SK280602B6 - Polynuclear complex compounds of magnesium with aminodicarboxylic acids, halogen, process of their preparation - Google Patents

Abstract

Disclosed are compounds of the general formula 7 Mg.4-[H- -aminodicarboxylic acid].10X.mH2O wherein aminodicarboxylic acid is aspartic acid or glutamic acid; X is halogen; and m is the number of water gram-molecules. The process disclosed comprises reacting magnesium asparaginate hydrogen or magnesium hydrogenglutamate and magnesium halogenide, or, reacting magnesium asparaginate hydrogenhalogenide and magnesium halogenide, or, reacting aspartic acid or glutamic acid or magnesium oxide or magnesium hydroxide, or magnesium carbonate and magnesium halogenide. All the reactions are carried out in an aqueous medium. The product is isolated by crystallisation, filtration, solutions concentration and by drying thus obtained product. Reaction solution from equimolar amounts of reaction components is converted by drying or crystallising into a solid form. As an effective L-enathiomer a complex compound with L-aspartic acid is prepared, particularly to be utilised as a medicament which exhibits a very good biological accessibility of magnesium in a chloride form.

Description

Disclosed are compounds of the general formula 7 Mg.4 [aminodicarboxylic acid-H], 1X.mH ₂ O, wherein the aminodicarboxylic acid is aspartic acid or glutamic acid, X is halogen and m is the number of moles of water. The process for the preparation of a novel substance is the reaction of magnesium asparaginate or magnesium hydrogen glutamate and magnesium halide, or the reaction of magnesium asparaginate and magnesium halide, or the reaction of aspartic acid or glutamic acid, magnesium oxide or magnesium hydroxide and carbonate. All reactions take place in an aqueous environment. The product is isolated by crystallization, filtration, solution concentration and drying of the product obtained. The reaction solution from equimolar amounts of the reactants is converted to solid form by drying or crystallization by completely evaporating water. As a potent L-enantiomer, a complex compound with L-aspartic acid is prepared, especially for the purpose of a drug with very good bioavailability of magnesium in chloride form.

Technical field

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

Mg. 4 [aminodicarboxylic acid-H], 10X. mH ₂ O where the aminodicarboxylic acid is aspartic acid or glutamic acid, 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-aspartate (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 L-asparaginate magnesium is recently 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.

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

SUMMARY OF THE INVENTION

The present invention provides 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 aspartic acid or glutamic acid, X is halogen and m is the number of moles of water, as well as the processes for their preparation.

The subject matter of the invention is explained by the complex compound of the trivial name:

magnesium L-hydrogenaspartate -magnesium chlorid- water (2: 5: 29), of the formula [Mg _{(OC-CH2-CH-COOH) 2]} .29 .5 _{MgCl2 H2O.}

NH _{2 of} chemical composition C ₁₆ H ₂ 4Cl | ₀ Mg ₇ N ₄ O ₁₆ .29 H ₂ O and process for its preparation.

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 is 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 full chemical analysis demonstrated the reproducibility and individuality of the substance prepared by all methods.

Physico-chemical properties:

Specific optical rotation [d] _D 20 = (+ 7.2 to 8.7) ° ml.dnf'.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 harmlessness.

Process for the preparation of magnesium L-hydrogen aspartate - magnesium chloride-water (2: 5: 29) according to the invention, characterized in that 2-moles of magnesium L-hydrogenasparaginate and 5 moles of magnesium chloride are used as reactants. of reaction scheme (Ia).

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

Process for the preparation of a compound according to the invention, characterized in that L-aspartic acid in an amount of 4 moles, hydrochloric acid in an amount of 10 moles and magnesium oxide in an amount of 7 moles are used as reactants. The disadvantage of this procedure is inaccurate experimentation, aggressiveness of the reaction solution and greater presence of by-products.

Process for preparing a compound 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 a one-step process. 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 processes for the preparation of a compound of 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 by adjusting the pH to 2.7-3.2 to the final crystallization solution.

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 are insoluble by filtration after the reaction has been carried out. It was found that when 4 moles of magnesium chloride were used for the reaction according to reaction scheme (Ia) and crystallization of the product was carried out by complete evaporation, the product was contaminated with magnesium hydrogen chloride L-asparaginate.

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-asparaginate 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 L-asparaginate magnesium chloride 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 successively dosed in the experiment, gradually warming to the reaction temperature and after the reaction was carried out. it was not filtered before product isolation.

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

After completion of the reaction, crystallization can also be carried out by azeotropic distillation of the water with n-butanol as a one-shot solution. 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 and MgCl ₂ .6H ₂ O were obtained.

Purification of the dry products can also be accomplished by extraction with absolute ethanol, followed by crystallization, or only by recrystallization from water.

A process for the preparation of a compound according to the invention, characterized in that the reaction solution formed from equimolar amounts of the reaction components according to reaction schemes (1), (2) and (3) is converted to solid form by complete drying or complete crystallization by evaporation. The complex compounds of the aminodicarboxylic acids, magnesium and halogen of the invention can be used in human and veterinary medicine as well as in agriculture and food.

It has been shown by numerous literary 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 Elemcnts, 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-hydrogen aspartate-magnesium chloride-water (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 ionic character.

The L-enantiomer of this complex compound increases the absorption of Mg, its bioavailability, and the ionic character of the chlorides prevents the development of metabolic alkalosis as opposed to the magnesium oxide or lactate which induces 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 increase as early as 1 hour and with persistence of higher 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 adjusted 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 manifestation 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 investigations, the novel compounds can be used in the indication of the treatment of hypertension and coronary heart disease, as well as all the consequences of magnesium deficiency (eg in pregnancy, in high physical exertion in athletes, in the treatment of acute myocardial infarction).

Complex compound magnesium L-hydrogen aspartate -

- Magnesium chloride-water (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 _{5 ()} could not be determined because no animal died after a dose of 10000 mg.kg ^-1 body weight. Do not irritate skin after repeated applications. It does not irritate the 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-HjJ.and H ₂ O + 5 MgX ₂ -> H ₂ O-> 7 Mg.4 [aminodicarboxylic acid-H]. 10X. MH ₂ 0 (1) [MgCO'C-CH 3] -CH? O-COOHjJ 5MgCl ₂ · 6H ₂ O =

I nh ₂

2.324.5 + 5.203.32 = [Mg (0 ° C-CH ₂ -CH-COOI Ih). 5MgCl ₂ .29H ₂ O + 3H ₂ O

I nh ₂

1575.56 + 54.04 (la)

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

H ₂ O

---> 7Mg.4 (aminodicarboxylic acid-H) .10X, 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

DETAILED DESCRIPTION OF THE INVENTION

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

The preparation of magnesium L-hydrogen aspartate-magnesium chloride-water (2: 5: 29) is illustrated in Examples 1 to 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. The solutions were mixed, filtered and for 1 hour. heated to 80 ° 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 a distillation volume of 25 ml, the temperature rising to 110 ° C. From the distillation residue after 16 h. 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%, [d] _D 20 = + 8.54 ° ml / d · 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%, [d] _D 20 = + 8.37 ° ml.dm'.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 indicate that the substance differs from magnesium L-hydrogen sulparaginate, in which the first effect occurs at 194 ° C and is stable up to 300 ° C from 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.

Unreacted L-asparaginate magnesium chloride remained in the product.

Analysis: Mg ² '= 10.66%, Cl = 20.5%, H ₂ O = 32.8%, [d] _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 absence of reactants.

Example 4

Weigh accurately into a precision weighed flask 9.8364 g (0.04 moles) magnesium hydrogen chloride L-asparaginate trihydrate and dissolve in 40 ml of water. An accurately weighed amount of magnesium chloride hexahydrate of 6.0900 g (0.03 moles) was added to the solution. After dissolution, the solution is worked up to the product of Example 2, except that the reaction is terminated at normal pressure and the reaction temperature reaches 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. The weight of the product 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 important for L-asparaginate magnesium chloride, with the complex compound obtained effects at 160 ° C and at 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%) and 200 ml of water are metered into a sulfonation flask equipped with a stirrer, reflux condenser and thermometer. Stirring is started very slowly so that the magnesium oxide does not stick to the walls of the sulfonation flask. 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 is filtered, cooled to 27 ° C over 5 hours and crystallization is complete with stirring for a further 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 hours at 80 ° C until the weight stabilizes.

Recrystallization from water (3.5 parts by weight to 1 part by weight of water) gave the product with unchanged physico-chemical criteria with the following formula: C ₁₆ H ₂₄ Cl _to Mg ₇ N ₄ O ₁₆ .29 H ₂ O (1575.4) .

C H CI Mg N Calculated 12.20 5.25 22.50 10.80 3.56 Established 12.40 5.22 22.5 10.8 3.50

Example 6

In the apparatus of Example 5, the reaction is carried out in the same manner with the following amounts of reagents 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).

Analysis: Mg ²⁺ = 10.92%, Cl = 22.3%, H ₂ O = 32.1%, [d] _D 20 = + 8.3 ° ml.dm ^-1 , pH (10 % solution) = 6.4, N = 3.7%.

Example 7

Preparation of a 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 according to the apparatus of Examples 1 and 2. The product of composition C ₂ oH _{3 2} Cl ₁₀ Mg ₇ N ₄ 0 ₁₆ .20 H _{2 is obtained.} ABOUT .

CI Mg NH ₂ O Calculated 24.12% 11.58% 3.8% 24.5% Estimated 24.4% 11.7% 3.83% 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 O

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 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 ₂ oH _{3 2} Br ₁₀ Mg ₇ N ₄ 0 ₁₆ 26H2O

Br Mg H ₂ O Calculated 39.51% 8.42% 23.2% Established 39.6% 8.4% 23.5%

SK 280602-6

Industrial usability

The magnesium L-hydrogen aspartate-magnesium chloride-water complex compound (2: 5: 29) is in the solid state suitable for the preparation of all dosage forms including injections and also in admixture with low soluble magnesium compounds.

Claims (13)

Multicore magnesium complexes with aminodicarboxylic acids and halogen of the general formula 7 Mg. 4 [aminodicarboxylic acid-Hj. 10 X. mH ₂ 0 wherein the aminodicarboxylic acid, aspartic acid or glutamic acid, X is halogen and m is the number of moles of water. Complex compound according to claim 1, the trivial name of magnesium L-hydrogenaspartate-magnesium chloride-water (2: 5: 29), of the formula 2 [Mg (O-C ₂ -CH-COOH) ₂ ] .5 MgCl ₂ .29 H ₂ O, I nh _{2 of the} chemical composition C ₁₆ l · 12 ₄ CI | ₀ Mg-N ₄ O _Id .29 _H2O. Process for the preparation of a compound according to claim 1, characterized in that magnesium hydrogenparparinate 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 halide or magnesium glutamate halide in an amount of 4 moles and magnesium halide in an amount of 3 moles are used as reactants, wherein the magnesium asparaginate hydrogen halide or magnesium hydrogen stearate an amount of 4 moles is prepared by using as reactants amounts of 4 moles of aspartic acid or glutamic acid, 2 moles of magnesium oxide or magnesium hydroxide or magnesium carbonate and 2 moles of magnesium halide and isolating the product. 5. A process for the preparation of a compound according to claim 1, which comprises reacting aspartic acid or glutamic acid in an amount of 4 moles, hydrohalic acid 10 moles, and magnesium oxide in an amount of 7 moles. A process for the preparation of a compound according to claim 1, characterized in that 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 are used as reactants. a magnesium halide, preferably 5 moles of magnesium halide. Process for the preparation of a compound 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 of the solutions and re-crystallization, or crystallization by azeotropic distillation of water with n-butanol, the crystallized product is filtered off and dried. A process for the preparation of a compound according to claim 7, characterized in that the prepared and dried product is purified, if necessary, by extraction with absolute ethanol and subsequent crystallization or only recrystallization. A process for the preparation of a compound 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. A process for the preparation of a compound of claim 2, characterized in that an equimolar amount of the pure reactants is reacted, i. 2 moles of L-hydrogenasparaginate magnesium and 5 moles of magnesium chloride, or 4 moles of L-asparaginate hydrogen chloride and 3 moles of magnesium chloride, or 4 moles of L-aspartic acid, 2 moles of magnesium oxide and 5 moles of magnesium chloride complex to form a concentrated aqueous solution 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. Use of a complex compound according to claim 2 for the manufacture of edible foods as an additive to an edible salt.