Applying moxonidine for treatment of post-infarction states

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention proposes applying moxonidine as an active component in preparing pharmaceutical compositions designated for treatment of injuries of heart muscle caused by infarction. Indicated compositions promote to prophylaxis in the infarction progression and to treatment of its complications also.

EFFECT: valuable medicinal properties of composition.

3 cl, 1 tbl, 1 ex

 

The present invention relates to the use of 4-chloro-5-[(4,5-dihydro-1H-imidazol-2-yl)amino]-6-methoxy-2-methylpyrimidine (moxonidine and its physiologically acceptable acid additive salts for treatment due to myocardial infarction lesions of the heart muscle and to obtain drugs for such treatment.

The basis of the invention was based on the task to get a new pharmaceutical composition, which could have an effective impact on the process of recovery and/or rehabilitation of patients after myocardial infarction, and could thus be used for treatment due to myocardial infarction lesions of the heart muscle in accordance with provided for the treatment of this disease, as well as post-infarction state.

According to the invention to obtain the corresponding pharmaceutical compositions intended for the treatment due to myocardial infarction lesions of the heart muscle, it is suggested to use 4-chloro-5- [(4,5-dihydro-1H-imidazol-2-yl)amino] -6-methoxy-2-methylpyrimidin formula I

and its physiologically acceptable acid additive salt.

As physiologically acceptable acid additive salts moxonidine suitable salts with organic acids, such as halogen-portly puss is otami, or with organic acids, for example lower aliphatic mono - or dicarboxylic acids, such as acetic acid, fumaric acid or tartaric acid, or aromatic carbolic acids, such as salicylic acid.

Used according to the invention compounds fall under the scope described in the application DE 2849537 derivatives of 5-[(2-imidazolin-2-yl)amino] pyrimidine, which have lower blood pressure properties and which are known from this application. Containing moxonidine pharmaceutical compositions are commercially available products under the trade name Physiotens®with protivogipertonicheskoe properties, and as such antihypertensive drugs used in medicine. These compounds can be obtained in a known manner by means described in the aforementioned application methods or similar.

Unexpectedly it was found that moxonidine and its physiologically acceptable acid additive salts have a positive, conducive to the treatment and/or rehabilitation, the impact on the state of the heart muscle after suffering a heart attack and thus suitable for the treatment of postinfarction myocardial lesions in humans and large mammals.

The term "myocardial infarction" refers mainly necrosis of one who does more areas of the heart muscle resulting from a sustained complete cessation of blood supply (- ) section (s) or its reduction to a critical level. In acute myocardial infarction, i.e. in the acute period of the disease, along with General therapeutic measures as analgesia, sedation sedatives, the introduction of oxygen, bed rest and diet, used primarily thrombolytic, respectively fibrinolytic therapy with the intention that due to reperfusion of the ischemic area as possible (initially) to protect not affected by ischemia of the heart muscle from the complete cell death (i.e. from the final necrosis) and thereby limit the development of heart attack is extremely small area. Other measures can be aimed at improving the condition of the heart muscle, especially in the area of infarction in the acute phase of the disease, and in the postinfarction period.

Used according to the invention for treatment due to myocardial infarction lesions of the heart muscle connection mainly suitable because of this for use in the treatment of the specified disease.

They can be used therefore, in the acute phase of the disease, and especially in post-infarction patients after conducting fibrinolytic therapy, and without this lysis. In postinfarction patients with lysis used according to the invention compounds have primarily preventive action,thus preventing the development of heart failure (functional failure of the myocardium), due to transferred myocardial infarction. This applies also to patients, in the treatment of used β-blockers.

We infarction patients without lysis disease becomes chronic phase. For such patients in the chronic phase of particular importance is the fact that the sympathetic nervous system (SNS) plays an important role in the regulation of the cardiovascular system. So, sympathetic stimulation is the most important mechanism to increase cardiac output, because this stimulation promotes as to increase the intensity of contraction of the cardiac muscles and increase heart rate. Acute myocardial infarction leads among other things to activation of the SNS, contributing to the maintenance of perfusion pressure and perfusion of tissue.

This serious situation can develop with the transition to the chronic phase, in which activation of the sympathetic nervous system promotes hypertrophy and perestroika (remodulate) is not affected myocardium. This process, however, may exceed the permissible level, and the ongoing SNA-activation can result for various reasons to undesirable consequences:

1) Chronic activation of the Central sympathetic nervous system, because it strengthens the heart failure should be considered as the sky is appopriately factor. When sustained adrenergic stimulation of the heart in the form of compensation decreases the number of adrenergic receptors. The consequence of this protective mechanism of the heart against the persistently elevated levels of catecholamines is a significant deterioration regulation of the rate and strength of cardiac contractions through the autonomic nervous system.

2) stimulation of the SNS increases vascular tone and thereby increases the workload of the heart.

3) Increased levels of circulating catecholamines induces focal (focal) necrosis in the heart and contributes to the development of hypertrophy of the heart.

4) Elevated levels of catecholamines in the plasma contributes to adverse increased heart rate and occurs in some cases of cardiac arrhythmias.

With this in mind to prevent, respectively, in order to avoid too strong activation of the sympathetic nervous system it may be appropriate to such a treatment strategy for patients with myocardial infarction, which would include primarily the prevention of the occurrence after the disease cardiac weakness.

Unexpectedly, it was found that the applied according to the invention in the treatment of myocardial infarction and/or post-infarction treatment moxonidine has the unexpected effect which manifests itself in an effective, contributing process is su recovery and/or rehabilitation effects on the functional state of the heart muscle and especially in post-infarction treatment in the chronic phase. The use of moxonidine in postinfarction treatment helps to reduce the mass of the heart and decrease sympathetic activation, which was confirmed by measuring the level of norepinephrine in the plasma. Thus, the moxonidine can be successfully used to reduce excessive hypertrophy of the heart, first of all subsequent phases in the postinfarction period. In addition, moxonidine can reduce the level of norepinephrine in the blood plasma, providing the ability to effectively normalize sympathetic activation after myocardial infarction.

With the proposed invention in the treatment of lesions of the heart muscle caused by myocardial infarction, moxonidine and its physiologically acceptable acid salt additive can be included in the composition of conventional pharmaceutical compositions and enter the oral, intravenous or transdermal. Thus, in particular, moxonidine and its physiologically acceptable acid salt additive may be contained in solid or liquid pharmaceutical compositions effective in promoting the process of treatment and/or rehabilitation of the functional state of the heart muscle quantity together with conventional pharmaceutical excipients and/or carriers. As examples of solid preparations intended for direct or p is the power (extended) release of the active substance, you can call such assigned for oral administration of drugs as tablets, pills, capsules, powders or granulates, and also suppositories and patches (so-called TTS, transdermal therapeutic systems). These solid preparations along with commonly used pharmaceutical excipients, such as oil, baking powder, tablets, etc. may contain in its composition also typically used in the pharmaceutical inorganic and/or organic carriers, such as lactose, talc or starch. In the case of plasters active substance is placed in the "tank", first of all, for example, in a matrix (in particular, in the polymer matrix). Liquid preparations such as solutions, suspensions or emulsions of the active substances can contain the usual diluents, such as water, oil and/or suspendresume agents such as glycols, etc. May require the addition of other excipients, such as preservatives, flavorings, etc.

Of the active substances together with pharmaceutical excipients and/or carriers is possible by the conventional methods to prepare the mixture and composition. For example, for the manufacture of solid dosage forms of the active substance can be mixed in the usual techno is Ogii with excipients and/or carriers, and then the mixture is pelletized wet or dry method. Granules or powders can be directly placed in capsules or as usual to tablet. Similarly it is possible to make pills. Patches, respectively transdermal therapeutic system can be produced by the conventional methods using, for example, coating film, "reservoir" for active substances (self-adhesive or adhesive layer) and remove the protective film, in such systems for the controlled release of active substances may provide a matrix or membrane (i.e. an additional control membrane).

Experimental studies and results

The efficacy of moxonidine in the treatment of myocardial infarction and primarily in the postinfarction period can be confirmed in a standard experiment for the determination of the pharmacological evidence about the impact of substances on such factors that affect the functional state of the heart muscle after suffering a heart attack. To confirm such effects on the factors that affect the functional state of the heart muscle, especially in the chronic stage of the disease, conduct appropriate experiments on animals, using for this purpose, for example, of Wistar rats with chronic myocardial infarction (mi-rats).

When you research on THEM-rats was mouth is owino, the level of norepinephrine in plasma after a heart attack increases dramatically. At later stages of heart failure the level of norepinephrine in plasma may continue to rise. A thorough research on THEM, the rats were allowed to establish that even three weeks after a heart attack, i.e. upon completion of the so-called period of healing, heart rate (in vivo measurements on randomly selected rats in the waking state), obviously, remained elevated, whereas the level of norepinephrine in the plasma is still about 50% higher than the so-called pseudoinfection rats (i.e. rats, subjected to a mock surgery without ligating (constriction of the coronary artery). In addition, in the Central nervous system of these animals was observed an increased level of metabolism in paraventrikulyarnoe the hypothalamus and Locus coeruleus (blue stain), which are regulated by the sympathetic effects on the periphery. Studies of behavioral reactions infarction in rats have shown that animals exhibit a heightened sense of fear. Conducted on THEM-rats observations allow us, therefore, to conclude that there has been a chronic increase in activation of the sympathetic nervous system.

Experimental animals and dosage

The following experiments were performed on male Wistar rats (weighing 270-320 g vendor is to firm Harlan Zeist, The Netherlands). Animals kept at the 12-hour cycle of light/dark, the animals received in each case in sufficient quantity standard rat feed and water. Some animals (MI-rats) were subjected to operations legirovaniem coronary (coronary) arteries, other, pseudoinfection, rats were subjected to surgery without imposing such ligatures (banners). After 24 h from among THEM-rats randomly selected a few individuals and then implanted them osmotic Minnesota (type Modell 2001 company Alzet) for subcutaneous administration of moxonidine in a daily dosage of 3, 6, mg/kg, or were introduced only inert filler. The treatment with moxonidine was performed continuously until the completion of the experiments, which lasted for 3 weeks after surgery.

Ligation (hauling) coronary artery

The left anterior descending coronary artery ligated with anesthesia pentobarbital (60 mg/kg intraperitoneally). A brief description of the operation: After intubation of the trachea above the fourth rib interval spent the incision in the skin. Adjacent muscles aside and relegated to the side. Then the animals were connected to an artificial lung ventilation (frequency 65-70 rpm, working volume of 3 ml) and the chest cavity was opened by separation of the intercostal muscles. Then opened the pericardium. Heart ostavlali position in situ and under the left coronary (coronary) artery near the origin (beginning) of the pulmonary artery superimposed seam silk 6-0. Then stitch it together. Pseudoinfection animals were subjected to the same procedure, but without the above banners artery. Ribs, pulled silk 3-0. At the end of the muscle is returned to its original position and the skin sutured.

Preparation and collection of blood samples

19 days after surgical intervention in order to effect shifting of the coronary artery of rats would repeatedly narcoticyou pentobarbital and through bederow artery was injected into the abdominal aorta catheter (PE-10, thermal welding with PE-50). The catheter is gradually moved subcutaneously to the neck of the animal, where it is, leaving one end protruding to the outside, secured and closed. After two days rest of the animals on the day of sampling to the catheter with a view to its extension was plugged treated with heparin and filled with physiological salt solution hose and after at least 60 minutes took 2 blood samples of 1 ml each. Then blood was collected in pre-chilled tubes prepared using 10 μl add (0,1M). After centrifugation the plasma was collected in pre-chilled tubes filled with either 1.2 mg of glutathione, or 10 μl of Aprotinin (100 ME); ME = international units) to determine the concentration of catecholamines or atrial natriuretic factor (BNF). Tubes with samples kept at -80°C. the Concentration n is adrenaline, adrenaline and dopamine in plasma were revealed using ghvd, while PNF analyzed using the method RIA (radioimmunoassay).

Studies of collagen hearts

The number of interstitial collagen was determined on 6-7 hearts of experimental animals randomly selected from each experimental group. To this end, the hearts were fixed by perfusion with the use of formaldehyde containing 3.6 wt.%-hydrated phosphate buffer. From the ventricles of the hearts after removal of the Atria and large vessels, starting from the apex of the heart and to the heart, cut to 4 rings, which are then at least within 24 h was kept in formaldehyde. After such a fixer ring obezvozhivani and filled with wax. Dewaxed samples with a thickness of 5 μm during the first 5 min were incubated with the use of 0.2 wt./about. %aqueous solution posterolaterally acid, and then for 45 min - 0.1 wt. %dye Sirius Red F3BA (firm Polysciencies Inc., Norhampton, UK) in saturated picric acid, and then washed for 2 min 0,01M hydrochloric acid, obezvozhivani and for subsequent microscopic studies were flooded with antillanum (Merck, Darmstadt, Germany). The content of interstitial collagen, remote from the zone of infarction was determined in the intraventricular septum intensively on the tee color dye Sirius Rot at 40-fold magnification on every heart.

Analysis of the obtained data

The obtained data, unless otherwise stated, expressed in the form of group medium ± the average standard deviation. It was analyzed only the data obtained in the infarction area, including the main part of the free wall of the heart left ventricle, as smaller areas of infarction is usually full hemodynamic compensation. The obtained data were analyzed using univariate analysis of variance" (ANOVA), after which conducted a post-hoc analysis according to Bonferroni.

Results studies

Studies were performed on four groups of rats, which included 2 groups infarction animals, which were introduced by moxonidine (daily doses of 3 and 6 mg/kg), one group infarction animals that did not enter the moxonidine, and a comparative group, subjected psevdoobratimy (pseudoinfection rats). Hauling coronary artery led to extensive infarction in the free wall of the left ventricle. Mortality of experimental animals accounted for approximately 29%, and this figure infarction in two groups was almost identical. Data on 5 animals whose daily dose of moxonidine was 6 mg/kg, had to be excluded because the scope of a heart attack at them was too small. The results of the experiments, which used a daily dose of 6 mg/kg and, respectively, 3 is g/kg, presented in table 1 and described in more detail below. In table 1 the results include data on groups of from 7 to 14 animals, with the exception of data on collagen, and separate data groups of 6-7 individuals.

If at the beginning of the experiments, control animals had approximately the same weight, then after treatment with moxonidine weight infarction rats compared with the weight infarction in rats, which did not enter the moxonidine was slightly less as compared with pseudoinfection rats their weight was significantly lower. The mass of the heart from infarction in rats, which was introduced by moxonidine was significantly less than that of infarction in rats not subjected to this treatment. These effects, as is evident from table 1, were due to differences in dosage, i.e. depended introduced if the daily dose of 3 or 6 mg/kg of the Obtained data allow to conclude that the introduction of moxonidine was possible to prevent the excessive hypertrophy of the heart.

The infarction animals that did not enter the moxonidine, have been somewhat based on the level of norepinephrine in plasma and PNF significantly higher neurohumoral activity. The level of PNF in the plasma of animals treated with moxonidine, compared with the levels in infarction of rats, which did not enter the moxonidine OS, which was evalca unchanged. Thanks to the use of moxonidine level of norepinephrine in plasma was reduced by approximately 50% compared with the same indicator pseudoinfection rats.

It was found that the level of norepinephrine in plasma infarction in animals that did not enter the moxonidine, was significantly increased at three times the rate of pseudoinfection rats. Thanks to the use of moxonidine level of norepinephrine in infarction of animals from a group that was administered a daily dose of 6 mg/kg was able to reduce almost 50% of this figure at pseudoinfection rats. The group of animals who were injected daily dose of 3 mg/kg, there was a significant decrease in the level of norepinephrine in the plasma. These data confirm that daily doses of moxonidine 3, or 6 mg/kg, can effectively reduce the activation of the sympathetic nervous system after myocardial infarction.

The results of measurements on collagen hearts of the groups that were administered a daily dose of 3, or 6 mg/kg, also presented in table 1.

Heart rate, infarction was diagnosed in animals in the waking state, was significantly higher compared with the levels in pseudoinfection rats. This tachycardia due to introduction of moxonidine not only avoided, but moreover: infarction, treated with moxonidine, compared with pseudoinfection rats was observed slowing of cardiac activity, i.e. ischemia normal rhythm (bradycardia).

Table 1

These experiments on the comparative group pseudoperiodic animals (PSEUDO)infarction animals, untreated (HEART attack), and animals, which were introduced by moxonidine (INF+MOX); the daily dose of 3 mg/kg daily dose of 6 mg/kg
PSEUDOHEART attackDETAILS+MOX (3 mg)DETAILS+MOX (6 MG)
The number of experimental animals8-147-1276-7
Body weight (g)333±7320±10301±5299±9*
The mass of the heart (mg)1174±371543±75*1408±1041076±24#
The ratio of the mass of the heart/body weight3,5±0,14,7±0,3*4,7±0,4*3,6±0,2#
Heart rate (beats/min)351±17387±8*334±12#321±6*#
GARDEN (mm RT. column)111#x000B1; 298±3*87±3*100±5
ON the level of plasma199±30578±143*345±10896±20#
PNF in plasma (PG/ml)38±353±5(54±2, n-3)61±8
Interstitial collagen (%)1,3±0,12,2±0,3*2,4±0,2*1,4±0,1

Abbreviations:

GARDEN - mean arterial pressure;

ON - noradrenaline;

PNF - atrial natriuretic factor;

* significantly different from pseudoinfection rats;

# significantly different from untreated infarction in rats.

The results of the experiments serve as unequivocal proof of the fact that thanks to the use of moxonidine in the treatment of myocardial infarction and primarily in the treatment of postinfarction period could effectively influence the functional state of the heart muscle. On the basis of data about the level of catecholamines in the plasma can be concluded that the moxonidine provides the ability to effectively normalize the activation of the sympathetic nervous system infarction in animals. This conclusion is confirmed by data on the heart rate (in vivo, W is the animals in the waking state), because the heart rate in rats, which was introduced by moxonidine was even lower than pseudoinfection rats. This factor presumably due to the action of moxonidine more likely in chronic but not in acute phase of myocardial infarction, because the treatment in the acute stage, the decrease in heart rate accompanied by an increase in mean arterial pressure, which, when treated in the chronic phase is not observed. This takes into account the effect of moxonidine in General. Although achieved positive effects on the ratio of the mass of the heart/body weight cannot, apparently, be measured unambiguously, and data on the content of interstitial collagen to explain the insignificant effect of remodulate (perestroika), however, the results indicate quite obvious trend: moxonidine has a preventive effect against excessive hypertrophy of the heart and unwanted remodulate.

Thus, the above experimental results suggest that moxonidine and its acid additive salts have an effective, contributing to the recovery and/or rehabilitation impacts on the condition of the heart muscle after myocardial infarction and can thus be used for treatment due to infarc the om lesions of the heart muscle in humans and large mammals, while such treatment may be carried out in the acute stage of the disease, and primarily in the postinfarction period. This moxonidine, especially in post-infarction treatment, may have a preventive effect on the progressive development of heart weakness after illness. Prescribed doses of moxonidine or acid additive salts can be selected individually in each case and vary depending on the specifics of the patient's condition and applications. Typically, in the treatment of myocardial infarction in the acute stage of the disease, respectively, in the postinfarction period, the daily dose for oral administration to a person appointed in the range from 0.05 to 5 mg, preferably from about 0.25 to 3 mg In the moxonidine and its acid salt additive in the composition of the corresponding pharmaceutical compositions can be used for both immediate and extended, controlled and/or controlled release of the active substance. For professionals it is obvious that the content of active substance in the compositions with prolonged, controlled and/or regulated by the release of the latter may be higher compared to compositions intended for his immediate release.

The following example is explained in more detail technology prepara what is possible and one of the possible pharmaceutical compositions containing moxonidine, for use in the treatment of myocardial infarction and/or post-infarction treatment, with this example in no way limits the scope of the invention.

Example 1

Containing moxonidine tablets in a film sheath

Composition:

The core tablets:

The moxonidine0,025 parts
Lactose9,575 parts
Povidone USP0,070 parts
Crosspovidone USP0,300 parts
Magnesium stearate0,030 parts
(Water0.750)
The total amount of solids10,000 parts

Film shell:

The hypromellose0,156 parts
a 30%aqueous dispersion of ethyl celluloseto 0.480 parts
(= solid)(0,144 parts)
Polyethylene glycol 60000,030 parts
Titanium dioxide0,150 parts
Talc0,1197 parts
Red iron oxide0,0003 parts
(Water3,864 parts)
The total amount of solids0,600 parts
The total number of suspensions film shell4,800 parts

For the application of sheath per 10,000 tablets weighing 100 mg each required 4.8 kg of the above suspension

Obtain core tablets

Of moxonidine and lactose prepare the mixture, after which this mixture is moistened with a solution of a binder povidone in water, thoroughly kneaded with stirring and the resulting product spread on slatted shelves and dried at a temperature of about 50°to the final moisture content to a maximum of 0.5%. The dried product is passed through a sieve with a mesh size of 0.75 mm (machine Fruita). After mixing the obtained granulate with crosspovidone and stearate exercise tableting with getting to the core tablets weighing 100 mg each and content of 0.25 mg of active substance, respectively.

Getting suspension for film shell

The hypromellose and polyethylene glycol 6000 are dissolved in one part water. Then to this solution is added with stirring a suspension of talc, titanium dioxide and iron oxide in the remaining amount of water. The resulting suspension with mild stirring, diluted with 30%aqueous dispersion of ethyl cellulose.

Application of a film coating on the CE is Davina tablets

The above suspension is deposited on the core tablets using the apparatus for coating film while heating the core to a temperature of about 40°heated to about 70°With air. In conclusion, to be manufactured tablet with a film coating was exposed for 16 h drying at a temperature of about 45°C.

1. Application of 4-chloro-5-[(4,5-dihydro-1H-imidazol-2-yl)amino]-6-methoxy-2-methylpyrimidine formula I

and its physiologically acceptable acid additive salts as the active agent in obtaining pharmaceutical compositions intended for the treatment due to myocardial infarction lesions of the heart muscle.

2. The use according to claim 1, characterized in that the compound of the formula I according to claim 1 or its physiologically acceptable acid salt additive is used to produce pharmaceutical compositions for the treatment of caused by myocardial infarction lesions of the heart muscle in the acute stage of the disease and/or postinfarction period.

3. The use according to claim 2, characterized in that the compound of the formula I according to claim 1 or its physiologically acceptable acid salt additive is used to produce pharmaceutical compositions intended for the treatment due to a heart attack m & e is Arda lesions of the heart muscle in chronic post-infarction phase.



 

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SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of piperazinylalkylthiopyrimidine of the formula (I): wherein R1 represents hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkanoyl or di-(C1-C4-alkyl)-amino-(C1-C4-alkyl); R2 means hydrogen atom or benzyl substituted with 1-3 substitutes taken among the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy-group, di-(C1-C4-alkyl)-amino-group, hydroxyl group and halogen atom; n = 2, 3 or 4, and to its pharmaceutically acceptable acid addition salt. Also, invention describes a method for preparing compounds and pharmaceutical composition based on thereof. Compounds are useful for treatment of diseases arising as result of the central nervous system injury.

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

14 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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