CA2046341A1 - Magnesium folates, process for their preparation and pharmaceutical compositions - Google Patents
Magnesium folates, process for their preparation and pharmaceutical compositionsInfo
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- CA2046341A1 CA2046341A1 CA002046341A CA2046341A CA2046341A1 CA 2046341 A1 CA2046341 A1 CA 2046341A1 CA 002046341 A CA002046341 A CA 002046341A CA 2046341 A CA2046341 A CA 2046341A CA 2046341 A1 CA2046341 A1 CA 2046341A1
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- magnesium
- folate
- folates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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Abstract
Abstract Magnesium folates, process for their preparation, pharmaceutical compositions containing such folates and therapeutical applications where their supply can advantageously correct disorders and various conditions caused by deficiencies and lack of folates. which are increasingly to be observed nowdays, especially in the elderly. Said folate is characterized in that it is based on the following two isomeric formulae (I) and (1').
(I) and (I')
(I) and (I')
Description
2 ~
WO 90/0938~ - 1 - PCT/FR90/00106 MAGNESI~M FOLATES, PROCESS FOR ~HEIR PREPARATION AND
PHARMACEUTICAL COMPOSITIONS
The present invention relates to magnesium folate~, to a process for their preparation, to S pharmaceutical compositions con~taining them and also to therapeutic applications where their supply may advantageously correct disorders and various conditions caused by de~iciencies and lack of folates, increasingly observed nowadays, especially in the elderly.
The lack of folates may have several causes and may result from malnutrition, malabsorption, increased requirements created following infection~ neoplasias, alcoholism, intestinal, hepatic or renal diseases, medications, thyrotoxicoses, systemic diseasès and the lS like. It is recognised that other factors, in particular psychological factors such as apathy, solitude, anxiety and depression may contribute to a poor diet in the elderly (MARCUS DL, FREEDMAN ML in J. Am. Geriat. Soc.
198S, 33 : 552-8). A nearly constant deficiency in the level of folates has been observed in patients admitted into gerontopsychiatric departments (ABALAN F. et al.
Encéphale 1984 ; X : 9-12). The low level of folates in the ceph~lorhachidian liquid (~.C.~.~, in the elderly in general, are also determined by alterations of the choroid plexus which may cause a decrease in the transport of water-soluble vitamins across the hemo-encephalic barrier. The lack of folates may not only induce haematological, peripheral neurological conditions but as demonstrated by some recent studies, may be the cause of neurological symptoms. While apparently no specific signs of hypofolatemia exist, behaviourial disorders in the elderly are early warning signs of folate deficiency, prevention and treatment of which are essential because this ageing symptomatology may have irreversible consequences.
Folates are a group of compounds synthetised by plants and mic:roorganisms.
The term folate is normally used to designate the various compounds of this family as a whole which 2 ~
WO 90/0938~ - 2 - PC~/FR90/00106 comprises:
- derivative~ con~ugated with glutamic acLd:
monoglutamate (folic acid) and polyglutamates;
- reduced compounds: dihydro and tetrahydro folates, e~pecially N5~formyltetrahydrofolate or even folinic acid in the form of the pentahydrate calcium salt, an active me~abolite used in clinical medicine.
Folates have important phy~iological roles. The various roles may be s~mmarised by the supply of the carbon group leading to the bio~ynthesis of most neuromediators. It thus intervenes a~ a coenzyme in ~he synthesis of all the neurotransmitterR of the dopaminergic, serotoninergic, cholinergic and adrenergic systems which dominate cerebral ~unckion, and the psychism. Folates are implicated in the synthesis of purine and pyrLmidine ba~es which con~titute nucleic acids, and consequen~ly in the protoin ~yntheses es~ential to the processes of cell renewal in the organism and to those of memorisation and vigilance.
Moreover, the intervention of folates in the synthesis of myelin and acetylcholine has bPen recognised.
Consequently, a deficiency may cause alterations in nerve conduction and interneuronal linkage and be translated into disorders a~ the le~el of the linking areas with loss of linking and structuralisation abilities. In addition, folic acid (folates) is essential for oxidative hydroxylations and, in particular for the limiting enzymes in the biosynthesis of monoamines. These different role~ may explain why folate deficiency may lead to asthenia and the tendency towards depres~ion.
These folates therefore appear as es~ential vitamins which are widely present in a number of foodstuffs, in particular fresh vegetables and liver, but which are easily destroyed.
Their deficiency was mainly known to produce anaemia, in particular in pregnant women, in alcoholics and in epileptics receiving phenytoin.
Several processes are known for preparing folic acid (pteroylglutamic acid) and in particular tha~
2 ~ t~
Wo 90/09382 - 3 - PC~/FR90/00106 described in Patent US 2 956 057, which make~ it poqsible to obtain a good yield by conclensLng 2,4,5-tr amino-6-hydroxypyrimidine with p-amirlobenzoylglutamic acid and a suitable haloacetone, in the presence of a reducing agent.
Patent US 2 786 056 which describes another process for preparing folic acid and novel intermediates for its preparation, is also known.
This patent describes a process for preparing 2-acylamino-4-hydroxy-6-di-R-methylpteridine by reacting a 2-amino-4-hydroxy-6-di-R with an alkylating agen-t and a proceqs for preparing 2-acylamino-4-hydroxy-6-formylpteridine by bringing a 2-acylamino-4-hydroxy-6-di-R-methylpteridine into contact with a hydrolysing agent.
Several processes for preparing 5-formyl-5,6,7,8-tetrahydrofolate or folinic acid are also known. Patent US 2 741 608 describes a process which comprises formylation and hydrogenation of pteroic acid compounds and then bringing the pH of the compound obtained to not less than 5. Thi~ patent specifie~ that the compounds obtained by this process exhibit a growth factor activity in microbiological tests.
These various patents specify ~he use of these derivatives especially during macrocytic anaemia, sprue and during other conditionq of the circulatory sys~eM.
A calcium salt of folinic acid, calcium folinate, is used as antidote for folic acid inhibitors such as methotrexate; during a symposium (20 March 1987), it was shown that the lack of folate~ in the elderly presenting behav.iourial disorders typical of depre sion and dementia could be corrected by parenteral administration o calcium folinate.
For its part, magnesium is recognised a a cation whose role is very important in the normal functioning of cells, transmission of nerve impulse, muscle contraction, antibody formation and the action of numerous enzymes~ It is involved especially in the synthesis of neuromediators, in storage processes and in the efficacy at receptor level. Lack of folates may be translated into the appearance of fatigue, cramps, anxie~y, hyperemotivity, palpi~ations and muscular pain.
The folates according to the prior art exhibit several disadvantage~:
. calcium folinate, which has been used in the elderly, may produce hypercalcifications due to the high supply of calcium;
folinic acid and its salt, calcium folinate, have a high cost price;
. it would be tempting to u~e several medicinal products, especially folic acid on the one hand and a magnesium derivative on the other hand; how~ver, their separate use has a number of disadvantages: the risk, especially in the elderly, of a decrease in compliance, no or very little synergistic action between the various medicinal products, which therefore does not allow the desired result to be obtained.
Consequently, the aim of the Applicant was to provide novel folates which better address the raquirements of practical u~e from the point o~ view of the undesirable effects, the preparation process, simplicity and low cost as well as compliance.
The aim of the invention is also to provide pharmaceutical composi~ions containing at least one o~
the said folates, alone or a combination with other active ingredients.
The subject of the present invention is a folate, characterised in that it correspond to one of the following two isomeric formulae (I) and (I'):
N ~ ~ N ~ CH2_N ~ C0-NH-CH-C00 0 R~ ~CH2)-coo ~ . _ .
¦ H
IH N ~ Nl ~ N ~ Mg2 ~ I CH2 NH ~3 CO-NH-CH-C00 ,~.
¦ OH R2 2 2 .
in which Rl represents a hydrogen atom, a lower alkyl group or a bond between the carbon in the 7 position and the nitrogen in the 8 position;
R2 represents a hydrogen atom, a CHO group or a bond be~ween the ni~rogen in the 5 position and the carbon in the 6 po ition;
and the two terminal free carboxylic acid functions are salified by magnesium.
These two biological elements which are essential to the organism (folate and magnesium), combined in salt form, exhibit a synergistic action, especially at the neurotransmitter level, the said salt thus making it possible to effectively combat the lack of these two 15 elements, especially in the elderly, while permitting : good compliance and avoiding a supply of unwanted calcium.
Magnesium folates exhibit a number of advantages relative to prior art products, their usefulness depends 20 especially on the biological properties arising from the synergy between the two constituent elements of the compound thus defined for combatting, in particular deficiency disorders found in individuals with a ' ~
W0 90/09382 - 6 - PCT/FR98~0glO~
deficiency, especially in geriatric patients, with the known but also poorly de~ined or even sometimes unsuspected consequences which they may cause. It is therefore a ma~ter of trying to re-establish the equilibrium which is disrupted by nutritional or absorption deficiencies or is a result of some organic or metabolic diseases which may cause askhenia, depres~ive behaviour, cramp, paraesthesia, fasciculation as well as other ensuing pathologies.
Among the folates conforming to the in~ention, there may be mentioned, preferably, the magne~ium salt of dihydrofolic acid, the magnesium salt of tetrahydrofolic acid and the magnesium salt o N5-formyltetrahydrofolic acid.
lS The subject of the present invention is also a process for preparing magnesium folates conforming to the in~ention, characterised by the following stages:
l - preparation of an alkali metal salt of the compound of formula A or its isomer of formula B, below:
H2N~N ~\CH2 -NUr~CO -N H--CH-COO
o R2 (C~2)-COO
and R
H N ~ N.l ~ N ~
CH 2 - N}~~ CO- NH- C H-COO
OHR2 ~ CEI2 ) -COO
2 - condensatlon of the alkali metal salt of the compound of formula A or the compound of formula B
~ J~
formed, with a magnesium halide in equ~nolecular quanti-ties, 3 - removal of the soluble alkali metal halide formed, 4 - successive washings and drying of the magnesium folate precipitate ol~ed.
The subject of the preslent invention i~ also a pharmaceutical composition, characterised in that it comprises at least one magnesium folate conforming to the invention, optionally combined with water-soluble vitamins of the B group and~or with lecithin, the said composition being in addition, optionally combined with at least one pharmaceutically acceptable vehicle.
The magnesium folates may be administered by the oral or parenteral route, but the oral route i5 preferred; the daily dose is in the range of S to 20 mg but this may be altered depending on requirements, given the absence of toxicity of the product.
When it is advantageously combined with the water-soluble vitamins of the B group such as vitamins Bl, B2, B6, PP and/or with compounds such as lecithin, it makes it possible to improve the various disorders mentioned above, which are more or less pronounced in the elderly with a dPficiency. Indeed, in the elderly, the food ration is wrongly reduced in quantity for numerous reasons: psychic, psychological and ~ocioeconomical but also as a re~ult of malabsorption and even of increased requirements. Compensation hecomes essential because the many clinical repercussions are all the more serious because they occur in a particularly fragile group, whose defences have physiologically diminished.
Magnesium folate may be provided in all the usual pharmaceutical forms for administration by the oral or parenteral routes. However, it will be preferably administered by the oral route and will be provided in the form of tablets, sugared pills, or hard capsules.
Combined with water-soluble vitamins and/or with lecithin in defined proportions, it will be provided advantageously in protected forms which will avoid 3 1~:
Wo 90/09382 - 8 - PCT/FR90/00106 po~sible oxidation or degradation of the active ingredients.
Inert agents and preser~ative~ may be added to magnesium folate alone or its compositions in order to allow their preparation by well known pharmaceutical proce~ses such as simple mixing, compres~ing, grinding of the constituents and the like.
In addition to the preceding provisions, the invention furthermore comprise~ other provisions which will emerge from the following de~cription which refers to an example of implementati.on of the procesa, to examples of formulation of the compositions con~orming to the present invention as well as to reports of experimentations relating to the therapeukic activity of the said compositions.
It should be clearly understood however that these examples are given solely as illustration of the subject of the invention and do not constitute in any manner a lLmitation thereof.
Example 1: Preparation of a magnesium folate . Dissolve 2.21 g of folic acid (MM 442, or 1/200 mol) in lO ml of a normal solution of sodium bicarbonate (0.84 g of NaHCO3), and then add lO ml of distilled water.
A light yellow solution of disodium folate is obtained ~5 (solution A3.
. Prepare, on the other hand, a solution containing lJ200 mol of magnesium bromide by dissolvin~
1.46 g of MgBr2 in 10 ml of distilled water and then add 30 ml of methyl ethyl ketone Isolution B).
. Slowly introduce solution A (disodium folate) into solution B (magne~ium bromide) with vigorous stirring.
A light yellow crystalline precipitate is formed immediately after the beginning of the addition.
Continue the addition while maintaining stirring and slightly warm the reaction mass in a water bath (between 30 and 40C). ~llow to stand for about one hour at the end of the addition~ In order to complete ~he formation of magnesium folate, reheat the mixture in a 2~3,~
boiling water bath fer one hour with stirring.
~ Cool and then recover the precipitate formed by spinning.
Dry in a ventilated oven.
. 2.30 g of magnasium folate are recovered which have the form of fine yellow-orange crystals which are insoluble in most organic solven~s and very slightly soluble in water.
The sodium bromide formed during the reaction is soluble in water in the proportion of l g for 1.10 ml of water. It is completely removed in the spinning mother liquors (water ~ methyl ethyl ketone).
Physicochemical characteristics of magnesium folate:
- elemental analysis C, H, N, O, Mg . calculated : C = 42.97%; H = 5.44%; N = 18.33%;
Mg = 4.55~;
found : C = 42.11%; H = 3.27%; N - 18.96%; Mg = 4.92%;
- Imperial formula : C1gH17N7O8Mg, 4H2O;
- MM . 535.72 - W spectrum : magnesium folate (in a 0.1 %
solution o~ 0.lN NaOH):
~ max. = 219 nm 256 nm 285 nm 368 nm Example 2 s Pharmaceutical composition Thiamine hydrochloride (vit B1~ : 5 mg Riboflavin phosphate ~vit B2) : 5 mg Pyridoxine hydrochloride (~it B6) : 2.5 mg Nicotinamide (vit PP) : 10.0 mg Magnesium folate : 2.5 mg Lecithin : 50.00 mg Excipient : aerosil, Mg carbonate, Mg stearate Q.S. 150 mg for a No. 3 hard capsule, coated with a gastro-reRistant resin of the ~ ~ ~ $ r~
WO 90/09382 - 10 - PCI'/FR90/00106 cellulose acetoph~halate type.
Dosage 2 per day, preferably in the morning, may be increased up to 6 per day (3 x 2).
Pharmacological tests Example A
PORSOL~ test or ~despairin~ behaviour~ test described by PORSO~T R.D. et al. in European Journal of Pharmacology (1978).
This test consists in inducing a depres~ive ~tate in rat-~.
Expèrimental procedure - The anLmal is placed in a cylinder (height :
40 cm, diameter : 18 cm) filled with lukewarm water (25C) up to 20 cm, and from which it cannot escape; the animal swims for some time and then adopts a very speciic immobile at~itude~ it remains at the surface and floats but no longer moves. The a~ministration of "antidepre~sants~ corrects this depressive state enabling a resumption in activity (that is to say a decrea~e in the time of immobility "Ti").
- In this study, magnesium folate (F.Mg) was studied in comparison with folic acid (AF)o The experiment was carried out on an homogeneous lot of Long Evans male rats weighing 480 ~ 10 g, aged 9 month~.
AF and F.Mg are suspended in a 5% solution of gum arabic.
The administration is carried out per os one hour before the test in a constant volume of 0.1 ml/100 g of rat.
The animals are ~eparated into 4 groups:
- control group: number of rats, n = 10; they receive gum arabic - group No. 1 : n = 10; they receive A.F. in a dose of 1 mgl}cg - group No. 2 : n = 10; they receive F.Mg in a dose of 1 mg~}cg WO 90/09382 ~ PCT/F~9~0~0~
- group No. 3 . n = lO; they receive F.Mg in a dose of 0.5 mg/kg.
Results and_comments The mean value~ of time o~ immobility Ti for each group are expressed in Table I below. By comparing the mean time of immobility (Ti in seconds) in each group, it can be seen that the animals treated with AE
and F.Mg are able to restore swimming, that is to say to behave like those that are treated with antidepressants.
The animals treated with magnee~ium folate (F.Mg) have a signi~icantly lower Ti than that of those treated with folic acid tA.F.).
The Student's t test is used in Table II below to check if these differences are ~iqnificant, that is to say the two means mA and m~ observed for nA and n~ values are compared and the value "t" found gives the level of significance.
It is ound that the differences control animals/animals treated with F.Mg at doses of 0.5 and mg/kg are significant (p s 0.001 at the 2 doses).
The same applies for the animals treated with AF
but to a lesser degree (p ~ 0.01).
The efficacy of F.Mg is thus demonstrated. It is also possible to determine the most e~feckive dose of F.Mg and ko differentiate between AF and F.Mg (p ~ 0.01).
TABLE I
._ _ , . _ Control AP lmg/kg FMg 0.5mg/kg FMg lmg/kg Ti (s) Ti (s) Ti (s) Ti (s) _ ~ ~ _ -m 254.3 205.2 172.4 177.7 ET 9.38 44.04 19.93 27.85 . _ _ __ _ ~.___ . ...
35StM 2.97 13.93 8.91 8.81 WO 90/09382 - 12 - PCT/F~
~E II
. .____ . _ .
T/FMg T/F~g T/AF AFlmg/kg/FM~
0.5 mg/kg lmg/kg lmg/kg 0.5 mg/kg S , _ ~
t 8.72 8.:24 3.45 1.983 . _ . . .... ,._ number 15 20 20 15 ~ .,__ _ . _._ , __ P ,__ O . 001 O . 001 O . 01 O . 1 Example B : Toxicology 1. Acute toxicity (investigation of the lethal dose 50) The ~tudy i5 carried out on female IOPS mice of a mean weight of about 4a g, obtained from IFA CREDO. The animals are obser~ed for one week.
Dose studied Numbers 100 mg/kg n = 8 300 m~/kg n = 4 500 mg/kg n = 5 1 g/kg n = 4 2 g/kg n = 5 4 g/kg n = 5 F.Mg is administered by the oral route in suspension in a 5~ solution of gum arabic in an amount of 0.2 ml/100 g. A single do~e is used in all cases. No death was observed under these conditions.
2. Subacu~ xl~LEy (3 weeks~
The study is carried out on male and female Wistar Rats aged 2 months of an average weight of 350 g (C~) and 2~0 c3 ( ~) obtained from C.E.R. Janvier.
The animals are observed for one month.
. F.Mg is studied at the dose of 0.5 mg/kg/day/per os in 10 males and 10 females and also at no 90/09382 - 13 - PCT/FR9~
the dose of 10 mg/kg/day/per os Ln 10 male~ and 10 females.
F.Mg is admini~tered by the oral route in suspen~ion in a 5% solution of gl~ arabic in an amount of 0.2 ml/100 g. The duration of treatment is 3 weaks and administration is once per day.
Under these conditions, no death or particular signs were observed. The development of body weight wa~
normal.
As evident from the above, the invention i5 not in the least limited to the implementations, embodiments and applications which have ~ust been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of a specialist in thi~ ~ield without departing rom the area or the scope of the present invention.
WO 90/0938~ - 1 - PCT/FR90/00106 MAGNESI~M FOLATES, PROCESS FOR ~HEIR PREPARATION AND
PHARMACEUTICAL COMPOSITIONS
The present invention relates to magnesium folate~, to a process for their preparation, to S pharmaceutical compositions con~taining them and also to therapeutic applications where their supply may advantageously correct disorders and various conditions caused by de~iciencies and lack of folates, increasingly observed nowadays, especially in the elderly.
The lack of folates may have several causes and may result from malnutrition, malabsorption, increased requirements created following infection~ neoplasias, alcoholism, intestinal, hepatic or renal diseases, medications, thyrotoxicoses, systemic diseasès and the lS like. It is recognised that other factors, in particular psychological factors such as apathy, solitude, anxiety and depression may contribute to a poor diet in the elderly (MARCUS DL, FREEDMAN ML in J. Am. Geriat. Soc.
198S, 33 : 552-8). A nearly constant deficiency in the level of folates has been observed in patients admitted into gerontopsychiatric departments (ABALAN F. et al.
Encéphale 1984 ; X : 9-12). The low level of folates in the ceph~lorhachidian liquid (~.C.~.~, in the elderly in general, are also determined by alterations of the choroid plexus which may cause a decrease in the transport of water-soluble vitamins across the hemo-encephalic barrier. The lack of folates may not only induce haematological, peripheral neurological conditions but as demonstrated by some recent studies, may be the cause of neurological symptoms. While apparently no specific signs of hypofolatemia exist, behaviourial disorders in the elderly are early warning signs of folate deficiency, prevention and treatment of which are essential because this ageing symptomatology may have irreversible consequences.
Folates are a group of compounds synthetised by plants and mic:roorganisms.
The term folate is normally used to designate the various compounds of this family as a whole which 2 ~
WO 90/0938~ - 2 - PC~/FR90/00106 comprises:
- derivative~ con~ugated with glutamic acLd:
monoglutamate (folic acid) and polyglutamates;
- reduced compounds: dihydro and tetrahydro folates, e~pecially N5~formyltetrahydrofolate or even folinic acid in the form of the pentahydrate calcium salt, an active me~abolite used in clinical medicine.
Folates have important phy~iological roles. The various roles may be s~mmarised by the supply of the carbon group leading to the bio~ynthesis of most neuromediators. It thus intervenes a~ a coenzyme in ~he synthesis of all the neurotransmitterR of the dopaminergic, serotoninergic, cholinergic and adrenergic systems which dominate cerebral ~unckion, and the psychism. Folates are implicated in the synthesis of purine and pyrLmidine ba~es which con~titute nucleic acids, and consequen~ly in the protoin ~yntheses es~ential to the processes of cell renewal in the organism and to those of memorisation and vigilance.
Moreover, the intervention of folates in the synthesis of myelin and acetylcholine has bPen recognised.
Consequently, a deficiency may cause alterations in nerve conduction and interneuronal linkage and be translated into disorders a~ the le~el of the linking areas with loss of linking and structuralisation abilities. In addition, folic acid (folates) is essential for oxidative hydroxylations and, in particular for the limiting enzymes in the biosynthesis of monoamines. These different role~ may explain why folate deficiency may lead to asthenia and the tendency towards depres~ion.
These folates therefore appear as es~ential vitamins which are widely present in a number of foodstuffs, in particular fresh vegetables and liver, but which are easily destroyed.
Their deficiency was mainly known to produce anaemia, in particular in pregnant women, in alcoholics and in epileptics receiving phenytoin.
Several processes are known for preparing folic acid (pteroylglutamic acid) and in particular tha~
2 ~ t~
Wo 90/09382 - 3 - PC~/FR90/00106 described in Patent US 2 956 057, which make~ it poqsible to obtain a good yield by conclensLng 2,4,5-tr amino-6-hydroxypyrimidine with p-amirlobenzoylglutamic acid and a suitable haloacetone, in the presence of a reducing agent.
Patent US 2 786 056 which describes another process for preparing folic acid and novel intermediates for its preparation, is also known.
This patent describes a process for preparing 2-acylamino-4-hydroxy-6-di-R-methylpteridine by reacting a 2-amino-4-hydroxy-6-di-R with an alkylating agen-t and a proceqs for preparing 2-acylamino-4-hydroxy-6-formylpteridine by bringing a 2-acylamino-4-hydroxy-6-di-R-methylpteridine into contact with a hydrolysing agent.
Several processes for preparing 5-formyl-5,6,7,8-tetrahydrofolate or folinic acid are also known. Patent US 2 741 608 describes a process which comprises formylation and hydrogenation of pteroic acid compounds and then bringing the pH of the compound obtained to not less than 5. Thi~ patent specifie~ that the compounds obtained by this process exhibit a growth factor activity in microbiological tests.
These various patents specify ~he use of these derivatives especially during macrocytic anaemia, sprue and during other conditionq of the circulatory sys~eM.
A calcium salt of folinic acid, calcium folinate, is used as antidote for folic acid inhibitors such as methotrexate; during a symposium (20 March 1987), it was shown that the lack of folate~ in the elderly presenting behav.iourial disorders typical of depre sion and dementia could be corrected by parenteral administration o calcium folinate.
For its part, magnesium is recognised a a cation whose role is very important in the normal functioning of cells, transmission of nerve impulse, muscle contraction, antibody formation and the action of numerous enzymes~ It is involved especially in the synthesis of neuromediators, in storage processes and in the efficacy at receptor level. Lack of folates may be translated into the appearance of fatigue, cramps, anxie~y, hyperemotivity, palpi~ations and muscular pain.
The folates according to the prior art exhibit several disadvantage~:
. calcium folinate, which has been used in the elderly, may produce hypercalcifications due to the high supply of calcium;
folinic acid and its salt, calcium folinate, have a high cost price;
. it would be tempting to u~e several medicinal products, especially folic acid on the one hand and a magnesium derivative on the other hand; how~ver, their separate use has a number of disadvantages: the risk, especially in the elderly, of a decrease in compliance, no or very little synergistic action between the various medicinal products, which therefore does not allow the desired result to be obtained.
Consequently, the aim of the Applicant was to provide novel folates which better address the raquirements of practical u~e from the point o~ view of the undesirable effects, the preparation process, simplicity and low cost as well as compliance.
The aim of the invention is also to provide pharmaceutical composi~ions containing at least one o~
the said folates, alone or a combination with other active ingredients.
The subject of the present invention is a folate, characterised in that it correspond to one of the following two isomeric formulae (I) and (I'):
N ~ ~ N ~ CH2_N ~ C0-NH-CH-C00 0 R~ ~CH2)-coo ~ . _ .
¦ H
IH N ~ Nl ~ N ~ Mg2 ~ I CH2 NH ~3 CO-NH-CH-C00 ,~.
¦ OH R2 2 2 .
in which Rl represents a hydrogen atom, a lower alkyl group or a bond between the carbon in the 7 position and the nitrogen in the 8 position;
R2 represents a hydrogen atom, a CHO group or a bond be~ween the ni~rogen in the 5 position and the carbon in the 6 po ition;
and the two terminal free carboxylic acid functions are salified by magnesium.
These two biological elements which are essential to the organism (folate and magnesium), combined in salt form, exhibit a synergistic action, especially at the neurotransmitter level, the said salt thus making it possible to effectively combat the lack of these two 15 elements, especially in the elderly, while permitting : good compliance and avoiding a supply of unwanted calcium.
Magnesium folates exhibit a number of advantages relative to prior art products, their usefulness depends 20 especially on the biological properties arising from the synergy between the two constituent elements of the compound thus defined for combatting, in particular deficiency disorders found in individuals with a ' ~
W0 90/09382 - 6 - PCT/FR98~0glO~
deficiency, especially in geriatric patients, with the known but also poorly de~ined or even sometimes unsuspected consequences which they may cause. It is therefore a ma~ter of trying to re-establish the equilibrium which is disrupted by nutritional or absorption deficiencies or is a result of some organic or metabolic diseases which may cause askhenia, depres~ive behaviour, cramp, paraesthesia, fasciculation as well as other ensuing pathologies.
Among the folates conforming to the in~ention, there may be mentioned, preferably, the magne~ium salt of dihydrofolic acid, the magnesium salt of tetrahydrofolic acid and the magnesium salt o N5-formyltetrahydrofolic acid.
lS The subject of the present invention is also a process for preparing magnesium folates conforming to the in~ention, characterised by the following stages:
l - preparation of an alkali metal salt of the compound of formula A or its isomer of formula B, below:
H2N~N ~\CH2 -NUr~CO -N H--CH-COO
o R2 (C~2)-COO
and R
H N ~ N.l ~ N ~
CH 2 - N}~~ CO- NH- C H-COO
OHR2 ~ CEI2 ) -COO
2 - condensatlon of the alkali metal salt of the compound of formula A or the compound of formula B
~ J~
formed, with a magnesium halide in equ~nolecular quanti-ties, 3 - removal of the soluble alkali metal halide formed, 4 - successive washings and drying of the magnesium folate precipitate ol~ed.
The subject of the preslent invention i~ also a pharmaceutical composition, characterised in that it comprises at least one magnesium folate conforming to the invention, optionally combined with water-soluble vitamins of the B group and~or with lecithin, the said composition being in addition, optionally combined with at least one pharmaceutically acceptable vehicle.
The magnesium folates may be administered by the oral or parenteral route, but the oral route i5 preferred; the daily dose is in the range of S to 20 mg but this may be altered depending on requirements, given the absence of toxicity of the product.
When it is advantageously combined with the water-soluble vitamins of the B group such as vitamins Bl, B2, B6, PP and/or with compounds such as lecithin, it makes it possible to improve the various disorders mentioned above, which are more or less pronounced in the elderly with a dPficiency. Indeed, in the elderly, the food ration is wrongly reduced in quantity for numerous reasons: psychic, psychological and ~ocioeconomical but also as a re~ult of malabsorption and even of increased requirements. Compensation hecomes essential because the many clinical repercussions are all the more serious because they occur in a particularly fragile group, whose defences have physiologically diminished.
Magnesium folate may be provided in all the usual pharmaceutical forms for administration by the oral or parenteral routes. However, it will be preferably administered by the oral route and will be provided in the form of tablets, sugared pills, or hard capsules.
Combined with water-soluble vitamins and/or with lecithin in defined proportions, it will be provided advantageously in protected forms which will avoid 3 1~:
Wo 90/09382 - 8 - PCT/FR90/00106 po~sible oxidation or degradation of the active ingredients.
Inert agents and preser~ative~ may be added to magnesium folate alone or its compositions in order to allow their preparation by well known pharmaceutical proce~ses such as simple mixing, compres~ing, grinding of the constituents and the like.
In addition to the preceding provisions, the invention furthermore comprise~ other provisions which will emerge from the following de~cription which refers to an example of implementati.on of the procesa, to examples of formulation of the compositions con~orming to the present invention as well as to reports of experimentations relating to the therapeukic activity of the said compositions.
It should be clearly understood however that these examples are given solely as illustration of the subject of the invention and do not constitute in any manner a lLmitation thereof.
Example 1: Preparation of a magnesium folate . Dissolve 2.21 g of folic acid (MM 442, or 1/200 mol) in lO ml of a normal solution of sodium bicarbonate (0.84 g of NaHCO3), and then add lO ml of distilled water.
A light yellow solution of disodium folate is obtained ~5 (solution A3.
. Prepare, on the other hand, a solution containing lJ200 mol of magnesium bromide by dissolvin~
1.46 g of MgBr2 in 10 ml of distilled water and then add 30 ml of methyl ethyl ketone Isolution B).
. Slowly introduce solution A (disodium folate) into solution B (magne~ium bromide) with vigorous stirring.
A light yellow crystalline precipitate is formed immediately after the beginning of the addition.
Continue the addition while maintaining stirring and slightly warm the reaction mass in a water bath (between 30 and 40C). ~llow to stand for about one hour at the end of the addition~ In order to complete ~he formation of magnesium folate, reheat the mixture in a 2~3,~
boiling water bath fer one hour with stirring.
~ Cool and then recover the precipitate formed by spinning.
Dry in a ventilated oven.
. 2.30 g of magnasium folate are recovered which have the form of fine yellow-orange crystals which are insoluble in most organic solven~s and very slightly soluble in water.
The sodium bromide formed during the reaction is soluble in water in the proportion of l g for 1.10 ml of water. It is completely removed in the spinning mother liquors (water ~ methyl ethyl ketone).
Physicochemical characteristics of magnesium folate:
- elemental analysis C, H, N, O, Mg . calculated : C = 42.97%; H = 5.44%; N = 18.33%;
Mg = 4.55~;
found : C = 42.11%; H = 3.27%; N - 18.96%; Mg = 4.92%;
- Imperial formula : C1gH17N7O8Mg, 4H2O;
- MM . 535.72 - W spectrum : magnesium folate (in a 0.1 %
solution o~ 0.lN NaOH):
~ max. = 219 nm 256 nm 285 nm 368 nm Example 2 s Pharmaceutical composition Thiamine hydrochloride (vit B1~ : 5 mg Riboflavin phosphate ~vit B2) : 5 mg Pyridoxine hydrochloride (~it B6) : 2.5 mg Nicotinamide (vit PP) : 10.0 mg Magnesium folate : 2.5 mg Lecithin : 50.00 mg Excipient : aerosil, Mg carbonate, Mg stearate Q.S. 150 mg for a No. 3 hard capsule, coated with a gastro-reRistant resin of the ~ ~ ~ $ r~
WO 90/09382 - 10 - PCI'/FR90/00106 cellulose acetoph~halate type.
Dosage 2 per day, preferably in the morning, may be increased up to 6 per day (3 x 2).
Pharmacological tests Example A
PORSOL~ test or ~despairin~ behaviour~ test described by PORSO~T R.D. et al. in European Journal of Pharmacology (1978).
This test consists in inducing a depres~ive ~tate in rat-~.
Expèrimental procedure - The anLmal is placed in a cylinder (height :
40 cm, diameter : 18 cm) filled with lukewarm water (25C) up to 20 cm, and from which it cannot escape; the animal swims for some time and then adopts a very speciic immobile at~itude~ it remains at the surface and floats but no longer moves. The a~ministration of "antidepre~sants~ corrects this depressive state enabling a resumption in activity (that is to say a decrea~e in the time of immobility "Ti").
- In this study, magnesium folate (F.Mg) was studied in comparison with folic acid (AF)o The experiment was carried out on an homogeneous lot of Long Evans male rats weighing 480 ~ 10 g, aged 9 month~.
AF and F.Mg are suspended in a 5% solution of gum arabic.
The administration is carried out per os one hour before the test in a constant volume of 0.1 ml/100 g of rat.
The animals are ~eparated into 4 groups:
- control group: number of rats, n = 10; they receive gum arabic - group No. 1 : n = 10; they receive A.F. in a dose of 1 mgl}cg - group No. 2 : n = 10; they receive F.Mg in a dose of 1 mg~}cg WO 90/09382 ~ PCT/F~9~0~0~
- group No. 3 . n = lO; they receive F.Mg in a dose of 0.5 mg/kg.
Results and_comments The mean value~ of time o~ immobility Ti for each group are expressed in Table I below. By comparing the mean time of immobility (Ti in seconds) in each group, it can be seen that the animals treated with AE
and F.Mg are able to restore swimming, that is to say to behave like those that are treated with antidepressants.
The animals treated with magnee~ium folate (F.Mg) have a signi~icantly lower Ti than that of those treated with folic acid tA.F.).
The Student's t test is used in Table II below to check if these differences are ~iqnificant, that is to say the two means mA and m~ observed for nA and n~ values are compared and the value "t" found gives the level of significance.
It is ound that the differences control animals/animals treated with F.Mg at doses of 0.5 and mg/kg are significant (p s 0.001 at the 2 doses).
The same applies for the animals treated with AF
but to a lesser degree (p ~ 0.01).
The efficacy of F.Mg is thus demonstrated. It is also possible to determine the most e~feckive dose of F.Mg and ko differentiate between AF and F.Mg (p ~ 0.01).
TABLE I
._ _ , . _ Control AP lmg/kg FMg 0.5mg/kg FMg lmg/kg Ti (s) Ti (s) Ti (s) Ti (s) _ ~ ~ _ -m 254.3 205.2 172.4 177.7 ET 9.38 44.04 19.93 27.85 . _ _ __ _ ~.___ . ...
35StM 2.97 13.93 8.91 8.81 WO 90/09382 - 12 - PCT/F~
~E II
. .____ . _ .
T/FMg T/F~g T/AF AFlmg/kg/FM~
0.5 mg/kg lmg/kg lmg/kg 0.5 mg/kg S , _ ~
t 8.72 8.:24 3.45 1.983 . _ . . .... ,._ number 15 20 20 15 ~ .,__ _ . _._ , __ P ,__ O . 001 O . 001 O . 01 O . 1 Example B : Toxicology 1. Acute toxicity (investigation of the lethal dose 50) The ~tudy i5 carried out on female IOPS mice of a mean weight of about 4a g, obtained from IFA CREDO. The animals are obser~ed for one week.
Dose studied Numbers 100 mg/kg n = 8 300 m~/kg n = 4 500 mg/kg n = 5 1 g/kg n = 4 2 g/kg n = 5 4 g/kg n = 5 F.Mg is administered by the oral route in suspension in a 5~ solution of gum arabic in an amount of 0.2 ml/100 g. A single do~e is used in all cases. No death was observed under these conditions.
2. Subacu~ xl~LEy (3 weeks~
The study is carried out on male and female Wistar Rats aged 2 months of an average weight of 350 g (C~) and 2~0 c3 ( ~) obtained from C.E.R. Janvier.
The animals are observed for one month.
. F.Mg is studied at the dose of 0.5 mg/kg/day/per os in 10 males and 10 females and also at no 90/09382 - 13 - PCT/FR9~
the dose of 10 mg/kg/day/per os Ln 10 male~ and 10 females.
F.Mg is admini~tered by the oral route in suspen~ion in a 5% solution of gl~ arabic in an amount of 0.2 ml/100 g. The duration of treatment is 3 weaks and administration is once per day.
Under these conditions, no death or particular signs were observed. The development of body weight wa~
normal.
As evident from the above, the invention i5 not in the least limited to the implementations, embodiments and applications which have ~ust been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of a specialist in thi~ ~ield without departing rom the area or the scope of the present invention.
Claims (6)
1. Folate, characterised in that it corresponds to one of the following two isomeric formulae (I) and (I')s (I) (I ') in which R1 represents a hydrogen atom, a lower alkyl group or a bond between the carbon in the 7 position and the nitrogen in the 8 position;
R2 represents a hydrogen atom, or a bond between the nitrogen in the 5 position and the carbon in the 6 position;
and the two terminal free carboxylic acid REPLACEMENT SHEET
functions are salified by magnesium.
R2 represents a hydrogen atom, or a bond between the nitrogen in the 5 position and the carbon in the 6 position;
and the two terminal free carboxylic acid REPLACEMENT SHEET
functions are salified by magnesium.
2. Folate according to Claim 1, characterised in that it consists of the magnesium salt of dihydrofolic acid.
3. Folate according to Claim 1, characterised in that it consists of the magnesium salt of tetrahydrofolic acid.
4. Process for preparing the folate according to Claim 1, characterised by the following stages:
1 - preparation of an alkali metal salt of the compound of formula A or its isomer of formula B, below:
(A) and (B) 2 - condensation of the alkali metal salt of the compound of formula A or the compound of formula B
formed, with a magnesium halide in equimolecular quantities, under stirring and at a temperature between 30 and 40°C, 3 - removal of the soluble alkali metal halide formed, 4 - successive washings and drying of the REPLACEMENT SHEET
magnesium folate precipitate formed.
1 - preparation of an alkali metal salt of the compound of formula A or its isomer of formula B, below:
(A) and (B) 2 - condensation of the alkali metal salt of the compound of formula A or the compound of formula B
formed, with a magnesium halide in equimolecular quantities, under stirring and at a temperature between 30 and 40°C, 3 - removal of the soluble alkali metal halide formed, 4 - successive washings and drying of the REPLACEMENT SHEET
magnesium folate precipitate formed.
5. Pharmaceutical composition, characterised in that it comprises magnesium folate, optionally combined with water-soluble vitamins of the B group and/or with lecithin, the said composition being in addition optionally combined with at least one pharmaceutically acceptable vehicle.
6. Pharmaceutical composition according to Claim 6, characterised in that it is provided especially in the form of hard capsules or tablets or sugared pills and in that it is administered by the oral route.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8901899A FR2643081B1 (en) | 1989-02-14 | 1989-02-14 | MAGNESIUM FOLATES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS |
| FR89/01899 | 1989-02-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2046341A1 true CA2046341A1 (en) | 1990-08-15 |
Family
ID=9378770
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002046341A Abandoned CA2046341A1 (en) | 1989-02-14 | 1990-02-14 | Magnesium folates, process for their preparation and pharmaceutical compositions |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0461145A1 (en) |
| JP (1) | JPH04505007A (en) |
| AU (1) | AU631407B2 (en) |
| CA (1) | CA2046341A1 (en) |
| FR (1) | FR2643081B1 (en) |
| WO (1) | WO1990009382A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE139799T1 (en) * | 1989-12-11 | 1996-07-15 | American Cyanamid Co | METHOD FOR PRODUCING OPTICALLY PURE DIASTEREOISOMERS OF TETRAHYDROFOLATE COMPOUNDS |
| CH680731A5 (en) * | 1990-04-12 | 1992-10-30 | Sapec Fine Chemicals | |
| CH681303A5 (en) * | 1991-01-16 | 1993-02-26 | Eprova Ag | |
| CH684270A5 (en) * | 1991-10-04 | 1994-08-15 | Sapec Fine Chemicals | A process for preparing alkaline earth metal salts of (6R) -N (10) formyl-5,6,7,8-tetrahydrofolic acid. |
| JP2002527484A (en) * | 1998-10-19 | 2002-08-27 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Natural formulations for the treatment and prevention of depression, containing St. John's wort and derivatives of dihydro and tetrahydrofolate |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4148999A (en) * | 1977-08-22 | 1979-04-10 | The Government Of The United States Of America | Preparation and purification of citrovorum factor |
| CH649550A5 (en) * | 1984-02-09 | 1985-05-31 | Eprova Ag | Process for the preparation of alkaline earth metal salts of 5-methyltetrahydrofolic acid |
| DE3821875C1 (en) * | 1988-06-29 | 1990-02-15 | Eprova Ag, Forschungsinstitut, Schaffhausen, Ch | |
| CH676981A5 (en) * | 1988-11-11 | 1991-03-28 | Eprova Ag |
-
1989
- 1989-02-14 FR FR8901899A patent/FR2643081B1/en not_active Expired - Fee Related
-
1990
- 1990-02-14 CA CA002046341A patent/CA2046341A1/en not_active Abandoned
- 1990-02-14 JP JP2504229A patent/JPH04505007A/en active Pending
- 1990-02-14 EP EP90903858A patent/EP0461145A1/en not_active Withdrawn
- 1990-02-14 AU AU51941/90A patent/AU631407B2/en not_active Ceased
- 1990-02-14 WO PCT/FR1990/000106 patent/WO1990009382A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990009382A1 (en) | 1990-08-23 |
| AU5194190A (en) | 1990-09-05 |
| JPH04505007A (en) | 1992-09-03 |
| FR2643081A1 (en) | 1990-08-17 |
| AU631407B2 (en) | 1992-11-26 |
| FR2643081B1 (en) | 1991-06-07 |
| EP0461145A1 (en) | 1991-12-18 |
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