RU2467745C1 - 3-(2,2,2-trimethylhydrazinium) propionate derivative - 3-(2,2,2-trimethylhydrazinium) potassium propionate 5-bromnicotinate exhibiting endothelioprotective activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new 3-(2,2,2-trimethylhydrazinium)propionate derivative, 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-bromnicotinate (CH3)3N⁺HCH2CH2COOKRCOO^- wherein

.

EFFECT: preparing the compound showing high endothelioprotective activity.

1 tbl, 2 ex

Description

The invention relates to medicine, in particular, to new chemical compounds, 5- bromonicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate having endothelioprotective 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 agents, angiotensin converting enzyme (ACE) inhibitors, antioxidants and 3- (2,2,2-trimethylhydrazinium) propionate, which reduces 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 succinic acid salt, in solid and / or liquid form, as an 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. Is known. "Endothelioprotective properties of enalapril and mildronate. Scientific statements of BelSU. Medicine series. Pharmacy 2011 No. 4, articles 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, articles 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 it 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 the endothelioprotective action of mildronate is indirect, i.e., by increasing the number of GBD it 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 endothelioprotective 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-bromonicotinic acid in the presence of a solvent when heated .

Where

,

,

possessing endothelioprotective activity.

Modification of 3- (2,2,2-trimethylhydrazinium) propionate - 5-bromonicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate - is a new chemical compound and exhibits the most pronounced endothelioprotective effect before the reference drug - mildronate, due to introducing a new functional group

(5-бромникотинат),

(5-bromonicotinate)

which made it possible to enhance the endothelioprotective property of the new chemical compound.

It is known that the introduction of a functional group, 5-bromonicotinate, helps to reduce the tone of cerebral and peripheral vessels, decrease cerebrovascular resistance, and, consequently, increase cerebral blood flow and increase metabolism at the level of the brain, exhibit antispasmodic activity, especially in relation to cerebral and peripheral vessels, increase blood flow, especially in patients with functional arteriopathy, improve the condition with impaired brain function due to vascular insufficiency, Chiva efficiency in disorders of the central and peripheral circulation, possess antiplatelet effect and have a positive effect hemorheological thus this group will provide increasing endotelioprotektornogo effect and to allow more use of a new derivative for the prevention and treatment of cardiovascular diseases.

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

An example of obtaining 5-bromonicotinate 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. 4.85 g (0.024 mol) of 5-bromonicotinic acid are charged into the resulting solution, and 8.18 g of 5- bromnicotinate of 3- (2,2,2-trimethylhydrazinium) potassium propionate are obtained, (yield 79.3%), crystalline, hygroscopic product, T _{decomposition} 210-212 ° C.

Found,%: C - 33.92; H - 5.37; N, 10.23; Br - 18.09; C ₁₂ H ₁₇ N ₃ O ₄ K ₁ Br ₁ · 2.5 N ₂ O;

Calculated,%: C - 33.42: H - 5.34; N, 9.74; Br - 18.54.

IR spectrum, cm ^-1 : 3472, 3360, 2968, 1628, 1588, 1556, 1488, 1384, 1320, 762, 688.

Pharmacological properties of the claimed compounds.

The experiments were carried out on white rats male Wistar strain 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.

An example of a specific implementation.

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 with the help of a long, daily, intraperitoneal injection of L-NAME (at a dose of 25 mg / kg) for 7 days 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), in experiments with 5- bromonicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate (at a dose of 237.3 mg / kg intraperitoneally) did not lead to a decrease in the initial BP values (SBP - 180.3 ± 8.8, DBP - 132.5 ± 6.3 mm Hg), therefore, both mildronate and the derivative under study 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 studied derivative 5-bromonicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate;

D ₂ - the dose for the drug comparison mildronate;

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

M ₂ - 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 NO synthase inhibitor L-NAME, this ratio corresponded to a value of 2.9 ± 0.4, and in the group with the administration of 5-bromonicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate - 1.8 ± 0.6 (table 1), which indicates the most pronounced endothelioprotective effect of the studied derivative.

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

Table 1. Groups of animals Functional test GARDEN, mmHg DBP, mmHg S of the vascular reaction during ESVD with AH and ENVD with NP, in conventional units QED, conventional 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 3322.7 ± 116.7 ^∗ 88.7 ± 4.7 50.8 ± 4.2 L-NAME (25 mg / kg) + Mildronate (90 mg / kg) Source 181.8 ± 9.3 ^∗∗ 128.8 ± 6.0 ^∗∗ OH 84.6 ± 3.6 52.2 ± 2.7 823.96 ± 111.4 ^∗∗ 2.9 ± 0.4 ^∗∗ NP 93.2 ± 4.9 57.6 ± 6.1 2389.5 ± 179.6 ^∗∗ L-NAME (25 mg / kg) + 5-bromonicotinate 3- (2,2,2-trimethylhydrazine-
Ny) of potassium propionate (237.3 mg / kg) Source 180.3 ± 8.8 ^∗∗ 132.5 ± 6.3 ^∗∗ OH 91.6 ± 8.5 61.5 ± 9.5 1579.2 ± 172.4 ^∗∗ 1.8 ± 0.6 ^∗∗ NP 84.0 ± 8.2 55.7 ± 10.2 2842.6 ± 224.7 ^∗∗ 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 obtained results allow us to ascertain the activation of correction of endothelial dysfunction against the background of the introduction of L-NAME, 3- (2,2,2-trimethylhydrazinium) propionate and its derivative 5-bromonicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate, but the endothelioprotective effect of the derivative of 5- bromonicotinate 3- (2,2,2-trimethylhydrazinium) propionate of potassium is significantly higher compared with the comparison drug mildronate due to the introduction of a new functional group with the most pronounced endothelioprotective properties. 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-bromonicotinate 3- (2,2,2-trimethylhydrazinium) potassium propionate, (CH3) 3N ⁺ NHCH2CH2COOKRCOO ^- ,

possessing endothelioprotective activity.