Azacyclic compounds to be used in treating serotonin-mediated diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) , where Z means where R means hydrogen, C4-C6cycloalkyl group attached either through one of ring carbon atoms, or through a lower alkylene group attached to the ring, or a linearly chained or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or a phenyl(lower alkyl) group optionally substituted with 1-2 substitutes chosen from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group where heteroaryl is chosen from the group consisting from thienyl, substituted with lower alkyl group, imidazolyl, and thiazolyl substituted with the lower alkyl group; n means 0 or 1; or Z means a group where R means the lower alkyl group; X1 means methylene or NH group; and X2 means methylene; or X1 means methylene and X2 means methylene or a bond; or X1 means methylene, and X2 means O, S or a bond; Y1 means methylene, and Y2 means methylene, vinylene, ethylene, or a bond; Ar1 means unsubstituted or substituted phenyl; Ar2 means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1 and Ar2 are substituted, each Ar1 and Ar2 are independently substituted with one or more substituted chosen from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di- and trihaloalkyl, di- and trihaloalkoxy, mono- and dialkylamino, alkilthio, alkyl ester and nitro; provided that Ar1 and Ar2 do not simultaneously mean unsubstituted phenyl; W means oxygen or sulphur; or to their pharmaceutically acceptable salts; provided those specified in cl. 1 of the patent claim. Besides the invention concerns the compounds chosen from the group, to compounds of formula (I), to pharmaceutical compositions, to a method of inhibition of monoamine receptor activity, to a method of inhibition of monoamine receptor activation, to a method of treating a diseased state associated with serotonin receptor, to a method of treating schizophrenia, to a method of treating migraine, and also to a method of treating psychosis.

EFFECT: preparation of the new biologically active compounds capable to inhibit monoamine receptor activity.

65 cl, 140 ex, 5 tbl

 

The present invention relates to new compounds that affect monoamine receptors, including serotonin receptors. Specifically, the present invention relates to compounds that are active as inverse agonists, and in this regard - as antagonists against subtype 5-HT2A receptors serotonin person. The present invention also relates to methods of using compounds according to the invention for modulation effects, mediated by 5-HT2A receptor, which can be useful in the treatment or alleviation of current painful condition in which the positive effect modification of the activity of these receptors.

Background of invention

Serotonin or 5-hydroxytryptamine (5-HT) plays an important role in the functioning of the mammalian organism. In the Central nervous system 5-HT is an important neurotransmitter and neuromodulator involved in such different behavioural responses, as sleeping, eating, physical activity, feeling pain, learning and memory, as well as sexual attraction, regulation of body temperature and blood pressure. In the spine serotonin plays an important role in control systems afferent peripheral nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)). 5-HT also assign peripheral functions in the cardiovascular, gemat the logical and gastrointestinal systems. It was shown that 5-HT mediates many of contractile, secretory, and electrophysiological phenomena, including the reduction of vascular and non-vascular smooth muscle and platelet aggregation. (Fuller, Biology of Serotonergic Transmissin, 1982; Boullin, Serotonin In Mental Abnormalities 1:316 (1978); Barchas, et al., Serotonin and Behavior, (1973)). Subtype receptor 5HT2A (also called a subclass) is characterized by a wide expression as a discrete subtype in the brain, including cortical, limbic areas, and areas of the forebrain, which indicates that it is involved in the modulation of higher cognitive and affective functions. The specified subtype receptor is also expressed on Mature platelets, where it is to some extent mediates platelet aggregation, one of the initial stages of the process of vascular thrombosis.

In light of the wide distribution of serotonin in the body it is not surprising that drugs that affect the serotonergic system, cause a very big interest (who, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et. al., J. Cardiovascular Pharmacol. 15:Supp.7 (1990)). Serotonin receptors are members of a large family of human genes encoding membrane-bound proteins, which function as transducers of extracellular signals. They are located on the surface of various cell types, including neurons and platelets, where their activation is under the action of either endogenous ligand serotonin or exogenously introduced medicines they change their conformation and consequently interact with mediators of cellular signal, located below the path of transmission of cellular signals. Many of these receptors, including the subclass of 5-HT2A, refer to the receptors associated with G-protein (GPCR), which send a signal upon activation of the guanine-nucleotidebinding proteins (G-proteins), resulting in the generation or inhibition of second messenger molecules such as cyclic AMP, insafety and diacylglycerol. These second messenger molecules modulate the function of various intracellular enzymes, including kinases and the transmission channels of the ions, which ultimately affect the excitability of cells and their function.

Identified at least 15 genetically razlichiya subtypes of receptors GT given the names of families from one to seven (5-HT1-7). Each subtype is characterized by a unique distribution, preference to different ligands and functionally correlated with the others.

Serotonin may be an important component in various types of pathological conditions, such as some mental illnesses (depression, aggressiveness, panic attacks, obsessive-compulsive disorder, psychosis, schizophrenia, suicidal tendencies), some neurodegenerative diseases (dementia of the Alzheimer's type, Parkinson's disease, Huntington's chorea), anorexia, bulimia, disorders associated with what lcoholism, cerebral-vascular phenomenon and migraine (Meltzer, Neuropsychopharmacology., 21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152 (1999); Glennon, Neurosci. Biobehavioral Rev., 14:35 (1990)). We have recently received data is serious evidence that subtype receptor 5-HT2 involved in the etiology of such clinical conditions as hypertension, thrombosis, migraine, vascular spasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorder, and disorder of appetite.

Schizophrenia is a particularly devastating neurological disease that affects approximately 1% of the population. It has been estimated that the total financial costs of diagnosis, treatment and maintenance of social activity, in connection with disability individuals affected by the specified disease, exceed 2% of gross national product (GNP) of the United States. The currently used treatment primarily based on pharmacotherapy medication from the class of antipsychotics. Antipsychotics are effective in mitigating the positive symptoms (e.g. hallucinations and delusions), but often they are not able to improve negative symptoms (e.g., social and emotional obednennost, apathy and poverty of speech).

Currently, for the treatment of psychotic symptoms prescribe medicine of the nine core to the Asses antipsychotica funds. However, the use of these compounds is limited by their side effects. Almost all of these "typical" connection or connections of the old generation drugs have significant side effects on the motor function of the person. "Extrapyramidal adverse reactions, so-called because of their effects on modulating the mechanisms of motility may be acute (eg, dystonic reactions; potentially life-threatening, but rare enough, neuroleptic malignant syndrome), and chronic (e.g., Acacias, tremor and late dyskinesia). The efforts of the professionals who develop drugs in this direction, focused on the new "atypical" agents that are free from these adverse reactions.

It was shown that antipsychotics interact with many monoaminergic of neurotransmitter receptors in the Central nervous system, including dopaminergic, serotonergic, adrenergic, muscarinic and histaminergic receptors. It is likely that therapeutic and side effects of these compounds is mediated by the nature of the various receptor subtypes. High level of genetic and pharmacological homology existing between these subtypes Retz is Perov, impedes the development of subtype selective compounds, as well as the definition of normal physiological or pathophysiological role of each specific subtype of receptor. In this regard, there is a need to develop drugs that would be selective for individual classes and subclasses of receptors in a group of monoaminergic receptor transmitters.

Prevailing at the present time theory of the mechanism of action of antipsychotic drugs is based on the antagonism of dopamine D2 receptors. Unfortunately, most likely the antagonism of the dopamine D2 receptor also mediates extrapyramidal side effects. Antagonism of 5-HT2A represents an alternative molecular mechanism of action of drugs with antipsychotic activity carried out, most likely through the antagonism increased or enhanced signal transduction via the serotonergic system. In this regard, the antagonists of 5-HT2A can be seen as a likely contender for the treatment of psychosis without related extrapyramidal side effects.

Traditionally it was believed that these receptors are located in a peaceful state, if not their activation upon binding of an agonist (a drug that activates the receptor). It is now recognized that many of the EU is not a large part, monoamino of GPCR receptors, including serotonin receptors can exist in a partially activated state in the absence of their endogenous agonists. Increased baseline activity (constitutive activity) can be suppressed by compounds called inverse agonists. And agonists and inverse agonists have inherent activity against receptor, and therefore they themselves can activate or inactivate these molecules, respectively. In contrast, classic or neutral antagonists compete with agonists and inverse agonists for access to the receptor, but do not have the inherent ability to inhibit elevated base or constitutive response of the receptor.

The authors were able recently to clarify an important aspect of the functioning of the 5HT2A-receptor using the methods of selection and amplification of the receptor (U.S. patent 5 707 798, 1998; Chem. Abstr. 128;111548 (1998) and references in these) in a study of a subclass of serotonin 5HT2A receptors. R-SAT is a phenotypic testing of receptor function, which comprises heterologous expression of receptors in mammalian fibroblasts. When using this technique, the authors were able to show that native 5HT2A receptors have significant constitutive or agonist-independent Retz is pornoi activity (application for U.S. patent, serial number 60/103 317, which is incorporated into this description by reference). In addition, with the direct testing of a large number of drug compounds Central action with known clinical activity in respect of neuropsychiatric disorders, the authors found that all compounds with antipsychotic efficacy have a common molecular feature. It was shown that nearly all of those connections that psychiatrists used to treat psychosis, are potent inverse agonists 5HT2A. This unique clinico-pharmacological correlation against one subtype of receptors is sufficient proof that the inverse agonism in respect of the 5HT2A receptor is a molecular mechanism of antipsychotic efficacy in humans.

Detailed pharmacological characterization of a large number of antipsychotic compounds revealed that they have broad activity against many relatives of receptor subtypes. A large portion of these compounds exhibits agonistic, competitive, antagonistic or inverse agonistic activity against multiple subtypes of monoaminergic receptors, including serotonergic, dopaminergic, adrenergic, muscarinic and histaminergic the e receptors. Specified broad activity responsible, most likely, sedative, hypotensive and motor side effects of these compounds. In this regard, it would be extremely useful to develop compounds that were selective inverse agonists 5HT2A-receptor, but which would have little or does not possess activity against other subtypes monoamine receptors, in particular dopamine D2 receptors. Such compounds may be useful in the treatment of human diseases (such as antipsychotics) and may avoid adverse effects associated with nonselective interaction with receptors.

A brief description of the invention

The present invention relates to compounds of General formula (I), which affect monoamine receptors, in particular the serotonin receptors, and have the common property to be inverse agonistic activity towards the 5-HT2A subtype of serotonin receptors person:

where Z denotes a group selected from

R means hydrogen, a cyclic or linear-chained or branched acyclic organising group, a lower hydroxyalkyl group, a lower aminoalkyl group or aracelio or g is cerealkiller group;

n means 0, 1 or 2;

X1means methylene, vanilinovoi, NH or N(lower alkyl) group; and

X2means methylene, or in the case when X1means methylene or vinile, X2means methylene or a bond; or in the case when X1means methylene, X2means O, S, NH or N (lower alkyl) or a bond;

Y1means methylene, and Y2means methylene, vinile, ethylene, propylene, or a bond;

or

Y1means communication and Y2means vinile; or

Y1means ethylene and Y2means O, S, NH or N (lower alkyl);

Ar1and Ar2independently denote unsubstituted or substituted aryl or heteroaryl group;

W stands for oxygen or sulfur; or

to their pharmaceutically acceptable salt, ether complex or prodrug.

The present invention also relates to pharmaceutical compositions comprising an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salts, esters or prodrugs.

The present invention also relates to methods of inhibiting the activity of monoamine receptor, including bringing into contact the monoamine receptor or a system containing the monoamine receptor with an effective amount of compounds of formula (I), and also in the kit, designed on the I implement the same function. Preferably the receptor is a serotonin receptor subclass of 5-HT2A. The specified receptor may be located either in the Central or peripheral nervous system, blood cells or platelets, and may be mutated or modified. In a preferred embodiment of the invention, the receptor is constitutively active.

In addition, the present invention relates to a method of inhibiting activation of a monoamine receptor comprising bringing into contact the monoamine receptor or a system containing the monoamine receptor with an effective amount of compounds of formula (I), and also in the kit is intended for realization of the same function. In a preferred embodiment of the invention the compound is selective for 5-HT2A-receptor serotonin. In another preferred embodiment of the invention, the compound has a small activity or, essentially, has no antidopaminergic activity. The receptors may be constitutively active or can be activated endogenous or exogenous agonist.

Another object of the present invention is a method for the treatment of painful conditions associated with monoamine receptor comprising the administration to a mammal, optionally Taco is about treatment, effective amounts of compounds of formula (I), as well as set to implement the same actions. Examples of painful conditions for which will be useful for such treatment using the compounds according to the present invention or pharmaceutical compositions comprising them include, not limited to the above list, neuropsychiatric diseases such as schizophrenia and related idiopathic psychoses, depression, anxiety, sleep disorder, disorder of appetite, affective disorders, such as depression, bipolar disorder and depression with psychotic elements, as well as disease Tourette's. These compounds may also be useful for the treatment of psychosis induced by drugs and psychosis, which is secondary to neurodegenerative diseases such as Alzheimer's or Huntington's. Compounds according to the present invention can be also useful for the treatment of hypertension, migraine, vasospasm, ischemia and during primary treatment and secondary prevention of a variety of thrombotic conditions including myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopenia, and peripheral vascular disease.

The invention also relates to a method and is entifically genetic polymorphism, determining the predisposition of a subject to sensitivity in relation to the compounds of formula (I), which includes an introduction to the subject an effective amount of the compounds, the identification of the sensitivity of the subject, having weakened painful condition associated with monoamine receptor, and the identification of genetic polymorphism in sensitive subject in the case when the genetic polymorphism determines the predisposition of a subject to sensitivity to this compound. The invention also provides kits for performing the same function.

The method of identification of the subject suitable for treatment with the compound of formula (I) and sets to implement the same identification, also suggested in the present invention. In accordance with this method revealed the presence of polymorphism, which determines the susceptibility of a subject to sensitivity to this compound, the presence of this polymorphism indicates that the subject is suitable for treatment.

Brief description of figures

Figure 1 shows a graph with data obtained on the basis of the analysis by type of dose - response for 26HCH17 and ritanserin as inverse agonists for 5-HT2A.

Figure 2 shows a graphical image of the pharmacological results obtained in vivo in mice with and the use of the hydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide. Figure 2 illustrates the effects of this new antipsychotic compounds in the behavioral model on the twitching head; figure 3 shows the results of experiments on the effect on motor function; and figure 4 shows the results of the study of inhibition when exposed to predispose mode.

Detailed description of the present invention

Definition

In the present description for definitions of technical terms will be used the following definitions in their entirety and in their entirety they will be used to determine the scope of the present compositions, which will be sought to protect the stated claims.

The term "constitutive activity" is defined as increased baseline activity of the receptor, which does not depend on the presence of agonist. Constitutive activity of the receptor can be measured using many different methods, including cellular (e.g., membrane) drugs (see, e.g., Barr & Manning, J. Biol. Chem. 272:32979-87 (1997)), peeled and restored receptors associated with G-protein in phospholipid vesicles or without (Cerione et al., Biochemistry 23:4519-25 (1984)), and functional cell tests (application for U.S. patent, serial number 60/103 317).

The term "agonist" is defined as a connection that is in contact with the receptor increases its activity.

The term "antagonist" is defined as a compound that competes with an agonist or inverse agonist for binding to the receptor and thereby blocking the action of an agonist or inverse agonist to the receptor. However, the antagonist, also called the "neutral antagonist", with no effect on the constitutive activity of the receptor.

The term "inverse agonist" is defined as a compound that reduces the basic activity of the receptor (for example, alarm function, mediated by the receptor). Such compounds are also known as negative antagonists. Inverse agonist is a ligand for a receptor, which causes the receptor to go inactive compared to its baseline condition, in the absence of ligand. Thus, while the antagonist can inhibit the activity of the agonist, inverse agonist is a ligand that can change the conformation of the receptor in the absence of agonist. The concept of inverse agonist was studied by bond et al.(Bond et al., in Nature 374:272 (1995)). More specifically, bond et al. suggested that is not associated with ligand β2-adrenergic receptors exist in equilibrium between an inactive conformation and spontaneously active conformation. Agonists proposed to stabilize the receptor in an active conformation. Conversely, education is by agonists, as I believe, will be to stabilize the inactive conformation of the receptor. Thus, while the antagonist exerts its activity by inhibiting the activity of the agonist, inverse agonist can further show their activity in the absence of the agonist by inhibiting spontaneous transition is not associated with the ligand of the receptor in the active conformation.

The term "5-HT2A-receptor" is defined as the receptor with activity, the activity subtype of serotonin receptor of a man who was described during molecular cloning and pharmacological studies and are described by Saltzman et al. and Julius et al. (Saltzman et al., Biochem. Biophys. Res. Comm. 181:1469-78; and Julius et al., Proc. Natl. Acad. Sci. USA 87: 928-932).

The term "subject" refers to an animal, preferably a mammal and most preferably to humans, which is the object of treatment, observation or experiment.

The term "selective" is defined as a property of the connection, whereby the number of connections, which is enough to provide the desired response to a particular type of receptor, subtype, class and subclass, is, essentially, to have a small impact or not will affect the activity of other receptor types. The term "selectivity" or "selective" in PR is the application to the inverse agonist should be understood as a property of the compounds according to the present invention, whereby the amount of compound that is effective as an inverse agonist for the 5-HT2A-receptor, while reducing its activity, shows a small inverse agonistic or antagonistic activity, or does it not show respect to other related or unrelated receptors. In particular, it was found that the compounds according to the present invention do not interact with other serotonin receptor (5HT 1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6 I) at the concentrations at which the alarm function 5-HT2A-receptor substantially or completely suppressed. Preferred compounds according to the present invention are selective against other monoamin-binding receptors, such as dopaminergic, histaminergic, adrenergic and muscarinic receptors. Compounds that have high selectivity for 5-HT2A receptors, can have a beneficial effect in the treatment of psychosis, schizophrenia or close neuropsychiatric disorders, while avoiding adverse effects associated with the use proposed for this purpose medicines.

The value of EC50for agonist means the concentration of compound required to achieve 50% of maximum response obtained in the TEC is e R-SAT. For inverse agonists EC50means the concentration of compound required to achieve 50% inhibition of the response in the test R-SAT relative to the base level, without making the connection.

In the context of the present description, the term "co-administration" pharmacologically active compounds refers to the delivery of two or more separate chemical groups, either in vitro or in vivo. Co-administration refers to the simultaneous, separate delivery means for simultaneous delivery of a mixture of agents; and to the delivery of a single agent with subsequent delivery of the second agent or additional agents. In all cases it is assumed that the agents that are administered together, and work together with each other.

The term "cyclic organelle group" includes aliphatic, alicyclic group in which the carbon atoms form a ring. In preferred embodiments of the invention, the ring containing four, five, six or seven carbon atoms as a substituent, are connected either directly via one of the ring atoms or via one or more of the attached carbon atoms. Specific examples of such groups include cyclopentyl, tsiklogeksilnogo, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl group and others

The term lean is Ino-chain alicyclic organelle group covers the replacement group, consisting of linearly spaced carbons, where each carbon atom binds to a maximum of two other carbon atoms, connected by single, double or triple bond. Linear-chain organelle groups can contain one or more multiple bonds or may not contain, and are, for example, groups, usually called alkyl, alkenylamine or alkenylamine or akadeemiline groups, respectively. Examples of linear-chain organising groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, propenyl, butenyl, pentadienyl, propargyl, butynyl.

The term "branched acyclic organelle group covers replacement group consisting of branched combining carbon atoms, where one or more carbon atoms can bind to more than two other carbon atoms, connected by single, double or triple bond. Extensive organelle groups can contain one or more branched multiple relationships or may not contain. Examples of branched organising groups include isopropyl, isobutyl, tert-butyl, methylbutyl, methylbutanal, methylbutanol.

"The lower alkoxygroup represent1-6cyclic or acyclic organelle group, United as Zam is stitely through an oxygen atom. Examples of lower alkoxy groups include methoxy, ethoxy, isopropoxy, butoxy, tert-butoxy.

"Lower alkyl group" represents a C1-6cyclic, linear-chain or branched aliphatic replacement group connected via a carbon atom. Examples include methyl, ethyl, propyl, butyl, methylbutyl, cyclopropyl, cyclohexyl, isopropyl, tert-butyl.

The term "lower alkylamino group" should be understood as a lower alkyl group, United as Vice through the nitrogen atom, which may carry one or two lower alkyl groups. Specific examples of such groups include methylamino, dimethylamino, isopropylamino. Lower aminoalkyl groups may optionally be composed of 4-6-membered nitrogen-containing rings, such as pyrrolidino.

"Lower aminoalkyl groups are lower alkyl groups bearing as substituent an additional amino group. Examples of such groups include aminomethyl and aminoethyl.

"Lower hydroxyalkyl group" should be understood as the lower alkyl groups bearing as substituent an additional hydroxy-group. Examples of such groups include hydroxymethyl, hydroxyethyl, 2-hydroxy-2-propyl, hydroxyphenyl.

"Acyl group" represent hydrogen or lower ALK the global group, United as Vice through a carbonyl group. Examples of such groups include formyl, acetyl, propanyl.

"Halogen group" should be understood as the fluorine-, chlorine-, bromine - or iodine-deputies, mainly preferred fluorine and chlorine.

"Lower alkylene group" represents a linear-chain related groups, which form of communication to connect fragments of molecules through their terminal carbon atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-) or butylene (-(CH2-)4-) group.

"Winninowie groups are ethen-1,2-dirinya group (-CHCH-), with (E) or (Z) configuration.

"Kalkilya groups are aryl groups United as Vice through the lower alkylenes group. Aryl groups in kalkilya groups can be substituted or unsubstituted. Examples of such groups include benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, nafcillin.

"Heteroalkyl group" should be understood as the heteroaryl group, United as Vice through the lower alkylenes group. Heteroaryl groups in heteroalkyl groups can be substituted or unsubstituted. Examples include 2-t is ylmethyl, 3-thienylmethyl, furylmethyl, titilate, pyrrolidinyl, pyridylethyl, isoxazolyl, imidazolylalkyl and their substituted and fused with a benzene ring analogues.

"Aryl groups are aromatic, preferably benzocaine or naphthene, groups, United through the forming ring carbon atoms and optionally bearing one or more substituents selected from halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl or trifloromethyl. Preferred aryl groups are phenyl and most preferably substituted phenyl group carrying one or two identical or different substituent listed above. The preferred substitution is a pair - and/or meta-substitution. Representative examples of aryl groups include, but are not limited to the above list, phenyl, 3-halogenfrei, 4-halogenfrei, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-AMINOPHENYL, 4-AMINOPHENYL, 3-were, 4-were, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimetilfenil, naphthyl, hydroxynaphthyl, hydroxymethylene, triptoreline.

"Heteroaryl group" should animate as aromatic With 2-6cyclic groups containing one atom of O or S or up to four N atoms, or a combination of one atom of O or S N, up to two atoms, and their substituted and benzo - or pyrido-condensed derivatives, preferably connected via one of the carbon atoms forming the ring. Heteroaryl group may bear one or more substituents selected from halogen, hydroxy, amino, cyano, nitro, alkylamino, acyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower alkylamino, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfamoyl or trifloromethyl. Preferred heteroaryl groups are 5 - and 6-membered aromatic heterocyclic systems bearing 0, 1 or 2 substituent which may be the same or different from each other and are selected from the above list. Representative examples of heteroaryl groups include, but are not limited to the above list, unsubstituted and one - or disubstituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, indole, oxazole, benzoxazole, isoxazol, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole and tetrazole, all of which are preferred, as well as furazan, 1,2,3-oxadiazole, 1,2,3-TIA is eazol, 1,2,4-thiadiazole, triazole, benzotriazole, pyridine, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazin, pteridine and triazine. The most preferred substituents are halogen, hydroxy, cyano, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower alkylamino and lower aminoalkyl.

The present invention relates to compounds, preferably demonstrate a relatively high selectivity for serotonin receptors, in particular 5-HT2A receptors, which can have a beneficial effect in the treatment of neuropsychiatric disorders.

In accordance with one of the options for implementing the present invention relates to compounds of General formula (I)

where Z means

in which R denotes hydrogen, a cyclic or linear-chain or branched acyclicity organising group, a lower hydroxyalkyl group, a lower aminoalkyl group or aracelio or heteroalkyl group;

n means 0, 1 or 2;

X1means methylene, vanilinovoi, NH or N(lower alkyl) group; and

X2means methylene, or in the case when X1means methylene or vinile, X2means methylene or a bond; or in the case when X1means methylene, X2means O, S, NH or N(lower alkyl) or a bond;

Y1means methylene, and Y2means methylene, vinile, ethylene, propylene, or a bond;

or Y1means communication and Y2means vinile; or

Y1means ethylene and Y2means O, S, NH or N(lower alkyl);

Ar1and Ar2independently denote unsubstituted or substituted aryl or heteroaryl group; and

W stands for oxygen or sulfur;

or their pharmacologically acceptable salts, ether complex or prodrug.

Basically, the compounds of formula (I) are active against monoamine receptors and specific serotonin receptors. Preferred compounds have the General ability to function as inverse agonists for the 5-HT2A receptor. Thus, in experiments on cells, temporarily expressing the human phenotype of the specified receptor, it was shown that the compounds of General formula (I) by the action of the receptor weaken the signaling ability of these receptors in the absence of additional ligands. Thus, it was shown that these compounds possess inherent activity against a specified receptor and is able to weaken the base, not stimulated by agonist constitutive signalling pathways, which demonstrates the receptor 5-HT2A. Evidence that compounds of General formula (I) are the reverse of the ago is Itami, also indicate that these compounds possess the ability to act as antagonists activation of 5-HT2A receptors that mediated by endogenous or exogenous agonists synthetic ligands agonists.

In a preferred embodiment, the present invention relates to compounds, which preferably are relatively high selectivity in regard to the 5-HT2A subtype of serotonin receptors in comparison with other subtypes of the family of serotonin (5-HT) receptors, and other receptors, and particularly in relation to aminergic G protein-coupled receptors such as dopamine receptors. In another preferred embodiment, compounds according to the present invention act as inverse agonists at 5-HT2A subtype of serotonin receptors.

In this regard, the compounds of General formula (I) can be useful to treat or ameliorate the symptoms of painful conditions associated with dysfunction of, in particular, with the increased level of activity, particularly 5-HT2A receptors, regardless of whether the breach of the function with a different level of stimulation of the receptor or phenotypic aberrations.

Previously, some researchers it has been hypothesized that some neuropsychological Soboleva what I can to be caused by altered level of constitutive activity monoamine receptors. This constitutive activity can be modified through contact relevant with synthetic receptor inverse agonist. With the direct testing of a large number of clinically active in neuropsychiatric diseases drug compounds, the authors found that all compounds effective as with antipsychotic drugs, characterized by a General molecular property. Almost all of these connections from the number used by psychiatrists to treat psychosis, as shown, are potent inverse agonist at 5-HT2A. This correlation is undeniable proof that the inverse agonism 5-HT2A receptor is the molecular mechanism of antipsychotic efficacy in humans.

Conducted by the inventors in their lab, detailed pharmacological characterization of a large number of antipsychotic compounds showed that they all have broad activity against many related receptor subtypes. A large portion of these compounds shows either agonistic or competitive antagonistic or inverse agonistic activity against multiple subtypes of monoaminergic receptors, including serotonergic, dopaminergic, adrenergic, muscarinic and histaminergic prescriptions is ora. This broad activity is likely responsible for sedative, hypotensive and locomotor side effects of these compounds. It follows from the above that disclosed in the present application connection will have activity as, for example, new antipsychotic drugs, but they will cause less weak or less severe side effects than the currently available connection.

The present invention also relates to pharmaceutical compositions comprising an effective amount of the compounds of General formula (I).

In a preferred embodiment of the invention in the compounds of formula (I), Y1means methylene, and Y2means a bond, methylene, ethylene or vinile, or Y1means ethylene and Y2means O or S, and X1means methylene, and X2means a bond, methylene, O, or S, or X1mean NH or N(lower alkyl).

In yet another preferred embodiment of the invention in the compounds of General formula (I) Z means

and W stands for oxygen.

In a more preferred embodiment of the invention in the compounds of formula (I) n is 1, Y1means methylene, Y2means a bond, methylene, ethylene or vinile, X1means methylene, and X2means a bond, or X1OZNA the AET NH or N(lower alkyl) and X 2means methylene. In yet another preferred embodiment of the invention in the compounds of formula (I), W stands for oxygen, and Ar1and Ar2do the different aryl or heteroaryl groups, especially preferred are various one-deputizing phenyl group. Preferably Ar1and Ar2don't mean simultaneously phenyl.

Also preferred compounds of formula (I) are those compounds in which Z is 1-(organic or aralkyl)-4-piperidinyl.

In another embodiment, the present invention relates to preferred compounds of the formula (II):

in which RNmeans hydrogen, lower alkyl, aralkyl or heteroalkyl;

ArLselected from lower alkyl, lower alkoxy and halogen-free

ArRselected from lower alkyl, lower alkoxy and halogen;

k is 1 or 2;

and-means acceptable anion.

In accordance with the present invention acceptable anion can represent any anion capable of forming pharmaceutically acceptable salts of the compounds, which will be described below in more detail.

The present invention also relates to a method for inhibiting the activity of monoamine receptor. This method involves bringing into contact monoamine receptorii system, containing the monoamine receptor with an effective amount of the compounds of formula (I). In accordance with one embodiment of the invention monoamine receptor is a serotonin receptor. In a preferred embodiment of the invention the compound is selective for the 5-HT2A subclass of receptors. In another preferred embodiment, the invention has a small activity or, in essence, it does not possess in relation to other types of receptors, including other serotonergic receptors, and most preferably aminergic G protein-coupled receptors, such as dopaminergic receptors.

The system containing the monoamine receptor can, for example, be a subject such as a mammal, a Primate, non-human, or human. The receptor may be located in the Central or peripheral nervous system, blood cells or platelets.

The system can be in vivo or to represent an experimental model in vitro, such as a model system for cell culture that expresses monoamine receptor, its cell-free extract, which contains the monoamine receptor or purified receptor. Non-limiting examples of such systems include cell culture, tissue, expresser the participating receptor, or their extracts or lysates. Cells that can be used in the procedure of the present method include any cells that can mediate signal transduction via monoamine receptors, particularly 5-HT2A-receptor, either via endogenous expression of the indicated receptor (in particular, certain types of neuronal cell lines, for example, expressing native 5-HT2A-receptor)or during expression after transfection of cells with plasmids containing the gene of the receptor. In a typical case, these cells are mammalian cells or other eukaryotic cells such as insect cells or Xenopus oocytes), because the cells of lower organisms mostly do not contain signal transduction pathways that are suitable for the purposes of this study. Examples of acceptable cells include cell lines of mice fibroblasts NIH 3T3 (ATCC CRL 1658), which are responsible for the transfection of 5-HT2A receptor stimulation of growth; RAT 1 cells (Pace et al., Proc. Natl. Acad. Sci. USA 88:7031-35 (1991)); and cells of the pituitary gland (Vallar et al., Nature 330:556-58 (1987)). Other useful for application in the framework of the present method for mammalian cells include HEK 293 cells, CHO cells and COS cells.

The present invention relates particularly to a method of inhibiting the activity of native, mutated or modified monoamine is eceptor. The present invention also relates to kits for performing the same function. In a preferred embodiment of the invention, the activity of the receptor is a signaling activity. In another preferred embodiment of the invention, the activity of the receptor is a basic constitutive activity of the receptor. The preferred compound is an inverse agonist selective for 5-HT2A-receptor. Most preferably the compound has a small activity or essentially does not have activity against other serotonergic or other monoaminergic receptors, such as dopaminergic receptors.

In one embodiment of the invention, the activity of the receptor is a reaction, such as signal response to endogenous agonist, such as 5-HT, or exogenous agonist, such as a drug or other synthetic ligand. The compounds of formula (I) preferably acts as an inverse agonist or antagonist of the receptor.

In addition, the present invention relates to a method of inhibiting activation of a monoamine receptor comprising bringing into contact the monoamine receptor or a system containing the monoamine receptor with one or more compounds according to the present and the attainment. Activation of the receptor may be related to exogenous or endogenous agent-agonist, or may be a constitutive activation associated with native, mutated or modified receptor. The receptor may be purified or may be in vitro or in vivo. The receptor may also be present in the Central or peripheral nervous system, blood cells or platelets, or in the body of the subject is non-human, or humans. The invention also offers kits for performing the same function.

In a preferred embodiment of the invention the compound is selective for 5-HT class of serotonin receptors, more preferably for 5-HT2A-subclass of serotonin receptors. In another preferred embodiment, the compound has a small activity or, essentially, has no antidopaminergic activity.

The present invention relates to methods for treating painful conditions associated with monoamine receptor comprising the administration to a mammal, in need of such treatment, an effective amount of the compounds of formula (I). The invention specifically relates to methods of treating or alleviating painful conditions associated with improper function or stimulation native, and m is adapted or otherwise modified forms of Central serotonin receptors, in particular, 5-HT class of such receptors, including the introduction if necessary of such treatment, an effective amount of a selective inverse agonist of General formula (I) in the host organism. The invention also provides kits for performing the same function.

In a preferred embodiment of the invention, the receptor belongs to the 5-HT2A-division. In one embodiment, the invention is a painful condition associated with a dysfunction of the serotonin receptor. In another embodiment, the invention is a painful condition associated with activation of serotonin receptor, preferably with unacceptably high or constitutive activation, increased serotonergic tone, and also includes painful conditions that are associated with secondary cellular functions, disturbances such disorders.

Examples of diseases for which can be useful for such treatment using the compounds according to the present invention or pharmaceutical compositions comprising such compounds, include, but are not limited to the above list, neuropsychiatric diseases such as schizophrenia and relatives idiopathic psychoses, anxiety, sleep disorders and appetite disorders, affective disorders, such as true what I depression, bipolar disorder and depression with psychotic component, as well as disease Tourette's, psychosis, induced by drugs, as well as psychosis, secondary to neurodegenerative diseases such as Alzheimer's or Huntington's. It is expected that the compounds according to the present invention, particularly a selective inverse agonist for the 5-HT2A, which show a slight activity or does not demonstrate activity against dopaminergic receptors, can be particularly useful for the treatment of schizophrenia. Treatment with compounds according to the present invention may also be useful in the case of migraine, angiospasm, hypertension, a variety of thrombotic conditions including myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopenia, and peripheral vascular disease.

In yet another embodiment, the invention provides methods of treating or alleviating the disease condition associated with inappropriate function, dysfunction, or stimulation of native and mutated or otherwise modified forms of the Central or peripheral serotonin receptors, and such methods include the introduction of an effective amount of compounds of General fo the formula (I) in the host organism in need of such treatment. Preferably monoamine receptor is a serotonin receptor in the peripheral nervous system, blood or platelets, and more preferably represents a 5-HT2A is a subclass of receptors. In additional embodiments of the invention painful condition associated with increased activity or activation of the serotonin receptor. The invention also provides kits for performing the same function.

The present invention also relates to the field of preventive medicine, providing for the use of pharmacogenomic methods for prognostic (predictive) purposes. Pharmacogenomic direction considers clinically significant hereditary variations that occur in response to drugs due to altered distribution of drugs in the body and abnormal exposure to sick people (see, for example, Eichelbaum, Clin Exp Pharmacol. Physiol., 23:983-985 (1996) and Linder, Clin Chem. 43:254-66 (1997)). In General, we can distinguish two types of pharmaco-genetic: genetic conditions transmitted as a single factor altering the way the impact of drugs on the body (altered drug action), and a genetic condition passed as single factors altering the way the impact of the body on the drug is the means (altered drug metabolism). These pharmacogenetic conditions can exist in the form of natural polymorphism.

One pharmacogenetic approach to identify genes that can predict response to the drug, known as "genome wide Association", is mainly based on the map of the human genome high-resolution, consisting of already known associated with the gene markers (e.g., "biallelic marker gene map, which consists of 60000-100000 polymorphic or variable sites on the human genome, each of which has two variants). Such a genetic map high resolution can be compared with the map of the genome of each of a statistically significant number of patients participating in the phase II/III trials of medicinal products for the identification of markers associated with a particular observed response to the drug or with the occurrence of side effect. An alternative, and this map is a high resolution can be obtained by combining several tens of millions of known single nucleotide polymorphisms (SNP) in the human genome. In the context of the present description, the term "SNP" refers to the normal changes that occur in a single nucleotide base in the DNA chain. For example, a SNP may occur every time for every thousand bases of the deposits of the DNA. SNP can participate in the development of the disease, but most of them may not be associated with the disease. In the presence of a genetic map, based on the occurrence of such SNP, individuals can be grouped according to genetic categories, dependent on the specific picture of the location of the SNP in their individual genome. In this approach, the treatment can be linked to groups of genetically similar individuals, it is considered that among these genetically similar individuals therapeutic approach may also have common features.

An alternative method, called the "approach based on gene-candidate"can be used to identify genes with which it is possible to predict the reaction of the organism to the drug. In accordance with its methodology, if you know the gene that encodes the target drug (e.g., protein or receptor according to the present invention), all common variants of this gene can be easily identified in the population and it can be determined if there is one version of the gene versus another version, which is associated with a specific reaction to a drug.

An alternative method, called "gene expression profile", can be used to identify genes, knowing which you shall be predskazati reaction to medicines. For example, the gene expression of the animal, which introduced the dose of the drug (e.g., molecule or modulator according to the present invention), can be considered as an indicator of whether included gene pathways related to toxicity.

Information obtained from more than one of the above pharmacogenetic approaches can be used to determine appropriate dosage and treatment regimens for the prevention or therapeutic treatment of an individual. These knowledge when used for dose selection or choice of medications to avoid adverse reactions or failure in treatment and thus increase therapeutic and prophylactic activity in the case of treatment of a subject with the use of a molecule or modulator according to the present invention, such as a modulator identified by one of the following as an example in screening tests in the present description. As mentioned previously, this approach can also be used to identify the new receptor candidate or other genes that are suitable for further pharmacological characterization in vitro and in vivo.

In accordance with the foregoing, the present invention also relates to methods and kits for identifying genetic is olymorphism, predisposing the subject to react to the described connection. This method includes the introduction to the subject an effective amount of the compounds, the identification of sensitive subject that has weakened a painful condition associated with monoamine receptor, and the identification of genetic polymorphism such a sensitive subject, in the case when the genetic polymorphism determines the sensitivity of the subject to connection. It is expected that this method will be useful for predicting whether certain individuals are sensitive to therapeutic effect of the compounds, and to identify or otherwise, which is likely the occurrence of adverse reactions. This approach may be useful for identification, for example, polymorphisms in the serotonin receptor, which leads to constitutive activation and thus subject to therapy inverse agonist. In addition, this method can be used to identify polymorphisms that lead to changes in the metabolism of drugs, resulting in the body produces toxic by-products. This mechanism works is rare but can lead to potentially life-threatening side effects, as in the case of atypical antipsychotics clause is Pina.

In a related embodiment, the invention features a method of identifying a subject suitable for treatment with the compound according to the present invention. In accordance with this method reveals the presence of polymorphism, which provides the predisposition of a subject to sensitivity to the compound, and the presence of such a polymorphism indicates that the subject is suitable for treatment. The invention also provides kits for performing the same function.

Compounds according to the present invention preferably exhibit selective activity as inverse agonists at 5-HT2A-receptor. This activity is determined by the ability of the ligand to weaken or eliminate the constitutive signaling activity of a specified receptor. Selectivity in this context should be understood as the ability of the compounds according to the present invention, whereby the number of connections, which effectively acts as an inverse agonist at 5-HT2A-receptor, while reducing its activity, shows a small activity or completely inactive as an inverse agonist or antagonist on other, related or unrelated to the receptors. In particular, it was found that the compounds according to the present invention does not take the strong interaction with other serotonin receptors (5-HT 1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6 and 7) at the concentrations at which the alarm function 5HT2A-receptor strongly or completely inhibited. Preferred compounds according to the present invention are selective for other monoaminoksidazoy receptors, such as dopaminergic, histaminergic, adrenergic and muscarinic receptors.

Particularly preferred implementation of the present invention includes

N-(1-(methylethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-(2,2-(dimethylethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-pentylpyridine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-hexylpyridine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-cyclohexylpiperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-cyclopentenopyridine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-cyclobutylmethyl-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-cyclopropylidene-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclopentylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclobutylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-IU is oxygenated;

N-(1-(2-hydroxyethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-(3-hydroxypropyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-((4-(were)methyl)-N-(piperidine-4-yl)-N'-phenylmethylene;

N-((4-(were)methyl)-N-(1-(2-methylpropyl " piperidine-4-yl)-N'-phenylmethylene;

N-(1-((2-bromophenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;

N-(1-((4-hydroxy-3-methoxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;

N-(1-((5-utilties-2-yl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;

N-(1-(imidazol-2-ylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;

N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;

N-(1-((4-forfinal)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;

N-((4-(were)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-ethylpiperazin-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-((4-(were)methyl)-N-(1-propylpiperidine-4-yl)-4-methoxyphenylacetamide;

N-(1-butylpiperazine-4-yl)-N-((4-were)-4-methoxyphenylacetamide;

N-(1-(3,3-dimethylbutyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-((methylphenyl)methyl)-4-methoxyphenylacetamide;

N-((4-(were)methyl)-N-(1-(2-methylpropyl " piperidine-4-yl)-4-methoxyphenylacetamide;

N-((4-(were)methyl)-N-(1-((4-(were)methyl)piperidine-4-yl)-4-methoxyphenylacetamide;

N-(1-((4-hydroxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(1-((2-hydroxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;

N-(3-phenylpropyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-(2-phenylethyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((2-methoxyphenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((2-chlorophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((3,4-acid)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((4-forfinal)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((2,4-dichlorophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((3-were)methyl-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-((3-bromophenyl)methyl-N-(piperidine-4-yl)-4-methoxyphenylacetamide;

N-(1-(phenylmethyl)piperidine-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphenylacetamide;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)phenylacetamide;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)-3-phenylpropionamide;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)-(phenylthio)ndimethylacetamide;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)phenoxyacetamide;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)-(4-horfe is hydroxy)ndimethylacetamide;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)-3-methoxyphenylacetamide;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)-4-perforated;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)-2,5-dimethoxyphenylacetone;

N-((4-(were)methyl)-N-(1-piperidine-4-yl)-4-chlorophenylacetic;

N-((4-(were)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N'-phenylmethylene;

N-((4-(were)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidine-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperazin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(piperidine-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide;

2-(phenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-forfinal)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-triptoreline)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl) ndimethylacetamide;

2-(4-forfinal)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-terbisil)-N(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(phenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-triptoreline)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-triptoreline)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-triptoreline)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(4-chloromethyl-2-triazolylmethyl)piperidine-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,3-dihydro-2H-benzimidazole-2-on-1-yl)propyl]piperidine-4-yl}ndimethylacetamide;

2-(4-methoxyphenyl)-N-(2-4-(forfinal)ethyl)-N-(1-methylpiperidin-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-[2-(2,5-acid)ethyl]-N-(1-methylpiperidin-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl is)ethyl]-N-(1-methylpiperidin-4-yl] ndimethylacetamide;

2-(4-methoxyphenyl)-N-[2-(3-forfinal)ethyl]-N-(1-methylpiperidin-4-yl]ndimethylacetamide;

2-(4-ethoxyphenyl)-N-[2-(4-florfenicol]-N-(1-methylpiperidin-4-yl]ndimethylacetamide;

2-(4-ethoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-hydroxyethoxy)ethyl]-piperidine-4-yl}ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-((2-chloro-5-thienyl)-methyl)piperidine-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-(imidazolidine-1-yl)ethyl)piperidine-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2,4-(1H,3H)hintlinin-3-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(1,3-dioxolane-2-yl)ethyl]piperidine-4-yl}ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(3-indolyl)ethyl]piperidine-4-yl}ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,2,4-triazole-1-yl)propyl]piperidine-4-yl}ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-benzofurazanyl)piperidine-4-yl}ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-chlorobenzo[b]Tien-3-ylmethyl)piperidine-4-yl]ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-phenyl-1,2,4-oxadiazol-3-ylmethyl)piperidine-4-yl]ndimethylacetamide;

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide;

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperazin-4-yl}ndimethylacetamide;

2-phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-harfe who yl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl}ndimethylacetamide;

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide;

2-(4-forfinal)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)piperidine-4-yl)ndimethylacetamide;

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylmethyl-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylmethyl-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(according to-4-yl)ndimethylacetamide;

N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-benzylcarbamoyl;

N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-phenylcarbamoyl;

N-phenethyl-N-(1-methylpiperidin-4-yl)-N'-benzylcarbamoyl;

2-phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-triptoreline)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-forfinal)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-were)-N-(4-chlorbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-hydroxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

N-phenethyl-N-(1-methylpiperidin-4-yl)-N'-phenylcarbamoyl;

N-(3-phenylpropyl)-N-(1-methylpiperidin-4-yl)-N'-benzylcarbamoyl;

N-(3-phenylpropyl)-N-(1-methylpiperidin-4-yl)-N'-phenylcarbamoyl;

2-(4-methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-alpha-methylbenzyl-N-(1-m is typoberlin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(3-Tropin-4-yl)ndimethylacetamide;

2-phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

N-phenethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)amine;

2-(4-methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-methoxybenzyl)urea;

2-(3,4-acid)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(3,4-methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-tert-butylpiperazine-4-yl)ndimethylacetamide;

N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-fenetylline;

N-phenethyl-N-(1-methylpiperidin-4-yl)-N'-fenetylline;

N-(4-methylbenzyl)-N-(1-tert-butylpiperazine-4-yl)-N'-(4-methoxybenzyl)urea;

2-(4-ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-isopropoxyphenyl)-N-(4-metranil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-tert-butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-butoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-propoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;

2-(4-isopropoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide and

2-(4-tert-butoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide.

Suitable pharmaceutically acceptable salts of the compounds according to the present invention include additive salt of the acid, which can be, for example, formed by mixing of a solution of the compounds according to the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds according to the present invention are acidic group, suitable pharmaceutically acceptable salts may include salts of alkaline metal such as sodium or potassium, salts of alkaline earth metal such as calcium salts or magnesium, and salts formed with suitable organic ligands, e.g. Quaternary ammonium salt. Examples of pharmaceutically acceptable salts include the acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, carbonate, chloride, clavulanate, citrate, dihydrochloride, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, nitrate, N-methylglucamine salt, oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tannat, tartrate, tosylate,triethiodide and salt valerianic acid.

The present invention includes prodrugs of the compounds according to the present invention. In General, such prodrugs are inactive derivatives of the compounds according to the present invention, which are easily converted in vivo into the required compound. Traditional selection procedures and obtaining the appropriate derivative prodrugs described, for example, guide the development of prodrugs (Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985). Metabolites of these compounds include active species, which is obtained by the introduction of the compounds according to the present invention in a biological environment.

In the case where the compounds according to the present invention contain at least one chiral center, they may exist in the form of a racemate or in the form of enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope covered by the present invention. In addition, some of the crystalline forms of the compounds according to the present invention may exist as polymorphs and as such they are also included in the scope of the present invention. In addition some compounds according to the present invention may form a solvate with water (i.e. hydrates) or common organic solvents. Such a solvate is also included in the scope of the present image is the shadow.

In that case, when obtaining the compounds according to the present invention can be formed of a mixture of stereoisomers, these isomers may be separated by conventional methods such as preparative chiral chromatography. The compound can be obtained in racemic form or in the form of individual enantiomers by stereoselective synthesis or by resolution. The compounds may be resolved on its enantiomeric components using standard techniques, such as the formation of diastereomeric pairs in salt formation with an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, subsequently, crystallization and regeneration of the free base. The connection can also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral additive.

Compounds according to the present invention can be introduced into the composition of any of the above compositions in accordance with the measuring mode, known in the art in the event of the need for specific pharmacological modification activity monoamine receptors.

The present invention also relates to pharmaceutical compositions comprising the one or more compounds according to the present invention together with a pharmaceutically acceptable diluent or excipient. Preferably such compositions are in the form of a standard dosage forms, such as tablets, pills, capsules (including songs prolonged or delayed release), powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral (e.g. intravenous, intramuscular or subcutaneous), intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation, and can be prepared in the form of a composition in an appropriate way and in accordance with the methods adopted in practice, such as disclosed in the management of Remington (Remington''s Pharmaceutical Sciences (Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, is incorporated into this description by reference)). Alternative compositions can be in the form prolonged release suitable for administration once a week or once a month, for example, in the form of insoluble salts of active compounds, such as decanoate salt, and can be adapted to obtain a depot preparation for intramuscular injection. The present invention also considers relevant local composition for administration, e.g., eyes, or skin, or mucous membranes.

the AK, for example, for oral administration in the form of tablets or capsules, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. in Addition, if desirable or necessary, suitable binders, sizing, tools, promotes the decomposition, flavorings and colorants can also be added to the mixture. Suitable binders include, but are not limited to the above list, starch, gelatin, natural sugars such as glucose or beta-lactose, natural and synthetic gums, such as Arabian gum, tragakant or sodium alginate, carboxymethylcellulose, polyethylene glycol, wax and other Oil used in these dosage forms include, but are not limited to the above list, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and other Means of promoting the decomposition, include, but are not limited to the above list, starch, methylcellulose, agar, bentonite, xanthan gum and other

For solid compositions such as tablets, the active ingredient is mixed with a suitable pharmaceutical excipient, such as described above, and other pharmaceutical diluent and, for example, with water, with formation of a solid pre-composition containing a homogeneous mixture of compounds according to the present invention or its pharmaceutically acceptable salt. The term "homogeneous" in the context of the present description means that the active ingredient is uniformly distributed in the composition so that the composition can be easily divided into equally effective standard dosage forms, such as tablets, pills and capsules. Solid pre-composition can then be divided into standard dosage forms of the type specified above, which contain from 0.1 to about 50 mg of the active ingredient compounds according to the present invention. Tablets or pills with this composition can be coated or otherwise to have a dosage form having the advantage of prolonged action. For example, the tablet or pill can comprise an inner core containing the active compound, and the outer layer as a covering sheath that surrounds the core. External covering shell can be intersolubility layer which serves to resist disintegration in the stomach and allows the inner core to pass in an intact form in the duodenum or allows you to keep it high is obozrenie. To obtain such intersolubility layers or covering membranes can be used a variety of materials, which include a variety of polymeric acids and mixtures of polymeric acids with traditional materials, such as shellac, cetyl alcohol and cellulose acetate.

Liquid form, which may have compositions according to the present invention for the introduction of the oral method or by injection include aqueous solutions, syrups with the addition of the respective flavoring substances, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable for aqueous suspensions contribute to a dispersion or suspendirovanie include synthetic and natural gums, such as tragakant, Arabian gum, alginate, dextran, sodium carboxymethyl cellulose, gelatin, methylcellulose or polyvinylpyrrolidone. Other means of facilitating dispersion, which can be used include glycerol, etc. For parenteral administration is desirable sterile suspensions and solutions. In the case where it is desirable intravenous use of isotonic drugs, which is s mainly contain suitable preservatives. The composition can also be prepared in the form of an ophthalmic solution or suspension of education, for example in the form of eye drops, intraocular injection.

In light of the above, the present invention also relates to a method of alleviating or treating a painful condition in which the modification of the activity of a monoamine receptor, in particular the activity of serotonergic 5-HT2A-receptor has a beneficial effect with the introduction of therapeutically effective amounts of compounds according to the present invention to a subject in need of such treatment. Such diseases or conditions may, for example, occur as a result of inadequate stimulation or activation of serotonergic receptors. It is expected that the use of compounds that are selective for a particular subtype of serotonin receptors, in particular 5-HT2A, you can largely avoid the problems associated with adverse side effects observed with the known antipsychotic means, such as extrapyramidal effects.

The term "therapeutically effective amount" in the context of the present description means the amount of active compound or pharmaceutical agent that causes a biological or medical response in a tissue is, system, animal or human body and which is the subject of the search researchers, veterinarians, physicians or other clinical specialists, and which involves the relief of symptoms of the disease to be treated.

Compounds according to the present invention can successfully be administered in single daily dose, or split the total daily dose on a separate dosage and implemented, for example, two, three or four times a day. In addition, the compounds according to the present invention can be administered in intranasal form via topical application of suitable intranasal carriers, through percutaneous techniques using those forms of transdermal patches, which are known to experts in this field, for example by means of an implantable pump or by other suitable techniques. In case of introduction through a percutaneous delivery system, for example, the dosage will constitute, of course, continuous, and not interspersed dosing regime.

The dosage used in the introduction of the compounds according to the present invention, are selected in accordance with many factors including type, species, age, weight, sex and medical condition of the patient, the severity of the condition, which prestitial, the method of administration, the status of renal and hepatic function of the patient and the nature of the specific connection. The physician or veterinarian with a medium level of skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or to stop the disease or disorder to be treated.

Daily dose products concerned can vary in a wide range from about 0.01 mg to 100 mg per adult human per day. For oral administration the compositions preferably are offered in the form of tablets containing 0,01, 0,05, 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0 or 50.0 mg of active ingredient with the aim of symptomatic dose selection for the patient to be treated. Standard dose contains typically from about 0.001 to 50 mg of active ingredient, preferably from about 1 mg to 10 mg of the active ingredient. An effective quantity of a drug usually comes in the form of a standard dose of approximately from 0.0001 mg/kg to 25 mg/kg of body weight per day. Preferably, the range of dosage is about 0.001 to 10 mg/kg of body weight per day and in particular from about 0.001 mg/kg to 1 mg/kg of body weight per day.

Compounds according to the present invention can be used separately in accordance with the adequate dosage, defined routine way to achieve optimal pharmacological effects on monoaminergic receptors, in particular 5-HT2A-the subtype of the serotonin receptor with concomitant minimization of any possible toxic or other undesirable effect. In addition, in some cases it may be desirable co-administration or sequential introduction of other tools that enhance the effect of this connection.

Pharmacological properties and selectivity of the compounds according to the present invention with respect to specific subtypes of serotonergic receptors can be demonstrated in various test methods using recombinant subtypes of receptors, preferably human receptors if they are available, for example, using conventional second messenger or tests on the binding. Especially convenient system for functional testing is the test selection and receptor amplification, as described in U.S. patent No. 5 707 798, which describes a method of screening biologically active compounds when using the ability of cells transfected with DNA encoding the receptor, for example, DNA that encodes a different subtypes of serotonergic, amplificates in the presence of ligand receptor. Cell am the qualification is identified to increase the level of the marker which is also expressed by the cells.

Getter

Compounds according to the present invention can be synthesized using the methods described below, or by modifications of these methods. Methods of modification techniques include among others the variation of temperature, solvents, reagents, etc. that is obvious to the experts in this field.

So, for example, the compounds of formula can be synthesized from the corresponding ketone And through reductive amination using any primary amine. The reaction is carried out usually by stirring the reactants in an inert solvent, such as methanol or ethanol containing acetic acid. As a reducing agent can be used NaBH4, NaCNBH3, BH3-pyridine or any similar reagents, including reagents on a solid substrate. The reaction is typically performed at room temperature. Ketone And, an example of which is piperidone may be selected from the above formula (I) list of compounds corresponding to the Z-group. Ketones can be either obtained commercially or synthesized according to methods described in the literature (Lowe et al., J. Med. Chem. 37:2831-40 (1994); Carroll et al., J. Med. Chem. 35:2184-91 (1992); or Rubiralta et al., Piperidine-Structure, Prparation, Reactivity and Synthetic Applications of Piperidine and its Derivatives. (Studies in Organic Chemistry 43, Elsevie, Amsterdam, 1991)). The protective group P includes such groups are described in Greene and Wuts (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, 3.Ed. John Wiley & Sons, 1999), which can be chosen in such a way that they are stable in the reaction conditions and is easily removed at a convenient stage, using known in the art techniques. Typical protective groups include N-Boc, N-Cbz, N-Bn.

Alternative amine can be synthesized from primary amine B through reductive amination using any of the aldehyde. The reaction is performed by stirring the reactants in an inert solvent, such as methanol or ethanol containing acetic acid. As a reducing agent can be used NaBH4, NaCNBH3, BH3-pyridine or any related reagents, including reagents on a solid substrate. The reaction is typically performed at room temperature. Primary amine B, an example of which can be 4-aminopiperidin may be selected from the above formula (I) list of compounds corresponding to the Z-groups. Amines can be either obtained commercially or synthesized from the corresponding ketones. The protective group P may be selected as described above.

Alternative amine can be synthesized from primary amine B by alkylation with lubog the alkylating agent (R-L 1). Delete group L1in the acceptable variant represents a halogen atom such as bromine atom or iodine, or a sulfonate, such as toilet or mesilate, or other removable group that is appropriate for this reaction. The reaction is usually carried out by stirring the reactants under alkaline conditions in an inert solvent, for example in diisopropylethylamine in acetonitrile or in K2CO3in N,N-dimethylformamide. The reaction is typically carried out at temperatures from room temperature to 80°C. Primary amine B, an example of which is 4-aminopiperidin may be selected from the above formula (I) list of compounds corresponding to the Z-groups. Amines can be either obtained commercially or synthesized from the corresponding ketones. The protective group P may be selected as described above.

In the above scheme R and R* have been defined for formula (I), P is a suitable protective group, and L1means suitable a group to delete.

Secondary amine C can be allerban using any isocyanate or isothiocyanate (Q1-N=C=W) with formation of the corresponding ureas or thioureas D. the Reaction is carried out in the typical case when mixing reagents using an excess of isocyanate or isothiocyanate in inert the m solvent, for example in dichloromethane, at a temperature of from 0°C. to room temperature and drying conditions. The amine can also be allerban using any halide of carboxylic acid (Q2COX, for example the acid chloride or carboxylic anhydride ((Q2C=O)2O) with the formation of amides of the General structure E. the Reaction is carried out in a typical case using Alliluyeva agent and a suitable base, such as triethylamine or diisopropylethylamine in an inert solvent, such as dichloromethane, at a temperature of from 0°C. to room temperature and drying conditions. Alternatively, the halides of carboxylic acids and anhydrides of carboxylic acids for acylation of amine can be used With carboxylic acid (Q2COOH) and the corresponding binding reagent, for example DCC or EDCI. The reaction is carried out in a typical case using excess Alliluyeva agent and a binding reagent, in an inert solvent, such as dichloromethane, at a temperature of from 0°C. to room temperature and drying conditions. Compounds of General structure (E) can be transformed into the corresponding thioamides using methods disclosed Varma et al. (Varma et al., Org. Lett. 1:697-700 (1999); Cherkasov et. al., Tetrahedron 41:2567 (1985); or Scheibye et. al., Bull.Soc. Chim. Belg. 87:229 (1978)).

In the above scheme R, Q1, Q2 and W were defined for formula (I), P is the corresponding protective group, and X represents a halide.

Deputy G on the nitrogen atom in the ring may be introduced during the two-stage procedure. First remove the protective group on the urea D or amide E using known techniques. So, for example, N-Boc-group is removed by treatment of the protected grounds 4M HCl in dioxane or triperoxonane acid in dichloromethane. In the second stage of secondary amines derived from D and E, can be alkylated by reductive amination using any of the aldehyde (T-CHO). The reaction is usually carried out when mixing the reagents in an inert solvent, such as methanol or ethanol. As a reducing agent can be used borohydride on a solid substrate, NaBH4, NaCNBH3, BH3-pyridine or any related reagents, including reagents on a solid substrate. The reaction is typically performed at room temperature.

Alternative connections F and G can be synthesized from secondary amine, obtained from D or E, as described above, by alkylation with any alkylating agent (T-L1). Delete group L1in the acceptable variant represents a halogen atom such as bromine atom or iodine, or a sulfonate, such as toilet or mesilate, or other discardable g is the SCP, suitable for this reaction. The reaction is performed by stirring the reactants under alkaline conditions in an inert solvent, for example in diisopropylethylamine in acetonitrile or in K2CO3in N,N-dimethylformamide. The reaction is typically carried out at temperatures from room temperature to 80°C.

Alternative T-group can be introduced at the first stage of the synthetic sequence, which leads to the formation of compounds according to the present invention via N-alkylation of compound N any alkylating agent (T-L1). Delete group L1is an acceptable variant halogen atom such as bromine atom or iodine, or a sulfonate, such as toilet or mesilate, or any other removable group that is appropriate for this reaction. The reaction is usually carried out by stirring the reactants under alkaline conditions in an inert solvent, for example in diisopropylethylamine in acetonitrile or in K2CO3in N,N-dimethylformamide. The reaction is typically carried out at temperatures from room temperature to 80°C. the Secondary amine N, an example of which is 4-piperidone may be selected from the above formula (I) list of compounds corresponding to the Z-groups. Amines can be either obtained commercially or synthesized according to described methods (Lowe e al., J. Med. Chem. 37:2831-40 (1994); Carroll et al., J. Med. Chem. 35:2184-91 (1992)).

Alternative compounds of General structure J can be synthesized according To, using the method described by Cone et al. (Kuehne et. al., J. Org. Chem. 56:2701 (1991) and Kuehne et. al., J. Org. Chem. (1991), 56:513).

where R, Q1Q2W and T have been defined for formula (I), and L1refers to the right of the deleted group.

In General, during any of the processes for producing compounds according to the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the participating molecules. This protection can be achieved by conventional protective groups such as those described in the corresponding manual (Protective Groups in Organic Chemistry (ed. J.F.W.McOmie, Plenum Press, 1973); and Green & Wuts, Protective Groups in Organic Synthesis , John Wiley & Sons, 1991)). Protective groups can be removed at the appropriate convenient subsequent stage using known in the art methods.

Examples

Further, the present invention is disclosed using these examples, which should not be construed as limiting the scope of the present invention.

General LC-MS procedure used for examples 1-41: all spectra obtained using the device HP1100 LC/MSD. Using setup consisting of a two-stroke pump, autosampler, column thermostat, diode detector and interface with ionization method electrocapillary. Use column reverse phase (C18 Luna particle size 3 mm, column size 7.5 cm x 4.6 mm, e) with the security system of the cartridge. Column support at a temperature of 30°C. the Mobile phase is acetonitrile/8 mm aqueous ammonium acetate. Use the 15-minute gradient program, start the gradient with 70% acetonitrile, after 12 minutes pass by 95% acetonitrile, 1 minute back to 70% acetonitrile, which hold for 2 minutes. The flow rate is 0.6 ml/min. Value of trthat shown in the specific examples below, obtained using this procedure.

Example 1:N-((4-(were)methyl)-N-(piperidine-4-yl)-N'-phenylmethylene (26HCH65)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in a mixture of dichloromethane:ethanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To the R. is the target of the carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (800 mg, 2,63 mmol) in dry dichloromethane (20 ml) is added benzylsuccinic (0.65 mg, 5,26 mmol) the Solution was stirred at room temperature. After 48 hours, add an excess of 2-diethylaminoethylamine. The mixture is stirred for 24 hours, then concentrated. The obtained solid material pererastayut in dichloromethane (20 ml), sequentially washed with HCl (0,2 N, 3x30 ml), water (20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography using a mixture of dichloromethane:ethanol (10:1) gives N-((4-(were)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-N'-phenylmethylene (760 mg, 66%)which was dissolved in diethyl ether (5 ml). Add HCl (4 M) in dioxane (3 ml) and the solution stirred at room temperature for 60 minutes and then concentrated. The oil obtained pererastayut in a mixture of dichloromethane and diethyl ether (4:1). The organic layer is extracted with HCl (0.2 M, 3h20 ml). The combined aqueous layers treated with NaOH (0.2 M) to alkaline (pH>8) and then extracted with dichloromethane (3h20 ml). The combined organic layers are dried (Na2SO4), filtered and concentrated to obtain specified in the connection header. Output: 406 mg 70%;13C-NMR (CDCl3): δ 21,3, 31,6, 45,0, 45,9, 46,4, 53,0, 126,3, 127,2, 127,4, 128,6, 129,8, 135,3, 137,4, 139,7, 158,5.

Example 2:N-((4-(were)methyl)-N-(1-(2-methylpropyl " piperidine-4-yl)-N'-feilmeier the amide (26HCH66-02)

The product obtained in example 1 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 2-methylpropionamide (of 0.08 ml, 0.6 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. IR: 1640, 1185, 1110 cm-1; LC-MS: (M+H)+394,2, trthe ceiling of 5.60 minutes.

Example 3:N-(1-(2-bromophenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene (26HCH66-03)

The product obtained in example 1 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 2-bromobenzaldehyde (of 0.07 ml, 0.6 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution was applied to the column, the carrier of silmarillon the second cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. IR: 1635, 1180, 1110 cm-1; LC-MS: (M+H)+506,1, trof 8.37 minutes.

Example 4:N-(1-((4-hydroxy-3-methoxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene (26HCH66-04)

The product obtained in example 1 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 4-hydroxy-3-methoxybenzaldehyde (91 mg, 0.6 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header.13C-NMR (CD3D selected): δ 19,9, 55,4, 126,5, 127,0, 128,1, 129,0, 140,3, 148,0, 148,1, 158,8.

Example 5:N-(1-((5-utilties-2-yl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene (26HCH66-05)

The product obtained in example 1 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 5-ethyl-2-thiophencarboxylic idigit (84 mg, 0.6 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. IR: 1640, 1185, 1110, 805, 700, 620 cm-1; LC-MS: (M+H)+462,3, tr7.52 minutes.

Example 6:N-(1-(imidazol-2-ylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene (26HCH66-06)

The product obtained in example 1 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add imidazol-2-carboxaldehyde (58 mg, 0.6 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3methanol, then concentrate to obtain specified in the connection header. IR: 1620, 1190, 1110, 805, 700, 620 cm-1; LC-MS: (M+H)+418, 2, tr2.05 minutes.

Example 7:N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene (26HCH66-09)

The product obtained in example 1 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add cyclohexanecarboxaldehyde (67 mg, 0.6 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. IR: 1635, 1175, 1110, 805, 695, 620 cm-1; LC-MS: (M+H)+434,4, tr7,44 minutes.

Example 8:N-(1-((4-forfinal)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene (26HCH66-10)

The product obtained in example 1 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 4-forbindelse (of 0.08 ml, 0.6 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture in himout at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. IR: 1640, 1175, 1110, 805, 700, 620 cm-1; LC-MS: (M+H)+446,3, tr5,62 minutes.

Example 9:The hydrochloride of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-N'-phenylmalonamide (26HCH16D)

To a solution of 1-benzyl-4-piperidone (1,74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) in small portions over 30 minutes, add sodium borohydride (525 mg). The reaction mixture was stirred at room temperature. After 16 hours the mixture is concentrated. Add water (30 ml) and the mixture extracted with dichloromethane (2 x 20 ml). The combined organic layers are dried (Na2SO4), filtered and concentrated to obtain 4-((4-(were)methyl)amino-1-phenylethylhpiperidinyl. The crude product was used further without additional purification.

4-((4-(were)methyl)amino-1-phenylmaleimide (800 mg, 2.7 mmol) dissolved in dry dichloromethane (30 ml). Add benzylsuccinic (543 mg, 4.1 mmol). The reaction mixture was AC who're asked at room temperature. After 16 hours, water is added (10 ml) and then NaOH (6 N, 2 ml). After 30 minutes additional stirring is filtered off white crystals. The organic layer is separated and dried (Na2SO4), filtered and concentrated. Flash chromatography in a mixture of dichloromethane/methanol (10:1) gives N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-N'-phenylmethylene. Yield: 820 mg, 71%. A sample of the concentrate using HCl (4 M in dioxane) and then spend recrystallization from a mixture of dichloromethane/diethyl ether, obtaining specified in the header of the connection.1H-NMR (Dl3): δ 1,87 (USD, 2 H), of 2.30 (s, 3 H), 2,59 (DQC, 2 H), was 2.76 (usqu, 2 H), 3,44 (USD, 2 H), 4.09 to (d, 2 H), 4,30 (d, 2 H), and 4.40 (s, 2 H), with 4.64 was 4.76 (m, 2 H), 6,98-to 7.64 (aromatic protons, 14 H).13C-NMR (CDCl3): δ 21,2, 26,7, 45,0, 46,0, 49,7, 52,2, 61,0, 126,2, 127,26, 126,31, 128,2, 128,6, 129,6, 129,9, 130,4, 131,6, 134,4, 137,6, 139,3, 158,5.13C-NMR (CD3D, rotamer): δ 19,8, 26,4, 27,8, 40,3, 44,3, 51,6, 51,9, 54,5, 60,5, 110,0, 112,1, 114,0, 114,2, 117,5, 125,9, 126,2, 126,7, 126,8, 128,9, 129,1, 129,2, 129,4, 129,7, 130,1, 131,2, 134,5, 137,4, 159,1, 173,8, 175,0. Tpl.109-112°C. the Data of elemental analysis: Found (%) : - 70,06; H - 7,62; N - 8,60; calculation for monohydrate With 69,76; N - 7,53; N - 8,72.

Example 10:Oxalate of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-N'-phenylmalonamide (34JJ59oxal)

N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-N'-phenylmethylene receive, as described above in example 9. The sample is precipitated as oxalate and p is recrystallization from ethyl acetate to obtain specified in the connection header. 13C-NMR (CDCl3): δ 21,2, 27,0, 45,0, 45,9, 49,9, 52,1, 60,6, 126,1, 127,3, 127,4, 128,5, 128,7, 129,6, 130,0, 130,4, 131,2, 134,3, 137,7, 139,3, 158,4, 163,4; Tpl.180-182°C; the Data of elemental analysis: Found (%) : - 69,54; N - Of 6.73; N - of 7.96; calculation for monoacetate: From - To 69.61; H - 6,82; N - 8,12.

Example 11:The hydrochloride of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide (26 HCH17)

To a solution of 1-benzyl-4-piperidone (1,74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) in small portions over 30 minutes, add sodium borohydride (525 mg). The reaction mixture was stirred at room temperature. After 16 hours the mixture is concentrated. Add water (30 ml) and the mixture extracted with dichloromethane (2 x 20 ml). The combined organic layers are dried (Na2SO4), filtered and concentrated to obtain 4-((4-(were)methyl)amino-1-phenylethylhpiperidinyl. The crude product was used further without additional purification.

To a solution of 4-((4-(were)methyl)amino-1-phenylethylhpiperidinyl (800 mg, 2.7 mmol) in dry dichloromethane (30 ml) add diisopropylethylamine (1.5 ml) and then 4-methoxyphenylacetylene (997 mg, 4.5 mmol). The reaction mixture was stirred at room temperature. After 16 hours the reaction mixture was concentrated, pererastayut in diethyl ether and extracted with HCl (0,6 N). The aqueous layer was separated, treated with NaOH (1 N) until an alkaline reaction and extrahypothalamic (20 ml). Separate the organic layer, dry it (Na2SO4), filtered and concentrated, then pererastayut in diethyl ether. Add HCl (4 M in dioxane) with the formation of the hydrochloride, which is re-crystallized from diethyl ether to obtain specified in the connection header. Yield: 600 mg, 50%.1H-NMR (CDCl3): δ of 1.75 (d, 2 H), 2,32 (s, 3 H), 2,50 (kV, 2 H), 2,70 (kV, 2 H), to 3.38 (d, 2 H), of 3.54 (s, 2 H), of 3.78 (s, 3 H)4,06 (d, 2 H), of 4.54 (s, 2 H), 4,82 (m, 1 H), 6,78-7,60 (aromatic protons, 13 H).13C-NMR (CDCl3): δ 21,0, 26,0, 40,3, 46,3, 49,0, 51,8, 55,3, 60,8, 114,2, 125,6, 126,6, 127,9, 129,4, 129,60, 129,62, 130,3, 131,4, 134,8, 137,1, 158,7, 172,9. Tpl.197-200°C. the Data of elemental analysis: Found (%) : 71,29; N - 7,25; N - 5,73; calculation for hydrate With 71,37; N - 7,43; N - 5,74.

Example 12:Oxalate of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide (34JJ61oxal)

N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide receive, as described above in example 11. The sample is precipitated as oxalate and re-crystallized from tetrahydrofuran to obtain specified in the connection header.13C-NMR (CDCl3): δ 21,2, 26,4, 40,6, 52,0, 55,5, 114,4, 125,9, 126,7, 128,4, 129,6, 129,8, 129,9, 130,4, 131,2, 134,6, 137,6, 158,9, 163,3, 172,9. Tpl.171-173°C. the Data of elemental analysis: Found (%) : - 69,56; N - 6,74; N - 5,16; calculation for monoacetate: 69,48; N Is 6.61; N - 5,40.

Example 13:N-((4-(were)methyl)-N-(piperidine-4-yl)-4-methoxyphenyl the ndimethylacetamide (26HCH71B)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in a mixture of dichloromethane:ethanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (862 mg, and 2.83 mmol) in dry dichloromethane (10 ml) add diisopropylethylamine (1.1 ml, 6.5 mmol) and then 4-methoxyphenylacetylene (0,66 ml, 4.3 mmol). The reaction mixture was stirred at room temperature. After 48 hours, add water (5 ml) and the mixture is stirred for 2 hours, then extracted with NaOH (0,2 N, 2 x 15ml), HCl (Or 0.2 N, 2 × 15 ml) and water (15 ml). The organic layer is dried (Na2SO4) and concentrated to obtain N-((4-(were)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((4-(were)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (3 ml, 4 M the dioxane). The reaction mixture was stirred at room temperature. After 2 hours, add water (5 ml) and the mixture extracted with HCl (0,1 N, 3 x 30 ml). The combined aqueous layers treated with NaOH (0.2 M) to alkaline (pH>8). The aqueous layer was extracted with diethyl ether (2 x 20 ml). The combined organic layers are dried (Na2SO4) and concentrated, then dissolved in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated. Additional flash chromatography in a mixture of dichloromethane:ethanol (1:1) and then with methanol containing 2% NH3gives specified in the header connection. Output: 466 mg 47%.13C-NMR (CD3D, rotamer): δ 19,9, 27,8, 29,7, 40,2, 40,3, 44,4, 44,45, 44,50, 52,4, 54,5, 55,5, 114,0, 114,1, 126,0, 126,7, 126,9, 127,3, 128,7, 129,3, 129,6, 129,7, 135,1, 136,1, 136,2, 137,1, 159,0, 159,1, 173,1, 173,7.

Example 14:N-(1-(3,3-dimethylbutyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide (26HCH79-5)

The product obtained in the above example 13 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 3,3-dimethylbutyramide (0,143 ml, 1.1 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution DOB is given in acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 26 mg;13C-NMR (CD3OD, rotamer): δ 19,9, 27,4, 28,4, 28,8, 29,2, 29,3, 38,3, 38,4, 40,2, 40,3, 44,3, 52,0, 52,3, 52,4, 53,9, 54,6, 54,9, 114,0, 114,1, 126,0, 126,8, 127,0, 127,3, 128,8, 129,4, 129,8, 129,9, 135,0, 136,1, 136,3, 137,1, 158,96, 159,05, 173,2, 173.8.

Example 15:N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide (26HCH79-6)

The product obtained in the above example 13 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add cyclohexanecarboxaldehyde (was 0.138 ml, 1.1 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 17 mg; HRMS FAB +, NBA) (M+H)+449,3163 For C29H41N2O2required 449,3168; LC-MS: (M+H)+449,2, tr7.92 min.

Example 16:N-((4-(were)methyl)-N-(1-(2-methylpropyl " piperidine-4-yl)-4-methoxyphenylacetamide (26HCH79-7)

The product obtained in the above example 13 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 2-methylpropionamide (0.104 g ml, 1.1 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+409,2858. For C26H37N2O2required 409,2855; LC-MS: (M+H)+409,2, tr5.97 minutes.

Example 17:N-((4-(were)methyl)-N-(1-((4-(were)methyl)piperidine-4-yl)-4-methoxyphenylacetamide (26HCH79-8)

The product obtained in the above from example 13 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 4-methylbenzaldehyde (0,134 ml, 1.1 mmol) and ZAT is mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution contribute to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 22 mg; HRMS (FAB+, NBA) (M+H)+457,2853. For C30H37N2O2required 457,2855; LC-MS: (M+H)+457,2, tr6,97 minutes.

Example 18:N-(1-((4-hydroxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide (26HCH79-9)

The product obtained in the above example 13 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 4-hydroxybenzaldehyde (139 mg, 1.1 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The mixture is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), iprovided the elution of 10% NH 3in methanol and then concentrated to obtain specified in the connection header. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+459,2655. For C29H35N2O3required 459,2648; LC-MS: (M+H)+459,1, tr2,84 minutes.

Example 19:N-(1-((2-hydroxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide (26HCH79-10)

The product obtained in the above example 13 (20 mg, 0.06 mmol), dissolved in absolute ethanol (2 ml). Add 2-hydroxybenzaldehyde (0,122 ml, 1.1 mmol) and then mixing on a solid substrate (150 mg, 2.5 mmol/g resin; Aldrich 32864-2). The solution is shaken at room temperature. After 48 hours the resin is filtered off and the organic solution was added acetic anhydride (0,02 ml, 0.2 mmol). After 24 hours the mixture is concentrated and pererastayut in methanol (2 ml). The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 16 mg; HRMS (FAB+, NBA) (M+H)+459,2633. For C29H35N2O3required 459,2648; LC-MS: (M+H)+459,2, tr5,81 minutes.

Example 20:N-((3-phenylpropyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-1)

To a solution of commercially available carboxylate tert-butyl 4-oxo-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 3-phenylpropylamine (0,143 ml, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-(3-phenylpropyl)aminopiperidine. Yield: 110 mg) To a solution of carboxylate tert-butyl 4-(3-phenylpropyl)aminopiperidine (50 mg, 0.16 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-(3-phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product is then used b is C additional purification. N-(3-phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 61 mg;13C-NMR (CD3OD, rotamer): δ 27,8, 29,4, 30,8, 32,3, 32,7, 33,3, 40,2, 40,5, 42,0, 44,5, 44,6, 44,9, 52,7, 54,56, 54,57, 54,9, 114,0, 114,1, 125,7, 126,1, 127,0, 127,4, 128,2, 128,3, 128,5, 129,47, 129,55, 141,2, 141,8, 158,9, 159,0, 172,5, 172,7.

Example 21:N-(2-phenylethyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-2)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 2-phenethylamine (0,143 ml, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererasti Aut in diethyl ether (20 ml) and extracted with HCl (0,1 N, 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-(2-phenylethyl)aminopiperidine. Output: 221 mg) To a solution of carboxylate tert-butyl 4-(2-phenylethyl)aminopiperidine (50 mg, 0.16 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. Rest the p applied on the column, carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 52 mg;13C-NMR (CD3OD, rotamer): δ 27,1, 28,5, 34,9, 36,6, 40,2, 40,4, 44,1, 44,2, 44,4, 53,3, 54,2, 54,6, 114,0, 114,1, 126,2, 126,6, 127,2, 127,4, 128,3, 128,6, 128,79, 128,82, 129,7, 138,5, 139,5, 158,96, 159,0, 172,7, 173,1.

Example 22:N-((2-methoxyphenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-4)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 2-methoxybenzylamine (0,130 ml, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-((2-methoxyphenyl)methyl)aminopiperidine. Output: 211 mg) To a solution of carboxylate tert-butyl 4-((2-methoxyp the Nile)methyl)aminopiperidine (50 mg, 0.16 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-((2-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((2-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 40 mg;13C-NMR (CD3OD, rotamer): δ 26,1, 27,4, 40,0, 40,1, 43,5, 43,9, 51,5, 53,4, 54,5, 54,58, 54,63, 54,78, 54,83, 110,1, 110,5, 113,76, 113,78, 113,84, 114,0, 114,1,120,1, 120,5, 125,4, 126,0, 126,5, 126,7, 127,1, 127,3, 127,7, 128,8, 129,8, 130,0, 130,08, 130,14, 156,5, 157,0, 159,0, 159,1, 173,2, 173,8.

Example 23:N-((2-chlorophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-5)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 2-chlorobenzylamino (0,121 ml, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-((2-chlorophenyl)methyl)aminopiperidine. Yield: 137 mg) To a solution of carboxylate tert-butyl 4-((2-chlorophenyl)methyl)aminopiperidine (50 mg, 0.15 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. Further, the MCA is ü sequentially washed with HCl (0.2 To N, 2 x 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-((2-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((2-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 45 mg;13C-NMR (CD3OD, rotamer): δ 25,8, 26,9, 40,0, 40,1, 42,9, 43,4, 43,7, 46,0, 51,1, 53,0, 54,6, 113,77, 113,84, 114,0, 114,1, 126,6, 126,8, 127,08, 127,13, 127,3, 127,4, 128,1, 129,0, 129,2, 129,8, 130,0, 130,2, 131,9, 132,2, 135,0, 135,3, 159,1, 173,4, 173,8.

Example 24:N-((3,4-acid)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-6)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 3,4-dimethoxyaniline (0,151 ml, 1 mmol) in methanol (1 ml) EXT the keys acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-((3,4-acid)methyl)aminopiperidine. Output: 162 mg To a solution of carboxylate tert-butyl 4-((3,4-acid)methyl)aminopiperidine (50 mg, 0.14 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-((3,4-acid)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((3,4-acid)methyl)-N-(1-(tert-Butylochka the Nile)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 54 mg;13C-NMR (CD3OD, rotamer): δ 25,9, 27,3, 40,0, 40,1, 43,5, 43,8, 44,1, 51,4, 53,5, 54,6, 55,4, 110,2, 111,0, 111,9, 112,2, 114,0, 114,2, 118,6, 119,4, 127,1, 127,4,129,9, 130,0, 130,5, 132,1, 148,2, 148,7, 149,2, 149,7, 158,98, 159,05, 173,3, 173,6.

Example 25:N-((4-forfinal)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-7)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 4-forbindelsen (0,114 ml, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH to alkali the reaction (pH> 8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-((4-forfinal)methyl)aminopiperidine. Yield: 130 mg To a solution of carboxylate tert-butyl 4-((4-forfinal)methyl)aminopiperidine (50 mg, 0.16 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-((4-forfinal)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((4-forfinal)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0,3 is mol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 45 mg;13C-NMR (CD3OD, rotamer): δ 26,1, 27,5, 40,1, 43,6, 43,8, 44,0, 51,6, 53,6, 54,6, 113,77, 113,84, 114,0, 114,1, 114,7, 114,9, 115,3, 115,6, 126,8, 127,2, 128,1, 128,6, 128,7, 129,8,130,0, 130,1, 130,6, 131,0, 133,8, 159,1, 173,3, 173,6.

Example 26:N-((2,4-dichlorophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-8)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 2,4-dichloroaniline (is 0.135 ml, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-((2,4-dichlorophenyl)methyl)aminopiperidine. Yield: 97 mg) To a solution of carboxylate tert-butyl 4-((2,4-dichlorophenyl)methyl)aminopiperidine (50 mg, 0.14 mmol) in dichloro is not (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-((2,4-dichlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((2,4-dichlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 39 mg;13C-NMR (CD3OD, rotamer): δ 25,7, 26,8, 40,0, 42,6, 43,3, 43,7, 51,2, 53,0, 54,5, 54,6, 113,8, 113,8, 114,0, 114,1, 127,0, 128,4, 128,8, 129,8, 130,0, 130,1, 131,0, 132,7, 132,9, 134,5, 159,1, 173,4, 173,6.

Example 27:N-((3-were)methyl)-N-(Pipa is one-4-yl)-4-methoxyphenylacetamide (26HCH80-9)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and 3-methylbenzylamine (0,125 ml, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for 1 hour, then concentrated. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layers are dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-((3-were)methyl)aminopiperidine. Yield: 136 mg) To a solution of carboxylate tert-butyl 4-((3-were)methyl)aminopiperidine (50 mg, 0.14 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-((3-were)m is Teal)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((3-were)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 48 mg;13C-NMR (CD3OD, rotamer): δ 20,4, 26,8, 28,3, 40,2, 43,9, 44,1, 44,5, 51,8, 54,2, 54,57, 54,61, 114,0, 114,1, 123,2, 123,7, 126,7, 127,0, 127,1, 127,3, 128,0, 128,1, 128,7, 129,8, 129,9, 137,9, 138,6, 138,9, 159,0, 159,1, 173,1, 173,7.

Example 28:N-((3-bromophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide (26HCH80-10)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (400 mg, 2 mmol) in methanol (1 ml) and hydrogen bromide 3-bromobenzylamine (222 mg, 1 mmol) in methanol (1 ml) is added acetic acid in methanol (1M, of 1.34 ml) and then NaCNBH3in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 hours, add water (2 ml) and the mixture is stirred for e is e within 1 hour then concentrate. The oil obtained pererastayut in diethyl ether (20 ml) and extracted with HCl (0,1 N 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until alkaline reaction (pH>8), followed by extraction with dichloromethane (20 ml). The organic layer is dried (Na2SO4), filter and concentrate to obtain the carboxylate tert-butyl 4-((3-bromophenyl)methyl)aminopiperidine. Yield: 142 mg) To a solution of carboxylate tert-butyl 4-((3-bromophenyl)methyl)aminopiperidine (50 mg, 0.14 mmol) in dichloromethane (6 ml) add diisopropylethylamine (0,070 ml, 0.4 mmol) and then 4-methoxyphenylacetylene (by 0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). The mixture is stirred for another 2 hours. The mixture is successively washed with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and water (10 ml), dried (Na2SO4), filtered and concentrated to obtain N-((3-bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide. The crude product was used further without additional purification. N-((3-bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidine-4-yl)-4-methoxyphenylacetamide dissolved in diethyl ether (2 ml) and add HCl (1 ml, 4 M in dioxane). The reaction mixture was stirred at room temperature. After 2.5 hours, add NaOH (1 ml, 6 N) and ZAT is dichloromethane (10 ml). The mixture is extracted with water (2 x 15 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol and then concentrated to obtain specified in the connection header. Yield: 49 mg;13C-NMR (CD3OD, rotamer): δ 26,6, 28,2, 40,2, 43,9, 44,0, 51,8, 54,1, 54,6, 113,76, 113,84, 114,1, 114,2, 122,2, 125,0, 125,5, 126,7, 127,1, 129,2, 129,5, 129,7, 129,8, 129,9, 130,0, 130,5, 130,6, 140,8, 141,8, 159,1, 173,3, 173,7.

Example 29:N-((1-phenylmethyl)piperidine-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphenylacetamide (26HCH76B)

To a solution of 4-amino-N-benzylpiperidine (200 mg, 1.05 mmol) in methanol (2 ml) was added TRANS-cinnamaldehyde (211 mg, 1.6 mmol) and then acetic acid in methanol (1 M, 1.4 ml) and Lamborghini sodium in methanol (0.3 M, 4.4 ml). The reaction mixture was stirred at room temperature. After 48 hours, add water (2 ml). The mixture is stirred for 2 hours, then concentrated and pererastayut in diethyl ether (20 ml). The organic layer is extracted with HCl (0,1 N, 2 x 10 ml). The combined aqueous layers treated with NaOH (0,2 N) to alkaline (pH>8). The mixture is extracted with dichloromethane (2 x 10 ml). The combined organic layers are dried (Na2SO4) and concentrate. The crude product is used without further complement Inoi cleaning, dissolved in dichloromethane (5 ml). Add diisopropylethylamine (284 mg, 2.1 EQ.) and then 4-methoxyphenylacetylene (387 mg, 2.0 EQ.). The reaction mixture was stirred at room temperature. After 18 hours, add water (2 ml). Even after 2 hours, add dichloromethane (10 ml). The mixture is extracted with NaOH (0,2 N, 3 x 15 ml) and water (15 ml). The organic layer is dried (Na2SO4) and concentrate. The crude product pererastayut in methanol (2 ml) and applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header.13C-NMR (CDCl3): δ 28,5, 38,1, 46,6, 47,4, 50,9, 54,7, 62,9, 113,7, 125,5, 126,4, 126,6, 127,4, 127,9, 128,5, 128,6, 129,6, 130,0, 135,2, 135,3, 138,0, 158,2, 173,2.

Example 30:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-phenylacetamide (26HCH78-1)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in dichloromethane:methanol (10:1) gives the carboxylate is pet-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then phenylacetylene (81 mg, of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 38 mg;13C-NMR (CD3OD, rotamer): δ 19,9, 26,9, 28,4, 41,0, 41,1, 44,0, 44,1, 44,4, 51,9, 54,4, 126,1, 126,7, 126,8, 126,9, 128,5, 128,7, 128,78, 128,81, 128,9, 129,4, 129,5, 134,9, 135,2, 135,6, 136,0, 136,3, 137,2, 172,8, 173,3.

Example 31:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-3-phenylpropionamide (26HCH78-2)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in dichloromethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then 3-phenylpropionamide (0,078 ml of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4and filter the Ute with obtaining a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 43 mg;13C-NMR (CD3OD, rotamer): δ 19,9, 27,4, 29,0, 31,4, 31,7, 34,7, 35,7, 44,2, 44,3, 51,6, 54,2, 125,9, 126,07, 126,15, 126,8, 128,3, 128,4, 128,7, 128,8, 129,3, 135,1, 136,1, 136,2, 137,0, 141,1, 141,2, 173,9, 174,4.

Example 32:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-(phenylthio)ndimethylacetamide (26HCH78-3)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in dichloromethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then (phenylthio)acetylchloride (0,078 ml of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture plumage is eshivot back in 2 hours then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4), filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 18 mg; HRMS (FAB+, NBA) (M+H)+355,1841. For C21H27N2OS required 355,1844; LC-MS: (M+H)+355, tr2,62 minutes.

Example 33:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-phenoxyacetamide (26HCH78-4)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, after which it concentrate. Flash chromatography in dichloromethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then phenoxyacetate (0,073 ml of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 24 mg;13C-NMR (CD3D, rotamer): δ 19,9, 25,8, 27,4, 43,5, 43,7, 44,4, 51,9, 52,3, 66,9, 114,7, 114,8, 116,7, 117,0, 121,4, 123,6, 126,3, 126,8, 128,4, 28,9, 129,3, 129,5, 129,6, 131,0, 134,4, 136,1, 137,4, 158,3, 169,8, 170,1.

Example 34:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-(4-chlorphenoxy)ndimethylacetamide (26HCH78-5)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in dichloromethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then 4-chlorophenoxyacetate (0,082 ml of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. Chere is C 2 hours add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 21 mg;13C-NMR (CD3D, rotamer): δ 19,9, 26,2, 27,8, 43,6, 43,9, 44,4, 52,2, 52,5, 67,0, 116,2, 116,4, 126,2, 126,3, 126,8, 128,6, 128,9, 129,1, 129,3, 129,5, 131,0, 134,4, 135,6, 136,4, 137,5, 157,1, 169,4, 169,7.

Example 35:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-3-methoxyphenylacetamide (26HCH78-6)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in dichloromethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then 3-methoxyp dilatational (97 mg, of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 26 mg;13C-NMR (CD3OD, rotamer): δ 19,9, 26,3, 27,7, 41,0, 43,7, 43,9, 44,4, 51,5, 53,8, 54,5, 54,6, 112,2, 112,6, 114,3, 114,5, 121,0, 121,2, 126,1, 126,8, 128,8, 129,4, 129,5, 129,8, 134,8, 136,0, 136,3, 136,5, 136,9, 137,2, 160,2, 160,3, 172,8, 173,2.

Example 36:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-4-perforated (26HCH78-7)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic sour is at in methanol (1M, of 6.7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in dichloromethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then 4-perforazione (0,072 ml of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% N 3in methanol, and then concentrated to obtain specified in the connection header. Yield: 26 mg;13C-NMR (CD3D, rotamer): δ 19,9, 26,1, 27,4, 39,7, 39,9, 43,5, 43,8, 44,4, 51,3, 53,4, 114,9, 115,1, 115,3, 126,1, 126,7, 128,5, 128,8, 129,4, 130,7, 130,8, 130,9, 131,0, 131,2, 131,6, 134,8, 136,0, 136,3, 137,2, 160,9, 163,3, 172,7, 173,2.

Example 37:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-2,5-dimethoxyphenylacetone (26HCH78-8)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography in dichloromethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then 2,5-dimethoxyphenylacetone (0,092 ml of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (0,2 N, 2x 15 ml), NaOH (of 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 36 mg;13C-NMR (CD3D, rotamer): δ 20,0, 26,5, 28,2, 35,1, 35,7, 44,0, 44,4, 51,6, 53,8, 54,99, 55,03, 55,2, 55,5, 111,4, 111,7, 112,4, 112,9, 116,6, 116,9, 124,98, 125,02, 126,1, 126,7, 128,8, 129,3, 135,0, 136,1, 136,3, 137,0, 151,3, 151,7, 153,9, 154,0, 173,1, 173,5.

Example 38:N-((4-(were)methyl)-N-(1-piperidine-4-yl)-4-chlorophenylacetic (26HCH78-9)

To a solution of commercially available carboxylate tert-butyl 4-oxo-1-piperidine (1.75 g, 8,8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) is added acetic acid in methanol (1M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 hours, add water (5 ml) and the mixture is stirred for 1 hour, then concentrated. Flash chromatography dichlormethane:methanol (10:1) gives carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine. Yield: 2.4 g, 98%. To a solution of carboxylate tert-butyl 4-(4-were)methyl)aminopiperidine (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) add diisopropylethylamine (of 0.11 ml, 2.4 EQ.) and then 4-chlorophenylacetyl (99 mg, of 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 hours, add water (1 ml). The mixture is stirred for 2 hours, then add diethyl ether (20 ml). Next, the mixture was sequentially extracted with HCl (Or 0.2 N, 2 × 15 ml), NaOH (To 0.2 N, 2 × 15 ml) and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 hours, add NaOH (6 N, 1 ml) and then dichloromethane (10 ml). The mixture is extracted with water (2 x 10 ml), dried (Na2SO4) and filtered to obtain a clear solution. The solution is applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 22 mg;13C-NMR (CD3D, rotamer): δ 19,9, 26,3, 27,7, 39,9, 40,0, 43,6, 43,9, 44,4, 51,5, 53,6, 126,1, 126,7, 128,2, 128,4, 128,6, 128,9, 129,4, 129,6, 130,7, 130,9, 131,2, 131,6, 132,5, 132,7, 133,9, 134,1, 134,4, 134,8, 135,9, 136,3, 137,2, 172,4, 172,9.

Example 39:N-((4-(were)methyl)-N-(1-(phenylmethyl)pyrrole the n-3-yl)-N'-phenylmethylene (26HCH50)

To a solution of 3-amino-1-phenylethylenediamine (353 mg, 2 mmol) and 4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20 ml) is added acetic acid in methanol (2M, 6,7 ml) and then NaCNBH3in methanol (0.3 M, 3 ml). The mixture is stirred at room temperature. After 24 hours, add water (5 ml). The mixture is stirred for 1 hour, then concentrated. Flash chromatography in a mixture of dichloromethane/methanol (10:1) gives N-((4-(were)methyl)amino-1-femalecelebrity.

N-((4-(were)methyl)amino-1-femalecelebrity (35 mg, 0.125 mmol) was dissolved in dichloromethane (1.5 ml) and add benzylsuccinic (0,09 ml, 0.3 mmol). The reaction mixture was stirred at room temperature. After 48 hours the crude reaction mixture was applied to a column carrying strongly acidic cation-exchange resin (0.3 mmol/g resin), which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, and then concentrated to obtain specified in the connection header. Yield: 48 mg, 92%.13C-NMR (CD3D): δ 20,0, 29,7, 44,2, 51,3, 53,4, 56,4, 57,8, 58,7, 126,8, 127,1, 127,3, 127,6, 128,3, 128,4, 128,9, 129,1, 135,9, 136,8, 140,3, 158,5.

Example 40:N-((4-(were)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide (26HCH52)

To a solution of 3-amino-1-phenylethylenediamine (353 mg, 2 mmol) and 4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20 ml) is added acetic acid in methanol (2 is, of 6.7 ml) and then NaCNBH3in methanol (0.3 M, 3 ml). The mixture is stirred at room temperature. After 24 hours, add water (5 ml). The mixture is stirred for 1 hour, then concentrated. Flash chromatography in a mixture of dichloromethane/methanol (10:1) gives N-((4-(were)methyl)amino-1-femalecelebrity.

To a solution of N-((4-(were)methyl)amino-1-phenylethylenediamine (35 mg, 0.125 mmol), diisopropylethylamine (0,14 ml) in dichloromethane (1.5 ml) is added 4-methoxyphenylacetylene (0.1 ml, 0.5 mmol). The reaction mixture was stirred at room temperature. After 48 hours the crude reaction mixture was concentrated and pererastayut in methanol. The solution is applied to a column carrying strongly acidic cation-exchange resin, which was washed with methanol (3 x 6 ml), and spend the elution of 10% NH3in methanol, then concentrated. Flash chromatography in a mixture of dichloromethane/methanol (10:1) gives a mixture specified in the connection header. Yield: 20 mg, 38%.13C-NMR (CD3D): δ 21,3, 30,2, 40,8, 47,8, 53,6, 53,9, 55,5, 57,5, 60,2, 114,4, 125,7, 127,0, 127,1, 127,3, 127,4, 128,4, 128,5, 128,7, 128,9, 129,2, 129,8, 130,0, 135,9, 137,0, 158,6.

Example 41:N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide (RO)

A mixture of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-(4-methoxyphenethyl)ndimethylacetamide (20 mg, 0.045 mmol) and reagent Lawesson (25 mg, 0,062 mmol) taken in a glass am the Ulu and thoroughly mixed using a magnetic stirrer. Then, the glass ampoule is irradiated in a microwave oven (900 W, Whirlpool M401) for 8 minutes. Upon completion of the reaction zheltoksany material is transferred to the ion exchange column using methanol (2 ml). The ion exchange column is sequentially washed with CH2Cl2(2 ml) and methanol (2 ml) and the product then elute from the ion exchange column (10% NH3in methanol, 2 ml) to give N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide (20 mg, 97%) as a white solid; LC-MS: (M+H)+459, tr9,60 minutes; TLC (CH2Cl2/methanol 20:1) Rf=0,38.

Example 42 -Tests for selection and receptor amplification (R-SAT)

Functional test on the receptor according to the method of selection and amplification of the receptor (R-SAT), the authors used (with minor modifications with respect to the previously described in U.S. patent 5 707 798 methods for screening compounds for efficacy against 5-HT2A receptor. In General, screening is that NIH3T3 cells grown in 96-cell tablets for tissue culture to 70-80% confluence. Cells transferout 12-16 hours with plasmid DNA using superfect (Qiagen Inc.), as indicated in the manufacturer's instructions. Tests R-SAT mostly performed using 50 ng/cell receptor and 20 ng/cell plasmid DNA that encodes beta-galactosidase. All used the design of receptor and G-protein is located in the expression vector mammalian pSI (Gomeda Inc.), as described in U.S. patent 5 707 798. Gene 5-HT2A receptor is amplified by the method vnutrivennoi PCR from cDNA of the brain using oligodeoxynucleotides selected on the basis of published sequences (see Saltzman et. al., Biochem. Biophys. Res. Comm. 181:1469-78 (1991)). For large-scale transfected cells transfairusa for 12-16 hours, then treated with trypsin and frozen in DMSO. The frozen cells are then thawed, placed in a 10 000 - 40 000 cells per cell in 96-cell tablet, which contains the drug. The procedure for both methods, the cells are then grown in humidified atmosphere in the presence of 5% CO2in the environment within five days. Then the medium is removed from the tablets and measure the activity of the marker gene when adding a substrate for beta-galactosidase ONPG (FBI with the addition of 5% NP-40). Passes colorimetric reaction, the intensity of which is measured in device for spectrophotometric measurements of plates (Titertek Inc.) at 420 nm. All data analyzed using the computer program XLFit (IDBSm). Efficiency in percent of maximum repression compared to the repression under the action of the control connection (ritanserin, in the case of 5-HT2A). Rick50represents the negative logarithm IR50where IR50represents the estimated concentration in moles, to ora causes 50% repression of the maximum level. The results obtained for the six compounds according to the present invention, is presented in the table below.

Table 1. The effectiveness of the compounds against

5-HT2A-receptor

ConnectionThe effectiveness of
(medium)
The effectiveness of
(RMS)
Rick50
(medium)
Rick50
(RMS)
26HCH52985,07,310,16
26HCH66-037613,37,420,01
26HCH66-051093,0at 7.550,15
26HCH80-2894,67,780,17
26HCH80-7873,77,700,26
26HCH80-10 91a 4.97,210,05

Example 43 -The efficiency of in vitro 26HCH17 as an inverse agonist at the 5-HT2A receptor

A graph is shown in figure 1, depicts the data obtained in the result of the analysis of the dose-response 26HCH17 and ritanserin as inverse agonists of the 5-HT2A-receptor. Briefly, the analysis is that the 5-HT2A receptor and the alpha subunit of Gq protein binding guanidoacetic, temporarily transferout in NIH3T3 cells and analyzed using a functional test on the receptor according to the method of selection and amplification of the receptor (R-SAT) essentially as described in U.S. patent 5 707 798. Conduct screening of each connection at seven serially diluted concentrations in the triple repetition. The obtained data is analyzed using the method of least squares on the program GraphPad Prism (San Diego, CA) and Express the reaction in the form of interest.

Example 44 -Profile selectivity inverse agonist 26HCH16D

Hold R-SAT assay (as described in example 42) using cells transfected receptors (listed below)to determine the selectivity profile of compound 26HCH16D in respect of the receptor. Data on inverse agonist at 5-HT2A (IR50nm; % efficiency) curves obtained from the dose-response (7 points in the triple repetition). the CE other data (initial concentration, in which there is at least 30% efficiency; actual performance) receive the procedure, during which connections are examined in a double repeat for 4 doses; nr = activity less than 30% in all investigated doses (3, 30, 300, 3000 nm), so EC50/IR50more than 3000 nm. The results are presented in the table below.

Table 2. Profile inverse agonist 26HCH16D

5-HT2A

nr
ReceptorEfficiency
NTA (human)Agonistnr
Inverse agonist0,9 nM; 79%
NTV (human)Agonistnr
Antagonist3000 nM; 60%
NTS (human)Agonistnr
Inverse agonist3000 nM; 79%
NTA (human)Agonistnr
Antagonistnr
NTA (rat)Antagonistnr
NTE (human)Agonistnr
D2 (human)Agonistnr
Antagonist3000 nM; 73%
H1 (human)Agonist
Antagonist3000 nM; 30%
Alpha1a/D (rat)Agonistnr
Antagonistnr
Alpha1b/B (hamster)Agonistnr
Antagonistnr
Alpha1/A (human)Agonistnr
Antagonist3000 nM; 46%
Alpha2 (human)Agonistnr
Antagonist nr
Alpha2 (human)Agonistnr
Antagonistnr
Alpha2 (human)Agonistnr
Antagonistnr
m1 (human)Agonistnr
Antagonistnr

As mentioned above, 26HCH16D is an inverse agonist with high selectivity for 5-HT2A receptor.

General procedure for LC-MS analysis in the implementation examples ELH01-46, MBT01-14 and AKU01-38

In the examples below analysis methods HPLC-MS is performed using either of two basic methods (method a or method B). The following values of pairs is m t rget using these procedures, as indicated in the specific examples.

These methods are listed below:

Method a: Agilent HP1100 HPLC/MSD

Two-stroke pump G1312A, autosampler G1313A, G1316A column, a diode detector G1315A (190-450 nm), the FFM A, a device for ionization electroepilation.

Chromatography:

8 mm ammoniated in a mixture of water/acetonitrile.

The gradient starts from 70% org. within 12 minutes, increase to 100% org., then for 0.5 minutes, reduce up to 70% of org. and incubated for 3.5 minutes. The total acceleration 16 minutes. Speed for 1 ml/min

Column: Phenomenex Luna C18(2) 3 μm, 75 x 4,6 mm

Parameters when performing MS:

Drying gas 10 l/min Pressure sprayer 40 f/inch2. Gas temperature 350aboutC. Vcap, 4000.

Method b: waters/Micromass (Waters/Micromass) device for HPLC/MS analysis

The pump 600 LC, the controller sampler 2700, dual beam detector 2487 absorbance (channel And 205 nm, the channel 235 nm), ZMD mass spectrometer (Micromass, a device for ionization electroepilation.

Chromatography:

0.15% of TFU in a mixture of water/acetonitrile.

The gradient starts from 30% org., within 10 minutes, increase to 100% org., stand for 3 minutes and then for 0.5 minutes, reduce to 30% org. and incubated for 4.5 minutes. The total acceleration 18 minutes. Speed for 1 ml/min

Column: Symmetry C18, 5 μm, 4.6 x 50 mm, or

10 mm and monoacetate in a mixture of water/acetonitrile.

The gradient starts from 30% org. for 2.5 minutes, then for 10 minutes increase to 100% org., incubated for 9 minutes and then for 0.5 minutes, reduce to 30% org. and incubated for 5 minutes. The total acceleration time of 27 minutes. Speed for 1 ml/min

Column: Phenomenex C12 Synergi, 4 μm, 4.6 x 50 mm

Parameters when performing MS:

Gas for desolvation - 404 l/H; Capillary - To 5.3 KV; Cone - 36 V; Extractor - 3; the Temperature in the compartment of initial products 130aboutC; Temperature desolvation 250aboutC.

Example 45:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidine-4-yl)ndimethylacetamide (50ELH87)

The reaction stage 1: N-TRIFLUOROACETYL-4-piperidone (50ELH84)

Monohydrate hydrochloride 4-piperidone (4.0 g, 26 mmol, 1.0 EQ.) dissolved in 130 ml of dichloromethane. After adding triethylamine (8,66 g, 3.3 EQ.) the reaction mixture is stirred for 10 minutes. The mixture is then cooled in an ice bath (0°C). With stirring, add dropwise triperoxonane anhydride (12.0 g, 2.2 EQ.). After 2 hours the reaction is quenched by adding distilled water. The aqueous phase is twice extracted with dichloromethane. The combined organic layers are collected and dried over sodium sulfate. Concentration gives N-TRIFLUOROACETYL-4-piperidone.

Reaction step 2: 4-(4-methylbenzylamino)-1-(TRIFLUOROACETYL)piperidine (50ELH85)

In the Erlenmeyer flask contribute methanol (150 ml) and paramashiva the AI add acetic acid to pH 5. Then in a round bottom flask of 250 ml add 4-methylbenzylamine (3,14 g of 25.9 mmol) and N-TRIFLUOROACETYL-4-piperidone (reaction stage 1) (5,065 g of 25.9 mmol) and dissolved in the previously prepared mixture of methanol/acetic acid (150 ml). The reaction mixture is stirred for 5 minutes and slowly, with stirring NaCNBH3(2,46 g of 38.9 mmol). After 20 hours the reaction mixture is concentrated and transferred into a separating funnel containing dichloromethane and distilled water. The aqueous phase is alkalinized by adding Na2CO3. Then the aqueous phase is extracted twice with dichloromethane. The combined organic layers are collected and dried over Na2SO4. Concentration gives 4-(4-methylbenzylamino)-1-(TRIFLUOROACETYL)piperidine. UV/MS 60/53 (M+301), tr(A, MS) 3,267.

The reaction stage 3: 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-triftoratsetatov-4-yl)ndimethylacetamide (50ELH86)

The product from the reaction stage 2 (7,8 g of 25.9 mmol) was dissolved in 100 ml dichloromethane and stirred, adding 4-methoxyphenylacetylene (4.8 g, of 25.9 mmol). After 4 hours, add heptane, the product precipitates in the form of cleaners containing hydrochloride salt. The solvent is removed by evaporation. The crude material is purified flash chromatography, EtOAc/heptane (1:2). Output (common to the reaction stages 1+2+3) 3,912 g (34%), UV/MS 91/58 (M+449), tr(A, MS) 4,319.1/sup> H-NMR (400 MHz, Dl3) δ 6,80-7,15 (Ah, 4H), with 4.64 (Ust, 1H), 4,4 (s, 2H), 3,95 (d, 2H), and 3.72 (s, 3H), 3,50 (s, 2H), to 3.09 (t, 2H), and 2.7(t, 2H), 2,32 (s, 3H), 1,75 (Ust, 2H).13C-NMR 172,5; 158,8; 137,4; 134,9; 129,9; 129,9; 129,8; 127,1; 125,8; 114,3; 55,4; 52,2; 47,3; 45,3; 43,4; 40,6; 30,1; 29,2; 21,2.

The reaction stage 4: 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidine-4-yl)ndimethylacetamide (50ELH87)

The product from the reaction stage 3 (3,9 g, 8,7 mmol) dissolved in methanol (12 ml). In a round bottom flask of 250 ml to prepare a saturated solution of potassium carbonate in methanol. To the specified solution is added with stirring a solution of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(N-triptorelin-4-yl)ndimethylacetamide. After 4 hours the solution is concentrated and the remaining solid material is selected when the alkalization in dichloromethane. The combined organic layers dried over sodium sulfate and concentrated. UV/MS 91/72 (M+353), tr(A, MS) 2,210.

Also receive appropriate cleaners containing hydrochloride salt by dissolving the free base in dichloromethane (1 ml) and added under stirring HCl (1 EQ., 2 M HCl in ether). Salt is precipitated by adding dichloromethane solution in heptane. Concentration on a rotary evaporator gives the product as white crystals.

Example 46:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH27)

The reaction stage 1: 4-(4-methylbenzylamino)-1-methylpiperidin (50ELH25)

In the Erlenmeyer flask contribute methane is l (50 ml) and with stirring, add acetic acid to pH 5. Then in a round bottom flask 100 ml add methylbenzylamine (1.0 g, 8,8 mmol) and 1-methyl-4-piperidone (1.1 g, 8,8 mmol) and dissolved in the previously prepared mixture of methanol/acetic acid (40 ml). The reaction mixture is stirred for 5 minutes and slowly, with stirring NaCNBH3(0,83 g, 13,2 mmol). After 20 hours the reaction mixture is concentrated and transferred into a separating funnel containing dichloromethane and distilled water. The aqueous phase is alkalinized by adding Na2CO3. Then the aqueous phase is extracted twice with dichloromethane. The combined organic layers are collected and dried over Na2SO4. Concentration gives specified in the header connection. Yield (crude product): 98%. UV/MS 89/88 (M+353), tr(A, MS) 3,982.

The reaction stage 2: 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH27)

The product from the reaction stage 1 (1.9 grams, 8,7 mmol) dissolved in 40 ml dichloromethane and stirred, adding 4-methoxyphenylacetylene (1,606 g, 8,7 mmol). After 4 hours, add heptane, the product precipitates in the form of cleaners containing hydrochloride salt. The solvent is removed by evaporation. The crude material is purified flash chromatography by elution first 10% of the Meon in CH2Cl2and then 0-29% Meon in CH2Cl2and 5% been certified with qi net3. Output (total for the reaction is stages 1+2) (77%), UV/MS 100/100 (M+367), tr(A, MS) 4,359, Rf0,15 (2% Meon in CH2Cl2).1H-NMR (400 MHz, Dl3) δ 12,6 (c, 1H), 7,16 (d, J=7,0 Hz, 2H), 7,10 (d, J=7,0 Hz, 2H),? 7.04 baby mortality (d, J=8.0 Hz, 2H), PC 6.82 (d, J=8.0 Hz, 2H), 4,87 (TT, J=to 11.0, 4.0 Hz, 1H), 4,53 ppm (s, 2H), of 3.78 (s, 3H), 3,55 (s, 2H), 3,42 (USD, J=of 11.0 Hz, 2H), 2,80 (usqu, J=11,0 Hz, 2H), 2.7 (l, J=4.0 Hz, 3H), 2,42 (DQC, J=13,0, 3.0 Hz, 2H), 2,34 (s, 3H), 1,78 (USD, J=13,0 Hz, 2H).13C-NMR 173,1; 158,9; 137,4; 134,8; 129,9; 126,7; 125,8; 114,4; 76,9; 55,5; 54,6; 48,8; 43,7; 40,5; 26,4; 21,2.

Example 47:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclohexylpiperidine-4-yl)ndimethylacetamide (42ELH45)

50ELH87 (cleaners containing hydrochloride salt) (0.5 g, 1,29 mmol, 1.0 EQ.) dissolved in ethanol (100 ml). Add cyclohexanecarboxaldehyde (2.5 g, 20 EQ.) and then sodium borohydride (0,084 g, 2.0 EQ.). The reaction mixture is stirred for 36 hours, then add acetic acid (3 ml). The reaction mixture is stirred for 2 hours and the extraction is carried out with sodium bicarbonate (3 times) and dichloromethane. The organic layers are dried with sodium sulfate and concentrated. The product was then purified flash chromatography (1-10% Meon in CH2Cl2). The obtained product is dissolved in diethyl ether (20 ml) and with stirring, add Meon (dropwise as dissolution) and HCl (1 EQ., 2 M HCl in ether). Deposited cleaners containing hydrochloride salt of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclohexylpiperidine-4-yl)acetamide", she then filtered white Krista the crystals. Yield 80 mg (16%), UV/MS 100/100 (M+449), tr(A, MS) 7,105, MP. 133-135, Rf0,25 (2% Meon/CH2Cl2).1H-NMR (400 MHz, CDCl3) δ 11,9 (Ushs, 1H), 7,12 (kV, 4H), 7,02 (d, 2H), 6,80 (d, 2H), 4,87 (m, 1H), 4,58 (s, 2H), of 3.77 (s, 3H), 3,55 (s, 2H), 3,48 (m, 2H), 2,70 (m, 4H), 2,31 (s, 3H), 1.91 a (d, 2H), of 1.75 (m, 3H), 1,64 (d, 1H), 1,22 (d, 2H), 1,13 (TT, 2H), 1,02 (usqu, 2H).13C-NMR 173,1; 158,8; 137,2; 135,1; 129,9; 129,8; 126,8; 125,8; 114,4; 64,1; 55,5; 53,4; 49,2; 46,5; 40,4; 33,9; 25,9; 25,8; 25,7; 21,2.

Example 48:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperazin-4-yl)ndimethylacetamide (42ELH80)

50ELH87 (0.25 g, 0.71 mmol, 1.0 EQ.) dissolved in acetonitrile (15 ml) and added dropwise with stirring, ethylbromide (0,232 g, 3.0 EQ.). After 2 hours add the base Hunnings (0,084 g, 10.0 EQ.). After 36 hours the solution is extracted with sodium bicarbonate and dichloromethane (3 times). The organic layers are dried with sodium sulfate and concentrated to obtain a yellow oil. Next the product was then purified flash chromatography (2% Meon in CH2Cl2). The obtained product is dissolved in dichloromethane (1 ml) and added under stirring HCl (1 EQ. 2 M HCl in ether). Salt is precipitated by adding dichloromethane solution to heptane. Concentration on a rotary evaporator gives the product as white crystals. Yield: 170 mg (63%). UV/MS 98/95 (M+381), MP. 153 to 155 C, rt(A, MS) 3,033, Rf0,35 (3% Meon/CH2Cl2).1H-NMR (400 MHz, CDCl3) δ 12,2 (c, 1H), 7,15 (d, 2H), 7,12 (d, 2H), was 7.08 (d, 2H), PC 6.82 (d, 2H), 4,89 (t, 1H), 4,58 (s,2H), 3,79 (s, 3H), to 3.58 (s, 2H), 3,50 (d, 2H), 2,90 (m, 1H), 2,7 (usqu, 2H), 2,45 (m, 2H), 2,34 (s, ZN), of 1.80 (d, 2H), of 1.44 (t, 3H).13C-NMR 173,1; 158,9; 137,3; 134,9; 129,9; 125,8; 114,4; 55,5; 52,3; 52,0; 49,2; 46,5; 40,5; 26,2; 21,2; 9,5.

Example 49:2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (42ELH85)

The specified connection get the procedure similar to that for obtaining 50ELH27.

The reaction stage 1: (42ELH84)

Starting materials: 1-methyl-4-piperidone (of 0.5 , 4.4 mmol, 1.0 EQ.), 4-chlorobenzylamino (0,626 g, 1.0 EQ.), Lamborghini sodium (0,279 g, 1.5 EQ.).

The reaction stage 2: (42ELH85)

Raw materials: 42ELH84, 4-methoxyphenylacetylene (0,774 g, 1.0 EQ.).

The receiving procedure is similar to that for 50ELH27, but the product was then purified by ion exchange chromatography and then HPLC. Cleaners containing hydrochloride salt obtained when dissolving the free base in dichloromethane (1 ml) and adding with stirring HCl (1 EQ. 2M HCl). Salt is precipitated by adding dichloromethane solution to the heptane followed by concentration on a rotary evaporator.

Product: white crystals: UV/MS 98/97 (M+387), rt(A, MS) 2,953.1H-NMR (400 MHz, CDCl3) δ of 12.6 (s, 1H), 7,35 (d, 2H), 7,18 (d, 2H), 7,05 (d, 2H), PC 6.82 (d, 2H), 4,89 (m, 1H), 4,55 (s, 2H), 3,80 (s, 3H), 3,55 (s, 2H), 3.45 points (Ushs, 2H), 2,80 (Ushs, 2H), 2,72 (s, 3H), 2,25 (Ushs, 3H), 1,80 (Ushs, 2H).13C-NMR 173,0; 158,9; 136,5; 133,6; 129,8; 129,4; 127,3; 126,3; 114,5; 55,5; 54,6; 48,7; 46,3; 43,7; 40,5; 26,3.

Example 50:2-(4-methoxyphenyl)-N-(4-methylbenzo the)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide (42ELH79)

Receive the procedure that was used to 42ELH80.

Raw materials: 50ELH87 (0.25 g, 0.71 mmol, 1.0 EQ.), Isopropylamine (0,262 g, 3.0 EQ.).

Product: yield 130 mg (46%), UV/MS 100/100 (M+395), rt(A, MS) 3,360.1H-NMR (400 MHz, CDCl3) δ 12,0 (c, 1H), 7,15 (d, 2H), 7,10 (d, 2H), 7,05 (d, 2H), PC 6.82 (d, 2H), 4,87 (m, 1H), 4,60 (s, 2H), 3,79 (s, 3H), of 3.57 (s, 2H), 3,38 (USD, 3H), and 2.79 (q, 2H), 2.63 in (q, 2H), 2,34 (s, 3H), of 1.80 (d, 2H), of 1.39 (d, 6H).13C-NMR 173,1; 158,9; 137,3; 135,1; 129,8; 126,8; 125,8; 114,4; 57,9; 49,4; 48,2; 46,5; 40,5; 25,9; 21,2; 16,9.

Example 51:2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(piperidine-4-yl)ndimethylacetamide (42ELH89)(As source material for other reactions used in crude form)

Follow the procedure for obtaining 50ELH27.

The reaction stage 1: N-TRIFLUOROACETYL-4-piperidone (42ELH86)

Raw materials: the monohydrate hydrochloride 4-piperidone (2.0 g, 13 mmol, 1.0 EQ.), triperoxonane anhydride (6,0 , 2.2 EQ.). The results of the TLC show, which achieved a complete transformation.

Product: Rfof 0.9 (10% MeOH/CH2Cl2).

Reaction step 2: 4-(4-chlorobenzylamino)-1-(TRIFLUOROACETYL)piperidine (42ELH87)

Raw materials: 42ELH86 (2.5 g, 12.8 mmol, 1.0 EQ.), 4-chlorobenzylamino (1.8 g, 1.0 EQ.).

The reaction stage 3: 2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-triftoratsetatov-4-yl)ndimethylacetamide (42ELH88)

Raw materials: 42ELH87 (4.0 g, 12.5 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (2,31 g, 1.0 EQ.).

The reaction stage 4:2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(piperidine-4-yl)ndimethylacetamide (42ELH89)

Product: output 2 g (57%), UV/MS 80/82 (M+373), Rf0,2 (50%, EtOAc/heptane).

Example 52:2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide (42ELH91)

Follow the procedure for obtaining 42ELH80, but the product was then purified by HPLC. Acid eluent is alkalinized with sodium carbonate and the extraction is carried out with dichloromethane (3 times). The combined organic layers are collected and dried with sodium sulfate and concentrated. The remaining product is dissolved in 1 ml dichloromethane and added dropwise with stirring HCl (1 EQ. 2 M HCl in ether). This solution is added dropwise to a large excess of n-heptane to precipitate the hydrochloride. The solvent is evaporated to obtain white crystals of the hydrochloride of 2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide.

Raw materials: 42ELH89 (0.25 g, 0.67 mmol, 1.0 EQ.), cyclopentylamine (0,3 , 3.0 EQ.).

Product: output: 211,2 mg (76%). When cleaning ion exchange chromatography receive: UV/MS 90/98. Purification: HPLC: UV/MS 100/100 (M+441), Rf0,2 (3%Meon/CH2Cl2), rt(A, MC) 4,067.1H-NMR (400 MHz, CDCl3) δ 12,2 (Ushs, 1H), 7,32 (d, 2H), 7,17 (d, 2H),? 7.04 baby mortality (d, 2H), PC 6.82 (d, 2H), 4,90 (Ust, 1H), 4,58 (s, 2H), 3,79 (s, 3H), to 3.58 (USD, 2H), 3,54 (s, 2H), 3,14 (usqu, 2H), 2,58 (usqu, 2H), 2,04 (m, 4H), 1,89 (m, 4H), 1,75 (USD, 2H).13C-NMR 173,0; 158,9; 133,5; 129,8; 129,3; 127,3; 126,4; 114,5; 68,4; 55,5; 51,9; 49,1; 46,2; 40,5; 28,5; 26,0; 23,8.

Example 53:2-(4-methoxyphenyl)-N-(4-harbe the ZIL)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide (42ELH90)

42ELH89 (0.25 g, 0.67 mmol, 1.0 EQ.) transferred into the vial of 4 ml and dissolved in acetonitrile (2 ml). Add Isopropylamine (0.25 g, 3.0 EQ.) together with the basis of Hongsa (Hunigs) (0.87 g, 10.0 EQ.). Bottle tightly closed and shaken for 4 days at 60aboutC. Then the reaction mixture was transferred into a separating funnel with distilled water and CH2Cl2. The aqueous phase is alkalinized with sodium bicarbonate and the extraction is carried out with dichloromethane (3 times). The organic layers collected, dried with sodium sulfate and concentrated with the formation of a yellow oil. The product was then purified flash chromatography (3% Meon in CH2Cl2). The obtained product is dissolved in dichloromethane (1 ml) and added under stirring HCl (1 EQ. 2 M HCl in ether). Salt is precipitated by adding dichloromethane solution to heptane. Concentration on a rotary evaporator gives the product as white crystals. Output: 101,2 mg (63%), UV/MS (M+415), Rf0,25 (3%Meon/CH2Cl2).

1H-NMR (400 MHz, CDCl3) δ 12,05 (Ushs, 1H), was 7.36 (d, 2H), 7,18 (d, 2H),? 7.04 baby mortality (d, 2H), PC 6.82 (d, 2H), 4,88(m, 1H), 4,60 (s, 2H), 3,79 (s, 3H), 3,55 (d, 2H), 3,36 (d, 3H), 2,80 (usqu, 2H), 2,65 (usqu, 2H), 1,76 (USD, 2H), 1.39 in (d, 6H).13C-NMR 173,0; 159,0; 137,0; 136,0; 129,7; 129,3; 127,4; 126,4; 114,5; 57,9; 55,5; 49,2; 48,2; 46,2; 40,5; 25,8; 16,9.

Example 54:2-(phenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14b)

Follow the procedure for obtaining 50ELH27. Cleaning providermetadata HPLC. Cleaners containing hydrochloride salt obtained when dissolving the free base in dichloromethane (1 ml) followed by the addition with stirring of HCl (1 EQ. 2 M HCl in ether). Salt is precipitated by adding dichloromethane solution to heptane, followed by concentration.

The reaction stage 1: 4-(4-triphtalocyaninine)-1-methylpiperidin (50ELH2).

Starting materials: 1-methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 EQ.), 4-triftormetilfosfinov (1.75 g, 1.0 EQ.).

Product: UV/MS 80/92 (M+273).

The reaction stage 2: 2-(phenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14b)

Raw materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 EQ.), phenylacetylene (0,068 g, 1.0 EQ.).

Product: UV/MS 100/97 (M+390), rt(A, MC) 3,797, Rf0,3 (5%Meon/CH2Cl2).1H-NMR (400 MHz, CDCl3, rotamer 54/46) δ 7,52 (d, 2H), 7,42 (d, 2H), 7,12-7,30 (m, 4H,), 4,63 and 3.74 (2m, 1H), to 4.38 (Ushs, 2H), 3,80, and a 3.50 (2s, 3H), 3,31 and 2,78 (2D, 2H), 2,33 and 2.18 (2s, 2H), 2,24 and 1,65-1,90 (t and m, 4H), 1,60 and 1.22 (2D, 2H), 1.13C-NMR 172,3; 171,8; 143,9; 135,1; 134,8; 129,1; 129,0; 128,9; 128,7; 127,4; 127,3; 127,2; 126,3; 126,1; 126,0; 56,0; 55,2; 54,9; 50,9; 46,8; 45,2; 44,9; 42,2; 41,7; 30,6; 28,4.

Example 55:2-(4-forfinal)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14)

Follow the procedure for obtaining 50ELH14.

The reaction stage 2: 2-(4-forfinal)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14)

Raw materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 EQ.), 4-ftoheia ethylchloride (0,076 g, 1.0 EQ.).

Product: output: 69,7 mg (36%), UV/MS 100/98 (M+409), rt(A, MC) 3,839, Rf0,3 (5%Meon/CH2Cl2).1H-NMR (400 MHz, DMSO, rotamer 65/35) δ 10,80 and or 10.60 (2s, 1H), 7,71 and 7.62 (2D, 2H), 7,47 and 7,38 (2D, 2H), 7,00 was 7.36 (t and m, 4H), 4,70 and 4.50 (2s, 2H), 4,30 (m, 1H), 3,93, and of 3.56 (2s, 2H), 3,34 (s, 2H), 3.00 and (usqu, 2H), 2,64 (s, 3H), 2,08 (m, 2H), 1,68 and 1.58 (2D, 2H).13C-NMR 176,8; 176,4; 167,6; 165,3; 150,0; 149,0; 136,6; 132,5; 131,0; 130,5; 120,6; 120,5; 120,5; 120,4; 58,1; 58,0; 57,0; 54,5; 52,0; 49,3; 47,6; 45,0; 32,4; 31,4.

Example 56:2-(4-methoxyphenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14d)

Follow the procedure for obtaining 50ELH14.

The reaction stage 2: 2-(4-methoxyphenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14d)

Raw materials: 50ELH2 (0.15 g, 0.55 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0.1 g, 1.0 EQ.).

Product: output: of 57.5 mg (29%), UV/MS 99/100 (M+421), rt(MC) 6,30, Rf0,25 (3%Meon/CH2Cl2).1H-NMR (400 MHz, CDCl3) δ 12,4 (ush s, 1H), 7,55 (in, 2H), 7,28 (d, 2H), of 6.96 (d, 2H), 4,84 (Ust, 1H), 4,59 (s, 2H), and 3.72 (s, 3H), 3.46 in (s, 2H), 3,38 (d, 2H), 2,78 (kV, 2H), 2,64 (s, 3H), of 2.38 (q, 2H), 1.70 to (d, 2H).13C-NMR 173,0; 159,0; 142,3; 130,0; 129,8; 126,3; 126,2; 114,7; 114,5; 55,5; 54,4; 48,7; 46,5; 43,6; 40,6; 26,3.

Example 57:2-(4-triptoreline)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14)

Follow the procedure for obtaining 50ELH14.

The reaction stage 2: 2-(4-triptoreline)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14)

The source material is: 50ELH2 (0.12 g, 0.44 mmol, 1.0 EQ.), 4-triftormetilfullerenov (0.1 g, 1.0 EQ.).

Product: output: 92,6 mg (42%), UV/MS, 89/93 (M+458), rt(A, MC) 4,211, Rf0,3 (5%Meon/CH2Cl2).1H-NMR (400 MHz, Dl3) δ 12,7 (Ushs, 1H), 7,56 (d, 2H), of 7.48 (d, 2H), 7,17 (d, 2H), a 4.86 (m, 1H), 4,63 (s, 2H), to 3.58 (s, 3H), 3,40 (d, 2H), 2,75 (kV, 2H), 2,65 (d, 3H), 2,46 (DQC, 2H), 1,73 (Ushs, 2H).13C-NMR 171,8; 141,9; 138,4; 129,4; 127,9; 126,3; 126,3; 126,2; 125,9; 125,8; 54,4; 48,8; 46,6; 43,6; 40,9; 26,2.

Example 58:2-(4-forfinal)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH6).

Follow the procedure for obtaining 50ELH14.

The reaction stage 1: 4-(4-forbindelsen)-1-methylpiperidin (50ELH4)

Starting materials: 1-methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 EQ.), 4-forbindelsen (1,25 g, 1.0 EQ.).

Product: output: 2,154 g (97%), UV/MS 79/89 (M+223).

The reaction stage 2: 2-(4-forfinal)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH14)

Raw materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 EQ.), 4-perforazione (0,096 g, 1.0 EQ.).

Product: yield: 57 mg (29%), UV/MS 100/100 (M+359), rt(A, MC) 3,763, Rf0,25 (3%Meon/CH2Cl2).1H-NMR (400 MHz, CDCl3) δ 12,6 (Ushs, 1H), 7,2 (DD, 2H), 7,06 (m, 4H), 6,98 (t, 2H), 4,88 (TT, 1H), 4,58 (s, 4H), of 3.45 (d, 2H), of 2.81 (q, 2H), 2,72 (d, 3H), 2,48 (usqu, 2H), 1,78 (Ushs, 2H).13C-NMR 172,5; 163,4; 160,8; 133,4; 130,6; 130,2; 127,5; 127,4; 116,3; 116,1; 115,9; 115,7; 54,5; 48,8; 46,2; 43,6; 40,3; 26,3.

Example 59:2-(4-methoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH8).

Mark what are the procedure for obtaining 50ELH14

Reaction step 2:

Raw materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0.1 g, 1.0 EQ.).

Product: yield: 54 g (26%), UV/MS 100/100 (M+371), rt(A, MC) 3,257, Rf0,25 (3%Meon/CH2Cl2).1H-NMR (400 MHz, CDCl3) δ 12,2 (Ushs, 1H), 7,12 (m, 2H), 6,97 (m, 4H), 6.75 in (d, 2H), 4,80 (Ust, 1H), 4,49 (s, 2H), 3,71 (s, 3H), 3,47 (s, 2H), 3,37 (d, 2H), and 2.8 (q, 2H), 2,64 (s, 3H), 2,35 (kV, 2H), 1.69 in (d, 2H).13C-NMR 173,0; 163,5; 161,1; 158,9; 133,7; 133,6; 129,8; 127,6; 127,5; 126,5; 116,2; 116,0; 114,6; 114,5; 55,5; 54,4; 48,8; 46,2; 43,6; 40,5; 26,4.

Example 60:2-(phenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH10).

Follow the procedure for obtaining 50ELH14

The reaction stage 2: 2-(phenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH10)

Raw materials: 50ELH4 made (0.13 g, 0.54 mmol, 1.0 EQ.), phenylacetylene (0,091 g, 1.0 EQ.).

Product: UV/MS 100/94 (M+341), rt(A, MC) 3,127, Rf0,25 (3%Meon/CH2Cl2).1H-NMR (400 MHz, DMSO, rotamer 54/56) δ 12,38 (Ushs, 1H), 7,35-to 7.00 (m, 9H), 4,55 and 4,40 (2s, 2H), 4,50 and 4.25 (Ust, 1H), 3,91 and of 3.56 (2s, 2H), 3,30 (Hidden under signal of water)(2H), 2,98 (d, 2H), 2,64 (s, 3H), 2,09 (Ust, 2H), 1.66, and 1,45 (USD, 2H).13C-NMR 171,9; 171,6; 162,8; 160,4; 136,5; 136,2; 135,4; 129,9; 129,7; 129,5; 129,2; 129,0; 128,9; 128,7; 127,2; 127,1; 116,2; 116,0; 115,6; 53,2; 52,5; 49,8; 46,9; 44,0; 42,8; 40,9; 40,6; 40,4; 40,2; 40,0; 39,8; 39,6; 27,7; 26,6.

Example 61:2-(4-triptoreline)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH122)

Follow the procedure for obtaining 50ELH14

The reaction stage 0: 4-t is AttorneyGeneral (50ELH12 1)

4-triftorperasin acid (1.0 g) and thionyl chloride (15 ml) is refluxed for 1 hour. The excess thionyl chloride is evaporated. The NMR analysis shows that the transformation has passed completely.

The reaction stage 2: 2-(4-triptoreline)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH122)

Raw materials: 50ELH4 (0.12 g, 0.55 mmol, 1.0 EQ.), 4-triftormetilfullerenov (50ELH121) (0.11 g, 0.5 mmol, 1.0 EQ.).

Product: output: 47,1 mg (24%), UV/MS 96/96 (M+409), rt(A, MC) 4,566, Rf0,25 (3%Meon/CH2Cl2).1H-NMR (400 MHz, CDCl3) δ 7,52 (d, 2H), 7,22 (d, 2H), 7,17 (DD, 2H),? 7.04 baby mortality (t, 2H), 4,86 (Ust, 1H), 4,58 (s, 2H), to 3.64 (s, 2H), 3.45 points (USD, 2H), 2,84 (usqu, 2H), 2,71 (d, 3H), 2,45 (usqu, 2H), 1.77 in (USD, 2H).13C-NMR 171,8; 163,6; 161,2; 138,7; 133,3; 129,8; 129,5; 127,5; 127,4; 125,8; 125,7; 116,4; 116,2; 54,4; 48,9; 46,3; 43,6; 40,8; 26,3.

Example 62:4-(4-methoxybenzylamine)-1-methylpiperidin (50ELH18)

Follow the procedure for obtaining 50ELH27

Starting materials: 1-methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 EQ.), 4-methoxybenzylamine (1,37 g, 1.0 EQ.).

Product: UV/MS 95/95 (M+235), rt(A, MC) 3,5091H-NMR (400 MHz, CDCl3) δ of 7.3 to 6.8 (m, 4H), of 3.77 (s, 3H), of 3.73 (s, 2H), 2,86 (m, 2H), by 2.55 (m, 1H), 2,30 (s, 3H), 2,1 (t, 2H), 1,96 (DD, 2H), 1,50 (m, 2H).

Example 63:2-(4-triptoreline)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20)

Follow the procedure for obtaining 50ELH14.

Reaction step 1: Methyl 4-(N-[1-ethylpiperazin-4-yl]aminomethyl)benzoate (50ELH19)

Starting materials: 1-methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 EQ.), the hydrochloride of methyl 4-(aminomethyl)benzoate (2.0 g, 1.0 EQ.).

Product: UV/MS 81/88 (M+263), rt(A, MC) 3,0601H-NMR (400 MHz, CDCl3) δ of 8.00 (d, 2H), 7,20 (m, 2H), 3,90 (c, 3H), 3,85 (c, 2H), 2,96 (dt, 2H), 2,7 (Ushs, 1H), 2,62 (m, 1H), 2.40 a (c, 3H), 2,28 (t, 2H), 1,96 (m, 2H), and 1.56 (m, 2H).

The reaction stage 2: 2-(4-triptoreline)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20)

Raw materials: 50ELH19 (0.20 g, 0.76 to mmol, 1.0 EQ.), 50ELH121(0,169 g, 1.0 EQ.).

Product: output: 108,9 mg (32%), UV/MS 100/100 (M+448), rt(A, MC) 3,327, Rf0,3 (5%Meon/CH2Cl2).1H-NMR (400 MHz, DMSO, rotamer 56/44) δ 10.7 and 10.4 (USS, 1H), of 7.96-7,28 (m, 8H), 4,70 and 4.51 (2s, 2H), 4,30 (Ust, 1H), 4.06 and of 3.69 (2s, 2H), 3,83 and 3,81 (2s, 3H), of 3.00 (m, 2H), 2.63 in (m, 3H), 2.05 is (OST, J=12 Hz, 2H), 1.69 in (Ust, J=12 Hz, 2H).13C-NMR (CDCl3) 171,9; 166,7; 142,9; 138,5; 130,7; 130,1; 129,7; 126,2; 125,9; 55,2; 52,5; 49,2; 47,4; 41,2; 32,1; 26,6; 22,9; 14,3.

Example 64:2-phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20)

Follow the procedure for obtaining 50ELH14

The reaction stage 2: 2-phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20)

Raw materials: 50ELH19 (0.2 g, 0.76 to mmol, 1.0 EQ.), phenylacetylene (0,117 g, 1.0 EQ.).

Product: yield: 82.5 g. (29%), UV/MS 100/100 (M+381), rt(A, MC) 2,625, Rf0,25 (3%Meon/CH2Cl2).1H-NMR δ (400 MHz, CDCl3) 12,2 (Ushs, 1H), 8,00 (d, J=7,4, 2H),and 7.4 to 7.2 (m, 4H), was 7.08 (d, J=7,4, 2H), 4,89 (Ust, 1H), to 4.62 (s, 2H), 3,90 (s, 3H), of 3.56 (s, 2H), 3,42 (d, J=11,0, 2H), 2,84 (kV, J=11,0, 2H), 2,68 (d, J=3,6, 3H), 2.40 a (kV, J=11,0, 2H), 1.77 in (USD, J=11,0, 2H).13C-NMR 173,0; 168,0; 143,3; 136,7; 130,6; 129,0; 127,4; 125,9; 54,5; 52,4; 48,8; 43,6; 41,4; 26,3.

Example 65:2-(4-chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20)

Follow the procedure for obtaining 50ELH14

The reaction stage 2: 2-(4-chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20)

Raw materials: 50ELH19 (0.2 g, 0.76 to mmol, 1.0 EQ.), 4-chlorophenylacetyl (0,131 g, 1.0 EQ.).

Product: output: 79,2 g (26%), UV/MS 100/96 (M+399), rt(A, MC) 2,3331H-NMR (400 MHz, DMSO, rotamer 62/38) δ 10.8 and 10.60 (USS, 1H), 7.95 and a 7.85 (2D, J=8,6, 2H), 7.4 and 7,28 (2D, 2H), 7,35 and 7,14 (m, 4H), 4,67 and 4.50 (2s, 2H), 4,29 (m, 1H), 3,93, and of 3.84 (2s, 2H), 3,81 (s, MN), 3,21 (d, J=11,9, 2H), 3.00 and (d, J=11,9, 2H), 2.63 in (s, MN), to 2.06 (m, 2H), 1,68 and 1.56 (d, J=11,9, 2H).13C-NMR (Dl3) 172,6; 166,7; 163,4; 161,0; 143,0; 130,7; 130,6; 130,5; 126,0; 115,9; 115,7; 54,7; 52,4; 48,9; 46,9; 44,0; 40,4; 26,4.

Example 66:2-(4-methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20D)

Follow the procedure for obtaining 50LH14.

The reaction stage 2: 2-(4-methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH20D)

Raw materials: 50ELH19 (0.2 g, 0.76 to mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,140 g, 1.0 EQ.).

Product: output: 108,6 g (26%), UV/MS 100/99 (M+410), rt(A, MC) 2,2801H-NMR (400 MHz, CDCl3) δ 12,38 (the SHS, 1H), 8,00 (d, J=7,2, 2H), 7,28 (d, J=7,2, 2H), 7,00 (d, J=7,2, 2H), 6,79 (d, J=7,2, 2H), 4,88 (Ust, 1H), br4.61 (s, 2H), 3,90 (s, 3H), of 3.75 (s, 3H), 3,42 (USD, J=10,7, 2H), 2,84 (kV, J=10,7,2H), 2,68 (d, J=3,6, 3H), 2.40 a (usqu, J=10,7, 2H), 1,75 (d, J=10,7, 2H).13C-NMR 173,0; 166,8; 159,0; 143,3; 130,5; 129,9; 129,8; 126,3; 125,9; 114,5; 55,5; 54,7; 52,4; 48,7; 46,7; 43,6; 40,6;

32,1; 26,3; 22,9; 14,3.

Example 67:N-(4-methylpentyl)-N-(1-methylpiperidin-4-yl)benzylamine (50ELH23)

Follow the procedure for obtaining 50ELH14

Reaction step 2: 1-phenyl-N-[2-(4-were)ethyl]-N-(1-methylpiperidin-4-yl)amide (50ELH23)

Raw materials: 4-(2-phenylethyl)amino-1-methylpiperidin (0.20 g, 0.86 mmol, 1.0 EQ.), the benzoyl chloride (0,158 g, 1.0 EQ.).

Product: output: 159 mg (50%), UV/MS 100/100 (M+337), rt(A, MC) 3,289, Rfof 0.55 (10%Meon/CH2Cl2)1H-NMR (400 MHz, DMSO (80°C)) δ 10,9 (Ushs, 1H), 7,44 (s, 2H), 7,34 (d, J=3.0 Hz, 2H),? 7.04 baby mortality (d, J=7,0 Hz, 2H), 6,95 (Ushs, 2H), 4.00 points (Ushs, 1H), 3,40 (d, J=4,2 Hz, 2H), 3,35 (d, J=4,2 Hz, 2H), 2.95 and (Ushs, 2H), 2,77 (t, J=3,2 Hz, 2H), 2.40 a (kV, J=6,4 Hz, 2H), 2,24 (s, 3H) 1,83 (d, J=6,4 Hz, 2H).13C-NMR (CDCl3) 171,6; 138,1; 136,3; 136,0; 129,8; 129,6; 129,1; 129,1; 126,7; 53,6; 52,4; 46,1; 42,9; 35,9; 27,3; 21,1.

Example 68:2-(4-methoxyphenyl)-N-(3-phenyl-1-propyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH65)

Follow the procedure for obtaining 50ELH14

The reaction stage 1: 4-(3-phenylaminopropyl)piperidine (50ELH59)

Starting materials: 1-methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 EQ.), 3-phenylpropylamine (1.35 g, 1.0 EQ.).

Product: UV/MS 100/94 (M+233), rt(A, MC) 3,5341H-NMR (400 MHz, CDCl3) δ 7,28 for 7.12 (m, 5H), 3,0 (Ushs, 1H), 2,84 (dt, J=12.3 and 3.5 Hz, 2H), 2,64 (kV, J=7,0 Hz, 4H), of 2.51 (m, 1H), and 2.27 (s, 3H), 2.05 is (OST, J=12.3 Hz, 2H), equal to 1.82 (m, 2H), 1,44 (m, 2H).

The reaction stage 2: 2-(4-methoxyphenyl)-N-(3-phenyl-1-propyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH65)

Raw materials: 50ELH59 (0.50 g, 2.2 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,398 g, 1.0 EQ.).

Product: yield: 153 mg (43%), UV/MS 100/100 (M+381), rt(A, MC) 2,9381H-NMR (400 MHz, DMSO, rotamer 55/45) δ 11.0 and 10,90 (USS, 1H), 7,30-7,10 (m, J=7.9 Hz, 6H), 6,97 (d, J=7.9 Hz, 1H), 4,22 and 4,06 (dt, dH), 3,70 (s, 3H), at 3.35 (t, J=10.4 Hz, 2H), 3.15 in (m, 2H), 3.00 and (kV, J=10.4 Hz, 2H), 2,66 (d, 3H), 2,52 (kV, J=7.9 Hz, 2H), 2,17 (usqu, J=12 Hz, 2H) 1,73 (m, 2H), 1.70 to and 1.52m (2D, J=12 Hz, 2H).13C-NMR (DMSO) 171,3; 171,0; 158,6; 142,2; 141,7; 130,0; 129,0; 128,0; 128,5; 128,2; 126,6; 114,5; 55,7; 55,7; 53,5; 53,3; 50,1; 44,5; 42,9; 41,9; 33,7; 33,1; 32,9; 31,4; 27,8; 26,8.

Example 69:2-(4-methoxyphenyl)-N-[2-(4-were)ethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH68)

Follow the procedure for obtaining 50ELH14

The reaction stage 1: 4-[2-(4-were)ethylamino]piperidine (50ELH58)

Starting materials: 1-methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 EQ.), 2-(4-were)ethylamine (1.0 g, 1.0 EQ.).

Product: UV/MS 100/91 (M+233), rt(A, MC) 3,9331H-NMR (400 MHz, CDCl3) δ of 7.4 (s, 5H), 3.27 to (Ushs, 1H), 2,84 (d, J=7,0 Hz, 4H), to 2.75 (m, 2H), 2,54 (m, 1H), 2,29 (Hz, 6H), 2,10 (OST, J=12.3 Hz, 2H), 1,86 (USD, 2H), 1,45 (m, 2H).

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(4-were)ethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH68)

Raw materials: 50ELH58 (0,30 g, 1.3 mmol, 1.0 EQ.), 4-methox phenylacetylene (0,238 g, 1.0 EQ.).

Product: yield: 125 mg (26%), UV/MS 100/99 (M+381), rt(A, MC) 3,1561H-NMR (400 MHz, DMSO, rotamer 50/50) δ 11.0 and 10,90 (USS, 1H), 7,25? 7.04 baby mortality (m, J=8,7 Hz, 6H), 6.87 in and 6,84 (2D, J=8.7 Hz, 2H), 4,30 and 4.09 to (dt, J=11.5 Hz, DN), to 3.73 and to 3.58 (2s, 2H), 3,71 and 3.70 (2s, 3H), at 3.35 (m, (underlying water peak) 3H), 3,24 (m, 1H), to 3.02 (m, J=11.5 Hz, 2H), 2,80-2,62 (m, 5H), 2,32 and 2,20 (2Q, J=11.5 Hz, 2H), 2.26 and 2.24 (2s, 3H) 1.78, and 1,49 (2D, J=11.5 Hz, 2H).13C-NMR (DMSO) 171,5; 171,2; 158,6; 136,8; 136,2; 136,0; 135,8; 130,7; 130,5; 129,7; 129,6; 129,4; 129,2; 128,4; 128,3; 114,5; 55,8; 55,7; 53,3; 53,3; 52,2; 50,2; 46,8; 43,9; 42,9; 36,8; 35,2; 27,6; 26,8; 21,3.

Example 70:2-(4-methoxyphenyl)-N-[2-(2-thienyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH71)

Follow the procedure for obtaining 50ELH14

The reaction stage 1: 4-[2-(2-thienyl)ethylamino]piperidine (50ELH67)

Starting materials: 1-methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 EQ.), thiophene-2-ethylamine (0,563 g, 1.0 EQ.).

Product: UV/MS 94/93 (M+225)

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(2-titilate]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH71)

Raw materials: 50ELH67 (0,243 g at 1.08 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0.2 g, 1.0 EQ.).

Product: output: 80,7 mg (33%), UV/MS 100/100 (M+373), rt(A, MC) 2,6131H-NMR (400 MHz, DMSO, rotamer 50/50) δ is 10.8 and 10.6 (USS, 1H), was 7.36 and 7,31 (2D, 7=a 4.7 Hz, 1H), 7.20 and 7,06 (2D, J=8,3 Hz, 2H), 7,00-6,92 (m, J=4.7 and 2.8 Hz, 2H), 6.87 in and 6,40 (2d, J=8,3 Hz, 2H), 4,22 and 4,08 (dt, J=and 12.2 Hz, 1H), 3,71 (s, 3H), 3,70 (s, 2H), 3.46 in-3,30 (m, 4H), 3,10-2,90 (m, 4H), to 2.67 (m, 2H), 2,28 2,12 and (2Q, J=12 Hz, 2H), of 1.80 and 1.50 (2D, J=12 Hz, 2H).13C-NMR (DMSO) 172,5; 158,9; 139,6; 130,0; 29,6; 126,8; 124,5; 114,5; 55,5; 54,7; 49,3; 45,8; 43,8; 41,3; 31,9; 29,9.

Example 71:2-(4-methoxyphenyl)-N-[2-(4-nitrophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH71)

Follow the procedure for obtaining 50ELH14

The reaction stage 1: 4-[2-(4-nitrophenyl)ethylamino]piperidine (50ELH67)

Starting materials: 1-methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 EQ.), 4-nitrophenyl-2-ethylamine (0,897 g, 1.0 EQ.).

Product: UV/MS 96/89 (M+264), rt(A, MC) 3,264

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(4-nitrophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH71)

Raw materials: 50ELH67 (0,285 g at 1.08 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0.2 g, 1.0 EQ.).

Product: output: 130,9 mg (30%), UV/MS 100/100 (M+412), rt(A, MC) 2,2191H-NMR (400 MHz, DMSO, rotamer 50/50) δ is 10.8 and 10.6 (USS, 1H), 8,17 8,12 and (2D, J=8.6 Hz, 2H), 7,58 and of 7.48 (2D, J=8.6 Hz, 2H), 7.2 and 7,1 (2D, J=8.6 Hz, 2H), 6.87 in and 6,40 (2D, 7-8,6 Hz, 2H), 4.25 in and 4.10 (dt, J=12 Hz, 1H), and 3.72 (s, 3H), 3,70 (s, 2H), 3,48-3,30 (m, 4H), 3,10-2,84 (m, 4H), 2.69 and to 2.67 (2D, J=4,7 Hz, 3H), 2,34 and 2.15 (2Q, J=13,2 Hz, 2H), 1,79 and 1.47 (2D, J=13,2 Hz, 2H).

Example 72:2-(4-methoxyphenyl)-N-(2-thienylmethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH73)

Follow the procedure for obtaining 50ELH14

The reaction stage 1: 4-[(2-thienylmethyl)amino]-1-methylpiperidin (50ELH66)

Starting materials: 1-methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 EQ.), 2-thienylmethyl (0.52 g, 1.0 EQ.).

Product: UV/MS 77/86 (M+211), rt(A, MC) 2,739

The reaction stage 2: 2-(4-methoxyphenyl)-N-(2-thienylmethyl-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH73)

Raw materials: 50ELH66 (0,228 g at 1.08 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0.2 g, 1.0 EQ.).

Product: output: to 178.4 mg (50%), UV/MS 100/98 (M+359), rt(A, MC) 3,1171H-NMR (400 MHz, DMSO) δ of 10.9 and 10.6 (USS, 1H), 7,47 and to 7.32 (2D, J=4.5 Hz, 1H), 7.20 and 7,03 (2D, J=8,4 Hz, 2H), 7.03, and 6,98 (2m, 1H), 6.87 in (m, 3H), 4,70 and 4.57 (2s, 2H), 4,42 and 4,16 (2T, J=11,9 Hz, 1H), of 3.77 and of 3.60 (2s, 2H), 3,51 (s, 3H)and 3.15 (m, 2H), 2,98 (m, J=11,9 Hz, 2H), 2,65 (2D, J=4.5 Hz, 3H), and 2.17 to 2.25 (2Q, J=11,9 Hz, 2H), 1,69, and 1.44 (2D, J=11,9 Hz, 2H).13C-NMR (DMSO) 171,4; 158,6; 143,2; 130,7; 128,1; 126,6; 126,3; 125,9; 114,5; 55,7; 53,3; 52,6; 50,0; 42,8; 27,7; 26,8.

Example 73:2-(4-methoxyphenyl)-N-(furfuryl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH73)

Follow the procedure for obtaining 50ELH14

The reaction stage 1: 4-(furfurylamine)-1-methylpiperidin (50ELH66)

Starting materials: 1-methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 EQ.), furfurylamine (of 0.43 g, 1.0 EQ.).

Product: UV/MS 77/92 (M+195), rt(A, MC) 2,812

The reaction stage 2: 2-(4-methoxyphenyl)-N-(furfuryl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH73)

Raw materials: 50ELH66 (0.21 g, a 1.08 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0.2 g, 1.0 EQ.).

Product: yield: 134 mg (36%), UV/MS 100/99 (M+343), rt(A, MC) 2,4011H-NMR (400 MHz, DMSO, rotamer 57/43) δ 10,95 and 10,75 (USS, 1H), 7,63 and of 7.48 (s, 1H), 7,18 and 7,06 (2D, J=7.7 Hz, 2H), 6,85 (t, J=7.7 Hz, 2H), 6,44 and 6,33 (2D, J=7.7 Hz, 1H), 6,37 and 6,11 (2s, 1H) 4,5 and 4.34 (2s, 2H), 4,42 and 4,18 (dt, J=11 and 2 Hz, 1H), 3,75, and the 3.65 (2s, 2H) 3,70 (s, 3H), 3.33 and (masked, 2H), 3.0 a (kV, 2H), 2,64 (d, J=4,7 Hz, 3H), 2,15 (DQC, J=11 and 2 Hz, 2), of 1.65 and 1.50 (2D, J=11 Hz, 2H).

Example 74:2-(2-thienyl)-N-(4-methylphenylethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH82)

Follow the procedure for obtaining 50L14.

The reaction stage 2: 2-(2-trimethyl)-N-(4-methylphenylethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH82)

Raw materials: 50ELH25 (0,30 g, 1.38 mmol, 1.0 EQ.), thiophene-2-acetylchloride (0,22 g, 1.0 EQ.).

Product: yield: 235 mg (62%), UV/MS 97/93 (M+343), rt(A, MC) 2,7951H NMR (400 MHz, DMSO, rotamer 54/46) δ 10,8 and or 10.60 (USS, 1H), 7,4 and 7.35 (2D, 1H), 7,2-6,76 (m, 6N), 4,55 and 4.4 (2s, 2H), 4,49 and 4.26 (dt, J=11 and 2 Hz, 2H), 4,15 and with 3.79 (2s, 2H), 3,32 (d, J=11 Hz, 2H), 2,99 (kV, 2H), 2.63 in (s, 3H), 2,27 and of 2.23 (2s, 3H), 2,09 (kV, J=11 Hz, 2H), 1.66, and 1.55V (2D, J=Hz, 2H).

Example 75:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide (42ELH75)

Follow the procedure for obtaining 42ELH80, except that the reaction is carried out at a temperature of 60aboutWith in 3 days.

Raw materials: 50ELH87 (0.25 g, 0.71 mmol, 1.0 EQ.), cyclopentylamine (in 0.288 g, 3.0 EQ.).

Product: output: 91,2 mg (34%), UV/MS 88/93 (M+421), rt(A, MC) 4,450

Example 76:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,3-dihydro-2H-benzimidazole-2-on-1-yl)propyl]piperidine-4-yl}ndimethylacetamide (50ELH89)

50ELH87 (0.05 g, 0.14 mmol, 1 EQ.) transferred into the vial of 4 ml and dissolved in 1 ml of acetonitrile. Then add 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazole-2-he (to 0.032 g, 1.1 equiv.) sodium carbonate (0,022 g, 1.1 EQ.) and KI (one crystal) flacon tightly closed and shaken for 20 hours at 82 aboutC. the mixture is extracted with distilled water (pH 10 sodium carbonate) and dichloromethane (3 times), the organic layers are dried with sodium sulfate and concentrated. Specified in the title compound purified HPLC and evaporated to dryness to obtain salt triperoxonane acid. Output: 8,8 mg (12%). UV/MS 100/100 (M+527), rt(A, MC) 2,851

Example 77:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-methylthiazole-4-ylmethyl)piperidine-4-yl]ndimethylacetamide (63ELH1)

50ELH87 (0.3 g, 0,852 mmol, 1 EQ.) and the hydrochloride of 4-(chloromethyl)-2-methylthiazole (0,235 g, 1.5 EQ.) bring in a bottle 7 ml and dissolved in acetonitrile (3 ml). Then add sodium carbonate (141,3 g, 1.2 EQ.) and one crystal of KI and the bottle tightly closed and shaken for 20 hours at 82aboutC. Then the reaction mixture is extracted with distilled water (which is alkalinized with potassium carbonate to pH 10) and dichloromethane. The crude product is dried with sodium sulfate and concentrated. After purification by HPLC the product in turn cleaners containing hydrochloride salt by dissolving the free base in 1 ml of dichloromethane and adding 1 EQ. HCl in ether (2 M). The mixture is added dropwise to an excess of heptane, which is the precipitation of the product. The solvent is removed by evaporation to obtain a white powder product. Output: is 83.8 mg (21%). UV/MS 100/90 (M+463), rt(MC) 11,82

Example 78:2-(4-netoxygen the l)-N-(2-4-forfinal)ethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93)

Follow the procedure for obtaining 50ELH14

The reaction stage 1: 4-[2-4-(forfinal)ethylamino]-1-methylpiperidin (50ELH92)

Starting materials: 1-methyl-4-piperidone (0.3 g, to 2.65 mmol, 1.0 EQ.), 4-(forfinal)ethylamine (0,369 g, 1.0 EQ.).

Product: UV/MS 60/92 (M+237), rt(A, MC) 3,422

The reaction stage 2: 2-(4-methoxyphenyl)-N-(2-4-forfinal)ethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93)

Raw materials: 50ELH92 (0.625 g, to 2.65 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,488 g, approx. 1.0 EQ.).

Product: output: 181 mg (18%), UV/MS 87/97 (M+385), rt(A, MC) 2,783, Rf0,8 (10%Meon/CH2Cl2)1H-NMR (400 MHz, DMSO, rotamer 50/50) δ 10,9 (Ushs, 1H), 7,56 to 6.8 (m, 8H), 4.26% and was 4.02 (Ust, 2H), 3,70, and 3.95 (2s, 3H), 3,59 and 3.57 (2s, 2H), 3,4-3,15 (m, 5H), 2,96-of 2.66 (m, 5H), 2,62, and 2,56 (2s, 3H), 2,29 and 2.10 (2Q, 2H), 1,73 and 1.41 (2D, 2H).13C-NMR (DMSO) 172,5; 171,4; 171,3; 162,9; 162,7; 160,5; 160,3; 158,9; 158,6; 136,1; 136,1; 135,3; 131,4; 131,3; 131,1; 131,0; 131,0; 130,6; 130,5; 128,4; 128,4; 126,9; 115,9; 115,8; 115,7; 115,6; 114,5; 55,7; 53,7; 53,5; 52,7; 52,3; 50,7; 46,7; 43,8; 43,2; 43,0; 36,3; 34,7; 27,9; 26,9.

Example 79:2-(4-methoxyphenyl)-N-[2-(2,5-acid)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93)

Follow the procedure for obtaining 50ELH14. A small amount purified by HPLC and evaporated to dryness with the formation of salt triperoxonane acid.

The reaction stage 1: 4-[2-(2,5-acid), ethylamino]-1-methylpiperidin (50ELH92)

Raw materials: methyl-4-piperidone (0.3 g, to 2.65 mmol, 1.0 EQ.), 2,5-(dimethoxyphenyl is)ethylamine (0,481 g, 1.0 EQ.).

Product: UV/MS 81/90 (M+279), rt(A, MC) 2,868

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(2,5-acid)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93)

Raw materials: 50ELH93 (0,737 g, to 2.65 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,488 g, approx. 1.0 EQ.).

Product: UV/MS 82/100 (M+427), rt(MC) 8,44, Rf0,8 (10%Meon/CH2Cl2)

Example 80:2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93D)

Follow the procedure for obtaining 50ELH14, but are cleaned by HPLC and evaporated to dryness with the formation of salt triperoxonane acid.

The reaction stage 1: 4-[2-(2,4-dichlorophenyl)ethylamino]-1-methylpiperidin (50ELH92D)

Starting materials: 1-methyl-4-piperidone (0.3 g, to 2.65 mmol, 1.0 EQ.), 2,5-(dichlorophenyl)ethylamine (0.5 g, 1.0 EQ.).

Product: UV/MS 82/92 (M+287), rt(A, MC) 4,875

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93D)

Raw materials: 50ELH93D (0,76 g, to 2.65 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,488 g, approx. 1.0 EQ.).

Product: UV/MS 100/96 (M+435), rt(A, MC) 4,415, Rf0,8 (10%Meon/CH2Cl2)

Example 81:2-(4-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93)

Follow the procedure for obtaining 50ELH14, but are cleaned by HPLC and evaporated to dryness formed with the eat salt triperoxonane acid.

The reaction stage 1: 4-[(3-chlorophenyl)ethyl)amino]-1-methylpiperidin (50ELH92)

Starting materials: 1-methyl-4-piperidone (0.3 g, to 2.65 mmol, 1.0 EQ.), 3-(chlorophenyl)ethylamine (0,413 g, 1.0 EQ.).

Product: UV/MS 86/88 (M+253), rt(A, MC) 3,175

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH93)

Raw materials: 50ELH93 (0,67 g, to 2.65 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,488 g, approx. 1.0 EQ.).

Product: UV/MS 100/100 (M+401), rt(A, MC) 3,464, Rf0,8 (10%Meon/CH2Cl2)

Example 82:2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH95)

Follow the procedure for obtaining 50ELH14. Carry out cleaning by HPLC and evaporated to dryness with the formation of salt triperoxonane acid.

The reaction stage 1: 4-[(4-methoxyphenyl)ethyl)amino]-1-methylpiperidin (50ELH94)

Starting materials: 1-methyl-4-piperidone (0.3 g, to 2.65 mmol, 1.0 EQ.), 4-methoxyphenylethylamine (0.40 g, 1.0 EQ.).

Product: UV/MS 74/87 (M+249), rt(A, MC) 2,935

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH95)

Raw materials: 50ELH94 (0,657 g, to 2.65 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,488 g, approx. 1.0 EQ.).

Product: UV/MS 100/100 (M+397), rt(A, MC) 2,389, Rf0,8 (10%Meon/CH2Cl2)

Example 83:2-(4-methoxyphenyl)-N-[2-(3-FPO is phenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH95D)

Follow the procedure for obtaining 50ELH14. Carry out cleaning by HPLC and evaporated to dryness with the formation of salt triperoxonane acid.

The reaction stage 1: 4-[2-((3-forfinal)ethyl)amino]-1-methylpiperidin (50ELH94D)

Starting materials: 1-methyl-4-piperidone (0.3 g, to 2.65 mmol, 1.0 EQ.), 3-forgenerations (0,369 g, 1.0 EQ.).

Product: UV/MS 74/89 (M+237), rt(A, MC) 2,946

The reaction stage 2: 2-(4-methoxyphenyl)-N-[2-(3-forfinal)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (50ELH95D)

Raw materials: 50ELH94D (0.625 g, to 2.65 mmol, 1.0 EQ.), 4-methoxyphenylacetylene (0,488 g, approx. 1.0 EQ.).

Product: UV/MS 100/95 (M+385), rt(A, MC) 2,946, Rf0,8 (10%Meon/CH2Cl2)

Example 84:2-(4-ethoxyphenyl)-N-[2-(4-forfinal)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (63ELH20)

The reaction stage 1: Chloride 4-ethoxyphenylacetic acid (63ELH19)

4-ethoxyphenylacetic acid (0.5 g, 2.8 mmol) is transferred into the vial 7 ml and dissolved in thionyl chloride (3 ml). The reaction mixture was shaken at 70aboutC for 2.5 hours. The thionyl chloride is evaporated and the remaining product is used without further purification.

The reaction stage 2: 2-(4-ethoxyphenyl)-N-[2-(4-forfinal)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide (63ELH20)

63ELH17 (0.11 g, 0.47 mmol) is transferred into the vial of 4 ml and dissolved in dichloromethane. Then add 63ELH19 (0,084 mg, 1 EQ.) and the bottle is tightly closed and the reaction is th mixture is shaken for 20 hours. Then the product is extracted with distilled water (which is alkalinized with potassium carbonate to pH 10) and dichloromethane. Dried with sodium sulfate and concentrated. Purify by HPLC. Extraction, drying and concentration is repeated and then the product pererastayut in dichloromethane (1 ml) and add HCl (1 EQ., 2 M in ether). The mixture is added dropwise to an excess of heptane, when this occurs the precipitation of the salt. Output: the 33.4 mg (18%). UV/MS 92/100 (M+399), rt(MC) 10,38

Example 85:2-(4-ethoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide (63ELH21)

50ELH4 (0.11 g, 0.49 mmol, 1.0 EQ.) transferred into the vial of 4 ml and dissolved in dichloromethane. Then add 63ELH19 (0,089 mg, 1 EQ.) and the bottle is tightly closed and the reaction mixture is shaken for 20 hours. Then the product is extracted with distilled water (which is alkalinized with potassium carbonate to pH 10) and dichloromethane. Dried with sodium sulfate and concentrated. Purify by HPLC. Extraction, drying and concentration is repeated and then the product pererastayut in dichloromethane (1 ml) and add HCl (1 EQ., 2 M in ether). The mixture is added dropwise to an excess of heptane, when this occurs the precipitation of the salt. Yield: 31.1 mg (16%). UV/MS, they set the 94/100 (M+385), rt(A, MC) 2,573

Example 86:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(3-hydroxy-4-methoxyphenyl)ndimethylacetamide (57MBT12B)

N-((4-(were)m is Teal)-4-amino-1-methylpiperidin (50ELH25) (105 mg; 0.48 mmol) and 3-hydroxy-4-methoxyphenylacetic acid (88 mg; 0.48 mmol) dissolved in DMF (10 ml). Add diisopropylethylamine (DIEA, 250 µl; 1.44 mmol) and then hexaphosphate bromo-Tris-pyrrolidinone (PyBrOP, 336 mg; to 0.72 mmol) and the mixture is stirred at room temperature for 1 hour. Add water (50 ml) and the reaction mixture extracted with EtOAc (g ml). Drying with the use of Na2SO4and concentration give 514 mg of the crude material, which was purified flash chromatography (0-30% MeOH in CH2Cl2). You get 105 mg (57%) indicated in the title compounds as white solids. Rf=0,20 (10% MeOH in CH2Cl2). The results of HPLC-MS (method a) to give MN+=383. UV/MS(%)=100/92.1H-NMR (400 MHz, CD3OD, rotamer 52:48): δ 7.18 in return of 6.58 (m, 7H), a 4.53 (s, 2H), 4 : 31 and of 3.97 (2m, 1H), 3,82 and 3,81 (2s, 3H), 3,80, and 3,55 (2s, 2H), 3.04 from and 2,85 (2m, 2H), 2.41 and 2,32 (2s, 3H), 2.35 and 2,12 (2m, 2H), 2,29 of 2.27 and (2s, 3H), 1.83 and of 1.74 (2m, 2H), 1,72 and 1,33 (2m, 2H).

Example 87:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(3,4-dihydroxyphenyl)ndimethylacetamide (57MBT24B)

N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(3-hydroxy-4-methoxyphenyl)ndimethylacetamide (57MBT12B) (52 mg; 0,136 mmol) dissolved in CH2Cl2(1 ml) and cooled to -78°C. is Added dropwise tribromide boron (1 M in CH2Cl2, 204 μl; 0,204 mmol) and remove the cooling bath. After stirring for 2 hours we use the t methanol (2 ml) and the mixture is evaporated. The resulting oil purified preparative HPLC to obtain 24 mg (48%) indicated in the title compounds as white solids. The results of the HPLC-MS (method a) to give MN+=369. UV/MS(%)=100/97.1H-NMR (400 MHz, CD3OD, rotamer 33:67): δ 7,19-6,47 (m, 7H), 4,54 and 4,53 (2s, 2H), 4,23 (m, 1H), 3,83 and to 3.58 (2s, 2H), 3.46 in and 3.40 (USD, J=12 Hz, 2H), 3,02 and 2.95 (OST, J=12 Hz, 2H), and 2.79 (s, 3H), 2,33, and of 2.28 (2s, 3H), 2,17 and 1,84 (DCV, J=4,12 Hz, 2H), 1,87 1.48 (USD, J=12 Hz, 2H).

Example 88:N-((3-hydroxy-4-were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-methoxyphenyl)ndimethylacetamide (57MBT54B)

N-((4-methoxyphenyl)methyl)-4-amino-1-methylpiperidine (1 g; 4,27 mmol) dissolved in 4% solution of formic acid in methanol (60 ml). In argon atmosphere, add 10% Pd/C (1 g) and the reaction mixture is heated to boiling point under reflux for 24 hours. The mixture is filtered through celite and the filtrate acidified with concentrated HCl to pH 1. Concentration gives a yellow oil, which was purified flash chromatography (MeOH/CH2Cl23:7 + 3.5% of NH4OH) to give 249 mg (51%) of 4-amino-1-methylpiperidine (57MBT36B) as a white solid. Rf=0,13 (10% MeOH in CH2Cl2+ 3,5% NH4OH). The results of HPLC-MS (method B) give MN+=115. UV/MS(%)=-/100.

4-Amino-1-methylpiperidin (57MBT36B) (26 mg; 0,231 mmol) dissolved in methanol (1 ml) and add 3-hydroxy-4-methylbenzaldehyde (32 mg; 0,231 mmol who) and acetic acid (33 ml). The mixture is cooled to 0°C. Add NaBH3CN (29 mg; 0,462 mmol) and remove the cooling bath. After 3 hours the mixture is evaporated and hold flash chromatography (0-30% MeOH in CH2Cl2), which gets 27 mg (50%)N-((3-hydroxy-4-were)methyl)-4-amino-1-methylpiperidine (57MBT44C) as a white solid. Rf=0,27 (10% MeOH in CH2Cl2+ 3,5% NH4OH). The results of HPLC-MS (method a) to give MN+=235. UV/MS(%)=99/99.

N-((3-Hydroxy-4-were)methyl)-4-amino-1-methylpiperidin (57MBT44C) (27 mg; 0,115 mmol) dissolved in CH2Cl2(2 ml). In the atmosphere of argon is added dropwise 4-methoxyphenylacetylene (17 μl; 0,115 mmol). After 3 hours addn-heptane (3 ml) and the mixture is evaporated. Flash chromatography (0-20% MeOH in CH2Cl2) give 14 mg (32%) indicated in the title compounds as white solids. Rf=0,32 (10% MeOH in CH2Cl2+ 3,5% NH4OH). The results of HPLC-MS (method a) to give MN+=383. UV/MS(%)=99/96.1H-NMR (400 MHz, CD3OD, rotamer 63:37); δ 7,28-6,55 (m, 7H), 4,48 (s, 2H), 4,37, and 3.95 (2m, 1H), 3,78, and of 3.77 (2s, 3H), 3,06 and 2,89 (USD, J=12 Hz, 2H), 2,42 and 2,32 (2s, 3H), 2.40 a and 2.12 (2m, 2H), 2,18 and 2.12 (2s, 3H), of 1.86 and 1.83 (2m, 2H), and 1.35 to 1.75 (USD, J=12hz, 2H).

Example 89:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-bromophenyl)ndimethylacetamide hydrochloride (57MBT70-1D)

4-bromoferrocene acid (54 mg; 0,252 mmol) dissolved in CH2Cl2(2 ml) is added N-((4-(were)methyl)-4-amino-1-methylpiperidin (in the form of the storage solution of 292 mg/ml in CH2Cl2; 171 μl; 0,229 mmol) and diisopropylethylamine on a polystyrene substrate (PS-DIEA with a load of 3.57 mmol/g; 192 mg; 0,687 mmol), and then add hexaphosphate bromo-Tris-pyrrolidinone (PyBrOP; the storage solution of 160 mg/ml; 1 ml; 0,334 mmol). The reaction mixture was shaken for 1 hour at room temperature and then filtered in a pre-washed (methanol) ion exchange column (0.88 mmol/g; 1 g). The column is washed with methanol (8×4 ml) and the remaining product is extracted from the column using 10% NH4OH in methanol (2×4 ml) and evaporated. The resulting oil was filtered through silica gel (N=4 cm, D=1 cm) in a mixture of methanol/CH2Cl21:9 (20 ml), evaporated and applied to a second ion exchange column (0.88 mmol/g; 1 g). The column is washed with methanol (8×4 ml) and the remaining product elute column with 10% NH4OH in methanol (2×4 ml) and evaporated on a rotary evaporator with an oil pump. The product was dissolved in CH2Cl2(0.5 ml) and added HCl in diethyl ether (1.0 M; 0.1 ml; 0.1 mmol). The solution is added ton-heptane (3 ml) and evaporated to obtain 29 mg (25%) indicated in the title compounds as white solids. Rf=0,31 (10% MeOH in CH2Cl2). The results of HPLC-MS (method B) give MN+=416. UV/MS(%)=100/99.

Example 90: N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-itfeel)ndimethylacetamide hydrochloride (57MBT70-2D)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 33 mg (26%). Rf=0,31 (10% MeOH in CH2Cl2). The results of HPLC-MS (method B) give MN+=463. UV/MS(%)=100/98.

Example 91:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-(2-propyl)phenyl)ndimethylacetamide hydrochloride (57MBT70-3D)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 36 mg (34%). Rf=0,31 (10% MeOH in CH2Cl2). The results of HPLC-MS (method B) give MN+=379. UV/MS(%)=100/97.

Example 92:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-trifloromethyl)ndimethylacetamide hydrochloride (57MBT70-4D)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 35 mg (30%). Rf=0,27 (10% MeOH in CH2Cl2). The results of HPLC-MS (method B) give MN+=421. UV/MS(%)=100/99.

Example 93:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-methylthiophenyl)ndimethylacetamide hydrochloride (57MBT70-5D)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 35 mg (33%). Rf=0,30 (10% MeOH in CH2Cl2). The results of HPLC-MS (method B) give MN+=383. UV/MS(%)=100/99.

Example 94:N-((4-(were)methyl)-N-(1 methylp is peridin-4-yl)-2-(4-( NN-dimethylamino)phenyl)ndimethylacetamide hydrochloride (57MBT70-6D)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 16 mg (15%). Rf=0,25 (10% MeOH in CH2Cl2). The results of HPLC-MS (method a) to give MN+=380. UV/MS(%)=100/100.

Example 95:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-nitrophenyl)ndimethylacetamide hydrochloride (57MBT70-7D)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 28 mg (27%). Rf=0,27 (10% MeOH in CH2Cl2). The results of HPLC-MS (method B) give MN+=382. UV/MS(%)=100/100.

Example 96:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-methoxy-3-were)ndimethylacetamide hydrochloride (57MBT70-8D)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 34 mg (32%). Rf=0,30 (10% MeOH in CH2Cl2). The results of HPLC-MS (method B) give MN+=381. UV/MS(%)=100/99.

Example 97:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-pyridyl)ndimethylacetamide hydrochloride (57MBT70-9F)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 18 mg (17%). Rf=0,09 (10% MeOH in CH2Cl2). The results of HPLC-MS (method a) to give MN+=338. UV/MS(%)=100/100.

Example 98:N-((4-(were)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-were)ndimethylacetamide hydrochloride(57MBT62B)

Specified in the header connection receive in accordance with the example of getting MBT04. Yield: 10 mg (35%). Rf= (10% MeOH in CH2Cl2). The results of HPLC-MS (method a) to give MN+=351. UV/MS(%)=100/100.

Example 99:N-((4-(hydroxymethyl)phenyl)methyl)-N-(1 methylpiperidin-4-yl)-2-(4-methoxyphenyl)ndimethylacetamide hydrochloride (57MBT72D)

To a stirred suspension of LiAlH4(285 mg; 7,52 mmol) in diethyl ether (10 ml) at 0°C is added dropwise within 15 minutes to a solution of 4-cyanobenzyl alcohol (0.5 g; 3,76 mmol) in diethyl ether (5 ml). Grey reaction mixture is heated to boiling point under reflux for 3 hours. After cooling to room temperature, the mixture is treated successively with water (1 ml), 2 M NaOH (2 ml) and water (2 ml) under vigorous stirring. The obtained white suspension was filtered and washed with CH2Cl2(20 ml). Extraction of additional CH2Cl2(20 ml) andn-butanol (20 ml) and evaporation produce oil, which after flash chromatography (0-15% MeOH in CH2Cl2) to give 152 mg (29%) 4-(aminomethyl)benzyl alcohol (57MBT52B) as a white solid. Rfor =0.51 (30% MeOH in CH2Cl2+ 3,5% NH4OH).

1-Methyl-4-piperidone (84 μl; 0.73 mmol) was dissolved in methanol (5 ml) and add 4-(aminomethyl)benzyl alcohol (57MBT52B) (100 mg; 0.73 mmol) followed by the addition of uksosn the th acid (125 μl). Then add NaBH3CN (92 mg; of 1.46 mmol) and the mixture is stirred for 3 hours. The reaction mixture is evaporated and added 2M NaOH (5 ml). Extraction of CH2Cl2(4×5 ml), drying with Na2SO4and evaporation give 152 mg (87%)N-((4-(hydroxymethyl)phenyl)methyl)-4-amino-1-methylpiperidine (57MBT56D). Analysis by HPLC-MS (method B) gives MN+=235. UV/MS(%)=100/100.

N-((4-(Hydroxymethyl)phenyl)methyl)-4-amino-1-methylpiperidin (57MBT56D) (20 mg; 0,0853 mmol) dissolved in CH2Cl2(2 ml) and added dropwise 4-methoxyphenylacetylene (26 μl; 0,171 mmol). The reaction mixture is stirred for 1 hour and add water (500 μl) followed by evaporation. Then add a solution of sodium (5 mg; 0,179 mmol) in methanol (2 ml). After stirring for 4 hours the solution is transferred into a pre-washed (methanol) ion exchange column (0.88 mmol/g; 1 g) and washed with methanol (4×4 ml). The remaining product elute column with 10% NH4OH in methanol (2×4 ml) and evaporated. The resulting oil was filtered through silica gel (h=4 cm, d=1 cm) in a mixture of methanol/CH2Cl22:8 (20 ml), evaporated and applied to a second ion exchange column (0.88 mmol/g; 1 g). The column is washed with methanol (8×4 ml) and the remaining product elute column with 10% NH4OH in methanol (2×4 ml) and evaporated on a rotary evaporator with an oil pump. The product was dissolved in CH Cl2(0.5 ml) and added HCl in diethyl ether (1.0 M; 0.1 ml; 0.1 mmol). The resulting solution is added ton-heptane (3 ml) and evaporated to obtain 14 mg (39%) indicated in the title compounds as white solids. Rf=0,16 (10% MeOH in CH2Cl2). Analysis by HPLC-MS (method B) gives MN+=383. UV/MS(%)=100/96.

Example 100:2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide (47AKU-7)

1-TRIFLUOROACETYL-4-piperidone (47AKU-2)

Monohydrate hydrochloride 4-piperidone (3,85 g; 25 mmol) and triethylamine (10.5 ml; 75 mmol) partially dissolved in 100 ml dichloromethane and stirred for 10 minutes. Then the reaction mixture was cooled in an ice bath and slowly added over 10 minutes triperoxonane anhydride (7.2 ml; 50 mmol). The ice bath removed and the mixture is stirred over night. Pay an additional amount triperoxonane anhydride (2 ml) and the mixture is stirred for 1 hour. Add water (200 ml). The phases are separated and the aqueous phase re-extracted with dichloromethane. The combined organic phases are washed with saturated saline solution, dried over MgSO4and concentrate (40°C) obtaining equal to 4.97 g (100 %) 47AKU-2 as yellow crystals. TLC (5% methanol in dichloromethane): Rf=0,8.1H-NMR (400 MHz, CDCl3): δ = a 3.87-3,99 (4H,m); 2,54-2,61 (4H, m).13C-NMR (CDCl3): δ= 204,7, 118,0, 115,1, 44,2, 42,8, 41,2 40,5.

4-(4-Methylbenzylamino)-1-triftoratsetatov (47AKU-3)

47AKU-2 (equal to 4.97 g; 25 mmol) is dissolved in 100 ml of methanol and add 4-methylbenzylamine (3.2 ml; 25 mmol). The mixture is stirred and add acetic acid (~2 ml) to pH~5. Slowly add NaCNBH3(3,15 g; 50 mmol). After stirring on a magnetic stirrer for 20 hours, the methanol is partially removed on the rotary evaporator (40°C). Add dichloromethane, 2M NaOH and water to pH~10. The phases are separated and the aqueous phase re-extracted twice with dichloromethane. The combined organic phases are washed with saturated saline and dried over MgSO4. Concentration (40°C) gives 6,94 g (92%) 47AKU-3. TLC (10% methanol in dichloromethane): Rfor =0.6. Analysis by HPLC-MS (method A): M+=301,0 (UV/MS(%)=they set the 94/100).

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-triftoratsetatov-4-yl)ndimethylacetamide (47AKU-4)

47AKU-3 (3,01 g; 10 mmol) in 25 ml of dichloromethane are placed in a 100-ml flask. Add triethylamine (1.4 ml; 10 mmol) and the mixture is cooled in an ice bath and stirred for 10 minutes. 4-chlorophenylacetyl (1,90 g; 10 mmol) is dissolved in 10 ml of dichloromethane and added slowly to a chilled on ice the reaction mixture. After 15 minutes the ice bath is removed and the mixture is left for 1 hour. Observed precipitation. Then the reaction mixture is concentrated by suction (40°C). The crude product is purified flash chrome is ografia (0-50% ethyl acetate in heptane) to give 2.38 g (53%) 47AKU-4. TLC (100% dichloromethane): Rfor =0.6. Analysis by HPLC-MS (method A): M+=453,0 (UV/MS(%)=89/84).

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(piperidine-4-yl)ndimethylacetamide (47AKU-6)

47AKU-4 (2.38 g; ~5 mmol) is dissolved in 50 ml of methanol. Add in one portion K2CO3(3.5 g; 25 mmol). After stirring on a magnetic stirrer for 20 hours bring an additional number of K2CO3(1 g). After stirring on a magnetic stirrer for 4 hours, the methanol is partially removed by evaporation (40°C). Add ethyl acetate (100 ml) and water. The phases are separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried over MgSO4and concentrate (40°C) obtaining 1,95 g (100%) 47AKU-6. TLC (20% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method A): M+=357,1 (UV/MS(%)=84/95).

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N(isopropylpiperazine-4-yl)ndimethylacetamide (47AKU-7)

47AKU-6 (358 mg; 1.0 mmol) was dissolved in 20 ml of acetonitrile. Add triethylamine (1.4 ml; 10 mmol) and the mixture is stirred for 10 minutes. Isopropylamine (370 mg; 3.0 mmol) dissolved in 5 ml of acetonitrile and added dropwise to the reaction mixture, which was stirred at room temperature for 20 hours and then heated to 60°C for 4 hours. After cooling, add ethyl acetate (25 ml) and water (25 ml). The phases are separated and the aqueous phase re e is stragiht with ethyl acetate. The combined organic phases are washed with saturated saline solution, dried over MgSO4and concentrate (40°C) to give 362 mg of crude product. Purification with flash chromatography (0-10% methanol in dichloromethane) and settling under the action of HCl from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane to give 76 mg (18%) 47AKU-7. TLC (10% methanol in dichloromethane): Rf=0,4. Tpl.=P.223-224°C. Analysis by HPLC-MS (method A): M+=399,1 (UV/MS(%)=100/99).1H-NMR (400 MHz, CDCl3): δ = 7.03 is-7,29 (8H, m); a 4.86 (1H, m); br4.61 (2H, m); to 3.58 (2H, m); 3,37 (3H, m); 2,82 (2H, m); of 2.64 (2H, m); of 2.34 (3H, s); of 1.80 (2H, m); of 1.39 (6H, d).13C-NMR (DCl3): δ= 172,4, 137,4, 134,8, 133,3, 133,1, 130,4, 129,9, 129,0, 125,8, 58,0, 49,5, 48,2, 46,6, 40,4, 26,0, 21,2, 17,0.

Example 101:2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperazin-4-yl)-2-(4-bromophenyl)ndimethylacetamide (47AKU-12)

47AKU-6 (358 mg; 1.0 mmol) was dissolved in 20 ml of acetonitrile. Add triethylamine (1.4 ml; 10 mmol) and the mixture is stirred for 10 minutes. Add ethylbromide (370 μl; 5.0 mmol). The mixture is then heated to 50°C. and stirred over night. After cooling, add water (25 ml) and ethyl acetate (25 ml). The phases are separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are washed with saturated saturated saline and dried over MgSO4. Evaporation (40°C) give 406 mg of crude product. Purification by ion exchange chromatography (flushing 10% aqueous NH4OH (5%) in methanol) to give 166 mg (43%) 47AKU-12. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. Analysis by HPLC-MS (method A): M+=385,1 (UV/MS(%)=100/99).1H-NMR (400 MHz, CDCl3, rotamer): δ = 7,02-7,34 (8H, m); to 4.62 (1H, m); 4,46 and a 4.53 (2H, 2s); 3,81 (1H, s); 3,55 (2H, s); 2,92 (2H, m); of 2.34 (3H, s); to 2.29 (1H, s); to 1.98 (2H, m); 1,52-of 1.84 (4H, m)of 1.03(3H, t).13C-NMR (DCl3): δ= 171,7, 137,2, 135,4, 133,9, 132,8, 130,4, 129,7, 128,9, 125,8, 52,8, 52,4, 46,5, 40,8, 31,2, 28,8, 21,2, 12,4.

Example 102:2-phenyl-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-13)

47AKU-5 (218 mg, 1.0 mmol) dissolved in 2 ml of dichloromethane in a flask of 50 ml Add phenylacetylene (134 μl; 1.0 mmol). After 3 hours stirring at room temperature the mixture is concentrated on a rotary evaporator (40°C). The crude product is purified by ion-exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) and flash chromatography (0-10% methanol in dichloromethane) to give 48 mg (14%) 47AKU-13. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=sauce 337,1 (UV/MS(%)=98/98).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,01-7,40 (9H, m); 4,63 (1H, m); 4.53-in and 4.45 (2H, 2s); 3,85 and 3,61 (2H, 2s); 2,86 and 2.77 (2H, 2m); 2.35 and to 2.29 (3H, 2s); 2,25 and of 2.20 (3H, 2s); of 2.09 (2H, m); 1,61 is 1.86 (4H, m).13C-NMR (CDCl3): δ= 172,2, 137,1, 135,5, 129,7, 128,9, 128,8, 127,2, 126,9, 125,8, 55,3, 51,6, 46,6, 46,1, 41,6, 29,5, 21,2.

Example 103:2-(4-chlorp the Nile)- N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-8)

4-(4-Methylbenzylamino)-1-methylpiperidin (47AKU-5)

1-Methyl-4-piperidone (1.13 g; 10 mmol) was dissolved in 20 ml of methanol and placed in a flask with 100 ml Add 4-methylbenzylamine (1,21 g; 10 mmol) in 10 ml of methanol. Then add acetic acid (~1.5 ml) to pH~5. Then slowly add NaCNBH3(1.26 g; 20 mmol). After stirring on a magnetic stirrer for 20 hours, the methanol is partially evaporated on a rotary evaporator (40°C). Add dichloromethane, water and 2M NaOH to pH~10. The phases are separated and the aqueous phase is twice extracted with dichloromethane. The combined organic phases are washed with saturated saline and dried over MgSO4. Concentration on a rotary evaporator (40°C) yields of 2.06 g of the crude (93 %) 47AKU-5. TLC (20% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method A): M+=219,1 (UV/MS(%)=89/98).

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-8)

47AKU-5 (437 mg; 2.0 mmol) dissolved in 10 ml dichloromethane in a flask of 50 ml Add triethylamine (280 μl; 2.0 mmol) and the mixture cooled to 0°C in an ice bath, and then stirred for 10 minutes. Then dissolve 4-chlorophenylacetyl (380 mg; 2.0 mmol) in 10 ml dichloromethane and added dropwise to the cooled mixture. After 2 hours stirring at room temperature make updat the additional amount of dichloromethane (10 ml) and water (20 ml). The phases are separated and the aqueous phase re-extracted with dichloromethane. The combined organic phases are dried over MgSO4and concentrate on a rotary evaporator (40°C) obtaining 755 mg of crude product. Purification with flash chromatography (0-10% methanol in dichloromethane) to give 485 mg (65%) of product. Further purification by ion exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) to give 239 mg (32%) 47AKU-8. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Tpl.=217-219°C. Analysis by HPLC-MS (method A): M+=371,1 (UV/MS(%)=99/99).1H-NMR (400 MHz, CD3OD): δ = 7,05-7,39 (8H, m); 4,80 (3H, s); 4,62 + 4,56 (2H, 2s); of 4.35 (1H, m); 4,00 (1H, s); 3,71 (1H, s); of 3.46 (2H, m); a 3.06 (2H, m); 2,80 (3H, s); 2,32 + of 2.27 (3H, 2s); 2,19 (1H,m).13C-NMR (CD3OD): δ= 173,0, 137,5, 134,5, 133,9, 132,6, 130,6, 129,5, 128,5, 126,2, 54,0, 51,4, 42,6, 40,2, 31,8, 26,6, 19,9.

Example 104:2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide (47AKU-11)

47AKU-6 (358 mg; 1.0 mmol) was dissolved in 20 ml of acetonitrile. Add triethylamine (1.4 ml; 10 mmol) and the mixture is stirred for 10 minutes. Then add cyclopentylamine (540 μl; 5.0 mmol) and the mixture is stirred at room temperature. After 20 hours the mixture is heated to 50°C for another 24 hours. Then the reaction mixture is cooled and water is added (25 ml) and ethyl acetate (25 ml). The phases are separated and the aqueous phase is again EXT Airout with ethyl acetate. The combined organic phases are washed with saturated saline and dried over MgSO4. Concentration on a rotary evaporator (45°C) gives 426 mg of crude product. Purification by ion exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) and flash chromatography (0-10% methanol in dichloromethane) to give 76 mg (18%) 47AKU-11. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. Analysis by HPLC-MS (method A): M+=425,1 (UV/MS(%)=100/97).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,01-7,34 (8H, m); of 4.67 (1H, m); 4,49 and to 4.52 (2H, 2s); of 3.54 (2H, s); 3,15 and to 3.02 (2H, 2m)of 2.64 (1H, m); 2,27 and was 2.34 (3H, 2s); of 2.20 (1H, m); of 1.85 (4H, m), 1.69 in (4H, m); of 1.53 (4H, m); of 1.37 (1H, m).13C-NMR (Dl3): δ= 171,9, 137,2, 135,2, 133,8, 132,9, 130,4, 129,7, 128,9, 125,8, 67,7, 52,4, 52,1, 46,5, 40,7, 30,2, 28,8, 24,3, 21,2.

Example 105:2-(4-forfinal)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-14)

47AKU-5 (218 mg, 1.0 mmol) dissolved in 3 ml of dichloromethane in a flask of 50 ml Add 4-perforazione (150 μl; 1.1 mmol). After 4 hours stirring at room temperature the mixture is concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 243 mg (68%) 47AKU-14. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. Analysis by HPLC-MS (method A): M+ =355,1 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3): δ = 6,92-7,33 (8H, m); to 4.73 (1H, m); to 4.52 (2H, s); of 3.56 (2H, 2s); 3,44 (5H, m); of 3.25 (2H, m); 2,52-to 2.67 (4H, m); of 2.33 (3H, s).13C-NMR (Dl3): δ= 172,5, 163,3, 160,9, 139,5, 134,8, 130,6, 129,8, 125,8, 115,8, 54,6, 50,8, 49,9, 46,7, 40,4, 27,2, 21,2.

Example 106:2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)-piperidine-4-yl)ndimethylacetamide (47AKU-18)

47AKU-6-2 (358 mg; 1.0 mmol) dissolved in 10 ml of acetonitrile in the flask to 50 ml Add triethylamine (1.4 ml; 10 mmol) and the mixture is stirred for 10 minutes.

Add 2-bromoethanol (215 μl; 3.0 mmol). Then the reaction mixture is heated to 60°C. and stirred over night. After cooling, add ethyl acetate (25 ml) and water (25 ml). The phases are separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are washed with saturated saline solution, dried over MgSO4and concentrate on a rotary evaporator (40°C) to give 406 mg of crude product. Purification with flash chromatography (0-10% methanol in dichloromethane) to give 253 mg (63%) 47AKU-18. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=401,1 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3, rotamer): δ=? 7.04 baby mortality-7,34 (8H, m); 4,60 (1H, m);and 4.45 to 4.52 (2H, 2s); 3,55 (4H, m); 3,03 (1H, Ushs); 2,92 (2H, m); 2,52 (2H, m); 2,36 and 2,31 (3H, 2s); 2,19 (2H, m); of 1.66 (4H, m).).13C-NMR (Dl3): δ= 171,7, 137,3, 135,2, 133,8, 132,9, 13,4, 129,8, 128,9, 125,8, 59,4, 58,1, 53,1, 52,3, 46,8, 40,8, 29,7, 21,2.

Example 107:2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylmethyl-4-yl)ndimethylacetamide (47AKU-19)

1-cyclobutyl-4-piperidone (47AKU-15)

Partially dissolved Quaternary salt (1.23 g; 3.7 mmol) (obtained according to the procedure described for the synthesis of 47AKU-47) slowly add to boiling under reflux the solution cyclobutylamine (178 mg; 2.5 mmol) and potassium carbonate (48 mg, 0.34 mmol) in ethanol. The mixture is refluxed for 1.5 hours. After cooling to room temperature, add water (10 ml) and dichloromethane (25 ml). The phases are separated and the aqueous phase re-extracted with dichloromethane. The combined organic phases are dried over MgSO4and concentrate on a rotary evaporator (40°C) to give 419 mg of the crude 47AKU-15. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=154,1 (MS(%)=75).

4-(4-methylbenzylamino)-1-cyclobutylmethyl (47AKU-16)

4-methylbenzylamine (215 mg; 1.8 mmol) dissolved in 5 ml of methanol and placed in a flask Add 50 ml solution 47AKU-15 (270 mg; 1.8 mmol) in 5 ml of methanol. Then add acetic acid (0.3 ml) until pH~5. Then slowly add NaCNBH3(226 mg; 3.6 mmol). There is gas. After 24 hours stirring on a magnetic stirrer, add dichloromethane, 2M NaOH and water to reach pH~10. F the s are separated and the aqueous phase re-extracted with dichloromethane. The combined organic phases are dried over MgSO4and concentrate on a rotary evaporator (40°C) to give 419 mg of the crude 47AKU-16. TLC (10% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method A): M+=259,1 (UV/MS(%)=44/87).

2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylmethyl-4-yl)ndimethylacetamide (47AKU-19)

47AKU-16 (209 mg; 0.8 mmol) is placed in a flask of 50 ml and add 5 ml of dichloromethane. Then add 4-chlorophenylacetyl (171 mg; 0.9 mmol) in 5 ml of dichloromethane. After 5 hours of stirring on the magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 101 mg (31%) of product. Further purification by ion exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) to give 55 mg (17%) 47AKU-19. Oxalate salt obtained from a solution of oxalic acid (1.1 equivalent) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rfor =0.6. Analysis by HPLC-MS (method B): M+=411,2 (UV/MS(%)=91/86).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,33-7,01 (8H, m); to 4.62 (1H, m); to 4.52 and to 4.46 (2H, 2s); of 3.80 (1H, s); 3.45 points and of 3.54 (2H, 2s); of 2.86 (2H, m); of 2.66 (2H, m); 2,28 and was 2.34 (3H, 2s); to 1.98 (2H, m); of 1.80 (2H, m); 1.70 to of 1.52 (6H,m).13C-NMR (Dl3): δ= 171,7, 137,2, 135,4, 133,9, 132,9, 130,4, 129,7, 128,9, 125,7, 60,4, 52,3, 49,4, 46,5, 40,7, 29,4, 27,6, 21,2, 14,2.

Example 108:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobuta piperidin-4-yl)ndimethylacetamide (47AKU-20)

47AKU-16 (209 mg; 0.8 mmol) is placed in a flask of 50 ml and add 5 ml of dichloromethane. Then add 4-methoxyphenylacetylene (167 mg; 0.9 mmol) in 5 ml of dichloromethane. After stirring for 5 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 72 mg (22%) of product. Further purification by ion exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) to give 67 mg (20%) 47AKU-20. Oxalate salt obtained from a solution of oxalic acid (1.1 equivalent) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rfor =0.6. Analysis by HPLC-MS (method B): M+=407,3 (UV/MS(%)=93/77).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,26-6,79 (8H, m); to 4.62 (1H, m); and 4.45 to 4.52 (2H, 2s); with 3.79 (1H, m); of 3.77 (3H, s); 3,52 and 3.45 (2H, 2s); 2,84 (2H, m); of 2.66 (2H, m); 2,34 and of 2.28 (3H, 2s); to 1.98 (2H, m); is 1.81 (2H, m); 1,72-is 1.51 (6H,m).13C-NMR (Dl3): δ= 172,5, 158,7, 137,0, 135,7, 130,4, 129,8, 127,4, 125,8, 114,3, 60,4, 55,5, 52,1, 49,4, 46,4, 40,6, 29,4, 27,6, 21,2, 14,2.

Example 109:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-azabicyclo[3.2.1]Oct-3-yl)-ndimethylacetamide (47AKU-21)

4-(4-methylbenzylamino)tropan (47AKU-17)

4-methylbenzylamine (607 mg; 5.0 mmol) dissolved in 10 ml of methanol and placed in a flask with 100 ml Add solution tropinona (697 mg; 5.0 mmol) in 10 ml of methanol. Then add acetic acid (0.75 ml) until pH~5. After this is about slowly add NaCNBH 3(628 mg; 10 mmol). There is gas. After 20 hours stirring on a magnetic stirrer, add dichloromethane, 2M NaOH and water to reach pH~10. The phases are separated and the aqueous phase re-extracted with dichloromethane. The combined organic phases are dried over MgSO4. Concentration on a rotary evaporator (40°C) gives to 1.14 g of the crude 47AKU-17. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=245,2 (UV/MS(%)=65/96).

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-according-4-yl)ndimethylacetamide (47AKU-21)

47AKU-17 (244 mg; 1.0 mmol) is placed in a flask of 50 ml and add 5 ml of dichloromethane. Then add 4-methoxyphenylacetylene (203 mg; 1.1 mmol) in 10 ml of dichloromethane. After stirring for 3 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product is purified by ion-exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) and flash chromatography (0-10% methanol in dichloromethane) to give 202 mg (51%) 47AKU-21. Oxalate salt obtained from a solution of oxalic acid (1.1 equivalent) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method B): M+=to 393.3 (UV/MS(%)=94/92).1H-NMR (400 MHz, Dl3, isomers): δ = 7,02-7,17 (6H, m); is 6.78-6.87 in (2H, m); 4,74 (1H, s); of 4.44 (1H, s); 3,78 and of 3.77 (3H, 2s); 3,68 (1H, m); 3,66 and 3,55 (3H, 2s); to 2.65 (2H, m); of 2.56 (2H, m); 2,32 (3H, s); 2,122,26 (6H, m); is 2.05 (2H, m).13C-NMR (Dl3): δ= 173,2, 171,4, 158,8, 137,1, 129,7, 127,6, 126,9, 126,0, 114,4, 63,4, 60,9, 55,5, 54,6, 47,5, 41,5, 40,4, 32,8, 31,1, 27,5, 24,9, 21,2.

Example 110:N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)-N'-benzylcarbamoyl (47AKU-22)

47AKU-5 (219 mg, 1.0 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml and Then add benzylsuccinic (160 mg; 1.2 mmol) in 5 ml of dichloromethane. After stirring for 16 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 236 mg (67%) 47AKU-22. Oxalate salt obtained from a solution of oxalic acid (1.1 equivalent) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. Analysis by HPLC-MS (method B): M+=352,3 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3): δ = 7,26-7,02 (9H, t); br4.61 (1H, m); to 4.41 (1H, m); 4,33 (4H, m); 2,87 (2H, m); 2,32 (3H, s); of 2.25 (3H, s); of 2.09 (2H, m); 1,79-of 1.62 (4H, m).13C-NMR (Dl3): δ= 158,6, 139,7, 137,3, 135,4, 129,8, 128,6, 127,4, 127,2, 126,2, 55,5, 52,2, 46,2, 45,8, 45,0, 30,2, 21,2.

Example 111:N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)-N'-phenylcarbamate (47AKU-24)

47AKU-5 (219 mg, 1.0 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml and Then add phenylisocyanate (143 mg; 1.2 mmol) in 5 ml of dichloromethane. After stirring for 4 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary and is the soaring glider (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 181 mg (54%) 47AKU-24. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=338,3 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3): δ = 7,12-7,24 (8H, m); 6,93-6,98 (1H, m); of 6.26 (1H, s); of 4.45 (3H, s); 2,90 (2H, d); a 2.36 (3H, s); of 2.28 (3H, s); 2,12 (2H,m); 1,69-of 1.85 (4H,m).13C-NMR (Dl3): δ= 156,1, 139,3, 137,8, 134,9, 130,1, 128,9, 126,3, 123,1, 119,9, 55,5, 52,3, 46,3, 46,2, 30,3, 21,3.

Example 112:N-phenethyl-N-(1 methylpiperidin-4-yl)-N'-benzylcarbamoyl (47AKU-25)

4-(2-phenylethyl)amino-1-methylpiperidin (110 mg; 0.5 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml and Then add benzylsuccinic (80 mg; 0.6 mmol) in 5 ml of dichloromethane. After stirring for 20 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 164 mg (84%) 47AKU-25. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=352,3 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3): δ = 7,34-to 7.09 (10H, m); to 4.52 (1H, m); of 4.35 (2H, d); 4,08 (1H, m); of 3.33 (2H, t); 2,92 (2H, m); 2,82 (2H, t); of 2.28 (3H, s); 2,07 (2H, m); 1,84-of 1.66 (4H, m).13C-NMR (Dl3): δ= 157,9, 139,8, 139,1, 129,0, 128,9, 128,8, 127,8, 127,4, 126,9, 557, 52,8, 46,2, 45,3, 44,8, 37,5, 30,6.

Example 113:2-phenyl-N-(4-methoxybenzyl)-N-(1 methylpiperidin-4-yl)-ndimethylacetamide (47AKU-26a)

50ELH-18 (118 mg; 0.5 mmol) dissolved in 5 ml of dichloromethane in a flask of 50 ml

Add 4-perforazione (104 mg; 0.6 mmol). After stirring for 20 hours at room temperature, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 87 mg (49%) 47AKU-26a. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. Analysis by HPLC-MS (method A): M+=353,1 (UV/MS(%)=96/88).

Example 114:2-(4-triptoreline)-N-(4-methoxybenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-26b)

50ELH-18 (118 mg; 0.5 mmol) dissolved in 5 ml of dichloromethane in a flask of 50 ml

Add 4-triftormetilfullerenov (134 mg; 0.6 mmol). After stirring for 20 hours at room temperature, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 81 mg (39%) 47AKU-26b. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. Analysis by HPLC-MS (method A): M+=421,1 (UV/MS(%)=90/100).

Example 115:2-(4-forfinal)-N-(4-methoxybenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-26C)

50ELH-18 (118 mg ,5 mmol) dissolved in 5 ml of dichloromethane in a flask of 50 ml

Add 4-perforazione (104 mg; 0.6 mmol). After stirring for 20 hours at room temperature, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 68 mg (37%) 47AKU-26C. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. Analysis by HPLC-MS (method A): M+=371,1 (UV/MS(%)=100/97).

Example 116:2-(4-methoxyphenyl)-N-(4-methoxybenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-26d)

50ELH-18 (118 mg; 0.5 mmol) dissolved in 5 ml of dichloromethane in a flask of 50 ml

Add 4-methoxyphenylacetylene (111 mg; 0.6 mmol). After stirring for 20 hours at room temperature, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 77 mg (40%) 47AKU-26d. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. Analysis by HPLC-MS (method A): M+=383,1 (UV/MS(%)=100/100).

Example 117:2-(4-were)-N-(4-chlorbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-28)

4-(4-chlorobenzylamino)-1-methylpiperidin (47AKU-27)

1-methyl-4-piperidone (566 mg; 5.0 mmol) dissolved in 10 ml of methanol and placed in a flask with 100 ml Add a solution of 4-chlorobenzylamino (708 mg; 5.0 mmol). The mixture is stirred and add in susnow acid (~0.75 ml) until pH~5. Then slowly add NaCNBH3(628 mg; 10 mmol). There is gas. After stirring on a magnetic stirrer for 16 hours, the methanol is partially removed on the rotary evaporator (40°C). Add dichloromethane, 2M NaOH and water to reach pH~10. The phases are separated and the aqueous phase re-extracted with dichloromethane. The combined organic phases are dried over MgSO4. Concentration on a rotary evaporator (40°C) gives to 1.14 g of the crude 47AKU-27. TLC (10% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method A): M+=239,1 (MS(%)=96).

2-(4-were)-N-(4-chlorbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-28)

p-Tolyloxy acid (1.5 g) dissolved in 10 ml of thionyl chloride and placed in a flask of 50 ml, the Mixture is heated to the boiling temperature under reflux for 2 hours and then concentrated on a rotary evaporator (40°C).

To 41AKU-27 (239 mg; 1.0 mmol) in 5 ml of dichloromethane added the acid chloridep-tolyloxy acid (202 mg; 1.2 mmol) in 5 ml of dichloromethane. After stirring for 4 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 104 mg (28%) 47AKU-28. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): R f=0,5. Analysis by HPLC-MS (method A): M+=371,1 (UV/MS(%)=100/90).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,34-6,99 (8H, m); of 4.57 (1H, m); 4,50 and of 4.44 (2H, 2s); of 3.80 (1H, s); 3,55 (2H, s); 2,96 and 2.82 (2H, 2m); 2,32 (3H, s); 2,24 and 2.15 (3H, 2s); at 1.91 (1H, m); 1,81-to 1.59 (4H, m).13C-NMR (Dl3): δ= 172,5, 13828, 136,8, 133,4, 131,8, 129,7, 129,2, 128,6, 127,4, 54,9, 51,3, 46,7, 41,3, 30,6, 28,6, 21,2.

Example 118:2-(4-hydroxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-29)

42ELH-77 (41 mg; 1.0 mmol) is dissolved in 1 ml of dry dichloromethane and placed in a dried in a drying oven flask of 10 ml, the Mixture is cooled to -78°C in a bath with a mixture of dry ice/isopropanol. Then at -78°C. slowly add tribromide boron (1.0 M in dichloromethane; 150 µl; 0.15 mmol). The ice bath removed and the mixture is left at room temperature for 2 hours. Add water (3 ml) and saturated NaCl (aqueous) and the aqueous phase is extracted with dichloromethane, ethyl acetate andn-butanol. The combined organic phases are dried over MgSO4and concentrate on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-20% methanol in dichloromethane) to give 22 mg (63%) 47AKU-29. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method A): M+=353,2 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,07-6,60 (8H, m); 4,48 (1H, m); 4,39 (2H, s); 3,76 and 3,66 (4H, OSS);to 3.41 (2H, C); is 3.08 (2H, m); 2.49 USD (1H, m), 2,42 (2H, Ushs); 2,22 and 2.16 (3H, 2s); 1,96-to 1.82 (2H, m); 1,66-of 1.56 (1H, m).13C-NMR (Dl3): δ= 173,7, 156,0, 137,3, 134,6, 129,7, 129,6, 125,7, 125,4, 115,7, 54,4, 50,4, 46,8, 44,0, 40,5, 27,3, 20,9.

Example 119:N-phenylethyl-N-(1 methylpiperidin-4-yl)-N'-phenylcarbamate (47AKU-30)

4-(2-phenylethyl)amino-1-methylpiperidin (110 mg; 0.5 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add phenylisocyanate (71 mg; 0.6 mmol) in 5 ml of dichloromethane. After stirring for 16 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product is purified twice flash chromatography (0-10% methanol in dichloromethane) to give 131 mg (78%) 47AKU-30. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4 Analysis by HPLC-MS (method A): M+=338,1 (UV/MS(%)=99/100).1H-NMR (400 MHz, Dl3): δ = of 7.36-6,93 (10H, m); 6,24 (1H, s); or 4.31 (1H, m); 3,50 (2H, t); 3,20 (2H, d); 2,89 (2H, t); to 2.57 (2H, m); of 2.50 (3H, s); and 2.26 (2H, m); to 1.79 (2H, m).13C-NMR (Dl3): δ= 155,8, 139,2, 139,0, 129,4, 129,3, 128,9, 127,3, 123,2, 120,4, 54,9, 51,3, 45,5, 44,3, 37,6, 28,3.

Example 120:N-(3-phenylpropyl)-N-(1 methylpiperidin-4-yl)-N'-benzylcarbamoyl (47AKU-31)

4-(3-phenylpropyl)amino-1-methylpiperidin (160 mg; 0.7 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add benzylsuccinic (107 mg; 0.8 mmol) in 5 ml of dichloromethane. After stirring for 2 hours the and the magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product is purified twice flash chromatography (0-10% methanol in dichloromethane) to give 156 mg (61%) 47AKU-31. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,3 Analysis by HPLC-MS (method A): M+=366,1 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3): δ = 7,34-7,07 (10H, m); 4,33 (3H, m), 4,14 (1H, m); 3.04 from (2H, m); 2,89 (2H, d); to 2.57 (2H, t); of 2.28 (3H, s); to 2.06 (2H, m); of 1.87 (2H, m); 1,75-of 1.62 (4H, m).13C-NMR (Dl3): δ= 157,5, 141,0, 140,0, 129,0, 128,6, 128,3, 128,0, 127,6, 126,6, 55,6, 52,1, 46,3, 45,1, 41,6, 33,4, 32,2, 30,6.

Example 121:N-(3-phenylpropyl)-N-(1 methylpiperidin-4-yl)-N'-phenylcarbamate (47AKU-32)

4-(3-phenylpropyl)amino-1-methylpiperidin (160 mg; 0.7 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add phenylisocyanate (95 mg; 0.8 mmol) in 5 ml of dichloromethane. After stirring for 20 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 106 mg (43%) 47AKU-32. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,3 Analysis by HPLC-MS (method A): M+=352,1 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3): δ = 7,35-6,95 (10H, m); of 5.99 (1H, s); 4,18 (1H, m); 3,17 (2H, t); only 2.91 (2H, d); to 2.65 (2H, t); of 2.28 (3H, s); 2,07 (2H, m); of 1.97 (2H, m); 1,81-of 1.66 (4H, m).13C-NMR (Dl3): δ= 154,9, 141,0, 139,3, 129,2, 129,0,129,0, 126,8, 123,1, 120,0, 55,6, 52,2, 46,2, 41,8, 33,4, 32,3, 30,6.

Example 122:2-(4-methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-33)

1-(4-methoxyphenyl)-1-cyclopropanecarbonyl acid (230 mg, 1.2 mmol) dissolved in 2 ml of thionyl chloride and placed in a flask of 50 ml, the Mixture is heated to the boiling temperature under reflux for 2 hours and then concentrated on a rotary evaporator (40°C). The acid chloride of acid (250 mg, 1.2 mmol) in 5 ml of dichloromethane is added to 47AKU-5 (220 mg; 1.0 mmol) in 5 ml of dichloromethane. After stirring for 2 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product is purified twice flash chromatography (0-10% methanol in dichloromethane) to give 201 mg (51%) 47AKU-33. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,6 Analysis by HPLC-MS (method A): M+=393,2 (UV/MS(%)=95/88).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,22-6,70 (8H, m); of 4.44 (2H, s); 4.26 deaths (1H, m), 3,74 (3H, s); 3,12 and 2,89 (2H, 2m); of 2.51 (1H, m); 2,32 (3H, m); and 2.26 (3H, s); 2,08-of 1.52 (4H, m); of 1.36 (2H, Ushs); 1,15-of 0.95 (3H, m).13C-NMR (Dl3): δ= 172,9, 158,6, 136,6, 132,7, 129,2, 128,6, 127,9, 127,4, 114,4, 55,5, 55,1, 54,4, 45,2, 45,0, 29,8, 29,2, 21,2, 13,8.

Example 123:2-(4-methoxyphenyl)-N-(1-phenylethyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-37)

4-andLLF-methylbenzylamino-1 methylpiperidin (47AKU-36)

DL (606 mg; 5.0 mmol) dissolved in 10 ml of methanol and add 1-methyl-4-piperidone (566 mg; 5.0 mmol) in 10 ml of methanol. The mixture is stirred and add acetic acid (~0.75 ml) until pH~5. Then slowly add NaCNBH3(628 g; 10 mmol). There is gas. After stirring on a magnetic stirrer for 20 hours, the methanol is partially removed on the rotary evaporator (40°C). Add ethyl acetate, 2M NaOH and water to reach pH~10. The phases are separated and the aqueous phase re-extracted with ethyl acetate and dichloromethane. The combined organic phases are dried over MgSO4. Concentration on a rotary evaporator (40°C) gives 838 mg of the crude 47AKU-36. TLC (10% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method A): M+=219,1 (UV/MS(%)=100/94).

2-(4-methoxyphenyl)-N-alpha-methylbenzyl-N-(1 methylpiperidin-4-yl)-ndimethylacetamide (47AKU-37)

47AKU-36 (218 mg, 1.0 mmol) dissolved in 10 ml dichloromethane and placed in a flask of 50 ml Add 4-methoxyphenylacetylene (185 mg; 1.2 mmol) in 10 ml of dichloromethane. After stirring for 16 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 256 mg (70%) 47AKU-37. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. And the Alize by HPLC-MS (method A): M +=367,3 (UV/MS(%)=100/99).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,34-7,06 (7H, m); at 6.84 (2H, d); 5,10 (1H, m); of 3.77 (3H, s); to 3.67 (2H, m); 3,17 (1H, m); 3,03 is 2.75 (3H, m); of 2.64 (3H, s); of 2.38 (2H, m); 1.77 in-1,05 (6H, m).13C-NMR (Dl3): δ= 172,0, 158,9, 139,9, 130,0, 129,0, 128,2, 127,1, 114,5, 55,5, 53,1, 51,4, 42,4, 41,3, 31,1, 29,5, 24,9, 18,1.

Example 124:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-azabicyclo[3.2.1]octene-3-yl)-ndimethylacetamide (47AKU-39)

4-methylbenzylamine (47AKU-38)

4-methylbenzylamine (1,21 g; 10 mmol) and tropinone (1.39 g; 10 mmol) is placed in a flask of 100 ml and dissolved in 50 ml of toluene. The mixture is heated to boiling point under reflux for 3 hours and remove the water using a water separator Dean/stark. The crude product is concentrated on a rotary evaporator (40°C) obtaining 47AKU-38. TLC (10% methanol in dichloromethane): Rf=0,3.1H-NMR (400 MHz, Dl3, isomers): 7,20-to 7.09 (4H, m); 4,47 (1H, m); 3,81 (1H, s); of 3.42 (1H, m), and 3.31 (1H, m); 2.77 - to of 2.56 (2H, m); 2,47 and 2.41 (3H, 2s); 2,33 and 2,31 (3H, 2s); 2,27-of 1.97 (4H, m); 1,69-and 1.54 (2H, m).

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(3-Tropin-4-yl)ndimethylacetamide (47AKU-39)

47AKU-38 (242 mg; 1.0 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add 4-methoxyphenylacetylene (185 mg; 1.2 mmol) in 10 ml of dichloromethane. After stirring for 16 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% of the ethanol in dichloromethane) to give 69 mg (18%) 47AKU-39. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=391,2 (UV/MS(%)=91/86).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,22-6,82 (8H, m); 5,41 (1H, Ushs); 4,71-to 4.52 (2H, m); of 3.78 (3H, s); 3,68 (2H, m); 3,44-3,24 (2H, m); 2,72-of 2.36 (5H, m); 2,32 (3H, s); 2,25 is 2.00 (2H, m); 1,80-and 1.54 (2H, m).13C-NMR (Dl3): δ= 170,8, 158,7, 137,4, 134,9, 130,1, 129,3, 128,9, 126,9, 114,2, 59,0, 58,0, 55,5, 49,5, 46,3, 39,7, 35,9, 33,8, 29,7, 21,3.

Example 125:2-phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-40)

2-phenylalanyl acid (197 mg; 1.2 mmol) dissolved in 2 ml of thionyl chloride and placed in a flask of 50 ml, the Mixture is heated to the boiling temperature under reflux for 2 hours and then concentrated on a rotary evaporator (50°C). The acid chloride of acid (1.2 mmol) in 5 ml of dichloromethane is added to 47AKU-5 (158 mg; to 0.72 mmol) in 5 ml of dichloromethane. After stirring for 20 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 196 mg (74%) 47AKU-40. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. Analysis by HPLC-MS (method A): M+=365,4 (UV/MS(%)=99/100).1H-NMR (400 MHz, Dl3), rotamer): δ = 7,32-6,98 (8H, m); of 4.77 (1H, Ushs); 4,50 (1H, d); the 4.29 (1H, is); 3,43, and 3.21 (3H, 2m)of 2.72 (2H, m); 2,62 (3H, s); 2,43 (1H, m); 2,32 (3H, s); of 2.21 (3H, m); 2,04 (2H, m); a rate of 1.67 (3H, m); 0,92 is 0.72 (3H, m).13C-NMR (Dl3): δ= 174,7, 139,9, 137,3, 135,2, 129,7, 129,0, 127,8, 127,3, 125,8, 54,5, 51,6, 49,4, 46,0, 43,8, 28,9, 26,7, 26,3, 21,2, 12,7.

Example 126:2-(4-methoxyphenyl)-N-(1 indanyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-43)

4-(1-indanamine)-1-methylpiperidin (47AKU-42)

1-aminoindan (666 mg; 5.0 mmol) dissolved in 10 ml of methanol and placed in a flask of 100 ml was Added 1-methyl-4-piperidone (566 mg; 5.0 mmol) in 10 ml of methanol. The mixture is stirred and add acetic acid (~0.75 ml) until pH~5. Then slowly add NaCNBH3(628 mg; 10 mmol). There is gas. After stirring on a magnetic stirrer for 16 hours, the methanol is partially removed on the rotary evaporator (40°C). Add dichloromethane, 2M NaOH and water to reach pH~10. The phases are separated and the aqueous phase re-extracted with ethyl acetate and dichloromethane. The combined organic phases are dried over MgSO4. Concentration on a rotary evaporator (40°C) give 1.06 g 47AKU-42. TLC (10% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method A): M+=231,1 (UV/MS(%)=72/91).

2-(4-methoxyphenyl)-N-(1 indanyl)-N-(1 methylpiperidin-4-yl)-ndimethylacetamide (47AKU-43)

47AKU-42 (230 mg; 1.0 mmol) dissolved in 10 ml dichloromethane and placed in a flask of 50 ml Add 4-methoxyphenylacetylene (185 mg; 1.2 mmol) in 10 ml dichlor the Tana. After stirring for 16 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 194 mg (51%) 47AKU-43. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. Analysis by HPLC-MS (method A): M+=to 379.2 (UV/MS(%)=94/90).

Example 127:N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)-N'(methoxybenzyl)carbamide (47AKU-44)

47AKU-5 (219 mg, 1.0 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add 4-methoxybenzylidene (196 mg, 1.2 mmol) in 10 ml of dichloromethane. After stirring for 16 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 192 mg (50%) 47AKU-44. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,3 Analysis by HPLC-MS (method A): M+=382,3 (UV/MS(%)=100/94).1H-NMR (400 MHz, CDCl3): δ = 7,10 (4H, m); 6,98 (2H, m); 6,76 (2H, m), 4,58 (1H, t); of 4.45 (1H, m); 4,33 (2H, s); 4.25 in (2H, d); 3,76 (3H, s); of 2.97 (2H, m); of 2.34 (3H, s); 2,32 (3H, s); 2,24 (2H, m); of 1.78 (4H, m).13C-NMR (Dl3): δ= 158,9, 158,5, 137,3, 135,2, 131,8, 129,8, 128,8, 126,2, 114,1, 55,5, 55,4, 51,7, 45,8, 45,7, 44,5, 29,7, 21,2.

Example 128:2-(3,4-acid)N-(Methylbenzyl)- N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-45)

3,4-dimethoxyphenylacetone acid (235 mg, 1.2 mmol) dissolved in 2 ml of thionyl chloride and placed in a flask of 50 ml, the Mixture is heated to the boiling temperature under reflux for 2 hours and then concentrated on a rotary evaporator (50°C). The acid chloride of acid (1.2 mmol) in 5 ml of dichloromethane is added to 47AKU-5 (219 mg, 1.0 mmol) in 10 ml of dichloromethane. After stirring for 16 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 129 mg (33%) 47AKU-45. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=397,4 (UV/MS(%)=98/89).1H-NMR (400 MHz, Dl3, rotamer): δ = 7,17-6,60 (7H, m); at 4.75 (1H, m); 4,51 (2H, s); a 3.83 (3H, s); with 3.79 (3H, s); of 3.53 (2H, s); of 3.27 (2H, d); to 2.65 (2H, t); of 2.58 (3H, s); 2,32 (3H, s); 2,24 (2H, m); 1,72 (2H, d).13C-NMR (Dl3): δ= 172,8, 149,3, 148,3, 137,4, 135,0, 129,8, 127,4, 125,8, 121,0, 112,2, 111,6, 56,2, 56,1, 54,6, 49,6, 46,7, 44,0, 40,9, 27,0, 21,2.

Example 129:2-(3,4-methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (47AKU-46)

3,4-methylenedioxyphenylacetic acid (216 mg, 1.2 mmol) dissolved in 2 ml of thionyl chloride and placed in a flask of 50 ml, the Mixture is heated to boiling point with reverse Kholodilin the com for 2 hours and then concentrated on a rotary evaporator (50°C). The acid chloride of acid (1.2 mmol) in 5 ml of dichloromethane is added to 47AKU-5 (219 mg, 1.0 mmol) in 10 ml of dichloromethane. After stirring for 2 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 188 mg (49%) of product. Further purification by ion exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) to give 149 mg (39%) 47AKU-46. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=381,2 (UV/MS(%)=96/95).1H-NMR (400 MHz, Dl3;, rotamer): δ = 7,17-7,02 (4H, m); 6,77-6,51 (3H, m); 5,91 and to 5.93 (2H, 2s); 4,70 (1H, m); to 4.52 and of 4.49 (2H, 2s); 3,51 (2H, s); 3,26 (2H, d); 2,49 (3H, s); of 2.33 (3H, s); 2,14-of 1.66 (6H, m).13C-NMR (Dl3): δ= 172,5, 148,1, 146,8, 137,3, 135,1, 129,8, 128,6, 125,8, 121,9, 109,4, 108,5, 101,2, 54,8, 50,2, 46,7, 44,6, 41,1, 27,7, 21,2.

Example 130:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-tert-butylpiperazine-4-yl)ndimethylacetamide (47AKU-49)

1-tert-butyl-4-piperidone (47AKU-47)

1-benzyl-4-piperidone (1.89 g; 10 mmol) is dissolved in 15 ml of acetone. Within 5 minutes, slowly add methyliodide (0,90 ml; 15 mmol). After 2 hours of stirring on the magnetic stirrer pay an additional amount under the conditions (1.8 ml; 30 mmol). After 1 hour stirring on a magnetic stirrer, add 20 ml of diethyl ether. accidenly product is collected by filtration and washed with a mixture of acetone/diethyl ether. The obtained white crystals are dried in vacuum to obtain 806 mg of the Quaternary salt. TLC (10% methanol in dichloromethane): Rf=0,7. Partially dissolved in 5 ml of water add salt to the heated to 50°With a mixture oftert-butylamine (120 mg; 1.6 mmol) and potassium carbonate (32 mg; 0.22 mmol) in 3 ml of ethanol. The resulting mixture is stirred and heated to the boiling temperature under reflux (~80°C) for 1 hour. After cooling, add water (20 ml) and dichloromethane (20 ml). The phases are separated and the aqueous phase re-extracted with dichloromethane and ethyl acetate. The combined organic phases are dried over MgSO4and concentrate on a rotary evaporator (40°C) to give 496 mg 47AKU-47. TLC (10% methanol in dichloromethane): Rf=0,3.1H-NMR (400MHz, Dl3): δ = 2,82 (4H, t); to 2.41 (4H, t); of 1.12 (9H, s).13C-NMR (Dl3): δ= 210,2, 54,3, 46,4, 42,4, 26,6.

The crude product contains ~25% (according to analysis1H-NMR) of starting material (1-benzyl-4-piperidone).

4-(4-methylbenzylamino)-1-tert-butylpiperazine (47AKU-48)

4-methylbenzylamine (268 mg; 2.2 mmol) dissolved in 5 ml of methanol and placed in a flask of 50 ml Add 47AKU-47 (305 mg; 2.0 mmol) in 5 ml of methanol. Then add acetic acid (0.3 ml) until pH~5. Then slowly add NaCNBH3(250 mg; 4.0 mmol). There is gas. After stirring on a magnetic stirrer for 4 hours add Aut dichloromethane, 2M NaOH and water to reach pH~10. The phases are separated and the aqueous phase re-extracted with dichloromethane and ethyl acetate. The combined organic phases are dried over MgSO4. Concentration on a rotary evaporator (40°C) gives 556 mg of the crude 47AKU-48. TLC (20% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=261,2 (MS(%)=57).

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-tert-butylpiperazine-4-yl)ndimethylacetamide (47AKU-49)

47AKU-48 (556 mg; 2.1 mmol) is placed in a flask of 50 ml and add 5 ml of dichloromethane. Then add 4-methoxyphenylacetylene (739 mg; 4.0 mmol) in 10 ml of dichloromethane. After stirring for 4 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 124 mg (15%) of the product. Further purification by ion exchange chromatography (flushing 10% aqueous NH4OH (25%) in methanol) to give 91 mg (11%) 47AKU-49. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.5 Analysis by HPLC-MS (method A): M+=409,4 (UV/MS(%)=100/90).1H-NMR (400 MHz, Dl3): δ = 7,11 (4H, m), 7,03 (2H, d); 6,79 (2H, d); 4,78 (1H, m); 4,56 (2H, s); 3,76 (3H, s); of 3.53 (2H, s); of 3.43 (2H, m); 2.63 in (2H, m); 2,47 (2H, m); 2,31 (3H, s); 1,74 (2H, d); of 1.36 (9H, s).13C-NMR (Dl3): δ= 173,0, 158,8, 137,1, 135,3, 129,8, 129,7, 127,0, 125,8, 114,3, 55,6, 55,5, 49,8, 46,5, 46,4, 40,5, 6,7, 25,1, 21,2.

Example 131:N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)-N'-phenylethylamine (58AKU-1)

47AKU-5-2 (219 mg, 1.0 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add generatesessionid (177 mg; 1.2 mmol) in 5 ml of dichloromethane. After 6 hours of stirring on the magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-15% methanol in dichloromethane) to give 134 mg (37%) 58AKU-1. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.5 Analysis by HPLC-MS (method A): M+=366,3 (UV/MS(%)=99/96).1H-NMR (400 MHz, Dl3): δ = 7,21-6,97 (9H, m); 4,33 (1H, m), 4.26 deaths (1H, m); is 4.21 (2H, s); 3,39 (2H, q); to 2.85 (2H, m); to 2.67 (2H, t); 2,31 (3H, s); of 2.24 (3H, s); to 2.06 (2H, m); 1,73-of 1.57 (4H, m).13C-NMR (Dl3): δ= 158,7, 139,5, 137,0, 135,4, 129,7, 128,8, 128,6, 126,3, 126,1, 55,6, 52,2, 46,2, 45,8, 42,2, 36,4, 30,2, 21,2.

Example 132:N-phenylethyl-N-(1 methylpiperidin-4-yl)-N'-fenetylline (58AKU-2)

4-(2-phenylethyl)amino-1-methylpiperidin (131 mg, 0.6 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add geneticization (103 mg; 0.7 mmol) in 5 ml of dichloromethane. After stirring for 4 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (45°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to p is the receiving 198 mg (90%) 58AKU-1. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,3 Analysis by HPLC-MS (method A): M+=366,3 (UV/MS(%)=100/100).1H-NMR (400 MHz, Dl3): δ = 7,33-7,16 (8H, m); 7,01 (2H, m); to 4.23 (1H, t); Android 4.04 (1H, m); 3,47 (2H, q); 3,17 (2H, t); 2,89 (2H, m), 2,78 (2H, t); of 2.66 (2H, t); of 2.28 (3H, s); is 2.05 (2H, m); 1,79-to 1.59 (4H, m).13C-NMR (Dl3): δ= 157,8, 139,6, 139,0, 129,0, 128,9, 128,8, 126,8, 126,7, 55,7, 52,5, 46,2, 44,6, 42,0, 37,3, 36,4, 30,5.

Example 133:N-(4-methylbenzyl)-N-(1-tert-butylpiperazine-4-yl)-N'-(4-methoxybenzyl)urea (58AKU-3)

47AKU-5-2 (404 mg; 1.6 mmol) dissolved in 5 ml dichloromethane and placed in a flask of 50 ml Add 4-methoxybenzylidene (326 mg; 2.0 mmol) in 5 ml of dichloromethane. After stirring for 20 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (45°C). The crude product was purified three times by flash chromatography (0-20% methanol in dichloromethane and 0-30% methanol in ethyl acetate) to give 155 mg (23%) 58AKU-3. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,3 Analysis by HPLC-MS (method A): M+=424,2 (UV/MS(%)=92/83).1H-NMR (400 MHz, Dl3): δ = 7,10 (4H, m); 6,99 (2H, m); 6,76 (2H, m); a 4.53 (1H, m), 4,35 (3H, s); 4.26 deaths (2H, d); of 3.77 (3H, s); to 3.09 (2H, m); 2,32 (3H, s); 2,22 (2H, m); 1,81-and 1.54 (4H, m); of 1.06 (9H, s).13C-NMR (Dl3): δ= 158,9, 158,6, 137,1, 135,6, 131,9, 129,7, 128,8, 126,2, 114,0, 62,6, 55,5, 53,0, 45,9, 45,7, 44,5, 31,0, 26,3, 21,2.

<> Example 134:2-(4-ethoxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (58AKU-4)

4-ethoxyphenylacetic acid (270 mg; 1.5 mmol) dissolved in 2 ml of thionyl chloride and placed in a flask of 50 ml, the Mixture is heated to the boiling temperature under reflux for 2 hours and then concentrated on a rotary evaporator (45°C). The acid chloride of acid (1.5 mmol) in 5 ml of dichloromethane is added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml of dichloromethane. After stirring for 20 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 272 mg (60%) 58AKU-4. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,4. Analysis by HPLC-MS (method A): M+=381,2 (UV/MS(%)=98/91).1H-NMR (400 MHz, Dl3): δ = 7,17-6,99 (6N, m); 6,82-6,76 (2H, m); to 4.73 (1H, m); 4,48 (2H, s); 3,98 (2H, kV)to 3.52 (2H, s); 3,22 (2H, d); 2,61 (2H, t); figure 2.54 (3H, s); 2,32 (3H, s); and 2.14 (2H, s); 1,71 (2H, d); to 1.38 (3H, t).13C-NMR (Dl3): δ= 172,9, 158,2, 137,3, 135,0, 129,9, 129,8, 126,8, 125,8, 114,9, 63,7, 54,6, 49,8, 46,7, 44,1, 40,6, 27,2, 21,2, 15,0.

Example 135:2-(4-butoxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (58AKU-5)

4-butoxyaniline acid (317 mg; 1.5 mmol) dissolved in 2 ml of thionyl chloride and placed in a flask of 50 ml, the Mixture is heated to the temperature of the pile is ia under reflux for 2 hours and then concentrated on a rotary evaporator (45°C). The acid chloride of acid (1.5 mmol) in 5 ml of dichloromethane is added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml of dichloromethane. After stirring for 20 hours on a magnetic stirrer, the reaction mixture was concentrated on a rotary evaporator (40°C). The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 230 mg (47%) 58AKU-5. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,5. Analysis by HPLC-MS (method A): M+=409,2 (UV/MS(%)=98/93).1H-NMR (400 MHz, Dl3): δ = 7,15-of 6.96 (6N, m); is 6.78 (2H, m); 4,74 (1H, m); 4,48 (2H, s); 3,91 (2H, t); to 3.52 (2H, s); of 3.27 (2H, d); a rating of 2.72 (2H, t); of 2.58 (3H, s); 2,32 (MN, C); of 2.23 (2H, m); 1,72 (4H, d); to 1.45 (2H, m); of 0.95 (3H t).13C-NMR (Dl3): δ= 173,0, 158,4, 137,3, 135,0, 129,8, 126,6, 125,8, 115,0, 67,9, 54,4, 49,5, 46,7, 43,8, 40,6, 31,5, 26,8, 21,2, 19,4, 14,0.

Example 136:2-(4-isopropoxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (58AKU-6)

47AKU-29-2 (245 mg; 0.7 mmol) dissolved in 10 ml of dimethylformamide and placed in a flask Add 50 ml KOH (196 mg; 3.5 mmol) and Isopropylamine (200 µl; 2.1 mmol). The mixture is heated to 50°C and stirred for 24 hours. After cooling, add water and ethyl acetate. The phases are separated and the aqueous phase re-extracted with dichloromethane. The combined organic phases are washed with saturated saline solution, dried over MgSO4and concentrate on a rotary evaporator (40°C) receipt is m 188 mg. The crude product was purified flash chromatography (0-10% methanol in dichloromethane) to give 136 mg (49%) 58AKU-6. HCl-salt derived from a mixture of 2M HCl/diethyl ether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0,3. Analysis by HPLC-MS (method B): M+=395 (UV/MS(%)=95/91).1H-NMR (400 MHz, Dl3, rotamer): δ = 7.23 percent-7,01 (6H, m); 6,79 (2H, m); 4,60 (1H, m); 4,51 (1H, m); of 4.44 (1H, s); of 3.77 (1H, s); 3,52 (1H, s); and 2.83 (2H, m); was 2.76 (2H, m); 2,28 and was 2.34 (3H, 2s); 2,19 and 2,22 (3H, 2s); is 2.05 (1H, m); 1,86-1.55V (4H, m); of 1.32 (6H, d).13C-NMR (Dl3): δ= 172,6, 157,0, 137,1, 135,6, 129,8, 129,7, 125,8, 116,2, 70,1, 55,3, 51,6, 46,6, 46,1, 40,8, 29,6, 22,3, 21,2.

Example 137:Test selection and amplification of the receptor (R-SAT)

Functional test on the receptor according to the method of selection and amplification of the receptor (R-SAT) was used (with minor modifications with respect to the previously described test in U.S. patent 5707798) for screening compounds for their effectiveness against receptor 5-HT2A. In General, the test is that of NIH3T3 cells grown in 96-well tablets for tissue culture to 70-80% confluence. The cells are then transferout 12-16 hours of plasmid DNA using superfect (Qiagen Inc.) according to the manufacturer's instructions. Mainly tests R-SAT performed using 50 ng/cell receptor and 20 ng/cell plasmid DNA encoding β-galactosidase. All used the design of receptor and G-protein is located in the expression vector is Lampedusa pSI (Promega Inc.), as described in U.S. patent 5707798. The gene encoding the receptor 5HT2A, amplified by the method vnutrivennoi PCR from cDNA of the brain using oligodeoxynucleotides based on the known sequence (see Saltzman et al.,Biochem. Biophys. Res. Comm.181:1469-78 (1991)). In the case of large-scale transpency cells transferout for 12-16 hours, then treated with trypsin and frozen in DMSO. Then the frozen cells are subjected to thawing, put in the amount of capabilities from 10,000 to 40,000 cells per cell in a 96-well plate that contains a drug. During both methods, cells are then grown in humidified atmosphere in the presence of 5% CO2within five days. Then the medium is removed from the tablets and determine the activity of the marker gene when adding a substrate for beta-galactosidase ONPG (FBI with the addition of 5% NP-40). The resulting colorimetric reaction was measured on the spectrophotometer for tablets (Titertek Inc.) at a wavelength of 420 nm. All the data is analyzed using a computer program XLFit (IDBSm). Efficiency represents the percentage of maximum repression in comparison with the repression of the control connection (ritanserin in the case of 5HT2A). Rick50represents the negative logarithm IR50where IR50mean calculated concentration in moles, which gives a 50% repression of the maximum ur is una. The results obtained for several compounds according to the present invention, are presented below in table 4.

Table 3. The effectiveness and importance Rick50compounds against 5-HT2A receptor compared to ritanserin

120
ConnectionEfficiency in %Rick50
SN948,3
SN1038,2
SN-051268,1
SN-5948,2
SN-6838,3
SN-101027,8
SV1247,9
42ELH451089,0
50ELH271088,7
47AKU-78,1
42ELH-801228,5
42ELH791108,5
42ELH911088,0
42ELH851187,8
42ELH751098,3
47AKU-121128,1
47AKU-81138,1
47AKU-221177,9
47AKU-211177,9
47AKU-201208,0
50ELH81297,8
50ELH68968,4
50ELH65927,9
47AKU-44 1128,5
TV757,7
58AKU-41109,6
58AKU-31118,1
58AKU-5999,5
58AKU-61019,8
TV957,9
50ELH951198,0
50ELH93728,1
50ELH93D587,8
50ELH93A1068,7
63ELH1A1048,3
50ELH89111the 9.7
63ELH20959,0
VT-D 1197,7
MW-5D1058,4
MW-4D988,5
MW-3D878,9
MW-2D1058,2
MW-1D1207,9
63ELH211008,5
TV1197,9
MT-6E1158,0

Example 138:The selectivity profile of the hydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide

Use test R-SAT (described above in example 137) to study the selectivity of the hydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide. Below, table 4 presents the results of the extensive screening of the compounds on multiple receptors. NR means "no reaction", that is investigated soy is inania shows no effect in relation receptor.

Table 4: Selectivity of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide

ReceptorTestREC50/Rick50
5-HT1AAgonistNR
AntagonistNR
5-HT1BAgonistNR
AntagonistNR
5-HT1DAgonistNR
AntagonistNR
5-HT1EAgonistNR
AntagonistNR
5-HT1FAgonistNR
AntagonistNR
5-HT2A AgonistNR
Inverse agonist8,8
5-HT2BAgonistNR
Inverse agonist6,9
5-HT2CAgonistNR
Inverse agonist7
5-HT4AgonistNR
Inverse agonistNR
5-HT6AgonistNR
Inverse agonist6,8
5-HT7AgonistNR
Inverse agonist6,9
m1AgonistNR
AntagonistNR
m2 AgonistNR
AntagonistNR
m3AgonistNR
AntagonistNR
m4AgonistNR
AntagonistNR
m5AgonistNR
AntagonistNR
D1AgonistNR
AntagonistNR
D2AgonistNR
AntagonistNR
D3AgonistNR
AntagonistNR
D5AgonistNR
NR
Histamine 1AgonistNR
Inverse agonistNR
Histamine 2AgonistNR
AntagonistNR
Histamine 3AgonistNR
AntagonistNR
alpha-1A(a/c)AgonistNR
AntagonistNR
alpha-1BAgonistNR
Inverse agonistNR
Alfa-2AAgonistNR
AntagonistNR
Alfa-2BAgonistNR
Antagonist NR
alpha-2CAgonistNR
AntagonistNR
beta 1AgonistNR
AntagonistNR
beta 2AgonistNR
AntagonistNR
EndothelinAgonistNR
SCQ-AAgonistNR
NK-1AgonistNR
VasopressinAgonistNR
K-opioidAgonistNR

Example 139:Pharmacyin vivohydrochloride of 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1 methylpiperidin-4-yl)ndimethylacetamide (AC-90179)

Methods

Animals and equipment

Animals used experimento with rats (for details, see the documentation for the equipment and measurements see Mal Non-Swiss Albino mice and male Spraque-Dawley rats (Harlan Spraque-Dawley)) contained (4 mice/cage; 2 rats/cage) in rooms with controlled temperature and humidity with free access to food and water (Harlan Teklad). Mice were kept in a 12-hour cycle of light:darkness, while the rats were kept under conditions of reverse 12-hour cycle of light:dark. For experiments on motor activity and observations of mice chambers HH cm, allowing the animals to be active, supplied with photoinitiators (AccuScan Instruments). Chambers (San Diego Instruments) is used for experiments with rats (details are contained in the regulations on the apparatus and measurement methods, see Mansbach et al., (1988)Psychopharmacology94:507-14).

Procedures

Monitoring twitching his head

Mice injected I/b 2.5 mg/kg DOI. Five minutes later the mice administered p/AC-90179 and put them in the camera for activity. Ten minutes later the mice are examined using the technique of repeated sampling. Each mouse is examined within 10 seconds and note the presence (1) or absence (0) jerking his head in total for 6 observations for 15 minutes and the overall level jerking his head on a scale from 0 to 6. Each combination dose experience in a separate group of animals (n=8), and the experiment is organized as blind in respect of a medicinal product. Determine the average value otsenochno the th grade jerking his head on the method of analysis of variants (ANOVA) and t-test comparisons post-hoc Dannette (post-hoc Dunnett's).

Motor activity

In experiments on hyperactivity in mice injected I/b 0.3 mg/kg of dizocilpine or 3.0 mg/kg d-amphetamine 15 minutes before the session. Five minutes after pre-treatment mice administered p/AC-90179 and put them in the camera for activity. To determine the spontaneous activity enter only one AC-90179. Data on locomotor activity collected during the 15-minute session without placing it in a lighted room. Each combination of doses examined in a separate group of animals (n=8). Calculate distance traveled (cm) and determine the average value according to the method of ANOVA and compared by t-test of post-hoc Dannetta.

Test fearfulness

Rats examined and pick up groups (n=10) on the level of response to fear and prepulse inhibition (PPI; PPI, see Mansbach et al., (1988)Psychopharmacology94:507-14). Two days later, start a session of tests, which includes a 5-min acclimatization period with constant background noise (65 dB) with subsequent 60 parcels audio stimuli to evaluate the response of fear in response to sound exposure. These 60 trials consist of twenty-two 40-millisecond (MS) parcels of broadband pulses with an intensity of 120 dB, ten 20-MS parcels pre-pulses for each intensity level (68, 71, 77 dB) for 100 MS before sending a 40-MS broadband pulse with intensive the spine 120 dB, and 8 NOSTIM trials (without stimulation), in which no stimulation is not applied, in order to assess the overall digitalnow activation in rats. Thirty minutes before testing, rats injected with sterile water (n/K), risperidone (1.0 mg/kg; in b/W) or AC-90179 (p/C). Five minutes later the rats injected DOI (0.5 mg/kg; p/C) or 0.9% saline solution (n/K). After one week, the rats administered the same pre-medicine or the media, and conduct cross-over study to achieve the treatment, the opposite of what they received during the previous week. The values of the degree of fearfulness and the percentage of PPI for three levels of intensity of the pre-pulse counting, as described in the literature (Bakshi, et al., (1994), J.Pharmacol. Exp. Ther.271:787-94) and repeated studies with treatment by ANOVA method.

Results

For further characteristics of the clinical applicability of selective inverse agonist of the receptor 5-HT2A as the new antipsychotics studied the effect of the AC-90179 on such behavioral models, as the twitching head, locomotor function and predispose inhibition. Mice treated with DOI (2.5 mg/kg; b/W; 15 minutes), showed the average score of the twitching head of 2.6 (±0.3; the RMS). AC-90179 (0.1 to 30 mg/kg; p/C; 10 min) caused a dose-dependent reduction in DOI-induced poderia the Oia head with a minimum effective dose of 1 mg/kg and higher doses are almost completely eliminated the twitching head (figure 2).

In locomotor experiments (figure 3) mice were on average 794 cm (±122 RMS) after the introduction of the media. Dizocilpine (0.3 mg/kg; b/W; 15 minutes) and d-amphetamine (3.0 mg/kg: in a/b; 15 min) caused an increase sailed distance, on average it was $ 2625 cm (±312) and 3367 (±532), respectively. AC-90179 (0.3 to 10 mg/kg; p/C; 10 min) attenuated the hyperactivity caused by dizocilpine, but not d-amphetamine. The minimum effective dose against dizocilpine was 1 mg/kg, whereas AC-90179 reduced spontaneous locomotor activity only at the highest investigated dose (30 mg/kg).

Conducted 3-directed re-analyses according to the method of ANOVA based on the PPI data on groups using AC-90179 revealed the presence of a common treatment effect [F(1,37) = 27,73; p = <0,01] and the interaction between treatment and pretreatment [F(3,37) = by 8.22; p = <0,01] (figs). DOI significantly violated the AUP, and AC-90179 was effective at restoring such violations, especially at higher doses. AC-90179 not impact the PPI, and no significant effect of pretreatment (p > 0,05) on the percentage of PPI. Risperidone was used as a positive control, since previous studies in the laboratory of the authors suggest that it is effective for blocking PPI-violating effect DOI. Re 3-directional measurement method ANOVA of data on FDI in the group rape idea also revealed a significant effect of treatment [F(1,18) = 14,08; p < 0,01] and the interaction between treatment and pre-treatment [F(1,18) = 24,48; p < 0,01]. As expected, risperidone was effective in recovery of PPI in rats treated with DOI. Risperidone also had no effect on the PPI, which follows from the absence of effect of pretreatment (p > 0,05). Because there is no significant interaction with predisposes intensity data are presented in summary form in three predisposes the intensities for the purposes of plotting.

Because there is a significant interaction between treatment and pretreatment was conducted paired 2-directional repeated measurement ANOVA method in groups with saline solution and the introduction of the DOI. In rats fed the media, there was no effect of AC-90179 (p > 0,025) or risperidone (p > 0,025) on FDI. In the groups treated with DOI, there was a significant effect of the AC-90179 [F(3,37) = 5,68; p < 0,01] and risperidone [F(1,18) = 16,73, p < 0,01) on the percentage of PPI.

3-re-directed processing method ANOVA data on the degree of fearfulness in the groups treated with AC-90179, revealed a significant effect of pretreatment [F(3,37) = 2,89; p = 0,048] and treatment [F(1,37) = 10,27; p < 0,01] on the degree of fearfulness, but not for processing under the influence of preprocessing (p > 0,05; figure 1, a block From the inside). Risperidone, on the other hand, did not influence the degree of fearfulness (p > 05).

Example 140 -Pharmacyin vivoadditional connections

The effect of various compounds on behavioral twitching his head in mice treated with DOI, watched as described above in example 139. The results are summarized below in table 5.

The effect of various compounds on the twitching head in mice treated with DOI, watched as described in example 139. Animals were injected subcutaneous injection of 0.1-30 mg/kg of the compounds. MED (MED) specifies the minimum effective dose at which a statistically significant decrease in the level jerking his head (described above). MED = minimum effective dosein vivo.

Table 5. Comparison of analogues for their ability to reduce induced DOI twitching his head in mice

ConnectionEDR
SN30
44ELH4530
50ELH271
42ELH80≤10
42ELH79≤10
47AKU-7≤10
42ELH85≤10
47AKU-8≤10
47AKU-12≤10
47AKU-13≤10
42ELH91>10
42ELH90~10
47AKU-20≤10
47AKU-19>10
47AKU-22≤10
47AKU-21>10
42ELH75≤10
47AKU-11~10
47AKU-14≤10
47AKU-18≥10
50ELH6≤10
47AKU-33≥10
47AKU-25>10
50ELH65≤10
50ELH68≤10
47AKU-49≤10
≤10
58AKU-4≤10
58AKU-5≤10
50ELH93A≤10
58AKU-6≤10
63ELH20≤10
63ELH21≤10

MED = minimum effective dosein vivo.

Description and formula of the present invention are not limited in the amount of a particular variant of the invention, as these options are considered only as illustrations of some aspects of the invention. Any equivalent options are included in the scope of the present invention. In fact, various modifications of the invention in addition to the shown and described in the present description will become apparent to experts in the art from the above description. Such modifications are also included in the amount declared by the attached claims.

The disclosures of all cited references are fully incorporated in the description by reference.

1. The compounds of formula (I)

where Z means

where
R is hydrogen, C4-the 6cycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or phenyl(lower alkyl)group, optionally substituted by 1-2 substituents selected from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group, where heteroaryl selected from the group consisting of teenie substituted lower alkyl group, imidazolyl, and thiazolyl substituted lower alkyl group;
n means 0 or 1; or
Z stands for a group

where R means a lower alkyl group;
X1means methylene or NH group; and
X2means methylene; or
X1means methylene, and X2means methylene or a bond; or
X1means methylene, and X2means O, S or a bond;
Y1means methylene, and Y2means methylene, vinile, ethylene, or Association;
Ar1means unsubstituted or substituted phenyl;
Ar2means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1and Ar2substituted,each Ar 1and Ar2independently substituted by one or more substituents selected from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di - and trihalomethyl, di -, trihaloacetic, mono - and dialkylamino, alkylthio, complex Olkiluoto ether and nitro;
provided that Ar1and Ar2don't mean simultaneously unsubstituted phenyl;
W stands for oxygen or sulfur; or
their pharmaceutically acceptable salts;
provided that
when Z means, R is H, n is 1, W means On, X1means methylene, X2means a bond, Y1means methylene, Y2means methylene, and Ar1means 3,4-acid, then Ar2cannot be selected from the group consisting of 3,4-dichlorophenyl, 3-triptoreline, 3,4,5-trimethoxyphenyl, 3,5-bis(tert-butyl)-4-hydroxyphenyl, 4-bromophenyl, benzo[b]thiophene-3-yl, 4-AMINOPHENYL, 4-triptoreline and 1H-indol-3-yl;
when Z means, R is H, n is 1, W means On, X1means methylene, X2means a bond, Y1means methylene, Y2means a bond, and Ar1means 2,6-differenl, then Ar2cannot be selected from the group consisting of 3,4-dichlorophenyl, 3-triptoreline, 3,4,5-trimethoxyphenyl, 3,5-bis(tert-butyl)-4-hydroxyphenyl, 4-bromophenyl, benzo[b]thiophene-3-yl, 4-amino the Nile, 4-triptoreline and 1H-indol-3-yl;
when Z, R is H, n is 1, W means On, X1means methylene, X2means methylene, Y1means methylene, Y2means methylene, and Ar1means 3,4-acid, then Ar2may not mean 3,4-acid;
when Z means, R is H, n is 1, W means On, X1means methylene, X2means methylene, Y1means methylene, Y2means a bond, and Ar1means 2,6-dipropenyl, then Ar2may not mean 3,4-acid;
when Z means, R is H, n is 1, X1mean NH; X2means methylene, Y1means methylene, Y2means methylene, Ar1means 3,4-acid, and Ar2means FSD-2-yl or naphtalen-1-yl, then W cannot mean S; and
when Z means, R is H, n is 1, X1mean NH; X2means methylene, Y1means methylene, Y2means of communication, Ar1means 2,6-differenl, and Ar2means naphtalen-1-yl, then W cannot mean S.

2. The compound according to claim 1, in which
Z meansn means 0 or 1, and
R is hydrogen, C4-Cbcycloalkyl group attached either h is cut one of the carbon atoms of the ring, or through attached to the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyalkyl group.

3. The compound according to claim 2, in which
Y1means methylene, and Y2means a bond, methylene, ethylene or vinile; and
X1means methylene, and X2means a bond, methylene, O or S; or
X1mean NH and X2means methylene.

4. The compound according to claim 3, in which Z signifies

and W stands for oxygen.

5. The compound according to claim 4, in which
Ar1means phenyl substituted with 1-2 substituents selected from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di - and trihalomethyl, di -, trihaloacetic, mono - and dialkylamino, alkylthio, complex Olkiluoto ether and nitro; and Ar2means phenyl substituted with 1-2 substituents selected from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di - and trihalomethyl, di -, trihaloacetic, mono - and dialkylamino, alkylthio, complex Olkiluoto ether and nitro.

6. The compound according to claim 5, in which
R is hydrogen, C4-C6cycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched what th lower alkyl group or a lower hydroxyalkyl group;
n means 1;
Y1means methylene, Y2means a bond, methylene, ethylene or vinile;
X1means methylene, and X2means the communication; or
X1mean NH and X2means methylene; and
Ar1and Ar2mean phenyl groups, independently n-substituted by groups selected from lower alkyl, lower alkoxy and halogen.

7. The compound according to claim 1, having the formula (II)

in which
RNmeans hydrogen, C4-C6cycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or phenyl(lower alkyl)group, optionally substituted by 1-2 substituents selected from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group, where heteroaryl selected from the group consisting of teenie substituted lower alkyl group, imidazolyl, and thiazolyl substituted lower alkyl group;
ArLselected from lower alkyl, lower alkoxy and halogen;
ArRselected from lower alkyl, lower alkoxy and halogen;
k is 1 or 2; and
And-means anion or pharmaceutical is Ki acceptable acid.

8. The compound according to claim 1, selected from the group including
N-((4-(were)methyl)-N-(piperidine-4-yl)-N'-phenylmethylene;
N-((4-(were)methyl)-N-(1-(2-methylpropyl " piperidine-4-yl)-N'-phenylmethylene;
N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;
N-((4-(were)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-(1-(3,3-dimethylbutyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;
N-(1-(cyclohexylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-4-methoxyphenylacetamide;
N-((4-(were)methyl)-N-(1-(2-methylpropyl " piperidine-4-yl)-4-methoxyphenylacetamide;
N-(3-phenylpropyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-(2-phenylethyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((2-methoxyphenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((2-chlorophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((3,4-acid)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((4-forfinal)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((2,4-dichlorophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((3-were)methyl-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((3-bromophenyl)methyl)-N-(piperidine-4-yl)-4-methoxyphenylacetamide;
N-((4-(were)methyl)-N-(1-piperidine-4-yl)phenylacetamide; and
N-((4-(were)methyl)-N-(1-piperidine-4-yl)-3-phenylpropionamide.

9. The compound according to claim 1, selected the second group, including
N-((4-(were)methyl)-N-(1-piperidine-4-yl)-(phenylthio)ndimethylacetamide;
N-((4-(were)methyl)-N - (1-piperidine-4-yl)phenoxyacetamide;
N-((4-(were)methyl)-N - (1-piperidine-4-yl)-(4-chlorphenoxy)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-piperidine-4-yl)-3-methoxyphenylacetamide;
N-((4-(were)methyl)-N-(1-piperidine-4-yl)-4-perforated;
N-((4-(were)methyl)-N-(1-piperidine-4-yl)-2,5-dimethoxyphenylacetone;
N-((4-(were)methyl)-N-(1-piperidine-4-yl)-4-chlorophenylacetic;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperazin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(piperidine-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide;
2-(phenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-forfinal)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-triptoreline)-N-(4-trifloromethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-forfinal)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide; and
2-(phenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide.

10. The compound according to claim 1, selected from the group including
2-(4-triptoreline)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-triptoreline)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(2-(4-forfinal)ethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-[2-(2,5-acid)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-[2-(3-forfinal)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-ethoxyphenyl)-N-[2-(4-forfinal)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-ethoxyphenyl)-N-(4-terbisil)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperazine-4-yl)ndimethylacetamide;
2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperazin-4-yl)ndimethylacetamide;
2-phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-meth is piperidin-4-yl)ndimethylacetamide;
2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide; and
2-(4-forfinal)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide.

11. The compound according to claim 1, selected from the group including
2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)piperidine-4-yl)ndimethylacetamide;
2-(4-chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylmethyl-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylmethyl-4-yl)ndimethylacetamide;
N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-benzylcarbamoyl;
2-phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-triptoreline)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-forfinal)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-were)-N-(4-chlorbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-hydroxyphenyl)-N-(1-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-methoxybenzyl)urea;
2-(3,4-acid)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-tert-butylpiperazine-4-yl)ndimethylacetamide;
N-(4-methylbenzyl)-N-(1-tert-butylpiperazine-4-yl)-N'-(4-methoxybenzyl)urea;
2-(4-ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-isoprop xifei)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(3-phenyl-1-propyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide; and
2-(4-methoxyphenyl)-N-[2-(4-nitrophenyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide.

12. The compound according to claim 1, selected from the group including
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclopentenopyridine-4-yl)ndimethylacetamide;
N-((4-(hydroxymethyl)phenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxyphenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(3-hydroxyl-4-methoxyphenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(3,4-dihydroxyphenyl)ndimethylacetamide;
N-((3-hydroxy-4-were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxyphenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-bromophenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-itfeel)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-(2-propyl)phenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-trifloromethyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methylthiophenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-(N,N'-dimethylamino)phenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-nitrophenyl)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxy-3-were)ndimethylacetamide;
N-((4-(were)methyl)-N-(1-IU is reprein-4-yl)-2-(4-were)ndimethylacetamide.

13. The compound according to claim 1, selected from the group including
N-(1-((2-bromophenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;
N-(1-((4-hydroxy-3-methoxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;
N-(1-((5-utilties-2-yl)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;
N-(1-(imidazol-2-ylmethyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;
N-(1-((4-forfinal)methyl)piperidine-4-yl)-N-((4-(were)methyl)-N'-phenylmethylene;
N-((4-(were)methyl)-N-(1-((4-(were)methyl)piperidine-4-yl)-4-methoxyphenylacetamide;
N-(1-((4-hydroxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)4-methoxyphenylacetamide;
N-(1-((2-hydroxyphenyl)methyl)piperidine-4-yl)-N-((4-(were)methyl)4-methoxyphenylacetamide;
N-(1-(phenylmethyl)piperidine-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphenylacetamide;
oxalate of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-N'-phenylmalonamide;
the hydrochloride of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-N-phenylmalonamide;
oxalate of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide;
the hydrochloride of N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide;
N-((4-(were)methyl)-N-(1-(phenylmethyl)piperidine-4-yl)-4-methoxyphenylacetamide; and
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-methylthiazole--ylmethyl)piperidine-4-yl]ndimethylacetamide.

14. The compound according to claim 1, selected from the group including
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-azabicyclo[3.2.1]Oct-3-yl)-ndimethylacetamide;
N-((4-(were)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N'-phenylmethylene; and
N-((4-(were)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide.

15. A compound selected from the group including
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,3-dihydro-2H-benzimidazole-2-on-1-yl)propyl]piperidine-4-yl}ndimethylacetamide;
N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-phenylcarbamoyl;
N-phenethyl-N-(1-methylpiperidin-4-yl)-N'-benzylcarbamoyl;
N-phenylethyl-N-(1-methylpiperidin-4-yl)-N'-phenylcarbamoyl;
N-(3-phenylpropyl)-N-(1-methylpiperidin-4-yl)-N'-benzylcarbamoyl;
N-(3-phenylpropyl)-N-(1-methylpiperidin-4-yl)-N'-phenylcarbamoyl;
1-(4-methoxyphenyl)-N-(1-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)cyclopropanecarboxamide;
2-(4-methoxyphenyl)-N-(1-phenylethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-azabicyclo[3.2.1]octene-3-yl)-ndimethylacetamide;
2-phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(3,4-methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-N'-phenylethylamine; and
N-phenylethyl-N-(1-methylpiperidin-4-yl)-N'-phenylethylamine;
2-(4-methoxyphenyl)-N-[2-(2-t is enyl)ethyl]-N-(1-methylpiperidin-4-yl)ndimethylacetamide;
2-(4-methoxyphenyl)-N-(2-thienylmethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide; and
2-(4-methoxyphenyl)-N-(furfuryl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide.

16. The compound of formula (I)

where Z means

where
R is hydrogen, C4-C6cycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or phenyl(lower alkyl)group optionally substituted by one or more substituents selected from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group, where heteroaryl selected from the group consisting of teenie substituted lower alkyl group, imidazolyl, and thiazolyl substituted lower alkyl group;
n means 0 or 1; or
Z stands for a group

where R means a lower alkyl group;
X1means methylene or NH group; and
X2means methylene; or
X1means methylene, and X2means methylene or a bond; or
X1means methylene, and X2means O, S or a bond;
Y1means methylene, and Y2means met the flax, vinile, ethylene, or Association;
Ar1means unsubstituted or substituted phenyl;
Ar2means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl;
and when Ar1and Ar2substituted, each Ar1and Ar2independently substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di - and trihalomethyl, di -, trihaloacetic, mono - and dialkylamino, alkylthio, complex Olkiluoto ether and nitro; Ar1and Ar2have different values;
W stands for oxygen or sulfur; or
their pharmaceutically acceptable salts;
provided that
when Z means, R is H, n is 1, W means On, X1means methylene, X2means a bond, Y1means methylene, Y2means methylene, and Ar1means 3,4-acid, then Ar2cannot be selected from the group consisting of: 3,4-dichlorophenyl, 3-triptoreline, 3,4,5-trimethoxyphenyl, 3,5-bis(tert-butyl)-4-hydroxyphenyl, 4-bromophenyl, benzo[b]thiophene-3-yl, 4-AMINOPHENYL, 4-triptoreline and 1H-indol-3-yl;
when Z means, R is H, n is 1, W means On, X1means methylene, X2 means a bond, Y1means methylene, Y2means a bond, and Ar1means 2,6-differenl, then Ar2cannot be selected from the group consisting of: 3,4-dichlorophenyl, 3-trifluoromethyl phenyl, 3,4,5-trimethoxyphenyl, 3,5-bis(tert-butyl)-4-hydroxyphenyl, 4-bromophenyl, benzo[b]thiophene-3-yl, 4-AMINOPHENYL, 4-triptoreline and 1H-indol-3-yl;
when Z, R is H, n is 1, W means On, X1means methylene, X2means methylene, Y1means methylene, Y2means methylene, and Ar1means 3,4-acid, then Ar2may not mean 3,4-acid;
when Z means, R is H, n is 1, W means On, X1means methylene, X2means methylene, Y1means methylene, Y2means a bond, and Ar1means 2,6-dipropenyl, then Ar2may not mean 3,4-acid;
when Z means, R is H, n is 1, X1mean NH; X2means methylene, Y1means methylene, Y2means methylene, Ar1means 3,4-acid, and Ar2means FSD-2-yl or naphtalen-1-yl, then W cannot mean S; and
when Z means, R is H, n is 1, X1mean NH; X2means methylene, Y1means methylene, Y 2
means of communication, Ar1means 2,6-differenl, and Ar2means naphtalen-1-yl, then W cannot mean S.

17. Connection P16, which
Z meansn means 0 or 1, and
R is hydrogen, C4-Cbcycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyalkyl group.

18. The connection 17, which
Y1means methylene, and Y2means a bond, methylene, ethylene or vinile; and
X1means methylene, and X2means a bond, methylene, O or S; or
X1mean NH and X2means methylene.

19. Connection p in which
Z means

and W stands for oxygen.

20. The connection according to claim 19, in which
Ar1means phenyl substituted with 1-2 substituents selected from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di - and trihalomethyl, di -, trihaloacetic, mono - and dialkylamino, alkylthio, complex Olkiluoto ether and nitro; and
Ar2means phenyl substituted with 1-2 substituents selected from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di - and trihalomethyl, di is trihaloacetic, mono - and dialkylamino, alkylthio, complex Olkiluoto ether and nitro.

21. Connection by claim 20, in which
R is hydrogen, C4-C6cycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyalkyl group, n is 1;
Y1means methylene, Y2means a bond, methylene, ethylene or vinile;
X1means methylene, and X2means the communication; or
X1mean NH and X2means methylene; and
Ar1and Ar2mean phenyl groups, independently n-substituted by groups selected from lower alkyl, lower alkoxy and halogen.

22. Connection P16, having the formula (II)

in which
RNmeans hydrogen, C4-C6cycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or phenyl(lower alkyl)group, optionally substituted by 1-2 substituents selected from lower alkyl, lower alkoxy, halogen and hydroxy, or Goethe is auril(lower alkyl)group, where heteroaryl selected from the group consisting of teenie substituted lower alkyl group, imidazolyl, and thiazolyl substituted lower alkyl group;
ArLselected from lower alkyl, lower alkoxy and halogen;
ArRselected from lower alkyl, lower alkoxy and halogen;
k is 1 or 2; and
And-means an anion or a pharmaceutically acceptable acid.

23. The pharmaceutical composition acting on the serotonin receptor, comprising an effective amount of one or more compounds according to claim 1 or its pharmaceutically acceptable salt; and a pharmaceutically acceptable diluent or filler.

24. Pharmaceutical composition for the treatment of painful conditions associated with serotonin receptor, comprising an effective amount of one or more compounds according to claim 2 or a pharmaceutically acceptable salt of the compounds; and a pharmaceutically acceptable diluent or filler.

25. A method of inhibiting the activity of monoamine receptor comprising bringing into contact the monoamine receptor or a system containing the monoamine receptor with an effective for inhibiting the activity of monoamine receptor with one or more compounds according to claim 1.

26. The method according A.25, in which monoamine receptor is serotoni the new receptor.

27. The method according to p in which serotonin receptor belongs to the subclass of 5-NTA receptors.

28. The method according to p in which serotonin receptor is located in the Central nervous system or peripheral nervous system.

29. The method according to p in which serotonin receptor is in the blood cells or platelets.

30. The method according to p in which serotonin receptor mutated or modified.

31. The method according A.25 in which this activity is a signaling activity.

32. The method according A.25 in which this activity is a constitutive activity.

33. The method according A.25, in which the activity is associated with activation of serotonin receptor.

34. Method of inhibiting activation of a monoamine receptor comprising bringing into contact the monoamine receptor or a system containing the monoamine receptor with an effective inhibiting activation of a monoamine receptor with one or more compounds according to claim 1.

35. The method according to clause 34, in which this activation is agonistic agent.

36. The method according to p, wherein said agonistic agent is exogenous.

37. The method according to p, wherein said agonistic agent is endogenous.

38. The method according to clause 34, in which this activation is institutional.

39. The method according to clause 34, in which the monoamine receptor is a serotonin receptor.

40. The method according to § 39, in which serotonin receptor belongs to the subclass of 5-NTA receptors.

41. The method according to § 39, in which serotonin receptor is located in the Central nervous system or peripheral nervous system.

42. The method according to § 39, in which serotonin receptor is in the blood cells or platelets.

43. The method according to § 39, in which serotonin receptor mutated or modified.

44. A method for the treatment of painful conditions associated with serotonin receptor comprising the administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds according to claim 1.

45. The method according to item 44, in which the compound according to claim 1 provides a reduction in side effects compared with the compound that exhibits agonistic, competitive, antagonistic or inverse agonistic activity against multiple subtypes onlinelicensing receptors.

46. The method according to item 45, in which subtypes onlinelicensing receptor selected from the serotonergic, dopaminergic, adrenergic, muscarinic and histaminergic receptors.

47. The method according to item 44, in which the disease state is selected from the group consisting of schizophrenia, psychosis, migraine, hypertension, thrombosis, angiospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders.

48. The method according to item 44, which is a painful condition associated with a dysfunction of the serotonin receptor.

49. The method according to item 44, which is a painful condition associated with activation of serotonin receptor.

50. The method according to item 44, in which the disease state is associated with increased activity of a serotonin receptor.

51. The method according to item 44, in which serotonin receptor belongs to the subclass of 5-NTA receptors.

52. The method according to item 44, wherein said serotonin receptor is located in the Central nervous system or peripheral nervous system.

53. The method according to item 44, in which serotonin receptor is in the blood cells or platelets.

54. The method according to item 44, in which serotonin receptor mutated or modified.

55. A method of treating schizophrenia, comprising introducing to a subject in need of such treatment, a therapeutically effective amount of one or more compounds according to claim 1.

56. The method of treatment of migraine comprising the administration to a subject in need of such treatment, a therapeutically effective amount of one or more compounds according to claim 1.

57. A method of treating psychosis comprising introducing to a subject in need of such treatment, a therapeutically effective amount is tion of one or more compounds according to claim 1.

58. The method according to § 57, in which the compound according to claim 1 provides a reduction of extrapyramidal side effects compared with antipsychotic drug, showing antagonistic activity against the dopamine D2 receptor.

59. The compound according to claim 1, in which Z signifiesn means 0 or 1, and R means4-Cbcycloalkyl group attached either through one of the carbon atoms of the ring or attached through the lower ring alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyl group.

60. The compound according to claim 1, in which
Z means

where
R denotes a linear-chain or branched lower alkyl group;
n means 1;
X1mean NH and X2means methylene;
Y1means methylene, Y2means a bond, methylene, ethylene or vinile;
W stands for oxygen; and
Ar1and Ar2means unsubstituted or substituted phenyl group.

61. The compound according to claim 1, in which
Z means

where
R denotes a linear-chain or branched lower alkyl group;
n means 1;
X1means NH, and X2means methylene;
Y1means methylene, Y2means communication;
W oxygen; and
Ar1and Ar2means unsubstituted or substituted phenyl group.

62. The compound according to claim 1, in which
Z means

where
R denotes a linear-chain or branched lower alkyl group;
n means 1;
X1means methylene, X2means methylene; or
X1means methylene, X2means communication;
Y1means methylene, Y2means methylene or a bond;
W stands for oxygen; and
Ar1and Ar2means unsubstituted or substituted phenyl group.

63. The compound according to claim 1, in which
Z means

where
R denotes a linear-chain or branched lower alkyl group;
n means 1;
X1means methylene, X2means communication;
Y1means methylene, Y2means methylene or a bond;
W stands for oxygen; and
Ar1and Ar2means unsubstituted or substituted phenyl group.

64. The compound according to claim 1, selected from the group consisting of
N-((4-(were)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-pyridyl)ndimethylacetamide; and
2-(2-thienyl)-N-(4-methylphenylethyl)-N-(1-methylpiperidin-4-yl)ndimethylacetamide.

65. The connection clause 16, in which Z signifiesn means 0 or 1, and R means4-C6cycloalkyl group attached either through one of the volumes of the carbon ring, or through attached to the lower alkylenes group, or a linear-chain or branched lower alkyl group or a lower hydroxyl group.



 

Same patents:

FIELD: medicine.

SUBSTANCE: in new compounds of the formula R1 represents hydrogen, halogen; R2 represents C3-4 alkyl, or C3-6 cycloalkyl; R3 represents hydrogen or C1-3 alkyl; R4 represents -S(O)2R6, or -C(O)R7; R5 represents hydrogen, C1-3 alkyl, C2-3 alkyl substituted with -OH or C1-3alkoxy, or -CH2-pyridyl; R6 represents C1-3 alkyl, or R5 and R6 taken together form a C3-4 alkylenyl; and R7 represents hydrogen, C1-3 alkyl or pyridyl; or their pharmaceutically acceptable salts or solvates or stereoisomers. The invention also refers to pharmaceutical composition, to compounds application, to method for treating mammals, to method for treating disorders of reduced motor activity of gastrointestinal tract in a mammal, to method for obtaining compounds according to any of Clauses 1-12, to method for obtaining compounds of formula (I'), as well as to compounds of formula (III).

EFFECT: obtaining new biologically active compounds having activity as 5-NT4 receptors.

24 cl, 29 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , in which: Ra and Ra' denote hydrogen, R1 denotes cycloalkyl; R2 denotes a group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which x=0, y=1, Y denotes -N-R11R12;- R11 and R12 denote alkyl; R3 denotes a halogen atom; R5 denotes a hydrogen atom; R4 is selected from: (1) a group of formula : in which each of the rings in formulae (a) and (b) can be substituted in any position with 1-4 R7 groups which are identical or different from each other, and in which: a=0; p=0, 1, 2 or 3; m=1; X is an oxygen or sulphur atom or a C(R6)(R7)- or -N(R10)- group; R6 is selected from: a hydrogen atom; a -(CH2)x-NR8R9 group in which x=0, aryl, alkylaryl; R7 is selected from hydrogen atoms; aryl, alkylaryl groups; -OR group; -NRR' groups; R8 and R9 are selected from a hydrogen atom; R10 is selected from: hydrogen atom; aryl, alkylaryl; R and R' denote a hydrogen atom; (2) a group of formula -A-R18, -A-CH=N-R19, in which A denotes a straight or branched alkyl; R18 denotes a halogen atom or a -NH2 group; R19 denotes hydroxyl; (3) a group of formula : in which r equals 1; s equals 1, and one of U, V and W denotes a nitrogen atom while the others denote a methylene group; or (4) -(CH2)r-heteroaryl, where r equals 1; where the heteroaryl denotes a 5-6-member aromatic group containing 1-2 heteroatoms such as nitrogen, oxygen, in form of a base or additive acid salt. The invention also relates to a method for synthesis of formula (I) compounds, to compounds of formulae (IV) and (V), to a medicinal agent, to a pharmaceutical composition, as well as to use of formula (I) compounds.

EFFECT: obtaining new biologically active compounds having melanocortin receptor agonist activity.

11 cl, 28 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds that comply with formula (I) , where: n is equal to 1, Ra, Ra', Rb, Rb', identical or different, mean atom of hydrogen or alkyl or cycloalkyl group, besides, Rb and Rb' may create carbon bridge having 4 links together with hydrogen atoms of cycle, to which they are connected, R1 means cyclohexyl group, R2 means 1,2,4-triazolyl group, R3 means 1-3 groups, selected from atoms of halogen, available in any position of cycle, to which they are connected, R5 means atom of hydrogen, R4 is selected from groups of formulas (a), (b) and (c), given below, mono- or polysubstituted with aryl group: (a), (b), (c), in which: p=0, 1, 2 or 3, m=0, 1 or 2, and either a) X means link -N(R10)-, where R10 is selected from: groups -CO-NR8R9, -COOR8, -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-COR8, in which x=1, 2, 3 or 4, heterocycloalkyl group, condensed with aryl group, cycloalkyl, aryl, heteroaryl, alkylaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-aryl, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarly substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CN, -COOR, COR; or R10 together with atom of nitrogen, to which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not in neighboring position to mentioned atom of nitrogen, creates a bridge that contains 3-5 links, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl or cycloalkyl groups; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, aryl groups; or b) X means link - C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, groups -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0, 1, 2, 3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl group, heterocycloalkyl group, condensed or non-condensed, available in spiro-position to cycle of formula (a), to which it is connected, heterocycloalkyl group, condensed with aryl group, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; and heterocycloalkyl groups are unnecessarily condensed with aryl group; R7 is selected from atoms of hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -OR, -O-aryl, -O-alkylaryl, -O-alkylheteroaryl, groups -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -(CH2)x-OR, where x=0, 1, 2, 3 or 4, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; or R8 and R9 create together cycloalkyl or heterocycloalkyl; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl, aryl, or may together create cycloalkyl or heterocycloalkyl; besides heteroaryl group represents aromatic group that contains from 5 to 10 atoms and from 1 to 4 heteroatoms, selected from nitrogen, oxygen or sulfur; heterocycloalkyl group represents cycloalkyl group, which contains from 5 to 10 atoms and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (IV) , (V), (VI), (XXVIII), (XXIX), (II).

EFFECT: production of new biologically active compounds, having activity of agonists of melanocortin receptors.

36 cl, 22 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a new uniformly tritium-labeled 4,4-fluoro-N-{(1S)-3-[3-(3-isopropyl-5-methyl-4H-1,2,4-trizol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexane carboiimide (maraviroc) of formula I .

EFFECT: said compound can be used in analysis of physiologically active compound-analogue.

1 cl, 1 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I), their optically active stereoisomers, as well as to pharmaceutically acceptable salts possessing properties of ORL1 and µ-opiate receptors. In general formula , R1 represents H, alkyl(1-6C), []m represents-(CH2)m-, in which m equals 0 or 1, R2 represents halogen, CF3, alkyl(1-6C), phenyl, cyano, cyanoalkyl(1-3C), hydroxy, (1-3C)alkoxy, OCF3, acyl(2-7C), trifluoroacetyl, (1-3C)alkylsulfonyl or trifluoromethylsulfonyl, and n represents integer number 0-4 on condition that when n equals 2, 3 or 4, R2 substituents can be similar or different, A represents saturated ring, []0 and []p represents -(CH2)o and -(CH2)p, and o and p independently correspond to 0, 1 or 2, R3, R4, R5 and R6 independently represent hydrogen, alkyl(1-3C), or (R4 and R6) together can form alkylene bridge, containing 1-3 carbon atoms on condition that when o equals 2, R3 represents hydrogen, and when p equals 2, R5 represents hydrogen, R7 represents H, halogen, alkyl(1-6C). Invention also relates to pharmaceutical composition, intermediate compounds for obtaining formula (1) compounds.

EFFECT: compounds can be used for preparing medication for treating disorders and diseases such as alimentary behaviour disturbances, arterial hypertension.

8 cl, 3 dwg, 1 tbl, 45 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: method involves production of N-substituted 3β-aminonortropanes of formula I or one of acid-additive salts , where R1 represents optionally substituted residue chosen from group, including C1-C8alkyl, C2-C8alkenyl, C3-C8cycloalkyl and C6-C10aryl-C1-C8alkyl, characterised that either a) related 3-oxonortropane of formula IIA reacts with arylmethylamine of formula IIIA H2N-CH2-Ar (IIIA) where Ar stands for optionally substituted phenyl residue or optionally substituted 5 or 6-merous heteroaromatic residue with at least one heteroatom chosen from group including N, O and S, or b) related 3α-aminonortropane of formula IIB reacts with arylaldehyde of formula IIIB O-CH-Ar (IIIB). Produced in each case imine of formula IVA or IVB is transformed to thermodynamically stable tautomer, respectively isomer of formula V , then hydrolysed and if required transformed to related acid-additive salt.

EFFECT: produced compounds of formula I are valuable intermediate in chemical synthesis of various pharmaceutical reactants or represent pharmaceutical reactant, first of all as NMDA-receptor modulators; method allows for high-yield commercial production of high-purity 3-aminonortropanes.

9 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, carboxypropyl, (C1- C4-alkoxy)carbonyl GRU

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. Disclosed compounds have inhibitory effect on CDK1 kinase and can be used to prepare medicinal agents for treating diseases associated with abnormal cell cycle development. In formula I , R1 is hydrogen, -C(O)OR9 or R2-(X)n-; X is (lower)alkylene, hydroxy(lower)alkylene, cyclised(lower)alkylne or mono- or dihalogen(lower)alkylene; R2 is a group, where denotes a phenyl or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from a group comprising oxygen, sulphur and nitrogen atoms; R5, R6 and R7 are independently selected from a group comprising hydroxy, hydrogen, (lower)alkyl, halogen and (lower)alkoxy; R4 is a halogen, , (O)k(CH2CH2O)y-R10, , -S-R12 or -O-(CH2)tR14, where denotes a phenyl, a cycloalkyl ring containing 3-6 carbon atoms, a 4-6-member heterocycloalkyl containing 3-5 carbon atoms and 1-2 heteroatoms selected from a group comprising oxygen, nitrogen and sulphur atoms; R9, R11, R15 and R16 independently denote (lower)alkyl; R10 and R12 denote (lower)alkyl; R14 denotes perfluoro(lower)alkyl or -NR15R16; R17 and R18 independently denote hydrogen, , F, OCH3 and -C(=O)CH3; n and k are equal to 0 or 1; m, w, y and z are equal an integer from 0 to 3; and t equals an integer from 0 to 6.

EFFECT: invention also relates to a pharmaceutical composition having antiproliferative activity, containing one or more of the disclosed compounds.

65 cl, 1 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula (I) where: A is an aryl or a 5-member heteroaryl containing a S heteroatom, possibly substituted with one or two substitutes selected from a group consisting of halogen, C1-6-alkyl or C1-6-alkoxy; n equals 1 or 2; p equals 1, 2, 3 or 4; q equals 1; r equals 0 or 1; R1 is C2-6-alkynyl substituted with aryl, or C1-6-alkyl possibly substituted with one-five substitutes selected from a group consisting of halogen, hydroxy, C1-6-alkyl, C1-6-halogenoalkyl, -OC(O)-C1-6-alkyl, C3-10-cycloalkyl, C1-6-alkoxy, possibly substituted with one, two or three halogens or aryl, aryl which is possibly substituted with a halogen or C1-6-alkoxy, 5-9-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N or O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl, and phenoxyl, or is C1-6-alkoxy, or is C3-10-cycloalkyl which is possibly substituted with one or more Ra, or is a 5- or 6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with one or more Ra, or is an aryl possibly substituted with one or more Ra, or is a 5-10-member heteraryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, possibly substituted with one or more Ra, or is -NRbRc, where Rb is H or C1-6-alkyl and where Rc is H, C1-6-alkyl or aryl, possibly substituted with one or more Ra, where Ra is selected from: halogen, cyano, oxo, hydroxy, halogenobenzenesulfonyl, C1-6-alkyl, possibly substituted with one, two or three substitutes selected from a group consisting of 5-10-member heterocycloalkyl and aryl, which is possibly substituted with halogen or C1-6-alkoxy, C1-6-halogenoalkyl, C1-6-halogenoalkoxy, C1-6-alkoxy, possibly substituted with aryl or 5-10-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, which is possibly substituted with C1-6-alkyl, aryloxy, -NH(CO)-C1-6-alkyl, -O(CO)-C1-6-alkyl, C1-6-alkylsulfonyl, aryl, 4-6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-6-alkyl or oxo, 5-10-member heteroaryl,one, two or three ring atoms of which are heteroatoms selected from N and O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl or oxo, and di(C1-6)alkylamino; R2 is H, OH, C1-6-alkyl or halogen; as well as their pharmaceutically acceptable salts. The invention also relates to medicine and to use of the compounds in any of paragraphs 1-24.

EFFECT: obtaining novel biologically active compounds with affinity to dopamine D3 receptor and to serotonin 5- HT2a receptor.

27 cl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

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

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

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: agent is a 6-bromo-5-methoxy-indole-3-carboxylic acid derivative of general formula (I) , where B is a N(R)2 group, where both R groups together with the nitrogen atom to which they are bonded form a 5-6-member heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, such as pyrrolidine, piperidine, piperazine or morpholine, where each of the said heterocyclic rings can be substituted with C1-4alkyl, phenyl, benzyl, phenethyl, carbonylamino, -COOC1-4alkyl group or -COOC1-4alkyl group and phenyl, which can also be substituted or have substitutes selected from halogen, C1-4alkyl, C1-4alkoxy, and alkyl in the said groups can be linear or branched; R1 is C1-4alkyl, phenyl, possibly substituted with C1-4alkyl or C1-4alkoxy, halogen atoms; R2 is -S-phenyl, -S-benzyl, -O-phenyl, where in each of the said groups, the phenyl ring is possibly substituted with C1-4alkyl, C1-4alkoxy, halogen atoms, or R2 denotes a -N(R)2 group, or pharmaceutically acceptable salts thereof.

EFFECT: agent has antiviral activity towards influenza A virus.

3 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns derivatives of thiazolidine-4-one of general formula (I) and general formula (II), to their isomers and pharmaceutically acceptable salts which can be used as a medical product with immunosuppressive activity. In formulae (I) and (II), R1 and R14 independently represent lower alkyl, lower alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl; phenyl group or phenyl group independently mono- or disubstituted with lower alkyl, halogen, lower alkoxy or group -CF3; R2 and R15 independently represent lower alkyl; allyl; cyclopropyl; or di- lower alkylamino; R3 represents -NR5R6 or -O-CR7R8-CR9R10-(CR11R12)n-O-R13; R23 represents hydrogen; hydroxycarbonyl-lower alkyl or 1-glyceryl. Values of the other radicals are specified in the patent claim. The invention also concerns application of one or more compounds of general formula (I) or (II) for preparation of a medical product with immunosuppressive activity.

EFFECT: agent exhibits improved efficiency.

24 cl, 1 tbl, 157 ex

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

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