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Benzodiazepines without Halogens?

For the 3-ring benzos, the 7 position has to have a strongly electron-withdrawing effect. The '2 position has to be small so that the ring can sit at an specific rotational position compared to benzodiazepine ring. Banzos have been hugely studied and the QSAR is complete. I cannot recall the name, but I bought a paper that went through several 100 different 3 & 4 ring compounds. It's the most addictive class of the lot.
 
Re addictive benzos...U mean qsar says this or you ate all of these?

clubcard said:
For the 3-ring benzos, the 7 position has to have a strongly electron-withdrawing effect. The '2 position has to be small so that the ring can sit at an specific rotational position compared to benzodiazepine ring. Banzos have been hugely studied and the QSAR is complete. I cannot recall the name, but I bought a paper that went through several 100 different 3 & 4 ring compounds. It's the most addictive class of the lot.
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clubcard said:
For the 3-ring benzos, the 7 position has to have a strongly electron-withdrawing effect. The '2 position has to be small so that the ring can sit at an specific rotational position compared to benzodiazepine ring. Banzos have been hugely studied and the QSAR is complete. I cannot recall the name, but I bought a paper that went through several 100 different 3 & 4 ring compounds. It's the most addictive class of the lot.
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If you remember the name of the paper please post it.
 
I've read several hundred patents and several hundred patents. Both at the '2 position and the 7 (or 8 for the tetracyclic derivatives), halogens and nitro groups appeared to be the only ones with decent activity.

You can go for the 8-ethynyl homologus. Pyeyzolam (mis-spelt pyeazolam on it's Wikipedia page) is more or less a5 selective and in our cohort of 134 participants, 132 of them considered it to fully substitute for ethanol. But it isn't potent. You won't feel much until you reach 20mg while 30mg will have you wobbling. Body mass is important in pyeyzolam because it's lower LogP means it's not concentrated into fatty tissue (e.g. the brain) as much as with most benzodiazepines.

But it worked, everyone seemed to like it and best of all, the patent rights were sold by the inventor not because it isn't an obvious alcohol alternative but because the alcohol industry is incredibly powerful and unless you have BILLIONS to spend on having the stuff tested to the levels of medicines (to prove intrinsic safetry) and then to fight people who produce alcohol, it won't reach market. They do NOT want competition.
 
deschloroetizolam feels more like ethanol to me or different type of GABAnergic buzz, for what thats worth. not identical as pyeyzolam sounds, but absolutely distinct

sad to see that novel benzos might follow the substitution trend of 'ethylbromazolam' and not any novel ones like we saw come from EU. always wondered cloflutizolam (swapping fluclotiz's halogens) or clobrotizolam (like a thieno phenazolam). some people seem to like it a lot, though, so maybe there's promise.
 
pcplease said:
deschloroetizolam feels more like ethanol to me or different type of GABAnergic buzz, for what thats worth. not identical as pyeyzolam sounds, but absolutely distinct
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That strikes me as being entirely reasonable. While the ethyl of deschloroetizolam isn't the same as the ethynyl of pyeyzolam, I can imagine them being more similer than a halogen or nitro.

Is deschloroetizolam potent? Because pyeyzolam most certainly isn't (for a benzo).

Professor James T. Cook of Milwaukee Institute of Drug Discovery issued a large number of patents and papers which were designed to 'elucidate the shape and volume of the benzodiazpine sites of the receptors subtypes' of the 1,4-benzodiazepines (and related compounds). I think the guy spent something like a decade on that project and AFAIK is THE expert.

I might have mangled that title a bit - I read the paper over a decade ago and figure if you just go through the guys work - it's close enough for anyone interested to spot it.
 
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taken without any tolerance to benzos/thienos, it is about half potency by weight as etizolam. However, most people feel it's more like 1/5th or less, that it is a trash/inactive chem. its different and gabanergics (IMHO) all have a point of diminishing returns and ive never gone past 15mg yet. but its a not-particularly anxiolytic, yet sometimes euphoric, physical intoxication. weirdly feels like a stronger anxiolytic/typical long-acting benzo the next day.

i'd be interested to read those patents/papers, but again unless something changes in the drug/RC scene, would just be wishful dreaming. it looks like Canada is still putting out some novelties
 
Yeah - that sounds a lot like pyeyzolam. Nothing until you reach 20mg but 30mg is like drinking two bottles of wine in 10 minutes.

Wasn't metizolam the other one that turned up when etizolam was banned? I was told that was about halve as active as the original but I never tasted it or even saw it so I have know direct knowledge of it's effects.
 
etiz-2/deschloroetiz was definitely the first, and then i heard of but never tried metizolam, IIRC the same as you 2-3x weaker by weight but maybe longer lasting? both clotizolam (triazolam thieno) and deschloroclotizolam reportedly circulated, along with flutizolam, but never got to try those. i liked fluclotizolam a lot, moreso than flubrotizolam. ill get around to high dose deschloroetiz someday, but believe reports of people with heavy habits claiming 20-50mg+ doses weak. seems to have some sort of ceiling
 
Well in the case of alprazolam, if you remove the 2-methyl (as the etizolam-->metizolam modification does), the result is estazolam which has half the potency of alprazolam and a shorter duration of action. I seem to recall it was trialled as a hypnotic because you can give someone a whacking dose to knock them out but the shorter half-life reduces hangover symptoms. But in the end triazolam, midazolam and brotizolam all proved superior.

But do you see the pattern? None of them are nitrobenzodiazepines. I think these compounds were all developed to replace nitrazepam, nimetazepam and flunitrazepam - all nitrobenzodiazepines. It turned out that the nitrobenzodiazepines were far more toxic than the others and possibly increased mortality-rates had been noted thus replacements were needed in a hurry.
 
ah, i have heard of and am a little familiar with estazolam but did not make the correlation between etiz/metiz.

as for the pattern, yesi learned that here by someone who said just that re: theoretical benzos. that said, i thought there was at least some who believe clonazepam one of the best indicated for long-term use due to a lack of active metabolites providing eventually stable levels. i would still be more concerned about the cognitive effects of long-term use than any the smaller therapeutic index, though i do have a very bad liver if that's where the toxicity lies
 
d1nach said:
Why? My guess is it would make it weaker because diethyl either is an example of ether bond being replaced by halogenated compounds which are used today for anesthesia. Also in generally most new drugs have the addition of a chloro fluoro or bromo an example of this is flonase via a fluorine and 25i mmobe albiet which almost killed me replacing methoxy groups on the mescaline trimethoxybenzeneketocarboxylic acid backbone with bromo
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I know that with Quinazolinones like Methaqualone, substitution of a F for the 2’-methyl group on the 3-Phenyl group of the 3-(2’-methylphenyl)-2-methyl-4-Quinazolinone molecule to make mefloqualone, increases the potency by about 3 fold, but makes it shorter acting. A substitution of Cl to make mecloqualone makes it shorter acting with similar potency & Br makes it slightly weaker.

Methaqualone and the other analogies bind to the β subunit of the GABA-A receptor, where its inhibitory, but unlike most benzodiazepines, which bind at the interface of the α & γ subunits of the GABA-A receptor, methaqualone acts as a negative allosteric modulator at a few GABA-A receptor subtypes, which tends to cause an excitatory response in neurons expressing those receptors. Because methaqualone can be either excitatory or inhibitory depending on the subunit composition of the GABA-A receptor, it can be characterized as a mixed GABA-A receptor modulator. The binding site is different than that of both benzodiazepines and barbiturates. There are also some data that Methaqualone may bind to σ and possibly even dopamine receptors

With 1,4 Benzodiazepines, substituting a methyl group for the halogen may increase the duration of action, but depending on whether it’s replacing a F, Cl or Br molecule, it may, analogous to Quinazolinones, either increase or decrease the potency based of the size of the halide. The desmethyl version of diazepam and the nor version of flurazapam are both active but have very long half-lives and both are only partial agonists.

So depending on the location and which halide it’s replacing, it’s likely that a methyl group would still allow the molecule to retain its inhibitory effects by affecting the chloride channels on the BdZ receptors on GABA-A receptors.
 
MobiusDick said:
I know that with Quinazolinones like Methaqualone, substitution of a F for the 2’-methyl group on the 3-Phenyl group of the 3-(2’-methylphenyl)-2-methyl-4-Quinazolinone molecule to make mefloqualone, increases the potency by about 3 fold, but makes it shorter acting. A substitution of Cl to make mecloqualone makes it shorter acting with similar potency & Br makes it slightly weaker.
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Say what?

it DOES turn up in Pubchem and you can order it as a reference sample, the studies I read suggested HQ-335 was the most potent of the series in man. Well, the most potent SAFE compound.

That's 2-(fluoromethyl)-3-(2-methylphenyl)quinazolin-4(3H)-one


Which is 2-3 times more potent in some of the animal models. The 2 methyl being swapped for a 2 fluoromethyl.

I found a dissertation by a South African post graduate student who obtained 127 samples from Mandrax pills seized by the local police. While various ortho and meta monosubstituted compounds as well as a number of ortho/meta disubstituted compounds were all detected, no fluro examples. I don't know why, but I presume after four decades, the 'cooks' have figured out what the consumers will accept. No para substitued examples, with good reason.

The 2'-methyl-3'-chloro homologue of methaqualone is also known to be more potent than methaqualone but less potent than HQ-355... in animal models at least.

I did point this out elsewhere. A Swedish guy had a sample of dimethaqualone i.e. ortho/para methyls on the pendent aromatic. But as I noted, nitromethaqualone was once stated as being ten times as potent as the parent compound but it turns out that whatever you place at the para, you get compounds that produce seizures in doses only slightly above the theraputic dose. It's well worth a read. For them something like 14mg smoked was perfect but at 24mg they started shaking. A TI of ONE seems too small to me. HQ-335 is more like 14 (still a little low).

I'm not saying you are wrong, only that it doesn't turn up on the streets of Johannesburg and I don't see any papers on it. But if you have the reference, I'm happy to be wrong.
 
4DQSAR said:
Say what?

it DOES turn up in Pubchem and you can order it as a reference sample, the studies I read suggested HQ-335 was the most potent of the series in man. Well, the most potent SAFE compound.

That's 2-(fluoromethyl)-3-(2-methylphenyl)quinazolin-4(3H)-one


Which is 2-3 times more potent in some of the animal models. The 2 methyl being swapped for a 2 fluoromethyl.

I found a dissertation by a South African post graduate student who obtained 127 samples from Mandrax pills seized by the local police. While various ortho and meta monosubstituted compounds as well as a number of ortho/meta disubstituted compounds were all detected, no fluro examples. I don't know why, but I presume after four decades, the 'cooks' have figured out what the consumers will accept. No para substitued examples, with good reason.

The 2'-methyl-3'-chloro homologue of methaqualone is also known to be more potent than methaqualone but less potent than HQ-355... in animal models at least.

I did point this out elsewhere. A Swedish guy had a sample of dimethaqualone i.e. ortho/para methyls on the pendent aromatic. But as I noted, nitromethaqualone was once stated as being ten times as potent as the parent compound but it turns out that whatever you place at the para, you get compounds that produce seizures in doses only slightly above the theraputic dose. It's well worth a read. For them something like 14mg smoked was perfect but at 24mg they started shaking. A TI of ONE seems too small to me. HQ-335 is more like 14 (still a little low).

I'm not saying you are wrong, only that it doesn't turn up on the streets of Johannesburg and I don't see any papers on it. But if you have the reference, I'm happy to be wrong.
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I no longer need to use SWIM in my posts since the 7 year statute of limitations is up and I no longer do the hard stuff But working as a Pharmacologist and dabbling in medicinal chemistry, Methaqualone is about a 2 on the scale of 1-10 insofar as how good a medicinal chemist you have to be to make it. It’s literally a 2 step reaction with a bunch of acetone washings to clean the brown product into a pretty white. Simple anthranilic acid with acetic anhydride and ortho-toluidine are all that’s needed along with an oil bath you can do on the stove. The hardest part is the repeated rexrystalizations from acetone to clean it up. Relative to the artistry required to put a fluorine on the Quinazolinone, it took level 7 medicinal chemistry to do and it took a lot more work. It’s no wonder that you never see that on the street. Plus all the friends I gave it to all complained it was too strong. I even had an evening with my ex wife at one of our favorite restaurants where apparently I was eating the foie gras pate with my hands and had to be carried to our car. My ex wife would never return to that restaurant with me. Lol. 🤣 I do miss Methaqualone though. It’s very similar to the feeling of MDMA without the trippy part. And I suspect most of you folks weren’t around before the Analogue Act went into effect. You could buy pure MDMA at bars in Houston and Atlanta. I used to put it on my credit card. I miss the legal days even though we had to be creative. To make sure people couldn’t OD on fentanyl (:I have to admit I was pretty damned good at figuring the right doses out for people,) , I would mix up the dose I thought the could handle in a 1cc syringe and I put it in 100ml brown glass bottles, with 5% Cetyl Alcohol) and bought rubber stoppers and a crimper from Fischer and I’d label the bottle and just hand it to my friends. I loved to surprise people. Now it’s like HL Mencken’s quote about running the circus from the monkey house out there. I’m glad I no longer have to deal with police and DEA breathing down my back. I’d still like to see all the DEA jobs program sons of bitches panhandling for change in the streets for what they did to Sasha after he and Anne wrote TIHKAL and PIHKAL. But I digress.
 
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MobiusDick said:
I no longer need to use SWIM in my posts since the 7 year statute of limitations is up and I no longer do the hard stuff But working as a Pharmacologist and dabbling in medicinal chemistry, Methaqualone is about a 2 on the scale of 1-10 insofar as how good a medicinal chemist you have to be to make it. It’s literally a 2 step reaction with a bunch of acetone washings to clean the brown product into a pretty white. Simple anthranilic acid with acetic anhydride and ortho-toluidine are all that’s needed along with an oil bath you can do on the stove. The hardest part is the repeated rexrystalizations from acetone to clean it up. Relative to the artistry required to put a fluorine on the Quinazolinone, it took level 7 medicinal chemistry to do and it took a lot more work. It’s no wonder that you never see that on the street. Plus all the friends I gave it to all complained it was too strong. I even had an evening with my ex wife at one of our favorite restaurants where apparently I was eating the foie gras pate with my hands and had to be carried to our car. My ex wife would never return to that restaurant with me. Lol. 🤣 I do miss Methaqualone though. It’s very similar to the feeling of MDMA without the trippy part. And I suspect most of you folks weren’t around before the Analogue Act went into effect. You could buy pure MDMA at bars in Houston and Atlanta. I used to put it on my credit card. I miss the legal days even though we had to be creative. To make sure people couldn’t OD on fentanyl (:I have to admit I was pretty damned good at figuring the right doses out for people,) , I would mix up the dose I thought the could handle in a 1cc syringe and I put it in 100ml brown glass bottles, with 5% Cetyl Alcohol) and bought rubber stoppers and a crimper from Fischer and I’d label the bottle and just hand it to my friends. I loved to surprise people. Now it’s like HL Mencken’s quote about running the circus from the monkey house out there. I’m glad I no longer have to deal with police and DEA breathing down my back. I’d still like to see all the DEA jobs program sons of bitches panhandling for change in the streets for what they did to Sasha after he and Anne wrote TIHKAL and PIHKAL. But I digress.
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Seven years?

So you produced the ortho-fluoro homolologue of methaqualone when? I mean, statute of limitations being what it is, I presume one can provide a year or at least approximate one.

Because fluorination has come a long way in the five decades since that paper was written.

Heck - you can buy 2-(2-fluoroacetamido)benzoic acid from a number of suppliers and AFAIK it's unwatched.

In fact, if you take a very close look at the method outline by Manhas (the original paper, not the Erowid 'explaination') and think carefully about reference 16 (which BTW was published in 1944, not 1942 as reference states), you will note a single step synthesis from an unwatched (and normally unisolated) intermediate. To the best of my understanding, an electron-withdrawing group would actually be a feature rather than a bug.
 
4DQSAR said:
Yeah - that sounds a lot like pyeyzolam. Nothing until you reach 20mg but 30mg is like drinking two bottles of wine in 10 minutes.

Wasn't metizolam the other one that turned up when etizolam was banned? I was told that was about halve as active as the original but I never tasted it or even saw it so I have know direct knowledge of it's effects.
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More qualitative studies have shown further similarities to pyeyzolam (as you describe). Studying its effects, relative to other benzos ,combined with equivalent prescribed doses of MPH-related reuptake inhibitors.

Still providing drunken qualities of intoxication and does not dominish certain effects that traditional benzodiazepines do. Compared both to a2,a3 heavy (Lorazepam+Delorazepam)-blocked effects at <2mg , or the equivalent to 10mg diazepam- and on the other end ~0.25mg phenazolam.
 
Well just as the -Br is swapped for an ethynyl moety here:

pubchem.ncbi.nlm.nih.gov

4-(2-Chloro-phenyl)-2-ethynyl-9-methyl-6H-1-thia-5,7,8,9a-tetraaza-cyclopenta[e]azulene

4-(2-Chloro-phenyl)-2-ethynyl-9-methyl-6H-1-thia-5,7,8,9a-tetraaza-cyclopenta[e]azulene | C17H11ClN4S | CID 14851902 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and...
pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov

I suggest that replace that pendend aromatic (the ortho chloro) with an ortho pyridyl moiety, you would end up with a much shorter acting but more potent alcohol mimic.
 
I'm sure your right. If I ever win the powerball, well if i ever start playing the powerball, I'll be contacting you shortly.

Aside from benzos, I'd really like to see a simple enzymatic XR methylphenidate developed and used over amphetamines. Vyavnse was far more therapeutic than dexedrine, but more of an energizing antidepressant. Didn't help nearly as much at pragmatic thought-process, the ability to switch from one task to another vs getting overly focused on one task. Far less cardiotoxic as well.
 
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