Anti-hypertension organic salt

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry and pharmaceutics and deals with novel anti-hypertension salt of general formula [(R1-COO-)·(H3N-R2)], where R1 is inhibitor of angiotensin-converting enzyme, selected from group, which consists of perindoprilat, ramiprilat, spiraprilat, benazeprilat, moexiprilat, trandalaprilat, fosinoprilat, enalaprilat, zofenoprilat or lisinopril, and R2 -calcium channel blocker, selected from group, consisting of amlodipine, lacidipine, felodipine, isradipine.

EFFECT: invention ensures reduction of therapeutic doses and side effects.

3 dwg, 2 tbl, 3 ex

 

The technical field

The invention relates to antihypertensive organic salt-based acid anion inhibitor of angiotensin converting enzyme (hereinafter ACEI) and alkaline cation of calcium channel blocker (hereafter BCA).

The level of technology

The effect of ACEI and type BCA has long been well known in cardiotherapy as a classic means of treatment and prevention of high blood pressure (Chigaco SV Comparative characteristics of pharmacodynamics and clinical efficacy of captopril and prazosin in patients with chronic heart failure: author. dis. Kida. the honey. Sciences. M.: 1988; 23 C.).

So, the first representative of this group of drugs - captopril - known in this capacity since 1978 (John Hakim, Those Heart Inst J. 2001; 28(1): 47-52).

Other antihypertensive drugs in this group are synthesized and used since the mid 80-ies of XX century. The efficacy depends on the degree of binding and blocking the active site of an enzyme, called angiotensinamidum (or kininase II), and, thus, their ability to reduce the formation of natural sosudosuzhivayuschih (for example, angiotensin II, vasopressin, endothelin, adrenaline etc) and increase the accumulation of vasodilator (angiotensin I, prostaglandins group E) biological substances.

Among inhibi the Directors of ACE there are drugs, forming the active center of this enzyme as relatively weak (captopril), and durable (ramipril, perindopril, lisinopril) link (Janashia PH, V.A. Nazarenko, Nikolenko S. Pharmacotherapy of cardiovascular diseases. - M.: Russian state medical University, 1998. - ñ.38-47). Thus, the constant of inhibition of angiotensin converting enzyme ramipril at 47 times greater than that of captopril, and 7 times greater than that of enalapril. It allows you to separate inhibitors into more and less powerful (calculated as milligrams per milligram).

However, only four ACEI (captopril, dibenzepin, lisinopril and ceronapril) itself have biological activity. Other known inhibitors are inactive by themselves and become effective antihypertensive agents only after certain metabolic transformations in the body. Therefore they are called prodrugs (from the English. prodrugs).

These prodrugs only after absorption in the digestive tract as a result of enzymatic hydrolysis in the lining of the tract and/or liver become active designee metabolites (to indicate that use end-Pilat). For example, enalapril is converted into enalaprilat, perindopril - in perindoprilat, fosinopril - fosinoprilata etc. Respectively, with gastrointestinal diseases and liver preparations that need transformation to acquisition activity, are weaker (Transformed raginsky A.I, Sidorenko B.A., Romanova N.E., Shatunova IM Clinical pharmacology of the major classes of antihypertensive drugs. Consilium Medicum 2000; No. 2, R.3).

In addition, the activity (and, partly, duration) ACEI depends on the degree of absorption in the digestive tract (see ibid.).

Pharmacokinetics of the active ACE is not the same. For example, lipophilic captopril partially metabolized in the liver with the formation of metabolites, some of which possesses a biological activity, whereas hydrophilic ACEI type of lisinopril, obenzaprine and ceronapril is not metabolized and are excreted in the urine unchanged. Systemic bioavailability of lipophilic inhibitors, are usually higher than their hydrophilic counterparts.

Pharmacokinetics proletarienne forms ACEI also different. As prodrugs, and active designee metabolites ACEI differ in solubility in fats. From liquid proletarienne forms ACEI largely depends on their absorption in the digestive tract. Along with the absorption of prodrugs systemic bioavailability inactive ACEI is determined by the speed and severity of their deesterification as a result of hydrolysis.

It is well known that biotransformation inactive inhibitors in the active designee metabolites occurs mainly in the liver, in particular, from 40 to 60% of enalapril in it turns into enalapr the lat. In addition to the liver, a role in metabolic transformation proletarienne forms of ACE inhibitors play hydrolases of the mucous membrane of the gastrointestinal tract, the blood and extravascular tissues. For example, unlike enalapril, fosinopril and perindopril rapidly and almost completely converted into fosinoprilata and perindoprilat, and their biotransformation occurs not only in liver but also in the mucosa of the gastrointestinal tract and in the blood. In other words, inactive ACEI significantly differ in how easily and completely they deesterified by hydrolysis, becoming active designee metabolites.

However, most of the ACEI (in addition to the above four drugs) is not used in the form of active, i.e. hydrolyzed, forms, containing a free acid group, because their absorption does not exceed 10-20% (CD Mosby, 2003), and residual dose may not be a systemic effect on lowering blood pressure. Therefore, to achieve therapeutic effect should be applied in high doses (sometimes 10-20-fold higher doses of the prodrugs).

However, now it is well known that even in relatively small doses of ACEI may have severe side effects like hypotension, impaired renal function, hyperkalemia, dry cough and angioedema.

So, dry to the Xel, forced to withdraw patients from treatment, according to the literature, occurs in the treatment of ACEI with a frequency of from 1 to 48%. Moreover, the frequency of such a cough essentially depends on the gender and race of the patients. Thus, in women, it occurs much more often than men (ratio of approximately 7:3), and the Negroes and Mongoloids more often than whites.

According to some observations, adding BCA weakens such a cough.

Angioedema (Quincke's edema) is also a typical side effect of ACEI. It is less frequent dry cough (0.1-0.5% of cases), however, unlike cough may be an immediate threat to patients ' lives.

In addition, all inhibitors can cause taste disorders, leukopenia (neutropenia), skin rashes, diarrhoea disorders, as well as isolated cases of damage to the kidneys and liver, and anaemia.

Of course that does not stop the search for better antihypertensive drugs, which should fully comply with such conditions:

(1) to ensure fast and stable in time therapeutic effect when used as smaller doses and

(2) to give less noticeable side effects.

Part of these requirements can be performed by applying active substance instead of prodrugs. However, as already mentioned, they are bad is absorbed from the digestive tract and require large doses. Perhaps in the future there will be more simple effective antihypertensive drugs. However, doctors and pharmacists are well aware that the combination of at least two separately known drugs are often able to enhance useful and/or reduce the side effects of their separate application.

If the mechanism of action of individual drugs are well studied, then combining them can sometimes be focused and give expected results. For example, as already mentioned, the combination of BCA with ACEI can loosen the cough. Moreover, during legislative EUROPA-2005 found that the sequential introduction of ACEI (perindopril) and CCBS (amlodipine) is more effective for the treatment of hypertension and prevention of complications, as it was possible to document a significant reduction in mortality of patients.

Therefore, on the basis of combined ACEI antihypertensive drugs that reduce the likelihood of developing (or at least the severity of side effects remains a challenge.

One of these drugs that the technical nature closest to the proposed further antihypertensive salt, is a mechanical mixture of lisinopril and amlodipine, known under the trademark "Equator".

It is used for the treatment and prevention value is about blood pressure, heart failure and complications of diabetes.

However, the combination of lisinopril amlodipine is not without side effects and is less effective in patients with liver diseases and digestive tract for the reasons described above. These side effects are especially noticeable in older patients (i.e. those people who are most likely to suffer heart disease).

The invention

The basis of the invention is by combining the anion of at least one ACE and a cation of at least one BCA to create such an antihypertensive drug that can easily be absorbed from the digestive tract and reduce therapeutic dose and side effects.

The problem is solved by the fact that according to the invention proposed antihypertensive organic salt of General formula [(R1-COO-)·(+H3N-R2)], where R1the angiotensin - converting enzyme inhibitor selected from the group consisting of:

of perindoprilat, that is, 1-[N-[1-carboxybutyl]alanyl]hexahydro-2-indolinecarboxylic acid,

ramiprilata, that is, [1-carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]-pyrrole-2-carboxylic acid,

spirapril, that is, (8S)-7-[(S)-N-[(S)-1-carboxy-3-phenylpropyl]alanyl]-1,4-dithia-7-azaspiro[4,4]nonan-8-carboxylic acid,

benazeprilat, that is, [S-(R*,R*)]-3-[[1-(to bonil)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid,

the moeksiprilat, i.e. (3S-[2[R*(R*)],3R*]]-2-[2-[[1-(carbonyl)-3-phenylpropyl]aminol]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-ethinlestradiol acid),

trandolaprilat, that is, 1-carboxy-3-phenylpropyl]alanyl]-hexahydro-2-indolinecarboxylic acid,

fosinoprilata, that is, [1-[S*(R*)]-alpha,beta]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy]-(4-phenylbutyl)phosphinyl]acetyl]-L-Proline,

enalaprilat, that is, S-1-[N-[1-carbonyl-3-phenylpropyl]-L-alanyl]-L-Proline,

zofenoprilat, i.e. (2S,4S)-[(2S)-3-(sulfonyl)-2-methylpropanoyl]-4-phenylpyrrolidine-2-carboxylic acid,

lisinopril, that is, (N-[N-[(15)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-Proline and R2- calcium channel blocker selected from the group consisting of:

amlodipine, i.e. 3-ethyl-5-methyl ester (±)-2-[(aminoethoxy)-methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid,

lacidipine, that is, 4-tert-butyl diethyl ether 4-[ortho-[2-carboxyvinyl]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridineboronic acid,

felodipina, that is, (+)- ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and

isradipine, i.e. isopropylethylene ester of 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid.

A brief description of the illustrations

To illustrate the principal possibility of the synthesis of the anti-Christ. hipertenzivni organic salt-based acid anion ACEI and cation of an alkaline BCA to the description of the attached illustrations, where shown on:

figure 1 - NMR-spectrum characterizing perindoprilat as such;

figure 2 - NMR-spectrum characterizing amlodipine as such;

3 is the NMR spectrum characterizing perindoprilat amlodipine.

The best examples of carrying out the invention

Further, the invention is illustrated:

description of laboratory methods of obtaining salt of perindoprilat amlodipine and

a description of the treatment of hypertension with the use of this salt in laboratory models and the obtained results in comparison with conventional antihypertensive drugs.

Raw material for synthesis in all cases served substances available on the pharmaceutical market as preparations or chemical reagents, quality not lower than "chemically pure".

Salt ACEI (in particular, perindoprilat) amlodipine received several competitive methods.

Method 1. Getting salt of perindoprilat amlodipine of perindopril of erbumine and amlodipine by hydrolysis without racemization.

Initially charged to the reactor equimolar amount of perindopril erbumine and amlodipine, then add an aqueous solution of potassium carbonate, which is pre-dissolved in a mixture of water, methanol and diethyl ether. After 2 days the reaction mass is evaporated in vacuum at room temperature to dry the residue to constant mass, PEFC is what to the residue add small portions of chilled to 5°C distilled water and sprinkled with citric acid to achieve a pH 6,5.

The output of perindoprilat amlodipine is about 90%.

The resulting product is a salt of amlodipine and perindoprilat, which is confirmed by spectrometrically.

Method 2. Getting salt of perindoprilat amlodipine of perindopril of erbumine and amlodipine by hydrolysis without racemization.

Initially charged to the reactor equimolar amount of perindopril erbumine and amlodipine, then added to an aqueous solution of sodium bicarbonate, which is pre-dissolved in a mixture of water, methanol and diethyl ether. After 2 days the reaction mass is evaporated in vacuum at room temperature to dry the residue to constant mass, and then to the residue add small portions of chilled to 5°C distilled water and sprinkled with citric acid to achieve a pH of 6.5.

The output of perindoprilat amlodipine is about 80-82%.

The resulting product is a salt of amlodipine and perindoprilat, which is confirmed by spectrometrically.

Method 3. Getting salt of perindoprilat amlodipine of perindopril of erbumine and amlodipine by hydrolysis without racemization.

Initially charged to the reactor equimolar amount of perindopril erbumine and amlodipine, then add an excess of sodium bicarbonate, which is pre-dissolved in methyl alcohol. the via 3 days, the reaction mass is evaporated in vacuum at room temperature to dry the residue to constant weight, then add small portions of chilled to 5°C distilled water and sprinkled citric acid balance to achieve a pH of 6.5.

The output of perindoprilat amlodipine is about 92%.

The resulting product is a salt of amlodipine and perindoprilat, which is confirmed by NMR spectra (see Fig.1-3).

Method 4. Getting salt of perindoprilat amlodipine from a mixture of perindoprilat and amlodipine.

Originally perindopril as ethyl monoether decollate get from albuminous salt of perindopril its decomposition in an aqueous solution of sodium hydroxide in the presence of tosylate followed by extraction with ether.

The output of perindopril was 100% from the estimated value.

Next perindopril dissolved in methanol containing excess sodium hydroxide, and then evaporated to dryness and neutralize the excess alkali citric acid. The precipitate perindoprilat is filtered and dried.

When the selected temperature of the hydrolysis yield of perindoprilat is over 90%.

Salt of perindoprilat amlodipine obtained by mixing them in equimolar amounts in absolute ethanol, followed by evaporation to obtain a solid residue to constant mass. The yield is about 100%.

The resulting product is a salt of amlodipine and perindoprilat, which is confirmed by the spectrum of traceski.

The fourth method of obtaining quite simple, and provides the high output salt of perindoprilat with amlodipine. Therefore this method can serve as a basis for industrial process procedure.

Professionals understand that other salt of the above ACEI and BCA can be obtained by using similar methods.

Research on the effectiveness received antihypertensive organic salts was performed on the breed of genetically hypertensive rats (SRH). Hypertension in these rats was officially recognized as an adequate experimental model of hypertension in humans (Methodical recommendations. K.: Pharm. The Committee of the MOH of Ukraine, 1995, 62 S.).

All manipulations of animals taken in the same groups of 6 animals, were executed under eleminal-sodium (40 mg/kg) anesthesia. Experimental drug and Comparators and a mechanical mixture of drugs was administered in equivalent doses through a tube directly into the stomach, dissolving them in starch slime.

Blood pressure (BP) was detected in the tail artery for 24 hours and evaluated after 1, 2, 3, 6, 12 and 24 hours. The data obtained were processed statistically. Icons (*) after the numbers indicate statistical differences at p<0.05 compared with control. According to the results of experiments comprehensively evaluated the activity of the drugs.

Table 1
Comparative data on antihypertensive efficacy in spontaneously hypertensive rats
Used medicines and dosesHELL, mm Hg
Source1 h2 hours3 hours6 h12 hours24 hours
Control (starch mucilage)152/88152/90154/92152/88152/90152/90154/92
Perindopril, 0.05 mg/kg152/88148/84140*/80138*/82142/88144/88150/90
Perindoprilat, 0.05 mg/kg154/88152/90145/86140*/80 148/86150/80150/90
Amlodipine, 0.05 mg/kg152/88150/80145/80145/80142/78150/80142/78
The mixture perindopril 0.05 mg/kg and 0.05 mg amlodipine/kg152/88150/80144/80140*/76150/84142/80144/80
A mixture of perindoprilat 0.05 mg/kg and 0.05 mg amlodipine/kg152/88150/80142*/86145/84150/80148/80142/78
Salt of perindoprilat amlodipine (anaprilin) 0.05 mg/kg152/88150/80140*/78135*/70*134*/70*136*/72*132*/70*

From table 1 it follows that:

all use the major drugs reduced the HELL most acted quickly perindopril,

mechanical mixture of perindopril or perindoprilat amlodipine with speed, strength and duration did not significantly differ from perindopril, however,

the most strong and stable action showed it salt of perindoprilat amlodipine (abbreviated named "anaprilin").

To determine the permeability through the wall of the digestive tract used method to study the transport of substances through cell culture SASO-2, which have morphological and functional properties similar to those of intestinal absorbent enterocytes.

Cells SASO-2 under cultivation form dense monolayers, Express key enzymes fleecy layer of the small intestine and have appropriate transport system, including the transport of amino acids, dipeptides, vitamins and drugs.

An unusually high degree of differentiation in combination with the ability to spontaneously differentiate under normal conditions of culturing transformed cells SASO-2 in primary cell model for studying epithelial permeability and transport of substances.

The time measurement of the concentration of drug in the acceptor chamber after passing through the monolayer of SASO-2 was evaluated at 30, 60, 90, 120 and 180 minutes After each measurement to calculate the permeability coefficient R formula:

P=[Va/A·Cd]·dCa/dt, where

Va- the volume of the acceptor part,

A - size of the membrane inserts (in this case 0.6 cm2),

Cdthe concentration of drug in donor part,

Withandthe concentration of drug in the acceptor part,

t is the exposure time.

The data obtained were averaged and summarized into table 2.

Table 2
The average values of the permeability coefficient P
The drug (in a single unit dose of 0.05 mg/kg)The average value of the coefficient of permeability, cm/s
Perindopril18,1±3,2·10-6
Perindoprilat9,1±2,8·10-6
Amlodipine23,1±3,0·10-6
Salt of perindoprilat amlodipine (anaprilin)18,1±3,0·10-6

As follows from table 2, the salt of perindoprilat amlodipine penetrates through the monolayer of cells SASO-2 is significantly harder than perindoprilat, and about the same as perindopril. Thus, the proposed salt may well be absorbed from W Is So

Below are typical examples of therapeutic and prophylactic anti-hypertensive activity of the preparations according to the invention.

Example 1. Rat breed SHR mass of 200 g with the original HELL 157/84 mm Hg inside through a tube introduced substance perindopril dose of 0.05 mg/kg After 3 hours of HELL was 148/80 mm Hg After 24 hours the HELL back to their original values.

Example 2. Rat breed SHR weight 180 g with the original HELL 155/84 mm Hg inside through the probe entered the substance of perindoprilat in a dose of 0.05 mg/kg After 3 hours of HELL was 144/80 mm Hg After 24 hours the AD showed a tendency to return to baseline values and was 150/80 mm Hg

Example 3. Rat breed SHR mass of 200 g with the original HELL 156/88 mm Hg inside through the probe entered the substance salt of perindoprilat with amlodipine at a dose of 0.05 mg/kg After 3 hours of HELL was 140/80 mm Hg within 24 hours of HELL remained reduced compared to baseline values and was 138/78 mm Hg

This indicates a pronounced and prolonged effect of the proposed salt.

Industrial applicability

Proposed salt can be easily made available on the pharmaceutical market of substances and used as a medicinal preparation:

for lowering blood pressure with mild asthma and the prevention of hypertension,

for the treatment and prophylaxis of cardiac defects in the accuracy on the background of coronary heart disease,

for the treatment and prevention of pulmonary hypertension and

for prophylaxis renal failure and/or vascular complications on the background of diabetes mellitus.

In addition, the preparations on the basis of the proposed salt in combination with β-adrenergic receptor blockers, lipid-lowering and antithrombotic drugs can be applied to prevent complications in the treatment of postinfarction patients.

Antihypertensive organic salt of General formula [(R1-COO-)·(+H3N-R2)], where R1the angiotensin - converting enzyme inhibitor selected from the group consisting of:
of perindoprilat, that is, 1-[N-[1-carboxybutyl]alanyl]hexahydro-2-indolinecarboxylic acid,
ramiprilata, that is, [[1-carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]-pyrrole-2-carboxylic acid,
spirapril, that is, (8S)-7-[(S)-N-[(8)-1-carboxy-3-phenylpropyl]alanyl]-1,4-dithia-7-azaspiro[4,4]nonan-8-carboxylic acid,
benazeprilat, that is, [S-(R*,R*)]-3-[[1-(carbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid,
the moeksiprilat, i.e. (3S-[2[R*(R*)],3R*]-2-[2-[[1-(carbonyl)-3-phenylpropyl]aminol]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-ethinlestradiol acid),
trandolaprilat, that is, [[1-carboxy-3-phenylpropyl]alanyl]-hexahydro-2-indolinecarboxylic acid,
Fawzi is opriate, that is, [1-[S*(R*)]-alpha,beta]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy]-(4-phenylbutyl)phosphinyl]acetyl]-L-Proline,
enalaprilat, that is, S-1-[N-[1-carbonyl-3-phenylpropyl]-L-alanyl]-L-Proline,
zofenoprilat, i.e. (2S,4S)-[(2S)-3-(sulfonyl)-2-methylpropanoyl]-4-phenylpyrrolidine-2-carboxylic acid,
lisinopril, i.e., N-[N-[(15)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-Proline, a R2- calcium channel blocker selected from the group consisting of:
amlodipine, i.e. 3-ethyl-5-methyl ester (±)-2-[(aminoethoxy)-methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid,
lacidipine, that is, 4-tert-butyl diethyl ether 4-[ortho-[2-carboxyvinyl]phenyl]1,4-dihydro-2,6-dimethyl-3,5-pyridineboronic acid,
felodipina, that is, (+)- ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and
isradipine, i.e. isopropylethylene ester of 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid.



 

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12 cl, 27 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to chemical derivatives of adamantane and specifically to a novel method of producing 2-(2-alkyl(dialkyl)amino)adamantyl-alkyl(aryl)ketones of general formula R=-NHCH3: R1=Et,-CH2-CH=CH2; : R1=Me, Et,-CH2-CH=CH2, Ph,-CH2Ph; : R1= Me, Etwhich can be used as intermediate products in synthesis of certain biologically active substances. The novel method involves reacting 2-alkylamino(dialkylamino)-2-cyanoadamantanes from the group: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents from the group: methylmagnesium iodide, ethylmagnesium bromide, allylmagnesium chloride, phenylmagnesiuim bromide, benzylmagnesium chloride in a medium of dry diethyl ether or a tetrahydrofuran-ether mixture in molar ratio of reagents equal to 1:2-2.03, respectively, at temperature 30-45°C for 4-5 hours.

EFFECT: wider range of adamantane derivatives, design of a method for synthesis of novel adamantane derivatives with high output.

9 ex

FIELD: chemistry.

SUBSTANCE: novel compounds have general formula (1), or salts thereof:

, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of

, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.

EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.

20 cl, 147 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: novel compounds have general formula (1), or salts thereof:

, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of

, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.

EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.

20 cl, 147 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: novel compounds have general formula (1), or salts thereof:

, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of

, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.

EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.

20 cl, 147 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula Ia and their pharmaceutically acceptable salts, hydrates, solvates, esters and amides. In formula Ia , A is specified from -C(O)OR5 where R5 represents hydrogen; W represents C1-3alkylene; Y is specified from phenyl and 5-6-member heteroaryl containing one heteroatom specified from N, S, O; where any phenyl or heteroaryl Y can be optionally substituted with 1 to 3 radicals specified from halogen, C1-6alkyl, C1-6alkoxygroup, halogen-substituted C1-6alkyl and halogen-substituted C1-6alkoxygroup; Z is specified from: where left and right asterisks Z specify an attachment point between -C(R3)(R4)- and A of formula la; R6 is specified from hydrogen and C1-6alkyl; or R6 can be attached to carbon atom in Y to form a 5-7-member ring; R1 is specified from phenyl and 5-member heteroaryl containing one heteroatom specified from S, O; where any phenyl or heteroaryl R1 is substituted with a radical specified from phenylC0-4alkyl, heteroarylC0-4alkyl where heteroaryl represents 5-6-member heteroary containing one heteroatom specified from N, S, O, C3-8cycloalkylC0-4alkyl, C3-8heterocycloalkylC0-4alkyl which contains nitrogen atom as heteroatom, or C1-6alkyl; where any phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group R1 can be optionally substituted with 1 to 3 radicals specified from halogen, C1-6alkyl, C1-6alkoxygroup, halogen-substituted C1-6alkyl group and halogen-substituted C1-6alkoxygroup; R2 represents C1-6alkyl group; R3 and R4 represent hydrogen.

EFFECT: preparation of the pharmaceutical composition exhibiting EDG/S1P receptor modulating properties, containing therapeutically effective amount of the compound under the invention, development of a method of treating the disease mediated by EDG/S1P receptor activity, application of the compounds for preparing a drug for prevention or treatment of the disease mediated by EDG/S1P receptor activity.

16 cl, 1 tbl, 86 ex

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: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula I in form of free base or acid-additive salt, method of their obtaining, pharmaceutical composition based on them and their application s antagonists of metabotropic glutamate receptors (mGluR5). The invention can be applied in the treatment of the illnesses connected with the disorder of glutamatic signal transfer and the disorder of nervous system partially or completety mediate mGluR5. In general formula T represents 0 or 1, A represents hydroxy, X represents hydrogen, Y represents hydrogen or A forms simple bond with X or Y; ring methylene group directly bound with CH(X)-, can be dimethylated; R0 represents hydrogen, C1-C4alkyl, C1-C4alkoxy, halogen, cyano, and R represents -COR3, -COOR3 or -SO2R6,where R3 represents C1-C4alkyl, C3-C7cycloakyl, and R6 represents C1-C4alkyl, C3-C7cycloakyl, or R represents -C(O)R3, where R3 represents furanyl, trifluoromethyl, pyridinyl, morpholinyl or methylpiperasinyl; or -C(O)OR3, where R3 represents tetrahydrofuranyl, R' represents hydrogen, C1-C4alkyl or 4-methoxybenzyl, and R" represents hydrogen or C1-C4alkyl, or R' and R" together form group -CH2-(CH2)p-, where p represents 0, 1 or 2, one of symbols n and p does not represent 0, on condition that R0 does not represent hydrogen, trifluoromethyl and methoxy, when m represents 1, n represents 0, A represents hydroxy, X and Y both represent hydrogen, R represents COOEt and R' and R" together form group -(CH2)2-.

EFFECT: efficient application of compounds for treatment of diseases caused by disturbance of transduction of glutamatergic signal and diseases of nervous system.

8 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

Compounds // 2327690

FIELD: chemistry.

SUBSTANCE: description is given of compounds with formula (I) in which A and B represent -(CH2)m- and -(CH2)n- groups respectively; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-6alkyl, C1-6alkoxy, -S-C1-6alkyl, -(CH2)pNR5R6 optionally substituted aryl, heteroaryl or optionally substituted heterocyclyl; R3 represents optionally substituted aryl or optionally substituted heteroaryl; R4 represents hydrogen, C1-6alkyl or halogen; R5 and R6 each independently represents hydrogen or C1-6akyl; Z represents -(CH2)rX-, in which the -(CH2)r- group is bonded to R3 radical, or -X(CH2)r-, in which X is bonded to R3 radical; X represents oxygen, -NR7 group or -CH2- group; R7 represents hydrogen or C1-6alkyl; m and n independently represent an integer, chosen from 1 and 2; p represents 0; r independently represents an integer, chosen from 0 and 1. The invention also relates to use of the given compounds in therapy, in particular, as antipsychotic agents. The result is achieved when using serotonin receptors 5-HT2c, 5-HT2A and 5-HT6.

EFFECT: given compounds have antagonist affinity to serotonin receptors.

12 cl, 9 tbl, 265 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

The invention relates to new derivatives of azabicycloalkanes possessing biological activity, in particular to derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol

The invention relates to new chemical compounds with valuable biological properties, in particular to derive hinolan and naphthyridinone acids with antibacterial activity, as well as to the isoindole derivative as starting compounds for obtaining the derivatives hinolan and naphthyridinone acid

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to amide of δ-amino-γ-hydroxy-ω-arylalcane acid of formula and its pharmaceutically acceptable salts. Also described are pharmaceutical compositions, which include said compounds, and application of said compounds for preparation of medication, intended for treatment of pathological states, associated with renin activity, in particular for treatment of hypertension.

EFFECT: obtaining pharmaceutically acceptable salts, which possess rennin-inhibiting ability.

21 cl, 161 ex

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