CA1051909A - Method of obtaining 5-hydroxytryptophan glutamate and its derivates - Google Patents
Method of obtaining 5-hydroxytryptophan glutamate and its derivatesInfo
- Publication number
- CA1051909A CA1051909A CA223,874A CA223874A CA1051909A CA 1051909 A CA1051909 A CA 1051909A CA 223874 A CA223874 A CA 223874A CA 1051909 A CA1051909 A CA 1051909A
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- serotonin
- hydroxytryptophan
- glutamate
- alkaline
- tryptophan
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Abstract
A B S T R A C T
A method of obtaining 5-hydroxytryptophan glutamate or use as an antidepressant having the general formula :
A method of obtaining 5-hydroxytryptophan glutamate or use as an antidepressant having the general formula :
Description
~O ~ 9 The present invention relates to the industrial production of 5-hydroxytryptophan glutamate and its derivatives.
These compounds have the general formula;
XOOC-C}I-C112-C~12-COO HOOC-ell-CU2 N CH
wherein X is hydrogen, alkaline or alkaline-earth metals, or organic compounds of a basic character.
The general method for the synthesis of these com-pounds is based on the dissolution, jointly ox separately, ofthe acid and the base in the smallest possible quantity of a suitable solvent. This solution can be neutralized by any type of basic organic or inorganic compound, or can be used as it stands. Any of the above-mentioned solutions can be deep-frozen in order to isolate the required product.
The following example illustrates the invention which is not limited thereto.
Example : X= H
Although the reaction was carried out in various solvents, both organic and inorganic, the example to be cited is that carried out in water, since this solvent is one of the best.
1.47 g (0.01 mol) of glutamic acid (in any of its L,D
-- 1 - .~k.
7~
1051~9 or racemic forrns) together with 2.20 g (0.01 mol) of 5-hydro-xytryptophan (in any of its L, D or racemic forms) was dissolved in 100 ml of distilled water at a temperature of 35C. To promote dissolution vigorous agitation was carried out using an elec~ro-magnetic stirring means or a standard laboratory stirring means connected to a motor. The solution was filtered and the filtered liquid was freeze-dried at ambient temperature and at a pressure of 2 x 10 2 mm E~g.
The nohydrated salt, in the form of broad white needles, was obtained with a practically quantitative yield and llad a melting point of 148 - 150C.
Analysis:
Calculated for C16H2lN307-H2 C.-49.86; H.-6.01; N.-10.90 Actual: C.-50.38; H.-6.22; N.-10.74 In the view of the Applic2nt, the product obtained by this method is new, and in the specific uses for which it is intended it has the advantage of great tolerability, vigorous pharmacological activity and ready solubility in water.
L-5 hydroxytryptophan monohydrate L-glutamate is a new synthetic compound in which glutamic acid potentiates the anti-depressive action of L-5 hydroxytryptophan.
~05~909 L-5 hydroXytryptophan monohydrate L-glutamate is a new synthetic compound in which glutamic acid potentiates the antidepressive action of L-5 hydroxytryptophan.
1 - Introduction Serotonin (5~011-tryptamine) is a neurotransmitting agent principally distributed in the mesencephalon, diencepha-lon and rhinencephalon, areas which control and modulate the autonomic nervous system (H3ss, 1954; Koada~ 1951; Gloor, 1955; Pribram and Kruger, 1954). Serotonin is formed from tryptophan, which is hydroxylated into 5-OH-tryptophan, the latter bein~ decarboxylated into serotonin by tryptophan-decarboxylase. It is presently thought that the psychic tonus of a person is controlled by the level of cerebral serotonin.
The hypothesis of serotonin says that there is a direct co-relationship between serotonin deficiency in th~ brain and certain depressive syndromes. This hypothesis is based on the work of Pare and Sandler, 1959, Van Praag, 1962, and Coppen et al., 1963, who established that monoamino-oxydase inhibi-tors (products which increase the concentration of serotonin and catecholamines in the brain) can have an antidepre~sive effect.
Imipramine, as well as othor tricyclic antidepres-sive agents, exercises its effect through an increase in the eficient concentration of monoamines on the receiver level, due to the fact that it produces an incorporation blockage (uptake I) on the presynaptic membrane level. Monoamino-oxydase inhibitors produce an increase of several amines, serotonin, 1051~9 noradrenaline, adrenaline, dopamine, etc.; not all authors agree on which of these amines is responsible for ~e anti-depressive a~tion. sartonieck thinks it is the increase in serotonin, wllereas Pletscher believes it is the increase in noradrenaline. The fact that a potentiation of the antide-pressive effects of the ~O inhibitors has been observed on administering tyrptophan and 5-hydroxytrypto~han, precursors of serotonin, but not with DOPA, precursor of noradrenaline, speaks in favour of the hypothesis that it is the serotonin level which plays the most important role in depression. Electo-convulsive therapy produces an increase of cerebral serotonin in all the laboratory animal species studied except mice (Garattini and Valzelli, 1971). The serotonin levels were not affected in other organs (liver, lung, intestine). In patients submitted to electroconvulsivant treatments it was demonstrated that the serotonin concentrationin the cerebrospinal fluid was higher after the said therapy than before. Summarising the foregoing, it can be observed how all antidepressive treatments have the same operating pattern, i.e., they increase the level of cerebral serotonin. Undenfriend et al. (1957) determined that when 5-hydroxytryptophan is administered to animals, it rapidly penetrates most tissues and, if there is decarboxylase, it is converted into serotonin. Bodanski et al. (1958) succeeded in raising 10 times the level of serotonin in the brains of dogs to which this precursor had been administered.
Bazelon used 5-hydroxytryptophan as a precursor of cerebral serotonin, thus saving the step of tryptophan, which, as is known, is a limiting factor on the biosynthesis of serotonin.
Ashcroff and Sharman (1960) suggest a possible relationship between the metabolism of tryptophan and depression: the level ~05190g of "5-hydroxy-indoles" fluorimetrically estimated in the cerebrospinal fluid was significantly lower in nine patients with depressive psychosis than in ten non-depressive patients.
Depressed patients eliminate les~ quantity of tryptamine through urine during the depressive phase than after recovery (Coppen et al., 1956). Treatment with monoamino-oxydase inhibitors produces an increase in the levels of serotonin in the brains of rats; the increase becomes higher if tryptophan is administered at the same time ~i~ess and Doepfner, 1961), this fact being clinically demonstrated in patients by Coppen et al. (1963).
Persson and Roos described a case of a depressive patient in whom the administration of amitryptiline together with anti-convulsivant therapy, for two months, did not produce any positive response; however, the instauration of treatment with 5-hydroxytryptophan for 5 days (total dose 150 mg) provided a rapid improvement in the state of mind and disappearance of the depressive symptoms was observed two weeks after the said treatment. It is interesting to point out that this patient was previously treated with L-DOPA, precursor of nora-drenaline, without obtaining any result. Isamu Sano (1970) treated 107 patients in depressive phase with L-5-hydro-xytryptophan for 5 weeks in the form of tablets (20, 50 and 100 mg three times a day), the symptoms remitting so rapidly that even the patients themselves were impressed. The same author treated patients affected by Parkinson's disease with L-5-hydroxytryptophan, finding an intense antidepressive action with improvement of the affective field, of the psychomotor impulse and activation of personal initiative; he also describes a visible anti-tremor effect. Kline and Sacks (1963, 1964) administered DL-5-OH-tryptophan to depressed patients intravenously (10-50 mg), together with a monoamino-oxydase 1051~ 3 inhibitor, rindin(~ spectacular re~;ults (improvef.~e~t of ~epression in one day obtained with a r~o inhibitor and 5-OI~ tryptophan, intravenously).
I~Jith all this, we explain the operating pattern of our product; this substance raises the levels of cerebral serotonin, in a greater way than the sole administration of L-5-hydroxytryptophan, as is demonstrated by the symptomatology of the animals injected. This product has been compared with another two of the same use: tranilcypromine and imipramine.
~ -~o~icity The studies of acute toxicity have been made with I.C.R. Swiss albino mice of both sexes. We express the toxicity date with the parameters of lethal dose 16 (LD16), lethal dose 50 ~LD50) and lethal dose 84 (LD84),in mg/kg.
of weight. The substance was administered intraperitoneally.
Our Product 260.5 323 401.4 Tranilcypromine 7.3 11.3 18 Iminpramine 33.3 51.6 80 As can be seen from the foregoing table, our anti-depressive product is 300 times less toxic than tranilcypromine and 6 times less toxic than imipramine.
3 - ~ctivity a) Irwin's schema The administration of our product to female mice weighing 28 - 2 g., atthe rate of 10 mg/kg. orally, produces an increase in the state of alertness, a reaction to cleanli-ness and an increase in spontaneous activity, in addition to ~ s~
~051909 restlessness and irritability. These sy~ptoms appear rapidly, 15 minutes after its administration, and last 120 minutès at least.
Thi~ symptomatology is not observed with the separate administration of L-glutamic acid and L-S hydroxytrypto- -phan at doses equimolecular to those te~ted with our product and the pharmacological activity of the combination is therefore superior to that of each ingredient separately. Neither is this symptomatology observed with tranilcypromine and imipramine.
b) Analgesic activity Our product has proved to have a significant analgesic action with the techniques of chemical analgesia ~ -and thermal analgesia (hot plate at 55C). At the oral dose ~ ~
.~ , .: . .
of lO mg/kg. it has the same analqesic effect as dextro-propoxyphene at the intraperitoneal dose of 50 mg/kg. ~`
~ ,.. " ~ ~ , c) Antiserotoninic activity With the technique of a rat's isolated uterus ; and at the dose of 40 mcg/ml., we have found a 36% inhibition of the responses to serotonin. j Its peripheral antise,rotoninic and central analgesic ~~
activity makes our product be particularly useful in . ~
migraines. `~
4 - Indications ;~ Y
Depressive psychosis and schizophrenia.
Neurosis, i Cephaleas of mental illnesses.
Migraines.
Morphine addiction cures. :' `-- 7 - ;
: ~. . , , , " ; ,,,, "
~05~90~
L-Dopa psychosis.
~lterations of sleep.
5 - Tests comparing activities Our product is principally indicated in all types of depressions. Its operating pattern is an increase in the levels of intracerebral serotonin. There are many substances which have been used in the field of depressions, but none of them has the same operating pattern.
We give a precursor, which pierces the hematoen-cephalic barrier and is transformed into serotonin,~ in the brain.
The most conventional antidepressive agents used so far have been: ~. MAO inhibitors. The most powerful one TR~ILCYPROMINE.
Tranilcypromine It is a powerful inhibitor of non-hydraxinic MAO.
Its operating pattern is different from that of our product.
Tranilcypromine has a direct stimulating action on the central nervous system which is responsible for its antidepressive action; to the contrary, since it is a MAO inhibitor, the cerebral serotonin raising action is very inferior to our product. Although it is a powerful antidepressive agent, its clinical use requires much care because of the great amount of adverse effects and secondary reactions which have been described with its use. ~o interesting secondary reactions have yet been described with L-5-hydroxytryptophan L-glutamate, for which reason the therapeutical margin is greater and more favourable for our product.
105~9 Imipramine:- It is a tricyclic antidepressive agent which exercises its effect through an increase of the efficient concentration of noradrenaline on the receiver level, due to the fact that it produces an incorporation blockage (uptake I) on the presynaptic membrane level. Not all authors agree on which amine is responsible for the antidepressive action (serotonin or noradrenaline). Bartonieck thinks it is the increase in noradrenaline. The fact that a potentiation of the antidepressive effects of the MAO inhibitors has been observed on administering tryptophan and 5-OH tryptophan, precursors of serotonin, but not with DOPA, precursor of noradrenaline, speaks in favour of the hypothesis that it is the serotonin level which plays the most important role in depression.
For all these reasons, we deduce that L-5-hydroxy-tryptophan L-glutamate is therapeutically superior to tranilcypromine and imipramine.
lOSl~O~
AS~ICROFF, G.W. and S~I~N~, D. F. 5-llydroxyindoles in human cerebrospinal fluids . Nature, 186, 1.050 - 1.051 -~1.960) .
AXELROD, J. Metabolism and inactivatin of noradrenaline -and adrenaline ande the effect of drugs. In Pharmacology-of Cholinergic and Adrenergic Transmision. The Macmillan -Co., N. Y. 205 (1.965).
B2~Rq~ONIECK, V. Medna Pharmac. Exp. 14, 365 (1.966) .
BAZELON, M. and al. The Lancet, 1130-1133, Mayo 27 (1972) BODANSKI, D. F. WEISS BACH, H. and UNDENFRIEND, S. Phar-macological studies with the serotonin precursor, 5-OH -tryptophan, Journal of pharmac. EXP. Ther, 122, 182 - 94 -(1.958) .
COPPEN, A. SHAW, D.M. and FARRELL, J. P. Potentiation of the antidepressive effect of a monoamine-oxidase inhibition by tryptophan. Lancet 1, 79-80 (1.963) .
1051~V9 COPPEN, A. S~IAW D. M and M~LLESC~I, A. G. Changes in -5-OIi-tryptophan meta~olism in depression, British Journal of Psychiatry 111, 105-107 (1.965j.
G~RATTI~I, S. VALZELLI, I. Psychotn~c Drugs, Edited by Garattini and ~IETTI 428, Amsterdam (1.957).
II~SS, S. ~. and DOEPENER, W. ~ehavioural effects and brain amine contents in rats. Arch. int. Pharmacod. 134, 89-99-(1.961).
ISU~lU S~NO L-5-hydroxytryptophan (L-5-HTP). Therapie bei endogener Depression. Munch. med. Wschr. 114, 1713-16 --(1.972).
SAMW, S. and KAZUNI, T. , L-5-hydroxytryptophan (L-5-HTP) Therapie des Morbus. Parkinson. Munchr. med. Wschr. 114, -1717-1719 (1.972).
KLINE. N. SACKS. W. Relief of depression within one-day using an MAOI and intravenous 5-HTP. American Journal of -Psychiatry 120, 274, 275 (1.963).
KLINE, N. SACKC W. and SIMPSON G. M. Further studies an- ~ ;
one-day treatment of depression with 5-HTP. American Journal - `
of Psychiatry 121, 379-81 (1.964).
.
;`
. . ~ , ~ . . .
lOS~909 PAR~, C. M. B. and SANDLER M. A clinical and biochemical of a trial of iproniazid in the treatment of depres~ion.
J. of Neurology, Neurosurgery and Psichiatry 22, 247-251 (1 . 959 ) -PERSSON, T. and ROOS B. E. "El 5-hidroxitriptofano en-la depresion" The Lancet, 987, (1.967).
P~ETSCliER, A. Arzneimittel Forch 14, supp 479 (1.964).
PRAAG. H. M. and LEIJNSE, B. Die Bedenteng der Monoamineo xydase-tenming als antidepressives Princp. Psychopharmaco-logia 4, 1-14 (1.962).
UDENFRIEND, S. and col. Ann. N.Y. Acd. Sci 66-602 (1.957).
UDENFRIEN, S. and col. J. Brul. Chem. 224, 803 (1.957).
lOS~909 Listed below are examples of pharmaceutical compo-sitions containing as active ingredient L-5-hydroxytryptophane monohydrate L-glutamate, combined with carriers and pharma-ceutical excipients.
T~e injectable dose of this product is 75 mcg. per kg. of weight and day. The dose for an average adult will be 5 mg. daily.
The oral dose is 100 mcg. per kg. of weight and day. An average individual will be administered 7.5 mg.
daily in three doses of 2.5 mg.
EXP~IPLE 1 INJECTABLE:- Comprising a freeze-dried vial and an ampoule with solvent.
Composition of the freeze-dried vial:
L-5-hydroxytryptophane L-glutamate ............ 5 mg.
Manitol ...................................... 45 mg.
Composition of the ampoule with solvent :
Sodium chloride ............................. 27 mg.
Water for injectables, q.s.p. ................. 3 ml.
20 E.YP*IPLE 2 CAPSULES : ~Iard gelatine.
L-5-hydroxytryptophane L-glutamate ......... 2.5 mg.
Lactose ..................................... 95 mg.
Magnesium stearate ........................... 1 mg.
These compounds have the general formula;
XOOC-C}I-C112-C~12-COO HOOC-ell-CU2 N CH
wherein X is hydrogen, alkaline or alkaline-earth metals, or organic compounds of a basic character.
The general method for the synthesis of these com-pounds is based on the dissolution, jointly ox separately, ofthe acid and the base in the smallest possible quantity of a suitable solvent. This solution can be neutralized by any type of basic organic or inorganic compound, or can be used as it stands. Any of the above-mentioned solutions can be deep-frozen in order to isolate the required product.
The following example illustrates the invention which is not limited thereto.
Example : X= H
Although the reaction was carried out in various solvents, both organic and inorganic, the example to be cited is that carried out in water, since this solvent is one of the best.
1.47 g (0.01 mol) of glutamic acid (in any of its L,D
-- 1 - .~k.
7~
1051~9 or racemic forrns) together with 2.20 g (0.01 mol) of 5-hydro-xytryptophan (in any of its L, D or racemic forms) was dissolved in 100 ml of distilled water at a temperature of 35C. To promote dissolution vigorous agitation was carried out using an elec~ro-magnetic stirring means or a standard laboratory stirring means connected to a motor. The solution was filtered and the filtered liquid was freeze-dried at ambient temperature and at a pressure of 2 x 10 2 mm E~g.
The nohydrated salt, in the form of broad white needles, was obtained with a practically quantitative yield and llad a melting point of 148 - 150C.
Analysis:
Calculated for C16H2lN307-H2 C.-49.86; H.-6.01; N.-10.90 Actual: C.-50.38; H.-6.22; N.-10.74 In the view of the Applic2nt, the product obtained by this method is new, and in the specific uses for which it is intended it has the advantage of great tolerability, vigorous pharmacological activity and ready solubility in water.
L-5 hydroxytryptophan monohydrate L-glutamate is a new synthetic compound in which glutamic acid potentiates the anti-depressive action of L-5 hydroxytryptophan.
~05~909 L-5 hydroXytryptophan monohydrate L-glutamate is a new synthetic compound in which glutamic acid potentiates the antidepressive action of L-5 hydroxytryptophan.
1 - Introduction Serotonin (5~011-tryptamine) is a neurotransmitting agent principally distributed in the mesencephalon, diencepha-lon and rhinencephalon, areas which control and modulate the autonomic nervous system (H3ss, 1954; Koada~ 1951; Gloor, 1955; Pribram and Kruger, 1954). Serotonin is formed from tryptophan, which is hydroxylated into 5-OH-tryptophan, the latter bein~ decarboxylated into serotonin by tryptophan-decarboxylase. It is presently thought that the psychic tonus of a person is controlled by the level of cerebral serotonin.
The hypothesis of serotonin says that there is a direct co-relationship between serotonin deficiency in th~ brain and certain depressive syndromes. This hypothesis is based on the work of Pare and Sandler, 1959, Van Praag, 1962, and Coppen et al., 1963, who established that monoamino-oxydase inhibi-tors (products which increase the concentration of serotonin and catecholamines in the brain) can have an antidepre~sive effect.
Imipramine, as well as othor tricyclic antidepres-sive agents, exercises its effect through an increase in the eficient concentration of monoamines on the receiver level, due to the fact that it produces an incorporation blockage (uptake I) on the presynaptic membrane level. Monoamino-oxydase inhibitors produce an increase of several amines, serotonin, 1051~9 noradrenaline, adrenaline, dopamine, etc.; not all authors agree on which of these amines is responsible for ~e anti-depressive a~tion. sartonieck thinks it is the increase in serotonin, wllereas Pletscher believes it is the increase in noradrenaline. The fact that a potentiation of the antide-pressive effects of the ~O inhibitors has been observed on administering tyrptophan and 5-hydroxytrypto~han, precursors of serotonin, but not with DOPA, precursor of noradrenaline, speaks in favour of the hypothesis that it is the serotonin level which plays the most important role in depression. Electo-convulsive therapy produces an increase of cerebral serotonin in all the laboratory animal species studied except mice (Garattini and Valzelli, 1971). The serotonin levels were not affected in other organs (liver, lung, intestine). In patients submitted to electroconvulsivant treatments it was demonstrated that the serotonin concentrationin the cerebrospinal fluid was higher after the said therapy than before. Summarising the foregoing, it can be observed how all antidepressive treatments have the same operating pattern, i.e., they increase the level of cerebral serotonin. Undenfriend et al. (1957) determined that when 5-hydroxytryptophan is administered to animals, it rapidly penetrates most tissues and, if there is decarboxylase, it is converted into serotonin. Bodanski et al. (1958) succeeded in raising 10 times the level of serotonin in the brains of dogs to which this precursor had been administered.
Bazelon used 5-hydroxytryptophan as a precursor of cerebral serotonin, thus saving the step of tryptophan, which, as is known, is a limiting factor on the biosynthesis of serotonin.
Ashcroff and Sharman (1960) suggest a possible relationship between the metabolism of tryptophan and depression: the level ~05190g of "5-hydroxy-indoles" fluorimetrically estimated in the cerebrospinal fluid was significantly lower in nine patients with depressive psychosis than in ten non-depressive patients.
Depressed patients eliminate les~ quantity of tryptamine through urine during the depressive phase than after recovery (Coppen et al., 1956). Treatment with monoamino-oxydase inhibitors produces an increase in the levels of serotonin in the brains of rats; the increase becomes higher if tryptophan is administered at the same time ~i~ess and Doepfner, 1961), this fact being clinically demonstrated in patients by Coppen et al. (1963).
Persson and Roos described a case of a depressive patient in whom the administration of amitryptiline together with anti-convulsivant therapy, for two months, did not produce any positive response; however, the instauration of treatment with 5-hydroxytryptophan for 5 days (total dose 150 mg) provided a rapid improvement in the state of mind and disappearance of the depressive symptoms was observed two weeks after the said treatment. It is interesting to point out that this patient was previously treated with L-DOPA, precursor of nora-drenaline, without obtaining any result. Isamu Sano (1970) treated 107 patients in depressive phase with L-5-hydro-xytryptophan for 5 weeks in the form of tablets (20, 50 and 100 mg three times a day), the symptoms remitting so rapidly that even the patients themselves were impressed. The same author treated patients affected by Parkinson's disease with L-5-hydroxytryptophan, finding an intense antidepressive action with improvement of the affective field, of the psychomotor impulse and activation of personal initiative; he also describes a visible anti-tremor effect. Kline and Sacks (1963, 1964) administered DL-5-OH-tryptophan to depressed patients intravenously (10-50 mg), together with a monoamino-oxydase 1051~ 3 inhibitor, rindin(~ spectacular re~;ults (improvef.~e~t of ~epression in one day obtained with a r~o inhibitor and 5-OI~ tryptophan, intravenously).
I~Jith all this, we explain the operating pattern of our product; this substance raises the levels of cerebral serotonin, in a greater way than the sole administration of L-5-hydroxytryptophan, as is demonstrated by the symptomatology of the animals injected. This product has been compared with another two of the same use: tranilcypromine and imipramine.
~ -~o~icity The studies of acute toxicity have been made with I.C.R. Swiss albino mice of both sexes. We express the toxicity date with the parameters of lethal dose 16 (LD16), lethal dose 50 ~LD50) and lethal dose 84 (LD84),in mg/kg.
of weight. The substance was administered intraperitoneally.
Our Product 260.5 323 401.4 Tranilcypromine 7.3 11.3 18 Iminpramine 33.3 51.6 80 As can be seen from the foregoing table, our anti-depressive product is 300 times less toxic than tranilcypromine and 6 times less toxic than imipramine.
3 - ~ctivity a) Irwin's schema The administration of our product to female mice weighing 28 - 2 g., atthe rate of 10 mg/kg. orally, produces an increase in the state of alertness, a reaction to cleanli-ness and an increase in spontaneous activity, in addition to ~ s~
~051909 restlessness and irritability. These sy~ptoms appear rapidly, 15 minutes after its administration, and last 120 minutès at least.
Thi~ symptomatology is not observed with the separate administration of L-glutamic acid and L-S hydroxytrypto- -phan at doses equimolecular to those te~ted with our product and the pharmacological activity of the combination is therefore superior to that of each ingredient separately. Neither is this symptomatology observed with tranilcypromine and imipramine.
b) Analgesic activity Our product has proved to have a significant analgesic action with the techniques of chemical analgesia ~ -and thermal analgesia (hot plate at 55C). At the oral dose ~ ~
.~ , .: . .
of lO mg/kg. it has the same analqesic effect as dextro-propoxyphene at the intraperitoneal dose of 50 mg/kg. ~`
~ ,.. " ~ ~ , c) Antiserotoninic activity With the technique of a rat's isolated uterus ; and at the dose of 40 mcg/ml., we have found a 36% inhibition of the responses to serotonin. j Its peripheral antise,rotoninic and central analgesic ~~
activity makes our product be particularly useful in . ~
migraines. `~
4 - Indications ;~ Y
Depressive psychosis and schizophrenia.
Neurosis, i Cephaleas of mental illnesses.
Migraines.
Morphine addiction cures. :' `-- 7 - ;
: ~. . , , , " ; ,,,, "
~05~90~
L-Dopa psychosis.
~lterations of sleep.
5 - Tests comparing activities Our product is principally indicated in all types of depressions. Its operating pattern is an increase in the levels of intracerebral serotonin. There are many substances which have been used in the field of depressions, but none of them has the same operating pattern.
We give a precursor, which pierces the hematoen-cephalic barrier and is transformed into serotonin,~ in the brain.
The most conventional antidepressive agents used so far have been: ~. MAO inhibitors. The most powerful one TR~ILCYPROMINE.
Tranilcypromine It is a powerful inhibitor of non-hydraxinic MAO.
Its operating pattern is different from that of our product.
Tranilcypromine has a direct stimulating action on the central nervous system which is responsible for its antidepressive action; to the contrary, since it is a MAO inhibitor, the cerebral serotonin raising action is very inferior to our product. Although it is a powerful antidepressive agent, its clinical use requires much care because of the great amount of adverse effects and secondary reactions which have been described with its use. ~o interesting secondary reactions have yet been described with L-5-hydroxytryptophan L-glutamate, for which reason the therapeutical margin is greater and more favourable for our product.
105~9 Imipramine:- It is a tricyclic antidepressive agent which exercises its effect through an increase of the efficient concentration of noradrenaline on the receiver level, due to the fact that it produces an incorporation blockage (uptake I) on the presynaptic membrane level. Not all authors agree on which amine is responsible for the antidepressive action (serotonin or noradrenaline). Bartonieck thinks it is the increase in noradrenaline. The fact that a potentiation of the antidepressive effects of the MAO inhibitors has been observed on administering tryptophan and 5-OH tryptophan, precursors of serotonin, but not with DOPA, precursor of noradrenaline, speaks in favour of the hypothesis that it is the serotonin level which plays the most important role in depression.
For all these reasons, we deduce that L-5-hydroxy-tryptophan L-glutamate is therapeutically superior to tranilcypromine and imipramine.
lOSl~O~
AS~ICROFF, G.W. and S~I~N~, D. F. 5-llydroxyindoles in human cerebrospinal fluids . Nature, 186, 1.050 - 1.051 -~1.960) .
AXELROD, J. Metabolism and inactivatin of noradrenaline -and adrenaline ande the effect of drugs. In Pharmacology-of Cholinergic and Adrenergic Transmision. The Macmillan -Co., N. Y. 205 (1.965).
B2~Rq~ONIECK, V. Medna Pharmac. Exp. 14, 365 (1.966) .
BAZELON, M. and al. The Lancet, 1130-1133, Mayo 27 (1972) BODANSKI, D. F. WEISS BACH, H. and UNDENFRIEND, S. Phar-macological studies with the serotonin precursor, 5-OH -tryptophan, Journal of pharmac. EXP. Ther, 122, 182 - 94 -(1.958) .
COPPEN, A. SHAW, D.M. and FARRELL, J. P. Potentiation of the antidepressive effect of a monoamine-oxidase inhibition by tryptophan. Lancet 1, 79-80 (1.963) .
1051~V9 COPPEN, A. S~IAW D. M and M~LLESC~I, A. G. Changes in -5-OIi-tryptophan meta~olism in depression, British Journal of Psychiatry 111, 105-107 (1.965j.
G~RATTI~I, S. VALZELLI, I. Psychotn~c Drugs, Edited by Garattini and ~IETTI 428, Amsterdam (1.957).
II~SS, S. ~. and DOEPENER, W. ~ehavioural effects and brain amine contents in rats. Arch. int. Pharmacod. 134, 89-99-(1.961).
ISU~lU S~NO L-5-hydroxytryptophan (L-5-HTP). Therapie bei endogener Depression. Munch. med. Wschr. 114, 1713-16 --(1.972).
SAMW, S. and KAZUNI, T. , L-5-hydroxytryptophan (L-5-HTP) Therapie des Morbus. Parkinson. Munchr. med. Wschr. 114, -1717-1719 (1.972).
KLINE. N. SACKS. W. Relief of depression within one-day using an MAOI and intravenous 5-HTP. American Journal of -Psychiatry 120, 274, 275 (1.963).
KLINE, N. SACKC W. and SIMPSON G. M. Further studies an- ~ ;
one-day treatment of depression with 5-HTP. American Journal - `
of Psychiatry 121, 379-81 (1.964).
.
;`
. . ~ , ~ . . .
lOS~909 PAR~, C. M. B. and SANDLER M. A clinical and biochemical of a trial of iproniazid in the treatment of depres~ion.
J. of Neurology, Neurosurgery and Psichiatry 22, 247-251 (1 . 959 ) -PERSSON, T. and ROOS B. E. "El 5-hidroxitriptofano en-la depresion" The Lancet, 987, (1.967).
P~ETSCliER, A. Arzneimittel Forch 14, supp 479 (1.964).
PRAAG. H. M. and LEIJNSE, B. Die Bedenteng der Monoamineo xydase-tenming als antidepressives Princp. Psychopharmaco-logia 4, 1-14 (1.962).
UDENFRIEND, S. and col. Ann. N.Y. Acd. Sci 66-602 (1.957).
UDENFRIEN, S. and col. J. Brul. Chem. 224, 803 (1.957).
lOS~909 Listed below are examples of pharmaceutical compo-sitions containing as active ingredient L-5-hydroxytryptophane monohydrate L-glutamate, combined with carriers and pharma-ceutical excipients.
T~e injectable dose of this product is 75 mcg. per kg. of weight and day. The dose for an average adult will be 5 mg. daily.
The oral dose is 100 mcg. per kg. of weight and day. An average individual will be administered 7.5 mg.
daily in three doses of 2.5 mg.
EXP~IPLE 1 INJECTABLE:- Comprising a freeze-dried vial and an ampoule with solvent.
Composition of the freeze-dried vial:
L-5-hydroxytryptophane L-glutamate ............ 5 mg.
Manitol ...................................... 45 mg.
Composition of the ampoule with solvent :
Sodium chloride ............................. 27 mg.
Water for injectables, q.s.p. ................. 3 ml.
20 E.YP*IPLE 2 CAPSULES : ~Iard gelatine.
L-5-hydroxytryptophane L-glutamate ......... 2.5 mg.
Lactose ..................................... 95 mg.
Magnesium stearate ........................... 1 mg.
Claims (3)
1. A method of obtaiing 5-hydroxytryptophan glutamate having the general formula :
wherein X is hydrogen, alkaline or alkaline-earth metals, characterized in that the acid and the base are dissolved, jointly or separately in the smallest possible quantity of a suitable solvent, whereafter this solution can be neutralized with any base or used as such, the salt being deep-frozen or precipitated with a suitable solvent.
wherein X is hydrogen, alkaline or alkaline-earth metals, characterized in that the acid and the base are dissolved, jointly or separately in the smallest possible quantity of a suitable solvent, whereafter this solution can be neutralized with any base or used as such, the salt being deep-frozen or precipitated with a suitable solvent.
2. A method according to Claim 1, characterized in that the solvent used is water.
3. New industrial products consisting of 5-hydroxy-tryptophan glutamate having the general formula wherein X is hydrogen, alkaline or alkaline-earth metals when prepared according to the method of Claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA223,874A CA1051909A (en) | 1975-04-04 | 1975-04-04 | Method of obtaining 5-hydroxytryptophan glutamate and its derivates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA223,874A CA1051909A (en) | 1975-04-04 | 1975-04-04 | Method of obtaining 5-hydroxytryptophan glutamate and its derivates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1051909A true CA1051909A (en) | 1979-04-03 |
Family
ID=4102729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223,874A Expired CA1051909A (en) | 1975-04-04 | 1975-04-04 | Method of obtaining 5-hydroxytryptophan glutamate and its derivates |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1051909A (en) |
-
1975
- 1975-04-04 CA CA223,874A patent/CA1051909A/en not_active Expired
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