MXPA98010488A - Creatine pyruvates and method for their production - Google Patents

Abstract

The invention relates to creatine pyruvates of the general formula (I) (creatine)x(pyruvate)y(H2O)n, in which x=1-100, y=1-10 and n=0-10. These creatine pyruvates can be produced by the relatively simple reaction of creatine with pyruvic acid. They can be used to increase stamina and strength in the field of sport, for weight and body fat reduction in health care, in the treatment of oxygen deficiency conditions (ischaemia), obesity and overweight, as a food supplement additive, and as a radical interceptor.

Description

PIRUVA OS DE CR-E? T --- N? AND METHOD FOR YOUR PRODUCTION SPECIFICATION This patent application is related to creatine pyruvates and their production, creatine pyruvates are anhydrous or hydrated salts of pyruvic acid and creatine as well as mixtures of these salts with creatine or pyruvic acid. It is well known that the salts of pyruvic acid, which are referred to as pyruvates, have valuable physiological and therapeutic properties for the treatment of various diseases, for example obesity and overweight, and can also be used to prevent the formation of radicals. free and to improve long-term operation (in this context see: US 5,508,308, US 5,480,909, US 5,472,980, US 5,395,822, US 5,312,985, US 5,283,260, US 5,256,697, US 4,548,937 and US 4,351,835). Alkaline and alkaline earth metal pyruvates are known from the prior art, and sodium and potassium pyruvate are unsuitable, however, for therapeutic applications or as food supplements when considering their content of sodium and potassium ions, respectively. Magnesium and calcium pyruvate, although safe from the physiological point of view, has the distinct disadvantage of not having a sufficiently long shelf life, since the magnesium and calcium ions rapidly accelerate the decomposition of pyruvic acid and pyruvate ions to form dimers, polymers, cyclic compounds and so on. The object of this invention is therefore to develop pyruvic acid forms which are physiologically safe and at the same time have a sufficiently long shelf life. This object is established according to the invention by providing creatine pyruvates having the formula (I) (creatine) x (pyruvate) and (H20) n, (I) where x = 1 to 100 y = 1 to 10 and n = 0, to 10. Based on the stoichiometric requirements, creatine is present in the compounds of formula (I) in uncharged or cationic form, and pyruvate as acid ascorbic or as anion. Surprisingly, it has been found that the creatine pyruvates of the invention have a prolonged shelf life, although pyruvic acid is a highly unstable 2-oxocarboxylic acid and the known creatine salts readily decompose to form creatinine. Since creatine is presented as an internal salt and is only a weak base, it is not predictable that stable creatine salts can be prepared from monocarboxylic acids. Specifically, according to the prior art, only creatine salts of strong dicarboxylic and polycarboxylic acids have been known to date (see WO 96/04 240). The creatine pyruvates of the invention, having the general formula (I), contain the physiologically safe creatine cation of formula (II).

Creatine is only an endogenous substance and a valuable food supplement, but it also has other useful therapeutic properties. It has been known for more than 100 years as a muscle substance and serves as a source of energy for the muscle. In a series of scientific studies it has been shown that the ingestion of creatine can lead to an increase in muscle tissue and muscle function. There are also scientific findings which indicate that the pancreas releases more insulin under the influence of creatine. Insulin promotes the uptake of glucose and amino acids by muscle cells and stimulates protein synthesis. Insulin also decreases the rate of protein catabolism. The pyruvate anion in the creatine pyruvates of the invention usually assume the structure of formula (III).

In these creatine pyruvates which contain water of crystallization, the pyruvate anion also assumes the 2,2-dihydroxy form, according to the formula (IV): The creatine pyruvates according to the invention comprise salts which preferably contain the cation creatine and the pyruvate anion or the anion 2., 2-dihydroxypropionate, in a molar ratio of 1: 1 and a molar ratio of approximately 1: 1. The compounds of the invention can also be mixtures of salts with creatine or pyruvic acid. The creatine pyruvates of the invention can be produced by means of a relatively simple reaction of creatine with pyruvic acid in the temperature range of -10 to 90 ° C, preferably in the temperature range of 10 to 30 ° C. Creatine and pyruvic acid react here in a molar ratio of 100: 1 to 1:10, preferably 5: 1 to 1: 2. For this reaction, creatine can be used in anhydrous form, as a monohydrate or as a wet product. The pyruvic acid can be used as anhydrous acid or in the form of an aqueous solution. The reaction can be carried out in the presence or absence of a solvent or dilution agent. A wide range of polar solvents are suitable as solvents or dilution agents. Preference is given to alcohols (such as methanol, ethanol, isopropanol or cyclohexanol), ethers (such as diethyl ether, tetrahydrofuran, 1,4-dioxane or ethylene dimethyl ether), ketones (such as acetone, methyl ethyl ketone or cyclohexanone), esters (such as acetate) of methyl, ethyl acetate or ethyl formate) or mixtures thereof. The reaction can be carried out using standard technical apparatuses such as mixers, blade driers and agitator vessels. Creatine pyruvates with water of crystallization are obtained by adding giant water or after the reaction of pyruvic acid with creatine and / or by using aqueous creatine and / or aqueous pyruvic acid. The scope of this invention also allows the addition - during or after the production of the creatine pyruvates - of other additional substances, such as pharmaceutical formulation additives, vitamins, mineral substances, trace elements, carbohydrates such as glucose, dextrose or maltose, and amino acids such L-carnitine or other food supplements. The subject matter of the invention therefore also comprises physiologically compatible compositions which contain creatine pyruvates and at least one additional, physiologically compatible substance, which is selected from the group comprising pharmaceutical adjuvants or carriers, vitamins, mineral substances, carbohydrates, amino acids or other food supplements. By virtue of their optimum properties, such as being physiologically safe, having a prolonged shelf life, being highly soluble in water and having good bioavailability, the creatine pyruvates of the invention are suitably located for therapeutic applications in medicine and as food supplements, They show useful biological and medical properties for both pyruvates and creatine. Surprisingly, when used in medicine and as food supplements, the creatine pyruvates of the invention show remarkable synergistic effects. They are especially suitable in this context to treat conditions of oxygen deficiency (ischemia) overweight and obesity, since the decomposition of the muscular substance during the treatment is reduced; an effect of muscular improvement of creatine pyruvate is particularly important in the case of food cures. These creatine pyruvates also prevent the formation of free radicals, and act as a scavenger of free radicals and oxygen oxidizing species. The synergistic effects are also especially evident when creatine pyruvate is used in the sports field to improve long-term performance. The following examples serve to explain the invention in greater detail.

Shaft-triplos Example 1 Dissolve 26.4 g (0.3 mole) of pyruvic acid at room temperature in 100 ml of ethyl acetate, add 26.2 g (0.2 mole) of creatine to this solution and stir the mixture for 4 hours. Then, the white, finely crystalline product is filtered off and washed twice with 25 ml of ethyl acetate. It is dried for 4 hours at 50 ° C in a vacuum drying chamber. The yield is 95.0%. Creatine pyruvate (1: 1) melts at 106 to 110 ° C and decomposes (capillary). Elemental analysis C17H13N305: calculated: C 38.36%, H 5.94%, N 19.18%; found: C 38.23%, H 6.06%, N, 19.28%, IR (KBr) [1 / cm]: 620, 829, 880, 976, 1049, 1110, 1177, 1209, 1269, 1354, 1404, 1605, 1663 , 1697, 1734, 1763, 2518, 2593, 3147, 3397; X H NMR (DzO, 300 MHz): d = 2.34 (s, 3 H, MeCO), 3.08 (s, 3 H, Me-N), 4.06 (s, 2 H, CH 2); content by CLAP: creatine 59.8%, pyruvic acid 40.2%.

Example 2 Mix 26.2 g (0.2 mole) of creatine with 17.6 g (0.2 moles) of pyruvic acid in a mortar. The mixture becomes increasingly viscous and finally solidifies into a white, finely crystalline product, the yield is quantitative (> 99%). Creatine pyruvate (1: 1) melts at 109 to 114 ° C and decomposes (capillary).

Example 3 29.8 g (0.2 mole) of creatine monohydrate is intimately mixed with 35.2 g (0.4 mole) of pyruvic acid in a glass beaker. The mixture is allowed to stand, and finally solidifies to a white, finely crystalline product. It is ground in a mortar and dried for 4 hours at 50 ° C in a vacuum drying chamber. The yield is quantitative (> 99%). The creatine pyruvate obtained in this way (1: 2) melts at 90-95 ° C and decomposes (capillary).

Example 4 29.8 g (0.2 mole) of creatine monohydrate are mixed in a mortar with 8.8 g (0.1 mole) of pyruvic acid and 20 ml of tetrahydrofuran are added. The mixture becomes increasingly viscous, and finally solidifies to a white, finely crystalline product, which dries for 4 hours at 50 ° C in a vacuum drying chamber. The yield is quantitative (> 99%). Creatine pyruvate (2: 1) melts at 118 to 120 ° C decomposes (capillary).

Claims (10)

1. Creatine pyruvates with the general formula (I) (creatine) x (pyruvate) and (H20) n, (I) where x = 1 to 100 y = 1 to 10 and n = 0, to 10.

2. Creatine pyruvates, according to claim 1, characterized in that x = 1 to 5, y = l to 2 and n = 0 to 23.

Creatine pyruvates, according to one of claims 1 and 2, characterized in that the pyruvate anion is present as a 2,2-dihydroxypropionate anion.

4. A method for producing creatine pyruvates, according to one of claims 1 to 3, characterized in that the pyruvic acid and creatine react in a molar ratio of 100: 1 to 1:10 of creatine relative to pyruvic acid at temperatures of - 10 to 90 ° C.

5. The method according to claim 4, characterized in that the molar ratio of creatine to pyruvic acid is from 5: 1 to 1: 2.

6. The method according to one of claims 4 and 5, characterized in that the reaction is carried out at temperatures between 10 and 30 ° C.

7. The method according to one of claims 4 to 6, characterized in that the reaction is carried out in the presence of a polar solvent.

8. The method according to claim 7, characterized in that alcohols, ethers, ketones, esters or mixtures thereof are used as solvents.

9. Physiologically compatible compositions which contain the creatine pyruvates according to one of claims 1 to 3, and at least one additional physiologically compatible substance selected from the group comprising pharmaceutical adjuvants or carriers, vitamins, mineral substances, carbohydrates, amino acids and other food supplements.

10. The use of creatine pyruvates according to one of claims 1 to 3, characterized in that it is used for the manufacture of an agent to improve long-term performance and strength in the field of sport, to reduce weight and fat body in the field of health, in the treatment of conditions of oxygen deficiency (ischemia), body fat and overweight, and to eliminate free radicals, as well as for food supplement.