Quinoline compounds suitable for treating disorders responding to modulation of serotonin 5-ht6 receptor

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

 

The LEVEL of TECHNOLOGY

The present invention relates to new compounds of quinoline. These compounds possess valuable therapeutic properties and are particularly suitable for the treatment of diseases that develop in response to modulation of the receptor 5-HT6serotonin.

Serotonin (5-hydroxytryptamine, 5-HT), monoamine neurotransmitter and local hormone, is formed by hydroxylation and decarboxylation of tryptophan. The highest concentration is found in enterochromaffin cells of the gastrointestinal tract, and the remainder is present mainly in platelets and Central nervous system (CNS). 5-HT is involved in numerous physiological and pathophysiological pathways. At peripheral level, it causes the reduction of many smooth muscles and causes endothelium-dependent vasodilation. It is believed that in the Central nervous system it is involved in the implementation of various functions, including the regulation of appetite, mood, anxiety, hallucinations, sleep, vomiting, and pain perception.

Neurons that secrete 5-HT, called serotoninergicheskie. The function of 5-HT is carried out after its interaction with certain (serotoninergicheskie) neurons. To date we have identified seven types of 5-HT receptors: 5-HT1(with subtypes 5-HT1A, 5-HT1B, 5-HTD , 5-HT1Eand 5-HT1F), 5-HT2(with subtypes 5-HT2A, 5-HT2Band 5-HT2C), 5-HT3, 5-HT4, 5-HT5(with subtypes 5-HT5Aand 5-HT5B), 5-HT6and 5-HT7. Most of these receptors are linked to G-proteins that affect the activity of adenylate cyclase or phospholipase Cγ.

Human 5-HT6receptors positively associated with adenylylcyclase. They are distributed in the limbic system, striatum and cerebral cortex and demonstrate a high affinity to brain.

It is expected that modulation of 5-HT6receptor suitable substances will improve in some disorders, including cognitive dysfunction, such as memory deficit, teaching, and learning, in particular associated with Alzheimer's disease, age-related decline in cognitive function and moderate deterioration in cognitive function, attention deficit disorder/hyperactivity, personality changes, such as schizophrenia, in particular cognitive deficits related functions schizophrenia, affective disorders such as depression, anxiety and obsessive-compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of circadian rhythm), eating disorders such as anorexia and Olimia, some gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord injury or head trauma and traumatic brain injuries, such as hydrocephalus, drug addiction and obesity.

The quinoline compounds having affinity for 5-HT6receptor, have been described in the prior art, for example, in US 2007/0027161, WO 2007/039219, WO 2006/053785, WO 05/026125, WO 05/113539 and WO 03/080580.

Compounds disclosed in US 2007/0027161, WO 05/026125 and WO 03/080580 bear if necessary substituted piperazine-1-ilen radical or homopiperazin-1-ilen radical in position 8 of the quinoline.

Compounds disclosed in WO05/113539, are amino-substituted piperidine-1-ilen radical or pyrrolidin-1-ilen radical in position 8 of the quinoline.

Compounds disclosed in WO05/113539, are aminomethyl, or aminoaniline radical in position 8 of the quinoline.

However, there remains a need for compounds having high affinity for 5-HT6the receptor and which would demonstrate high selectivity for this receptor. In particular, these compounds should have low affinity for adrenergic receptors, such as α1-adrenergic receptor, histamine receptors, such as H1-receptor and dopaminergic receptors, such as the D2-the receptor to allow and which to flee or to reduce side effects, associated with modulation of these receptors, such as postural hypotension, reflex tachycardia, potentiation of hypotensive effect of prazosin, terazosin, doxazosin and labetalola or dizziness associated with blockade of α1-adrenergic receptor, increase body weight, sedation, drowsiness or potentiation of Central depressant actions associated with the closure of H1-receptor, or extrapyramidal movement disorders such as dystonia, parkinsonism, akathisia, late dyskinesia or syndrome rabbit, or endocrine effects, such as increased prolactin (galactorrhea, gynecomastia, menstrual changes, sexual dysfunction in men), associated with the closure of D2-receptor.

The aim of the present invention to provide compounds that have high affinity and selectivity for 5-HT6receptor, thus allowing for the treatment of disorders associated with or mediated by 5-HT6the receptor.

Connections must also have good pharmacological profile, for example a good ratio of brain/plasma, good bioavailability, and good metabolic stability or reduced inhibition of mitochondrial respiration.

The INVENTION

Now discovered that compounds of quinoline f is rmula (I), defined here, their physiologically acceptable salts joining with acid and N-oxides exhibit surprising and unexpectedly high selective binding to 5-HT6the receptor. Therefore, the present invention relates to compounds of formula (I)

in which

R denotes a group of the formula

in which * indicates the binding site with hyalinella radical;

A stands for (CH2)awhere a denotes 0, 1, 2 or 3;

B represents (CH2)bwhere b stands for 0, 1, 2 or 3;

X' represents (CH2)xwhere x is 0, 1, 2 or 3;

Y represents (CH2)ywhere y is 0, 1, 2 or 3;

provided that a + b = 1, 2, 3 or 4, x + y = 1, 2, 3, or 4 and a + b + x + y = 3, 4, 5, 6, or 7;

Q denotes N or CH;

R1denotes hydrogen, C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-halogenated, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-halogenoalkane-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-halogenosilanes, C3-C6-cycloalkyl-C1-C4-alkyl, aryl-C1-C4-alkyl, hetaryl-C1-C4-alkyl, C3-C6alkenyl,3-C6-halogenoalkanes, formyl, C1-C4-alkylsulphonyl, C1-C4-alkoxide is of IMT, phenoxycarbonyl or benzyloxycarbonyl, where the phenyl ring in the last two mentioned groups are unsubstituted or carry 1, 2 or 3 substituent selected from halogen, C1-C4-alkyl or C1-C4-halogenoalkane, in particular hydrogen, C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-halogenoalkane, C1-C6-alkoxy-C1-C4-alkyl,C1-C6-halogenoalkane-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-halogennitroalkane, C3-C6-cycloalkyl-C1-C4-alkyl, aryl-C1-C4-alkyl, hetaryl-C1-C4-alkyl, C3-C6-alkenyl, C3-C6-halogenoalkane, formyl, C1-C4-alkylcarboxylic or C1-C4-alkoxycarbonyl;

R2denotes hydrogen, C1-C4-alkyl or C1-C4-halogenated;

R3denotes hydrogen, C1-C4-alkyl or C1-C4-halogenated;

p = 0, 1, or 2;

q = 0, 1, or 2;

R4in his presence, represents C1-C4-alkyl or C1-C4-halogenated and is associated with X and/or Y,

or,

if p = 1 or 2, one radical R4that is linked to a carbon atom of X or Y is adjacent to the nitrogen atom, together with R1can also refer to a direct C2-C5the alkyl is, which may carry 1 or 2 radicals R6; or,

if p = 2, the two radicals R4that are bound to adjacent carbon atoms of X or Y together may also denote a straight C2-C5-alkylene, which may carry 1 or 2 radicals R6;

R5in his presence, represents C1-C4-alkyl or C1-C4-halogenated and associated with A and/or B;

R6represents C1-C4-alkyl, C1-C4-halogenated, C1-C4-alkoxy or C1-C4-halogenoalkane;

n = 0, 1, or 2;

m = 0, 1, 2 or 3;

Ra, Rbindependently selected from the group consisting of halogen, CN,C1-C4-of alkyl,C1-C4-halogenoalkane,C1-C4-alkoxy,C1-C4-halogenoalkane, C(O)RaaC(O)NRccRbband NRccRbb; and Raadenotes hydrogen, C1-C4-alkyl, C1-C4-halogenated, C1-C4-alkoxy or C1-C4-halogenoalkane, and Rcc, Rbbindependently selected from the group consisting of hydrogen and C1-C4-alkyl;

X denotes CH2C(O), S, S(O) or S(O)2; located in positions 3 or 4 of the quinoline;

Ar represents a radical Ar1, Ar2-Ar3or Ar2-O-Ar3and Ar1, Ar2and Ar3each independently selected from the group consisting of aryl or hetaryl, where the aryl or hetaryl may be unsubstituted or may carry 1, 2, 3 substituent Rxand Rxdenotes halogen, CN,NO2,C1-C6-alkyl,C1-C6-halogenated,C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C4-alkyl, C2-C6alkenyl,C2-C6-halogenoalkanes, C3-C6-cycloalkyl, C3-C6-halogenosilanes, C1-C6-alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C4-alkoxy, C1-C6-halogenoalkane, C1-C6-alkylthio, C1-C6-allogenicity, C1-C6-alkylsulfonyl, C1-C6-halogenacetylenes, C1-C6-alkylsulfonyl, C1-C6-halogenallylacetic, C1-C6-alkylsulphonyl, C1-C6-halogenoalkanes, C1-C6-alkylcarboxylic, C1-C6-galogenirovannami, carboxy, NH-C(O)-NRx1Rx2, NRx1Rx2, NRx1Rx2-C1-C6-alkylene, O-NRx1Rx2and Rx1and Rx2in the last 4 mentioned radicals independently of one another denote hydrogen, C1-C6-alkyl,C1-C6-halogenated or C1-C6-alkoxy, or R1 and Rx2in the last 4 mentioned radicals together with the nitrogen atom form a N-linked 5-, 6 - or 7-membered saturated, a heterocycle or N-linked 7-, 8-, 9 - or 10-membered saturated heterobicycle, which are unsubstituted or which are 1, 2, 3 or 4 radicals selected from C1-C4-alkyl, C1-C4-halogenoalkane, C1-C4-hydroxyalkyl and C1-C4-alkoxy, and 2 of the radical Rxthat are bound to adjacent carbon atoms in Ar, can form a saturated or unsaturated 5 - or 6-membered carbocyclic or heterocyclic ring, which may carry a radical Rx;

and to their physiologically acceptable salts joining with acid and N-oxides.

The present invention also relates to a pharmaceutical composition that contains at least one compound quinoline of formula (I), and/or at least one physiologically acceptable salt of Association with an acid of the compounds of formula (I), and/or at least one N-oxide compounds of formula (I), if appropriate together with physiologically acceptable carriers and/or auxiliary substances.

The present invention further relates to the use of quinoline compounds of formula (I) and/or its physiologically acceptable salts joining with this acid and/or measures at the one N-oxide compounds of formula (I) to obtain a pharmaceutical composition, if necessary together with at least one physiologically acceptable carrier or auxiliary substance.

Compounds according to the present invention (i.e. compounds of quinoline of formula (I), physiologically acceptable salts of Association with an acid of the compounds of formula (I), N-oxides of compounds of formula (I) and their physiologically acceptable salts accession acid) are selective ligands of 5-HT6the receptor. Thus, the compounds according to the present invention are particularly suitable for use as a medicine, in particular for the treatment of Central nervous system disorders, diseases associated with addiction, or obesity, since these disorders, and diseases are likely responsible for the effect of ligands of 5-HT6the receptor. Therefore, the present invention also relates to a method of treating disorders in mammals comprising the administration to a patient an effective amount of at least one of the compounds of formula (I), and/or at least one physiologically acceptable salt of Association with an acid of the compounds of formula (I), and/or at least one N-oxide compounds of formula (I).

The invention also relates to the use of compounds according to the present invention as a drug, in cast the STI drugs for the treatment of medical disorders, as defined here and in the claims.

DETAILED description of the INVENTION

Diseases that can be treated by the compound according to the present invention, include, for example, disorders, and diseases of the Central nervous system, in particular cognitive dysfunction, such as memory deficit, teaching, and learning, in particular associated with Alzheimer's disease, age-related decline in cognitive function and moderate deterioration in cognitive function, attention deficit disorder/hyperactivity disorder (ADHD), personality changes, such as schizophrenia, in particular cognitive deficits related functions schizophrenia, affective disorders such as depression, anxiety and obsessive-compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of circadian rhythm), eating disorders such as anorexia and bulimia, certain gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord injury or head trauma and traumatic brain injuries, such as hydrocephalus, drug addiction and obesity.

According to the invention, at least one compound according to the present invention, ntsoelengoe quinoline General formula (I), having the values defined in the beginning, a physiologically acceptable salt of Association with an acid of the compounds of formula (I), N-oxide compounds of formula (I) or a physiologically acceptable salt of accession with the acid used for the treatment for the above reasons. If the compounds of formula (I) of this structure may exist in different spatial configurations, for example, if they have one or more centers of asymmetry, preparation of polysubstituted rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers, diastereomers and tautomers of compounds of formula (I), and/or their salts and/or their N-oxides.

Similarly, it is possible to use the physiologically acceptable salts of the compounds of formula (I), especially salt accession acid obtained with physiologically acceptable acids. Examples of suitable physiologically acceptable organic and inorganic acids are hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, C1-C4-alkylsulfonate acid, such as methanesulfonate acid, aromatic sulfonic acid, such as benzolsulfonat acid and toluols Ivanova acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other usable acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966.

Similarly, it is possible to use N-oxides of compounds of formula (I), if these compounds contain a basic nitrogen atom such as nitrogen atom of the quinoline.

Compounds according to the present invention may also be in the state by introducing at least one radionuclide, such as3H,11C,13N15O,18F,75Br,76Br,77Br,82Br,123I125I and/or131I. Introduction at least one radionuclide may be carried out by standard methods of introduction of radionuclides, for example similar to the one described in WO2006/053785. Radiolabelled compounds according to the present invention can be used, for example, for labeling of 5-HT6receptors for diagnostic display 5-HT6receptors in mammals, particularly in humans. Radiolabelled compounds according to the present invention can be used for diagnostic display tissue expressing the 5-HT6receptors in mammals, in particular for diagnostic presentation of the texts of the brain.

Private options radiolabelled compounds according to the present invention pertain to compounds of formula I, which include at least one positron-emitting radionuclide, such as11C,13N15O or18F, in particular radionuclide selected from the11C and18F. Particularly preferred variants of radiolabelled compounds according to the present invention are those in which R1indicates11C-methyl, or Ar denotes18F-substituted phenyl. Radiolabelled compounds according to the present invention that include at least one positron-emitting radionuclide are especially useful for labeling and diagnostic display functionality of 5-HT6receptors by positron emission tomography (PET). These compounds are also particularly suitable for diagnostic display tissue expressing the 5-HT6receptors in mammals, in particular for diagnostic display brain by PET. PET can be performed, for example, by analogy with the methods described in WO2006/053785.

Organic groups specified in the above definitions of the variables are, as in the case of the term halogen-collective terms for individual lists the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

The term "C1-C6-alkyl" in the context of the invention, and in the alkyl groups, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, C1-C6-alkylsulphonyl, C1-C6-alkylcarboxylic, C3-C6-cycloalkyl-C1-C4-alkyl, aryl-C1-C4-alkyl or hetaryl-C1-C4-alkyl denotes in each case the alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

The term "C1 -C6-halogenated" in the framework of the invention and in halogenating groups C1-C6-allogenicity, C1-C6-halogenatedsolvents, C1-C6-halogenallylacetic, C1-C6-halogenoalkane, C1-C6-galogenirovannami denotes in each case the alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, and hydrogen atoms of this group are partially or completely replaced by halogen atoms. Preferred halogenoalkane group selected from C1-C4-halogenoalkane, particularly preferably from C1-C2-halogenoalkane, such as chloromethyl, methyl bromide, dichloromethyl, trichloromethyl, vermeil, deformity, trifluoromethyl, CHLOROFORMATES, dichloromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromacil, 1-foretel, 2-foretel, 2,2-dottorati, 2,2,2-triptorelin, 2-chloro-2-foretel, 2-chloro-2,2-dottorati, 2,2-dichloro-2-foretel, 2,2,2-trichlorethyl, pentafluoroethyl etc.

The term "C1-C4-alkylen" in the framework of the invention denotes a divalent landiolol group with a straight or branched chain, containing from 1 to 4 carbon atoms, examples of which include methylene, 1,1-ethylene (1,1-ethandiyl), 1,2-ethylene (1,2-ethandiyl), 1,1-propanediyl, 1,2-propanediyl, 2,2-propanediyl, 1,3-PROPANEDIOL, 1,1-butandiol, 1,2-butandiol, 1,3-butandiol, 1,4-bulandi is l, 2,3-butanediol, 2,2-butandiol. The term "direct C1-C4-alkylen" in the framework of the invention denotes a divalent landiolol group with a straight chain containing from 1 to 4 carbon atoms, examples of which include methylene, 1,2-ethylene, 1,3-PROPANEDIOL and 1,4-butanediol.

The term "C1-C6-alkoxy" in the framework of the invention and alkoxy groups C1-C6-alkoxy-C1-C4-alkyl denotes in each case, the alkoxy group is straight or branched chain, containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of the alkoxy group are methoxy, ethoxy, n-propoxy, isopropoxy, n-Butylochka, 2-Butylochka, isobutoxy, tert-Butylochka, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3 methylbutoxy, 2,2-di methylpropyloxy, 1 ethylpropoxy, hexyloxy, 1,1-dimethylpropyl, 1,2-dimethylpropylene, 1 methylpentylamino, 2-methylpentylamino, 3 methylpentane, 4-ethylpentane, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, 1 ethylbutyrate, 2-ethylbutylamine, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropyloxy.

The term "C1-C6-halogenoalkane" in the framework of the invention and in halogenoalkane groups C1-C6-halogenoalkane-C1-C4-al the sludge represents in each case, the alkoxy group is straight or branched chain, containing from 1 to 6 carbon atoms, and hydrogen atoms of this group are partially or completely replaced by halogen atoms, in particular fluorine atoms. The preferred halogenoalkane groups include C1-C4-halogenoalkane, in particular, C1-C2-feralcode, such as formatosi, deformedarse, triptoreline, 1 floratone, 2-floratone, 2,2-diflorasone, 2,2,2-triptoreline, 2-chloro-2-floratone, 2-chloro-2,2-diflorasone, 2,2-dichloro-2-floratone, 2,2,2-trichloroethane, pentaverate etc.

The term "C1-C6-hydroxyalkyl" denotes an alkyl group with straight or branched chain, containing from 1 to 6, especially from 1 to 4 carbon atoms (= C1-C4hydroxyalkyl), in particular from 1 to 3 carbon atoms (= C1-C3hydroxyalkyl), in which one of the hydrogen atoms replaced by a hydroxyl group such as 2-hydroxyethyl or 3-hydroxypropyl.

The term "C1-C6-alkoxy-C1-C4-alkyl" denotes an alkyl group with straight or branched chain, containing from 1 to 4 carbon atoms, in which one of the hydrogen atoms substituted C1-C6-alkoxy group, such as methoxymethyl, ethoxymethyl, propoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 2-ethoxypropan, 3-methoxypropyl or 3-ethoxypropan.

The term "C1-C6 1-C4-alkyl" denotes an alkyl group with straight or branched chain, containing from 1 to 4 carbon atoms, in which one of the hydrogen atoms substituted C1-C6-halogenoalkane-group.

The term "C3-C6-cycloalkyl" in the framework of the invention and in cycloalkyl groups C3-C6-cycloalkyl-C1-C4-alkyl and C3-C6-halogennitroalkane denotes in each case, a cycloaliphatic radical containing from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl radical may be unsubstituted or may carry 1, 2, 3 or 4 C1-C4is an alkyl radical, preferably a methyl radical.

The term "C3-C6-halogenosilanes" in the framework of the invention and in halogencontaining groups C3-C6-halogenosilanes-C1-C4-alkyl denotes in each case, a cycloaliphatic radical containing from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and at least one hydrogen, such as 1, 2, 3, 4 or 5 hydrogen is replaced by halogen, in particular fluorine. Examples include 1-forciblepoppy, 2-forciblepoppy, 2,2-divorcecare, 1-forceclosure, 2-forceclosure, 2,2-diversilobum, 3-forceclosure, 3,3-diversilobum, 1,3-diversilobum etc,

The term "C -C6alkenyl" in the framework of the invention and in alkenyl groups C3-C6-halogenoalkane and aryl-C2-C4-alkenyl denotes in each case, unsaturated hydrocarbon radical with one unsaturated bond, having 2, 3, 4, 5 or 6 C atoms, for example vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-EN-1-yl), 2-butene-1-yl, 3-butene-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-EN-1-yl, 2-aterproof-2-EN-1-yl, etc.

The term "aryl" in the context of the invention represents in each case carbocyclic radical selected from the group consisting of phenyl and phenyl fused with a saturated or unsaturated 5 - or 6-membered carbocyclic ring such as a naphthyl, 1,2-dihydronaphtho, 1,2,3,4-tetrahydronaphthyl, indenyl or indanyl, provided that in the condensed ring aryl linked through the phenyl part of the condensed rings.

The term "hetaryl" in the context of the invention represents in each case heterocyclic radical selected from the group consisting of monocyclic 5 - or 6-membered heteroaromatic radical comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S, and 5 - or 6-membered heteroaromatic ring fused with the phenyl ring or 5 - or 6-membered heteroaromatic radical, where the heterocyclic ring includes the as ring members 1, 2 or 3 heteroatoms selected from N, O and S.

Examples of 5 - or 6-membered heteroaromatic radicals include pyridyl, or 2-, 3 - or 4-pyridyl, pyrimidinyl, i.e. the 2-, 4 - or 5-pyrimidinyl, pyrazinyl, pyridazinyl, that is, 3 - or 4-pyridazinyl, thienyl, i.e. the 2 - or 3-thienyl, furyl, or 2 - or 3-furyl, pyrrolyl, i.e. the 2 - or 3-pyrrolyl, oxazolyl, i.e. the 2-, 3 - or 5-oxazolyl, isoxazolyl, that is, 3-, 4 - or 5-isoxazolyl, thiazolyl, i.e. the 2-, 3 - or 5-thiazolyl, isothiazolin, that is, 3-, 4 - or 5-isothiazole, pyrazolyl, that is, 1-, 3-, 4 - or 5-pyrazolyl, imidazolyl, that is, 1-, 2-, 4 - or 5-imidazolyl, oxadiazolyl, for example 2 - or 5-[1,3,4]oxadiazolyl, 4 - or 5-(1,2,3-oxadiazol)Il, 3- or 5-(1,2,4-oxadiazol)yl, 2 - or 5-(1,3,4-thiadiazole)Il, thiadiazolyl, for example, 2 - or 5-(1,3,4-thiadiazole)yl, 4 - or 5-(1,2,3-thiadiazole)yl, 3 - or 5-(1,2,4-thiadiazole)Il, triazolyl, for example, 1H-, 2H or 3H-1,2,3-triazole-4-yl, 2H-triazole-3-yl, 1H-, 2H or 4H-1,2,4-triazolyl and tetrazolyl, that is, 1H - or 2H-tetrazolyl.

Examples of 5 - or 6-membered heteroaromatic ring fused with the phenyl ring or 5 - or 6-membered heteroaromatic radical, include benzofuranyl, benzothiazol, indolyl, indazoles, benzimidazoles, benzoxadiazole, benzoxadiazole, benzothiadiazole, benzoxazines, chinoline, ethenolysis, purinol, 1,8-naphthyridin, pteridyl, pyrido[3,2-d]pyrimidyl or predominately etc These condensed getaline radicals can be linked to the remainder of the molecule (more precisely, group X) through any ring atom a 5 - or 6-membered heteroaromatic ring or via a carbon atom condensed phenyl group.

Examples of the rings Ar, in which 2 of the radical Rxthat are bound to adjacent carbon atoms in Ar, form a saturated or unsaturated 5 - or 6-membered carbocyclic or heterocyclic ring include 2,3-dihydrobenzofuranyl, 2,3-dihydroindole, dihydroisoquinolyl, dihydroisoxazole, tetrahydroisoquinoline, benzomorphans, bromanil, bromanil, 1,2-dihydronaphtho, 1,2,3,4-tetrahydronaphthyl, indenyl and indanyl.

The term "saturated or unsaturated heterocyclic ring" in each case denotes a 3-7-membered cyclic radical containing at least one heteroatom selected from the group consisting of N, O and S. Examples of such saturated or unsaturated 3-7 membered heterocyclic rings include saturated or unsaturated aromatic or non-aromatic heterocyclic ring. Examples therefore include, in particular above 5 - or 6-membered heteroaromatic radicals, ezyrider, diaziridines, oxiranyl, azetidine, athetini, di - and tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, oxopyrrolidin, pyrazolines, pyrazolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, oxo-oxazolidinyl, isoxazolyl, isoxazolidine is l, piperidinyl, piperazinil, morpholinyl, thiomorpholine, Osotimehin, diocletianopolis etc.

N-linked 5-, 6 - or 7-membered saturated heterocycles are usually saturated heterogenities radicals containing one nitrogen atom as ring member, which is attached to the remainder of the molecule, and, if necessary, one or more, for example 1 or 2 further heteroatoms such as O, S or N, as ring member, having a total of 5, 6 or 7 ring atoms. Examples of "N-linked 5-7 membered saturated heterocycle" are pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, morpholine-4-yl, thiomorpholine-4-yl, imidazolidin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl or hexahydroazepin-1-yl, especially pyrrolidin-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, piperidine-1-yl and morpholine-4-yl.

N-linked 7-10-membered saturated heterobicycle are usually saturated heterobicycle containing one nitrogen atom as ring member, which is attached to the remainder of the molecule, and, if necessary, one or more, for example 1 or 2 further heteroatoms such as O, S or N as a ring member, having a total of 7, 8, 9 or 10 ring atoms. Examples of N-linked 7-10-membered saturated heterobicycle radicals are R, in which Q represents N and a+b+x+y = 3, 4, 5 or 6.

Regarding their ability to bind to 5-HT6receptors preference is given to compounds of the formula (I), in which the variables Ar, A, X, n, m, R1, R2, R3, R4, Raand Rbhave the meanings given below.

The observations made hereinafter relative to preferred aspects of the invention, for example, in relation to the preferred values of the variables in the compound (I), preferred compounds (I) and preferred embodiments of the method or use according to the invention, applicable in each case individually or in combination.

Preference is given to compounds of the formula I and their salts, in which the group R variables x and y = 0, 1 or 2. Preferably x + y = 1, 2, or 3. In particular, x + y = 1 or 2.

Preference is given to compounds of the formula I and their salts, in which the group R variables a and b = 0, 1 or 2. Preferably a + b = 1, 2, or 3. In particular, a + b = 1 or 2.

Preferably a + b + x + y = 3, 4, 5 or 6, in particular 3, 4 or 5.

More preferred compounds of formula I and their salts, in which the group R variables a and b = 0, 1, or 2, x and y = 0, 1, or 2, a + b = 1, 2, or 3, x + y = 1, 2, or 3 and a + b + x + y = 3, 4, 5 or 6, in particular 3, 4 or 5.

Preference is given to compounds of the formula I and their salts, in which the group R, the variable Q denotes n

Another option OS the implement of the invention relates to compounds of formula I and their salts, where the group R, the variable Q denotes CH.

Preference is given to compounds of the formula I and their salts, in which the group R variable R1denotes hydrogen, C1-C4-alkyl, C3-C4alkenyl or cyclopropylmethyl. In a particularly preferred embodiment, R1denotes hydrogen.

Similarly, preference is given to compounds of the formula I and their salts, in which the group R variable R1denotes benzyl, benzyloxycarbonyl or C1-C4-alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl. These compounds are intermediate compounds suitable for preparing compounds I, in which R1denotes hydrogen.

Preference is given to compounds of the formula I and their salts, in which the group R variable R2denotes hydrogen. Preference is also given to compounds of the formula I and their salts, in which the group R variable R3denotes hydrogen. In particular, R2and R3both represent hydrogen.

Preference is given to compounds of the formula I and their salts, in which the group R variable q = 0.

Preference is given to compounds of the formula I and their salts, in which the group R variable p = 0.

Another variant embodiment of the invention relates to compounds of formula I and their salts, where p = 2 and two happy the Kala R 4that are bound to adjacent carbon atoms of X or Y together denote a straight C2-C5-alkylene, which is unsubstituted or may carry 1 or 2 radicals R6as defined here.

Another variant embodiment of the invention relates to compounds of formula I and their salts, where p = 1 and the radical R1together with the radical R4that is linked to a carbon atom of X or Y is adjacent to the nitrogen atom, denote a straight C2-C5-alkylene, which is unsubstituted or may carry 1 or 2 radicals R6as defined here.

Particular preference is given to compounds of the formula I and their salts, in which the group R variables a, b, x, y, p, q, Q, R1, R2and R3defined as follows:

a = 0, 1, or 2,

b = 0, 1, or 2,

x = 0, 1, or 2,

y = 0, 1, or 2,

provided that a + b = 1, 2, or 3, x + y = 1, 2, or 3 and a + b + x + y = 3, 4, 5 or 6, in particular 3, 4 or 5,

p = 0,

q = 0,

Q denotes N

R1denotes hydrogen, C1-C4-alkyl, C3-C4alkenyl or cyclopropylmethyl, in particular hydrogen, or R1denotes benzyl or butoxycarbonyl,

R2denotes hydrogen and

R3denotes hydrogen.

Particular preference is given to compounds of the formula I and their salts, in which R denotes a radical of the formulae R-1 to R-44:

and R1has the meanings given in claim 1 of the claims, and * indicates a binding site with hyalinella radical.

More preferred compounds of formula I, their N-oxides and their salts, in which the group R is selected from radicals of the formulae R-1 to R-38 and R-44, in particular, radicals of the formulae R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 and R-44. Particular preference is given to compounds of the formula I, their N-oxides and their salts, in which the group R is selected from radicals of the formula R-5, R-11, R-12, R-15, R-16, R-25, R-26 and R-44, and greater preference is given to compounds in which R is selected from R-11 and R-12. Special preference is also given to compounds according to the present invention, in which R denotes the R-44.

In polycyclic radicals R forms a bridge linking carbon atom (i.e. the carbon atoms bearing R2and R3respectively) can create centers of chirality. The invention relates to compounds, in which R represents a mixture of enantiomers, as well as compounds in which R is enantiomerically enriched or enantiomerically pure. Possible enantiomers of the radicals R, in particular radicals of R-5, R-12, R-15, R-16, R-25, R-26 and R-44, shown below:

p> Especially preferred embodiment of the invention relates to compounds of the formula I, in which X denotes SO2.

Another variant embodiment of the invention relates to compounds of the formula I, in which X is CH2.

Another variant embodiment of the invention relates to compounds of the formula I, in which X is a carbonyl group, that is, X is C(=O).

In one preferred embodiment of the invention X is located at position 3 of chinoline, i.e. this variant implementation relates to compounds of the following formula Ia:

In another embodiment of the invention X is located at position 4 of chinoline, i.e. this variant implementation relates to compounds of the following formula Ib:

Among the compounds Ia and Ib, preference is given to compounds in which X denotes SO2.

Among the compounds Ia and Ib, preference is given to compounds Ia, Ib and their salts, in which the group R variables a, b, x, y, p, q, Q, R1, R2and R3has one of the preferred meanings and, in particular, is defined as follows:

a = 0, 1, or 2,

b = 0, 1, or 2,

x = 0, 1, or 2,

y = 0, 1, or 2,

provided that a + b = 1, 2, or 3, x + y = 1, 2, or 3 and a + b + x + y = 3, 4, 5 or 6, in particular 3, 4 or 5,

p = 0,

q = 0,

Q appears the t N,

R1denotes hydrogen, C1-C4-alkyl, C3-C4alkenyl or cyclopropylmethyl, in particular hydrogen, or R1denotes benzyl or butoxycarbonyl,

R2denotes hydrogen, and

R3denotes hydrogen.

Among the compounds Ia and Ib particular preference is given to compounds Ia and Ib and their salts, in which X denotes SO2and in which R represents a group of the formulae R-1 to R-44, in particular, the group R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 or R-44, and more preferably the group R-5, R-11, R-12, R-15, R-16, R-25, R-26 or R-44, and most preferably the group R-11 or R-12 or R-44 and R1has the values defined above and, in particular, denotes hydrogen.

A very preferred embodiment of the invention relates to compounds of the following formula Ia.a:

in which n, m, Ar, Raand Rbhave the meanings defined herein, and in which R has the meanings given above, for example, is a group of the formulae R-1 to R-44, in particular, the group R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 or R-44, and more preferably the group R-5, R-11, R-12, R-15, R-16, R-25, R-26 or R-44, and most preferably the group R-11 or R-12 or R-44 and R1has the values defined above and, in particular, oznachaet hydrogen.

Another preferred embodiment of the invention relates to compounds of the following formula Ia.b:

in which n, m, Ar, Raand Rbhave the meanings defined herein, and in which R has the meanings given above, for example, is a group of the formulae R-1 to R-44, in particular, the group R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 or R-44, and more preferably the group R-5, R-11, R-12, R-15, R-16, R-25, R-26 or R-44, and most preferably the group R-11 or R-12 or R-44 and R1has the values defined above and, in particular, denotes hydrogen.

Another preferred embodiment of the invention relates to compounds of the following formula Ia.c:

in which n, m, Ar, Raand Rbhave the meanings defined herein, and in which R has the meanings given above, for example, is a group of the formulae R-1 to R-41, in particular, the group R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 or R-44, and more preferably the group R-5, R-11, R-12, R-15, R-16, R-25, R-26 or R-44, and most preferably the group R-11 or R-12 or R-44 and R1has the values defined above and, in particular, denotes hydrogen.

Another preferred embodiment of the invention relates to the joining the following formula Ib.a:

in which n, m, Ar, Raand Rbhave the meanings defined herein, and in which R has the meanings given above, for example, is a group of the formulae R-1 to R-41, in particular, the group R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 or R-44, and more preferably the group R-5, R-11, R-12, R-15, R-16, R-25, R-26 or R-44, and most preferably the group R-11 or R-12 or R-44 and R1has the values defined above and, in particular, denotes hydrogen.

Another preferred embodiment of the invention relates to compounds of the following formula Ib.b:

in which n, m, Ar, Raand Rbhave the meanings defined herein, and in which R has the meanings given above, for example, is a group of the formulae R-1 to R-41, in particular, the group R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 or R-44, and more preferably the group R-5, R-11, R-12, R-15, R-16, R-25, R-26 or R-44, and most preferably the group R-11 or R-12 or R-44 and R1has the values defined above and, in particular, denotes hydrogen.

Another preferred embodiment of the invention relates to compounds of the following formula Ia.c:

in which n, m, Ar, Raand Rbhave C is achene, defined here, and in which R has the meanings given above, for example, is a group of the formulae R-1 to R-41, in particular, the group R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 or R-44, and more preferably the group R-5, R-11, R-12, R-15, R-16, R-25, R-26 or R-44, and most preferably the group R-11 or R-12 or R-44 and R1has the values defined above and, in particular, denotes hydrogen.

Especially preferred embodiment of the invention relates to compounds of the following formula Ia.a1:

in which n, m, Ar, R1, Raand Rbhave the meanings defined here. R1means, in particular, hydrogen.

Another especially preferred embodiment of the invention relates to compounds of the following formula Ia.a2:

in which n, m, Ar, R1, Raand Rbhave the meanings defined here. R1means, in particular, hydrogen.

Another especially preferred embodiment of the invention relates to compounds of the following formula Ia.a2a:

in which n, m, Ar, R1, Raand Rbhave the meanings defined here. R1means, in particular, hydrogen.

Another particularly preferred variant implementation of the ia of the invention relates to compounds of the following formula Ia.a2b:

in which n, m, Ar, R1, Raand Rbhave the meanings defined here. R1means, in particular, hydrogen.

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-1 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a3).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is the radical R 3, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a4).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-5 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a5).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-5a and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a5a).

Another preferred variant implementation is tvline invention relates to compounds of formula Ia, as defined above, in which R represents the radical R 5b and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a5b).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-6 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a6).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-8 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a7).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-9 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a8).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-10 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a9).

Another predpochitayut embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-13 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a10).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-15 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a11).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-15a, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a11a).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-15b, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a11b).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-17 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a12.

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-21 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a13).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-22 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a14).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-24 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a15).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-25 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a16).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-25a, and R1they are the et values defined above, and R1means, in particular, hydrogen (Compounds Ia.a16a).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-25b, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a16b).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-27 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a17).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-28 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a18).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-29 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a19).

Another preferred embodiment of the invention relates to compounds of four who uly AA, as defined above, in which R is a radical R-34 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a20).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-35 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a21).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-36 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a22).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-37 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a23).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-38 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a24).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-16 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a25).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-16a, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a25a).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-16b, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a25b).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-26 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a26).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-26a, and R1the meet value, defined above, and R1means, in particular, hydrogen (Compounds Ia.a26a).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-26b, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a26b).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-44 and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a27).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-44a, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a27a).

Another preferred embodiment of the invention relates to compounds of formula Ia, as defined above, in which R is a radical R-44b, and R1has the values defined above, and R1means, in particular, hydrogen (Compounds Ia.a27b).

In formula I, and likewise in formulae Ia, Ib, Ia.a, Ia.b, Ia.c, Ia.a1-Ia.a27 Deputy Ar predpochtitelney a radical Ar 1in particular radical selected from phenyl, naphthyl, teinila, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, chinoline, izochinolina, tetrahydroisoquinoline, benzofuranyl, benzothiophene, benzoxazine, benzothiazole, benzoxadiazole, benzothiadiazole, benzomorphans or indanyl, and a cyclic radical Ar1unsubstituted or may carry 1, 2 or 3 substituent Rxas defined here. Likewise preferred are the compounds of formula I in which Ar represents a radical Ar2-Ar3in which Ar2and Ar3independently from each other selected from the group consisting of phenyl, teinila, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, and Ar1and Ar2unsubstituted or may carry 1, 2 or 3 substituent Rxas defined here. The radicals Ar2-Ar3the radical Ar2preferably selected from phenyl, pyridyl and tanila, and the radical Ar3preferably represents phenyl, thienyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl or thiadiazolyl, and Ar1and Ar2unsubstituted or may carry 1, 2 or 3 substituent Rxas defined here. Analogion the preferred are the compounds of formula I, in which Ar represents a radical Ar2-O-Ar3in which Ar2and Ar3independently from each other selected from the group consisting of phenyl, teinila, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl or thiadiazolyl, and Ar1and Ar2unsubstituted or may carry 1, 2 or 3 substituent Rxas defined here. The radicals Ar2-Ar3the radical Ar2preferably selected from phenyl, pyridyl and tanila, and the radical Ar3preferably represents phenyl, and Ar1and Ar2unsubstituted or may carry 1, 2 or 3 substituent Rxas defined here.

In formula I, and likewise in formulae Ia, Ib, Ia.a, Ia.b, Ia.c, Ia.a1-Ia.a27 Deputy Ar preferably represents phenyl, which is unsubstituted or may carry 1, 2 or 3 substituent Rxas defined here.

If Rxpresent, Rxpreferably selected from halogen, CN, C1-C4-alkyl, C1-C4-halogenoalkane, C1-C4-alkoxy, C1-C4-halogenoalkane,C3-C6-cycloalkyl and group NRx1Rx2. More preferably Rxselected from halogen, C1-C4-halogenoalkane or C1-C4-halogenoalkane.

In formula I, and likewise in formulae Ia, Ib, Ia.a, Ia.b, Ia.c, Ia.a1-Ia.a2 variable m preferably has a value of 0. If m is different from 0, Rapreferably selected from halogen, CN,C1-C4-of alkyl, in particular methyl,OCH3, CF3, CHF2, OCHF2and OCF3.

In formula I, and likewise in formulae Ia, Ib, Ia.a, Ia.b, Ia.c, Ia.a1-Ia.a27 variable n preferably has the value 0. If m is different from 0, Rbpreferably selected from halogen, CN,C1-C4-of alkyl, in particular methyl,OCH3, CF3, CHF2, OCHF2and OCF3.

Examples of preferred compounds of formula I are given in the following tables 1-32b.

Table 1: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-11, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-1-Ia.a-225).

Table A
ArR1
1phenylN
22-forfinalN
33-forfinalN
42,3-differeni the N
52,4-differenlN
62.5-differenlN
72,6-differenlN
83,4-differenlN
93,5-differenlN
102-chlorophenylN
113-chlorophenylN
122-tolylN
133-tolylN
142-isopropylphenylN
153-isopropylphenylN
162-deformationalN
173-iformatter N
182-triptorelineN
193-triptorelineN
20biphenyl-2-ylN
21biphenyl-3-ylN
222-methoxyphenylN
233-methoxyphenylN
242-deformationalN
253-deformationalN
262-trifloromethylN
273-trifloromethylN
282-phenoxyphenylN
293-phenoxyphenylN
304-(oxazol-5-yl)phenylN
313-(pyrrolidin-1-yl)phenylN
321-naphthylN

5-(pyridine-2-yl)Tien-2-yl
332-naphthylN
34pyridine-2-ylN
35pyridine-3-ylN
36pyridine-4-ylN
372-(pyrrolidin-1-yl)pyridine-4-ylN
386-morpholinopropan-3-ylN
396-phenoxypyridine-3-ylN
40Tien-2-ylN
415-methyltin-2-ylN
42N
435-(2-methylthiazole-4-yl)-Tien-2-ylN
445-chloro-3-methyl-benzo[b]Tien-2-ylN
452-methylthiazole-5-ylN
462,4-dimethylthiazol-5-ylN
474-methylthiazole-2-ylN
485-methylthiazole-2-ylN
493,5-dimethylisoxazol-4-ylN
501-Mei-4-ylN
51benzothiazole-7-ylN
524-methylbenzofuran-8-ylN
53the quinoline-8-ylN
54 N
552,1,3-benzoxadiazole-4-ylN
564-forfinalN
574-deformationalN
584-triptorelineN
594-deformationalN
604-trifloromethylN
614-methoxyphenylN
624-(oxazol-2-yl)phenylN
634-(oxazol-4-yl)phenylN
643-(oxazol-2-yl)phenylN
653-(oxazol-5-yl)phenylN
663-(oxazol-4-yl)phenyl N

673-(piperazine-1-yl)phenylN
683-(morpholine-4-yl)phenylN
693-(4-methylpiperazin-1-yl)phenylN
702-cyanophenylN
713-cyanophenylN
724-cyanophenylN
736-methylpyridin-3-ylN
746-triptorelin-3-ylN
753-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)phenylN
76phenyln-propyl
772-forfinaln-propyl
78 3-forfinaln-propyl
792,3-differenln-propyl
802,4-differenln-propyl
812.5-differenln-propyl
822,6-differenln-propyl
833,4-differenln-propyl
843,5-differenln-propyl
852-chlorophenyln-propyl
863-chlorophenyln-propyl
872-tolyln-propyl
883-tolyln-propyl
892-isopropylphenyln-propyl
903-isopropy is phenyl n-propyl
912-deformationaln-propyl
923-deformationaln-propyl
932-triptorelinen-propyl
943-triptorelinen-propyl
95biphenyl-2-yln-propyl
96biphenyl-3-yln-propyl
972-methoxyphenyln-propyl
983-methoxyphenyln-propyl

992-deformationaln-propyl
1003-deformationaln-propyl
1012-trifloromethyl1023-trifloromethyln-propyl
1032-phenoxyphenyln-propyl
1043-phenoxyphenyln-propyl
1054-(oxazol-5-yl)phenyln-propyl
1063-(pyrrolidin-1-yl)phenyln-propyl
1071-naphthyln-propyl
1082-naphthyln-propyl
109pyridine-2-yln-propyl
110pyridine-3-yln-propyl
111pyridine-4-yln-propyl
1122-(pyrrolidin-1-yl)pyridine-4-yln-propyl
1136-mortal Celerity-3-yl n-propyl
1146-phenoxypyridine-3-yln-propyl
115Tien-2-yln-propyl
1165-methyltin-2-yln-propyl
1175-(pyridine-2-yl)Tien-2-yln-propyl
1185-(2-methylthiazole-4-yl)-Tien-2-yln-propyl
1195-chloro-3-methyl-benzo[b]Tien-2-yln-propyl
1202-methylthiazole-5-yln-propyl
1212,4-dimethylthiazol-5-yln-propyl
1224-methylthiazole-2-yln-propyl
1235-methylthiazole-2-yln-propyl
1243,5-dimethylisoxazol-4-yln-impregnated the
1251-Mei-4-yln-propyl
126benzothiazole-7-yln-propyl
1274-methylbenzofuran-8-yln-propyl
128the quinoline-8-yln-propyl
129isoquinoline-4-yln-propyl
1302,1,3-benzoxadiazole-4-yln-propyl
1314-forfinaln-propyl
1324-deformationaln-propyl

3,5-differenl
1334-triptorelinen-propyl
1344-deformationaln-propyl
1354-trifloromethyln-impregnated the
1364-methoxyphenyln-propyl
1374-(oxazol-2-yl)phenyln-propyl
1384-(oxazol-4-yl)phenyln-propyl
1393-(oxazol-2-yl)phenyln-propyl
1403-(oxazol-5-yl)phenyln-propyl
1413-(oxazol-4-yl)phenyln-propyl
1423-(piperazine-1-yl)phenyln-propyl
1433-(morpholine-4-yl)phenyln-propyl
1443-(4-methylpiperazin-1-yl)phenyln-propyl
1452-cyanophenyln-propyl
1463-cyanophenyln-propyl
147 4-cyanophenyln-propyl
1486-methylpyridin-3-yln-propyl
1496-triptorelin-3-yln-propyl
1503-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)phenyln-propyl
151phenylMethyl
1522-forfinalMethyl
1533-forfinalMethyl
1542,3-differenlMethyl
1552,4-differenlMethyl
1562.5-differenlMethyl
1572,6-differenlMethyl
1583,4-differenlMethyl
159Methyl
1602-chlorophenylMethyl
1613-chlorophenylMethyl
1622-tolylMethyl
1633-tolylMethyl
1642-isopropylphenylMethyl
1653-isopropylphenylMethyl

1662-deformationalMethyl
1673-deformationalMethyl
1682-triptorelineMethyl
1693-triptorelineMethyl
170biphenyl-2-ylMethyl
171biphenyl-3-ylMethyl
1722-methoxyphenylMethyl
1733-methoxyphenylMethyl
1742-deformationalMethyl
1753-deformationalMethyl
1762-trifloromethylMethyl
1773-trifloromethylMethyl
1782-phenoxyphenylMethyl
1793-phenoxyphenylMethyl
1804-(oxazol-5-yl)phenylMethyl
1813-(pyrrolidin-1-yl)phenylMethyl
1821-naphthylMethyl
1832-naphthylMethyl
184pyridine-2-ylMethyl
185pyridine-3-ylMethyl
186pyridine-4-ylMethyl
1872-(pyrrolidin-1-yl)pyridine-4-ylMethyl
1886-morpholinopropan-3-ylMethyl
1896-phenoxypyridine-3-ylMethyl
190Tien-2-ylMethyl
1915-methyltin-2-ylMethyl
1925-(pyridine-2-yl)Tien-2-ylMethyl
1935-(2-methylthiazole-4-yl)-Tien-2-ylMethyl
1945-chloro-3-methyl-benzo[b]Tien-2-ylmethyl
1952-methylthiazole-5-ylMethyl
1962,4-dimethylthiazol-5-ylMethyl
1974-methylthiazole-2-ylMethyl
1985-methylthiazole-2-ylMethyl
1993,5-dimethylisoxazol-4-ylMethyl

2001-Mei-4-ylMethyl
201benzothiazole-7-ylMethyl
2024-methylbenzofuran-8-ylMethyl
203the quinoline-8-ylMethyl
204isoquinoline-4-ylMethyl
2052,1,3-benzoxadiazole-4-ylMethyl
2064-forfinalMethyl
2074-deformationalMethyl
2084-triptorelineMethyl
2094-deformationalMethyl
2104-trifloromethylMethyl
2114-methoxyphenylMethyl
2124-(oxazol-2-yl)phenylMethyl
2134-(oxazol-4-yl)phenylMethyl
2143-(oxazol-2-yl)phenylMethyl
2153-(oxazol-5-yl)phenylMethyl
2163-(oxazol-4-yl)phenylMethyl
2173-(piperazine-1-yl)phenylMethyl
2183-(morpholine-4-yl)phenylMethyl
2193-(4-methylpiperazin-1-yl)phenylMethyl
2202-cyanophenylMethyl
2213-cyanophenylMethyl
2224-cyanophenylMethyl
2236-methylpyridin-3-ylMethyl
2246-triptorelin-3-ylMethyl
2253-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)phenylmethyl

Table 2: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-12, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-226 - Ia.a-450).

Table 2a: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-12a, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (with the unity Ia.a-226a - Ia.a-450a).

Table 2b: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-12b, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-226b - Ia.a-450b).

Table 3: Compounds of formula I.b.a, in which m and n = 0, and R denotes a group of the formula R-11, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ib.a-1 - Ib.a-225).

Table 4: Compounds of formula I.b.a, in which m and n = 0, and R denotes a group of the formula R-12, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ib.a-226 - Ib.a1-450).

Table 4a: the compounds of formula I.b.a, in which m and n = 0, and R denotes a group of the formula R-12a, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ib.a-226a - Ib.a1-450a).

Table 4b: the compounds of formula I.b.a, in which m and n = 0, and R denotes a group of the formula R-12a, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ib.a-226b - Ib.a1-450b).

Table 5: Compounds of formula I.a.b, in which m and n = 0, and R denotes a group of the formula R-11, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.b-1 - Ia.b-225).

Table 6: Compounds of formula I.a.b, in which m and n = 0, and R denotes a group of the formula R-12, and C is mstiteli Ar and R 1have the meanings given in one of rows 1-225 of table a (compounds Ia.b-226 - Ia.b-450).

Table 6a: the compounds of formula I.a.b, in which m and n = 0, and R denotes a group of the formula R-12a, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.b-226a - Ia.b-450a).

Table 6b: the compounds of formula I.a.b, in which m and n = 0, and R denotes a group of the formula R-12b, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.b-226b - Ia.b-450b).

Table 7: Compounds of formula I.a.c, in which m and n = 0, and R denotes a group of the formula R-11, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.c-1 - Ia.c-225).

Table 8: Compounds of formula I.a.c, in which m and n = 0, and R denotes a group of the formula R-12, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.c-226 - Ia.c-450).

Table 8a: the compounds of formula I.a.c, in which m and n = 0, and R denotes a group of the formula R-12a, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.c-226a - Ia.c-450a).

Table 8b: the compounds of formula I.a.c, in which m and n = 0, and R denotes a group of the formula R-12b, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.c-226b - Ia.c-450b).

Table 9:Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-1, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-451 - Ia.a-675).

Table 10: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of formula R-3, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-676 - Ia.a-900).

Table 11: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-5, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-901 - Ia.a-1125).

Table 11a: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-5a, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-901a - Ia.a-1125a).

Table 11b: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-5b, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-901b - Ia.a-1125b).

Table 12: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-8, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-1126 - Ia.a-1350).

Table 13: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-9, and the substituents Ar and R1matter, Pref is given in one of rows 1-225 of table a (compounds Ia.a-1351 - Ia.a-1575).

Table 14: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-10, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-1576 - Ia.a-1800).

Table 15: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-13, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-1801 - Ia.a-2025).

Table 16: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-15, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-2026 - Ia.a-2250).

Table 16a: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-15a, whereby the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-2026a - Ia.a-2250a).

Table 16b: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-15b, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-2026b - Ia.a-2250b).

Table 17: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-17, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-2251 - Ia.a-2475).

Table 18: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-21, the rich substituents Ar and R 1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-2476 - Ia.a-2700).

Table 19: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-22, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-2701 - Ia.a-2925).

Table 20: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-24, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-2926 - Ia.a-3150).

Table 21: Compounds of the formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-25, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-3151 - Ia.a-3375).

Table 21a: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-25a, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-3151 - Ia.a-3375a).

Table 21b: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-25b, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-3151b - Ia.a-3375b).

Table 22: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-27, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-3376 - Ia.a-3600).

That the face 23: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-28, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-3601 - Ia.a-3825).

Table 24: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-29, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-3826 - Ia.a-4050).

Table 25: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-34, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-4051 - Ia.a-4275).

Table 26: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-35, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-4276 - Ia.a-4500).

Table 27: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-36, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-4501 - Ia.a-4725).

Table 28: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-37, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-4726 - Ia.a-4950).

Table 29: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-38, and the substituents Ar and R1matter, p is evidenee in one of the rows 1-225 of table a (compounds Ia.a-4951 - Ia.a-5175).

Table 30: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-16, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5176 - Ia.a-5400).

Table 30a: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-16a, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5176a - Ia.a-5400a).

Table 30b: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-16b, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5176b - Ia.a-5400b).

Table 31: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-26, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5401 - Ia.a-5625).

Table 31a: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-26a, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5401 - Ia.a-5625a).

Table 31b: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-26b, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5401b - Ia.a-5625b).

Table 32: Compounds of formula I.a.a, in which m and n = 0, and R denotes a group R-44, moreover, the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5626 - Ia.a-5850).

Table 32a: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-44a, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5626a - Ia.a-5850a).

Table 32b: the compounds of formula I.a.a, in which m and n = 0, and R denotes a group of the formula R-44b, and the substituents Ar and R1have the meanings given in one of rows 1-225 of table a (compounds Ia.a-5626b - Ia.a-5850b).

The compounds of formula I according to the present invention can be obtained, as shown in the ways of synthesis is shown below.

1. Common path synthesis

The compounds of formula I in which Q represents N, can be obtained, for example, on the basis of the appropriate 8-halogen-substituted compounds quinoline of the formula II and polycyclic amines III base catalyzed reaction combinations, as shown in figure 1.

Scheme 1:

In scheme 1, the variables R1, R2, R3, R4, R5, A, B, X, Y, Ra, Rb, Ar, m and n have the meanings defined here. R1ahas one of the meanings given for R1preferably different from hydrogen, or denotes a suitable N-protective group, for example butyloxycarbonyl (Vos), benzyloxycarbonyl (Cbz), 9-fluo telmatochromis (Fmoc), triphenylmethyl (Trt), nitrobenzenesulfenyl (Nps), allyl or benzyl. Hal represents halogen, in particular Br or I.

According to the scheme 1 polycyclic amine compound III is introduced into the reaction in the presence of a base with a compound of gelegenheden according to standard processes, for example the processes described in WO2005/113539 or US 2007/0027161, or without a base in a polar aprotic solvent such as dimethyl sulfoxide (DMSO)as described in Bioorg. Med. Chem. Lett., 2003, 13, 1329. The reaction of compounds II and III can also be carried out in the presence of Pd(0)-connection by analogy with the methods described in WO2002/059107, in particular, on page 112, WO03/03197, US 2007/0027161 and Organic Letters, 2003, 5, 897-900.

Suitable bases include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, an alcoholate of an alkali metal such as sodium methylate, sodium ethylate, propylate sodium, n-butyl sodium, tert-butyl sodium, lithium methylate, ethylate, lithium, propilot lithium, n-butyl lithium, tert-butyl lithium, potassium methylate, potassium ethylate, propylate potassium, n-butyl potassium, tert-butyl potassium, alkali metal hydrides, such as lithium hydride, sodium hydride or potassium hydride. The amount of base is preferably at least 0.9 mole per mole of amine,in particular at least 1.0 mol per mole of amine, for example from 1.1 to 10 mol per mol of amine III.

In a preferred embodiment, the reaction mix II and III is carried out in the presence of a catalytically effective amount of compounds of palladium (0) or palladium compounds, which are capable of forming a compound of palladium (0) under the reaction conditions, such as palladium dichloride, palladium (II)acetate, tetrakis(triphenylphosphine)palladium (0) or Tris(dibenzylideneacetone)diplegia (0) (= Pd2(DBA)3), preferably in combination with phosphine ligands, such as triarylphosphine, such as triphenylphosphine, trialkylphosphines, such as tri-n-butylphosphine, three-tert-butylphosphine, and cycloalkylation, such as tricyclohexylphosphine, and especially with the ligand chelates of phosphine, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,1'-bis(diphenylphosphino)ferrocene or 1,4-bis(diphenylphosphino)butane. A catalytically effective amount is preferably from 1 to 500 mmol, in particular from 10 to 300 mmol per mole of compound II.

In General, the reaction mix II and III is carried out in an inert solvent. Suitable inert solvents include aromatic hydrocarbons such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene, butylbenzoyl, tert-butylbenzoyl, chlorobenzene, dichlorobenzene, anisole, simple aliphatic or alicyclic ethers, such as tetrahedra is furan, methyltetrahydrofuran, dioxane, aliphatic or alicyclic sulfones and sulfoxidov, such as dimethylsulfoxide, sulfolane and the like, N,N-dialkylamide aliphatic C1-C3-carboxylic acids and N-alkilany, such as dimethylformamide, dimethylacetamide, N-organic N-methylpiperidine and N-ethylpyrrolidin.

The compounds of formula I in which R1denotes hydrogen, can be obtained from compounds of the formula I' splitting N-R1alink if R1represents a suitable protective group.

If the resulting quinoline compound I' radical R1ais not desired radical R1and its predecessor, the connection may be modified, as shown below, to give the desired substituent R1. The predecessor is a radical, which can be easily removed and replaced by the desired group R1or which can be modified with the formation of R1. The precursor may also be an N-protecting group (PG)such as butyloxycarbonyl (Vos), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trt), nitrobenzenesulfenyl (Nps), allyl and benzyl.

If R1adenotes allyl, allyl group may be cleaved to obtain the compounds of formula I in which R1denotes hydrogen. Cleavage of the allyl group made tlaut, for example, introducing a compound I', where R1a= allyl, reaction with breathtaking allyl agent such as mercaptobenzoic acid or 1,3-dimethylbarbituric acid, in the presence of catalytic amounts of the compounds of palladium (0) or palladium compounds, which are capable of forming a compound of palladium (0) under the reaction conditions, such as palladium dichloride, tetrakis(triphenylphosphine)palladium (0) or Tris(dibenzylideneacetone)diplegia (0), preferably in combination with phosphine ligands, for example, triarylphosphine, such as triphenylphosphine, trialkylphosphines, such as tributylphosphine, and cycloalkylation, such as tricyclohexylphosphine, and especially with the ligand chelates phosphine, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 1,4-bis(diphenylphosphino)butane, using methods known to the expert (relative to the removal of N-allyl in the presence of mercaptobenzoic acid see WO94/24088; relative to the cleavage in the presence of 1,3-dimethylbarbituric acid, see J. Chem. Soc. 2001, 123 (28), PP. 6801-6808 and J. Org. Chem. 2002, 67 (11) PP. 3718-3723). Alternatively, cleavage of the N-allyl may also be carried out by introducing into the reaction of the compound (I', where R1adenotes allyl in the presence of rhodium compounds, such as Tris(triphenylphosphine)chloride (I), by analogy with the methods described in J. Chem. Soc, Perkin Transaction I: Organic and Bio-Organic Chemisty 1999 (21) pp. 3089-3104 and Tetrahedron Asymmetry 1997, 8(20), pp. 3387 - 3391).

If R1adenotes benzyl, this Vice can also be derived by obtaining the compounds I, in which R1denotes N. The reaction conditions for the cleavage are known from the prior art. As a rule, the benzyl group is removed by hydrogenation reaction in the presence of a suitable catalyst based on Pd, such as Pd on coal or palladium hydroxide.

R1acan also be tsepliaeva acid protecting group. The protective group can be removed to obtain compounds I in which R1adenotes hydrogen. Suitable protective groups are known in the art and, for example, can be selected from tert-butoxycarbonyl (Vos), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trt) and nitrobenzenesulfenyl (Nps). The preferred protecting group is BOC. The protective group can be removed by known methods, such as processing protected amine acid, for example halogenation acid, such as HCl or HBr, formic acid or triperoxonane acid or by hydrogenation, if necessary in the presence of a catalyst based on Pd.

The obtained compound I, in which R1denotes H, can then be introduced into the reaction in a known manner, in the sense of alkylation, with a compound R1b-X, that is R 1bhas one of the meanings given for R1that is different from hydrogen. In this connection, R1bpreferably represents C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-halogenated, C1-C4-alkoxy-C1-C4-alkyl, aryl-C1-C4-alkyl, hetaryl-C1-C4-alkyl or C3-C6-cycloalkyl-C1-C4-alkyl and X denotes nucleophile replaced the deleted group, for example halogen, triftormetilfullerenov, alkylsulfonate, arylsulfonate, alkylsulfate and other reaction Conditions that are required for alkylation, are disclosed, for example in Bioorganic and Medicinal Chemistry Lett. 2002, 12(7), pp. 2443-2446 and 2002, 12(5), pp. 1917-1919.

The alkylation can also be carried out, in the sense of a reductive amination, the introduction of compound I, in which R1= H, in a reaction with a suitable ketone or aldehyde in the presence of a reducing agent, for example in the presence of a borohydride such as sodium borohydride, cyanoborohydride sodium or triacetoxyborohydride sodium. Specialist known reaction conditions that are required for reductive amination, for example, Bioorganic and Medicinal Chemistry Lett. 2002, 12(5), pp. 795-798 and 12(7) pp. 1269-1273.

If R1denotes hydrogen, compound I may also be introduced into the reaction allelochemical with getting connected to the I formula I, in which R1represents formyl or C1-C3-alkylsulphonyl. Carbonyl group in these compounds can be recovered by DIBORANE with obtaining compounds of General formula I, in which R1represents C2-C4-alkyl. The carbonyl group may also be introduced into reaction with a fluorinating agent to obtain compounds I in which R1denotes 1,1-diferuloyl. The acylation and recovery can be carried out by standard methods, which are discussed in Jerry March, Advanced Organic Chemistry, 3rd ed. J. Wiley & Sons, New York 1985, p.370 and 373 (acylation) and p. 1099 f. and in the literature cited in this publication (relatively acylation see also Synth. Commun. 1986, 16, p. 267, and relative recovery see also J. Heterocycl. Chem. 1979, 16, p. 1525).

The compounds of formula I in which Q represents CH may be obtained, for example, on the basis of the appropriate 8-halogen-substituted compounds quinoline of the formula II and polycyclic amines IIIa Pd-catalyzed cross-reaction combinations, as shown in diagram 2.

Scheme 2:

Figure 2 variables R1, R2, R3, R4, R5, A, B, X, Y, Ra, Rb, Ar, m and n have the meanings defined here. R1ahas one of the meanings given for R1preferably different from hydrogen, or denotes a suitable N for itnow group, for example butyloxycarbonyl (Vos), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Trt), nitrobenzenesulfenyl (Nps), allyl or benzyl. Hal and Hal' represent halogen, in particular Br or I. According to scheme 2, the compound of halogen IIIa turn in tsinkorganicheskih connection IIIb according to standard processes, for example by the process described in Tetrahedron 1987, 43, 2203-2212; J. Org. Chem. 1988, 53, 2390-2392. Tsinkorganicheskih connection is then injected into the reaction Pd(0)-mediated cross-combination type Negeshi with a suitable connection 8-gelegenheden II, receiving 8-substituted compound I', by analogy with the method described in Synlett 1998, 4, 379 - 380; J. Am. Chem. Soc. 2003, 125, 12527-12530. Alternatively, the intermediate tsinkorganicheskih connection IIIb can be transmetallation, for example with CuCn*2LiCl and then introduced into reaction with the compound 8-gelegenheden formula II.

Connection 8-gelegenheden formula II are commercially available or they can be obtained according to conventional methods of organic synthesis known to the person skilled in the art, for example, by analogy with the method described in WO2003/080580. The compounds of formula II in which X represents S(O)2can be obtained, for example, from compounds 8-nitroquinoline formula XII, as depicted in scheme 3.

Scheme 3:

Commercially available is nye nitroquinoline, such as IV can be converted to 3-izlesene derivatives processing Jodorowsky reagent, such as N-jodatime, in a solvent such as acetic acid, to obtain the compound 3 - or 4-athineon V. 3 - And 4-isomers can be separated at this stage or a later stage. Compound V is then injected into the reaction with a salt of an alkali metal sulfinol acid Ar-S(O)OH, for example the sodium salt Ar-S(O)2Na, in the presence of a salt of copper (I), such as triplet copper (I), in a polar solvent such as N,N-dimethylacetamide (DMA) or DMF, to obtain the compounds of quinoline VI. The restoration of the nitro group VI gives aminosidine VII. Recovery can be done in various ways, including the restoration of "non-hydrogen" reducing agent, such asSnCl2or methods of catalytic hydrogenation, well-known specialist. The amino group VII is then converted into iodine Sandmeyer reaction using source microzone (for example, NaNO2, nBuNO2) and iodide (e.g., CuI or nBu4NI) in a suitable solvent such as water or CH3CN.

The compounds of formula III are commercially available or known from the prior art or can be obtained from the corresponding polycyclic amines having a free NH-group, by selective attaching/removing the protective groups the desired NH-groups solenostemon methods NH-protection, as described in P. Kocienski, "Protecting Groups, Thieme Verlag, Stuttgart 2000, pp. 185-243 and are there links. The compounds of formula III, for example, described in Journal of Medicinal Chemistry (2007), 50(22), 5493-5508, WO2001/081347, WO2008/060767, WO2008/041090, WO2007/100990 and Bioorganic & Medicinal Chemistry Letters (2006), 16(11), 2891-2894.

Unless otherwise stated, the above reaction is usually carried out in a solvent at temperatures from ambient temperature up to the boiling point of the used solvent. Alternatively, the activation energy required for the reaction may be introduced into the reaction mixture using a microwave reactor, something that has proven value, in particular, in the case of reactions catalyzed by transition metals (relative to reactions using microwave reactors, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in General, "Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH 2002.

Salt accession acid compounds I get the usual manner by mixing the free base with the appropriate acid, optionally in solution in an organic solvent, for example acetonitrile, a lower alcohol, such as methanol, ethanol or propanol, simple ether, such as diethyl ether, methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, complex ether, such as ethyl acetate, and their mixtures, and their mixtures with water.

Connect the s according to the invention may be an agonist of 5-HT 6receptor, including partial agonistic activity, or an antagonist of 5-HT6receptor, including inverse agonistic activity.

The compounds of formula I according to the present invention have a surprisingly high affinity for 5-HT6the receptors. The high affinity of the compounds according to the invention to 5-HT6receptors is reflected in a very low constant of the receptor binding in vitro (values of Ki(5-HT6)), typically less than 50 nm (nmol/l), preferably less than 10 nm and in particular less than 5 nm. Offset3H-LSD may, for example, be used in the study of the receptor binding to determine the binding affinity of 5-HT6the receptors.

In addition, the compounds of formula I are selective ligands of 5-HT6receptor, which, because of their low affinity for other receptors such as dopamine receptors, adrenergic receptors, muscarinic receptors, histamine receptors, opiate receptors, in particular dopamine receptors D2α1-adrenergic receptors of histamine H1cause fewer side effects than other, less selective 5-HT6the ligands.

For example, 5-HT6/D2, 5-HT61-adrenergic and 5-HT6/H1the selectivity of the compounds according to the present invention, i.e. the relations Ki(D2 )/Ki(5-HT6), Ki1-adrenergic)/Ki(5-HT6orKi(H1)/Ki(5-HT6) constants of the receptor binding, are, as a rule, at least 25, preferably at least 50, even better at least 100.

The displacement of [3H]SCH23390 and [125I]spiperone can be used, for example, for studies of binding to receptors of D1D2and D4.

In addition, the compounds of formula I in virtue of their structural features may exhibit increased penetration in the brain compared with other known ligands of 5-HT6the receptor.

Because of their profile of binding of these compounds can be used for the treatment of diseases that respond to ligands of 5-HT6receptor (or which may be subjected to treatment with ligand 5-HT6receptor), i.e. they are effective for treating those medical disorders or diseases in which the influence (modulation) of 5-HT6receptors leads to clinical improvement or cure of the disease. Examples of these diseases are disorders or diseases of the Central nervous system.

Disorders or diseases of the Central nervous system is understood as meaning disorders that affect the spinal cord and, in particular, the brain. In R is mcah of the invention, the term "violation" means a disorder and/or anomalies, which, as a rule, are regarded as being pathological conditions or functions and which can manifest itself directly in the form of specific signs, symptoms and/or dysfunctions. Although the treatment according to the invention can be directed to individual violations, i.e. anomalies or pathological condition, it is also possible for several anomalies that may be etiological connected to each other, United by the picture, that is, syndromes that can be treated in accordance with the invention.

Disorders that can be treated in accordance with the invention are, in particular, disorders that respond to modulation of 5-HT6the receptor. They include cognitive dysfunction, such as memory deficit, teaching, and learning, in particular associated with Alzheimer's disease, age-related decline in cognitive function and moderate deterioration in cognitive function, attention deficit disorder/hyperactivity, personality changes, such as schizophrenia, in particular cognitive deficits related functions schizophrenia, affective disorders such as depression, anxiety and obsessive-compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, rasstroistvami (including disturbances of circadian rhythm), eating disorders such as anorexia and bulimia, certain gastrointestinal disorders such as irritable bowel syndrome, diseases associated with neurodegeneration, such as stroke, spinal cord injury or head trauma and traumatic brain injuries, such as hydrocephalus, drug addiction and obesity.

Diseases associated with addiction include mental disorders and behavioural disorders caused by the abuse of psychotropic substances, such as pharmaceuticals or drugs, and other diseases associated with addiction, such as the tendency to games (abnormal pulse monitor, unclassified elsewhere). Examples of substances causing dependence: opioids (e.g. morphine, heroin and codeine), cocaine; nicotine; alcohol; substances that interact with a channel complexes GABA-chloride, sedatives, sleeping pills, and tranquilizers, such as benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylendioxy-N-methylamphetamine (ecstasy), amphetamine and amphetamine-like substances such as methylphenidate and other stimulants, including caffeine. Substances that cause addiction, which is particularly aimed the present invention are opioids, cocaine, amphetamine or amp is tapinophobia substances, nicotine and alcohol.

Regarding the treatment of diseases associated with addiction, particular preference is given to compounds of the formula I according to the invention, which does not directly have any psychotropic effects. It can also be observed in the test using rats, which, after the introduction of compounds that can be used in accordance with the invention, by themselves, reduce the consumption of psychotropic substances, such as cocaine.

According to another aspect of the present invention, the compounds according to the invention are suitable for treating disorders that can at least partially be attributed to abnormal activity of 5-HT6receptors.

According to another aspect of the present invention, the treatment is directed, in particular, on those violations that can be influenced, within reasonable medical treatment, linking, preferably exogenous input binding partners (ligands) with 5-HT6the receptors.

Diseases that can be treated by the compounds according to the invention, are often characterized by a progressive development, that is, the above-described state changes over time; as a rule, the severity increases, and States can pass each other, or may experience other state in more the existing.

The compounds of formula I can be used to treat a large number of signs, symptoms and/or dysfunctions that are associated with disorders of the Central nervous system, and, in particular, the above conditions. These signs, symptoms and/or dysfunctions include, for example, violated the relation to reality, the lack of understanding and ability to conform to generally accepted social norms or requirements, changes in temperament, changes in individual motivation, such as hunger, sleep, thirst and so on, and mood, impaired ability to observe and combine, personality changes, in particular, emotional lability, hallucinations, disorders of ego, confusion, ambivalence, autism, depersonalization, and a false perception, delusions, repetitions in speech, lack of synkinesia, mincing gait, flexion posture of the body and limbs, tremor the poverty of facial expression, monotonous speech, depression, apathy, decreased spontaneity and determination, deterioration of the Association, anxiety, nervous excitement, stuttering, social phobia, panic disorder, abstinence in combination with addiction, expansive syndromes state of excitement and confusion, dysphoria, dyskinetic syndromes and teak, for example, Huntington's chorea and the syndrome of Gilles de La Tourette, syndromes of the head is ugenia, for example, peripheral positional, rotational and vibrational dizziness, depression, hysteria, hypochondria, etc.

In the framework of the invention, the treatment also includes preventive treatment (prophylaxis), in particular the prevention of the recurrence or phase prevention, and treatment of acute or chronic signs, symptoms and/or dysfunctions. Treatment may focus on symptoms, such as suppression of symptoms. It may be held for a short period, average duration, or may represent a long-term treatment, for example, within the context of supportive therapy.

Compounds according to the invention are preferably suitable for the treatment of diseases of the Central nervous system, more preferably for the treatment of cognitive dysfunction, and in particular, for the treatment of cognitive dysfunction associated with schizophrenia or Alzheimer's disease.

According to another aspect of the invention the compounds of formula (I) are particularly suitable for the treatment of diseases associated with addiction, caused, for example, by the abuse of psychotropic substances, such as pharmaceuticals, drugs, nicotine or alcohol, including associated mental disorders and behavioral disorders.

According to another aspect is the invention of the compounds of formula (I) are particularly suitable for the treatment of eating disorders, such as obesity, and related diseases such as cardiovascular diseases, digestive tract diseases, respiratory diseases, cancer or type 2 diabetes.

Within the context of the treatment use according to the invention described compounds include method. In this method, an effective amount of one or more compounds, as a rule, prepared in accordance with the pharmaceutical and veterinary practice, introduce a subject to treatment to a person, preferably a mammal, in particular human, productive animal or domestic animal. Shows whether such treatment and in what form it should take place depends on the individual case and should be the object of medical research (diagnosis), which should take into account the signs, symptoms and/or dysfunctions that are present, the risk of development of specific signs, symptoms and/or dysfunctions and other factors.

As a rule, treatment is implemented by a single or repeated daily introduction to the subject of the treatment of the face, if necessary, together or alternating with other active compounds or containing active compound preparations, so that the daily dose is preferably from about 0.1 to 1000 mg/kg of body weight in the case of Perera inogo introduction or from about 0.1 to 100 mg/kg of body weight in the case of parenteral administration.

The invention also relates to the production of pharmaceutical compositions for the treatment of a person, preferably a mammal, in particular human, productive animal or pet. Thus, the compounds of formula I is usually administered in the form of pharmaceutical compositions that include pharmaceutically acceptable excipient together with at least one compound according to the invention and, if necessary, other active compounds. These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally.

Examples of suitable pharmaceutical formulations are solid dosage forms such as powders, granules, tablets, in particular, film tablets, lozenges, sachets, pills, tablets, coated with a sugar shell, capsules such as hard capsules and soft gelatin capsules, suppositories or vaginal dosage forms, semi-solid dosage forms such as ointments, creams, hydrogels, pastes or patches, and liquid dosage forms such as solutions, emulsions, particularly emulsions of the type oil-in-water, suspensions, such as lotions, preparations for injection and preparations for infusions, and eye and ear drops. The implantable device to release the mod is ut also be used for injection of the inhibitors according to the invention. In addition, it is also possible to utilize liposomes or microspheres.

Upon receipt of the compositions of the compounds according to the invention, if necessary, is mixed or diluted with one or more excipients. Excipients can be solid, semi-solid or liquid materials that are the foundations, the media, or medium for the active connection.

Suitable excipients are listed in specialized medical monographs. In addition, the compositions can include pharmaceutically acceptable carriers or conventional excipients, such as glidant; wetting agents; emulsifying and suspendresume agents; preservatives; antioxidants; anti-irritation; chelating agents; means for creating coatings; stabilizers of emulsions; film formers; geleobrazovanie; masking the scent of the product; editors of taste; resins; hydrocolloids; solvents; soljubilizatory; neutralizing agents; accelerators diffusion; pigments; Quaternary ammonium base; perejivayuschie additives, raw materials for ointments, creams or oils; silicone derivatives; auxiliary means for controlling distribution over the surface; stabilizers; sterilizers, principles of suppository; auxiliary means for tableting, such as binders, fillers, glidant, de the integrators or coating; propellants; dehumidifiers; fogging components; thickening agents; waxes; softeners and white mineral oil. The composition in this regard is based on specialist knowledge, as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [encyclopedia of excipients for pharmaceuticals, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

The following examples serve to illustrate the present invention without limiting its scope.

Connection or okharakterizovali using proton NMR in d6-sulfoxide or d-chloroform on the device for NMR at 500 MHz or 400 MHz (Bruker AVANCE), or mass spectrometry, typically, by HPLC-MS in fast gradient on C18-material (method ionization elektrorazpredelenie (ESI)), or by melting point.

Spectral properties of nuclear magnetic resonance (NMR) refer to chemical shifts (δ)expressed in parts per million (ppm). The relative area of the shifts in the spectrum of1H NMR corresponds to the number of hydrogen atoms for private functional type in the molecule. The nature of the shift, with regard to the multiplicity, is designated as singlet (s), broadened singlet (s usher.), doublet (d), broadened doublet (d user.), triplet (t), broadened triplet (t OSiR.), Quartet (q), quintet (Quint.) and multiplet (m).

8-Nitro-3-(phenylsulfonyl)quinoline was when breten Insight Chemical Solutions and also obtained using the procedures described in the patent application WO2003/80580.

3-iodine-8-nitroquinoline was purchased from Insight Chemical Solutions and also obtained using the procedure described in the patent application WO2003/080580.

(3aS,6aS)-hexahydro-pyrrolo[3,4-b]pyrrole-5-ethylcarboxylate was obtained using the procedures described in WO2008060767, WO2008041090, WO2007100990 and Bioorganic & Medicinal Chemistry Letters (2006), 16(11), 2891-2894.

(3aS,6aS)-hexahydro-pyrrolo[3,4-b]pyrrole-5-tert-butylcarbamoyl commercially available from Focus Synthesis and Apamin.

Tert-butyl ether (1R,5S)-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid was obtained from phenyl ether (1S,5S)-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid protection of the free amine di-tert-butyl-dicarbonate and subsequent removal of the benzyloxy-carbonyl group. Phenyl ester of (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylic acid was synthesized according to Journal of Medicinal Chemistry (2007), 50(22), 5493-5508 and WO 2001081347, but it is also available commercially from Asta Tech.

Tert-butyl ether (1S,5R)-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid was obtained from phenyl ether (1R,5R)-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid as described for tert-butyl ether (1R,5S)-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid.

I. Receiving connections

EXAMPLE 1: 8-(Hexahydropyrazino[3,4-b]pyrrol-5(1H)-yl)-3-(phenylsulfonyl)quinoline hydrochloride

1.1 3-(Phenylsulfonyl)quinoline-8-amine

K R is the target 8-nitro-3-(phenylsulfonyl)quinoline (3,70 g, 11,77 mmol) in acetic acid (40 ml) at 80°C was added in portions over 5 minutes iron powder (3,29 g, 58,86 mmol). The resulting suspension was stirred for another 30 minutes. Then it was cooled to ambient temperature and filtered. The solid was washed with acetic acid and the collected filtrates were concentrated. The residue was dissolved in CH2Cl2and washed with ammonium hydroxide solution (25%), water and then dried over MgSO4. The organic layer was filtered and then evaporated, obtaining the target compound (3,20 g, 96%) in the form of a solid yellow color.

MS (ESI+) m/z = 285,1 [M+H]+

1.2 8-Iodine-3-(phenylsulfonyl)quinoline

8-Iodine-3-(phenylsulfonyl)quinoline was obtained from 3-(phenylsulfonyl)quinoline-8-amine according to the procedure previously described in the patent application WO2003080580.

MS (ESI+) m/z = 395,9 [M+H]+

1.3 5-(3-(Phenylsulfonyl)quinoline-8-yl)hexahydrofuro[2,3-c]pyrrol-1(2H)-tert-butylcarbamoyl

A solution of tert-butyl sodium (70 mg, 0.71 mmol) and hexahydrofuro-[2,3-c]pyrrol-1(2H)-tert-BUTYLCARBAMATE (537 mg, 2,53 mmol) in dioxane (3 ml) was stirred in nitrogen atmosphere. To it was added 1,1'-bis(diphenylphosphino)ferrocene (25 mg, 0.05 mmol), Pd2(DBA)3(12 mg, 0.02 mmol) and 8-iodine-3-(phenylsulfonyl)quinoline (200 mg, 0.51 mmol), then add an additional 2 ml of dioxane. The mixture then was heated at 40°C in accordance with is their 12 hours, then was divided between CH2Cl2and water. The mixture was filtered through Celite and the organic phase was separated. The aqueous phase was extracted twice, CH2Cl2and the combined extracts were dried (Na2SO4), filtered and concentrated in vacuum to give crude material which was purified flash chromatography, obtaining the target compound (92 mg, 38%) in the form of a light yellow oil.

MS (ESI+) m/z = 480,1 (M+H)+

1H NMR (400 MHz, DMSO): δ (ppm) rotamer to 1.38 (d, 9H), is 1.82 (m, 1H), 2,02 (m, 1H), 3,00 (m, 1H), 3,40 (m, 2H), 3,68 (m, 2H), 3,82 (m, 1H), 3,95 (m, 1H), 4,25 (m, 1H), 7,02 (s, 1H), 7,53 (s, 2H), 7,65 (m, 5H), 8,09 (d, 1H), 8,97 (s, 1H), 9,10 (users, 1H).

1.4 8-(Hexahydropyrazino[3,4-b]pyrrol-5(1H)-yl)-3-(phenylsulfonyl)quinoline hydrochloride

A solution of 5-(3-(phenylsulfonyl)quinoline-8-yl)hexahydrofuro[2,3-c]pyrrol-1(2H)-tert-BUTYLCARBAMATE (92 mg, 0,19 mmol) in CH2Cl2(5 ml) was treated with hydrochloric acid (4M in dioxane, 2 ml) at 0°C and then stirred at 50°C for 16 hours. After concentration, the product washed with EtOAc and dried in vacuum, obtaining the target compound (80 mg, 100% in the form of a solid white color.

MS (ESI+) m/z = 380,1 (M+H)+

1H NMR (400 MHz, DMSO): δ (ppm) 1,95 (m, 1H), measuring 2.20 (m, 1H), 3,12 (m, 1H), 3,26 (m, 2H), to 3.67 (m, 2H), 3,97 (m, 1H), 4,15 (m, 1H), or 4.31 (m, 1H), 7,12 (d, 1H), 7,65 (m, 5H), 8,10 (d, 1H), cent to 8.85 (users, 1H), 9,05 (, 1H), which 9.22 (users, 1H).

EXAMPLE 2: 6-(3-(phenylsulfonyl)quinoline-8-yl)-3,6-diazabicyclo[3,2,heptan-3-benzylcarbamoyl

A solution of tert-butyl sodium (49 mg, 0.51 mmol) and (1S,5S)-benzyl-3,6-diazabicyclo[3,2,0]heptane-3-carboxylate (98 mg, 0.24 mmol) in toluene (3 ml) was stirred in nitrogen atmosphere. To it was added tri-tert-butylphosphine (25 mg, 0.05 mmol), palladium (II) acetate (6.9 mg, 0.03 mmol) and 8-iodine-3-(phenylsulfonyl)quinoline (80 mg, 0,202 mmol). The mixture then was heated at 60°C for 2 hours, after which it was divided between CH2Cl2and water. The mixture was filtered through Celite and the organic phase was separated. The aqueous phase was extracted twice, CH2Cl2and the combined extracts were dried (Na2SO4), filtered and concentrated in vacuum to give crude material which was purified flash chromatography, obtaining the target compound.

MS (ESI+) m/z = 500,2 (M+H)+

EXAMPLE 3: 2-(3-(phenylsulfonyl)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-butylcarbamoyl

A solution of tert-butyl sodium (49 mg, 0.51 mmol) and (1S,5S)-benzyl-3,6-diazabicyclo[3,2,0]heptane-3-carboxylate (98 mg, 0.24 mmol) in toluene (3 ml) was stirred in nitrogen atmosphere. To this solution was added tri-tert-butylphosphine (25 mg, 0.05 mmol), palladium (II) acetate (6.9 mg, 0.03 mmol) and 8-iodine-3-(phenylsulfonyl)quinoline (80 mg, 0,202 mmol). The mixture then was heated at 60°C for 2 hours. The reaction mixture is then shared between CH2Cl2and water. The mixture was filtered through Celite and the organic the second phase was separated. The aqueous phase was extracted twice, CH2Cl2and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuum to give crude material which was purified flash chromatography, obtaining the target compound.

MS (ESI+) m/z = of 494.5 (M+H)+

EXAMPLE 4: 3-(Phenylsulfonyl)-8-(1H-pyrrolo[3,4-c]pyridine-2 (3H,3aH,4H,5H,6H,7H,7aH)-yl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that used 2-(3-(phenylsulfonyl)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-butylcarbamoyl. 25 mg (51%) of target compound was obtained in the form of a solid of light yellow color.

MS (ESI+) m/z = 394,1 (M+H)+

EXAMPLE 5: (1R,5S)-3-(3-(phenylsulfonyl)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-6-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that he used (1R,5S)-3,6-diazabicyclo[3,2,0]heptane-6-tert-butylcarbamoyl.

MS (ESI+) m/z = 465,1 (M+H)+

EXAMPLE 6: 8-((1S,5S)-3,6-diazabicyclo[3,2,0]heptane-3-yl)-3-(phenylsulfonyl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that he used (1R,5S)-3-(3-(phenylsulfonyl)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-6-tert-butylcarbamoyl.

MS (ESI+) m/z = 365,1 (M+H)+

EXAMPLE 7: (3aS,6aS)-1-(3-(phenylsulfonyl)quinoline-8-yl)who hexahydrofuro[3,4-b]pyrrol-5(1H)-ethylcarboxylate

A solution of 8-fluoro-3-(phenylsulfonyl)quinoline (100 mg, 0,348 mmol), (3aS,6aS)-hexahydrofuro[3,4-b]pyrrol-5(1H)-ethylcarboxylate (2R,3R)-2,3-bis(benzoyloxy)succinate (944 mg, of 1.74 mmol) and K2CO3(577 mg) in DMF (3 ml) was stirred under nitrogen atmosphere and was heated at 100°C for 7 hours. The cooled mixture was diluted with 10 ml saturated NaCl, and the precipitate was collected and dried, obtaining the target compound.

MS (ESI+) m/z = 454,1 (M+H)+

EXAMPLE 8: 5-(3-(4-perpenicular)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-1(2H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that used 3-(4-perpenicular)-8-athineon and hexahydrofuro[3,4-b]pyrrol-1(2H)-tert-butylcarbamoyl. 250 mg (69%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 498,2 (M+H)+

EXAMPLE 9: 5-(3-(phenylsulfonyl)quinoline-8-yl)octahydro-1,5-naphthiridine-1(2H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that used octahydro-1,5-naphthiridine-1(2H)-tert-butylcarbamoyl. 120 mg (9%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 508,2 (M+H)+

EXAMPLE 10: 1-(3-(phenylsulfonyl)quinoline-8-yl)decahydro-1,5-naphthiridine

The target compound was obtained by analogy with the procedure of Example 1.4, for the claim is ucheniem, they used 5-(3-(phenylsulfonyl)quinoline-8-yl)octahydro-1,5-naphthiridine-1(2H)-tert-butylcarbamoyl. 1 mg (8%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 408,2 (M+H)+

EXAMPLE 11: 2-(3-(4-perpenicular)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that used hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-butylcarbamoyl and 3-(4-perpenicular)-8-athineon. 130 mg (55%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 512,2 (M+H)+

EXAMPLE 12: 8-((3aS,6aS)-hexahydrofuro[3,4-b]pyrrol-1(2H)-yl)-3-(phenylsulfonyl)-quinoline

A solution of (3aS,6aS)-1-(3-(phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-5(1H)-ethylcarboxylate (60 mg, 0.133 mmol) and (trimethylsilyl)-iodide (160 mg, 0,797 mmol) in chloroform (1 ml) was stirred at reflux for 1.5 hours. Was added methanol (4 mg) and the solution was separated between ethyl acetate and aqueous solution of NaOH (1M). The organic extract was dried (MgSO4), filtered and concentrated, gaining 11 mg (22%) of target compound in the form of a light yellow oil.

MS (ESI+) m/z = 380,1 (M+H)+

EXAMPLE 13: 3-(4-perpenicular)-8-(1H-pyrrolo[3,4-c]pyridine-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)quinoline

Target connection polucheniya analogy with the procedure of Example 1.4, except that used 2-(3-(4-perpenicular)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-butylcarbamoyl. 81 mg (77%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 412,2 (M+H)+

EXAMPLE 14: 3-(4-perpenicular)-8-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that used 5-(3-(4-perpenicular)quinoline-8-yl) hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl. 121 mg (92%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 398,1 (M+H)+

EXAMPLE 15: 5-(3-(3-(triptoreline)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that used hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl and 8-iodine-3-(3-(triptoreline)phenylsulfonyl)quinoline. 140 mg (79%) of target compound was obtained in the form of a solid of light yellow color.

MS (ESI+) m/z = 564,2 (M+H)+

EXAMPLE 16: 8-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)-3-(3-(triptoreline)-phenylsulfonyl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that used 5-(3-(3-(triptoreline)phenylsulfonyl)quinoline-8-yl)gexa the draw pyrrolo[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl. 79 mg (74%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 464,1 (M+H)+

EXAMPLE 17: 5-(3-(3-(5-(tert-butoxycarbonyl)hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of 1.3, except that used hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl and 3-(3-brompheniramine)-8-athineon. 18 mg (12%) of target compound was obtained in the form of a solid of light yellow color.

MS (ESI+) m/z = 690,3 (M+H)+

EXAMPLE 18: 8-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)-3-(3-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)phenylsulfonyl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that used 5-(3-(3-(5-(tert-butoxycarbonyl)hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl. 9 mg (58%) of Target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 490,1 (M+H)+

EXAMPLE 19: 2-(3-(3-(triptoreline)phenylsulfonyl)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that used hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-BUTYLCARBAMATE the ATA and 8-iodine-3-(3-(triptoreline)phenylsulfonyl)quinoline. 130 mg (54%) of target compound was obtained in the form of a solid of light yellow color.

MS (ESI+) m/z = 578,2 (M+H)+

EXAMPLE 20: 8-(1H-pyrrolo[3,4-c]pyridine-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-(triptoreline)phenylsulfonyl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that used 2-(3-(3-(triptoreline)phenylsulfonyl)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-tert-butylcarbamoyl. 67 mg (63%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 478,1 (M+H)+

EXAMPLE 21: 5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-1(2H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that used hexahydrofuro[3,4-b]pyrrol-1(2H)-tert-butylcarbamoyl and 8-iodine-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline. 133 mg (56%) of target compound was obtained in the form of a solid of light yellow color.

MS (ESI+) m/z = 548,2 (M+H)+

EXAMPLE 22: 8-(hexahydropyrazino[3,4-b]pyrrol-5(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that used 5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinoline-8-yl)hexahydro-pyrrolo[3,4-b]pyrrol-1(2H)-tert-butylcarbamoyl. 17 mg (17%) of target compound was obtained in formicola-yellow oil.

MS (ESI+) m/z = 448,1 (M+H)+

EXAMPLE 23: (3aR,6aS)-5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl

The target compound was obtained by analogy with the procedure of Example 1.3, except that he used (3aR,6aS)-hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl and 8-iodine-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline. 107 mg (60%) of target compound was obtained in the form of a solid of light yellow color.

MS (ESI+) m/z = 548,2 (M+H)+

EXAMPLE 24: 8-((3aR,6aS)-hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline

The target compound was obtained by analogy with the procedure of Example 1.4, except that he used (3aR,6aS)-5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-c]pyrrol-2(1H)-tert-butylcarbamoyl. 103 mg (97%) of target compound was obtained in the form of a light yellow oil.

MS (ESI+) m/z = 448,1 (M+H)+

EXAMPLE 25: (3aS,6aS)-ethyl-1-(3-(3-Perpenicular)quinoline-8-yl)hexahydro-pyrrolo[3,4-b]pyrrol-5(1H)-carboxylate

25.1 3-(3-perpenicular)-8-nitroquinoline

15 g of 3-iodine-8-nitroquinoline (50 mmol), 0,476 g CuJ (2.5 mmol) and 21,22 g K3PO4(100 mmol) suspended in 150 ml of ethylene glycol. Added being 9.61 g of 3-fermentation, and the reaction mixture was stirred at 80°C for 6 hours, followed by stirring for 14 hours at pace is the atur environment. The reaction mixture was divided between 150 ml of dichloromethane and 150 ml of water and, after stirring for 15 minutes, the organic phase was separated. The aqueous layer was extracted again with dichloromethane, the combined organic layers were washed with water and stirred with 5 g of activated charcoal for 15 minutes, the Filtrate was added to a suspension of 54.1 g (87 mmol) of uranyl salts of magnesium, monoprice-phthalic acid in 300 ml of a mixture of dichloromethane/methanol at 10-25°C within 30 minutes After stirring for 16 hours at ambient temperature the reaction mixture was cooled and slowly added to 250 ml of an aqueous solution of sodium pyrosulfite. The organic phase and the residue was separated and washed with 250 ml of an aqueous solution of sodium bicarbonate. After stirring for 15 minutes the precipitate was filtered, washed with water and simple with ether, and dried under vacuum, obtaining of 11.7 g of the product.

MS (ESI+) m/z = 333,0 [M+H]+

25.2 3-(3-Perpenicular)quinoline-8-amine

10,13 g of 3-(3-perpenicular)-8-nitroquinoline (30,5 mmol) suspended in 150 ml of acetic acid and was heated to 110°C. 8,51 g of iron powder (152 mmol) was added in small portions with stirring. Stirring was continued for 1 hour. Then the reaction mixture was cooled to ambient temperature, was divided between water and ethyl acetate. The organic phase was separated and the aqueous layer which was xtraceroute three times with ethyl acetate. To the combined organic layer was added water, and the pH was brought to alkaline values aqueous solution of ammonium hydroxide with rapid stirring. The organic layer was separated, was extracted twice with water, dried over magnesium sulfate, filtered and the solvents evaporated, receiving of 9.2 g of product.

MS (ESI+) m/z = 303,0 [M+H]+

25.3 3-(3-Perpenicular)-8-iodine-quinoline

9,214 g of 3-(3-perpenicular)quinoline-8-amine (30,5 mmol) was dissolved in 50 ml triperoxonane acid. The mixture was concentrated, receiving trifenatate salt, which was then dissolved in acetonitrile. 4.71 g of n-butylnitrite (of 45.7 mmol) in 150 ml of acetonitrile was cooled to 0°C and the solution triptoreline salt 3-(3-perpenicular)quinoline-8-amine in acetonitrile (dissolved in 100 ml of acetonitrile) was added dropwise at a temperature from 0 to +5°C. After stirring for 10 minutes was added parts 22,52 g of Tetra-n-butylammonium and the reaction mixture was stirred for 2 hours at ~0°C. After evaporation of the solvents the residue was dissolved in dichloromethane and washed twice in 10%aqueous solution of thiosulfate of sodium. The organic phase was evaporated to dryness and the residue was treated with isopropanol. The precipitate was filtered off, washed with small amounts of isopropanol and n-heptane, and dried in vacuum, obtaining the product. The additional amount is the product was obtained by evaporation of the filtrate to dryness and purification of the residual material by chromatography on silica gel (eluent: n-Heptane/ethyl Acetate), receiving in the amount of 6.4 g of the product.

MS (ESI+) m/z = 413,9 [M+H]+

25.4 (3aS,6aS)-ethyl-1-(3-(3-perpenicular)quinoline-8-yl) hexahydrofuro[3,4-b]pyrrol-5(1H)-carboxylate

0,255 g of 3-(3-Perpenicular)-8-athineon (0,617 mmol), 0,114 g of (3aS,6aS)-ethylhexanediol[3,4-b]pyrrol-5(1H)-carboxylate (0,617 mmol), 0,404 g of cesium carbonate (1,234 mmol), of 0.014 g of palladium acetate (0,062 mmol) and 0,029 g X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, holding 0.062 mmol) in 5 ml of toluene was stirred at 90°C for 8 hours The reaction mixture was directly purified by chromatography on silica gel (eluent toluene/methanol 10/1 + 2.5% triethylamine). The fractions containing the product were combined and the solvent evaporated, getting 0,271 g of the desired product which was used in example 26 without further purification.

MS (ESI+) m/z = 470,1 [M+H]+

EXAMPLE 26: 3-(3-fluoro-benzazolyl)-8-(3aS,6aS)-hexahydrofuro[3,4-b]pyrrol-1-yl-quinoline hydrochloride

The solution 0,264 g of (3aS,6aS)-1-(3-(3-fluoro-phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-5(1H)-ethylcarboxylate (0,562 mmol) and 0,338 g of trimethylsilyl iodide (1,687 mmol) was stirred at reflux in chloroform (5 ml) for 1.5 hours and further at ambient temperature for 16 hours. Added additional amount of trimethylsilyl iodide and the reaction mixture was stirred under heating OBR is Tim refrigerator for 6 hours. The mixture was cooled to ambient temperature. Then 0.27 g of methanol (8,43 mmol) was added under stirring and the stirring was continued for 30 minutes the Solvent is evaporated, the residual material was treated with water and the pH brought to alkaline values concentrated aqueous solution of ammonia. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel and preparative HPLC. The hydrochloride was obtained by adding 2 N. HCl in simple diethyl ether to a solution of free base in a mixture of tetrahydrofuran/simple diethyl ether. Thus formed precipitate, which was filtered, washed simple diethyl ether and dried under vacuum to give 10 mg of the product.

MS (ESI+) m/z = 398,1 [M+H]+

EXAMPLE 27: (1S,5R)-3-(3-(3-perpenicular)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-6-tert-butylcarbamoyl

0,153 g of (1S,5R)-3-(3-(3-perpenicular)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-6-tert-BUTYLCARBAMATE received by analogy with the method of Example 25.4 reaction combinations of 3-(3-perpenicular)-8-athineon and (1S,5R)-3,6-diazabicyclo[3,2,0]heptane-6-tert-BUTYLCARBAMATE.

MS (ESI+) m/z = 484,2 [M+H]+

EXAMPLE 28: 8-(1R,5R)-3,6-diaza-bicyclo[3,2,0]hept-3-yl-3-(3-torbenson-sulfonyl)-Hino is in hydrochloride

0,150 g of (1S,5R)-3-(3-(3-perpenicular)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-6-tert-butylcarbamoyl from Example 27 was dissolved in 5 ml of ethanol. Added 5 ml of 5 N. HCl in isopropanol and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue was dissolved in small quantities of ethanol and precipitated by adding simple diethyl ether. By recrystallization from a mixture of ethanol/isopropanol (2:1) received 0,0275 g of the product.

MS (ESI+) m/z = 384,1 [M+H]+

EXAMPLE 29: 3-(3-fluoro-benzazolyl)-8-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-quinoline hydrochloride

0,088 g of 5-(3-(3-perpenicular)quinoline-8-yl)octahedral[3,4-b]pyrrol-1-s chloride was obtained by analogy with the methods of Examples 27 and 28 of the reaction mix 3-(3-perpenicular)-8-athineon with 1-(tert-butoxycarbonyl)-octahedral[2,3-c]pyrrol-5-s chloride and subsequent removal of the protective group derived from tert-butyl-oxycarbonyl with HCl in isopropanol.

MS (ESI+) m/z = 398,1 [M+H]+

EXAMPLE 30: 3-(3-fluoro-benzazolyl)-8-(3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-quinoline hydrochloride

0,145 g of 3-(3-fluoro-benzazolyl)-8-(3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-quinoline hydrochloride was obtained by analogy with the methods of Examples 27 and 28 of the reaction mix 3-(3-perpenicular)-8-athineon with commercial dostupnymi-butyl ether (3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid and subsequent removal of the protective group derived from tert-butyl-oxycarbonyl using HCl in isopropanol.

MS (ESI+) m/z = 398,1 [M+H]+

EXAMPLE 31: 6-(3-(3-perpenicular)quinoline-8-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-s chloride

0,073 g of 6-(3-(3-Perpenicular)quinoline-8-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-s chloride was obtained by analogy with the methods of Examples 27 and 28 of the reaction mix 3-(3-perpenicular)-8-athineon with commercially available tert-butyl ether, octahydro-pyrrolo[3,4-b]pyridine-6-carboxylic acid and subsequent removal of the protective group derived from tert-butyl-oxycarbonyl with HCl in isopropanol.

MS (ESI+) m/z = 412,2 [M+H]+

EXAMPLE 32: (1S,5S)-3-(3-(3-perpenicular)quinoline-8-yl)-3-Aza-6-azoniabicyclo[3,2,0]heptane hydrochloride

of 0.081 g of (1S,5S)-3-(3-(3-perpenicular)quinoline-8-yl)-3-Aza-6-azoniabicyclo[3,2,0]heptane hydrochloride was obtained by analogy with the methods of Examples 27 and 28 of the reaction mix 3-(3-perpenicular)-8-athineon with (1R,5S)-3,6-diazabicyclo[3,2,0]heptane-6-tert-butylcarbamoyl and the subsequent removal of the protective group derived from tert-butyl-oxycarbonyl with HCl in isopropanol.

MS (ESI+) m/z = 384,1 [M+H]+

EXAMPLE 33: 5-(3-(3-perpenicular)quinoline-8-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-2-s chloride

0,072 g of 5-(3-(3-Perpenicular)quinoline-8-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-2-s chloride was obtained by analogy with the methods of Examples 27 and 28 of the reaction mix 3-(3-forfei sulfonyl)-8-athineon with commercially available hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-tert-butylcarbamoyl and the subsequent removal of the protective group derived from tert-butyl-oxycarbonyl with HCl in isopropanol.

MS (ESI+) m/z = 412,2 [M+H]+

EXAMPLE 34: 8-(5-benzyl-1H-pyrrolo[3,4-c]pyridine-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-perpenicular)quinoline

34.1 5-Ventiljacija-1H-pyrrolo[3,4-c]pyridine-2(3H)-tert-butylcarbamoyl

0,777 g Benzylbromide (of 4.54 mmol) was added dropwise to the mixture 1,028 g of commercially available hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-tert-BUTYLCARBAMATE (of 4.54 mmol), 1,883 g of potassium carbonate (13,62 mmol) and measured at the tip of the blade 18-crown-6 in 25 ml of tetrahydrofuran. The reaction mixture was stirred for 16 hours at ambient temperature, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane, the organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated, obtaining 1,413 g of product which was used in the next stage without further purification.

MS (ESI+) m/z = 317,2 [M+H]+

34.2 5-Benzylester-1H-pyrrolo[3,4-c]pyridine-2,5-DIY chloride

1,355 g 5-ventiljacija-1H-pyrrolo[3,4-c]pyridine-2(3H)-tert-BUTYLCARBAMATE (4,28 mmol) was dissolved in 10 ml of ethanol. To the solution was added 20 ml of 5 N. HCl in isopropanol, and the resulting mixture was stirred at ambient temperature for 16 hours. After adding a simple diethyl ether the product was deposited. The product was filtered and, after further washing simple diethyl ether, the product was dried. Consequently, the sustained fashion the amount of product was obtained by concentration of the filtrate and crystallization from simple diethyl ether. The combined amount of the product was 1,07,

MS (ESI+) m/z = 217,2 [M+H]+

34.3 8-(5-benzyl-1H-pyrrolo[3,4-c]pyridine-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-perpenicular)quinoline

0,367 g of 8-(5-benzyl-1H-pyrrolo[3,4-c]pyridine-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-perpenicular)quinoline was obtained by analogy with the method of Example 27, reaction of a combination of 3-(3-perpenicular)-8-athineon 5 benzylester-1H-pyrrolo[3,4-c]pyridine-2,5-DIY chloride.

MS (ESI+) m/z = 502,2 [M+H]+

EXAMPLE 35: 3-(3-fluoro-benzazolyl)-8-(octahydro-pyrrolo[3,4-c]pyridine-2-yl)-quinoline hydrochloride

A suspension of 0.05 g of Pd/C (10%) in 1 ml of water was added to the solution 0,331 g of 8-(5-benzyl-1H-pyrrolo[3,4-c]pyridine-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-perpenicular)quinoline (0.66 mmol) in 10 ml of ethanol. The mixture was heated to 80°C. Then was added 0,41 g of ammonium formate (6,61 mmol) in 2 ml of water. After 1 hour at 80°C was added catalyst and ammonium formate. Stirring was continued for 1 hour at 80°C. Then the catalyst was filtered and the filtrate was concentrated. The residue was separated between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (eluent: toluene/methanol 10/1 + 2.5% triethylamine, Analogix SF 15/24g). The fractions containing the product, about zeinali, concentrated and the hydrochloride was obtained by adding HCl in simple diethyl ether. Received 0,018 g of the product.

MS (ESI+) m/z = 412,2 [M+H]+

EXAMPLE 36: 8-((3aS,6aS)-1-benzyloxypropionic[3,4-b]pyrrol-5(1H)-yl)-3-(3-perpenicular)quinoline

of) 0.157 g of 8-((3aS,6aS)-1-benzyloxypropionic[3,4-b]pyrrol-5(1H)-yl)-3-(3-perpenicular)quinoline was obtained by analogy with the method of Example 27, reaction of a combination of 3-(3-perpenicular)-8-athineon with (3aS,6aS)-1-benzisothiazolinone[3,4-b]pyrrole.

MS (ESI+) m/z = 488,2 [M+H]+

EXAMPLE 37: 3-(3-fluoro-benzazolyl)-8-((3aR,6aS)-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-quinoline hydrochloride

0.05 g of 3-(3-fluoro-benzazolyl)-8-((3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-quinoline hydrochloride (0,117 mmol) was dissolved in methanol. Added 1 equivalent of sodium hydroxide in methanol and the mixture was concentrated. The residue was dissolved in 5 ml of dichloromethane and then added to 0.007 g of acetic acid (0,117 mmol), 8,7 μl of an aqueous solution of formaldehyde (0,117 mmol) and 0.025 g of triacetoxyborohydride sodium (0,117 mmol). After completion of the reaction was added dichloromethane. The organic layer was washed with an aqueous solution of sodium bicarbonate, and the aqueous layer was re-extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran, the hydrochloride was obtained by adding HCl in simple diethyl ether. After filtration the product was washed simple diethyl ether, and dried in vacuum (received 0,033 g of the product).

MS (ESI+) m/z = 412,2 [M+H]+

EXAMPLE 38: 5-(3-(4-perpenicular)quinoline-8-yl)octahedral[3,4-c]pyrrol-2-s chloride

0,045 g of 5-(3-(4-perpenicular)quinoline-8-yl)octahedral[3,4-c]pyrrol-2-s chloride was obtained by analogy with the methods of Examples 27 and 28 of the reaction mix 3-(3-perpenicular)-8-athineon with commercially available tert-butyl ether (3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid and subsequent removal of the protective group derived from tert-butyl-oxycarbonyl with HCl in isopropanol.

MS (ESI+) m/z = 398,2 [M+H]+

Connection examples 39-44 received by analogy with the methods of Examples 1-38.

EXAMPLE 39: 3-(4-perpenicular)-8-(hexahydropyrazino[3,4-b]pyrrol-5(1H)-yl)quinoline

MS (ESI+) m/z = 398,2 [M+H]+

EXAMPLE 40: 8-(5-benzyloxypropionic[3,4-c]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)-quinoline

MS (ESI+) m/z = 470,2 [M+H]+

EXAMPLE 41: 8-(5-methyl-1H-pyrrolo[3,4-c]pyridine-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(phenylsulfonyl)quinoline

MS (ESI+) m/z = 408,2 [M+H]+

EXAMPLE 42: 2-(3-(phenylsulfonyl)quinoline-8-yl)dodecahydro-1H-pyrido[4,3-b]indole

MS (ESI+) m/z = 448,1 [M+H]+

EXAMPLE 43: 8-(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)quinoline

MS (ESI+) m/z = 380,1 [M+H]+

EXAMPLE 44: 8-(1H-pyrrolo[3,4-c]p is ridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline.

MS (ESI+) m/z = 462,2 [M+H]+

II. Biological studies

The displacement of the labeled ligand to bind with the following cloned human receptors

1. Obtaining membranes by treatment with ultrasound and differential centrifugation

Cells stable clonal cell lines expressing the appropriate receptor (5-HT6α1-adrenergic, dopamine D2or histamine H1receptors), washed with PBS (w/o Ca++, Mg++) and collected in PBS with 0.02% of EDTA. The cells were collected by centrifugation at 500 g for 10 min at 4°C, washed with PBS and centrifuged (500 g, 10 min, 4°C). Sediments were preserved at -80°C until use. For membrane preparation is thawed sediment cells re-suspended in ice-cold sucrose buffer (0.25 M sucrose, 10 mm Hepes (pH of 7.4), 1 mm phenylmethylsulfonyl (PMSF) in DMSO, 5 μg/ml of Pepstatin-A, 3 mm EDTA, 0.025% bacitracin) and homogenized by ultrasonic disintegrator Branson Sonifier W-250 (Settings: Timer 4; Output Control 3; constant work cycle; 2-3 cycles). The destruction of the cells were examined under a microscope. The remaining intact cells were besieged at 1,000 g for 10 min at 4°C. the Supernatant sucrose buffer and then centrifuged at 60000 g for 1 hour at 4°C (Beckman Ultrazentrifuge XL 80). The precipitate is re-suspended in 30 ml ice is of Tris buffer (20 mm TRIS (pH 7,4), 5 µg/ml Pepstatin A, (0.1 mm PMSF, 3 mm EDTA), measuring through serological pipette 10 ml, and centrifuged for 1 hour at 4°C for up to 60000 g. The final suspension was carried out in a small volume of ice-cold Tris buffer (see above) through serological pipette, and then carried out the sonication using an ultrasonic disintegrator Branson Sonifier W-250 (Settings: Timer 1; Output Control 3; constant work cycle; 1 cycle). Determined the protein concentration (BCA Kit; Pierce) and aliquots were kept at -80°C or in liquid nitrogen for long term storage.

2. Experiments on binding to receptors

All experiments on binding to receptors was carried out in the appropriate test buffer in a total volume of 200 μl in the presence of various concentrations of test compounds (10-5M to 10-9M, a ten-fold series of dilutions, the determination in duplicate). The tests were completed by filtering the pre-moistened with polyethylenimine (PEI of 0.1% or 0.3%) tablets Packard Unifilter Plates (GF/C or GF/B) using the collector Tomtec MachIII for 96-well plates. After drying of the tablets for 2 hours at 55°C in a drying Cabinet (BetaPlate Scint; PerkinElmer) was added to the scintillation cocktail. Radioactivity was measured in a Microbeta Trilux two hours after addition of scintillation mixture. Data obtained p is discotom liquid scintillation, analyzed an iterative analysis of nonlinear regression using the Statistical Analysis System (SAS): programs such as "LIGAND", as described by Munson and Rodbard (Analytical Biochemistry 107, 220-239 (1980).

a) Test the binding of 5-HT6receptor

The HEK293 cells, stably expressing h-5-HT6receptor (NCBI reference sequence XM 001435), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10%fetal calf serum and 1 to 2 mm glutamine. The membrane preparation was obtained as described in section 1. For these membranes KD1,95 nm for [3H]-LSD (Lysergic Acid Diethylamide; Amersham, TRK1038) was determined by means of experiments on saturation binding. On the test day, the membranes were thawed, diluted in a test buffer (50 mm Tris-HCI, 5 mm CaCl2, of 0.1% ascorbic acid, 10 μm of pargyline, pH of 7.4) at a concentration of 8 μg protein/test and homogenized gentle vortexing. For studies of inhibition of 1 nm diethylamide [3H]-lysergic acid diethylamide incubated in the presence of various concentrations of test compounds in the test buffer. Nonspecific binding was defined with 1 μm methiothepin. The binding reaction was carried out for 3.5 hours at ambient temperature. During incubation, the tablets were shaken on a plate shaker at 100 rpm and was completed by filtration on tablets Packard Unifilter GF/C (in 0.1% PEI) followed by 2 cycles is romawki ice-cold mixture of 50 mm Tris-HCl, 5 mm CaCl2.

a) Test of the receptor binding of dopamine D2

The HEK293 cells, stably expressing the receptor dopamine D2(NCBI reference sequence NM_000795), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10%fetal calf serum and 1 to 2 mm glutamine. The membrane preparation was obtained as described in section 1. For these membranes KD0,22 nm for [125I]-adspypro (PerkinElmer Life Sciences, NEX284) was determined by means of experiments on saturation binding. On the test day, the membranes were thawed, diluted in a test buffer (50 mm Tris-HCl, 120 mm NaCl, 5 mm MgCl2, 5 mm KCl, 1.5 mm CaCl2, a pH of 7.4) at a concentration of 15 μg protein/test and homogenized gentle vortexing. For studies of inhibition of 0.01 nm [125I]-ispiron (PerkinElmer Life Sciences, NEX284) were incubated in the presence of various concentrations of test compounds in the test buffer. Nonspecific binding was defined with 1 μm haloperidol. The binding reaction was carried out for 1 h at ambient temperature and terminated by filtration on tablets Packard Unifilter GF/B (0,1% PEI) followed by 6 cycles of washing with ice a solution of 7% peg.

b) Test binding with α1-adrenergic receptor

Cells CHO-K1stably expressing α1-adrenergic receptor (NCBI reference follow etelnost NM_033303), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10%fetal calf serum and 1 to 2 mm glutamine. The membrane preparation was obtained as described in section 1. For these membranes KDof 0.12 nm for [3H]-prazosin (PerkinElmer Life Sciences, NET823) was determined by means of experiments on saturation binding. On the test day, the membranes were thawed, diluted in a test buffer (50 mm Tris-HCl, pH of 7.4) at a concentration of 4 μg protein/test and homogenized gentle vortexing. For studies of inhibition of 0.01 nm [3H]-prazosin (PerkinElmer Life Sciences, NET823) were incubated in the presence of various concentrations of test compounds in the test buffer. Nonspecific binding was defined with 1 μm fentolamina. The binding reaction was carried out for 1 h at ambient temperature and terminated by filtration on tablets Packard Unifilter GF/C (in 0.1% PEI) followed by 3 cycles of washing the ice test buffer.

c) Test the receptor binding N1

Cells CHO-K1stably expressing the receptor of histamine H1(Euroscreen-ES-390-C, NCBI reference sequence NM_000861), were cultured in RPMI1640 medium, supplemented with 25 mm HEPES, 10%fetal calf serum and 1 to 2 mm glutamine. The membrane preparation was obtained as described in section 1. For these membranes KDof 0.83 nm for [3H]-pyrilamine (PerkinElmer Life Sciences, NET594) determine elali through experiments on saturation binding. On the test day, the membranes were thawed, diluted in a test buffer (50 mm Na2HPO4, 50 mm KH2PO4, a pH of 7.4) at a concentration of 6 μg protein/test and homogenized gentle vortexing. For studies of inhibition of 1 nm of [3H]-pyrilamine (PerkinElmer Life Sciences, NET594) were incubated in the presence of various concentrations of test compounds in the test buffer. Nonspecific binding was defined with 1 μm of pyrilamine. The binding reaction was carried out for 50 minutes at ambient temperature and terminated by filtration on tablets Packard Unifilter GF/C (with 0.3% PEI) followed by 2 wash cycles ice test buffer.

3. Data analysis

The data obtained by counting liquid scintillation, were analyzed by iterative analysis of nonlinear regression using the Statistical Analysis System (SAS): programs such as "LIGAND", as described by Munson and Rodbard (Anal. Biochem. 1980, 107, 220-239). The construction was carried out according to the formulas described by Feldman (Anal. Biochem. 1972, 48, 317-338). The values of the IC50, NN and Kiwere expressed as geometric values. For receptors with low affinity to the test compound, where the highest tested concentration inhibited less than 30% of specific binding of labeled ligand, the values of Kidetermined according to the equation of Cheng and Prusoff (Biochem. Pharmacol. 1973, 22, 2099-2108) and expressed ka is more than (> ).

The results of studies of binding to receptors expressed in the form of constants, binding to receptors Ki(5-HT6), Ki(D2), Ki1-adrenergic) and Ki(H1), respectively, as described above, and are listed in table I.

In these tests, the compounds according to the invention show a very good affinity for 5-HT6receptors (Ki< 250 nm or < 50 nm or < 20 nm or < 10 nm and often < 5 nm or < 1 nm). In addition, these compounds selectively bind to 5-HT6receptor compared with the affinity of the receptors D2α1-adrenergic or H1. These compounds show little affinity for the receptors D2α1-adrenergic or H1(Ki> 250 nm or > 1000 nm and often > 10000 nm).

Table I
ExampleKi(5-HT6)
1+++
2+
3+
4+++
10+
1213+++
14+++
15++
16+++
18+++
19++
20+++
22+++
24+++
26+++
28+++
29+++
30+++
31+++
32+++
39+++
40+++
41++
42+
43+++
44 +++

In table I, "n.d". means not determined; "+++" means Ki< 10 nm; "++" means Ki< 50 nm; "+" means Ki<250 nm; "-" means Ki> 250 nm; "--" means Ki> 1000 nm; "---" means Ki> 10000 nm.

1. The quinoline compounds of formula (I)

in which
R is a polycyclic group of the formula

in which * indicates the binding site with hyalinella radical;
And means (CH2)andwhere a represents 0, 1, 2 or 3;
In denotes the (CH2)bwhere b stands for 0, 1, 2 or 3;
X' represents (CH2)xwhere x is 0, 1, 2 or 3;
Y represents (CH2)ywhere denotes 0, 1, 2 or 3;
provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3, or 4 and a+b+x+y=3, 4, 5, 6, or 7;
Q denotes N;
R1denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylsulphonyl,1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where the phenyl ring in the last two mentioned groups are unsubstituted or carry 1, 2 or 3 substituent selected from halogen, C1-C4-alkyl or C1-C4-halogenoalkane;
R2denotes hydrogen;
R3denotes hydrogen;
p=0, 1, or 2;
R4in case the e of his presence, stands With1-C4-alkyl and is associated with X and/or Y, if p=2, the two radicals R4that are bound to adjacent carbon atoms of X or Y together may also denote a straight line With the2-C5-alkylen;
q=0;
n=0;
m=0;
X represents S(O)2; which is located at position 3 of the quinoline;
Ar represents a radical Ar1and Ar1represents phenyl, whereby phenyl may be unsubstituted or may carry 1 substituent Rxand
Rxdenotes halogen, CN, C1-C6-alkyl, C1-C6-halogenated,1-C6-alkoxy, C1-C6-halogenoalkane,1-C6-alkylthio,1-C6-allogenicity, NRx1Rx2and Rx1and Rx2independently of one another denote hydrogen, C1-C6-alkyl, or Rx1and Rx2together with the nitrogen atom form a N-linked 5-, 6 - or 7-membered saturated heteromantic or N-linked 7-, 8-, 9 - or 10-membered saturated heterobicycle, which are unsubstituted or which are 1, 2, 3 or 4 radicals selected from C1-C4-alkyl;
and their physiologically acceptable salts joining with acid and N-oxides.

2. Compounds according to claim 1, in which the group R variables x and y=0, 1, or 2, provided that x+y=1, 2, or 3.

3. Compounds according to claim 1, in which the group R variables a and b=0, 1, or 2, if the condition is and, that a+b=1, 2, or 3.

4. Compounds according to claim 1, in which the group variable R R=0.

5. Compounds according to claim 1, in which R1denotes hydrogen.

6. Compounds according to claim 1, in which the group R represents a radical of the formulae R-1 to R-44:



in which R1matter defined in claim 1, and * indicates a binding site with hyalinella radical.

7. Compounds according to claim 6, in which the group R is selected from radicals of the formulae R-1, R-3, R-5, R-6, R-8, R-9, R-10, R-11, R-12, R-13, R-15, R-17, R-21, R-22, R-24, R-25, R-27, R-28, R-29, R-34, R-35, R-36, R-37, R-38 and R-44.

8. The connection according to claim 6, where the group R represents a radical R-16.

9. The compound according to claim 1 of the formula 1a.a

in which n=0, m=0, where R is a radical R-16 as defined in claim 8, in which R1denotes hydrogen.

10. The connection according to claim 9, where R is a radical R-16,

in which R1denotes hydrogen.

11. The compound according to any one of the preceding paragraphs, selected from the group consisting of
8-(hexahydropyrazino[3,4-b]pyrrol-5(1H)-yl)-3-(phenylsulfonyl)quinoline
6-(3-(phenylsulfonyl)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-3-benzylcarbamoyl
2-(3-(phenylsulfonyl)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-C]pyridine-5(6N)-tert-BUTYLCARBAMATE
3-(phenylsulfonyl)-8-(1H-PI is Rolo[3,4-C]pyridine-2(3H,UN,4N,5N,6N,7N,an)-yl)quinoline
(1R,5S)-3-(3-(phenylsulfonyl)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-6-tert-BUTYLCARBAMATE
8-((1S,5S)-3,6-diazabicyclo[3,2,0]heptane-3-yl)-3-(phenylsulfonyl)quinoline
(A,6aS)-1-(3-(phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-5(1H)-ethylcarboxylate
5-(3-(4-perpenicular)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-1(2H)-tert-BUTYLCARBAMATE
5-(3-(phenylsulfonyl)quinoline-8-yl)octahydro-1,5-naphthiridine-1(2H)-tert-BUTYLCARBAMATE
1-(3-(phenylsulfonyl)quinoline-8-yl)decahydro-1,5-naphthiridine
2-(3-(4-perpenicular)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-C] pyridine-5(6N)-tert-BUTYLCARBAMATE
8-((3aS,6aS)-hexahydrofuro[3,4-b]pyrrol-1(2H)-yl)-3-(phenylsulfonyl)-quinoline
3-(4-perpenicular)-8-(1H-pyrrolo[3,4-C]pyridine-2(3H,UN,4N,5N,6N,7N,an)-yl)quinoline
3-(4-perpenicular)-8-(hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)quinoline
5-(3-(3-(triptoreline)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)-tert-BUTYLCARBAMATE
8-(hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)-3-(3-(triptoreline)-phenylsulfonyl)quinoline
5-(3-(3-(5-(tert-butoxycarbonyl)hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)-tert-BUTYLCARBAMATE
8-(hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)-3-(3-(hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)phenylsulfonyl)quinoline
2-(3-(3-(triptoreline)phenylsulfonyl is)quinoline-8-yl)hexahydro-1H-pyrrolo[3,4-C]pyridine-5(6N)-tert-BUTYLCARBAMATE
8-(1H-pyrrolo[3,4-C]pyridine-2(3H,UN,4N,5N,6N,7N,an)-yl)-3-(3-(triptoreline)phenylsulfonyl)quinoline
5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-1(2H)-tert-BUTYLCARBAMATE
8-(hexahydropyrazino[3,4-b]pyrrol-5(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline
(3aR,6aS)-5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinoline-8-yl)hexahydrofuro[3,4-C]pyrrol-2(1H)-tert-BUTYLCARBAMATE
8-((3aR,6aS)-hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline
(3aS,6aS)-ethyl-1-(3-(3-perpenicular)quinoline-8-yl)hexahydrofuro[3,4-b]pyrrol-5(1H)-carboxylate
3-(3-fluoro-benzazolyl)-8-(3aS,6aS)-hexahydrofuro[3,4-b]pyrrol-1-yl-quinoline
(1S,5R)-3-(3-(3-perpenicular)quinoline-8-yl)-3,6-diazabicyclo[3,2,0]heptane-6-tert-BUTYLCARBAMATE
8-(1R,5R)-3,6-diaza-bicyclo[3,2,0]hept-3-yl-3-(3-torbenson-sulfonyl)-quinoline
3-(3-fluoro-benzazolyl)-8-(hexahydropyrazino[3,4-b]pyrrol-5-yl)-quinoline
3-(3-fluoro-benzazolyl)-8-(3aR,6aS)-hexahydrofuro[3,4-C]pyrrol-2-yl-quinoline
6-(3-(3-perpenicular)quinoline-8-yl)octahydro-1H-pyrrolo [3,4-b] pyridine-1-FL
(1S,5S)-3-(3-(3-perpenicular)quinoline-8-yl)-3-Aza-6-azoniabicyclo[3,2,0]heptane
5-(3-(3-perpenicular)quinoline-8-yl)octahydro-1H-pyrrolo[3,4-C]pyridine-2-FL
8-(5-benzyl-1H-pyrrolo[3,4-C]pyridine-2(3H,UN,4N,5N,6N,7N,an)-yl)-3-(3-perpenicular)quinoline
3-(3-fluoro-benzols hanil)-8-(octahedral[3,4-C]pyridine-2-yl)-quinoline
8-((3aS,6aS)-1-benzyloxypropionic[3,4-b]pyrrol-5(1H)-yl)-3-(3-perpenicular)quinoline
3-(3-fluoro-benzazolyl)-8-((3aR,6aS)-5-methyl-hexahydrofuro[3,4-C]pyrrol-2-yl)-quinoline
5-(3-(4-perpenicular)quinoline-8-yl)octahedral[3,4-C]pyrrol-2-FL
3-(4-perpenicular)-8-(hexahydropyrazino[3,4-b]pyrrol-5(1H)-yl)quinoline
8-(5-benzyloxypropionic[3,4-C]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)-quinoline
8-(5-methyl-1H-pyrrolo[3,4-C]pyridine-2(3H,UN,4N,5N,6N,7N,an)-yl)-3-(phenylsulfonyl)quinoline
2-(3-(phenylsulfonyl)quinoline-8-yl)dodecahydro-1H-pyrido[4,3-b]indole
8-(hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)quinoline
8-(1H-pyrrolo[3,4-C]pyridine-2(3H,UN,4N,5N,6N,7N,an)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline and its pharmaceutically acceptable salts joining with acid and N-oxides.

12. Pharmaceutical composition having the property of selective binding to the receptor 5-HT6containing at least one compound according to any one of claims 1 to 11, optionally together with at least one physiologically acceptable carrier or auxiliary substance.

13. A method of treating medical disorders selected from diseases of the Central nervous system, diseases associated with addiction, or obesity, comprising administration to the patient an effective amount of at least one soedineniya any one of claims 1 to 11.

14. The method according to item 13, in which a health disorder is a disease of the Central nervous system.

15. The method according to item 13 for the treatment of cognitive dysfunction.

16. The method according to item 13 for the treatment of cognitive dysfunction associated with Alzheimer's disease.

17. The method according to item 13 for the treatment of cognitive dysfunction associated with schizophrenia.

18. The method according to item 13, in which a health disorder is a disease associated with the dependency.

19. The method according to item 13, in which a health disorder is the obesity.

20. The use of compounds according to any one of claims 1 to 11 to obtain a pharmaceutical composition having the property of selective binding to the receptor 5-HT6.

21. The use of compounds according to any one of claims 1 to 11 to obtain a pharmaceutical composition for the treatment of medical disorders where medical abuse is a disease selected from disorders of the Central nervous system, diseases associated with addiction, or obesity.

22. The compound according to any one of claims 1 to 11 for use as a medicinal product having the properties of selective binding to the receptor 5-HT6.

23. The compound according to any one of claims 1 to 11 for use as a drug for the treatment of medical disorders where a violation of the medical assessability, selected from diseases of the Central nervous system, diseases associated with addiction or obesity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 , where X and T are N or C, Q is a (3-7)-member aromatic ring which contains 0-3 nitrogen atoms as ring members, and which is optionally benzo-condensed and is substituted with oxo; C1-C6-alkyl; halogen- C1-C6-alkyl; hydroxy-C1-C6-alkyl; C1-C6-alkoxy; C6-C10-aryl; or a (3-7)-member heteroaryl containing 1-3 oxygen atoms, P is C1-C6-alkyl, optionally substituted with a halogen, and R is a group selected from: (i) -C1-C6-alkyl-R1, (ii) -NR2R3, (iii) -O-R4, (iv) -S-R5, (v) -C (=O))-R6, (vi) optionally substituted (3-7)-member heteroaryl containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vi) optionally substituted (3-7)-member heteroatom containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (vii) optionally substituted, saturated or partially unsaturated, separate or condensed (3-10)-member heterocyclic ring containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulphur atom, (viii) azido; where each R1, R2, R3, R4, R3, R6, is as described in the claim. The invention also relates to a pharmaceutical composition for preventing and treating a vascular disease, which contains a compound of formula 1.

EFFECT: compounds of formula 1 with inhibitory activity with reference to aggregation of thrombocytes.

7 cl, 7 dwg, 2 tbl, 519 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R1,R2 means H; R3 means C1-10alkyl; R4 means -[CH2CH(OH)]rCH2NR9R10, -(CH2)nNR9R10; provided X means N, R5 is absent, each R6, R7, R8 means H, halogen; provided X means C, each R5, R6, R7, R8 means H, halogen, hydroxyC1-10alkyl, C1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9 and -NHCO2R10, wherein said phenyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; or R9 and R10 together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to anhydrous crystalline vinflunine salts of general formula (I) prepared with 1 or 2 equivalents of a pharmaceutically acceptable inorganic or organic acid. . In formula (I) [The acid] represents hydrobromic, lactic or fumaric acid for a group of water-soluble crystalline salts, as well as para-toluenesulphonic, benzoic, mandelic and para-hydroxybenzoic acid for a group of relatively water-insoluble crystalline salts.

EFFECT: preparing the anhydrous crystalline vinflunine salts.

8 cl, 8 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new tetracyclic compounds of general formula (I), wherein is a single or double bond; no bonds or a single bond; or V means N; T and X as shown in structure fragments above; U and W independently mean C or N with one of them shall be N; R3, R4, R5 and R6 - H; Rv is absent; Ru and Rw are independently absent or mean (C1-12)alkyl; Y =N-OR1 or NP'1, wherein R1 - H, (C1-12)alkyl optionally substituted by phenyl, phenyloxy, carboxy, (C1-12)alkoxy, (C1-12)alkoxycarbonyl, or (C2-12)alkenyl; R'1 is phenyl, or pharmaceutically acceptable salts thereof, or diastereomers thereof, or regioisomers thereof, or: mixtures thereof, a pharmaceutical composition containing them, and specific compounds for cysteine protease inhibition.

EFFECT: compounds may be used in medicine in treating cancer, neurodegenerative diseases, inflammatory disorders, cardiovascular diseases, etc.

8 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new pyrimidine substituted macrocyclic compounds of genral formula (I) , wherein A= -C(=O)OR1 or -C(=O)-NH-SO2-R2; R1 = H or C1-6alkyl; R2 = phenyl, thienyl, C3-7cycloalkyl optionally substituted by C1-6alkyl; X = N or CH; E = NR5; R5 = H or C1-6alkyl; n = 4 or 5; R7=H, C1-6alkyl, C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy; R8 =C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy, morpholino or -NRaRb, wherein Ra and Rb independently mean H or C1-6alkyl; R9 = Rq = H; or their pharmaceutically acceptable addition salts, or stereoisomers, and pharmaceutical compositions containing them.

EFFECT: compounds are inhibitors of HCV NS3 serine protease and can find application in treating chronic hepatic disorders, particularly chronic hepatitis.

10 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to producing new 5,8,9,10-tetrahydropyrimido[4,5-d]azocine derivatives having triflate, secondary and tertiary amino groups in the 4th position of general formula specified below. In general structural formula: 2-12 2 X=OTf (Tf means triflate), X means NR1R22 related to the groups 3-12

.

The method consists in the fact that 6-isopropyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one reacts with methyl propyolate in methanol at room temperature to produce methyl 8-isopropyl-4-oxo-2-phenyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (1). Thereafter, the prepared compound reacts with triftalane hydride in dichloromethane in the presence of pyridine at t°=-10°C; it is recovered and purified with by means of column chromatography to prepare methyl 8-isopropyl-2-phenyl-4-{[(trifluoromethyl)sulphonyl]oxy}-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (2); then the solution I mmole of the prepared product (2) in absolute dioxide is added with 2 mmole of K2CO3 and 1.5 mmole of appropriate amine. After being boiled for two hours and removing the solvent, respective 4-amino substituted 5,8,9,10-tetrahydropyrimido[4,5-d]azocine of formula 3-12 is prepared. The method is directed to prepare the products in the form of white or yellow powder, or in the form of drying oil.

EFFECT: after the primary screening, the compounds appeared to be acetyl- and butyrylcholin esterase inhibitors and can find application as scaffolds in searching the preparations for treating neurodegenerative diseases.

10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (VIII):

X represents NR7; Y represents O or N-(CH2)nR19; n is equal to 1 or 2; m is equal to 1 or 2; R1 represents H or C1-6alkyl; R2 independently represents H, C1-6alkyl or C5-6cycloalkyl; each of R4 and R4 independently represents H or C1-6alkyl; or R4 and R4 together form spiro-C3-6cycloalkyl group; R19 represents H, C1-6alkyl, C6aryl or C3cycloalkyl group; R6 represents OR8 ; and each of R7 and R8 independently represents H or C1-6alkyl. The invention also refers to compounds of formula VI, VII, a pharmaceutical composition containing said compounds, and a method of treating a proliferative disease, such as cancer.

EFFECT: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a PLK1 kinase inhibitor.

24 cl, 8 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, to a based composition, the use of said crystalline form 1, methods for preparing it.

EFFECT: what is prepared is the new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide effective for treating cancer.

10 cl, 9 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

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