4DQSAR
Bluelighter
- Joined
- Feb 3, 2025
- Messages
- 809
I'm prescribed clobazam and have been for most of my adult life. They were only discovered a decade after the common 1,4-benzodiazepines (e.g. diazepam, clonazepam. alprazolam, flunitrazolam, brotizolam and so on).
Over the last few weeks I decided to obtain every patent and every paper that deals with the research on 1,5-benzodiazepines. Several people have PMed me and asked 'how potent IS clobazam?' and my answer is that clobazam should be considered the chlorodiazepoxide (chlorodiazepoxie being a prodrug of nordiazepam and first benzodiazepine to become a prescription medicine). Like chlorodiazepoxide, clobazam it only about half the potency of diazepam - but compared with most classes of drug, that's still PRETTY potent. Would anyone even notice if they consumed 10mg of ketamine? 10mg of cocaine? So a small Italian team wondered if 1,5-benzodiazepines might eliminate the problems associated with 1,4-benzodiazepines and clobazam was born.
Of course, by the 1970s, the problems associated with benzodiazepines was becoming apparent and given that it took a decade from a compound first being discovered to it ending up as a medicine, researchers knew that by the time their drug was tested, even if if were to be adopted, it would only enter the pharmacopia in the 19803. In fact it took almost exactly 10 years to the day. Patent issued 21st August 1974, first commercial productionon 22nd Augist, 1984.
postimg.cc
But it was in the 1970s when researchers discovered that nitrobenzodiazepines were particularly effective in the treatment of certain forms of epilepsy and that the simple substitution of the 7-chloro of diazepam with a 7-nitro (nimetazepam) approximately doubled the potency. With this in mind a German team set out to test various different 7-substitutions and just as diazepam gave rise to nimetazepam, they discovered that the 7-nitro homologue of clobazam was around twice as potent as it's parent.
Now the reason sthey settled on a prodrug rather than the active are manifold, but from what I could glean, it was to reduce the potential for abuse. The onset was much faster than clobazam and the 7-nitro reduced duration. So to produce a compound that could simply substitute for clobazam, CP-1414S was chosen.
So we learn that the 7-substitution of 1,4 and 1,5 benzodiazepines has an almost idential alteration in activity i.e. nitrobenzodiazepines tend to be more hypnotic, are more active at the a1 subunit and the nitro is the MOST potent 7-substitution. So alrealy we can predict that if someone were to produce 'nitroclobazam', it's potency would be around that of diazepam. In fact, there is a simple high-yielding 1-pot reaction that will convert clonazapam to nitroclobazam (nitrazapam?).
postimg.cc
Being the tourough researchers the German team were, they then decided to test if the adition of a 2-methyl triazolo ring would similarly increase potency. It turns out it does. So clobazolam or whatever common or garden term you selett was shown to be an order of magnitude more potent that clobazam i.e. 5x more potent than diazepam. But what about that 7-nitro? Did they check that as well? Yes, yes they did.
postimg.cc
I've note checked if the names have been used before. It became apparent that sometimes vendors would adopt names that didn't strictly follow the naming conventions of 1,4-benzodiazepines and I imagine people have their own thoughts.
I primarily mentioned this because I thought it of academic interest but also because I note that even UK law ONLY covers clobazam whereas there is a blanket ban on all 1,4-benzodiazepine derivatives. In nations where clobazam is available,, nitration is simple and dobles potency. The synthesis adds the 2-methyl in the last step so any clobazam supplier will by definition have just as much desmethyl clobazam in stock awaiting N-methylation. With that in hand, the potent triazolo derivatives are easily produced via the thioamine. In fact, IF you are able to obtain demethyl clobazam, the supplier is likely to be able to sell thionorclobazam for a lower price than anyone else could make it. That would leave a single-step in with acetyl hydrazone is reacted with the thioamide to produce the triazolo ring.
I forgot to mention that the 2-methyl common to almost all triazolo benzodiazepines may be omitted. Synthetically, that just means the acetylhydrazine is substituted for an equimolar quantity of formylhydrazine. But without that 2 methyl, the products are half as potent.
Long ago when etizolam came under legal control, one large UK vendor simply asked the Indian manufacturer to do just that. To replace the acetylhydrazine with formylhydrazone. The result was metizolam - a drug with almost idenitcal activirty to etizolam but with only half the potency. So I was surprised that as benzos were banned, nobody else considered this simple modification.
I will conclude by mentioning what we know DOESN'T work and what has yet to be tested properly.
1- '2 substitutions do not appear to increase activity. It appears that the German team systemtatically introduced moieties to the '2, '3, '4 as well as the '2,'6 disubstitution of there compounds and none of them appeared to be active.
2- Omission of the 2-methyl of triazolo derivatives are half as potent as their parent drugs.
3- No research appears to have been carried out on the addition of a (chiral) 3-moieties to the diazepine ring. At the time only 3-OH derivatives (e.g. temazepam) were known and the (chiral) 3-substitution hadn't beene discovered by Cook et al. e.g. meclonazepam*
*Meclonazepam showed that it was possible to make benzodiazepines more selective for specific receptor subtypes. While meclonazepam itselt was designed to be a more active drug for the treatment of epilepsy, the raecemic product had to be synthesized and the final product resolved. In practice, this would mean half of the product would be discarded. Only in very specific action(s) are required such as in an alcohol mimic, 3-methyl derivatives are not facile targets.
This may be explained by the fact that it was only in the late 1980s when Cook et all modelled the various benzodiazepine receptors with the startling discovery of
Over the last few weeks I decided to obtain every patent and every paper that deals with the research on 1,5-benzodiazepines. Several people have PMed me and asked 'how potent IS clobazam?' and my answer is that clobazam should be considered the chlorodiazepoxide (chlorodiazepoxie being a prodrug of nordiazepam and first benzodiazepine to become a prescription medicine). Like chlorodiazepoxide, clobazam it only about half the potency of diazepam - but compared with most classes of drug, that's still PRETTY potent. Would anyone even notice if they consumed 10mg of ketamine? 10mg of cocaine? So a small Italian team wondered if 1,5-benzodiazepines might eliminate the problems associated with 1,4-benzodiazepines and clobazam was born.
Of course, by the 1970s, the problems associated with benzodiazepines was becoming apparent and given that it took a decade from a compound first being discovered to it ending up as a medicine, researchers knew that by the time their drug was tested, even if if were to be adopted, it would only enter the pharmacopia in the 19803. In fact it took almost exactly 10 years to the day. Patent issued 21st August 1974, first commercial productionon 22nd Augist, 1984.
clo — Postimages
But it was in the 1970s when researchers discovered that nitrobenzodiazepines were particularly effective in the treatment of certain forms of epilepsy and that the simple substitution of the 7-chloro of diazepam with a 7-nitro (nimetazepam) approximately doubled the potency. With this in mind a German team set out to test various different 7-substitutions and just as diazepam gave rise to nimetazepam, they discovered that the 7-nitro homologue of clobazam was around twice as potent as it's parent.
Now the reason sthey settled on a prodrug rather than the active are manifold, but from what I could glean, it was to reduce the potential for abuse. The onset was much faster than clobazam and the 7-nitro reduced duration. So to produce a compound that could simply substitute for clobazam, CP-1414S was chosen.
So we learn that the 7-substitution of 1,4 and 1,5 benzodiazepines has an almost idential alteration in activity i.e. nitrobenzodiazepines tend to be more hypnotic, are more active at the a1 subunit and the nitro is the MOST potent 7-substitution. So alrealy we can predict that if someone were to produce 'nitroclobazam', it's potency would be around that of diazepam. In fact, there is a simple high-yielding 1-pot reaction that will convert clonazapam to nitroclobazam (nitrazapam?).
Album — Postimages
Being the tourough researchers the German team were, they then decided to test if the adition of a 2-methyl triazolo ring would similarly increase potency. It turns out it does. So clobazolam or whatever common or garden term you selett was shown to be an order of magnitude more potent that clobazam i.e. 5x more potent than diazepam. But what about that 7-nitro? Did they check that as well? Yes, yes they did.
3 — Postimages
I've note checked if the names have been used before. It became apparent that sometimes vendors would adopt names that didn't strictly follow the naming conventions of 1,4-benzodiazepines and I imagine people have their own thoughts.
I primarily mentioned this because I thought it of academic interest but also because I note that even UK law ONLY covers clobazam whereas there is a blanket ban on all 1,4-benzodiazepine derivatives. In nations where clobazam is available,, nitration is simple and dobles potency. The synthesis adds the 2-methyl in the last step so any clobazam supplier will by definition have just as much desmethyl clobazam in stock awaiting N-methylation. With that in hand, the potent triazolo derivatives are easily produced via the thioamine. In fact, IF you are able to obtain demethyl clobazam, the supplier is likely to be able to sell thionorclobazam for a lower price than anyone else could make it. That would leave a single-step in with acetyl hydrazone is reacted with the thioamide to produce the triazolo ring.
I forgot to mention that the 2-methyl common to almost all triazolo benzodiazepines may be omitted. Synthetically, that just means the acetylhydrazine is substituted for an equimolar quantity of formylhydrazine. But without that 2 methyl, the products are half as potent.
Long ago when etizolam came under legal control, one large UK vendor simply asked the Indian manufacturer to do just that. To replace the acetylhydrazine with formylhydrazone. The result was metizolam - a drug with almost idenitcal activirty to etizolam but with only half the potency. So I was surprised that as benzos were banned, nobody else considered this simple modification.
I will conclude by mentioning what we know DOESN'T work and what has yet to be tested properly.
1- '2 substitutions do not appear to increase activity. It appears that the German team systemtatically introduced moieties to the '2, '3, '4 as well as the '2,'6 disubstitution of there compounds and none of them appeared to be active.
2- Omission of the 2-methyl of triazolo derivatives are half as potent as their parent drugs.
3- No research appears to have been carried out on the addition of a (chiral) 3-moieties to the diazepine ring. At the time only 3-OH derivatives (e.g. temazepam) were known and the (chiral) 3-substitution hadn't beene discovered by Cook et al. e.g. meclonazepam*
*Meclonazepam showed that it was possible to make benzodiazepines more selective for specific receptor subtypes. While meclonazepam itselt was designed to be a more active drug for the treatment of epilepsy, the raecemic product had to be synthesized and the final product resolved. In practice, this would mean half of the product would be discarded. Only in very specific action(s) are required such as in an alcohol mimic, 3-methyl derivatives are not facile targets.
This may be explained by the fact that it was only in the late 1980s when Cook et all modelled the various benzodiazepine receptors with the startling discovery of
