Dipyrazoles as central nervous system agents

FIELD: chemistry.

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

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

16 cl, 2 tbl, 39 ex

 

The SCOPE of the INVENTION

The present invention relates to new deperatly compounds, compositions and methods of treatment and prevention of neuropsychiatric disorders resulting primarily dysfunction of glutamate receptors AMPA and NMDA.

BACKGROUND of the INVENTION

Glutamate is one of the most common excitatory neurotransmitter in the Central nervous system (CNS) of mammals. He mediates fast and slow neurotransmission such normal physiological processes, as remembering and processing of memory and synaptic plasticity. The results of the post mortem and pharmacological studies clearly indicate the violation of glutamate neurotransmission in the pathophysiology of several neuropsychiatric disorders, including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, attention deficit disorder with hyperactivity disorder, dementia caused by AIDS, neurogenic pain, depression, mild cognitive impairment, impaired memory, and memory and other (Lehohla, et al.,Metab Brian Dis, 2004; Coyle, et al.,Ann. NY Acad. Sci., 2003; Coyle, et al.,Curr. Drug Targets CNS Neurol. Disord., 2002; Krystal, et al., Arch Gen Psychiatry, 2002; Dingledine et al.,Pharmacol. Rev., 1999; and Ozawa, et al.,Prog. Neurobiol., 1998).

Neurotransmission glutamate is mediated by three ionotropic receptors of glutama the and. These receptors are cation-selective ion channels that regulate synaptic neurotransmission. Ionotropic glutamate receptors can be divided into three types: receptor alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)receptors, kainic acid (KA) receptors N-methyl-D-aspartate (NMDA), has a unique pharmacological, electrophysiological and biochemical properties (Nakanishi,Science, 1992). In addition, each of these ionotropic glutamate receptors consists of many heteromeric subunits, which contribute to the heterogeneity of the receptor in different tissues (Ozawa, et al., Prog Neurobiol, 1998). However, each of ionotropic glutamate receptors contains the dominant subunit, including those required for functionality, which are believed to play a major role in the regulation of the function.

Regulation of ionotropic glutamate receptors partly achieved by phosphorylation of specific residues of tyrosine, threonine and serine several kinases and, conversely, dephosphorylation these residues specific phosphatase. (Carvalho, et al.,Neurochem. Res., 2000 and Swope, et al., Adv Second Messenger Phosphoprotein Res. 1999). From whether subunit of the receptor is phosphorylated state, to a large extent depends on the activity of the receptor. For example, NMDA receptors are regulated by several key the basics and phosphatase, acting on its subunit NR1. It was shown that the protein kinase C (PKC) and camp-dependent protein kinase (PKA) to phosphorylate serine residues 896 and 897 subunit NR1, respectively (Tingley et al.,J. Biol. Chem.1997 , Snyder, et al.,Neuropharmacology, 2003). Similarly, AMPA receptors are regulated by multiple kinases and phosphatases acting on the GluR1 subunit; PKA phosphorylates residue serine 845 (Roche, et al.,Neuron16: 1179-1188, 1999; Wang, et al.,Science253: 1132-1135, 1991). Proteinopathy I (PP1) dephosphorylate these residues serine, causing switching of molecules on receptor activity.

Spinophilin (also called naraina II) is an auxiliary protein that facilitates interaction of proteins enriched in dendritic spines of neurons in the CNS that serve as the main place of glutamatergic synapses in the brain (Allen, et al.,Proc. Natl. Acad. Sci.USA, 1997; Hsieh-Wilson, et al.,Biochemistry, 1999). Spinophilin was originally identified by its ability to bind F-actin and proteinopathy I (PP1). Interaction spinophilin with PP1 is most important for the functioning of ionotropic glutamate receptors, as spinophilin acts as a modulator of glutamatergic synaptic neurotransmission by regulating the ability of PP1 to dephosphorylate ionotropic glutamate receptors through localization. Evidence of such functions were PRODEMA the reported method of fixing the potential of the entire cell AMPA upon transmission induced by kainic acid and AMPA currents in a separate acutely dissociated prefrontal cortical neurons (Yan, et al.,Nature Neurosci. 1999). In these experiments, agonist-induced flow caused by kainic acid currents inhibited by a peptide corresponding to the binding domain PP1 spinophilin, and not the same peptide, which contains a point mutation, which suggests that when spinophilin no longer interacts with PP1, AMPA receptors (in this example) is no longer dephosphorylated with decreasing function and therefore remain more active.

In order to find compounds with small molecules that mimic'd the above-described action of the peptide spinophilin, we used a new analysis of protein-protein interaction between PP1 and spinophilin to identify inhibitors of the binding. Then by the method of fixing the voltages of all cells, we investigated the ability of these compounds to inhibit agonist-induced leakage currents AMPA and to modulate the currents caused by NMDA.

Thus, as described in this patent, the compounds may find use in the treatment of several neuropsychiatric disorders associated with dysfunction of glutamate neurotransmission.

BRIEF description of the INVENTION

The subject of this invention is a compound of the formula I:

or a stereoisomer or pharmaceutically acceptable salt, where:

R1choose from a group that includes but is silt, benzyl, C3-8cycloalkyl, C1-10alkyl, C3-8cycloalkyl1-6alkyl, heteroaryl, arylcarbamoyl, arils1-6alkyls3-8cycloalkylcarbonyl, C1-10alkylsulphonyl, heteroarylboronic and

where X represents hydrogen, benzyl, arils2-6alkyl, C3-8cycloalkyl, C1-10alkyl or C3-8cycloalkyl1-6alkyl;

where these aryl, benzyl or heteroaryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, or aryl;

R2selected from the group including C1-6alkyl, C3-8cycloalkyl or aryl, where aryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R3selected from the group including aryl, C3-8cycloalkyl, C1-6alkyl or heteroaryl, where the aryl or het is roarin optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R4selected from the group including hydrogen, aryl, arils2-6alkyl, benzyl, hydroxys2-6alkyl, C1-6perfluoroalkyl, C3-8cycloalkyl or C1-6alkyl, where the aryl or benzyl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R5means H, C1-6alkyl or C3-8cycloalkyl; and

provided that

a) when R1and R4selected from the group comprising phenyl or 4-chlorophenyl, and R5means hydrogen, R2and R3both cannot be metelli;

b) when R1selected from the group comprising phenyl or 4-chlorophenyl, and R4and R5means hydrogen, R2and R3both cannot be metelli;

The present invention is also directed to pharmaceutical compositions that contain Asia the compounds of formula (I).

Another aspect of the present invention describes a method of treating neuropsychiatric disorders amenable to correction modulation of AMPA receptors and NMDA receptors, consisting in the introduction to a mammal in need of treatment of this disorder, a therapeutically effective amount of the compounds of formula I

or its stereoisomer or pharmaceutically acceptable salts, where:

R1selected from the group including aryl, benzyl, C3-8cycloalkyl, C1-10alkyl, C3-8cycloalkyl1-6alkyl, heteroaryl, arylcarbamoyl, arils1-6alkyls3-8cycloalkylcarbonyl, C1-10alkylsulphonyl, heteroarylboronic and

where X represents hydrogen, benzyl, arils2-6alkyl, C3-8cycloalkyl, C1-10alkyl or C3-8cycloalkyl1-6alkyl;

where these aryl, benzyl or heteroaryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, or aryl;

R2selected from the group including C1-6alkyl, C3-8cycloalkyl or aryl, where the aryl neobyazatel is substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R3selected from the group including aryl, C3-8cycloalkyl, C1-6alkyl or heteroaryl, where the aryl or heteroaryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R4choose from the groups that include hydrogen, aryl, arils2-6alkyl, benzyl, hydroxys2-6alkyl, C1-6perfluoroalkyl, C3-8cycloalkyl or C1-6alkyl, where the aryl or benzyl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R5means H, C1-6/sub> alkyl or C3-8cycloalkyl.

FULL description of the INVENTION

Used in this patent, the terms have the following meanings:

In this patent application, the expression "C1-6alkyl", used alone or with other terms, means alkyl (or alkylene as appropriate) with a linear or branched chain, having in its composition of methyl and ethyl groups, and also through butylene, Pintilie or hexylene group with a linear or branched chain. To alkyl groups include methyl, ethyl,n-propyl, isopropyl andtert-butyl. In line with this, we must understand the expression "C1-6alkoxy, C1-6alkoxyl1-6alkyl, hydroxys1-6alkyl, C1-6alkylaryl", "C1-6alkoxycarbonyl1-6alkyl, C1-6alkoxycarbonyl", "amino1-6alkyl, C1-6alkylcarboxylic1-6alkyl, C1-6diallylbarbituric1-6alkyl", "mono - or di-C1-6alkylamino1-6alkyl, amino1-6alkylaryl", "diphenyls1-6alkyl, panels1-6alkyl, phenylcarbinol1-6alkyl and venoxis1-6alkyl".

In this patent application, the expression "C2-6alkenyl" can mean atenilol or having straight or branched chain propenyloxy, butenyloxy, pentanediol or hexanediol group. Similarly, an expression is "C 2-6quinil" can mean etinilnoy, propenyloxy having a straight or branched chain butenyloxy, Punchinello and hexylamino group.

In this patent application, the expression "C1-6perfluoroalkyl" means that all the hydrogen atoms in these alkyl group substituted by fluorine atoms. Examples of such groups are triptoreline and panafcortelone, as well as having a linear or branched chain heptafluoropropyl, nonattribution, undecafluoropentyl and tridecafluorohexyl group. In accordance with this, it should be understood derived the expression "C1-6performace".

In this patent application, the expression "C3-8cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In this patent application, the expression "C3-8cycloalkyl1-6alkyl" means that the corresponding here to the definition of C3-8cycloalkyl attached to the corresponding here to the definition of C1-6the alkyl. Typical examples are cyclopropylmethyl, 1-cyclobutylmethyl, 2-cyclopentylpropionyl, cyclohexylmethyl, 2-cyclohexylethyl and 2-cyclooctylmethyl and similar groups.

In this patent "halogen" or "halo" means chlorine, fluorine, bromine or iodine.

In this patent application, the expression "carbarnoyl" means --NC(O)-- group, where the moiety is connected on the two floor is the practice with two separate additional groups.

In this patent, the term "aryl" means a carbocyclic aromatic ring system such as phenyl, biphenyl, naphthyl, anthracene, phenanthrene, fluorene, indenyl, pentalene, azulene, biphenylene and similar groups. To arram also include the partially hydrogenated derivatives of the above carbocyclic aromatic systems. Particular examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphtho and similar groups.

In this patent application "heteroaryl" means a heterocyclic aromatic ring system containing one or more heteroatoms, which may be nitrogen, oxygen and sulfur, such as furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazole, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophene (tianeptine), indazole, benzimidazole, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, purinol, hintline, hemolysins, chinoline, ethenolysis, honokalani, naphthyridine, pteridine, carb which was Salil, azepines, diazepines, acridines and similar groups. To heteroaryl also include the partially hydrogenated derivatives of the above heterocyclic systems. Particular examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolyl, pyrazolyl, indolyl, oxazolidinyl, oxazolyl, oxazepines and similar groups.

In this patent heterocyclyl" means a saturated ring of from 3-8 atoms with one or more heteroatoms, which may be nitrogen, oxygen and sulfur. Typical examples are pyrrolidyl, piperidyl, piperazinil, morpholinyl, thiomorpholine, aziridinyl, tetrahydrofuranyl and similar groups.

In this patent application "tautomer" or "tautomerism" means the coexistence of two (or more) of compounds that differ from each other only by the position of one (or more) moving atoms and the electron density distribution, for example, keto-enol tautomers and tautomerism.

In this patent a "treatment" or "therapy" refers to any treatment, in particular, debilitating symptoms, eliminating, for a while or permanently, the cause of symptoms and to prevent or slow the appearance of symptoms and the development of diseases, disorders, and disorders.

"Therapeutically effective amount" means the amount of coupling, effective the CSOs in the treatment of the specified disease or disorder.

In this patent the "patient" refers to warm-blooded animal such as rat, mouse, dog, cat, Guinea pig and Primate, such as a person.

In this patent, the terms "pharmaceutically acceptable carrier" means a non-toxic solvent, a dispersant, a carrier, adjuvant, or other substance that is mixed with the compound constituting the object of the present invention, to obtain the drug, i.e. the dosage form, suitable for administration to a patient. One example of such a carrier is a pharmaceutically acceptable oil, often used for parenteral administration.

The term "pharmaceutically acceptable salts" in this patent means salts of the compounds constituting the subject matter of this invention, which can be used in medical preparations. However, other salts may be useful in obtaining compounds that are the subject of this invention, or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds constituting the subject matter of this invention include salts formed by attaching acids formed, for example, mixing of a solution of the compound constituting the subject matter of this invention, with a solution of the pharmaceutically acceptable acid such as hydrochloric acid, b is motovational acid, sulfuric acid, methanesulfonate acid, 2-hydroxyethanesulfonic acid,pair-toluensulfonate acid, fumaric acid, maleic acid, hydroxymaleimide acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. Can also be acidic metal salts, for example, monohydrogenphosphate sodium and potassium hydrosulfate. In addition, the thus obtained salt may be a mono - or disubstituted salts are acidic and can exist in the form of hydrates or be substantially dehydrated. Moreover, if the compounds of the present invention include acid function, suitable their pharmaceutically acceptable salts can be classified as alkali metal salts, e.g. sodium or potassium, salts of alkaline earth metals such as calcium salt or magnesium, and salts formed with suitable organic ligands, e.g. Quaternary ammonium salts.

The term "stereoisomers" is shared by those who min, used for all isomers of individual molecules that differ only in the spatial orientation of their atoms. To them, as a rule, are mirror isomers, which usually exist in the presence of at least one center of asymmetry (enantiomers). If the connection in accordance with the present invention have two or more centers of asymmetry, they may also exist in the form of diastereoisomers, in addition, some individual molecules can exist in the form of geometric isomers (CIS/TRANS). It should be understood that all such isomers and mixtures thereof in any proportion are also subject of the present invention.

In the following examples and descriptions of synthesis used terms should be understood in the following values: kg - kilograms, "g" for grams, "mg" - milligrams, "μg" - micrograms, "PG" - picogram, "mol" - moles, "mmol" mmol "nmol" - nanamoli, "l" - liters, "ml - milliliters, "μl" - Microlitre, "°C" degrees Celsius, "Rf" is the coefficient of retention, "TPL" melting point "location." - decay, "as" boiling point, "mm of RT. Art." is the pressure in millimeters of mercury, "cm" - centimeters, "nm" nm, "[α]20D" is the specific rotation of the D line of sodium at 20°C, obtained in a 1 decimeter cell, "c" is the concentration in g/ml, "THF" - tetr hydrofuran, "DMF - dimethylformamide, "NMP" - 1-methyl-2-pyrrolidinone, MP-carbonate" - macroporous polystyrene anion-exchange resin, the resin has an associated equivalent of tetraalkylammonium carbonate, "saline" - saturated aqueous sodium chloride solution, "M" molar, "mm - millimolar, "μm" - micromolar, "nm" - nanomolar, "TLC" - thin layer chromatography, "HPLC" is a high - performance liquid chromatography, "MVR" - the mass spectrum of high resolution, "she" - mass spectrometry with chemical ionization, "tR" - retention time, "lb" lb, "Gal." - gallons, "puis." - loss on drying, "µci - microcurie, "I.P. Pavlova." - IPR, "i.v." intravenous.

One aspect of the present invention is dissolved compounds having the General structure represented by the formula I:

or a stereoisomer or pharmaceutically acceptable salt, where:

R1selected from the group including aryl, benzyl, C3-8cycloalkyl, C1-10alkyl, C3-8cycloalkyl1-6alkyl, heteroaryl, arylcarbamoyl, arils1-6alkyls3-8cycloalkylcarbonyl, C1-10alkylsulphonyl, heteroarylboronic and

where X represents hydrogen, benzyl, arils2-6alkyl, C3-8cycloalkyl, C1-10alkyl or C3-8cycloalkyl1-6alkyl;

where these aryl, benzyl or heteroaryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, or aryl;

R2selected from the group including C1-6alkyl, C3-8cycloalkyl or aryl, where aryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R3selected from the group including aryl, C3-8cycloalkyl, C1-6alkyl or heteroaryl, where the aryl or heteroaryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R4choose from the groups the, including hydrogen, aryl, arils2-6alkyl, benzyl, hydroxys2-6alkyl, C1-6perfluoroalkyl, C3-8cycloalkyl or C1-6alkyl, where the aryl or benzyl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R5means H, C1-6alkyl or C3-8cycloalkyl; and

provided that

a) when R1and R4represent phenyl or 4-chlorophenyl, and R5means hydrogen, R2and R3both cannot be metelli;

b) when R1represents phenyl or 4-chlorophenyl, and R4and R5mean hydrogen, R2and R3both cannot be metelli;

In the following implementation of the compounds of formula I, comprising the subject matter of this invention, R1selected from the group including aryl, benzyl, C3-8cycloalkyl, C1-10alkyl, aryls1-6alkyl andwhere X is benzyl, R2and R3mean C1-6alkyl, and R5means hydrogen or C1-6alkyl.

In another implementation of the compounds of formula I, constitute the subject on the frame of the invention, R1means aryl, R2and R3mean C1-6alkyl, R4means hydrogen, R5means hydrogen or C1-6alkyl.

Typical examples of the compounds which are the implementation of the compounds of formula I include 2'-(2-forfinal)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2'-(4-isopropylphenyl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2'-(4-forfinal)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(4-triptoreline)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(4-methoxyphenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2'-(3-forfinal)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2'-(2-were)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,,5'-dimethyl-2'-(4-trifloromethyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(4-were)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(3-were)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(2-ethylphenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(3,4-dichlorophenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(3-chlorophenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2'-(4-tert-butylphenyl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(3-triptoreline)-2H, 2'H-[3,4'] piperazinyl-3'-ol and 5'-methoxy-5,3'-dimethyl-1'-phenyl-2H,1'H-[3,4']piperazinyl.

In the following implementation of the compounds of formula I, comprising the subject matter of this invention, R1represents aryl, R2and R3mean C1-6alkyl, R4means arils2-6 alkyl or benzyl, R5means hydrogen or C1-6alkyl.

Typical examples of the compounds which are the implementation of the compounds of formula I include: 5,5'-dimethyl-2-phenylethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2-benzyl-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, and 2-benzyl-5'-methoxy-5,3'-dimethyl-1'-phenyl-2H,1'H-[3,4']beparasy, and 2-(3-hydroxybenzyl)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol.

In another implementation of the compounds of formula I, comprising the subject matter of this invention, R1represents aryl or benzyl, R2and R3mean C1-6alkyl, R4means hydraxis1-6alkyl, C1-6perfluoroalkyl, C3-8cycloalkyl or C1-6alkyl, and R5means hydrogen.

Typical examples of the compounds which are the implementation of the compounds of formula I include: 5,5'-dimethyl-2'-phenyl-2-(2,2,2-triptorelin)-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2-cyclohexyl-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2-(2-hydroxyethyl)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol and 2,5,5'-trimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol.

In another implementation of the compounds of formula I, comprising the subject matter of this invention, R1represents aryl, R2and R3means C1-6alkyl, R4means aryl, and R5means hydrogen.

Typical examples of the compounds depict alausa the implementation of compounds with formula I, include: 2-(4-methoxyphenyl)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol and 2-(4-forfinal)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol.

In another implementation of the compounds of formula I, comprising the subject matter of this invention, R1selected from a group comprising arils2-6alkyl or benzyl, R2and R3represents a C1-6alkyl, and R4and R5means hydrogen.

Typical examples of the compounds which are the realization of the connection with formula I, include: 5,5'-dimethyl-2'-phenethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, 2'-(3-hydroxybenzyl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol, and 2'-benzyl-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol.

In the following implementation of the compounds of formula I, comprising the subject matter of this invention,

R1doeswhere X is benzyl, R2and R3mean C1-6alkyl, and R4and R5mean hydrogen.

A typical example of this implementation, the compounds of formula I is 2'-(1-benzylpiperidine-4-yl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol.

In another implementation of the compounds of formula I, comprising the subject matter of this invention, R1represents a C3-8cycloalkyl, R2and R3denote C1-6alkyl, and R4and R5denote hydrogen.

A typical example of this implementation is connected to the I of formula I is 2'-cyclohexyl-5,5'-dimethyl-2H, 2'H-[3,4]piperazinyl-3'-ol.

In another implementation of the present invention is disclosed connection 5,1',5'-trimethyl-2'-phenyl-1', 2'-dihydro-2H-[3,4']piperazinyl-3'-Oh.

In another implementation of the present invention are disclosed pharmaceutical preparation comprising an effective amount of the compounds of formula I and a pharmaceutically acceptable carrier.

Another aspect of the present invention describes a method of treating neuropsychiatric disorders amenable to correction modulation of AMPA receptors and NMDA receptors, comprising the administration to a mammal in need of treatment of this disorder, a therapeutically effective amount of the compounds of formula I

or its stereoisomer or pharmaceutically acceptable salts, where:

R1selected from the group including aryl, benzyl, C3-8cycloalkyl, C1-10alkyl, C3-8cycloalkyl1-6alkyl, heteroaryl, arylcarbamoyl, arils1-6alkyls3-8cycloalkylcarbonyl, C1-10alkylsulphonyl, heteroarylboronic and

where X represents hydrogen, benzyl, arils2-6alkyl, C3-8cycloalkyl, C1-10alkyl or C3-8cycloalkyl1-6alkyl;

where these aryl, benzyl or heteroaryl optionally substituted by one or more substituents, each of which is independently selected from Csub> 1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, or aryl;

R2selected from the group including C1-6alkyl, C3-8cycloalkyl or aryl, where aryl optionally substituted by one or more substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R3selected from the group including aryl, C3-8cycloalkyl, C1-6alkyl or heteroaryl, where the aryl or heteroaryl optionally substituted by one or more substituents, each selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl or alkoxy;

R4selected from the group including hydrogen, aryl, arils2-6alkyl, benzyl, hydroxys2-6alkyl, C1-6perfluoroalkyl, C3-8cycloalkyl or C1-6alkyl, where the aryl or gasoline is optionally substituted by one or more substituents, each of which is selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, CnHxFy-6alkoxy, where n has value of 1-4, x has a value of 0-8, y has a value of 1-9, and x+y has a value of 2n+1, C1-C6alkoxy, nitro, aryl, or alkoxy; and

R5means H, C1-6alkyl or C3-8cycloalkyl.

In another implementation of the method constituting the subject matter of this invention, called neuropsychiatric disease can be depression, epilepsy, schizophrenia, Alzheimer's disease, disorders of memory and memory, mild cognitive disorder.

In another implementation of the method constituting the subject matter of this invention, called the violation is schizophrenia.

In yet another implementation of the method constituting the subject matter of this invention, called the violation is depression.

In yet another implementation of the method constituting the subject matter of this invention, called the violation is a violation of remembering and memory.

The compounds forming the subject of this invention, can be obtained using methods of synthesis are shown in the following schemes, or other methods known to experts in this field. The substituents R are the same that were defined above for formula (I), unless otherwise noted. If the necessity is the following synthesis schemes having high reactivity of the functional group of compounds, described in this invention may be protected with appropriate protective groups. The protective group can be removed in one of the subsequent stages of the synthesis. Description of methods of protection, with high reactivity of functional groups and the subsequent removal of the protective groups can be found in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, Wiley and Sons, 1991.

Scheme A

In the diagram A shows the synthesis of compounds of formula I, where R4and R5means hydrogen. In stage A1 6-substituted pyrone1connection commercially available or synthesized using well known methods (Lokot, et al,Tetrahedron, 55, 4783-4792, 1999), is reacted with a carboxylic acid chloride, a compound2in the presence of a strong organic acid, resulting in a 3-acylated derivative3. Examples of strong organic acids that can be used in the reaction, are trigalogenmetany acid, such as triperoxonane acid, and triftoratsetofenona acid. This reaction is usually carried out at temperatures from 50°C to the boiling point of the acid reflux.

In stage A2 connection3reacts with hydrazine4with the formation of the hydrazone, compound5. The reaction is usually carried out in an inert organic solvent such as alcohol, in some of the cases in which the presence of a suitable base, if the reagent used is a salt of hydrazine. Among suitable alcohols include methanol, ethanol, isopropanol or ethylene glycol, and among the appropriate grounds - alkali carbonates such as sodium carbonate, potassium or cesium, or carbonates associated with resin, for example, MP-carbonate. The temperature at which it is possible to conduct the reaction from room temperature up to the boiling point of the organic solvent under reflux.

As shown in stage A3, hydrazone, compound5you can turn in pyrazolidine 6 through intramolecular cyclization5in the presence of a suitable organic acid, such as acetic, propionic or triperoxonane acid. This reaction is usually conducted at elevated temperatures from 50°C to the boiling point of the organic acid under reflux.

In stage A4 reaction Dion6with hydrazine7gives the desired beparasy8. The reaction is usually carried out in an inert organic solvent such as alcohol at the boiling temperature of the solvent under reflux or close to the temperature.

Scheme B

Scheme B illustrates a method that can be used for the synthesis of compounds of formula I, where R5represents a C1-6alkyl, C3-8cycloalkyl. In stage B1 not having substituents at the m nitrogen in the ring ipirate 8protect alkoxycarbonyl group receiving the mixture of positional isomers, compounds9and10. The reaction is carried out using methods well known to experts in the field; for example, a processing8tert-BUTYLCARBAMATE can give the connection9. Cm. Kashuma, et al, Tetrahedron,54, 14679, 1998.

In stage B2 conduct the reaction mixture of isomers9and10alkylating/cycloalkylation substance11,where Lg is a leaving group such as halogen, alkylsulfonate or arylsulfonate, resulting in a mixture of O-alkyl compounds12and13and N-alkyl compounds14and15. The reaction can be carried out in a polar aprotic solvent such as DMF, DMSO or acetonitrile in the presence of a suitable base. Suitable bases are carbonates and bicarbonates of alkali metals such as sodium carbonate and potassium bicarbonate and sodium. This reaction is carried out at a temperature from room temperature up to the boiling point of the organic solvent under reflux. After completion of the reaction by chromatography on silica gel get two different mixtures. One mixture consists of O-alkyl compounds12and13and the other of N-alkyl compounds14and15.

O-alkilirovanie desired connection16can be obtained, as shown in stage B3, by means of which deplane N-alkoxycarbonyl from positional isomers 12and13. Cleavage can be performed by methods well known to specialists in this field, for example, a processing12and13acid or base.

Similarly, in stage B4 uses the same conditions as in stage B3, to obtain the N-alkylated compounds17.

BIOLOGICAL EXAMPLES

To test the biological properties of the compounds constituting the subject matter of this invention, the following test protocols. The following examples are presented to further illustrate the invention. However, one should not assume that they in any way limit the invention.

The analysis of interaction spinophilin/proteinopathy-I

Materials

Standard solution 10X phosphate physiological Tris buffer (Tris-Buffered Saline) manufactured by Bio-Rad. Spinophilin (6xHis) and proteins GST-PP1 clone, Express and purify in the laboratory methods of protein synthesis. Antibodies Eu-anti-GST, analytical buffer kits are used and stimulating solution kits are used - production Wallac (now Perkin Elmer). 384-well tablets with a high degree of binding production Greiner.

Methods time-resolved fluorescence 384-well ELISA analysis:

The tablets covered with 50 μl of a solution spinophilin/TBS (50 μg/ml) or 50 μl of TBS buffer (control 0) and incubated over night at 4°C. Prepare test compounds and izbavlyayut in 96-well polypropylene plate with the fluid dispenser Labsystems Wellpro. After 3 times washing tablet phosphate physiological Tris buffer TBS, using the device for washing the tablet Elx-405 (Biotek) compounds are transferred from 96-well plates 384-well plate using the dispenser of liquids Multimek (Beckman). Then in the tablet type GST-PP1, 50 μl (2.5 µg/ml). Tablets incubated for 36 h at room temperature. Tablets washed three times as described above, add 50 ál of antibody Eu-anti-GST (~50 ng/ml) using a Multidrop module (Titertek) and incubated for 30 minutes at room temperature. Tablets washed three times as described above, add 100 ál of stimulating solution using a Multidrop module and incubated for 1 h at room temperature. Tablets read through fluorimetry Farcyte (Tecan) with the setting of europium. Measurement of attenuation of the fluorescence assess the ability of compounds to inhibit the interaction spinophilin (6xHis) and GST-PP1.

Fixing the potential of the currents of AMPA and NMDA all cells in prefrontal cortical neurons

Method acute dissociation of neurons

Prefrontal cortical (PFC) neurons of young adult (3-5 weeks after birth) of rats subjected to acute dissociation using previously described methods (Feng, et al., J Neurosci, 2001; Chen, et al., Proc Natl Acad Sci USA, 2004). After incubation of slices of the brain in NaHCO3-buffer saline solution P Is To remove and put in a cell with oxygen, containing papain (Sigma, 0.8 mg/ml) in a balanced salt solution Hanks HEPES buffer (HBSS, Sigma) at room temperature. After 40 minutes of treatment with the enzyme fabric washed three times in a weak Ca+2, HEPES-buffered saline solution and mechanically dissociated using a set of measuring pipettes glass fire polished Pasteur. The suspension of cells is then transferred to 35-mm Petri dish Lux, which is placed on the table inverted Nikon microscope.

Fixing the potentials of all cells AMPA and NMDA

Measurements for all cells on fixing currents of ion channels is carried out using standard methods of fixation potentials (Yan et al.,Nat Neuroscience, 1999; Wang et al.,J Neurosci, 2003; Tyszkiewicz et al.,J Physiol., 2004). The composition of the internal solution (within trial pipette) composed of (in mm): 180 (N-methyl-d-glucamine (NMG), 40 HEPES, 4 MgCl2, 0,1 BAPTA, 12 phosphocreatine, 3 Na2ATP and 0.5 Na2GTP, 0,1 leupeptin, pH=7,2-7,3, 265-270 mOsm/l In the composition of the external solution composed of (in mm): 127 NaCl, 20 CsCl, 10 HEPES, 1 CaCl2, 5 BaCl2, 12 glucose, of 0.001 TTX, 0.02 glycine, pH=7.3 to 7.4, 300-305 mOsm/L. measured at the amplifier for fixing the potential of the Axon Instruments 200B, managed with IBM PC software pCLAMP (version 8) serial DigiData 1320 (Axon instruments). The resistance of the electrodes, usually is 2-4 Mω in the bath. After the destruction of the seal to achieve the conditions of measurement for the entire cell, series resistance (4-10 Mω) offset (70-90%) and periodically measured. The potential of the cell membrane support equal to -60 mV.

The use of KA (200 μm) or NMDA (100 μm, in solution, not containing Mg2+) causes partially desensitizing current, inward. KA or NMDA injected for 2 seconds every 30 seconds to minimize induced desensitization reduction in current amplitude. Drugs are introduced with a "drain" system, the feed of the substance by gravity. An array of application capillaries (inner diameter of about 150 microns) have a distance of several hundred microns from the studied cells. Changes of the solution is carried out by means of high-speed devices for the introduction of incentives into the solution SF-77B (Warner Instruments). Data are collected using PCLAMP and analyze in AXOGRAPH, KALEIDOGRAPH and STATVIEW.

Described in this patent compounds inhibit KA-induced current flows AMPA or through stabilization caused by the agonist current or by increasing current. Similarly, as described in this patent compounds increase caused by the NMDA current. The minimum effective dose (MED) was determined by measuring the minimum concentration of inhibitor at which the effect is observed in each of the functional analysis.

The results of these analyses are shown in table I and table II.

Table I
Inhibition of KA-AMPA induced current
# exampleThe minimum effective concentration (µm)
40,1*
50,1*
151,0
181,0
251,0
* Minimum used in the analysis of the concentration rate can be less than 100 nm).

Table II
The increase was due to NMDA current
# exampleThe minimum effective concentration (µm)The average rate of growth of current NMDA (10 μm)
81303%
(n=3 neurons)
18555%
(n=4 neurons)

Test the forced swimming the Porsolt

The effects measured in this model were compared with eff what aktivnosti drugs as antidepressants. The principle of this model is that, under the action of a compound that is an effective antidepressant, the rat will make more effort to get out of the water-filled cylinder than a rat that received only the solvent.

Used in this study, animals neinfectine male rats Sprague Dawley weighing 225-350 grams. The test apparatus is a 6 transparent Plexiglas cylinder with a height of 40 cm and a width of 19 cm poured Into the cylinders 18 cm water temperature of 25°C. Each rat is placed in the cylinder for 15 minutes getting used to. After sub-chronic or acute dosage of a solvent (0.5% methylcellulose) or compounds of animals after 24 hours again placed in water for 5 minutes for the test. These test dives recorded on video for subsequent counting.

Sub-chronic dosing is a drug three times per 24 hours between addictive and analysis. The drug is administered for 24 hours, 5 hours and 1 hour before the test. Acute dose is a single injection of the drug 1 hour before the test. The calculation is made on the time intervals with the aid of computer programs. Every five seconds of animals assessed by demonstration of one of three types of behavior: stillness, calm swimming and trying to get out of the asuda. Then the results of the count is converted into percentages of the test session.

The present invention is additionally illustrated by the following examples which are given for purposes of explanation and not in any way limit the scope of the present invention.

Test of object recognition

Test recognition of an object is the memory test. It measures the ability of the mice (and rats) to distinguish between known and unknown objects, so it is suitable to determine the ability of compounds constituting the subject matter of this invention, to improve memory.

In General, the test can be performed as described in the literature. (Blokland et al.NeuroReport1998, 9, 4205-4208; Ennaceur, A., Delacour, J.,Behav. Brain Res.1988, 31, 47-59; Ennaceur, A., Meliani, K.,Psychopharmacology1992, 109, 321-330; Prickaerts et al.Eur. J. Pharmacol.1997, 337, 125-136).

During the first pass in front of the mouse on a large observational arena, where nothing more, put two of the same object. The mouse carefully studying both subjects, smelling and touching them. Take into account the time the mouse spends with each of the objects. During the second pass, after 24 hours, the mouse is again tested at the observation stage. This time one of the known objects replaced by another, unknown object. When the mouse learns a familiar object, it is more thoroughly exploring the unknown object. After 24 hours, mice, however, usually is abyway, which of the objects she has studied during the first pass, and equally examines in detail both objects. The use of a substance that can improve learning ability and memory, will cause the mouse recognizes the object that she had already seen 24 hours ago, during the first pass, as known. It will explore new, unknown object in more detail than is already known. This storage capability is expressed in the form of discriminatory index. The discriminatory index of zero means that the mouse is studying both old and new - in for the same time, i.e. it does not recognize the old object and perceive both objects as if they were both unfamiliar and new. The discriminatory index greater than zero means that the mouse explores a new object for a longer time than the old one, i.e. the mouse was identified as the old object.

Model MK-801-induced psychosis

Non-competitive antagonist of NMDA receptor MK-801 induces stereotypie and hyperactivity in rodents (Contreras et al.,Synapse2: 240-243, 1988), interacting with the ion channel associated with the NMDA receptor. Phencyclidine, also affecting the NMDA receptor is a person psychotic symptoms, in many ways similar to schizophrenia. These facts indicate that the failure of the transmission of glutamate may be responsible septology schizophrenia (Javitt & Zukin,Am. J. Psychiatr., 48: 1301-1308, 1991). The neuroleptics haloperidol, clozapine and raclopride able to bring changes in behavior caused by MK-801 in rats (Carlsson et al.,Biol. Psychiatr. 46: 1388-1395, 1999). The so called MK-801 activity and stereotypie rats may represent a suitable animal model for testing the efficacy of antipsychotic drugs.

The procedure of the experiment

Male Wistar rats weighing 250-300 g are placed in cell 2 with the cycle of light and dark, 12 h/12 h (light on at 7 : 00) at room temperature 21±0.2 degrees Celsius for at least 5 days prior to analysis. All animals have unrestricted access to regular food and water.

On the day of experiment, rats injected drug control solution, the control of substances haloperidol and clozapine, the solution of the analyzed compounds or of the analyzed compounds. After the introduction of rats return to the cells for 15 minutes. Animals, which was introduced haloperidol, clozapine, analyzed compound or control solution, get intraperitoneally injection of 0.3 mg/kg MK-801. The remaining rats that received placebo, receive the second injection control solution. The standard amount of injection is 2.0 ml/kg After 10 minutes of content in their cells of rats moving in the analysis box (plexiglass, HH cm) C is 5 minutes prior to analysis for addiction. Before each analysis analytical Boxing wash with 70% ethanol. For 5-minute periods evaluated stereotypie defined as contacts nose to walls and locomotor activity, defined as the turns 180 degrees.

Analysis of the potentiation of metrazol

Used male mice CD-1 (20-30 grams). In test-day animal is brought to the laboratory and randomly distributed into groups. For the primary selection of the analyzed compound is transferred administered intraperitoneally (I.P. Pavlova., 10 ml/kg) to groups of 10 mice for 60 minutes prior to stimulation metrazole (55 mg/kg subcutaneously). After the introduction of metrazol animals put one in transparent plastic cylinders (12×5 inches), and then see them in the presence of clonic convulsions. Clonic spasm is defined as a single episode of clonic spasms lasting for at least 3 seconds. The mouse, which was introduced metrazol, are considered to be "potentiated", if there are such clonic convulsions.

When 50% of the animals show a potentiation in the primary selection, it is necessary to apply a range of dosages. The analyzed compounds tested at the time before the drug is 60 minutes using 3 or more doses, while the control group received the control solution. The ED50 value determined by the method of linear regression.

Spermicidally stun analysis

Used male mice CD-1 (18-30 g). Medicines are prepared with distilled water, in case of their insolubility used surfactant. Control animals receive the control solution. Typically, medications administered intraperitoneally injected. The route of administration may vary (orally, subcutaneously). The volume of dose is 10 ml/kg

Stimulator DC, similar to the apparatus described in Woodbury and Davenport (Arch. Int. Pharmacodyn. 92: 97-107, 1952) gives 60 Hz shock, the current strength and duration of which can be changed via corneal electrodes. Kick 0.3 s, 25 mA (50) is sufficient to cause the tone of the extensor 95% of the control mice.

The connection is able to provide protection if the mouse does not show the tone of the extensor. Protection is expressed as a normalized percentage compared with the control group. The time response is determined by 6 mice per group. Animals are tested in 30, 60 and 120 minutes after drug administration. Tests with additional periods, if required by the results of previous tests. After determination of peak activity, you will analyze the dependence of the effect of dose using 10 animals per group in a given time period. The value of ED50 and 95% of emerytalny interval are calculated by computer probit analysis.

Examples synthesis

General information

Commercially available reagents and solvents used without additional processing.1H NMR spectra were recorded on a spectrometer Varian MercuryPlus-300 (300 MHz) or Varian Unity Inova (400 MHz), as indicated. The magnitude of the proton chemical shift is indicated in δ ppm relative to internal standard tetramethylsilane (0,0 ppm). Data MS (LC/MS) receive time-of-flight mass spectrometer with ionization elektrorazpredelenie Micromass LCT time of registration 5 minutes for m/z 100 to 1000. LC (LC/MS) performed on a column of Hypersil C18 (of 4.6×50 mm, 3.5 µm with a mobile phase of 0.1% TFA in H2O (A) and 0.1% TFA in ACN (B) with a gradient from 5% to 100% B over 3 minutes, then 2 minutes at 100% b can Also be used platform LC/MS source elektrorazpredelenie system HP1100 LC with a flow rate of 2.0 ml/min, with a flow of 200 µl/min on source ionization elektrorazpredelenie with built-in detection using a diode matrix detector (DAD) HP1100 and spectroscopy of the electron energy losses (ELS) SEDEX. Column Luna C18(2) (30×4.6 mm 3 µm is used with a gradient from 5% to 95% B over 4.5 min with a mobile phase of 0.1% formic acid in H2O and 0.1% formic acid in ACN (B). Purification HPLC runs in the system Varian ProStar using columns for reversed-phase C18 chromatography with a linear gradient of ACN /H2O content ,1% triperoxonane acid.

Example 1

3-Acetyl-4-hydroxy-6-methylpyran-2-he

4-Hydroxy-6-methylpyran-2-he (of 12.6 g, 100 mmol) dissolved in triperoxonane acid (50 ml) and added dropwise to 7.8 g (100 mmol) of acetylchloride. This mixture is heated under reflux for 5 hours. The reaction mixture is evaporated under reduced pressure. Add 50 ml of water, extracted with ethyl acetate (50 ml x 3) and mixed organic layers. Washed with brine and dried (sodium sulfate). Chromatographic on silica gel with elution by chloroform and obtain 5.8 g (34.5 mmol) of 3-acetyl-4-hydroxy-6-methylpyran-2-it.

LC/MS (M+H): m/z 169, retention time 3,24 minutes

Example 2

3-{1-[(2-Forfinal)hydrazono]ethyl}-4-hydroxy-6-methylpyran-2-he

The hydrochloride of 2-forfamilies (0.16 g, 1.0 mmol) in methanol (8 ml) was added MP-carbonate (1.0 g, 3.3 equivalents). The mixture is shaken at room temperature for 1 hour. The resin is filtered and washed with methanol. To the filtrate add (2-forfinal)-hydrazine (0,134 g, 0.80 mmol). The reaction mixture was shaken at room temperature for 2 hours and then the solvent is evaporated under reduced pressure. Solid material is recrystallized from a minimum volume of methanol and receive 0,185 g (0.67 mmol) of 3-{1-[(2-forfinal)hydrazono]ethyl}-4-HYDR the STI-6-methylpyran-2-it.

LC/MS (M+H): m/z 277, retention time 2,74 minutes

Example 3

1-[1-(2-Forfinal)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione

Within 1 hour, heated 3-{1-[(2-forfinal)-hydrazono]ethyl}-4-hydroxy-6-methylpyran-2-he (0,045 g, 0,163 mmol) under reflux in acetic acid (0.3 ml). Add heptane (3 ml) and the mixture is evaporated until dry, receiving 1-[1-(2-forfinal)-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione (0,045 g, 0,163 mmol). This substance is used in the next stage without additional purification.

LC/MS (M+H): m/z 277, retention time of 2.05 minutes

Example 4

2'-(2-Forfinal)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

1-[1-(2-forfinal)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione (0,045 g, 0,163 mmol) added hydrazinehydrate (0,016 g, 0.32 mmol) in ethanol (1.6 ml). The reaction mixture is heated under reflux for 1.5 hours and then evaporated ethanol. The residue was washed with dichloromethane and get 2'-(2-forfinal)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol (0,028 g is 0.102 mmol).

LC/MS (M+H): m/z 273, retention time of 2.16 minutes

Example 5

2'-(4-Chlorophenyl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 4-chlorophenylhydrazone method and, in examples 2, 3 and 4.

LC/MS (M+H): m/z 289, retention time 2,72 minutes

Example 6

2'-(4-Isopropylphenyl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 4-isopropylpiperazine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 297, retention time 2,85 minutes

Example 7

2'-(4-Forfinal)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 4-forfamilies the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 273, retention time 2,00 minutes

Example 8

5,5'-Dimethyl-2'-(4-triptoreline)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-it 4-triftormetilfullerenov the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 323, retention time 2,88 minutes

Example 9

2`-Cyclohexyl-5,5`-dimethyl-2H, 2'H-[3,4]piperazinyl-3`-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride cyclohexylpiperazine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 261, retention time 1,80 minutes

Example 10

5,5'-Dimethyl-2'-(4-methoxyphenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 4-methoxyphenylhydrazine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 285, retention time 1,96 minutes

Example 11

2'-(3-Forfinal)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 3-forfamilies the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 273, retention time of 2.45 minutes

Example 12

2'-(2-Were)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 2-methylphenylhydrazine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 269, retention time 1,70 minutes

Example 13

5,5'-Dimethyl-2'-(4-trifloromethyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 4-triftormetilfullerenov the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 339, retention time to 3.02 min

Example 14

5,5'-Dimethyl-2'-(4-were)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-AC is Tyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 4-methylphenylhydrazine methods in examples 2, 3 and 4.

LC/MS (M+H): m/z 269, retention time 2,44 minutes

Example 15

5,5'-Dimethyl-2'-(3-were)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 3-methylphenylhydrazine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 269, retention time 2,46 minutes

Example 16

5,5'-Dimethyl-2'-(2-ethylphenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 2-ethylphenethylamine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 283, retention time 2,32 minutes

Example 17

5,5'-Dimethyl-2'-(3,4-dichlorophenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 3,4-dichloropyridazine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 323, the retention time of 3.04 from minutes

Example 18

5,5'-Dimethyl-2'-(3-chlorophenyl)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 3-chlorophenylhydrazone the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 289, retention time of 2.28 minutes

Example 19

2'-(4-tert-Butylphenyl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride 4-tert-butylphenylmethyl the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 311, retention time 2,62 minutes

Example 20

5,5'-Dimethyl-2'-phenethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she sulfate penitenciaria the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 283, retention time 2,07 minutes

Example 21

5,5'-Dimethyl-2'-(3-triptoreline)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she hydrochloride and 3-triftormetilfullerenov the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 323, retention time 2,62 minutes

Example 22

2'-(1-Benzylpiperidine-4-yl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-it dihydrochloride and 1-benzylpiperidine-4-algerina the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 352, retention time of 1.52 minutes

Example 23

2'-(3-Hydroxybenzyl)-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

Search soybean is inania obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-it dihydrochloride and 3-hydrazinoacetate methods in examples 2, 3 and 4.

LC/MS (M+H): m/z 285, retention time of 1.57 minutes

Example 24

2'-Benzyl-5,5'-dimethyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-it dihydrochloride of benzylpiperazine the methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 269, retention time 1,95 minutes

Example 25

5,5'-Dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 3-acetyl-4-hydroxy-6-methylpyran-2-she and phenylhydrazine methods described in examples 2, 3 and 4.

LC/MS (M+H): m/z 255, retention time 1,77 minutes

Example 26

5'-Methoxy-5, 3'-dimethyl-1'-phenyl-2H, 1'H-[3,4']piperazinyl

(A)tert-Butyl ether 5'-hydroxy-5,3'-dimethyl-1'-phenyl-1'H-[3,4']piperazinyl-2-carboxylic acid

(B)tert-Butyl ether 5'-hydroxy-5,3'-dimethyl-1'-phenyl-1'H-[3,4']piperazinyl-1-carboxylic acid

To 5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-Olu (amount of 0.118 g, 0,457 mmol) (example 25) in ethanol (4 ml) addedtert-BUTYLCARBAMATE (0,120 g, 0,914 mmol). Heated under reflux for 1.5 hours and then evaporated ethanol. After chromatography on silica gel with elution with a mixture of 50% ethyl acetate/heptane get 0,101 g of a mixture of point the s isomers A and B. This mixture is used in the next stage.

LC/MS (M+H): m/z 355, retention time of 1.97 min or 3.24 min, respectively.

(C)tert-Butyl ether 5'-methoxy-5,3'-dimethyl-1'-phenyl-1'H-[3,4']piperazinyl-2-carboxylic acid

(D)tert-Butyl ether 5'-methoxy-5,3'-dimethyl-1'-phenyl-1'H-[3,4']piperazinyl-1-carboxylic acid

(E)tert-Butyl ether 5,1',5'-trimethyl-3'-oxo-2'-phenyl-2',3'-dihydro-1'H-[3,4']piperazinyl-2-carboxylic acid

(F)tert-Butyl ether 5,1',5'-trimethyl-3'-oxo-2'-phenyl-2',3'-dihydro-1'H-[3,4']piperazinyl-1-carboxylic acid

In the mixture of compounds (A) and (B) (0,100 g, 0,282 mmol) in DMF (5 ml) is added NaHCO3(0,071 g, 0,845 mmol) and jodean (0.40 g, 2.82 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25 ml), washed with water (30 ml × 5) and dried (sodium sulfate). After chromatography on silica gel with elution with a mixture of 50% ethyl acetate/heptane get 0,013 g O-methylated products ((C) and (D); LC/MS (M+H): m/z 369, retention time 3,30 min) and 0,012 g N-methylated product (E) and (F), LC/MS (M+H): m/z 369, retention time 2,63 min). In the next stage are O-methylated products.

5'-Methoxy-5, 3'-dimethyl-1'-phenyl-2H,1'H-[3,4']piperazinyl

In a mixture of O-methylated product is, compounds (C) and (D) (0,013 g, 0.035 mmol), in dichloromethane (1 ml) add triperoxonane acid (1 ml). This mixture was stirred at room temperature for 1 hour and then evaporated to dryness. The residue is dissolved in dichloromethane, washed sequentially with water, aqueous sodium bicarbonate solution and water. The organic layer is dried (sodium sulfate) and concentrated, obtaining 0,006 grams (of 0.022 mmol) of the desired compound.

LC/MS (M+H): m/z 269, retention time of 2.83 min

Example 27

5,1',5'-Trimethyl-2'-phenyl-1',2'-dihydro-2H-[3,4']piperazinyl-3'-Oh

In a mixture of N-methylated isomers, compounds (E) and (F) of example 26 (0,012 g, 0.035 mmol), in dichloromethane (1 ml) add triperoxonane acid (1 ml). This mixture was stirred at room temperature for 1 hour and then evaporated to dryness. The residue is dissolved in dichloromethane, washed sequentially with water, aqueous sodium bicarbonate solution and water. The organic layer is dried (sodium sulfate) and concentrated, obtaining 0,009 g (0.035 mmol) of the desired compound.

LC/MS (M+H): m/z 269, retention time of 2.06 minutes

Example 28

2'-(4-Methoxyphenyl)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

In hydrochloride (4-methoxyphenyl)hydrazine (0.083 g, 0.48 mmol) in ethanol (5 ml) is added sodium bicarbonate (0,067 g, 0.80 mmol), after which displaced the more of the mixture for 10 minutes. Add 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-4-yl]-butane-1,3-dione (0,103 g, 0.40 mmol). The mixture is heated under reflux for 1.5 hours and then evaporated to dryness. After chromatography on silica gel with elution with a mixture of from 50 to 100% ethyl acetate/heptane get 0,071 g of the desired compound.

LC/MS (M+H): m/z 361, retention time 2,43 minutes

Example 29

5,5'-Dimethyl-2-phenethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]-butane-1,3-dione and sulfate penitenciaria methods described in example 28.

LC/MS (M+H): m/z 359, retention time of 2.55 minutes

Example 30

2-(4-Forfinal)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]-butane-1, 3-dione hydrochloride and 4-forfamilies methods described in example 28.

LC/MS (M+H): m/z 349, retention time 2,48 minutes

Example 31

5,5'-Dimethyl-2'-phenyl-2-(2,2,2-triptorelin)-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione and 2,2,2-cryptgetuserkey (70% in water) by the methods described in example 28.

LC/MS (M+H): m/z 337, retention time min 2,35

When is EP 32

2-Cyclohexyl-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]-butane-1,3-dione and its hydrochloride cyclohexylpiperazine methods described in example 28.

LC/MS (M+H): m/z 337, retention time 2,50 minutes

Example 33

2-(3-Hydroxybenzyl)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione dihydrochloride and 3-hydroxyethylhydrazine methods described in example 28.

LC/MS (M+H): m/z 361, retention time 2,18 minutes

Example 34

2-(2-Hydroxyethyl)-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione and 2-hydroxyethylhydrazine methods described in example 28.

LC/MS (M+H): m/z 299, retention time 1,83 minutes

Example 35

5,5'-Dimethyl-2,2'-diphenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione and phenylhydrazine methods described in example 28.

LC/MS (M+H): m/z 331, retention time 2,42 minutes

Example 36

2-Ben is Il-5, 5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione and its hydrochloride benzoylhydrazone methods described in example 28.

LC/MS (M+H): m/z 345, retention time 2,69 minutes

Example 37

2,5,5'-Trimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol

The desired compound is obtained from 1-[1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazole-4-yl]butane-1,3-dione and methylhydrazine methods described in example 28.

LC/MS (M+H): m/z 269, retention time 2,10 minutes

Example 38

2-Benzyl-5,1',5'-trimethyl-2'-phenyl-1',2'-dihydro-2H-[3,4'] piperazinyl-3'-Oh

2-benzyl-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4'] piperazinyl-3'-ol (example 36, 0,200 g of 0.58 mmol) in DMF added cesium carbonate (0,944 g, 2,90 mmol), and then logmean (0,823 g, 5.8 mmol). The mixture is stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (25 ml × 5) and dried (sodium sulfate). After chromatography on silica gel with elution with a mixture of from 50 to 100% ethyl acetate/heptane get 0,045 g of the desired compound.

LC/MS (M+H): m/z 359, retention time 2,84 minutes

This reaction also allows you to get the O-methylated compound. Cm. example 39 below.

Example 39

2-Benzyl-5'-methoxy-5,3'-dim the Teal-1'-phenyl-2H,1'H-[3,4']beparasy

The desired compound allocate by chromatography as described in example 38, and receive 0,033 g O-methylated isomer.

LC/MS (M+H): m/z 359, retention time 3,51 minutes

Although the invention is illustrated by the above examples, they should not be construed as any limitation of the present invention. On the contrary, the invention covers all the above scope in whole. You can implement various modifications and implementation of the present invention without deviation from its extent and nature.

1. The compound of formula (I)

or its pharmaceutically acceptable salt, where
R1selected from the group comprising phenyl, benzyl, panels2-6alkyl, C3-8cycloalkyl,1-10alkyl, C3-8cycloalkyl1-6alkyl, and

where X represents benzyl;
where mentioned phenyl, benzyl, optionally substituted by one or two substituents, each of which is independently selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, perfors1-4alkoxy, C1-C6alkoxy;
R2represents a C1-6alkyl;
R3represents a C1-6alkyl;
R4selected from the group including hydrogen, panels2-6alkyl, benzyl, CF3CH2With3-8cycloalkyl or-6 alkyl, where phenyl or benzyl optionally substituted by the Deputy, is selected from C1-6of alkyl, C1-6of perfluoroalkyl, halogen, hydroxyl group, and C1-C6alkoxy;
R5means H, C1-6alkyl; and
provided that
a) when R1represents phenyl or 4-chlorophenyl, a R4and R5mean hydrogen, R2and R3both cannot be metelli.

2. The compound according to claim 1, where
R1selected from the group comprising phenyl, benzyl, C1-6cycloalkyl,
With1-10alkyl, panels2-6alkyl and

where X is benzyl;
R2and R3mean C1-6alkyl; and
R5represents hydrogen or C1-6alkyl.

3. The compound according to claim 1, where
R1means phenyl;
R2and R3mean1-6alkyl;
R4means hydrogen; and
R5represents hydrogen or C1-6alkyl.

4. The compound according to claim 1, which is selected from the group including
2'-(2-forfinal)-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol, 2'-(4-isopropylphenyl)-5,5'-dimethyl-2H, 2 N-[3,4']piperazinyl-3'-ol, 2'-(4-forfinal)-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol, 5,5'-dimethyl-2'-(4-triptoreline)-2N,2 N-[3,4']piperazinyl-3'-ol, 5,5'-dimethyl-2'-(4-methoxyphenyl)-2H,2 N-[3,4']piperazinyl-3'-ol, 2'-(3-forfinal)-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol, 2'-(2-were)-5,5'-dimethyl-2H,2'is-[3,4'] piperazinyl-3'-ol, 5,5'-dimethyl-2'-(4-trifloromethyl)-2N,2 N-[3,4']piperazinyl-3'-ol, 5,5'-dimethyl-2'-(4-were)-2N,2 N-[3,4']piperazinyl-3'-ol, 5,5-dimethyl-2'-(3-were)-2N,2 N-[3,4']piperazinyl-3'-ol, 5,5'-dimethyl-2'-(2-ethylphenyl)-2N,2 N-[3,4']piperazinyl-3'-ol, 5,5'-dimethyl-2'-(3,4-dichlorophenyl)-2H,2 N-[3,4']piperazinyl-3'-ol, 5,5'-dimethyl-2'-(3-chlorophenyl)-2H,2 N-[3,4']piperazinyl-3'-ol, 2'-(4-tert-butylphenyl)-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol, 5,5'-dimethyl-2'-(3-triptoreline)-2N,2 N-[3,4']piperazinyl-3'-ol and 5'-methoxy-5,3'-dimethyl-1'-phenyl-2H,1 N-[3,4']piperazinyl.

5. The compound according to claim 1, where
R1means phenyl;
R2and R3mean C1-6alkyl;
R4means finals2-6alkyl or benzyl; and
R5represents hydrogen or C1-6alkyl.

6. The compound according to claim 1, which is selected from the group including
5,5'-dimethyl-2-phenethyl-2'-phenyl-2H,2 N-[3,4'] piperazinyl-3'-ol, 2-benzyl-5,5'-dimethyl-2'-phenyl-2H,2 N-[3,4']piperazinyl-3'-ol, 2-benzyl-5'-methoxy-5,3'-dimethyl-1'-phenyl-2H,1 N-[3,4']beparasy and 2-(3-hydroxybenzyl)-5,5'-dimethyl-2'-phenyl-2H,2 N-[3,4']piperazinyl-3'-ol.

7. The compound according to claim 1, where
R1means phenyl;
R2and R3mean C1-6alkyl;
R4means3-8cycloalkyl or2-6alkyl; and
R5means hydrogen.

8. Compound which is selected from the group including
5,5'-dimethyl-2'-phenyl-2-(2,2,2-triptorelin)-2N,2 N-[3,4']piperazinyl-3'-the l 2-cyclohexyl-5,5'-dimethyl-2'-phenyl-2H,2 N-[3,4']piperazinyl-3'-ol, and 2,5,5'-trimethyl-2'-phenyl-2H,2 N-[3,4']piperazinyl-3'-ol.

9. Compound which is selected from the group including
2-(4-methoxyphenyl)-5,5'-dimethyl-2'-phenyl-2H,2 N-[3,4']piperazinyl-3'-ol and 2-(4-forfinal)-5,5'-dimethyl-2'-phenyl-2H,2 N-[3,4']piperazinyl-3'-ol.

10. The compound according to claim 1, where
R1means finals2-6alkyl or benzyl;
R2and R3mean1-6alkyl; and
R4and R5mean hydrogen.

11. The compound according to claim 1, which is selected from the group including
5,5'-dimethyl-2'-phenylethyl-2N,2 N-[3,4'] piperazinyl-3'-ol, 2'-(3-hydroxybenzyl)-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol, and 2'-benzyl-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol.

12. The compound according to claim 1, where
R1means;
where X is benzyl;
R2and R3mean1-6alkyl; and
R4and R5mean hydrogen.

13. The connection section 12, which represents a 2'-(1-benzylpiperidine-4-yl)-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol.

14. The compound according to claim 1, where
R1means3-8cycloalkyl;
R2and R3mean1-6alkyl; and
R4and R5mean hydrogen.

15. The connection 14, which represents a 2'-cyclohexyl-5,5'-dimethyl-2H,2 N-[3,4']piperazinyl-3'-ol.

16. Pharmaceutical composition for modulation of AMPA receptors and NMDA, aderasa the effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid, which produces an endothelial antagonistic effect and is suitable for treating diseases associated with abnormal vascular tone and endothelial dysfunction, such as heart failure, pulmonary hypertension etc. The crystalline modification which is denoted modification B is characterised by a powder X-ray diffractogram with characteristic peaks expressed through the d-parametre value (interplanar distance) (Å) obtained on a conventional X-ray powder diffractometre using Cuka radiation: 10.7 (m), 9.4 (m), 8.6 (vs), 8.3 (m), 7.6 (m), 6.7 (m), 6.4 (m), 6.0 (m), 5.69 (m), 5.30 (m), 5.17 (m), 4.95 (vs), 4.76 (m), 4.56 (m), 4.43 (s), 4.13 (vs), 3.80 (s), 3.45 (s), 3.41 (s), 3.37 (s) and 3.03 (m). The invention also relates to crystalline pseudopolymorphous modifications of [6-methoxy-5-(2-methoxyphenoxy)-2-pyridin-4-ylpyrimidin-4-yl]amide-5-methylpyridine-2-sulfonic acid selected from: a) pseudopolymorphous modification, solvate with ethanol, denoted modification D; b) pseudopolymorphous modification, polysolvate with acetone, denoted modification E; c) pseudopolymorphous modification, solvate with tetrahyrofuran, denoted modification F; d) pseudopolymorphous modification, solvate with methanol, denoted modification G; e) pseudopolymorphous modification, solvate with isopropanol, denoted modification H; f) pseudopolymorphous modification, solvate with dichloromethane, denoted modification I; and g) pseudopolymorphous modification, solvate with 2-butanol, denoted modification J. The invention also relates to a method of obtaining crystalline modification B, a pharmaceutical composition and use.

EFFECT: wider field of use of the compounds.

8 cl, 9 dwg, 9 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) or their pharmaceutically acceptable salts which possess inhibiting activity with respect to focal adhesion kinase (FAK), proteintyrosinekinase ZAP-70, receptor of insulin-like growth factor 1 (IGF-1R), tyrosinekinase activity of anaplastic lymphoma (ALK) and fusion protein NPM-ALK. In formula (I) , R0, R1 and R2 independently represent hydrogen, C1-C8 alkyl, 5- or 6-member heterocycle, containing 1,2 or 3 heteroatoms, selected from N, O and S, C1-C8alkoxy group, C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, halogen, carbamoyl, sulphamoyl, etc.; R3 represents C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, carbamoyl or sulphamoyl; R4 represents hydrogen or C1-C8alkyl; R5 represents chlorine or bromine; R6 represents hydrogen; R7, R8, R9 and R10 independently represent C1-C8alkyl, C5-C10aryl, possibly substituted by 5- or 6-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N, O and S, where substituents are selected from C1-C8alkyl, hydroxy, hydroxy-C1-C8alkyl, C1-C8alkoxy C1-C8alkyl, cyano, oxo, C1-C8alkylamino, diC1-C8alkylamino, carbamoyl, C1-C8alkylcaronyl, 5-10-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N and O, which is probably substituted by C1-C8alkyl; C1-C8alkoxy group, halogen- C1-C8alkoxy group, etc; A represents C. Invention also relates to pharmaceutical composition and to application of compounds of formula (I) for preparation of medication.

EFFECT: novel compounds possess useful biologic activity.

15 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: novel 1,2,4-triazole derivatives - protein kinase inhibitors of formula (I) are described, where X - N; Y - CH2, NH, NR or 0; R1 and R2 each independently denote hydrogen; R3 is phenyl, substituted with -CN, 6-member heteroaryl containing 1-2 N atoms, possibly substituted with a 7-member heterocyclyl containing 2 nitrogen atoms, which in turn is substituted with C1-6alkylcarbonyl; R4 is hydrogen; R5 is hydrogen or -CN; and R is a C1-6alkyl group, C1-6alkylcarbonyl group substituted with -CN, or a C3-6cycloalkyl group, a method of inhibiting FLT-3 or c-KIT protein kinase.

EFFECT: obtaining novel compounds and their use in making a medicinal agent for treating or relieving acute myelogenic leucosis.

11 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

The invention relates to an improved process for the preparation of 1-(4’-tolyl)-3-methyl-5-pyrazolone used in the manufacture of dyes and pigments

The invention relates to a method for producing 1,1-di(1-phenyl-2,3-dimethyl-5-pyrazolone-4-yl)-2-methylpropane, which is the complexing agents with a large number of elements of the periodic system
The invention relates to chemical technology of obtaining pyrazolones

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts
The invention relates to a method for producing derivatives of pyrazolone namely, 1-phenyl-3-methylpyrazole-5, used in the synthesis of dyes and drugs

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a 5-hydroxy-4-thiomethylpyrazole compound, where a pyrazole compound of general formula is reacted with a sulphur compound of general formula X-S(O)n-R (2) in the presence of a base and formaldehyde to form a 5-hydroxy-4-thiomethyl compound of general formula , where radicals and symbols in the said formulae are defined in the formula of invention.

EFFECT: easier synthesis of the desired 5-hydroxy-4-thiomethylpyrazole compound with high output in mild conditions in a single step without using special equipment, expensive catalyst or a transition metal etc, where the process can be carried out virtually without formation of hazardous wastes from a catalyst etc; owing to this, the method is environmentally safe and can be used in industry.

6 cl, 16 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of 1-phenyl-2,3-dimethyl-4-iodopyrazolone-5 (iodoantipyrine) representing a medicinal preparation. Invention proposes a method for synthesis of iodoantipyrine by electrophilic iodination of antipyrine or antipyrine benzene sulfoacid under conditions of mechanical activation without solvent being both at the synthesis step and the isolation step. Using the proposed method provides preparing pharmacopoeia iodoantipyrine with the yield 57-96% depending on the parent substrate and an iodinating reagent, significant simplifying the process for its synthesis and the complete excluding an organic solvent.

EFFECT: improved method of synthesis.

4 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

The invention relates to the field of synthesis of biologically active compounds, and to methods of producing N-ACI-derivatives of 4-aminoantipyrine, analgesic and anti-inflammatory action
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