Salts of nitrogen-containing heterocyclic derivatives and 5 - hydroxynicotinic acid, which has antianginal and antiarrhythmic properties

 

(57) Abstract:

Usage: for the treatment of ischemic heart disease and arrhythmias. The inventive product: salt of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid formula

,

where X, O, NH or CH2. Reagent 1:5 - hydroxynicotinic acid. Reagent 2: morphology. Reaction conditions: under stirring at an elevated temperature. 5 table.

The invention relates to the synthesis of biologically active compounds, namely, salts of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid of General formula:

< / BR>
where X 0(1a), CH2(1B), NH(1B).

has antianginal and antiarrhythmic activity.

These properties suggest the possibility of using the compounds for treatment of ischemic heart disease and arrhythmias.

Known means inderal showing antianginal and antiarrhythmic activity, but has a relatively high toxicity and cardiodepressive action.

The purpose of the invention, the search and synthesis of new compounds with antianginal and antiarrhythmic properties, low toxic the x compounds by the interaction of 5-hydroxynicotinic acid with the corresponding cyclic amines in the presence of a solvent under heating.

Compounds are white crystalline substances, soluble in water and alcohol.

P R I m e R 1. To a mixture of 40 mmol of 5-hydroxynicotinic acid in 200 ml of atacora add 40 mmol of the research or piperidine, or piperazine. The reaction mixture was stirred 15 min at 76-78oC, treated with 1 g of activated charcoal, filtered, the filtrate evaporated to a residual volume of 50 ml, cooled to 5-7oC, the target product is separated, dried, get, respectively: morpholino-5-hydroxynicotinate 1A, piperidine-5-hydroxynicotinate (1B) and piperazine-5 - hydroxynicotinate (1B).

Physico-chemical data and results of analyses are given in table. 1.

P R I m m e R 2. The study of the cardioprotective action of heterocyclic derivatives of 5-hydroxynicotinic acid.

Determination of acute toxicity.

Studied the acute toxicity of substances in experiments on white mice weighing 18-20 g with the definition of LD50according to the method of Litchfield and Wilcoxon signed intraperitoneal injection. Observation of animals should be performed within 48 h after injection of the drug. The results are shown in table.2 and indicate low toxicity of the claimed compounds.

eriment put on rabbits of the Chinchilla breed weighing 3-3 .5 kg with pre-implanted in the coronary artery by occluder (Y. B. Rozanov, T. C. Morozova "Bulletin of experimental biology and medicine, 1984, 10, S. 460-462). Compound is injected immediately after the establishment of stable threshold myocardial ischemia (table. 3).

1A at a dose of 0.2 mg/kg in all 4 experiments consistently increased the threshold for myocardial ischemia in experimental animals with duration of antianginal effect 15-20 minutes 1B in a dose range of 0.2 to 5 mg/kg had antianginal effect in all experimental animals, and the duration of prophylactic anti-ischemic action of the compounds increased with increasing dose in the dose of 5 mg/kg over 60 minutes 1B in a dose of 0.2 mg/kg had antianginal effect of duration of 15-20 min, and at a dose of 1 mg/kg 30-40 minutes

Comparison drug from the group of --blockers inderal in effective anti-ischemic dose of 1 mg/kg steadily increased the threshold of an ischemia of a myocardium of rabbits with a duration of antianginal effect 30-40 minutes

Thus, studies have shown that the heterocyclic derivatives of 5-hydroxynicotinic acids have antianginal effect and are not inferior in efficacy to the comparator drug from the group of --blockers.

2. Antiarrhythmic activity of what you put on bisexual Wistar rats, mass 160-240 g, anesthetized by intraperitoneal injection of sodium thiopental dose of 50 mg/kg Occlusion of the descending branch of the left coronary artery is performed during artificial ventilation of the lungs. Produce thoracotomy in the fourth intercostal space to the left and opened the pericardium. Under the anterior descending branch of the left coronary artery at the level of the left atrial appendage down the thread using atraumatic needles. In experiments on rats coronary flow block for 10 min, after which the circulation is restored and continue to monitor the heart rate during the next 5 minutes

Compound injected, inkjet, simultaneously for 5 min prior to occlusion of a coronary artery (the EYE).

Comparison drug inderal slowly injected directly in front of the EYE.

The results are shown in table. 4, 5. At intravenous introduction of the claimed compounds in doses of 5% LD50not registered cardiodepressive effect on the basic electrophysiological parameters of the heart muscle. On the model of early postocclusion arrhythmias, all compound at a dose of 5% LD50showed antifibrillatory effect, and the compound 1A was significantly (the awn ventricular arrythmia (GA). 1B reduced the duration of adipose tissue, reduced the intensity IA and 1B reduced the intensity IA. In isomolar doses (for 1A and 1B is approximately equal to 2% LD50) have been the most effective compounds 1A and 1B, which together with antifibrillatory effect reduced the duration of VT and intensity IE. Comparison drug inderal dose of 1.0 mg/kg showed a cardiotoxic effect, which was expressed in the impaired function of the conductance of myocardium. At this dose inderal had antifibrillatory effect and significantly (p < 0,05) was affected only for the duration of VT and intensity IA, i.e. inferior to one of the claimed compounds (1A).

Dose not calling cardiodepressive effect (0.1 mg/kg), inderal significantly (p < 0,05) was affected only on the latent period of arrhythmia, i.e., inferior in the efficiency of the claimed compounds.

On the model of reperfusion arrhythmias among the tested compounds, taken in isotoxicity doses (5% LD50the most effective was the connection 1B, which was significantly (P < 0,05) reduced the incidence of ventricular fibrillation (Fi), duration adipose tissue and the intensity IA and increased latent period. In isomolar doses (about 2% LD50) the greatest effect was shown by the compounds comparison of inderal dose of 1 mg/kg (causing dysfunction of the conductance of myocardium) reduced the incidence of Fi, extended latent period and reduced the duration of VT, i.e., the characteristic of the antiarrhythmic actions yielded compound 1B in a dose of 5% LD50. At a dose of 0.1 mg/kg inderal yielded in the antiarrhythmic activity of the claimed compounds.

Thus, the claimed heterocyclic derivatives of 5-hydroxynicotinic acid, have antianginal and antiarrhythmic properties. On antianginal activity of these compounds do not yield --the blocker inderal and have much lower toxicity. In the investigated dose range of the claimed compounds do not show cardiotoxic properties are not inferior, and in some cases superior to antiarrhythmic activity of inderal. When you save the spectrum and intensity of antiarrhythmic effect of these compounds less toxic compared with similar-blocker-inderal and isoeffective doses not have cardiodepressive effect.

Salts of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid of General formula

< / BR>
where X is O, NH or CH2,

has antianginal and antiarrhythmic properties.

 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

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m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

18 cl, 3 tbl, 23 ex

FIELD: organic chemistry, medicine.

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EFFECT: valuable properties of compounds and pharmaceutical compositions.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compound with formula (I) or to its tartrate salt. The invention also relates to application of the composition as well as the method of inhibiting of monoamine receptor activation to inverse agonist and anti-dyskinesia agent in the combination with inverse agonist.

EFFECT: production of the new biologically active compound having inverse agonist activity of serotonin receptor.

54 cl, 7 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

FIELD: medicine.

SUBSTANCE: invention refers to a method of treating neurodegenerative disorders, neuropsychiatric disorders, as well as psychosis secondary to neurodegenerative disorders by introducing a compound of formula or its tartrate salt into a patient.

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15 cl, 3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,3-dicarbonyl derivatives of adamantane of general formula I where R=H, X=OH, OMe, OEt, OPri, OBus, OCH2CH(Et)Bu, OCH2CF3, OCH(CH3)CF3, OCH2CF2CF2H, OCH2CH2CH2Br, OCH2C=CH, NEt2, NC5H10 (piperdyl), NC4H8O (morpholyl), C6H5NH, C6H4OMe, C4H3O (furyl); R=Me, X-OH, Me, OMe, O-Pri, X=NC4H8O (morpholyl), C4H3O (furtyl), NEt2, C6H5NH, C6H4OMe; involving carbonylation of an adamantane compound in the presence of electrophilic catalysts, where the adamantane compound used is adamantane or 1,3-dimethyladamantane and carbonylation is carried out under the action of CO at atmospheric pressure in a solution of CH2Br2 at temperature of 0-25°C for 0.5-3 hours, and the catalyst used is a super-electrophilic CBr4·2AlBr3 complex, in molar ratio [CBr4-2AlBr3]: [adamantane compound] = (1.5-2):1, and a nucleophilic substrate - water or alcohol - is added to the carbonyl derivative formed in situ, without extraction thereof, in an atmosphere of CO, said substrate containing an alkyl or acetylene or bromoalkyl or polyfluoroalkyl group; or an amine of an aliphatic or heterocyclic or aromatic series; or an aromatic hydrocarbon or an aromatic heterocycle; and reaction with a nucleophile is carried out at temperature of 0-25°C.

EFFECT: single-step method of producing 1,3-dicarbonyl derivatives of adamantanes with two identical carbonyl-containing groups in nodal positions of the adamantane nucleus enables to use readily available adamantane compounds as starting compounds.

25 ex

FIELD: medicine, pharmaceutics.

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EFFECT: compounds may be used for treating an ophthalmic disease or disorder in an individual which can represent age-related macular degeneration or Stargardt macular degeneration.

17 cl, 14 tbl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining derivatives of carboxylic acids, in particular to novel method of reamidating amides of carboxylic acids. Method is realised by interaction of carboxylic acid amide with amine with heating in presence of catalyst - copper nanoparticles. As carboxylic acid amide formamide, acetamide, dimethylformamide or isovaleramide is applied, as amine - cyclohexylamine, piperidine, morpholine or 2-aminoethanol. Process is carried out with molar ratio carboxylic acid amide : amine : catalyst, equal 1:1-1.2:0.02-0.05, at temperature 20-100°C for 0.5-3 hours.

EFFECT: simplified method of reamidation of carboxylic acid amides due to application of cheaper catalyst and carrying out process in milder conditions.

8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining monofluoridated complex pyridinil and pyrimidinil beta-ketoesters of the formula (I) , where R1 is a 4-pyridine or 4-pyrimidine ring; R2 is a hydrogen atom, C1-6 alkyl group or halogen atom; and R3 is a C1-6 alkyl group. The method involves interaction of fluorine gas with a compound of the formula (II) , where R1, R2 and R3 are the same as above. The invention also concerns compounds of the formula (I).

EFFECT: possible application as intermediary products for pharmaceutical compounds.

12 cl, 1 dwg, 3 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention concerns carboxylic acid compounds of the formula (I) , where R1 is hydrogen or C1-4alkyl; m is 2 or 3; n is 0-2; R2 is phenyl, naphtyl, benzofuran, benzothiophene; Q is -CH2-O-Cyc1, -CH2-Cyc2, -L-Cyc3, each of R3a and R3b radicals is independently a hydrogen, alkyl, or the R3a and R3b radicals together form tetrahydro-2H-pyran; pharmaceutically acceptable salts, method of obtaining them, and pharmaceutical agent including this compound as active component. Compound of the formula (I) displays antagonistic effect on PGE2 receptor, especially EP3 receptor, which is its subtype, and is applied in prevention and/or treatment of itching, pain, urination disorder or diseases caused by stress.

EFFECT: increased efficiency of compounds.

11 cl, 37 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), including its pharmaceutically acceptable salts, solvates, ethers and amides, possessing ability to bind ERα- and ERβ-estrogen receptors, to pharmaceutical composition based on them, to versions of applying claimed compounds in medication preparation and to method of binding ERα- and ERβ-estrogen receptors. (I), where R1 represents H, OH or C1-12alkoxy, or halogen; R2 represents H, OH or halogen; R3 represents C1-12alkyl, halogeno-C1-12alkyl, C3-10cycloalkyl, C1-12alkoxy or C1-12alkoxyC1-12alkyl; R4 represents H or C1-12alkoxy; R5 represents H, halogen or halogeno-C1-12alkyl; R6 represents -(Y)z-R7; R8 represents phenyl or 5- or 6-member heteroaryl, containing N, O or S as heteroatom, where said phenyl and heteroaryl are possibly substituted with OH, halogeno, halogenoC1-12alkyl or C1-12alkoxy. Values R7, Y and z are presented in invention formula.

EFFECT: novel compounds possess useful biological properties.

19 cl, 7 dwg, 1 tbl, 70 ex

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