Alternately bis(2-hydroxy-n,n,n-trimethylmethanaminium) for the treatment of insulin resistance, diabetes, hyperlipidemia and dyslipidemia

 

(57) Abstract:

The invention relates to the field of medicine and relates to a treatment for insulin resistance, diabetes, hyperlipidemia and dyslipidemia, containing a new salt of choline alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium), and method of its production. The tool has a high efficiency. 3 S. and 1 C.p. f-crystals, 1 table.

The invention relates to new salts of choline, namely Encarnacion bis(2-hydroxy-N,N,N-trimethylmethanaminium), the way to obtain this salt and use it in medicine, in particular for the treatment of insulin resistance, diabetes, hyperlipidemia and dyslipidemia.

Insulin is the major anabolic hormone of the body that have many biological effects in tissues. Insulin stimulates the uptake of glucose by muscle and adipose tissue, inhibits the production of glucose by the liver, regulates lipid metabolism in plasma and tissues, protein synthesis, cell growth and the balance of electrolytes.

Insulin resistance is defined terminology as "impaired biological response to exogenous or endogenous insulin" (Consensus development conference on insulin resistance. Diabetes Care. 1998, vol. 21(2): p.310). the about diabetes and groups of anomalies, including hyperlipidemia, dyslipidemia, impaired glucose tolerance, high blood pressure and reduced fibrinolytic activity of blood plasma (Reaven, G. M. Physiol-Rev., 1995, vol. 75(3): p 473). Insulin resistance is accompanied by a number of diseases, such as diabetes, obesity, aging, atherosclerosis, cardiovascular X syndrome, HIV, cancer, sepsis; trauma associated with burns; malnutrition, lupus and other autoimmune diseases, endocrine diseases, polycystic ovarian syndrome; or complications arising as a result of sports activities.

Clinically, insulin resistance is manifested in the pathologically elevated levels of insulin and plasma can be estimated by measuring the concentration of insulin in plasma shock.

Who defines diabetes as a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia resulting due to defects in insulin secretion, insulin action, or both".

Clinically diabetes is manifested in the pathologically elevated levels of glucose and can be estimated by measuring the concentrations of plasma glucose on an empty stomach.

Choline is an essential component of food, improve the function Pease with insulin resistance and does not reduce the level of plasma glucose in diabetes.

Succinic acid and its salts have been described in Japanese patent JP 61171417 as antidiabetic, useful for stimulating insulin secretion. Contrary to the patent JP 61171417, in later work it was proved that succinic acid and its salts are not able to stimulate the secretion of insulin by the pancreas (MacDonald, M. J. and Fahien, L. A. Diabetes 37(7): 997-999, 1988). Succinic acid has been described in Japanese patent JP 6062798 as a component of food for people with impaired glucose tolerance in combination with acetic, lactic and gluconic acid. Alternately sodium has been described as a component of the composition along with citric and acetic acid to reduce the level of glucose in the blood of rabbits with alloxan diabetes (Dzvonkevich, N. D. et al., Ukr. Biokhim. Zh., 46(5):547-552(1974). Treatment of insulin resistance succinic acid or its salts has been described in international application PCT/EN 99/00055.

The lack of treatments for insulin resistance and diabetes on the basis of succinic acid is the low efficiency of these funds, especially for the treatment of disorders of lipid metabolism associated with insulin resistance.

The objective of the invention is to provide an effective means of treating insulin resistance, diabetes Diab is sulinowo resistance, diabetes mellitus, hyperlipidemia and dyslipidemia new salt of choline, yantarnokislogo bis(2-hydroxy-N,N,N-trimethylmethanaminium) having a chemical formula of:

[(CH3)3N+CH2CH2HE]-2OOCCH2CH2SOO-

Alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium) is obtained by reaction of the base of choline with succinic acid in a suitable solvent, for example water, ethyl or methyl alcohol. Preferably, the base choline is introduced into the reaction with succinic acid in a molar ratio of 2:1, but not less than 1.9:1 and not higher than 2.1:1. The reaction is carried out at ambient temperature. The desired product is obtained in the form of white crystalline substance with reproducible properties.

The preferred effect in the treatment of insulin resistance achieved using yantarnokislogo bis(2-hydroxy-N,N,N-trimethylmethanaminium), is to reduce the levels of insulin in plasma.

The preferred effect in the treatment of diabetes achieved using yantarnokislogo bis(2-hydroxy-N,N,N-trimethylmethanaminium), is to reduce the pathologically elevated levels of glucose in the blood plasma.

N the-N,N,N-trimethylmethanaminium), is to reduce the pathologically elevated levels of triglycerides and cholesterol in plasma.

The preferred effect in the treatment of dyslipidemia made using yantarnokislogo bis(2-hydroxy-N,N,N-trimethylmethanaminium), is to reduce the pathologically elevated levels of LDL and increase pathologically low levels of HDL in plasma.

The following examples illustrate the invention.

Example 1. Alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium) and how to obtain it.

To a solution of 121 g (1 mol) of the Foundation of choline in methanol was added 59 g (0.5 mol) of succinic acid. The reaction mixture was stirred at room temperature for 20 min and then concentrated at a temperature of 40-50C under vacuum until crystallization. Alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium) obtained with a quantitative yield: So pl. 135-S (tert-butanol); NMR1N (D2): 2,24 (s, 4H), of 3.07 (s, N), to 3.38 (m, 4H), 3,93 (m, 4H). NMR13WITH (D2About): 34,5, 54,2, 56,0, 67,8, 182,6. Calculated (C14H32ABOUT6), %: 51,83; N 9,94. Found, %: 51,66; N 9,86.

Example 2. Alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium) for the treatment of insulin resistance, diabetes, hyperlipidemia) and rat insulin (Novo Research Institute, Denmark) as standard. The concentration of glucose in plasma was determined using a set of "agate" (Russia). The concentration of triglycerides and cholesterol in plasma was determined using reagents FS, "DiaSys" (Germany), HDL "Cormay" (Poland), LDL Boehringer Mannheim (Germany).

Diabetes was induced in rats male Wistar (age 8-10 weeks, weight 210-230 g) twice intravenous injection alloxan (40 mg/kg) with an interval of 48 hours, the Rats were used in experiments on the sixth day.

Alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium) was injected into the tail vein of rats (n=10) at a dose of 120 mg/kg in aqueous solution for three days. In the control rats (n=10) was injected with saline. The levels of glucose, insulin, cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride levels were measured in plasma taken on an empty stomach on the seventh day, beginning with the first day of treatment. The data presented in the table as the average standard deviation. Significant differences of the results obtained in the experiment to control, was evaluated by t-criterion of student.

Sources of information

1. The Japan Patent N 61171417.

2. P is 1974, vol. 46(5): pp.547-552.

International application PCT/EN 99/00055.

1. Alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium).

2. The method of obtaining yantarnokislogo bis(2-hydroxy-N,N,N-trimethylmethanaminium), characterized in that the base choline is introduced into the reaction with succinic acid.

3. The method of obtaining yantarnokislogo bis(2-hydroxy-N,N,N-trimethylmethanaminium) under item 2, characterized in that the molar ratio of the base of choline to succinic acid is about 2:1, but not below 1.9:1 and not more than 2,1:1.

4. Alternately bis(2-hydroxy-N,N,N-trimethylmethanaminium) for the production of the means of treating insulin resistance, diabetes, hyperlipidemia and dyslipidemia.

 

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