New phenylpiperazines

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

 

The invention relates to new derivatives phenylpiperazine.

Known phenylpiperazine, which are strong inhibitors of the uptake of serotonin (DE 19730989 A1). Various phenylpiperazine derivatives with as inhibiting the uptake of serotonin activity and high affinity to 5-HT1Areceptors, known from DE 4333254 A1, WO-A-99/05140, while EP-A-376607 already reveals another group of phenylpiperazines with high affinity to 5-HT1Athe receptors.

None of the compounds of the above patents has no pharmacological effect, which may be used to treat both negative and positive symptoms of psychosis, viz combination of high affinity for dopamine D2receptors and high activity as an inhibitor of the uptake of serotonin.

The purpose of this invention is to provide compounds suitable for the treatment of both negative and positive symptoms of psychosis.

The present invention relates to compounds of formula (I):

where X represents 1) a group of the formula

where S1represents a hydrogen atom or halogen,

- S2and S3independently from each other represent an atom

hydrogen, alkyl(1-6C), phenyl or benzyl,

- S4before the hat is two hydrogen atoms or oxo group

- S5represents H or alkyl(1-4C), and

- Y represents a CH2, O or S,

or 2) a group of the formula

where S1has the above value, a R represents H, alkyl(1-4C), alkoxyalkyl(2-6C), alkenyl(2-4C) or quinil-(2-4C), or 3) a group of the formula

where S1has the above value, a Z represents CH2, O or N, or 4) a group of the formula

where S1has the above value,

or 5) a group of the formula

where S1has the above meanings and a represents O or N, connected with piperazinone ring in position 5 or 8, or 6) a group of the formula

where S1has the above value, a S6and S7represent hydrogen atoms or oxo group, or 7) a group of the formula

where one of the dotted line can represent a double bond, S1has the above value, and

P=T=Q=nitrogen; or R=T=nitrogen and Q=CH or CH2

or P=Q=nitrogen, T=CH, CH2CH-CH3or-CH3

or R=n, and T represents CH or CH2,

Q = represents sulphur,

- m has a value from 2 to ; n has the value 0-2;

- R5and R6independently of one another represent H or alkyl(1-3C); or R5+R6represent a group -(CH2)p-where R has a value of 3-5, and

- R7represents an alkyl(1-3C)alkoxy(1-3C), halogen atom or cyano group; or R6+R7(R7in position 7 of the indole group) are a group -(CH2)qwhere q has a value of 2-4, and their salts, which exhibit high affinity for dopamine D2-receptor and are good inhibitors of reuptake of serotonin (SRI).

Preferred compounds of the present invention are compounds having the formula (I), where X represents a group of formula (1), (2) or (3)where the symbols have the meanings given above, and their salts. Especially preferred are compounds having the formula (I), where X represents a group of formula (1), where S1=H, S2=CH3, S3=N, S4=oxo, S5=H and Y represents an oxygen atom, m is 3, R5=R6= a hydrogen atom, n is 0 or 1, a R7represents 5-fluoro, and their salts.

It is established that compounds in accordance with the present invention exhibit high affinity for dopamine D2the receptor and the site re-absorption of serotonin. This combination is useful when cured and schizophrenia and other mental disorders, allowing a more complete treatment of all symptoms (e.g., positive symptoms and negative symptoms).

However, some compounds having the formula (I), show (partial) agonistic activity at dopamine receptors, which makes them particularly useful in the treatment of Parkinson's disease.

The compounds exhibit activity as antagonists at dopamine D2receptors, as they effectively act antagonistically on apomorphine-induced desire for climbing in mice. The compounds also show activity as inhibitors of reuptake of serotonin, as they make it possible induced 5-NTR behavior in mice.

Compounds active in therapeutic model, susceptible to clinically relevant antipsychotic agents (for example, when the conditioned-reflex avoidance; Van der Heyden & Bradford, Behav.Brain Res., 1988, 31:61-67) and antidepressants or anxiolytics (for example, when the suppression is caused by stress osvechenie voice; van der Poel et al., Psychopharmacology, 1989, 97: 147-148), the data are given in table 3.

In contrast to clinically relevant antagonists dopamine D2receptors described compounds have a low susceptibility to induce catalepsy in rodents and of themselves they are, apparently, cause less noticeable of extrapyramidal the side effects than existing antipsychotics.

Inhibitory activity relative to the re-absorption of serotonin inherent in these compounds, may be the cause therapeutic effects observed in behavioral models, susceptible to any antidepressants or anxiolytics.

Connections can be used to treat lesions or diseases of the Central nervous system, caused by an imbalance in the systems that generate or dopamine, or serotonin, such as: aggression, fear, autism, vertigo, depression, disorders of cognitive ability or memory, Parkinson's disease and, in particular, schizophrenia and other mental diseases.

Pharmacologically acceptable acids which the compounds of the present invention can form a suitable acid additive salts are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluensulfonate acid, methanesulfonate acid and naphthalenesulfonate acid.

When the compounds contain a chiral centre, the invention includes both the racemic mixture and the individual enantiomers.

Connection and and the acid additive salts can be converted in form, acceptable for introduction using the appropriate methods, with the use of auxiliary substances such as liquid and solid media.

Compounds having the formula (I)can be obtained by reaction of compounds of formula

under basic conditions with a compound of the formula

and in this formula the symbols have the meanings given above, L represents a leaving group such as halogen atom or mutilata group.

Piperazinovogo compounds having the formula (II)can be obtained as described in the publications EP 0138280, EP 0189612 and/or EP 0900792, or similar methods.

Getting piperazines having the formula (II)may be carried out as shown in the following schemes (i)-(iv). Some paths lead to optically pure piperazinonyl derived.

Schemes (i)-(iv)

Scheme (iv)

Starting compound having the formula (III)can be obtained in accordance with methods known for analogous compounds are described, for example, Organic Process Res. and Dev., 1997(1), 300-310.

The invention is explained using the following examples.

Example 1: getting a connection,i (see scheme i)

Stage 1 (scheme i): To a solution of chloronitromethane (6,45 g, 34 mmol) is dry DMSO (50 ml) is added powdered NaOH (2,72 g, 68 mmol). After stirring for 30 min add solution nelfinavir R-glycerides (8.0 g, 38 mmol) in DMSO (20 ml) and the resulting mixture is heated at 80° C for 24 hours. After cooling to room temperature the reaction mixture was poured into water (200 ml), acidified with 1 n Hcl and extracted with methyl tert-butyl ether. The organic fraction was washed with water and dried over MgS4. After removal of drying agent and solvent in vacuum, the resulting oil is subjected to flash chromatography (SiO2, eluent PE/acetone = 3/1). Output 9,29 g (90%) of S-Catala.

Stage 2 (scheme i): To a solution of S-Catala (31 g, 102 mmol) in acetic acid (120 ml) was added 35%Nug in acetic acid (80 ml), the mixture was rotated for 2 h on a rotary evaporator in a water bath with a temperature of 50° C. the Reaction mixture was diluted with ethanol (96%, 250 ml), cooled in a mixture of salt/ice, and then slowly add NaOH (50% in water, 250 ml), keeping the temperature below 15° C. After adding ethanol (250 ml) and water (250 ml), the reaction mixture was stirred at room temperature for 16 hours. Then add concentrated Hcl (approximately 300 ml) and water, the mixture extracted with ethyl acetate. After washing the organic fraction of 5%NaHCO3(4× 500 ml) the solvent is removed in vacuo and the resulting oil is subjected to flash chromatography (SiO2, eluent PE/acetone = 3/1). You are the od of 20.5 g (81%) R-benzodioxane in the form of a yellow oil.

Stage 3 (scheme i): To a solution of R-benzodioxane (20 g, 81 mmol) in DMF (200 ml) is added KOH (4,56 g, 81 mmol). After cooling, add red solution dimethylsulfate in a mixture of ice/acetone (23 ml) and the reaction mixture was stirred 1.5 hours at room temperature. Then add another CON (4,56 g, upon cooling, and the mixture is stirred at room temperature for 16 hours. After adding water (700 ml) and the product extracted with ethyl acetate. The ethyl acetate is removed in vacuo and the resulting oil is subjected to flash chromatography (SiO2, eluent PE/acetone = 4/1). Get R-methoxymethylethoxy (12.3 g, 58%) as a yellow oil, [α ]

25
D
=-97° (methanol).

Stage 4 (scheme i): To a solution of R-methoxymethylethoxy (5 g, 19 mmol) in ethanol (100 ml) and ethyl acetate (50 ml) is added a catalytic amount of 10% Pd/C and the solution is shaken out at atmospheric pressure H2at room temperature. After absorption of the reaction mixture estimated number of H2the catalyst is filtered off and the filtrate was concentrated in vacuo. Yield 3.7 g (100%) of the corresponding aniline compounds.

Stage 5 (scheme i): Aniline compound (4 g, 2 mmol) and SEA (BHEA), that is, HN (CH2CH2Cl)2·HCl (3.7 g, 2 mmol), dissolved the chlorobenzene (100 ml). The mixture is heated at 150° 16 h, concentrated in vacuo, and purified flash chromatography (SiO2, eluent dichloromethane/methanol/ammonium hydroxide = 92/7,5/0,5). Output to 3.67 g (68%) piperazine a.i.

Example 2: obtain the compound No. 126

The method of obtaining described above, i.e. the interaction of the compound (II) with compound (III). The mesylates of formula (III) are obtained from the corresponding alcohols by standard methods, for example, using sl/Et3N.

A mixture of piperazine a (3.6 g, to 13.6 mmol), 5-forintermediate (4.1 g, 15.1 mmol), triethylamine (2 ml) and catalytic amount of KI in CH3SP (100 ml) is heated at the boil under reflux for 18 h, after which the reaction mixture was concentrated in vacuo and purified by chromatography (SiO2, eluent dichloromethane/methanol/ammonium hydroxide = 92/7,5/0,5). The output of 3.77 g of the free base (oil). The free base is dissolved in ethanol and add 1 equivalent of fumaric acid in ethanol. After removal of the solvent to obtain the compound No. 126 (4.3 g, 57%). [α ]

25
D
=-2° (methanol).

Example 3: obtaining connection b,ii (see scheme ii)

Stage 1 (scheme ii): a Solution of aminophenol (37,3 g, 198 mmol) of the methyl ester of S-lactic acid (20 ml) and triphenylphosphine (5 g, 220 mmol) in THF (2000 ml) is cooled with a mixture of ice/salt (temperature <10°). Then slowly add a solution of the ester of azodicarboxylic acid (DIAD, 43 ml, 218 mmol) in THF (400 ml). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and to the residue is added ethanol (500 ml) and 36%Hcl (125 ml). The mixture is heated to 100° With (evolution of gas). After cooling, the compound is filtered off and washed with 96%ethanol (approximately 100 ml). Yield 42 g (87%).

Stage 2 (scheme ii): This stage is similar to stage 4 as described in scheme i.

Stage 3 (scheme ii): This stage is similar to stage 5, as described in scheme i, and leads to the formation of piperazine b,ii.

Example 4: obtaining compound No. 89

The method of obtaining described above, i.e. the interaction of the compound (II) with compound (III). The reaction is carried out as described in example 2, on the basis of piperazine b,ii. The output 58% of compound No. 89. [α ]

25
D
=-24° (methanol).

Example 5: receiving connection with,iii (see scheme iii)

Stage 1 (scheme iii): a Solution of benzomorphan (10 g, 41 mmol, see scheme ii, step 1) and powdered KOH (2.3 g, 41 mmol) in DMF (100 ml) cooled with ice (temperature <10°). After adding 1 equivalent Me (2.55 ml, 41 mmol) reactiona the mixture was stirred at room temperature for about 1.5 hours and then poured into water. The precipitate is filtered off, washed with water and dried. Yield 10 g (95%) N3connection TPL 191-192; [α ]

25
D
=+7,5° (in THF).

Stage 2 (scheme iii): This stage is similar to stage 4 as described in scheme i.

Stage 3 (scheme iii): This stage is similar to stage 5, as described in scheme i, and leads to the formation of piperazine with, iii.

Example 6: obtain the compound No. 121

The method of obtaining described above, i.e. the interaction of the compound (II) with compound (III). The reaction is carried out as described in example 2, on the basis of piperazine with,iii. Exit 44% of compound No. 121. [α ]

25
D
=-28° (methanol).

Example 7: getting connection d, iv (see scheme iv)

Stage 1 (scheme iv): Pyridine (81 ml, 1 mol) are added to a solution of 2-hydroxy-5-Chloroaniline (143,5 g, 1 mol) in dry CH2Cl2. The mixture is cooled with ice (temperature <10° (C), and then slowly add a solution of 2-bromo-2-methylpropionamide (163 ml, 1 mol) in CH2Cl2(100 ml). The mixture is stirred at room temperature for 18 h and then poured into CH2CL2(5000 ml) and water (2000 ml). The organic layer is washed with water, dried and concentrated in vacuo AP is sustained fashion to 1 L. The precipitate is filtered off, washed with CH2Cl2and dried. Exit 231 g (79%) of bromo derivatives, TPL 172° C.

Stage 2 (scheme iv): To a suspension of bromo derivatives (60 g, 205 mmol) in water (95 ml) slowly while cooling with ice add concentrated sulfuric acid (7 ml), and then 70%NGO3(16 ml) and stirred for 2 hours at room temperature. After cooling with ice water the precipitate is filtered off, washed with water and purified by chromatography (SiO2, eluent methyl tert-butyl ether). Yield 49 g (71%) nitrocompounds.

Stage 3 (scheme iv): To a solution of nitro compounds (49 g, 145 mmol) in DMF (500 ml) is added To a2The POPs. The resulting mixture is heated at 150° C for one hour, then cooled and poured into a mixture of water/ethyl acetate. The organic fraction is washed with sodium bicarbonate (5% in water), Hcl (2 n) and water, in that order. The solvent is removed in vacuo and the residue purified flash chromatography (SiO2, methyl tert-butyl ether/PE = 1/1). Yield 23 g (62%).

Stage 4 (scheme iv): This stage is similar to stage 4 as described in scheme i.

Stage 5 (scheme iv): This stage is similar to stage 5, as described in scheme i, and leads to the formation of piperazine d,iv.

Example 8: getting connection No. 115

The method of obtaining described above, i.e. the interaction of the compound (II) with compound (III). The reaction is carried out as described Primera 2, based on piperazine d,iv. A yield of 20% of compound No. 115.

The compounds listed in the following tables 1 and 2 obtained in accordance with the method described in the above examples.

1. Derived phenylpiperazine formula (I)

where X represents 1) a group of the formula

where S1represents a hydrogen atom or halogen,

S2and S3independently from each other represent a hydrogen atom, alkyl(1-6C), phenyl or benzyl,

S4represents two hydrogen atoms or oxoprop,

S5represents H or alkyl(1-4C),

Y represents CH2, O or S,

or 2) a group of the formula

where S1has the above value, a R represents H, alkyl(1-4C), alkoxyalkyl(2-6C), alkenyl(2-4C) and the and quinil-(2-4C), or 3) a group of the formula

where S1has the above value, a Z represents CH2, O or N,

or 4) a group of the formula

where S1has the above value,

or 5) a group of the formula

where S1- has the above meanings and a represents an O or N that is connected with piperazinone ring in position 5 or 8, or 6) a group of the formula

where S1has the above value, and S6and S7represent hydrogen atoms or oxoprop,

or 7) a group of the formula

where one of the dotted line can represent a double bond, S1has the above value, and

P=T=Q=nitrogen:

or P=T=nitrogen and Q=CH or CH2,

or P=Q=nitrogen, T=CH, CH2CH-CH3or-CH3,

or R=nitrogen and T represents CH or CH2

Q represents a sulphur,

m has a value from 2 to 6;

n has the value 0-2;

R5and R6independently from each other represent H or alkyl(1-3C); or R5+R6represent a group -(the H 2)p-where

p has a value of 3-5,

R7represents an alkyl(1-3C)alkoxy(1-3C), halogen atom or cyano; or R6+R7(R7in position 7 of the indole group) are a group -(CH2)qwhere q has a value of 2-4, and their salts.

2. The compound according to claim 1, where X represents the formula (1), (2) or (3)where the symbols have the meanings given in claim 1.

3. The compound according to claim 1, where X is a group having the formula (1), where S1=S3=S5=H, S4=oxo and S2=CH3, m is 3, R5=R6=H, n is 0 or 1, R7represents 5-fluoro, and its salts.

4. Method of preparing compounds according to claim 1, characterized in that the compound having the formula (II)

interacts in basic conditions with a compound having the formula (III)

in these formulas, the symbols have the meanings given in claim 1, L represents a leaving group.

7. The method of treatment of diseases of the Central nervous system, characterized in that it includes an introduction to the subject the compound according to claim 1.



 

Same patents:

FIELD: organic chemistry, pharmacy.

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

or its isomeric form of the formula (Ia):

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

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

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

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

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

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

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

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

The invention relates to the field of chemistry, particularly the proton pump inhibitors

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

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

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

The invention relates to chemistry and medicine, in particular relates to new chemical compounds - derivatives of 3,4-bis(furazan-3-yl)furoxan General formula I:

where R = R1= HE, NH2N3lowest alkoxy or a group of the General formula NR2R3where R2= R3= N or R2and R3together with the nitrogen atom form piperidinyl cycle, or R = NH2and R1- (lower alkanoyl)amino group, provided that R and R1not represent methoxy, possessing pharmacological activity

The invention relates to organic chemistry and pharmacology, and relates new connection - 1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride, increasing resistance to acute hypoxia with hypercapnia

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

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