Ethylidene hydrazide of 2-[6-methyl-1-(thiethan-3-yl)uracyl-3-yl]acetic acid, demonstrating hypotensive activity

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to mixture of E- and Z-isomers of (4-bromophenyl)ethylidene hydrazide of 2-[6-methyl-1-(thiethan-3-yl)uracyl-3-yl]acetic acid in molar ratio 3.5:1 of general formula: .

EFFECT: obtained is novel mixture of isomers, demonstrating hypotensive activity.

2 cl, 4 tbl, 4 ex

 

The invention relates to organic chemistry and medicine, namely to a mixture of E - and Z-isomers - (4-bromophenyl)utilitygrid 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid, which has anti-hypertensive activity.

Known anti-hypertensive drugs, which are widely used for the treatment of hypertension, are the nebivolol, lisinopril and amlodipine [Mashkovsky M. D. Medicines. // M LLC "New wave", 2004, 2, S. 423, 416-417].

Nebivolol is a selective blocker of β1-adrenergic receptors with vasodilating action. Contraindications to the use of the drug are: sinus bradycardia (less than 45-50 beats./min), arterial hypotension, cardiogenic shock, weakness syndrome, the sinus node, AV blockade II-III degree, resistant to therapy of severe heart failure; disorders of the peripheral circulation, sinoatrial block, bronchial asthma, bronchospasm, abnormal liver function, pregnancy, lactation, infancy. The drug has a limitation for use in diabetes mellitus (can mask signs of hypoglycemia), hyperthyroidism (likely tachycardia), tendency to bradycardia, burdened allergological anamnesis, the elderly (over 75 years). Therapy with nebivolol is recommended to stop gradually (within 1-2 weeks). Reduce the dose of the drug is necessary when ischemia choose to 55 beats./min The drug can exacerbate reactions to pollen and other allergens. For 24 h before surgery using General anesthesia (including dental surgery) nebivolol should be abolished or select an anaesthetic agent with the lowest negative inotropic effect. The drug should be used with caution during operation, the drivers of vehicles and people skills are related to high concentration of attention. In the study of nebivolol in the two-year study in mice at a dose of 40 mg/kg per day, there was a statistically significant increase in the incidence of hyperplasia of testicular tissue and adenomas of the testis. The FDA classifies nebivolol category C reproduction in animals have revealed adverse effects on the fetus. With the introduction of nebivolol rats in the early stages of pregnancy at doses of 20-40 mg/kg per day in calves was observed a decrease in body mass, the time delay of ossification of the sternum and ribs, the increase of bone resorption. Doing nebivolol rabbits during gestation at a dose of 20 mg/kg / day adverse effects on the offspring did not. It was also shown that nebivolol and its metabolites are able to penetrate through genitoplasty barrier. With the introduction of nebivolol to female rats during late pregnancy, during childbirth and during lactation in dose is 1.25 mg/kg and 2.5 mg/kg / day decreased body weight in newborn calves. Doses of 5 mg/kg per day and above nebivolol in the rat caused cases of advanced pregnancy, and the violation of labor activity and a decrease in the care of offspring, which was accompanied by increase in foetal deaths fruit and stillbirth, calving with reduced body weight and reduced survival of offspring. Due to insufficient number of surviving cubs to evaluate the reproductive performance of offspring failed. In rats nebivolol and its metabolites are able to be excreted in breast milk, however it is unknown excreted do it with breast milk in humans. Nevertheless, given the potential adverse effects of β-blockers that may occur in the newborn, particularly bradycardia, nebivolol is not recommended for use in breastfeeding women [RLS 2012].

Lisinopril is an ACE inhibitor. Lisinopril has a number of side effects on the cardiovascular system: the reduction of blood pressure, arrhythmia, chest pain, rarely orthostatic hypotension, tachycardia; nervous system: headache, dizziness, drowsiness, fatigue, twitching of muscles of limbs and lips, rarely fatigue, mood lability, confusion; digestive system: nausea, dyspepsia, loss of appetite, changes in taste, stomach pain, diarrhea, dry mouth; the bodies to whom betweenie: leukopenia, thrombocytopenia, neutropenia, agranulocytosis, anemia (reduced hemoglobin, eritrotsitopeniya). It is also possible allergic reactions: angioedema, skin rashes, itching. The drug affect laboratory values, causing hyperkalemia, hyperuricemia, rarely - increased activity of "liver" transaminases, hyperbilirubinemia. When using lisinopril is also likely to experience dry cough, decreased potency; rarely acute renal failure, arthralgia, myalgia, fever, swelling of the tongue, lips or extremities, impaired development of the fetal kidney. In regard to side effects from the nervous system must be wary of lisinopril people skills are related to high concentration of attention.

When using lisinopril is necessary to estimate the ratio of the risk-benefit in the following cases: cerebrovascular disease (including cerebral circulation insufficiency), ischemic heart disease, coronary insufficiency, when collagenoses (including systemic lupus erythematosus, scleroderma), while inhibition of bone marrow hematopoiesis, arterial hypotension, aortic mitral stenosis or other obstructive changes, obstructing the outflow of blood from the heart; if hyperpotassemia or high risk of its occurrence (diabetes mellitus, severe renal not dostatochnosti, concurrent administration of diuretics), azotemii, hyponatremia or restriction of sodium in the diet. Caution is required in the use of lisinopril in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, the presence of the transplanted kidney, primary aldosteronism, hyperuricemia, old age and pregnancy [instructions for medical use of the drug lisinopril. Reg. number: LS-000779].

Amlodipine is a calcium antagonist of the second generation, representing a derivative of dihydropyridines. Side effects of amlodipine is well known and has been studied in long-term clinical studies (Osterloh, 1989, 1991; Circo al., 1992; Hofling al., 1991; Heynen 1992). The disadvantages of this drug are swelling of legs and feet. Due to vasodilation there is an increase in capillary hydrostatic pressure, which contributes to the filtration of fluid in the tissues; the process of autoregulation of capillary blood flow and lymph drainage are calciseptine and therefore inhibited by calcium antagonists. Side effects of amlodipine cardio-vascular system and blood: redness of skin, heart; rarely, arrhythmias (bradycardia, ventricular tachycardia, atrial flutter), pain in the chest; on the part of the digestive tract: constipation, nausea, stomach pain; from the created system and sensory organs: fatigue, headache, dizziness, drowsiness.

Amlodipine limit for use in heart failure, unstable angina, severe aortic stenosis, abnormal liver function and the age of 18 (not determined the safety and effectiveness). Drug use during pregnancy is possible if the expected effect of therapy outweighs the potential risk to the fetus. According to the FDA amlodipine belongs to the category C, that is, the reproduction in animals have revealed adverse effects on the fetus and adequate and well-controlled studies in pregnant women have not been conducted, however, the potential benefit to the pregnant woman can justify its use [instructions for medical use of the drug "Amlodipine", Reg. number: LSR-004932/07 from 17.12.2007,].

In patent SU # 1672929, 1991, "Method for obtaining derivatives of hydrazine or of their pharmaceutically compatible salts" of the compounds of General formula:

where: X - o-Cl or m-Br,

From data of compounds 1-(2-oxyisobutyric)-2-(1-o-chlorophenyl-1-ethylidene)hydrazine reduces blood pressure in spontaneously hypertensive rats SHR.

The closest analogue of the invention is the preparation urapidil-6-[[3-[4-(2-methoxyphenyl)-1-piperazinil]propyl]-amino]-1,3-dimethyl-uracil. Urapidil - anticipate the invasive drug with Central and peripheral effects. Blocks postsynaptic α1-adrenergic receptors, which reduces the total peripheral vascular resistance. Regulated by the Central mechanism for maintaining vascular tone due to the stimulation of serotonin 5-HT1A receptors vasomotor center (prevents reflex increase of a sympathetic tone). Usually specified drug used to reduce blood pressure in hypertensive crises [Patent US 4131678 A 09.02.77].

The objective of the invention is to expand the Arsenal of biologically active substances, including having anti-hypertensive activity.

The technical result - obtaining biologically active substances exhibiting hypotensive activity.

The inventive mixture of E - and Z-isomers (4-bromophenyl)utilitygrid 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid in a molar ratio of 3.5:1 in the General formula (I):

exhibiting hypotensive activity.

The specified connection and its properties are not described in literature.

The inventive compound is synthesized as follows.

The interaction of 6-methyl-1-(tietan-3-yl)uracil with ethyl ether monochloracetic acid in the presence of potassium carbonate receive the ethyl ester of 2-[6-methyl-1-(iatan-3-yl)uracil-3-yl]acetic acid, which reacts with hydrazinehydrate, forming hydrazide 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid. The resulting hydrazide 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid is condensed with 4-bromoacetophenone, forming a mixture of isomers (4-bromophenyl)utilitygrid 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid.

Example 1. The synthesis of the claimed compounds.

6-Methyl-1-(tietan-3-yl)uracil synthesized according to the method described in [Kataev C. A., Meshcheryakova S. A., Lazarev centuries, Kuznetsov Century. Century. // Synthesis diethanolamine pyrimidine-2,4(1H,3H)-diones. - Journal. organic. chemistry - 2013. - So 49. Vol.5. - S. 760-762; patent RU 2485118 from 20.06.2013,]

A suspension of 4.0 g (20 mmol) of 6-methyl-1-(tietan-3-yl)uracil and to 4.14 g (30 mmol) of calcined powdered potassium carbonate in 125 ml of acetone boil on the mantle for 30 minutes, add 3,68 g (30 mmol) of ethyl ether monochloracetic acid and continue boiling for another 7 hours. The reaction mass is then cooled, the precipitate is filtered off, washed on the filter with acetone. The filtrate is evaporated under reduced pressure to dryness. The dry residue is dissolved in 55 ml ethanol, add 4.7 grams of 85% aqueous solution of hydrazine hydrate is added and boiled for 3 hours. Cooled at 0°C for 12 hours, the precipitate is filtered off, washed with water and dried. Get to 2.29 g (53%) of a mixture of Z - and E-isomers of hydrazide 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]vinegar is Oh acid in a molar ratio of 7:1, purify by crystallization from ethanol. MP. = 199-201°C.

IR spectrum, ν, cm-1: 3365-3215 (N-H), 1692, 1654,1631 (C=O, C=C), 1439, 1385 (C-N).

An NMR spectrum1H (500 MHz, DMSO-d6), δ, M. D.:

and 2.14 (s, 3H, 6-CH3);

3,07-3,11 [m, 2H, S(CH)2]; 4,15-4,19 [m, 2H, S(CH)2];

the 4.29 (s, 2H, NH2, Z); of 4.54 (s, 2H, NH2E);

was 4.42 (s, 2H, 3-CH2, Z); rate 4.79 (s, 2H, 3-CH2E);

to 5.66 (s, 1H, 5-H);

6,03-6,07 (m, 1H, NCH);

8,77 (ush.s, 1H, NH, E), 9,36 (ush.s, 1H, NH, Z).

Elemental analysis.

Found, %: C 44,44; H 5,19; N 20,74 - C10H14N4O3S.

Calculated, %: C 44,71; H 5,11; N 20,89.

To a solution of 2.16 g (8 mmol) of hydrazide 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid in 15 ml of ethanol is added at 1.91 g (9.6 mmol) of 4-bromoacetophenone, the mixture is boiled for 4 hours, cooled. The precipitation is filtered off, washed with ethanol and dried. Get 2,96 g (82%) of a mixture of E - and Z-isomers (4-bromophenyl)utilitygrid 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid in a molar ratio of 3.5:1, purified by crystallization from n-butanol. MP. = 251-253°C.

IR spectrum, ν, cm-1: 3198 (N-H), 1718, 1661,1626 (C=O, C=N, C=C), 1434, 1399 (C-N).

An NMR spectrum1H (500 MHz, DMSO-d6), δ, M. D.:

and 2.14 (s, 3H, 6-CH3);

of 2.25 (s, 3H, N=C-CH3E); to 2.29 (s, 3H, N=C-CH3, Z);

is 3.08-3,11 [m, 2H, S(CH)2]; 4,14-4,17 [m, 2H, S(CH)2];

4,69 (s, 2H, 3-CH2, Z); 5,04 (s, 2H, 3-CH2E);

of 5.68 (s, 1H, 5-H);

6,02-6,09 (m, 1H, NCH);

to 7.61 (d, 2H, H-arene, J 4.3 Hz), to 7.77 (d, 2H, H-arene, J 4.3 Hz

10,84 (ush.s, 1H, NH, Z), 11,09 (ush.s, 1H, NH, E).

An NMR spectrum13C (300 MHz, DMSO-d6), δ, M. D.: 13,55 (N=C-WithH3); 19,15 (6-CH3); 31,47 [S(CH2)2)]; 46,16 (3-CH2); 47,01 (NCH); 100,24 (5); 122,80 (4arene); 128,25 (2,6arene); 131,32 (3,5arene); 137,06 (1arene); 148,02 (N=With-CH3); 151,68 (6); 153,95 (2); 161,23 (4); 169,32 (3-CH2-C=O).

The quantitative composition of both isomers is determined by comparing the integral intensities of the signals corresponding to protons E-(4-bromophenyl)utilitygrid 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid and Z-(4-bromophenyl)utilitygrid 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid, confirming the molar ratio of 3.5:1.

Elemental analysis.

Found, %: C 39,91; H 4,21; N 12,42 - C18H19BrN4O3S.

Calculated, %: C 40,09; H 4,29; N 12,56.

The inventive compound is a light yellow crystalline powder, insoluble in water, ethanol, ether, soluble in dimethylformamide, dimethylsulfoxide.

Example 2. The study of the antihypertensive effect of a mixture of E - and Z-isomers - (4-bromophenyl)utilitygrid 2-[6-methyl-1-(tietan-3-yl)uracil-3-yl]acetic acid in a molar ratio of 3.5:1 when administered intravenously using the technique of non-invasive measurement of arterial pressure in cheerful is adequate rats.

Assessment of the antihypertensive actions carried out by the method, which is the basic model studies of substances with anti-hypertensive activity [Guidance for preclinical testing of drugs. Part one. - M.: Grif, 2012. - 944 S.].

To study the effect of the claimed compounds I in systolic blood pressure (SBP) and heart rate (HR) were formed 2 groups of female rats weighing 280-320 g (6 animals each). The investigated compound was dissolved in 50% solution of dimethyl sulfoxide (DMSO) and were injected into the tail vein at a dose of 15 mg/kg Control group animals were administered 50% solution of DMSO in the equivalent volume. Indicators GARDEN and heart rate were recorded after 30, 60 and 90 minutes after administration of the compounds from the tail of the animal using the device in a non-invasive measurement of blood pressure - title 29 (IITC Life Science Inc., USA). For the initial level of accepted values a GARDEN, and heart rate recorded before the introduction of the investigated compounds. To prepare for non-invasive measurement of blood pressure in animals previously accustomed to finding in plastic canisters-holders to do this for three days was placed in canisters-holders for 1 hour to familiarize yourself with the environment. Method of measuring the HELL was in the room watching the animal in the box-holder, tail zivotnog who wore the cuff with integrated fotosession, which blows air (10-15 mm RT.article above are the estimated HELL) and then slowly stravovali and indicators GARDEN and heart rate were automatically recorded by the device.

Found that when administered intravenously at a dose of 15 mg/kg of the inventive compound I has a marked hypotensive effect (table 1) and causes a decrease in heart rate (table 2).

Example 3. The study of dependence "dose hypotensive effect and duration of action of the claimed compounds I by oral administration using the method of non-invasive measurement of arterial blood pressure in awake rats in comparison with reference drugs.

The effect of the claimed compounds I the GARDEN and heart rate were studied in awake rats females weighing 280-320 g (6 animals in each group). Analyzed the connection suspensively in 2% starch mucus and intragastrically administered orally in doses of 15 mg/kg, 30 mg/kg and 60 mg/kg as Comparators used nebivolol (nebilet, Berlin-Chemie AG, Germany) at a dose of 2 mg/kg, lisinopril (Diroton, Gedeon Richter, Hungary) at a dose of 10 mg/kg and amlodipine (normodipina, Gedeon Richter, Hungary) at a dose of 1 mg/kg Control group of animals received 2% starch mucilage in the equivalent volume. Indicators GARDEN and heart rate were recorded after one hour after administration of the compounds from the tail of the animal at intervals of 1 hour for the of 8 hours and 24 hours. For the initial level of accepted values a GARDEN, and heart rate recorded before the introduction of the investigated compounds. Methods of measuring blood pressure described in example 2.

The study has found that the claimed compound I has the most pronounced hypotensive effect at a dose of 30 mg/kg (table 3), similar to those of the Comparators.

Performed research suggests that the claimed compound I has a pronounced anti-hypertensive activity. In experimental animal studies the effect of the drug observed in its oral administration in a dose of 30 mg/kg For anti-hypertensive activity of the inventive compound I is not inferior to the Comparators. The inventive compound I is of interest to further study its hypotensive activity and development on its basis of a hypotensive drug.

Example 4. The study of prevention of antihypertensive action of the claimed compounds I on the model of the stress of hypertension when oral administration.

For modeling hypertension caused by chronic stress, was formed 5 groups of female rats weighing 280-320 g (6 animals each): group 1 - positive control, intact animals treated with 2% starch mucilage in 0.2 ml per 100 g and not exposed to stress; gr is the PAP 2 - animals treated with 2% starch mucilage in 0.2 ml per 100 g weight and exposed to stress; group 3 experienced, animals treated with the inventive compound I in a dose of 30 mg/kg; group 4 - Diroton at a dose of 10 mg/kg; group 5 - normodipina dose of 1 mg/kg of the Studied compound at a dose of 30 mg/kg and Comparators - lisinopril (Diroton, Gedeon Richter, Hungary) at a dose of 10 mg/kg and amlodipine (normodipina, "Gedeon Richter", Hungary) at a dose of 1 mg/kg was suspensively in 2% starch mucus and intragastrically administered orally, daily for 30 minutes before stressaway. Then the animals were stressaway for 30 minutes in a dark cell, width 28 cm, length 36 cm, height 28 cm, mounted on an inclined flat metal platform with a slope angle of 10°, on its walls on the perimeter, there are vent holes for air circulation. The platform is equipped with electric drive, making swinging movement with variable speed from 10 to 40 oscillations per minute. The camera has an opaque cover, which includes a source of audio noise and 3 light sources arranged at a height of 28 see the light Sources are equipped with relay-tripped with a time delay of 2 seconds, which provides pulses of light. The chamber is divided into 6 isolated compartments of the same size and is designed for the simultaneous tressirovanye the t 1 to 6 animals. Rats were placed in isolated compartments and were subjected to stressors: pulsed light, loud sound and vibration. The installation allows you to combine multiple stress stimuli or to use them in mono. For the initial level of the GARDEN and HR took the values recorded on day 1 of the experiment to stressaway animals, measurements were repeated on the 7th and 14th day of the experiment.

It is estimated that of the control group animals after 7 days of stressaway GARDEN grew by 12.6%, and 14 days - 16.7% (table 4). Oral administration at a dose of 30 mg/kg of the claimed compounds I warned improving the GROUNDS, caused by the combined stress effects. Preventive antihypertensive activity of the claimed compounds I are comparable with Comparators.

Table 1
The effect of the claimed compounds I to HELL with intravenous
Compound doseExodus30 minutes60 minutes90 minutes
Control, 50% DMSO in equival. volume M±S122,1±6,8124,3±5,5122,3±2,5122,9±2,6
%1,80,20,6
I, 15 MG/KGM±S125,7±5,5116,5±10,6108,1±10,1a 99.0±12,5
%is 7.3-14,0-21,2

Table 2
The effect of the claimed compounds I in HR intravenous
Compound doseExodus30 minutes60 minutes90 minutes
Control, 50% DMSO in equival. volumeM±S398,6±20,1383,3±20,7408,7±42,2398,2±11,1
%-3,82,5-0,1
I, 15 MG/KGM±S407,78±54,75381,33±22,63351,33±51,10375,22±34,62
%-6,49-13,84-7,98

Table 3
Duration and effect of the claimed compounds I in AD in comparison with reference drugs
Compound doseExodus1 h2 hours3 h..4 hours5 hours6 hours8 hours24 hours
Control 2% krahm. mucusM±S123,4±1,4123,6±2,2123,9±1,5 123,6±1,5123,3±2,3123,7±1,8123,9±1,0125,0±0,6was 124.9±1,3
%0,10,40,1-0,10,20,41,31,2
I, 15 mg/kgM±Sand 125.4±1,3122,4±1,8119,0±4,5to 114.4±7,5114,0±2,8of 114.3±3,6of 111.9±6,7112,9±4,2116,6±6,9
%-2,4-5,1-8,8-9,18.9bn-10,8-10,0-7,1
I, 30 mg/kgM±SUSD 128.0±3,8output reached 125.5±2,1to 119.8±0,2 116,3±3,8112,0±3,8109,2±1,2106,3±9,0111,5±2,1119,3±16,0
%-2,0sphere-6,4-9,1is 12.5-14,7-16,9-12,9-6,8
I, 60 mg/kgM±S130,3±1,5to 127.9±2,2and 125.4±2,3122,2±1,9121,3±1,7119,6±3,2120,2±3,0119,6±2,3122,1±5,8
%-1,9-3,8is 6.2-6,9-8,3-7,8-8,3-6,3
Amlodipine 1 mg/kgM±S125,0±1,2125,±1,5 of 124.8±3,0118,9±2,2or 115.1±4,7112,1±5,7byr111.4±5,1109,2±5,9120,8±2,7
%0,5-0,2-4,9vs.-7.9bn-10,3-10,8-12,6-3,4
Lisinopril 10 mg/kgM±Sto 129.2±0,7124,0±6,0118,9±1,8115,4±2,2113,3±0,9to 107.4±3,9to 106.2±2,8106,1±3,1120,9±0,7
%-4,0-8,0-10,7-12,3-16,9about 17.8 mln-17,9sphere-6,4
Nebivolol 2 mg/kgM±S 128,2±2,4119,1±4,8to 118.0±2,6115,3±3,5112,7±1,2106,7±3,1105,0±2,5103,7±2,7118,9±8,1
%-7,1-8,0-10,1-12,1-16,8-18,1-19,2is 7.3

Table 4
The effect of the claimed compounds I in a dose of 30 mg/kg when administered orally for 14 days in HELL stressed rats
Substance doseExodus7 days14 days
Positive control 2% krahm. mucusM±S121, 1million±0,8to 121.7±1,5121,3±0,9
%0,5 0,1
Negative control 2% krahm. mucusM±S120,8±0,7136,1±4,2141,1±4,4
%12,616,7
I, 30 mg/kgM±S122,6±2,2124,3±1,5the 122.7±1,4
%1,40,0
Amlodipine 1 mg/kgM±Sthe level of 121.8±3,9for 125.8±1,6of 124.6±2,8
%3,32,2
Lisinopril 10 mg/kgM±S123,1±1,3of 124.1±3,1122,0±3,1
%0,8-0,9

1. The mixture of E - and Z-isomers (4-bromophenyl)utilitygrid 2-[6-methyl-1-(tiet the n-3-yl)uracil-3-yl]acetic acid in a molar ratio of 3.5:1 the General formula:

2. Connection on p. 1, exhibiting hypotensive activity.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to agriculture. Pesticidal composition contains compound of formula ,

where X represents NO2, CN or COOR4; L represents single bond or R1, S and L, taken together represent 4-, 5- or 6-membered ring; R1 represents (C1-C4)alkyl; R2 represents methyl, ethyl, chlorine or bromine, and R3 represents hydrogen; n equals 1, when L represents single bond, or equals 0, when R1, S and L, taken together represent 4-, 5- or 6-membered ring; Y represents (C1-C4)halogenalkyl, F, Cl, Br or I; and R4 represents (C1-C3)alkyl; and organic acid or its salt. Composition is applied for fighting insects.

EFFECT: invention makes it possible to increase composition stability.

15 cl, 10 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-(2-thienyl)pyrrole, which involves reacting 2-acetylthiophene with hydroxylamine, potassium hydroxide and acetylene in a medium of dimethyl sulphoxide; the process is carried out at atmospheric pressure and temperature of 80-120°C for 3-5 hours, with molar ratio 2-acetylthiophene:hydroxylamine chloride:potassium hydroxide of 1:1-1.2:2-2.5, using acetylene as the saturated solution in dimethyl sulphoxide, and hydroxylamine is generated directly in the reaction medium from hydroxylamine chloride and potassium hydroxide.

EFFECT: novel selective method of producing said compound, which is simple and environmentally safe.

3 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, possessing a modulating action with respect to the CC chemokine receptor 3 (CCR3), a based on them pharmaceutical composition, versions of treatment methods and a method of controlling the CCR3 activity. In the general formula I R1 and R2 represent halogen or C1-6alkyl; R3 represents cyano or nitro; R4 represents or ; R5 represents oxo; C1-6alkyl, optionally substituted with halogen atoms; or C(O)OR1a; X represents O or S; Y represents -O-, -S-, -N(R1a)-, -C(R1a)(R1d)- or -C(R1a)(NR1bR1c)-; m represents an integer number from 0 to 2; n represents 1; p represents an integer number from 0 to 2; r represents 1 or 2; and each R1a, R1b, R1c and R1d represents (a) hydrogen; (b) C3-7cycloalkyl; or (c) C1-6alkyl, optionally substituted with hydroxyl, or each pair R1b and R1c together with a N atom, which they are bound to, form imidazoimidazolyl, substituted with oxo, butyl or chlorine, or heterocycle, containing 5 or 6 atoms in a cycle.

EFFECT: improvement of the composition properties.

41 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydroindenamide specified in compounds described by general formula II, or their pharmaceutically acceptable salts. In general formula II, R1 represents piperazinyl which can be optionally substituted by one R1a; R1a represents H, CH3, C(O)Rd or C(O)ORa; Y represents pyrimidyl; Z represents pyridyl or pyrimidyl; Ra represents tert-butyl and Rd represents CH3. The above compounds represent tert-butyl-4-{5-[({(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl)-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate; N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide; 1-[4-acetylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide and (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide sulphate.

EFFECT: compounds inhibit activity of protein kinases specified in Abl, c-Kit and PDGFR, and can find application for treating diseases related to disturbed activity of the above protein kinases, eg leukaemia and other cancers.

4 cl, 4 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazole derivatives of general formula or its pharmaceutically acceptable salt, wherein R1 means halogen, C1-6-alkyl or C1-6-alkoxy; R2 means C1-6-alkyl; R3 means hydrogen, C1-6-alkyl; Q means -N= or -CH=; R4 represents a group of formula or , wherein X, Y and Z independently represent -CH= or -N=, and only one of X or Y can be a nitrogen atom; R5 and R6 independently represent a hydrogen atom, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, -(CH2)m-(CO)O-C1-6-alkyl, -(CH2)m-S(O)2-C1-6-alkyl, -(CH2)m-C(O)-NR'R" and wherein m=1 and R' and R" independently represent hydrogen or C1-6-alkyl. Also, the invention refers to a therapeutic agent based on the compound of formula (I) and using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective for treating and preventing mGluR5 receptor mediated disorders.

26 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

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