Sandmeyer
National Hazard
Posts: 784
Registered: 9-1-2005
Location: Internet
Member Is Offline
Mood: abbastanza bene
|
|
Quinazolinone family SAR
I'll post in this thread as I find more info on SAR of this family of downer euphoriants, starting with US4183931, it contains interesting info
regarding SAR as well as refs to SAR studies ( some non-patent). If someone finds additional info - please post!
I remember a user, namely josef_k from hive making a post containing several patents regarding very potent analogues (IIRC), does anyone happen to
have this post or the patents! To me it seems that the analoguing effort has been exclusivly focused on the 3-aryl nucleus and not on the
"anthranillic part", surprisingly.
[Edited on 24-4-2007 by Sandmeyer]
Attachment: US4183931A1.pdf (1.9MB)
This file has been downloaded 729 times
|
|
|
PainKilla
Hazard to Others
Posts: 306
Registered: 29-4-2004
Member Is Offline
Mood: No Mood
|
|
All I could find in archive:
US3162634
US3406173
------------
josef_k - No 469185
Synth of a methaqualone analogue
This is what i did:
6.4g (0.04mol) isatoic anhydride and 6.1g (0.04mol) 4-methyl-2-nitroaniline was put in a 100ml flask and heated to 120C. At that temp the
4-methyl-2-nitroaniline melted. But after a while the contents seemed to solidfy again, so I had to raise the temp more and more. I kept it on the
heat for 2 hours. I noticed that some yellow crystals were crystallizing in the neck of the flask. After the 2 hours I dissolved the residue in
acetone and added water to crash out the brown crystals. I should probably have recrystalized them, but I had no pet. ether mad, so they just had to
do without. They weighed 12g (0.044mol) which is pretty unreasonable. I just assumed that it was really 0.03mol.
Then I put the crystals + 3g acetyl acetone and 6ml 30% HCl into 35ml ethanol/methanol and refluxed it for 1 hour. There was some bumping which was
annoying. After it had cooled and I filtered the crystals I got 7g of some beige colored crystals. I tried to recrystalize them from ethanol, and
after that they weighed 5g but were still beige and probably pretty unpure.
To test them out I first took 60mg, and after an hour 60mg more. Then I felt very mildly sedated. Next day I took about 800mg and then I felt more
sedated. But the crystals must be VERY unpure since this analogue is supposed to be 5x regular methaqualone.
Next time I will get me some pet. ether and recrystallize the intermediate. And I think perhaps I should run the first reaction in some solvent, as I
think that because I had to turn up the heat so much maybe ruined the yield.
Anyone have any other ideas on where i screwed up?
The method I used is described here: https://www.rhodium.ws/chemistry/quaalude.html.
And the analogue is described here: Patent US3162634.
toad - No 470677
Synth of a methaqualone analogue
Hi Bees,
Just another toad tid bit to help fellow bees avoid any
dead ends that have been tried before. targets
were selected from several journal articles
(only have ref for one of them easily handy at the moment),
pharm and animal testing looked extremely promising,
but unfortunately all 3 compounds made and tested turned
out to be no go in humans. all were tried up to
very high amounts with little to no effects noted.
materials were verified with nmr and gcms so dont
think the synth was the problem.
Compound # 22 in JMedChem 1979, Vol. 22, No1,
2-(Fluoromethyl)-3-(o-tolyl)-4(3H)-quinazolinone
and
{2-methyl-3-(2,4-dimethylphenyl)-4-quinazolone}
and
{2-methyl-3-(4-ethylphenyl)-4-quinazolone}
still dreaming of analude xmas...
cheers,
toadie
-----
pHarmacist - No 469827
Synth/pharm data on methaqualone analogs (compil.)
Synthesis and anticonvulsant activity of some new 2-substituted 3-aryl-4(3H)-quinazolinones
James F. Wolfe, Terry L. Rathman, Mark C. Sleevi, James A. Campbell, Thomas D. Greenwood
J. Med. Chem.; 1990; 33(1); 161-166 (http://pharmacist-hive.tripod.com/2substquaalude.pdf)
A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3)were synthesized and evaluated for
anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 61 and 8i,
8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 61 and 8i possessing
3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low
neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50)
and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats,
they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In
drug differentiation tests, compound 61 was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some
protection against picrotoxin-induced seizures.
____ __ _
Synthesis of 3,4-Dihydro-4-oxoquinazoline Derivatives as Potential Anticonvulsants
Niteen A. Vaidya, C. H. Panos, A. Kite, W. Ben Iturrian, and C. DeWitt Blanton, Jr.
J. Med. Chem. 1983,26, 1422-1425 (http://pharmacist-hive.tripod.com/quaalude3.pdf)
Abstract: Twenty-three substituted 3,4-dihydro-4-oxoquinazolines or 3,4-dihydro-4-oxoazaquinazolines have been synthesized utilizing
2-amino-3-cyano-4,5-dimethylfuran and methyl acrylate as precursors for synthesis of the required substituted anthranilates. Six additional
azaquinazolones were synthesized from 2-aminonicotinic or 3-aminopicolinic acid for comparison studies. All compounds were evaluated in mice with the
maximal electroshock (MES) seizure and pentylenetetrazol (sc Met) seizure threshold tests for potential anticonvulsant activity and in the rotorod
test to evaluate neurotoxicity. Nine of the twenty-nine compounds in the series demonstrated anticonvulsant action. The azaquinazolones were found to
possess the most significant activity.
____ __ _
2-amino-3-cyano-4,5-dimethylfuran + Me-Acrylate -> Diels-Alder adduct -> anthranilate is a pretty damn sexy synthetic approach, nice
illustration of the power of the absolutely genious Diels-Alder transformation... wink
2-Amino-3-cyanofurans as Precursors for Anthranilic Acid Derivatives
Nixon Jr, W. J.; Garland, J. T.; Blanton Jr, C. Dewitt
Synthesis; 1980, 56 (http://pharmacist-hive.tripod.com/aminocyanofurans.pdf)
____ __ _
Synthesis and Central Nervous System Activity of Quinazolones Related to 2-Methyl-3-(o-tolyl)-4(3H)-quinazolone (Methaqualone)
I. R. Ager, D. R. Harrison, P. D. Kennewell, and J. B. Taylor
J. Med. Chem.; 1977; 20(3); 379-386 (http://pharmacist.the-hive.tripod.com/qaaludeanal4.pdf)
Abstract: A number of derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone bearing new substituents on the 2-methyl group have been synthesized. It
was established that most substitutions at this position reduce or remove the CNS depressant activity of methaqualone. From the series prepared only
the 2-fluoromethyl derivative or certain isothiouronium salts, which-could be hydrolyzed in vivo to the 2-mercaptomethyl derivative, showed activity
of the same magnitude as methaqualone.
____ __ _
A survey of reported synthesis of methaqualone and some positional and structural isomers
Etienne F. van Zyl
Forensic Science International 122 (2001) 142-149 (http://pharmacist-hive.tripod.com/quaalude.pdf)
DOI:doi:10.1016/S0379-0738(01)00484-4
Abstract: Methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone) is the illicit synthetic drug of choice amongst South African drug users. Historically
police and forensic investigation has proven that all methaqualone seized by the South African Police Service originates from illicit manufacturing
sites both inside, and outside South Africas borders. From a drug enforcement, and forensic point of view it is, thus, of utmost importance that the
various synthetic routes available to the illicit "chemist" are fully documented and understood. This is a prerequisite for effective illicit
laboratory investigation, as well as chemical and precursor monitoring. This paper gives a brief introduction to the current status with regard to
methaqualone use and production in South Africa, as well as an extensive review of the synthesis of methaqualone and selected isomers reported since
1946. A table summarizing synthetic routes reported in 32 reference sources is provided.
Rh's archive is included in the refs section, cool
[Edited on 25-4-2007 by PainKilla]
|
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
