CA1048549A - Pharmacologically active n-butylamine derivatives and process for the preparation thereof - Google Patents
Pharmacologically active n-butylamine derivatives and process for the preparation thereofInfo
- Publication number
- CA1048549A CA1048549A CA75227044A CA227044A CA1048549A CA 1048549 A CA1048549 A CA 1048549A CA 75227044 A CA75227044 A CA 75227044A CA 227044 A CA227044 A CA 227044A CA 1048549 A CA1048549 A CA 1048549A
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- Prior art keywords
- propyl
- acid
- butylamine
- process according
- ethyl
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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
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/70—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by reduction of unsaturated amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/03—Monoamines
- C07C211/08—Monoamines containing alkyl groups having a different number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/126—Acids containing more than four carbon atoms
- C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
Abstract
ABSTRACT OF THE DISCLOSURE:
n-Butylamine derivatives having the general formula:
n-Butylamine derivatives having the general formula:
Description
~(148S49 This invention relates to novel pharmacologically active derivatives of n-butylamine, to pharmaceutically acceptable acid addition salts thereofandto a process for the preparation thereof.
More particularly, the present invention provides novel n-butylamine derivatives having the general formula:
CH3-CH2-C1~2 \
Rl C-NH2 (I) and the pharmaceutically acceptable acid addition salts thereof, wherein Rl represents ethyl or n-propyl and R2 represents:
(a) ethyl, n-propyl, isopropyl, isobutyl or tert-butyl when Rl is n-propyl, and (b) n-butyl or isobutyl when Rl is ethyl, with the proviso that R1 and R2 simultaneously represent n-propyl only when the derivative is in the form of its acid fumarate.
The compounds of the invention are obtained by treating, in an appropriate medium, with a strong acid, such as, for example, hydrochloric or sulphuric acid, an isocyanate or a N-formyl amine of the general formula:
C 3 2 2 \
R1 - C-A (II) wherein Rl and R2 have the aforesaid meanings and A represents the group N=C=O or NH-C-H, to form the corresponding acid addition salt of the compound of formula (I) which, when required, is reacted with a base such as, for example, sodium hydroxide to obtain the desired compound in free base from which, when required, is further reacted with an organic or inorganic ~2 - 1 -10~8549 acid to give the desired pharmaceutically acceptable acid - -addition salt thereof. .:
The treatment of the compound of formula (II) with the acid may be carried out by utilizing the reagents involved at a temperature between 15C and 100C, and preferably between 50C and 90C.
Regarding l,l-di-n-propyl-n-butylamine acid fumarate, this can be prepared by treating in an appropriate medium, with a strong acid, such as for example, hydrochloric acid or sulphuric acid, l,l-di-n-propyl-n-butylisocyanate or N-formylated l,l-di-n-propyl-n-butylamine, to form the corresponding acid addition salt of l,l-di-n-propyl-n-butylamine which is thereafter reacted with a base such as, for example, sodium hydroxide to form l,l-di-n-propyl-n-butylamine in free base form which is then reacted with fumaric acid.
The compounds of formula (II) may be prepared in varlous ways, namely:
(a) When A represents the radical N-C=O;
either by reacting an acetamide derivative of the general formula:
CH -CH -CH
1 / C-C-NH (III) in which Rl and R2 have the same meaning as in the formula (I) above, with chlorine or bromine in an alkaline medium such as, for example, in an aqueous solution of sodium or potassium hydroxide, or by reacting an acetic acid derivative of the general formula:
Rl - C-C-OH (IV) ~ ~, - 2 - .
4~5~9 in which Rl and R2 have the same meaning as in formula (I) above, with a chlorinating agent such as, for example, thionyl or oxalyl chloride, to obtain the corresponding acyl chloride which is then treated with an alkali metal azide such as, for example, sodium azide, which provides the required compound of formula (II), or following another process, by heating a compound of formula (IV) directly with hydrogen azide in an acid medium, for example, sulphuric acid, to obtain the desired compound of formula (II). In this latter case, the isocyanate thus formed is immediately converted by hydrolysis to the corresponding amine of formula (I). l,l-Di-n-propyl-n-butyl isocyanate can be obtained by the same method as that described hereabove. O
(b) When A represents the radical NH-C-H:
by heating a tertiary alcohol of the general formula:
\ .
1 / C-OH (V) in which Rl and R2 have the same meaning as that given for the above compounds of formula (II), with an alkali metal cyanide such as, for example, sodium or potassium cyanide in the presence of an acid such as, for example, sulphuric acid. N-Formylated l,l-di~n-propyl-n-butylamine can be obtained by the same method as that described hereabove under (b).
The compounds of formula (III) can be obtained by reacting anhydrous ammonia with the corresponding acids of formula (IV) or preferably with the halides of these acids.
The acids can be prepared from the alcohols of formula (V) and formic acid in a sulphuric acid medium.
' . :
~048549 The compounds of formula (V) are either known compounds or can be prepared in accordance with known procedures such as, for example, by reacting an organo-lithium compound with an appropriate ketone in an anhydrous ether medium such as, for example, tetrahydrofuran.
It has been discovered that the compounds of the ; invention possess valuable pharmacological properties which are ;
likely to render them useful in human and veterinary therapy.
In particular, it has been found that the compounds 10 of the invention present central noradrenergic and central dopaminergic properties. These latter properties manifest ; themselves by an inhibitory action on reserpine-induced and ; neuroleptic-induced catatonia and catalepsy.
Pharmacological trials performed with the compounds of the invention have shown that tri-n-propylmethylamine acid fumarate or l,l-di-n-propyl-n butylamine acid fumarate, which is the preferred compound of the present invention, possesses a marked degree of activity. Fur*hermore, it was , surprisingly and quite unexpectedly observed that l,l-di-n-propyl-n-butylamine acid fumarate presents a degree of activity which is even markedly greater than that of the corresponding hydrochloride which does not form part of the invention. It was,in fact, observed that l,l-di-n-propyl-_-butylamine acid fumarate i5 from 20 to 40~ more active than the . corresponding hydrochloride in tests involving reserpine-induced and neuroleptic-induced catatonia.
Furthermore, at doses which completely suppress neuroleptic-induced catatonia and catalepsy, it was observed that the compounds of the invention do not influence the anti-amphetamine effects of the neuroleptics in the rat and their anti-apomorphine effects in the dog. Furthermore, the , ;: , .- ; .
~., ~)"
.. . . . .
- ' , .: :
109~8S49 compounds of the invention have no emetic action in the dog at any doses and are not cholinolytic agents.
These pharmacological properties taken as a whole are likely to render the compounds of formula (Ij useful in treating Parkinson's disease as well as for correcting ; extra-pyramidal disturbances provoked by neuroleptics.
Parkinson's disease is a chronic and progressive affection characterized in particular by a dopamine deficiency in the thalamus and the caudate and lenticular nuclei, with akinesia, rigidity and trmor as visible symptoms.
Many active drugs have already been proposed for combating Parkinson's syndrome. Most of these products are central anti-cholinergic agents with peripheral anti-cholinergic effects. These compounds are of natural origin, such as, for example atropine or are obtained synthetically as, for example, diethazine, benztropine or trihexyphenidyl.
However, these drugs may present undesirable side-effects, due in most cases to their peripheral anti-cholinergic properties, such side-effects taking the form, for example, of dryness of the mouth, difficulty in optical accommodation, tachycardia, constipation and retention of urine. These products will thus be contraindicated in cases of glaucoma and hypertrophy of the prostate.
L-Dopa or levodopa, a precursor of dopamine, has also been proposed in parkinsonism. However, in view of its partial destruction in the digestive system, L-dopa must be administered at very high doses, which very often induce undesirable side-effects. The most serious of these side-effects are cardio-vascular in nature and in particular take the form of disturbances of cardiac rhythm and orthostatic hypotension.
Patients treated with L-dopa must, therefore, not present contraindications on the cardiac plane.
B
. . . ~ . ; ~
1~4~35~9 ~:
Recently, amantadine, i.e. l-amino-adamantane has been proposed for antiparkinsonian therapy. This product, which stimulates the liberation of dopamine is very active but produces several undesirable side-effects and also decreases in activity after a certain length of time.
For this reason, it is very difficult for the doctor to select amongst the various antiparkinsonian drugs, that which will be effective for the case under treatment. Each patient must be considered as an individual case. All the known methods of treating Parkinson's disease are symptomatic and, in spite of the medication used, the disease continues to progress. The treatment of parkinsonism requires the successive use of one or more therapeutic substances and it is often necessary to institute therapeutic cycles. Frequently, two antiparkinsonian agents must be simultaneously administered, the first being considered as the basic drug and the second as an auxiliary or additional drug. Furthermore, since treatment is of long duration the alternating use of different products is necessary.
The search for new antiparkinsonian agents is therefore of primary importance. From this point of view, the compounds of formula (I) will constitute valuable additions to anti-parkinsonian therapy, since at present there is no ideal agent for the treatment of this disease as explained in detail hereabove.
The compounds of the invention will consequently constitute valuable additions to the therapeutic arsenal at the disposal of the doctor and will provide useful replacement medication for any drug which has become ineffective for any reason such as a change in the state of the patient or habituation.
~?
~ .
~ 048549 Although the pharmacological spectrum of the compounds of the invention is very similar to that of amantadine, pharmacological trials performed with the compounds of formula (I) have revealed marked differences in comparison with aman-tadine. For example, when comparing the doses of the compounds of the invention and of amantadine which have a certain degree of activity, it has been observed that the active dose in question is always proportionally farther from the toxic dose in the case of the compounds of the invention than in the case of amantadine. In other words, the safety margin offered by the compounds of the invention is superior to that of amantadine. Other differences which are particularly evident have been observed with the preferred compound of the invention, namely, tri-_-propylmethylamine acid fumarate or l,l-di-n-propyl-n-butylamine acid fumarate.
For example, on the cardiovascular plane, it has been observed that the preferred compound of the invention does not ; cause any undesirable effect on the electrocardiogram whereas a dose of 5 mg/kg of amantadine injected into the dog provokes cardiac arrhythmia due to ventricular extrasystoles. It has also been found that the preferred compound of the invention does not potentiate the peripheral effects of norepinephrine and is not a ganglioplegic agent while tests performed with amantadine have demonstrated that this compound potentiates the peripheral adrenergic effects and furthermore exerts a ganglioplegic action.
The preferred compound of the invention which does not present these undesirable side-effects observed with amantadine will not therefore induce cardiac disturbances or disorders of arterial pressure.
t : ` -` 1048S49 As mentioned above, certain types of antiparkinsonianagents such as diethazine and benztropine frequently provoke undesirable side-effects of an anti-cholinergic nature -(dryness of the mouth, difficulty in optical accommodation, etc.).
The preferred compound of the invention, being devoid of anti-cholinergic activity, does not present these disadvantages.
Similarly, as the preferred compound of the invention is devoid of emetic properties and of undesirable side-effects on ~ 10 the electrocardiogram, it will not provoke vomiting or cardiac '~ arrhythmia, which are two frequent side-effects of L-dopa.
Pharmacological trials have been performed with a view to determining the various properties of the compounds of the invention which, taken *ogether, are capable of rendering the said compounds useful in the treatment of Parkinson's disease and for the correction of extra-pyramidal disturbances induced by neuroleptics.
I. Inhibition of reserpine-induced and neuroleptic-induced catatonia (dopaminergic properties) 1. Inhibition of reserpine-induced catatonia After sufficient doses of reserpine have been administered to the rat, a series of symptoms occur, more particularly ptosis, catatonia and a drop in central temperature. These symptoms are caused by the depletion of the intragranular reserve pool of biogenetic amines at the synaptic terminals.
The antidepressants of the tricyclic type as well as the inhibitors of monoamine oxydase (I.M.A.O.) antagonize more particularly the appearance of ptosis and the drop in central temperature. On catatonia, the action of such compounds is not non-existent but is considerably less marked.
1~48549 As against this, the synthetic antiparkinsonian agents principally influence catatonia while their activity on ptosis and hypothermia is non-existent or weaker.
An oral dose of the compound to be studied in aqueous solution was administered to batches of 10 male rats of the OFA strain weighing about 150 to 200 g. Thirty minutes later a dose of 5 mg/kg of reserpine was given by intraperitoneal route. Three hours after the injection of reserpine, the animals were suspended by the four paws from a horizontally stretched wire fixed at 15 cm from the ground~ The catatonic animals were those which maintained the position so given for at least 30 seconds. Each animal which maintained the position so given received the score of 1 and those which -.~
did not maintain the said position were given the score of 0. The maximum score was therefore 10 per batch. An identical trial was undertaken with control animals which received reserpine but none of the compounds being studied.
The following compounds of formula (I) were tested in comparison with amantadine in accordance with the process indicated hereabove. These compounds were preferably studied in the form of a pharmaceutically acceptable acid addition salt such as the hydrochloride or the fumarate.
l-Ethyl-l-n-propyl-n-butylamine(Compound 1) l-Ethyl-l-isobutyl-n-butylamine(Compound 2) l-Ethyl-l-_-butyl-n-butylamine(Compound 3) l-n-Propyl-l-isobutyl-n-butylamine ` (Compound 4) l-n-Propyl-l-isopropyl-n-butylamine (Compound 5) l-n-Propyl-l-tert-butyl-n-butylamine (Compound 6) The same test was also performed with l,l-di-_-propyl-n-butyl-amine acid fumarate (Compound 7).
The results obtained with the compounds of formula (I) listed hereabove as well as with amantadine are given in Table I
hereunder. These results are expressed in the following manner:
~. _ 9 -. ,. . . . . .:
- , : : .
104~S~19 0 : represents Q% inhibition of catatonia in comparison with the controls (namely a score of 10 per studied batch).
1 : represents 20 to 30~ inhibition of catatonla in comparison with the controls (namely a score of 7 or 8 per studied batch).
. 2 : represents 50~ inhibition of catatonia in comparison ; with the controls (namely a score of 5 per studied batch).
10 3 : represents 70 to 80% inhibitlon of catatonia in , comparison with the controls (namely a score of 2 or 3 per studied batch).
4 : represents 100% inhibition of catatonia in comparison with the controls (namely a score of 0 per studied batch).
, ' Table I
,', . _ ' :' .' CompoundDose administered Inhibition of reserpine-in mg/kg induced catatonia ~ T, ,.',. ' - "' .
Amantadine 100 _ ., These results show that Compound 7 which is the preferred compound of the invention is as active as amantadine but at , a dose which is more than thirty times inferior to that of amantadine.
~ .
, .
- . -~041~54~
More particularly, the present invention provides novel n-butylamine derivatives having the general formula:
CH3-CH2-C1~2 \
Rl C-NH2 (I) and the pharmaceutically acceptable acid addition salts thereof, wherein Rl represents ethyl or n-propyl and R2 represents:
(a) ethyl, n-propyl, isopropyl, isobutyl or tert-butyl when Rl is n-propyl, and (b) n-butyl or isobutyl when Rl is ethyl, with the proviso that R1 and R2 simultaneously represent n-propyl only when the derivative is in the form of its acid fumarate.
The compounds of the invention are obtained by treating, in an appropriate medium, with a strong acid, such as, for example, hydrochloric or sulphuric acid, an isocyanate or a N-formyl amine of the general formula:
C 3 2 2 \
R1 - C-A (II) wherein Rl and R2 have the aforesaid meanings and A represents the group N=C=O or NH-C-H, to form the corresponding acid addition salt of the compound of formula (I) which, when required, is reacted with a base such as, for example, sodium hydroxide to obtain the desired compound in free base from which, when required, is further reacted with an organic or inorganic ~2 - 1 -10~8549 acid to give the desired pharmaceutically acceptable acid - -addition salt thereof. .:
The treatment of the compound of formula (II) with the acid may be carried out by utilizing the reagents involved at a temperature between 15C and 100C, and preferably between 50C and 90C.
Regarding l,l-di-n-propyl-n-butylamine acid fumarate, this can be prepared by treating in an appropriate medium, with a strong acid, such as for example, hydrochloric acid or sulphuric acid, l,l-di-n-propyl-n-butylisocyanate or N-formylated l,l-di-n-propyl-n-butylamine, to form the corresponding acid addition salt of l,l-di-n-propyl-n-butylamine which is thereafter reacted with a base such as, for example, sodium hydroxide to form l,l-di-n-propyl-n-butylamine in free base form which is then reacted with fumaric acid.
The compounds of formula (II) may be prepared in varlous ways, namely:
(a) When A represents the radical N-C=O;
either by reacting an acetamide derivative of the general formula:
CH -CH -CH
1 / C-C-NH (III) in which Rl and R2 have the same meaning as in the formula (I) above, with chlorine or bromine in an alkaline medium such as, for example, in an aqueous solution of sodium or potassium hydroxide, or by reacting an acetic acid derivative of the general formula:
Rl - C-C-OH (IV) ~ ~, - 2 - .
4~5~9 in which Rl and R2 have the same meaning as in formula (I) above, with a chlorinating agent such as, for example, thionyl or oxalyl chloride, to obtain the corresponding acyl chloride which is then treated with an alkali metal azide such as, for example, sodium azide, which provides the required compound of formula (II), or following another process, by heating a compound of formula (IV) directly with hydrogen azide in an acid medium, for example, sulphuric acid, to obtain the desired compound of formula (II). In this latter case, the isocyanate thus formed is immediately converted by hydrolysis to the corresponding amine of formula (I). l,l-Di-n-propyl-n-butyl isocyanate can be obtained by the same method as that described hereabove. O
(b) When A represents the radical NH-C-H:
by heating a tertiary alcohol of the general formula:
\ .
1 / C-OH (V) in which Rl and R2 have the same meaning as that given for the above compounds of formula (II), with an alkali metal cyanide such as, for example, sodium or potassium cyanide in the presence of an acid such as, for example, sulphuric acid. N-Formylated l,l-di~n-propyl-n-butylamine can be obtained by the same method as that described hereabove under (b).
The compounds of formula (III) can be obtained by reacting anhydrous ammonia with the corresponding acids of formula (IV) or preferably with the halides of these acids.
The acids can be prepared from the alcohols of formula (V) and formic acid in a sulphuric acid medium.
' . :
~048549 The compounds of formula (V) are either known compounds or can be prepared in accordance with known procedures such as, for example, by reacting an organo-lithium compound with an appropriate ketone in an anhydrous ether medium such as, for example, tetrahydrofuran.
It has been discovered that the compounds of the ; invention possess valuable pharmacological properties which are ;
likely to render them useful in human and veterinary therapy.
In particular, it has been found that the compounds 10 of the invention present central noradrenergic and central dopaminergic properties. These latter properties manifest ; themselves by an inhibitory action on reserpine-induced and ; neuroleptic-induced catatonia and catalepsy.
Pharmacological trials performed with the compounds of the invention have shown that tri-n-propylmethylamine acid fumarate or l,l-di-n-propyl-n butylamine acid fumarate, which is the preferred compound of the present invention, possesses a marked degree of activity. Fur*hermore, it was , surprisingly and quite unexpectedly observed that l,l-di-n-propyl-n-butylamine acid fumarate presents a degree of activity which is even markedly greater than that of the corresponding hydrochloride which does not form part of the invention. It was,in fact, observed that l,l-di-n-propyl-_-butylamine acid fumarate i5 from 20 to 40~ more active than the . corresponding hydrochloride in tests involving reserpine-induced and neuroleptic-induced catatonia.
Furthermore, at doses which completely suppress neuroleptic-induced catatonia and catalepsy, it was observed that the compounds of the invention do not influence the anti-amphetamine effects of the neuroleptics in the rat and their anti-apomorphine effects in the dog. Furthermore, the , ;: , .- ; .
~., ~)"
.. . . . .
- ' , .: :
109~8S49 compounds of the invention have no emetic action in the dog at any doses and are not cholinolytic agents.
These pharmacological properties taken as a whole are likely to render the compounds of formula (Ij useful in treating Parkinson's disease as well as for correcting ; extra-pyramidal disturbances provoked by neuroleptics.
Parkinson's disease is a chronic and progressive affection characterized in particular by a dopamine deficiency in the thalamus and the caudate and lenticular nuclei, with akinesia, rigidity and trmor as visible symptoms.
Many active drugs have already been proposed for combating Parkinson's syndrome. Most of these products are central anti-cholinergic agents with peripheral anti-cholinergic effects. These compounds are of natural origin, such as, for example atropine or are obtained synthetically as, for example, diethazine, benztropine or trihexyphenidyl.
However, these drugs may present undesirable side-effects, due in most cases to their peripheral anti-cholinergic properties, such side-effects taking the form, for example, of dryness of the mouth, difficulty in optical accommodation, tachycardia, constipation and retention of urine. These products will thus be contraindicated in cases of glaucoma and hypertrophy of the prostate.
L-Dopa or levodopa, a precursor of dopamine, has also been proposed in parkinsonism. However, in view of its partial destruction in the digestive system, L-dopa must be administered at very high doses, which very often induce undesirable side-effects. The most serious of these side-effects are cardio-vascular in nature and in particular take the form of disturbances of cardiac rhythm and orthostatic hypotension.
Patients treated with L-dopa must, therefore, not present contraindications on the cardiac plane.
B
. . . ~ . ; ~
1~4~35~9 ~:
Recently, amantadine, i.e. l-amino-adamantane has been proposed for antiparkinsonian therapy. This product, which stimulates the liberation of dopamine is very active but produces several undesirable side-effects and also decreases in activity after a certain length of time.
For this reason, it is very difficult for the doctor to select amongst the various antiparkinsonian drugs, that which will be effective for the case under treatment. Each patient must be considered as an individual case. All the known methods of treating Parkinson's disease are symptomatic and, in spite of the medication used, the disease continues to progress. The treatment of parkinsonism requires the successive use of one or more therapeutic substances and it is often necessary to institute therapeutic cycles. Frequently, two antiparkinsonian agents must be simultaneously administered, the first being considered as the basic drug and the second as an auxiliary or additional drug. Furthermore, since treatment is of long duration the alternating use of different products is necessary.
The search for new antiparkinsonian agents is therefore of primary importance. From this point of view, the compounds of formula (I) will constitute valuable additions to anti-parkinsonian therapy, since at present there is no ideal agent for the treatment of this disease as explained in detail hereabove.
The compounds of the invention will consequently constitute valuable additions to the therapeutic arsenal at the disposal of the doctor and will provide useful replacement medication for any drug which has become ineffective for any reason such as a change in the state of the patient or habituation.
~?
~ .
~ 048549 Although the pharmacological spectrum of the compounds of the invention is very similar to that of amantadine, pharmacological trials performed with the compounds of formula (I) have revealed marked differences in comparison with aman-tadine. For example, when comparing the doses of the compounds of the invention and of amantadine which have a certain degree of activity, it has been observed that the active dose in question is always proportionally farther from the toxic dose in the case of the compounds of the invention than in the case of amantadine. In other words, the safety margin offered by the compounds of the invention is superior to that of amantadine. Other differences which are particularly evident have been observed with the preferred compound of the invention, namely, tri-_-propylmethylamine acid fumarate or l,l-di-n-propyl-n-butylamine acid fumarate.
For example, on the cardiovascular plane, it has been observed that the preferred compound of the invention does not ; cause any undesirable effect on the electrocardiogram whereas a dose of 5 mg/kg of amantadine injected into the dog provokes cardiac arrhythmia due to ventricular extrasystoles. It has also been found that the preferred compound of the invention does not potentiate the peripheral effects of norepinephrine and is not a ganglioplegic agent while tests performed with amantadine have demonstrated that this compound potentiates the peripheral adrenergic effects and furthermore exerts a ganglioplegic action.
The preferred compound of the invention which does not present these undesirable side-effects observed with amantadine will not therefore induce cardiac disturbances or disorders of arterial pressure.
t : ` -` 1048S49 As mentioned above, certain types of antiparkinsonianagents such as diethazine and benztropine frequently provoke undesirable side-effects of an anti-cholinergic nature -(dryness of the mouth, difficulty in optical accommodation, etc.).
The preferred compound of the invention, being devoid of anti-cholinergic activity, does not present these disadvantages.
Similarly, as the preferred compound of the invention is devoid of emetic properties and of undesirable side-effects on ~ 10 the electrocardiogram, it will not provoke vomiting or cardiac '~ arrhythmia, which are two frequent side-effects of L-dopa.
Pharmacological trials have been performed with a view to determining the various properties of the compounds of the invention which, taken *ogether, are capable of rendering the said compounds useful in the treatment of Parkinson's disease and for the correction of extra-pyramidal disturbances induced by neuroleptics.
I. Inhibition of reserpine-induced and neuroleptic-induced catatonia (dopaminergic properties) 1. Inhibition of reserpine-induced catatonia After sufficient doses of reserpine have been administered to the rat, a series of symptoms occur, more particularly ptosis, catatonia and a drop in central temperature. These symptoms are caused by the depletion of the intragranular reserve pool of biogenetic amines at the synaptic terminals.
The antidepressants of the tricyclic type as well as the inhibitors of monoamine oxydase (I.M.A.O.) antagonize more particularly the appearance of ptosis and the drop in central temperature. On catatonia, the action of such compounds is not non-existent but is considerably less marked.
1~48549 As against this, the synthetic antiparkinsonian agents principally influence catatonia while their activity on ptosis and hypothermia is non-existent or weaker.
An oral dose of the compound to be studied in aqueous solution was administered to batches of 10 male rats of the OFA strain weighing about 150 to 200 g. Thirty minutes later a dose of 5 mg/kg of reserpine was given by intraperitoneal route. Three hours after the injection of reserpine, the animals were suspended by the four paws from a horizontally stretched wire fixed at 15 cm from the ground~ The catatonic animals were those which maintained the position so given for at least 30 seconds. Each animal which maintained the position so given received the score of 1 and those which -.~
did not maintain the said position were given the score of 0. The maximum score was therefore 10 per batch. An identical trial was undertaken with control animals which received reserpine but none of the compounds being studied.
The following compounds of formula (I) were tested in comparison with amantadine in accordance with the process indicated hereabove. These compounds were preferably studied in the form of a pharmaceutically acceptable acid addition salt such as the hydrochloride or the fumarate.
l-Ethyl-l-n-propyl-n-butylamine(Compound 1) l-Ethyl-l-isobutyl-n-butylamine(Compound 2) l-Ethyl-l-_-butyl-n-butylamine(Compound 3) l-n-Propyl-l-isobutyl-n-butylamine ` (Compound 4) l-n-Propyl-l-isopropyl-n-butylamine (Compound 5) l-n-Propyl-l-tert-butyl-n-butylamine (Compound 6) The same test was also performed with l,l-di-_-propyl-n-butyl-amine acid fumarate (Compound 7).
The results obtained with the compounds of formula (I) listed hereabove as well as with amantadine are given in Table I
hereunder. These results are expressed in the following manner:
~. _ 9 -. ,. . . . . .:
- , : : .
104~S~19 0 : represents Q% inhibition of catatonia in comparison with the controls (namely a score of 10 per studied batch).
1 : represents 20 to 30~ inhibition of catatonla in comparison with the controls (namely a score of 7 or 8 per studied batch).
. 2 : represents 50~ inhibition of catatonia in comparison ; with the controls (namely a score of 5 per studied batch).
10 3 : represents 70 to 80% inhibitlon of catatonia in , comparison with the controls (namely a score of 2 or 3 per studied batch).
4 : represents 100% inhibition of catatonia in comparison with the controls (namely a score of 0 per studied batch).
, ' Table I
,', . _ ' :' .' CompoundDose administered Inhibition of reserpine-in mg/kg induced catatonia ~ T, ,.',. ' - "' .
Amantadine 100 _ ., These results show that Compound 7 which is the preferred compound of the invention is as active as amantadine but at , a dose which is more than thirty times inferior to that of amantadine.
~ .
, .
- . -~041~54~
2. Inhibition of neuroleptic-induced catatonia ~ he blocking of dopaminergic receptors by neuroleptics in the extra-pyramidal system induces catatonia in the rat.
Catatonia is differentiated form sedative properties by means of the test used hereabove for reserpine-induced catatonia. m e same system of scoring was also employed in the present case.
An oral dose of the compound to be studied in aqueous solution was administered to batches of 10 male rats of the OFA
strain weighing about 150 to 200 g. Thirty minutes later a dose of 12.5 mg/kg of prochlorperazine was given by intraperitoneal route. Three hours after the injection of this latter compound, catatonia was measured. An identical trial was also carried out with control animals which received prochlorperazine but none of the compounds under study.
The results obtained with the above listed compounds in comparison with amantadine are set out in the following Table II. The scoring system used was that given hereabove in Table I.
Table II
Compound Dose administered Inhibition of the neuroleptic-in mg/kg induced catatonia '.......... '1 -' . 1
Catatonia is differentiated form sedative properties by means of the test used hereabove for reserpine-induced catatonia. m e same system of scoring was also employed in the present case.
An oral dose of the compound to be studied in aqueous solution was administered to batches of 10 male rats of the OFA
strain weighing about 150 to 200 g. Thirty minutes later a dose of 12.5 mg/kg of prochlorperazine was given by intraperitoneal route. Three hours after the injection of this latter compound, catatonia was measured. An identical trial was also carried out with control animals which received prochlorperazine but none of the compounds under study.
The results obtained with the above listed compounds in comparison with amantadine are set out in the following Table II. The scoring system used was that given hereabove in Table I.
Table II
Compound Dose administered Inhibition of the neuroleptic-in mg/kg induced catatonia '.......... '1 -' . 1
3 20 3 6 50 4 , Amantadine 100 _ -, , . ~
104~549 These results show that Compound 7 is also more than thirty times more active than amantadine in this test and that Compound
104~549 These results show that Compound 7 is also more than thirty times more active than amantadine in this test and that Compound
4 is five times more active than amantadine.
II. Acute toxycity In the acute toxycity test the LD50 was determined on mice by oral route using the method of LICHFIELD and WILCOXON
~- (J. Pharmacol. 1938, 2, 192-216). The compounds were administered in aqueous solution and the period of observation was 10 days after administration of the compound under study.
The following results were recorded in comparison with amantadine.
Compound LD50 (in mg/kg) Amantadine 1050 These results show that compounds of the invention are generally more toxic than amantadine. However, when a comparison is made between the LD50 given hereabove and the effective dose to obtain inhibition of reserpine-induced or neuroleptic-induced catatonia, it is seen that such comparisons are always more favourable to the compounds of the invention than to amantadine. The index 50 was determined. In this index, ED20_30 represent 20-30 effective dose to obtain 20 to 30 % inhibition of the catatonia, this value being represented by the figure 1 in Tables I and II.
The following result was registered :
Compound Index ~; 1 30 ~ The corresponding index for amantadine is 155 = 21, which shows that the compound of the invention presents greater advantages than amantadine.
.~
: 1~4~3S~9 ; ~ 5o Similarly, an index EDloo was determined, ED
representing the effective dose to obtain 100% inhibition of the catatonia.
This latter value is represented in Tables I and II
- by the figure 4.
The following results were recorded :
Compound Index 7 ~33 Amantadine 10 . ~ ~
These figures show that Compound 7 represents a total ' inhibitory action on reserpine-induced and neuroleptic - induced catatonia at a dose which is proportionally more than three times , as far from the toxic dose as in the case of amantadine. Compound 7 possesses, consequently, a higher safety margin than that of amantadine.
It will be appreciated that for therapeutic use the compounds of the invention will normally be administered in the ; form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, the -~ 20 composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the . form of, for example , a coated or uncoated tablet, a hard- or soft-gelatin capsule, a suspension or a syrup. The composition may alternatively take the form of a suppository for rectal ' administration, or of a solution or suspension for parenteral administration.
; When in dosage unit form the composition may contain from 5 to 50 mg, preferably from 5 to 10 mg, of the active ingredient per dosage unit for oral administration, from 5 to 50 mg of the i;i~ active ingredient per dosage unit for rectal administration, or from 1 to 10 mg of the active ingredient per dosage unit for B~
1041~5~
by the figure 4.
The following results were recorded:
` Com~ound Index ~ 7 ~~ 33 ;~ Amantadine 10 -t:" ' These figures show that Compound 7 presents a total inhibitory action on reserpine-induced and neuroleptic-induced catatonia at a dose which is proportionally more than three times as far from the toxic dose as in the case of amantadine.
Compound 7 possesses, consequently, a higher safety margin than that of amantadine.
~, ` It will be appreciated that for therapeutic use the -compounds of the invention will normally be administered in ; the form of a pharmaceutical or veterinary composition in a .
't"~ dosage unit form appropriate to the required mode of adminis-tration , the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the , composition may take the form of, for example, a coated or ', 20 uncoated tablet, a hard- or soft-gelatin capsule, a suspension i or a syrup. The composition may alternatively take the form of a suppository for rectal administration, or of a solution or suspension for parenteral administration.
When in dosage unit form the composition may contain ~; from 5 to 50 mg, preferably from 5 to 10 mg, of the active r~:~ ingredient per dosage unit for oral administration, from 5 to 50 mg of the active ingredient per dosage unit for rectal administration, or from 1 to 10 mg of the active ingredient per dosage unit for parenteral administration.
The therapeutic compositions in question will be prepared by associating at least one compound of the invention with at least one appropriate carrier or excipient therefor.
'' ~3i ' ~ 1~4~4~
.` ~
- Examples of suitable carriers or excipients are talc, magnesium ;~
stearate, milk sugar, saccharose, carboxymethylcellulose, ;~ starches, kaolin, levilite and cocoa butter.
The following Examples illustrate the preparation of compounds of the invention.
Preparation of l,l-di-n-propyl-n-butylamine acide fumarate (or tri-n-propyl-methylamine acid fumarate) (a) l,l-Di-n-propyl-n-butylisocyanate.
In a 2-litre three-necked flask fitted with a water condenser, a mechanical stirrer, a thermometer and a dropping-funnel were placed 144 g. of sodium hydroxide in tablet form and 1200 ml. of water. The obtained solution was cooled to 5C and, under stirring, 48 ml. of bromine were slowly added. The opera-tion of adding the bromine lasted two hours and then, at a tempe-rature of 0C, 111 g. of 2,2-di-n-propyl-valeramide were added to the yellowish-green solution. Stirring of the mixture was ; maintained at about 0C for 4 hours. The oily phase was then extracted with three fractions of ether each of 300 ml. and the ethereal phase was washed twice with 100 ml. of water, dried over ~` magnesium sulphate and evaporated under vacuum. The light yellow oil so obtained was distilled under reduced pressure of 5 mmHg.
In this manner 105g. of colourless l,l-di-n-propyl-n-butyl-isocyanate were obtained.
B.P. 78-79C under 5 mmHg.
Yield : 95%.
By following the same procedure as that described hereabove but using the appropriate starting products, the compound hereunder was prepared:
CCompoundBoilinq point C
l-n-Propyl-l-isopropyl-n- 97 butylisocyanate (15 mmHg) .~
:
: ` :
: ~4~549 (b) l,l,-Di-n-propyl-n-butylamine hydrochloride.
Into a three-necked flask equipped with a mechanical stirrer, a dropping-funnel, a thermometer and a condenser, were introduced 200 ml. of water and 90 ml. of concentrated hydrochloric acid (d=l.l9). The acid solution was heated to 90C and then, under vigorous stirring, 105 g. of l,l-di-n-propyl-n-butyl-isocyanate, prepared as previously described, were slowly added. The operation of addition lasted one hour, after which the reaction medium was heated for a further 104 hours at a temperature betweem about 95 and 100C. The mixture was then cooled to about 0C and the colourless crystals so obtained were filtered off and dried by exposure to the air and then in a dessicator in the presence of potassium hydroxide. In this manner, 99 g. of l,l-di-n-propyl-n-butylamine hydrochloride were isolated in the form of a white crystalline powder.
, The product does not melt but sublimates from 220C.
'- Yield: 90%.
By following the same procedure as that described hereabove but using the appropriate starting products, the ~. .
compounds hereunder were obtained:
Compound .:
l-Ethyl-l-n-propyl-n-butylamine hydrochloride (sublimation) l-Ethyl-l-isobutyl-n-butylamine hydrochloride (sublimation) l-n-Propyl-l-isobutyl-n-butylamine hydrochloride M.P. 260C
l-Ethyl-l-n-butyl-n-butylamine hydrochloride M.P. 230C
(decomposition) - l-n-Propyl-l-isopropyl-n-butylamine hydrochloride M.P. 260C
(decomposition) 30tc) l,l-Di-n-propyl-n-butylamine acid fumara~e.
To a solution of 1,16 g. (0.01 mol) of fumaric acid in 20 ml. of acetone, were slowly added 1.57 g. (0~01 mol) of ~.. ,i, 1~4~549 l,l-di-n-propyl-n-butylamine (nD1 = 1.4349) dissolved in 10 ml.
of acetone, this amine having been prepared from its hydrochlor-ide and a 30% aqueous solution of sodium hydroxide. The mixture was stirred for one hour and then the crystals which formed were suction-filtered, washed with acetone and dried under vacuum.
In this manner, l,l-di-n-propyl-n-butylamine acid fumarate was obtained in the form of a white powder.
M.P. 216C with sublimation~
Yield : 100%.
By following the same procedure as that described above but using the appropriate starting products, the compound here-under was prepared:
Compound l-n-Propyl-l-tert-butyl-n-butylamine acidM.P. 180C
fumarate (sublimation) Preparation of l-n-propyl-l-isobutyl-n-butylamine hydrochloride (a) 1-n-Propyl-l-isobutyl-n-butanol.
~:! 20 Into a 250 ml. three-neckèd flask equipped with a mechanical stirrer, a nitrogen inlet, a dropping-funnel and a thermometer were introduced under a nitrogen atmosphere 2.8 g. (0.2 mol) of lithium in small portions and 100 ml. of anhydrous and purified tetrahydrofuran. The suspension of lithium in tetrahydrofuran was cooled to -20C and then while stirring a mixture of 22.8 g. (0.2 mol) of di n-propylketone and 30 g. (0.2 mol plus a 10% excess) of isobutyl bromide were slowly added. The operation of addition lasted about 3 hours during which time a temperature of about -20C was maintained. The solution was allowed to stand for about 12 hours at room temperature and then concentrated. The oil so obtained was taken up in water, extracted with ether and , 1g)48S~9 distilled under reduced pressure.
In this manner, 21 g. of l-n-propyl-l-isobutyl-n-butanol were obtained in the form of a clear liquid which was , slightly yellow.
B.P. 74-76C under 5 mn~lg.
Yield : about 60%.
Following the same procedure as that described above ; but using the appropriate starting products, the compounds , ....
listed hereunder were prepared:
Com~ound Boilina point C
l-Ethyl-l-n-propyl-n-butanol 178-179 (Yield : 35 %) (760 mmHg) Y .
- l-Ethyl-l-isobutyl-n-butanol 78-79 (Yield : 40%) (15 mmHg) l-n-Propyl-l-isopropyl-n-butanol(15 mmHg) l-n-Propyl-l-tert-butyl-n-butanol 90-92 l-Ethyl-l-n-butyl-n-butanol 87 . ~ .
(Yield : 35%) (11 mmHg) (b) l-n-Propyl-l-isobutyl-n-butylamine hydrochloride.
~ Into a 250 ml. three-necked flask equipped with a ; mechanical stirrer, a dropping-funnel, a condenser and a dip thermometer, were introduced 6.5 g. (0.1 ml) of dry potassium cyanide in powder form, 14.4 g. (0.083 mol) of l-n-propyl-l-isobutyl-n-butanol and 12 ml. of acetic acid. While stirring, a mixture of 25 g. of concentrated sulphuric acid (d = 1.83) and 12 ml. of acetic acid was slowly added. The operation of addition lasted about 2 hours during which time a temperature of about 50C was maintained. The reaction mixture was heated to 70C for 2 hours and was then slowly poured into 100 ml.
of iced water. After this, it was neutralized with a 20%
aqueous solution of sodium hydroxide and extracted with ether.
B
The ether was evaporated out and an oil comprising N-formylated l-n-propyl-l-isobutyl-n-butylamine was collected.
; The N-formylated amine thus obtained was refluxed -for 2 hours in the presence of 20 ml. of concentrated hydro-chloric acid. While cooling, the hydrochloride of this amine crystallized. It was then filtered off and washed with acetone.
In this manner, 11 g. of l-n-propyl-l-isobutyl-n-butylamine hydrochloride was collected in the form of a white powder.
M.P. 260C with decomposition without melting at about 280C.
Yield : 6470.
In a thin layer chromatographic assay performed on silica gel plates using a system of solvents comprising 79 parts of benzene, 14 parts of methanol and 7 parts of acetic acid and with iodine as revealing agent, a Rf of 0.6 was recorded.
Following the same procedure as that described here-above but using the appropriate starting products, the compounds listed hterunder were prepared. The Rf value given for each of these compounds was determined in a thin layer chromatographic assay using the same support, the same system of solvents and the same revealing agent as those mentioned in the Example hereabove described.
Compound l-Ethyl-l-n-propyl-n-butylamine hydrochloride 180C
(Yield : 25%) (sublimation) Rf = 0.64 l-Ethyl-l-isobutyl-n-butylamine hydrochloride 230C
(Yield : 30%) (sublimation) Rf = 0.60 l-n-Propyl-l-isopropyl-n-butylamine hydrochloride~M.P. 260C
(decomposition) ;~ l-Ethyl-l-n-butyl-n-butylamine hydrochloride M.P. 230C
~ . -- 19 --` ,~
.
- 16)48549 (Yield : 30%) (decomposition) Rf = 0.60 Example 3 reparation of l~ethyl-l-n-butyl-n-butylamine hydrochloride - (a) 2-Ethyl-2-n-propyl-hexanoic acid.
,~ Into a three-necked flask fitted with a mechanical stirrer, a thermometer and two dropping-funnels, were placed ; 204 g. of 96% sulphuric acid cooled to 5C. and 4 ml. of formic acid. While maintaining the mixture at a temperature of about 10C, 23 g. (0.5 mol) of formic acid and 15.8 g.
(0.1 mol) of l-ethyl-l-n-propyl-n-pentanol in 100 ml. of pentane were simultaneously added. The operation of addition lasted 40 minutes, after which the reaction mixture was allowed to return to room temperature in 2 hours. The mixture was poured onto 100 g. of crushed ice and the acid was extract-ed with ether. The acid was purified by preparing its sodium salt with a 20% aqueous solution of sodium hydroxide. The aqueous phase was acidified with 50% hydrochloric acid and extracted with ether.
The organic fraction was then dried over magnesium sulphate and concentrated under vacuum.
In this manner, 2-ethyl-2-n-propyl-hexanoic acid was obtalned in the form of a colourless liquidO
B.P. 130-132C under 20 mmHg.
Yield : about 20%.
Using the same method as that described above, the following compound was prepared:
Compound B.P.
2-Ethyl-2-n-propyl-pentanoic acid 122C
(12 mm~Ig) (b) l-Ethyl-l-n-butyl-n-butylamine.
Into a three-necked flask equipped with a mechanical _ 20 ~
-- . .,J
. 1~48549 , . .
.. .. ~ .
stirrer and a condenser, were introduced 70 ml. of chloroform, 18 ml. of concentrated sulphuric acid (d = 1.83) and 11 g.
(0.06 mol) of 2-ethyl-2-n-propyl-hexanoic acid prepared as described above. The mixture was heated to 50C and while -~
stirring 7.5 g. of sodium azide in powder form were added.
The operation of addition lasted 90 minutes after which the r ~ . ' .
; reaction mixture was heated to 50C for 2 hours. The mixture was then neutralized with a 40% aqueous solution of sodium hydroxide, previously cooled to 0C. The amine was extracted with ether and the ethereal phase was washed with water and dried over magnesium sulphate. The ether was evaporated out under vacuum and the oil so obtained was taken up in dry ether, which provided l-ethyl-l-n-butyl-n-butylamine in free base form.
' (c) l-Ethyl-l-n-butyl-n-butylamine hydrochloride.
, The hydrochloride of the amine, previously obtained, ... .
~ was precipitated by bubbling dry gaseous hydrochloric acid ';!.' through a solution of the said amine.
~, . .
v In this manner, l-ethyl-l-n-butyl-n-butylamine hydro-chloride was obtained in the form of colourless crystals ; which sublimated from 200C. Yield : 45Y0.
By following the same procedure as that described above, the following compounds were prepared: `
Compound Ethyl-l-n-propyl-n-butylamine hydrochloride 180C
(sublimation) i" l-Ethyl-l-isobutyl-n-butylamine hydrochloride 230C
(sublimation) '; l-n-Propyl-l-isobutyl-n-butylamine hydrochloride M.P. 260C
l-n-Propyl-l-isopropyl-n-butylamine hydrochloride M.P. 260C
~; (decomposition) .. . .
,.~ .
~ - 21 -:
... .. .
, --- = ,. . .
II. Acute toxycity In the acute toxycity test the LD50 was determined on mice by oral route using the method of LICHFIELD and WILCOXON
~- (J. Pharmacol. 1938, 2, 192-216). The compounds were administered in aqueous solution and the period of observation was 10 days after administration of the compound under study.
The following results were recorded in comparison with amantadine.
Compound LD50 (in mg/kg) Amantadine 1050 These results show that compounds of the invention are generally more toxic than amantadine. However, when a comparison is made between the LD50 given hereabove and the effective dose to obtain inhibition of reserpine-induced or neuroleptic-induced catatonia, it is seen that such comparisons are always more favourable to the compounds of the invention than to amantadine. The index 50 was determined. In this index, ED20_30 represent 20-30 effective dose to obtain 20 to 30 % inhibition of the catatonia, this value being represented by the figure 1 in Tables I and II.
The following result was registered :
Compound Index ~; 1 30 ~ The corresponding index for amantadine is 155 = 21, which shows that the compound of the invention presents greater advantages than amantadine.
.~
: 1~4~3S~9 ; ~ 5o Similarly, an index EDloo was determined, ED
representing the effective dose to obtain 100% inhibition of the catatonia.
This latter value is represented in Tables I and II
- by the figure 4.
The following results were recorded :
Compound Index 7 ~33 Amantadine 10 . ~ ~
These figures show that Compound 7 represents a total ' inhibitory action on reserpine-induced and neuroleptic - induced catatonia at a dose which is proportionally more than three times , as far from the toxic dose as in the case of amantadine. Compound 7 possesses, consequently, a higher safety margin than that of amantadine.
It will be appreciated that for therapeutic use the compounds of the invention will normally be administered in the ; form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, the -~ 20 composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the . form of, for example , a coated or uncoated tablet, a hard- or soft-gelatin capsule, a suspension or a syrup. The composition may alternatively take the form of a suppository for rectal ' administration, or of a solution or suspension for parenteral administration.
; When in dosage unit form the composition may contain from 5 to 50 mg, preferably from 5 to 10 mg, of the active ingredient per dosage unit for oral administration, from 5 to 50 mg of the i;i~ active ingredient per dosage unit for rectal administration, or from 1 to 10 mg of the active ingredient per dosage unit for B~
1041~5~
by the figure 4.
The following results were recorded:
` Com~ound Index ~ 7 ~~ 33 ;~ Amantadine 10 -t:" ' These figures show that Compound 7 presents a total inhibitory action on reserpine-induced and neuroleptic-induced catatonia at a dose which is proportionally more than three times as far from the toxic dose as in the case of amantadine.
Compound 7 possesses, consequently, a higher safety margin than that of amantadine.
~, ` It will be appreciated that for therapeutic use the -compounds of the invention will normally be administered in ; the form of a pharmaceutical or veterinary composition in a .
't"~ dosage unit form appropriate to the required mode of adminis-tration , the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the , composition may take the form of, for example, a coated or ', 20 uncoated tablet, a hard- or soft-gelatin capsule, a suspension i or a syrup. The composition may alternatively take the form of a suppository for rectal administration, or of a solution or suspension for parenteral administration.
When in dosage unit form the composition may contain ~; from 5 to 50 mg, preferably from 5 to 10 mg, of the active r~:~ ingredient per dosage unit for oral administration, from 5 to 50 mg of the active ingredient per dosage unit for rectal administration, or from 1 to 10 mg of the active ingredient per dosage unit for parenteral administration.
The therapeutic compositions in question will be prepared by associating at least one compound of the invention with at least one appropriate carrier or excipient therefor.
'' ~3i ' ~ 1~4~4~
.` ~
- Examples of suitable carriers or excipients are talc, magnesium ;~
stearate, milk sugar, saccharose, carboxymethylcellulose, ;~ starches, kaolin, levilite and cocoa butter.
The following Examples illustrate the preparation of compounds of the invention.
Preparation of l,l-di-n-propyl-n-butylamine acide fumarate (or tri-n-propyl-methylamine acid fumarate) (a) l,l-Di-n-propyl-n-butylisocyanate.
In a 2-litre three-necked flask fitted with a water condenser, a mechanical stirrer, a thermometer and a dropping-funnel were placed 144 g. of sodium hydroxide in tablet form and 1200 ml. of water. The obtained solution was cooled to 5C and, under stirring, 48 ml. of bromine were slowly added. The opera-tion of adding the bromine lasted two hours and then, at a tempe-rature of 0C, 111 g. of 2,2-di-n-propyl-valeramide were added to the yellowish-green solution. Stirring of the mixture was ; maintained at about 0C for 4 hours. The oily phase was then extracted with three fractions of ether each of 300 ml. and the ethereal phase was washed twice with 100 ml. of water, dried over ~` magnesium sulphate and evaporated under vacuum. The light yellow oil so obtained was distilled under reduced pressure of 5 mmHg.
In this manner 105g. of colourless l,l-di-n-propyl-n-butyl-isocyanate were obtained.
B.P. 78-79C under 5 mmHg.
Yield : 95%.
By following the same procedure as that described hereabove but using the appropriate starting products, the compound hereunder was prepared:
CCompoundBoilinq point C
l-n-Propyl-l-isopropyl-n- 97 butylisocyanate (15 mmHg) .~
:
: ` :
: ~4~549 (b) l,l,-Di-n-propyl-n-butylamine hydrochloride.
Into a three-necked flask equipped with a mechanical stirrer, a dropping-funnel, a thermometer and a condenser, were introduced 200 ml. of water and 90 ml. of concentrated hydrochloric acid (d=l.l9). The acid solution was heated to 90C and then, under vigorous stirring, 105 g. of l,l-di-n-propyl-n-butyl-isocyanate, prepared as previously described, were slowly added. The operation of addition lasted one hour, after which the reaction medium was heated for a further 104 hours at a temperature betweem about 95 and 100C. The mixture was then cooled to about 0C and the colourless crystals so obtained were filtered off and dried by exposure to the air and then in a dessicator in the presence of potassium hydroxide. In this manner, 99 g. of l,l-di-n-propyl-n-butylamine hydrochloride were isolated in the form of a white crystalline powder.
, The product does not melt but sublimates from 220C.
'- Yield: 90%.
By following the same procedure as that described hereabove but using the appropriate starting products, the ~. .
compounds hereunder were obtained:
Compound .:
l-Ethyl-l-n-propyl-n-butylamine hydrochloride (sublimation) l-Ethyl-l-isobutyl-n-butylamine hydrochloride (sublimation) l-n-Propyl-l-isobutyl-n-butylamine hydrochloride M.P. 260C
l-Ethyl-l-n-butyl-n-butylamine hydrochloride M.P. 230C
(decomposition) - l-n-Propyl-l-isopropyl-n-butylamine hydrochloride M.P. 260C
(decomposition) 30tc) l,l-Di-n-propyl-n-butylamine acid fumara~e.
To a solution of 1,16 g. (0.01 mol) of fumaric acid in 20 ml. of acetone, were slowly added 1.57 g. (0~01 mol) of ~.. ,i, 1~4~549 l,l-di-n-propyl-n-butylamine (nD1 = 1.4349) dissolved in 10 ml.
of acetone, this amine having been prepared from its hydrochlor-ide and a 30% aqueous solution of sodium hydroxide. The mixture was stirred for one hour and then the crystals which formed were suction-filtered, washed with acetone and dried under vacuum.
In this manner, l,l-di-n-propyl-n-butylamine acid fumarate was obtained in the form of a white powder.
M.P. 216C with sublimation~
Yield : 100%.
By following the same procedure as that described above but using the appropriate starting products, the compound here-under was prepared:
Compound l-n-Propyl-l-tert-butyl-n-butylamine acidM.P. 180C
fumarate (sublimation) Preparation of l-n-propyl-l-isobutyl-n-butylamine hydrochloride (a) 1-n-Propyl-l-isobutyl-n-butanol.
~:! 20 Into a 250 ml. three-neckèd flask equipped with a mechanical stirrer, a nitrogen inlet, a dropping-funnel and a thermometer were introduced under a nitrogen atmosphere 2.8 g. (0.2 mol) of lithium in small portions and 100 ml. of anhydrous and purified tetrahydrofuran. The suspension of lithium in tetrahydrofuran was cooled to -20C and then while stirring a mixture of 22.8 g. (0.2 mol) of di n-propylketone and 30 g. (0.2 mol plus a 10% excess) of isobutyl bromide were slowly added. The operation of addition lasted about 3 hours during which time a temperature of about -20C was maintained. The solution was allowed to stand for about 12 hours at room temperature and then concentrated. The oil so obtained was taken up in water, extracted with ether and , 1g)48S~9 distilled under reduced pressure.
In this manner, 21 g. of l-n-propyl-l-isobutyl-n-butanol were obtained in the form of a clear liquid which was , slightly yellow.
B.P. 74-76C under 5 mn~lg.
Yield : about 60%.
Following the same procedure as that described above ; but using the appropriate starting products, the compounds , ....
listed hereunder were prepared:
Com~ound Boilina point C
l-Ethyl-l-n-propyl-n-butanol 178-179 (Yield : 35 %) (760 mmHg) Y .
- l-Ethyl-l-isobutyl-n-butanol 78-79 (Yield : 40%) (15 mmHg) l-n-Propyl-l-isopropyl-n-butanol(15 mmHg) l-n-Propyl-l-tert-butyl-n-butanol 90-92 l-Ethyl-l-n-butyl-n-butanol 87 . ~ .
(Yield : 35%) (11 mmHg) (b) l-n-Propyl-l-isobutyl-n-butylamine hydrochloride.
~ Into a 250 ml. three-necked flask equipped with a ; mechanical stirrer, a dropping-funnel, a condenser and a dip thermometer, were introduced 6.5 g. (0.1 ml) of dry potassium cyanide in powder form, 14.4 g. (0.083 mol) of l-n-propyl-l-isobutyl-n-butanol and 12 ml. of acetic acid. While stirring, a mixture of 25 g. of concentrated sulphuric acid (d = 1.83) and 12 ml. of acetic acid was slowly added. The operation of addition lasted about 2 hours during which time a temperature of about 50C was maintained. The reaction mixture was heated to 70C for 2 hours and was then slowly poured into 100 ml.
of iced water. After this, it was neutralized with a 20%
aqueous solution of sodium hydroxide and extracted with ether.
B
The ether was evaporated out and an oil comprising N-formylated l-n-propyl-l-isobutyl-n-butylamine was collected.
; The N-formylated amine thus obtained was refluxed -for 2 hours in the presence of 20 ml. of concentrated hydro-chloric acid. While cooling, the hydrochloride of this amine crystallized. It was then filtered off and washed with acetone.
In this manner, 11 g. of l-n-propyl-l-isobutyl-n-butylamine hydrochloride was collected in the form of a white powder.
M.P. 260C with decomposition without melting at about 280C.
Yield : 6470.
In a thin layer chromatographic assay performed on silica gel plates using a system of solvents comprising 79 parts of benzene, 14 parts of methanol and 7 parts of acetic acid and with iodine as revealing agent, a Rf of 0.6 was recorded.
Following the same procedure as that described here-above but using the appropriate starting products, the compounds listed hterunder were prepared. The Rf value given for each of these compounds was determined in a thin layer chromatographic assay using the same support, the same system of solvents and the same revealing agent as those mentioned in the Example hereabove described.
Compound l-Ethyl-l-n-propyl-n-butylamine hydrochloride 180C
(Yield : 25%) (sublimation) Rf = 0.64 l-Ethyl-l-isobutyl-n-butylamine hydrochloride 230C
(Yield : 30%) (sublimation) Rf = 0.60 l-n-Propyl-l-isopropyl-n-butylamine hydrochloride~M.P. 260C
(decomposition) ;~ l-Ethyl-l-n-butyl-n-butylamine hydrochloride M.P. 230C
~ . -- 19 --` ,~
.
- 16)48549 (Yield : 30%) (decomposition) Rf = 0.60 Example 3 reparation of l~ethyl-l-n-butyl-n-butylamine hydrochloride - (a) 2-Ethyl-2-n-propyl-hexanoic acid.
,~ Into a three-necked flask fitted with a mechanical stirrer, a thermometer and two dropping-funnels, were placed ; 204 g. of 96% sulphuric acid cooled to 5C. and 4 ml. of formic acid. While maintaining the mixture at a temperature of about 10C, 23 g. (0.5 mol) of formic acid and 15.8 g.
(0.1 mol) of l-ethyl-l-n-propyl-n-pentanol in 100 ml. of pentane were simultaneously added. The operation of addition lasted 40 minutes, after which the reaction mixture was allowed to return to room temperature in 2 hours. The mixture was poured onto 100 g. of crushed ice and the acid was extract-ed with ether. The acid was purified by preparing its sodium salt with a 20% aqueous solution of sodium hydroxide. The aqueous phase was acidified with 50% hydrochloric acid and extracted with ether.
The organic fraction was then dried over magnesium sulphate and concentrated under vacuum.
In this manner, 2-ethyl-2-n-propyl-hexanoic acid was obtalned in the form of a colourless liquidO
B.P. 130-132C under 20 mmHg.
Yield : about 20%.
Using the same method as that described above, the following compound was prepared:
Compound B.P.
2-Ethyl-2-n-propyl-pentanoic acid 122C
(12 mm~Ig) (b) l-Ethyl-l-n-butyl-n-butylamine.
Into a three-necked flask equipped with a mechanical _ 20 ~
-- . .,J
. 1~48549 , . .
.. .. ~ .
stirrer and a condenser, were introduced 70 ml. of chloroform, 18 ml. of concentrated sulphuric acid (d = 1.83) and 11 g.
(0.06 mol) of 2-ethyl-2-n-propyl-hexanoic acid prepared as described above. The mixture was heated to 50C and while -~
stirring 7.5 g. of sodium azide in powder form were added.
The operation of addition lasted 90 minutes after which the r ~ . ' .
; reaction mixture was heated to 50C for 2 hours. The mixture was then neutralized with a 40% aqueous solution of sodium hydroxide, previously cooled to 0C. The amine was extracted with ether and the ethereal phase was washed with water and dried over magnesium sulphate. The ether was evaporated out under vacuum and the oil so obtained was taken up in dry ether, which provided l-ethyl-l-n-butyl-n-butylamine in free base form.
' (c) l-Ethyl-l-n-butyl-n-butylamine hydrochloride.
, The hydrochloride of the amine, previously obtained, ... .
~ was precipitated by bubbling dry gaseous hydrochloric acid ';!.' through a solution of the said amine.
~, . .
v In this manner, l-ethyl-l-n-butyl-n-butylamine hydro-chloride was obtained in the form of colourless crystals ; which sublimated from 200C. Yield : 45Y0.
By following the same procedure as that described above, the following compounds were prepared: `
Compound Ethyl-l-n-propyl-n-butylamine hydrochloride 180C
(sublimation) i" l-Ethyl-l-isobutyl-n-butylamine hydrochloride 230C
(sublimation) '; l-n-Propyl-l-isobutyl-n-butylamine hydrochloride M.P. 260C
l-n-Propyl-l-isopropyl-n-butylamine hydrochloride M.P. 260C
~; (decomposition) .. . .
,.~ .
~ - 21 -:
... .. .
, --- = ,. . .
Claims (12)
1. A process for the preparation of n-butylamine derivatives having the general formula:
(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 represents ethyl or n-propyl and R2 represents (a) ethyl, n-propyl, isopropyl, isobutyl or tert-butyl when R1 is n-propyl and (b) n-butyl or isobutyl when R1 is ethyl, with the proviso that R1 and R2 simultaneously represent n-propyl only when the derivative is in the form of it acid fumarate, which comprises treating with a strong acid in an appropriate medium an iso-cyanate or a N-formyl amine of the formula:
wherein R1 and R2 have the aforesaid meanings and A represents the group N=C=O or , to form the corresponding acid addition salt of the butylamine derivative, and there-after, when required,reacting said salt with a base to obtain the desired compound in free base form which, when required, is further reacted with an organic or inorganic acid to give the desired pharmaceutically acceptable acid addition salt of the butylamine derivative.
(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 represents ethyl or n-propyl and R2 represents (a) ethyl, n-propyl, isopropyl, isobutyl or tert-butyl when R1 is n-propyl and (b) n-butyl or isobutyl when R1 is ethyl, with the proviso that R1 and R2 simultaneously represent n-propyl only when the derivative is in the form of it acid fumarate, which comprises treating with a strong acid in an appropriate medium an iso-cyanate or a N-formyl amine of the formula:
wherein R1 and R2 have the aforesaid meanings and A represents the group N=C=O or , to form the corresponding acid addition salt of the butylamine derivative, and there-after, when required,reacting said salt with a base to obtain the desired compound in free base form which, when required, is further reacted with an organic or inorganic acid to give the desired pharmaceutically acceptable acid addition salt of the butylamine derivative.
2. Process according to claim 1, wherein the treatment is carried out at a temperature of from 15 to 100°C.
3. Process according to claim 2, wherein the treatment is carried out at a temperature of from 50 to 90°C.
4. Process according to claim 1, wherein the strong acid is hydrochloric acid or sulphuric acid.
5. Process according to claim 1, wherein the base is sodium hydroxide.
6. Process according to claim 1, for the preparation of 1,1-di-n-propyl-n-butylamine acid fumarate, which comprises treating with a strong acid in an appropriate medium 1,1-di-n-propyl-n-butyl isocyanate or N-formylated 1,1-di-n-propyl-n-butylamine, to form the corresponding acid addition salt of 1,1-di-n-propyl-n-butylamine and thereafter reacting said salt with a base to obtain 1,1-di-n-propyl-n-butylamine in free base from which is then reacted with fumaric acid.
7. Process according to claim 6, wherein the treatment is carried out at a temperature of from 15 to 100°C.
8. Process according to claim 7, wherein the treatment is carried out at a temperature of from 50 to 90°C.
9. Process according to claim 6, wherein the strong acid is hydrochloric acid or sulphuric acid.
10. Process according to claim 6, wherein the base is sodium hydroxide.
11. n-Butylamine derivatives having the general formula:
(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 represents ethyl or n-propyl and R2 represents (a) ethyl, n-propyl, isopropyl, isobutyl or tert-butyl when R1 is n-propyl and (b) n-butyl or isobutyl when R1 is ethyl, with the proviso that R1 and R2 simultaneously represent n-propyl only when the derivative is in the form of it acid fumarate, whenever obtained by a process according to claims 1, 2 or 4, or their obvious chemical equivalents.
(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R1 represents ethyl or n-propyl and R2 represents (a) ethyl, n-propyl, isopropyl, isobutyl or tert-butyl when R1 is n-propyl and (b) n-butyl or isobutyl when R1 is ethyl, with the proviso that R1 and R2 simultaneously represent n-propyl only when the derivative is in the form of it acid fumarate, whenever obtained by a process according to claims 1, 2 or 4, or their obvious chemical equivalents.
12. 1,1-Di-n-propyl-n-butylamine acid fumarate, whenever obtained by a process according to claims 6, 7 or 9 or their obvious chemical equivalents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA310,149A CA1056730A (en) | 1974-05-20 | 1978-08-28 | Pharmaceutical and veterinary compositions for use in the treatment of parkinson's disease and the correction of extra-pyramidal disturbances provoked by neuroleptics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE144519A BE815273A (en) | 1974-05-20 | 1974-05-20 | METHYLAMINE ACTIVE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1048549A true CA1048549A (en) | 1979-02-13 |
Family
ID=3842664
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA75227044A Expired CA1048549A (en) | 1974-05-20 | 1975-05-15 | Pharmacologically active n-butylamine derivatives and process for the preparation thereof |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS569498B2 (en) |
| AR (1) | AR208548A1 (en) |
| AT (1) | AT341488B (en) |
| BE (1) | BE815273A (en) |
| CA (1) | CA1048549A (en) |
| CH (1) | CH605606A5 (en) |
| DE (1) | DE2522218C3 (en) |
| DK (1) | DK145779C (en) |
| ES (1) | ES437790A1 (en) |
| FI (1) | FI61182C (en) |
| FR (1) | FR2271811B1 (en) |
| GB (2) | GB1467739A (en) |
| HU (1) | HU173890B (en) |
| IE (1) | IE41032B1 (en) |
| IT (1) | IT1049427B (en) |
| NL (1) | NL172120C (en) |
| NO (1) | NO139733C (en) |
| OA (1) | OA05004A (en) |
| SE (1) | SE434262B (en) |
| SU (1) | SU1292666A3 (en) |
| YU (1) | YU39318B (en) |
| ZA (1) | ZA752863B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4201725A (en) * | 1974-05-20 | 1980-05-06 | Labaz | Secondary amines |
| GR61148B (en) * | 1976-06-03 | 1978-09-27 | Labaz | Preparation process of active methylamine derivatives |
| JPS5427369A (en) * | 1977-08-01 | 1979-03-01 | Hitachi Ltd | Pattern formation method |
| FR2470758A1 (en) | 1979-12-07 | 1981-06-12 | Sanofi Sa | METHOD FOR FIXING ALKYL GROUPS ON A CARBONIC CHAIN CARRYING A FUNCTIONAL GROUP |
| NZ516888A (en) * | 1999-07-30 | 2004-02-27 | Vertex Pharma | Acyclic and cyclic amine derivatives |
| CN114235991A (en) * | 2021-11-27 | 2022-03-25 | 山东省烟台市农业科学研究院 | High performance liquid chromatography for determining sec-butylamine content |
-
1974
- 1974-05-20 ES ES437790A patent/ES437790A1/en not_active Expired
- 1974-05-20 BE BE144519A patent/BE815273A/en not_active IP Right Cessation
-
1975
- 1975-04-30 IE IE974/75A patent/IE41032B1/en unknown
- 1975-05-02 ZA ZA00752863A patent/ZA752863B/en unknown
- 1975-05-09 HU HU75LA865A patent/HU173890B/en unknown
- 1975-05-14 YU YU1226/75A patent/YU39318B/en unknown
- 1975-05-15 AT AT371575A patent/AT341488B/en not_active IP Right Cessation
- 1975-05-15 SE SE7505606A patent/SE434262B/en not_active IP Right Cessation
- 1975-05-15 FR FR7515118A patent/FR2271811B1/fr not_active Expired
- 1975-05-15 GB GB2073875A patent/GB1467739A/en not_active Expired
- 1975-05-15 CA CA75227044A patent/CA1048549A/en not_active Expired
- 1975-05-15 GB GB2833676A patent/GB1467740A/en not_active Expired
- 1975-05-16 DK DK216575A patent/DK145779C/en active
- 1975-05-16 NL NLAANVRAGE7505853,A patent/NL172120C/en not_active IP Right Cessation
- 1975-05-16 NO NO75751771A patent/NO139733C/en unknown
- 1975-05-17 OA OA55502A patent/OA05004A/en unknown
- 1975-05-19 AR AR258840A patent/AR208548A1/en active
- 1975-05-20 FI FI751468A patent/FI61182C/en not_active IP Right Cessation
- 1975-05-20 CH CH643975A patent/CH605606A5/fr not_active IP Right Cessation
- 1975-05-20 DE DE2522218A patent/DE2522218C3/en not_active Expired
- 1975-05-20 IT IT23511/75A patent/IT1049427B/en active
- 1975-05-20 JP JP6086675A patent/JPS569498B2/ja not_active Expired
-
1983
- 1983-03-25 SU SU833567049A patent/SU1292666A3/en active
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