RU2467744C1 - 3-(2,2,2-trimethylhydrazinium) propionate derivative - 3-(2,2,2-trimethylhydrazinium) potassium propionate 5-nicotinate hydroxide exhibiting endothelioprotective activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate derivative, namely 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-nicotinate hydroxide showing endothelioprotective activity.

EFFECT: preparing the compound which can find application in medicine in the integrated treatment for endothelial dysfunction correction in cardiovascular diseases.

1 tbl, 2 ex

Description

The invention relates to medicine, specifically to new chemical compounds - 5- hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate with endothelial protective activity.

Known pharmaceutical composition containing 3- (2,2,2-trimethylhydrazinium) propionate, D-glucuronic acid, isotonic solution to stimulate hematopoiesis (RU No. 2033152, publ. 20.04.1995).

Known combination, which includes oral hypoglycemic drugs, angiotensin converting enzyme (ACE) inhibitors, antioxidants and 3- (2,2,2-trimethylhydrazinium) propionate, which allows to reduce the severity of symptoms of perineural ischemia (RU No. 2402325, publ. 10.27.2010) .

The proposed pharmaceutical compositions are a combination comprising two or more compounds with 3- (2,2,2-trimethylhydrazinium) propionate acting unidirectionally to increase effectiveness in the treatment of diseases of the cardiovascular system. But the use of several components in treatment increases the possibility of side effects of a single drug, the inconvenience of use for the patient, and the likelihood of an unpredictable effect when interacting.

It is known to use pharmaceutical compositions containing 3- (2,2,2-trimethylhydrazinium) propionate dihydrate (mildronate) and a salt and / or salts of succinic acid, in solid and / or liquid form, as anti-ischemic, antihypoxic, antioxidant when used in acute and subacute stages of various hypoxic conditions, in particular in patients with acute myocardial infarction and heart failure (RU No. 2005125660, publ. 02.20.2007).

The endothelioprotective efficacy of 3- (2,2,2-trimethylhydrazinium) propionate (mildronate) itself (M.V. Korokina and E.V. Artyushkova et al. (Endothelioprotective properties of enalapril and mildronate) is known. Scientific statements of the Belarusian State University. Series of Medicine. Pharmacy 2011 , No. 4, pp. 57-61, “Endothelio- and cardioprotective effects of the cytoprotector of the metabolic action of meldonium in experimental modeling of nitric oxide deficiency”, collection of tr. Interuniversity scientific conferences, dedicated to the memory of Prof. Vladislav Pichugin and the 75th anniversary of KSMU , Kursk 2009, p. 95-97).

In experimental modeling of arterial hypertension in animals, an increase in reactive oxygen species leads to endothelial dysfunction, which is confirmed by an improvement in endothelium-dependent relaxation with the introduction of antioxidants. Currently, drugs with antioxidant properties are considered promising for the correction of endothelial dysfunction, since the main mechanism underlying endothelial dysfunction is a decrease in the production and bioavailability of NO while increasing the superoxide anion, which has the ability to inhibit the expression and activity of endothelial NO synthase ( eNOS), as well as bind and inactivate NO, reduce its content in the cell. A shift in the physiological equilibrium between NO and O ² leads to the formation of highly toxic pyroxynitrite (ONOO ^- ), 3- (2,2,2-trimethylhydrazinium) propionate (mildronate) itself does not have antioxidant properties, but increases the concentration of gamma-butyrobetaine (GBB) in the body , since under the influence of mildronate it is more slowly oxidized to carnitine. In turn, GBB is able to induce the formation of nitric oxide (NO), which acts as one of the most active natural agents that bind free radicals in the body. The mechanism of endothelioprotective action of mildronate is indirect, i.e. By increasing the amount, GBB is able to protect cells from the effects of free radicals, but this is done through the induction of NO biosynthesis.

Taking into account the importance of changing antioxidant status as one of the most important ways of realizing an increase in the endothelioprotective activity of mildronate, it is necessary to increase its antioxidant effect, which contributes to an increase in endothelial protective properties.

The objective of the invention is the creation of a new derivative of 3- (2,2,2-trimethylhydrazinium) propionate, which has a more pronounced endothelioprotective activity.

This object is achieved in that a new derivative of 3- (2,2,2-trimethylhydrazinium) propionate is created, obtained by reacting 3- (2,2,2-trimethylhydrazinium) propionate with potassium hydroxide and 5-hydroxynicotinic acid in the presence of a solvent when heated .

possessing endothelioprotective activity.

Modification of 3- (2,2,2-trimethylhydrazinium) propionate - 5-hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate - is a new chemical compound and exhibits the most pronounced endothelioprotective and antioxidant effects before the reference drug - mildronate, by introducing a new functional group

(5-hydroxynicotinate), which allowed to strengthen the endothelioprotective property of the new chemical compound.

It is known that the introduction of the functional group of 5-hydroxynicotinate in the molecule allows one to exhibit antidiabetic (Liepinsh E. et al.), Lipid-lowering effects, as well as antioxidant activity of this group, which is realized by normalizing the content of lipid peroxidation products in red blood cells (Smirnov L.D. ., Terekhina et al., 1999), thereby this group will provide an increase in the endothelioprotective effect and enable wider use of the new derivative for the prevention and treatment of se dechno disease.

The proposed new derivative is not described in patent and scientific literature.

An example of obtaining 5-hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate.

To a solution of 1.46 g (0.024 mol) of potassium hydroxide in 40 ml of 2-propanol at 30-32 ° C with stirring, add 3.5 g (0.024 mol) of 3- (2,2,2-trimethylhydrazinium) propionate and incubated 20 -25 minutes. 3.34 g (0.024 mol) of 5-hydroxynicotinic acid are loaded into the resulting solution, stirred for 30 minutes, cooled to 5-8 ° C, crystallized. The precipitate formed is separated, washed with 2 × 5 ml of chilled 2-propanol, dried, and 8.1 g (yield 91.8%) of a fine crystalline hygroscopic product are obtained, T _{decomposition} 220-222 ° C.

Found,%: C - 38.91; H - 6.05; N, 11.29; C ₁₂ H ₁₈ N ₃ O ₅ K ₁ • 2.5 H ₂ O;

Calculated,%: C - 39.13; H, 6.25; N - 11.41.

IR spectrum, cm ^-1 : 3476, 3416, 2960, 2892, 1584, 1484, 1396, 1312, 1156, 792 (sodium chloride).

Pharmacological properties of the claimed compounds

The experiments were carried out on white rats, Wistar male males weighing 250-300 g. L-NAME (N-nitro-L-arginine methyl ether) was administered intraperitoneally at a dose of 25 mg / kg / day. On the 8th day from the start of the experiment, under anesthesia (chloral hydrate 300 mg / kg), a catheter is inserted into the left carotid artery to record blood pressure (BP), bolus administration of pharmacological agents is carried out in the right femoral vein. Hemodynamic parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) are measured continuously using a sensor and the Biopac Systems, Inc. computer program. Functional tests: endothelium-dependent vasodilation (ESV) - intravenous administration of acetylcholine (AH) at a dose of 40 μg / kg, endothelium-independent vasodilation (ENZV) - intravenous administration of sodium nitroprusside (NP) at a dose of 30 μg / kg. When statistical data processing was calculated, the average value, the standard deviation. Differences were considered significant at p <0.05.

Concrete example

A bolus intravenous administration of AH for 3-5 s led to a sharp drop in blood pressure, reaching a peak in intact animals for systolic pressure (SBP) of 84.3 ± 4.4, for diastolic pressure (DBP) - 38.7 ± 2.8 , during the first 2-3 seconds, a sharp bradycardia developed up to 130-150 beats per minute. ENZV was also characterized by a decrease in SBP to 83.0 ± 3.7, DBP to 42.1 ± 4.4 with subsequent recovery. Blockade of NO synthase using long-term, daily, for 7 days intraperitoneal administration of L-NAME (at a dose of 25 mg / kg) caused arterial hypertension (SBP - 190.3 ± 6.7, DBP - 145.0 ± 3.9 mmHg) and led to a lower decrease in blood pressure after administration of AH (SBP to 110.6 ± 5.2, DBP to 82.8 ± 6.6 mmHg) and NP (SBP to 88.7 ± 4.7, DBP up to 50.8 ± 4.2 mm Hg) compared with intact animals.

The simultaneous administration of L-NAME and 3- (2,2,2-trimethylhydrazinium) propionate led to the following indicators of blood pressure (SBP - 181.8 ± 9.3, DBP - 128.8 ± 6.0 mm Hg), and in experiments with 5-hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate (at a dose of 199.1 mg / kg intraperitoneally) did not lead to a decrease in the baseline blood pressure (CAD - 183.1 ± 3.8, DBP - 125.1 ± 4.5 mm Hg), therefore, both mildronate and the studied derivative did not have a statistically significant effect on SBP and DBP and did not prevent the development of severe hypertension in the experiments. The dose of the derivative was calculated by the formula:

,

,

where D ₁ is the dose of the test derivative of 5- hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate;

D ₂ - the dose for the comparison drug is Mildronate;

M ₁ is the molecular weight of 5- hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate;

M ₂ is the molecular weight of 3- (2,2,2-trimethylhydrazinium) propionate (mildronate);

When choosing a dose of mildronate, we proceeded from the minimum therapeutic dose of the drug using the dose conversion factor for animals, in this case for rats (Freireich et al., 1966, IP Ulanova et al. 1968).

The fundamental difference in EDV and ENZV in intact animals and animals with the introduction of an inhibitor of NO synthase L-NAME naturally led to the need to derive a special indicator characterizing the degree of endothelial dysfunction, which is the ratio of the area of the triangle over the trend of the restoration of blood pressure (BP) in response to the introduction NP (endothelium-independent vasodilation) to the area of the triangle above the trend of the restoration of blood pressure in response to the introduction of AH (endothelium-dependent vasodilation).

This ratio was calculated in each animal of the intact group and rats after modeling the blockade of NO synthase and obtained a difference of this indicator by 5 times — 1.1 ± 0.1 in intact and 5.4 ± 0.6 in animals treated with L-NAME, respectively .

Thus, to further evaluate the effect of AH and NP in ESV and ENZV, this ratio was used as an indicator of the correction of endothelial dysfunction. So, in the group where mildronate was administered against the background of the administration of the L-NAME synthase inhibitor L-NAME, this ratio corresponded to a value of 2.9 ± 0.4, and in the group with the administration of 5-hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate - 2.3 ± 0.2 (table 1). This indicates the most pronounced endothelioprotective effect of the studied derivative.

Results of the effect of 3- (2,2,2-trimethylhydrazinium) propionate and 5- hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate on the coefficient of endothelial dysfunction when modeling L-NAME-induced (25 mg / kg ip, once within 7 days) nitric oxide deficiency are shown in table 1.

Table 1. Groups of animals Functional test GARDEN, mmHg DBP, mmHg S vascular reaction when conducting EDVD with AH and ENVD with NP, in mustache. units QED, mustache units Intact Source 137.7 ± 3.7 101.9 ± 4.3 OH 84.3 ± 4.4 38.7 ± 2.8 1268.0 ± 74.8 1.1 ± 0.1 NP 83.0 ± 3.7 42.1 ± 4.4 1375.3 ± 93.7 Receiving L-NAME (25 mg / kg) Source 190.3 ± 6.7 ^∗ 145.0 ± 3.9 ^∗ OH 110.6 ± 5.2 ^∗ 82.8 ± 6.6 ^∗ 695.3 ± 87.6 ^∗ 5.4 ± 0.6 ^∗ NP 88.7 ± 4.7 50.8 ± 4.2 3322.7 ± 116.7 ^∗ L-NAME (25 mg / kg) + Mildronate (90 mg / kg) Source 181.8 ± 9.3 ^∗∗ 128.8 ± 6.0 ^∗∗ 2.9 ± 0.4 ^∗∗ OH 84.6 ± 3.6 52.2 ± 2.7 823.96 ± 111.4 ^∗∗ NP 93.2 ± 4.9 57.6 ± 6.1 2389.5 ± 179.6 ^∗∗ L-NAME (25 mg / kg) + 5-hydroxy-blue co -inate of 3- (2,2,2-trimethyl hydrate razini) potassium propionate (199.1 mg / kg) Source 183.1 ± 3.8 ^∗∗ 125.1 ± 4.5 ^∗∗ OH 91.5 ± 3.4 64.5 ± 2.6 821.0 ± 99.2 ^∗∗ 2.3 ± 0.2 ^∗∗ NP 104.7 ± 6.5 63.0 ± 6.7 1888.3 ± 177.2 ^∗∗ Note: ^∗ - p <0.05 in comparison with the intact group, ^∗∗ - p <0.05 in comparison with L-NAME, SBP - systolic blood pressure, DBP - diastolic blood pressure, S - area above the arterial recovery curve pressure during functional tests, QED - coefficient of endothelial dysfunction.

Thus, the results obtained allow us to ascertain the activation of the correction of endothelial dysfunction against the background of the introduction of L-NAME, 3- (2,2,2-trimethylhydrazinium) propionate and its derivative 5-hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate, but the endothelioprotective effect of the derivative of 5- hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate is higher compared with the comparison drug mildronate due to the introduction of a new functional group. These properties of the proposed derivative can be used in medicine in complex treatment for the correction of endothelial dysfunction in cardiovascular diseases.

Claims (1)

The derivative of 3- (2,2,2-trimethylhydrazinium) propionate is 5-hydroxynicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate, (CH3) 3N ⁺ NHCH2CH2COOKRCOO ^- ,
Where

possessing endothelioprotective activity.