SK370892A3 - Multicores complex compounds of magnesium with aminobicarbone acids, halogene and method of their preparation - Google Patents

Description

Areas: techniques

The present invention relates to multicore complex compounds of magnesium with aminodicarboxylic acids and halogen of the formula

Mg.4 [aminodicarboxylic acid-H]. 10 X. mH ₂ O, wherein the aminodicarboxylic acid is acid. aspartic or acidic; glutamic, X is halogen and m is the number of moles of water.

BACKGROUND OF THE INVENTION

Complex compounds of aminodicarboxylic acids, magnesium and halogen in a molar ratio of 1: 1: 1 are known (DP 2228101, 1972). Magnesium chloride L-asparaginate magnesium (Magnesium [L-aspartato (1-)) chloro] is described by Fischer et al. (Arzneim.Forsch.Drug.Res. 28 (I), Heft.5, 1978) to eliminate magnesium deficiency in the body.

Magnesium bromide L-asparaginate magnesium has recently been described in Spanish patent 550,166 (Buenaventura R.P.:C.A.Appl.Chem.Eng.S., 107, 1987, No. 13) as a sedative for veterinary purposes.

No.

Complex compounds of the present invention have not been found after the literature review.

SUMMARY OF THE INVENTION

The present invention relates to complex compounds of aminodicarboxylic acids, magnesium and halogen of the general formula

Mg.4 [aminodicarboxylic acid-H]. 10 X. mH ₂ O, wherein the aminodicarboxylic acid is acid. aspartic or acidic; glutamic, X is halogen, and m is the number of moles of water, as well as methods for their preparation.

The invention explains the complex compound common name: Magnesium L-hydrogenaspartate-aqua-magnesium chloride (2: 5: 29) and trivial formula [Mg _{(OOC-CH2-CH-COOH) 2].} 5 MgCl ₂ . 29 H ₂ 0, i nh ₂ . ^C 16 ^H 24 ^C 10 ^M 4 ^N 4 ° 16 * ^{29 H} 2 °.

It is a white crystalline substance, normally physically, chemically and microbially stable. It dissolves very well in water (2: 1), slightly in 96% ethanol and practically does not dissolve in organic solvents. Its saturated solutions are biostatic. It is preferably isolated by crystallization. Its crystallinity is relatively low, but sufficient to evaluate a substance that has been prepared in several ways by X-ray powder diffraction analysis. This method, IR spectra, thermal analysis as well as complete chemical analysis demonstrated the reproducibility and individuality of the substance prepared by all methods.

Physico-chemical properties:

Specific optical rotation [α] _D ²⁰ = (+ 7.2 to 8.7) ° ml.dm ¹ · g ^-1 , magnesium ion content 10.26 to 11.34%, chloride anion content 21.38 to

23.62%, water content 30.7-36.7%, actual acidity (pH) 4.8-7.2 and microbiological safety.

Process for the preparation of magnesium L-hydrogenaspartate-magnesium, chloride-aqua (2: 5: 29) according to the invention, characterized in that 2-moles L-hydrogenasparaginate and 5 moles of magnesium chloride are used as reactants. according to Reaction Scheme (Ia).

A process for the preparation of a compound according to the invention which comprises using 4 moles of magnesium L-asparaginate hydrogen chloride (Magnesium [L-aspartato (1 -)] chloro-) and 3 moles of magnesium chloride as reactants.

The process according to the invention is characterized in that L-aspartic acid in moles, hydrochloric acid in 10 moles and magnesium oxide in 7 moles are used as reactants. The disadvantages of this procedure are inaccurate experimentation, aggressiveness of the reaction solution and greater presence of by-products.

Process for preparing a substance according to the invention, characterized in that 4 moles of L-aspartic acid, 2 moles of magnesium oxide and 5 moles of magnesium chloride are used as reactants. This method of preparation is • one-stage. It is most preferred because it is based on the basic compounds.

The novel complex compound of the invention prepared by the above procedures is identical to X-ray powder diffraction analysis.

Magnesium hydroxide or magnesium carbonate may also be used in place of magnesium oxide. Magnesium oxide or magnesium hydroxide or magnesium carbonate is preferably used in an amount of 2 to 2.2 moles. This excess adjusts the pH of the reaction solution optimally, optimizing yield and quality.

All the processes for the preparation of the substance according to the invention have in common the fact that the reaction is carried out in an aqueous medium. The reaction temperature is 20 to 120 ° C and the actual acidity of the reaction solution is 4.5 to 7.8. After the reaction, the product is isolated from the reaction solution by filtration and crystallization. The solution after crystallization is concentrated to recrystallize or used as the reaction medium instead of water.

The actual acidity of the reaction medium at a higher value is adjusted by L-aspartic acid. Aspartic acid is precipitated from the last crystallization solution by adjusting the pH to 2.7-3.2.

The advantages of all methods are that the reaction medium is water, works in small volumes, high product yield, low cost, and is practically an environmentally clean process. Another advantage of water as the reaction medium is that the unreacted reactants, by-products remain in the crystallization solution and insoluble are removed by filtration after the reaction has taken place. It has been found experimentally that when according to reaction scheme (1a) 4 moles of magnesium chloride were used to react and crystallize the product by complete evaporation, the product was contaminated with L-asparaginate hydrogen chloride.

Similarly, when L-aspartic acid, MgO and MgCl ₂ .6H ₂ O were used in the molar ratio of 4: 2: 6, the product was completely contaminated with unreacted magnesium chloride to obtain the product by complete drying in a laboratory spray dryer. When the product was isolated by sequential crystallization, unreacted magnesium chloride or unreacted magnesium L-aspartic acid hydrochloride remained dissolved in the crystallization solution. This fact was found out by chemical analysis and overall mass balance. The presence of unreacted magnesium chloride and the presence of magnesium L-asparaginate hydrochloride in the products was confirmed by X-ray powder diffraction analysis. X-ray powder analysis also confirmed the presence of Mg (OH) Cl type compounds when water, MgCl ₂ .6H ₂ O, MgO and L-aspartic acid were gradually added in the experiment, gradually warming to the reaction temperature and after the reaction was carried out. no filtration was performed prior to product isolation.

The process of product isolation by gradual crystallization also has the advantage that reactants, especially MgCl ₂ , can be used. 6 H ₂ O, of lower quality, with the accompanying impurities remaining in the crystallization solution.

After completion of the reaction, crystallization can also be carried out by azeotropic distillation of water with n-butanol as a one-shot process. At the wrong ratio of reactants, unreacted magnesium chloride remains in the aqueous butanol solution. (Product purity confirmed by X-ray powder analysis). In an attempt to isolate the product from the aqueous solution by precipitation with ethanol, magnesium hydrogen chloride L-asparaginate was obtained and

MgCl ₂ .6H ₂ O.

The purification of the dry products can also be carried out, if necessary, by extraction with absolute ethanol and subsequent crystallization, or only by recrystallization from water.

Process for the preparation of a substance according to the invention, characterized in that the reaction solution formed from equimolar amounts of reaction

The component according to reaction schemes (1), (2) and (3) is converted to solid form by complete drying or complete evaporative crystallization.

The complex compounds of the aminodicarboxylic acids, magnesium and halogen according to the invention can be used in human and veterinary medicine as well as in agriculture and food.

It has emerged from multiple sources that the use of Mg in therapy is very wide: in cardiology, neurology, psychiatry, nephrology, paediatrics, allergology, gynecology as an anti-stress factor, in nutrition (Special Periodicals: Magnesium and Magnesium and Trace Elements, Brooklyn, NY - BMAltura, Magnesium Bulletin, Heidelberg Dr. E. Fisher).

For a drug with a wide range of indications, the pharmacologically and clinically tested complex compound: Magnesium L-hydrogenaspartate-magnesium chloride-aqua (2: 5: 29) was developed. It is suitable for all dosage forms and also as an additive to food salt for patients suffering from unsalted diet.

The complex compound has the active ingredient magnesium, which is linked to L-aspartic acid and chlorine. The substance is crystalline, of an ionic nature.

- The L-enantiomer of this complex compound increases Mg resorption, bioavailability and ionic character of chloride prevents development

- metabolic alkalosis, in contrast to magnesium oxide or lactate, which induce it.

In dogs, it has been shown that it is absorbed gradually and persists at elevated blood concentrations of about 12 hours. In single-dose volunteer follow-up, it is also resorbed gradually as levels rise as early as 1 hour and persist with elevated plasma levels of approximately 24 hours. In a collaborative study in patients with essential hypertension, its efficacy in the treatment of hypertension was established in long-term follow-up. In patients with low Mg levels, this was corrected if patients had normal Mg levels prior to follow-up, this did not increase. In both groups, Mg excretion increased during the follow-up as a result of its sufficient resorption from GIT. Investigations in patients with ischemic heart disease have been shown to reduce the incidence of stenocardia. Based on these observations, the new agent can be used in the indication of treatment of hypertension and coronary heart disease as well as all the consequences of magnesium deficiency (eg in pregnancy, in high physical exertion in sportsmen, in the treatment of acute myocardial infarction).

The complex compound magnesium L-hydrogenaspartate - magnesium chloride agua (2: 5: 29) is an effective and promising drug with wide application in practice, a very suitable composition and good tolerability.

Her toxicological evaluation showed that acute oral LD ₅₀ could not be determined because no animal died after a dose of 10,000 mg.kg ^-1 body weight. Do not irritate skin after repeated applications. Do not irritate mucous membranes of eyes after single application.

Its concentrated aqueous solution of 50 to 70% by weight is physically and microbially stable. When pure reagents are used in the preparation, the complex compound solution can be directly used to prepare a liquid dosage form.

Overview of Reaction Schemes [Mg (aminodicarboxylic acid-H) ₂ ] .aH ₂ O + 5 MgX ₂ ->

h ₂ o

-> 7 Mg.4 [kys.aminodikarboxylová -H] X .10 MH @ ₂ O (1) [Mg _{(OOC-CH2-CH-COOH) 2]} 2H ₂ O + 5MgCl ₂ · 6H ₂ O = i

i nh ₂ . 324.5 + 5. 203.32 = = 2 [Mg _{(OOC-CH2-CH-COOH) 2].} 5MgCl ₂ · 29H ₂ O + 3H ₂ O i

i nh ₂ • 1575.56 + 54.04 (la) ^C 16 ^H 24 ^C 10 ^M g7 ^N 4 ° 16 ' ^29H 2 °

Magnesium L-hydrogenaspartate-magnesium chloride-aqua (2: 5: 29) [Mg (aminodicarboxylic acid-H) Cl]. bH ₂ O + 3 MgX ₂ ->

h ₂ °

-> 7 Mg.4 [aminodicarboxylic acid-H] .10 X .mH ₂ 0 (2) aminodicarboxylic acid + 2 Mgo + 5 MgX ₂ ->

h ₂ o

-> 7 Mg.4 [aminodicarboxylic acid-H] .10 X .mH ₂ 0 (3)

Examples

The subject matter of the invention is illustrated in the examples without being limited thereto.

The preparation of magnesium L-hydrogenaspartate-magnesium chloride-aqua (2: 5: 29) is illustrated in Examples 1-6.

Example 1

A solution of 12.98 g (0.04 mol) of magnesium L-hydrogenasparaginate in 50 ml of water and a solution of 20.32 g (0.1 mol) of magnesium chloride hexahydrate in 25 ml of water are prepared. for 1 hour heat up to 80

The solutions were combined, filtered and ° C. The solution is concentrated under reduced pressure to a volume of about 40 ml on a rotary evaporator and the concentration process is terminated at 25 ml distillation volume, leaving the temperature at 110 ° C., From the distillation residue after 16 hours.

crystallization, the product is filtered off, dried for 6 hours. at 80 ° C, stored in a dredger and after 16 hours. consider and analyze. Yield 14.9 g. Analysis: Mg ²⁺ = 10.8%, Cl = 22.5%, h ₂ O = 32.5%, [α] _D ²⁰ = + 8.54 ° ml.dm ^-1 .g ^-1 , pH ( 10% solution) = 6.23, N = 3.6%.

Example 2

The procedure is as in Example 1, except that the solution of the complex compound is converted to a crystalline product by crystallization by evaporation of water under reduced pressure, at a temperature of 70 to 80 ° C on a rotary evaporator. After removal, the solid, brittle product is sprayed and dried as in Example 1.

Analysis: Mg ²⁺ = 11.0%, Cl "= 23.2%, H ₂ O = 33.3%, [α] _β ^2θ = + 8.37 ° ml.dm ^-1 · g ¹ , * pH (10% solution) = 6.23.

Thermal analysis of the product shows two effects on the DTG curves at 160 ° C and then at 480 ° C when complete decomposition occurs. These data suggest that the substance differs from magnesium L-hydrogenasparaginate, the first effect of which appears at 194 ° C and is stable up to 300 ° C at this temperature.

Example 3

The procedure was as in Example 2 except that 0.08 moles of magnesium L-hydrogenasparaginate used 0.08 moles of magnesium chloride hexahydrate.

L-asparaginate magnesium chloride remained unreacted in the product.

Analysis: Mg ²⁺ = 10.66%, Cl = 20.5%, H ₂ 0 = 32.8%, [a] _D ²⁰ = + 8.7 ° ml.dm ^"1 .g ^-1. This was confirmed by X-ray powder diffraction analysis. In contrast, the products prepared according to Examples 1 and 2 were free of this intermediate as well as the impurities of the reactants.

Example 4

Weigh accurately into a precision weighed flask 9.8364 g (0.04 mol) magnesium hydrogen chloride L-asparaginate trihydrate and dissolve in 40 ml water. An accurately weighed amount of chloride hexahydrate was added to the solution. magnesium was 6.0909 g (0.03 moles). After dissolution, the solution was worked up to the product of Example 2 except that the reaction was terminated at normal pressure and the reaction temperature reached 110 ° C to the end. The surface of the crystallized product flask is cleaned and then the product flask is placed in an oven. The dried product is weighed accurately with the flask after 6 days in a dredger. Product weight is 15.7400 g.

Analysis: Mg ²⁺ = 10.96%, Cl = 22.95%, H ₂ O = 32.9%.

The results of the thermal analysis showed that the X-ray curves showed no thermal effect at 210 ° C, which is significant for L-asparaginate magnesium chloride hydrochloride, with the complex compound obtained having significant effects at 160 ° C and 480 ° C when its full decomposition. The absence of this starting reagent was also confirmed by X-ray powder diffraction analysis.

Example 5

44.6 g (1.069 mol) of magnesium oxide (96.68%) Q ₍ and 200 ml of water) are metered into a sulphonation flask equipped with a stirrer, reflux condenser and thermometer. It is dosed into this suspension

266.2 g (2 moles) of L-aspartic acid. The temperature exotherms to 40-50 ° C. The mixture was heated to 100-105 ° C with the reaction components going into solution and after 2 hours. The pH of the reaction solution was stabilized at 6.7. The temperature of the solution was then reduced to 80 ° C and 507.5 g (2.5 mol) of magnesium chloride hexahydrate was metered in. The reaction mixture was then heated to 115-120 ° C. After 1 hour at steady temperature, the reaction is complete.

The reaction solution was filtered, cooled to 27 ° C over 5 hours and crystallization was complete with stirring for another 5 hours. The product was filtered off and well blended. The crystallization solutions are concentrated and crystallized to give the product quantitatively. The product is dried for 6 hours at 80 ° C until weight stabilizes.

Recrystallization from water (3.5 parts by weight to 1 part by weight of water) yields a product with unchanged physicochemical criteria with the following general formula: ^C 16 ^H 24 ^cl 10 ^M 4 7 ^N 4 ° 16 ^{'29 H} 2 ° ¹⁵⁷⁵ » ⁴ ) ·

C H Cl mg N calculated 12.20 5.25 22.50 10.80 3.56 Fixed 12.40 5.22 22.5 10.8 3.50

Example 6

In the apparatus of Example 5, the reaction was carried out in the same manner with the following amounts of reactants in 30 ml of distilled water: 6.46 g (0.156 mol) of magnesium oxide, 40 g (0.3 mol) of L-aspartic acid and 91.5 g (0.45 mol) of magnesium chloride hexahydrate. After carrying out the reaction and filtering the reaction solution, the apparatus is adjusted by placing a phase separator under reflux and allowing 300 g of n-butanol to be azeotroped over a period of 3.5 hours with 38 ml of the aqueous phase with vigorous stirring in the range of 102 to 112 ° C. The resulting crystalline suspension is cooled to 20 ° C. The crystalline product is filtered off and dried at 80 ° C and 16 kPa. Yield 105 g. (Unreacted magnesium chloride was isolated from the aqueous butanol filtrate).

• ς analysis: Mg2 ⁺ = 10.92%, C1 = 22.3%, H ₂ 0 = 32.1%, [a] _D ²⁰ = + 8.3 ° ml.dm ¹ .g ^-1, pH (10% solution) = 6.4, N = 3.7%.

Example 7

Preparation of multicore complex compound of magnesium, glutamic acid and chlorine.

Mg. 4 [glutamic acid -H]. 10 Cl. mH ₂ O A mixture of 7.35 g of glutamic acid (0.05 mol), 1.09 g of MgO (0.025 mol) and 20 ml of water was brought into solution by stirring and heating. To this solution was added a solution of 12.7 g MgCl ₂ .6H ₂ O (0.0625 mol) in 15 mL water. The solution is filtered, evaporated first at 80-90 ° C and finally at 110-120 ° C by the apparatus of Example 1a 2. The product of the formula is obtained: 20 20 ^ 32 ^ ¹ 10 ^^ 7 ^ 4θ16 * 20 H ₂ 0 ·

calculated

Fixed

Cl

24,12%

24.4%

mg

11,58%

11.7%

N

3.8% 3.83% h ₂ °

24.5% 24.14%

Example 8

Preparation of a multicore complex compound of magnesium, glutamic acid and bromine of the total composition

Mg. 4 [glutamic acid -H]. 10 Br. mH ₂ 0

Preparation in the apparatus and procedure of Example 5 with the reactants: 20.84 g (0.5 mol) of magnesium oxide, 147.13 g of acid. glutamic acid (1 mol) and 365.28 g (1.25 mol) of magnesium bromide hexahydrate in 770 ml of distilled water. Maximum reaction temperature 70-80 ° C.

After cooling and filtering, the reaction solution is dried in a laboratory spray drier at an air outlet temperature of 110-115 ° C. The product with stable humidity has the following composition: ^C 20 ^H 32 ^Br 10 ^Mg 7 ^N 4 ° 16 ^{'26 H} 2 ° *

calculated

Fixed

Br Mg ₂ o

39,51% 8,42% 23,2%

39.6% 8.4% 23.5%

Industrial efficiency

The complex compound magnesium L-hydrogenaspartate-magnesium chloride-aqua (2: 5: 29) is suitable in the solid state for the preparation of all dosage forms including injections and also in a mixture with low soluble magnesium! compounds.

Claims (13)

PATENT CLAIMS Multicore magnesium complexes with aminodicarboxylic acids and halogen of the general formula 7 Mg.4 [aminodicarboxylic acid-H]. 10 X. mH ₂ 0, And wherein the aminodicarboxylic acid is acid. aspartic or acidic; glutamic, • X is halogen and m is the number of moles of water. Complex compound according to claim 1, the trivial name magnesium L-hydrogenaspartate - magnesium chloride - aqua (2: 5: 29), of the formula 2 [Mg _{(00C-CH2-CH-C00H) 2].} 5 MgCl ₂ . 29 H ₂ O, i nh _{2 of} chemical composition C ₁₆ H ₂₄ Cl ₁₀ Mg ₇ N ₄ O ₁₆ . 29 H ₂ 0. A process for the preparation of a compound according to claim 1, characterized in that magnesium hydrogenparaginate or magnesium hydrogen glutamate in an amount of 2 moles and magnesium halide in an amount of 5 moles are used as reactants. A process for the preparation of a compound according to claim 1, characterized in that magnesium asparaginate or magnesium glutamate hydrogen halide in an amount of 4 moles and magnesium halide in an amount of 3 moles are used as reactants, wherein magnesium asparaginate hydrogen halide or glutamate hydrogen halide is used. 4 moles were prepared by using 4 moles of aspartic acid or acidic acid as reactants. glutamic acid, 2 moles of magnesium oxide or magnesium hydroxide, or magnesium carbonate, and 2 moles of magnesium halide, and the product is isolated. A process for the preparation of a compound according to claim 1, characterized in that aspartic acid or acid is reacted. 4 moles of glutamic acid, 10 moles of hydrohalic acid, and magnesium oxide of 4 moles Ί moles. 6. A process according to claim 1, wherein the amounts of 4 moles of aspartic acid or glutamic acid, 2 to 2.2 moles of magnesium oxide or magnesium hydroxide or magnesium carbonate and 4 to 6 moles of halide are used as reactants. of magnesium halide, preferably 5 moles of magnesium halide. Process according to claims 1 to 6, characterized in that the reaction is carried out in an aqueous medium at a temperature of 20 to 120 ° C, in the range of pH 4.5 to 7.8, the product is isolated from the reaction solution by filtration, crystallization, concentration solutions, and by recrystallization or by azeotropic distillation of water with n-butanol, the crystallized product is filtered off and dried. Process according to claim 7, characterized in that the prepared and dried product is, if necessary, purified by extraction with absolute ethanol followed by crystallization or only recrystallization. A process according to claims 3,4 and 6, characterized in that the solution resulting from equimolar amounts of the reactants is converted to solid form by drying or crystallization by complete evaporation of water. • from A process for the preparation of a compound according to claim 2, characterized in that an equimolar amount of the pure reactants is reacted, i. 2 moles of magnesium L-hydrogenasparaginate and 5 moles of magnesium chloride, or 4 moles of magnesium L-asparaginate and 3 moles of magnesium chloride, or 4 moles of L-aspartic acid, 2 moles of magnesium oxide and 5 moles of magnesium chloride to form a concentrated aqueous solution of a complex compound. The complex compound of claim 2 for use as a medicament. Use of a complex compound according to claim 2 for the manufacture of a medicament for lowering blood pressure, for treating coronary artery disease and for treating the consequences of magnesium deficiency in the body. -phenyl Use of a complex compound according to claim 2 for the manufacture of edible foods as an additive to an edible salt.