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

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

 

The invention relates to medicine, specifically to new chemical compounds, 5-bromonicotinate 3-(2,2,2-trimethylhydrazine) potassium propionate with endotheliopathy activity.

Renowned pharmaceutical composition comprising 3-(2,2,2-Trimethylhydrazinium) propionate, D-glucuronic acid, isotonic solution for stimulation of hemopoiesis (RU # 2033152, publ. 20.04.1995).

Known combination, which consists of oral hypoglycemic drugs, inhibitors of angiotensin converting enzyme (ACE)inhibitors, antioxidants, and 3-(2,2,2-Trimethylhydrazinium) propionate, allowing to reduce the severity of symptoms perineurally ischemia (RU # 2402325, publ. 27.10.2010).

The proposed pharmaceutical compositions are a combination of two or more compounds with 3-(2,2,2-Trimethylhydrazinium) propionate, acting unilaterally, to improve the efficiency in the treatment of diseases of the cardiovascular system. But the use of multiple components in treatment increases the possibility of side effects individual product, inconvenience of use for the patient and the likelihood of unpredictable effect in the interaction.

Know the use of pharmaceutical compositions containing 3-(2,2,2-Trimethylhydrazinium) propionate dihydrate (mil is ronet) and salt and/or salt of succinic acid, in solid and/or liquid form, as anti-ischemic, hypoxic, antioxidant tool when used in the acute and subacute stages of different hypoxic conditions, in particular in patients with acute myocardial infarction and heart failure (RU # 2005125660, publ. 20.02.2007).

Known endotheliopathy the effectiveness of the 3-(2,2,2-Trimethylhydrazinium) propionate (mildronata) (Mwiraria and Eventuslly with co-workers. "Endotheliopathy properties of enalapril and mildronata. Belgorod state University scientific Bulletin. Series Medicine. Pharmacy 2011. No. 4 tbsp. 57-61. Endothelio - and cardioprotective effects cytoprotector metabolic actions of maldonia in experimental modeling of deficiency of nitric oxide. Sat. Tr. meiwes. scient. Conf., ]. the memory of Professor Vladislav V. Pichugin and the 75th anniversary of Crimean state medical University, Kursk 2009, St-97).

In experimental modeling of arterial hypertension in animals, the increase in reactive oxygen species leads to endothelial dysfunction, as evidenced by the improvement in endothelium-dependent relaxation in the introduction of antioxidants. At the present time for the correction of endothelial dysfunction are considered to be promising drugs with antioxidant properties, as the main mechanism underlying endothelial dysfunction, is the red eye reduction is the production and bioavailability of NO simultaneous increase of superoxide anion, who has the ability to inhibit the expression and activity of endothelial NO synthase (eNOS), and to bind and inactivate NO, to reduce its content in the cell. The shift of the physiological equilibrium between NO and O2leads to the formation of highly toxic peroxynitrite (ONOO-). 3-(2,2,2-Trimethylhydrazinium) propionate (Mildronate) himself antioksidantnymi properties not possessed, but increases in the body the concentration of gamma-butirobetaina (GBD), as under the influence mildronata he slowly oxidized to carnitine. In turn, GBD 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 endotheliazation actions mildronata is indirect, i.e. by increasing the number of GBD is able to protect cells from the effects of free radicals, but it is through the induction of the biosynthesis of NO.

Taking into account the importance of changes in the antioxidant status as one of the most important ways of achieving improvement endotheliopathy activity mildronata must improve its antioxidant action, contributing to an increase endotheliopathy properties.

The objective of the invention is the creation of a new derivative of 3-(2,2,2-Trimethylhydrazinium) propionate, obl is giving more pronounced endotheliopathy activity.

This object is achieved in that creates a new derived 3-(2,2,2-Trimethylhydrazinium) propionate obtained by the interaction of 3-(2,2,2-Trimethylhydrazinium) propionate with potassium hydroxide and 5-bromonicotinic acid in the presence of a solvent under heating.

where

,

with endotheliopathy activity.

Modification of 3-(2,2,2-Trimethylhydrazinium) propionate - 5-bromonicotinate 3-(2,2,2-Trimethylhydrazinium) propionate potassium - is a new chemical compound and exhibits the most pronounced endotheliazation action before drug comparison - Mildronate, due to the introduction of new functional groups

(5-bromonicotinate),

which allowed more endotheliazation property of a new chemical entity.

It is known that the introduction of a functional group, 5-bromonicotinate helps reduce the tonus of cerebral and peripheral vessels, decrease in cerebrovascular resistance, and therefore, increase cerebral blood flow and enhance metabolism at the level of the brain, to show spasmolytic activity, especially in the brain and peripheral vessels, increase blood flow, especially in patients with functional arteriopathy, luceti condition with brain dysfunction due to vascular insufficiency, to increase the efficiency of disorders of the Central and peripheral circulation, possess antiplatelet effect and have a positive hemorheological effect, thus this group will allow you to improve endotheliazation effect and allow wider use of new derivative for the prevention and treatment of cardiovascular diseases.

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

Example of getting a 5-bromonicotinate 3-(2,2,2-Trimethylhydrazinium) propionate potassium.

To a solution of 1.46 g (0,024 mole) of potassium hydroxide in 40 ml of 2-propanol at 30-32°C and stirring, 3.5 g (0,024 mole) of 3-(2,2,2-Trimethylhydrazinium) propionate and incubated for 20-25 minutes. In the resulting solution download 4,85 g (0,024 mole) 5-bromonicotinic acid and get 8,18 g 5-bromonicotinate 3-(2,2,2-Trimethylhydrazinium) propionate potassium (output 79,3%), crystalline, hygroscopic product, TRazlog210-212°C.

Found, %: C - 33,92; N - lower than the 5.37; N - 10,23; Br - 18,09; C12H17N3O4K1Br1·2,5 H2About;

Calculated, %: C - 33,42: N - Of 5.34; N - 9,74; Br - 18,54.

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

Pharmacological properties of the claimed compounds.

Experiments carried out on white rats male Wistar weighing 250-300 g L-NAME (N is the Jethro-L-arginine methyl ester) is injected intraperitoneally at a dose of 25 mg/kg/day. On the 8th day from the beginning of the experiment under anesthesia (chloral hydrate 300 mg/kg) catheter in the left carotid artery for recording blood pressure (BP), a bolus of pharmacological agents in the right femoral vein. Hemodynamic parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) was measured continuously by a sensor and the computer program "Biopac Systems, Inc.". Functional tests: endothelium-dependent vasodilatation (ESV) - intravenous administration of acetylcholine (ach) at a dose of 40 mcg/kg, endothelial-independent vasodilatation (ANSW) - intravenous sodium nitroprusside (NP) at a dose of 30 µg/kg In statistical data processing was calculated average value, the standard deviation value. The differences were considered significant at p<0,05.

An example of a specific implementation.

Bolus intravenous AH 3-5 with led to a sharp drop in blood pressure, reaching a peak in the intact animals for systolic blood pressure (SBP) of 84.3±4,4, for diastolic blood pressure (DBP) - 38,7±2,8, during the first 2-3 with developed sudden bradycardia up to 130-150 beats per minute. ANSW was also characterized by a decrease in the GARDEN to 83.0±3,7, dad to 42.1±4.4 with subsequent recovery. Blockade of NO-Sint the PS using a long, daily, within 7 days of intraperitoneal administration of L-NAME at a dose of 25 mg/kg) caused arterial hypertension (GARDEN - 190,3±6,7, dad, 145,0±3.9 mm Hg) and lead to a smaller decline in HELL after the introduction of AH (the GARDEN to 110,6±5,2, dad to 82,8±6,6 mm Hg) and NP (GARDEN up to 88.7±4,7, dad to 50.8±4.2 mm Hg) compared with intact animals.

Co-administration of L-NAME and 3-(2,2,2-Trimethylhydrazinium) propionate resulted in the following indicators HELL (GARDEN - 181,8±9,3, dad - of 128.8±6.0 mm Hg), in experiments with 5-bromonicotinate 3-(2,2,2-trimethylhydrazine) potassium propionate (dose 237,3 mg/kg intraperitoneally) did not lead to reduction of the initial values of AD (GARDEN - 180,3±8,8, DBP - 132,5±6.3 mm Hg), therefore, Mildronate and analyzed derivative did not prevent the development of severe hypertension in experiments. The dose of the derivative was calculated by the formula:

,

where D1the dose of the investigational derived 5-bromonicotinate 3-(2,2,2-trimethylhydrazine) potassium propionate;

D2the dose for the comparison drug Mildronate;

M1molecular weight of 5-bromonicotinic 3-(2,2,2-trimethylhydrazine) potassium propionate;

M2molecular weight of 3-(2,2,2-Trimethylhydrazinium) propionate (Mildronate)

When selecting dose mildronata proceeded from the minimum therapeutic dose pre is Arata using the conversion factor of doses for animals, in this case, rats (Freireich et.al., 1966, Ulanova I.P. and others 1968).

A fundamental difference in ASW and ANSW in the intact animals and animals with the introduction of the inhibitor of NO-synthase L-NAME has naturally led to the need to launch a special measure of endothelial dysfunction, which is the ratio of the area of the triangle above the trend of the reduction reaction of blood pressure (BP) in response to the introduction of the NP (endothelial-independent vasodilatation) to the area of the triangle above the trend of the reduction reaction of blood pressure in response to the introduction of AH (endothelium).

Was calculated this ratio for each animal intact group and rats after modeling blockade of NO synthase and got the difference of this indicator 5 times, respectively, 1,1±0,1 in the intact and 5.4±0,6 in animals treated with L-NAME.

Thus, to further assess the impact of AH and TM when ASW and ANSW used this ratio as an indicator correction of endothelial dysfunction. So, in the group where the infusion of an inhibitor of NO-synthase L-NAME was administered Mildronate, this ratio corresponded to the value of 2.9±0,4 and in the group with the introduction of 5-bromonicotinic 3-(2,2,2-Trimethylhydrazinium) propionate potassium - 1,8±0,6 (table 1), indicating that the most pronounced endothelialisation effect studied is derived.

The effects of 3-(,2,2-Trimethylhydrazinium) propionate and 5-bromonicotinate 3-(2,2,2-trimethylhydrazine) potassium propionate by a factor of endothelial dysfunction in the modeling of the L-NAME-induced (25 mg/kg intraperitoneally, once daily for 7 days) deficiency of nitric oxide are shown in table 1.

Table 1.
Groups of animalsFunctional testGARDEN, mm HgDBP, mm Hg's vascular reactions when conducting EDVD with AH and AND with NP, usledQED, usled
The intactSource137,7±3,7101,9±4,3
OHof 84.3±4,438,7±2,81268,0±74,8
1,1±0,1
NP83,0±3,742,1±4,41375,3±93,7
Treated with L-NAME (25 mg/kg)Source190,3±6,7145,0±3,9∗∗
OH110,6±5,2of 82.8±6,6695,3±87,65,4±0,6
NP3322,7±of 116.7
88,7±4,750,8±4,2
L-NAME (25 mg/kg)+Mildronate (90 mg/kg)Source181,8±9,3∗∗to 128.8±6,0∗∗
OH84,6±3,652,2±2,7823,96±byr111.4∗∗2,9±0,4∗∗
NP93.2±4,957,6±6,12389,5±179,6∗∗
L-NAME (25 mg/kg)+5-Branko tint 3-(2,2,2-trimethylhydrazine-
s) propionate is potassium(237,3 mg/kg)
Source180,3±8,8∗∗132,5±6,3∗∗
OH
to 91.6±8,561,5±9,51579,2±172,4∗∗1,8±0,6∗∗
NP
84,0±8,255,7±10,22842,6±224,7∗∗
Note:-- p<0,05 in comparison with the intact group∗∗- p<0,05 in comparison with L-NAME, a GARDEN - sistoliceski the e blood pressure, DBP - diastolic blood pressure, S is the area above the curve recovery of blood pressure when carrying out functional tests of QED - factor for endothelial dysfunction.

Thus, the results obtained lead to the conclusion that the activation of the correction of endothelial dysfunction the infusion of L-NAME, 3-(2,2,2-Trimethylhydrazinium) propionate and its derivative 5-bromonicotinate 3-(2,2,2-Trimethylhydrazinium) propionate potassium, but endotheliopathy effect derived 5-bromonicotinate 3-(2,2,2-Trimethylhydrazinium) propionate potassium is significantly higher than the comparison drug Mildronate due to the introduction of new functional groups, with the most pronounced endotheliopathy properties. These properties offer a derived can be used in medicine in treatment for the correction of endothelial dysfunction in cardiovascular diseases.

The derived 3-(2,2,2-Trimethylhydrazinium) propionate - 5-bromonicotinate 3-(2,2,2-trimethylhydrazine) potassium propionate, (CH3)3N+NHCH2CH2COOKRCOO-,
with endotheliopathy activity.



 

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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

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of 1,3-dicarbonyl compounds and specifically to a method of producing ethyl ether of 3-oxo-3-(2,6-dichloropyridin-3-yl) propanoic acid of formula: . The method involves acylation of potassium 3-oxo-3-ethoxypropanoate with 2,6-dichloronicotinoyl chloride in the presence of anhydrous solvent, ethylamine and magnesium chloride, followed by treatment of the reaction mass with aqueous hydrochloric acid solution and extraction of the end product, characterised by that the solvent used is ethylacetate, where the molar ratio 2,6-dichloronicotinoyl chloride: potassium 3-oxo-3-ethoxypropanoate is equal to 1:1.4-1.6.

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FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula used as herbicides, in which Q1 is H or F; Q2 is a halogen provided that when Q1 is H, Q2 is Cl or Br; R1 and R2 independently denote H, C1-C6-acyl; and Ar is a polysubstituted aryl group selected from a group consisting of

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30 cl, 136 ex, 1 tbl

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27 cl, 34 ex, 8 dwg

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49 cl, 9 ex

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8 cl, 1 tbl, 602 ex

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

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10 cl, 16 tbl, 12 dwg, 13 ex

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25 cl, 1 dwg, 10 ex

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4 cl, 2 tbl, 12 ex

FIELD: medicine.

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2 ex, 1 tbl

FIELD: medicine.

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EFFECT: group of inventions provides higher therapeutic and preventive effectiveness.

6 cl, 10 ex, 3 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology and deals with increase of antihypertensive therapy efficiency and reduction of left ventricle hypertrophy in patients with arterial hypertension of 2-nd degree with high risk of development of cardio-vascular complications (risk 3). For this purpose antihypertensive therapy is performed taking into account prevailing temperament or prevailing part of vegetative nervous system, as well as personality anxiety. With account of said factors elaborated are versions of complex therapy, namely: a) beta-adrenoreceptor antagonist (BAA) and diuretic in average day dose in combination with anxiolytic in minimal day dose; b) BAA and diuteric in minimal day dose; c) ACE inhibitor and diuretic in average day dose in combination with antidepressant in minimal day dose; d) ACE inhibitor and diuretic in minimal day dose and antidepressant in minimal day dose.

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5 ex, 23 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel polyfunctional fullerene C60 amino acid derivatives of formula (1) , wherein R is H, mono- or dinitroxyC1-6alkyl, maleinimide; N-Z denotes a α, β, γ, ω-amino acid fragment of general formula where m=2-5 and M is a nitroxyC1-6alkyl group, a C1-6alkyl group or an alkali metal salt, having biological activity, as well as methods for production thereof and a method for covalent bonding of fullerene derivatives with SH-containing proteins. The invention also relates to the use of nitroxyalkyl-N-(fullerenyl)amino acids as nitrogen monoxide donors and to use of nitroxyalkyl-N-(fullerenyl)amino acids as quick-acting vasodilatators for antihypertensive therapy. The invention also relates to a method of inhibiting a metastasis process and a method of enhancing antileukemic activity of cyclophosphamide. Disclosed nitroxyalkyl-N-fullerenyl amino acid derivatives have an effect on coronary, contractile and pumping ability of the isolated heart of Vistar rats and are quick-acting vasodilatators which reduce arterial pressure and heart rate and cause relaxation of coronary vessel with less depressive effect on myocardial function compared to nitroglycerine.

EFFECT: disclosed compounds considerably intensify antileukemic activity of cyclophosphamide, increase chemosensitising activity when combined with cyclophosphamide.

9 cl, 8 ex, 3 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics. As active ingredients, a composition for blood pressure reduction contains an effective amount of lycopene and lutein a combination of which provides a synergetic therapeutic effect. A method for blood pressure reduction involves a stage of the introduction of the effective amount of the composition to a patient.

EFFECT: use of the declared invention enables higher effectiveness of blood pressure reduction.

1 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely pharmacology in cardiology, and may be used for preparing herbal teas for treating arterial hypertension. Herbal tea for treating adolescents suffering sympathicotonic vasomotor dyscrasia and degree 1 and 2 arterial hypertension contains dry ground herbal raw material. quinquelobate motherwort herb, red haw, melissa herb, Baikal woundwort herb, Baikal skullcap roots in certain proportions. The tea is presented in the form of an aqueous infusion.

EFFECT: herbal tea is effective in treating arterial hypertension in patients of various age groups including adolescent patients.

2 cl

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

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