Note: Descriptions are shown in the official language in which they were submitted.
1~6S~7S
~. .
The invention concerns novel (2-oxo-pyrrolidine-1)
acetic hydrazides. These hydrazides and 1,2 bis-hydrazides,
respectively, offer special advantages as starting substances
in the preparation of piracetam. These hydrazides also have
as such a superior pharmacological effect e.g. as psychopharmacons
(nootropic substances).
The substance (2-oxo-pyrrolidine-1)-a~et:amide has
been used recently under the generic name piracetam as a drug
against traveling sickness, for the treatment Oe senile invol-
lû ution (A.J. Stepink, Arzmeimittelforschung 22, 1972, No. 6,
p. 975/977) and as a nootropic agent for influencing the learning
capacity. (W. Strehl, A. Brosswitz, Therapiewoche 36, 1972,
p. 2975). Ac~ording to ~. Charbaut et al (Ann. Med Psychol. 1,
1973, p. 281/286) an improvement was found only in 4596 of
geriatric patientsr while 40% showed no improvement.
From German Offenlegungschrift No. 1,620,608 it
is known to prepare (2-oxo-pyrrolidine-1) acetamide from
- (2-oxo-pyrrolidine-1) acetic ethyl ester by amidation with
ammonia. But the products obtained according to this process
are very impure and must be recrystal}ized repeatedly for purifi-
cation. This requires not only a considerable technical effort,
but also leads to yield losses. Besides, an ext:reme
excess of ammonia is equired in this process, namely
10 times more NH3 than is stoichiometrically required
for the reaction. Thus, more than 9 moles of ammonia
must be removed per mole (2-oxo-pyrrolidine-1)
acetamide and be processed at great costs and/or be
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removed. Besides, this known process requires considerable amounts
of solvent~ This complicates the process further and increases the
cost. Other disadvantages are present in the known process, e.g~
in handling the apparatus and in view of environment protection,
resulting from the fact that ammonia is constantly introduced
in gaseous form duxing the reaction.
One o~ject of the,,invention is to provide comPounds
and methods for their preparation which have a superior effective-
ness as psychopharmacons. Another object of the invention is
to make chemical compounds available which permit,simplification
of the reaction and in the handling of the apparatus during the
reaction to the corresponding acatamides, which avoid at the
same time the use of great excesses of reaction components. ' ,
These objective's axe achieved according to the
invention by means of the new (2-oxo-pyrrolidine-l) acetic
hydrazides of the formula
~= O ' '
~ le
2~ C ~ NHNHRl
where Rl denotes a hydrogen atom or a group of khe formula '
0 II
C~I2--C
These new hydrazides are obtained by reacting
(2-oxo-pyrrolidine-1) acetic esters of the
jrc~ 2 -
.
,.- - .
:. i ,,, . ~
.: :
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formula
~ > = o III
11
CH2 - C-OR2
where R2 denotes an alkyl group with 1 to 4 C~atoms r
with hydrazine or with a hydrazine derivative o~ formula I,
where Rl denotss a hydrogen atom.
In a special embodiment, it is provided in this
process that (2-oxo-pyrrolidine-1) acetic ester of ~ormula III
is used, where R2 denotes -CH3 or -C~H5.
A special advantage of this process is that the
(2-oxo-pyrrolidine-1) acetic ethyl ester used as a starting sub-
stance, for example, can be employed in a technical quality or in
crude form, as it is obtained from its method of production~
If we want to use presen~ly known (2-oxo-pyrrolidine-1) acetic
esters, we find that these are available only in a very impure
form and are difficult and expensive to purify because of their
high boiling points. The impurity oi these acetic esters is of
no importance in the pr-ocess according to the invention, because
the hydrazide is always ~ormed in a smooth reaction and the
hydra~ides obtained are very pure.
The reaction of the (2-oxo-pyrrolidine-1) acetic
esters of formula III with hydrazine is generally exothermic and
therefore begins spontaneously when the components are mixad with
each other. The reaction rate depends, among other things, upon
the reactivity of the ester ~rou~ingsO The temperature of the
mixture J which already hegins to react at room t,3mperature~
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1~6S~37~
for example, can b~ increased either by developing its own heat
of reaction ox by supplying external heat~ This way the reaction
rate is adapted to the reactivity of the components.
- The use of (2-oxo-pyrrolidine-1) acetic methyl
ester is preferred, because of the reactivity of the ester. But
we could also just as well use the ethyl ester, propyl ester,
isopropyl ester or the butyl esters.
It is advisable to use additionally for this reac~ion
- low alkanols, such as methanol or isopropanol. The use of a sol-
vent permits one to control the reaction more accurately and to
regulate the temperature increase up to a certain amount. The
additional use of a solvent also affects the heat distribution
in the reaction mixture, the reaction rate, and, therefore, alsa
the total reaction time. If the temperature o~ the mixture
i5 increased, after mixing the components (by adding into the
ester), up to the boiling point of the solvent, this temperatur~
can also be regulated accurately by the selected solvent. Thus,
for example, in thè reaction with acetic methyl ester in methanol
or isopropanol, the heating is continued for several hours with
reflux after the components have been mixed. Subsequently, the
desired hydrazide is crystallized from the cold reaction mixture
and can be easily isolated, washed with a solvent, and dried at
room temperature.
Substantially molar ratios are required for the re-
action of the ester of formula III with hydrazine for
the formation of hydrazides, o.g. 1 mole ester per 1 mole
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hydra2ine. Pr~f~rably, however, a slight ~xcess of hydrazine
is used, e.g., 1.1 or 1.2 mole hydrazine per 1 mole ester. In
this process the ordinary available technical yrade hydrazine
hydrate can be used. If solvents are used which contain small
amounts of water, and/or hydrazine hydrate, the water is first
separated by azeotropic distillation, so that it does ~ot inter-
fere with the reac-tion.
If less than 1 mole hydrazine is used per mole
ester, for example, 0.9 mole hydrazine, this does not
result in any disadvantages, despite the theoretical excess of
ester in the reaction mixture- With excess ester, the originally
formed hydrazine of formula I, where Rl denotes a hydrogen atom,
can urther react with the ester, forming the hyarazide of
formula I, wherein Rl denotes a group of formula II. When
both hydrazines are formed this way, side by side, it is not
difficult to separate these two substances from each other.
~he hydrazide of formula I, where Rl denotes hydrogen,
is soluble, for example, in hot methanol or hot isopropanol,
but the hydrazide of formula I where Rl denotes a group of formula
II is only soluble in hot methanol~ This means that one com-
pound can be separated first with hot isopropanol~
The hydrazide offormula I ~here Rl denotes a group
of formula II, namely 1,2-bis-(2-oxo-pyrrolidine-1) acetic hydra-
zide, is generally formed at elevated temperature ~above 50C, and
preferably between 100 and 180C), with only small amounts of
irc: -i .
i5875
solvent, or without any solvent, and with a corres-
ponding excess of ester, if we start from hydrazine as
the second reaction component, or by direct reaction
between the t2-oxo-pyrrolidine-1) acetic hydrazide and
the t2-oxo-pyrrolidine-1) acetic ester. If solvents
with a hizher boil;n~ point are used and in smaller
amountsl for example, such as bukanols or isopropanol
or mixtures thereof, the formation of 1,2-bis-hydrazide
can be increased with the corresponding quantitative
ratios of the starting substances. The use o~
small amounts of solvent has the advantage that a
crystal sludge is obtained which is suspended in the
solvent and which can be easily processed. ~esides,
~2-oxo-pyrrolidine-1) acetic hydrazide and (2-oxo-
pyrrolidine-l) ace~ic methyl ester can be mixed as
starting components without a solvent, heated and the
pure l,2-bis-hydrazide can be obtained by redissolution
in methanol.
(2-oxo-pyrrolidine-1) acetic methyl ester is
obtained by reacting a (2-oxo~pyrrolidine-1) metal
compound of the formula
A
~ ~o
N I~r
Me
. - : - . - : . :
~6S~75
where Me denotes an alkaline meta] atom, with monohalogen acetic
ester, using a monohalogen acetic methyl ester as a monohalogen
acetic ester.
Preferably monochIorine and/or monobromine acetic
methyl ester is used. Preferred metal compounds of the above
formula IV are (2-oxo-pyrrolidine-1) lithium, ~2-oxo-pyrrolidine-
1) sodiùm or (2-oxo-pyrrolidine-1) potassium. The reaction ls
preferably ~arried out in a non-polar or slightly polar organic
solvent or in mixtures ~hereof. Prç~erred solvents are
e. g . benzene, toluene and/or hexane.
The (2-oxo-pyxxolidine-1) acetic methyl ester thus
obtained is much more suitable for further reaction on the ester
grouping. This methyl ester has a boiling point which is lower
by 12 C than the corresponding ethyl ester; consequently it
can be purified much more easily and very gently by distillation.
! This is of particular importance since the pyrrolidine ring can
be split by higher thermal stress, so that deep black resinous
impurities are formed. Furthermor~, the use of the acetic
methyl ester results in a better space-time yield in consequent
reactions. The acetamide obtained over the corresponding
hydrazide or a hydrazide derivative is much purer than that
obtained by starting ~rom (2-oxo-pyrrolidine-13 acetic ethyl
ester.
The (2-oxo-pyrrolidine-1) metal compound of formula
IV is obtained from pyrrolidine of the formula
r~
,~, O
'
H
; - 7 -
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1~)65~375
in an organic solvent with an alkali amide, for example,
sodium amide, or with a~ alkaline metal alkyl, such as
butyl-lithium. Instead of sodium amide or butyl lithium the
analogous derivatives of the other alkaline metals or other alkyls -
can also be used. ~he (2-oxo-pyrrolidine-l) metal compounds ara
produced in the known manner. The metal compounds thus obtained
need not be isolated from the corresponding solution of the
of the (2-oxo-pyrrolidine-l) metal compounds. Rather, these
solutions can be u~ed directly ~or further reaction with the
monohalogen-acetic me~hyl ester, which is a special advantage
of the process of the inven~ion, since it permits one to work
continuously in the same apparatus. Thus, no yields are lost
in the isolation of intermediate products. Of particular
advantage also are the low equipment costs~
The (2-oxo-pyrrolidine-l) acetic hydrazides of
formula T can be transformed by reduction or hydration into
(2-oxo-pyrrolidine-l) acetamide of extremely pure form. For
this reaction the hydrazides of formula I can be used, both in
the form of where Rl denoteshydrogen, and in the other form
where Rl denotes a group of formula II. Mixture of these two
substances can also be used without any disadvan1:age. Consequently
the hydrazides according to the invention, which can be easily
isolated in a very pure form, or need not be isolated if they
are obtained from a process variant (solvent, temperature, molar
` ratios etc.~ in a mixture.
With the process according to ehe invention the
,
- 81 `:'
. . : . . . : . . :
the hydrazides are obtained in a substantially quantitative yield:
Pharmacological effectiveness:
,
The compounds according to the invention showed a
greater nootropic activity in animal tests than piracetam
according to the state of the art, and thus they represenk an
enrichment of the phaxmacological field.
For a pharmacological comparison between the
compound 1,2-bis-(2-oxo-pyrrolidine-1) acetic hydrazine accord-
ing to the invention with pirace~am we used male rats of 150-
200 g. weight, which were divided by means of a random table
into three groups of 10 animals each. After we had made sure in
a preliminary test that the animals could not find their way
to the exit of a water labyrinth within 5 minutes (method based
on C. Giurgea et al, Pharmacol. (Paris) 3, 1972, p. 17-30), the
. .;
groups were exposed before the test proper on four successive
days and on the 7th day to a deficit of oxygen, in order to
cause brain damage. T ~s was done by introducing nitrogen into
a desiccator after displacing the air~ The animals remained in
the vessel for a suficient length of time until ~hey assumed a
lateral position under anoxamic cramps. 30 minutes hefore they
were int~oduced into the nitrogen atmosphere each animal of a
group was given introperitoneally (i.p.) 100 mg. 1,2-bis-(2-oxo-
pyrrolidine-l) acetic hydrazide, or 100 mg piracetam or, in the
control group, a corresponding volume of a physiological salt sol-
ution per kg body weight. On the days when the passage through
the water labyrinth was tested, the animals were put into the
: :
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labyrinth ~fter the nitrogen atmosphere had been removed, and
the mistakes which the animals made until they reached the exit
and the number of animals whi~h did not find the exit at all
within ~he test period were recorded~
The tests were carried out according to the mekhod
of the simple blind tests, that is, the laboratory technician
who supervised the tests was not informed as to which animals
belonged to w~ich g:roup.
It can be seen from the curve~ in Fi~. 1, the
piracetam did not influence the frequency o~ mistakes in
the test animals, that is, control animals and piracetam
animals made the same number o~ mistakes, but those treated
; with the compound according to the invention made far fewer
mistakes. In the evaluation of the curves according t~ the
test, a statistical security with an error probabilit~ of less
than 5~ was found in individual points of the curves
: . In Fig. 2 the percentage of animals which had not
fou~d the exit of the labyrinth in a yiven time unit is
plotted on the ordinate. In this type of evaluation it
could also be shown that piracetam did not inf;luence the be-
havior of the animals, while more animals of the group
- treated with the compound according to the invention had
reached the exit of the labyrinth.
It should be emphasized that these results were
obtained with equal doses of the compound acco.rding
to the invention and of piracetam, namely 100 mcJ per kg
body weight. Since the molar weights of l-bis-(2-oxo-
pyrrolidine-l) acetic hydrazine and piracetam are in
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a ratio of 1:2, it could be shown by these tests that the
compound according to the invention is twice as effective
as piracetam.
In order to further prove the pharmacological
superiority of the compound according to the invention
over piracetam, rabbits were initially given (2-oxo-
pyrrolidine-l) acetic hydrazide and, one hour later, given
the sodium salt of 5~ethyl-3-(1-methylbutyl)-barbituric
acid to produce artificial intoxication~
Piracetam and (2-oxo-pyrrolidine-1~ acetic hydra--
zide were administered in a dose of 100 mg/kg, one hour
before 5-ethyl-5-(1-methylbutyl)-barbituric acid (phenol-
barbital sodium 40 mg/kg i.v.) was given and ~he following
results were obtained: -
lethality: control ~NaCl i~v.) 3/7 = 43~
piracetam 2/5 = 40%
t2-oxo-pyrrolidine-1~ acetic hydrazide 0/5 = 0~
It was thus found that the compound according to
the invention completely prevented death. ::.
2~ The present invention also comprises pharmaceutical
preparations which contain, in addition to non~toxic, inert
. pharmace-utical carrier substances, the active substance accord-
ing to the invention~ as well. as methods.for the preparation
of these compounds. ~ .
- The present invention also comprises pharmaceutical .:. .
prèparations in dosage units. This means that the preparations
are available in the form of individual parts, e.g. tablets,
dragees, capsules, pills, whose active substance is a fraction or
a multiple of a single dose. The dosing units can contain for -~:~
example, 1,2, 3 or 4 single doses or 1~2, 1/3 or 1/4 of a
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single dose. A single dose contains preferably the amount of
active 3ubstance which is administered in one application and
which corresponds usually to a whole, a half, a third or quarter
o~ a single dose.
By non-toxic, inert pharmaceutically suitable carrier
substances we mean solid, semi-solid, or liquid diluents, fillers
or formulation aids of any type.
Preferred pharmaceutical preparations are tablets,
dragees, capsules, pills, pellets, solutions, suspension3 and
emulsions/ as well as powders.
Tablets, dragees, capsules, pills and pellets
can contain the active subst~nce, in addition to the common
carrier substances, like fillers and diluents, binders, moist-
urizers, explosives, solution inhibitors, resorption accel-
erators, wetting agents, adsorbents, lubricants or mixtures of
th2se substances.
The tablets, dragees, capsules, pills and pellets
can be provided with the usual coatings and coverings contain-
ing opaquing agents, if necessary.
The ac~ive substance can also be contained in micro-
capsules with one or more of the above indicated carrier
substances.
The therapeutically effective compounds should be
contained in the a~ove-mentioned pharmaceutical preparations
preferably in a concentration of about 0.1 to 99.5%, and
preferably 0.5 to 95%, by weight of the total mixture.
The above indicated pharmaceutical preparations can
- also contain additional pharmaceutically active substances,
- 12 -
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'
~ V65 5175
in additioll to the active substance according to the invention.
The above indicated pharmaceutical preparations are
produced in the known manner according to known methods, for
example, by mixing the active substance(s) with the carrier
substance(s).
The present invention also comprises the use of the
active substance according to th~ invention, as well as of
pharmaceutical preparations which contain the active subst~nce
according to the i~vention, in human and veterinary medicine
to prevent, improve or cure diseases which can occur in the
cerebral ~unctional region. Thase are, for example, chronic
brain disfunctions, such as cerebral schlerosis, weakness of
memory after circulatory disorders as a result of alcoholism
or traumatic experiences.
In general, it was found expedient to administer the
active substance according to the invention in total amounts of
about 1~2 to about 2.4 g per 24 hours, if necessary, in the form
of several single doses to obtai~ the desired results. A
single dose contains the active substance according to the
invention preferably in amounts of about 100 to 500 mg, and
- preferably~ 300 to 400 mg. But, it may be necessary to deviate
from the above indicated doses, depending on the type and the
body weight of the object to be treated, and on the type and
severity of the disease.
- . : :'
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The invention will now be described more full~
by way of example.
Example 1
.
Preparation of (2-oxo-pyrrolidine-1) acetic hydrazide
Into a solution of 38 g hydrazine in 200 ml
isopropanol, 157 g (1 molè) of(2-oxo-pyrrolidine-1) acetic
methyl ester was added with stirring. The reaction was
exothermic; so the addition rate was regulated.
By external influence and by regulating the
addition rate, the temperature rises slowly to ahout 50~C.
Then the reaction muxture was heated for another 3 hours with
reflux. Subsequently, the reaction mixture was allowed to
cool. From the cool reaction mixture the hydrazine crystallized
in the form of colorless crystals. The crystal sludge was
drained off, washed twice with cold isopropanol and dried at
room temperature.
The hydrazide yield was 1429 g (91% of the
theoretical); the melting point was 58C.
The nitrogen determination had the following result :
N-calc. 26.74%
N found 26.8%
The mother liquor was used again, in unchanged
form, in the next batch and the yield increased slightly to
96% of the theoretical.
Example 2
Preparation of 1,2-bis-(2-oxo-pyrrolidine-1) acetic hydrazine
A mixture of 157 g (1 mole) of ~2-oxo-pyrrolidine-1)
- 14 -
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acetic hydrazide and 157 g tl mole) of ~2-oxo-pyrrolidine-1)
acetic methyl ester was heated for 24 hours under stirring to
150 to 170C. The reaction mixture was allowed to cool off.
After the reaction mixture had cooled $o room temperature, it
was heated under stirring with reflux in 400 ml methanol, until
it completely dissolved.
After cooling the mixture crystallized in color-
less crystals w~ich were drained off, washed with isopropanol,
and dried at 50C. The desired hydrazide ~as obtained in a
10 yield of 234.3 g (83~ of the theoretical); the melting point
was 203C.
The nitrogen determination had ths following
result: . .
N-calc.: 19.85~
N--found: 19.84%
! The mother liquor was used again in unchanged
form for several batches and the yields increased to 94%.
Example 3
. .: .
Preparation of (2-oxo-pyrrolidine-1) acetamide : ::
,
20 . 157 g (1 mole) of (2-oxo-pyrrolidine-1) acetic .
hydrazide was dissolved in 400 ml dry methanol and hydrated
with 10 g Raney nickel at 20 excess atmospheres in a closed
vessel at 100 to 120C until hydrogen adsorption had stopped.
- After opening the pressure vessel, the solution was filtered
. off hot from the catalyst; the catalyst could be used again
for a new batch.
~ - The filtrate was concentrated; the still hot concen-
~' ' .
- 15 -
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trate ~as mixed with 400 ml isopropanol; subsequently
the mixture was stirred cold and, after draining
and washing with isopropanol, 140 g (2-oxo-pyrrolidine-
1) aceta~ide (S9~ of the theory) was ob.ained in the
form of colorless crystals with a melting point of
151C.
- The ~other liquor was used again in unchanged
for~ for several batches so thatthe yicld increased
to 95~.
The nitrogen determination had the following
reslllt:
~-calc.: 19.72
Found : 19.73
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