Subject:      Challenge for enterprising chemists
From:         an158353@anon.penet.fi
Date:         1995/07/12
Newsgroups:   alt.drugs.chemistry 


Nope, this is _not_ an LSD-25 synthesis, but something more interesting.

It's an idea that based on something that Dr. Shulgin writes in Pihkal.  In
one of the entries (forget which one), he starts talking about _homologues_
of the phenethylamines--that is to say, compounds that are similar, but have
extra (or missing) carbons in the -CH2-CH2-NH2 chain.  (Hence names like
"homopiperonylamine", but I digress.)

He mentions that N-benzylpiperazine, which has the structure:

         CH2-CH2
        /     \
Ph-CH2-N       NH
        \     /
         CH2-CH2

resembles amphetamine in that it's a sympathomimetic and stimulant.  This
is unusual enough, considering that N-benzylpiperazine is _not_ a phenethyl-
amine (only one carbon separates the aromatic ring from nitrogen, and not
two.)  He then speculates that substituent patterns on the aromatic ring
_similar_ to those on known psychoactives, might yield new, interesting
compounds.  E. g. 2,5-dimethoxy-4-bromobenzylpiperazine, which would be a
homologue of 2C-B (or maybe of DOB):

 MeO
    \
     C--CH        CH2-CH2
    /    \       /     \
Br-C  O   C-CH2-N       NH
    \    /       \     /
     CH-C         CH2-CH2
         \
          OMe

The chemistry would be simple--simpler than making the homologous phenethyl-
amines, I'd think.  A method to the above compound might be:

hydroquinone -> bromhydroquinone -> 2-bromo-1,4-dimethoxybenzene ->
4-bromo-2,5-dimethoxybenzyl chloride ("chloromethylation" with paraformal-
dehyde and HCl/ZnCl2); and reaction of the benzyl chloride with piperazine
should give the final product.
(Or, start out hydroquinone -> 1,4-dimethoxybenzene, and brominate to
2-bromo-1,4-dimethoxybenzene, and continue from there.)

Last time I had a chance to get ahold of some of the starting materials
(including a few grams of piperazine monohydrochloride), I attempted to
start this synthesis, but got no farther than the second step.  Conventional
methods of methylated hydroquinone to 1,4-dimethoxybenzene require methyl
iodide (toxic and expensive as hell!) or dimethyl sulfate (toxic and muta-
genic); I was forced to fall back on an unconventional method (using
dimethyl oxalate) which failed miserably.
(There are several methods of O-methylating phenols to their methyl ethers;
also, it's possible to get 1,4-dimethoxybenzene by reducing quinone in the
presence of methanol.  I'd try that method, if I ever got another chance,
but that's not likely, since I'm no longer a chemistry major.)

Anyway, I think there's some interesting chemistry here--and in other "loose
ends" that Shulgin mentions in Pihkal but didn't follow up on.  And if
these new compounds turned out to be anything like their phenethylamine
homologues, it'd be, well, really cool.

 
----------------------------------------------------------------------------

Subject:      Re: Challenge for enterprising chemists
From:         jkenner@cello.gina.calstate.edu (Jason Kennerly)
Date:         1995/07/11
Newsgroups:   alt.drugs.chemistry 


{{{Added ascii art may be wrong but I do not believe this to be the case}}}
 
 IDENTIFICATION OF A GBR12935 HOMOLOG, LR1111, WHICH IS OVER 4,000-FOLD
 SELECTIVE FOR THE DOPAMINE TRANSPORTER, RELATIVE TO SEROTONIN AND
 NOREPINEPHRINE TRANSPORTERS.
 
Rothman RB; Lewis B; Dersch C; Xu H; Radesca L; de Costa BR; Rice KC; Kilburn
RB; Akunne HC; Pert A
 
 Clinical Psychopharmacology Section, NIDA Addiction Research Center,
 NIH, Baltimore, Maryland 21224.
 
 Synapse 14: 34-9 (1993) 
 
 Abstract
 The di-substituted piperazines,
 
 GBR12909
1-[2-{bis(4-fluorophenyl)-methoxy}ethyl]- 4-[3-phenylpropyl] piperazine
        
        F  
         \_____
         /  _  \    
        <  (_)  >
         \_____/                  CH2-CH2                 _____
               \                 /     \                 /  _  \
                CH--O--CH2-CH2--N       N--CH2-CH2-CH2--<  (_)  >
          _____/                 \     /                 \_____/
         /  _  \                  CH2-CH2
        <  (_)  >
         \_____/
         /
        F
 
 -and-
 GBR12935
 1-[2-(diphenyl-methoxy)-ethyl]-4-(3-phenylpropyl)piperazine
          _____
         /  _  \    
        <  (_)  >
         \_____/                  CH2-CH2                 _____
               \                 /     \                 /  _  \
                CH--O--CH2-CH2--N       N--CH2-CH2-CH2--<  (_)  >
          _____/                 \     /                 \_____/
         /  _  \                  CH2-CH2
        <  (_)  >
         \_____/
          
 
 are potent and selective (20-to 100-fold) inhibitors of [3H]dopamine
 reuptake, relative to [3H]5-HT and [3H]norepinephrine uptake.
 The GBR12935 analog, (LR1111),
 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)homopiperazine
          _____
         /  _  \    
        <  (_)  >
         \_____/                  CH2CH2-CH2  
               \                 /       |
                CH--O--CH2-CH2--N        N               _____
          _____/                 \      / \             /  _  \
         /  _  \                  CH2--CH2 CH2-CH2-CH2-<  (_)  > 
        <  (_)  >                                       \_____/
         \_____/
 
 was synthesized as part of a systematic structure-activity
 study of analogs of GBR12935 and GBR12909. LR1111 differs from
 GBR12935 by the addition of a methylene group into the piperazine ring
 to yield a compound with a seven-member homopiperazine ring. The IC50
 values for LR1111 at the dopamine, norepinephrine, and serotonin
 transporters were 7.2 nM, 34,072 nM, and greater than 20,000 nM,
 respectively, whereas the IC50 values of GBR12935 were 3.7 nM, 289 nM,
 and 1261 nM for these same transporters. This demonstrates that the
 addition of a single methylene group in the piperazine ring results in
 a compound with similar affinity but significantly higher selectivity
 for the dopamine transporter. LR1111 increased motoric activity in
 rats after intravenous administration. These indicate that LR1111 is a
 potent and highly selective inhibitor of the dopamine transporter.

------

Okay, so they aren't ?phenmethylamines? or PEA's, but they do have that 
damn piperizine, and would probably be stimulating, right? So I am 
wondering...


The simplest of these compounds ought to be READILY made from 
phenpropylamine, ethylenechlorohydrin, and 
???di-desmethyl-diphenhydramine??? [Okay... how ya gonna make that? maybe 
exaustively methylate benedryl, heat, and collect the (C6H5)2-CHOCH2CH2OH 
produced, then... hey wait a second...

that crap above from benedryl made from exaustive methylation and thermal 
decomposition of the quearenary amine + piperizine and your half way 
there [proceed via... the halide of the alcohol???]

     ____   ______  ________ _____
    /    \ |      \|   /\   |     \   jkenner@cello.gina.calstate.edu
   /      \|   _   \   \/   |  _   \  
  /___/\   \___|>   >       |__|>   > BORN TO BE WIRED... 
 /         |       /   /\  |       /  All the sugar and twice the 
 \_________|______/|___\/__|______/   caffeine of regular netusers!



s336261@student.uq.edu.au (Ryan Jones) writes:
>    ___                   ___                     ___
>   /   \    H     H  H   /   \   H  H  H     H   /   \
>  <  O  >---C--O--C--C--N     N--C--C--C--O--C--<  O  >
>   \___/    |     H  H   \___/   H  H  H     |   \___/
>           _|_                              _|_
>          /   \                            /   \
>         <  O  >                          <  O  >
>          \___/                            \___/
> The title compounds, (I; R1,R2 = H, halo, alkyl, trihalomethyl, lower alkoxy)
> were prepared for treatment of diseases associated with degeneration of 
> the dopaminergic system. 4,4-Difluorobenzhydrol and NaH were refluxed in 
> PhMe [I assume that's toluene] and then a PhMe solution of 
> 1-(2-chloroethyl)-4-(3-=chloropropyl)piperazine was added. The mixt. was 
> refluxed for 2 hours to give I (R1 = R2 = 4 Fluorine) (II). II dimaleate 
> at 30mg/kg orally increased locomotor activity in rats by 75%.

Thats a pretty hefty dosage... for a person my size you'd be looking at 3 
or 4 grams!!! Okay, so rats are like notoriously insensitive to drugs, 
this one still doesnt look all that more potent than.. say... caffeine...

