3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds, method for their preparing and medicinal agents containing these compounds

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

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

 

The present invention relates to new 3,7,9,9-Tetra-substituted 3,7-diazabicyclo[3,3,1]nonanoyl compounds, which in position 3 are substituted phenyl, their salts, and pharmaceutical compositions containing these compounds, and to a method for producing these compounds.

In EP-A 0665014 already described 3-benzoyl-3,7-diazabicyclo[3,3,1]nonanone derivative with antiarrhythmic properties.

In addition, in EP-A 0665228 described 3-phenylsulfonyl-3,7-diazabicyclo[3,3,1]nonanone derivatives, as well as containing drugs having anti-arrhythmic properties.

The present invention was based on the task of obtaining new active substances which possess antiarrhythmic activity, and also have a superior mode of action. In addition, the task of the invention was to obtain new 3,7-diazabicyclo[3,3,1]Romanovyh compounds which have valuable pharmacological properties.

In the claimed invention, it was found that new 3,7,9,9-Tetra-substituted 3,7-diazabicyclo[3,3,1]nonanone compounds that at position 3 are substituted phenyl, have valuable pharmacological properties, in consequence of which they can be used for the treatment and/or prevention of cardiac arrhythmias, as well as different antiarrhythmic profile, with which they can be successfully used for the treatment of cardiac arrhythmias, first of all, tachycardia arrhythmias.

In accordance with this invention offers new compounds of General formula I

in which

R1denotes an alkyl group with 1-6 carbon atoms or cycloalkenyl group of 4-7 carbon atoms,

R2means (ness.)alkyl,

R3means (ness.)alkyl or

R2and R3together form alkylenes chain with 3-6 carbon atoms and

R4denotes phenyl, monosubstituted in the ortho - or para-position to the nitro-, cyano or (ness.)alkanoyl or disubstituted in the ortho - and para-position by a nitro-group,

and their physiologically acceptable acid additive salt.

If in the compounds of the formula I R1denotes an alkyl group, it may be a straight or branched chain with 1 to 6, preferably 3 to 5, most preferably 4 carbon atoms. Preferred cycloalkyl group, R1is cyclopropylmethyl. The most preferred values of the radical R1are alkyl groups with 3 to 5 carbon atoms.

If the substituents R2and R3denote (ness.)alkyl, such alkyl groups may be straight or branched chain with 1-4, preferably 1-3 carbon atoms, and preferably represent methyl. If R2and R3together represent lkilebu group, it may contain 3-6, preferably 4-5 carbon atoms. Preferred are compounds in which R2and R3together denote alkylenes chain with 4-5 carbon atoms.

The substituent R represents a substituted phenyl, the phenyl substituents are in the ortho - or para-position. Deputy representing (ness.)alkanoyl may contain 2-5, preferably 2-3 carbon atoms. Preferably R4represents phenyl substituted in the para-position by cyano or (ness.)alkanoyl, most preferably a cyano.

According to the invention the new compounds of formula 1 and their acid additive salts get known methods by the interaction of the compounds of formula II

where R1, R2and R3have the above values,

with compounds of General formula III

where R4has the above meanings and X denotes halogen, and optionally available compounds of formula I translate in their acid additive salt or acid salt additive is transferred into the free compounds of formula I.

The interaction of compounds of the formula II with compounds of formula III can be carried out in a known manner under normal conditions, in which the aromatic halides can Sames the e-amino group. The preferred halogen in the compounds of formula II are chlorine or fluorine. The interaction is carried out in the presence of an inert organic solvent at a temperature from room temperature up to the boiling temperature of the reaction mixture. As the organic solvent can be used, for example, ethers, especially cyclic ethers such as tetrahydrofuran, lower alkanols such as butanol, lower aliphatic ketones, such as acetone, dimethylsulfoxide, dimethylformamide, aromatic hydrocarbons, such as benzene or toluene, or mixtures of the above solvents. The reaction should be carried out in alkaline conditions, for example in the presence of at least an equivalent amount of base. Examples suitable for this purpose bases are inorganic bases, such as hydroxides of alkali metals, carbonates of alkali metals, amides of alkali metals or hydrides of alkali metals or organic bases, such as tertiary (ness.)the alkylamines followed.

The compounds of formula I can be isolated from the reaction mixture and purify known methods. Acid additive salts can be translated by standard methods available in the base, and when necessary, you can convert the known methods in pharmacologically acceptable acid additive salt.

the quality of the pharmacologically acceptable acid additive salts of compounds of formula I can be applied, for example, the usual salts of these compounds with inorganic acids, for example with halogenoalkane acids, especially hydrochloric acid, sulfuric acid or phosphoric acid, and with organic acids, for example lower aliphatic mono-, di - or tricarboxylic acids such as maleic acid, fumaric acid, lactic acid, tartaric acid, acetic acid or citric acid, sulphonic acids, for example with (ness.)alkanesulfonyl acids such as methanesulfonate acid, or with benzosulfimide acids optionally substituted in the benzene ring by halogen or (ness.)the alkyl, such as para-toluensulfonate acid.

In that case, if in the compounds of formula I the substituents R2and R3are different, such compounds have chiral center and may exist in two optically active forms or in the form of a racemate. In the scope of the present invention is included as racemic mixtures and the optical isomers of such compounds of formula I. Optically active compounds can be isolated from racemic mixtures in a known manner using standard separation techniques, for example by chromatography using chiral separating fillers or by using fractionated crystallization of the corresponding salt, and the use of optically active acids. Connections in the form of pure enantiomers can also be obtained by synthesis from the corresponding pure enantiomers of the parent compounds of formula II.

The initial compounds of formula II are described in DE-OS 2658558, EP-A 0103833 and in EP-A 0306871 and/or you can get them in the usual way as described in these documents methods or by methods analogous to those described in these documents. The initial compounds of formula III are known and/or can be obtained by the known methods or methods analogous to known.

With the invention it has been unexpectedly found that the proposed compounds of formula 1 and their physiologically acceptable acid additive salts are especially effective antiarrhythmic action. Such compounds belong to the class III and have, in particular, anti-arrhythmic activity, causing an increase in QT intervals on the ECG and the increase in the effective refractory period of the heart. Compounds have a favorable profile of action and are characterized by good tolerability of prolonged activity and high selectivity in respect of antiarrhythmic actions compared to lowering blood pressure effect that the use of doses of anti-arrhythmic effective interval does not exert undesirable from a therapeutic point of view of their effect on blood pressure. Link is characterized by their antiarrhythmic effect is manifested to the greatest extent in terms of tachycardia. In addition, taking into account the characteristics of the compounds according to the invention it is possible to conclude that their antiarrhythmic action is accompanied by a surprisingly very low pruritogens side effects.

Antiarrhythmic activity of the compounds can be assessed in standard pharmacological test methods. Non of the examples specified for a particular test compounds in the test methods that correspond to the numbers indicated in the examples below was received.

Description pharmacological methods

1. Determination of the minimum toxic dose

The male mice weighing 20-25 g orally was administered the test compound at the maximum dose of 300 mg/kg for 3 h after the animals were carefully observed in order to identify toxic symptoms. In addition, within 72 h after injection was additionally recorded all symptoms and deaths. In addition, we have identified and registered accompanying symptoms. If the animal was killed or if it was revealed marked toxic symptoms, the following mice tested compounds were introduced in declining doses up until not ceased to manifest toxic symptoms. In the table And the taken as the minimum that is classical dose lowest dose which caused the death of, or resulted in a pronounced toxic symptoms.

Table a
The test compound from example No.The minimum toxic dose mg/kg body weight of the mouse by oral administration
1300
2300

2. In vivo anti-arrhythmic properties of compounds under conditions of tachycardia on anesthetized Guinea pigs

The effect of the compounds when administered intravenously on the effective refractory period (ETA) and blood pressure elevated heart rate was investigated in the anesthetized Guinea pigs. Animals in a state of complete anaesthesia via the jugular vein into the right ventricle was injected bipolar irritation of the catheter. With its help by electrical stimulation frequency of contractions of the heart muscle of animals during the entire experience was maintained at approximately 150% of the normal rate. In other jugular vein was introduced cannula for intravenous administration of test compounds. In the research process with a manometer (pressure gauge company Statham) was measured systolic and diastolic blood pressure (SBP and DBP) in the carotid Arte the AI. Test compounds were administered intravenously in increasing doses (cumulative). Before the first dose and every time after 8 min after administration of the appropriate dose was determined ETA using Protocol dicrotism pulse. Effective dose (ETA-ED115) took the dose, which caused increase in ETA by 115% compared to the original value. As of the effective dose for the evaluation of the reduction of the pressure steps were taken dose, which caused a decrease in the GARDEN by 85% relative to its original value (GARDEN-ED85)and the dose that caused a decrease in DBP of 85% relative to its original value (DBP-ED85).

The following table B shows the results obtained in the above experiment.

Table B
Example No.Antiarrhythmic action

ETA-ED115in mcmash/kg, I.V
Low blood pressure* ED85in mcmash/kg, I.V
DadGARDEN
10,4≫10≫10
2155
*Note:

"≫" means that for the studied what's doses found no trend toward low blood pressure.

3. Evaluation of the in vitro effect of the compounds on the functional refractory period using stimulated by an electric current papillary muscles from the hearts of Guinea pigs

The effectiveness of compounds in relation to increasing the refractory period may be defined by evaluating the functional refractory period (FER) in experiments in vitro using selected papillary muscles of the right ventricle of the heart Guinea pigs.

In Guinea pigs, dead blow on the head, quickly removed the heart and papillary muscle of the right ventricle was placed in a special bath for the body, through which at constant temperature missed oxygenated nutrient solution. The selected muscle is irritated by means of an electric current with a frequency of 3 Hz. In the bath for organ was added in increasing concentrations (cumulative) of the tested compounds. After 20 min after each addition of test compounds were evaluated the functional refractory period according to the Protocol of measurement dicrotism pulse.

On the basis of measured values built a graph of reaction from cumulative concentration. On the basis of this dependence was calculated concentration at which there was an increase in the FER 12 milliseconds (MS), and it took over effective concentration (FER-EC+12 MS).

The following table presents the results obtained in the above experiment.

Table
Example No.Antiarrhythmic effect of FER-EC+MSin mcmole/l
10,6
20,7
30,6
40,8

4. Assessment of potential pruritogens action of compounds in in vitro experiments using dedicated hearts of rabbits subjected to perfusion

Potential pruritogens action with antiarrhythmic activity of the compounds belonging to the class III can be estimated on the basis of electrophysiological measurements of these parameters as "instability" and "triangulation" (see below), when exposed to single-phase bioelectric potential with dedicated hearts of rabbits subjected to perfusion. Discussed below pharmacological study was carried out according to the method described by Hondeghem L.M., etc., Circulation, 103, 2004-2013 (2001) (hereinafter Hondeghem and others), and Hondeghem L.M., Journal of Cardiovascular Electrophysiology 5(8), 711-721 (1994) (hereinafter Hondeghem).

In rabbits immediately after the killing blow on the head was removed heart, which was immediately placed in the device Langendorff at constant pressure the Sri (80 cm H 2About, where it at a constant temperature were subjected to perfusion of nutrient solution, saturated with oxygen. With two stimulating electrodes, which were introduced respectively in the region of the right and left bundle branch, can stimulate the heart according to different stimulation protocols (cf. Hondeghem and others). Two other electrode (the drain electrode, which was introduced endocardial in the region of the septum of the left ventricle of the heart, and the reference electrode, which was introduced epicardial in the left ventricle) was used to measure single-phase bioelectric potential.

For the duration of the single-phase bioelectric potential at different repolarization (APD 10-90; "APD10" denotes the duration of the bioelectric potential to occur 10%of repolarization) has identified the following parameters that serve as signs of pruritogens:

(1) Instability: the instability understand the change APD60 between two consecutive heartbeats. In control experiments, this value is an average of approximately 7 milliseconds (MS). Higher deviations from this average value in the direction of a more extended periods of time (>7 MS) indicate a higher probability of proaramme caused by the investigated compounds.

p> (2) Triangulation: triangulation understand the repolarization time (in MS) from APD30 to APD90. In control experiments, this value is usually around 90 MS. A significant increase in comparison with the nominal value of the time to repolarization occurring due to exposure to the test compound, indicates a slow repolarization, which in turn can lead to increased speed of the subsequent polarization (proaramme).

The following table G presents the results obtained in the above experiments using each time the three of hearts (n=3).

Table G
Example No.ConcentrationInstability (MS)Triangulation (MS)
40,3 ám6/3/348/64/62
1 micron6/25/752/79/79

5. Blocking the action applied quickly, consequently gradually slowed unidirectional flow of potassium ("rapid", "slow delayed rectifier potassium current": "iKr", "iKs")

Action with antiarrhythmic activity of the compounds belonging to the so-called class III (according to the classification of Vaughan-Williams), the basis of the ANO on the blockade of the various threads of potassium from the cells, involved in repolarization of cardiac bioelectric potential. This process leads to an increase in refractory period of the heart, making it possible to reduce cardiac rhythm. While the risk of pruritogens reactions resulting from the application of possessing antiarrhythmic activity of the compounds belonging to the so-called class III, depends on which of the threads potassium, respectively, which of the combinations of threads potassium is blocked. From literature it is known that selective blockade of iKr may be accompanied by high risk of proaramme, whereas simultaneous blockade of iKr and iKs accompanied by a significantly lower risk of proaramme.

The magnitude of iKs can be separately estimated in the following way. We are anesthetized dogs immediately remove the heart and through the blood vessel is subjected to perfusion area of the muscle tissue of the left ventricle with a solution containing collagenase. Completely destroyed the fabric is crushed and individual cardiac muscle cells subjected to electrophysiological study using the patch-clamp method for whole cells (cf. Hamill O.R. and others, Pflügers Archive 391(2), 85-100 (1981)), while for election assessment blocking activity on iKs incoming stream of calcium block by adding 1 mm nisoldipine (the election is entrusted blocker incoming potassium), to evaluate the blocking actions on iKr add 2 μm E-4031 (selective iKr blocker), a rapid inflow of sodium and short-term output stream potassium block with a fixed potential of -40 mV. After that, the current amplitude immediately determine the magnitude of iKs according to a 5-second Protocol of the measurement pulse when changing the fixed potential of -40 mV to a maximum degree of depolarization of +50 mV.

The value of the iKr (HERG) can be separately measured in the following way. To measure iKr use line cells (kidney cells of a human embryo, NEC; for example, taken from the American type culture collection (ATSS), number CRL-1573), stable transfectional genome iKr (HERG) (cf. Z. Zhou and others, Biophysical Journal 74(1), 230-241 (1998)). Because your cells are no other threads ions interfering with the measurements, it is possible not to apply the additive to the blockade of the respective channels. The value iKr amplitude of the current at a fixed potential of -40 mV are determined according to a 500-millisecond Protocol measurement immediately after changing the fixed potential from -75 mV to the maximum value of the degree of depolarization of +10 mV.

Based on the assessment of the degree of inhibition of the corresponding thread, depending on the different concentrations of the compound to determine the concentration of compounds kotorayarabotaet to blockade flow at 50% of its maximum value (IC 50, %). The following table D presents the results obtained in the above experiment.

Table D
Example No.IC50, % - iKsIC50, % - iKr
30.7 mcm0,09 ám
40.7 mcm0.02 mm

In one experiment in vivo, which was performed on anesthetized cats, the compound of example 4 after oral and intravenous administration caused a dose-dependent marked and prolonged increase of the threshold for the occurrence of atrial fibrillation, in which the atrium is manifested to a greater degree than in the ventricle. Such election in respect of the Atria raising the threshold of occurrence of atrial fibrillation is an indication that the test compound has a favorable profile of action and its use is associated with a small risk of pruritogens.

The above results show that the compounds of formula I possess anti-arrhythmic effect and cause a pronounced increase in the effective refractory period of cardiac muscle, an effective blood pressure lowering effect of the compounds nachine is to appear only when using doses which considerably exceed the dose effective to increase the refractory period. The above results show that there is a relationship between the unexpectedly low ability of the compounds according to the invention to cause pruritogens side effects and their specific profile of activity against different threads potassium, coming out of the heart cells of large mammals and humans, for example in respect of iKr and iKs.

Proposed in the invention compounds of the described profile of their actions can be applied to reduce the related tachycardia heart rhythm disorders, as well as for prevention and treatment of cardiac arrhythmias in large mammals and humans. Preferably such compounds should be used to prevent tachyarrhythmias, i.e. arrhythmias, accompanied by an increase in the frequency of contractions of the heart.

The used doses may be different in each case and can, obviously, be varied depending on the type of condition to be treated, from which connection to use and route of administration. In General, the introduction of large mammals, especially humans, you can use dosage forms containing from 0.5 to 100, preferably from 1 to 25 mg of active substance based on onocr is a great introduction.

On the basis of the compounds of formula I in combination with conventional pharmaceutical auxiliary substances, you can obtain drugs in the form of galenic forms, such as tablets, capsules, suppositories or solutions. These herbal compositions can be prepared with known methods using conventional solid or liquid carriers, such as lactose, starch or talcum powder or liquid paraffins (vaseline), and/or with conventional pharmaceutical auxiliary substances, such as leavening for tablets, substances which improve the solubility, or preservatives.

Below the invention is illustrated in the examples, not limiting its scope.

Example 1

7-(n-butyl)-3-(2,4-dinitrophenyl)-9,9-dimethyl-3,7-diazabicyclo[3,3,1] nonan

To a solution of 4.2 g of 2,4-dinitrofluorobenzene in 40 ml of acetone is added dropwise with stirring was added a solution of 4.7 g of 7-(n-butyl)-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane in 10 ml of acetone. The reaction mixture continued to stir at room temperature and allowed to stand over night. Then remove the acetone, the residue was diluted aqueous citric acid solution and the resulting mixture was extracted twice with ethyl ether, acetic acid. For further processing the aqueous residue was podslushivaet with dilute caustic soda solution. The resulting mixture was again two the water was extracted with ethyl ester of acetic acid. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was recrystallized from a mixture of simple ether/hexane. The result was obtained 5.5 g of 7-(n-butyl)-3-(2,4-dinitrophenyl)-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane with a melting point 119°C.

0,61 g specified in the title compound was dissolved in 10 ml of isopropanol are heated in an oil bath. To the solution was added 0.7 ml of 3.8 n solution of hydrochloric acid in isopropanol. Then the reaction mixture was allowed to cool and was filtered formed crystals. In this way received 0.5 g of the hydrochloride is indicated in the title compound with a melting point of 136-138°C.

Using the above method or by using a similar method can be obtained the compounds of formula I are given below in table E.

Table E
Example No.R1R2R3R4SoltPL,°
2n-C4H9-CH3-CH3-4-NO2-phenylcore.116-118
3n-C4H9--(CH2)4-4-CH3-CO-phenyl1 GTA111
4n-C4H9--(CH2)4-4-CN-phenyl1 GTA115
5n-C4H9-n-C3H7-CH3-4-CN-phenyl1 GTAam.
6n-C6H13-CH3-CH3-4-CN-phenyl1 GTAam.
7citu-CH2--(CH2)4-4-CN-phenylcore.101-103
8and-C4H9--(CH2)5-4-CN-phenyl1 HCl138-142
9CH3--(CH2)5-4-CN-phenyl1 HCl270

Notes: citu denotes cyclopropyl, n means normal, and stands out, GTA denotes hydrotartrate, HCl denotes a hydrochloride, inorg. refers to the base, am. indicates amorphous.

Example I

Tablets containing hydrotartrate 7-(n-butyl)-3-(4-tzia is openil)-9.9-tetramethylene 3,7-diazabicyclo[3,3,1]nonane

Produce tablets of the following composition (data shown is based on per tablet):

hydrotartrate 7-(n-butyl)-3-(4-cyanophenyl)-9,9-tetramethylene 3,7-diazabicyclo[3,3,1]nonane20 mg
corn starch60 mg
lactose135 mg
gelatin (10%solution)6 mg

The active ingredient, corn starch and lactose thicken with a 10%aqueous solution of gelatin. The resulting paste is crushed, the resulting granules are placed on the appropriate tray and dried at 45°C. the Dried granules are passed through a crusher and mixed in a mixer with the following excipients:

talc5 mg
magnesium stearate5 mg
corn starch9 mg

and then pressed to tablets weighing 240 mg

1. Compounds of General formula I

in which R1denotes an alkyl group with 1-6 carbon atoms or cycloalkenyl group of 4-7 carbon atoms;

R2means (ness.)alkyl;

R3means (ness.)alkyl; or

R2 and R 3together form alkylenes chain with 3-6 carbon atoms and

R4denotes phenyl, monosubstituted in the ortho - or para-position to the nitro-, cyano or (ness.)alkanoyl or disubstituted in the ortho - and para-position by a nitro-group;

and their physiologically acceptable acid additive salt.

2. Compounds according to claim 1, where R4denotes phenyl, monosubstituted in the para-position by cyano or (ness.)alkanoyl.

3. Compounds according to any one of the preceding paragraphs, where R1denotes alkyl group having 3-5 carbon atoms, and R2and R3together denote alkylenes chain with 3-6 carbon atoms.

4. The compound according to claim 1, which represents a 7-(n-butyl)-3-(4-cyanophenyl)-9,9-tetramethylene 3,7-diazabicyclo[3,3,1]nonan.

5. The compound according to claim 1, which represents a 7-(n-butyl)-3-(4-acetylphenyl)-9,9-tetramethylene 3,7-diazabicyclo[3,3,1]nonan.

6. Drug, possess antiarrhythmic activity and intended for the treatment and/or prevention of cardiac arrhythmias characterized in that it comprises a pharmacologically effective amount of a compound according to claim 1 and pharmaceutical excipients and/or carriers.

7. The compounds of formula I according to claim 1, having antiarrhythmic activity to obtain a pharmaceutical composition intended for the treatment and/or prevention is IKI cardiac rhythm.

8. The method of obtaining compounds of General formula I

in which R1denotes an alkyl group with 1-6 carbon atoms or cycloalkenyl group of 4-7 carbon atoms;

R2means (ness.)alkyl;

R3means (ness.)alkyl; or

R2and R3together form alkylenes chain with 3-6 carbon atoms; and

R4denotes phenyl, monosubstituted in the ortho - or para-position to the nitro-, cyano or (ness.)alkanoyl or disubstituted in the ortho - and para-position by a nitro-group; and

their physiologically acceptable acid additive salts, characterized in that compounds of General formula II

where R1, R2and R3have the above meanings, is subjected to the interaction with compounds of General formula III

where R4has the above meanings and X denotes halogen, and optionally available compounds of formula I translate in their acid additive salt or acid salt additive is transferred into the free compounds of formula I.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

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

9 cl, 5 sch, 36 tbl, 70 ex

The invention relates to (DL)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-diazaspiro[4.5]decane-2-ONU formula (1)

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

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

8 cl, 11 tbl, 463 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel chemical compound, namely, to biologically active compound of the formula (I): possessing anti-arrhythmic activity and representing 5'-bromolappaconitine hydrobromide. Toxicity of this compound is by 4.8-fold less toxic as compared with analog used in medicinal practice and representing lappaconitine hydrobromide. Proposed compound possesses the expressed anti-arrhythmic activity in models with calcium chloride and adrenaline arrhythmia and provides the complete blocking both types of arrhythmia after administration of the dose that is 10-fold less of the therapeutic dose of lappaconitine hydrobromide.

EFFECT: improved and valuable medicinal properties of compound.

2 cl, 2 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a whitening composition comprising: (a) monomeric ligand or catalyst with transient metal of ligand of the formula (I): wherein R represents hydrogen atom; R1 and R2 are chosen independently from (C1-C4)-alkyl, pyridine-2-yl-methyl and (C2-C4)-alkylmethyl; X represents -C=O; R3 and R4 are similar and represent -(CH2)nC(O)O-(C1-C4)-alkyl; n = 0-4, and (b) equilibrating carriers and additional components. This composition is useful for catalytic whitening substrates with atmosphere oxygen. Also, invention describes a method for whitening the substrate involving applying step of the whitening composition on substrate in aqueous medium.

EFFECT: valuable properties of substances, improved whitening method.

11 cl, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: compounds of formula I are disclosed, wherein R1, R2, R3, R4, R5, R6, R7, R41, R42, R43, R44, R45, R46, A, and B are as described in description.

EFFECT: new compounds with increased electrophysiological activity useful in treatment of cardiac arrhythmias.

132 cl, 1 tbl, 37 ex

The invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine to obtain an image

The invention relates to chemical-pharmacological industry and relates to new biologically active chemical compounds of the hydrochloride of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene of formula (1) with high antiarrhythmic activity and low toxicity
The invention relates to the selection of triethylenediamine, which is used as a catalyst in obtaining polyurethane foam and which is a hardener of epoxy resins and vulcanizer polyester oils

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to dihydropyrimidine compounds of the formula (I*): their enantiomers, diastereoisomers and pharmaceutically acceptable salts wherein X1, X2 and X3 in common with atoms to which they are added form ring of the formula: or ; R1 represents hydrogen atom; R2, R3*, R4, R5, R6 and R7 have values given in cl. 1 of the invention claim. Also, invention relates to separate dihydropyrimidine compounds. Proposed compounds are inhibitors of calcium channel function being especially inhibitors of Kv1 subfamily of potential-overlapping K+-channels and especially inhibitors of Kv 1.5 that associated with super-rapid activating delayed cleaning K+-flow of Ikur and can be used in treatment of arrhythmia and Ikur-associated diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 589 ex

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