5-ht2a- and d3-receptor double modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

, wherein X represents a halogen atom or C1-6-alkyl; and has the value of 0, 1, 2 or 3; R1 represents H; R2 represents or ; R3 represents C1-6-alkyl, C3-10-cycloalkyl, phenyl, 6-member heterocycloalkyl representing tetrahydropyranyl, or 5-10-member heteroaryl specified in pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzo[1,3]dioxolyl and 2,3-dihydrobenzo[1,4]dioxynyl; which be substituted and contains one to five substitutes specified in the patent claim. The invention also refers to pharmaceutical compositions possessing high affinity to dopamine D3 receptor and serotonin 5-HT2A receptor containing said compounds, and the use thereof in preparing drugs.

EFFECT: preparing the compounds of formula (I) possessing high affinity to dopamine D3 receptor and serotonine 5-HT2A receptor.

15 cl, 4 dwg, 5 tbl, 78 ex

 

The present invention relates to compounds of General Formula (I)

,

where

X independently represents a halogen atom, cyano, C1-6-alkyl, C1-6-alkoxy or C1-6-halogenoalkane;

n is 0, 1, 2 or 3;

R1represents N or C1-6-alkyl;

R2representsor;

R3represents a hydrogen atom, a C1-6-alkyl, C2-6alkenyl,2-6-quinil, C1-6-alkoxy, C3-10-cycloalkyl, aryl, 4-10-membered heteroseksualci or 5-10-membered heteroaryl, that may be substituted and contain from one to five substituents selected from the group consisting of

halogeno,

cyano,

-SO2-C1-6-alkyl,

hydroxyl,

With1-6-alkyl,

With1-6-halogenoalkane,

-CO(O)-C1-6-alkyl,

With1-6-alkoxy, possibly substituted by one or more of Ra,

With3-10-cycloalkyl, possibly substituted by one or more of Ra,

4-10-membered geterotsiklicheskie, possibly substituted by one or more of Ra,

aryl, possibly substituted by one or more of Ra,

5-10-membered heteroaryl, possibly substituted by one or more of Raand

-NRbRc, where the R brepresents N or C1-6-alkyl, and where Rcrepresents H, C1-6is alkyl or aryl, possibly substituted by one or more of Ra;

where Raselected from the

halogeno,

cyano,

oxo,

hydroxyl,

halogenosilanes,

With1-6-alkyl,

With1-6-halogenoalkane,

-NH(CO)1-6-alkyl,

di(C1-6)alkylamino,

-O(CO)1-6-alkyl,

With1-6-alkylsulfonyl,

With1-6-alkoxy,

With1-6-halogenoalkane,

4-10-membered geterotsiklicheskie,

aryl,

aryloxy or

5-10-membered heteroaryl;

and their pharmaceutically acceptable salts.

It has been unexpectedly found that the compounds of formula (I) according to the invention are modulators of the two types of receptors, the serotonin receptor 5-HT2Aand dopamine receptor D3.

Compounds according to the invention have a high affinity to dopamine receptor D3and serotonin (5-hydroxytryptamine; 5-HT) receptor 5-HT2Aand are effective in the treatment of psychotic disorders, as well as other diseases, such as depression and anxiety, drug dependence, dementia and memory impairment. Psychotic disorders include a range of diseases, which include schizophrenia, schizoaffective disorder, bipo the popular disorder, mania, psychotic depression, and other psychoses, including paranoia and delusions.

In particular, schizophrenia is characterized by a complex of symptoms, including positive symptoms (i.e. delusions and hallucinations) and negative symptoms (such as anhedonia, slow of speech, and the delay of thinking). In addition, it is now recognized that the impaired cognitive abilities, characterized by loss of working memory, as well as other violations, is the third main diagnostic criteria of schizophrenia. Other symptoms include aggression, depression and anxiety (Stahl, S.. (2000) Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Cambridge University Press, second edition, Cambridge, UK). Classification and clinical features of this disorder are given in such diagnostic schemes, as the DSM-IV (Diagnostic and statistical manual of mental disorders, 4th edition) or ICD-10 (international classification of diseases, 10th edition). Drugs currently used to treat schizophrenia, bipolar mania and other psychoses include as typical antipsychotics (preferably D2/D3), and atypical, more modern neuroleptics, which have polypharmacological action, interacting with several types of receptors (for example, D1D2D3D4, 5-HT1A, 5-HT2A, 5-HT2CH1, M1, M2, M4/sub> and so on; Roth, .L. et al. (2004) Magic shotguns versus magic bullets: selectively nonselective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3, 353-359). Although these doses are relatively successful (some patients are resistant to these tools) used in the treatment of the positive symptoms of schizophrenia, the treatment of negative symptoms, cognitive disorders and associated depression and anxiety, all of which lead to a deterioration of the quality of life of the patient and the emergence of socio-economic problems, they are less effective (Lieberman, J.A. et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353, 1209-1223). In addition, compliance sick mode and a treatment regimen is impossible due to such common side effects as weight gain, extrapyramidal symptoms (EPS) and the action on the cardiovascular system (Lieberman, J.A. et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353, 1209-1223). In the present invention is described and proposed for the treatment of psychosis and other disorders of the compounds with high affinity and high selectivity for receptors D3and 5-HT2Acausing more than minor adverse effects.

Dopamine, a major neurotransmitter in the group of catecholamines, uchastvuet the regulation of many functions, including emotions, cognitive function, motor function, and positive reinforcement (Purves, D. et al. (2004) Neuroscience. Sinauer, third edition, Sunderland, Massachusetts). The biological activity of dopamine mediated through G-protein-coupled receptors (GPCR); a person identified five different dopamine receptors (D1-D5from which D2-like receptors (D2D3and D4) associated with G-protein GαI(Missale, C. et al. (1998) Dopamine receptors: from structure to function. Physiol. Rev. 78, 189-225). Dopamine receptor D3most strongly expressed in the adjacent core (Gurevich, .V., Joyce, J.N. (1999) Distribution of dopamine D3receptor expressing neurons in the human forebrain: comparison with D2receptor expressing neurons. Neuropsychopharmacology. 20, 60-80), and assume that it modulates the mesolimbic path consisting of neural projections from the ventral region of the tire, the hippocampus and the amygdala in the nucleus accumbens, which allows projections in the prefrontal cortex and cingulate cortex, as well as in various thalamic nuclei. The limbic loop is considered to be important for emotional behavior, and, accordingly, it is assumed that the receptor antagonists D3modulate psychotic symptoms such as hallucinations, delusions and disorders of thinking (Joyce, J.N. and Millan, M.J. (2005) Dopamine D3receptor antagonists as therapeutic agents. Drug Discovery Today, 1 Jul, Vol.10, No. .13, 917-25), at the same time, these antagonists do not affect the D2modules the veins has been created extrapyramidal system (associated with the induction of EPS). In addition, according to the published data in patients with schizophrenia and not receiving medication, changed the expression level of the receptor D3(Gurevich, E.V. et al. (1997) Mesolimbic dopamine D3receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch. Gen. Psychiatry 54, 225-232) and release of dopamine (Laruelle, M. (2000) Imaging dopamine dysregulation in schizophrenia: Memorandum for treatment. Presented at Workshop Schizophr.: Pathol. Bases and Mech. Antipsychotic Action, Chicago), which suggests that the disturbance of the homeostasis of dopamine plays an important role in the etiology of schizophrenic symptoms.

The neurotransmitter serotonin is associated with some psychiatric conditions, including schizophrenia (Kandel, .R. et al. (eds.; 2000) Principles of Neural Science, 3rd edition, Appleton & Lange, Norwalk, CT). Numerous studies, including use in the treatment of people psychotropic drug, lysergic acid diethylamide (LSD, agonist serotonin), which can induce symptoms of schizophrenia, such as hallucinations (Leikin, J.. et al. (1989) Clinical features and management of intoxication due to hallucinogenic drugs. Med. Toxicol. Adverse Drug Exp.4, 324-350), suggest that serotonin is involved in psychotic disorders. In addition, patients suffering from schizophrenia, the detected change in the distribution of serotonin receptors in the brain, as well as changes serotonergic activity (Harrison, P.J. (1999) Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antisychotics. Focus on dopamine D1D3D4) and 5-HT2Areceptors. Br. J. Psychiatry Suppl. 38, 12-22). In mammals, serotonin exerts its biological activity through 14 5-HT receptors belonging to the GPCR family (Barnes, N. M., Sharp, T. (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38, 1083-1152). In the brain receptor 5-HT2Amost strongly expressed in the prefrontal cortex and at lower levels in the basal nuclei and the hippocampus (Pompeiano, M. et al. (1994) Distribution of the serotonin 5-HT2Creceptor family mRNAs: comparison between 5-HT2Aand 5-HT2Creceptors. Brain Res. Mol. Brain Res. 23, 163-178; Pazos, A., Probst, A., Palacios, J.M. (1987) Serotonin receptors in the human brain--IV. Autoradiographic mapping of serotonin-2 receptors. Neuroscience 21, 123-139) and is associated mainly with G-protein Gαq(Roth, .L. et al. (1998) 5-Hydroxytryptamine2-family receptors (5-hydroxytryptamine2A, 5-hydroxytryptamine2B, 5-hydroxytryptamine2C): where structure meets function. Pharmacol. Ther. 79, 231-257). Research results genetic relationship of polymorphism of the 5-HT2Awith schizophrenia (Spurlock, G. et al. (1998) A family based association study of T102C polymorphism in 5HT2Aand schizophrenia plus identification of new polymorphisms in the promoter. Mol. Psychiatry 3, 42-49), and reactivity to neuroleptics (Arranz, .J. et al. (2000) Pharmacogenetic prediction of clozapine response. Lancet 355, 1615-1616) provide an additional basis for assumptions about the role of the receptor 5-HT2Ain the treatment and pathology of psychosis. In addition, the receptor 5-HT2Aapparently carries afferent regulation of dopaminergic neurotrans the hurt (Porras, G. et al. 5-HT2Aand 5-HT2C/2Breceptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and the striatum. Neuropsychopharmacology. 26, 311-324 - 2002). It is assumed that, in General, antagonists of the receptor 5-HT2Asuitable for treatment of disorders associated with dysfunctional dopaminergic system. In addition, it was found that antagonism of the receptor 5-HT2Ais a favorable factor in the treatment of psychosis (review, de Angelis, L. (2002) 5-HT2Aantagonists in psychiatric disorders. Curr. Opin. Investig. Drugs 3, 106-112) and is indeed one of the defining properties of the so-called atypical antipsychotics, which are characterized by a relatively high affinity to the receptor 5-HT2Acompared with receptor D2(Meltzer, NO et al. (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp.Ther. 251, 238-246).

As noted in the description above, the compounds according to the invention have a high affinity to dopamine receptor D3and serotonin receptor 5-HT2Aand it is expected that these compounds will be effective in the treatment of psychotic disorders, including schizophrenia, schizoaffective disorder, bipolar disorder, mania, psychotic depression, and other psychoses, including paranoia and delusions (Reavill C, et al. (2000) Pharmacological actions of a novel, high-affinity and selective human dopamine D3receptor antagonist,SB-277011-A. JPET 294:1154-1165; Harrison, P.J. (1999) Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics. Focus on dopamine D1D3D4) and 5-HT2Areceptors. Br. J. Psychiatry Suppl. 38, 12-22; de Angelis, L. (2002) 5-HT2Aantagonists in psychiatric disorders. Curr. Opin. Investig. Drugs 3, 106-112; Joyce, J.N. and Millan, M.J. (2005) Dopamine D3receptor antagonists as therapeutic agents. Drug Discovery Today, 1 Jul, Vol.10, No.13, P.917-25); drug dependence, addiction and withdrawal symptoms (Vorel, S.R. et al. (2002) Dopamine D3receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats. J. Neurosci., 22, 9595-9603; Campos, A.C. et al. (2003) The dopamine D3receptor antagonist SB277011A antagonizes nicotine-enhanced brain-stimulation reward in the rat. Soc. Neurosci. Abstr., 322.8; Ashby, et al., (2003) Acute administration of the selective D3receptor antagonist SB-277011-A blocks the acquisition and expression of the conditioned place preference response to heroin in male rats. Synapse, 48, 154-156); anxiety and depression (Reavill C et al. (2000) Pharmacological actions of a novel, high-affinity and selective human dopamine D3receptor antagonist, SB-277011-A. JPET 294:1154-1165; Drescher, K. et al. (2002) In vivo effects of the selective dopamine D3receptor antagonist A-437203. Am. Soc. Neurosci. 894.6).

The compounds of formula (I) can form salts accession acids with acids such as standard pharmaceutically acceptable acid, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulfate, pyruvate, citrate, lactate, mandelate, tartrate and methanesulfonate. Preferred are cleaners containing hydrochloride salt. In the scope of the present invention also includes a solvate and hydrate compounds fo the formula I and their salts.

The compounds of formula (I) can have one or more than one asymmetric carbon atom and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric of racemates or mixtures diastereoisomeric racemate. Data optically active forms may be obtained, for example, by separation of racemates by asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluant). The invention includes all the form data.

It is necessary to take into account that compounds of General formula (I) in this invention can be modified by functional groups with obtaining derivatives, which can again be transformed into the corresponding parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are able to give the parent compound of General formula I in vivo, are also included in the scope of this invention.

The following definitions of common terms used in this description apply regardless of use these terms alone or in combination.

It should be noted that in the context of this description and the attached claims form one of the n number of nouns include the corresponding plural forms, unless the context clearly requires otherwise.

The term "aryl" means an aromatic carbocyclic group, consisting of one ring or one or more condensed rings, where at least one ring is aromatic in nature. Preferred aryl groups are aryl groups having from 6 to 10 ring atoms. Preferred aryl groups include phenyl and naphthyl and aryl groups, illustrated with specific examples given in this description below.

The term "aryloxy" means aryl group, such as defined herein above, attached via an oxygen atom. An example of aryloxy is phenoxy.

The term "C1-6-alkyl" means a hydrocarbon group with a normal or branched chain, containing from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, and With1-6is an alkyl group, illustrated by the specific examples given in this description below.

The term "di(C1-6-alkyl)amino" means a nitrogen atom, having as substituents two1-6is an alkyl group, such as defined herein above. Examples of di(C1-6-alkyl)amino groups are dimethylamino, diethylamino, dipropylamino, methylethylamine, and d is(C 1-6-alkyl)amino, illustrated with specific examples given in this description below.

The term "halogen" or "halogen atom" means a chlorine atom, iodine, fluorine and bromine.

The term "C1-6-halogenated" means1-6is an alkyl group such as defined above, which is substituted by one or more than one halogen atom. Examples1-6-halogenoalkane groups include methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more than one atom of Cl, F, Br or I, and C1-6-halogenoalkane group, illustrated by the specific examples given in the description below, but are not limited to them. Preferred1-6-halogenoalkane groups are debtor or trifter-methyl or ethyl.

The term "C1-6-alkylsulfonyl" means sulfonyloxy group (SO2), which is substituted With1-6is an alkyl group, such as defined above.

The term "C1-6-alkoxy" means a group that is an alkyl group such as defined above, attached via an oxygen atom.

The term "C1-6-halogenoalkane" means1-6-alkoxygroup, such as defined above, which is substituted by one or more than one halogen atom. Examples1-6-halogenoalkanes VK is ucaut methoxy or ethoxy, substituted by one or more than one atom of Cl, F, Br or I, and C1-6-halogenoalkanes, illustrated with specific examples given in the description below, but are not limited to them. Preferred1-6-halogenocarboxylic are debtor or trifter-methoxy or ethoxy.

The term "lower alkenyl" means a hydrocarbon group with a normal or branched chain, containing from 2 to 7, preferably from 2 to 4 carbon atoms, where at least one bond is a double.

The term "thioalkyl" means the group-SR, where R is an alkyl group such as defined above.

The term "C3-10-cycloalkyl" means a monovalent saturated cyclic group, consisting of one, two or three carbon rings and containing from 3 to 10 ring carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and palestinography, such as bicyclo[2,2,2]octenyl, bicyclo[2,2,1]heptenyl, bicyclo[3,2,1]octenyl or adamantanol and3-10-cycloalkyl group, illustrated by the specific examples given in the description below, but is not limited to.

The term "thiophenyl" in the context of this description is synonymous with "thienyl and means titanovyi Deputy, that is, C4H4S.

The term "5-to 10-membered gets roarer" means a monocyclic, bicyclic or tricyclic radical containing from 5 to 10 ring atoms having at least one aromatic ring and additionally containing one, two or three ring heteroatoms selected from N, O and S (the remaining ring atoms are C). Heteroaryl may possibly be substituted by one, two, three or four substituents, each of which is independently represents hydroxy, cyano, alkyl, alkoxy, thioalkyl, halogen, halogenated, hydroxyalkyl, alkoxycarbonyl, amino, acetyl, -NHCOOC(CH3)3or halogeno-substituted benzyl, and oxo in part of cyclic non-aromatic radical, unless specifically provided otherwise. Examples of heteroaryl groups include possibly substituted imidazolyl, possibly substituted thiophenyl, possibly substituted oxazolyl, possibly substituted isoxazolyl, possibly substituted thiazolyl, possibly substituted pyrazinyl, possibly substituted pyrrolyl, possibly substituted pyridinyl, possibly substituted pyrimidinyl, possibly substituted pyridazinyl, possibly substituted indolyl, possibly substituted isoindolyl, possibly substituted 2,3-dihydroindole, possibly substituted indazoles, possibly substituted naphthyridines, possibly substituted ethenolysis, possibly substituted carbazole-9-yl, possibly substituted furanyl, possibly substituted the initial benzofuranyl, possibly substituted chinoline, possibly substituted benzo[1,3]dioxole, possibly substituted benzo[1,2,3]thiadiazolyl, possibly substituted benzo[b]thiophenyl, possibly substituted 9H-thioxanthene, possibly substituted thieno[2,3-C]pyridinyl, possibly substituted 3H-imidazo[4,5,b]pyridinyl, possibly substituted phthalazines, possibly substituted 2,3-dihydrobenzo[1,4]dioxines and the like, or heteroaryl groups, are illustrated in the specific examples given in this description, but is not limited to them. Preferred 5-10-membered heteroaryl groups are 5 - or 6-membered heteroaryl.

The term "4-10-membered heteroseksualci" means a monovalent saturated group consisting of one, two or three rings, incorporating one, two or three heteroatoms (chosen from nitrogen atom, oxygen or sulfur). Heteroseksualci may possibly be substituted by one, two, three or four substituents, each of which is independently represents hydroxy, alkyl, alkoxy, thioalkyl, halogen, halogenated, hydroxyalkyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl or carbylamine, unless specifically provided otherwise. Examples of heterocyclic groups include piperidinyl, piperazinil, homopiperazine, azepine, pyrrolidinyl, pyrazolidine, imidazoline, imidazole the sludge, oxazolidinyl, isoxazolidine, morpholine, thiazolidine, isothiazolinones, hinokitiol, chinoline, ethenolysis, benzimidazolyl, bromanil, thiadiazolidine, benzothiazolyl, benzoapyrene, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thiomorpholine, diocletianopolis, dimorpholinyldiethyl, thiomorpholine, dihydroquinoline, dihydroisoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, 1-oxo-thiomorpholine, 1,1-dioxo-thiomorpholine, 1,4-diazepan, 1,4-oxazepan, and heterocyclic groups, illustrated with specific examples given in the description below, but are not limited to them. Preferred 5-10-membered heteroseksualnymi are 5 - or 6-membered heterocicluri.

The term "one or more than one" in the context of this specification means 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5, and more preferably 1, 2 or 3.

The term "oxo" refers to the group =O.

When R3represents a group, R8and R9may form a 3-, 4-, 5 - or 6-membered saturated ring, possibly containing one or two heteroatoms selected from oxygen atom and nitrogen, and R10may be substituents on the ring formed by R8and R9. In such cases, R10can represent, e.g. the measures halogen atom, cyano, hydroxyl, C1-6alkyl, C1-6halogenoalkane and C1-6alkoxy.

The term "pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, salt and so forth, means pharmacologically acceptable, safe, and essentially non-toxic to the subject, which enter the connection, either from a biological point of view, nor for any other reasons.

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable in accordance with the order, as defined in the description above, and which possess the desired pharmacological activity of the corresponding parent compound. Such salts include salts accession acids, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or salts of joining acids formed with organic acids such as acetic acid, benzolsulfonat acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, malacacheta, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonate acid, propionic acid, salicylic acid, succinic acid, tartaric acid, para-toluensulfonate acid, trimethylarsine acid and the like.

The term "therapeutically effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or increasing the life expectancy of the subject, which is treated.

Compounds of the present invention also include compounds of Formula (I), where

X independently represents a halogen atom, cyano; C1-6-alkyl, C1-6-alkoxy or C1-6-halogenoalkane;

n is 0, 1, 2 or 3;

R1represents N or C1-6-alkyl;

R2representsor;

R3represents a hydrogen atom, a C1-6-alkyl, C2-6alkenyl,2-6-quinil, C1-6-alkoxy, C3-10-cycloalkyl, 4-10-membered heteroseksualci or 5-10-membered heteroaryl, that may be substituted and contain from one to five substituents selected from the group consisting of

halogeno,

hydroxy,

With1-6-alkyl,

With1-6-halogenous the sludge,

-CO(O)-C1-6-alkyl,

With1-6-alkoxy, possibly substituted by one or more of Ra,

With3-10-cycloalkyl, possibly substituted by one or more of Ra,

4-10-membered geterotsiklicheskie, possibly substituted by one or more of Ra,

aryl, possibly substituted by one or more of Ra,

5-10-membered heteroaryl, possibly substituted by one or more of Raand

-NRbRcwhere Rbrepresents N or C1-6-alkyl, and where Rcrepresents H, C1-6is alkyl or aryl, possibly substituted by one or more of Ra;

where Raselected from the

halogeno,

cyano,

oxo,

hydroxy,

halogenosilanes,

With1-6-alkyl,

With1-6-halogenoalkane,

-NH(CO)1-6-alkyl,

di(C1-6)alkylamino,

-O(CO)1-6-alkyl,

With1-6-alkylsulfonyl,

With1-6-alkoxy,

With1-6-halogenoalkane,

4-10-membered geterotsiklicheskie,

aryl,

aryloxy or

5-10-membered heteroaryl;

and their pharmaceutically acceptable salts.

Compounds of the present invention also include compounds of Formula (I), where

X represents a fluorine atom or a chlorine atom;

n is 0, 1 or 2;

R1represents at the m hydrogen;

R2representsand

R3is as defined above in the description of Formula (I),

and their pharmaceutically acceptable salts.

The compounds of Formula (I) also include compounds of Formula (Ia)

,

where

X represents a fluorine atom or a chlorine atom;

n is 0, 1 or 2;

m is 0, 1, 2 or 3;

R4selected from the group consisting of

halogeno,

cyano,

hydroxy,

With1-6-alkyl,

With1-6-halogenoalkane,

di(C1-6)alkylamino,

-CO(OH)1-6-alkyl,

With1-6-alkoxy, possibly substituted by one or more of Ra,

With3-10-cycloalkyl, possibly substituted by one or more of Ra,

4-10-membered geterotsiklicheskie, possibly substituted by one or more of Ra,

aryl, possibly substituted by one or more of Ra,

5-10-membered heteroaryl, possibly substituted by one or more of Raand

-NRbRc,

where Ra, Rband Rcare as defined above in the description of Formula (I).

and their pharmaceutically acceptable salts.

Preferred compounds of Formula (Ia) are compounds of Formula (Ia), where

X represents a fluorine atom or atom PI is RA;

n has a value of 1;

m is 0, 1 or 2;

R4selected from the group consisting of halogeno,

With1-6-alkoxy, possibly substituted by one or more of Ra,

6-membered geterotsiklicheskie, possibly substituted by one or more of Raand

5-6-membered heteroaryl, possibly substituted by one or more of Ra,

where Raselected from halogen, oxo, hydroxyl and C1-6-alkyl,

and their pharmaceutically acceptable salts.

Especially preferred compounds of Formula (Ia) are, for example, the following connections:

3-Fluoro-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,

N-TRANS-(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzamide,

4-tert-Butoxy-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide,

4-Chloro-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide,

N-TRANS(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-pyrrol-1-yl-benzamide,

Benzo[1,3]dioxol-5-carboxylic acid TRANS - (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide and

Benzo[1,3]dioxol-5-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-qi is logical)-amide.

The compounds of Formula (I) also include compounds of Formula (Ib)

,

where

X represents a fluorine atom or a chlorine atom;

n is 0, 1 or 2;

m, R independently of one another are 0, 1 or 2;

R4and R5selected from the group consisting of

halogeno,

cyano,

hydroxy,

With1-6-alkyl,

With1-6-halogenoalkane,

-CO(O)-C1-6-alkyl,

With1-6-alkoxy, possibly substituted by one or more of Ra,

With3-10-cycloalkyl, possibly substituted by one or more of Ra,

4-10-membered geterotsiklicheskie, possibly substituted by one or more of Ra,

aryl, possibly substituted by one or more of Ra,

5-10-membered heteroaryl, possibly substituted by one or more of Raand

-NRbRc,

where Ra, Rband Rcare as defined in claim 1 of the claims;

Y represents an oxygen atom or-SO2-;

one, two or three of And1And2And3And4and5represent the nitrogen atom and the others represent CR6or And1And2And3And4and5represent CR6where

each R6independently represents a hydrogen atom, or R7 ; and

each R7independently represents a C1-6alkyl, C1-6alkyloxy, hydroxyl, amino, C1-6alkylamino, N,N-di-(C1-6alkyl)-amino, halogeno, halogeno-C1-6alkyl, halogeno-C1-6alkoxy, hetero-C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfonyl, cyano;

and their pharmaceutically acceptable salts.

Preferred compounds of Formula (Ib) are compounds of Formula (Ib), where

X represents a fluorine atom;

n, m have values of 0 or 1;

p has a value of 0;

R4selected from the group consisting of

halogeno,

cyano,

hydroxy,

With1-6-alkyl,

With1-6-halogenoalkane,

Y represents an oxygen atom or-SO2-;

one or two of And1And2And3And4and5represent the nitrogen atom and the others represent CH2;

and their pharmaceutically acceptable salts.

Especially preferred compounds of Formula (Ib) are, for example, the following connections:

N-TRANS-(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,

N-TRANS (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-6-morpholine-4-the-nicotinamide,

5-Morpholine-4-yl-pyrazin-2-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,

6-Morpholine-4-yl-pyridazin-3-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,

2-Morpholine-4-yl-pyrimidine-5-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,

3-Fluoro-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,

4-(1,1-Dioxo-1,6-thiomorpholine-4-yl)-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide,

N-TRANS (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-morpholine-4-yl-isonicotinamide,

N-TRANS (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-piperidine-1-yl-benzamide,

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-piperidine-1-yl-benzamide,

4-(2,6-Dimethyl-morpholine-4-yl)-N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide,

4-(2,6-Dimethyl-morpholine-4-yl)-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide and

4-(1,1-Dioxo-1,6,4-thiomorpholine-4-yl)-N-TRANS-(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide.

The compounds of Formula (I) also include with the unity of Formula (Ic)

,

where

X represents a fluorine atom or a chlorine atom;

n is 0, 1 or 2;

R8and R9form a 3-, 4-, 5 - or 6-membered saturated ring, possibly containing one or two heteroatoms selected from oxygen atom and nitrogen atom;

R10can be a Deputy on the ring formed by R8and R9and selected from the group consisting of halogen atom, cyano, hydroxy, C1-6-alkyl, C1-6-halogenoalkane and C1-6-alkoxy;

and their pharmaceutically acceptable salts.

The compounds of Formula (I) also include compounds of Formula (Id)

,

where

X1represents N and X2represents a fluorine atom or a chlorine atom; or

X2represents N and X1represents a fluorine atom or a chlorine atom; and

R11selected from the group consisting of C1-6-alkyl and C1-6-alkoxy, possibly substituted by halogen atom, hydroxy, C1-6-alkyl, C1-6-halogenoalkanes,1-6-alkoxy and C5-6-cycloalkyl, possibly substituted C1-6-alkyl or C1-6-alkoxy;

and their pharmaceutically acceptable salts.

Especially preferred are the compounds of Formula (Id')

,

where X1, X2and R 11are as defined above in the description of Formula (Id),

and their pharmaceutically acceptable salts.

Especially preferred compounds of Formula (Id') are, for example, the following connections:

4N-TRANS(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she

Tetrahydro-Piran-4-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,

N-TRANS (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,

TRANS 4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin,

2,3-Dihydro-benzo[1,4]dioxin-2-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,

N-TRANS (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-pyrazole-1-yl)-acetamide", she

3,3,3-Cryptor-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-propionamide,

2-(3,5-Dimethoxy-phenyl)-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-CEC is hexil)-3-methoxy-propionamide,

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3,3,3-Cryptor-2-hydroxy-propionamide,

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-Piran-2-yl)-acetamide", she

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-TRANS - (4-methoxy-cyclohexyl)-acetamide", she

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(1,4-dioxa-Spiro[4,5]Dec-8-yl)-ndimethylacetamide and

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide.

The compounds of Formula (I) also include compounds of Formula (Ie)

,

where

X1represents N and X2represents a fluorine atom or a chlorine atom; or

X2represents N and X1represents a fluorine atom or a chlorine atom; and

R12selected from the group consisting of halogeno, hydroxy, cyano, C1-6-alkyl, C1-6-halogenoalkane and C1-6-alkoxy;

and their pharmaceutically acceptable salts.

Especially preferred are the compounds of Formula (Ie')

,

where X1, X2and R12are as defined above in the description is ormula (Ie)

and their pharmaceutically acceptable salts.

Particularly preferred compounds of the Formula (Ie') are, for example, the following connections:

1-Hydroxy-cyclopropanecarboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide and

1-Trifluoromethyl-cyclobutanecarbonyl acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide.

The compounds of Formula (I) also include compounds of Formula (Ig)

,

where

X represents a fluorine atom or a chlorine atom;

n is 0, 1 or 2;

R13selected from the group consisting of C1-6-alkyl, C1-6-halogenoalkane,1-6-alkoxy, aryl, possibly substituted by one or more of Raand 5-10-membered heteroaryl, possibly substituted by one or more of Ra;

where Rarepresents halogeno,1-6-alkyl and C1-6-alkoxy;

and their pharmaceutically acceptable salts.

Especially preferred compounds of Formula (Ig) are, for example, the following connections:

Econsultancy acid (4-TRANS - {2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,

4-Chloro-N-TRANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzosulfimide,

N-TRANS(4-{2-[4-(6-Fluoro-benzo is[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzosulfimide and

Pyridine-3-sulfonic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide.

Especially preferred compounds are the following compounds:

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-cyano-propionamide,

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-cyano-acetamide", she

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-furan-2-yl-acetamide", she

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-cyclopropyl-ndimethylacetamide,

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide", she

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-methanesulfonyl-ndimethylacetamide,

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxane-2-yl-acetamide", she

N-TRANS-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide", she

N-TRANS-(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide,

N-TRANS-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,

N-TRANS-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(t is trihydro-furan-2-yl)-acetamide", she

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-methoxy-acetamide", she

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-methoxy-cyclopentyl)-ndimethylacetamide,

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide", she

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide", she

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-propionamide,

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-cyclohexyl)-acetamide", she

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-hydroxy-cyclopentyl)-ndimethylacetamide,

Tetrahydro-Piran-4-carboxylic acid TRANS-(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxane-2-yl-acetamide", she

N-TRANS-(4-{2-[4-(6-Methyl-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide.

Another aspect of altoadige invention relates to pharmaceutical compositions, containing compounds of Formula (I), (Ia), (Ib), (Ic), (Id) (Id'), (Ie), (Ie') and (Ig), for the treatment of schizophrenia, cognitive disorders and drug addiction.

Another aspect of the present invention relates to a method for producing compounds of Formula (I)such as defined above.

To obtain the compounds of formula (I) according to the present invention can be used in sequential or convergent synthesis. The synthesis of compounds according to the invention shown in the diagrams below. Specialists in the art will possess the expertise needed to perform these reactions and purification of the products obtained. Unless otherwise specified, the designation of the substituents and indices used in the following description of the synthesis methods, have the meanings given in the description above.

In more detail, the compounds of formula (I) can be obtained using the techniques below, using the techniques described in the examples, or using similar techniques. Suitable reaction conditions used in the individual stages of reactions known to the person skilled in the art. The original substances either are commercially available or can be obtained using techniques similar to the techniques given below, using the techniques described in the literature cited in the description or in the examples or by methods known in Dan is the second field of technology.

Scheme 1

4-(Benzo-isoxazol-3-yl)-piperidine-1-yl, TRANS-ethyl-cyclohexyl-amides or TRANS-1,4-cyclohexyl ethyl derivatives of Formula IA can be obtained in accordance with Scheme 1 of 4-nitro-phenylacetic acid as the starting material, by hydrogenation using a catalyst of Raney Nickel. Hydrogenation using Nickel results in predominantly the desired TRANS-isomer (according to Journal of Medicinal Chemistry, 1998, 41, 760-771). Specified in the scheme complex ethyl ester can be obtained in accordance with techniques known to experts in the art and described in the literature (for example, by treatment with ethanol in the presence of acid, such as HCl). Retrieved HCl-salt can be crystallized, and then the mixture of CIS/TRANS isomers may be separated to obtain pure TRANS-aminoethane hydrochloride Century Interaction with a protective group such as tert-butyl-dicarbonate, in the presence of a base, such as triethylamine, and a catalyst, such as dimethylaminopyridine and the subsequent restoration by diisobutylaluminium (DIBAH) in a suitable solvent, for example toluene, at -78°C leads to the aldehyde, which can be used without purification in the next stage. Vosstanovit the Noah amination of the aldehyde With a substituted 4-(benzo[d]isoxazol-3-yl)-piperidine D can be performed using techniques described in the literature, the methods described herein, or methods known in the art. Reductive amination can be carried out in the presence of a solvent, such as 1,2-dichloromethane, and/or a reducing agent, such as triacetoxyborohydride sodium, to obtain the intermediate compounds that Removal of the BOC-protective group under acidic conditions, for example in the presence of triperoxonane acid, in a suitable solvent, such as THF (tetrahydrofuran), leads to the production of TRANS-aminocyclohexanol-ethyl intermediate compound F (usually in the form of a salt triperoxonane acid (TFU)). The reaction between the amine intermediate compound F and carboxylic acids (which are either available commercially or can be obtained using the techniques described in the above references, or using methods known in the art) are well described in the literature (see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999) and can be performed using cross-linking reagents, such as, for example, N,N-carbonyldiimidazole (CDI), 1-hydroxy-1,2,3-benzotriazole (NOVT) or O-benzotriazol-1-yl-N,N,N,N-tetramethylurea tetrafluoroborate (TBTU)in a suitable solvent, such as dimethylformamide (DMF) or dioxane, in the presence of a base (in the example, triethylamine or diisopropylethylamine) to obtain the compounds of formula IA. In other cases, it may be used as the acid chloride in the presence of a base (e.g. triethylamine or diisopropylethylamine) in a solvent such as dichloromethane.

Scheme 2A

Some substituted 4-(benzo[d]isoxazol-3-yl)-piperidine formula D can be obtained by acylation according to the Friedel-Crafts corresponding benzene derivatives using a suitable Lewis acid such as aluminum chloride, in the presence of 1-acetylpenicillamine, in a solvent such as dichlorobenzene using heating to a temperature of approximately 70°C, in accordance with the order, as described in Journal of Medicinal Chemistry, 1985, 28, 761-769, Journal of Medicinal Chemistry, 1970, 13, 1-6, or in US Patent No. 4355037.

Scheme 2B

Alternative 4-(benzo[d]isoxazol-3-yl)-piperidine formula D can be obtained using as the starting material the appropriate substituted benzaldehyde containing a leaving group such as, for example, F in the ortho-position (by analogy with WO 02066446). The benzaldehyde can be turned into dimethylacetal using this reagent, as orthomorphisms acid timetravel ether, in the presence of catalytic amount of acid, such as pTsOH. obtained acetal with triethylorthoformate in the presence of a Lewis acid for example, TiCl4in a solvent such as CH2Cl2results phosphonate, which can be deprotonated using a base, such as n-BuLi, in a solvent such as THF, and subjected to interaction with 1-benzyl-piperidine-4-one to obtain ealovega ether in accordance with figure 2B. The processing of this ealovega ether acid, such as concentrated aqueous HCl, in a solvent such as acetone, leads to the corresponding ketone. The interaction of this ketone with NH2OH·HCl in the presence of a base, such as DIPEA (N,N-diisopropylethylamine), in a solvent such as EtOH, followed by deprotonation of the resulting oxime base, such as KOtBu, THF and intramolecular cyclization yield benzo[d]isoxazole derived. 4-(Benzo[d]isoxazol-3-yl)-piperidine formula D is obtained by dibenzylamine using techniques known in the art, for example by reacting benzo[d]isoxazole derived from α-chloroethyl chloroformate and subsequent processing Meon (methanol) at a temperature of reflux distilled.

Scheme 3

In other cases, the intermediate compound F can also be subjected to interaction with sulphonylchloride in the presence of a base, such as triethylamine, to receive the receiving appropriate sulfonylurea derivative of formula IA.

The ability of compounds to bind to receptor sites of 5-HT2AD3and D2was determined by analysis of the binding of radio-with cloned receptors selectively expressed in cells of SOME 293 EBNA.

Preparation of membrane preparations with receptors person D2D3and 5-HT2A

Cells of SOME 293 EBNA temporarily transfusional expressing plasmids, encoding, respectively, dopamine receptor human D2or D3or serotonin receptor human 5-HT2A. Cells were collected 48 h after transfection, washed three times with cold PBS (phosphate-salt buffer) and stored at -80°C. the Precipitate suspended in cold 50 mm Tris-HCl-buffer, containing 10 mm EDTA (pH of 7.4), and homogenized using a homogenizer transmitter station (Kinematica AG, Basel, Switzerland) for 20-30 s at 12000 rpm After centrifugation at 48000g for 30 min at 4°C. the precipitate resuspendable in cold 10 mm Tris-HCl-buffer, containing 0.1 mm EDTA (a pH of 7.4), homogenized and centrifuged as described above. Then the precipitate resuspendable in a small volume, cooled to 0°C, 10 mm Tris-HCl buffer containing 0.1 mm EDTA (pH of 7.4), and homogenized using a homogenizer transmitter station for 20-30 s at 12000 rpm protein Content in the homogenate of the definition is whether using a Bio-Rad (Bradford) Protein Assay (Biorad Laboratories GmbH, München, Germany) according to the manufacturer's instructions, using as a standard gamma-globulin. This homogenate was stored in aliquot at -80°C and thawed immediately prior to use.

Conditions analysis of the binding of radio -

Aliquots of membrane preparations were thawed at room temperature, resuspendable buffer for analysis (D2D3: 50 mm Tris-HCl, 120 mm NaCl, 5 mm MgCl2, 1 mm EDTA, 5 mm KCl, 1.5 mm CaCl2, a pH of 7.4; 5-HT2A: 50 mm Tris-HCl, 10 mm MgCl2, 1 mm EGTA, pH of 7.4), homogenized using a homogenizer transmitter station for 20-30 s at 12,000 rpm and brought up to a final concentration constituting approximately 7.5 μg protein/well (D2D3) and 15 μg of protein/well (5-HT2A), respectively.

The binding affinity of (Ki) of the compounds were determined by analysis of the binding of the radio. Membranes were incubated in a total volume of 200 μl containing radioligand in the set, the same in all samples, the concentration (final concentration of approximately 0.7 nm [3N]-spiperone for D2, 0.5 nm [3N]-spiperone for D3and 1.1 nm [3N]-ketanserina for 5-HT2A) and investigated the connection in one of the ten concentrations in the range from 10 μm to 0.1 nm for 1 h at room temperature. At the end of the incubation the reaction mixture was filtered through be the haunted 96-well tablets UniFilter with filters GF/C (Packard Bioscience, Zürich, Switzerland; pre-incubated for 1 h in 0.1% polyethylenimine (PEI) in the buffer for analysis) using a harvester Filtermate 196 Harvester (Packard Bioscience) and washed 3 times with cold buffer for analysis. Nonspecific binding was determined using reaction mixtures having the same composition, in the presence of 10 μm of unlabeled spiperone. To each well was added 45 μl of Microscint 40 (Perkin Elmer, Schwerzenbach, Switzerland), the tablets were sealed, shaken for 20 min and counted for 3 min on the counter Topcount Microplate Scintillation Counter (Canberra Packard SA, Zürich, Switzerland) with a correction for extinction.

Data calculations

To calculate the average CPM (counts per minute) of two independent samples for each of the concentrations of competing compounds (y1), then calculate percent specific binding according to the equation (((y1 - nonspecific binding)/(total binding - nonspecific binding))×100). Based on the calculated values of % specific binding built graphics using XLfit, curve fitting, in which the graphing method iteration algorithm is used Levenburg-Marquardt. For describing competitive binding model monospitovo binding used the following equation: y=A+((B-A)/(1+((x/C)D))), where y represents the % specific binding, And not only is em a minimum value of y, Represents a maximum value of y, represents IR50x represents log10concentrations of competing compounds and D represents the slope of the curve (hill coefficient). These curves were determined by IR50(inhibitory concentration at which displaced 50% of specifically bound radioligand) and the hill coefficient. The binding constant (Ki) was calculated using the equation of Cheng-Prusoff: Ki=IR50/(1+[L]/Kd)where [L] is the concentration of radioligand and Kd represents the dissociation constant of radioligand and receptor, as defined by the isotherm saturation.

Compounds of the present invention are selective modulators of two types of receptors, the serotonin receptor 5-HT2Aand dopamine receptor D3as follows from the table below activities, where as the example shows Ki values in μm for the serotonin receptor 5-HT2A, dopamine receptor D3and dopamine receptor D2some compounds of the present invention.

The present invention also proposed pharmaceutical compositions containing the compounds according to the invention, for example the compounds of Formula I, or their pharmaceutically acceptable salts, and pharmaceutically acceptable carrier. Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. Data pharmaceutical compositions can also be in the form of suppositories or injectable solutions.

The pharmaceutical compositions according to the invention along with one or more than one compound according to the invention contain a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. For example, as such carriers for tablets, is Ableton, coated tablets and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; in the case of soft gelatin capsules carriers usually are not required, but it depends on the nature of the active substance. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. To prepare aqueous injection solutions of water-soluble salts of compounds of Formula I can be used adjuvants such as alcohols, polyols, glycerine, vegetable oils and the like, but usually this is not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, moistening agents, emulsifiers, sweeteners, colorants, corrigentov, salts for regulating the osmotic pressure, buffer agents, masking agents or antioxidants. They can also stage niteline contain other therapeutically useful substances.

In the present invention is also a method for preparation of pharmaceutical compositions. This method includes the use of one or more than one compounds of Formula I and/or pharmaceutically acceptable salts accession acids, and optionally one or more than one other therapeutically useful substances in the form Galanova of the drug, together with one or more than one therapeutically inert carrier.

Compounds and compositions of the present invention can be introduced in a standard way, for example, oral, rectal or parenteral. The pharmaceutical compositions according to the invention can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. Pharmaceutical compositions can also be introduced rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

As noted in the description above, the compounds according to the invention have a high affinity to dopamine receptor D3and serotonin receptor 5-HT2Aand it is expected that these compounds will be effective in the treatment of psychotic disorders, including schizophrenia, schizoaffective disorder, bipolar disorder, mania, PS is goticheskuyu depression and other psychoses, including paranoia and delusions (Reavill C, et al. (2000) Pharmacological actions of a novel, high-affinity and selective human dopamine D3receptor antagonist, SB-277011-A. JPET 294:1154-1165; Harrison, P.J. (1999) Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics. Focus on dopamine D1D3D4) and 5-HT2Areceptors. Br. J. Psychiatry Suppl. 38, 12-22; de Angelis, L. (2002) 5-HT2Aantagonists in psychiatric disorders. Curr. Opin. Investig. Drugs 3, 106-112; Joyce, J.N. and Millan, M.J. (2005) Dopamine D3receptor antagonists as therapeutic agents. Drug Discovery Today, 1 Jul, Vol.10, No.13, P.917-25); drug dependence, addiction and withdrawal symptoms (Vorel, S.R. et al. (2002) Dopamine D3receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats. J. Neurosci., 22, 9595-9603; Campos, A.C. et al. (2003) The dopamine D3receptor antagonist SB277011A antagonizes nicotine-enhanced brain-stimulation reward in the rat. Soc. Neurosci. Abstr., 322.8; Ashby, et al. (2003) Acute administration of the selective D3receptor antagonist SB-277011-A blocks the acquisition and expression of the conditioned place preference response to heroin in male rats. Synapse, 48, 154-156); anxiety and depression (Reavill C et al. (2000) Pharmacological actions of a novel, high-affinity and selective human dopamine D3receptor antagonist, SB-277011-A. JPET 294:1154-1165; Drescher, K. et al. (2002) In vivo effects of the selective dopamine D3receptor antagonist A-437203. Am. Soc. Neurosci. 894.6).

Of course, injected dose of the compounds according to the invention can be varied within wide limits and is generally in each case it should be selected in accordance with individual needs. In the General case, the effective dose for oral or parenteral administration is in the range of 0.01-20 mg/kg/what the duck and dose of 0.1-10 mg/kg/day is preferred for all the above indications. The daily dose for an adult weighing 70 kg, respectively, is in the range of 0.7-1400 mg per day, preferably 7-700 mg per day.

The following examples are given to further explain the invention.

Example 1

4N-TRANS(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

The intermediate connection

TRANS-(4-Amino-cyclohexyl)-acetic acid ethyl ester

Stage 1

To the solution prepared from 22,08 g 50% sodium hydroxide solution and 450 ml of deionized water, with stirring was added (4-nitro-phenyl)-acetic acid (50 g, 276 mmol). The obtained transparent yellow solution was transferred into a high pressure autoclave, which was also made of 30 g (511 mmol) of water-soaked sponge Nickel catalyst. The autoclave was tightly closed, purged with nitrogen and then filled with hydrogen, thereby increasing the pressure up to 115 bar (1,15·107PA). This reaction mixture was stirred and heated to 125°C for 48 hours and Then the autoclave was cooled, removed the gas and the nitrogen atmosphere was introduced 30 g (511 mmol) of sponge Nickel catalyst. The autoclave was again purged with nitrogen and then filled with hydrogen, thereby increasing the pressure up to 115 bar (1,15·107PA)was heated to 10°C under stirring (maximum pressure was 130 bar (1,3·10 7PA)). The hydrogenation was continued for 5 days at a temperature of 130°C. Then, the autoclave was cooled, removed gas and purged with nitrogen, the contents were removed, the catalyst was removed by filtration through the filter layer. After removal of solvent received 74 g of the crude substance. The obtained intermediate compound was used as is without purification in the next stage. MS (mass/charge): 158,3 (M+N+).

Stage 2

The solution obtained TRANS-(4-amino-cyclohexyl)-acetic acid (74 g, 476 mmol) was brought to pH 5 by addition of 25% HCl. The mixture was evaporated to dryness and dried under vacuum over night. The residue is suspended in 146 ml of 6.5 n HCl solution in ethanol, and to this mixture was added 0.6 l of ethanol. After reflux distilled for 4 hours the mixture was cooled and filtered, and the obtained filtrate was concentrated to dryness under vacuum. The residue was dissolved in ethanol, was treated with diethyl ether and cooled overnight in the refrigerator to give the desired TRANS-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (19.7 g, yield 32% over two stages) in the form of a white solid, which was filtered and dried under vacuum. MS (mass/charge): 186,1 (M+N+).

The intermediate connection With

Stage 1

TRANS-(4-tert-Butoxycarbonylamino-cyclohexyl)-acetic acid ethyl ester

<> To a solution of TRANS-(4-amino-cyclohexyl)-acetic acid ethyl ester (1.28 g, 7 mmol) in dichloromethane (15 ml) was added di-tert-butyl-dicarbonate (of 2.26 g, 10 mmol), triethylamine (0,699 ml, 7 mmol) and 4-dimethylaminopyridine (0,042 ml, 0.35 mmol). This mixture was stirred for 8 h, until completion of the reaction according to the results of TLC (thin layer chromatography)analysis. Was added water, and the resulting solution three times was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a mixture of hexane:ethyl acetate (4:2-3:2), to obtain 1.2 g (60%) of product as a white solid. MS (mass/charge): 284,4 (N-N+).

Stage 2

TRANS-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamino acid tert-butyl methyl ether

To a solution of TRANS-(4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid ethyl ester (1.04 g, 4 mmol) in toluene (10 ml) at -78°C was added 1.2 M solution DEBUG (5,1 ml, 6 mmol) in toluene. This mixture was stirred at -78°C for 0.5 hour to complete the reaction according to the results of the TLC analysis. Was added water, and the resulting solution three times was extracted with dichloromethane. The combined organic layers were washed with water and saline, with the sewed over magnesium sulfate, filtered and evaporated. The crude product was used without purification in the next stage. MS (mass/charge): 242,3 (M+N+).

Intermediate compound E

TRANS (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butyl methyl ether

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4 g, to 18.1 mmol), TRANS-[4-(2-oxo-ethyl)-cyclohexyl]-carbamino acid tert-butyl ester (5.4 g, 22.7 mmol) in 1,2-dichloroethane (55 ml) was stirred for 4 h at room temperature, was slowly added triacetoxyborohydride sodium (6.9 g, to 32.7 mmol)and the resulting solution was stirred for 12 hours, until completion of the reaction according to the results of the TLC analysis. The mixture was filtered, concentrated to dryness and purified by column chromatography on silica gel using CH2Cl2-CH2Cl2/MeOH (1-9:1). The fractions containing the desired product were concentrated to obtain 9.4 g (21 mmol, yield 100%) of light brown solid. MS (mass/charge): 446,3 (M+N+).

The intermediate compound F

TRANS 4-{2-{4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin (could be obtained in salt form triperoxonane acid)

9.4 g (21 mmol) of (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butile the CSOs ether was dissolved in dichloromethane (100 ml), was added at 0°C triperoxonane acid (13.3 ml, 174 mmol)and the mixture was stirred at room temperature overnight. Was slowly added NaHCO3to obtain pH 9 and the mixture 3 times were extracted with dichloromethane and ethyl acetate. The solvent is evaporated to obtain 5.5 g (16 mmol, 77%) of light brown solid, which was used without purification in the subsequent stages. MS (mass/charge): 346,5 (M+N+).

4N-TRANS (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin (0.03 g, 0,087 mmol) suspended in dichloromethane (0,600 ml), was added triethylamine (of 0.013 ml, 0,096 mmol) and then acetylchloride (0,008 ml, in 0.104 mmol), this mixture was stirred for 30 minutes at room temperature until completion of the reaction according to the results of the TLC analysis. Added the sodium bicarbonate solution to obtain a pH of 9, and the reaction mixture 3 times was extracted with dichloromethane. The organic phase was dried and purified by column chromatography on silica gel using CH2Cl2-CH2Cl2/Meon (1-9:1). The fractions containing the desired product were concentrated with the receipt of 0.022 g (0,056 mmol, yield 65%) of white solids. MS (mass/charge): 388,5 (M+N+).

Example 2

Tetrahydro-Piran-4-carboxylic acid t is ANS (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide

Tetrahydro-Piran-4-carboxylic acid (0,013 g 0,096 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0,026 g, 0.08 mmol) and N-ethyldiethanolamine (0.04 ml, 0.24 mmol) was stirred in 0.6 ml DMF for 0.5 h at room temperature, and was added TRANS-4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin (could be obtained in salt form triperoxonane acid) (salt triperoxonane acid) (0,030 g, 0.08 mmol). This mixture was stirred for 12 hours at room temperature. The mixture was concentrated to dryness, and the residue was transferred into methanol and purified by preparative obraniakowi Ehud using for elution of a mixture of acetonitrile/water. Combined fractions containing the desired product were evaporated under reduced pressure to get 0,027 g of yellowish solid (0.06 mmol, 74%). MS (mass/charge): 458,5 (M+N+).

In accordance with the methods of synthesis described in Example 2 from TRANS 4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (could be obtained in salt form triperoxonane acid) and the appropriate acid were synthesized derivatives. These derivatives are shown in Table 1 (Examples 2-41).

Example 24

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

Intermediate compound E

TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butyl methyl ether

A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.3 g, 5 mmol), TRANS-[4-(2-oxo-ethyl)-cyclohexyl]-carbamino acid tert-butyl ester (Example 1, intermediate connection) (1.6 g, 6 mmol), triethylamine (of 0.64 ml, 5 mmol) in 1,2-dichloroethane (27 ml) was stirred for 4 h at room temperature, was slowly added triacetoxyborohydride sodium (1.9 g, 9 mmol)and the resulting the solution was stirred for 12 hours, until completion of the reaction according to the results of the TLC analysis. The mixture was filtered, concentrated to dryness and purified by column chromatography on silica gel using CH2Cl2-CH2Cl2/Meon (1-9:1). The fractions containing the desired product were concentrated to obtain 2.3 g (5.1 mmol, yield 100%) of a yellowish solid. MS (mass/charge): 446,3 (M+N+).

The intermediate compound F

TRANS 4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin; salt triperoxonane acids is

2.3 g (5 mmol) of TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butyl ester was dissolved in dichloromethane (15 ml)was added at 0°C triperoxonane acid (10,7 ml, 46 mmol), the mixture was stirred at room temperature overnight. Was slowly added NaHCO3to obtain pH 9 and the mixture 3 times were extracted with dichloromethane and ethyl acetate. The solvent is evaporated to obtain 1.86 g (5.3 mmol, 100%) of a white solid, which was used without purification in the subsequent stages. MS (mass/charge): 346,3 (M+N+).

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

Received as described in Example 1 from TRANS 4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine in dichloromethane using triethylamine and acetylchloride. MS (mass/charge): 388,3 (M+N+).

Example 25

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide

4-Morpholinomethyl acid (0,153 g of 0.74 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0,026 g, 0.69 mmol) and N-ethyldiethanolamine (0,350 ml, 2.02 mmol) was stirred in 5 ml of DMF for 0.5 h at room temperature, and was added TRANS-4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohex the Lamin (salt triperoxonane acid) (0,300 g, 0.69 mmol). This mixture was stirred for 12 hours at room temperature. The mixture was concentrated to dryness, and the residue was transferred into methanol and was purified by chromatography using elution CH2Cl2-CH2Cl2/Meon (1-9:1). Combined fractions containing the desired product were evaporated under reduced pressure to obtain 0.24 g of a yellowish solid (0.5 mmol, 70%). MS (mass/charge): 535,3 (M+N+).

Example 26

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

Received as described in Example 25 using 3-methoxy-propionic acid and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium of tetrafluoroborate, N-ethyldiethanolamine in DMF and TRANS 4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) as a white solid (0,023 g, 0.05 mmol, 37%). MS (mass/charge): 332,4 (M+N+).

Example 27

N-TRANS (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-piperidine-1-yl-benzamide

Received as described in Example 26 using 4-piperidine-1-yl-benzoic acid, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium of tetrafluoroborate, N-ethyldiethanolamine in DMF and TRANS 4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl) - Rev. ina (in salt form triperoxonane acid). This mixture was stirred for 12 hours at room temperature. The mixture was concentrated to dryness, and the residue was transferred into methanol and purified by preparative obraniakowi Ehud using for elution of a mixture of acetonitrile/water. Combined fractions containing the desired product were evaporated under reduced pressure to get 0,028 g of yellowish solid (0.05 mmol, 49%). MS (mass/charge): 533,0 (M+N+).

In accordance with the methods of synthesis described in Example 26, from TRANS 4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) and the appropriate acid were synthesized derivatives. These derivatives are shown in Table 2 (Examples 28-30).

Example 32

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

The intermediate compound D

1-[4-(2,4-Dichloro-benzoyl)-piperidine-1-yl]-alanon

In 23 ml of dichlorobenzene (200 mmol) was added in portions aluminium chloride (11, 24 g, 84 mmol). To this suspension also portions were added 8 g of 1-acetylpenicillamine (42 mmol). The mixture was stirred 10 minutes at room temperature and then at 90°C for 4 hours, until completion of the reaction according to the results of the TLC analysis; the colour of the solution when heated is inalas from yellow-orange to dark orange. Was added water, and this solution three times was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. This crude product was purified by flash chromatography on silica gel, using hexane:ethyl acetate (1:0-0:1), to obtain 6.3 g (50%) of product as an orange oil. MS (mass/charge): to 300.2 (M+).

1-(4-{(2,4-Dichloro-phenyl)-[(E)-hydroxyimino]-methyl}-piperidine-1-yl)-alanon

1-[4-(2,4-Dichloro-benzoyl)-piperidine-1-yl]-Etalon (5.6 g, 19 mmol) was dissolved in ethanol (140 ml). Added hydroxylamine (5,2 g, 75 mmol), then N,N-diisopropylethylamine (12,8 ml, 75 mmol)and this reaction mixture was subjected to reflux distilled at 100°C for 12-20 hours to complete the reaction according to the results of the TLC analysis. Was added water, and this solution three times was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. This crude product was purified by flash chromatography on silica gel, using hexane:ethyl acetate (1:0-0:1), to obtain 2.15 g (37%) of product as a white solid and 1.12 g of educt, which had not been spent. MS (mass/charge): 315,1 (M+N+).

1-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]alanon

1-(4-{(2,4-Dich the EOS-phenyl)-[(E)-hydroxyimino]-methyl}-piperidine-1-yl)-Etalon (2.15 g, 7 mmol) was dissolved in THF (34 ml) was added tert-butyl potassium (services, 0.844 g, 7.5 mmol). This mixture was stirred for 2 hours, until completion of the reaction according to the results of the TLC analysis. The solvent was removed and the mixture was purified by flash chromatography on silica gel, using hexane:ethyl acetate (1:0-0:1). Combined fractions containing the desired product were evaporated under reduced pressure to obtain 1.45 g of colorless oil (75%).

MS (mass/charge): 279,1 (M+N+).

6-Chloro-3-piperidine-4-yl-benzo[d]isoxazol hydrochloride

1-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-Etalon (1.45 g, 5.3 mmol) was diluted 6 N. aqueous solution of HCl (to 13.8 ml, 16 mmol)and the mixture was subjected to reflux distilled during the night. After cooling, was added diethyl ether (2×20 ml), and the mixture was extracted. To the aqueous phase solution was added NaOH to obtain a pH of 11, and this mixture three times were extracted with ethyl acetate. United an ethyl acetate fraction was dried and evaporated under reduced pressure to get to 1.14 g of light brown solid (93%). MS (mass/charge): EUR 236.9 (M+N+).

Intermediate compound E

TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butyl methyl ether

Received in accordance with the method of synthesis of intermediate compound F (Example 1) of a mixture of 6-the ENT-3-piperidine-4-yl-benzo[d]isoxazol hydrochloride (0,942 g, 4 mmol), TRANS-[4-(2-oxo-ethyl)-cyclohexyl]-carbamino acid tert-butyl ester (1.06 g, 4 mmol) and triacetoxyborohydride sodium (1.51 g, 7 mmol) in 1,2-dichloroethane (9.8 ml). The fractions containing the desired product were concentrated to obtain 1.2 g (2.6 mmol, yield 64,3%) of light brown solid. MS (mass/charge): 462,4 (M+N+).

The intermediate compound F

TRANS 4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin (could be obtained in salt form triperoxonane acid)

Received as described in Example 1 from TRANS (4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butyl ether and triperoxonane acid at 0°C. the product was obtained as a pale yellow solid (0,197 g, 52%). MS (mass/charge): 362,4 (M+N+).

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

Received as described in Example 2, from 3-methoxy-propionic acid, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium of tetrafluoroborate, N-ethyldiethanolamine and TRANS 4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) in DMF, the reaction was carried out for 12 hours at room temperature. The mixture was concentrated to dryness, and the residue was transferred into meth is Nol and purified by chromatography using elution CH2Cl2-CH2Cl2/Meon (1-9:1). Combined fractions containing the desired product were evaporated under reduced pressure to get to 0.022 g of yellowish solid (0.05 mmol, 45%). MS (mass/charge): 448,3 (M+N+).

In accordance with the methods of synthesis described in Example 32 from TRANS-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine and the corresponding acids, which are either available commercially or can be produced using techniques known in the art (for example, by hydrolysis of the corresponding esters), or using the techniques described in this description above, other derivatives were synthesized (see Table 3).

Example 42

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl]piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-4-methyl-cyclohexyl)-ndimethylacetamide

8-Methyl-1,4-dioxa-Spiro(4,5)decane-8-ol

Was obtained by treatment of 1,4-cyclohexandione of monoethyleneglycol methyllithium in diethyl ether or MeMgI in accordance with the method described in Journal of Organic Chemistry, 71(22), 2006, 8424-8430.

4-Methoxy-4-methyl-cyclohexanone

Pikantnoi temperature of 8-methyl-1,4-dioxa-Spiro (4,5) decane-8-ol (11.7 g, 68 mmol), NaH (137 mmol), MeI (273 mmol) and Me4NBr (17 mmol) in tetrahydrofuran (150 ml) was received ortho-methylated 1,4-dioxa Spiro compound, which was treated with 25% HCl (13,5 ml) in acetone to give the desired 4-methoxy-4-methyl-cyclohexanone (9,48 g, which is 97.6%) as oil.

(4-Methoxy-4 methyl-cyclohexylidene)-acetic acid methyl ester

The mixture phosphonooxy acid trimethylboron ether (9,11 ml, 56 mmol) and 1.6 n n-BuLi (40 ml, 64 mmol) in DME (1,2-dimethoxyethane) (60 ml) was stirred for 10 minutes at 0°C. was Added 4-hydroxy-4-methyl-cyclohexanone (8 g, 56 mmol)and the mixture was stirred at 0°C for 2.5 hours, until completion of the reaction according to the results of the TLC analysis. After extraction with dichloromethane was obtained the desired product (7,71 g, 69%).

(4-CIS/TRANS-Methoxy-4-methyl-cyclohexyl)acetic acid methyl ester

Received from (4-methoxy-4-methyl-cyclohexylidene)-acetic acid methyl ester (7 g, 35 mmol) in the presence of Pd/C (10%) (35 mmol) in ethyl acetate in a hydrogen atmosphere, the reaction was carried out at room temperature over night. MS (mass/charge): 201,2 (M+N+).

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-CIS,TRANS-methoxy-4-methyl-cyclohexyl)-ndimethylacetamide

(4-CIS/TRANS-Methoxy-4-methyl-cyclohexyl)acetic acid (in the form of anhydrous potassium salt) was obtained by the reversine (4-CIS/TRANS-methoxy-4-methyl-cyclohexyl)acetic acid methyl ester (of) 0.157 g, 1 mmol) in anhydrous potassium salt of the appropriate acid using trimethylsilanol potassium KOtSiMe3(0,202 g, 2 mmol) and mixing with 2 ml of dichloromethane during the night in accordance with Tet. Letters, 25(51), 1984, 5831-5834. The solvent is evaporated, and the resulting salt was dissolved in DMF (2 ml) and was treated with TRANS 4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) (0,300 g, 1 mol), 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0,328 g, 1 mmol) and N-ethyldiethanolamine (0,530 ml, 3 mmol) within 12 hours at room temperature in accordance with the order, as described in Example 32. MS (mass/charge): 530,0 (M+N+).

Example 42A

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-TRANS-methoxy-4-methyl-cyclohexyl)-ndimethylacetamide

Received by separation on a chiral column (chiralpak AD) mixture of CIS - and TRANS-isomers of N-TRANS (4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-4-methyl-cyclohexyl)-ndimethylacetamide. MS (mass/charge): 530,0 (M+N+).

Example 42

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-CIS-methoxy-4-methyl-cyclohexyl)-ndimethylacetamide

Received by separation on a chiral column (chiralpak AD) mixture of CIS - and TRANS-isomers of N-TRANS (4-{2-[4-(6-chloro-d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-CIS-methoxy-4-methyl-cyclohexyl)-ndimethylacetamide. MS (mass/charge): 530,1 (M+N+).

Example 43

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide

Received as described in Example 32, 3-methoxy-butyric acid and TRANS 4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) in DMF, the reaction was conducted within 4-12 hours at room temperature. MS (mass/charge): 462,3 (M+N+).

Example 43A

(R)-N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide

Received by separation on a chiral column (chiralpak AD) mixture of CIS - and TRANS-isomers of N-TRANS (4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide. MS (mass/charge): 462,5 (M+N+).

Example V

(S)-N-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide

Received by separation on a chiral column (chiralpak AD) mixture of CIS - and TRANS-isomers of N-TRANS (4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide. MS (mass/charge): 462,5 (M+N+).

Example 44

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-TRANS - (4-methoxymethyl-cyclohexyl)-ndimethylacetamide

8-Methoxymethyl-1,4-dioxa-Spiro[4,5]Decan

+).

(4-Methoxymethyl-cyclohexylidene)-acetic acid methyl ester

4-Methoxymethyl-cyclohexanone was obtained by processing 8-methoxymethyl-1,4-dioxa-Spiro[4,5]decane (1.45 g, 8 mmol) 1 N. HCl (15.6 ml, 16 mmol) in acetone (35 ml). The acetone was removed, and the product was extracted with dichloromethane. The crude 4-methoxymethyl-cyclohexanone were dissolved in 1 ml of dimethoxyethane and was added to the mixture which was prepared in advance by adding n-BuLi (3,54 ml, 6 mmol) to diethylphosphonate acid methyl ether (of 1.03 g, 5 mmol) in DME under stirring for 10 minutes at 0°C. After 2 hours, according to the TLC analysis was obtained (4-methoxymethyl-cyclohexylidene)-acetic acid methyl ester (0,552 g, 2.7 mmol). MS (mass/charge): 199,1 (M+N+).

(4-Methoxymethyl-cyclohexyl)-acetic acid methyl ester

Received from (4-methoxymethyl-cyclohexylidene)-acetic acid methyl ester (0,550 g, 3 mol) by hydrogenation using Pd/C (10%) (0,295 g, 0.3 mmol) in ethyl acetate (15 ml) 1/3 CIS/TRANS mixture.

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl]piperidine-1-yl]-ethyl}-cyclohexyl)-2-TRANS - (4-methoxymethyl-cyclohexyl)-ndimethylacetamide

From KOtSiMe3and (4-methoxymethyl-cyclohexyl)-acetic acid methyl ester was obtained potassium salt of the specified acid (in accordance with the order, as described in Example 42), the obtained Sol was treated with TRANS 4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and N-ethyldiethanolamine within 12 hours at room temperature. Added diethyl ether and filtered to obtain mainly the TRANS isomer as a white solid. MS (mass/charge): 530,2 (M+N+).

Example 45

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-4-methyl-cyclohexyl)-ndimethylacetamide

(4-Oxo-cyclohexyl)-acetic acid

Received as a result of hydrolysis (4-oxo-cyclohexyl)-acetic acid methyl ester (commercially available) using LiOH.

(4-Hydroxy-4-methyl-cyclohexyl)-acetic acid

Received from MeMgBr (taken in excess; 26 mmol) in THF (20 ml) and (4-oxo-cyclohexyl)-acetic acid (13 mmol) according to the fact, as described in Journal of American Society 93 (1), 1971, 121-129.

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isox the evil-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-4-methyl-eclogical)-ndimethylacetamide

Received as described in Example 32, from (4-hydroxy-4-methyl-cyclohexyl)-acetic acid and TRANS 4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) in DMF, the reaction was conducted within 4-12 hours at room temperature. MS (mass/charge): 516,1 (M+N+).

Example 46

N-TRANS (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

Received as described in Example 1 from TRANS 4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) in dichloromethane using triethylamine and acetylchloride. MS (mass/charge): 404,4 (M+N+).

Example 47

Econsultancy acid (4-TRANS - {2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide

TRANS 4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin (could be obtained in salt form triperoxonane acid (intermediate compound F, Example 1) (0,038 g, 0.11 mmol) was dissolved in THF (0.6 ml), was added acanaloniidae, then triethylamine (0,018 ml, 0.13 mmol)and the solution was stirred over night. The mixture was concentrated to dryness, and the residue was transferred into methanol and purified by preparative obraniakowi Ehud using for elution of a mixture of acetonitrile/water. United fra is tion, containing the desired product were evaporated under reduced pressure to obtain the product (0,023 g, 49%) as a white solid. MS (mass/charge): 438,1 (M+N+).

In accordance with the methods of synthesis described in Example 47, from TRANS 4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (could be obtained in salt form triperoxonane acid) and related sulphonylchloride other derivatives were synthesized. These derivatives are given in Table 4 (Examples 48-50).

Example 51

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-cyano-ndimethylacetamide

Received by analogy with the compound of Example 32 from TRANS-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) and tsianuksusnogo acid using triethylamine as the base. MS (mass/charge): 429,4 (M+N+).

Example 52

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-cyano-propionamide

Received by analogy with the compound of Example 40 TRANS-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (in salt form triperoxonane acid) and potassium salt of 3-cyanopropionic acid (obtained by the conversion ratio is estoodeeva methyl ester under the action of KOtSiMe 3in the anhydrous potassium salt of the specified acid in accordance with Tett. Letters, 25(51), 1984, 5831-5834). MS (mass/charge): 443,2 (M+N+).

Example 53

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-furan-2-yl-ndimethylacetamide

Received by separation on a chiral column (chiralpak AD) mixture of isomers of N-TRANS-(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-ndimethylacetamide (Example 38). MS (mass/charge): 474,2 (M+N+).

Example 54

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-cyclopropyl-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 444,3 (M+N+)) received in compliance with the General method described in Example 32 from TRANS-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (hydrochloride) and cyclopropylacetic acid.

Example 55

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 420,2 (M+N+)) received in compliance with the General method described in Example 32 from TRANS-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (hydrochloride) and glycolic acid.

Example 56

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-Piperi the Jn-1-yl]-ethyl}-cyclohexyl)-2-methanesulfonyl-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 482,1/484,0 (M+N+)) received in compliance with the General method described in Example 32 from TRANS-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine (hydrochloride) and methanesulfonate acid.

Example 57

N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]ethyl}-cyclohexyl)-2-[1,3]dioxane-2-yl-ndimethylacetamide

Stage 1: [1,3]Dioxane-2-yl-acetic acid methyl ester

Propane-1,3-diol (at 2.45 ml, 36 mmol) was dissolved in 100 ml of THF and was cooled to 0-5°C. was Added sodium hydride (1,43 g, 40 mmol, 55%), and this reaction mixture was stirred for 15 minutes at 0-5°C. was Added dropwise propionic acid methyl ester (2,97 ml, 36 mmol), dissolved in 10 ml of THF, and stirred for 3 hours at 0-5°C. This reaction mixture is extinguished 2 N. HCl solution and two times were extracted with ethyl acetate. The organic extracts were washed with saline, dried with sodium sulfate, filtered and evaporated. This crude product was purified by flash chromatography on silica gel (dichloromethane). The desired compound was obtained as a colourless liquid (2,96 g, 52%).

Stage 2: N-TRANS-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxane-2-yl-ndimethylacetamide

[1,3]Dioxane-2-yl-acetic acid methyl ester (130 mg, 0.81 mmol who) (stage 1) was dissolved in 2 ml of THF, 1 ml methanol and 1 ml of water. Added monohydrate of lithium hydroxide (102 mg, 2,43 mmol)and this reaction mixture was stirred for 16 hours at room temperature. The organic solvent evaporated, and the aqueous mixture was acidified by adding 2 N. HCl to pH 1. The mixture was evaporated to dryness, and was added TRANS-4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamin (hydrochloride) (150 mg, 0.41 mmol) (Example 32, Intermediate compound F) in 1 ml DMF. Was added N,N-diisopropylethylamine (205 μl, 1,22 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate [TBTU] (157 mg, 0.49 mmol)and this reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was extinguished with saturated solution of NaHCO3and was extracted with dichloromethane. The organic extract was washed with saline, dried with sodium sulfate, filtered and evaporated. This crude product was purified by flash chromatography on silica gel (using a gradient of 100:0→90:10 dichloromethane/methanol). The desired compound was obtained as a pale yellow solid (61 mg, 33%), MS: mass/charge = 490,3 (M+N+).

Example 58

N-TRANS-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-ndimethylacetamide

Stage 1: 5-Chloro-3-piperidine-4-yl-benzo[d]isoxazol hydrochloride

Specified in the title compound can be obtained in accordance with the techniques described in the patent WO 02066446 (Examples 46 and 48), using as the starting material 5-chloro-2-forventelige.

Stage 2: TRANS-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butyl methyl ether

Specified in the title compound (MS: mass/charge = 462,3 (M+N+)) received in accordance with the General procedure described in Example 1 (production of intermediate compound E), of a mixture of 5-chloro-3-piperidine-4-yl-benzo[d]isoxazol hydrochloride and TRANS-[4-(2-oxo-ethyl)-cyclohexyl]-carbamino acid tert-butyl ester (Example 1, Intermediate connection).

Stage 3: TRANS-4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride

TRANS-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-carbamino acid tert-butyl ester (1.35 g, of 2.92 mmol) was dissolved in 2 ml dichloromethane was added 4 N. HCl in dioxane (8,8 ml, to 38.8 mmol). The obtained white suspension was stirred for 4 hours at room temperature, was diluted with diisopropyl ether and filtered. The crystals are washed with diisopropyl ether and was dried for 2 hours at 50°C and a pressure of <20 mbar (2000 PA) to give the desired salt as a white solid (1.65 g, Ihad quantitative) [MS: mass/charge = 362,2 (M+N +)].

Stage 4: N-TRANS-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-ndimethylacetamide

Received as described in Example 40, from TRANS-4-{2-[4-(5-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 58, step 3) and the potassium salt of TRANS-(4-methoxy-cyclohexyl)-acetic acid (which was obtained from methyl 4-hydroxyphenylacetate by processing the Nickel-aluminum alloy in the Meon and the subsequent methylation using NaH, MeI and transformations of the obtained methyl ester using KOtSiMe3in an appropriate anhydrous potassium salt of the acid according to Tett. Letters, 25(51), 1984, 5831-5834). MS: the mass/charge = 516,0/517,1 (M+N+).

Example 59

N-TRANS-(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide

Step 1: TRANS-4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride

Specified in the title compound (MS: mass/charge = 346,2 (M+N+)) received in accordance with the General procedure described in Example 58 (stages 1, 2 and 3), using as the starting material 2,5-diferentialglea.

Stage 1: N-TRANS-(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide

Specified in the title compound (MS: mass/charge = 424,2 (M+N +)) received in accordance with the General procedure described in Example 47, from TRANS-4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride and methanesulfonanilide.

Example 60

N-TRANS-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

Step 1: TRANS-4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride

Specified in the title compound (MS: mass/charge = 380,3/382,3 (M+N+)) received in accordance with the General procedure described in Example 58 (stages 1, 2 and 3), using as the starting material 4-chloro-2,5-diferentialglea.

Stage 2: N-TRANS-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

Specified in the title compound (MS: mass/charge = 466,1/468,3 (M+N+)) received in accordance with the General procedure described in Example 32 from TRANS-4-{2-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride and 3-methoxypropionate acid.

Example 61

N-TRANS-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 492,3 (M+N+)) received in accordance with the General method of vannoy in Example 60, from TRANS-4-{2-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride and 2-(tetrahydro-furan-2-yl)-acetic acid (which was obtained by hydrolysis of the commercially available corresponding methyl ester).

Example 62

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-methoxy-ndimethylacetamide

Step 1: TRANS-4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride

Specified in the title compound (MS: mass/charge = 364,4 (M+N+)) received in accordance with the General procedure described in Example 58 (stages 1, 2 and 3), using as initial substance 2,4,5-tripersonality.

Stage 2: N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-methoxy-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 436,3/437,4 (M+N+)) received in accordance with the General procedure described in Example 32 from TRANS-4-{2-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride and methoxybutanol acid.

Example 63

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-methoxy-cyclopentyl)-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 504,3 (M+N+)) received in compliance with the General methodology, described in Example 40, from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and the potassium salt rat-TRANS-(3-methoxy-cyclopentyl)-acetic acid (which was obtained from the rat-TRANS-(3-hydroxy-cyclopentyl)-acetic acid methyl ester (Helvetica Chimica Acta - Vol.75 (1992) page 1945, 1950) by methylation using NaH, MeI and transformations of the obtained methyl ester using KOtSiMe3in an appropriate anhydrous potassium salt of the acid according to Tett. Letters, 25(51), 1984, 5831-5834).

Example 64

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 518,4 (M+N+)) received in accordance with the General procedure described in Example 40, from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and the potassium salt of TRANS-(4-methoxy-cyclohexyl)-acetic acid (which was obtained from methyl 4-hydroxyphenylacetate by processing the Nickel-aluminum alloy in the Meon and the subsequent methylation using NaH and MeI transformations of the obtained methyl ester using KOtSiMe3in an appropriate anhydrous potassium salt of the acid according to Tett. Letters, 25(51), 1984, 5831-5834).

Example 65

-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide

Specified in the title compound (MS: mass/charge = 450,3 (M+N+)) received in accordance with the General procedure described in Example 32 from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and 3-methoxypropionate acid.

Example 66

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 406,3 (M+N+)) received in accordance with the General procedure described in Example 32 from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and acetic acid.

Example 67

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 422,2 (M+N+)) received in accordance with the General procedure described in Example 32 from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and glycolic acid.

Example 68

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-propionamide

Specified in the title compound (MS: mass/charge = km 436.0 (M+N+)) received in accordance with the General methodology, the op is pulling in Example 32, from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and 3-hydroxypropionic acid.

Example 69

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-cyclohexyl)-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 504,1 (M+N+)) received in accordance with the General procedure described in Example 40, from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and the potassium salt of TRANS-(4-hydroxy-cyclohexyl)-acetic acid (which was obtained from methyl 4-hydroxyphenylacetate by processing the Nickel-aluminum alloy in the Meon and transformations of the obtained methyl ester using KOtSiMe3in an appropriate anhydrous potassium salt of the acid according to Tett. Letters, 25(51), 1984, 5831-5834).

Example 70

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-hydroxy-cyclopentyl)-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 490,4 (M+N+)) received in compliance with the General method described in Example 40, from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and the potassium salt rat-TRANS-(3-hydroxy-cyclopentyl)-acetic acid the acid (for which used the technique described in Helvetica Chimica Acta - Vol.75 (1992) p.1945 and p.1950, and then the obtained methyl ester was converted using KOtSiMe3in an appropriate anhydrous potassium salt of the acid according to Tett. Letters, 25(51), 1984, 5831-5834).

Example 71

Tetrahydro-Piran-4-carboxylic acid TRANS-(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-1-ethyl}-cyclohexyl)-amide

Specified in the title compound (MS: mass/charge = 476,3 (M+N+)) received in accordance with the General procedure described in Example 32 from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and tetrahydro-Piran-4-carboxylic acid.

Example 72

N-TRANS-(4-{2-[4-(5,6-Debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxane-2-yl-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 492,3 (M+N+)) received in accordance with the General procedure described in Example 40, from TRANS-4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride (Example 62, step 1) and potassium salt [1,3]dioxane-2-yl-acetic acid (to obtain which used the procedure described in Example 57 (step 1), and then the obtained methyl ester was converted using KOtSiMe3in an appropriate anhydrous potassium salt of the acid according to Tett. Letters, 25(51), 1984, 5831-5834).

Example 73

N-TRANS-(4-{2-[4-(6-Methyl-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

Stage 1: Grans-4-{2-[4-(6-Methyl-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride

Specified in the title compound (MS: mass/charge = 342,3 (M+N+)) received in accordance with the General procedure described in Example 58 (stages 1, 2 and 3), using as the starting material 2-fluoro-4-methylbenzaldehyde.

Stage 2: N-TRANS-(4-{2-[4-(6-Methyl-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide

Specified in the title compound (MS: mass/charge = 384,3 (M+N+)) received in accordance with the General procedure described in Example 32 from TRANS-4-{2-[4-(6-methyl-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine hydrochloride and acetic acid.

An example of a

Tablets, film-coated, containing the following ingredients can be manufactured in a standard way.

Ingredientsmg tablet
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Lactose water60,0 mg70.0 mg
Povidone K12.5 mg15,0 mg
Sodium salt of starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(The mass of the nucleus)120,0 mg350,0 mg
Film coating:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0,8 the g 1.6 mg

The active ingredient is sifted and mixed with microcrystalline cellulose, the mixture granularit with a solution of polyvinylpyrrolidone in water. The obtained granulate is mixed with the sodium salt starch glycolate and magnesium stearate and compressed to obtain a tablet cores weighing 120 or 350 mg, respectively. Then the kernel is applied an aqueous solution/suspension of the above-mentioned film coating.

Example B

Capsules containing the following ingredients can be manufactured in a standard way.

Ingredientsmg/capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

These components are sieved and mixed, and fill capsules of size 2.

The example In

Injectable solutions may have the following composition:

The compound of formula (I)3.0 mg
Gelatin150,0 mg
Phenol4,7 mg
Sodium carbonateto obtain pH 7
Water for injection solutionsto 1.0 ml

Example G

Soft gelatin capsules containing the following ingredients can be manufactured in a standard way.

The contents of the capsules
The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg
Gelatin capsule
Gelatin75,0 mg
Glycerol 85%32,0 mg
Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm molten mass other ingredients, and this mixture fill soft gelatin capsules of suitable size. Then filled soft gelatin capsules are processed in accordance with standard techniques.

Example D

The bags containing the following ingredients can be manufactured in a standard way.

The compound of formula (I)50.0 mg
Lactose, fine powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
Sodium salt of carboxymethylcellulose14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Flavorings 1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium salt of carboxymethylcellulose and granularit with a mixture of polyvinylpyrrolidone in water. The obtained granules are mixed with magnesium stearate and flavors, and fill the bags.

1. The compound of Formula (I)

where
X independently represents a halogen atom or With1-6-alkyl;
n is 0, 1, 2 or 3;
R1represents H;
R2representsor
R3represents a C1-6-alkyl, C3-10-cycloalkyl, phenyl, 6-membered heteroseksualci representing tetrahydropyranyl, or 5-10-membered heteroaryl selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzo[1,3]dioxole and 2,3-dihydrobenzo[1,4]dioxine; that may be substituted and contain from one to five substituents selected from the group consisting of
halogeno,
cyano,
-SO2-C1-6-alkyl,
hydroxyl,
C1-6-halogenoalkane,
With1-6-alkoxy,
With3-10-cycloalkyl, possibly substituted by one or more of Ra,
4-10-membered geterotsiklicheskie selected from morpholinyl, 1,1-dioxothiazolidine, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl 1,4-dioxaspiro[4,5]decyl, [1,3]dioxolane, [1,3]dioxane, possibly substituted by one or more of Ra, phenyl, possibly substituted by one or more of Ra,
5-10-membered heteroaryl selected from benzo[1,3]dioxole, pyrazolyl, pyrrolyl, possibly substituted by one or more of Raand
-NRbRcwhere Rbrepresents N or C1-6-alkyl, and where Rcrepresents N or C1-6-alkyl;
Raselected from
hydroxyl,
C1-6-alkyl,
C1-6-alkoxy; as well as its pharmaceutically acceptable salt.

2. The compound of Formula (I) according to claim 1, where X represents a fluorine atom or a chlorine atom;
n is 0, 1 or 2;
R1represents a hydrogen atom;
R2represents
where R3is such as defined according to claim 1; and its pharmaceutically acceptable salts.

3. The compound of Formula (Ia) according to claim 1

where X represents a fluorine atom;
n has a value of 1;
m is 1 or 2;
R4selected from the group consisting of
halogeno,1-6-alkoxy,
4-10-membered geterotsiklicheskie selected from morpholinyl, possibly substituted di(C1-6)alkyl, 1,1-dioxothiazolidine, piperidinyl, 5-10-membered heteroaryl selected from pyrrolyl, and
-NRbRc,
R a, Rband Rcare as defined in claim 1, and its pharmaceutically acceptable salts.

4. The compound of Formula (Ib) according to claim 1

where
X represents a fluorine atom;
n has a value of 1;
m and p independently of one another are 0 or 1;
R4and R5selected from the group consisting of halogeno,1-6-alkyl,
Y represents an oxygen atom or-SO2;
one or two of And1And2And3And4and a5represent the nitrogen atom and the others represent CR6or a1And2And3And4and a5represent CR6where each R6independently represents a hydrogen atom; and its pharmaceutically acceptable salts.

5. The compound of Formula (Ib) according to claim 4, where X represents a fluorine atom;
n, m have values of 0 or 1;
p has a value of 0;
Y represents an oxygen atom
one or two of And1And2And3And4and a5represent a nitrogen atom, and the other
represent CH2;
as well as its pharmaceutically acceptable salt.

6. The compound of Formula (Ic) according to claim 1

where X represents a fluorine atom;
n has a value of 1;
R8and R9form a 3-, 4 - or 6-membered saturated ring may sod is rashee one heteroatom, selected from oxygen atom;
R10can be a Deputy on the ring formed by R8and
R9and selected from the group consisting of hydroxy and C1-6-halogenoalkane;
as well as its pharmaceutically acceptable salt.

7. The compound of Formula (Id) according to claim 1

where X1represents N and X2represents a fluorine atom or a chlorine atom; or
X2represents N and X1represents a fluorine atom or a chlorine atom; and
R11represents a C1-6-alkyl, which may substituted by halogen atom, hydroxy, C1-6-halogenoalkanes,1-6-alkoxy and C5-6-cycloalkyl, possibly substituted C1-6-alkyl or C1-6-alkoxy;
as well as its pharmaceutically acceptable salt.

8. The compound of Formula (Id') according to claim 7

where X1, X2and R11are as defined in claim 7;
as well as its pharmaceutically acceptable salt.

9. The compound of Formula (Ie) according to claim 1

where X2represents N and X1represents a fluorine atom; and R12selected from the group consisting of hydroxy and
With1-6-halogenoalkane;
as well as its pharmaceutically acceptable salt.

10. The compound of the Formula (Ie') according to claim 9

where X1, X2and R12are as defined in claim 9;
as well as its pharmaceutically acceptable salt.

11. The compound of Formula (Ig) according to claim 1

where X represents a fluorine atom;
n has a value of 1;
R13selected from the group consisting of C1-6-alkyl, phenyl, substituted by halogen or C1-6-alkoxy, and pyridinyl;
as well as its pharmaceutically acceptable salt.

12. The compound of Formula (I) according to claim 1, where the specified connection selected from the group consisting of
4N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she
tetrahydro-Piran-4-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-6-morpholine-4-yl-nicotinamide,
5-morpholine-4-yl-pyrazin-2-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
6-morpholine-4-yl-pyridazin-3-carboxylic acid TRANS - (4-{2-[4-(6-toranzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
2-morpholine-4-yl-pyrimidine-5-Carbo the OIC acid TRANS - (4-{2-[4-(6-toranzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
3-fluoro-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,
3-fluoro-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,
TRANS 4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexylamine,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzamide,
4-tert-butoxy-N-TRANS(4-{2-[4-(6-fluoro-benzo[(1]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide
4-chloro-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide
4-(1,1-dioxo-1,6-thiomorpholine-4-yl)-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-morpholine-4-yl-isonicotinamide,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-methoxy-isonicotinamide,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-piperidine-1-yl-benzamide,
2,3-dihydro-benzo[1,4]dioxin-2-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl]-cyclohexyl)-2-(3-methyl-pyrazole-1-yl)-acetamide", she
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl-cyclohexyl)-4-pyrrol-1-yl-benzamide,
1-hydroxycyclohexanone acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
1-trifluoromethyl-cyclobutanecarbonyl acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
3,3,3-Cryptor-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-propionamide,
2-(3,5-dimethoxy-phenyl)-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she
4-(2,6-dimethyl-morpholine-4-yl)-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide
benzo[1,3]dioxol-5-carboxylic acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
N-TRANS(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-morpholine-4-yl-benzamide,
N-TRANS(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,
N-TRANS(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-piperidine-1-yl-benzamide,
4-(2,6-dimethyl-morpholine-4-yl)-N-TRANS(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide
4-(1,1-dioxo-1,6,4-thiomorpholine-4-yl)-TRANS-(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzamide
is Enzo[1,3]dioxol-5-carboxylic acid TRANS - (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3,3,3-Cryptor-2-hydroxy-propionamide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-Piran-2-yl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-Piran-2-yl-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(S)-tetrahydro-Piran-2-yl-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-TRANS - (4-methoxy-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(1,4-dioxa-Spiro[4,5]Dec-8-yl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide", she
(R)-N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-butyramide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-((S)-2,2-dimethyl-[1,3]dioxolane-4-yl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-((1S,3S)-3-methoxy-cyclopentyl)-and is etamide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-4-methyl-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-TRANS-methoxy-4-methyl-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-CIS-methoxy-4-methyl-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,
(R)-N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,
(S)-N-(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-TRANS - (4-methoxymethyl-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-4-methyl-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she
econsultancy acid (4-TRANS - {2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
4-chloro-N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-benzosulfimide,
N-TRANS(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzosulfimide,
pyridine-3-Sul the background acid TRANS - (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-cyano-propionamide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-cyano-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-furan-2-yl-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-cyclopropyl-ndimethylacetamide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide", she
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-methanesulfonyl-ndimethylacetamide,
N-TRANS(4-{2-[4-(6-chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxane-2-yl-acetamide", she
N-TRANS(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide,
N-TRANS(4-{2-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,
N-TRANS(4-{2-[4-(6-chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide", she
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-methoxy-acetamide", she
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)2-((1R,3R-3-methoxy-cyclopentyl)-ndimethylacetamide,
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide", she
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-propionamide,
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-cyclohexyl)-acetamide", she
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-hydroxy-cyclopentyl)-ndimethylacetamide,
tetrahydro-Piran-4-carboxylic acid TRANS-(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-amide,
N-TRANS(4-{2-[4-(5,6-debtor-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxane-2-yl-acetamide", she
N-TRANS(4-{2-[4-(6-methyl-benzo[d]isoxazol-3-yl)-piperidine-1-yl]-ethyl}-cyclohexyl)-ndimethylacetamide.

13. The compound according to any one of claims 1 to 12, as well as its pharmaceutically acceptable salt with high affinity to dopamine receptor D3and serotonin receptor 5-HT2A.

14. Pharmaceutical composition having high aff is a oneness to dopamine receptor D 3and serotonin receptor 5-HT2Acontaining an effective amount of one or more than one compound according to any one of claims 1 to 12, and pharmaceutically acceptable excipients.

15. The use of compounds according to any one of claims 1 to 12, as well as its pharmaceutically acceptable salts in the manufacture of drugs with high affinity to dopamine receptor D3and serotonin receptor 5-HT2A.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a phenylpyrazol derivative presented by formula (1) or to its pharmaceutically acceptable salt: wherein R1 and R2, which may be identical or different, each represents C1-C6 alkyl, or R1 and R2 are coupled together with an adjacent nitrogen atom to form a 5-6-merous saturated heterocylic ring (wherein the mentioned saturated heterocylic ring may be substituted by halogen or C1-C6 alkyl), n represents an integer 0 to 2, T represents a hydrogen atom, halogen or C1-C6 alkyl, and R has one of formulas (I)-(V), (VII) or (VIII):

(wherein Z1 and Z2, which may be identical or different, each represents -CH2-, -O- or -NR11-, p represents an integer 0 to 3, q represents an integer 0 to 1, r and s which may be identical or different, which represents an integer 0 to 2, R3 represents halogen, C1-C6 alkyl, or hydroxy, R4 and R5 which may be identical or different, each represents a hydrogen atom, C1-C6 alkyl (wherein said C1-C6 alkyl may be substituted by hydroxy, hydroxy- C1-C6 alkoxy, C2-C7 alkoxycarbonyl or carboxy), or formula -(CH2)m-Ar1 (wherein Ar1 represents wherein (wherein said phenyl is substituted by halogen or C1-C6 alkyl), and m represents an integer 0 to 1), R6 represents oxo, R7 represents a hydrogen atom or C1-C6 alkyl, R8 represents C1-C6 alkyl (wherein said C1-C6 alkyl may be substituted by halogen), C1-C6 alkoxy (wherein said C1-C6 alkoxy is substituted by halogen) or formula -(CH2)1-Ar2 (wherein Ar2 represents phenyl (wherein said phenyl is substituted by C1-C6 alkoxy, hydroxyl or cyano) or pyridinyl, and 1 represents an integer O to 1), G represents -CO- or -SO2-, R9 represents C1-C6 alkyl, C1-C6 alkoxy, phenyl (wherein said phenyl may be substituted by halogen or pyridinyl, and R11 represents C1-C6 alkyl)}.

EFFECT: there are produced new compounds and a preventive or therapeutic agent on the basis of said compounds which can find application in medicine for treating dementia, Alzheimer's disease, attention deficit/hyperactivity disorder, schizophrenia, epilepsy, convulsions of central genesis, eating behaviour disorders, obesity, diabetes, hyperlipidemia, sleep disturbances, narcolepsy, sleeping apnoea syndrome, circadian rhythm disorder, depression or allergic rhinitis.

12 cl, 3 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenyl-bipyrrolidine ureas of formula (I) ,

where values of R, R1, R2, R3, R4 and R5 are given in claim 1.

EFFECT: compounds are capable of binding with the H3 receptor, which enables use thereof to prepare a pharmaceutical composition and for diseases associated with the central nervous system.

10 cl, 36 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 relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing heterocycle-substituted pyridine derivatives of general formula (I) by reacting a compound of general formula (III) with a compound of formula (II) in a solvent and in the presence of a catalyst based on palladium or a base, where R1, R2, X, Y, Q, A, Z, R, R3 and R4 are described in the claim.

EFFECT: method enables to obtain pyridine derivatives on an industrial scale.

7 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a mTOR kinase inhibitor. In formula (I): A represents a 6-8-member mono- or bicyclic heterocyclic ring containing 1 to 2 heteroatoms optionally specified in N and O as apexes of the ring and having 0-2 double bonds; and wherein the ring A is additionally substituted by 0 to 2 substitutes RA specified in a group consisting of -ORa, -Rc and -(CH2)1-4-ORa wherein Ra is optionally specified in hydrogen and C1-6alkyl; Rc represents C1-6alkyl; G is specified in a group consisting of -C(O)-, -OC(O)-, -NHC(O)- and -S(O)0-2-; B is specified in a group consisting of phenylene and 5-6-member heteroarylene consisting 1-2 nitrogen heteroatom as apexes of the ring, and substituted by 0 to 1 substitutes RB specified in F, Cl, Br, I and Rp; wherein Rp represents C1-6 alkyl; D is specified in a group consisting of -NR3C(O)NR4R5, -NR4R5, C(O)NR4R5, -NR3C(=N-CN)NR4R5, -NR3C(O)R4, -NR3C(O)OR4 and -NR3S(O)2R4, and wherein the group D and a substitute placed on an adjoining atom in the ring B, optionally combined to form a 5-6-member heterocyclic or heteroaryl ring containing 1 to 3 heteroatoms specified in N, O and S, as apexes of the ring and substituted by the substitute 0-1 RD. The R1-R5 radical values are presented in the patent claim.

EFFECT: invention also refers to a pharmaceutical composition containing said compounds, and to the use of the compounds for preparing a drug for treating a malignant tumour mediated by mTOR kinase activity.

33 cl, 13 dwg, 4 tbl, 498 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: chemistry.

SUBSTANCE: invention relates to a compound which is 7-methyl-5-(3-piperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having potentiating activity on glutamate receptors, containing the compound described above; also described is use of the compound or a pharmaceutically acceptable salt in claim 1 in producing a medicinal agent for therapy of neurological and mental disorders associated with glutamate dysfunction.

EFFECT: novel compound which can be used in therapy of neurological and mental disorders is obtained and described.

5 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II , where Q is (CR4R5)n3; n1 equals 1 or 2; n2 equals 1 or 2; n3 equals 1; R2 is R2-1 or R2-2 , Ar is phenyl or a heteroaryl ring consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S; X denotes 1-2 substitutes located on Ar, each independently selected from a group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9 and CN; R3-R5 denote H; R8 is H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted with one or more halogens or heteroatom-containing substitutes selected from a group consisting of OR11, NR11R12, CO2R11, CONR11R12, NRnC(=O)Ri2; R9 is H or alkyl; R11-R12 independently denote H, alkyl, pyridinyl or morpholinyl.

EFFECT: compounds are inhibitors of rho-associated protein kinase which can be used in medicine to prevent or treat diseases or conditions associated with cytoskeleton readjustment, specifically treat high intraocular pressure such as primary open angle glaucoma.

10 cl, 3 tbl, 226 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing heterocycle-substituted pyridine derivatives of general formula (I) by reacting a compound of general formula (III) with a compound of formula (II) in a solvent and in the presence of a catalyst based on palladium or a base, where R1, R2, X, Y, Q, A, Z, R, R3 and R4 are described in the claim.

EFFECT: method enables to obtain pyridine derivatives on an industrial scale.

7 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, specifically to 16-(1,2,4-oxadiazol-3-yl)-15,16-epoxilabdanoids of formula

wherein R=Me(Ia), Ph(1b), CH2Cl(lc) possessing an ability to inhibit human tumour cell growth. The compounds are produced of lambertianic acid contained in Siberian cedar gum and fir needles.

EFFECT: there are produced new compounds which possess considerable cytotoxic activity on human tumour cells.

1 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of compounds of formula (wherein R1, R2, X, Y and n have the values specified in the patent claim) or their pharmaceutically acceptable salts for treating the diseases related to the biological function of the trace amine associated receptors, namely depression, anxiety disorders, bipolar disorders, attention deficit/hyperactivity disorder, stress-induced disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, addictions, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy consumption and assimilation disorders, thermal homeostasis disorders and disturbances, sleeping and circadian rhythm disorders, and cardiovascular diseases. Besides, the invention refers to compounds of formulas I-A, I-B, I-C, I-D, l-E, l-F, I-G, I-H (structural formulas of which are presented in the patent claim) and to a pharmaceutical composition based on the compounds of formula (I) for treating the diseases related to the biological function of the trace amine associated receptors.

EFFECT: use of the compounds of formula 1 in preparing the drugs for treating the diseases related to the biological function of the trace amine associated receptors.

45 cl, 9 dwg, 1 tbl, 379 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: invention relates to condensed bicyclic compounds, having affinity with mineralocorticoid receptor (VR) of formula [I] and formula [ii], as well as to pharmaceutical compositions on their basis. In general formula [I[ and [ii] ring A represents benzene ring, which has substituent R1, condensed with adjacent 6-membered heterocyclic ring, and said benzene ring additionally optionally is substituted with one or two substituent(s), selected from halogen atom and C1-8-alkyl group, R1 represents C1-8-alkylsulfonyl amino group or C1-8-alkyl aminosulfonyl group, R2 and R3 (a) are similar or different and represent group, selected from hydrogen atom, C1-8-alkyl group, and from 6- to 10-membered monocyclic or bicyclic aryl group (said aryl group is optionally substituted with halogen atom), (b) are combined with each other with formation of oxogroup or (c) are combined with each other on their ends together with adjacent carbon atom with formation of C3-10-cycloalkyl group, X represents the following group =N-, =C(R4)- or -CH(R4)-, R4 represents hydrogen atom, cyanogroup, halogen atom, C1-6-alkyl group, C2-6-alkenyl group, C3-10-dicloalkyl group, C1-7-alkanoyl group, carbamoyl group or C3-8cycloalkenyl group, Ar represents from 6- to 10-membered monocyclic or bicyclic aryl group, optionally containing one or several heteroatom(s), selected from sulphur atom, oxygen atom and nitrogen atom (said aryl group is optionally substituted with similar or different, one or two substituent(s), selected from halogen atom, cyanogroup, C1-8-alkyl group, trihalogen- C1-8-alkyl group and C1-8alkoxygroup), and dotted line represents presence or absence of double bond, Xa represents the following group =N- or =C(CN)-, RZ represents hydrogen atom or halogen atom, R25 and R35 represent alkyl group, and Ar3 represents phenyl group, optionally substituted with one or two group(s), which is(are) selected from halogen atom and trihalogenalkyl group.

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new 1,2,4-triazine-3,5-dione derivatives of general formula (I) wherein A is a saturated hydrocarbon chain with chain length 4 to 6 atoms; R1 and R2 are optionally hydrogen or C1-C3-alkyl; R3 is branched C4-C6-alkyl or C3-C6-cycloalkyl; R4 - C1-C6-alkyl, C3-C6-cycloalkyl or fluorinated C1-C3-alkyl, their physiologically acceptable salts and N-oxides, and a pharmaceutical composition containing them.

EFFECT: new compounds show dopamine D3 receptor activity and may be used in treating the central nervous system diseases.

24 cl, 8 ex, 1 tbl

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