2,6-dimethylaniline n-cyclopropylidene-2-carboxylic acid and pharmaceutically acceptable salts with acids and method of production thereof

 

(57) Abstract:

The invention relates to novel 2,6-dimethylaniline N - cyclopropylmethyl-2-carboxylic acid f-ly I, where R is cyclopropyl or methylcyclopropyl in the form of a racemic mixture or the individual enantiomers or their salts, which exhibit increased antiarrhythmic and local anestesiologia properties and can find application in medicine. The method of obtaining compounds f-ly I is that chloride 2,6-dibromohexane subjected to interaction with 2,6-dimethylaniline in an aprotic solvent in the presence of a second equivalent of base with 0-25oC obtaining 2,6-dimethylaniline 2,6-dibromohexane to you, which is subjected to cyclization in the presence of cyclopropyl or methylcyclopropene and two equivalents of a base in an aprotic solvent at 70-100oC. 3 S. and 2 C.p. f-crystals, 3 ill.

The invention relates to the field of production of substances with antiarrhythmic and local Anastasiya activity.

More specifically, the present invention offers new cyclopropylamine connection with antiarrhythmic and local Anastasiya activity, and the way they are received.

It is known to present the th activity. From the point of view of the latter, all of these inhibitors cause a decrease sensorial (receptor) conduction of nerve impulses close to the place of their introduction. This activity is reversible and the effects disappear within a few minutes.

Application of local analiziruemykh funds has increased over the last few years due to their application in certain types of anesthesia, such as spinal anesthesia, brachial anesthesia, and so on, together with the increase in surgical procedures on outpatients and new, causing less bleeding surgical techniques designed to reduce hospital costs.

Therapeutic family of local analiziruemykh means is characterized, on the one hand, extensive use of it in various fields of surgery and, on the other hand, a large number of known compounds with the local Anastasiya activity. Despite the large number of known compounds, physicians may choose only a few of them, no more than 3 or 4 connections now available for sale. Among them, the most used are mepivacaine and bupivacaine, which provide excellent results in most patients. However, in 5-10% of cases Zabluda with increasing duration of anesthesia.

In fact, most of the local analiziruemykh means that well-known, very quickly into the process of metabolism and, in addition, they increase the blood flow in the injection area, forcing you to enter in the finished formulation vasoconstrictor agent. Therefore, we can conclude that it would be desirable to exclude cardiac risk, which is determined by the use of adrenaline, while maintaining the duration analiziruemykh funds.

The authors of the present invention concluded that the introduction of cyclopropene group in the overall structure of local analiziruemykh funds family mepiwakaina and bupivacaine has a beneficial effect on the activity and duration of action. Cyclopropyl group is characterized, in fact, that it has lipophilic properties similar to the corresponding alkyl groups of normal structure, but at the same time, increases resistance to metabolism and improves the distribution of organic liquids.

Therefore, the present invention offers new products that contain cyclopropyl groups have local anasthesiologie and complications Southeast.

Thus, the present invention relates to new cyclopropylamine compounds, method of their production and their use as antiarrhythmic and local analiziruemykh funds.

New cyclopropylamine compounds of the present invention are characterized by the fact that they have the following General formula (I)

< / BR>
where R represents cyclopropyl or methylcyclopropyl,

moreover, this formula (I) includes racemic mixtures, as well as their individual enantiomers or optical isomers and pharmaceutically acceptable salts with acids, in particular the hydrochloride.

The compounds of formula (I), which have a chemical name N-(cyclopropyl or methylcyclopropyl) piperidine-2-carboxanilide get that reaction chloride 2,6-dibromohexane with 2,6-dimethylaniline in a suitable solvent and in the presence of a second equivalent of base at a temperature between 0oand the 25oC first get 2,6-dimethylaniline 2,6-dibromohexane acid, which process for the cyclization cyclopropyl or methylcyclopropene, receiving N-cyclopropyl - or N-methylcyclopropyl-dl-piperidine-2-carbox-(2,6-dimethylaniline).

This connection can be turned Mering hydrochloride is obtained by reaction with dry hydrochloric acid in acetone.

In the reaction of chloride 2,6-dibromohexane with 2,6-dimethylaniline can be applied to any suitable base, which does not impede the reaction. In particular, we can apply the trimethylamine and pyridine. Used in this reaction, the solvent must be aprotic solvent.

The reaction of 2,6-dimethylaniline 2,6-dibromohexane acid with cyclopropyl or methylcyclopropene (which can be represented in General formula R-NH2where R has the above values may be arranged in or with the application of the excess R-NH2(3 equivalents per 1 equivalent of anilide), or with one equivalent of R-NH2and two equivalents other suitable base similar to the base used in the first stage of the method of obtaining. In addition, this reaction is carried out in an aprotic solvent and at a temperature of from 70 to 100oapproximately. Specified aprotic solvent may be dioxane, acetonitrile or a similar solvent.

The products of both stages of the method can easily be distinguished by removing from the reaction mixture of a solvent and stirring the residue with water to dissolve the salts formed with subsequent filtration and purification in the usual way, usually the STI can be obtained by carrying out the above method of obtaining a stereoselective manner or allocation of individual optical isomers from a racemic mixture by ordinary methods, for example by fractional crystallization, chromatography, etc.

In Fig. 1 shows a graph of the surface Anastasiya activity substances IQB-9302 according to the invention in comparison with the activity mepiwakaina.

In Fig. 2 shows a graph of vnutriaortalina local Anastasiya compounds IQB-9301 and IQB-9302 of the invention in comparison with the activity mepiwakaina.

In Fig. 3 shows another graph intradermal local Anastasiya activity of the compounds of the invention IQB-9301 and IQB-9302 compared to mepivacaine at concentrations that differ from the concentrations used in Fig. 2.

The following examples describe the invention in detail without limiting its scope.

Example 1. Getting hydrochloride d1-N-cyclopropylidene-2-carbox-(2,6-dimethylaniline) (IQB-9301).

A) Obtaining 2,6-dimethylaniline 2,6-dibromohexane acid.

A mixture of 4.04 g (0.04 mol) of triethylamine and 4,84 g (0.04 mol) of 2,6-dimethylaniline in 10 ml of dichloromethane is added dropwise to 11.3 g (0.40 mol) of chloride 2,6-dibromohexane dissolved in 50 ml of dichloromethane, with stirring and cooling in an ice bath. The reaction mixture was stirred at room temperature for 30 minutes

Yield 70%.

1H NMR spectrum: (Cl3CD) 300 MHz mn-17,71 (s, 1H), 7,25-7,05 (m, 3H), and 4.5 (m, 1H), 3.43 points (t, 2H), of 2.23 (s, 6H), 2.40 a-1,50 (m, 6H).

B) Obtaining d1-N-cyclopropylidene-2-carboxyl-(2,6-dimethylaniline).

of 4.04 g (0.04 mol) of triethylamine and 1.19 g (0,021 mol) of cyclopropylamine added to the solution rate of 7.54 g (0.02 mol) of 2,6-dimethylaniline 2,6-dibromohexane acid in 100 ml of dioxane. The reaction mixture was gently refluxed for 10 hours Then left to cool and the formed bromohydrin of triethylamine is separated by filtration.

The filtrate is evaporated in vacuum and the residue is stirred with water and filtered. The hard part is dissolved in 50 ml of 0.1 N HCl and the solution extracted with dichloromethane. The acid solution is neutralized using NaOH and the solid portion was separated by filtration.

Cleanse it by the washing with hot n-hexane and by passing through silica gel using a mixture of dichloromethane and acetone (95:5) as eluent. Get 4 g of white solid product.

Yield: 73%

So pl.: 175-176oC

1H NMR spectrum: (Cl3CD) 300 MHz mn-18,54 (s, 1H), 7,06 (m, 3H), of 3.56 (m, 1H), 3,09-2,84 (Amoxil-(2,6-dimethylaniline) (IQ-9301)

3.5 g of the base obtained in the preceding stage, dissolved in 50 ml of acetone. After the solution is passed a stream of dry hydrochloric acid. Educated hydrochloride is separated by filtration and washed with acetone. For recrystallization apply absolute ethanol. Obtain 3.2 g of product.

Yield: 80%.

So pl.: 249-250oC

1H NMR spectrum; (DMSO-d6) 300 MHz mn-110,46 (s, 1H), 9,54 (s, 1H), 7,06 (m, 3H), 4,39 (m, 1H), 3,26 (m, 2H), 2,89 (m, 1H), 2,16 (m, 6H), 1,95 of 0.77 (m, 10H).

Example 2. Getting hydrochloride d1-N-methylcyclopropyl-2-carboxyl-(2,6-dimethylaniline) (IQB-9302).

Under the conditions described in part B of example 1, from a rate of 7.54 g (0.02 mol) of 2,6-dimethylaniline 2,6-dibromohexane acid and 1.42 g (0.02 mol) of methylcyclopropene and 4.04 g (0.04 mol) of triethylamine receive the corresponding base. The weight of the product, 4,4

Yield: 77%.

So pl.: 123-124oC.

1H NMR spectrum: (DMSO-d6) 300 MHz mn-1to 8.20 (s, 1H), 7,05 (m, 3H), 3.43 points (2T, 1H), 2.95 and (m, 2H), 2,24 (d, 6H), is 2.09 (m, 2H), 1,99 to 1.31 (m, 6H), 0,89 (m, 1H), 0,57 (DD, 2H), 0,15 (DD, 2H).

Getting hydrochloride d1-N-methylcyclopropyl-2-carbox-(2,6-dimethylaniline) (IQB-9302).

A stream of dry hydrochloric acid was passed through a 2.5 guise of ethanol was obtained 2.2 g of product.

Yield: 80%.

So pl. 264-265oC.

1H NMR spectrum: (DMSO-d6in million-1to 10.62 (s, 1H), 9,84 (s, 1H), was 7.08 (m, 3H), 4,27 (m, 1H), 3,10 (m, 2H), 2,89 (m, 2H), and 2.14 (m, 1H), 2.06 to (m, 6H), 1,90 of 1.00 (m, 6H), of 0.68 (t, 2H), 0,36 (t, 2H).

Comparative example local Anastasiya activity of the compounds of the invention.

Surface anaesthesia in rabbits.

Local anasthesiologie action of the compounds of the invention was compared with the effect of a commercially available mepiwakaina in accordance with the method of Pose (1931) on the inhibition palpebral reflex. In normal conditions the stimulation (irritation) of the cornea of the rabbit with the help of hair causes the closing of the century. If the cornea was pre-exposed local anestesiologi tools, reflex never played a single stimulation. To call it, the stimulation must be repeated a certain number of times and, if anaesthesia is deep, it is seen that the cornea is practically immune.

This study used the following concentrations of drugs, %:

- Mepivacain 1

- IQB-9301 1

- IQB-9302 1

which was injected in a volume of 0.1 ml in one eye series Albino rabbits of New Zealand. Stimulation started the reflex.

For each of the drugs used 5 - 7 animals.

Anesthesia infiltration.

Used Albino Guinea pigs of both sexes weighing from 400 to 600 g, the hair of which was removed the day before the experiment. Used medicines (mepivacain, IQB-9301 and IQB-9302) were injected with in a volume of 0.2 ml intradermal in 4 places back. For control used the same volume of saline. Anasthesiologie action was assessed by recording the responses (all or none) to a stimulus (stimulus) (6 injections in each place), called in intervals of 5 min for 30 minutes

Used the following drugs, %:

- Mepivacain 1

- IQB-9301 1

- IQB-9302 1

- IQB-9302 0,5

- IQB-9302 0,1

For each of these concentrations was applied to the group of 8 animals.

In Fig. 1, 2 and 3 summarizes the results obtained with the use of products of the invention, in comparison with mepivacaine, one of the previously described local analiziruemykh funds.

1% mepiwakaina effectively inhibited rabbits ' eyes only 80% of the animals. In addition, it was rather fleeting, disappearing after 10 minutes the Connection IQB-9301 was almost effectivedate for more than 45 minutes

In Fig. 2 shows that 1% of IQB-9301 and mepivacaine were equally effective in anasthesiologie infiltration. In both cases, achieved 100% efficiency within 10-15 minutes the Connection IQB-9302 was much more effective than the other two products at the same concentration: 60 min anasthesiologie action was still 100%.

In Fig. 3 shows the comparative effect of 1% mepiwakaina and 0.5 and 0.1% IQB-9302. Both concentrations of IQB-9302 were more effective than mepivacain. At a concentration of 0.5% connection IQB-9302 supported 100% through 60 minutes

These results allow to draw the following conclusions:

two product according to the invention act as a strong local analiziruemykh funds equally with mepivacaine or stronger than him;

- early action to three products are practically the same;

connection IQB-9302 5-15 times stronger than mepivacain, because when concentration is 10 times smaller than the observed stronger effects;

- the duration of IQB-9302 also more than mepiwakaina (2-5 times).

1. 2,6-Dimethylaniline N-cyclopropylidene-2-carboxylic acids of General formula (I)

< / BR>
where R represents cyclopropyl or methylcyclopropyl, Raplamaa salts with acids.

2. Connection on p. 1, which is selected from the group comprising dl-N-cyclopropylidene-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l) hydrochloride, dl-N-cyclopropylidene-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l), dl-N-methylcyclopropyl-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l), hydrochloride dl-N-methylcyclopropyl-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l).

3. The method of obtaining 2,6-dimethylaniline N-cyclopropylidene-2-carboxylic acids of General formula (I)

< / BR>
where R represents cyclopropyl or methylcyclopropyl,

in the form of a racemic mixture and the individual enantiomers or optical isomers and pharmaceutically acceptable salts with acids, characterized in that the chloride 2,6-dibromohexane subjected to interaction with 2,6-dimethylaniline in an aprotic solvent in the presence of a second equivalent of base at a temperature of 0 - 25oC obtaining 2,6-dimethylaniline 2,6-dibromohexane acid, which is subjected to cyclization in the presence of cyclopropyl or methylcyclopropene and two equivalents of a base in an aprotic solvent at 70 - 100oC generated 2, is needed to turn it into a pharmaceutically acceptable salt with an acid and/or share a racemic mixture of its enantiomers or optical isomers.

4. The method according to p. 3, characterized in that the compound of formula (I) selected from the group comprising dl-N-cyclopropylidene-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l) hydrochloride, dl-N-cyclopropylidene-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l), dl-N-methylcyclopropyl-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l), hydrochloride dl-N-methylcyclopropyl-2-carbox-2,6-dimethylaniline or its optical isomers (d) and (l).

5. 2,6-Dimethylaniline N-cyclopropylidene-2-carboxylic acids of General formula (I)

< / BR>
where R represents cyclopropyl or methylcyclopropyl,

in the form of racemic mixtures, as well as their individual enantiomers or optical isomers and pharmaceutically acceptable salts with acids, showing antiarrhythmic and local anaesthetic properties.

 

Same patents:

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to a method for producing (+) (2R)-endo-norbornene and (-)-(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-Exo-bicyclo [2.2.1] gate-2-yloxy] - 4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)he is of the formula:

,

and its enantiomer, 5-(3- [(2R.) -Exo-bicyclo [2.2.1.]hept-2 - yloxy]- 4 - methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)-he, of the formula:

The invention relates to new derivatives isoindoline General formula:

< / BR>
in which the radicals R represent hydrogen atoms or together form a single bond; the radical R' represents a hydrogen atom or easily removable and the radicals R" are identical, represent phenyl radicals which may be substituted by a halogen atom or a methyl radical in the ortho - or meta-position, as well as their salts

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

The invention relates to a series of new derivatives of 1-[(2-benzhydrylamine)-4-piperidyl]aliphatic acid having excellent antihistaminic, anti-allergic and anti-asthma activity, which do not have side effects that are typical for compounds with activity of this type

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

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

14 cl, 36 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to biologically active compounds. Invention represents dipeptide nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters of the general formula:

wherein X means -CH or nitrogen atom (N); R means (C1-C7)-(lower)-alkyl, (C1-C7)-(lower)-alkoxy-(C1-C7)-(lower)-alkyl, (C5-C10)-aryl-(C1-C7)-(lower)-alkyl or (C3-C8)-cycloalkyl.

EFFECT: valuable biochemical properties of compounds.

6 cl, 12 ex

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes dipeptide-nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters that are used in therapeutic or prophylaxis treatment of disease of morbid state mediated by cathepsin K.

EFFECT: valuable medicinal properties of inhibitors.

3 cl, 11 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention describes compound of the formula (I): wherein R1 means hydrogen atom (H); R2 means -SH, -S-C(O)-R8, -P(O)(OR5)2, -P(O)(OR5)R6, -P(O)(OR5)-R7-C(O)-R8, -P(O)(OR5)-R7-N(R5)-S(O)2-R9 or -P(O)(OR5)-R7-N(R5)-C(S)-N(R6)2; R3 means tetrazole, -C(O)OR6, -C(O)O-R7-OC(O)R5; R4 means optionally substituted aryl, or R4 means N-heterocyclyl. Also, invention describes compounds of the formula (II): and (III): wherein X means -CH2- or -O-, and pharmaceutical compositions comprising indicated compounds. Proposed compounds possess inhibitory effect on activity of plasma carboxypeptidase B and used as anti-thrombosis agents.

EFFECT: valuable medicinal and biochemical properties of compounds.

34 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of the formula (I) R is radical selected out of i) , ii) , iii) , iv) , where R7 is halogen, cyano, C1-4alkyl, C1-4alkoxy; p is integer within 0 to 3; R1 is hydrogen, C2-4alkenyl or C1-4alkyl; R2 is hydrogen or C1-4alkyl; R3 and R4 are independently hydrogen or C1-4alkyl; R5 is: phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; naphthyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; benzofurane substituted with 1-3 groups selected independently out of C1-4alkyl or halogen; R6 is hydrogen or (CH2)qR8; R8 is hydrogen; m is zero or 1; n is 1; q is an integer within 1 to 4; r is 1 or 2; provided that if R5 is phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen, then R is not radical i) ; and pharmaceutically acceptable salts or solvates thereof. The invention also refers to method (A) of compound obtainment, to compound application, to pharmaceutical composition, as well as to mammal treatment method.

EFFECT: obtainment of novel bioactive compounds with tachykinin receptor antagonist activity.

16 cl, 116 ex

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: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to certain (R)-arylalkylamino derivatives of formula , wherein R is specified in the following values: - 2-thiazolyl substituted by a trifluoromethyl group; -CORa, SO2Ra, wherein Ra is specified in the following values -C1-C5-alkyl, C3-C6- cycloalkyl, phenyl, a heteroaryl group specified in thiophen, furan and pyridine with heteroaryl being unsubstituted or substituted by a group specified in COOH and C1-C4-acyloxy; - ω-aminoalkylamino group of formula , wherein X represents: - linear or branched C1-C6 alkylene; R2 and R3 together with N atom bound therewith form a 3-7-member nitrogen-containing heterocyclic ring of formula , wherein Y represents a single bond; and p is equal to 0 or represents an integer 1 to 3; R1 represents linear or branched C1-C5 alkyl; Ar represents a phenyl group substituted by one or more groups independently specified in benzoyl, heteroarylcarbonyl wherein the heteroaryl group represents furan, 4'-trifluoromethane sulphonyloxy-, 4'-[1-methyl-1-(phenylsulphonyl)ethyl]- and 4'-benzole sulphonyloxy-. The compounds under the invention provides unexpectedly strong inhibiting action on C5a-induced chemotaxis of human PMN.

EFFECT: preparing (R)-arylalkylamino derivatives applicable in treating the pathologies dependent from chemotaxic activity of neutrophils and monocytes induced by the C5a complement fraction.

6 cl, 1 tbl, 10 ex

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