Substituted (pyridinylamino)-benzisoxazole or their pharmaceutically acceptable additive salts of acids and method of production thereof

 

(57) Abstract:

Substituted (pyridinylamino) - benzisoxazole and - benzo[p]tifany, method of their production and their use as medicines. Describes the different compounds having the formula presented below:

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where R1, W, X, Y and Z have the meanings defined in the description; which are used as antidepressants. 2 S. and 3 C.p. f-crystals, 2 tab.

The invention relates to compounds of the formula

(I)

where R1represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl lower alkyl, cycloalkyl lower alkyl, lower alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono - or di-lower alkyl, amino lower alkyl, formyl, lower alkylsulphonyl, amino lower alkylsulphonyl, lower alkoxycarbonyl, mono - or di-aryl-substituted lower alkyl, arylcarbamoyl lower alkyl, aryloxy lower alkyl, or lower alkylene

< / BR>
X represents O or S;

W represents hydrogen, halogen, hydroxy, lower alkoxy, aryl lower alkoxy, nitro, trifluoromethyl or

< / BR>
where R3represents hydrogen, lower alkyl or aryl lower alkyl, and R4represents lower alkyl or a is slim-alkyl, the aryl or aryl lower alkyl; and

Z represents hydrogen, halogen, lower alkyl, nitro or amino,

which are used as antidepressants.

General formula I, above, covers less of the General formula (Ia) and (IB) below, in which R6represents hydrogen or lower alkyl, and R7represents hydrogen or lower alkyl:

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The following definitions will be used in the description and appended claims, unless specified or indicated otherwise.

The term lower alkyl is taken to mean a straight or branched alkyl group having 1-6 carbon atoms. Examples of such lower alkyl include methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, t-butyl and pentyl and hexyl straight or branched chain.

The term halogen will mean fluorine, chlorine, bromine or iodine.

The term aryl would mean a phenyl group substituted by 0,1 or 2 substituents each of which independently represents lower alkyl, lower alkoxy, lower alkylsulphonyl, halogen or trifluoromethyl.

The term cycloalkyl will mean cycloalkyl group of 3-8 carbon atoms.

Throughout the description and the definition and tautomeric isomers, if such isomers exist.

The compounds of this invention are receiving, using one or more stages of synthesis described below.

Everywhere in the description of the stages of synthesis denote R1, R3-R7, W, X, Y and Z will have the respective meanings given above unless specified or indicated otherwise, and other designations will have their corresponding values that are defined at their first occurrence.

The original 3-amino-1,2-benzisoxazole formula II can be obtained using various methods known in the art. For example, it is possible to obtain compound I using the procedure outlined below, and described in Shutske, Kapples, J. Heterocyclic Chem. 26, 1293 (1989)

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3-Amino-1,2-benzisothiazol formula IIIA known in the art. This compound can be synthesized by various methods known in the art (Behagen, U.S. patent 3, 682, 795; Flag and other U.S. patent 4, 140, 692; and UK patent 1, 249, 459). You can enter different substituents W, defined earlier, in the benzene ring is 3-amino-1,2-benzisothiazole using different methods of synthesis known in the art for various compounds of formula V, which are used as starting compounds of this izobreteny is ESA, described above, is subjected to the interaction with chloropyridine hydrochloride to obtain the compounds of formula IV.

< / BR>
The above reaction is usually carried out in an ethereal solvent such as bis(2-methoxyethyl) ether, diethyl ether dimethoxyethan, doksan or tetrahydrofuran, or a polar aprotic solvent such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoramide or dimethylsulfoxide, or proton solvent such as ethanol or isopropanol, at a temperature of about 20-150oC.

Stage B. Compound IV is subjected to interaction with the lower alkyl-chloroformiate formula Cl-CO-OR8where R8is lower alkyl, to obtain the compounds of formula V.

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The above reaction is typically conducted in a suitable solvent, such as dichloromethane, in the presence of a suitable base, such as sodium bicarbonate or triethylamine, at a temperature of about 20-60oC.

Stage C. the Compound IV is subjected to interaction with a halide compound of the formula R9-Gal, where R9represents lower alkyl, lower alkenyl, lower quinil, or aryl lower alkyl, at a temperature of about 10-80oC, predpochtitelnye solvent, such as dimethylformamide, dimethylsulfoxide, ether solvents or aromatic hydrocarbon, in the presence of a suitable base such as sodium hydride or potassium, or potassium-t-piperonyl.

Compound IV is subjected to interaction with the compound of the formula

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where ALK represents lower alkylenes group, and Gal is Cl or Br, in the usual way known in the art, to obtain the compounds of formula VI. After this connection VI is treated with hydrazine or methylamine in the usual way known in the art, to obtain the compounds of formula VII.

< / BR>
< / BR>
Compound IV is subjected to interaction with dihalo lower alkanol formula Gal-Ala-Gal in the usual way known in the art, to obtain the compounds of formula VIII, and after this last is subjected to interaction with the compound of the formula R NH2where R' represents hydrogen or lower alkyl, a conventional known method, to obtain the compounds of formula IX.

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< / BR>
Stage D. the Compound IV is subjected to interaction with galogenangidridy formula where R10represents lower alkyl, a conventional known method for obtaining compounds of formula X.

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Alternative wisesa is 10-CO-O-CO-R10the usual well-known way to achieve the same purpose.

Compound IV is subjected to interaction with the compound of the formula where R" is t-butyl or benzyl, the usual well-known way to obtain the compounds of formula XI, and after this last hydrolyzing or subjected to catalytic hydrolysis conventional known method, to obtain the compounds of formula XII.

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< / BR>
Alternative to the foregoing, the compound IV is subjected to interaction with the carboxylic acid of the formula XIII in the presence of dicyclohexylcarbodiimide to obtain compound XI, which in turn compound XII as described above,

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Stage E. the Compound Xa, obtained in stage D, restore LiAlH4or other suitable reducing reagents conventional known method for obtaining compounds of formula XIV.

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With respect to the foregoing description of the stages of the synthesis, then, if it is desired compound in which the group Z represents-NH2it can be obtained by recovery of the corresponding compounds in which the group Z is-NO2suitable reducing agent, such as zinc and hydrochloric acid, or catalytically Votorantim way.

The compounds of formula I of the present invention are used as antidepressants.

Use demonstrates the ability of these compounds to inhibit the activity of monoamine oxidase (enzyme) and thereby to increase the concentration in brain biogenic amine(s). This ability demonstrates the use as an antidepressant.

The inhibition activity monoamine oxidase type A and type B in synaptosomal rat brain.

Purpose. To determine the selective inhibition of the two forms of monoamine oxidase (MAO).

Introduction. Metabolic diaminononane amines known over a hundred years, but not so long ago, Johnston [1] described two forms of monoamine oxidase, which are called "type A" and "type B". The existence of two forms based on different substrate and specificnosti inhibitor. Serotonin (5HT) and norepinephrine (NE) are substrates for MAO type A, phenethylamine (PEA) and benzylamine are substrates for MAO type B, while dopamine (DA) and tyramine are substrates for both types. Clorgyline is a selective inhibitor of the enzyme type A, deprenil, pargyline are selective inhibitors of the enzyme type B, and tranilcipromin and promised the two is tx2">

Although for measuring the activity of MAO-known various methods described method involves extraction of radiolabelled diaminononane metabolites [3H] 5HT or [14C]-b-phenethylamine. This procedure allows to measure the activity of MAO-A and MAO-B, either simultaneously or separately [3]

Procedure. A. Reagents.

1. Phosphate buffer (0,5 M) pH 7,4: RUR 134.4 g of NaH2PO47 H2O, brought to 1 liter in distilled H2O (A); 17.3 g of Na2HPO4brought to 250 ml with distilled H2O(B). Fitting A pH to 7.4 by slowly adding B (volumes as needed). Dilution 1:10 in distilled H2O (0,05 M PO4buffer, pH 7,4).

2. 0.25 M sucrose (bateriafina PO4): 21,4 g sucrose, brought to 250 ml of 0.05 M PO4buffer.

3. Substrate for MAO-A:

A. Serotonin creatinine SO4(5HT) was obtained from Sigma chemical Company. 5 mm the basic solution was made 0.01 NHCl. It was used to dilute the specific activity of [3H]-5HT.

B. [3H] -5-hydroxytryptamine creatinine SO4(20-30 Ci/mmol) was obtained from new England Nuclea.

C. Add 12 μl of [3H]-5HT to 2 ml of a 5 mm solution of 5HT (final concentration of amine in the tested chemical company. 5 mm basic solution was prepared in 0.01 NHCl. It was used to dilute the specific activity of [14C]-PEA.

B. b-[ethyl-1-14C]-phenethylamine hydrochloride (40-50 MCI/mmol) was obtained from new England Nuclea.

C. Add 12 μl of [14C]-PEA to 2 ml of a 5 mm solution of PEA (final concentration of amine in the test was 200 μm: see below).

5. An equal number of substrates of MAO-A (5HT) and MAO-B (PEA) connected for simultaneous testing of both types of MAO, i.e., mixed basic solutions of 2.5 mm 5HT and 2.5 mm PEA, 40 μl of this mixed solution network 200 μm final concentration of each amine in the test. When experiencing only one type of MAO, then you need a separate key 5 mm solutions can be diluted 1:1 with distilled water before adding 40 ál to the incubation mixture, i.e., the same 200 μm final concentration of amine.

C. Preparation of tissue.

Rats of Wistar male, weighing 150-250 g, were killed and quickly removed the brain. Whole brain minus cerebellum was homogenized in 30 volumes of ice, buferiruemoi phosphate, 0.25 M sucrose using a Potter homogenizer-Elvejhem. Homogenate was centrifuged at 1000 g for 10 min, and the pooled liquid (S1) decantation, recently the fresh 0.25 M sucrose and used as a source of tissue for mitochondrial MAO.

C. The Test.

10 μl of 0.5 M PO4buffer. a pH of 7.4

50 μl of H2O or the corresponding concentration of medication

400 µl of the Suspension fabric

Tube pre-incubated for 15 min at 37oC, and the test was started by adding 40 μl of the combined substrate ([3H]-5HT and [14C] -PEA) with 15 second intervals. The tubes were incubated for 30 min at 37oC, and the reaction was stopped by adding 0.3 ml of 2 NHCl. Benchmarks tissue was determined by adding acid before radioactive substrate. The oxidation reaction products were extracted with ethyl acetate/toluene (1: 1), 5 ml of this mixture was added in a test tube. The resulting mixture was subjected to vortex moving in 15 seconds for the extraction diaminononane metabolites in the organic phase, and the latter was separated from the aqueous phase. The tubes were placed in a bath with a mixture of dry ice with acetone to freezing of the water layer. When this layer was frozen, the upper organic layer was poured into a scintillation vial. Added 10 ml of Liquescent (Liquiscint), and believed samples using the window settings for the14C in one channel and3H in the second channel. The values of I C50determined by logarithimic compounds of this invention are presented in table. 1.

In addition, activity antidepressants evaluated in this invention based on the prevention of ptosis in mice induced tetrabenazine. The test method and results are described below.

Prevention of ptosis in mice induced tetrabenazine.

Tetrabenazine (TBZ) induces behavioral depression with associated ptosis in mice, similar to reserpine. It is known that compounds-antidepressants like monoamine oxidase inhibitors and tricyclics, prevent or antagonizing these effects, and the degree of antagonism correlates with clinical efficacy. Prevention of ptosis in mice induced TBZ, used as a preliminary screenings for possible antidepressant activity. The method used in this invention, consisted of the following:

In the test groups of five subjects used male mice weighing 20-30, All compounds were dissolved or suspended suitable surface-active substance in distilled water and injected in volumes of 10 ml/kg of body weight. The TBZ solution was prepared from methansulfonate salt and injected at a concentration of 60 mg/kg base by intraperitoneal injection (i.p. ).

Thirty minutes after TBZ animals were placed in individual plastic containers (10,HH inches) in the presence of white noise and one minute after the movement was evaluated by ptosis according to the following scale: closed eyes= 4, closed 3/4 eyes=3, closed 1/2 eyes=2, closed to 1/4 eye= 1, open eyes=0. Therefore, the total score for each group of five in the primary screening will be 0-20, and these points were used as indices of activity of drugs.

Points in the control group, which was introduced filler, used as the basis for the validity of each test. If the control points was less than 17, the results were ignored, and the test was repeated. Calculation of percentage inhibition of ptosis following:

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To assess ED50appointed four or five doses, to determine the estimated value, and accepted only the control points of the group, which centuries the Oia ED50used linear regression and 95% confidence intervals.

The results for some compounds of this invention are shown in the table. 2 together with the results for desipramine (connection-analogue).

Effective amounts of compounds of the invention can enter the patient by any of various methods, for example, orally in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The final products, representing the free base, although they are themselves effective, can be prepared and put in the form of their pharmaceutically acceptable salts accession acid with the purpose of stability, convenience of crystallization, increased solubility, etc.

The acid used to obtain the pharmacologically acceptable salts of accession of the acid include inorganic acids such as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric, Perlina acid, and organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.

Active compounds of the present invention it is possible to enter apsule, or they can be compressed into tablets. For the purpose of oral therapeutic introduction of the active compounds of the present invention can be mixed with excipients and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gum, etc., These preparations should contain at least 0.5% of active compounds, but may vary depending on the particular form and may for convenience to include 4-70% by weight of the units. The number of active compound in these compositions is to get the right dose. Preferred compositions and preparations according to the present invention are prepared so that an oral form of unit doses contained 1.0 to 300 mg of active compound.

Tablets, pills, capsules, lozenges, etc. can also contain the following ingredients: a binder, such as microcrystalline cellulose, resin tragakant or gelatin; an excipient such as starch or lactose; disintegrity agent, such as alginic acid. Primogel, corn starch, etc., a lubricant such as magnesium stearate or Sarotex; a means to slip, such as colloidal silicon dioxide; and a sweetening substance, such as say a flavoring. When the form of a unit dosage is a capsule, it may contain in addition to the substances of the above type, a liquid carrier such as fatty oil. Other forms of unit doses may contain various other substances that alter the physical form of a unit dose, for example, as coatings. Thus, tablets or pills may be coated with sugar, Wellcom or other substances for intersolubility shells. Syrup in addition to the active compounds, may contain sucrose as a sweetening substances and certain preservatives, dyes, tint and fragrances. Substances that are used in obtaining these various compositions should be pharmaceutically pure and non-toxic in the quantities used.

For the purpose of parenteral therapeutic introduction of the active compounds of the invention can be introduced into the solution or suspension. These preparations should contain at least 0.1% of active compound, but may vary between 0.5 and about 30% of their mass. The number of active compound in such compositions is to get the right dose. Preferred compositions and preparations in accordance with izaberete the ptx2">

The solutions or suspensions may also include the following components: sterelny diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol and other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be placed in disposable syringes or vials for multiple doses, made of glass or plastic.

Examples of compounds of this invention include: 3-[4-pyridinyl)amino]-1,2-benzisoxazol; 3-[(1-propyl)(4-pyridinyl)amino]-1,2-benzisoxazol; 6-chloro-3 [(4-pyridinyl)amino] -1,2-benzisoxazol; 6-chloro-3-[(4-pyridinyl) (propyl)amino] - 1.2 benzisoxazol.

Example 1. 3-[(4-pyridinyl) amino]-1,2-benzisoxazol.

A mixture of 3-amino-1,2-benzisoxazol (9,94 g, 74,18 mmol), obtained in accordance with the method described in G. M. Shutske, K. J. Kapples, J. Heterocyclic Chem. 26, 1293 (1989), 4-chloropyridine hydrochloride (22,27 g, 197 and, diluted NaHCO3and was extracted with EtOAc, then the organic phase is washed with water, dried (MgSO4) and evaporated. The residue was purified by thin-layer chromatography (Florisil, EtOAC), and then triturative diethyl ether obtaining of 4.04 g (26%) of fine-grained brown solid. 2.0 g portion was dissolved in boiling methanol and treated with charcoal (Darko), after which the product was recrystallized from getting to 1.38 g of pale yellow crystals, melting point 203oC (decomposition).

Analysis:

Calculated for C12H9N3O 68,24% C, 4,29% H, 19,89% n

Found: 68,14% C, 4,12% H, grade of 20.06% n

Example 2. 3-[(1 - propyl) (4-pyridinyl)amino]-1,2-benzisoxazole maleate.

To a suspension of sodium hydride (0,48 g, 11,99 mmol), washed with pentane) in DMF (10 ml) at 0oC was added dropwise a solution of 3 - [(4-pyridinyl)amino]-1,2-benzisoxazole (2,41 g, 11,42 mmol) in DMF (20 ml). The reaction mixture was stirred at 0oC for 15 min and was added 1-bromopropane (1,09 ml, 11,99 mmol). The reaction mixture was stirred at room temperature for 1 h and added additional sodium hydride (50 mg) and 1-bromopropane (0.1 ml), after which the reaction mixture was heated at 60oC for half an hour. After the Ali (MgSO4). The resulting solution was treated with charcoal (Darko) to remove the yellow color and was filtered through a column of Florisil with EtOAc to remove polar impurities. Evaporation of the fractions gave 750 mg of product. The maleate salt was formed in methanol/diethyl ether to yield 912 mg of the product of the two charges, the melting point of 145-146,5oC.

Analysis:

Calculated for C15H15N3OC4H4O4: 61,78% C, 5,18% H, 11,38% n

Found: 61,68% C, 5,07% H, 11,36% n

Example 3. Part A. 3-Amino-7,6-chloro-1,2-benzisoxazol.

4-Chloro-2-[(isopropylidene) - amino)]hydroxy benzonitrile (30 g) were heated in a flask with reflux condenser for 1 h in a mixture of 1:1 ethanol and 5% HCl (1 l). The reaction mixture was cooled, podslushivaet saturated NaHCO3, was extracted several times with ethyl acetate, dried (MgSO4) and evaporated to obtain a semi-solid substance. It was trituration with pentane and dried under vacuum at 50oC for 3 h to obtain 17.9 g of product. An analytical sample was obtained by recrystallization from ethyl acetate/heptane, melting point 130-130,5oC.

Analysis:

Calculated for C7H5ClN2O: 49,87% C, 2,99% H, 16,62% n

Found: 493-amino-6-chloro-1,2-benzisoxazole (5.0 g, 29.67 per mmol) in NMP (60 ml) was added 4-chloropyridin hydrochloride (9.1 g). This mixture was intensively stirred under heating at 130oC for 1.5 h, the Reaction mixture was cooled and neutralized with saturated NaHCO3and added water to obtain a thick brown sludge (total volume 600 ml), which was filtered, washed with water and dried with air. It was subjected to thin-layer chromatography (7x15 cm column, silica gel), elwira first ethyl acetate and then 10% methanol/ ethyl acetate with the receipt of 1.93 g of product contaminated NMP. The maleate salt was formed in methanol and recrystallized from ethanol to obtain 1,17 g of product, melting point 203oC (decomp.), after drying under high vacuum over delaviradine the xylenes.

Analysis:

Calculated for C16H12ClN3O5: 53,13% C, 3,34% H, are 11.62% n

Found: 53,02% C, 3,14% H, 11,44% n

Example 4. 6-Chloro-3-[(4-pyridinyl) (propyl)amino]-1,2-benzisoxazole maleate.

To a suspension of sodium hydride (380 mg, 9,49 mmol), washed with pentane) in DMF (5 ml) was added 1-bromopropane (0,862 ml) and then 6-chloro-3-(4-pyridinyl)amino-1,2-benzisoxazol (2,33 g, 9,49 mmol) in DMF (10 ml) was added dropwise. After stirring for 1.5 h actionnow the mixture was cooled and distributed between diethyl ether and water, and the resulting mixture was filtered with the release of 6-chloro-3-[(1-propyl-N-4(1H)pyridinyl] -1,2-benzisoxazole, which is the main reaction product. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was collected, washed with water, dried (MgSO4), evaporated and subjected to thin-layer chromatography (silica gel) with ethyl acetate to obtain 354 mg of pure product in the form of oil. The maleate salt was formed in methanol, it evaporated, recrystallized from methanol/diethyl ether, and dried under high vacuum, P2O5and dephlegmation ethanol to obtain 274 mg of the product as a white fluffy solid, melting point 141-146,5oC.

Analysis:

Calculated for C15H14N3OC C4H4O4: 56,51% C, 4,49% H, 10,41% n

Found: 56,60% C, 4,42% H, 10,57% n

Literature.

1. Johnston, J. P., Some remarks about a new inhibitor of monoamine oxidase in brain tissue. 17 1285-1297 (1968)

2. Fowler, C. J. and Ross, S. B. Selective inhibitors of monoamine oxidase A and B: biochemical, pharmacological and clinical properties. Med. Res. Rev. 4 323 328 (1984).

3. Kindt, M. V. Youngster, S. K. Sonsalla, P. K. Duvoisin, R. C. Heikkila, K. E. Roma-MPTP. Eur. J. Pharmacol. 46 313 318 (1988).

1. Substituted (pyridinylamino)-benzisoxazole General formula I

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where W is hydrogen or halogen,

or their pharmaceutically acceptable additive salt of the acid.

2. Connection on p. 1, characterized in that it is a 3-[(4-pyridinyl)amino]-1,2-benzisoxazol.

3. Connection on p. 1, characterized in that a represents a 6-chloro-[(4-pyridinyl)amino]-1,2-benzisoxazol.

4. Connection PP.1 to 3, characterized in that they possess antidepressant properties.

5. The method of obtaining substituted (pyridinylamino)-benzisoxazole formula I

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where W is hydrogen or halogen,

or their pharmaceutically acceptable additive salts of the acid, characterized in that the compound of General formula II

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where W has the value

subjected to interaction with the compound of the formula III

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with subsequent isolation of the target product in free form or in the form of its pharmaceutically acceptable additive salt of the acid.

 

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The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

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where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

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