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Meeting of the German Pharmacological Society.

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Table 1. 1,2,4-Triazolidines
R
I R'
corresponding to I. On heating above their melting points,
the thiocyanate adducts 111 ( R = S-Alkyl) undergo fragmentation and are transformed into triazolethiones (IV).
I Yield [%I
I R"
95
91
97
96
NO2
c1
H
H
H
H
H
H
H
Received, May 29th. 1962
[Z 293/125 IE]
[I] R. Huisgen, R. Grashey, P.Laur, and H. Leitermann, Angew.
Chem. 72, 416 (1960).
[21 R. Huisgen, Naturwiss. Rundschau 14, 43 (1961); R. Huisgen, Proc. Chem. SOC. (London) 1961, 357.
[3] R. Grashey and K.Adelsberger, Angew. Chem. Internat. Edit.
I, 267 (1962).
91
83
80
72
53
methanol from I-methoxy-2-(p-nitrophenylamino)-1,2,3,4tetrahydroisoquinoline in boiling benzene.
Acid hydrolysis opens up the triazolidine ring: I1 (R = H;
R = CH3; R" = CsH5) yields 96 % benzaldehyde (as its 2,4dinitrophenylhydrazone), 65 % methylamine (as its hydrochloride), and the hydrazonium salt corresponding to I, which
was identified as the carbon disulphide adduct (formula XI1
'of ref. [I]) (86 %).
The thermolability of the triazolidines 11, is less than that of
the 1,3,4-oxadiazolidines [3]. Nevertheless, by heating I1
(R = H ; R = CH3; R" = p-Cl-C&) with phenyl isothiocyanate to 90 "C, one obtains quantitative yield of the mustard-oil adduct (formula X ofref. [I]). This finding, as well as
the reversible thermochromism observed on heating I1 in
2,3,6,7-Tetrahydroxy-9,1O-dimethyl-9,10ethanoanthracene
By Dr. E. Le Goff
Mellon Institute, Pittsburgh, Pa. (USA)
Niederl and Nagel [l] reported the isolation of a white compound (m.p. 30OoC) from the reaction of 1,2-dihydroxybenzene and 2,5-hexanedione in 70 % sulfuric acid. On the
basis of its elemental analysis and conversion to a tetraacetate (mp.. 238-240 "C) this compound was assigned
structure I.
Table 2. A3-1,2,4-Triazolines
I
Yield
[%I
~
NO2
H
NO2
NO2
NO2
NO2
CH3
91
91
SCHzGHs
SCH2GH5
SCHz-p-CI-GH4
S-cyclohexyl
SCH(CH3)z
SCH(CH,)C02CzHs
77
66
73
20
I
+ IV
solution, shows that the 1,3-addition leading to I1 is reversible.
If I is prepared in the presence of nitriles or thiocyanates
A3-1,2,4-triazolines (111) (Tab. 2) are produced.
Acid hydrolysis of I11 (R = N 0 2 ; R' = p-C&4N02) produces
p-nitrobenzoic acid, ammonia, and the hydrazonium salt
IIa, R = H
CH2
IIb, R = CH3CO-
Another formulation, 2,3,6,7-tetrahydroxy-9,lO-dimethyl9,10-ethanoanthracene (IIa) seemed from a mechanistic
standpoint to be a probable choice for the structure of this
condensation product. The N . M . R . spectrum of the tetraacetate of the condensation product (m.p. 243-244.5 "C) is in
complete agreement with the structure IIb. It exhibits a fourproton singlet at T = 2.95 (aromatic =CH), a twelve-proton
singlet at T = 7.75 (CH3CO-), a six-proton singlet at T = 8.13
I
(-C-CH3),and
I
a four-proton singlet at T= 8.37 (-CH2-)
Received, June 4th. 1962
[2].
[Z 298/124 IE]
[I] J. B. Niederl and R. H. Nagel, J. Amer. chem. SOC.62, 3070
(1940).
[2] N.M.R. spectra were obtained on a Varian A-60 spectrometer
in deuterochloroform. The author thanks Dr. B. L. Shapiro for
obtaining these spectra.
CONFERENCE REPORTS
Meeting of the German Pharmacological Society
April 8th to llth, 1962 in-Mdnz (Germany)
From the papers :
A Quinazolinone Derivative with Strong
Anticonvulsant Properties
Karl-Heinz Boltze, Dietrich Lorenz and
Maria Riiberg-Schweer, Koln-Miilheim (Germany)
Among compounds of the quinazolinone series, 2-(2-pyrid)1vinyl) -3 -0-tolyl- 3,4-dihydroquinazolin-4-one
(experimental
code B 169) is distinguished by its particularly strong anticonvulsant action.
After maximum electrical shock, the effective dose ED5o in
mice was 14.5::;
mg/kg (single administrationper 0s). Thus,
Angew. Chem. internat. Edit. / Vol. I (1962) / N o . 7
B 169 is just as effective as phenobarbital, diphenylhydantoin, and phenacetylurea, definitely more effective than
primidone, and about twice as effective as phenylchloroacetylurea, methsuximide, and N-(4-sulfamoylphenyl)butane1,Csultam.
After pentylenetetrazole shock, the ED50 per 0 s for mice was
1452:; mg/kg (i.e. dose which doubles the intravenous pentylenetetrazol administration required for the convulsion
threshold to be reached). In strychnine convulsion, we found
an EDSOof 200';
mg/kg (dose which counteracts the toxicity of strychnine in 50 % of the animals). From these tests,
it would appear that B 169 is in some ways more and in some
ways less effective than the reference compounds mentioned
above.
407
The sedative action of B 169 was tested on mice by means of
the balancing test on a horizontal rod and by observing their
reactions in the rotating squirrel cage. In the balancing test,
the EDSOwas 120 mg/kg (dose at which 50 % of the animals
fall from the rod within 5 minutes); in the treadmill test, it
was 57.5 mg/kg (dose at which the performance of trained
mice is decreased by 50 %). Thus, like other reference substances which have proved effective in grand ma1 epilepsy,
B 169 shows a relatively strong action in these tests. On the
other hand, its hypnotic effect is considerably less than that
of other anticonvulsant drugs. For this particular effect, the
ED50 for B 169 determined on mice was 1600 mg/kg (dose at
which 50 % of the animals lie dormant in the lateral position
for one hour).
The toxicity of B 169 is so low that no LDs0 could be determined after oral administration; even doses of 6000 mg/kg
were tolerated. The index of > 414 after electrical shock and
> 41 after pentylenetetrazol shock, calculated from the
quotient LDso/EDso, is not even approached by any of the
reference compounds.
In chronic feeding experiments, rats showed no toxic symptoms whatever after a 13-week period during which their
average daily consumption was 500 to 600 mg/kg.
Clinical reports on B 169 are not yet available.
Pharmacological Analysis of Acetylpyridine
Poisoning
H. Coper and H. Herken, Berlin-Dahlem (Germany)
After injection of 3-acetylpyridine, a very peculiar toxicological picture develops in rats, the most prominent feature being
the disturbance of neurological functions. On investigating
tumors, Kaplan et al. found that DPN-nucleosidase catalyzes an exchange of nicotinamide for acetylpyridine in
DPN, so that an abnormal DPN structure is formed. Previous
attempts to isolate this acetylpyridine-DPN from brain
tissues failed. We have now detected this compound in the
brains of animals suffering from acetylpyridine poisoning.
After separating the DPN zone from the remaining free
nucleotides of the brain by ion-exchange chromatography,
paper-chromatographical analysis showed that the DPN zone
from acetylpyridine-poisonedanimals was nonuniform. Chemical and spectrophotometric investigations revealed that the
second substance in the DPN zone was 3-acetylpyridineDPN. The spectra obtained after reduction of the compound
with alcohol dehydrogenase and subsequent treatment with
KCN were identical with those reported by Kaplan et al. The
proportion of 3-acetylpyridinenucleotidein the total DPN of
the brain was between 6 and 10%. It must be taken into
account, however, that the acetylpyridine compound concentrates mainly in those areas of the brain in which DPNase activity is particularly high. This is primarily the case in
the hypothalamus and apparently also in the hippocampus.
The enzyme is not very active in the cerebral cortex. Since
acetylpyridine-DPN behaves differently from DPN in various
dehydrogenase systems, replacement of nicotinamide with
3-acetylpyridine in DPN may have far-reaching consequences
upon tissue metabolism. Intoxication with 3-acetylpyridine
demonstrates the damage that may occur when an important
enzyme of the central nervous system becomes non-specific.
Thin Layer Chromatography in the Toxicological
Detection of Hypnotics
H . Eberhardt and K . .
I
Freundt,
.
Tubingen (Germany)
First, the hypnotics are extracted from body fluids with ether
in a Kutscher-Steudel extractor. The concentrate is then applied to silica gel plates impregnated with eosine. Piperidine/
petroleum ether (15) serves as eluent. The spots on the
chromatogram become visible under UV light against the
background by intensification or extinction of fluorescence.
In addition, mercuric nitrate may be sprayed on in order to
increase the contrast of the spots. The hypnotics bearing the
408
proprietary names Veronal, Luminal, Phanodorm, Medomin,
Adalin, Bromural, Persedon, Noludar, Doriden, Valamin,
and Revonal distribute themselves along the strip from
RF = 0.1 to RF = 0.9. Several hypnotics, when ingested in
therapeutic doses, are excreted only in the form of their metabolites. In the piperidine/petroleum ether system, however,
characteristic metabolite distributions are also obtained.
Amine Formation by X-Ray Irradiation
K. Flemming, Heiligenberg/Baden (Germany)
Pharmacologically active amines are formed in solutions of
certain aromatic amino acids by ultraviolet irradiation. Such
amine formation is also feasible with X-rays, as has been confirmed by the detection of histamine in histidine solutions
irradiated by X-rays. In the extracts of solutions of phenylalanine, tryptophan, and tyrosine irradiated with X-rays, the
corresponding amines, phenylethylamine, tryptamine, and
tyramine were found. - The presence of oxygen inhibits the
formation of amines by X-rays, but the presence of cysteine
and other reducing agents (homocysteine, thioglycerol, ascorbic acid) enhances it. The adjuvant effect of reducing compounds is also evident in solutions free from oxygen; the
effect is even greater than in the presence of oxygen. - It
could be shown that the formation of amine was due to OH
radicals. In histidine solutions, in which such radicals were
produced by a means other than X-rays (photochemical
cleavage of H202), histamine was also detected. The radical
mechanism permits a unified interpretation to be made of
the influence of oxygen and of the reducing agents, if it is
assumed that HO2 radicals inhibit the amine formation and
that the ratio of tRe 8H and HO2 radicals formed is shifted
by oxygen in favor of the HO2 mdicals, and by reducing
substances in favor of OH radicals.
Liberation of Catecholamines by Calcium
A. Philippu and H. J. Schiimann, Frankfurt/Main (Gmnany)
In perfusion experiments on isolated adrenal glands of cats,
Douglas and Rubin showed that acetylcholine liberates catecholamines only in the presence of calcium. Our experiments
with perfused isolated adrenals of cattle showed that in contrast to acetylcholine, the action of the indirectly acting sympathomimetic amines tyramine and P-phenylethylamine is
independent of calcium.
In incubation experiments with isolated cytoplasmic particles, the storage granules of the medullary hormones epinephrine and norepinephrine, the authors found that calcium
as well as tyramine and phenylethylamine liberate catecholamines. Even the physiological calcium concentration of blood
plasma (2.5 p moles/ml.) proved to be effective. However, the
action of calcium differs in two respects from the action of the
sympathomimetic amines investigated : 1. besides amines,
calcium liberates ATP in almost equal proportion; tyramine
and phenylethylamine, on the other hand, liberate only catecholamines; 2. calcium-induced amine liberation occurs at
37 "C as well as at 0 "C, while the sympathomimetic amines
are ineffective at 0 'C.
Acetylcholine, the physiological liberator of the catecholamines from the medullary cells, cannot liberate any of these
amines from storage granules isolated from the same cells,
even in the presence of calcium.
The following picture can be drawn up of the physiological
processes which lead to the liberation of the medullary hormones. Acetylcholine, which is released during excitation of
the splanchnic nerve, depolarizes the membrane of the chromaffine cell and thus creates conditions leading to increased
calcium influx, as is indicated by 45Ca experiments of Douglas
and Poisner. The calcium then liberates hormones and ATP
from the storage granules. Any calcium entering the cytoplasm
is probably removed from the cell by active transport.
[VB 581132 IE]
Angew. Chem. internat. Edit. / VoI. I (1962) I No. 7
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