a long time now, there is remimazolam which is an ultra short-acting hypnotic for induction of anaesthesia with a more favourable pharmacokinetic profile than midazolam.

If you mean benzodiazepines strictly for the RC market, well, it's a business like any other as well with its own characteristics of course. In this particular case apart from costs of production which may certainly vary greatly among analogues of the same class, legal situation is a major factor to be taken into consideration. If you were an RC vendor making serious money on it and your every day depended on it, then you would plan carefully what analogues to research and release onto the market based on what is legal at the moment and what is to be banned soon. It makes no sense for RC vendors to release 10 structurally similar compounds if there is no analogue act in the target market and compounds get banned one by one. It is also crucial to keep compounds to be released in the near future secret so that legal authories don't ban them in advance and your competitors don't release them sooner.

 

[Solipsis]

Does phenazolam exist though? I can find an incorrect formula posted for it (with 1-methyl) and some other links that are basically worthless...
It would seem like a terrible idea though, phenazepam is already prone to amnesia / blackouts...

The triazolo of diazepam/nordiazepam is just alprazolam... which yes is a nice compound to imitate imo (see etizolam)

The image in the OP would be basically flualprazolam, at least that would be the obvious way to name it.

I'd say no more things like flubromazolam, flunitrazolam or clonazolam are needed anyway... apparently only marketed to addicts (disgusting and bad idea for people with low tolerance imo, similar to the fents), good at getting a really wasted tolerance and shit like that.
Maybe the fents are a godsend to people who can't afford analgesics otherwise but then the regular selfmedication with highly addictive substances concerns apply. You don't really need a zillion analogues for that though.

What is the point of getting beyond mentally relaxed on a superpotent anxiolytic? Do you still just like the relaxation or do you just want to lose yourself?

Personally I'd find it far more interesting to see some 1-methylated pam derivatives to mimic say temazepam or nitrazepam, some of which are indeed immobilizing and perhaps less physically safe in combinations but at least just simply pleasant and reasonable imo.

Disappointing to see what RC's people settle for, which seem too good to be true and are... Nice that superpotent compounds are good for vendors but it shouldn't be about them.

I quite liked flunitrazepam and was somewhat excited to see juiced up benzo's appearing in theory, for me it turns out that various of these triazolos turn out to be worse in most aspects (including what i read from others). Overreactions, negative and paradoxical reactions etc.

 

[white55]

I've only seen it (phenazolam) mentioned on a few online boards where some people claimed that they've made it from phenazepam... the reaction they posted looked feasible but involved some nasty chemicals so who knows if they had indeed made it.


>Personally I'd find it far more interesting to see some 1-methylated pam derivatives to mimic say temazepam or nitrazepam, some of which are indeed immobilizing and perhaps less physically safe in combinations but at least just simply pleasant and reasonable imo.
Nitemazepam (3-oh nimetazepam) is available online and if it takes after it's parents (temazepam and nimetazepam aka some of the most abusable benzos) it should be nice. Haven't heard it mentioned often which either means it's not all that or that the price per dose is just too high to be worth it (seems likely considering the fact that most 1,4 benzos cost roughly the same amount of money per g and that if the potency is in the middle between nimetazepam and temazepam we are still talking recreational dose of 10s of mgs). Imo it would make more sense to make something like n-methyl clonazepam or n-methyl nifoxipam (the patent from which nifoxipam comes contains the n-methyl version too and it is actually stronger and safer than flunitrazepam).

 

[Limpet_Chicken]

Wouldn't mind seeing more nitrobenzodiazepines really, mostly in this case for exploration purposes. But those tried, the fluorinated and nitro substitutions, along with good old nitrazepam have to be favourites (flunitrazepam, haven't tried. Sure wouldn't mind but the chance of coming across it here is absolutely bugger all, not prescribable on the NHS afaik. Neither, IIRC is flurazepam, sadly. Would have been interesting to make comparisons)

 

[Captain.Heroin]

Why aren't there more imidazo RC benzos?

 

[Hodor]

Why aren't there more imidazo RC benzos?

If Midazolam is any indication they suffer from poor oral bioavailability (~40% ) and thus relatively low potency (10 mg of Diazepam = ~7.5 mg of oral Midazolam), as well as very short half-lives.

So I guess there's little reason for them to make an Imidazo-benzo as long as the triazolo-benzos offer pretty much the same effects at ten times the potency. I guess imidazos have the dubious advantage of being injectable (at 90%+ b.a.), although that's probably just going to end up causing insta-blackouts most of the time. I guess you could try turning it into a nasal spray, but still, as long as the RC triazolos are still more or less legal in most places...

 

[Captain.Heroin]

If Midazolam is any indication they suffer from poor oral bioavailability (~40% ) and thus relatively low potency (10 mg of Diazepam = ~7.5 mg of oral Midazolam), as well as very short half-lives.

So I guess there's little reason for them to make an Imidazo-benzo as long as the triazolo-benzos offer pretty much the same effects at ten times the potency. I guess imidazos have the dubious advantage of being injectable (at 90%+ b.a.), although that's probably just going to end up causing insta-blackouts most of the time. I guess you could try turning it into a nasal spray, but still, as long as the RC triazolos are still more or less legal in most places...

I was very fond of loprazolam, and I know others are as well.

A lower oral BA for a benzo wouldn't be a bad thing, considering what people end up doing when they order a gram or more of phenazepam, etc...

I appreciate your answer though, as it does make sense.

 

[Solipsis]

I think the phenazepam problem has to do with therapeutic index of how quickly anterograde amnesia is reached, I don't see how it has anything to do with potency or BA. Also during such a black hole you are not a complete idiot AFAIK, people get on planes or drive, just impaired as if drunk... so if there is any way to use or abuse a benzo you'd still know it during that black hole, although clearly you are disinhibited as fuck and just don't give a damn and have little self-control. That is why locking the rest away somewhere just like with zolpidem should have limited effect, though you might be so out of it from the sedation that some tasks get difficult.
The amnesia means that no memories are formed during the black hole, not that you don't remember where you hid it while in the hole.

Surely that therapeutic index for amnesia has to do with GABAa selectivity of effects through subtype affinities (alpha1 and alpha5) and perhaps some functional selectivity. Benzo's are not found to impair memory retrieval but the 'learning' stage of creating novel associations leading to memory formation.

So what should be preferable is a benzo low on alpha1 and alpha5 affinity, this should also limit addiction although for that even better would be one with functional selectivity to not activate the mesolimbis dopamine system. Something like pyrazolam is not that interesting to abuse though at least IME (was never my intention anyway so I might not be the one to judge), so yea people don't seem to want the responsible stuff anyway. Making less addictive ones is mostly interesting to people looking for functional use. Should therefore limit the 'accidental addiction' as a result of a prescription rather than addiction as a result from 'intentional abuse'.

Lower BA might make it a little less easy to eat way too much, but I have had an experience with LSD, alprazolam and maybe a diazepam where appropriate administration did not stop me from taking more during a black hole. Phenazepam also just lasts way too long, increasing the chance that you keep redosing.

 

[Dinne]

Hi.
Now phenazolam is being release in Sweden.
It only different a fluoro to a chloro. From flubromazolam so i tink it Will be a verry nice benzo.
4e juli They release it.

 

[roi]

Clobromazolam?

 

[Coolwhip]

This is probably a stupid question, but why don't you see nitro groups at 2'/6'? Or a trifluoro at 7?

 

[Captain.Heroin]

What is the point of getting beyond mentally relaxed on a superpotent anxiolytic? Do you still just like the relaxation or do you just want to lose yourself?

It'd be nice to find long/longer lasting benzos.

Flurazepam was so, so, so lovely. But not potent at all.

Potent long lasting hypnotic benzos please!

 

[Bottle of water]

Phenazolam is my favourite I've ever tried. You wake up fresh

 

[Bottle of water]

Clobromazolam?

Yes

 

[Fertile]

Every combination of halogens at the 8 and '2 positions have been made, tested, patented. Someone even put nitro groups in both spots - to get around patents.

The thienotriazolodiazepines and such have not all been made. not a surprise since the QSAR is understood and by the time someone made them (you cannot patent what you cannot make), they were on their way out.

The 1,5 benzidiazepines are the best hunting grounds.

 

[Bottle of water]

Every combination of halogens at the 8 and '2 positions have been made, tested, patented. Someone even put nitro groups in both spots - to get around patents.

The thienotriazolodiazepines and such have not all been made. not a surprise since the QSAR is understood and by the time someone made them (you cannot patent what you cannot make), they were on their way out.

The 1,5 benzidiazepines are the best hunting grounds.

Hello Fertile. Your knowledge of benzo chemistry is vastly superior to mine I must say. I'm familiar with the well known benzos but only the duration of effect, half life and potency. I have recently acquired some silver bars containing phenazolam or clobromazolam. They seem to have a very subtle but strong effect. Very amnesia inducing. Not very sedative until I wake up with my phone stuck to my forehead and feeling AWAKE! NO Xanax type drowsiness. What can you tell me about this phenazolam? Has it a long effect and short half life,? Has it a short effect and long half life?
All I can tell you is- it's no joke. Serious, serious benzo type med
And hunting ground for what?

 

[Bottle of water]

I think the phenazepam problem has to do with therapeutic index of how quickly anterograde amnesia is reached, I don't see how it has anything to do with potency or BA. Also during such a black hole you are not a complete idiot AFAIK, people get on planes or drive, just impaired as if drunk... so if there is any way to use or abuse a benzo you'd still know it during that black hole, although clearly you are disinhibited as fuck and just don't give a damn and have little self-control. That is why locking the rest away somewhere just like with zolpidem should have limited effect, though you might be so out of it from the sedation that some tasks get difficult.
The amnesia means that no memories are formed during the black hole, not that you don't remember where you hid it while in the hole.

Surely that therapeutic index for amnesia has to do with GABAa selectivity of effects through subtype affinities (alpha1 and alpha5) and perhaps some functional selectivity. Benzo's are not found to impair memory retrieval but the 'learning' stage of creating novel associations leading to memory formation.

So what should be preferable is a benzo low on alpha1 and alpha5 affinity, this should also limit addiction although for that even better would be one with functional selectivity to not activate the mesolimbis dopamine system. Something like pyrazolam is not that interesting to abuse though at least IME (was never my intention anyway so I might not be the one to judge), so yea people don't seem to want the responsible stuff anyway. Making less addictive ones is mostly interesting to people looking for functional use. Should therefore limit the 'accidental addiction' as a result of a prescription rather than addiction as a result from 'intentional abuse'.

Lower BA might make it a little less easy to eat way too much, but I have had an experience with LSD, alprazolam and maybe a diazepam where appropriate administration did not stop me from taking more during a black hole. Phenazepam also just lasts way too long, increasing the chance that you keep redosing.

How can phenazepam last too long? Isn't that a good thing,? I mean, if you're not anxious, don't take any more? Do you mean the effects last too long, or the elimination half-life?

 

[Fertile]

Phenazepam seems hazardous with a slow onset and long durations. I have read of many 'adventures' where people have lost days or even weeks. The stuff isn't very hypnotic but it DOES seem to severely impair executive function and so people have been known to do crazy things.

I think the safest benzodiazepine is pyrazolam. Fast onset, moderate duration and a3/a4 selective so it doesn't have suffer the issues of phenazepam.


Believe it or not, the triazolo derivatives of the 1,5-benzodiazepines have been looked into. This is an example:

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

It's worth noting that this class of benzodiazepine binds at different subreceptor types. That means if you have a 1,4-benzodiazepine habit, a 1,5-benzodiazepine will not help much. A bit, but not much. The 1,5 class seems less dependence-forming which is important, I think.