HK1020718B - Creatine pyruvates and method for their production - Google Patents

Description

Creatine pyruvate and production method thereof

The present invention relates to creatine pyruvates, which are pyruvic acid and the anhydrous or hydrated forms of creatine and mixtures of these salts with creatine or pyruvic acid, and to a process for their production.

It is well known that salts of pyruvic acid, i.e. pyruvate, have very valuable physiological and therapeutic properties for the treatment of various diseases, such as obesity and overweight, and can be used for the prevention of free radical formation and for enhancing endurance (see US5508308, US5480909, US5472980, US5395822, US5312985, US5283260, US5256697, US4548937 and US 4351835).

Alkali and alkaline earth metal pyruvates are known in the art, however, the sodium and potassium salts of pyruvic acid are unsuitable for therapeutic use or as dietary supplements due to the sodium and potassium ions, respectively, they contain. Magnesium and calcium salts of pyruvic acid, while safe from a physiological point of view, have the obvious disadvantage of not having a sufficiently long shelf life, since magnesium and calcium ions strongly accelerate the decomposition of pyruvic acid and pyruvate ions to form dimers, polymers, cyclic compounds, etc.

It was therefore an object of the present invention to develop a pyruvic acid product which is physiologically safe and at the same time has a sufficiently long shelf life.

In particular, it is an object of the present invention to provide creatine pyruvates of formula (I)

(creatine)_x(pyruvic acid)_y(H₂O)_n(I) Wherein x is 1-100

y＝1－10

n＝0－10。

In a preferred embodiment of the present invention, x is 1 to 5, y is 1 to 2, and n is 0 to 2.

Depending on the stoichiometric requirement, in the compounds of the formula (I), creatine is present in uncharged form or in cationic form and pyruvate in pyruvic acid or in anionic form.

Surprisingly, the creatine pyruvates of the present invention have a long shelf life, although pyruvic acid is a very unstable 2-oxocarboxylic acid and known creatine salts decompose easily to form creatinine. Since creatine is present as an internal salt and is a weak base, it is difficult to predict that stable creatine salts can be prepared from monocarboxylic acids. According to the state of the art, only strong creatine salts of di-and polycarboxylic acids have been known so far (see WO 96/04240).

The creatine pyruvate of the invention has the general formula (I) and contains physiologically safe creatine cations of formula (II).

Creatine is not only an endogenous substance and a valuable dietary supplement, but also has valuable therapeutic properties. Creatine has been known for over 100 years ago as an intramuscular substance and a source of muscle energy. A series of scientific studies have demonstrated that creatine uptake can lead to increased muscle tissue and improved muscle performance. Scientific studies have also shown that under the influence of creatine, the pancreas releases more insulin. Insulin promotes glucose and amino acid uptake by muscle cells and stimulates protein synthesis. Insulin also decreases the rate of protein catabolism.

The pyruvate anion in creatine pyruvate according to the invention generally exhibits the structure of formula (III).

In creatine pyruvate with crystal water, the pyruvate anion can also be in the form of 2, 2-dihydroxy of formula (IV):

the creatine pyruvates of the present invention include salts in which the molar ratio of creatine cation to pyruvate anion or 2, 2-dihydroxypropionate anion is preferably 1: 1 or in a molar ratio close to 1: 1. The compounds of the invention may also be mixtures of these salts with creatine or pyruvic acid.

The creatine pyruvates of the invention may be produced by a relatively simple reaction of creatine and pyruvic acid, carried out at a temperature of-10 to 90 c, preferably 10 to 30 c. Creatine and pyruvic acid are reacted in a molar ratio of 100: 1 to 1: 10, preferably 5: 1 to 1: 2. The creatine used in the reaction may be in anhydrous form, monohydrate form or a wet product. The pyruvic acid used may be in the form of an anhydrous acid or an aqueous solution.

The reaction is carried out with or without solvent or diluent. A wide variety of polar solvents are suitable as solvents or diluents. Among them, preferred are alcohols (e.g., methanol, ethanol, isopropanol or cyclohexanol), ethers (e.g., diethyl ether, tetrahydrofuran, 1, 4-dioxane or ethylene glycol dimethyl ether), ketones (e.g., acetone, methyl ethyl ketone or cyclohexanone), esters (e.g., methyl acetate, ethyl acetate or ethyl formate) or a mixture thereof.

The reaction can be carried out using conventional apparatus such as mixers, blade dryers and stirred vessels.

Creatine pyruvate containing crystal water can be produced by adding water and/or aqueous creatine and/or aqueous pyruvic acid to the reaction during or after the reaction between pyruvic acid and creatine. The invention also comprises the addition of other substances, such as pharmaceutical formulation additives, vitamins, minerals, trace elements, carbohydrates such as glucose, dextrose or maltose and amino acids such as L-carnitine or other dietary supplements, during or after the production of creatine pyruvate.

Accordingly, the object of the present invention also includes physiologically compatible compositions comprising creatine pyruvate in combination with at least one other physiologically compatible substance selected from the group consisting of pharmaceutical adjuvants or carriers, vitamins, minerals, carbohydrates, amino acids or other food additives.

The creatine pyruvates of the present invention are particularly suitable for pharmaceutical therapeutic applications or as dietary supplements and may exhibit both the valuable biological and pharmaceutical properties of pyruvate and creatine due to their excellent properties, such as being physiologically safe, long shelf life, highly soluble in water and highly bioavailable.

Surprisingly, the creatine pyruvates of the present invention exhibit a significant synergistic effect when used in medicine as well as a dietary supplement. They are particularly suitable for the treatment of hypoxic conditions (ischemia), overweight and obesity, since the catabolism of muscle mass is reduced during the treatment; the muscle-strengthening effect of creatine pyruvate is particularly important in dietetic therapy. These creatine pyruvates also prevent the formation of free radicals and can act as scavengers for free radicals and oxidative species of oxygen. The synergistic effect is also particularly evident when creatine pyruvate is used to enhance endurance.

The following examples serve to illustrate the invention in more detail. Examples

Example 1

26.4g (0.3mol) of pyruvic acid are dissolved in 100ml of ethyl acetate at room temperature. To this solution 26.2g (0.2mol) of creatine are added and the mixture is stirred for 4 hours. The white, finely crystalline product is then isolated by filtration and washed 2 times with 25ml of ethyl acetate.It was dried in a vacuum drying chamber at 50 ℃ for 4 hours. The yield thereof was found to be 95.0%. The creatine pyruvate (1: 1) melts and decomposes at 106-110 deg.C (capillary). Elemental analysis C₇H₁₃N₃O₅: calculated values: 38.36% of C, 5.94% of H and 19.18% of N; measured value: 38.23% of C, 6.06% of H and 19.28% of N; IB (KBr) [1/cm]：620，829，880，976，1049，1110，1177，1209，1269，1354，1404，1605，1663，1697，1734，1763，2518，2593，3147，3397；¹H-NMR(D₂O，300MHz)：6＝2.34(s，3H，MeCO)，3.08(s，3H，Me-N)，4.06(s，2H，CH₂) (ii) a HPLC content: creatine 59.8% and pyruvic acid 40.2%.

Example 2

26.2g (0.2mol) of creatine are mixed with 17.6g (0.2mol) of pyruvic acid in a mortar. The mixture gradually increased in viscosity and finally solidified into a white, finely crystalline product. The yield was quantitative (> 99%). The creatine pyruvate (1: 1) melts and decomposes at 109-114 deg.C (capillary).

Example 3

29.8g (0.2mol) of creatine monohydrate are intimately mixed with 35.2g (0.4mol) of pyruvic acid in a glass beaker. The mixture was left to solidify to a white fine crystalline product. It was ground in a mortar and dried in a vacuum drying chamber at 50 ℃ for 4 hours. The yield was quantitative (> 99%). The creatine pyruvate thus obtained (1: 2) melts and decomposes at 90-95 deg.C (capillary tube).

Example 4

29.8g (0.2mol) of creatine monohydrate are mixed with 8.8g (0.1mol) of pyruvic acid in a mortar and 20ml of tetrahydrofuran are added. The mixture gradually increased in viscosity and finally solidified to a white fine crystalline product, which was dried in a vacuum drying chamber at 50 ℃ for 4 hours. The yield was quantitative (> 99%). The creatine pyruvate (2: 1) melts and decomposes at 118-120 deg.C (capillary).

Claims (10)

1. Creatine pyruvates of the general formula (I)

(creatine)_x(pyruvic acid)_y(H₂O)_n (I)

Wherein x is 1-100

y＝1－10

n＝0－10。

2. The creatine pyruvate of claim 1, wherein the creatine is,

wherein

x＝1－5，y＝1－2，n＝0－2。

3. The creatine pyruvate of any one of claims 1 and 2,

wherein

The pyruvate anion is present as a 2, 2-dihydroxypropionate anion.

4. A process for producing creatine pyruvate according to any one of claims 1 to 3,

wherein

Pyruvic acid and creatine are mixed in a molar ratio of 100: 1 to 1: 10 creatine: pyruvic acid is reacted at a temperature of-10 to 90 ℃.

5. The method of claim 4, wherein the step of treating the substrate,

wherein

The molar ratio of creatine to pyruvic acid is 5: 1 to 1: 2.

6. The method of any one of claims 4 and 5,

wherein

The reaction is carried out at a temperature of 10 to 30 ℃.

7. The method of claim 4 or 5, wherein,

wherein

The reaction is carried out in the presence of a polar solvent.

8. The method of claim 7, wherein the step of treating the substrate,

wherein

Alcohols, ethers, ketones, esters or mixtures thereof are used as solvents.

9. Physiologically compatible compositions comprising creatine pyruvate according to any of claims 1 to 3 and at least one other physiologically compatible substance selected from the group consisting of pharmaceutical adjuvants or carriers, vitamins, minerals, carbohydrates, amino acids or other food additives.

10. Use of creatine pyruvate according to any of claims 1 to 3 for the preparation of a preparation for increasing endurance and strength in the field of sports, for reducing body weight and body fat in the health field, for treating hypoxic conditions, obesity and overweight, and for scavenging free radicals and as a dietary supplement.