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Potential Psychotomimetics - Bromomethoxyamphetamines

Charles F. Barfknecht & David E. Nichols
J. Med. Chem. 14(4), 370-372 (1971)

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In the study of psychotomimetic amphetamines, 2,5-dimethoxy-4-methylamphetamine (DOM) is the most potent compound yet discovered (50-150 times mecaline)2. At least part of its potency is related to the nature of the para substituent. In the light of Knoll's3 studies on the psychotomimetic effects of p-bromo-methampethamine and its cross-tolerance to LSD, the synthesis and evaluation of bromomethoxyamphetamines appeared to be a logical extension. Br has a comparable size, but different electronic character than Me. Kand and Green4 have recently demonstrated a correlation between the electronic character of the ring and the hallucinogenic potency of the methoxylated amphetamines. The substitution of Br into various ring positions of methoxylated amphetamines allows for several electronic arrangements.

Chemistry

Table I
Substitued 1-Phenyl-2-nitropropenes

R2 R3 R4 R5 R6
Mp, C
Yield
Br H H OCH3 H
73-74.5
61.8%
H Br OCH3 H H
73-74
45%
H OCH3 Br H H
73-74.5
36.8%
Br H OCH3 OCH3 H
105-106
59.4%
H OCH3 Br OCH3 H
121-121.5
46.8%
OCH3 H Br OCH3 H
113.5-115
57%

The general synthetic route involved preparation of the appropriately substituted benzaldehydes, condensation with EtNO2 and reduction to the bromomethoxymethamphetamines. Tables I and II summarize the compounds which have been prepared.

Attention is called to the report by Pandya and co-workers5 concerning the bromination of m-hydroxybenzaldehyde. The product of this reaction is claimed to be 3-hydroxy-4-bromobenzaldehyde; however the product which we isolated proved to be 2-bromo-5-hydroxybenzaldehyde. This assignment was verified by NMR spectroscopy and chemical conversion by O-methylation and permanganate oxidation to 2-bromo-5-methoxybenzoic acid. The physical properties of this material agree with the literature values6.

Table II
Bromomethoxyamphetamines, HCl salts

# R2 R2 R2 R2 R2
Mp, C
Yield
1 Br H H OCH3 H
151.5-153
20%
2 H Br OCH3 H H
210-213
28.8%
3 H OCH3 Br H H
161.5-163
32%
4 Br H OCH3 OCH3 H
214-215.5
42%
5 H OCH3 Br OCH3 H
221-222
36.8%
6 OCH3 H Br OCH3 H
198-199
29.5%

The LAH reduction of 1-(bromomethoxyphenyl)-2-nitropropenes was complicated by the extreme ease of debromination. Low temperatures and equimolar amounts of reagents prevented the debromination, but resulted in poor yields of the bromomethoxyamphetamines.

Table III
Biological Results

Compound
Tresholdα
dose
Action
1
25 mg/kg
Inactive
2
9 mg/kg
CNS stimulation;
onset of amphetamine-type
toxicity at 18 mg/kg
3
7.5 mg/kg
Mescaline-like
4
25 mg/kg
Inactive
5
<10 mg/kg
Mescaline-like with some deaths
at 10; inactive at 5 mg/kg
6
<2.5 mg/kg
Mescaline-like;
effect much more profound than
that caused by 2.5 mg/kg of DOM

α Dose at which action wasobserved; any compd
which does not show mescaline-like effect at 25
mg/kg (the "effective" dose of mescaline) is
considered inactive. The treshold dose of
3,4-dimethoxyamphetamine.HCl and DOM.HCl
are 12.5 and 2.5 mg/kg, respectively.

Biological Results

The compounds were tested for an effect on a conditioned avoidance response in male rats. The detailed procedure has been reported previously7. The effects were compared with those produced by mescaline, 3,4-dimethoxy- methamphetamine, DOM, and the CNS-stimulant dextroamphetamine. This assay gives an indication wether the compound possesses stimulant action or one more like that of mescaline, 3,4-DMA, and DOM. Table III summarizes the biological data. All the compounds which exhibited an effect similar to mescaline-type compounds have the p-Br substituent8. The data on the 2-bromo-5-methoxy analog (3) must be considered tentative, since 2,5-dimethoxyamphetamine which does not have a para substituent is active in humans but inactive in rats9. A correlation has been demonstrated between the degree of fluorescence and the psychotomimetic potency for methoxylated amphetamines; no such relationship seems to exist for this series10. For example, 2 and 6 have nearly the same degree of fluorescence, but differ widely in their biological effects. A detailed study of the pharmacology is in progress.

Experimental11

All substituted benzaldehydes have been reported previously with the exception of 2,5-dimethoxy-4-bromobenzaldehyde and 3,5-dimethoxy-4-bromobenzaldehyde, whose syntheses are described below.

3,5-Dimethoxy-4-bromobenzaldehyde

3,5-Dihydroxy-4-bromobenzoic acid (K & K Laboratories, Inc.) was di-O-methylated with Me2SO4 in the usual manner: yield 78% (EtOH-H2O); mp 249-250C (lit.12 249-50). The acid chloride was obtained by reaction with SOCl2. The crude product (mp 124-128) was used in the next step without further purification. The aldehyde was obtained by reduction of the acid chloride by LiAlH(O-tert-Bu)3 as described by Ho, et al.13 The crude aldehyde was recrystd from MeOH-H2O; yield 52%; mp 112-114C.

2,5-Dimethoxy-4-bromobenzaldehyde

2,5-Dimethoxybenzaldehyde (66.5 g, 0.4 mole) was dissolved in 300 ml of CH2Cl2. Anhyd SnCl4 (115 g, 0.44 mole) was added, followed by 64 g of Br2 over a 1-hr period. The resulting soln was refluxed for 2 hr and stirred overnight at room temp. The orange suspension was poured over 500 g of ice, and the layers were sepd. The CH2Cl2 layer was washed with 10% NaHCO3 and H2O and dried (Na2SO4). After filtration the solvent was removed in vacuo, and the solid residue recrystd from MeOH-H2O to yield 64 g (66%) of the aldehyde, mp 132-133. The structure was confirmed by the oxidation with MnO4- to 2,5-dimethoxy-4-brombenzoic acid, mp 170C (lit.14 mp 170C).

Substitued-1-phenyl-2-nitropropenes

The substitued benzaldehydes were refluxed with EtNO2 and NH4OAc in AcOH as described by Gairaud and Lappin.15

Bromomethoxyamphetamine Hydrochlorides

All amphetamines were prepared from the corresponding 1-phenyl-2-nitropropenes by LAH reduction.16

References

  1.  
  2. A.T. Shulgin, T. Sargent, and C. Naranjo, Nature (London), 221, 537 (1969)
  3. J. Knoll in "Amphetamines and Related Compounds", E. Costa and S. Garttini, Ed., Raven Press, New York, N. Y., 1970, p 761.
  4. S. Kang and J.P. Green, Nature (London), 226, 645 (1970)
  5. K. C. Pandya, R. B. K. Pandya, and R. N. Singh. J. Indian Chem. Soc., 29, 363 (1952)
  6. P. H. Beyer, Rec. Trav. Chim. Pays-Bas, 40, 621 (1921)
  7. C. F. Barfknecht, J. M. Miles, and J. L. Leseney, J. Pharm. Sci., 59, 1842 (1970)
  8. During the revision of this manuscript, Dr. A. T. Shulgin informes us that 4-bromo-2,5-dimethoxyamphetamine has a potency in humans greater than DOM and an effect similar to 3,4-methylenedioxyamphetamine; Pharmacology 5, 103-107 (1971)
  9. J. R. Smythies, Neurosci. Res. Program Bull., S, 79 (1970)
  10. F. Antun, J. R. Smythies, F. Benington, R. D. Morin, C. F. Barfknecht, and D. E. Nichols, Experentia, in press.
  11. Melting points were taken on a Hoover Uni-Melt apparatus and are corrected. Where analyses are indicated only by symbols of the elements, anal. results obtained for those elements were within 0.4% of the theoretical values. NMR spectra for all compounds were obtained on a Varian Associates T-60 and are consistent with the assigned structures.
  12. H. Erdtman and B. Leopold, Acta Chem. Scand., 2, 34 (1948)
  13. B. T. Ho, W. M. McIssac, R. An, L. W. Tansey, K. E. Walker, L. F. Englert, Jr., and M. B. Noel, J. Med. Chem., 13, 26 (1970)
  14. A. Luttringhaus and H. Gralheer, Justus Liebigs Ann. Chem., 550, 67 (1941)
  15. C. B. Gairaud and G. R. Lappin, J. Org. Chem., 18, 1-3 (1953)
  16. L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis", Wiley, New York, N. Y., 1967, p 581.