CA1322525C - Use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressants - Google Patents
Use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressantsInfo
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- CA1322525C CA1322525C CA000566768A CA566768A CA1322525C CA 1322525 C CA1322525 C CA 1322525C CA 000566768 A CA000566768 A CA 000566768A CA 566768 A CA566768 A CA 566768A CA 1322525 C CA1322525 C CA 1322525C
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- pyrrolidin
- benzyl
- aminomethyl
- acid addition
- acceptable acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Abstract
Abstract The invention relates to the use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressants.
Description
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
~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~
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?~
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~
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 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~
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 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 ~
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 ~ ~
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 ' : ;' ~. .. ' . ~.
:' , 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:
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 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 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~
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.
. : .
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
~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~
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?~
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~
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 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~
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 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 ~
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 ~ ~
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 ' : ;' ~. .. ' . ~.
:' , 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:
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 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 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~
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.
. : .
Claims (6)
1. The use of compounds of general formula I
wherein R1 represents a hydrogen atom or an alkyl group;
R2 represents a phenyl group which may be mono-or disubstituted by fluorine, chlorine, or bromine atoms, or trifluoromethyl, alkoxy, alkyl, hydroxy or nitro groups, or R2 represents a pyridyl group;
R3 represents a hydrogen atom or an alkyl group;
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 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 imidazole ring; and the aminoalkyl group is in the 4 or 5 position, and the pharmacologically acceptable acid addition salts thereof, as anti-depressants.
wherein R1 represents a hydrogen atom or an alkyl group;
R2 represents a phenyl group which may be mono-or disubstituted by fluorine, chlorine, or bromine atoms, or trifluoromethyl, alkoxy, alkyl, hydroxy or nitro groups, or R2 represents a pyridyl group;
R3 represents a hydrogen atom or an alkyl group;
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 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 imidazole ring; and the aminoalkyl group is in the 4 or 5 position, and the pharmacologically acceptable acid addition salts thereof, as anti-depressants.
2. The use of 1-benzyl-4-aminomethyl-pyrrolidin-2-one and the pharmacologically acceptable acid addition salts thereof as antidepressants.
3. The use of a compound as defined in claim 1 for preparing a pharmaceutical composition for the treatment of depression.
4. The use of 1-benzyl-4-aminomethyl-pyrrolidin-2-one and the pharmacologically acceptable acid addition salts thereof for preparing a pharmaceutical composition for the treatment of depression.
5. A commercial package containing, as active pharmaceuti-cal ingredient, a compound of formula I as defined in claim 1 or a pharmacologically acceptable acid addition salt thereof, together with instructions for its use for alleviating depression.
6. A method of preparing an agent for use in treatment of depression, which method comprises incorporating in the agent, as an active ingredient a compound of formula I as defined in claim 1 or a pharmacologically acceptable acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000566768A CA1322525C (en) | 1986-10-08 | 1988-05-13 | Use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressants |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863634220 DE3634220A1 (en) | 1986-10-08 | 1986-10-08 | USE OF 1-BENZYL-AMINOALKYL-PYRROLIDINONES AS AN ANTIDEPRESSIVE |
| CA000566768A CA1322525C (en) | 1986-10-08 | 1988-05-13 | Use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressants |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1322525C true CA1322525C (en) | 1993-09-28 |
Family
ID=25671897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000566768A Expired - Fee Related CA1322525C (en) | 1986-10-08 | 1988-05-13 | Use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressants |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1322525C (en) |
-
1988
- 1988-05-13 CA CA000566768A patent/CA1322525C/en not_active Expired - Fee Related
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