Note: Descriptions are shown in the official language in which they were submitted.
397
This invention relates to new 2-amino-cyclopcnt-1-ene-1-dithiocar-
boxylic acid derivatives and pharmaceutical compositions containing the same,
furthermore to a process for the preparation thereof.
The novel compounds according to the invention correspond to the
general formula I
NH-R
~ - CSSH
wherein R is a C2 ~ alkenyl group, a C3 8 cycloalkyl group, phenyl group or
a Cl 6 alkyl group having optionally a Cl ~ alkoxy, hydroxy, carboxy and/or
amino substituent, ~ith the proviso that if R is an unsubstituted alkyl group,
this group contains at least 5 carbon atoms.
One aspect of the invention is a process for the preparation of a
2-amino-cyclopent-1-ene-1-dithiocarboxylic acid compound of the general
formula I,
Nlll R
CSSH
and pharmaceutically acceptable salts thereof, wherein R is a C2 4 alkenyl
group, a C3 8 cycloalkyl group, phenyl group or a Cl 6 alkyl group which is
unsubstituted or is substituted by a Cl ~ alkoxy, hydroxy, carboxy or amino
substituent, with the proviso that if R is an unsubstituted alkyl group, this
group contains at least 5 carbon atoms, which process comprises reacting 2-
amino-cyclopent-l-ene-l-dithiocarboxylic acid or a salt thereof with an amine
of the general formula II,
R-NH2 II
wherein R is as defined above to obtain the acid of formula I or a salt
thereof and, if required, converting a salt to the free acid or, if required,
converting the free acid to a pharmaceutically acceptable salt.
The novel compounds of formula I exert dopamine-~-hydroxylase in-
hibiting effect.
As known, substances influencing nervous functions exert their
-1- ~
6397
activities almost exclusively on the level of the stimulus transfer process-
es. These processes are relatively known, thus it is possible to prepare
compounds by which such processes can be influenced in a more or less con-
trolled manner. The intervention into elementary nervous processes involves,
howeverJ not only the influencing of the nervous system itself, but also
influencing the processes being under the control of the nervous system.
The efforts made in this respect in the last few years also encompass the
research work performed in connection with dopamine-~-hydroxylase and
,
`~ - la -
.
~ ~6~
compounds inhibiting its effects.
Dopamine-~-hydroxylase catalyzes the last enzymatic step of the
biosynthesis of noradrenaline, the conversion oE dopamine into noradrenaline.
The normal level of noradrenaline, a substance playing an essential role
in the transport processes of symphatic ncrvous stimuli, is an essential
factor with respect to the normal nervous functions and to the normal
functions of processes being under the control of the nervous system.
Substances with dopamine-~-hydroxylase inhibiting effects enable one to
influence the noradrenergic functions. This fact is of great importance
with respect of both research work and therapy, since, in the field of
research work, the consequences of the partial or total extinction of
noradrenergic functions can be examined by decreasing the noradrenaline
level with dopamine-~-hydroxylase inhibitors, and, in the field of therapy,
the hyperfunction of the noradrenergic system can be compensated with
dopamine-~-hydroxylase inhibitors. To our recent knowledge dopamine-~-hydro-
xylase inhibitors can be applied in the therapy of hypertension and Parkin-
sonism.
As known, benzyloxyamine and benzylhydrazine exert dopamine-~-hy-
droxylase inhibiting effects /van der Schoot et al.: Advances in Drug
Research, Vol. 2, p. 47; Harper and Simmons, Nikodijevic et al.: J. Pharm.
Exp. Ther. 140, 224 /1963/7. These compounds, however, exert their
activities for a short period, thus they are not applied in the therapy.
Disulfiram and diethyl dithiocarbamate, the reduction metabolite of the
- former compound !Goldstein et al.: Life Sci. 3, 763 /1964/7, furthermore
several N,N-disubstituted dithiocarbamates /Maj et al.: Eur. J. Pharmacol.
9, 183 /1970/; Lippman et al.: Arch. Int. Pharmacodyn. Ther. 189, 348 /1971/7
are substances known to exert strong dopamine-~-hydroxylase inhibiting
effects~ 2,2-Dipyridyl proved to be also effective under in vitro conditions
/Green: Biochim. Biophys. Acta 81, 394 /1964/7. Bis/l-methyl-4-homopipera-
zinyl-thiocarbonyl/-disulfide is one of the most potent dopamine-~
,,
: ~k
;3~7
:
-- 3 --
-hydroxylase inhibitors under in vivo conditions ~Florvall et al : Acta.
Pharmaceut. Sulcica 7, 7 /1970~7. Aromatic and alkyl thiourea derivatives
exert long-acting dopamine-~-hydroxylase inhibiting effects /Johnson et al.:
J. Pharm. Exptl. Ther. 171, 80 /1970/7.
Of the microbial substances fusaric acid /5-butylpicolinic acid/
and its derivatives /Hidaka et al.: Molec. Pharmacol. 9, 172 /1973/7,
oosponol /Umezawa et al.: J. Antibiotics 25, 239 /1972/7 and dopastine
Iinuma et al.: J. Agr. Biol. Chem. 38, 2107 /1974/7 are known to exert
strong dopamine-~-hydroxylase inhibiting effects.
Subsequent examina-tions have shown that some of the kno~n and
commercially available drugs, such as hydralazine, methimazol and
amphetamine, also possess dopamine-~-hydroxylase inhibiting effects.
Most of the above compounds have, however, the disadvantage
that although they possess dopamine-~-hydroxylase inhibiting effects, they
are rather toxic in prolonged treatments, thus they can be applied in
the therapy in a res~ricted manner, if at all.
The new compounds according to the invention possess strong
dopamine-~-hydroxylase inhibiting effects and are less toxic than the
known compounds with similar activities. Consequently the new compounds
can be applied to great advantage in the therapy.
The dopamine-~-hydroxylase inhibiting effects of the new compounds
; according to the invention were examined by the following tests:
The tests were perEormed on male Wistar rats weighing 150 to
200 g. The dopamine-~-hydroxylase inhibiting effects of the compounds
were evaluated by determining the change of noradrenaline, dopamine and
adrenaline levels of the cerebrum, heart, spleen and adrenal gland.
The serotonine and 5-hydroxy-indolyl-acetic acid levels of the cerebrum were
also determined. The measurements were performed as follows:
9~
- ~ -
The animals were decapitated, the cerebrum, heart, spleen and
adrenal gland were removed quickly, and the organs were frozen by
; placing them onto a metal sheet cooled with dry ice. The frozen
organs were stored for maximum one night at -20C.
' Determination of the adrenaline content of adrenal gland
The adrenal glands were freed f:rom fat and homogenized in 3.0 ml
of ice-cold O.~ n perchloric acid. The homogenized mixtures were centrifuged
for 10 minutes at 0C with a speed of 3200 r.p.m. on a Janetzky K-70 type
centrifuge. 0.05 ml samples were taken from the supernatant, and the
adrenaline level was determined directly by the method of Laverty et al.
/Anal. Biochem, 22, 269 /1968/7.
'Determination'of the noradrenaline content of heart and spleen
;' The organs were weighed in frozen state and then homogenized in
5.0 ml of 0.~ n perchloric acid containing 0.05% of EDTA-Na2 and 0.1% of
` Na2S2O5. The homogenized mixtures were centrifuged as described above
for the treatment of adrenal gland, the supernatants were decanted, and
the pH was adjusted to 8.0+0.1 with a 0.1 molar tris buffer containing
20 g/l of NaOH and 25 g/l of EDTA-Na2 lO0 mg of prepared A1203 ~Anton et
al.: J. Pharm. Ther. 138, 360 /1962/7 were added to the samples, and the
; 20 mixtures were shaken mechanically for 20 minutes. Thereafter A12O3 was
washed with 2x10 ml of distilled water, and the noradrenaline was eluted
' with 1.0 ml of 0.05 n perchloric acid, 0.5 ml samples of ~he eluate
were applied for the determination of noradrenaline. Noradrenaline
was determlned according to the method of Shellenberger et al. !Anal.
Biochem~'39~ 356 /1971!7, with the following modifications of the basic
' procedure: 0.5 ml of 0.1 molar Na-K-phosphate buffer, containing 9 g/l of
FDTA-Na2, were added to 0.5 ml of the eluate, and the catecholamines
~ /noradrenaline in the examination of heart and spleen and noradrenaline and
.~ dopamine in the examination of the cerebrum/ were oxidized with 0.1 ml of
a 0.1 n iodine solu-tion in 5% potassium iodide. After exactly 2 minutes
'
,
3~317
-- 5 --
oxidation was stopped by adding 0.25 ml oE a 2.5% sodium sulfite solution
in 4.4 n aqueous sodium hydroxide to the mixture. 2 minutes after the
introduction of the alkaline sulfite solution 0.2 ml of concentrated acetic
acid were added to the samples, upon which the pH decreased to 4.4 to
4.5. Thereafter the samples were placed Eor 5 minutes into a drying oven
heated to 100C, and then the samples were cooled with ice water. The
fluorescency of noradrenaline was measured with an OPTON spectrophotometer
at wavelengths of 390 nm /excitation/ and 490 nm /emission/.
Determination of the noradrenaline, dopamine, _erotonine and
5-hydroxy-indolylacetic acid contents of cerebrum
The brains were homogenized in 10 parts by volume of 0.4 n
perchloric acid. The homogenized mixture was stored at -20C overnight,
thereafter it was thawed and centrifuged as described above. A sample of
homogenized mixture corresponding to 0.5 g of brain was removed, the pH
of the sample was adjusted to 8.0~0.1 with O.l molar tris-buffer of the
`- above composition, and the sample was processed as described above for
the determination of the noradrenaline content of heart and spleen,
with the difference that 1.5 ml of 0.05 n perchloric acid were applied
as eluting agent. 0.5 ml of the eluate were applied to determine the
noradrenaline and dopamine content. The measurement was performed as
described above, with the difference that samples of 0.5 ml were applied
for the recording of the fluorescency of noradrenaline. The residue was
placed for 50 minutes into a drymg oven heated to 100C, thereafter the
sample was cooled with ice water, and the fluorescency of dopamine was
recorded at wavelengths of 325 nm /excitation/ and 380 nm /emlssion/.
In a further test series the serotonine and 5-hydroxy-
indolylacetic acid contents were also determined, beside the determination
of the noradrenaline and dopamine content, from the same sample. In
this instance the b:rains were homogenized in 10 ml of 75% ethanol, 0.2 ml
of EDTA-Na2 and 5% of ascorbic acid were added to the homogenized mixtures,
., ~
397
and the homogenized mixtures were maintained at -20C overnight, The
mixtures were centrifuged as described above, and 5.0 ml samples of the
supernatant were removed. The samples were diluted with equal volumes
of distilled water, and poured onto ion exchange columns of O.5x1.5 cm
dimensions, filled with buffered Amberlite* CG-30 /200 to 400 mesh/. The
columns were washed with 5 ml of distilled water followed with l.0 ml
of 0~2 n hydrochloric acid, and the first effluent and the aqueous
wash were collected for the cletermination of 5-hydroxy-indolylacetic acid.
Elution was continued with further 1.2 ml of 0.2 n hydrochloric acid in
order to remove noradrenaline, dopamine and serotonine. Samples of
0.3 ml were used for the determinations.
Noradrenaline and dopamine were determined by the method of
Shellenberger, modified as described above, whereas serotonine was
determined by the method of Curzon et al. /Brit. J. Pharmacol. 39, 653
/1970/7. The basic method was modified as follows: A 0.5% solution of
ortho-phthal/di/aldehyde in absolute ethanol was diluted with lO n hydro-
; chloric acid to 50-fold of its original volume, and 0.6 ml of the resulting
0,01% ortho-phthal/di/aldehyde solution were added immediately to 0.5
ml of the serotonine-containing sample. The sample was placed into a
hot water bath for 10 minutes, thereafter cooled with tap water, and the
fluorescency was recorded at wavelengths of 360 nm /excitation/ and 490 nm
/emission/.
5-Hydroxy-indolylacetic acid was determined from the mixture of
the first effluent and the aqueous wash. lO ml of distilled water and
0.2 ml of concentrated hydrochloric acid were added to the mixture, and
the sample was poured onto a 0.8 x ~.0 cm column filled with Sephadex* G-lO.
The column was washed with 15 ml of 0.1 n hydrochloric acid followed by
I,8 to 200 ml of 0.02 n aqueous ammonia, and then 5-hydroxy-indolylacetic
acid was eluted with f`urther 2.0 ml of aqueous ammonia. 0.5 ml samples
were used in the measurements, and the determination was performed
*Trade Mark
;x
' , : .
6397
- 7 -
according to the method oE Korf et al. !Biochem. Pharmacol. 20, 659 /1971/7.
The test results are summarized in Table 1. In the tests
disulfiram, 2,2-dipyridyl, bis/1-methyl-4-homopiperazinyl-thiocarbonyl/-
disulfide~ sodium diethyldithiocarbamate and N-phenyl-N'-/2-thiazolyl/-
thiourea were applied as reference substances. The values indicated in
Table 1 are the percentages in relation to the amine levels of the
controls measured in the same tests /~ Standard Error/. The statistical
calculations were performed on a TPA/i type computer, using Student's t test.
The meanings of the abbreviations used in Table 1 are as follows:
NA: noradrenaline
DA: dopamine
SE: serotonine
5-HIAA: 5-hydroxy-indolylacetic acid
AD: adrenaline
M-l: 2-/N-methoxyethyl/-amino-cyclopent-l-ene-dithiocarboxylic acid
M-2: 2-/N-allyl/-amino-cyclopent-l-ene-dithiocarboxylic acid
M-3: 2-/N-isoamyl/-amino-cyclopent-l-ene-dithiocarboxylic acid
M-4: 2-/N-hydroxyethyl/-amino-cyclopent-l-ene-dithiocarboxylic acid
M-5: 2-/N-/4-carboxy-4.-amino/-butyl7-amino-cyclopent-1-ene-dithiocarboxylic
acid
M-6: 2-/N-cyclohexyl/-amino-cyclopent-l-ene-dithiocarboxylic acid
M-7: 2-!N-/5-carboxy-5-amino/-pentyl7-amino-cyclopent-1-ene-dithiocarboxylic
acid
M-8: 2-/N-phenyl/-amino-cyclopent-l-ene-dithiocarboxylic acid
DS: disulfiram!bis(diethylthiocarbamoyl)-disulfide7
DDC-Na: sodium diethyldithiocarbamate
2,2-D: 2,2-dipyridyl
~LA-63: bis/1-methyl-4-homopiperazinyl/-thiocarbonyl-disulfide
U-14624: N-phenyl-N'-/2-thiazolyl/-thiourea
n = number of animals
6397
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- 10 -
The data of Table 1 clearly demonstrate that the new compounds
according to the invention considerably decrease the noradrenaline level
in the brainO Depending on the dosage, the method of administration and
the duration of treatment, the extent of decrease is 50 to 70 %. At the
same time a considerable /20 to 30%t incrcase in dopamine level can also
be observed. The increase of serotonine level is less significant, the
5-hydroxy-indolylacetic acid level increases, however, occasionally by
50 to go %,
The noradrenaline levels of heart and spleen, and the adrenaline
level of adrenal gland decrease as well, these decreases are, however,
not always significant even for compounds strongly decreasing the cerebral
noradrenaline level. This phenomenon can be attributed presumably to the
fact that the catecholamine turnovers of these organs are slow, furthermore
that adrenal gland possesses a relatively great depot of catecholamines
/noradrenaline and adrenaline/, and the missing noradrenaline contents of
spleen and heart are quickly supplemented by circulation. A unequivocal
decrease of catecholamine level cannot be observed in these organs with
-~ known dopamine-Ei-hydroxylase inhibitors, either.
- The toxicity data of the compounds according to the invention
are as follows:
Table 2
., .
Compound Animal Method of ad- LD50 mg/kg
,~ . . . mini strati on .
. ,~ - -- . ~. .
M-l mice i.p, ~400
M-2 mice i.p. ~500
- M-4 mice i,p. ~800
M-5 mice i.p. ~700
M-6 mice i.p. ~1000
M-7 mice i.p. ~900
M-8 mice i.p. ~1000
:
6;~9'7
Co3npound AnimalMethod o ad-LD m~/kg
ministration 50
FLA-63 mice i.p. ~150
2,2-D mice i.p. 280
rats i.p. 150
Hydralazine mice i.p. 83
DS rats p.o. 8600 + 370
rabbitsp.o. 1800 ~ 130
Dopastine mice i.p. 250 - 500
i.p. 460
P O 750
Fusaric acid mice p.o. 230 + 25
Chlorofusaric
acid mice p.o. 470 + 85
Oosponol mice i.p. 40
p.o. 280
U-14624 mice i.p. ~680
.. p.o. >1000
The data of Table 2 indicate that the LD50 values of the new
- compounds according to the invention are very favourable, thus these
compounds can be administered for prolonged time,
The new compounds of the general formula /I/ are prepared
; according to the in~ention by reacting 2-amino-cyclopent-1-ene-dithio-
carboxylic acid or a salt thereof with an amine of the general formula
/II/ ~
R-NH2 /II/
wherein R is as defined above. The reaction is performed in a manner
known per se /Bordas et al.: J. Org. Chem. 37, 1727 /1972/7. 2-Amino-
cyclopent-l~ene-dithiocarboxylic acid and the amines of the general formula
/II/, applied as starting substances, are known compounds,
, . ~. ~ , - . ,
6397
- 12 _
The reaction is performed preferably in a solvent medium, such
as in an inert organic solvent /e.g. an alcohol/ or in an aqueous inert
organic solvent. The reaction is carried out preferably at elevated
temperatures, particularly at the boiling point of the reaction mixture.
The invention is elucidated in detail by the aid of the
following non-limiting Examples.
Example 1
2-/N-Allyl/-amino-cyclo~ent-l-ene-l-d _h ocarboxylic acld
6.0 g /0.2 moles/ of allylamine are added to a suspension of 7.1
g /0,04 moles/ of ammonium 2-amino-1-cyclopent-1-ene-1-dithiocarboxylate in
60 ml of methanol, and the mixture is refluxed for 3 hours. The mixture is
cooled, diluted with 180 ml of water, decolourized with charcoal, and filtered.
The filtrate is acidified with 12 ml of acetic acid. The separated
substance is filtered off, washed with water and dried in a vacuum desiccator.
The title compound, melting at 100-104C, is obtained with a yield of 48%.
Analysis:
;- Calculated: S: 32.3 %, N: 7.03 %
~ Found: S: 31.5 %, N: 6.7 %
; Example 2
2-/N-Isoamyl!-amino-cyclopent-l-ene-l-dithiocarboxylic acid
17.0 g /0.2 moles/ of isoamylamine are added to a solution of
12.6 g /0.08 moles/ of 2-am1no-cyclopent-l-ene-l-dithiocarboxylic acid in
; 120 ml of methanol. The mixture is refluxed for 3 hours, then it is
cooled, diluted with 360 ml of water, and filtered. The filtrate is
` acidified with 12 ml of acetic acid. The separated solid is filtered off,
washed with water, and taken up in a mixture of 30 ml of water and 20 ml
of 10% sodium hydroxide solution. The non-dissolved substance is removed
by filtration and the filtrate is acidified with acetic acid. The
separated substance is filtered off, washed with water, and dried in a
desiccator. The title compound, melting at 65-79C, is obtained with a
yield of 3.62 %.
.
- 13 -
Analysis:
Calculated: S: 27.9 %, N: 6.1 %
Found: S: 27.5 %, N: 6.17%
Example 3
2-/N-/4-Carboxy-~-amino/-butyl7-amino-cyclopent-1-ene-1-
dithiocarboxylic-acid
A suspension of 3.36 g /0.02 moles/ of 2-ornithine hydrochloride
and 5.0 g /0.06 moles/ of sodium hydrocarbonate in 50 ml of methanol and
15 ml of water is refluxed for 1.5 hours. Thereafter 20 ml of methanol
and 3.52 g /0.02 moles/ of 2-amino-cyclopent-1-ene-1-dithiocarboxylic acid
ammonium salt are added to the mixture, and refluxing is continued for
further 10 hours. The mixture is cooled, diluted with 200 ml of water,
decolourized with charcoal, and filtered. The filtrate is acidified with
25 ml of acetic acid. The separated substance is filtered off, washed with
water and dried in a desiccator. The title compound, melting at 155C, is
obtained with a yield of 15.5 %.
Analysis:
Calculated: S: 23.4 %, N: 10.2 %
Pound: S: 26.04%, N: 7.86%
Example 4
2-/N-Methoxyethyl/-amino-cyclopent-l-ene-l-dithiocarboxylic acid
15.0 g /0.2 moles/ of 2-methoxyethylamine are added to a suspension
of 12.6 g /0.08 moles/ of ammonium 2-amino-cyclopent-1-ene-1-dithiocarboxy-
late in 120 ml of methanol. The mixture is refluxed for 3 hours, then it
is cooled, diluted with 360 ml of water, and the hazy mixture is decolourized
with charcoal. 12 ml /0.2 moles/ of acetic acid are added to the resulting
light red solution. The separated yellow, amorphous substance is filtered
off, washed with water, and dried in a vacuum desiccator. 6.1 g of the
resulting crude product are taken up in 50 ml of water/ 20 ml of 10%
sodium hydroxide solution are added, and the mixture is stirred for
some minutes~ The insolubles are filtered off on a rumpled filter and
~ 1~;16~9'7
:'
- 14 -
washed with a small amount of water. The clear filtrate is admixed with
acetic acid to precipitate the product completely. The precipitate is
filtered off, washed with water, and dried in a desiccator. The title
; compound, melting at 64-70C, is obtained with a yield of 35.7 %.
: Analysis:
Calculated: S: 2904 %, N: 6.45 %
Found: S: Z9.4 %, N: 5.81 ~ .
~.
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