CZ370892A3 - Polynuclear complex compounds of magnesium with aminodicarboxylic acids, halogen, process of their preparation and use - Google Patents

Description

Technical field

The present invention relates to polynuclear magnesium complexes with aminodicarboxylic acids and halogen of the general formula.

Mg.4 [acid. aminodicarbon-H]. 10 X. mH _: 0, wherein aminodicarbonic 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 L-aspartate (L-aspartato (1-chloro)) hydrogen chloride L-asparaginate 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 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.

We have not found the complex compounds which are the subject of this application 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 [acid. aminodicarbon-H]. 10 X. mH _: O, wherein aminodicarbonic 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 preparing them.

-2The essence of the invention is explained by the complex compound of the trivial name: Magnesium L-hydrogenaspartate-magnesium chloride-aqua (2: 5: 29) and the trivial formula

2 [Mg (OOC-CH 2 -CH-COOH)]. 5 _MgCl. 29 H, O

I nh _{2 of the} chemical composition C ₁₆ H ₂ 4Cl ₁₀ Mg ₇ N ₄ O, ₆ .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 solution is 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 [α] _D ²⁰ = (+ 7.2 to 8.7) ml.dnri.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 of magnesium L-hydrogenasparaginate and 5-moles of magnesium chloride are used as teation components. Reaction scheme (1a).

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-) and 3 moles of magnesium chloride as reactants.

The process according to the invention is 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 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 a one-step process. It is most preferred because it is based on the parent compounds.

The novel complex compound of the invention prepared by the above methods is identical to the 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 the substance of the invention have the common essence 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 for recrystallization 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 pure process. A further advantage of water as the reaction medium is that unreacted reactants, by-products remain in the crystallization solution and insoluble are removed by filtration after the reaction has been carried out. It has been found that when according to reaction scheme (1a) 4 moles of magnesium chloride were used for the reaction and the product was crystallized by complete evaporation, the product was contaminated with magnesium L-asparaginate chloride.

Similarly, as used for the reaction of acid. L-aspartic, MgO and MgCl ₂ .6H ₂ O in a molar ratio 4: 2: 6, to give the product thorough drying on the laboratory spray drier remained product is contaminated with unreacted magnesium chloride. When the product was recovered by successive crystallization, unreacted magnesium chloride or unreacted magnesium L-asparaginate 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 hydrogen chloride L-asparaginate in the products was confirmed by X-ray powder diffraction analysis. X-ray powder analysis

-4 confirmed also 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, the mixture was gradually heated to the reaction temperature and after the reaction was carried out before isolation product was not filtered.

The method of product isolation gradual crystallization has the advantage that it is possible to employ the reaction components, especially MgCl ₂ .6H ₂ O, lower quality, with accompanying impurities remain 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 and MgCl ₂ .6H ₂ O were obtained.

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

The process 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 carried out by complete drying or complete crystallization by evaporation to a solid form.

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

AND

It has emerged from multiple literature sources that the use of Mg in therapy is very wide: in cardiology, neurology, psychiatry, nephrology, pediatrics, allergology, gynecology, as an anti-stress factor, in nutrition (Special Periodicals: Magnesium and Magnesium and Trace Elements, Brooklyn, No. -BM Altura, ~ Magnesium Bulletin, Heidelberg - Dr. E. Fischer).

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

The complex compound has the active ingredient magnesium, which is bonded to L-aspartic acid and chlorine. The substance is crystalline, of ionic character. The L-enantiomer of this complex compound increases Mg resorption, its bioavailability, and the ionic character of chlorides prevents the development of metabolic alkalosis as opposed to the magnesium oxide or lactate that induces it.

Dog monitoring has been shown to resorb gradually and persist at elevated blood concentrations for about 12 hours. In single-dose volunteer follow-up, it is also resorbed gradually with a rise in level as early as 1 hour and a persistence of higher plasma levels of approximately 24 hours. In a collaborative study in patients with essential hypertension, its effectiveness in the treatment of hypertension has been established in long-term follow-up. In patients with low Mg levels, this was adjusted when patients had normal Mg levels prior to follow-up, this did not increase. In both groups, Mg excretion increased during the follow-up period as a manifestation of its sufficient absorption 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 to indicate the treatment of hypertension and ischemic heart disease as well as all the consequences of magnesium deficiency (eg, during pregnancy, in high physical exertion in athletes, in the treatment of acute myocardial infarction).

The complex compound magnesium L-hydrogenaspartate-magnesium chloride-aqua (2: 5: 29) is an effective and promising drug with wide application in practice, 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.k -1 body weight. It does not irritate the skin after repeated applications. It does not irritate the mucous membranes of eyes after single application.

I - -

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.

- 6Review of reaction schemes

2 [Mg (anunodicarbonic acid-H) J.aH ₂ O + 5 MgX ₂ -> H ₂ 0 * 7 Mg.4 [acid. aminodicarbon-H 10 X. mH ₂ O

0)

2JMg (OOC-CH ₂ -CH-COOH) j3.2H ₂ O 5 + _MgCl2 .6H ₂ 0 =

I nh ₂

2.324,5 + 5.203,32 = = Ζ ^ ΟΟΟ-ΟΗ ^ ΟΗ-ΟΟΟΗ ^. 5MgCl ₂ .29H ₂ O + 3H ₂ O

I nh ₂ = 1575.56 + 54.04 (la)

C ₁₆ H ₂₄ Cl ₁₀ Mg ₇ N ₄ O ₁₆ .29H ₂ O

Magnesium L-hydrogenaspartate-magnesium chloride - aqua (2: 5: 29)

t 4 [Mg (aminodicarbonic acid-H) Cl]. bH ₂ O + 3 MgX ₂ - * 7 Mg.4 [acid. aminodicarbon-HJ.10 X. mH ₂ 0 H ₂ 0 (2) 4 aminodicarbonate + 2 MgO + 5 MgX _{2 -} 7 Mg.4 [acid. aminodicarbon-H 10 X 10mH ₂ O - H ₂ 0 (3)

- 7 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 are prepared. The solutions are mixed, filtered and heated at 80 ° C for 1 hour. 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 at 110 ° C. from the distillation residue after 16 hours of crystallization, the product was filtered off and dried for 6 hours at 80 ⁰ C and stored in a desiccator for 16 h, weighed and analyzed. Yield 14.9 g.

Analysis: Mg ² * = 10.8%, Cl ₂ = 22.5%, H ₂ O = 32.5%, [α] 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 the crystalline product by crystallization by evaporation of water under reduced pressure, at a temperature of 70 to 80 ° C on a rotary evaporator. The solid, brittle product after removal is sprayed and dried as in Example 1.

Analysis: Mg ² * = 11%, Cl 2 = 23.2%, H ₂ O = 33.3%, [α] _D ²⁰ = + 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 indicate that the substance differs from magnesium L-hydrogenasparaginate, the first effect of which is 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.

L-asparaginate magnesium chloride remained unreacted in the product.

Analysis: Mg ² * = 10.66%, Cl ₂ = 20.5%, H ₂ O = 32.8%, [α] _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 free of reactants.

-8Example 4

Weigh accurately into the accurately weighed flask 9.8364 g (0.04 moles) magnesium L-asparaginate trihydrate and dissolve in 40 ml water. An accurately weighed amount of magnesium chloride hexahydrate of 6.0900 g (0.03 mol) was added to the solution. After dissolution, the solution was processed to the product of Example 2 except that the reaction was terminated at normal pressure and the reaction temperature reached 110 ° C at the end. The surface of the flask with the crystallized product was cleaned and then the product flask was placed in an oven. Product weight is 15.7400 g.

Analysis: Mg ² * = 10.96%, Cl ₂ = 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 magnesium hydrogen chloride L-asparaginate, whereas the complex compound obtained has significant effects at 160 ° C and at 480 ° C when its complete decay. The absence of this starting reagent was confirmed by X-ray powder diffraction analysis.

Example 5

To a sulfonation flask equipped with a stirrer, reflux condenser and thermometer was charged 44.6 g (1.069 mol) of magnesium oxide (96.68%) and 200 ml of water. Stirring is started very slowly so that the magnesium oxide does not deposit on the walls of the sulfonation flask. 266.2 g (2 moles) of L-aspartic acid are metered into this suspension. The temperature exotherms to 40-50 ° C. The mixture is heated to 100-105 ° C, whereby the reaction components go into solution and after 2 hours the pH of the stock solution is 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 is then heated to 115-120 ° C. After 1 hour at steady temperature, the reaction is complete.

t

The reaction solution was filtered, cooled to 27 ° C over 5 hours and crystallization was complete with stirring for an additional 5 hours. The product is filtered off and well mixed. The crystallization solutions are concentrated and crystallized to give the product by crystallization. The product is dried for 6 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 physicochemical criteria of the summary formula.

C ₁₆ H ₂₄ Cl, ₁₀ mg of ₇ N ₄ O ₆ .29 H ₂ O (1575.4).

C H Cl Mg N Calculated 12.20 5.25 22.50 10.80 3.56 Determined 12.40 5.22 22.5 10.8 3.50

-9Example 6

In the apparatus of Example 5, the reaction was 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 adding 300 g of n-butanol, with which 38 ml of the aqueous phase is azeotropically distilled for 3.5 hours under vigorous stirring in the range of 102 ° C. The resulting crystalline suspension is cooled to 20 ° C. The crystalline product is filtered off and dried at 80 ° C and 16 kPa. The product yield is 105 g. (Unreacted magnesium chloride was isolated from the aqueous butanol filtrate).

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

Example 7

Preparation of a multi-nucleated complex compound of magnesium, glutamic acid and chlorine.

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

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 with 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 filtered solution is evaporated first at 80 to 90 ° C and end at 110 to 120 ° C, the procedure in the apparatus of Example 1 and 2 to give the product composition of the C ₂ oH ₃₂ Mg ₁₀ Cl ₄ N ₇ 0 _{16 2} .20 H O.

AND

Cl Mg N H ₂ O Calculated 24,12% 11,58% 3.8% 24.5% Determined 24.4% 11.7% 3.83% 24,14%

Example 8

Preparation of a multicadmium complex of magnesium, glutamic acid and bromine compounds

Mg. 4 [acid. glutamic -HJ. 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 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 to 80 ° C.

- 10After profiltrování cooled and the reaction solution was dried in a laboratory spray dryer at an outlet air temperature of 110-115 ° C. The product was a stable moisture content is as follows: C ₀ cíÍ32®tj IVIG N ₄ O _{7] 6} .26 HJO.

Br Mg H ₂ O Calculated 39,51% 8,42% 23.2% Determined 39.6% 8.4% 23.5%

Industrial applicability

The complex compound meg magnesium L-hydrogenaspartate-magnesium chloride-aqua (2: 5: 29) is suitable for the preparation of all dosage forms including injections, as well as in admixture with low soluble magnesium compounds.

Claims (13)

Multicore magnesium complexes with aminodicarboxylic acids and halogen of the general formula 7 Mg.4 [acid. aminodicarbon-H]. 10 X. 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. Complex compound according to claim 1, of the trivial name magnesium L-hydrogenaspartate magnesium chloride - aqua (2: 5: 29), of the formula 2 [Mg (OOC-CH ₂ -CH-COOH) J. 5 MgCl ₂ . 29 H _: O of the general formula C ₁₆ H ₂₄ Cl, ₀ Mg, N ₄ O ₁₆ . 29 H ₂ O A 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 reacted as reactants. 4. A process for the preparation of a compound according to claim 1, which comprises reacting asparaginate hydrogen halide or magnesium glutamate halide in an amount of 4 moles and magnesium halide in an amount of 3 moles, wherein the magnesium asparaginate hydrogen halide or the magnesium glutamate hydrogen halide in An amount of 4 moles is also prepared by reacting the reactants in an amount of 4 moles of aspartic acid or glutamic acid, 2 moles of magnesium oxide or magnesium hydroxide, or magnesium carbonate, or magnesium hydroxide or magnesium carbonate, and 2 moles of magnesium halide. with insulation 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. 6. A process according to claim 1, wherein 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 magnesium halide are reacted as reactants, 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, by concentration of the solutions and repeated crystallization, or crystallization 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 dried product prepared is purified as necessary by extraction with absolute ethanol and subsequent crystallization or only recrystallization. A process according to claims 3, 4, and 6, characterized in that the solution resulting from an equimolar amount of the reactants is converted to solid form by drying or crystallization by complete evaporation of water. A process for preparing a compound according to claim 2, characterized in that an equimolar amount of pure reactants is reacted, i.e. 2 moles of magnesium hydrogen L-asparaginate 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 the complex. 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 ischemic heart disease and for treating the consequences of magnesium deficiency in an organism. Use of a complex compound according to claim 2 for the manufacture of edible foods as an additive to an edible salt.