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

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate derivative - 3-(2,2,2-trimethylhydrazinium)potassium propionate nicotinate, (CH3)3N+NHCH2CH2COOKRCOO--wherein R= , showing endothelioprotective activity.

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

1 cl, 2 ex, 1 tbl

 

The invention relates to medicine, specifically to new chemical compounds - nicotinate 3-(2,2,2-Trimethylhydrazinium)propionate potassium 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 (Mildronate) and with the l and/or salts of succinic acid, in solid and/or liquid form, used 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 et al. ("Endotheliopathy properties of enalapril and mildronata" Belgorod state University Scientific Bulletin. Series Medicine. Farmacia, 2011, No. 4, p.57-61, "Endothelio - and cardioprotective effects cytoprotector metabolic actions of maldonia in experimental modeling of deficiency of nitric oxide" SB. Tr. meiwes. scient. Conf., ]. the memory of Professor Vladislav V. Pichugin and the 75th anniversary of Crimean state medical University, Kursk, 2009, p.95-97).

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, one is by reducing 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 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 increase 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 having irarenai 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 nicotinic acid in the presence of a solvent when heated

where R=with endotheliopathy activity.

Modification of 3-(2,2,2-Trimethylhydrazinium)propionate-nicotinate 3-(2,2,2-Trimethylhydrazinium)propionate potassium - is a new chemical compound and exhibits the most pronounced endotheliazation action before drug comparison - Mildronate by introducing a new functional group(nicotinate), which allowed more endotheliopathy property of a new chemical entity.

It is known that nicotinic acid plays a significant role in the life of the organism, as the prosthetic group of enzymes - kodegidrazy I (diphosphopyridine) and kodegidrazy II (triphosphopyridine), which act as vectors of hydrogen and carry out in the body of redox processes. The most important effects of nicotinic acid is expressed vasodilating effect, which manifests itself correction microcirculation, f is not weak antikoaguliruyuschey activity. In addition, nicotinic acid reduces the level of total cholesterol, low-density lipoproteins, triglycerides and raising high density lipoprotein, has antiatherogenic effect. The above properties of nicotinic acid can enhance endotheliopathy activity derived 3-(2,2,2-trimethylhydrazine propionate-nicotinate 3-(2,2,2-Trimethylhydrazinium)propionate potassium, thereby 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 nicotinate 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 2,95 g (0,024 mole) of nicotinic acid. Get of 5.84 g nicotinate 3-(2,2,2-Trimethylhydrazinium)propionate potassium (yield of 91.8%), crystalline, hygroscopic product, TRazlog218-220°C.

Found, %: C - 43,41; H - 5,96; N - 12,69; C12H18N3O4K1·1,5 H2O;

Calculated, %: C - 43,11; H - 6,29; N - 12,57.

The infrared spectrum, cm-1: 3432, 3392, 2972, 1596, 1552, 1480, 1400, 1324, 762, 704.

Pharmacological properties of the claimed compounds

Experiments carried out on white rats male Wistar weighing 250-300 g L-NAME (N-nitro-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 a computer program "Voras 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.

Specific example

Bolus intravenous AH 3-5 with led to a sharp drop in blood pressure, reaching a peak in the intact animals for systolic is Alenia (GARDEN) 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 synthase by a long-term, daily, for 7 days 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 nicotinate 3-(2,2,2-trimethylhydrazine)potassium propionate (dose 189,2 mg/kg intraperitoneally) did not lead to reduction of the initial values of AD (GARDEN - 179,4±4,1, dad, 123,3±3.9 mm Hg), therefore, Mildronate, and analyzed the 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 nicotinate 3-(2,2,2-trimethylhydrazine)potassium propionate;

D2the dose for the comparison drug Mildronate;

M1molecular mass is Catinat 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 of the drug 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, uh what about the attitude matches the value of 2.9±0,4, and in the group with the introduction of nicotinate 3-(2,2,2-Trimethylhydrazinium)propionate potassium - 1,6±0,3 (see table). The most pronounced endothelialisation effect studied is derived.

The effects of 3-(2,2,2-Trimethylhydrazinium)propionate and nicotinate 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 in the table.

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±4,538,7±2,81268,0±74,81,1±0,1
NP83,0±3,742,1±4,4137,3±93,7
Treated with L-NAME (25 mg/kg)Source190,3±6,7*145,0±3,9**
OH110,6±5,2*of 82.8±6,6*695,3±87,6*5,4±0,6*
NP88,7±4,750,8±4,23322,7±of 116.7*
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-nicotinate 3-(2,2,2-Trimethylhydrazinium)propionate potassium (189,2 mg/kg)Source179,4±4,1** 123,3±3,9**
OH86,0,±5,250,8±2,9**1151,8±205,9**1,6±0,2**
NP82,6±7,340,8±3,41842,9±224,7**
* p<0,05 in comparison with the intact group; ** p<0,05 in comparison with L-NAME, GARDEN - systolic 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 derivatives nicotinate 3-(2,2,2-Trimethylhydrazinium)propionate potassium, but endotheliopathy effect derived nicotinate 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 pharmacological properties. These properties offer proizvodnogo to find medical use in treatment for the correction of endothelial dysfunction in cardiovascular diseases.

The derived 3-(2,2,2-Trimethylhydrazinium)propionate - nicotinate 3-(2,2,2-trimethylhydrazine)potassium propionate, (CH3)3N+NHCH2CH2COOKRCOO-,
where R=with endotheliopathy activity.



 

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23 cl, 3 tbl, 89 ex

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13 cl, 2 tbl, 15 ex

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34 cl, 2 tbl, 179 ex

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49 cl, 9 ex

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16 cl, 433 ex, 6 tbl

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13 cl, 2 tbl, 15 ex

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20 cl, 14 ex, 1 dwg

FIELD: medicine.

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EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of preparing optically pure amlodipine gentisate involving the following steps: a) preparation of diastereomeric mixture of amlodipine dibenzoyltartrate from racemic (R,S)-amlodipine using isopropanol solvent and optically pure O,O'-dibenzoyltartaric acid with subsequent optical isolation; and b) treatment of the isolated amlodipine dibenzoyltartrate diastereomer with a base and then obtaining optically pure amlodipine gentisate by adding gentisic acid to the resulting free form in a single continuous step.

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11 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining optically active amlodipine trough optical separation of (R,S)-amlodipines where (R,S)-amlodipine reacts with optically active O,O'-dibenzoyl- tartaric acid in an isopropanol solvent to obtain optically active salt of amlodipine-hemi-dibenzoyl-L-tartrate or its solvate, and the optically active salt of amlodipine-hemi-dibenzoyl-L-tartrate or its solvate is treated with a base to obtain optically active amlodipine. The invention also relates to (R)-(+)-amlodipine-hemi-dibenzoyl-L-tartrate, (S)-(-)-amlodipine-hemi-dibenzoyl-D-tartrate, (S)-(-)-amlodipine-hemi-dibenzoyl-L-tatrate, (R)-(+)- amlodipine-hemi-dibenzoyl-D-tatrate or solvates thereof.

EFFECT: obtaining enantiomerically pure amlodipine isomers with activity calcium channel blocker properties.

23 cl, 18 ex, 1 tbl

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