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#90 IDNNA
2,5-DIMETHOXY-N,N-DIMETHYL-4-IODOAMPHETAMINE
SYNTHESIS: To a stirred
solution of 0.4 g
2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in 12 mL MeOH
containing 4 mL of a 40%
formaldehyde solution there was added 1 g
sodium cyanoborohydride. The
pH was kept at about 6 by the occasional
addition of HCl. When the
pH was stable (about 48 h) the reaction
mixture was poured into 250 mL H2O and made strongly basic by the
addition of aqueous
NaOH. This was extracted with 3x75 mL
CH2Cl2, the
extracts pooled, and extracted with 2x75 mL dilute H2SO4, and the
pooled acidic extracts again made basic and again extracted with
CH2Cl2. The
solvent was removed under vacuum to give 0.38 g of a
colorless oil. This was
dissolved in 2 mL IPA and treated with a
solution of 0.13 g oxalic acid
dihydrate in 1.5 mL warm IPA, and then
anhydrous Et2O was added dropwise until a turbidity persisted. Slowly
a granular white solid appeared, which was filtered off,
Et2O washed,
and air dried to give 0.38 g of
2,5-dimethoxy-N,N-
dimethyl-4-
iodoamphetamine oxalate (IDNNA) with a mp
of 145-146 °C. Anal. (
C15H22INO6) C,H. The
hydrochloride salt of
this base proved to be
hygroscopic.
DOSAGE: greater than 2.6 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This base, if it were given a code name
based upon its
substituents arranged in their proper
alphabetical
order, would have to be called something like DNDIA, which is quite
unpronounceable. But by a rearrangement of these terms, one can
achieve IDNNA (Iodo-Dimethoxy-N,N-
dimethyl-Am
phetamine) which has a
nice lilt to it.
One of the major goals of research in
nuclear medicine is a drug that
can be used to demonstrate the brain blood flow pattern. To do this
job, a drug should demonstrate four properties. First, it must carry
a
radioactive isotope that is a
positron emitter (best, a
fluorine or
an
iodine atom, for use with the
positron camera) that can be put onto
the molecule quickly,
synthetically, and which will stay on the
molecule,
metabolically. Second, as to brain entry, the drug should
be rapidly and extensively taken up by brain
tissue, without being
selectively absorbed or concentrated at any specific sites. In other
words, it should go where the blood goes. Thirdly, the
absorption
should be strong enough that it will stay in the brain, and not be
washed out quickly. This allows time to both locate and count the
radioactivity that was carried in there. And lastly, the drug must be
without
pharmacological action.
IDNNA looked like a promising candidate when tried with a
radioactive
iodine label, and there was quite a flurry of interest in using it
both as an ex-perimental drug, and as a prototype material for the
synthesis of structural variants. It went in quickly, extensively and
quite
diffusely, and it stayed in for a long time.
But was it
pharmacologically active? Here one finds a tricky road to
walk. The animal toxicity and behavioral properties can be determined
in a straightforward manner. Inject increasing amounts into an
experimental animal and observe him closely. IDNNA was quite inert.
But, it is a very close
analogue to the extremely potent
psychedelic
DOI, and it is widely admitted that animal assays are of no use in
trying to determine this specific
pharmacological property. So, a
quiet human assay was called for. Since it did indeed go into the
brain of experimental animals, it could quite likely go into the brain
of man. In fact, that would be a needed property if the drug were to
ever become useful as a diagnostic tool.
It was assayed up to levels where DOI would have been active, and no
activity was found. So one could state that it had none of the
psychedelic properties of DOI at levels where DOI would be active
(this, at 2.6 milligrams orally). But you don't assay much higher,
because sooner or later, something might indeed show up. So it can be
honestly said, IDNNA is less active than DOI itself, in man. Let's
wave our hands a bit, and make our statement with aggressive
confidence. IDNNA has shown no activity in the human CNS at any level
that has been evaluated. This sounds pretty good. Just don't go too
far up there, and don't look too carefully. This is not as
unscrupulous as it might sound since, in practical terms, the
extremely high specific activities of the
radioactive 122I that would
be used, would dictate that only an extremely small amount of the drug
would be required. One would be dealing, not with milligram
quantities, but with microgram quantities, or less.
Some fifteen close
analogues of IDNNA were prepared, to see if any had
a better balance of
biological properties. A valuable intermediate
was an iodinated
ketone that could be used either to
synthesize IDNNA
itself or, if it were to be made radio-labelled, it would allow the
preparation of any desired
radioactive analogue in a single
synthetic
step. The
iodination of
p-dimethoxybenzene with
iodine monochloride
in acetic acid gave
2,5-diiodo-1,4-dimethoxybenzene as white
crystals
from
acetonitrile, with a mp of 167-168 °C. Anal. (
C8H8I2O2) C,H.
Treatment of this with an
equivalent of
butyllithium in
ether,
followed with N-
methyl formanilide, gave
2,5-dimethoxy-4-iodobenzaldehyde as pale yellow
crystals from
ethanol,
with a mp of 136-137 °C. Anal. (
C9H9IO3) C,H. This, in
solution in
nitroethane with a small amount of
anhydrous ammonium acetate, gave
the
nitrostyrene 1-(2,5-dimethoxy-4-iodophenyl)-2-nitropropene as
gold-colored
crystals from
methanol, mp 119-120 °C. Anal.
(
C11H12INO4) C,H. This was smoothly reduced with ele-mental iron in
acetic acid to give
2,5-dimethoxy-4-iodophenylacetone as white
crystals from
methylcyclopentane. These melted at 62-63 °C and were
both spec-troscopically and
analytically correct. Anal. (
C11H13IO3)
C,H.
This intermediate, when reductively
aminated with
dimethylamine, gives
IDNNA identical in all respects to the product from the
dimethylation
of DOI above. But it has also been reacted with 131I NaI in acetic
acid at 140 °C for 10 min, giving the
radioactive compound by
exchange, and this was reductively
aminated with over a dozen
amines
to give
radioactive products for animal assay. There was produced in
this way,
2,5-dimethoxy-4-iodo-N-alkyl-
amphetamine where the alkyl
group was
methyl,
isopropyl,
cyclopropylmethyl, hexyl,
dodecyl,
benzyl,
cyanomethyl, and 3-(
dimethylaminopropyl). Several
dialkyl
homologue were made, with the alkyl groups being
dimethyl (IDNNA
itself),
diethyl,
isopropyl-methyl, and
benzyl-methyl. These specific
homologues and
analogues are tallied in the index, but a number of
other things, such as
hydrazine or
hydroxylamine derivatives, were
either too impure or made in amounts too small to be valid, and they
are ignored.
The
diethyl compound without the
iodine is
2,5-dimethoxy-N,N-
diethylamphetamine, which was prepared by the
reductive
alkylation of DMA with
acetaldehyde and
sodium
cyanoborohydride. This product, DEDMA, was a clear white oil, bp
82-92 °C at 0.15 mm/
Hg which did not form a
crystalline hydrochloride.
An interesting measure of just how different these N,N-
dialkylated
homologues can be from the
psychedelic primary
amines,
pharmacologically, can be seen in the published report that the
beta-hydroxy derivative of DEDMA is an antitussive, with a potency the
same as
codeine.
None of these many iodinated IDNNA
analogues showed themselves to be
superior to IDNNA itself, in the rat model, and none of them have been
tasted for their
psychedelic potential in man.
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