Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- 1 - 27400-91
1322~2~
Use of l-benzyl-aminoalkyl-pyrrolidinones
as antidepressants
This invention relates to the use of l-benzyl-aminoal-
kyl-pyrrolidinones as antidepressants.
In our European Patent Application No. 135658, we have
described a range of l-benzyl-aminoalkyl-pyrrolidinones.
Our Canadian Patent Application Serial No. 559,893 (274
00-88) relates to synergistic antidepressant compositions com- t
posed of an antidepressant of the structural type of a 10,11-
dihydro-dibenzo [b,f] azepine, a dibenzo [a,d] [1,4] cyclohept-
adiene and/or a [10,11]-dihydro-dibenzo-[b,f] oxepine or a pharm-
acologically acceptable acid salt thereof as component [A] and a
l-benzyl-aminoalkyl-pyrrolidinone as component [B].
We have now surprisingly found that l-benzyl-aminoal-
kyl-pyrrolidinones themselves exhibit an antidepressant activity.
Accordingly, we provide, in one aspect of the invention,
the use of compounds of formula I
R3
~N - CH 2
I ~
N O
Hf - Rl
wherein R2
Rl represents a hydrogen atom or an alkyl group;
R2 represents a phenyl group which may be mono- or di-
- la - 27400-91 1322~25
substituted by fluorine, chlorine, or bromine atoms, or tri-
fluoromethyl, alkoxy, alkyl, hydroxy or nitro groups, or R2 rep-
resents a pyridyl group;
R3 represents a hydrogen atom or an alkyl groupi and
R4 may represent a hydrogen atom or an alkyl group or
the two groups R3 and R4 together with the nitrogen atom to which
they are attached represent a saturated 5- or 6-membered ring
which may
~ ,, , ' ' , ' ,
' - 2 - ~22~25
optionally contain an oxygen or nitrogen atom
as a further heteroatom and may optionally
be substituted by a methyl group or they may
form an imida~ole ring; and the aminoalkyl group
is in the 4 or 5 position, and the pharmacologically
acceptable acid addition salts thereof, as
antidepressants.
In general formula I:
The term ~alkyl~ indicates a straight-chain or branched
alkyl group preferably with 1 to 4 carbon atoms such
( as, for example, methyl, ethyl, propyl, isopropyl,
n-butyl or tert.-butyl. The term "alkoxy~ preferably
indicates a group with 1 to 2 carbon atoms. The
pyridyl ring given as a definition of R2 is preferably
linked to the methylene bridge in the 2, 3 or 4
position. Methyl and ethyl are the preferred alkyl
groups.
..
Compounds of general formula T and processes for
preparing them are known from the above European
Patent Application 136 658, which discloses only
the efficacy of the compounds in cases of restricted
cerebral performance.
Surprisingly, the compounds of general formula
I have been found to be highly effective antidepressants
of a new structural type.
Preferred compounds are the compounds of general
formula I wherein Rl represents a hydrogen atom,
R2 represents a phenyl group optionally substituted
by one or two fluorine or chlorine atoms, or methyl
or methoxy groups in the o or p position and R3
and R4 which may be identical or different each
represent a hydrogen atom or a methyl group or
1 ~ 2 ~
R3 and R4 together with the nitrogen atom to w~ich
they are attached represent morpholine or N-methyl-
piperazine.
Other suitable compounds include:
1-(3,4-Dimethoxybenzyl)-4-aminomethyl-pyrrolidin-
2-one
(4-Methylbenzyl)-4-aminomethyl-pyrrolidin-2-one
. 1-(3-Trifluoromethylbenzyl)-4-aminomethyl-pyrrolidin-
2-one
1-(~-Methylbenzyl)-4-aminomethyl-pyrrolidin-2-one
l-Benzyl-4-piperidinomethyl-pyrrolidin-2-one
l-Benzyl-4-~N-methylpiperazinomethyl)~pyrrolidin~
2-one
l-Benzyl-4-(imidazol-1-yl-methyl~-pyrrolidin-2-
one
( l-Benzyl-4-methylaminomethyl-pyrrolidin-2-one
l-(p-Fluorobenzyl)-4-dimethylaminomethyl-pyrrolidin-
2-one
1-(4-Nitrobenzyl)-4-aminomethyl-pyrrolidin-2-one
1-(4-Hydroxybenzyl)-4-aminomethyl-pyrrolidin-2-
one
l-(o-Chlorobenzyl)-4-aminomethyl-pyrrolidin-2-one
.
:
~23~
-- 4 --
l-(o-Chlorobenzyl)-4-diethylaminomethyl-pyrrOlidin-
2-one
l-Benzyl-4-isopropylaminomethyl-pyrrolidin-2-one
l-(p-Methylbenzyl)-4-diethylaminomethyl-pyrrolidin-
2-one
l-Benzyl-5-dimethylaminomethyl-pyrrolidin-2-one
l-Benzyl-S-morpholinomethyl-pyrrolidin-2-one
l-Benzyl-5-(4-methylpiperazino)-methyl-pyrrolidin-
2-one
1-(4-Methylbenzyl)-5-dimethylaminomethyl-pyrrolidin-
2-one
.. 1-(4-Methylbenzyl-5-diethylaminomethyl-pyrrolidin-
2-one
l-tp-Chlorobenzyl)-5-diethylaminomethyl-pyrrolidin-
2-one
( 1-(3,4-Dichlorobenzyl)-5-dimethylaminomethyl-pyrrolidin-
2-one
1-(3,4-Dichlorobenzyl)-S-diethylaminomethyl-pyrrolidin-
2-one
1-(p-Methoxybenzyl-5-dimethylaminomethyl-pyrrolidin-
2-one
l-(p-Methoxybenzyl)-5-diethylaminomethyl-pyrrolidin-
2-one
~ 32~2~
l-Benzyl-5-aminomethyl-pyrrolidin-2-one
Preferred compounds are:
1-(4-~ethoxybenzyl)-4-aminomethyl-pyrrolidin-2-
one
1-Benzyl-4-N,N-diethylaminomethyl-pyrrolidin-2-
one
1-(4-Fluorobenzyl)-4-aminomethyl-pyrrolidin-2-one
1-(4-Chlorobenzyl)-4-aminomethyl-pyrrolidin-2-one
1-(4-Pyridylmethyl)-4-aminomethyl-pyrrolidin-2-
one
1-(4-Fluorobenzyl)-4-(morpholinomethyl)-pyrrolidin-
2-one `
l-Benzyl-4-(N-methylpiperazinylmethyl)-pyrrolidin-
2-one
1-Benzyl-4-methylaminomethyl-pyrrolidin-2-one.
(
l-Benzyl-4-aminomethyl-pyrrolidin-2-one
l-Benzyl-5-pyrrolidinomethyl-pyrrolidin-2-one
l-Benzyl-5-diethylDminomethyl-pyrrolidin-2-one
l-(p-Chlorobenzyl)-5-dimethylaminomethyl-pyrrolidin-
2-one are particularly preferred.
A sensitive test for preclinical demonstration
of antidepressant properties is the chick call
test. The call frequency of isolated one-day-old
,
~2?~
-- 6 --
chicks which decreases during the course of the
test is taken as an experimental behavioural model
for manifestations of resignation in depression.
The method was validated by testing numerous neurotropic-
ally active substances; it is characterised byhighly reproducible selectivity for antidepressants
which are already clinically tried and tested and
which are capable of reactivating the lowered call
rate, as a function of dosage (distress call activation
in isolated chicks; A new behavioural model for
antidepressants, E. Lehr, Psychopharmacol. 89.
21 (1986); Activierung des Rontaktrufens als tierexperi-
mentelles Verhaltensmodell zur Depressionsforschung,
[Activation of contact calling as an experimental
behavioural model for researching depression],
E. Lehr, Fortschr. Neurol. Psychiat. 54, 26 (19R6).
~ . .. . ..
_ 7 _ ~3~ 2a
Table I gives the pharmacological data for l-benzyl-
4-aminomethyl-pyrrolidin-2-one (fumarate) tComPound A~.
By comparison the corresponding values for l-acetamido-
2-pyrrolidinone ~Compound 8~, a structurally similar
nootropic, are also given.
Table 1 Compound A Compound B
Chick call test
. 10 ED150, mg/kg i.p. 40 ~160
Tetrabenazine
antagonism
(ptosis alleviation,
mouse) 110 640
50~ mouse
- mg/kg by oral route . >~ 2000
Effect on cholinergic Demand none
function
Receptor bonding none none
(adrenergic, seroto-
nergic)
IC50 [10 9mol/ltr] > 10 000
,.
. .
132~
-- 8 --
Table II gives the pharmacological data of the above
mentioned chick call test for a number of compounds
according to the invention.
Table II
R-CH ~
N O
102 R2 HCl or Fu
Chick call test
( R (4-position) R2 ED150 i-p- mg/kg
C -NR2 ~3--OCH3 25
D -NH2 ~F 20
2 0 E N 10 0
F -NH2 _~ Cl 10
2 5 -N~ O _~ F 8 0
H -Nr--\N--CH ~ 18
R (5-position)
J -N (C2H5) 2 ~ 0 . 01
K -N~ ~ 0.1
L -N (CH3 ) 2 ~ Cl 0 . 1
g ~L ~r~
On ~he basis of the data shown, there is clear
evidence of preclinically antidepressant properties,
whilst the compounds according to the invention
do not show the typical side effects of conventional
antidepressants, such as sedation. The absence
of receptor bonding properties and/or inhibition
of resorption of biogenic amines indicates a completely
new mechanism of activity for compounds with an
antidepressant effect. The cholinomimetic property
of the compounds of general formula I rules out
any cardiotoxicity, which is caused in conventional
antidepressants by their anticholinergic side effects
and is one of the most serious undesirable drawbacks
of such drugs. Owing to the cholinergic property
of the compounds of general formula I it is possible
to use the compounds in cases of depression even
in geriatric patients in whom, owing to their cholinergic
malfunction, conventional antidepressants are contra-
indicated on account of their anticholinergic side
effects.
Processes for preparing compounds of general formula
I and the pharmacologically accept~ble acid addition
salts thereof are described in European Patent
( Application 136 658, the contents of which are
referred to herein.
The compounds of general formula I may be used
on their own or in conjunction with other active
substances according to the invention, and possibly
in con~unction wi~h other pharmacologically active
substances. Suitable forms for administrat~on
include tablets, capsules, suppositories, solutions,
syrups, emulsions and dispersible powders~ Tablets
may be produced, ~or example, by mixing the active
substance or substances with known excipients,
e.g. inert diluents such as calcium carbonate,
calcium phosphate or lactose, disintegrants such
I
~ ~ :
~32~
-- 10 --
as corn starch or alginic acid, binders such as
starch or gelatine, lubricants such as ~agne~um
stearate or talc and/or agents for obtaining delayed
release, such as carboxypolymethylene, carboxymethyl-
cellulose, cellulose acetate phthalate or polyvinylacetate. The tablets may also consist of several
layers.
Coated tablets may be prepared in the same way
by coating cores produced analogously to the tablets
with substances conventionally used for tablet
1 coatings, e.g. collidone or shellack, gum arabic,
talc, titanium dioxide or sugar. In order to obtain
delayed release or avoid intolerance, the core
may also consist of several layers. Similarly,
lS the tablet coating may also consist of several
layers in order to obtain delayed release, and
the excipients mentioned for the tablet~ may be
used.
. .
Syrups containing the active substances or combinations
of active subs~ances accord~ng to the invention
may additionally contain a sweetener such as saccharin,
cyclamate, glycerol or sugar and a flavour~enhancing
( agent, e.g. a 1avouring such as vanillin or orange
extract. They may also contain suspension adjuvants
or thickeners such as sodium carboxymethylcellulose,
wettinq agents, e.g. condensation products of fatty
alcohols with ethylene oxide, or preservatives
such as p-hydroxybenzoates.
Injection solutions are produced in the usual way,
e.g. by adding preservatives such as p-hydroxybenzoates
or stabilisers such as alkali metal salts or ethylene
diamine tetraacetic acid and the solutions are
transferred into injection vials or ampoules.
. -:,. . ..
13 2 2 ~ ~ 3
27400-gl
Capsules containing one or more active substances or
combinations of active substances may be produced, for example, by
mixing the active substances with inert carriers such as lactose
or sorbitol and sealing the mixture in gelatine capsules.
Suitable suppositories may be produced, for example, by mixing
with the carriers provided for this purpose, such as neutral fats
or polyethylene glycol or the derivatives thereof.
The therapeutically effective dosage is generally from 1
to 150 mg, preferably from 50 to 100 mg for each single dose.
The invention also extends to a commercial package
containing, as active pharmaceutical ingredient, a compound of
formula I or a pharmacologically acceptable acid addition salt
thereof, together with instructions for its use for alleviating
depression.
The Examples which follow illustrate the preparation of
compounds used in the invention without restricting its scope:
1 3 2 2 ~ h 3
- 12 -
Exam~le 1
l-B nzyl-4-aminomethYl-pyrrolidin-2-one
54 9 (0.16 mol) of 4-phthalimidomethyl-1-
benzyl-pyrrolidin-2-one are stirred into 1.3 litres
of ethyl alcohol after the addition of 32 9 of
hydrazine hydrate for 4 hours at ambient temperature.
The precipitate (phthalic acid hydrazide) is suction
filtered and the filtrate is concentrated by evaporation.
500 ml of methylene chloride are added to the residue
and it is extracted three times with 100 ml of
water. The organic phase is dried and evaporated.
- The residue remaining is dissolved in 500 ml of
methanol and 20 g (0.17 mol) of solid fumaric acid
are added in batches at boiling temperature with
stirring. When the mixture cools, colourless crystals
are precipitated which are suction filtered and
then washed with methanol and ether. Yield: 20 - 25 9
(48 - 60% of theory), m.p. 209 - 211C.
The compound contains ~ mol of fumaric acid.
The starting material i~ obtained as follows:
a) 94 9 (0.46 mol) of 1-benzyl-4-hydroxymethyl-
pyrrolidin-2-one are stirred with 700 ml of
methylene chloride and 40 ml (0.54 mol) of thionyl-
chloride for 25 hours while refluxing and the
reaction mixture is then neutralised with dilute
ammonia whilst being cooled. After separation,
drying and evaporation, 85 - 90 9 of a dark
oil are left behind, which is used directly
for further reaction.
b) 43.5 g (0.195 mol) of crude 1-benzyl-4-chloromethyl-
pyrrolidin-2-one, 36 9 (0.195 mol) of phthalimide
potassium and 700 ml of dimethylformamide are
refluxed for 2 hours. The reaction mixture
is then evaporated in vacuo and the residue
is taken up in methylene chloride. It is extracted
several times with water, the organic phase
2 ~ 2 ~
- 13 -
is dried and after chromatography on SiO2 45 g
(70% of theory) of the phthalimido compound
are obtained, m.p. 108 - 109~C.
Example 2
l-Benzyl-4-aminomethyl-pyrrolidin-2-one
a~ 58 g (0.29 mol) of 1-benzyl-4-nitrilo-pyrrolidin-
2-one are dissolved in methanol and catalytically
hydrogenated with the addition of liquid ammonia
over Raney nickel. Ater the reaction solution
~- has been concentrated by evaporation, it is
dissolved in methanol, the residual catalyst
is filtered off and after the filtrate has been
heated to about 50C it is mixed with 17 9 of
fumaric acid. The fumaric acid briefly goes
into solution when stirred, then the crystallisation
of the l-benzyl-4-aminomethyl-pyrrolidin-2-one
fumarate beg~ns.-
Yield: 68 g (- 91% of theory); m.p. 192 - 194C.
b) The nitrilo compound is obtained in a 96% yield
in the form of an oil from the corresponding
amide, m.p. 162 - 166C, by dehydration using
( POC13 in dimethylformamide at about 60C.
Example 3
Racemate cleaving of l-benzyl-4-aminomethyl-~yrrolidin-
2-one
a) 24.0 g (0.117 ~ol) of 1-benzyl-4-aminomethyl-
pyrrolidin-2-one are dissolved in 200 ml of
hot methanol and 17.6 9 (0.117 mol) of L(+)-
tartaric acid are also dissolved in 200 ml of
hot methanol. The two solutions are combined
and cooled to ambient temperature with stirring,
whereupon the salt crystallises out. The crystals
are suction filtered while cold, washed with
:,
- 14 _ ~ ~ 7
cold methanol and dried.
Yield: 18.0 9 of 4-aminomethyl l-benzyl-pyrrolidin-
2-one tartrate, ~.p. 204 - 206C (from methanol),
~D = +6.3 (c = 1.0; water).
b) In order to convert the tartrate into the base
the tartrate is dissolved cold in 20 ml of water
and 10 ml of concentrated sodium hydroxide solution
and extracted three times with methylene chloride,
then the combined methylene chloride phases
are dried over MgS04 and the solvent is eliminated
in vacuo. The (-)-4-aminomethyl-1-benzyl-pyrrolidin-
2-one is obtained, ~D = -8.4 (c = 1.0; water).
c) The mother liquors obtained in the processing
described in a) are concentrated by evaporation
in vacuo. 38.0 g of the tartrate is obtained,
which is taken up cold in 140 ml of water and
50 ml of concentrated sodium hydroxide solution
and extracted thrêe times with methylene chloride.
The combined methylene chloride phases are dried
over MgS0~ and the solvent is eliminated in
vacuo. 19.3 9 of base are obtained, which is
converted into the corresponding tartrate with
( D-(-)-tartaric acid as described in a). Yield:
19.0 g m.p. 204 - 205C.
d) The conversion of the tartrate into the base
i8 carried out as described in b). 5.7 g of
(+)-4-~minomethyl-1-benzyl-pyrrolidin-2-one
are obtained with a rotation ~D = +8.4 (c =
1.0; water).
Example 4
(-)-l-Benz~1-4-dimethylaminomethyl-pyrrolidin-2-
one
4.0 g (0.02 mol) of (-)-1-benzyl-4-aminomethyl-
pyrrolidin-2-one and 5.4 g of 85~ formic acid are
t ~ ~
- 15 -
mixed with 4.8 ml of formalin solution and stirred
overni~ht at 100C (oil bath). Then the excess
acid is distilled off in vacuo and the residue
is taken up in water, made alkaline with concentrated
S sodium hydroxide solution and extracted three times
with methylene chloride. The combined methylene
chloride phases are washed with water, dried over
sodium sulphate, the solvent is concentrated in
vacuo and the residue is filtered over an SiO2
column (eluant: methylene chloride:methanol =
97:3). The uniform f-~ction is concentrated by
evaporation in vacuo. The title compound is obtained
in a yield of 3.5 g (in the form of an oil).
D = -7.6 (c = 1.0; methanol)
15 ~D = -16.8 (c = 1.0; water).
Analogously to Example 4, 6.1 g of (+)-1-
benzyl-4-dimethylaminomethyl-pyrrolidin-2-one are
obtained, ~D = +7 9 (c = 1.0; methanol), from
5.8 g (0.028 mol) of (~)-1-benzyl-4-aminomethyl-
20 pyrrolidin-2-one, 7.9`9 of 85~ formic acid and
7 ml of formalin solution.
ExamPle 5
l-Benzyl-4-di-ethylaminomethyl-pyrrolidin-2-one
( 25 14 9 (0.06 mol) of crude 1-benzyl-4-chloromethyl-
pyrrolidin-2-one, prepared as in Example la), 10 9
of diethylamine and 50 ml of dimethylformamide
are stirred or shaken for 2 hours at 150C in the
autoclave. The mixture is evaporated to drynes~
in vacuo and the residue is taken up in methylene
chloride then washed first with water and finally
the title compound is extracted twice with 25 ml
of 2 N HCl. The aqueous phase is removed, made
alkaline with sodium hydroxide solution and the
organic base is extracted with methylene chloride.
The methylene chloride phase is concentrated by
evaporation and the residue is distilled in vacuo.
Yield: 10 9 ~61~ of theory), bpo 05 = 155 - 158C.
I
,
- 16 - 1 3223 ~af
Example 6
~ Benzyl-4-d~ethYlaminomethYl-pyrrolidin-2
one
11.5 g (0.056 mol) of l~ benzyl-4-aminomethyl-
S pyrrolidin-2-one, 130 ml of water, 13 g of acetaldehyde,
5.8 ml of concentrated hydrochloric acid and 6.5 g
of Pd/C 20% are hydrogenated for 5 1/4 hours at
S bar and at 25C. ~he residue is evaporated,
taken in 30 ml of water and extracted with methylene
chloride. The aqueous hydrochloric acid solution
is made alkaline and also extracted with methylene
chloride. By distillation in a bulbed tube, 11.2 g
(76.4% of theory) of the title compound are obtained,
~D = ~9-4 (c = 1.0; methanol).
Analogously to Example 6, by hydrogenating
8.4 g (0.041 mol) of (~ benzyl-4-aminomethyl-
pyrrolidin-2-one, 95 ml of water, 9.5 9 acetaldehyde,
4.2 ml of concentrated hydrochloric acid and 4.7 g
of Pd/C 20%, (+)-1-benzyl-4-diethylaminomethyl-
pyrrolidin-2-one is obtained, ~D = +9 4 (c = 1.0;
methanol~.
Example 7
1-(4-Fluoro-benzyl)-4-N-methylpiperazin~lmeth
pyrrolidin-2-one
a) 24 g (0.11 mol) of 1-(4-fluorobenzyl)-4-hydroxymethyl-
pyrrolidin--2-one are refluxed with 10 ml (0.14 mol)
of thionyl chloride in 200 ml of methylene chloride
first of all for 10 hours and then, after the
addition of another 10 ml of thionyl chloride,
for a further 6 hours. Whilst cooling with
ice, the product is neutralised with ammonia
and after the organic phase has been separated
off it is dried and concentrated by evaporation.
23 g (92~ of theory) of a reddish-brown oil
remain, which is used without any further purification.
- 17 - ~ r~3
b) 5 9 (0.002 mol) of the above oil are refluxed
for 1 - 2 hours with 4.4 g (0.04 mol) of l-methyl-
piperazine in 30 ml of dlmethylformamide. ~be
dimethylformamide is then substantially distilled
S off in vacuo, the residue is taken up in methylene
chloride and washed with water and then the
organic phase is dried and evaporated again.
The residue is chromatographed on SiO2 with
methylene chloride/methanol 95:5 as eluant.
The main fraction is concentrated by evaporation
and the residue (5 g) is dissolved in 30 ml
of methanol. 2.8 g of fumaric acid are added
to this solution. S.2 g (48% of theory) of
the title compound are precipitated in crystalline
form as the fumarate.
M.p. 179 - 180C.
Example 8
1-(4-Fluorobenzvl)-4-morPholinomethyl-pyrrolidin
2-one
a) 8.9 g (0.04 mol) of 1-(4-fluorobenzyl)-4-hydroxymethyl-
pyrrolidin 2-one in 100 ml of absolute methylene
chloride and 4.8 9 of pyridine are mixed with
( 6.9 g (0.06 mol) of methanesulphonic acid chloride.
The mixture is refluxed for 2.5 hours then cooled
and extracted with dilute ammonia and water.
The organic phase is dried and concentrated
by ev~poration. 11 g (93~ of theory) of crude
ester are obtained, m.p. 84 - 86C.
b) 6.7 9 (0.023 mol) of ester and 2.6 9 (0.03 mol)
of morpholine are refluxed for 2 hours in 20 ml
of dioxan. The solvent is evaporated off in
vacuo and the residue is taken up in methylene
chloride and extracted with 50 ml of 2 N hydrochloric
acid. The aqueous extracts are made alkaline
with ammonia and the oily base is extracted
' : ;' ~. .. '
. ~.
:' ,
- 18 -
with methylene chloride. The methylene chloride
phase i8 dried and concentrated by evaporation.
The residue (4.2 g) is taken up in 30 ml of
methanol and 1.2 g of fumaric acid are added
in the warm. After cooling, the fumarate of
the title compound is precipitated in crystalline
form.
Yield: 7 g = 57% of theory of colourless crystals
m.p. 175 - 176C.
Example 9
1-(4-FluorobenzY~ 4-amino-pyrrolidin-2-one
a) 4.0 g (0.013 mol) of mesyl ester, prepared according
to Example 7, are refluxed for 30 minutes with
2.8 g (0.015 mol) of phthalimide potassium in
50 ml of dimethylformamide. The mixture is
concentrated by evaporation in vacuo and the
residue i8 taken up in methylene chloride, washed
with water, the organic phase is dried and again
concentrated by evaporation. The residue is
triturated with ether and yields 3.6 g (78%
of theory) of light grey crystals, m.p. 124 - 125C.
b) 3.5 9 (0.1 mol) of the above phthalimide compound
are stirred with 5.5 g of hydrazine hydrate
in 200 ml of alcohol for 4 hours at ambient
temperature. The mixture is worked up as described
in Example 1. 2.5 g (89% of theory) of the
fumarate of the title compound are obtained,
m.p. 214 - 215CC.
The title compound may also be obtained by
dissolving 5 g (16 mmol) of mesyl ester (see Example
7) in 100 ml of dimethylformamide and, after the
addition of 1.3 g of sodium azide, heating the
mixture to 100C for 2 hours, hydrogenating the
oil which is obtained in due course with Raney
- : :
~ ` :
19 ~ ~ 3 .d
nickel in methanol and converting the base into
the fumarate as described above.
Yield: 4.2 9 (90% of theory).
The following end products were also obtained
analogously to the procedure described in the above
Examples:
- 20 -
R - CH2
H ~
_, R2
. '
¦E~le R ¦ ~ R2 MP-Oc / ~ ~-C
l . . l .__
2 H ~ OCH3(Fumarate)
11 2 H ~ OCH3~Fumarate)
12N~2 H ~CH3M p, 225 - 226
(Fumarate)
13 2 H ~ ClMp, 189 - 19
(~umarate)
14 2 H ~Mp. 168 - I.69
. CF3(Fumarate)
-~H2 ~ H .~ Mp, 179 - 181
. .(Fumarate)
1 6 ~ -NH ¦-CH3 ~ ~) OCH31 MP 1;7 168 1 ~1
17 ~ H ~ Mp 58 - 60
(~ase~
~i
; . ~
- 21 -~ ~? ~ 2
;~xample R ~ R2
~-~, ) I ~p.190-192
. . 3 .( Fuma rate )
(' 19 --N~ H ~Bp - o, o5 230
, . (~se~
2~ -HN-CH3 H ~ P o ,05
. Cl (~e)
21 --NH2 H ~M p . 179 -- 1~0
C2~ . Cl(Fumarate)
22 -N ~ H5 H ~ P o, 05
C2 5 (Baa~)
Z3- ~H-CH(CH'5 2 H 4~Po,O(5 )5
L ~ C2H5 H ~C~13B p o 05 175
:' ~ .; , ,
t
~ 3
- 22 -
Example 25
l-Benzyl-S-dimethylaminomethyl-pY!rrol~din-?-one
a) A solution of 10.26 g (0.05 mol) of l-ben~yl-
5-hydroxymethyl-pyrrolidin-2-one (m.p. 76 - 77C)
and 5.6 g (0.055 mol) of triethylamine in
80 ml of methylene chloride is mixed with
6.3 g (0.055 mol) of methanesulphonic acid
chloride in 20 ml of methylene chloride.
The reaction mixture is then refluxed for
1 hour and, after being cooled, extracted
f with water. The organic phase is dried over
anhydrous sodium sulphate and then concentrated
by evaporation in a rotary evaporator. 14.1 g
(yellow oil) of crude l-benzyl-5-hydroxymethyl-
pyrrolidin-2-one methanesulphonic acid ester
is obtained, which is used in the next reaction
step without any further purification.
i
20 b) 8.5 g (0.03 mol;~ of the mesylate obtained
in a) are heated to 150C for 3 hours with
a solution of 10 g of dimethylamine in 60 ml
of dioxan in an autoclave. After cooling
the reaction mixture is concentrated to dryness
in vacuo. The residue is dissolved in 2 N
hydrochloric acid and extracted with ether.
The acidic aqueous phase is made alkaline
with concentrated ammonia and extracted with
methylene chloride. The methylene chloride
solution is dried and concentrated by evaporation.
The residue (6.5 g) is converted into the
acid fumarate of the title compound with
an equivalent amount of fumaric acid.
Yield: 6.4 g (61% of theory); m.p. 137 - 138C.
' ~''
- 23 _ ~ ~ 2 ~
The following were also prepared analogously
to Ex~mple 25:
R-C~2'~
H -Rl 1,
.~ R2 ~ '
( ~ - R2 ~P-4 / ~-C
26 N(C2H5)2 H ~ Mp. 163 - 164
~ (Hydrochloride3
. .
27 _ ~ H ~ (Oxalate3
28 --hCN--CH H ~ M p~ 258
~ . (Dihydrochloride)
29 ~ H ~ M p . 188 -- 190
(Hydrochloride)
~O -N(CH3)2 H ~ CH3 Mp. 163 - 164
(Eumarate)
~1 -N(C2H5)2 H ~ CH3 Mp. 152 - 153
(Hydrochloride)
. 32 -N(CH3)2 H ~ Cl (Fumarate)
53 N( 2 5'2 ~ ~ Cl Mp. 149 - 151
t
'~
- 24 .- 1~22~23
. ~ __. ~
Example R ~ ~Mp-OC 1 BpoOC
I .__ ~ . .... _.
34 -N(CH3)2 H ~ ClMp. 167 - 16B
_- . 1(Fumarate)
3~ . -N(C H ) H ~ ClMp, 159 - 161
.2 5 2 (Hydrochloride)
( ~6-N(CH3)2 H ~ ~Oi(lBhse)
37 N(C2H5)2 H ~ OCH~ Oil
Example 38
l-Benzyl-5-aminomethyl-pyrrolidin-2-one
16.4 g (0.07 mol) of 1-benzyl-5-hydroxymethyl-
pyrrolidin-2-one methanesulphonic acid ester (see
Example 25 a~) are dîssolved in 200 ml of dimethyl-
formamide and stirred for 90 minutes at 100C after
the addition of 4.6 9 (0.07 mol) of sodium azide.
After evaporation, distributing between water and
methylene chloride and working up of the organic
phase, 13.8 g (92% of ~heory) of oil are obtained,
which can be reacted further in its crude form.
It is dissolved in 200 ml of methanol and, after
1~ the addition of Raney nickel, hydrogenated at 20C
and 5 bar. After the catalyst has been removed
by suction filtering and the filtr.ate has been
evaporated, 11 9 (85~ of theory) of oil are obtained
which when dissolved in methanol and after the
addition of fumaric acid yields the desired hemifumarate
of the title compound (m.p. 187 - 188C).
., , ~
~2~i~5
- 25 -
Pharmaceutical formulation Examples
A~ Tablets per tablet
Active substance 100 mg
Lactose (powdered) 140 mg
Corn starch 240 mg
Polyvinylpyrrolidone 15 mg
Magnesium stearate 5 mq
500 mg
The finely ground active ingredient, lactose
and part of the corn starch are mixed together.
The mixture is screened and then moistened with
a solution of polyvinylpyrrolidone in water, kneaded,
granulated whilst moist and then dried. The granulate,
the remaining corn starch and the magnesium stearate
are screened and mixed together. The mixture is
compressed to form tablets of suitable shape and
size.
B) Tablets per tablet
Active substance 80 mg
Corn starch 190 mg
Lactose 55 mg
Microcrystalline cellulose35 mg
Polyvinylpyrrolidone 15 mg
Sodium carboxymethyl starch 23 mg
Magnesium stearate 2 mq
400 mg
The finely ground active substance, some
of the corn starch, lactose, microcrystalline cellulose
and polyvinylpyrrolidone are mixed together, the
mixture is screened and processed with the remaining
corn starch and water to form a granulate which
is dried and screened. The sodium carboxymethyl
starch and the magnesium stearate are added and
the mixture is compressed to form tablets of suitable
size.
~22~
- 26
C) Ampoules
l-Benzyl-4-aminomethyl-
pyrrolidin-2-one fumarate 50.0 mg
Sodium chloride 10.0 mg
Doubly distilled water q.s. ad 1.0 ml
Method
The active substance and sodium chloride
are dissolved in doubly distilled water and the
solution is transferred into ampoules under sterile
conditions.
(
D) ~ro~s
l-Benzyl-4-aminomethyl- ~
pyrrolidin-2-one fumarate 5.0 g
methyl p-hydroxybenzoate 0.1 g
propyl p-hydroxybenzoate 0.1 g
demineralised water q.s. ad 100.0 ml
Method
The active substance and preservatives are
dissolved in demineralised water and the solution
i5 filtered and transferred into vials each containing
100 ml.
. : .
