Piperazine-substituted benzothiophenes for treating psychiatric disorders

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic compounds of formula (1) , where ring Q represented by is , (where is NH-CH2-, -N-CH-, -CH2-NH- or -CH=N-; and the carbon-carbon bond between the 3rd position and the 4th position of the heterocyclic skeleton which contains Z and Y, is a single or double bond); ring Q can have at least one substitute selected from a group consisting of a lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogenated lower alkyl group, aryl group, aryl lower alkyl group, aryl lower alkoxy group, arylcarbonyl group, lower alkenyloxy group, lower alkanoyl group, lower alkanoyloxy group, cycloalkyl group, cycloalkyl lower alkyl group, halogen atom, carbamoyl group which can have a lower alkyl group, carboxy group, lower alkoxycarbonyl group, amino group which can have a lower alkanoyl group, nitro group, hydroxy lower alkyl group, amino lower alkyl group which can have a lower alkyl group, thienyl group, lower alkyl group substituted with a saturated 3-8-member monoheterocyclic group containing 1-2 nitrogen atoms, and an oxo group; R2 is a hydrogen atom or a lower alkyl group; and A is -O-A1- (where A1 is an alkylene group which can be substituted with a hydroxy group (where the alkylene group may contain one oxygen atom) or a lower alkenylene group or a lower alkylene group; provided that if A is a lower alkylene group, Q is a bicyclic group selected from a group consisting of: (where the carbon-carbon bond is a single or double bond)] or salts thereof. The invention also relates to a pharmaceutical composition, to a method of preparing the pharmaceutical composition, to use of the formula (1) heterocyclic compound, as well as a method for synthesis of the heterocyclic compound.

EFFECT: obtaining novel biologically active compounds which have activity as a dopamine D2 receptor partial agonist and a serotonin receptor 5-HT2A antagonist, and an adrenaline receptor α1 antagonist, and serotonin uptake inhibitor or serotonin reuptake inhibitor.

15 cl, 197 ex, 24 tbl

 

The technical field

The present invention relates to new heterocyclic connection.

The level of technology

As a causal factor in schizophrenia and bipolar disorder, mood disorders and emotional disorders is heterogeneous, it is desirable that the drug had multiple pharmacological effects and, therefore, possessed a broad spectrum of action. In WO2004/026864 A1 noted that the derived barbastella represented by the General formula

(where A' represents -(CH2)mCH2-, -(CH2)mO - and the like; m is an integer from 1 to 4; and RArepresents a hydrogen atom, a C1-4alkyl group which may be substituted by 1-3 fluorine atoms, and the like, has an antagonistic activity against receptor D2and antagonistic activity against serotonin 2A (5-HT2Aand effective for the treatment of schizophrenia and other disorders of the Central nervous system.

However, in WO2004/026864A1 did not indicate that the derived barbastella, disclosed in this document, has partial agonistic activity against receptor D2, antagonistic activity against receptor 5-HT2A, antagonistic activity against re is aptara α 1and inhibitory activity of serotonin uptake, and has a wide range of therapeutic actions. In WO 2005/019215 A1 discloses compounds represented by the following formula:

(where A represents -(CH2)mCH2-, -(CH2)mO - or the like; m is an integer from 2 to 5; and D represents N, C or the like; Z and Q independently represents N, C or CH, provided that at least one of Z and Q represents N; X and Y independently represent C, N, or the like, and the relationship between X and Y is single or double; R1represents hydrogen, (C1-C3)alkyl group or the like; each of R4, R5, R6and R7represents hydrogen, alkyl group or the like; and G represents a group of monocyclic or bicyclic compounds)that bind to receptors of dopamine D2. In WO 2005/019215 A1 notes that some of the compounds disclosed therein have the activity of partial agonists of receptors D2or activity of the receptor antagonists D2and can be effective for the treatment of schizophrenia and other disorders of the Central nervous system.

However, in WO 2005/019215 A1 does not describe the specific compounds of the present invention.

Description of the invention

The object of the present invention is an antipsychotic drug that has a wide range of actions, has few side effects, is well tolerated and safe in comparison with the known typical and atypical antipsychotic drugs.

The authors of the present invention conducted a comprehensive study of the above problem, and as a result they were able to synthesize a new compound which has partial agonistic activity against receptor dopamine D2(partial agonistic activity against receptor D2), antagonistic activity against serotonin receptor 5-HT2A (antagonistic activity against receptor 5-HT2A) and antagonistic activity against adrenaline receptor α1(antagonistic activity against receptor α1), and also, along with these effects, has inhibitory activity of serotonin uptake (inhibitory activity of serotonin reuptake). The present invention is entirely based on these experimental data.

The present invention relates to a heterocyclic compound represented by General formula (1):

[where the ring Q, presents

represents a

(where

represents-NH-CH2-, -N=CH-, -CH2-NH - or-CH=N-; and carbon-carbon bond

between the 3-position and 4-position of the heterocyclic skeleton containing Z and Y represents a single or double bond);

the ring Q may have at least one Deputy, selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl groups, aryl groups, aryl lower alkyl groups, aryl lower alkoxygroup, arylcarbamoyl group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cycloalkyl group, cycloalkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group, a lower alkyl group, substituted saturated 3 to 8-membered managerialism group containing 1-2 nitrogen atom and oxo is the group;

R2represents a hydrogen atom or a lower alkyl group; and

And is a-O-A1(where A1represents alkylenes group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom), or lower alkynylamino group) or lower alkylenes group;

provided that if a is a lower alkylenes group ring Q represents a bicyclic group selected from the group consisting of:

(where the carbon-carbon bond

represents a single or double bond)] or its salt.

The present invention relates to a heterocyclic compound represented by General formula (1), where the ring Q represents a bicyclic group selected from the group consisting of:

and

(where the carbon-carbon bond

between the 3-position and 4-position of the bicyclic heterocyclic skeleton is a single or double bond);

the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, NISS the th alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo C3-C8alkyl group, cyclo C3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group and a lower alkyl group, substituted saturated 5-6-membered managerialism group containing 1-2 nitrogen atom; and

A represents a-O-A1(where A1represents a C1-C6alkylenes group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom), or its salt.

The present invention relates to a heterocyclic compound represented by General formula (1),

where the ring Q represents a bicyclic group selected from the group consisting of:

ring the Q may have from 1 to 3 substituents, selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo C3-C8alkyl group, cyclo C3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, phenyl group, thienyl groups and pyrrolidinyl lower alkyl group; and

A represents a-O-A1(where A1represents a C1-C6alkylenes group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom)), or its salt.

The present invention relates to a heterocyclic compound represented by General formula (1),

where the ring Q represents bizi the symbolic group, selected from the group consisting of

(the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo C3-C8alkyl group, cyclo C3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group and pyrrolidinyl lower alkyl group), or its salt.

The present invention relates to a heterocyclic compound represented by General formula (1),

where the ring Q represents a bicyclic group selected from the group consisting of

(where the carbon-carbon bond

p>

between the 3-position and 4-position of the above bicyclic heterocyclic skeleton is a single or double bond);

the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo C3-C8alkyl group, cyclo C3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group, pyrrolidinyl lower alkyl group and the carbonyl group; and

A represents the lower alkylenes group, or its salt.

The present invention relates to a heterocyclic compound represented by General what armoloy (1),

where the ring Q represents a bicyclic group selected from the group consisting of

(where the carbon-carbon bond

between the 3-position and 4-position of the above bicyclic heterocyclic skeleton is a single or double bond);

the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo C3-C8alkyl group, cyclo C3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group and pyrrolidinyl lower alkyl groups; or salts thereof./p>

Among the heterocyclic compounds or their salts represented by the formula (1), preferred compounds include a compound or its salt selected from:

(1) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it,

(2) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-1H-quinoline-2-it,

(3) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-it,

(4) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it,

(5) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinoline-2-she

(6) 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-it; or its salt.

In addition, among the heterocyclic compounds or their salts represented by the formula (1), preferred compounds include a compound or its salt selected from:

(1) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-it,

(2) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it,

(3) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it,

(4) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-3,4-dihydro-2H-isoquinoline-1-it,

(5) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2H-isoquinoline-1-it

(6) 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-it; or its salt.

The present and the finding relates to pharmaceutical compositions, containing as active ingredient a heterocyclic compound represented by formula (1)or its salt, mixed with a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be effectively used for the treatment or prevention of disorders of the Central nervous system.

The pharmaceutical composition of the present invention can be used for treatment or prevention of disorders of the Central nervous system selected from the group consisting of schizophrenia; refractory, resistant to therapeutic intervention or chronic schizophrenia; emotional disorders; mental disorders; mood disorders; bipolar disorder type I, bipolar disorder type II; depression; endogenous depression; major depression; melancholy and refractory depression; estimatesare disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; sociophobia; obsessive compulsive disorder; posttraumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatic disorders psychogenic nature; conversive disorder; pain disorder; hypochondriacal syndrome; simulates the CSOs disorders; dissociated disorders; sexual dysfunction; disorders of sexual desire; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorders; alcoholism; alcohol intoxication; misuse of drugs; poisoning by psychostimulants; drug abuse; anhedonia; iatrogenic anhedonia; anhedonia as a result of mental or mental causes; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive disorders; cognitive disorders associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive disorders caused by Alzheimer's disease, Parkinson's disease and related neurodegenerative disease; cognitive disorders in schizophrenia; cognitive disorders caused refractory, resistant to therapeutic intervention or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; disease Tourette's; teak disorders; attention deficit disorder/hyperactivity disorder; conduct disorder; and down's syndrome.

The present invention relates to a method for producing a pharmaceutical composition, comprising the Pach is the use of heterocyclic compounds, represented by the above formula (1)or its salt with a pharmaceutically acceptable carrier.

The present invention relates to the use of heterocyclic compounds represented by the above formula (1)or its salts as a drug specifically to the use of heterocyclic compounds represented by the above formula (1)or its salt as a partial agonist of the receptor of dopamine D2and/or antagonist of the serotonin receptor 6-HT2Aand/or antagonist adrenaline receptor α1and/or inhibitor of serotonin uptake (or inhibitor of serotonin reuptake). The present invention relates to a method of treatment or prophylaxis of disorders of the Central nervous system, including the introduction of compounds represented by the above formula (1)or salts thereof to the human or animal.

The present invention relates to a method for producing heterocyclic compounds represented by the above formula (1)

or its salt, which differs in that it includes the interaction of the compounds represented by the formula

(where the ring Q and A are defined above and X1represents a halogen atom or a group which causes a substitution reaction, such as the ATO is halogen), or its salt with a compound represented by the formula

(where R2defined above)or its salt.

In particular, the corresponding groups represented in the General formula (1), above represent the following groups.

As the lower alkyl group may be mentioned linear or branched alkyl group having from 1 to 6 carbon atoms. In particular, the lower alkyl group includes groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl.

As the lower alkoxygroup may be mentioned linear or branched alkoxygroup having from 1 to 6 carbon atoms. In particular, the lowest alkoxygroup includes groups: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentylamine, neopentane, n-hexyloxy, isohexane, 3 methylpentane.

As the lower alkenylphenol group may be mentioned linear or branched Alchemilla group having from 1 to 3 double bonds and from 2 to 6 carbon atoms, including asTRANSandCIS-configuration. In particular, the lower Alchemilla group includes groups: vinyl, 1-propenyl, 2-propenyl 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatriene, 1,3-hexadienyl, 1,4-hexadienyl.

As the lower alkenylphenol group may be mentioned linear or branched Alchemilla group having from 2 to 6 carbon atoms. In particular, the lower Alchemilla group includes groups: ethinyl, 2-PROPYNYL, 2-butynyl, 3-butynyl, 1-methyl-2-PROPYNYL, 2-pentenyl, 2-hexenyl.

As the halogen atom may include fluorine atom, chlorine atom, bromine atom and iodine.

As a halogenated lower alkyl group can be mentioned lower alkyl group defined above, substituted by 1 to 7 halogen atoms, preferably 1 to 3 halogen atoms. In particular, halogenated lower alkyl group includes groups: vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, dichloromethyl, 2,2-dottorati, 2,2,2-triptorelin, pentafluoroethyl, 2-foretel, 2-chloroethyl, 3,3,3-cryptochromes, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-tripcomputer, 4,4,4,3,3-PENTACARBONYL, 4-chlorobutyl, 4-bromobutyl, 2-chlorobuta is, 5,5,5-tryptophanyl, 5-chloropentyl, 6,6,6-triptorelin, 6-chlorhex, perferences.

As the aryl group can be mentioned, for example, phenyl, biphenylene, naftalina group, and as the substituent of the phenyl ring or naphthalene ring may be mentioned lower alkyl group (preferably, a linear or branched alkyl group having from 1 to 6 carbon atoms), defined above, lower alkoxygroup (preferably, linear or branched alkoxygroup having from 1 to 6 carbon atoms), defined above and the aryl group includes phenyl, biphenylene or naftalina group that may have 1 to 3 groups selected from nitro and an atom halogen.

Specific examples of aryl groups include: phenyl, 2- (or 3-, or 4-)were, 2- (or 3-, or 4-)nitrophenyl, 2-(or 3-, or 4-)methoxyphenyl, 2- (or 3-, or 4-)chlorophenyl, biphenyl, α-naphthyl, β-naphthyl.

As aryl lower alkyl groups may be mentioned lower alkyl group (preferably, a linear or branched alkyl group having from 1 to 6 carbon atoms), defined above, which is from 1 to 3, preferably one aryl group as defined above.

Specific examples of the aryl lower alkyl groups include: benzyl, 2- (or 3-, or 4-)methylbenzoyl, 2- (or 3-, or 4-)nitrobenzyl, - (or 3-, or 4-)methoxybenzyl, 2-(or 3-, or 4-)Chlorobenzyl, 1- (or 2-)phenylethyl, 1-methyl-1-phenylethyl, 1,1-dimethyl-2-phenylethyl, 1,1-dimethyl-3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl.

As aryl lower alkoxygroup can be specified lowest alkoxygroup (preferably, linear or branched alkoxygroup having from 1 to 6 carbon atoms), defined above, which is from 1 to 3, preferably one aryl group as defined above. Specific examples of the aryl lower alkoxygroup include groups: benzyloxy, 2- (or 3-, or 4-)methylbenzylamine, 2- (or 3-, or 4-)nitrobenzyloxy, 2- (or 3-, or 4-)methoxybenzyloxy, 2- (or 3-, or 4-)Chlorobenzyl, 1- (or 2-)phenylethane, 1-methyl-1-phenylethane, 1,1-dimethyl-2-phenylethane, 1,1-dimethyl-3-phenylpropoxy, α-aftermatket, β-aftermatket.

As the aryl residue arylcarboxylic group may be mentioned aryl group defined above. Specific examples arylcarboxylic groups include: benzoyl, 2- (or 3-, or 4-)methylbenzoyl, 2- (or 3, or 4-)nitrobenzoyl, 2- (or 3-, or 4-)methoxybenzoyl, 2- (or 3-, or 4-)chlorbenzoyl, α-naphtol, β-naphtol.

As the lower alkenylacyl can be specified lowest alkenylacyl with lower alkenylphenol group (preferably a linear or branched alkenylacyl having from 1 to 3 double bonds and 2 to 6 ATO is s carbon), defined above. In particular, the lowest alkenylamine group includes: vinyloxy, 1 propenyloxy, 1-methyl-1-propenyloxy, 2-methyl-1-propenyloxy, 2-propenyloxy, 2-butenyloxy, 1 butenyloxy, 3 butenyloxy, 2-pentyloxy, 1 pentyloxy, 3 pentyloxy, 4-pentyloxy, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yloxy, 2-hexenoate, 1 hexenoate, 5-hexenoate, 3 hexenoate, 4-hexenoate, 3,3-dimethyl-1-propenyloxy, 2-ethyl-1-propenyloxy, 1,3,5-hexatriene, 1,3-hexadienyl, 1,4-hexadienyl.

As the lower alkanoyloxy group may be mentioned linear or branched alcoolica group having from 1 to 6 carbon atoms. In particular, the lower alcoolica group includes groups: formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbamoyl, hexanoyl.

As the lower alkanoyloxy may be mentioned linear or branched alkanoyloxy having from 1 to 6 carbon atoms. In particular, the lowest alkanoyloxy includes group formyloxy, atomic charges, propionyloxy, butyryloxy, isobutyryloxy, pentanoate, tert-BUTYLCARBAMATE, hexanoate.

As cycloalkyl group can be specified cyclo C3-C8an alkyl group having from 3 to 8 carbon atoms. Examples cycloalkyl groups include: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

As cycloalkyl lower alkyl group can be mentioned lower alkyl group defined above, which is from 1 to 3, preferably one cycloalkyl group (preferably, cyclo C3-C8an alkyl group having from 3 to 8 carbon atoms), defined above. In particular, cycloalkyl lower alkyl group includes groups: cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylmethyl, cyclopentylmethyl, 3-cyclopentylpropionyl, 4-cyclohexylmethyl, 5-cycloheptylmethyl, 6-cyclooctylmethyl, 1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylmethyl.

As carbamoyl group which may have lower alkyl group, can be specified carnemolla group which may have 1 to 2 lower alkyl groups (preferably alkyl group having from 1 to 6 carbon atoms), which are defined above. In particular, such carnemolla group includes groups: carbarnoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamate.

As the lower alkoxycarbonyl group can be specified alkoxycarbonyl group, which has the lowest alkoxygroup defined above, preferably a linear or branched alkoxycarbonyl group having from 1 to 6 carbon atoms. In private the tee, alkoxycarbonyl group includes groups: methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, tert-butoxycarbonyl, second-butoxycarbonyl, n-pentyloxybenzoyl, neopentane, n-hexyloxymethyl, isohexadecane, 3-methylbenzyloxycarbonyl.

As the amino group which may have lower alkanoyloxy group, may be mentioned amino group having one of the lowest alkanoyloxy group defined above (preferably a linear or branched alcoolica group having from 1 to 6 carbon atoms). In particular, examples of such amino groups include the groups: amino, N-formylamino, N-acetylamino.

As a hydroxy lower alkyl group can be mentioned lower alkyl group (preferably, a linear or branched alkyl group having from 1 to 6 carbon atoms), defined above, having from 1 to 5, preferably from 1 to 3, hydroxyl groups. In particular, a hydroxy lower alkyl group include groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxyphenyl, 6-hydroxyhexyl, 3,3-dimethyl-3-hydroxypropyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutane, perhydroxyl.

As amino lower McIlroy group, which may have lower alkyl group, may be mentioned lower alkyl group (preferably, a linear or branched alkyl group having from 1 to 6 carbon atoms), defined above, having from 1 to 5, preferably one amino group that may have 1 to 2 lower alkyl groups (preferably linear or branched alkyl group having from 1 to 6 carbon atoms), which are defined above. In particular, examples of such amino lower alkyl group which may have lower alkyl group include groups: aminomethyl, 2-amino-ethyl, 1-amino-ethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-methyl-3-aminopropyl, N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, N-methylaminomethyl, 2-(N-methylamino)ethyl, 1-methyl-2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, 2-(N,N-diisopropylamino)ethyl, 3-(N,N-dimethylamino)propyl, 3-(N,N-diethylamino)propyl.

As saturated 3 to 8-membered managerialism group containing 1 to 2 nitrogen atoms, can be mentioned, for example, groups: azetidinol, pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidine, piperazinil morpholinyl, thiomorpholine (preferably, saturated 5-6-membered monoheterocycles group containing 1 to 2 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperid the Nile, piperidino, pyrazolidine and piperazinil).

As the lower alkyl group, substituted saturated 3 to 8-membered managerialism group containing 1 to 2 nitrogen atoms, may be mentioned lower alkyl group (preferably, a linear or branched alkyl group having from 1 to 6 carbon atoms), defined above, having from 1 to 2 (preferably, one) saturated 3 to 8-membered (preferably, 5 to 6-membered) managerialistic groups containing 1 to 2 nitrogen atoms, which are defined above. In particular, this group includes groups: [(1-, 2 - or 3-)azetidine]methyl, [(1-, 2 - or 3-)pyrrolidinyl]methyl, [(1-, 2 - or 4-)imidazolidinyl]methyl, [(1-, 3 - or 4-)pyrazolidine]methyl, [(1-, 2-, 3 - or 4-)piperidyl]methyl, [(2-, 3 - or 4-)morpholinyl]methyl, 2-[(1-, 2 - or 3-)pyrrolidinyl]ethyl, 1-[(1-, 2 - or 3-)pyrrolidinyl]ethyl, 3-[(1-, 2 - or 3-)piperidyl]propyl, 4-[(1-, 2 - or 3-)pyrrolidinyl]butyl, 5-[(1-, 2 - or 3-)piperidyl]pencil.

Examples alkalinous group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom)include linear or branched alkylenes group (where Allenova group may contain one oxygen atom)having from 1 to 12 (preferably 1 to 6) carbon atoms, such as groups include methylene, ethylene, trimethylene, 2-metallisation, 2-hydroxytrimethylene, 3 hydroc tetramethylene, 3-methyltyramine, 2,2-dimethyltrimethylene, 1-metallisation, METROTILE, utilitiles, tetramethylene, pentamethylene, hexamethylene, 2-ethoxyethylene (-CH2CH2OCH2CH2-), methoxymethyl (-CH2OCH2-), 1-ethoxyethylene (-CH2CH2OCH(CH3)-), 2-methoxyaniline (-CH2OCH2CH2-), 2-propoxyethyl (-CH2CH2CH2OCH2CH2-), 3-isopropoxyaniline (-CH(CH3)CH2OCH2CH2-), 4-butoxyaniline (-CH2CH2CH2CH2OCH2CH2CH2CH2-), 5-Interoceanmetal (-CH2CH2CH2CH2CH2OCH2CH2CH2CH2CH2-), 6-hexyloxymethyl (-CH2CH2CH2CH2CH2CH2OCH2CH2CH2CH2CH2CH2-), 1,1-dimethyl-2-methoxyaniline (-CH2OCH2C(CH3)2-), 2-methyl-3-amoxicillin (-CH2CH2OCH2CH(CH3)CH2-), 3-methoxytrityl (-CH2OCH2CH2CH2CH2-).

Examples of the lower alkynylamino groups include linear or branched alkynylamino group having from 1 to 3 double bonds and from 2 to 6 carbon atoms, such as groups: vinile, 1-propanole, 1-methyl-1-propanole, 2-methyl-1-propanole, 2-propanole, 2-butylen, 1-butylen, 3-butylen, 2-penttinen, 1-pentene the Yong, 3-penttinen, 4-penttinen, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-ilen, 2-hexarelin, 1-hexarelin, 5-hexarelin, 3-hexarelin, 4-hexarelin, 3,3-dimethyl-1-propanole, 2-ethyl-1-propanole, 1,3,5-hexatriene, 1,3-hexadienyl, 1,4-hexadienyl.

Examples of the lower alkalinous groups include linear or branched alkynylamino group having from 1 to 6 carbon atoms, such as groups include methylene, ethylene, trimethylene, 2-metallisation, 3-methyltyramine, 2,2-dimethyltrimethylene, 1-metallisation, METROTILE, utilitiles, tetramethylene, pentamethylene and hexamethylene.

Heterocyclic compound represented by the above General formula (1)may be obtained in various ways, for example, it can be obtained by the method represented by the following reaction formula.

[Reaction formula 1]

(where the ring Q, A and R2defined above, and X1represents a halogen atom or a group which causes a substitution reaction, such as a halogen atom).

In the present application examples of the group which causes a substitution reaction, such as, for example, halogen atom, include lower alkanesulfonyl, arylsulfonate and Arakishvili.

Halogen atom, shown as X1in the General formula (2), defined above.

Examples of nassaucommunitycollege, shown as X1include linear or branched alkanesulfonyl having from 1 to 6 carbon atoms, such as groups: methansulfonate, econsultancy, n-propanesulfonate, isopropanolamine, n-butanesulfonate, tert-butanesulfonate, n-pentanesulfonate and n-hexanesulfonate.

Examples of arylsulfonate shown as X1include group: vinylsulfonate, naftiliaki, which may have 1 to 3 substituents selected from the group consisting of linear or branched alkyl group having from 1 to 6 carbon atoms, linear or branched alkoxygroup having from 1 to 6 carbon atoms, nitro and halogen atom on the phenyl ring, for example. Specific examples of phenylsulfonylacetate, which may have a Deputy, include groups: phenylsulfonyl, 4-methylphenylsulfonyl, 2-methylphenylsulfonyl, 4-nitrophenylacetylene, 4-methoxyphenylalanine, 2-nitrophenylacetylene, 3 chlorophenylsulfonyl. Specific examples of aftersalesbrochurepru include α-naftiliaki, β-naftiliaki.

Examples of Arakishvili shown as X1include linear or branched alkanesulfonyl having from 1 to 6 carbon atoms and substituted phenyl the group, linear or branched alkanesulfonyl having from 1 to 6 carbon atoms and substituted naftilos group, where groups can have from 1 to 3 substituents selected from the group consisting of linear or branched alkyl group having from 1 to 6 carbon atoms, linear or branched alkoxygroup having from 1 to 6 carbon atoms, nitro and halogen atom on the phenyl ring, for example. Specific examples of phenylsulfonylacetate, substituted naftilos group, as defined above, include groups: benzylmalonate, 2-phenylethylperoxo, 4-phenylmethylsulfonyl, 4-methylbenzenesulfonate, 2-methylbenzenesulfonate, 4-nitrobenzenesulfonate, 4-methoxybenzenesulfonyl, 3 chlorobenzenesulfonate. Specific examples of alkanesulfonyl, substituted naftilos group, as defined above, include groups: α-naphthylenediisocyanate, β-naphthalenyloxy.

The interaction of the compounds represented by the General formula (2), and compounds represented by the General formula (3), carried out without solvent or with an inert solvent in the absence or the presence of a basic compound.

Examples of the inert solvent include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, dimethyl ether of diethylene glycol, dimethylvaleric of ethylene glycol; aromatic hydrocarbons, such as benzene, toluene, xylene; lower alcohols such as methanol, ethanol, isopropanol; ketones, such as acetone, methyl ethyl ketone; polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), triamide hexamethylphosphoric acid, acetonitrile.

As the basic compounds may be used are well known compounds, and their examples include hydroxides of alkaline metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; alkali metals such as sodium, potassium; inorganic bases such as sodium amide, sodium hydride, potassium hydride and such alcoholate of alkali metals as sodium methoxide, sodium ethoxide, potassium methoxide, ethoxide potassium; such organic bases like triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonan-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO).

As such basic compounds can be used one joint is or a combination of two or more compounds. The amount of basic compound is usually from 0.5 to 10, preferably from 0.5 to 6, the molar amount of compounds of General formula (2).

If necessary, the above reaction can be carried out by adding as a catalyst of alkali metal iodide such as potassium iodide, sodium iodide.

With regard to use of the relationship of the compounds of General formula (2) and compounds of General formula (3) in the above reaction formula 1, the latter can usually be used in a molar amount constituting at least 0.5, preferably from 0.5 to 5, the first.

The above reaction is carried out usually at a temperature from room temperature up to 200°C, preferably from room temperature up to 150°C, and complete, typically within about 1 to 30 hours.

[Reaction formula 2]

(where the ring Q, R2and A1defined above. X2represents a hydroxy-group, a halogen atom or a group which causes a substitution reaction, such as a halogen atom).

The interaction of the compounds represented by the General formula (4), and compounds represented by the General formula (5a), carried out under the reaction conditions similar to the conditions of the reaction, the compound represented by General formula (2), and compounds represented by the General formula (3), the above formula the reaction is AI 1.

In the case of compound (5a)in which X2represents a hydroxy-group, the interaction of compounds (4) and compound (5a) can be performed in a suitable solvent in the presence of a condensing agent.

Specific examples of the solvent that can be used in this reaction include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane; such esters as methyl acetate, ethyl acetate, isopropylacetate; such a polar solvent like acetonitrile, pyridine, acetone, DMF, DMSO, triamide hexamethylphosphoric acid or a mixture of these solvents. As the condensing agent can be specified such isocarboxazid as diethylazodicarboxylate and a mixture of such phosphorus compounds such as triphenylphosphine. The amount of the condensing agent is usually at least equimolar, preferably equimolar 2 parts of the compound (4).

The amount used of the compound (5a) is usually at least equimolar, preferably equimolar 2 parts of the compound (4).

This reaction is carried out usually at a temperature of from 0 to 200°C, preferably from 0 to 150°C, and usually end the Ute for 1 to 10 hours.

[Reaction formula 3]

[where R2defined above, X3represents a halogen atom or a group which causes a substitution reaction, such as, for example, a halogen atom, A2represents the lowest alkylenes group,

and the ring Q1 represents a bicyclic group selected from the group consisting of

(where the carbon-carbon bond

represents a single bond or a double bond);

ring Q1 may have at least one Deputy, selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, aryl group, aryl lower alkyl groups, aryl lower alkoxygroup, low alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cycloalkyl group, cycloalkyl (lower) alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group, a lower alkyl group, Zam is on saturated 3 to 8-membered managerialism group, containing 1 to 2 nitrogen atoms and the carbonyl group].

The interaction of the compounds represented by the General formula (6), and compounds represented by the General formula (5b), carried out under the reaction conditions similar to the conditions of the reaction, the compound represented by General formula (2), and compounds represented by the General formula (3), the above reaction formula 1.

The connection represented by the General formula (2), which is used as starting material may be obtained, for example, in accordance with the following reaction formula 4 and the compound represented by General formula (5)can be obtained, for example, in accordance with the reaction formula 5 below, respectively.

[Reaction formula 4]

(where the ring Q, A1X1and X3defined above).

The interaction of the compounds represented by the General formula (4), and compounds represented by the General formula (8), carried out under the reaction conditions similar to the conditions of the reaction, the compound represented by General formula (4), and compounds represented by the General formula (5A), the above reaction formula 2.

[Reaction formula 5]

(where R2A and X2defined above, and X4represents a halogen atom or a group which causes a substitution reaction, such as, for example, atomanlagen).

The interaction of the compounds represented by the General formula (3), and compounds represented by the General formula (9), carried out under the reaction conditions similar to the conditions of the reaction, the compound represented by General formula (2), and compounds represented by the General formula (3), the above reaction formula 1. Both compounds, the compound of General formula (3) and the compound of General formula (9), a well-known and easily available.

In the compound (1), a compound with a hydroxy-group in the ring Q may be obtained by treating compound having a methoxy group in ring Q in compound (1), in the presence of acid in a suitable solvent or without solvent.

Examples of suitable inert solvent in this case include water; aromatic hydrocarbons such as benzene, toluene, xylene; ethers like diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; fatty acids, as acetic acid; esters like ethyl acetate, methyl acetate; ketones such as acetone, methyl ethyl ketone; acetonitrile, pyridine, DMF, DMSO, triamide hexamethylphosphoric acid or a mixture of these solvents.

Examples of CIS is the notes include such inorganic acids, as Hydrobromic acid, hydrochloric acid, sulfuric acid; such fatty acids as formic acid, acetic acid and such organic acids as p-toluensulfonate acid; a Lewis acid as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron TRIFLUORIDE, tribromide boron; iodides such as sodium iodide, potassium iodide; a mixture of Lewis acid and iodide defined above.

Usually it is convenient to use the primary connection in the amount of from 0.1 to 15, preferably from 0.5 to 10 molar amount of compound (1). If the reaction takes place without solvent, the acid is usually used in an excessive amount.

This reaction is usually carried out at a temperature from 0 to 150°C, preferably from about 0 to 100°C, and is usually completed within from about 0.5 to 75 hours.

The original compounds used in each reaction formula above, may be in the form of suitable salts, and the target compound obtained in each reaction, may be in the form of a suitable salt. Such suitable salts include the preferred salts of the compounds (1), examples of which are given below.

Preferred salts of the compounds (1) are pharmaceutically acceptable salts, and examples include metal salts, such as alkali metal salts (e.g. sodium salt, potassium salt and the like),salts of alkaline earth metals (for example, the calcium salt, magnesium salt and the like), salts of inorganic bases, such as ammonium salt, carbonates of alkali metals (e.g. lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate and the like), carbonates of alkali metals (such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and the like), hydroxides of alkali metals (e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide and the like); for example, salts of organic bases, such as tri(lower)alkylamine (e.g. trimethylamine, triethylamine, N-ethyldiethanolamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-research (for example, N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonan-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; organic acid salts such as format, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, aconsultant, p-toluensulfonate, glutamate.

In addition, the source and destination connections, shown in each formula the reaction include compounds in the form of MES (for example, hydrate, ethanolate the like). As the preferred MES you can specify the hydrate. Each target compound obtained in each General formula, can be isolated and purified from the reaction mixture, for example, subjecting the reaction mixture after cooling this allocation process, as filtration, concentration and extraction, to separate a crude reaction product with subsequent conventional cleaning process, such as column chromatography or recrystallization.

The connection represented by the General formula (1), according to the present invention, of course, covers isomers such as geometric isomer, a stereoisomer and the enantiomer.

The compound of General formula (1) and its salt can be obtained in the usual form pharmaceuticals. Pharmaceutical means get using conventional diluents or excipients such as fillers, diluents, binders, moisturizing agents, disintegrating agents, surface-active substances and substances that contribute to the slide. With regard to pharmaceutical drug can be selected in various forms depending on the goals of treatment, and typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories and forms for injection (solution, suspension).

For forming the tablets can be used on lesofat different materials, well known in this area as carriers. As filler can be used, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicates; as bonding agents can be used, for example, water, ethanol, propanol, syrup, glucose liquid, starch, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, as baking powder can be used, for example, dry starch, sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, ester of fatty acid with polyoxyethylenesorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose; as a structure-forming substances can be used, for example, sucrose, stearin, cacao butter, hydrogenated oil; as enhancers of absorption can be used, for example, Quaternary ammonium bases, sodium lauryl sulfate; as moisturizing agents can be used, for example, glycerol, starch; as absorbents can be used, for example, starch, lactose, kaolin, bentonite, colloidal silica; as substances that promote the slip, can be used, for example, purified talc, stearate, borates in the IDA powders, the polyethylene glycol. In addition, if necessary, the tablet can be a tablet with a commonly used coating, such as tablets, sugar coated tablets, encapsulated in gelatin capsules, enteric-soluble tablets, tablets, film-coated, or dual tablets, multilayered tablets.

For forming pills, you can use a variety of materials well known in the field as carriers. As filler can be used, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; as bonding agents can be used, for example, Arabian gum in powder form, tragakant in the form of a powder, gelatin, ethanol; as baking powder can be used, for example, kelp, agar.

For forming the suppository can be used various materials well known in the field as carriers. Their examples include, for example, polyethylene glycol, cacao butter, higher alcohol esters of higher alcohols, gelatin, polysynthetic glycerides.

Capsules are usually obtained in accordance with standard methods by mixing the active ingredient with various media, examples of which are outlined above, and filling hard gelatin capsules, soft gelatin is howling capsules or the like obtained by the mixture.

When receiving a fluid for injection preferably, solution, emulsion and suspension were sterile and isotonic with blood, and for obtaining this form can be used by any usually used in this field diluent, for example water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol, ester of fatty acid with polyoxyethylenesorbitan and the like.

In this case, the pharmaceutical agent may contain standard salt, glucose or glycerin in an amount sufficient to obtain an isotonic solution, and can also be added usually used soljubilizatory, buffers, soothing funds. If necessary, can also be included pigments, preservatives, flavourings, colourings, sweeteners and other pharmaceutical agents.

The amount of compounds of General formula (1) or its salt in the pharmaceutical composition of the present invention is not specifically limited, but is usually from about 1 to 70% by weight of the pharmaceutical composition, preferably from about 1 to 30% by mass.

There are no particular limitations on the method of introduction of the pharmaceutical agents of the present invention, it may be a way appropriate to the specific fo the IU composition, age, sex and other conditions of the patient, the severity of the disease, and the like. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules introduction is oral. In the case of fluid injection introduction is intravenous, the composition is administered as such or in a mixture with conventional such replacement fluids, such as glucose and amino acids, and, if necessary, and the song itself can also be injected intramuscularly, transdermally, subcutaneously or intraperitoneally. In the case of a suppository introduction is rectal.

The applied dose of the pharmaceutical agents according to the present invention is appropriately selected depending on the dosage, age, sex and other conditions of the patient, the severity of the disease, and the like, but is suitable amounts of the active ingredient, typically from about 0.1 to 10 mg per 1 kg of body weight per day. In addition, it is desirable that the active ingredient was obtained in the dosage form within about 1 to 200 mg

The compound of the present invention has partial agonistic activity against receptor D2, antagonistic activity against receptor 5-HT2A and inhibitory activity of serotonin uptake (inhibitory activity of reverse takeover serot is Nina).

Partial agonistic activity against receptor D2suppresses dopaminergic (DA) nanoperiodic if it is reinforced, and stimulates the DA nanoperiodic if it is lowered, and, thus, stabilizes the DA nanoperiodic to a normal state (the stabilizer system of dopamine). This activity achieved excellent clinical results without the side effects of conditions associated with pathological DA neuropterida (enhanced and low), for example improved positive and negative symptoms, better cognitive function, improves the condition of depressive symptom and the like (see Michio Toru: Seishin-Igaku (Psychiatry), Vol. 46, pp. 855-864 (2004), Tetsuro Kikuchi and Tsuyoshi on Hirose: Nou-no-Called (Brain Science), Vol. 25, pp. 579-583 (2003) and Harrison, T. S. and Perry, C.M.: Drugs 64: 1715-1736, 2004).

Antagonistic activity against receptor 5-HT2A reduce extrapyramidal side effects, provides excellent clinical results, for example, improves negative symptoms, improves cognitive function, improves the condition of depression, reduces insomnia (see Jun Ishigooka and Ken Inada: Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), Vol. 4, pp. 1653-1664 (2001), Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), Vol. 1, pp. 5 - 22 (1998), Puller, I.A. et al., Eur. J. Pharmacol., 407:39-46, 2000, Meltzer H. Y. et al, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).

Inhibitory activity of capture serot is Nina (or inhibitory activity of serotonin reuptake) improves, for example, the condition when the symptoms of depression (see Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), Vol. 1, pp. 5 - 22 (1998)).

All three steps of the compounds of the present invention is equally effective, or one or two of these three actions prevail.

In addition, some compounds of the present invention, in addition to the above effects, have antagonistic activity against receptor α1. Antagonistic activity against receptor α1effective for improvement of positive symptoms in schizophrenia (see Svensson T.H.: Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).

Therefore, the compounds of the present invention have a wide range of activities and excellent clinical effect in schizophrenia and other disorders of the Central nervous system.

Therefore, the compounds of the present invention is extremely effective in the treatment or prevention of disorders of the Central nervous system, including the group consisting of schizophrenia; refractory, resistant to therapeutic intervention or chronic schizophrenia; emotional disorders; mental disorders; mood disorders; bipolar disorders (such as bipolar disorder type I or bipolar disorder type II); depression; endogenous depression; great depres the AI; melancholy and refractory depression; estimatesare disorder; cyclothymic disorder (e.g. panic attacks, panic disorder, agoraphobia, sociophobia, obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, acute stress disorder, and the like); somatoform disorders (e.g., hysteria, somatic disorders psychogenic nature, conversing disorders, pain disorders, hypochondriacal syndrome and the like); simulation disorders; dissociated disorders; sexual disorders (e.g., sexual dysfunction, disorders of sexual desire disorders, sexual arousal, erectile dysfunction, and the like); disorders of food behavior (e.g., anorexia nervosa, bulimia nervosa, and the like); sleep disorders; adjustment disorders; mental disorders associated with substance use (e.g., alcoholism, alcohol intoxication, abuse of drugs, intoxication with stimulants, drugs and the like); anhedonia (e.g., iatrogenic anhedonia, anhedonia as a result of mental or mental reasons, anhedonia associated with depression, anhedonia, CBE is Anna with schizophrenia and the like); delirium; cognitive disorders; cognitive disorders associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive disorders caused by Alzheimer's disease, Parkinson's disease and related neurodegenerative disease; cognitive disorders in schizophrenia; cognitive disorders caused refractory, resistant to therapeutic intervention or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; disease Tourette's; teak disorders; attention deficit disorder/hyperactivity disorder; conduct disorder; and down's syndrome.

In addition, the compounds of the present invention have no or a small number of side effects, well tolerated and have a high safety index.

EXAMPLES

The present invention will be better understood in connection with reference to reference examples, examples, pharmacological experimental examples and examples, get, below.

Reference example 1

Obtain 7-(4-chloroethoxy)-1H-quinoline-2-it

After addition of 14.7 g of potassium hydroxide to a suspension of 30 g of 7-hydroxy-1H-quinoline-2-she in methanol (250 ml) and stirring at 50°C to obtain the solution, we use the and 65 ml of 1-bromo-4-chlorobutane and boiled under reflux for 8 hours. After cooling to room temperature, precipitated crystals were separated by filtration. Their was purified by chromatography on a column of silica gel (dichloromethane:methanol = 100:3) and got to 29.6 g of 7-(4-chloroethoxy)-1H-quinoline-2-it is in the form of white powder.

1H-NMR (CDCl3) δ ppm:

1,95-2,15 (4H, m), 3,60-3,70 (2H, m), 4,10 (2H, t, J=5.6 Hz), 6,56 (1H, DD, J=9,0 Hz, 3.8 Hz), for 6.81 (1H, DD, J=8.7 Hz, 2.4 Hz), 6,85 (1H, d, J=2.3 Hz), was 7.45 (1H, d, J=8.7 Hz), of 7.75 (1H, d, J=9.4 Hz), 12,54 (1H, users).

Reference example 2

Obtain 7-(4-chloroethoxy)-4-methyl-1H-quinoline-2-it

7-(4-chloroethoxy)-4-methyl-1H-quinoline-2-it was obtained from 7-hydroxy-4-methyl-1H-quinoline-2-it in a manner analogous to the method described in reference example 1.

The white powder.

1H-NMR (DMSO-d6) δ ppm:

1,80-2,00 (4H, m), is 2.37 (3H, s), and 3.72 (2H, t, J=6.0 Hz), of 4.05 (2H, t, J=6.0 Hz), of 6.20 (1H, s), 6.75 in-6,90 (2H, m), 7,60 (1H, d, J=8.5 Hz), 11,42 (1H, users).

Reference example 3

Obtain 7-methoxy-3-methyl-1H - quinoline-2-it

To stir while cooling on ice to a solution of 13 g of 7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde in triperoxonane acid (300 ml) was added a 30.7 ml of triethylsilane and stirred at room temperature overnight. The reaction solution was poured into ice water and was extracted with dichloromethane and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Remainder the eyes of the Ali chromatography on a column of silica gel (dichloromethane:methanol = 30:1), and obtained 11.1 g of 7-methoxy-3-methyl-1H-quinoline-2-it is in the form of white powder.

1H-NMR (DMSO-d6) δ ppm:

2,02 (3H, s), of 3.77 (3H, s)6,70-to 6.80 (2H, m), 7,45 (1H, d, J=8,4 Hz), to 7.64 (1H, s), to 11.56 (1H, users).

Reference example 4

Obtain 7-hydroxy-3-methyl-1H-quinoline-2-it

Suspension 2,12 g of 7-methoxy-3-methyl-1H-quinoline-2-it in 47% Hydrobromic acid (60 ml) was boiled under reflux for six hours. After cooling, to the reaction solution was added water, and the precipitated crystals were separated by filtration. The crystals were dissolved in a solvent mixture of dichloromethane and methanol and was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure and obtained 1.7 g of 7-hydroxy-3-methyl-1H-quinoline-2-it is in the form of a brown powder.

1H-NMR (DMSO-d6) δ ppm:

to 1.99 (3H, s), to 6.57 (1H, DD, J=8,5 Hz, 2.5 Hz), of 6.65 (1H, d, J=2.5 Hz), 7,34 (1H, d, J=8.5 Hz), 7,58 (1H, s), for 9.90 (1H, s), of $ 11.48 (1H, users).

Reference example 5

Obtain 7-(3-chloropropoxy)-3-methyl-1H-quinoline-2-it

In a manner analogous to the method of reference example 1, from 7-hydroxy-3-methyl-1H-quinoline-2-she's got 7-(3-chloropropoxy)-3-methyl-1H-quinoline-2-it is in the form of a white powder using 1-bromo-3-chloropropane.

1H-NMR (DMSO-d6) δ ppm:

is 2.05 (3H, s), 2,15 was 2.25 (2H, m), 3,81 (2H, t, J=6.5 Hz), 4,11 (2H, t, J=6.0 Hz), 6.75 in-6,85 (2H, m), of 7.48 (1H, d, J=8.5 Hz), to 7.67 (1H, s), 11,59 (1H, users).

Reference example 6

Obtain 7-(4-chloroethoxy)-3-methyl-1H-quinoline-2-it

In a manner analogous to the method of reference example 1, from 7-hydroxy-3-methyl-1H-quinoline-2-she's got 7-(4-chloroethoxy)-3-methyl-1H-quinoline-2-it is in the form of a white powder using 1-bromo-4-chlorobutane.

1H-NMR (DMSO-d6) δ ppm:

1,80-of 1.95 (4H, m), 2,04 (3H, s), and 3.72 (2H, t, J=6.0 Hz), a 4.03 (2H, t, J=6.0 Hz), 6.75 in-to 6.80 (2H, m), 7,47 (1H, d, J=8.5 Hz), 7,66 (1H, s), 11,58 (1H, users).

Reference example 7

Obtaining 1-(4-chlorobutyl)-1H-quinoline-2-it

To stir while cooling on ice to a solution of dimethylformamide (20 ml) of 1.0 g of 1H-quinoline-2-it was added to 0.30 g of sodium hydride (60% in oil) and stirred at room temperature for 0.5 hours, after which was added to 1.6 ml of 1-bromo-4-chlorobutane and stirred at room temperature for 14 hours. To the reaction solution was added water, then was extracted with ethyl acetate and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate = 3:1), and received of 1.02 g of 1-(4-chlorobutyl)-1H-quinoline-2-it is in the form of a colorless oil.

1H-NMR (CDCl3) δ ppm:

1,85 is 2.00 (4H, m), 3,60-the 3.65 (2H, m), 4,35 (2H, t, J=7.0 Hz), 6,70 (1H, d, J=9.5 Hz), 7.23 percent (1H, DD, J=8.6 Hz, 7.5 Hz), 7,38 (1H, d, J=8,9 Hz), 7,54 to 7.62 (2H, m), 7,68 (1H, d, J=9.5 Hz).

Reference example 8

Obtaining 1-(5-chloropentyl)-1H-hee is Olin-2-it

In a manner analogous to the method of reference example 7, from 1H-quinoline-2-she's got 1-(5-chloropentyl)-1H-quinoline-2-it is in the form of a colorless oil, using 1-bromo-5-chloropentane.

1H-NMR (CDCl3) δ ppm:

1,55-1,70 (2H, m), 1,75-of 1.95 (4H, m), of 3.56 (2H, t, J=6.6 Hz), or 4.31 (2H, t, J=7.8 Hz), 6,70 (1H, d, J=9.5 Hz), 7.23 percent (1H, DD, J=7,3 Hz and 7.3 Hz), 7,35 (1H, d, J=8,9 Hz), 7,54-of 7.60 (2H, m), to 7.67 (1H, d, J=9.4 Hz).

Reference example 9

Obtain 7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinoline-2-it

A mixture of 1.0 g of 7-hydroxy-3,4-dihydro-1H-quinoline-2-it, 1.7 g of potassium carbonate, 3.2 ml CIS-1,4-dichloro-2-butene and 50 ml of dimethylformamide was stirred at room temperature overnight. To the reaction solution was added water, then was extracted with ethyl acetate and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate = 3:1), and obtained 7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinoline-2-he (1.3 g) as white powder.

1H-NMR (CDCl3) δ ppm:

2,62 (2H, t, J=6.3 Hz), 2,90 (2H, t, J=6.3 Hz), 4,16 (2H, d, J=6.3 Hz), to 4.62 (2H, d, J=4.6 Hz), 5,86-5,90 (2H, m), of 6.31 (1H, d, J=2.5 Hz), is 6.54 (1H, DD, J=8,3 Hz, 2.5 Hz), 7,06 (1H, d, J=8,3 Hz), 7,56 (1H, users).

Reference example 10

Obtain methyl ester of 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyric acid

To a solution of 5 g of ester 4-chloro-2-matelasse the th acid in acetonitrile (70 ml) was added to 4.98 g of sodium iodide and heated under reflux for 3 hours. To the reaction solution was added water, then was extracted with dichloromethane and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was added to the mixture to 4.33 g of 7-hydroxy-3,4-dihydro-1H-quinoline-2-it, 6.0 g of potassium carbonate and dimethylformamide (90 ml) and stirred at 80°C for 6 hours. To the reaction solution was added water, then was extracted with ethyl acetate and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol = 100:3), and was obtained 6.0 g of methyl ester of 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyric acid in the form of a yellow oil.

1H-NMR (CDCl3) δ ppm:

of 1.23 (3H, d, J=7,1 Hz), 1,75-1,90 (1H, m), 2,10-of 2.25 (1H, m), 2,55-to 2.65 (2H, m), of 2.72 (1H, square, J=7,0 Hz), 2,80-2,90 (2H, m), 3,68 (3H, s), of 3.95 (2H, t, J=6.2 Hz), 6,33 (1H, d, J=2.3 Hz), of 6.49 (1H, DD, J=8,3 Hz, of 2.21 Hz), 7,02 (1H, d, J=8,3 Hz), to 8.41 (1H, users).

Reference example 11

Obtain 7-(4-hydroxy-3-methylbutoxy)-3,4-dihydro-1H-quinoline-2-it

To stir while cooling on ice, the suspension of 1.6 g of lithium aluminum hydride in tetrahydrofuran (200 ml) was added dropwise 6 g of methyl ester of 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyric acid and stirred at the same temperature for 2 hours. Stirring while cooling the ice, was added a saturated salt solution of Rochelle, was extracted with diethyl ether and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol = 40:1) and was obtained 2.8 g of 7-(4-hydroxy-3-methylbutoxy)-3,4-dihydro-1H-quinoline-2-it is in the form of a yellow oil.

1H-NMR (CDCl3) δ ppm:

0,99 (3H, d, J=6.5 Hz), 1.60-to was 2.05 (3H, m), 2,60-to 2.65 (2H, m), 2,85-2,95 (2H, m), 3,55 (2H, t, J=5.3 Hz), 3.95 to-4,10 (2H, m), 6,38 (1H, d, J=2.5 Hz), 6,53 (1H, DD, J=8,3 Hz, 2.4 Hz),? 7.04 baby mortality (1H, d, J=8,3 Hz), 8,59 (1H, users).

Reference example 12

Obtaining 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ether methanesulfonate acid

To stir while cooling on ice to a solution of 2.8 g of 7-(4-hydroxy-3-methylbutoxy)-3,4-dihydro-1H-quinoline-2-it, and 2.4 ml of triethylamine in dichloromethane (80 ml) was added methanesulfonamide (1.0 ml) and stirred at room temperature overnight. To the reaction solution was added water, then was extracted with dichloromethane and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol = 30:1), and obtained 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ether methanesulfonate acid (2.8 g) in powder form Seele is wow color.

1H-NMR (CDCl3) δ ppm:

of 1.07 (3H, d, J=6.8 Hz), 1,60-1,80 (1H, m), 1,90-2,00 (1H, m), 2,15 was 2.25 (1H, m), 2,50-to 2.65 (2H, m), 2,90 (2H, t, J=7,3 Hz), 3.95 to-4,10 (2H, m), 4,10-4,20 (2H, m), 6,33 (1H, d, J=2.5 Hz), 6,51 (1H, DD, J=8,3 Hz and 2.5 Hz), 7,05 (1H, d, J=8,3 Hz), 8,16 (1H, users).

Reference example 13

Obtain 7-(4-bromo-(E)-2-butenyloxy)-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method of reference example 9, from 7-hydroxy-3,4-dihydro-1H-quinoline-2-she's got 7-(4-bromo-(E)-2-butenyloxy)-3,4-dihydro-1H-quinoline-2-it is in the form of a white powder using TRANS-1,4-dibromo-2-butene.

1H-NMR (CDCl3) δ ppm:

2,61 (2H, t, J=7.5 Hz), 2,89 (2H, t, J=7.5 Hz), 3,98 (2H, d, J=7,0 Hz), 4,51 (2H, d, J=4,8 Hz), 5,90-6,10 (2H, m), to 6.43 (1H, d, J=2.1 Hz), 6,51 (1H, DD, J=8,2 Hz, 2.1 Hz), 7,03 (1H, d, J=8,2 Hz), 9,35 (1H, users).

Reference example 14

Obtain 7-(4-chloroethoxy)-4-methyl-3,4-dihydro-1H-quinoline-2-it

To stir while cooling on ice to a solution of 0.54 g of 7-methoxy-4-methyl-3,4-dihydro-1H-quinoline-2-it is in dichloromethane (5 ml) was added tribromide boron (1M dichloromethane solution of 6.2 ml) and was separated by filtration to 0.23 g of precipitated crude crystals. To a solution of crude crystals in acetonitrile (2.5 ml) and water (2.5 ml) was added 0.2 g of potassium carbonate and 0.45 ml of 1-bromo-4-chlorobutane and boiled under reflux for 6 hours. To the reaction solution was added water, then was extracted with ethyl acetate and, after washing with water, dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol = 50:1), and obtained 7-(4-chloroethoxy)-4-methyl-3,4-dihydro-1H-quinoline-2-he (to 0.29 g) as white powder.

1H-NMR (DMSO-d6) δ ppm:

of 1.28 (3H, d, J=7.0 Hz), 1.85 to was 2.05 (4H, m), 2,35 at 2.45 (1H, m), 2,65 is 2.75 (1H, m), 3.00 and is 3.15 (1H, m), 3,62 (2H, t, J=6.0 Hz), of 3.97 (2H, t, J=6.0 Hz), 6,32 (1H, d, J=2.5 Hz), 6,55 (1H, DD, J=8,5 Hz, 2.5 Hz), 7,08 (1H, d, J=8.5 Hz), of 7.96 (1H, users).

Reference example 15

Obtain 7-[2-(2-chloroethoxy)ethoxy]-3,4-dihydro-1H-quinoline-2-it

A mixture of 7.0 g of 7-hydroxy-3,4-dihydro-1H-quinoline-2-it, and 7.1 g of potassium carbonate, 30 ml of bis-2-hloretilova ether and 400 ml of acetonitrile was heated under reflux for 2 days. To the reaction solution was added water, then was extracted with dichloromethane and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol = 40:1), and received of 8.3 g of 7-[2-(2-chloroethoxy)ethoxy]-3,4-dihydro-1H-quinoline-2-it is in the form of white powder.

1H-NMR (CDCl3) δ ppm:

2,61 (2H, t, J=7.4 Hz), 2,90 (2H, t, J=7.4 Hz), 3,66 (2H, t, J=5.8 Hz), 3,74-3,88 (4H, m), 4,11 (2H, t, J=4,7 Hz), 6,36 (1H, d, J=2.2 Hz), is 6.54 (1H, DD, J=8,3 Hz, 2.2 Hz), 7,05 (1H, d, J=8,3 Hz), 8,01 (1H, m).

Reference example 16

Getting 6-(3-chloropropoxy)-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method of reference example 9, from 6 to guide the hydroxy-3,4-dihydro-1H-quinoline-2-it, using 1-bromo-3-chloropropane received 6-(3-chloropropoxy)-3,4-dihydro-1H-quinoline-2-it is in the form of white powder.

1H-NMR (CDCl3) δ ppm:

of 2.15 to 2.35 (2H, m), 2,55-to 2.65 (2H, m), 2,90-of 3.00 (2H, m), 3,50-of 3.80 (2H, m), 4,00-4,10 (2H, m), 6.73 x (3H, users), 8,68 (1H, users).

Reference example 17

Getting 6-(4-bromobutoxy)-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method of reference example 9, from 6-hydroxy-3,4-dihydro-1H-quinoline-2-it, using 1,4-dibromobutane received 6-(4-bromobutoxy)-3,4-dihydro-1H-quinoline-2-it is in the form of white powder.

1H-NMR (DMSO-d6) δ ppm:

a 1.75-of 1.85 (2H, m), 1,90-2,00 (2H, m), 2,30 at 2.45 (2H, m), of 2,75 2,85 (2H, m)to 3.58 (2H, t, J=6.5 Hz), 3,91 (2H, t, J=6.5 Hz), 6,70-to 6.80 (3H, m), 9,88 (1H, users).

Reference example 18

Obtaining 1-(5-chloropentyl)-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method of reference example 7, from 3,4-dihydro-1H-quinoline-2-it, using 1-bromo-5-chloropentane, was obtained 1-(5-chloropentyl)-3,4-dihydro-1H-quinoline-2-it is in the form of a colorless oil.

1H-NMR (CDCl3) δ ppm:

1,45-to 1.60 (2H, m), 1,60-1,75 (2H, m), 1,75-1,90 (2H, m), 2,60-2,70 (2H, m), 2,85-2,95 (2H, m), of 3.54 (2H, d, J=6.6 Hz)and 3.59 (2H, d, J=7,7 Hz), 6,76? 7.04 baby mortality (2H, m), 7,15-7,29 (2H, m).

Reference example 19

Getting 2-(5-chloropentyl)-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 7, from 3,4-dihydro-2H-isoquinoline-1-it, using 1-bromo-5-chloropentane, received 2-(5-chloropentyl)-3,4-dihydro-H-isoquinoline-1-it is in the form of a brown oil.

1H-NMR (CDCl3) δ ppm:

1,50-2,00 (6H, m)to 2.99 (2H, t, J=6.6 Hz), 3,52-of 3.60 (6H, m), 7,17 (1H, d, J=7,3 Hz), 7,31-7,44 (2H, m), 8,07 (1H, DD, J=1.3 Hz, 7.5 Hz).

Reference example 20

Obtain 7-(3-chloropropoxy)-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 9, from 7-hydroxy-3,4-dihydro-2H-isoquinoline-1-it, using 1-bromo-3-chloropropane received 7-(3-chloropropoxy)-3,4-dihydro-2H-isoquinoline-1-it is in the form of a brown oil.

1H-NMR (CDCl3) δ ppm:

2,20-2,40 (2H, m), 2,90-of 3.00 (2H, m), 3,50-of 3.80 (4H, m), 4,15-4,20 (4H, m), 6.48 in (1H, users), 7,01 (1H, DD, J=4.0 Hz, 1.5 Hz), 7,13 (1H, d, J=4.0 Hz), to 7.59 (1H, d, J=1.4 Hz).

Reference example 21

Obtain 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 4, from 7-methoxy-2-methyl-3,4-dihydro-2H-isoquinoline-1-she's got 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of a brown powder.

1H-NMR (DMSO-ds) δ ppm:

2,84 (2H, t, J=6.5 Hz), 3,01 (3H, s), 3,47 (2H, t, J=6.6 Hz), 6,85 (1H, DD, J=8,1 Hz, 2.5 Hz), was 7.08 (1H, d, J=8.1 Hz), 7,29 (1H, d, J=2.5 Hz), 9,49 (1H, s).

Reference example 22

Obtain 7-(4-chloroethoxy)-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 9, from 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinoline-1-it, using 1-bromo-4-chlorobutane received 7-(4-chloroethoxy)-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of a brown oil color is the same.

1H-NMR (CDCl3) δ ppm:

1,90-2,00 (4H, m), with 2.93 (2H, t, J=6,8 Hz)and 3.15 (3H, s), 3.45 points-of 3.65 (4H, m), Android 4.04 (2H, t, J=5.8 Hz), to 6.95 (1H, DD, J=8,3 Hz, 2.5 Hz), 7,07 (1H, d, J=8,3 Hz), to 7.59 (1H, d, J=2.5 Hz).

Reference example 23

Obtain 7-(4-chloroethoxy)-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 9, from 7-hydroxy-3,4-dihydro-2H-isoquinoline-1-it, using 1-bromo-4-chlorobutane received 7-(4-chloroethoxy)-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

1H-NMR (CDCl3) δ ppm:

1,93 is 2.00 (4H, m), 2,88-2,96 (2H, m), 3,51-to 3.58 (2H, m), 3,62 (2H, t, J=6.2 Hz), of 4.05 (2H, t, J=5.7 Hz), and 6.25 (1H, s), 7,00 (1H, DD, J=8,3 Hz, 2.7 Hz), 7,13 (1H, d, J=8,3 Hz), EUR 7.57 (1H, d, J=2.7 Hz).

Reference example 24

Obtaining 2-(4-chlorobutyl)-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 7, from 2H-isoquinoline-1-it, using 1-bromo-4-chlorobutane, received 2-(4-chlorobutyl)-2H-isoquinoline-1-it is in the form of a yellow oil.

1H-NMR (CDCl3) δ ppm:

1,80-2,00 (4H, m)and 3.59 (2H, t, J=6.3 Hz), of 4.05 (2H, t, J=7.0 Hz), 6,51 (1H, d, J=7,4 Hz), 7,05 (1H, d, J=7,4 Hz), 7,46-7,52 (2H, m), 7,63 (1H, m), 8,42 (1H, d, J=8,1 Hz).

Reference example 25

Obtain 7-(3-chloropropoxy)-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 9, from 7-hydroxy-2H-isoquinoline-1-it, using 1-bromo-3-chloropropane received 7-(3-chloropropoxy)-2H-isoquinoline-1-it is in the form of white powder.

1H-NMR (CDCl3) δ ppm:

2,30 (2, Quint., J=6,1 Hz), of 3.78 (2H, t, J=6.4 Hz), 4,28 (2H, t, J=5,9 Hz), is 6.54 (1H, d, J=7,1 Hz), 7,06 (1H, d, J=6.6 Hz), 7,29 (1H, DD, J=8.7 Hz, 2.7 Hz), 7,51 (1H, d, J=8.7 Hz), 7,82 (1H, d, J=2.7 Hz), at 10.64 (1H, s).

Reference example 26

Obtain 7-(3-chloropropoxy)-2-ethyl-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 7, from 7-(3-chloropropoxy)-2H-isoquinoline-1-using her ethyliodide received 7-(3-chloropropoxy)-2-ethyl-2H-isoquinoline-1-it is in the form of a colorless oil.

1H-NMR (CDCl3) δ ppm:

to 1.38 (3H, t, J=7.2 Hz), to 2.29 (2H, Quint., J=6,1 Hz), 3,76 (2H, t, J=6.4 Hz), 4,07 (2H, square, J=7,2 Hz), 4,25 (2H, d, J=5.8 Hz), 6.48 in (1H, d, J=7,3 Hz), 6,98 (1H, d, J=7,3 Hz), 7.23 percent (1H, DD, J=8.7 Hz, 2.7 Hz), 7,44 (1H, d, J=8.7 Hz), the 7.85 (1H, d, J=2,6 Hz).

Reference example 27

Obtaining 2-(4-chlorobutyl)-7-methoxy-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 7, from 7-methoxy-2H-isoquinoline-1-it, using 1-bromo-4-chlorobutane, received 2-(4-chlorobutyl)-7-methoxy-2H-isoquinoline-1-it is in the form of a colorless oil.

1H-NMR (CDCl3) δ ppm:

1,64 is 2.00 (4H, m)and 3.59 (2H, t, J=6.3 Hz), 3,93 (3H, s)4,06 (2H, t, J=6.9 Hz), of 6.49 (1H, d, J=7,3 Hz), of 6.96 (1H, d, J=7,3 Hz), 7,25 (1H, DD, J=8.6 Hz, 2.7 Hz), was 7.45 (1H, d, J=8.7 Hz), 7,83 (1H, d, J=2,7 Hz).

Reference example 28

Getting 6-(3-chloropropoxy)-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 9, from 6-hydroxy-2H-isoquinoline-1-it, using 1-bromo-3-chloropropane received 6-(3-chloropropoxy)-2H-isoquinoline-1-it is in the form of powder is as light yellow color.

1H-NMR (CDCl3) δ ppm:

of 2.30 (2H, Quint., J=6.0 Hz), of 3.78 (2H, t, J=6.2 Hz), 4,24 (2H, t, J=5,9 Hz), 6,46 (1H, d, J=7,2 Hz), 6,93 (1H, d, J=2.4 Hz), 7,05 for 7.12 (2H, m), with 8.33 (1H, d, J=8,9 Hz), 10,33 (1H, s).

Reference example 29

Obtain 7-(3-chloropropoxy)-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method of reference example 9, from 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinoline-1-it, using 1-bromo-3-chloropropane received 7-(3-chloropropoxy)-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of a brown powder.

1H-NMR (CDCl3) δ ppm:

of 2.15 to 2.35 (2H, m), 2,85-of 3.00 (2H, m)and 3.15 (3H, s), 3,50-of 3.80 (4H, m), 4,10-4,20 (2H, m), of 6.96 (1H, DD, J=8,3 Hz, 2.7 Hz), was 7.08 (1H, d, J=8,3 Hz), a 7.62 (1H, d, J=2.7 Hz).

Reference example 30

Getting 1-benzo[b]thiophene-4-yl-piperazine hydrochloride

A mixture of 14.4 g of 4-bromobenzo[b]thiophene, to 29.8 g of piperazine anhydride, 9.3 g of tert-butoxide sodium, 0.65 g of (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 0,63 g of Tris(dibenzylideneacetone)diplodia and 250 ml of toluene was boiled under reflux for 1 hour in nitrogen atmosphere. In the reaction solution was poured water, then was extracted with ethyl acetate and, after washing with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol: 25%aqueous ammonia = 100:10:1) and obtained 9.5 g of 1-benzo[b]thiophene-4-yl-piperazine is the form of a yellow oil.

To a solution of 1-benzo[b]thiophene-4-yl-piperazine 9.5 g in methanol was added to 3.7 ml of concentrated hydrochloric acid, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and precipitated crystals were filtered, recrystallized from methanol and obtained the hydrochloride of 1-benzo[b]thiophene-4-reperusing in the form of colorless needle-like crystals form.

The melting point 276-280°C

1H-NMR (DMSO-ds) δ ppm:

of 3.25 to 3.35 (8H, m)6,94 (1H, d, J=7,6 Hz), 7,30 (1H, DD, J=7.8 Hz, 7.8 Hz), 7,51 (1H, d, J=5.5 Hz), to 7.68 (1H, d, J=8.1 Hz), 7,73 (1H, d, J=5.5 Hz), 9,35 (2H, users).

Reference example 31

Obtain tert-butyl 4-benzo[b]thiophene-4-yl-3-methylpiperazin-1-carboxylate

In a manner analogous to the method described in reference example 30, from tert-butyl 3-methylpiperazine-1-carboxylate and 4-bromobenzo[b]thiophene was obtained tert-butyl 4-benzo[b]thiophene-4-yl-3-methylpiperazin-1-carboxylate.

1H-NMR (CDCl3) δ ppm:

1,85-of 1.95 (3H, m)of 1.50 (9H, s), 2,8-2,9 (1H, m), 3,15-to 3.35 (2H, m), 3,4-3,5 (1H, m), 3,5-of 3.65 (1H, m), the 3.65 to 3.7 (1H, m), of 3.7-3.9 (1H, m), 6,98 (1H, d, J=7.5 Hz), 7,29 (1H, DD, J=8,8 Hz), 7,38 (1H, d, J=5.5 Hz), to 7.61 (1H, d, J=8 Hz).

Reference example 32

Getting dihydrochloride of 1-benzo[b]thiophene-4-yl-2-methylpiperazine

To triperoxonane acid (6 ml) was added a solution of 1.22 g (3.7 mmol) of tert-butyl 4-benzo[b]thiophene-4-yl-3-methylpiperazin-1-carboxylate in methylene chloride (12 ml)and the mixture was stirred at to matnog temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, then the residue was added an aqueous solution of 5% potassium carbonate, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. To the residue was added concentrated hydrochloric acid (6 ml) and methanol (10 ml)and the resulting mixture was concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain the dihydrochloride of 1-benzo[b]thiophene-4-yl-2-methylpiperazine (0,98 g) in the form of powder light brown.

1H-NMR (DMSO-d6) δ ppm:

to 0.92 (3H, d, J =6.5 Hz), 2,8-3,6 (6H, m), 3.6 and 4.0 (1H, m), 5,3-6,8 (1H, m), 7,20 (1H, usher.), 7,38 (1H, DD, J=8,8 Hz), 7,5-8,0 (3H, m), and 9.4 to 10.1 (2H, m).

Reference example 33

Getting dihydrochloride of 1-benzo[b]thiophene-4-yl-3-methylpiperazine

2-methylpiperazine and 4 bromobenzo[b]thiophene in a manner analogous to the method described in reference example 30, received the dihydrochloride of 1-benzo[b]thiophene-4-yl-3-methylpiperazine.

1H-NMR (DMSO-d6) δ ppm:

of 1.34 (3H, d, J=6.5 Hz), 2,85-2,95 (1H, m), 3,05 is 3.15 (1H, m), 3,2-3,6 (6H, m), 6,97 (1H, d, J=7.5 Hz), 7,31 (1H, DD, J=8,8 Hz), 7,54 (1H, d, J=5.5 Hz), 7,69 (1H, d, J=8 Hz), of 7.75 (1H, d, J=5.5 Hz), 9,2 and 9.3 (1H, m), for 9.64 (1H, usher.).

Reference example 34

Obtain ethyl 3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propionate

To aqueous sodium hydroxide solution was added of 5.05 g (19,8 mm is l) of the hydrochloride of 1-benzo[b]thiophene-4-yl-piperazine, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethanol was added acrylate (2,44 ml, and 21.8 mmol), then the reaction mixture is boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue was added isopropyl ether to filter insoluble substances. Insoluble matter was washed with isopropyl ether and dried to obtain ethyl 3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propionate (5,26 g) as white powder.

Reference example 35

Obtaining 3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propan-1-ol

To a solution of 5.26 g (16.5 mmol) of ethyl 3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propionate in tetrahydrofuran (55 ml) was added alumoweld lithium (1.18 g, 24,8 mmol) under cooling in an ice bath, then stirred at room temperature for 4 hours. Water (1.2 ml), 15%aqueous sodium hydroxide solution (1.2 ml) and water (3.6 ml) was added, in this order, to the reaction mixture under stirring at room temperature. Insoluble substances were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate = 3:2 is ethyl acetate), then concentrated and dried under reduced pressure to obtain 3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propan-1-ol (0,23 g) as white powder.

1H-NMR (CDCl3) δ ppm:

a 1.75-of 1.85 (2H,m)to 2.74 (2H, t, J=5.8 Hz), of 2,75 2,85 (4H, m), 3.15 and is 3.25 (4H, m), 3,85 (2H, t, J=5.3 Hz), 5,19 (1H, users), to 6.88 (1H, d, J=7,6 Hz), 7,27 (1H, DD, J=7,9, and 7.8 Hz), 7,39 (2H, s), 7,56 (1H, d, J=8.0 Hz).

Reference example 36

Getting 4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl acetate

In 20 ml of dimethylformamide (DMF) suspended 1.0 g (3.9 mmol) of the hydrochloride of 1-benzo[b]thiophene-4-reperusing was added potassium carbonate (1.3 g, 9.4 mmol) and 4-bromobutyrate (0.7 ml, 4.8 mmol), then stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, then added water and the resulting mixture was extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (methylene chloride:methanol = 30:1), then concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl acetate (0,72 g) as a pale yellow oil.

Reference example 37

Getting 4-(4-benzo[b]thiophene-4-reparation-1-yl)butane-1-ol

Potassium carbonate (a 3.87 g, 28 mmol) was added to a solution 7,76 g (23,3 mmol) of butyl 4-(4-benzo[b]thiophene-4-yl-piperazine-yl)acetate in 90% methanol (150 ml), then was stirred at room temperature for 2 hours. Added water and the reaction mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (n-hexane: ethyl acetate= 2:1 → 1:1), then was concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butane-1-ol (6,65 g) as a colourless oil.

Reference example 38

Getting 1-benzo[b]thiophene-4-yl-4-(3-chloropropyl)piperazine

In 30 ml of methylene chloride suspended of 3.56 g (12.9 mmol) of 3-(4-benzo[b]thiophene-4-reparation-1-yl)propan-1-ol was added carbon tetrachloride (30 ml) and triphenylphosphine (4,06 g of 15.5 mmol), then stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature, then, to make a homogeneous mixture was added methanol and methylene chloride. To the homogeneous solution was added silica gel (30 g), and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (silica gel: 300 g, n-hexane:ethyl acetate = 2:1), then concentrated under reduced pressure to obtain 1-benzo[b]thiophene-4-yl-4-(3-chloropropyl)piperazine (2,36 g) as a colourless oil.

1H-NMR (CDCl3) δ ppm:

1,95 is 2.10 (2H, m), 2,60 2H, t, J=7.2 Hz), 2,65 is 2.75 (4H, m), 3.15 and is 3.25 (4H, m), the 3.65 (2H, t, J=6.6 Hz), 6.89 in (1H, DD, J=I,6, and 0.7 Hz), 7,27 (1H, DD, J=7,9, and 7.8 Hz), 7,38 (1H, d, J=5.6 Hz), 7,41 (1H, d, J=5.7 Hz), 7,55 (1H, d, J=8,0 Hz).

Example 1

Obtaining 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it

A mixture of 9.0 g of 7-(4-chloroethoxy)-1H-quinoline-2-it, 10 g of the hydrochloride of 1-benzo[b]thiophene-4-yl-piperazine, 14 g of potassium carbonate, 6 g of sodium iodide and 90 ml of dimethylformamide was stirred for 2 hours at 80°C. To the reaction solution were added water and the precipitated crystals were separated by filtration. The crystals were dissolved in a mixed solvent consisting of dichloromethane and methanol, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol = 100:3). Recrystallized from ethanol, got to 13.6 g of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it is in the form of white powder.

The melting point 183,5-184,5°C

1H-NMR (DMSO-d6) δ ppm:

1,6-of 1.75 (2H, m), 1,75-1,9 (2H, m)2,44 (2H, t, J=7 Hz), of 2.5-2.8 (4H, m), 2,9-3,2 (4H, m)4,06 (2H, t, J=6.5 Hz), 6,30 (1H, d, J=9.5 Hz), 6.75 in-6,85 (2H, m), to 6.88 (1H, d, J=7.5 Hz), 7,27 (1H, DD, J=8 Hz, 8 Hz), 7,40 (1H, d, J=5.5 Hz), 7,55 (1H, d, J=9.5 Hz), to 7.61 (1H, d, J=8 Hz), 7,69 (1H, d, J=5.5 Hz), 7,80 (1H, d, J=9.5 Hz), 11,59 (1H, users).

Example 2

Obtain 3-[2-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)ethoxy]-1H-quinoline-2-it

In a manner analogous to the method described in p is the iMER 1, from 3-(2-bromoethoxy)-1H-quinoline-2-she's got 3-[2-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)ethoxy]-1H-quinoline-2-it.

The white powder (chloroform)

The melting point reach 201.9-204,5°C

1H-NMR (CDCl3) δ ppm:

2,90-2,95 (4H, m), 3,10 (2H, t, J=5,9 Hz), 3,23-of 3.27 (4H, m), 4,30 (2H, t, J=5,9 Hz), make 6.90 (1H, d, J=7,7 Hz), was 7.08 (1H, s), 7,15-to 7.32 (2H, m), 7,37-7,41 (4H, m), 7,47-7,49 (1H, m), 7,55 (1H, d, J=8.1 Hz), 11,33 (1H, users).

Example 3

Obtain 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-4-methyl-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(3-chloropropoxy)-4-methyl-1H-quinoline-2-she's got 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-4-methyl-1H-quinoline-2-it.

Powder, light brown (ethyl acetate)

The melting point 202-208°C

1H-NMR (DMSO-d6) δ ppm:

1,95-2,0 (2H, m), is 2.37 (3H, s)to 2.55 (2H, t, J=7 Hz), 2,6-2,7 (4H, m), 3,05 is 3.2 (4H, m), 4.09 to (2H, t, J=6.5 Hz), 6,21 (1H, users), 6,8-6,85 (2H, m), 6.90 to (1H, d, J=7.5 Hz), 7,28 (1H, DD, J=8 Hz, 8 Hz), 7,41 (1H, d, J=5.5 Hz), and 7.6 to 7.7 (2H, m), of 7.69 (1H, d, J=5.5 Hz), 11,41 (1H, users).

Example 4

Obtaining 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-4-methyl-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(4-chloroethoxy)-4-methyl-1H-quinoline-2-she's got 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-4-methyl-1H-quinoline-2-it.

The white powder (ethyl acetate)

The melting point 164-168°C

1H-NMR (DMSO-d6) δ ppm:

1,6-1,7 (2H, m), 1,75-of 1.85 (2H, m), 2,37 (3, C)of 2.44 (2H, t, J=7 Hz), 2,55 is 2.7 (4H, m), to 3.0-3.2 (4H, m), 4,0-to 4.15 (2H, m), of 6.20 (1H, users), 6,8-6,85 (2H, m), to 6.88 (1H, d, J=7.5 Hz), 7,27 (1H, DD, J=8 Hz, 8 Hz), 7,40 (1H, d, J=5.5 Hz), and 7.6 to 7.7 (2H, m), of 7.69 (1H, d, J=5.5 Hz), 11,42 (1H, users).

Example 5

Obtain 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3-methyl-1H-quinoline-2-it

By the way, is similar to that described in example 1 from 7-(3-chloropropoxy)-3-methyl-1H-quinoline-2-she's got 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3-methyl-1H-quinoline-2-it.

The white powder (ethyl acetate)

The melting point 185-187ºC

1H-NMR (DMSO-d6) δ ppm:

1,9-2,0 (2H, m), 2,04 (3H, s)to 2.55 (2H, t, J=7 Hz), 2,6-of 2.75 (4H, m), to 3.0-3.2 (4H, m), 4,07 (2H, t, J=6.5 Hz), 6.75 in-6,85 (2H, m), 6.90 to (1H, d, J=7.5 Hz), 7,28 (1H, DD, J=8 Hz, 8 Hz), 7,40 (1H, d, J=5.5 Hz), of 7.48 (1H, d, J=8.5 Hz), to 7.61 (1H, d, J=8 Hz), 7,65 is 7.7 (2H, m), 11,57 (1H, users).

Example 6

Obtaining 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3-methyl-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(4-chloroethoxy)-3-methyl-1H-quinoline-2-she's got 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3-methyl-1H-quinoline-2-it.

The white powder (ethyl acetate)

The melting point 197-199°C

1H-NMR (DMSO d6) δ ppm:

1,6-1,7 (2H, m), 1,75-1,9 (2H, m), 2,04 (3H, s), is 2.44 (2H, t, J=7 Hz), 2,55 is 2.7 (4H, m), 3,0-3,15 (4H, m), Android 4.04 (2H, t, J=6.5 Hz), 6.75 in-6,85 (2H, m), to 6.88 (1H, d, J=7.5 Hz), 7,27 (1H, DD, J=8 Hz, 8 Hz), 7,40 (1H, d, J=5.5 Hz), 7,47 (1H, d, J=8.5 Hz), to 7.61 (1H, d, J=8 Hz), the 7.65 to 7.75 (2H, m), 11,59 (1H, users).

Example 7

Obtain 7-[3-(benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(3-chloropropoxy)-1H-quinoline-2-she's got 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-1H-quinoline-2-it.

The white powder (ethyl acetate-diethyl ether)

The melting point 204-207°C

1H-NMR (DMSO-d6) δ ppm:

of 1.97 (2H, t, J=6.8 Hz), 2,50-2,60 (2H, m), 2,60-to 2.65 (4H, m), 3,05-3,10 (4H, m), 4,08 (2H, t, J=6.4 Hz), of 6.29 (1H, d, J=9.5 Hz), 6.75 in-6,85 (2H, m), 6.90 to (1H, d, J=7,7 Hz), 7,25-7,30 (1H, m), 7,40 (1H, d, J=5.6 Hz), 7,55 (1H, d, J=8,4 Hz), 7,60-the 7.65 (1H, m), of 7.69 (1H, d, J=5.5 Hz), 7,80 (1H, d, J=9.5 Hz), 11,57 (1H, s).

Example 8

Obtain hydrochloride of 1-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 1-(4-chlorobutyl)-1H-quinoline-2-she's got 1-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-1H-quinoline-2-he, after obtaining the ethanol solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration and, thus, received hydrochloride 1-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-1H-quinoline-2-it is in the form of white powder.

The melting point 282,0°C (decomp.)

1H-NMR (DMSO-d6) δ ppm:

1,60-2,00 (4H, m), 3,10 is 3.40 (6H, m), 3,50-3,60 (4H, m), or 4.31 (2H, t, J=7.4 Hz), 6,63 (1H, d, J=9.4 Hz), of 6.96 (1H, d, J=7,6 Hz), 7.24 to to 7.35 (2H, m), of 7.48 (1H, d, J=5.4 Hz), to 7.59 for 7.78 (5H, m), to 7.93 (1H, d, J=9.5 Hz), 10,00-10,20 (1H, m).

Example 9

Obtain hydrochloride of 1-[5-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)pentyl]-1H-quinoline-2-on the Sabbath.

In a manner analogous to the method described in example 1 from 1-(5-chloropentyl)-1H-quinoline-2-she's got 1-[5-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)pentyl]-1H-quinoline-2-he, after obtaining the ethanol solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration and, thus, received hydrochloride 1-[5-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)pentyl]-1H-quinoline-2-it is in the form of white powder.

The melting point 225,0-227,0°C

1H-NMR (DMSO-d6) δ ppm:

1,35 of 1.50 (2H, m), 1,60-1,80 (4H, m), 3,10-3,30 (6H, m), 3,50-3,60 (4H, m), 4,27 (2H, t, J=7.4 Hz), is 6.61 (1H, d, J=9.5 Hz), of 6.96 (1H, d, J=7.5 Hz), 7,20-7,34 (2H, m), 7,47 (1H, d, J=5.5 Hz), to 7.61-to 7.77 (5H, m), to $ 7.91 (1H, d, J=9.5 Hz), 10,30-10,50 (1H, m).

Example 10

Obtain 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(3-chloropropoxy)-3,4-dihydro-1H-quinoline-2-she's got 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-it.

The white powder (methanol)

The melting point of 163-165°C

1H-NMR (DMSO-d6) δ ppm:

of 1.8-2.0 (2H, m), is 2.41 (2H, t, J=7.5 Hz), 2,45 of 2.6 (2H, m), 2,6-2,7 (4H, m), 2,78 (2H, t, J=7.5 Hz), 2.95 and is 3.2 (4H, m), of 3.97 (2H, t, J=6.3 Hz), 6,46 (1H, d, J=2.3 Hz), 6,50 (1H, DD, J=2,4 Hz and 8.2 Hz), 6.90 to (1H, d, J=7,6 Hz),? 7.04 baby mortality (1H, d, J=8,2 Hz), 7,27 (1H, DD, J=7.8 Hz, 7.8 Hz), 7,40 (1H, d, J=5.6 Hz), to 7.61 (1H, d, J=8.0 Hz), 7,69 (1H, d, J=5.5 Hz), becomes 9.97 (1H, users).

Example 11

Obtaining 7-[4-(4-benzo[b]thiophene-4-the-piperazine-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(4-chloroethoxy)-3,4-dihydro-1H-quinoline-2-she's got 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it.

The white powder (methanol)

The melting point 147-148°C

1H-NMR (DMSO-d6) δ ppm:

1,55-1,65 (2H, m), 1,65-1,8 (2H, m), 2,35-2,5 (4H, m), by 2.55 to 2.7 (4H, m), 2,78 (2H, t, J=7.5 Hz), 3,0-3,15 (4H, m), 3,93 (2H, t, J=6.4 Hz), 6,44 (1H, d, J=2.5 Hz), of 6.49 (1H, DD, J=2,5 Hz and 8.3 Hz), 6.89 in (1H, d, J=7.5 Hz),? 7.04 baby mortality (1H, d, J=8,3 Hz), 7,27 (1H, DD, J=7.8 Hz, 7.8 Hz), 7,35-7,45 (1H, m), to 7.61 (1H, d, J=8.1 Hz), to 7.68 (1H, d, J=5.6 Hz), becomes 9.97 (1H, users).

Example 12

Obtain hydrochloride of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it

To the ethanol solution of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it, obtained in example 11, was added an ethanolic solution of 1H. hydrochloric acid, and precipitated crystals were filtered and recrystallized from 90% aqueous ethanol and obtained the hydrochloride of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it is in the form of needle crystals light brown color.

The melting point 237-239°C

1H-NMR (DMSO-d6) δ ppm:

a 1.75-of 1.85 (2H, m), 1.85 to a 2.0 (2H, m), 2,42 (2H, t, J=7.5 Hz), and 2.79 (2H, t, J=7.5 Hz), 3,15-3,5 (6H, m), of 3.5-3.7 (4H, m), of 3.96 (2H, t, J=6 Hz), 6,46 (1H, d, J=2.5 Hz), 6,5-6,55 (1H, m), 6,97 (1H, d, J=7.5 Hz), 7,07 (1H, d, J=8.5 Hz), 7,32 (1H, DD, J=8 Hz, 8 Hz), to 7.50 (1H, d, J=5.5 Hz), 7,71 (1H1, d, J=8 Hz), to 7.77 (1H, d, J=5.5 Hz), there is a 10.03 (1H, s), 10,65 (1, users).

Example 13

Obtaining 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)-(Z)-2-butenyloxy]-3,4-dihydro-1H-quinoline-2-it

By the way, is similar to that described in example 1 from 7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinoline-2-she's got 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)-(Z)-2-butenyloxy]-3,4-dihydro-1H-quinoline-2-it.

The white powder (methanol)

The melting point of 68-70°C

1H-NMR (DMSO-d6) δ ppm:

to 2.42 (2H, t, J=7.5 Hz), of 2.64 (4H, users), and 2.79 (2H, t, J=7.5 Hz), 2,9-of 3.25 (6H, m), br4.61 (2H, d, J=3 Hz), 5,65-5,9 (2H, m), 6.48 in (1H, d, J=2.5 Hz), is 6.54 (1H, DD, J=2.5 and 8.5 Hz), 6.89 in (1H, d, J=7.5 Hz), 7,06 (1H, d, J=8.5 Hz), 7,27 (1H, DD, J=8 Hz, 8 Hz), 7,40 (1H, d, J=5.5 Hz), to 7.61 (1H, d, J=8 Hz), 7,69 (1H, d, J=5.5 Hz), 10,0l (1H, users).

Example 14

Obtain hydrochloride of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)-3-methylbutoxy]-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ether methanesulfonate acid was obtained 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)-3-methylbutoxy]-3,4-dihydro-1H-quinoline-2-it, and after obtaining the ethanol solution was added 0,5h. a methanol solution of hydrochloric acid, the precipitated crystals were separated by filtration, recrystallized from isopropyl alcohol and, thus, received hydrochloride 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)-3-methylbutoxy]-3,4-dihydro-1H-quinoline-2-it is in the form of powder is light is yellow.

The melting point 217-219°C (decomp.)

1H-NMR (DMSO-d6) δ ppm:

of 1.12 (3H, d, J=6.5 Hz), of 1.55 to 1.7 (1H, m), 1,9-2,05 (1H, m), 2,2-2,3 (1H, m), is 2.41 (2H, t, J=7.5 Hz), and 2.79 (2H, t, J=7.5 Hz), 3,05 is 3.15 (1H, m), 3.15 and is 3.25 (1H, m), of 3.25 to 3.45 (4H, m), 3,45-3,55 (2H, m), 3,55-3,7 (2H, m), 3,9-4,1 (2H, m), of 6.49 (1H, d, J=2.5 Hz), is 6.54 (1H, DD, J=2.5 Hz, 8.5 Hz), 6,97 (1H, d, J=7.5 Hz), 7,06 (1H, d, J=8.5 Hz), 7,33 (1H, DD, J=8 Hz, 8 Hz), 7,49 (1H, d, J=5.5 Hz), of 7.70 (1H, d, J=8 Hz), to 7.77 (1H, d, J=5.5 Hz), there is a 10.03 (1H, users), 10,66 (1H, usher.).

Example 15

Obtaining 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)-(E)-2-butenyloxy]-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(4-bromo-(E)-2-butenyloxy)-3,4-dihydro-1H-quinoline-2-she's got 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)-(E)-2-butenyloxy]-3,4-dihydro-1H-quinoline-2-it.

The white powder (dichloromethane-diisopropyl ether)

The melting point 147,8-149,7°C

1H-NMR (CDCl3) δ ppm:

2,61 (2H, t, J=7.5 Hz), 2,65 is 2.75 (4H, m), 2,90 (2H, t, J=7.5 Hz), 3,1-3,2 (6H, m)to 4.52 (2H, d, J=4.3 Hz), 5,9-6,0 (2H, m), of 6.31 (1H, d, J=2.3 Hz), 6,55 (1H, DD, J=8,3 Hz, 2.3 Hz), make 6.90 (1H, d, J=7,6 Hz), 7,05 (1H, d, J=8,3 Hz), 7,27 (1H, m), 7,37-7,41 (2H, m), 7,53-of 7.60 (2H, m).

Example 16

Obtaining 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-4-methyl-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 7-(4-chloroethoxy)-4-methyl-3,4-dihydro-1H-quinoline-2-she's got 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-4-methyl-3,4-dihydro-1H-quinoline-2-it.

The white powder (methanol)

<> The melting point 112-115°C

1H-NMR (DMSO-d6) δ ppm:

to 1.14 (3H, d, J=7 Hz), 1,55-1,7 (2H, m), 1,7-1,8 (2H, m), 2,19 (1H, DD, J=7,16 Hz), 2,43 (2H, t, J=7 Hz), to 2.5-2.7 (5H, m), of 2.9-3.0 (1H, m), 3,0-3,1 (4H, m), of 3.94 (2H, t, J=6.5 Hz), of 6.45 (1H, d, J=2,5 Hz), 6,53 (1H, DD, J=2.5 and 8.5 Hz), 6.89 in (1H, d, J=7.5 Hz), 7,07 (1H, d, J=8.5 Hz), 7,27 (1H, DD, J=8 Hz, 8 Hz), 7,39 (1H, d, J=5.5 Hz), to 7.61 (1H, d, J=8 Hz), 7,69 (1H, d, J=5.5 Hz), 9,98 (1H, users).

Example 17

Getting dihydrochloride of 7-{2-[2-(4-benzo[b]thiophene-4-reparation-1-yl)ethoxy]ethoxy}-3,4-dihydro-1H-quinoline-2-it

By the way, is similar to that described in example 1 from 7-[2-(2-chloroethoxy)ethoxy]-3,4-dihydro-1H-quinoline-2-she's got 7-{2-[2-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)ethoxy]ethoxy}-3,4-dihydro-1H-quinoline-2-he, after obtaining the ethanol solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from isopropyl alcohol - diisopropyl ether and received, therefore, the dihydrochloride of 7-{2-[2-(4-benzo[b]thiophene-4-reparation-1-yl)ethoxy]ethoxy}-3,4-dihydro-1H-quinoline-2-it is in the form of white powder.

The melting point 172,3-177,2°C

1H-NMR (CDCl3) δ ppm:

of 2.53 (2H, t, J=7.5 Hz), 2,80 (2H, t, J=7.5 Hz), 3,40 (2H, m), 3,54-3,59 (2H, m), 3,79-of 3.94 (6H, m), 4,16-4,30 (6H, m), 6,50-6,53 (2H, m), 7,01 (1H, d, J=8.0 Hz), was 7.36 (1H, DD, J=8 Hz, 8 Hz), 7,53 to 7.62 (2H, m)of 7.82 (1H, d, J=8.0 Hz), to $ 7.91 (1H, m), 8,02 (1H, users), 13,31 (1H, users).

Example 18

Obtain hydrochloride of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)BU the oxy]-1-methyl-3,4-dihydro-1H-quinoline-2-it

To a solution of 0.40 g of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it is in dimethylformamide (5 ml) and tetrahydrofuran (5 ml) with stirring under cooling in ice, was added 48 mg of sodium hydride (60%oil solution) and stirred at room temperature for 1 hour, then added 0,07 ml methyliodide and stirred at room temperature for 1 hour. To the reaction solution, which was then extracted with ethyl acetate, was added water and, after washing with water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (dichloromethane:methanol = 30:1). The solvent was evaporated under reduced pressure, and ethanol was added a solution of 0,5h. hydrochloric acid, precipitated crystals were separated by filtration and, thus, obtained 0.15 g of the hydrochloride of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinoline-2-it is in the form of powder light yellow color.

The melting point 275,6-277,6°C

1H-NMR (DMSO-d6) δ ppm:

1,70-of 1.94 (4H, m), 2,48-2,52 (2H, m), 2,77 (2H, t, J=7.2 Hz), 3,15-3,30 (9H, m), 3,52-3,63 (4H, m), a 4.03 (2H, t, J=6.0 Hz), 6,58-6,63 (2H, m), of 6.96 (1H, d, J=7.5 Hz), 7,11 (1H, d, J=8.1 Hz), 7,31 (1H, DD, J=7.8 Hz, 7.8 Hz), of 7.48 (1H, d, J=5.5 Hz), 7,69 (1H, d, J=8.0 Hz), of 7.75 (1H, d, J=5.5 Hz), 10,61 (1H, usher.).

Example 19

Obtain hydrochloride of 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)is robaxi]-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 6-(3-chloropropoxy)-3,4-dihydro-1H-quinoline-2-she's got 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-it, and, after receiving his methanolic solution was added a methanol solution of 0,5h. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from a mixed solvent of ethyl acetate-diethyl ether and, thus, have obtained the hydrochloride of 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-it is in the form of white powder.

The melting point 231-234°C

1H-NMR (DMSO-d6) δ ppm:

2,20-of 2.30 (2H, m), 2,35 at 2.45 (2H, m), and 2.83 (2H, t, J=7.5 Hz), 3,20-3,70 (10H, m), was 4.02 (2H, t, J=5,9 Hz), 6,70-6,85 (3H, m), of 6.96 (1H, d, J=7,6 Hz), 7,31 (1H, DD, J=7.9 Hz, 7.9 Hz), of 7.48 (1H, d, J=5.6 Hz), 7,69 (1H, d, J=8.1 Hz), 7,76 (1H, d, J=5.5 Hz), to 9.93 (1H, users), 10,90 (1H, users).

Example 20

Obtain 6-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it

By the way, is similar to that described in example 1 from 6-(4-bromobutoxy)-3,4-dihydro-1H-quinoline-2-she's got 6-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it.

The white powder (ethyl acetate-diethyl ether)

The melting point 175-178°C

1H-NMR(CDCl3) δ ppm:

1,65-1,90 (4H, m), 2,52 (2H, t, J=7,3 Hz), 2,55-to 2.65 (2H, m), 2,65 is 2.75 (4H, m)to 2.94 (2H, t, J=7.5 Hz), 3.15 and is 3.25 (4H, m), 3,90-4,00 (2H, m), 6,65 to 6.75 (3H, m), 6.89 in (1H, DD, J=0.7 Hz and 7.6 Hz), 7,27 (1H, DD, J=7,Hz, 7.9 Hz), 7,35-7,45 (2H, m), 7,55 (1H, d, J=8.0 Hz), 8,02 (1H, users).

Example 21

Obtain hydrochloride of 1-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 1-(4-chlorobutyl)-3,4-dihydro-1H-quinoline-2-she's got 1-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-3,4-dihydro-1H-quinoline-2-he, after obtaining the ethanol solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration and, thus, received hydrochloride 1-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-3,4-dihydro-1H-quinoline-2-it is in the form of white powder.

The melting point to 257.0-259,0°C

1H-NMR (DMSO-d6) δ ppm:

1,60-1,80 (4H, m), of 2.54 (2H, t, J=8,3 Hz), 2,87 (2H, t, J=7.9 Hz), 3,10-3,30 (6H, m), 3,50-3,60 (4H, m), of 3.95 (2H, t, J=7.0 Hz), 6,94? 7.04 baby mortality (2H, m), 7,14-to 7.35 (4H, m), of 7.48 (1H, d, J=5.6 Hz), of 7.70 (1H, d, J=8.0 Hz), 7,76 (1H, d, J=5.6 Hz), 10,00-10,20 (1H, m).

Example 22

Obtain hydrochloride of 1-[5-(4-benzo[b]thiophene-4-reparation-1-yl)pentyl]-3,4-dihydro-1H-quinoline-2-it

In a manner analogous to the method described in example 1 from 1-(5-chloropentyl)-3,4-dihydro-1H-quinoline-2-she's got 1-[5-(4-benzo[b]thiophene-4-reparation-1-yl)pentyl]-3,4-dihydro-1H-quinoline-2-he, after obtaining the ethanol solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration and, thus, received hydrochloride 1-[5-(4-what Enzo[b]thiophene-4-yl-piperazine-1-yl)pentyl]-3,4-dihydro-1H-quinoline-2-it.

The melting point 242,0-244,0°C

1H-NMR (DMSO-d6) δ ppm:

1,30-1,45 (2H, m), 1,50-of 1.65 (2H, m), 1.70 to of 1.85 (2H, m), of 2.53 (2H, t, J=8,2 Hz), 2,85 (2H, t, J=8.0 Hz), 3,10-3,30 (6H, m), 3,50-3,60 (4H, m), 3,91 (2H, t, J=7,3 Hz), 6,94-7,03 (2H, m), 7,13-7,34 (4H, m), 7,47 (1H, d, J=5.6 Hz), 7,69 (1H, d, J=8.0 Hz), 7,76 (1H, d, J=5.5 Hz), 10,30-10,50 (1H, m).

Example 23

Obtain hydrochloride of 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1 from 2-(4-chlorobutyl)-3,4-dihydro-2H-isoquinoline-1-she's got 2-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-3,4-dihydro-2H-isoquinoline-1-he, after obtaining the ethanol solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from a mixed solvent of isopropyl alcohol - ethanol and, thus, received hydrochloride 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-3,4-dihydro-2H-isoquinoline-1-it.

The melting point 257,5-265,5°C

1H-NMR (DMSO-d6) δ ppm:

1,6-1,9 (4H, m), 2,98-3,60 (16H, m), 6,98 (1H, d, J=7,7 Hz), 7,30-7,38 (3H, m), 7,46-7,51 (2H, m), 7,71 (1H, d, J=8,2 Hz), to 7.77 (1H, d, J=5.5 Hz), 7,89 (1H, d, J=7,7 Hz), 10,10 (1H, users).

Example 24

Obtain 2-[5-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)pentyl]-3,4-dihydro-2H-isoquinoline-1-it

By the way, is similar to that described in example 1 from 2-(5-chloropentyl)-3,4-dihydro-2H-isoquinoline-1-she's got 2-[5-(4-benzo[b]thiophene-4-reparation-1-yl)pentyl]3,4-dihydro-2H-isoquinoline-1-it.

The white powder (ethyl acetate-diisopropyl ether)

The melting point of 91.8-93,3°C

1H-NMR(CDCl3) δ ppm:

of 1.32 to 1.37 (2H, m), 1.56 to of 1.64 (4H, m), of 2.38 (2H, t, J=7,6 Hz), 2,62 (4H, m), of 2.92 (2H, t, J=6.5 Hz), 3,09-3,11 (4H, m), 3,47-3,55 (4H, m), for 6.81 (1H, d, J=7.5 Hz), 7,08-7,11 (2H, m), 7,17-to 7.35 (4H, m), 7,47 (1H, d, J=8.0 Hz), 8,01 (1H, DD, J=7.5 Hz, 1.4 Hz).

Example 25

Obtain 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1 from 6-(3-chloropropoxy)-3,4-dihydro-2H-isoquinoline-1-she's got 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-it.

The white powder (ethyl acetate-diethyl ether)

The melting point of 203-205°C

1H-NMR (CDCl3) δ ppm:

2,00-2,10 (2H, m), 2,60-2,70 (2H, m), is 2.74 (4H, users), 2,96 (2H, t, J=6.5 Hz), 3,20 (4H, users), 3,50-3,60 (2H, m), 4,11 (2H, t, J=6.3 Hz), 6,09 (1H, users), was 6.73 (1H, s), 6,85-to 6.95 (2H, m), 7,25-7,30 (1H, m), 7,35-7,45 (2H, m), 7,55 (1H, d, J=8.1 Hz), 8,01 (1H, d, J=8.6 Hz).

Example 26

Obtain 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

By the way, is similar to that described in example 18, from 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-using her methyliodide received 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it.

The white powder (ethyl acetate-diethyl ether)

The melting point 110-113°C

1 H-NMR (CDCl3) δ ppm:

is 2.05 (2H, t, J=6.9 Hz), to 2.65 (2H, t, J=7,3 Hz), is 2.74 (4H, users), of 2.97 (2H, t, J=6,7 Hz), 3,14 (3H, s), 3,21 (4H, users), of 3.54 (2H, t, J=6,7 Hz), 4,11 (2H, t, J=6.4 Hz), of 6.68 (1H, s)6,86 (1H, DD, J=2.3 Hz, 8,6 Hz), 6,91 (1H, d, J=7,7 Hz), 7,25-7,30 (1H, m), 7,40 (1H, d, J=5.5 Hz), 7,42 (1H, d, J=5.5 Hz), 7,56 (1H, d, J=7.9 Hz), 8,03 (1H, d, J=8.6 Hz).

Example 27

Obtain 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method described in example 18, from 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-using her ethyliodide received 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinoline-1-it.

The white powder (ethyl acetate-diethyl ether)

The melting point 128-131°C

1H-NMR (CDCl3) δ ppm:

to 1.21 (3H, t, J=7.2 Hz), was 2.05 (2H, t, J=6.9 Hz), to 2.65 (2H, t, J=7,3 Hz), is 2.74 (4H, users), 2,96 (2H, t, J=6.6 Hz), 3,21 (4H, users), of 3.54 (2H, t, J=6,7 Hz), 3,62 (2H, square, J=7,2 Hz), 4,11 (2H, t, J=6.3 Hz), 6,68 (1H, d, J=1.7 Hz), 6,86 (1H, DD, J=2.3 Hz and 8.2 Hz), 6,91 (1H, d, J=7,7 Hz), 7,25-7,30 (1H, m), 7,40 (1H, d, J=5.5 Hz), 7,42 (1H, d, J=5.5 Hz), 7,56 (1H, d, J=7.8 Hz), 8,03 (1H, d, J=8.6 Hz).

Example 28

Obtain 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1 from 7-(3-chloropropoxy)-3,4-dihydro-2H-isoquinoline-1-she's got 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-it.

The white powder (utilized the t-diethyl ether)

The melting point 176-179°C

1H-NMR (CDCl3) δ ppm:

2,00-2,10 (2H, m)of 2.64 (2H, t, J=7,3 Hz), 2,73 (4H, users), to 2.94 (2H, t, J=6.6 Hz), 3,20 (4H, users), 3,50-3,60 (2H, m), of 4.12 (2H, t, J=6.3 Hz), of 5.92 (1H, users), of 6.90 (1H, d, J=7,7 Hz), 7,03 (1H, DD, J=2,8 Hz, 8,3 Hz), 7,13 (1H, d, J=8,3 Hz), 7,25-7,30 (1H, m), 7,39 (1H, d, J=5.5 Hz), 7,42 (1H, d, J=5.5 Hz), 7,55 (1H, d, J=8.1 Hz), a 7.62 (1H, d, J=2.7 Hz).

Example 29

Obtain 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

By the way, is similar to that described in example 18, from 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-using her methyliodide received 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it.

White powder (ethanol)

The melting point 115-117°C

1H-NMR(CDCl3) δ ppm:

1,95 is 2.10 (2H, m)of 2.64 (2H, t, J=7,3 Hz), 2.70 height is 2.80 (4H, m)to 2.94 (2H, t, J=6,7 Hz), 3,10-of 3.25 (4H, m), and 3.16 (3H, s)to 2.54 (2H, t, J=6,7 Hz), 4,11 (2H, t, J=6.5 Hz), make 6.90 (1H, d, J=7,0 Hz), 6,98 (1H, DD, J=2.7 Hz, 8,3 Hz), was 7.08 (1H, d, J=8,3 Hz), 7,28 (1H, DD, J=7.9 Hz, 7.9 Hz), 7,35-7,45 (2H, m), 7,55 (1H, d, J=8.1 Hz), 7,63 (1H, d, J=2,6 Hz).

Example 30

Obtain hydrochloride of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

After receipt of an ethanol solution of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it was added to the ethanol solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, Perekrest lizovyvatj from ethanol and thus was obtained the hydrochloride of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

The melting point 229-233°C

1H-NMR (DMSO-d6) δ ppm:

2,20-of 2.30 (2H, m), 2,89 (2H, t, J=6,7 Hz), 3,01 (3H, s), 3,21 (2H, t, J=6.9 Hz), 3,30-of 3.60 (8H, m), 3,60-3,70 (2H, m), 4,11 (2H, t, J=6.0 Hz), 6,97 (1H, d, J=7,7 Hz), 7,06 (1H, DD, J=2,8 Hz and 8.3 Hz), 7,22 (1H, d, J=7.9 Hz), 7,31 (1H, DD, J=7.8 Hz, 7.8 Hz), 7,41 (1H, d, J=2.7 Hz), 7,49 (1H, d, J=5.5 Hz), 7,69 (1H, d, J=8.1 Hz), 7,76 (1H, d, J=5.5 Hz), 10,70 (1H, users).

Example 31

Getting dihydrochloride of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method described in example 18, from 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-using her ethyliodide received 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinoline-1-he, after receiving his methanolic solution of added a methanol solution of 0,5h. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from a mixed solvent of methanol-ethyl acetate and, thus, received the dihydrochloride of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-ethyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

The melting point 210-213°C

1H-NMR (DMSO-d6) δ ppm:

of 1.09 (3H, t, J=7,1 Hz), 2,20-of 2.30 (2H, m), 2,87 (2H, t, J=6.5 Hz), 3,20-3,70 (14H, m), 4,11 (2H, t, J=5.9 G is), of 6.96 (1H, d, J=7,7 Hz), 7,00-7,10 (1H, m), 7,22 (1H, d, J=8,3 Hz), 7,25-to 7.35 (1H, m), 7,41 (1H, d, J=2.7 Hz), of 7.48 (1H, d, J=5.5 Hz), 7,69 (1H, d, J=7,7 Hz), 7,76 (1H, d, J=5.5 Hz), 11,08 (1H, users).

Example 32

Obtain hydrochloride of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1, 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it was obtained from 7-(4-chloroethoxy)-2-methyl-3,4-dihydro-2H-isoquinoline-1-it, and, after receiving his methanolic solution was added a methanol solution of 0,5h. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from a mixed solvent of methanol-ethyl acetate and, thus, received hydrochloride 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

The melting point 213-218°C

1H-NMR (DMSO-d6) δ ppm:

1,70 is 2.00 (4H, m), is 2.88 (2H, t, J=6.6 Hz), 3,01 (3H, s), 3,10-3,70 (12H, m), a 4.03 (2H, t, J=5.8 Hz), to 6.95 (1H, d, J=7.5 Hz),? 7.04 baby mortality (1H, DD, J=2,8 Hz, 8.5 Hz), 7,20 (1H, d, J=8,4 Hz), 7,31 (1H, DD, J=7,8 Hz, 7,8 Hz), 7,39 (1H, d, J=2.7 Hz), of 7.48 (1H, d, J=5.7 Hz), 7,69 (1H, d, J=8.1 Hz), of 7.75 (1H, d, J=5.5 Hz), 10,71 (1H, users).

Example 33

Obtain hydrochloride of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-3,4-dihydro-2H-isoquinoline-1-it

By the way, is similar to that described in example 1 from 7-(4-chloroethoxy)-3,4-dihydro-2H-isoquinoline-1-she's got 7-4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3,4-dihydro-2H-isoquinoline-1-he, upon receipt of an ethyl acetate solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from ethyl acetate and, thus, received hydrochloride 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

The melting point 223,8-226,8°C

1H-NMR (DMSO-d6) δ ppm:

1,81-of 1.93 (4H, m), and 2.83 (2H, t, J=6.5 Hz), 3,16-of 3.32 (8H, m), 3.43 points-of 3.64 (4H, m)4,06 (2H, t, J=5,9 Hz), 6,97 (1H, d, J=7,6 Hz), 7,07 (1H, DD, J=8,3 Hz, 2.7 Hz), 7,24 (1H, d, J=7,7 Hz), 7,32 (1H, DD, J=7.9 Hz, 7.9 Hz), 7,39 (1H, d, J=2.7 Hz), to 7.50 (1H, d, J=5.6 Hz), 7,71 (1H, d, J=8.0 Hz), to 7.77 (1H, d, J=5.5 Hz), 7,95 (1H, s), to 10.62 (1H, s).

Example 34

Getting 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-2H-isoquinoline-1-it

By the way, is similar to that described in example 1 from 2-(4-chlorobutyl)-2H-isoquinoline-1-she's got 2-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-2H-isoquinoline-1-it.

Powder, light brown (ethyl acetate-diisopropyl ether)

The melting point 141,1-142,7°C

1H-NMR (CDCl3) δ ppm:

of 1.62 (2H, m)to 1.87 (2H, m)of 2.50 (2H, t, J=7.4 Hz), 2,66-a 2.71 (4H, m), 3,16-3,19 (4H, m)4,06 (2H, t, J=7.2 Hz), 6,50 (1H, d, J=7,3 Hz), 6.89 in (1H, d, J=7,7 Hz), was 7.08 (1H, d, J=7,3 Hz), 7.24 to the 7.65 (7H, m), 8,44 (1H, d, J=7.9 Hz).

Example 35

Obtain 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1 from 7-(3-chloropropoxy)-2H-skinoren-she's got 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2H-isoquinoline-1-it.

The white powder (ethyl acetate)

The melting point to 220.1-222,5°C

1H-NMR (DMSO-d6) δ ppm:

to 1.99 (2H, Quint, J=6.6 Hz), to 2.57 (2H, t, J=7,0 Hz)to 2.66 (4H, users), to 3.09 (4H, users), to 4.16 (2H, t, J=6.3 Hz), of 6.52 (1H, d, J=7,1 Hz), make 6.90 (1H, d, J=7,4 Hz),? 7.04 baby mortality (1H, DD, J=6,9 Hz, 6.9 Hz), 7,26 (1H, d, J=7.9 Hz), 7,33 (1H, DD, J=8,8 Hz, 2.8 Hz), 7,41 (1H, d, J=5.5 Hz), to 7.59-7,63 (3H, m), of 7.69 (1H, d, J=5.5 Hz), 11,21 (1H, d, J=4,9 Hz).

Example 36

Obtain hydrochloride of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-it

By the way, is similar to that described in example 18, from 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2H-isoquinoline-1-using her methyliodide received 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-he, upon receipt of an ethyl acetate solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from ethyl acetate and, thus, received hydrochloride 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-it is in the form of white powder.

The melting point 227,6-230,2°C

1H-NMR (DMSO-d6) δ ppm:

2,31 (2H, Quint, J=7.0 Hz), 3,20-3,40 (6H, m), 3,52 (3H, s), 3,54-3,70 (4H, m)to 4.23 (2H, t, J=5.8 Hz), 6,60 (1H, d, J=7,3 Hz), of 6.99 (1H, d, J=7,7 Hz), 7,30-7,38 (3H, m), 7,51 (1H, d, J=5.6 Hz), 7,63-7,73 (3H, m), 7,78 (1H, d, J=5.5 Hz), 10,88 (1H, s).

Example 37

Obtain hydrochloride of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-ethyl-2H-eskinol the n-1-it

By the way, is similar to that described in example 1 from 7-(3-chloropropoxy)-2-ethyl-2H-isoquinoline-1-she's got 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-ethyl-2H-isoquinoline-1-he, upon receipt of an ethyl acetate solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from ethyl acetate and, thus, received hydrochloride 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-ethyl-2H-isoquinoline-1-it is in the form of white powder.

The melting point 229,9-231,2°C

1H-NMR (DMSO-d6) δ ppm:

of 1.25 (3H, t, J=7,1 Hz)to 2.29 (2H, users), 3,14-to 3.49 (6H, m), 3,56-and 3.72 (4H, m)4,00 (2H, square, J=7,2 Hz), to 4.23 (2H, t, J=5,9 Hz), 6,62 (1H, d, J=7,3 Hz), of 6.99 (1H, d, J=7,6 Hz), 7,27-7,39 (3H, m), 7,51 (1H, d, J=5.6 Hz), 7,62-7,73 (3H, m), 7,78 (1H, d, J=5.5 Hz), 10,38 (1H, s).

Example 38

Obtain hydrochloride of 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-7-methoxy-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1 from 2-(4-chlorobutyl)-7-methoxy-2H-isoquinoline-1-she's got 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-7-methoxy-2H-isoquinoline-1-he, upon receipt of an ethyl acetate solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from ethyl acetate and, thus, received hydrochloride 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-7-methoxy-2H-isoquinoline-one in the form of white powder.

The melting point 243,5-to 245.6°C

1H-NMR (DMSO-d6) δ ppm:

of 1.78 (4H, users), 3,10-of 3.28 (6H, m), of 3.56 (4H, t, J=9.6 Hz), a 3.87 (3H, s), Android 4.04 (2H, t, J=5.3 Hz), only 6.64 (1H, d, J=7,3 Hz), of 6.96 (1H, d, J=7,6 Hz), 7,30 (1H, d, J=8.0 Hz), 7,34 (1H, DD, J=8.6 Hz, 2.9 Hz), 7,41 (1H, d, J=7,3 Hz), 7,49 (1H, d, J=5.6 Hz), 7,63 (1H, d, J=8.6 Hz), 7,69 (1H, DD, J=8.0 Hz, 8.0 Hz), to 7.77 (1H, d, J=5.5 Hz), or 10.60 (1H, s).

Example 39

Getting hydrobromide 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-7-hydroxy-2H-isoquinoline-1-it

To a solution (50 ml) of 2-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butyl]-7-methoxy-2H-isoquinoline-1-she (0.16 g) in dichloromethane under stirring while cooling on ice was added bartered (2M solution of dichloromethane, 1.0 ml) and stirred at room temperature for 3 days. To the reaction solution were added water and then stirred at room temperature for 0.5 hours. Precipitated crystals were separated by filtration, recrystallized from ethyl acetate and, thus, received the hydrobromide of 2-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butyl]-7-hydroxy-2H-isoquinoline-1-she made (0.13 g) as white powder.

The melting point 273,6-275,7°C

1H-NMR (DMSO-d6) δ ppm:

of 1.75 (4H, users), is 3.08 (2H, t, J=11,1 Hz), 3,16 of 3.28 (4H, m)and 3.59 (2H, t, J=10.5 Hz), 4,01 (2H, users), to 6.58 (1H, d, J=7,3 Hz), 6,97 (1H, d, J=7.5 Hz), 7,19 (1H, DD, J=8.6 Hz, 2.6 Hz), 7.29 trend was 7.36 (2H, m), 7,49-the 7.65 (3H, m), 7,71 (1H, d, J=8.0 Hz), 7,78 (1H, d, J=5.5 Hz), 9,50 (1H, users), for 9.95 (1H, s).

Example 40

Obtain 6-[3-(4-benzo[b]thiophene-ipipiri-1-yl)propoxy]-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1 from 6-chloropropoxy-2H-isoquinoline-1-she's got 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2H-isoquinoline-1-it.

The white powder (ethyl acetate)

The melting point 228,8-230,7°C

1H-NMR (DMSO-d6) δ ppm:

to 1.98 (2H, Quint, J=6,7 Hz), of 2.56 (2H, t, J=7.0 Hz), 2,65 (4H, users), to 3.09 (4H, users), 4,17 (2H, t, J=6.3 Hz), 6,47 (1H, d, J=7,1 Hz), make 6.90 (1H, d, J=7,6 Hz), 7,05 (1H, DD, J=8,8 Hz, 2.4 Hz), 7,10-to 7.15 (2H, m), 7,28 (1H, d, J=7.8 Hz), 7,41 (1H, d, J=5.5 Hz), a 7.62 (1H, d, J=8.0 Hz), of 7.70 (1H, d, J=5.5 Hz), 8,07 (1H, d, J=8,8 Hz), 11,03 (1H, s).

Example 41

Obtain hydrochloride of 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-it

By the way, is similar to that described in example 18, from 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2H-isoquinoline-1-using her methyliodide received 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-he, upon receipt of an ethyl acetate solution, ethanol was added a solution of 1H. hydrochloric acid, precipitated crystals were separated by filtration, recrystallized from ethyl acetate and, thus, have obtained the hydrochloride of 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-it is in the form of white powder.

The melting point 241.4 M.-244,8°C

1H-NMR (DMSO-d6) δ ppm:

2,31 (2H, t, J=7,6 Hz), of 3.46 (3H, s), 3,19-3,70 (10H, m), 4,24 (2H, t, J=5,9 Hz), is 6.54 (1H, d, J=7,4 Hz), of 6.99 (1H, d, J=7,6 Hz), 7,10 (1H, DD, J=8,8 Hz, 2,4 Hz), to 7.15 (1H, d, J=2.3 Hz), 7,33 (1H, DD, J=7.9 Hz, 7.9 Hz), was 7.45 (1H, d, J=7,1 Hz), 7,51 (1H, d, J=5.5 Hz), 7,71 (1H, d, J=8.0 Hz), 7,78 (1H, d, J=5.5 Hz), 8,14 (1H, d, J=8,8 Hz), 10,86 (1H, s).

Example 42

Obtain hydrochloride of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it

To a solution of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it in methanol and dichloromethane was added an aqueous solution of 1H. hydrochloric acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 70% ethanol and, thus, received hydrochloride 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it is in the form of white powder.

The melting point 238-241°C

1H-NMR (DMSO-d6) δ ppm:

1,80-2,00 (4H, m), 3,20 is-3.45 (6H, m), 3,50-3,60 (4H, m)4,06 (2H, t, J=5.6 Hz), 6,28 (1H, d, J=9.5 Hz), 6.75 in-6,85 (2H, m), to 6.95 (1H, d, J=7.5 Hz), 7,30 (1H, DD, J=7.8 Hz, 7.8 Hz), 7,47 (1H, d, J=5.7 Hz), 7,56 (1H, d, J=8,4 Hz), to 7.68 (1H, d, J=8.1 Hz), 7,70-a 7.85 (2H, m), 10,92 (1H, users), to 11.61 (1H, users).

Example 43

Getting sulfate 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it

To a solution of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it in methanol and dichloromethane was added to dilute sulfuric acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 60% ethanol and, thus, received the sulfate 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it is in the form of white powder.

The melting point 248-251°C

1H-NMR (DMSO-d6) δ ppm:

1,80-of 1.95 (4H, m), 2,50-4,00 (10H, m), 4,00-4,10 (2H, m), 6,30 (1H, d, J=8,2 Hz), 6.75 in-6,85 (2H, m), 6,97 (1H, d, J=7,6 Hz), 7,31 (1H, DD, J=7.8 Hz, 7.8 Hz), 7,49 (1H, d, J=5.6 Hz), 7,55-of 7.60 (1H, m), of 7.70 (1H, d, J=8.0 Hz), 7,75-a 7.85 (2H, m), 9,25 is 9.75 (1H, usher.), are 11.62 (1H, users).

Example 44

Getting maleate 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it

To a solution of 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it in methanol and dichloromethane was added a methanol solution of maleic acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 80% ethanol and, thus, received maleate 7-[4-(4-benzo[b]thiophene - 4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it is in the form of white powder.

The melting point 181,6-182,8°C

1H-NMR (DMSO-d6) δ ppm:

of 1.87 (2H, users), 3,26-3,47 (10H, m), 4,10 (2H, s), 6,07 (2H, s), 6,33 (1H, d, J=9.5 Hz), 6,82-6,84 (2H, m), of 6.99 (1H, d, J=7,6 Hz), 7,33 (1H, d, J=7.8 Hz), 7,51 (1H, d, J=5.5 Hz), to 7.59 (1H, d, J=9.3 Hz), 7,70-a 7.85 (3H, m), 11,65 (1H, s).

Example 45

Getting fumarata 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it

To a solution of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it in methanol and dichloromethane was added fumaric acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol and obtained, thus, fumarate 7-[4-(4-benzo[b]thiophene-4-yl-piperaz the n-1-yl)butoxy]-1H-quinoline-2-it is in the form of white powder.

The melting point 209-211°C

1H-NMR (DMSO-d6) δ ppm:

1,60-1,90 (4H, m), 2,47-of 2.50 (2H, m), 2,60-of 2.75 (4H, m), 3.00 and-3,15 (4H, m), of 4.05 (2H, t, J=6.3 Hz), 6,28 (1H, d, J=9.4 Hz), 6,60 (2H, s), 6,76-PC 6.82 (2H, m), to 6.88 (1H, d, J=7,4 Hz), 7,26 (1H, DD, J=7.9 Hz, 7,8 Hz), 7,39 (1H, d, J=5,9 Hz), 7,54 (1H, d, J=9.4 Hz), to 7.61 (1H, d, J=8.0 Hz), 7,69 (1H, d, J=5.5 Hz), 7,79 (1H, d, J=9.5 Hz), 11,58 (1H, users).

Example 46

Getting citrate 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it

To a solution of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it in methanol and dichloromethane was added citric acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 50% ethanol and, thus, received citrate 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it is in the form of white powder.

The melting point of 183-185°C

1H-NMR (DMSO-d6) δ ppm:

1,50-2,00 (4H, m), 2,58 (2H, s), 2,62 (2H, s), of 2,75 2,85 (2H, m), 2.95 and was 3.05 (4H, m), of 3.10-3.20 (4H, m), of 4.05 (2H, t, J=5.3 Hz), 6,28 (1H, d, J=9.4 Hz), 6.75 in-6,85 (2H, m), 6.90 to (1H, d, J=7,6 Hz), 7,27 (1H, DD, J=7.9 Hz, 7.9 Hz), 7,42 (1H, d, J=5.5 Hz), 7,55 (1H, d, J=9.3 Hz), to 7.64 (1H, d, J=8.0 Hz), 7,71 (1H, d, J=5.5 Hz), 7,79 (1H, d, J=9.5 Hz), 11,59 (1H, users).

Example 47

Obtaining p-toluensulfonate 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-it

To a solution of 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-methanol and dichloromethane were added monohydrate p-toluensulfonate acid and the solvent was evaporated when s is low pressure. The residue was recrystallized from methanol and, thus, the received p-toluensulfonate 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it is in the form of white powder.

The melting point to 121.0-125,0°C

1H-NMR (DMSO-d6) δ ppm:

1,73 is 2.00 (4H, m), of 2.28 (3H, s), of 3.07 (2H, J=11,0 Hz), 3,23-of 3.43 (4H, m), 3,62 (4H, t, J=15,0 Hz), 4.09 to (2H, t, J=7,1 Hz), of 6.31 (1H, DD, J=9.5 Hz, 2.3 Hz), to 6.80 (1H, s), at 6.84 (1H, d, J=2.3 Hz), 6,98 (1H, d, J=7.5 Hz), 7,11 (2H, d, J=8.0 Hz), 7,33 (1H, DD, J=7.5 Hz, 7.5 Hz), 7,46-7,52 (3H, m), 7,58 (1H, d, J=9.5 Hz), 7,72 (1H, d, J=7.5 Hz), 7,78 (1H, d, J=Il,3 Hz), 7,81 (1H, d, J=9.5 Hz), 9,31-9,49 (1H, m), 11,54-11,63 (1H, m).

Example 48

Getting sulfate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

To a solution of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it in ethanol and dichloromethane was added to dilute sulfuric acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 85% ethanol and, thus, received the sulfate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

The melting point 222-224°C

1H-NMR (DMSO-d6) δ ppm:

2,10-of 2.30 (2H, m), only 2.91 (2H, t, J=6.6 Hz), 3,03 (3H, s), 3,05-4,00 (12H, m), of 4.13 (2H, t, J=5,9 Hz), of 6.99 (1H, d, J=7.5 Hz), to 7.09 (1H, DD, J=2.7 Hz, 8,3 Hz), 7,24 (1H, d, J=8,4 Hz), 7,33 (1H, DD, J=7,8 Hz, 7,8 Hz), 7,44 (1H, d, J=2.7 Hz), 7,51 (1H, d, J=5.5 Hz), 7,72 (1H, d, J=8.1 Hz), 7,78 (1H, d, J=5.5 Hz), 9,00 of 10.05 (1H, users).

Por the measures 49

Getting fumarata 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

To the ethanol solution of 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it was added fumaric acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 70% ethanol and, thus, received fumarate 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of powder light yellow color.

The melting point 149-151°C

1H NMR (DMSO-d6) δ ppm:

1,85 is 2.00 (2H, m), 2,58 (2H, t, J=7.2 Hz), 2,65 is 2.75 (4H, m), is 2.88 (2H, t, J=6,7 Hz), 3,01 (3H, s), 3,05-3,15 (4H, m), 3,50 (2H, t, J=6,7 Hz), of 4.05 (2H, t, J=6.3 Hz), 6,60 (2H, s), 6.89 in (1H, d, J=7,6 Hz), 7,03 (1H, DD, J=8,3 Hz, 2.7 Hz), 7,19 (1H, d, J=8,3 Hz), 7,27 (1H, DD, J=7.9 Hz, 7.8 Hz), 7,38 (1H, d, J=3.0 Hz), 7,40 (1H, d, J=5,9 Hz), to 7.61 (1H, d, J=8.0 Hz), 7,69 (1H, d, J=5,5 Hz).

Example 50

Getting difumarat 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

To the ethanol solution of 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it was added fumaric acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 90% ethanol and, thus, received difumarat 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of white crystals in the case of the form.

The melting point 188-189°C

1H-NMR (DMSO-d6) δ ppm:

1,85 is 2.00 (2H, m)2,60 (2H, t, J=7.0 Hz), 2,65 is 2.75 (4H, m), is 2.88 (2H, t, J=6.6 Hz), 3,01 (3H, s), 3.00 and-3,10 (4H, m), 3,50 (2H, t, J=6,7 Hz), of 4.05 (2H, t, J=6.4 Hz), is 6.61 (4H, s), make 6.90 (1H, d, J=7.5 Hz),? 7.04 baby mortality (1H, DD, J=8,2 Hz, 2.8 Hz), 7,19 (1H, d, J=8,4 Hz), 7,27 (1H, DD, J=7.9 Hz, 7.8 Hz), 7,38 (1H, d, J=3.0 Hz), 7,40 (1H, d, J=6.2 Hz), to 7.61 (1H, d, J=8.0 Hz), 7,69 (1H, d, J=5,5 Hz).

Example 51

Getting maleate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

To a solution of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it in methanol and dichloromethane was added a methanol solution of maleic acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol and ethyl acetate and, thus, received maleate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

The melting point 134,6-135,5°C

1H-NMR (DMSO-d6) δ ppm:

2,17 (2H, users), only 2.91 (2H, t, J=6,7 Hz), 3,03 (3H, s), 3.33 and (10H, users), 3,52 (2H, t, J=6,7 Hz), of 4.12 (2H, t, J=5,9 Hz), 6,04 (2H, s), of 6.99 (1H, d, J=7,6 Hz), 7,07 (1H, DD, J=8,3 Hz, 2.6 Hz), 7,24 (1H, d, J=8.4 and Hz), 7,32 (1H, DD, J=7.9 Hz, 7.9 Hz), the 7.43 (1H, d, J=2.6 Hz), to 7.50 (1H, d, J=5.5 Hz), 7,71 (1H, d, J=7.9 Hz), to 7.77 (1H, d, J=5,5 Hz).

Example 52

Obtaining p-toluensulfonate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

To a solution of 7-[3-(4-benzo[b]thiophene-4-yl-Pipa is Azin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it in methanol and dichloromethane were added monohydrate p-toluensulfonate acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol and ethyl acetate, and thus, p-toluensulfonate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of white powder.

The melting point 173, 0mm-175,5°C

1H-NMR (DMSO-d6) δ ppm:

2,00 is 2.33 (2H, m), of 2.28 (3H, s), only 2.91 (2H, t, J=6.6 Hz), to 3.02 (3H, s), 3.00 and-and 3.16 (2H, m), 3,29-of 3.80 (10H, m), of 4.12 (2H, t, J=5.5 Hz), of 6.99 (1H, d, J=7.9 Hz), 7,06 (1H, d, J=2.5 Hz), 7,11 (2H, d, J=7.9 Hz), from 7.24 (1H, d, J=8.0 Hz), 7,33 (1H, DD, J=8.0 Hz, 8.0 Hz), 7,44 (1H, d, J=2.5 Hz), of 7.48 (1H, d, J=7.9 Hz), 7,51 (1H, d, J=5.5 Hz), 7,72 (1H, d, J=8.0 Hz), 7,82 (1H, d, J=5.5 Hz), 9,39-9,58 (1H, m).

Example 53

Obtain 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

In a manner analogous to the method described in example 1 from 7-(3-chloropropoxy)-2-methyl-3,4-dihydro-2H-isoquinoline-1-she's got 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it.

White powder (ethanol)

The melting point 115-117°C

1H-NMR (CDCl3) δ ppm:

1,95 is 2.10 (2H, m)of 2.64 (2H, t, J=7,3 Hz), 2.70 height is 2.80 (4H, m)to 2.94 (2H, t, J=6,7 Hz), 3,10-of 3.25 (4H, m), and 3.16 (3H, s)to 2.54 (2H, t, J=6,7 Hz), 4,11 (2H, t, J=6.5 Hz), make 6.90 (1H, d, J=7,0 Hz), 6,98 (1H, DD, J=2.7 Hz, 8,3 Hz), was 7.08 (1H, d, J=8,3 Hz), 7,28 (1H, DD, J=7.9 Hz, 7.9 Hz), 7,35-7,45 (2H, m), 7,55 (1H, d, J=8.1 Hz), 7,63 (1H, d, J=2,6 Hz).

Example 54

Getting methansulfonate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it

To the ethanol solution of 7-[3(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-she added methanesulfonyl acid and the solvent was evaporated under reduced pressure. The residue was recrystallized from 80% ethanol and received, thus, methanesulfonate 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of crystals of pale yellow prismatic shape.

The melting point 147-149°C

1H-NMR (DMSO-d6) δ ppm:

2,10-of 2.25 (2H, m)to 2.29 (3H, s), 2,90 (2H, t, J=6,7 Hz), to 3.02 (3H, s), 3,05 is 3.15 (2H, m), 3,40-to 3.50 (4H, m), 3,51 (2H, t, J=6,7 Hz), 3,55-3,70 (4H, m), of 4.12 (2H, t, J=6.0 Hz), 6,98 (1H, d, J=7,6 Hz), 7,06 (1H, DD, J=8,3 Hz, 2.7 Hz), 7.23 percent (1H, d, J=8,4 Hz), 7,32 (1H, DD, J=7.9 Hz, 7.8 Hz), the 7.43 (1H, d, J=2.7 Hz), to 7.50 (1H, d, J=5.5 Hz), 7,71 (1H, d, J=8.1 Hz), to 7.77 (1H, d, J=5.5 Hz), 9,40-a 9.60 (1H, m).

Example 55

Getting hydrochloride 4-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]quinoline

To dimethylformamide (10 ml) was added 4-chlorhydrin (230 mg, was 1.58 mmol), 3-(4-benzo[b]thiophene-4-reparation-1-yl)propan-1-ol (310 mg, 1.05 mmol) and potassium carbonate (220 mg, 1.6 mmol), then stirred at 80°C for 5 hours. The reaction mixture was cooled to room temperature, then added water, and the reaction mixture was extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure after filtration. The residue was purified primary chromatography on a column of silica gel (n-hexane:ethyl acetate = 4:1) and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (3 ml) and the solution was added 1N. HCl-this is ol (1 ml). The obtained insoluble substance was filtered and dried to obtain the hydrochloride of 4-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]quinoline (360 mg, yield: 78%) in the form of powder light yellow color.

Melting point: 240-242°C

Example 56

Getting hydrochloride 3-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]isoquinoline

To dimethylformamide (8 ml) was added 3-hydroxyisoquinoline (170 mg, at 1.17 mmol), 1-benzo[b]thiophene-4-yl-4-(3-chloropropyl)piperazine (290 mg, 1.0 mmol) and potassium carbonate (200 mg, 1,45 mmol), then stirred at 80°C for 7 hours. The reaction mixture was cooled to room temperature, then added water, and the reaction mixture was extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure after filtration. The residue was purified primary chromatography on a column of silica gel (n-hexane:ethyl acetate = 9:1) and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (2 ml) and the solution was added 1N. HCl-ethanol (0.5 ml). The obtained insoluble substance was filtered and dried to obtain the hydrochloride of 3-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]isoquinoline (160 mg, yield: 37%) as white powder.

Melting point: 227-229°C

Example 57

Getting dihydrochloride of 7-[3-(4-benzo[b]thiophene-4-reparation-1 and is)propoxy]-6-methoxy-3,4-dihydroisoquinoline

To a solution of 7-hydroxy-6-methoxy-3,4-dihydroisoquinoline (80 mg, 0.45 mmol) and 3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propan-1-ol (83 mg, 0.3 mmol) in tetrahydrofuran (1 ml) was added PS-triphenylphosphine (110 mg, 3 mmol/g) and dibenzyldithiocarbamate (70 mg, 0.3 mmol), then stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified primary chromatography on a column of silica gel (n-hexane:ethyl acetate = 1:1) and concentrated under reduced pressure. The obtained residue was dissolved in 2-propanol and the solution was added 1N. HCl-ethanol. Then was added isopropyl ether, and the resulting precipitated crystals were filtered and dried to obtain the dihydrochloride of 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-6-methoxy-3,4-dihydroisoquinoline (26 mg, yield: 17%) in the form of powder light yellow color.

Melting point: 211,0-213,0°C

Example 58

Obtain hydrochloride of 1-acetyl-7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline

To a solution of 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline (0,49 g, 1.2 mmol) in methylene chloride (10 ml) with cooling in an ice bath was added acetic anhydride (0,34 ml, 3.6 mmol) and pyridine (0,34 ml, 4.3 mmol), then paramashiva and at room temperature over night. The reaction mixture was concentrated under reduced pressure, to separate the organic phase from the aqueous phase, to the residue were added water and ethyl acetate. The organic phase was washed with water, aqueous saturated solution of sodium bicarbonate and saturated saline solution in this order, and concentrated under reduced pressure. The residue was purified primary chromatography on a column of silica gel (n-hexane:ethyl acetate = 1:1) and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (10 ml) and the solution was added 1N. HCl-ethanol. Then the precipitated crystals were filtered and dried to obtain the hydrochloride of 1-acetyl-7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline (0.27 g, yield: 52%) as white powder.

Melting point: of 123.2-124,3°C

Example 59

Obtain hydrochloride of 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline

To a solution of 6-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-she (1.6 g, 3.8 mmol) in tetrahydrofuran (40 ml) was added alumoweld lithium (160 mg, 4.2 mmol), then stirred at reflux for 1 hour. The reaction mixture was cooled in an ice bath was added water (0.16 ml), 15%aqueous sodium hydroxide solution (0.16 ml) and water (0.5 ml) in that order. After premesis the mixture of insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified primary chromatography on a column of silica gel (n-hexane:ethyl acetate = 1:1) and concentrated under reduced pressure to obtain an amorphous solid (1.4 g). The obtained amorphous solid (0.6 g) was dissolved in ethyl acetate (15 ml). Then the solution was added 1N. HCl-ethanol (1,45 ml), then precipitated crystals were filtered and dried to obtain the hydrochloride of 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline (0.55 g) as white powder.

Melting point: of 123.2-124,3°C

Example 60

Obtain hydrochloride of 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-1,2,3,4-tetrahydroquinoline

To a solution of 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-1,2,3,4-tetrahydroisoquinoline (0.25 g, 0.6 mmol) in methanol (20 ml) was added 37%aqueous formaldehyde solution (0.15 ml, 1.8 mmol), MP-cyanoborohydride (2,41 mmol/g, from 0.76 g, 1.8 mmol) and a catalytic amount of acetic acid, then stirred at room temperature overnight. Resinous substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified primary chromatography on a column of silica gel (methylene chloride:methanol = 20:1) and concentrated under reduced pressure. The residue (175 mg) was dissolved in ethyl acetate (5 ml). Then obavljale a solution of 1H. HCl-ethanol (0,42 ml), then precipitated crystals were filtered and dried to obtain hydrochloride of 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-1,2,3,4-tetrahydroquinoline (103 mg, yield: 37%) as white powder.

Melting point: 260,1-262,8°C

Example 61

Getting dihydrochloride 4-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]quinoline-2-carboxymethylamino

To a methanol solution of 40% methylamine (10 ml) was added ethyl 4-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]quinoline-2-carboxylate (0.28 g), then stirred at room temperature for two days. The reaction mixture was concentrated under reduced pressure. The residue was purified primary chromatography on a column of silica gel (ethyl acetate:methanol = 11:1) and concentrated under reduced pressure. The residue (166 mg) was dissolved in ethyl acetate. Then the solution was added 1N. HCl-ethanol (0.7 ml), then precipitated crystals were filtered and dried to obtain dihydrochloride 4-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]quinoline-2-carboxymethylamino (0.17 g, yield: 54%) as white powder.

Melting point: 224,0°C (decomp.)

Example 62

Getting hydrochloride 4-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]quinoline-2-carboxylic acid

To a methanol solution (7 ml) of ethyl 4-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]quinoline-2-carbox the lats (1.5 g) was added an aqueous solution of 4n. of lithium hydroxide (3 ml) and then stirred at room temperature overnight. Then optionally added water (10 ml) and aqueous solution (3 ml), 4n. of lithium hydroxide, and then stirred at 50°C for 11 hours. The reaction mixture was cooled in an ice bath was added an aqueous solution (4 ml) and 6N. HCl. Next, the precipitated crystals were filtered off, washed with water and dried to obtain hydrochloride of 4-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]quinoline-2-carboxylic acid (1,43 g, yield: 98%) as white powder.

Melting point: 235,0°C

Example 63

Getting 4-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]quinoline-2-carboxamide

To a solution (10 ml) of 4-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]quinoline-2-carboxylic acid (of 0.53 g, 1.2 mmol) in acetonitrile under cooling in an ice bath was added triethylamine (0.25 ml, 1.8 mmol) and isobutylparaben (to 0.19 ml, 1.4 mmol), then stirred at 0°C for 3 hours. Added 28%aqueous ammonia solution (0.15 ml)and the reaction mixture was stirred at room temperature for 5 minutes. Then added ethyl acetate, and the reaction mixture was washed with water and concentrated under reduced pressure. The residue was purified primary chromatography on a column of silica gel (n-hexane:ethyl acetate = 3:1) and concentrated under reduced pressure. The residue (0.2 g) was dissolved p is recrystallization of the mixed solvent, consisting of ethyl acetate and isopropyl ether to obtain 4-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]quinoline-2-carboxamide (79 mg, yield: 16%) as white powder.

Melting point: 153,0-154,5°C

Examples 64-196

Connection examples 64-196 shown in the following tables 1-21, can be obtained in a similar way as described in example 1, using appropriate starting materials. In the following tables actually got connection with physical properties such as crystal shape, TPL (melting point), salt,1H-NMR and MS (mass spectrum).

Table 1
ExampleR1nCrystalline form (a solvent in the recrystallizationTPL(°C)Sol
643The white powder (methanol)125-127-
654 The white powder
(ethanol-ethylacetate)
217-221the dihydrochloride
664The white powder
(ethyl acetate)
123-130 (Razlog.)-

Table 2
ExampleR1nCrystalline form (a solvent in the recrystallizationTPL(°C)Sol
673White powder (ethanol)253-255 (Razlog.)hydrochloride
684White powder (ethanol-ethyl acetate-acetonitrile)151-153the dihydrochloride
69 4White powder (ethanol)156-159hydrochloride

Table 3
ExampleR1Crystalline form (a solvent in the recrystallizationTPL(°C)Sol
70Colorless needle-like crystals (ethanol)to 106.0-108,0-
71The white powder
(ethanol)
192,0-194,0hydrochloride
72The light yellow colour powder (ethanol)240-242hydrochloride
73Powder light yellow what about the color (ethanol) 199,0-201,0hydrochloride
74The white powder
(ethanol)
233,0-235,0hydrochloride
75Powder yellow199,0-204,5the dihydrochloride
76The solid white product (ethyl acetate-hexane)of 123.2-124,3-
77The solid white product (ethyl acetate)231.3 of which-232,9hydrochloride
78The solid white product (ethyl acetate)229,6-231,8hydrochloride
79Poro is OK white
(ethyl acetate)
237,0-238,5hydrochloride
80The white powder
(ethyl acetate)
214,5-216,8hydrochloride

188-190
Table 4
ExampleR1Crystalline form (a solvent in the recrystallization)TPL(°C)Sol
81Solid white (ethyl acetate)207,9-208,7hydrochloride
82The light yellow colour powder (ethyl acetate - isopropyl ether)to 106.0-level 113.0-
83The white powder
(the acetate is a simple broadcast)
-

Table 5
ExampleR1n1H-NMRSol
8431H-NMR (CDCl3) δ ppm: 2,05-of 2.20 (2H, m), 2,65-2,77 (6H, m), 3.15 and is 3.25 (4H, m)to 4.23 (2H, t, J=6.3 Hz), 6,91 (1H, d, J=7,1 Hz), 7,15-to 7.35 (3H, m), 7,35-7,45 (3H, m), 7,55 (1H, d, J=8.0 Hz), of 7.70 (1H, d, J=8,9 Hz), 8,05-8,15 (1H, m), 8,83 (1H, DD, J=1,7, at 5.3 Hz)-
8541H-NMR (DMSO-d6) δ ppm: 1,90-2,00 (4H, m), 3.25 to 3.40 in (6H, m), 3,50-the 3.65 (4H, m), 4,20 is 4.35 (2H, m), to 6.95 (1H, d, J=7,4 Hz), 7,30 (1H, DD, J=7,9, 7.9 Hz), of 7.48 (1H, d, J=5.5 Hz), 7,65-7,80 (3H, m), 7,80-of 7.95 (2H, m), 8,32 (1H, d, J=9,2 Hz), 9,05-9,20 (2H, m), of 11.29 (1H, users)the dihydrochloride

Table 7
ExampleR1n/td> 1H-NMR (solvent)Sol
9431H-NMR (DMSO-d6d: 2,01-2,12 (2H, m), 3,0-3,7 (16H, m), 6,98 (1H, d, J=7,7 Hz), 7,29-7,39 (3H, m), 7,47-7,52 (2H, m), of 7.70 (1H, d, J=8.0 Hz), to 7.77 (1H, d, J=5.6 Hz), 7,89 (1H, d, J=7,7 Hz), 9,85 (1H, users)hydrochloride
9521H-NMR (CDCl3d: 3,0-4,1 (16H, m)6,94 (1H, d, J=7,4 Hz), 7,20-7,47 (6H, m), of 7.64 (1H, d, J=8.1 Hz), of 8.04 (1H, d, J=7,4 Hz)oxalate

Table 8
ExampleR1Crystalline form (a solvent in the recrystallization)TPL(°C)Sol
96The white powder (ethyl acetate)185,5-190,0Hydrochloride
97The white powder (ethyl acetate - simple broadcast)134-136-
98The white powder (ethyl acetate - simple broadcast)103-105-
99The white powder (ethyl acetate - simple broadcast)126-128-
100The white powder (ethyl acetate - simple broadcast)97-99-
101Brown powder (methanol)240-242hydrochloride
102The white powder
(the acetate is a simple broadcast)
143-145-
103 The white powder (ethyl acetate - simple broadcast)161-163-
104The white powder (ethyl acetate - simple broadcast)122-124-

Table 9
ExampleR1Crystalline form (a solvent in the recrystallization)TPL(°C)Sol
105The white powder (ethyl acetate)212,5-216,0hydrochloride
106The white powder (ethyl acetate)224,5-230,0hydrochloride
107 The white powder (ethyl acetate)172,0-of 174.5hydrochloride
108The white powder (ethyl acetate)196,5-201,5hydrochloride
109The white powder (ethyl acetate)200,5-205,5hydrochloride
110The white powder (ethyl acetate)202,5-206,5hydrochloride
111The white powder (ethyl acetate)218,0-223,5hydrochloride
112The white powder (ethyl acetate-isopropyl ether)125,0-129,0-

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 18

Table 19

Table 20

Table 21

Pharmacological test 1

1) analysis of the binding of the receptor dopamine D2

The analysis was carried out in accordance with the method of Kohler et al. (Kohler C, Hall H, Ogren SO and Gawell L. Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain. Biochem. Pharmacol., 1985; 34: 2251-2259).

Male Wistar rats were decapitated immediately removed the brain and separated striped body. Striped body homogenized in 50 mm buffer on the basis of three(hydroxymethyl)aminomethane (Tris)-hydrochloric acid (pH 7,4), which amount to 50 times greater than the mass of tissue using a homogenizer, high-speed rotating blade, and centrifuged at 4°C, 1000×g for 10 minutes. The obtained supernatant is again suspended in the specified buffer, the number of which is 50 times greater than the mass of tissue, and after incubation at 37°C for 10 minutes under the above conditions. The precipitate was suspendable in 50 mm buffer (Tris)-hydrochloric acid (containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2, 1 mm MgCl2pH 7,4), the number of which is 25 times greater than the mass of tissue, and stored frozen at -85°C before use in the analysis of binding as a model membrane.

The analysis of binding was performed using 40 μl of the sample membrane, 20 μl of [3H]-raclopride (end who oncentrate from 1 to 2 nm), 20 μl of the investigational medicinal product and 50 mm buffer Tris-hydrochloric acid (pH of 7.4) containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2, 1 mm MgCl2pH 7,4), the total number, therefore, was 200 μl (final concentration of DMSO was 1%). The reaction was carried out at room temperature for 1 hour and stopped by filtering with suction, collecting the cells on the glass fiber filter. The glass fiber filter was washed with 50 mm buffer Tris-hydrochloric acid (pH 7,4) and, after drying, was added to the mixture for liquid scintillation in microplasma, and measured the radioactivity using a scintillation counter for microplates. Radioactivity in the presence of 10 μm (+)-butaclamol took for nonspecific binding.

The value of the IC50expected reaction depending on the concentration using a nonlinear analysis program. The value of Kicalculated from the value of the IC50using the formula of Cheng-Prusova. The results are shown in table 22.

Table 22
The analyzed connectionKi (nm)
Connection example 10,2
The compound of example 3 0,5
The compound of example 40,5
The compound of example 50,6
The compound of example 60,8
The compound of example 70,5
The compound of example 100,4
The compound of example 110,1
The compound of example 120,1
The compound of example 132,4
The compound of example 143,2
The compound of example 150,2
The compound of example 160,7
The compound of example 172,2
The compound of example 182,6
The compound of example 191,2
The compound of example 201,5
The compound of example 22 4,0
The compound of example 230,7
The compound of example 245,0
The compound of example 263,5
The compound of example 27a 4.9
The compound of example 281,2
The compound of example 300,7
The compound of example 311,4
The compound of example 321,5
The compound of example 331,1
The compound of example 341,2
The compound of example 351,6
The compound of example 361,0
The compound of example 371,9
The compound of example 381,2
The compound of example 391,2
The compound of example 40 4,8
The compound of example 411,9
The compound of example 643,2
The compound of example 681,0
The compound of example 690,8
The compound of example 734,0
The compound of example 79the 4.7
The compound of example 801,5
The compound of example 810,8
The compound of example 842,4
The compound of example 852,0
The compound of example 900,4
The compound of example 911,4
The compound of example 921,7
The compound of example 1164,5
The compound of example 117the 4.7
The compound of example 118 3,5
The compound of example 1223,3
The compound of example 1281,3
The compound of example 1390,2
The compound of example 1552,3
The compound of example 1632,8
The compound of example 1842,6
The compound of example 1852,7
The compound of example 1862,3
The compound of example 1881,6
The compound of example 1900,8

2) analysis of the binding of the serotonin receptor 5-HT2A

The analysis was carried out in accordance with the methodology Leysen JE et al. (Leysen JE, Niemegeers CJE, Van Nueten JM and Laduron PM. [3H] Ketanserin (R 41 468), a selective 3H-ligand for serotonin 2 receptor binding sites. Mol. Pharmacol., 1982, 21: 301-314).

Male Wistar rats were decapitated immediately removed the brain and separates the frontal lobe. Frontal share homogenized in 0.25 M sucrose, which amount to 10 times the mass of tissue using a glass Teflon homogenizer, and centrifuging the Ali at 4°C, 1000×g for 10 minutes. The obtained supernatant was transferred to another centrifuge tube and suspended in 0.25 M sucrose, which amount to 5 times greater than the mass of tissue and the precipitate was centrifuged under these conditions. The resulting supernatant was combined with the supernatant obtained above, and brought to more than 40 times the mass of tissue, using a 50 mm buffer Tris-hydrochloric acid (pH of 7.4) and centrifuged at 4°C, 35000×g for 10 minutes. The precipitate is again suspended in the above buffer, the number of which is 40 times greater than the mass of tissue and centrifuged under the above conditions. The precipitate suspended in the above buffer, the number of which is 20 times greater than the mass of tissue, and stored frozen at -85°C before use in the analysis of binding as a model membrane.

The analysis of binding was performed using 40 μl of the sample membrane, 20 μl of [3H]-ketanserina (final concentration of from 1 to 3 nm), 20 μl of the investigational medicinal product and 50 mm buffer Tris-hydrochloric acid (pH 7,4), the total number, therefore, was 200 μl (final concentration of DMSO was 1%). The reaction was carried out at 37°C for 20 minutes and was stopped by filtration, collecting the cells on the glass fiber filter.

The glass fiber filter flushing and 50 mm buffer Tris-hydrochloric acid (pH 7,4) and after drying, was added to the mixture for liquid scintillation in microplasma, and measured the radioactivity using a scintillation counter for microplates. Radioactivity in the presence of 10 μm of spiperone took for nonspecific binding.

The value of the IC50expected reaction depending on the concentration using a nonlinear analysis program. The value of Kicalculated from the value of the IC50using the formula of Cheng-Prusova. The results are shown in table 23.

Table 23
The analyzed connectionKi (nm)
Connection example 12,3
The compound of example 21,5
The compound of example 32,3
The compound of example 4a 4.9
The compound of example 56,4
The compound of example 74,0
The compound of example 80,6
The compound of example 9 2,6
The compound of example 103,0
The compound of example 11the 5.7
The compound of example 122,1
The compound of example 153,3
The compound of example 167,0
The compound of example 172,8
The compound of example 188,0
The compound of example 191,2
The compound of example 203,3
The compound of example 211,0
The compound of example 222,9
The compound of example 231,7
The compound of example 242,3
The compound of example 254,6
The compound of example 264,4
The compound of example 27 4,1
The compound of example 282,8
The compound of example 302,0
The compound of example 314,5
The compound of example 328,6
The compound of example 336,6
The compound of example 341,5
The compound of example 352,1
The compound of example 362,1
The compound of example 373,1
The compound of example 387,3
The compound of example 392,1
The compound of example 405,1
The compound of example 413,2
The compound of example 648,2
The compound of example 687,0
The compound of example 69 6,1
The compound of example 731,3
The compound of example 795,5
The compound of example 802,5
The compound of example 812,6
The compound of example 843,3
The compound of example 893,1
The compound of example 905,3
The compound of example 916,5
The compound of example 92the 5.7
The compound of example 1164,2
The compound of example 1171,3
The compound of example 1183,4
The compound of example 1222,9
The compound of example 1286,3
The compound of example 1394,0
The compound of example 155 3,0
The compound of example 1637,4
The compound of example 1844,3
The compound of example 1855,0
The compound of example 1868,8
The compound of example 1886,3
The compound of example 1902,9

3) analysis of the binding of adrenaline receptor α1

The analysis was carried out in accordance with the methodology Groβ G et al. (Groβ G, Hanft G and Kolassa N. Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for α1-adrenoceptor binding sites. Naunyn-Schmiedeberg''s Arch Pharmacol., 1987, 336: 597-601).

Male Wistar rats were decapitated immediately removed the brain and separates the cerebral cortex. The cerebral cortex homogenized in 0.50 mm buffer Tris-hydrochloric acid (100 mm NaCl containing 2 mm distorta-disodium ethylenediaminetetraacetate, pH 7,4), the number of which is 20 times greater than the mass of tissue using a homogenizer, high-speed rotating blade, and centrifuged at 4°C, 80000×g for 20 minutes. The precipitate suspended in the above buffer, the number of which is 20 times greater than the mass of tissue, and then what was inkubirovali at 37°C for 10 minutes, centrifuged under the above conditions. The precipitate is again suspended in the above buffer, the number of which is 20 times greater than the mass of tissue and centrifuged under the above conditions. The precipitate suspended in 50 mm buffer (Tris)-hydrochloric acid (containing 1 mm distorta-disodium ethylenediaminetetraacetate, pH 7,4), the number of which is 20 times greater than the mass of tissue, and stored frozen at -85°C before use in the analysis of binding as a model membrane.

The analysis of binding was performed using 40 μl of the sample membrane, 20 μl of [3H]-prazosin (final concentration of 0.2 to 0.5 nm), 20 μl of the investigational medicinal product and 50 mm buffer Tris-hydrochloric acid (containing 1 mm EDTA, pH 7,4), the total number, therefore, was 200 μl (final concentration of DMSO was 1%). The reaction was carried out at 37°C for 45 minutes and was stopped by filtration, collecting the cells on the glass fiber filter.

The glass fiber filter was washed with 50 mm buffer Tris-hydrochloric acid (pH 7,4) and, after drying, was added to the mixture for liquid scintillation in microplasma, and measured the radioactivity using a scintillation counter for microplates. Radioactivity in the presence of 10 μm hydrochloride fentolamina took for nonspecific binding.

The value of the IC50expected reaction depending on the concentration using a nonlinear analysis program. The value of Kicalculated from the value of the IC50using the formula of Cheng-Prusova.

Pharmacological test 2

Evaluation of partial agonistic activity against receptor dopamine D2using cells expressing the receptor D2

Partial agonistic activity against receptor dopamine D2was evaluated by determining the inhibitory effect of the compounds on the number of produced cyclic AMP in cells expressing the receptor of dopamine D2where the production of adenosine 3',5'-cyclic monophosphate (cyclic AMP) induced through stimulation of Forskolin.

Cells of the ovary of the Chinese hamster, DHFR (-)expressing the recombinant receptor dopamine D2man, were cultured in culture medium (environment Dulbecco, modified by the method of Claims (culture medium IMDM), 10% fetal bovine serum, 50 I.U./ml penicillin, 50 μg/ml streptomycin, 200 μg/ml of geneticin, 0.1 mm gipoksantina sodium, 16 μm thymidine) at 37°C and 5%carbon dioxide. Cells in 104cells/well were sown in 96-well microtiter plate coated with poly-1-lysine, and were grown under the same conditions is 2 days. Each well was washed with 100 μl of culture medium (culture medium IMDM, 0.1 mm gipoksantina sodium, 16 μm thymidine). The culture medium was replaced by 50 μl of culture medium (culture medium IMDM, 0.1% sodium ascorbate, 0.1 mm gipoksantina sodium, 16 μm thymidine), dissolved in 3 μm of the investigated compounds. After incubation at 37°C in 5%carbon dioxide for 20 minutes, the culture medium was replaced by 100 ál of stimulating cultural environment Forskolin culture medium IMDM, 0.1% sodium ascorbate, 0.1 mm gipoksantina sodium, 16 μm thymidine, 10 μm of Forskolin, 500 μm 3-isobutyl-1-methylxanthines), dissolved in 3 µm tested compound, and incubated at 37°C in 5%carbon dioxide for 10 minutes. After removal of the culture medium was applied to 200 μl of an aqueous solution for lysis 1B (Amersham Bioscience, the system for enzyme immunoassay Biotrack with reagent attached to the cyclic AMP) and was shaken for 10 minutes. An aqueous solution of each well was used as a sample for measurement. In the samples for measurement, repeated four times, determined the amount of cyclic AMP, using the above system for immunoassay analysis. The percentage inhibition of the respective test compounds was calculated by taking the amount of cyclic AMP in the hole without the add is placed under test compounds at 100%. In this empirical system as control compounds used dopamine, which inhibits the amount of cyclic AMR to about 10% at maximum activity.

It was confirmed that the tested compounds possessed partial agonistic activity against receptor dopamine D2in the study above.

Since the tested compounds possess partial agonistic activity against receptor dopamine D2they can stabilize dopamine neurotransmission to a normal state in patients with schizophrenia and, as a result, to demonstrate, for example, positive and negative effect of improving the effect of improvements in cognitive impairment and the effect of improvements in other symptoms without causing side effects.

Pharmacological test 3

Inhibitory effects on stereotyped behavior in rats induced by apomorphine

As experimental animals used Wistar rats (males, age six or seven weeks old, Japan SLC, Inc.). The test compound suspended in 5% gum Arabic/(saline or water), using agate mortar and, if appropriate, diluted in the same solvent.

Experimental animals were deprived for a night of food the day before the start of the experiment. Within 1 hour after oral administration each the test compounds (5 ml/kg) subcutaneously (1 ml/kg) was administered apomorphine (0.7 mg/kg). Stereotyped behavior was observed for 1 minutes, respectively, after 20, 30 and 40 minutes after injection of apomorphine.

Stereotyped behavior of each animal was evaluated in accordance with the following condition and summarized points three times and evaluated protivopolozhny effect. Each group used six of the investigated animals.

0: the appearance of the animal is the same as with the introduction of saline;

1: Intermittent noisy breathing (wheezing), a constant search activity;

2: Constant noisy breathing, periodic search activity;

3: Constant noisy breathing, alternating biting, gryzenia or licking. Very short periods of locomotor activity;

4: Constant biting, gryzenia or licking; activity search is missing.

For all statistical treatments were used non-clinical statistical analysis system. When the probability is below 0.05, the decision about the absence of a significant difference. The difference scores in the group that was administered the solvent, and each group was administered the test compound was analyzed using the criteria of rank sums test or test Steele. In addition, to calculate dose with 50%efficiency, used linear regression analysis (95 percent confidence interval).

So castasterone compounds showed inhibitory effects on stereotyped behavior, caused by apomorphine, it was confirmed that the tested compounds have antagonistic activity against receptor D2.

Pharmacological test 4

The inhibitory effect in rats with convulsive movements of the head, caused by (±)D-2,5-dimethoxy-4-iodoamphetamine (DOI)

As experimental animals used Wistar rats (males, age six or seven weeks old, Japan SLC, Inc.). The test compound suspended in 5% gum Arabic/(saline or water), using agate mortar and, if appropriate, diluted in the same solvent.

Experimental animals were deprived for a night of food the day before the start of the experiment. Within 1 hour after oral administration of each test compound (5 ml/kg) subcutaneously (1 ml/kg) was administered DOI (5.0 mg/kg). Counted the number of convulsive movements of the head for 10 minutes immediately after the injection of DOI. Each group used six experimental animals.

For all statistical treatments were used non-clinical statistical analysis system. When the probability is below 0.05, the decision about the absence of a significant difference. The difference in the number of convulsive movements of the head in the group that was administered the solvent, and each group was administered the test compound was analyzed using t-test or test Done the TA. In addition, to calculate dose with 50%efficiency, used linear regression analysis (95 percent confidence interval).

Since the tested compounds showed inhibitory effect on the convulsive movements of the head, caused by the DOI, it was confirmed that the tested compounds have antagonistic activity against serotonin receptor 5HT2A.

Pharmacological test 5

Induction of catalepsy in rats

As experimental animals used Wistar rats (males, age six or seven weeks old, Japan SLC, Inc.). The test compound suspended in 5% gum Arabic/(saline or water), using agate mortar and, if appropriate, diluted in the same solvent.

Experimental animals were deprived for a night of food the day before observation catalepsy and ptosis, which was performed after 1, 2, 4, 6 and 8 hours after oral administration of each test compound (5 ml/kg). Each group used six experimental animals.

One front paw of the rat was placed on the edge of a small steel frame (width: 6.5 cm depth: 4.0 cm, height: 7.2 cm) (unnatural posture) and, if the rat remained in this position for more than 30 seconds, we considered this case as a positive catalepsy. This observation was carried out three times at each moment of time and, and if there was at least one positive case, it is believed that rats have catalepsy.

In the cataleptic effect of the test compound was not associated with inhibitory effects on stereotyped behavior induced by apomorphine, therefore, it was concluded that the alleged extrapyramidal side effects should be negligible.

Pharmacological test 6

Measurement of inhibitory effect on the reuptake of serotonin (5-HT) have tested the connection using the synaptosomes structures of the rat brain

Male Wistar rats were decapitated immediately removed the brain and separates the frontal part that homogenized in of 0.32 M sucrose solution, the number of which is 20 times greater than the mass of tissue using a homogenizer type Potter. The homogenate was centrifuged at 4°C, 1000×g for 10 minutes, the resulting supernatant was additionally centrifuged at 4°C, 20000×g for 20 minutes, and the cell residue is suspended in incubation buffer (20 mm Hepes buffer (pH 7,4)containing 10 mm glucose, 145 mm NaCl, 4.5 mm KCl, 1.2 mm magnesium chloride, 1.5 mm calcium chloride) and used in the form of a crude fraction synaptosomes structures.

The reuptake of 5-HT was carried out in a volume of 200 μl using a 96-well plate with round-bottomed wells in the reaction used the incubation buffer, containing the s, pargyline (final concentration 10 μm) and sodium ascorbate (final concentration 0.2 mg/ml).

To each well was added to the incubation buffer (total count), unlabeled 5-HT (final concentration 10 μm, the non-counting) and diluted test compound (final concentration 300 nm). Added one-tenth of the total synaptosomal fraction and after preincubation at 37°C for 10 minutes was added 5-HT solution, labeled with tritium (final concentration of 8 nm), and the reaction of the reverse takeover was started at 37°C. the time of the reverse takeover was 10 minutes, and the reaction was stopped by vacuum filtration through a 96-well glass fiber filter paper layer, and then the filter paper was washed with cold saline solution, well dried and the filter was added Microscint0 (Perkin-Elmer) and the measured remaining on the filter radioactivity.

Inhibitory activity of serotonin reuptake (%) was calculated by the total radioactivity count as 100%, nonspecific count as 0% and counting with the test compound.

% inhibition of 5-HT(%) = 100 -[(count obtained with the tested compound - non-counting (0% capture))/(total count (100% capture) - non-specific counting (0% capture))] × 100

The results are presented in the following table 24.

Table 24
Test connectionThe inhibitory ratio of serotonin reuptake (%) 300 nm
Connection example 192,4
The compound of example 278,8
The compound of example 384,3
The compound of example 491,0
The compound of example 5of 89.1
The compound of example 6for 91.3
The compound of example 791,0
The compound of example 895,0
The compound of example 997,3
The compound of example 1092,6
The compound of example 1192,5
The compound of example 1377,0
The compound of example 14to 85.2
The compound of example 1587,2
With the unity of example 16 86,7
The compound of example 1786,3
The compound of example 18to 91.1
The compound of example 1986,3
The compound of example 2092,8
The compound of example 2181,4
The compound of example 2290,8
The compound of example 2395,5
The compound of example 2497,5
The compound of example 2591,9
The compound of example 2692,0
The compound of example 2794,0
The compound of example 28for 95.3
The compound of example 3095,8
The compound of example 3196,3
The compound of example 3296,9
The compound of example 3394,3
The compound of example 34a 94.2
The compound of example 35for 93.4
The compound of example 3697,4
The compound of example 3797,7
The compound of example 3896,7
The compound of example 3999,2
The compound of example 40to 91.6
The compound of example 4195,1
The compound of example 6473,0
The compound of example 6572,9
The compound of example 6674,1
The compound of example 6793,9
The compound of example 6395,7
The compound of example 6996,3

Examples get

100 g of the compound of the present invention, 40 g is vizela (a trademark of Asahi Chemical Industry Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate were mixed and polished and alloy preformed with a pestle and mortar in glycocalyx R10 mm

The resulting tablet was coated film using a ready agent for applying films 10 g TC-5 (trade mark, product of Shin-Etsu Chemical Co., Ltd., the hypromellose), 3 g of polyethylene glycol 6000, 40 g of castor oil and a suitable amount of ethanol to obtain tablets with a film coating of the above composition.

1. Heterocyclic compound represented by formula (1)

[where the ring Q, presents

represents a

(where

represents-NH-CH2-, -N=CH-, -CH2-NH - or-CH=N-; and carbon-carbon bond

between the 3-position and 4-position of the heterocyclic skeleton containing Z and Y represents a single or double bond);
the ring Q may have at least one Deputy, selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl groups, aryl groups, aryl lower alkyl groups, aryl lower alkoxygroup, arylcarbamoyl group, lower alkenyl is gruppy, lower alkanoyloxy group, lower alkanoyloxy, cycloalkyl group, cycloalkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group, a lower alkyl group, substituted saturated 3 to 8-membered managerialism group containing 1-2 nitrogen atom and the carbonyl group;
R2represents a hydrogen atom or a lower alkyl group; and
And is a-O-A1(where A1represents alkylenes group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom), or lower alkynylamino group) or lower alkylenes group;
provided that, if a represents a lower alkylenes group ring Q represents a bicyclic group selected from the group consisting of:
and
(where the carbon-carbon bond

represents a single or double bond), or its salt.

2. Heterocyclic compound Faure the uly (1) according to claim 1, where the ring Q represents a bicyclic group selected from the group consisting of

and

(where the carbon-carbon bond

between the 3-position and 4-position of the bicyclic heterocyclic skeleton is a single or double bond);
the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo3-C8alkyl group, cyclo3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group, the which may have lower alkyl group, thienyl group and a lower alkyl group, substituted saturated 5-6-membered managerialism group containing 1-2 nitrogen atom; and
And is a-O-A1(where A1represents a C1-C6alkylenes group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom), or its salt.

3. Heterocyclic compound of the formula (1) according to claim 2, where the ring Q represents a bicyclic group selected from the group consisting of
and
the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo3-C8alkyl group, cyclo3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, amino group, which can and who know the lower alkanoyloxy group, nitro, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, phenyl group, thienyl groups and pyrrolidinyl lower alkyl group; and
And is a-O-A1(where A1represents a C1-C6alkylenes group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom)), or its salt.

4. Heterocyclic compound of the formula (1) according to claim 2,
where the ring Q represents a bicyclic group selected from the group consisting of

(the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo3-C8alkyl group, cyclo3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl lower alkoxycarbonyl group, amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group and pyrrolidinyl lower alkyl group), or its salt.

5. Heterocyclic compound of the formula (1) according to claim 1, where the ring Q represents a bicyclic group selected from the group consisting of
and
(where the carbon-carbon bond

between the 3-position and 4-position of the bicyclic heterocyclic skeleton is a single or double bond);
the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo3-C8alkyl group, cyclo3-C8alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group is, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group, pyrrolidinyl lower alkyl group and the carbonyl group; and
And represents the lowest alkylenes group, or its salt.

6. Heterocyclic compound of the formula (1) according to claim 5, where the ring Q represents a bicyclic group selected from the group consisting of
and
(where the carbon-carbon bond

between the 3-position and 4-position of the bicyclic heterocyclic skeleton is a single or double bond);
the ring Q may have from 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl group, phenyl group, phenyl lower alkyl group, a naphthyl lower alkyl group, phenyl lower alkoxygroup, naphthyl lower alkoxygroup, bentilee group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cyclo3-C8alkyl group, cyclo3-C8 alkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro group, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group and pyrrolidinyl lower alkyl group; or its salt.

7. Heterocyclic compound of the formula (1) according to claim 3, selected from the group consisting of:
(1) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1H-quinoline-2-it,
(2) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-1H-quinoline-2-it,
(3) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-1 H-quinoline-2-it,
(4) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-3,4-dihydro-1H-quinoline-2-it,
(5) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinoline-2-it
(6) 6-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-1H-quinoline-2-it; or its salt.

8. Heterocyclic compound of the formula (1) according to claim 4, selected from the group consisting of:
(1) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-3,4-dihydro-2H-isoquinoline-1-it,
(2) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-it,
(3) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinoline-1-about the and,
(4) 7-[4-(4-benzo[b]thiophene-4-reparation-1-yl)butoxy]-3,4-dihydro-2H-isoquinoline-1-it,
(5) 7-[3-(4-benzo[b]thiophene-4-reparation-1-yl)propoxy]-2H-isoquinoline-1-it
(6) 7-[3-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)propoxy]-2-methyl-2H-isoquinoline-1-it; or its salt.

9. Pharmaceutical composition having activity as a partial agonist of the receptor of dopamine D2and/or antagonist of the serotonin receptor 5-HT2A, and/or antagonist adrenaline receptor α1and/or inhibitor of serotonin uptake or reuptake inhibitor of serotonin-containing heterocyclic compound of the formula (1) or its salt according to any one of claims 1 to 8 as an active ingredient and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9 for the treatment or prevention of disorders of the Central nervous system.

11. The pharmaceutical composition of claim 10 for the treatment or prevention of disorders of the Central nervous system selected from the group consisting of schizophrenia; refractory, resistant to therapeutic intervention or chronic schizophrenia; emotional disorders; mental disorders; mood disorders; bipolar disorder type I, bipolar disorder type II; depression; endogenous depression; major depression; melancholy and refractory depression; disty the systematic disorders; cyclothymic disorder; panic attack; panic disorder; agoraphobia; sociophobia; obsessive compulsive disorder; posttraumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatic disorders psychogenic nature; conversive disorder; pain disorder; hypochondriacal syndrome; simulation disorders; dissociated disorders; sexual dysfunction; disorders of sexual desire; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorders; alcoholism; alcohol intoxication; misuse of drugs; poisoning by psychostimulants; drug abuse; anhedonia; iatrogenic anhedonia; anhedonia in the psychic or mental causes; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive disorders; cognitive disorders associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive disorders caused by Alzheimer's disease, Parkinson's disease and related neurodegenerative disease; cognitive disorders in schizophrenia; cogniti the aqueous disorders, called refractory, resistant to therapeutic intervention or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; disease Tourette's; teak disorders; attention deficit disorder/hyperactivity disorder; conduct disorder; and down's syndrome.

12. A method of obtaining a pharmaceutical composition comprising mixing heterocyclic compounds of the formula (1) or its salt according to any one of claims 1 to 8 with a pharmaceutically acceptable carrier.

13. The use of the heterocyclic compounds of formula (1) or its salt according to any one of claims 1 to 8 as a drug that has activity as a partial agonist of the receptor of dopamine D2and/or antagonist of the serotonin receptor 5-HT2And/or antagonist adrenaline receptor α1and/or inhibitor of serotonin uptake or reuptake inhibitor of serotonin.

14. The use of the heterocyclic compounds of formula (1) or its salt according to any one of claims 1 to 8 as a partial agonist of the receptor of dopamine D2and/or antagonist of the serotonin receptor 5-HT2A, and/or antagonist adrenaline receptor α1and/or inhibitor of serotonin uptake or reuptake inhibitor of serotonin.

15. The method of obtaining the heterocyclic compounds represented by formulas is th (1):

[where the ring Q, presents

represents a

(where

represents-NH-CH2-, -N=CH-, -CH2-NH - or-CH=N-; and carbon-carbon bond

between the 3-position and 4-position of the heterocyclic skeleton containing Z and Y represents a single or double bond);
the ring Q may have at least one Deputy, selected from the group consisting of lower alkyl groups, lower alkenylphenol group, lower alkenylphenol group, a hydroxy-group, the lower alkoxygroup, halogenated lower alkyl groups, aryl groups, aryl lower alkyl groups, aryl lower alkoxygroup, arylcarbamoyl group, lower alkenylacyl, lower alkanoyloxy group, lower alkanoyloxy, cycloalkyl group, cycloalkyl lower alkyl group, halogen atom, carbamoyl group which may have lower alkyl group, carboxypropyl, lower alkoxycarbonyl group, an amino group which may have lower alkanoyloxy group, nitro, hydroxy lower alkyl groups, amino lower alkyl group which may have lower alkyl group, thienyl group, a lower alkyl group, substituted saturated the 3-8-membered managerialism group, containing 1-2 nitrogen atom and the carbonyl group;
R2represents a hydrogen atom or a lower alkyl group; and a represents-O-A1(where A1represents alkylenes group which may be substituted by a hydroxy-group (where Allenova group may contain one oxygen atom), or lower alkynylamino group) or lower alkylenes group;
provided that, if a represents a lower alkylenes group ring Q represents a bicyclic group selected from the group consisting of
and
(where the carbon-carbon bond

represents a single or double bond), or its salt,
characterized in that includes the interaction of the compounds represented by the formula

(where the ring Q and a As defined above, and X1represents a halogen atom or a group which causes a substitution reaction, such as, for example, halogen atom, or its salt, with a compound represented by the formula

(where R2defined above) or its salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts which involves the use as a parent compound, (phenylthio)acetic acid derivative or its salts presented by general formula: where X1 represents halogen atom, and is applicable as a safe method of volume production of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts effective as an agent in disorders of the central nervous system and peripheral nervous system.

EFFECT: there is provided high yield, safety for human body, low environment loads.

36 cl, 1 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (II) and to their pharmaceutically acceptable salts. In formula R1 means phenyl optionally substituted on one or more carbon atoms with one or more R9; where R9 is specified of halogen, amino, C1-6alkyl and C1-6alkoxy, one of R2 and R3 represents -C(=O)NR6R7, and the other represents -NHC(=O)NHR4; R4 and R6 represent N, and R7 represents piperidine-3-yl. Besides the invention refers to a pharmaceutical composition containing the compound of the invention, to application of the compound for preparing a drug, and also to an intermediate compound of formula (XI) or its salts, where A represents thienyl ring.

EFFECT: preparation of new compounds exhibiting inhibitory properties with respect to SNK1 kinase.

7 cl, 263 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1), their tautomers and pharmaceutically acceptable salts. The disclosed compounds have thromobopoietin receptor agonist properties. In formula (1) , A is a nitrogen atom or CH, when A is a nitrogen atom, B is NR9 (where R9 is a C1-10 alkyl group), and when A is CH, B is a sulphur atom, R1 is a phenyl group (the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10 alkyl groups and C1-10 alkoxy groups (C1-10 alkyl groups and C1-10 alkoxy groups are unsubstituted or substituted with one or more halogen atoms)), L1 is bond, X is OH, R2 is a C1-10 alkyl group, L2 is a bond, L3 is NH, L4 is a bond or NH, Y is a sulphur atom, and when L4 is a bond, R3 is a piperidinyl group, a piperazinyl group (the piperidinyl group and the piperazinyl group are substituted with substitutes selected from a group containing C1-10 alkoxycarbonyl groups, carboxyl group, hydroxyl groups, di-C1-10 alkylaminocarbonyl groups, C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups (C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups are substituted with a substitute selected from a group containing pyridyl groups, hydroxyl groups and carboxyl groups)), or when L4 is NH, R3 is a C1-10 alkyl group (C1-10 alkyl group is substituted with a substitute selected from a group containing C1-10 alkoxy groups, C1-10 alkoxycarbonyl groups or carboxyl groups).

EFFECT: obtaining a thrombopoietin receptor activator which is a formula (1) compound and a medicinal agent which contains the disclosed compound as an active ingredient.

10 cl, 3 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: invention describes an amide of formula:

where A and B are independently selected from CH or N; D is H; Z is selected from hydrogen, unsubstituted C1-8alkyl, each L is independently selected from -CraRb-, -CRa=, -CO-, -O- or -NRa-; k, m, n, q, x and w are integers independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, provided that k+m+n+q+x+w equals at least 4; R1-R6 are independently selected from hydrogen, CN or halogen; Ra and Rb are independently selected from hydrogen, unsubstituted C1-8alkyl, or its pharmaceutically acceptable salt. The invention describes a pharmaceutical composition, use of the compounds to treat AChE-mediated diseases, a treatment method, as well as an amide synthesis method and use of the formula (I) amide as a chemical agent for inhibiting acetylcholinesterase in biological research.

EFFECT: compounds have high acetylcholinesterase or butyrylcholinesterase inhibiting activity.

24 cl, 27 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: in embodiments of the invention, specific compounds are used to prepare a medicinal agent for treating, relieving and preventing conditions associated with dysfunction of monoamine transmission. The compounds have general formula (1) , where: R1 and R2 are identical or different and denote hydrogen, alkyl, alkenyl, alkynyl, aryl, thio or alkylthio, or R1 and R2 may have extra substitutes which are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyloxy, morpholin-4-ylalkoxy, piperidin-1-ylalkyloxy, alkylamino, dialkylamino, arylamino.

EFFECT: more efficient use of compounds in preparing medicinal agents.

8 cl, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel malonamide derivatives of general formula , to their pharmaceutically acceptable salts of acid bonding and to all forms of their optically pure enantiomers, racemates or diastereomers and diastereomer mixtures, possessing inhibiting activity with respect to γ-secretase, as well as to pharmaceutical preparation, containing one or more than one of claimed compounds, and to application of claimed compounds for manufacturing of drugs. Values of substituents R, R1, R2, R3, as well as X, n are given in invention formula.

EFFECT: obtaining compounds that can be applied in treatment of Alzheimer's disease.

19 cl, 6 dwg, 111 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, ophthalmology, and can be used for treatment of optic atrophy in children of age from 1 to 6 months. For this purpose regions of large and small fontanelles of head and upper sympathetic ganglia at the level of cervical spine at C1-C2 level are exposed to polarised light of apparatus "Bioptron". Exposures to light are carried out daily during 10 days in therapeutic dose 12 J/cm2 from the distance 5 cm from skin surface with light spot diametre 5 cm, irradiation intensity 40 mW/cm2 exposure duration 30 seconds on region of fontanelles and 1 minute on regions of ganglia. On finishing light impact nootropic medications cortexin and/or actovegin or cerebrolisin are introduced in age dose. Courses of treatment are carried out from 1 month to 6 month age until desired therapeutic effect is obtained.

EFFECT: method allows to improve cerebral and intraocular blood supply and metabolic processes of brain and optic nerve, improve delivery of nootropic medications to optic analyser, obtain therapeutic concentrations of medications without side effects.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention is aimed at dipyrazole compounds of formula I and their pharmaceutically acceptable salts, where radicals and groups are defined in claim 1 of the formula of invention. Disclosed compounds modulate AMPA and NMDA receptor functioning. A pharmaceutical composition based on formula I compounds and separate dipyrazole compounds are also part of the subject of invention.

EFFECT: possibility of using compounds as pharmaceutical agents, mainly for treating psychoneurological diseases.

16 cl, 2 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention is aimed at dipyrazole compounds of formula I and their pharmaceutically acceptable salts, where radicals and groups are defined in claim 1 of the formula of invention. Disclosed compounds modulate AMPA and NMDA receptor functioning. A pharmaceutical composition based on formula I compounds and separate dipyrazole compounds are also part of the subject of invention.

EFFECT: possibility of using compounds as pharmaceutical agents, mainly for treating psychoneurological diseases.

16 cl, 2 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted tetracyclic derivatives of tetrahydropyran, pyrrolidine and tetrahydrothiophene of general formula (I), their pharmaceutically acceptable addition salts, their stereochemically isomeric forms, their N-oxide forms, in which all substitutes are defined in claim 1 of the formula of invention. These compounds have binding affinity to serotonin receptors, particularly 5-HT2A and 5-HT2C receptors, and to dopamine receptors particularly D2 dopamine receptors, and have norepiniphrine reuptake inhibition properties. The invention also relates to a pharmaceutical composition containing said compounds, method of preparing said composition and use of said compounds as medicinal agents, particularly for preventing and/or treating several psychiatric and neurological disorders.

EFFECT: new compounds have useful biological properties.

12 cl, 3 tbl, 49 ex

FIELD: medicine.

SUBSTANCE: method involves the intravenous and/or intramuscular introduction of the drugs used in myelopathy, balneotherapy in the form of baths. Acupressure and manual therapy are applied in addition. The manual therapy requires such techniques, as ischemic compression, release phenomenon, fascial broach, postisometric relaxation of the muscles involved in a pathological process. Discontinuous therapeutic plasmapheresis is applied with using either Baxter, or Bekman, or Haemophoenix apparatuses, and/or extracorporal ultraviolet blood irradiations is ensured by the apparatus Isolda MD 73 M. The apparatus Cryo-Jet is used for cryotherapy with cooled dry air at the level of degenerative dystrophic changed vertebral motor cervical segments and muscle attachment points.

EFFECT: method improves clinical effectiveness due to fast pain management, enlarged range of active and passive motions, normalised muscular tonus, increased muscular strength and corrected vegetovascular disorders.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

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