WO2015118488A1 - Agent de traitement de maladies cardiovasculaires - Google Patents

Agent de traitement de maladies cardiovasculaires Download PDF

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WO2015118488A1
WO2015118488A1 PCT/IB2015/050897 IB2015050897W WO2015118488A1 WO 2015118488 A1 WO2015118488 A1 WO 2015118488A1 IB 2015050897 W IB2015050897 W IB 2015050897W WO 2015118488 A1 WO2015118488 A1 WO 2015118488A1
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compound
rats
animals
group
control
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PCT/IB2015/050897
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Russian (ru)
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Кенес Тагаевич ЕРИМБЕТОВ
Владимир Константинович ПОДГОРОДНИЧЕНКО
Виктор Владимирович ХОМИЧЕНОК
Анна Яковлевна ГОНЧАРОВА
Рахимджан Ахметджанович РОЗИЕВ
Алексей Викторович КЛЕЙМЕНОВ
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Ооо "Диборнол Девелопмент"
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Priority to EA201691465A priority Critical patent/EA201691465A1/ru
Publication of WO2015118488A1 publication Critical patent/WO2015118488A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the invention relates to medicine, specifically to pharmacology, and relates to agents having hemorheological, antiaggregatory, antithrombogenic, retinoprotective, endothelium protective, neuroprotective, antiarrhythmic and anti-ischemic activity, as well as increasing cerebral blood flow.
  • An agent having antiradical, hemorheological cytoremic antithrombogenic activity [Patent N ° 2347561, A61K 31/05, 2008].
  • this compound is a mixture of structural isomers [Patent N ° 2502719, ⁇ 07 ⁇ 39/17, 2013]; however, the ratio of these isomers to the mixture and the effect of their ratio on the pharmacological activity they exhibit are not known.
  • the objective of the invention is to expand the arsenal of drugs with simultaneous hemorheological, antiplatelet, antithrombogenic, retinoprotective, endothelium protective, neuroprotective, antiarrhythmic and anti-ischemic activity that increase cerebral blood flow. Also, the objective of the invention was to identify the pharmacological activity of the indicated agent exhibiting these properties.
  • New in the present invention is that as a hemorheological, antiaggregate, antithrombogenic, retinoprotective, endothelium protective, neuroprotective, antiarrhythmic, antiischemic, cerebral blood flow increasing agent, a mixture of these diastereomers of 2,6-di diastereomers is used (1, 7, 7 -trimethylbicyclo [2.2.1] hept-2-yl) -4-methylphenol and 2- (1,7,7-trimethylbicyclo [2.2.1] hept-2-yl), 6- (2,2, 1-trimethylbicyclo [2.2.1] hept-5-yl) -4-methylphenol with an isomer ratio of 60: 40% by mass ⁇ -95: 5% by mass, which can be used Xia for the treatment of cardiovascular disease.
  • Compound 2 is a mixture of structural isomers and their diastereomers: 2,6-di (1, 7, 7-trimethylbicyclo [2.2.1] hept2-yl) -4-methylphenol and 2- (1,7,7-trimethylbicyclo [2.2. 1] hept-2-yl), 6- (2,2, 1-trimethylbicyclo [2.2.1] hept5 ⁇ yl) -4-methylphenol with a ratio of isomers from 60% to 95% of the mass. for the first isomer and from 40% to 5% of the mass. for the second isomer.
  • Example 1 The experiments were performed on 90 female Wistar rats weighing 190-210 g. Rats were divided into 3 groups of 30 animals each. On the model of total transient cerebral ischemia using the method of WA Pulsinelli, JB Brierley [1979], neuroprotective effects were evaluated. For this, 1 day before the ischemia simulation in anesthetized rats (thiopental sodium 60 mg / kg, intraperitoneally), thermocoagulation of both vertebral arteries was performed at the level of the first cervical vertebra. 24 hours later, under ether anesthesia, occluders were applied to both carotid arteries for 30 minutes. The consistency of the model was assessed by blanching of the visible part of the choroid, expansion of the pupils, and development of hyperventilation.
  • Reperfusion was carried out by the removal of occluders.
  • 1 ml of 1% starch gel was administered intragastrically to rats of the control group, and compounds 1 and 2 were administered intragastrically to the animals of the experimental group at a dose of 100 mg / kg in 1 ml of starch gel once a day for 7 days.
  • the first administration was carried out 1 hour after model of ischemia, the last injection - 1 hour before blood sampling. In the first 2-5 hours after the reproduction of the model of total transient cerebral ischemia in rats, the most severe symptoms of damage to the central nervous system were observed in the form of areflexia, seizures, spastic paralysis of the limbs, tonic tension of the muscles of the trunk, and lateral position.
  • the functional state of higher nervous activity was evaluated on the 1st, 4th, 5th and 7th days after the creation of the model with total transient cerebral ischemia using the Stroke-index scale [McGraw CP., 1977] according to the following indicators: spontaneous engine - Naya activity (normal, increased or decreased, absence), gait disorders (stiffness, shakiness, slow movement, disorientation), reflexes of tail jerking, both fore and hind legs, reaction to sound, tremor, cramps, muscle tone of the trunk and extremities (normal, rep Weighted, absence), signs of ptosis (no, one-sided, two-sided).
  • Each indicator was evaluated in points: 0 points - normal; 1 point - moderate changes; 2 points - pronounced changes.
  • the neurological deficit of the animal was assessed by the sum of points for all indicators.
  • the proportion of animals with severe neurological disorders (6 points or more), with moderate impairment (3-5 points) and with mild changes (up to 2 points) was determined.
  • Animal survival was recorded on the 1st, 4th, 5th and 7th day after total transient cerebral ischemia. At the end of the experiments, animal euthanasia was performed.
  • compound 2 in the treatment of ischemic brain damage to the greatest extent compared with compound 1 reduces the death of animals and accelerates the restoration of neurological status in embroidered animals.
  • Example 2 A study of the endothelial protective activity of compounds 1 and 2 was carried out on models of pathological conditions (incomplete cerebral ischemia and diabetes mellitus).
  • SBP systemic blood pressure
  • animals were implanted with a catheter filled with a mixture of saline and heparin in the right carotid artery.
  • Endothelium-dependent vasodilation was recorded with bolus intravenous administration of acetylcholine (5 ⁇ g / kg), endothelium-independent vasodilation with bolus intravenous administration of sodium nitroprusside (30 ⁇ g / kg).
  • Acetylcholine and sodium nitroprusside were injected into the femoral vein.
  • the functional state of the endothelium was assessed using the coefficient of endothelial dysfunction (QED), calculated as the ratio of the areas under the blood pressure reduction curves in response to the intravenous administration of sodium nitroprusside and in response to the intravenous administration of acetylcholine [Tyurenkov I.Yu., Voronov A.V. , 2008].
  • QED coefficient of endothelial dysfunction
  • Rat groups intact, control, pseudo-operated and treated with compounds 1 and compound 2. Animals of the control, pseudo-operated and intact groups were administered intragastrically 1 ml of starch gel. Rats treated with compounds 1 and 2 were administered drugs at a dose of 100 mg / kg. The starch gel and suspension of compounds 1 and 2 in the starch gel were administered to the animals once a day for 5 days. The first introduction was through 1 an hour after creating a model of incomplete cerebral ischemia. On the 5th day, 1 hour after the last administration of compounds 1 and 2 or starch gel, the rats were anesthetized (thiopental sodium 60 mg / kg, ip) and the endothelial function was evaluated.
  • Compound 2 exhibits higher endothelial protective activity compared to Compound 1 under the conditions of the model of incomplete cerebral ischemia in rats.
  • mice of the Wistar strain were injected with intraperitoneal injection of streptozotocin at a dose of 60 mg / kg in citrate buffer. Animals with a blood glucose level of 19 to 26 mmol / L were selected for the experiment. Whole blood glucose was measured using a glucometer (Hand- guidelines for preclinical studies of drugs. Part one. - M.: Grif and K, 2012 .-- 944 s).
  • compound 2 exhibits higher endothelial protective activity in diabetes mellitus in rats compared to compound 1.
  • Example 3 On the model of diabetic retinopathy, the retinoprotective effects of compounds 1 and 2 were evaluated. The experiments were performed on 40 female rats Wistar strain, weight 220-250 g. The model of diabetic retinopathy in rats was reproduced by a single intraperitoneal administration of streptozotocin at a dose of 60 mg / kg body weight. The level of hyperglycemia (over 18 mmol / L), weight loss, the severity of polyuria and polydipsia were the criteria for the severity of diabetes. 30 days after the administration of streptozotocin, rats were divided into 3 groups.
  • Compounds 1 and 2 were administered intragastrically to rats of experimental groups with a glucose concentration of 21.8 ⁇ 2.5 (compound 1) and 22.0 ⁇ 1 5 9 (compound 2) mmol / l daily for 30 days at a dose of 100 mg / kg body weight in suspension in 1 ml of starch gel. Animals of the control group with a glucose concentration of 22.3 ⁇ 2.2 mmol / L were injected with the same amount of starch gel according to the same scheme. A group of intact animals in similar conditions. The central sections of the retina of rats were the material of the study, which were prepared (60 days after the start of streptozotocin injection) immediately after euthanasia by ether anesthesia of animals.
  • the central parts of the posterior wall of the eye were fixed in a 2.5% solution of glutaraldehyde in 0.2 M cacodilate buffer (pH 7.4), after which they were fixed in a 2% solution of osmium tetroxide and poured into a mixture of epon-araldite resins.
  • Semi-thin sections were stained with toluidine blue, ultra-thin sections were contrasted with uranyl acetate and lead citrate, viewed and photographed using an electron microscope.
  • Quantitative analysis showed a threefold increase in the percentage of neurosensory cells with pycnosis of the nucleus, characterized by an increase in osmiophilia of the nucleus and cytoplasm, and a 1.56-fold decrease in the density distribution of the nuclei of neurosensory cells in the outer nuclear layer in relation to intact control (table 5). Changes in associative neurons are reactive in nature. In streptozotocin diabetes, rats in the control group showed an increase in the percentage of hyperchromic neurons as compared with intact control (Table 6). Degeneration of multipolar neurons with prolonged hyperglycemia in the presence of streptozotocin diabetes is characterized mainly by varying degrees of chromatolysis.
  • Compound 2 treatment more effectively prevents the destruction of neurosensory cells, which is reflected in a decrease in the percentage of pyknotic nuclei of neurons to intact control values and an increase in the number of rows of nuclei relative to the control group and the group of rats treated with compound 1 (Table 5).
  • the density distribution of the nuclei of neurosensory cells in the outer nuclear layer remains reduced, which is probably due to the proliferative-progressive reaction of radial glia in the form of proliferation and hypertrophy of scleral processes.
  • Example 4 The effect of compounds 1 and 2 upon single parenteral and triple intragastric administration to rats on cerebral blood flow was studied by recording the velocity of blood flow in the carotid artery using an electromagnetic flow meter.
  • Example 5 A study of hemorheological, antitrobocytic and antithrombogenic activities of compounds 1 and 2 was carried out on ex vivo models of blood hyperviscosity, intravascular thrombosis in rats.
  • Blood viscosity and erythrocyte aggregation were evaluated in blood samples immediately after collection and 1 hour after blood incubation at a temperature of 20.0 ⁇ 0.4 ° C.
  • Blood was drawn from the common carotid artery under ether anesthesia.
  • a 3.8% sodium citrate solution in a ratio of 1: 9 blood was used as an anticoagulant.
  • Blood viscosity was measured on a rotational viscometer in the range of shear rates from 5 to 300 s "1 before and after incubation of the samples at a temperature of 20.0 ⁇ 0.4 ° C for 60 minutes.
  • spontaneous aggregation of erythrocytes was studied using the sillectometric method.
  • the criterion for the aggregation activity of erythrocytes was the half-period of aggregation Tm — the time during which the magnitude of the photometric signal is halved.
  • the initial values of the blood viscosity of animals of the control group at shear rates from 5 to 300 s "1 were in the range from 8.3 ⁇ 0.1 to 4.5 ⁇ 0.1 MPa s.
  • Incubation of these blood samples for 60 minutes at a temperature of 20.0 ⁇ 0.4 ° C led to a significant (16–31%) increase in blood viscosity.
  • Pentoxifylline caused a significant decrease in blood viscosity at low shear rates prior to incubation compared to control. After incubation, an increase in blood viscosity was observed throughout the investigated range of shear rates, however, the values of this indicator would whether significantly lower compared with the values in the control group.
  • compound 2 is able to limit the development of blood hyperviscosity and increase ex vivo red blood cell aggregation.
  • the effect of compound 2 is more pronounced than the effect of compound 1 and is comparable to pentoxifylline.
  • BTP rich
  • BeTP poor
  • platelet count was calculated.
  • BTP was diluted with the required amount of BeTP to 400 ⁇ 27 thousand platelets in 1 mm 3 in the sample.
  • BTP and BeTP of intact donor rats were used.
  • Platelet aggregation was evaluated in a standardized plasma on the instrument, aggregatograms were recorded using a recorder. After the addition of the aggregation inducer, a change in the optical density level of BTP was recorded.
  • An indicator of the degree of aggregation (in%) was used as a criterion for platelet aggregation activity, characterized by a change in the optical density of BTP after adding an aggregation inducer to the cuvette.
  • the optical density of BeTP was taken as 100%, and the optical density of BTP was taken as 0%.
  • ADP was used as an aggregation inducer at a final concentration of 4 ⁇ 10 "6 M.
  • compound 2 in comparison with compound 1 has a pronounced effect on vascular platelet hemostasis.
  • Antithrombogenic activity of compound 2 may be due to both antiplatelet and endothelium protective properties.
  • Measurements of the amount of blood flow in the artery were carried out from the moment of application of iron chloride on the left carotid artery to the complete stop of the blood flow in it (time of thrombus formation). The calculation of the decrease in blood flow relative to the initial value of blood flow was expressed as a percentage. The mass of the thrombus was estimated by the gravimetric method.
  • compound 2 in comparison with compound 1 has a pronounced antithrombogenic activity.
  • Example 6 The study of anti-ischemic and anti-arrhythmic activity of compounds 1 and 2 was performed according to the Guidelines for conducting preclinical studies of drugs (Part One. - M.: Grif and K, 2012.- 944 p.) On the model of ischemia and rat myocardial reperfusion, which is recommended for the reproduction of ischemia and ventricular arrhythmias.
  • Rats were randomized into 3 groups.
  • Compounds 1 and 2 were administered to rats of the experimental groups at a dose of 100 mg / kg in the form of a suspension on 1% starch gel (2 ml) intragastrically through a probe 1 time per day for 3 days before and 3 days after model creation.
  • the animals of the control group were injected with an equivalent volume of starch gel according to a similar scheme.
  • Compounds 1 and 2 were investigated using electrocardiographic (ECG) and morphological methods. To reproduce the model, the animals were anesthetized with sodium thiopental (60 mg / kg, intraperitoneally), intubated, and connected to a ventilator.
  • ECG electrocardiographic
  • occlusion of the left coronary artery was performed at the level of the lower edge of auricula sinistra without disturbing the topography of the heart in the chest by the method of Kogan [Kogan A.Kh. The surgical method for modeling coronary occlusion infarction and heart aneurysm in rats // Pathological physiology and experimental therapy. 1979. N ° 3. from. 79-81].
  • the duration of occlusion of the left coronary artery was 20 min, after which the ligature was untied and postischemic reperfusion was carried out. During the period of ischemia and 10 minutes of reperfusion, ECG monitoring was carried out in standard II lead using a computer electrocardiograph.
  • Verification of the correctness of the ligature and the adequacy of the model was monitored by the degree of change in the height of the ST segment on the ECG. In false-operated animals, a similar surgical intervention was performed without ligature on the left coronary artery.
  • the rats were again anesthetized with sodium thiopental (60 mg / kg, intraperitoneally), intubated and connected to a ventilator, and a ligature was applied.
  • sodium thiopental 60 mg / kg, intraperitoneally
  • a ligature was applied to identify the hypoperfusion zone.
  • 0.2 ml of a 5% patent blue violet dye solution was bolus injected into the femoral vein, and the heart was removed for the next 20-30 seconds. Parts of the myocardium with preserved perfusion were stained green, non-perfused remained unpainted.
  • Heart sections were prepared on a freezing microtome. Some of the sections were left in their native form to assess the hypoperfusion zone. Another part of the sections was stained with nitro-blue tetrazolium (HCT) in order to detect dehydrogenase activity in the tissue. Slices were enclosed in a glycerol-gelatin gel and scanned. The size of hypoperfusion zones and changes in dehydrogenase activity was estimated using Adobe Photoshop. Zones with a sharp decrease in dehydrogenase activity were taken as a heart attack zone.
  • HCT nitro-blue tetrazolium
  • the size of the hypoperfusion zone did not differ significantly from the total area of myocardial transverse sections.
  • the therapeutic and prophylactic administration of compound 2 at a dose of 100 mg / kg reduces the mortality of animals after an episode of ischemia / reperfusion and significantly reduced the infarction area both from the total myocardial area and from the area of hypoperfusion compared to the same indices of the control group and the group of animals treated with the compound 1 (Table 18).
  • Compound 2 at a dose of 100 mg / kg of body weight in contrast to control and compound 1, when it was administered under the conditions of a model of myocardial ischemia and reperfusion, statistically significantly reduced the incidence and severity of arrhythmias, and reduced animal mortality due to fatal arrhythmias.
  • the present invention expands the arsenal of agents that simultaneously have hemorheological, antiplatelet, antithrombogenic, retinoprotective, endothelial, neuroprotective, antiarrhythmic and anti-ischemic activity that increase cerebral blood flow.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

L'invention concerne un produit de traitement des maladies cardiovasculaires constitué d'un mélange de deux isomères structurels de de 4-méthyl-2,6-diisobornylphénole avec un rapport d'isomères compris entre 60:40% en masse et 95:5% en masse.
PCT/IB2015/050897 2014-02-06 2015-02-06 Agent de traitement de maladies cardiovasculaires WO2015118488A1 (fr)

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EA201691465A EA201691465A1 (ru) 2014-02-06 2015-02-06 Средство для лечения сердечно-сосудистых заболеваний

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RU2014104145/15A RU2555335C9 (ru) 2014-02-06 2014-02-06 Средство для лечения сердечно-сосудистых заболеваний
RU2014104145 2014-02-06

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RU2619330C1 (ru) * 2016-03-24 2017-05-15 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии и регенеративной медицины имени Е.Д. Гольдберга" Средство для профилактики и лечения патозооспермии
RU2625039C1 (ru) * 2016-07-12 2017-07-11 Федеральное Государственное Бюджетное Учреждение Науки Институт Химии Коми Научного Центра Уральского Отделения Российской Академии Наук Инъекционная лекарственная форма гидрофильного конъюгата гидроксиэтилкрахмала и 2,6-диизоборнил-4-метилфенола, способ ее получения и применения для лечения сердечно-сосудистых заболеваний
RU2016138751A (ru) * 2016-09-30 2018-04-02 Общество с ограниченной ответственностью "Диборнол Девелопмент" Средство для лечения сердечно-сосудистых заболеваний

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RU2347561C2 (ru) * 2007-04-23 2009-02-27 Государственное учреждение Научно-исследовательский институт фармакологии Томского научного центра Сибирского отделения Российской Академии медицинских наук (ГУ НИИ фармакологии ТНЦ СО РАМН) Средства, обладающие гемореологической, антиагрегантной и антитромбогенной активностью
WO2013006099A2 (fr) * 2011-07-06 2013-01-10 Федеральное Государственное Бюджетное Учреждение Науки Институт Химии Коми Научного Центра Уральского Отделения Российской Академии Наук 2,6-diisobornyl phénols

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RU2347561C2 (ru) * 2007-04-23 2009-02-27 Государственное учреждение Научно-исследовательский институт фармакологии Томского научного центра Сибирского отделения Российской Академии медицинских наук (ГУ НИИ фармакологии ТНЦ СО РАМН) Средства, обладающие гемореологической, антиагрегантной и антитромбогенной активностью
WO2013006099A2 (fr) * 2011-07-06 2013-01-10 Федеральное Государственное Бюджетное Учреждение Науки Институт Химии Коми Научного Центра Уральского Отделения Российской Академии Наук 2,6-diisobornyl phénols

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