RU2228174C2 - Bis-(2=hydroxy-n,n,n-trimethylethaneaminium) succinate for treatment of insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia - Google Patents

Abstract

FIELD: organic chemistry, medicine, endocrinology. SUBSTANCE: invention concerns an agent used for treatment of insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia. Agent comprises bis-(2-hydroxy-N,N, N-trimethylethaneaminium) choline salt succinate. Invention relates also to method for it preparing. EFFECT: valuable medicinal properties and enhanced effectiveness of agent. 4 cl, 2 ex

Description

The invention relates to a new salt of choline, namely succinic acid bis (2-hydroxy-N, N, N-trimethylethanamine), a method for producing this salt and its use in medicine, in particular for the treatment of insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia.

Insulin is the main anabolic hormone of the body, which has many biological effects in the tissues of the body. Insulin stimulates the absorption of glucose by muscles and adipose tissue, inhibits the production of glucose by the liver, regulates lipid metabolism in plasma and tissues, protein synthesis, cell growth and electrolyte balance.

Insulin resistance is defined terminologically as "a disturbed biological response to exogenous or endogenous insulin" (Consensus development conference on insulin resistance. Diabetes Care. 1998, vol. 21 (2): p.310).

It is known that insulin resistance is an important cause of non-insulin-dependent diabetes mellitus and a group of abnormalities including hyperlipidemia, dyslipidemia, glucose tolerance, high blood pressure and decreased fibrinolytic activity of blood plasma (Reaven, GM Physiol-Rev., 1995, vol. 75 (3): p. 473). Insulin resistance accompanies a number of diseases, such as diabetes, obesity, aging, atherosclerosis, cardiovascular syndrome X, HIV, cancer, sepsis; burn injury; malnutrition, lupus and other autoimmune diseases, endocrine diseases, polycystic ovary syndrome; or complications arising from sports.

Clinically, insulin resistance manifests itself in pathologically elevated plasma insulin levels and can be assessed by measuring fasting plasma insulin concentrations.

WHO defines diabetes as "metabolic disorders of multiple etiologies, characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both."

Clinically, diabetes mellitus manifests itself in pathologically elevated glucose levels and can be assessed by measuring fasting plasma glucose concentrations.

Choline is a necessary component of food that improves the function of the liver, cardiovascular system and lowers cholesterol. At the same time, choline does not reduce plasma insulin levels with insulin resistance and does not reduce plasma glucose levels in diabetes.

Succinic acid and its salts were described in Japanese patent JP 61171417 as antidiabetics useful for stimulating insulin secretion. Contrary to JP 61171417, a later work 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 was described in Japanese patent JP 6062798 as a food component for a person with impaired glucose tolerance in combination with acetic, lactic and gluconic acid. Sodium succinic acid has been described as a component of the composition along with citric and acetic acid to lower blood glucose in rabbits with alloxan diabetes (Dzvonkevich, ND et al., Ukr. Biokhim. Zh., 46 (5): 547-552 (1974). The treatment of insulin resistance with succinic acid or its salts has been described in international application PCT / RU 99/00055.

A disadvantage of the treatment of insulin resistance and succinic acid diabetes is the low effectiveness of these drugs, especially for the treatment of lipid metabolism disorders associated with insulin resistance.

The objective of the invention is to provide an effective treatment for insulin resistance, diabetes, hyperlipidemia and dyslipidemia.

The problem is achieved by using for the treatment of insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia of a new salt of choline, succinic bis (2-hydroxy-N, N, N-trimethylethanaminium), having the chemical formula:

[(CH ₃ ) ₃ N ⁺ CH ₂ CH ₂ OH] $\genfrac{}{}{0ex}{}{\text{-}}{\text{2}}$ OOCCH ₂ CH ₂ COO ^-

Succinic bis (2-hydroxy-N, N, N-trimethylethanamine) is prepared by reacting a choline base with succinic acid in a suitable solvent, for example, water, ethyl or methyl alcohol. Preferably, the choline base is reacted with succinic acid in a molar ratio of 2: 1, but not lower 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 a white crystalline substance with reproducible properties.

The preferred effect in the treatment of insulin resistance achieved with the use of succinic bis (2-hydroxy-N, N, N-trimethylethanaminium) is to reduce plasma insulin levels.

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

The preferred effect in the treatment of hyperlipidemia achieved with the use of succinic bis (2-hydroxy-N, N, N-trimethylethanaminium) is to reduce pathologically elevated plasma triglycerides and cholesterol levels.

The preferred effect in the treatment of dyslipidemia, achieved with the use of succinic bis (2-hydroxy-N, N, N-trimethylethanaminium), is to reduce pathologically elevated levels of LDL and increase pathologically lower levels of HDL in plasma.

The following examples demonstrate the invention.

Example 1. Succinic bis (2-hydroxy-N, N, N-trimethylethanamine) and the method for its preparation.

To a solution of 121 g (1 mol) of a choline base in methanol was added 59 g (0.5 mol) of succinic acid. The reaction mixture was stirred at room temperature for 20 minutes and concentrated at 40-50 ° C in vacuo until crystallization. Succinic bis (2-hydroxy-N, N, N-trimethylethanamine) was obtained in quantitative yield: mp. 135-137 ° C (from tert-butanol); NMR ¹ H (D ₂ O): δ 2.24 (s, 4H), 3.07 (s, 18H), 3.38 (m, 4H), 3.93 (m, 4H). ¹³ C NMR (D ₂ O): 34.5, 54.2, 56.0, 67.8, 182.6. Calculated (C ₁₄ H ₃₂ O ₆ ),%: C 51.83; H, 9.94. Found,%: C 51.66; H, 9.86.

Example 2. Succinic bis (2-hydroxy-N, N, N-trimethylethanamine) for the treatment of insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia.

Plasma insulin concentration was determined using the Daco kit (Holland) and rat insulin (Novo Research Institute, Denmark) as a standard. Plasma glucose concentration was determined using the Agat kit (Russia). Plasma triglycerides and cholesterol concentrations were determined using reagents FS, DiaSys (Germany), HDL Cormay (Poland), and LDL Boehringer Mannheim (Germany).

Diabetes mellitus was caused in male Wistar rats (age 8-10 weeks, weight 210-230 g) by double intravenous injection of alloxan (40 mg / kg) with a break of 48 hours. Rats were used in experiments on the sixth day.

Succinic bis (2-hydroxy-N, N, N-trimethylethanamine) was injected into the tail vein of rats (n = 10) at a dose of 120 mg / kg in the form of an aqueous solution for three days. In the control, rats (n = 10) were injected with saline. Levels of glucose, insulin, cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL) and triglycerides were measured in fasting plasma on the seventh day, starting from the first day of treatment. The data are presented in the table as mean ± standard deviation. The reliability of the difference between the results obtained in the experiment and the control was evaluated by the t-student criterion.

Sources of information

1. Japan patent N 61171417.

2. Japan Patent N 6062798.

3. MacDonald, M.J. and Fahien, L.A., Diabetes, 1988, vol. 37 (7): pp. 997-999.

4. Dzvonkevich, N.D. et al., Ukr. Biokhim. Zh., 1974, vol. 46 (5): pp. 547-552.

International application PCT / RU 99/00055.

Claims (4)

1. Succinic bis (2-hydroxy-N, N, N-trimethylethanamine). 2. A method of producing succinic bis (2-hydroxy-N, N, N-trimethylethanamino), characterized in that the choline base is reacted with succinic acid. 3. The method of producing succinic bis (2-hydroxy-N, N, N-trimethylethanamino) according to claim 2, characterized in that the molar ratio of choline base to succinic acid is approximately 2: 1, but not lower than 1.9: 1 and no higher than 2.1: 1. 4. Succinic bis (2-hydroxy-N, N, N-trimethylethanamine) for the manufacture of a treatment for insulin resistance, diabetes mellitus, hyperlipidemia and dyslipidemia.